Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles

Supporting Information Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles Using Linear Selective Hydroacylation Reactions Manjeet K. Majhail, Paul M. Ylioja, and Michael C. Willis*[a]

chem_201600311_sm_miscellaneous_information.pdf

Direct'Synthesis'of'Highly'Substituted'Pyrroles'and' Dihydropyrroles'Using'Linear'Selective'Hydroacylation' Reactions' ' Manjeet'K.'Majhail,'Paul'M.'Ylioja'and'Michael'C.'Willis' ' Department)of)Chemistry,)Chemistry)Research)Laboratory,)University)of)Oxford,) Mansfield)Road,)Oxford,)OX1)3TA,)UK) ) [email protected]! !

Supporting'Information! ! Table'of'Contents' 1.!

General!experimental!methods!

S2!

2.!

Synthesis!of!novel!aldehydes!for!hydroacylation!

S3!

3.!

Synthesis!of!novel!α>amido!sulfones!(intermediates!for!the!formation!

S7!

of!propargylic!and!allylic!amines)!! 4.!

Synthesis!of!novel!propargylic!amines!!

S10!

5.!

Synthesis!of!novel!allylic!amines!

S19!

6.!

Hydroacylation!products!from!aldehyde!and!propargylic!amine!

S22!

coupling! 7.!

One>pot!formation!of!functionalised!pyrrole!rings!

S32!

8.!

Functionalising!existing!pyrroles!

S48!

9.!

Synthesis!of!pyrroles!via!a!telescoped!hydroacylation>Suzuki>

S51!

cyclisation!!

'

!

10.! One>pot!synthesis!of!dihydropyrroles!

S54!

11.! Reduction!of!dihydropyrrole!products!

S59!

12.! References!

S66!

13.! NMR!Spectra!of!novel!compounds!

S67!

'

S1!

1.'General'experimental'methods' ' Reactions! were! conducted! with! continuous! magnetic! stirring! under! an! inert! atmosphere!of!nitrogen!and!using!dry!solvents!unless!otherwise!stated.!Nitrogen! gas! was! passed! through! a! Drierite®!and! silica! filled! drying! tube! before! use.! Glassware! was! oven>dried! (>200!°C),! and! allowed! to! cool! to! room! temperature! under! vacuum! once! assembled.! Reagents! were! purchased! from! Sigma>Aldrich! Chemical!Co.!Ltd.,!Acros!Organics!Ltd,!Alfa!Aesar!or!Fluorochem!Ltd.!and!used!as! supplied.!PNP(Cy)!was!synthesised!according!to!a!reported!procedure1!and!was! weighed! out! in! air! and! stored! in! a! Schlenk! tube! under! nitrogen! after! use.! Solvents! were! collected! fresh! from! an! in>house! solvent! purification! system,! which!involves!passing!the!solvent!through!anhydrous!alumina!columns!using!an! Innovative! Technology! Inc.! PS>400>7! solvent! purification! system.! Acetone,! for! use! in! rhodium! reactions,! was! purchased! from! Sigma>Aldrich! (HPLC! grade),! distilled!over!Drierite®!and!degassed!prior!to!use.!! ! Reactions!were!monitored!by!thin!layer!chromatography!(TLC)!using!pre>coated! aluminium!backed!silica!plates!(Merck!Kieselgel!60!F254).!Plates!were!visualised! under! ultraviolet! light! (254! nm)! followed! by! staining! with! potassium! permanganate,! vanillin! or! Seebach’s! stain! (Magic).! Flash! column! chromatography!was!carried!out!using!matrix!60!silica.! ! 1H! NMR! spectra! were! obtained! on! a! Bruker! AVIII400! (400! MHz)! spectrometer! using! the! residual! solvent! as! an! internal! standard.! 13C! NMR! spectra! were! obtained! on! a! Bruker! AVIII400! (101! MHz)! spectrometer! using! the! residual! solvent! as! an! internal! standard.! Chemical! shifts! were! reported! in! parts! per! million! (ppm)! with! the! multiplicities! of! the! spectra! reported! as! following:! s,! singlet;! d,! doublet;! t,! triplet;! q,! quartet;! m,! multiplet;! br,! broad;! app,! apparent.! Low>resolution! ESI! mass! spectra! were! recorded! on! a! Waters! LCT! Premier! spectrometer.! High>resolution! ESI! mass! spectrometry! measurements! were! recorded! on! a! Brucker! Daltronics! microTOF! (ESI+)! spectrometer! or! Micromass! LCT! under! the! conditions! of! field! iniosation! (FI)! by! the! internal! service! at! the! Department!of!Organic!Chemistry,!University!of!Oxford.!Values!quoted!are!a!ratio! of! mass! to! charge! in! Daltons! and! relative! intensities! of! peaks! observed! are! quoted! as! a! percentage.! Infra>red! spectra! were! recorded! as! thin! films! on! a! Bruker! Tensor! 27! FT>IR! spectrometer! with! internal! calibration! in! the! range! 4000>600!cm>1.!Melting!points!were!determined!using!a!Stuart!Scientific!Melting! Point!Apparatus!SMP1.! ! ! !

!

S2!

2.'Synthesis'of'novel'aldehydes'for'hydroacylation' ! The! following! aldehydes! are! commercially! available! and! were! distilled! prior! to! use:!! Me

S

O

Me

S

Me

O

H

O H

Me

H

2-(Methylthio)benzaldehyde 1a

S

3-(Methylthio)propanal 1b

3-(Methylthio)butanal 1c

! The! synthetic! procedures! and! characterisation! have! previously! been! reported! for!the!following!aldehydes:!! Me

S

Me

O

Me S

O

MeO

Br 2-(Methylthio)cyclohex-1ene-1-carbaldehyde2 1d

O H

H

H

S

OMe 4,5-Dimethoxy-2-(methylthio) benzaldehyde 4 1f

4-Bromo-2-(methylthio) benzaldehyde 3 1e

Me Me N O

N H

O H

2-(Dimethylamino) benzaldehyde 5 1g

2-(Pyrrolidin-1-yl) benzaldehyde 5 1h

! General' procedure' A' for' the' synthesis' of' ßLsulfur' tethered' aldehydes,' exemplified'by'the'preparation'of'3LmethoxyL2L(methylthio)benzaldehyde,' 1i" Me MeO

S

O H

! Methanethiol! sodium! salt! solution! (1.28! mL,! 3.0! M! in! water,! 3.84! mmol,! 1.2! equiv.)! was! added! dropwise! to! 2>fluoro>3>methoxybenzaldehyde! (0.50! g,! 3.20! mmol,! 1.0! equiv.)! in! DMF! (4! mL)! at! 0! °C.! The! stirring! solution! was! warmed! to! room! temperature! over! 16! hrs,! after! which! it! was! diluted! with! water! (15! mL).! The! aqueous! mixture! was! extracted! with! Et2O! (3! ×! 10! mL)! and! the! combined! organic! extracts! were! washed! with! sat.! LiCl(aq)! (3! ×! 10! mL),! dried! over! MgSO4! and! concentrated! under! reduced! pressure.! Purification! via) flash! column! chromatography!(20%!Et2O!in!petrol)!afforded!title!aldehyde!1i!as!a!white!solid! (0.27!g,!46%).!! !

!

S3!

1H! NMR! (400! MHz,! CDCl

3):! δ! 10.80! (1H,! s,! CHO),! 7.53! (1H,! dd,! J! 8.0,! 1.5,! Ar>H),!

7.41!(1H,!app!t,!J!8.0,!Ar>H),!7.14!(1H,!dd,!J!8.0,!1.5,!Ar>H),!3.98!(3H,!s,!OCH3),!2.43! (3H,! s,! SCH3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 192.6,! 160.4,! 138.5,! 129.4,! 128.7,! 120.2,!115.8,!56.3,!18.9;!IR:!νmax!(neat)/cm>1!2750,!1691,!1571,!1464,!1264,!1237,! 1064,! 906,! 729;! LRMS! (ESI+):! m/z! 183! ([M+H]+,! 25%),! 205! ([M+Na]+,! 100%);! HRMS!(ESI+)!found!m/z!183.04719![M+H]+,!C9H11O2S+!requires!183.04743;!mp:! 59>60!°C!(EtOAc/hexane).! ' 2LFluoroL6L(methylthio)benzaldehyde,'1j" Me

S

O H F

! Prepared! according! to! general! procedure! A! using! methanethiol! sodium! salt! solution! (1.52! mL,! 3.0! M! in! water,! 15.5! mmol,! 1.1! equiv.)! and! 2,! 6> difluorobenzaldehyde! (1.52! mL,! 14.1! mmol,! 1.0! equiv.)! in! DMF! (20! mL).! The! crude! oil! was! purified! by! flash! column! chromatography! (20>50%! DCM! in! toluene)!to!obtain!aldehyde!1j!as!a!pale!yellow!solid!(0.95!g,!40%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 10.51! (1H,! s,! CHO),! 7.51! (1H,! dd,! J! 8.0,! 5.0,! Ar>H),! 3 7.08!(1H,!d,!J!8.0,!Ar>H),!6.91!(1H,!app!t,!J!8.0,!Ar>H),!2.48!(3H,!s,!SCH3);! 13C!NMR! (101!MHz,!CDCl3):!δ!187.2,!166.7!(d,! 1JCF!260.0),!146.1,!134.9!(d,! 2JCF!22.0),!120.6! (d,! 3JCF! 4.0),! 119.80! (d,! 3JCF! 3.5),! 110.8! (d,! 2JCF! 21.5),! 15.4;! 19F! NMR! (377! MHz,! CDCl3):!δ!>120.3;!IR:!νmax!(neat)/cm>1!2885,!1684,!1560,!1557,!1454,!1323,!1237,! 1204,! 908,! 832,! 777,! 662;! LRMS! (ESI+):! m/z! 171! ([M+H]+,! 10%),! 193! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 193.00933! [M+Na]+,! C8H7OFSNa+! requires! 193.00939;!mp:!51>53!°C!(EtOAc/hexane).! ! 4LMethoxyL2L(methylthio)benzaldehyde,'1k' Me

S

O H

MeO

! Prepared! according! to! general! procedure! A' using! methanethiol! sodium! salt! solution! (5.60! mL,! 3.0! M! in! water,! 16.9! mmol,! 1.3! equiv.)! and! 2>fluoro>4> methoxybenzaldehyde!(2.00!g,!13.0!mmol,!1.0!equiv.)!in!DMF!(18!mL).!The!crude! was!purified!by!flash!column!chromatography!(5>10%!EtOAc!in!petrol)!to!obtain! aldehyde)1k!as!an!off>white!solid!(2.03!g,!86%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 10.11! (1H,! s,! CHO),! 7.78! (1H,! d,! J! 8.5,! Ar>H),! 6.82> 3 6.78! (2H,! m,! Ar>H),! 3.92! (3H,! s,! OCH3),! 2.49! (3H,! s,! SCH3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 189.7,! 164.0,! 145.7,! 136.2,! 126.5,! 111.0,! 109.1,! 55.6,! 15.1;! IR:! νmax! !

S4!

(neat)/cm>1! 2839,! 1671,! 1589,! 1551,! 1278,! 1234,! 1064,! 1035,! 891,! 805,! 611;! LRMS!(ESI+):!m/z!205!([M+Na]+,!100%);!HRMS!(ESI+)!found!205.02926![M+Na]+,! C9H10O2SNa+!requires!205.02937;!mp:!84>85!°C!(EtOAc/petrol).! ' 2,4LBis(methylthio)benzaldehyde,'1l' Me

S

O H

Me

S

! Prepared! according! to! general! procedure! A' using! methanethiol! sodium! salt! solution! (10.4! mL,! 3.0! M! in! water,! 31.1! mmol,! 2.1! equiv.)! and! 2>fluoro>4> bromobenzaldehyde!(3.00!g,!14.8!mmol,!1.0!equiv.)!in!DMF!(18!mL).!The!crude! was!purified!by!flash!column!chromatography!(10>30%!Et2O!in!petrol)!to!obtain! aldehyde!1l!as!off>white!needles!(0.96!g,!33%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 10.15! (1H,! s,! CHO),! 7.70! (1H,! dd,! J! 8.0,! 1.0,! Ar>H),! 3 7.34>7.22! (1H,! m,! Ar>H),! 7.07! (1H,! d,! J! 8.0,! Ar>H),! 2.56! (3H,! s,! ortho>SCH3),! 2.50! (3H,! s,! para>SCH3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 190.2,! 147.7,! 143.8,! 133.5,! 129.5,! 121.3,! 120.5,! 15.4,! 14.7;! IR:! νmax! (neat)/cm>1! 2920,! 2835,! 1675,! 1574,! 1534,!1286,!1108,!955,!862;!LRMS!(ESI+):!m/z!199!([M+H]+,!10%),!221!([M+Na]+,! 100%);! HRMS! (ESI+)! found! 199.02465! [M+H]+,! C9H11OS2+! requires! 199.02458;! mp:!64>66!°C!(DCM/petrol).!! ' 3L(Methylthio)thiopheneL2Lcarbaldehyde,'1m' Me S

O H S

! Prepared! according! to! general! procedure! A' using! methanethiol! sodium! salt! solution!(5.80!mL,!3.0!M!in!water,!17.3!mmol,!1.1!equiv.)!and!3>bromothiophene> 2>carboxaldehyde! (1.70! mL,! 15.7! mmol,! 1.0! equiv.)! in! DMF! (19! mL).! The! crude! was!purified!by!flash!column!chromatography!(10%!Et2O!in!petrol)!to!obtain!a! brown! solid,! which! was! recrystalised! (DCM/hexane)! to! afford) aldehyde! 1m! as! white!needles!(0.91!g,!37%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 10.06! (1H,! s,! CHO),! 7.74! (1H,! dd,! J! 5.0,! 1.0,! Ar>H),! 3 7.12! (1H,! d,! J! 5.0,! Ar>H),! 2.61! (3H,! s,! SCH3);! 13C! NMR! (101! MHz,! CDCl3):! 181.5,! 146.0,! 135.2,! 134.6,! 128.1,! 17.1;! IR:! νmax! (neat)/cm>1! 3101,! 2839,! 1648,! 1478,! 1365,!1223,!1777,!907,!665;!LRMS!(ESI+):!m/z!159!([M+H]+,!50%),!181!([M+Na]+,! 100%);! HRMS! (ESI+)! found! 180.97536! [M+Na]+,! C6H6OS2Na+! requires! 180.97523;!mp:!34>35!°C!(DCM/hexnae).! '

!

S5!

2L(Methylthio)L5L(trifluoromethyl)benzaldehyde,'1n' Me

S

O H

CF3

! Prepared! according! to! general! procedure! A' using! methanethiol! sodium! salt! solution! (1.90! mL,! 3.0! M! in! water,! 5.75! mmol,! 1.1! equiv.)! and! 2>fluoro>5> (trifluoromethyl)benzaldehyde!(0.74!mL,!5.20!mmol,!1.0!equiv.)!in!DMF!(10!mL).! The!crude!was!purified!by!flash!column!chromatography!(30%!Et2O!in!petrol)!to! afford)aldehyde!1n!as!a!white!solid!(0.85!g,!74%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 10.28! (1H,! s,! CHO),! 8.07! (1H,! d,! J! 1.5,! Ar>H),! 7.77! 3 (1H,!dd,!J!8.5,!1.5,!Ar>H),!7.46!(1H,!d,!J!8.5,!Ar>H),!2.57!(3H,!s,!SCH3);!13C!NMR!(101! MHz,!CDCl3):!190.0,!148.4,!130.2!(q,! 3JCF!3.5),!129.9!(q,! 3JCF!3.5),!127.0,!126.6!(q,! 2J !30.5),!125.1,!123.6!(q,! 1J !250.0),!15.2;! 19F!NMR!(377!MHz,!CDCl ):!>62.5;!IR:! CF CF 3 νmax! (neat)/cm>1! 3041,! 1686,! 1611,! 1556,! 1350,! 1334,! 1310,! 1262,! 1114;! LRMS! (ESI+):! m/z! 221! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 221.02435! [M+H]+,! C9H8OF3S+!requires!221.02425;!mp:!102>104!°C!(DCM/petrol).! !

'

!

'

S6!

3.' Synthesis' of' novel' αLamido' sulfones' (intermediates' for' the' formation'of'propargylic'and'allylic'amines)' ' The! synthetic! procedures! and! characterisation! have! previously! been! reported! for!the!following!α>amido!sulfones:!!

O

O

O

O Me

NH

Me

O

O

O

tert-Butyl (1-tosylethyl)carbamate6 9a

O

O Br tert-butyl [(4-bromophenyl) (phenylsulfonyl)methyl]carbamate8 9c

O NH

O

O

NH

S O

O

F 3C tert-Butyl [(phenylsulfonyl)[4(trifluoromethyl)phenyl]methy]carbamate8 9d

O

S O MeO tert-Butyl [(4-methoxyphenyl) (phenylsulfonyl)methyl]carbamate9 9e

NH

S

O

S O

O

NH

O

O O

NH

O

O

O

NC

NH S

S

S O

O

tert-butyl [(phenylsulfonyl)(thiophen-2-yl)methyl]carbamate 9 9f

O

O O

O

O

tert-Butyl [phenyl(phenylsulfonyl) methyl]carbamate 7 9b

O

NH S

S

S O

O

NH

Me

O

O

O

O tert-Butyl [furan-2-yl(phenylsulfonyl) tert-Butyl [(4-cyanophenyl)(phenylsulfonyl)- Methyl 4-{[(tert-butoxycarbonyl)amino] methy]carbamate 9 methyl]carbamate 9 (phenylsulfonyl)methyl}benzoate10 9g 9h 9i

' General'procedure'B'for'the'synthesis'of'αLamido'sulfones,'exemplified'by' the' preparation' of' tertLbutyl[(6LmethoxypyridinL2Lyl)L(phenylsulfonyl)L methyl]carbamate,'9j' O O

NH S N O

O

OMe

' Prepared! following! an! adapted! literature! procedure.7! To! a! stirring! solution! of! tert>butyl>carbamate!(1.60!g,!13.3!mmol,!1.0!equiv.)!and!sodium!phenylsulfinate! (4.80!g,!26.6!mmol,!2.0!equiv.)!in!H2O/MeOH!(2:1,!v/v)!(34.2!mL)!was!added!6> methoxypyridine>2>carbaldehyde! (1.93! mL,! 16.0! mmol,! 1.2! equiv.)! and! formic! acid! (1.51! mL,! 39.9! mmol,! 1.5! equiv.)! at! room! temperature.! The! mixture! was!

!

S7!

stirred!for!60!hrs.!The!resulting!white!precipitate!was!filtered!with!10%!DCM!in! petrol! and! triturated! (10%! DCM! in! petrol)! for! 2! hrs.! After! filtration! the! white! solid!was!dried!under!vacuum!to!afford!pure!αJamido)sulfone!9j!as!a!white!solid! (3.74!g,!74%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.87!(2H,!d,!J!7.5,!Ar>H),!7.64!(2H,!t,!J!7.5,!Ar>H),!7.53! 3 (2H,!t,!J!7.5,!Ar>H),!7.17!(1H,!d,!J!7.0,!Ar>H),!6.79!(1H,!d,!J!8.0,!Ar>H),!6.47!(1H,!br!d,! J!9.5,!NH),!5.98!(1H,!d,!J!9.5,!NHCH),!3.86!(3H,!s,!OCH3),!1.34!(9H,!s,!CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl ):! δ! 163.8,! 153.7,! 145.4,! 139.1,! 136.8,! 133.8,! 129.7,! 3 128.8,!118.4,!112.0,!81.0,!74.6,!53.5,!28.1;!IR:!νmax!(neat)/cm>1!2979,!1719,!1603,! 1576,! 1447,! 1416,! 1368,! 1344,! 1143,! 989;! HRMS! (FI+)! found! 378.1389! [M]+,! C18H22N2O5S+!requires!378.1249;!mp:!!136>137!°C!(EtOAc/hexane).! " tertLButyl'[(2Lbromophenyl)(phenylsulfonyl)methyl]carbamate,'9k' O O

NH S O Br

O

! Prepared! according! to! general! procedure! B! using! tert>butyl>carbamate! (1.50! g,! 12.8!mmol,!1.0!equiv.),!sodium!phenylsulfinate!(5.70!g,!32.0!mmol,!2.5!equiv.)!in! H2O/THF! (2:1,! v/v)! (38.4! mL),! 2>bromobenzaldehyde! (1.80! mL,! 15.4! mmol,! 1.2!equiv.)! and! formic! acid! (0.72! mL,! 19.2! mmol,! 2.0! equiv.).! The! mixture! was! stirred! for! 60! hrs.! Trituration! afforded! αJamido) sulfone! 9k! as! a! white! powder! (3.02!g,!55%).! ! 1H! NMR! (400! MHz,! CD Cl ):! δ! 7.97! (2H,! d,! J! 8.0,! Ar>H),! 7.69! (1H,! t,! J! 7.5,! Ar>H),! 2 2 7.65>7.63!(1H,!m,!Ar>H),!7.61>7.56!(3H,!m,!Ar>H),!7.45!(1H,!app!td,!J!7.5,!1.0,!Ar> H),!7.33>7.30!(1H,!m,!Ar>H),!6.66!(1H,!d,!J!10.5,!NH),!5.88!(1H,!d,!J!10.5,!NHCH),! 1.31! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CD2Cl2):! δ! 153.3,! 137.2,! 134.2,! 133.9,! 133.2,! 131.2,! 131.0,! 129.4,! 129.2,! 128.0,! 125.8,! 81.2,! 72.4,! 27.7;! IR:! νmax! (neat)/cm>1! 2975,! 1986,! 1704,! 1511,! 1447,! 1276,! 1144,! 1027,! 727;! HRMS! (FI+)! found! 427.0262! [M]+,! C18H2081BrNO4S+! requires! 427.0277;! mp:! 163>164! °C! (EtOAc/hexane).! ! " "

!

S8!

tertLButyl'[2,2LdimethylL1L(phenylsulfonyl)propyl]carbamate,'9l' O O

NH S O

O

! Prepared!according!to!general!procedure!B!using!tert>butyl>carbamate!(1.0!g,!8.5! mmol,! 1.0! equiv.),! sodium! phenylsulfinate! (2.8! g,! 17! mmol,! 2.0! equiv.)! in! H2O/THF! (2:1,! v/v)! (11.9! mL),! trimethylacetaldehyde! (1.8! mL,! 17! mmol,! 2.0! equiv.)!and!formic!acid!(3.2!mL,!8.5!mmol,!1.0!equiv.).!The!mixture!was!stirred! for! 72! hrs.! Trituration! afforded! pure! αJamido) sulfone! 9l! (2.05! g,! 74%).! Due! to! rapid!decomposition!HRMS!data!was!not!retrieved!and!the!compound!was!used! directly!in!propargylic!amine!synthesis.! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.88!(2H,!dd,!J!7.5,!2.0,!Ar>H),!6.95>6.92!(3H,!m,!Ar> 3 H),!5.20!(1H,!d,!J!11.5,!NH),!4.84!(1H,!d,!J!11.5,!NHCH),!1.15!(9H,!s,!CO2C(CH3)3),! 1.13!(9H,!s,!CHC(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!153.9,!139.3,!133.4,!129.1,! 128.8,! 80.6,! 36.7,! 28.3,! 27.4,! 25.3;! IR:! νmax! (neat)/cm>1! 3294,! 2982,! 2030,! 1692,! 1552,!1516,!1366,!1177,!1048,!997;!mp:!!86>88!°C!(EtOAc/hexane).! " tertLButyl'[cyclopropyl(tosyl)methyl]carbamate,'9m' O O

Me

NH S O

O

! Prepared!according!to!general!procedure!B!using!tert>butyl>carbamate!(0.7!g,!6.0! mmol,! 1.0! equiv.),! sodium! p>toluenesulfinate! (1.18! g,! 6.60! mmol,! 1.1! equiv.)! in! H2O/MeOH! (2:1,! v/v)! (9.5! mL),! cyclopropanecarboxaldehyde! (0.5! mL,! 3.97! mmol,!1.5!equiv.)!and!formic!acid!(0.89!mL,!23.5!mmol,!6.5!equiv.).!The!mixture! was! stirred! for! 16! hrs.! Trituration! afforded! pure! αJamido) sulfone! 9m! (0.69! g,! 35%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.82! (2H,! d,! J! 8.0,! Ar>H),! 7.35! (2H,! d,! J! 8.0,! Ar>H),! 3 5.13!(1H,!d,!J!10.0,!NH),!4.37!(1H,!app!t,!J!10.0,!NHCH),!2.44!(3H,!s,!Ar>CH3),!1.39> 1.32! (1H,! m,! NHCHCH),! 1.28! (9H,! s,! CO2C(CH3)3),! 0.86>0.79! (1H,! m,! NHCHCHCHaHbCHaHb),! 0.73>0.66! (1H,! m,! NHCHCHCHaHbCHaHb),! 0.63>0.59! (1H,! m,! NHCHCHCHaHbCHaHb),! 0.47>0.41! (1H,! m,! NHCHCHCHaHbCHaHb);! 13C! NMR! (101!MHz,!CD2Cl2):!δ!153.8,!145.0,!134.5,!129.6,!129.2,!80.5,!74.3,!27.7,!21.3,!9.0,! 4.2,! 2.0;! IR:! νmax! (neat)/cm>1! 2978,! 1716,! 1597,! 1516,! 1368,! 1163,! 1140,! 950;! HRMS!(FI+)!found!325.1274![M]+,!C16H23NO4S+!requires!325.1348;!mp:!126>127! °C!(EtOAc/hexane).!

!

S9!

4. Synthesis of novel propargylic amines! ! The! following! propargylic! amine! is! commercially! available! and! was! used! as! supplied!from!Sigma>Aldrich!Chemical!Co.!Ltd.:! Boc N H N-Boc-propargyl amine 2a

! The! synthetic! procedures! and! characterisation! have! previously! been! reported! for!the!following!propargylic!amines:! N H

Cbz

Benzyl prop-2-yn-1-ylcarbamate11 2s

Ts N H 4-Methyl-N-(prop-2-yn-1-yl) benzenesulfonamide12 2t

tertLButyl'butL3LynL2Lylcarbamate,'2b' O HN

O Me

! A! solution! of! n>butyllithium! (1.94! mL,! 1.8! M! in! hexanes,! 3.50! mmol,! 2.1! equiv.)! was! added! dropwise! to! a! stirring! solution! of! trimethylsilylacetylene! (0.48! mL,! 3.40! mmol,! 2.0! equiv.)! in! THF! (15! mL)! at! >15! °C.! The! reaction! mixture! was! stirred! at! >15! °C! for! 30! mins.! The! temperature! was! lowered! to! >78! °C! and! a! solution! of! α>amido! sulfone! 9a6! (0.50! g,! 1.70! mmol,! 1.0! equiv.)! in! THF! (5! mL)! was! added.! The! mixture! was! warmed! to! room! temperature! over! 1! hr.! Quick! addition!of!sat.!NH4Cl(aq)!(5!mL)!at!>78!°C!quenched!the!reaction!and!the!mixture! was! allowed! to! warm! to! room! temperature.! The! product! was! extracted! with! DCM!(3!×!10!mL)!and!washed!with!brine!(10!mL).!The!organic!layer!was!dried! over!MgSO4,!filtered!and!concentrated!under!reduced!pressure.!With!no!further! purification! the! crude! propargyl! amine! (0.37! g,! 1.52! mmol,! 1.0! equiv.)! was! dissolved!in!MeOH!(29!mL).!Potassium!carbonate!(0.21!g,!1.52!mmol,!1.0!equiv.)! was! added! to! the! solution! at! room! temperature! and! stirred! for! 4! hrs.! The! reaction!mixture!was!diluted!with!water!(15!mL)!and!extracted!with!Et2O!(3!×!10! mL).!The!combined!organic!extracts!were!washed!with!brine!(15!mL),!dried!over! MgSO4,! filtered! and! concentrated! in) vacuo.! The! crude! mixture! was! purified! by! flash! column! chromatography! (20%! EtOAc! in! petrol)! to! give! title! propargylic) amine!2b!as!a!white!solid!(0.23!g,!80%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!4.73!(1H,!br!s,!NH),!4.51!(1H,!app!br!s,!NHCH),!2.28! 3 (1H,!d,!J!2.5,!CHCCHNH),!1.48!(9H,!s,!CO2C(CH3)3),!1.43!(3H,!d,!J!7.0,!CHCCH(CH3));! 13C! NMR! (101! MHz,! CDCl ):! δ! 154.6,! 84.6,! 79.9,! 70.1,! 38.2,! 28.4,! 22.5;! IR:! ν 3 max! >1 (neat)/cm ! 2864,! 1691,! 1562,! 1312,! 1293,! 1252,! 989,! 899,! 722;! ! LRMS! (ESI+):!

!

S10!

m/z!192!([M+Na]+,!100%);!HRMS!(ESI+)!found!192.09963![M+Na]+,!C9H15NO2Na+! requires!192.09950;!mp:!69>70!°C!(EtOAc/petrol).! ! tertLButyl'(4,4LdimethylpentL1LynL3Lyl)carbamate,'2c" ! O HN

O

! A! solution! of! n>butyllithium! (3.51! mL,! 1.8! M! in! hexanes,! 6.41! mmol,! 2.1! equiv.)! was!added!dropwise!to!a!solution!trimethylsilylacetylene!(0.86!mL,!6.10!mmol,! 2.0!equiv.)!in!THF!(22!mL)!at!>15!°C.!The!reaction!mixture!was!stirred!at!>15!°C! for!30!mins.!The!temperature!was!lowered!to!>78!°C!and!a!solution!of!α>amido! sulfone! 9l! (1.00! g,! 3.05! mmol,! 1.0! equiv.)! in! THF! (10! mL)! was! added! to! the! mixture.! The! mixture! was! stirred! at! >78! °C! for! 1! hr.! Sat.! NH4Cl(aq)! (10! mL)! was! added!at!>78!°C!and!the!mixture!was!warmed!to!room!temperature.!The!product! was! extracted! with! DCM! (3! ×! 10! mL)! and! washed! with! brine! (10! mL).! The! organic! layer! was! dried! over! MgSO4,! filtered! and! concentrated! under! reduced! pressure.!With!no!further!purification,!the!crude!propargylic!amine!(0.80!g,!2.80! mmol,! 1.0! equiv.)! was! dissolved! in! in! MeOH! (53! mL)! and! potassium! carbonate! (0.39!g,!2.80!mmol,!1.0!equiv.)!was!added,!the!reaction!was!stirred!for!16!hrs!at! room! temperature.! Water! (15! mL)! was! added! to! the! reaction! mixture! and! the! product! was! extracted! with! Et2O! (3! ×! 10! mL)! and! washed! with! brine! (15! mL).! The!organic!layer!was!dried!over!MgSO4,!filtered!and!concentrated!in)vacuo.!The! crude! mixture! was! purified! by! flash! column! chromatography! (5>10%! EtOAc! in! petrol)!to!give!the!title!propargylic)amine!2c!as!a!pale!yellow!solid!(0.36!g,!61%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!4.72!(1H,!d,!J!8.0,!NH),!4.27!(1H,!d,!J!8.0,!NHCH),!2.28! 3 (1H,!d,!J!2.5,!CHCCHNH),!1.48!(9H,!s,!CO2C(CH3)3),!1.01!(9H,!s,!NHCHC(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 155.3,! 82.5,! 79.8,! 71.7,! 52.2,! 35.4,! 28.4,! 25.8;! IR:! νmax! (neat)/cm>1!3296,!2968,!1692,!1515,!1367,!1249,!1171,!1049,!998,!906,!731,!649;! LRMS!(ESI+):!m/z!234!([M+Na]+,!100%);!HRMS!(ESI+)!found!234.14666![M+Na]+,! C12H21NO2Na+! requires! 234.14645;! mp:! 64>65! °C! (EtOAc/petrol).! 1H! and! 13C! NMR!data!is!consistent!with!literature.13! ' ' '

!

S11!

General' procedure' C' for' the' synthesis' of' terminal' propargylic' amines' as' exemplified' by' the' preparation' of' tertLbutyl' (1LphenylpropL2LynL1L yl)carbamate,'2d! O HN

O

! Following! a! procedure! adapted! from! Shin! et) al.13! A! solution! of! ethynylmagnesium!bromide!(20.2!mL,!0.5!M!in!THF,!9.50!mmol,!2.2!equiv.)!was! added! dropwise! to! a! solution! of! a>amido! sulfone! 9b7! (1.5! g,! 4.32! mmol,! 1.0! equiv.)! in! THF! (35! mL)! at! >78! °C.! The! reaction! mixture! was! warmed! to! room! temperature! over! 3! hrs.! Upon! completion! the! reaction! was! quenched! with! sat.! NH4Cl(aq)! (mL)! at! >78! °C! and! was! allowed! to! warm! to! room! temperature.! The! product! was! extracted! with! DCM! (3! ×! 10! mL)! and! washed! with! brine! (10! mL).! The!combined!organic!layers!were!dried!over!MgSO4,!filtered!and!concentrated! under! reduced! pressure.! The! crude! product! was! purified! by! flash! column! chromatography!(5>10%!EtOAc!in!petrol)!to!give!the!title!propargylic)amine!2d! as!a!white!solid!(0.89!g,!89%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.53! (2H,! d,! J! 7.5,! Ar>H),! 7.40>7.33! (3H,! m,! Ar>H),! 3 5.71!(1H,!d,!J!7.0,!NHCH),!5.24!(1H,!br!s,!NH),!2.52!(1H,!d,!J!2.5,!CHCCHNH),!1.49! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 154.8,! 138.8,! 128.7,! 128.1,! 126.9,! 82.2,! 80.3,! 73.0,! 46.1,! 28.4;! IR:! νmax! (neat)/cm>1! 3305,! 2979,! 1696,! 1495,! 1393,! 1368,! 1246,! 1166,! 1020,! 911,! 876,! 698;! LRMS! (ESI+):! m/z! 254! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 254.11523! [M+Na]+,! C14H17NO2Na+! requires! 254.11515;!mp:!93>95!°C!(EtOAc/petrol).!1H!and!13C!NMR!data!is!consistent!with! literature.13! ! tertLButyl'[1L(4Lmethoxyphenyl)propL2LynL1Lyl]carbamate,'2e' O HN

O

OMe

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (23.4!mL,! 0.5! M! in! THF,! 11.7! mmol,! 2.2! equiv.)! and! a>amido! sulfone! 9e9!(2.00g,! 5.30!mmol,!1.0!equiv.)!in!THF!(37!mL)!for!1!hr.!The!crude!product!was!purified! by! flash! column! chromatography! (5>10%! EtOAc! in! petrol)! to! give! propargylic) amine)2e!as!an!off>white!solid!(1.22!g,!88%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.45! (2H,! d,! J! 8.5,! Ar>H),! 6.91! (2H,! d,! J! 8.5,! Ar>H),! 3 !

S12!

5.63!(1H,!d,!J!6.0,!NHCH),!5.05!(1H,!br!s,!NH),!3.83!(3H,!s,!OCH3),!2.51!(1H,!d,!J!2.5,! CHCCHNH),!1.48!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!159.4,!154.7,! 130.9,! 128.1,! 114.0,! 82.4,! 80.2,! 72.7,! 55.3,! 45.7,! 28.4;! IR:! νmax! (neat)/cm>1! 2943,! 2253,! 1703,! 1612,! 1511,! 1247,! 1165,! 1035,! 909,! 732;! LRMS! (ESI+):! m/z! 284! ([M+Na]+,!100%),!545!([2M+Na]+,!80%);!HRMS!(ESI+)!found!284.12571![M+Na]+,! C15H19O3NNa+!requires!284.12571;!mp:!94>96!°C!(EtOAc/petrol).!1H!and!13C!NMR! data!is!consistent!with!literature.13! ! tertLButyl'[1L(furanL2Lyl)propL2LynL1Lyl]carbamate,'2f! O HN

O

O

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (6.94!mL,!0.5!M!in!THF,!3.26!mmol,!2.2!equiv.)!and!a>amido!sulfone!9g9!(0.50!g,! 1.48! mmol,! 1.0! equiv.)! in! THF! (6! mL)! for! 45! mins.! The! crude! product! was! purified! by! flash! column! chromatography! (5>15%! EtOAc! in! petrol)! to! give! propargylic)amine!2f!as!an!off>white!solid!(0.14!g,!43%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.39!(1H,!dd,!J)2.0,!1.0,!Ar>H),!6.39!(1H,!dd,!J!3.0,!1.0,! 3 Ar>H),!6.34!(1H,!dd,!J!3.0,!2.0,!Ar>H),!5.71!(1H,!d,!J!6.0,!NHCH),!5.19!(1H,!br!s,!NH),! 2.44! (1H,! d,! J! 2.5,! CHCCHNH),! 1.47! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 154.5,! 150.8,! 142.8,! 110.4,! 107.4,! 80.5,! 80.0,! 71.9,! 40.5,! 28.3;! IR:! νmax! (neat)/cm>1! 3299,! 2980,! 1698,! 1503,! 1392,! 1246,! 1166,! 1012,! 862,! 740,! 656;! LRMS!(ESI+):!m/z!244!([M+Na]+,!100%);!HRMS!(ESI+)!found!244.09413![M+Na]+,! C12H15O3NNa+! requires! 244.09441;! mp:! 71>72! °C! (EtOAc/petrol).! 1H! and! 13C! NMR!data!is!consistent!with!literature.13! ! tertLButyl'[1L(4Lcyanophenyl)propL2LynL1Lyl]carbamate,'2g' O HN

O

CN

' Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (12.6!mL,!0.5!M!in!THF,!5.90!mmol,!2.2!equiv.)!and!a>amido!sulfone!9h9!(1.00!g,! 2.68!mmol,!1.0!equiv.)!in!THF!(21!mL)!for!2!hrs.!The!crude!product!was!purified! by!flash!column!chromatography!(5%!EtOAc!in!petrol)!to!give!propargylic)amine! 2g!as!a!white!solid!(0.466!g,!68%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.69>7.66!(4H,!m,!Ar>H),!5.73!(1H,!d,!J!6.0,!NHCH),! 3 5.15! (1H,! br! s,! NH),! 2.58! (1H,! d,! J! 2.5,! CHCCHNH),! 1.48! (9H,! s,! CO2C(CH3)3);! 13C! !

S13!

NMR! (101! MHz,! CDCl3):! δ! 154.7,! 144.1,! 132.5,! 127.6,! 118.5,! 112.0,! 80.9,! 80.7,! 74.2,!45.9,!28.3;!IR:!νmax!(neat)/cm>1!3301,!2980,!1694,!1609,!1504,!1392,!1164,! 1020,! 733;! LRMS! (ESI+):! m/z! 257! ([M+H]+,! 10%),! 279! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 279.11003! [M+Na]+,! C15H16O2N2Na+! requires! 279.11040;! mp:! 106> 108!°C!(EtOAc/petrol).!1H!and!13C!NMR!data!is!consistent!with!literature.13! ! tertLButyl'{1L[4L(trifluoromethyl)phenyl]propL2LynL1Lyl}carbamate,'2h" ! O HN

O

CF3

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (11.3!mL,!0.5!M!in!THF,!5.30!mmol,!2.2!equiv.)!and!a>amido!sulfone!9d8!(1.00!g,! 2.41!mmol,!1.0!equiv.)!in!THF!(19!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (5>15%! EtOAc! in! petrol)! to! give! propargylic) amine!2h'as!a!white!solid!(0.426!g,!59%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.65>7.60!(4H,!m,!Ar>H),!5.75!(1H,!app!br!s,!NHCH),! 3 5.44! (1H,! br! s,! NH),! 2.55! (1H,! d,! J! 2.5,! CHCCHNH),! 1.46! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 154.8,! 142.9,! 130.3! (q,! 2JCF! 32.4),! 127.2,! 125.6! (q,! 3JCF! 3.5),!124.0!(q,!1JCF!272.3),!81.3,!80.6,!73.7,!45.8,!28.2;!19F!NMR!(377!MHz,!CDCl3):!> 62.6;!IR:!νmax!(neat)/cm>1!3310,!3100,!1689,!1620,!1496,!1386,!1124,!1018,!909,! 732,!661;!LRMS!(ESI+):!m/z!322!([M+Na]+,!100%);!HRMS!(ESI+)!found!322.10200! [M+Na]+,!C15H16O2NF3Na+!requires!322.10253;!mp:!92>93!°C!(EtOAc/petrol).! ! tertLButyl'[1L(thiophenL2Lyl)propL2LynL1Lyl]carbamate,'2i' O HN

O

S

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (6.60!mL,!0.5!M!in!THF,!3.10!mmol,!2.2!equiv.)!and!a>amido!sulfone!9f9!(0.50!g,! 1.41!mmol,!1.0!equiv.)!in!THF!(11!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (10%! EtOAc! in! petrol)! to! give! propargylic) amine!2i!as!a!pale!yellow!solid!(0.154!g,!46%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.27!(1H,!dd,!J!5.0,!1.0,!Ar>H),!7.19!(1H,!dd,!J!=!3.5,! 3 1.0,!Ar>H),!6.97!(1H,!dd,!J!5.0,!3.5,!Ar>H),!5.90!(1H,!app!br!s,!NHCH),!5.26!(1H,!br!s,! NH),!2.53!(1H,!d,!J!2.5,!CHCCHNH),!1.49!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,! CDCl3):! δ! 154.4,! 142.6,! 126.7,! 125.7,! 125.6,! 81.5,! 80.5,! 72.5,! 42.1,! 28.3;! IR:! νmax! !

S14!

(neat)/cm>1! 3304,! 2979,! 1695,! 1488,! 1367,! 1161,! 1018,! 909,! 864,! 731;! LRMS! (ESI+):! m/z! 260! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 260.07123! [M+Na]+,! C12H15O2NSNa+! requires! 260.07157;! mp:! 58>59! °C! (EtOAc/petrol).! 1H! and! 13C! NMR!data!is!consistent!with!literature.13! ! tertLButyl'[1L(2Lbromophenyl)propL2LynL1Lyl]carbamate,'2j" O HN

O

Br

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (12.1!mL,! 0.5! M! in! THF,! 5.70! mmol,! 2.2! equiv.)! and! a>amido! sulfone! 9k! (1.1! g,! 2.59!mmol,!1.0!equiv.)!in!THF!(21!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (5>20%! EtOAc! in! petrol)! to! give! propargylic) amine!2j!as!a!white!solid!(0.578!g,!72%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.64!(1H,!dd,!J!8.0,!1.5,!Ar>H),!7.55!(1H,!dd,!J!8.0,!1.0,! 3 Ar>H),!7.32!(1H,!app! td,!J)8.0,!1.0,!Ar>H),!7.16!(1H,!app!td,!J!8.0,!1.5,!Ar>H),!5.86! (1H,!app!br!s,!NHCH),!5.37!(1H,!br!s,!NH),!2.48!(1H,!d,!J!2.5,!CHCCHNH),!1.43!(9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 154.3,! 137.8,! 133.3,! 129.7,! 128.7,! 127.8,!123.1,!81.4,!80.3,!73.2,!46.6,!28.3;!IR:!νmax!(neat)/cm>1!3299,!2978,!1696,! 1489,!1366,!1159,!1024,!753,!641;!LRMS!(ESI+):!m/z!332!([79Br]![M+Na]+,!95%),! 334! ([81Br]! [M+Na]+,! 100%);! HRMS! (ESI+)! found! 332.02503! [[79Br]! M+Na]+,! 334.02289! [[81Br]! M+Na]+,! C14H16O2N79BrNa+! requires! 332.02566,! C14H16O2N81BrNa+!requires!334.02362;!mp:!96>97!°C!(EtOAc/petrol).!! ! tertLButyl'[1L(4Lbromophenyl)propL2LynL1Lyl]carbamate,'2k! O HN

O

Br

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (8.80!mL,!0.5!M!in!THF,!4.14!mmol,!2.2!equiv.)!and!a>amido!sulfone!9c8!(0.80!g,! 1.88!mmol,!1.0!equiv.)!in!THF!(15!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (5>10%! EtOAc! in! petrol)! to! give! propargylic) amine!2k!as!a!white!solid!(0.29!g,!50%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.52>7.49! (2H,! m,! Ar>H),! 7.43>7.38! (2H,! m,! Ar>H),! 3 5.64!(1H,!app!br!s,!NHCH),!5.13!(1H,!br!s,!NH),!2.53!(1H,!d,!J!2.5,!CHCCHNH),!1.48! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 154.7,! 138.0,! 131.8,! 128.6,!

!

S15!

122.1,! 81.5,! 80.5,! 73.4,! 45.7,! 28.3;! IR:! νmax! (neat)/cm>1! 3300,! 2978,! 1690,! 1487,! 1367,!1161,!1011,!876,!646;!LRMS!(ESI+):!m/z!332!([79Br]![M+Na]+,!100%),!334! ([81Br]![M+Na]+,!95%);!HRMS!(ESI+)!found!332.02490![[79Br]!M+Na]+,!334.02277! [[81Br]! M+Na]+,! C14H16O2N79BrNa+! requires! 332.02566,! C14H16O2N81BrNa! requires!334.02362;!mp:!99>100!°C!(EtOAc/petrol).! ' Methyl'4L{1L[(tertLbutoxycarbonyl)amino]propL2LynL1Lyl}benzoate,'2l! O HN

O

CO2Me

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (13.9!mL,!0.5!M!in!THF,!6.51!mmol,!2.2!equiv.)!and!a>amido!sulfone!9i10!(1.20!g,! 2.96!mmol,!1.0!equiv.)!in!THF!(24!mL)!for!2!hrs.!The!crude!product!was!purified! by!flash!column!chromatography!(5%!EtOAc!in!petrol)!to!give!propargylic)amine! 2l'as!a!white!solid!(0.624!g,!73%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 8.05>8.02! (2H,! m,! Ar>H),! 7.58! (2H,! d,! J! 8.0,! Ar>H),! 3 5.73!(1H,!app!br!s,!NHCH),!5.25!(1H,!br!s,!NH),!3.92!(3H,!s,!CO2CH3),!2.54!(1H,!d,!J! 2.5,! CHCCHNH),! 1.47! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! 166.7,! 154.7,! 143.8,! 129.9,! 129.8,! 126.8,! 81.4,! 80.6,! 73.6,! 52.2,! 45.9,! 28.3;! IR:! νmax! (neat)/cm>1! 3304,! 2984,! 1704,! 1612,! 1509,! 1280,! 1162,! 1019,! 910,! 732;! LRMS! (ESI+):! m/z! 312! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 312.11994! [M+Na]+,! C16H19O4NNa+! requires! 312.12063;! mp:! 110>111! °C! (EtOAc/petrol).! 1H! and! 13C! NMR!data!is!consistent!with!literature.13! " tertLButyl'[1L(6LmethoxypyridinL2Lyl)propL2LynL1Lyl]carbamate,'2m' O HN

O

N OMe

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (17.8!mL,! 0.5! M! in! THF,! 8.71! mmol,! 2.2! equiv.)! and! a>amido! sulfone! 9j! (1.50! g,! 3.96!mmol,!1.0!equiv.)!in!THF!(32!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (5>10%! EtOAc! in! petrol)! to! give! propargylic) amine!2m!as!a!light!brown!solid!(0.522!g,!50%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.60!(1H,!dd,!J!8.0,!7.5,!Ar>H),!7.02!(1H,!d,!J!7.5,!Ar> 3 H),!6.71!(1H,!d,!J!8.0,!Ar>H),!5.67!(1H,!app!br!s,!NHCH),!5.58!(1H,!br!s,!NH),!3.98!

!

S16!

(3H,! s,! OCH3),! 2.42! (1H,! d,! J! 2.5,! CHCCHNH),! 1.50! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101!MHz,!CDCl3):!163.9,!154.9,!154.0,!139.5,!113.9,!110.3,!82.3,!80.2,!72.0,!53.5,! 47.0,! 28.4;! IR:! νmax! (neat)/cm>1! 3299,! 2931,! 1701,! 1493,! 1167,! 908,! 731;! LRMS! (ESI+):! m/z! 263! ([M+H]+,! 100%),! 285! ([M! +! Na]+,! 35%);! HRMS! (ESI+)! found! 285.12029! [M+Na]+,! C14H18O3N2Na+! requires! 285.12096;! mp:! 42>43! °C! (EtOAc/petrol).! ! tertLButyl'(1LcyclopropylpropL2LynL1Lyl)carbamate,'2n' O HN

O

! Prepared! according! to! general! procedure! C! using! ethynylmagnesium! bromide! (5.05!mL,!0.49!M!in!THF,!2.02!mmol,!2.2!equiv.)!and!a>amido!sulfone!9m!(0.30!g,! 0.92!mmol,!1.0!equiv.)!in!THF!(7.5!mL)!for!2!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (10>20%! Et2O! in! toluene)! to! give! propargylic) amine!as!a!white!solid!(154!mg,!86%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!4.93!(1H,!br!s,!NH),!4.39!(1H,!app!br!s,!NHCH),!2.21! 3 (1H,! d,! J! 2.5,! CHCCHNH),! 1.44! (9H,! s,! CO2C(CH3)3),! 1.15>1.07! (1H,! m,! NHCHCH),! 0.47>0.43!(4H,!m,!NHCHCH(CH2)2);! 13C!NMR!(101!MHz,!CDCl3):!154.8,!81.2,!71.1,! 45.5,!28.3,!15.1,!2.7,!1.6;!IR:!νmax!(neat)/cm>1!3008,!2978,!1691,!1492,!1366,!1243,! 1163,! 1045,! 1021;! LRMS! (ESI+):! m/z! 218! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 218.11496! [M+Na]+,! C11H17O2NNa+! requires! 218.11515;! mp:! 64>65! °C! (DCM/petrol).! ! General' procedure' D' for' the' synthesis' of' internal' propargylic' amines' as' exemplified'by'the'synthesis'of'tertLbutyl'decL3LynL2Lylcarbamate,'2o' O HN Me

O Me

! A!procedure!adapted!from!Shin!et)al.13!A!solution!of!n>butyllithium!(1.37!mL,!2.5! M! in! hexanes,! 3.43! mmol,! 2.05! equiv.)! was! added! dropwise! to! a! solution! of! 1> octyne!(0.49!mL,!3.34!mmol,!2.0!equiv.)!in!THF!(15!mL)!at!>15!°C.!The!reaction! mixture!was!stirred!at!>15!°C!for!30!mins.!The!temperature!was!lowered!to!>78! °C!and!a!solution!of!a>amido!sulfone!9a6!(0.50!g,!1.67!mmol,!1.0!equiv.)!in!THF!(5! mL)! was! added! dropwise.! The! mixture! was! allowed! to! warm! to! room! temperature! for! 2! hrs.! Upon! completion,! the! reaction! was! quenched! by! quick! addition!of!sat.!NH4Cl(aq)!at!>78!°C!!and!then!warmed!to!room!temperature.!The! product! was! extracted! with! DCM! (3! ×! 10! mL)! and! washed! with! brine! (10! mL).! !

S17!

The! organic! layer! was! dried! over! MgSO4,! filtered! and! concentrated! under! reduced! pressure.! The! crude! product! was! purified! by! flash! column! chromatography!(10>20%!EtOAc!in!petrol)!to!afford!title!propargylic)amine!2o!as! a!colourless!oil!(297!mg,!70%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!4.69!(1H,!br!s,!NH),!4.47!(1H,!app!br!s,!NHCH),!2.17! 3 (2H,! td,! J! 7.0,! 2.0,! CH3(CH2)4CH2),! 1.53>1.49! (2H,! m,! CH3(CH2)3CH2),! 1.47! (9H,! s,! CO2C(CH3)3),! 1.39>1.27! (9H,! m,! CH3(CH2)3! and! NHCHCH3),! 0.91! (3H,! t,! J! 7.0,! CH3(CH2)5);! 13C! NMR! (101! MHz,! CDCl3):! 154.7,! 82.6,! 80.7,! 31.3,! 28.9,! 28.6,! 28.5,! 28.4,! 28.0,! 23.3,! 22.5,! 18.6,! 14.0;! IR:! νmax! (neat)/cm>1! 2932,! 2860,! 1704,! 1495,! 1367,! 1163,! 1053,! 908;! LRMS! (ESI+):! m/z! 276! ([M! +! Na]+,! 100%);! HRMS! (ESI+)! found!276.1934![M+Na]+,!C15H27O2NNa+!requires!276.1940.! " tertLButyl'(1LphenylnonL2LynL1Lyl)carbamate,'2p! O HN

O

Me

! Prepared!according!to!general!procedure!D!using!n>butyllithium!(4.70!mL,!2.5!M! in!hexanes,!11.8!mmol,!2.05!equiv.),!1>octyne!(1.7!mL,!11.5!mmol,!2.0!equiv.)!in! THF!(25!mL)!and!a>amido!sulfone!9b7!(1.5!g,!5.74!mmol,!1.0!equiv.)!in!THF!(50! mL).! The! mixture! was! stirred! for! 30! mins.! The! crude! product! was! purified! by! flash!column!chromatography!(10>30%!Et2O!in!petrol)!to!give!propargylic)amine! 2p!as!a!colourless!oil!(1.44!g,!78%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.52! (2H,! d,! J! 7.5,! Ar>H),! 7.43>7.35! (2H,! m,! Ar>H),! 3 7.34>7.29!(1H,!m,!Ar>H),!5.67!(1H,!app!br!s,!NHCH),!5.03!(1H,!br!s,!NH),!2.27!(2H,! td,! J! 7.0,! 2.0,! CH3(CH2)4CH2),! 1.59>1.52! (2H,! m,! CH3(CH2)3CH2),! 1.50! (9H,! s,! CO2C(CH3)3),! 1.46>1.39! (2H,! m,! CH3(CH2)2CH2),! 1.37>1.27! (4H,! m,! CH3(CH2)2),! 0.91!(3H,!t,!J!10.0,!CH3(CH2)5);! 13C!NMR!(101!MHz,!CDCl3):!δ!154.8,!140.3,!128.5,! 127.7,!126.8,!85.5,!79.9,!78.3,!46.5,!31.3,!29.4,!28.6,!28.4,!22.5,!18.8,!14.0;!IR:!νmax! (neat)/cm>1! 2931,! 1703,! 1493,! 1367,! 1243,! 1167,! 1019,! 907,! 730;! LRMS! (ESI+):! m/z!338!([M+Na]+,!100%),!653!([2M+Na]+,!50%);!HRMS!(ESI+)!found!338.20918! [M+Na]+,!C20H29NO2Na+!requires!338.20905.! ! tertLButyl'(1LcyclopropyldecL2LynL1Lyl)carbamate,'2q' O HN

O

Me

' Prepared!according!to!general!procedure!D!using!ethylmagnesium!bromide!(2.2!

!

S18!

mL,! 1.0! M! in! THF,! 2.2! mmol,! 2.05! equiv.),! 1>octyne! (0.32! mL,! 2.16! mmol,! 2.0! equiv.)! in! THF! (3.8! mL),! a>amido! sulfone! 9m! (0.35! g,! 1.08! mmol,! 1.0! equiv.)! in! THF!(7.5!mL).!The!mixture!was!stirred!for!4!hrs.!The!crude!product!was!purified! by! flash! column! chromatography! (5>10%! EtOAc! in! petrol)! to! give! propargylic) amine!2q!as!a!colourless!oil!(0.22!g,!73%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!4.77!(1H,!app!br!s,!NHCH),!4.48!(1H,!br!s,!NH),!2.16! 3 (2H,! td,! J! 7.0,! 2.0,! CH3(CH2)4CH2),! 1.64>1.56! (2H,! m,! CH3(CH2)3CH2),! 1.48! (9H,! s,! CO2C(CH3)3),!1.39>1.28!(6H,!m,!CH3(CH2)3),!1.17>1.09!(1H,!m,!NHCHCH),!0.91!(3H,! t,! J! 7.0,! CH3(CH2)5),! 0.49>0.42! (4H,! m,! NHCHCH(CH2)2);! 13C! NMR! (101! MHz,! CDCl3):! 154.9,! 83.7,! 79.6,! 69.8,! 31.3,! 28.7,! 28.4,! 22.5,! 18.6,! 15.4,! 14.0,! 10.4,! 2.6,! 1.2;! IR:! νmax! (neat)/cm>1! 2928,! 2861,! 1710,! 1494,! 1320,! 1241,! 1017,! 912,! 732;! LRMS!(ESI+):!m/z!302!([M+Na]+,!100%);!HRMS!(ESI+)!found!302.20866![M+Na]+,! C17H29O2NNa+!requires!302.20905.!! ! 'tertLButyl'[4L(benzyloxy)L1LcyclopropylbutL2LynL1Lyl]carbamate,'2r' O HN Ph

O

O

! Prepared!according!to!general!procedure!D!using!n>butyllithium!(0.56!mL,!2.25! M! in! hexanes,! 1.25! mmol,! 2.05! equiv.),! [(prop>2>yn>1>yloxy)methyl]benzene! (0.18!mg,!1.22!mmol,!2.0!equiv.)!in!THF!(3.0!mL)!and!a>amido!sulfone!9m!(0.20! g,!0.61!mmol,!!1.0!equiv.)!in!THF!(4.0!mL).!The!mixture!was!stirred!for!30!mins.! The!crude!product!was!purified!by!flash!column!chromatography!(5>10%!EtOAc! in!petrol)!to!give!propargylic)amine,!2r!as!a!colourless!oil!(0.134!g,!73%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.39>7.36! (4H,! m,! Ar>H),! 7.35>7.33! (1H,! m,! Ar>H),! 3 4.84!(1H,!br!s,!NH),!4.60!(2H,!s,!ArCH2O),!4.50!(1H,!app!br!s,!NHCH),!4.19!(2H,!d,!J! 2.0,!OCH2CCCHNH),!1.49!(9H,!s,!CO2C(CH3)3),!1.19>1.14!(1H,!m,!NHCHCH),!0.54> 0.47!(4H,!m,!NHCHCH(CH2)2);! 13C!NMR!(101!MHz,!CDCl3):!δ!154.8,!137.4,!128.4,! 128.2,!127.9,!84.0,!78.8,!71.5,!57.3,!28.4,!15.4,!2.8,!1.7;!IR:!νmax!(neat)/cm>1!3338,! 2979,!1701,!1495,!1366,!1159,!1069,!909,!732;!LRMS!(ESI+):!m/z!338!([M+Na]+,! 100%);! HRMS! (ESI+)! found! 338.17132! [M+Na]+,! C19H25O3NNa+! requires! 338.17266.! !

5.'Synthesis'of'novel'allylic'amines!

! The! synthetic! procedures! and! characterisation! have! previously! been! reported! for!the!following!allylic!amine:! H N Ph

O O

tert-Butyl (1-phenylallyl)carbamate 10a 7

!

S19!

' General'procedure'E'for'the'synthesis'of'terminal'allylic'amines'as' exemplified'by'the'preparation'of'tertLbutyl'butL3LenL2Lylcarbamate,'10b:' H N Me

O O

! Following!a!procedure!adapted!from!Petrini!et)al.7!A!solution!of!vinylmagnesium! bromide!(6.16!mL,!1.0!M!in!THF,!6.16!mmol,!2.2!equiv.)!was!added!dropwise!to!a! solution!of!a>amido!sulfone!9a6!(0.8!g,!2.8!mmol,!1.0!equiv.)!in!THF!(26.5!mL)!at!> 20!°C.!The!reaction!mixture!was!stirred!at!>20!°C!for!30!min!and!then!warmed!to! room! temperature! over! 30! min.! Upon! completion! the! reaction! was! quenched! with!sat.!NH4Cl(aq)!(mL)!at!>20!°C!and!was!allowed!to!warm!to!room!temperature.! The! product! was! extracted! with! Et2O! (3! ×! 10! mL)! and! washed! with! brine! (10! mL).! The! combined! organic! layers! were! dried! over! MgSO4,! filtered! and! concentrated! under! reduced! pressure.! The! crude! product! was! purified! by! flash! column!chromatography!(10%!Et2O!in!petrol)!to!give!title!allylic)amine!10b'as!a! colourless!oil!(80!mg,!17%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!5.84!(1H,!ddd,!J!17.0,!10.5,!5.0,!CH CHCHNH),!5.19> 3 2 5.06!(2H,!m,!CH2CHCHNH),!4.48!(1H,!br!s,!NH),!4.24!(1H,!app!br!s,!NHCH),!1.47! (9H,!s,!CO2C(CH3)3),!1.23!(3H,!d,!J!7.0,!NHCHCH3);! 13C!NMR!(101!MHz,!CDCl3):!δ! 140.2,!116.4,!113.6,!79.5,!48.2,!28.4,!20.7;!IR:!νmax!(neat)/cm>1!2979,!1701,!1497,! 1392,!1170,!910;!HRMS!(FI+)!found!171.1258![M]+,!C9H17NO2+!requires!171.1259.! " tertLButyl'[1L(thiophenL2Lyl)allyl]carbamate,'10c' H N S

O O

! Prepared!according!to!general!procedure!E!using!vinylmagnesium!bromide!(2.5! mL,!1.0!M!in!THF,!2.5!mmol,!2.2!equiv.),!a>amido!sulfone!9f9!!(0.40!g,!1.13!mmol,! 1.0! equiv.)! in! THF! (11! mL).! The! crude! product! was! purified! by! flash! column! chromatography!(5>10%!Et2O!in!petrol)!to!give!allylic)amine!10c!as!a!white!solid! (175!mg,!65%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.28!(1H,!ddd,!J!5.0,!3.0,!2.5,!Ar>H),!7.13>7.11!(1H,!m,! 3 Ar>H),!7.02>7.00!(1H,!m,!Ar>H),!6.02!(1H,!ddd,!J!17.0,!10.5,!6.0,!CH2CHCHNH),!5.36! (1H,!app!br!s,!NHCH),!5.27>5.20!(2H,!m,!CH2CHCHNH),!5.00!(1H,!br!s,!NH),!1.46! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 155.0,! 142.2,! 137.6,! 126.7,! 126.2,!121.6,!115.3,!79.7,!52.5,!28.4;!IR:!νmax!(neat)/cm>1!2971,!1712,!1520,!1416,! 1521,! 1244,! 1077,! 794;! LRMS! (ESI+):! m/z! 262! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 262.08729! [M+Na]+,! C12H17O2NSNa+! requires! 262.08777;! mp:! 64! °C! !

S20!

DCM/hexane).! ! tertLButyl'[1L(4Lmethoxyphenyl)allyl]carbamate,'10d! H N

O O

OMe

! Prepared!according!to!general!procedure!E!using!vinylmagnesium!bromide!(1.12! mL,!1.0!M!in!THF,!1.12!mmol,!2.2!equiv.),!a>amido!sulfone!9e9!(0.20!g,!0.53!mmol,! 1.0! equiv.)! in! THF! (5! mL).! The! crude! product! was! purified! by! flash! column! chromatography! (15>30%! Et2O! in! petrol)! to! give! allylic) amine! 10d! as! a! white! solid!(112!mg,!80%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.24>7.22! (2H,! m,! Ar>H),! 6.90>6.87! (2H,! m,! Ar>H),! 3 6.00!(1H,!ddd,!J!17.0,!10.0,!5.5,!CH2CHCHNH),!5.28>5.21!(3H,!m,!CH2CHCHNH!and! NHCH),!4.94!(1H,!br!s,!NH),!3.80!(3H,!s,!OCH3),!1.46!(9H,!s,!CO2C(CH3)3);! 13C!NMR! (101! MHz,! CDCl3):! δ! 158.9,! 155.0,! 138.2,! 133.2,! 128.2,! 115.1,! 114.0,! 79.5,! 56.0,! 55.2,!28.4;!IR:!νmax!(neat)/cm>1!2979,!1715,!1612,!1366,!1245,!1108,!1036;!LRMS! (ESI+):! m/z! 286! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 286.12130! [M+Na]+,! C15H21O3NNa+!requires!286.14136;!mp:!!74>75!°C!(DCM/petrol).! 1H!and! 13C!data! consistent!with!literature.14! ! tertLButyl'{1L[4L(trifluoromethyl)phenyl]allyl}carbamate,'10e' H N

O O

CF3

! Prepared!according!to!general!procedure!E!using!vinylmagnesium!bromide!(1.32! mL,! 1.0! M! in! THF,! 1.32! mmol,! 2.2! equiv.),! a>amido! sulfone! 9d8! (0.25! g,! 0.60! mmol,! 1.0! equiv.)! in! THF! (5.7! mL).! The! crude! product! was! purified! by! flash! column! chromatography! (15>20%! Et2O! in! petrol)! to! give! allylic)amine! 10e! as! a! white!solid!(163!mg,!90%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.61! (2H,! d,! J! 8.0,! Ar>H),! 7.43! (2H,! d,! J! 8.0,! Ar>H),! 3 5.98!(1H,!ddd,!J!17.0,!10.5,!6.0,!CH2CHCHNH),!5.36!(1H,!br!s,!NH),!5.27!(1H,!d,!J! 10.5,! CHaHbCHCHNH),! 5.22! (1H,! d,! J! 17.0,! CHaHbCHCHNH),! 5.10! (1H,! app! br! d,! J! 7.0,!NHCH),!1.45!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!155.0,!145.2,! 137.1,! 129.6! (q,! 2JCF! 32.5),! 127.3,! 125.5! (q,! 3JCF! 3.5),! 124.1! (q,! 1JCF! 275.0)! 116.6,! 80.0,!56.4,!28.3;! 19F!NMR!(377!MHz,!CDCl3):!δ!>62.5;!!IR:!νmax!(neat)/cm>1!2982,! !

S21!

1700,!1619,!1492,!1367,!1297,!1107,!1067,!990;!LRMS!(ESI+):!m/z!324!([M+Na]+,! 100%);! HRMS! (ESI+)! found! 324.1180! [M+Na]+,! C15H18O2NF3Na+! requires! 324.11818;! mp:! 80>81! °C! (DCM/petrol).! 1H! and! 13C! data! consistent! with! literature.14! ! tertLButyl'(1Lcyclopropylallyl)carbamate,'10f! H N

O O

! Prepared!according!to!general!procedure!E!using!vinylmagnesium!bromide!(3.50! mL,!1.0!M!in!THF,!3.52!mmol,!2.2!equiv.),!a>amido!sulfone!9m!(0.50!g,!1.60!mmol,! 1.0! equiv.)! in! THF! (15! mL).! The! crude! product! was! purified! by! flash! column! chromatography!(10%!Et2O!in!petrol)!to!give!allylic)amine!10f!as!a!colourless!oil! (160!mg,!51%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!5.80!(1H,!ddd,!J!17.0,!10.5,!5.5,!CH CHCHNH),!5.21> 3 2 5.06!(2H,!m,!CH2CHCHNH),!4.70!(1H,!app!br!s,!NHCH),!3.58!(1H,!br!s,!NH),!1.43! (9H,! s,! CO2C(CH3)3),! 0.89>0.81! (1H,! m,! NHCHCH(CH2)2),! 0.53>0.45! (2H,! m,! NHCHCH(CH2CH2)),!0.37!(1H,!dt,!J!9.0,!4.5,!NHCHCH(CH2CHaHb)),!0.27>0.22!(1H,! m,!NHCHCH(CH2CHaHb));! 13C!NMR!(101!MHz,!CDCl3):!δ!155.3,!137.9,!114.4,!79.2,! 56.3,! 28.4,! 15.6,! 2.7;! IR:! νmax! (neat)/cm>1! 2979,! 1688,! 1497,! 1390,! 1243,! 1164,! 1018,! 989;! LRMS! (ESI+):! m/z! 220! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 220.13142![M+Na]+,!C11H19O2NNa+!requires!220.13080;!! !

6.' Hydroacylation' products' from' aldehyde' and' propargylic' amine'coupling' ! General' procedure' F' for' the' synthesis' of' linear' γLamino' enones' via' rhodiumLcatalysed'hydroacylation'of'propargylic'amines'as'exemplified'by' the' synthesis' of' tertLbutyl' (E)L[4L(2L(methylthio)phenyl)L4LoxobutL2LenL1L yl]carbamate,'3aLBoc' " Me

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' An!oven>dried!microwave!vial!was!charged!with![Rh(nbd)2BF4]!(1.1!mg,!2!mol%)! and! PNP(Cy)! (1.3! mg,! 2! mol%),! once! under! an! inert! atmosphere,! they! were! dissolved!in!acetone!(1.0!mL).!Hydrogen!gas!was!bubbled!through!the!solution!at! room! temperature! for! 1>2! mins! in! order! to! generate! the! active! catalyst! species! (colour! change! from! red! to! pale! yellow).! The! hydrogen! gas! was! purged! using!

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nitrogen! gas,! and! this! was! bubbled! through! the! catalyst! to! dryness.! The! dry! catalyst!was!dissolved!in!acetone!(75! µL,!1.0!M!with!respect!to!aldehyde!minus! starting! materials)! and! this! was! transferred! to! a! nitrogen>filled! microwave! vial! containing!2>(methylthio)benzaldehyde!1a!(19!µL,!0.15!mmol,!1.0!equiv.)!and!N> Boc>propargylamine!2a!(30.2!mg,!0.195!mmol,!1.3!equiv.).!The!reaction!mixture,! once! homogenous! (on! occasion,! sonication! was! required),! was! then! stirred! at! room!temperature.!The!reaction!was!monitored!by!TLC!until!complete.!After!20! mins,!the!reaction!mixture!was!filtered!through!a!plug!of!silica!(acetone,!10!mL)! and!the!solvent!removed!in)vacuo!to!obtain!the!crude!product.!The!crude!product! was! analysed! by! 1H! NMR! spectroscopy! to! measure! the! ratio! of! the! linear! to! branched! products! (17:1,! linear! 3aLBoc:! branched3a’LBoc).! The! regioisomers! were! then! separated! by! flash! column! chromatography! (5%! EtOAc! in! petrol)! to! afford!title!linear!γJamino)enone!3aLBoc'as!a!pale!yellow!oil!(39.7!mg,!86%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.63!(1H,!d,!J!7.5,!Ar>H),!7.47!(1H,!app!t,!J!7.5,!Ar>H),! 3 7.37!(1H,!d,!J!7.5,!Ar>H),!7.21!(1H,!app!t,!J!7.5,!Ar>H),!6.86>6.76!(2H,!m,!COCHCH),! 4.82! (1H,! br! s,! NH),! 4.02! (2H,! app! br! s,! NHCH2),! 2.46! (3H,! s,! SCH3),! 1.46! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 182.1,! 155.6,! 145.6,! 140.8,! 136.3,! 131.6,!129.7,!127.9,!126.1,!124.0,!79.9,!41.8,!28.4,!16.4;!IR:!νmax!(neat)/cm>1!3370,! 2977,!1710,!1514,!1434,!1366,!1250,!1167,!1026;!LRMS!(ESI+):!m/z!308!([M+H]+,! 50%),! 330! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 330.1132! [M+Na]+,! C16H21NO3SNa+!requires!330.1134.!! " tertLButyl'{2L[2L(methylthio)benzoyl]allyl}carbamate,'3a’LBoc! " Me

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! Prepared! following! a! procedure! adapted! from! Willis! et.! al.,2! An! oven>dried! microwave! vial! was! charged! with! [Rh(nbd)2BF4]! (11.2! mg,! 10! mol%)! and! dppe(orhto>iPr)!(17.0!mg,!10!mol%),!once!under!an!inert!atmosphere,!they!were! dissolved!in!acetone!(1.0!mL).!Hydrogen!gas!was!bubbled!through!the!solution!at! room! temperature! for! 1>2! minutes! in! order! to! generate! the! active! catalyst! species.!The!hydrogen!gas!was!purged!using!nitrogen!gas,!and!this!was!bubbled! through! the! catalyst! to! dryness.! The! dry! catalyst! was! dissolved! in! acetone! (0.5! mL)! and! this! was! transferred! to! a! nitrogen>filled! microwave! vial! containing! 2> (methylthio)benzaldehyde! 1a! (39! µL,! 0.30! mmol,! 1.0! equiv.)! and! N>Boc> propargylamine! 2a! (93.1! mg,! 0.60! mmol,! 2.0! equiv.).! The! reaction! was! monitored! by! TLC! until! complete.! After! 6! hrs! the! vial! was! opened! to! air! and! filtered! through! a! plug! of! silica! (acetone,! 15! mL)! and! the! solvent! removed! in) vacuo.!The!crude!product!was!purified!by!flash!column!chromatography!(5>10%!

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EtOAc!in!petrol)!to!afford!title!branched!γJamino)enone!3a’LBoc!as!a!pale!yellow! oil!(78.2!mg,!85%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.45!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!7.40>7.38!(2H,!m,! 3 Ar>H),!7.22!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!6.13!(1H,!app!s,!NHCH2CCHaHbCO),!5.69! (1H,!app!s,!NHCH2CCHaHbCO),!5.10!(1H,!br!s,!NH),!4.14!(2H,!d,!J!6.0,!NHCH2),!2.45! (3H,!s,!SCH3),!1.45!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!198.0,!155.6,! 145.4,! 138.4,! 137.9,! 131.0,! 129.3,! 129.2,! 127.5,! 124.6,! 79.4,! 41.5,! 28.4,! 17.0;! IR:! νmax! (neat)/cm>1! 3361,! 2978,! 1695,! 1655,! 1585,! 1513,! 1434,! 1392,! 1367,! 1310,! 1281,! 1251,! 1169,! 1029;! LRMS! (ESI+):! m/z! 308! ([M+H]+,! 60%),! 330! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 330.1135! [M+Na]+,! C16H21NO3SNa+! requires! 330.1134.! ! Benzyl' (E)L{4L[2L(methylthio)phenyl]L4LoxobutL2LenL1Lyl}carbamate,' 3aL Cbz'' Me

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! Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde' 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (benzyl! prop>2>yn>1> ylcarbamate! 2s)! (42.6! mg,! 0.225! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(88! µL,!1!M).!After!stirring!for! 30!min!at!room!temperature!the!reaction!gave!a!crude!mixture!of!regioisomers! (12:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5>20%! EtOAc! in! petrol)! to! yield! linear! γJamino)enone! 3aLCbz' as!a!yellow!oil!(38.8!mg,!76%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.61! (1H,! d,! J! 7.5,! Ar>H),! 7.49>7.45! (1H,! m,! Ar>H),! 3 7.38>7.35!(6H,!m,!Ar>H),!7.20!(1H,!app!t,!J!7.5,!Ar>H),!6.87>6.78!(2H,!m,!COCHCH),! 5.16! (3H,! br! s,! NH! and! CO2CH2),! 4.09! (2H,! dd,! J! 5.5,! 3.5,! NHCH2),! 2.45! (3H,! s,! SCH3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 192.3,! 156.2,! 144.9,! 141.0,! 136.3,! 136.1,! 131.7,! 129.8,! 128.6,! 128.3,! 128.2,! 127.9,! 126.0,! 124.0,! 67.1,! 42.2,! 16.3;! IR:! νmax! (neat)/cm>1! 2919,! 2777,! 1704,! 1667,! 1619,! 1528,! 1249;! LRMS! (ESI+):! m/z! 342! ([M+H]+,! 100%),! 364! ([M+Na]+,! 95%);! HRMS! (ESI+)! found! 364.0979! [M+Na]+,! C19H19NO3SNa+!requires!364.0978.!! ' Benzyl'{2L[2L(methylthio)benzoyl]allyl}carbamate,'3a’LCbz' Me

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' Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde' !

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1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (benzyl! prop>2>yn>1> ylcarbamate! 2s)! (42.6! mg,! 0.225! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)!and!dcpm!(3.1!mg,!5!mol%)!in!acetone!(88! µL,!1!M).!After!stirring!for!16! hrs!at!room!temperature!the!reaction!gave!a!crude!mixture!of!regioisomers!(4:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography!(5>20%!EtOAc!in!petrol)!to!yield!branched!γJamino)enone!3a’L Cbz'as!a!cream!oil!(9.3!mg,!18%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.45!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!7.40>7.35!(7H,!m,! 3 Ar>H),!7.22!(1H,!app!t,!J!7.5,!Ar>H),!6.16!(1H,!app!s,!NHCH2CCHaHbCO),!5.71!(1H,! app!s,!NHCH2CCHaHbCO),!5.37!(1H,!t,!J!5.0,!NH),!5.15!(2H,!s,!CO2CH2),!4.22!(2H,!d,!J! 6.5,!NHCH2),!2.43!(3H,!s,!SCH3);!13C!NMR!(101!MHz,!CDCl3):!δ!156.4,!145.0,!138.2,! 137.8,!136.5,!131.0,!129.92,!129.88,!129.1,!128.5,!128.1,!128.0,!127.7,!124.6,!66.8,! 41.9,!17.1;!IR:!νmax!(neat)/cm>1!2970,!2931,!1702,!1467,!1378,!1160;!LRMS!(ESI+):! m/z! 364! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 364.09781! [M+Na]+,! C19H19NO3SNa+!requires!364.09779.! ! (E)L4LMethylLNL{4L[2L(methylthio)phenyl]L4LoxobutL2LenL1L yl}benzenesulfonamide,'3aLTs' Me

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! Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde' 1a!(19! µL,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(4>methyl>N>(prop>2>yn>1> yl)benzenesulfonamide!2t)!(47.1!mg,!0.225!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8! mg,! 5! mol%)! and! PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (84! µL,! 1! M).! After! stirring! for! 10! min! at! room! temperature! the! reaction! gave! a! crude! mixture! of! regioisomers! (4:1,! linear:! branched).! The! compounds! were! separated! by! flash! column!chromatography!(5>20%!EtOAc!in!petrol)!to!yield!linear!γJamino)enone! 3aLTs'as!a!yellow!solid!(17.4!mg,!32%).! ! 1H! NMR! (500! MHz,! CDCl ):! δ! 7.79! (2H,! d,! J! 8.0,! Ar>H),! 7.56! (1H,! d,! J! 7.5,! Ar>H),! 3 7.48!(1H,!app!t,!J!7.5,!Ar>H),!7.35!(3H,!dd,!J!12.5,!8.0,!Ar>H),!7.21!(1H,!t,!J!7.5,!Ar> H),!6.84!(1H,!d,!J!15.5,!COCH),!6.74>6.69!(1H,!m,!COCHCH),!4.68!(1H,!t,!J!6.0,!NH),! 3.89!(2H,!t,!J!5.0,!NHCH2),!2.46!(3H,!s,!SCH3),!2.44!(3H,!s,!Ar>CH3);! 13C!NMR!(125! MHz,! CDCl3):! δ! 191.4,! 143.9,! 142.4,! 141.4,! 136.8,! 135.6,! 132.0,! 129.91,! 129.72,! 128.7,!127.1,!125.9,!123.9,!44.3,!21.6,!16.3;!IR:!νmax!(neat)/cm>1!2941,!2831,!1716,! 1554,!1433,!1328,!1159;!LRMS!(ESI+):!m/z!362!([M+H]+,!100%),!384!([M+Na]+,! 55%);! HRMS! (ESI+)! found! 384.0700! [M+Na]+,! C18H19NO3S2Na+! requires! 384.0699;!mp:!107>109!°C!(DCM/hexane).! ' ' ' !

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4LMethylLNL{2L[2L(methylthio)benzoyl]allyl}benzenesulfonamide,'3a’LTs' Me

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' Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde' 1a!(19! µL,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(4>methyl>N>(prop>2>yn>1> yl)benzenesulfonamide!2t)!(47.1!mg,!0.225!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8! mg,!5!mol%)!and!dcpm!(3.1!mg,!5!mol%)!in!acetone!(84! µL,!1!M).!After!stirring! for! 16! hrs! at! room! temperature! the! reaction! gave! a! crude! mixture! of! regioisomers! (1:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5>20%! EtOAc! in! petrol)! to! yield! branched! γJamino) enone!3a’LTs'as!a!cream!oil!(21.9!mg,!40%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.80>7.78!(2H,!m,!Ar>H),!7.44!(1H,!ddd,!J!8.0,!7.0,!1.5,! 3 Ar>H),!7.37!(1H,!d,!J!7.5,!Ar>H),!7.33!(2H,!dd,!J!8.5,!0.5,!Ar>H),!7.19>7.15!(1H,!m,!Ar> H),!7.15>7.11!(1H,!m,!Ar>H),!6.15!(1H,!app!s,!NHCH2CCHaHbCO),!5.68!(1H,!app!s,! NHCH2CCHaHbCO),!5.18!(1H,!t,!J!6.5,!NH),!4.00!(2H,!d,!J!6.5,!NHCH2),!2.46!(3H,!s,! SCH3),! 2.43! (3H,! s,! Ar>CH3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 197.6,! 143.5,! 139.4,! 138.5,!137.2,!137.1,!131.21,!131.17,!129.8,!129.1,!127.5,!127.2,!124.4,!44.2,!21.6,! 16.9;!IR:!νmax!(neat)/cm>1!2923,!2852,!1652,!1598,!1434,!1329,!1184,!1093;!LRMS! (ESI+):! m/z! 384! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 384.06992! [M+Na]+,! C18H19NO3S2Na+!requires!384.06989.! ! tertLButyl' (E)L{5L[2L(methylthio)phenyl]L5LoxopentL3LenL2Lyl}carbamate,' 3b' Me

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! Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde' 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! but>3>yn>2> ylcarbamate! 2b)! (38.0! mg,! 0.225! mmol,! 1.5! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(93!µL,!1!M).!After!stirring!for!1! hr!at!room!temperature!the!reaction!gave!a!crude!mixture!of!regioisomers!(25:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography!(5>10%!EtOAc!in!petrol)!to!yield!linear!γJamino)enone!3b' as!a! yellow!oil!(42.8!mg,!89%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.64!(1H,!dd,!J!7.5,!1.5,!Ar>H),!7.46!(1H,!app!td,!J!7.5,! 3 1.5,!Ar>H),!7.36!(1H,!d,!J!7.5,!Ar>H),!7.20!(1H,!app!t,!J!7.5,!Ar>H),!6.81>6.73!(2H,!m,! COCHCH),!4.65!(1H,!br!s,!NH),!4.49>4.47!(1H,!m,!NHCH(CH3)),!2.45!(3H,!s,!SCH3),!

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1.47! (9H,! s,! CO2C(CH3)3),! 1.32! (3H,! d,! J! 7.0,! NHCH(CH3));! 13C! NMR! (101! MHz,! CDCl3):!δ!192.7,!155.0,!149.9,!141.0,!136.3,!131.7,!129.8,!126.6,!126.0,!123.9,!47.5,! 28.4,!27.3,!20.4,!16.4;!IR:!νmax!(neat)/cm>1!3343,!2977,!1694,!1619,!1586,!1511,! 1434,!1366,!1247,!1209,!1165,!1049,!1009;!LRMS!(ESI+):!m/z!322!([M+H]+,!10%),! 344! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 344.1292! [M+Na]+,! C17H23NO3SNa+! requires!344.1291." ! tertLButyl' (E)L{4L[2L(methylthio)phenyl]L4LoxoL1LphenylbutL2LenL1L yl}carbamate,'3c' Me

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Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde! 1a!(0.39!mL,!3.0!mmol,!1.0!equiv.),!propargylic!amine!(tert>butyl!(1>phenylprop> 2>yn>1>yl)carbamate!2d)!(0.90!g,!3.9!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(11.2!mg,! 1!mol%)!and!PNP(Cy)!(14.2!mg,!1!mol%)!in!acetone!(1.7!mL,!1!M).!After!stirring! for!15!mins!at!room!temperature!the!reaction!gave!the!linear! γ>amino!enone,!as! the! only! regioisomer! detectable! by! 1H! NMR.! The! crude! reaction! mixture! was! purified! by! flash! column! chromatography! (10>40%! Et2O! in! petrol)! to! yield! γJ amino)enone!3c'as!a!yellow!solid!(1.01!g,!88%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.67!(1H,!dd,!J!7.5,!1.5,!Ar>H),!7.49>7.45!(2H,!m,!Ar> 3 H),!7.41>7.29!(5H,!m,!Ar>H),!7.21!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!7.00!(1H,!dd,!J!15.5,! 5.0,!COCHCH),!6.87!(1H,!dd,!J!15.5,!1.5,!COCHCH),!5.55!(1H,!br!s,!NH),!5.02!(1H,!d,! J! 5.0,! NHCH),! 2.46! (3H,! s,! SCH3),! 1.48! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 192.4,! 154.8,! 147.4,! 141.1,! 139.3,! 136.2,! 131.7,! 129.9,! 129.0,! 128.2,! 127.3,!126.1,!124.0,!80.2,!55.9,!30.3,!28.4,!16.4;!IR:!νmax!(neat)/cm>1!3343,!2939,! 1692,!1619,!1495,!1434,!1366,!1249,!1167,!1025;!LRMS!(ESI+):!m/z!384!([M+H]+,! 100%),! 406! ([M+Na]+,! 25%);! HRMS! (ESI+)! found! 406.1444! [M+Na]+,! C22H25NO3SNa+!requires!406.1447;!mp:!144>145!°C!(DCM/hexane).! ! tertLButyl' (E)L{2,2LdimethylL6L[2L(methylthio)phenyl]L6LoxohexL4LenL3L yl}carbamate,'3d' Me

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! Prepared! according! to! general! procedure! F! using! 2>(methylthio)benzaldehyde! 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! (4,4> dimethylpent>1>yn>3>yl)carbamate! 2c)! (47.5! mg,! 0.225! mmol,! 1.5! equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(79!

!

S27!

µL,!1!M).!After!stirring!for!3!hrs!at!room!temperature!the!reaction!gave!the!linear! γ>amino! enone,) as! the! only! regioisomer! detectable! by! 1H! NMR.! The! crude! reaction! mixture! was! purified! by! flash! column! chromatography! (25%! EtOAc! in! petrol)!to!yield!γJamino)enone!3d!as!a!yellow!solid!(49.6!mg,!91%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.68!(1H,!dd,!J!7.5,!1.5,!Ar>H),!7.48!(1H,!app!td,!J!7.5,! 3 1.5,!Ar>H),!7.38!(1H,!d,!J!7.5,!Ar>H),!7.23!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!6.91!(1H,!dd,! J! 15.5,! 6.0,! COCHCH),! 6.83! (1H,! d,! J! 15.5,! COCHCH),! 4.68! (1H,! d,! J! 9.0,! NH),! 4.20! (1H,!dd,!J!9.0,!6.0,!NHCH),!2.47!(3H,!s,!SCH3),!1.48!(9H,!s,!CO2C(CH3)3),!0.99!(9H,!s,! NHCHC(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 192.3,! 155.4,! 146.5,! 141.1,! 131.7,! 129.8,! 128.6,! 126.0,! 123.9,! 79.7,! 60.5,! 35.0,! 28.4,! 26.5,! 25.4,! 16.4;! IR:! νmax! (neat)/cm>1!2968,!1698,!1618,!1501,!1366,!1247,!1169,!1050,!1011;!LRMS!(ESI+):! m/z! 364! ([M+H]+,! 45%),! 386! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 386.1755! [M+Na]+,!C20H29NO3SNa+!requires!386.1760;!mp:!130>131!°C!(EtOAc/petrol).! ! tertLButyl'(E)L{4L[2L(methylthio)benzoyl]decL3LenL2Lyl}carbamate,'3e' Me

S

O

H N Me

O O

Me

! An!oven>dried!microwave!vial!was!charged!with![Rh(nbd)2BF4]!(2.8!mg,!5!mol%)! and! dppm! (2.9! mg,! 5! mol%).! Once! under! an! inert! atomosphere,! they! were! dissolved!in!acetone!(1.0!mL).!Hydrogen!gas!was!bubbled!through!the!solution!at! room!temperature!for!1>2!mins!in!order!to!generate!the!active!catalyst!species.! The!hydrogen!gas!was!purged!using!nitrogen!gas,!and!this!was!bubbled!through! the!catalyst!to!dryness.!The!dry!catalyst!was!dissolved!in!acetone!(74! µL,!1.0!M! with!respect!to!aldehyde!minus!starting!materials)!and!this!was!transferred!to!a! nitrogen>filled! microwave! vial! containing! 2>(methylthio)benzaldehyde! 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.)! and! propargylic! amine! (tert>butyl! dec>3>yn>2> ylcarbamate! 2o)! (57.0! mg,! 0.225! mmol,! 1.5! equiv.).! The! reaction! mixture,! once! homogenous! (on! occasion,! sonication! was! required),! was! then! stirred! at! room! temperature.! The! reaction! was! monitored! by! TLC! until! complete.! After! 16! hrs,! the! reaction! mixture! was! filtered! through! a! plug! of! silica! (acetone,! 10! mL)! and! the! solvent! removed! in) vacuo! to! obtain! the! crude! product.! The! crude! product! was! analysed! by! 1H! NMR! spectroscopy! to! measure! the! ratio! of! the! linear! to! branched! products! (8:1,! linear:! branched).! The! regioisomers! were! then! separated!by!flash!column!chromatography!(5%!EtOAc!in!petrol)!to!afford!title! linear!γJamino)enone!3e'as!a!pale!yellow!oil!(49.3!mg,!81%).! !

!

S28!

1H!NMR!(400!MHz,!CDCl ):!δ!7.42!(1H,!ddd,!J!8.0,!7.0,!1.5,!Ar>H),!7.36!(1H,!d,!J!!7.0,! 3

Ar>H),!7.32!(1H,!d,!J!7.0,!Ar>H),!7.19!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!5.86!(1H,!d,!J!9.0,! COCCH),!4.61!(1H,!br!s,!NH),!4.46!(1H,!app!br!s,!NHCH),!2.53!(2H,!dd,!J!9.0,!6.0,! COCCH2),! 2.44! (3H,! s,! SCH3),! 1.61>1.48! (2H,! m,! COCCH2CH2),! 1.46! (9H,! s,! CO2C(CH3)3),! 1.41>1.32! (6H,! m,! CH3(CH2)3),! 1.24! (3H,! d,! J! 7.0,! NHCH(CH3)),! 0.91! (3H,!t,!J!7.0,!CH3(CH2)5);! 13C!NMR!(101!MHz,!CDCl3):!δ!198.8,!167.8,!146.7,!141.9,! 138.8,! 130.4,! 129.3,! 127.2,! 124.5,! 100.0,! 68.6,! 45.1,! 31.7,! 29.6,! 29.2,! 28.4,! 26.6,! 22.6,!21.0,!16.9,!14.1;!IR:!νmax!(neat)/cm>1!2961,!2926,!2855,!1710,!1644,!1492,! 1366,! 1247,! 1166,! 1052,! 908;! LRMS! (ESI+):! m/z! 428! ([M+Na]+,! 100%);! HRMS! (ESI+)!found!406.24124![M+H]+,!C23H36O3NS+!requires!406.24104.! ! tertLButyl' (E)L{4L[4LbromoL2L(methylthio)phenyl]L4LoxobutL2LenL1L yl}carbamate,'3f! Me

Br

S

O

H N

O O

! Prepared! according! to! general! procedure! F! using! 4>bromo>2> (methylthio)benzaldehyde! 1e3! (34.6! mg,! 0.15! mmol,! 1.0! equiv.),! N>Boc> propargylamine!2a!(35.7!mg,!0.225!mmol,!1.5!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(79!µL,!1!M).!After!stirring!for!1! hr!at!room!temperature!the!reaction!gave!a!crude!mixture!of!regioisomers!(18:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5%! EtOAc! in! petrol)! to! yield! linear! γJamino) enone! 3f! as! a! yellow!solid!(46.2!mg,!80%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.52! (1H,! d,! J! 8.0,! Ar>H),! 7.44! (1H,! d,! J! 1.5,! Ar>H),! 3 7.33! (1H,! dd,! J! 8.0,! 1.5,! Ar>H),! 6.85! (1H,! dt,! J! 15.5,! 4.0,! COCHCH),! 6.76! (1H,! d,! J! 15.5,!COCHCH),!4.84!(1H,!br!s,!NH),!4.02!(2H,!app!br!s,!NHCH2),!2.46!(3H,!s,!SCH3),! 1.48!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!191.3,!155.6,!146.0,!143.8,! 134.4,!131.1,!128.2,!127.3,!126.9,!80.0,!41.8,!28.4,!27.4,!16.3;!IR:!νmax!(neat)/cm>1! 2832,! 1707,! 1573,! 1539,! 1367,! 1281,! 1166;! LRMS! (ESI+):! m/z! 408! ([79Br]! [M+Na]+,! 100%),! 410! ([81Br]! [M+Na]+,! 95%);! HRMS! (ESI+)! found! 408.0235! [[79Br]!M+Na]+,!410.0218![[81Br]!M+Na]+,!C16H20O3N79BrSNa+!requires!408.0239,! C16H20O3N81BrSNa+!requires!410.0219;!mp:!90>92!°C!(DCM/hexane).! ! " "

!

S29!

tertLButyl'(E)L[6L(methylthio)L4LoxohexL2LenL1Lyl]carbamate,'3g' Me

S

O

H N

O O

! Prepared! according! to! general! procedure! F! using! 3> (methylthio)propionaldehyde! 1b! (15! µL,! 0.15! mmol,! 1.0! equiv.),! N>Boc> propargylamine!2a!(35.7!mg,!0.225!mmol,!1.5!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(99!µL,!1!M).!After!stirring!for!3! hrs! at! room! temperature! the! reaction! gave! a! crude! mixture! of! regioisomers! (25:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5%! EtOAc! in! petrol)! to! yield! linear! γJamino) enone! 3g! as! a! yellow!oil!(24.8!mg,!64%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!6.81!(1H,!dt,!J!16.0,!5.5,!COCHCH),!6.22!(1H,!d,!J!16.0,! 3 COCHCH),! 4.84! (1H,! br! s,! NH),! 3.96! (2H,! app! br! s,! NHCH2),! 2.90>2.76! (4H,! m,! SCH2CH2),! 2.13! (3H,! s,! SCH3),! 1.46! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 198.1,! 155.6,! 143.4,! 129.2,! 80.1,! 41.5,! 40.1,! 28.4,! 28.2,! 15.9;! IR:! νmax! (neat)/cm>1!3352,!2978,!1693,!1634,!1513,!1392,!1366,!1248,!1164;!LRMS!(ESI+):! m/z! 282! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 282.1132! [M+Na]+,! C12H21NO3SNa+!requires!282.1134.! ! tertLButyl' (E)L{4L[2L(methylthio)cyclohexL1LenL1Lyl]L4LoxobutL2LenL1L yl}carbamate,'3h' Me

S

O

H N

O O

' Prepared!according!to!general!procedure!F!using!2>(methylthio)cyclohex>1>ene> 1>carbaldehyde!2d2!(23.4!mg,!0.15!mmol,!1.0!equiv.),!N>Boc>propargylamine!2a! (35.7!mg,!0.225!mmol,!1.5!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)! (3.2!mg,!5!mol%)!in!acetone!(91! µL,!1!M).!After!stirring!for!15!mins!at!0!ºC!the! reaction! gave! a! crude! mixture! of! regioisomers! (12:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5%! EtOAc! in! petrol)!to!yield!linear!γJamino)enone!3h!as!a!pale!yellow!solid!(33.2!mg,!71%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!6.80!(1H,!dt,!J!15.5,!5.0,!COCHCH),!6.54!(1H,!d,!J!15.5,! 3 COCHCH),!4.72!(1H,!br!s,!NH),!3.97!(2H,!app!s,!NHCH2),!2.48!(2H,!t,!J!6.0,!SCCH2),! 2.41! (2H,! t,! J! 6.0,! COCCH2),! 2.26! (3H,! s,! SCH3),! 1.76>1.69! (4H,! m,! SCCH2(CH2)2),! 1.48!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!192.8,!155.6,!145.1,!142.8,! 132.4,! 127.8,! 79.8,! 41.8,! 29.9,! 28.4,! 28.3,! 23.0,! 21.9,! 15.0;! IR:! νmax! (neat)/cm>1! 2930,! 1703,! 1609,! 1510,! 1366,! 1250,! 1169;! LRMS! (ESI+):! m/z! 312! ([M+H]+,! !

S30!

100%),! 334! ([M+Na]+,! 90%);! HRMS! (ESI+)! found! 334.1456! [M+Na]+,! C16H25NO3SNa+!requires!334.1447;!mp:!99>102!°C!(DCM/hexane).! ! tertLButyl' (E)L{4L[3L(methylthio)thiophenL2Lyl]L4LoxobutL2LenL1L yl}carbamate,'3i! Me

S

O

H N

S

O O

! Prepared! according! to! general! procedure! F! using! 3>(methylthio)thiophene>2> carbaldehyde! 1m! (23.7! mg,! 0.15! mmol,! 1.0! equiv.),! N>Boc>propargylamine! 2a! (35.7!mg,!0.225!mmol,!1.5!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (90! µL,! 1! M).! After! stirring! for! 16! hrs! at! room! temperature! the! reaction! gave! a! crude! mixture! of! regioisomers! (6:1,! linear:! branched).! The! compounds! were! separated! by! flash! column! chromatography! (5%! EtOAc! in! petrol)! to! yield! linear! γJamino)enone! 3i! as! a! yellow! oil! (36.2! mg,! 77%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.60! (1H,! d,! J! 5.0,! Ar>H),! 7.08! (1H,! d,! J! 5.0,! Ar>H),! 3 7.03!(1H,!dt,!J!15.0,!5.0,!COCHCH),!6.79!(1H,!dt,!J!15.0,!2.0,!COCHCH),!4.84!(1H,!br! s,!NH),!4.02!(2H,!app!br!s,!NHCH2),!2.56!(3H,!s,!SCH3),!1.49!(9H,!s,!CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl ):! δ! 180.9,! 155.6,! 143.7,! 131.3,! 128.6,! 126.4,! 125.0,! 3 110.5,!83.5,!28.4,!23.9,!16.7;!IR:!νmax!(neat)/cm>1!2978,!2928,!1687,!1655,!1585,! 1495,! 1402,! 1242,! 1163,! 908;! LRMS! (ESI+):! m/z) 314! ([M+H]+,! 50%),! 336! ([M+Na]+,!100%);!HRMS!(ESI+)!found!314.08762![M+H]+,!C14H20O3NS2+!requires! 314.08791.! ! tertLButyl' (E)L{4L[2L(dimethylamino)phenyl]L4LoxobutL2LenL1L yl}carbamate,'3j' Me

N

Me O

H N

O O

! Prepared! according! to! general! procedure! F! using! 2> 5 (dimethylamino)benzaldehyde! 1g ! (22.4! mg,! 0.15! mmol,! 1.0! equiv.),! N>Boc> propargylamine!2a!(35.7!mg,!0.225!mmol,!1.5!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(92!µL,!1!M).!After!stirring!for!6! hrs!at!room!temperature!the!reaction!gave!the!linear! γ>amino!enone,)as!the!only! regioisomer!detectable!by! 1H!NMR.!The!crude!reaction!mixture!was!purified!by! flash!column!chromatography!(25%!EtOAc!in!petrol)!to!yield!γJamino)enone!3j!as! a!yellow!solid!(45.3!mg,!99%).! ! !

S31!

1H!NMR!(400!MHz,!CDCl

3):!δ!7.46!(1H,!dd,!J!7.5,!2.0,!Ar>H),!7.38!(1H,!ddd,!J!8.0,!

7.5,!2.0,!Ar>H),!6.99!(1H,!dd,!J!8.0,!1.0,!Ar>H),!6.94!(1H,!dd,!J!7.5,!1.0,!Ar>H),!6.88! (1H,! d,! J! 12.0,! COCHCH),! 6.82! (1H,! dt,! J! 12.0,! 2.0,! COCHCH),! 4.81! (1H,! br! s,! NH),! 3.98! (2H,! app! br! s,! NHCH2),! 2.80! (6H,! s,! N(CH3)2),! 1.47! (9H,! s,! CO2C(CH3)3);! 13C! NMR!(101!MHz,!CDCl3):!δ!194.7,!152.1,!142.7,!132.0,!130.5,!129.0,!119.8,!116.7,! 79.7,! 44.2,! 41.6,! 28.4,! 21.1,! 14.2;! IR:! νmax! (neat)/cm>1! 3352,! 2978,! 1698,! 1668,! 1619,!1595,!1497,!1433,!1366,!1280,!1250,!1165;!LRMS!(ESI+):!m/z!305!([M+H]+,! 100%);! HRMS! (ESI+)! found! 327.1681! [M+Na]+,! C17H24N2O3Na+! requires! 327.1679;!mp:!89>91!°C!(DCM/hexane).!

' 7.'OneLpot'formation'of'functionalised'pyrrole'rings! ! General'procedure'G'for'the'synthesis'of'NLBoc'pyrroles'as'exemplified'by' the' synthesis' of' tertLbutyl' 2L[2L(methylthio)phenyl]L1HLpyrroleL1L carboxylate,'4a' Me

S N Boc

! An!oven>dried!microwave!vial!was!charged!with![Rh(nbd)2BF4]!(2.8!mg,!5!mol%)! and!PNP(Cy)!(3.2!mg,!5!mol%)!(for!use!with!terminal!alkynes)!or!dppm!(for!use! with!internal!alkynes).!Once!under!an!inert!atmosphere,!they!were!dissolved!in! acetone! (1! mL).! Hydrogen! gas! was! bubbled! through! the! solution! at! room! temperature! for! 1>2! mins! in! order! to! generate! the! active! catalyst! species.! The! hydrogen!gas!was!purged!using!nitrogen!gas,!and!this!was!bubbled!through!the! catalyst!to!dryness.!The!dry!catalyst!was!dissolved!in!acetone!(75! µL,!1.0!M!with! respect! to! aldehyde! minus! starting! materials)! and! this! was! transferred! to! a! nitrogen>filled! microwave! vial! containing! 2>(methylthio)benzaldehyde! 1a! (19! µL,!0.15!mmol,!1.0!equiv.)!and!N>Boc>propargylamine!2a!(30.2!mg,!0.195!mmol,! 1.3!equiv.).!The!reaction!mixture,!once!homogenous!(on!occasion,!sonication!was! required),! was! then! stirred! at! room! temperature! and! monitored! by! TLC! until! complete.! After! 20! mins,! the! reaction! vessel! was! opened! to! air! followed! by! the! addition! of! acetonitrile! (1.5! mL)! and! p>TSA! (42.8! mg,! 0.230! mmol,! 1.5! equiv.).! The!reaction!mixture!was!further!stirred!until!complete,!after!3!hrs,!the!solution! was! diluted! with! acetonitrile! (5! mL)! and! neutralised! by! the! addition! of! sat.! NaHCO3! (aq)!(10!mL)!in!a!separatory!funnel.!The!aqueous!mixture!was!extracted! with! EtOAc! (3! ×! 5! mL)! and! the! combined! organic! extracts! were! washed! with! brine! (10! mL)! and! dried! over! MgSO4.! The! solvent! was! removed! in) vacuo! to! obtain!the!crude!product!and!purified!by!flash!column!chromatography!!(5>10%! Et2O!in!petrol)!to!afford!title!pyrrole!4a!as!a!colourless!oil!(34.8!mg,!81%).! !

!

S32!

1H!NMR!(400!MHz,!CDCl

3):!δ!7.44!(1H,!dd,!J!3.5,!2.0,!NCH),!7.35!(1H,!ddd,!J!8.0,!

7.5,!1.5,!Ar>H),!7.25!(2H,!app!qd,!J!3.5,!1.5,!Ar>H),!7.18!(1H,!app!td,!J!7.5,!1.5,!Ar>H),! 6.31!(1H,!app!t,!J!3.5,!NCHCH),!6.18!(1H,!dd,!J!3.5,!2.0,!NCCH),!2.38!(3H,!s,!SCH3),! 1.28!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!149.1,!139.9,!134.2,!132.0,! 130.3,! 128.3,! 124.8,! 124.3,! 121.7,! 114.4,! 110.5,! 83.1,! 27.4,! 15.5;! IR:! νmax! (neat)/cm>1!2981,!1738,!1438,!1396,!1370,!1340,!1313,!1152,!1085;!LRMS!(ESI+):! m/z! 290! ([M+H]+,! 100%),! 312! ([M+Na]+,! 50%);! HRMS! (ESI+)! found! 312.1033! [M+Na]+,!C16H19NO2SNa+!requires!312.1029.! ! tertLButyl'2LmethylL5L[2L(methylthio)phenyl]L1HLpyrroleL1Lcarboxylate,'4b' Me

S N Boc

Me

' Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! (19! µL,! 0.15! mmol,! 1.0! equiv),! propargylic! amine! (tert>butyl! but>3>yn>2> ylcarbamate! 2b)! ! (33.0! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(98!µL,!1!M).!After!stirring!for!4! hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and!p>TSA!(42.8!mg,!0.230!mmol,! 1.5!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further!3!hrs.!The! crude! product! was! purified! by! flash! column! chromatography! !! (5>10%! Et2O! in! petrol)!to!afford!pyrrole!4b'as!a!colourless!oil!(37.2!mg,!82%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.33!(1H,!ddd,!J!8.0,!7.5,!2.0,!Ar>H),!7.24>7.19!(2H,!m,! 3 Ar>H),!7.16!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!6.06!(1H,!d,!J!3.0,!NC(Ar)CH),!6.03!(1H,! dq,! J! 3.0,! 1.0,! NC(CH3)CH),! 2.52! (3H,! d,! J! 1.0,! NC(CH3)),! 2.37! (3H,! s,! SCH3),! 1.21! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 149.9,! 139.4,! 135.0,! 132.9,! 131.8,! 130.2,! 128.0,! 124.3,! 124.2,! 112.7,! 110.5,! 82.8,! 27.4,! 15.8,! 15.3;! IR:! νmax! (neat)/cm>1! 2942,! 2832,! 1742,! 1367,! 1313,! 1149,! 1024;! LRMS! (ESI+):! m/z! 304! ([M+H]+,! 100%),! 326! ([M+Na]+,! 95%);! HRMS! (ESI+)! found! 326.1184! [M+Na]+,! C17H21NO2SNa+!requires!326.1185.! ! tertLButyl' 2L(tertLbutyl)L5L[2L(methylthio)phenyl]L1HLpyrroleL1L carboxylate,'4c' Me

S tBu

N Boc

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! (4,4> dimethylpent>1>yn>3>yl)carbamate! 2c)! (41.2! mg,! 0.195! mmol,! 1.3! equiv.),!

!

S33!

[Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(90! µL,! 1! M).! After! stirring! for! 30! mins! at! room! temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (72.5! mg,! 0.600! mmol,! 4.0! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 3.5! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4c! as! colourless!oil!(42.6!mg,!82%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.33!(1H,!ddd,!J!8.0,!7.5,!1.5,!Ar>H),!7.24!(1H,!dd,!J! 3 7.5,! 1.0,! Ar>H),! 7.20! (1H,! dd,! J! 8.0,! 1.0,! Ar>H),! 7.15! (1H,! app! td,! J! 7.5,! 1.0,! Ar>H),! 6.11!(1H,!d,!J!3.5,!NCCH),!6.09!(1H,!d,!J!3.5,!NCCH),!2.36!(3H,!s,!SCH3),!1.48!(9H,!s,! CO2C(CH3)3),!1.15!(9H,!s,!NCC(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!151.3,!147.0,! 144.9,!139.6,!134.2,!130.6,!128.0,!124.2,!124.1,!111.0,!107.4,!83.1,!33.1,!30.4,!27.0,! 15.2;!IR:!νmax!(neat)/cm>1!2966,!1748,!1457,!1393,!1368,!1326,!1299,!1257,!1159,! 1144,!1084,!1003;!LRMS!(ESI+):!m/z!346!([M+H]+,!100%),!368!([M+Na]+,!20%);! HRMS!(ESI+)!found!368.1650![M+Na]+,!C20H27NO2SNa+!requires!368.1655.! ! tertLButyl'2L[2L(methylthio)phenyl]L5LphenylL1HLpyrroleL1Lcarboxylate,'4d' ! Me

S N Boc

Ph

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! (0.41! mL,! 3.20! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! (1> phenylprop>2>yn>1>yl)carbamate! 2d)! (0.96! g,! 4.16! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (23.9! mg,! 2! mol%)! and! PNP(Cy)! (30.3! mg,! 2! mol%)! in! acetone! (1.8! mL,! 1! M).! After! stirring! for! 30! mins! at! room! temperature,! acetonitrile! (10! mL)!and!p>TSA!(0.61!g,!3.20!mmol,!1.0!equiv.)!were!added!and!stirred!at!room! temperature!for!a!further!4!hrs.!The!crude!product!was!purified!by!flash!column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4d! as! a! white! solid! (1.04!g,!88%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.48>7.45! (2H,! m,! Ar>H),! 7.43>7.39! (3H,! m,! Ar>H),! 3 7.38>7.34!(2H,!m,!Ar>H),!7.28!(1H,!dd,!J!8.0,!1.0,!Ar>H),!7.23!(1H,!td,!J!7.5,!1.0,!Ar> H),!6.33!(1H,!d,!J!3.5,!NCCH),!6.25!(1H,!d,!J!3.5,!NCCH),!2.42!(3H,!s,!SCH3),!1.16!(9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 149.2,! 139.8,! 136.0,! 134.5,! 133.9,! 133.6,! 130.6,! 128.8,! 128.5,! 127.7,! 127.0,! 124.6,! 124.3,! 112.9,! 112.6,! 83.2,! 27.1,! 15.4;! IR:! νmax! (neat)/cm>1! 2980,! 1748,! 1748,! 1482,! 1368,! 1304,! 1147;! LRMS! (ESI+):! m/z! 366! ([M+H]+,! 100%),! 388! ([M+Na]+,! 25%);! HRMS! (ESI+)! found! 388.1338! [M+Na]+,! C22H23NO2SNa+! requires! 388.1342;! mp:! 94>95! °C! (DCM/hexane).! !

!

S34!

tertLButyl' 2L(4Lmethoxyphenyl)L5L[2L(methylthio)phenyl]L1HLpyrroleL1L carboxylate,'4e' Me

S N Boc

OMe

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! [1>(4> methoxyphenyl)prop>2>yn>1>yl]carbamate! 2e)! (51.0! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)! and! PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (70! µL,! 1! M).! After! stirring! for! 2! hrs! at! room! temperature,! acetonitrile! (1.5!mL)!and!p>TSA!(42.8!mg,!0.230!mmol,!1.5!equiv.)!were!added!and!stirred!at! room! temperature! for! a! further! 3! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4e' as! colourless!oil!(46.8!mg,!79%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.39>7.35!(3H,!m,!Ar>H),!7.32!(1H,!dd,!J!7.5,!1.5,!Ar> 3 H),!7.25!(1H,!d,!J!7.5,!Ar>H),!7.21!(1H,!app!t,!J!7.5,!Ar>H),!6.94!(2H,!d,!J!8.5,!Ar>H),! 6.25!(1H,!d,!J!3.5,!NCCH),!6.22!(1H,!d,!J!3.5,!NCCH),!3.87!(3H,!s,!OCH3),!2.40!(3H,!s,! SCH3),!1.15!(9H,!s!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!158.8,!149.3,!139.8,! 135.9,!134.1,!133.2,!130.6,!130.0,!128.3,!127.0,!124.5,!124.3,!113.2,!112.9,!112.1,! 83.1,!55.3,!27.1,!15.4;!IR:!νmax!(neat)/cm>1!2979,!1744,!1613,!1493,!1367,!1302,! 1246,! 1176,! 730;! LRMS! (ESI+):! m/z! 396! ([M+H]+,! 90%),! 418! ([M+Na]+,! 100%);! HRMS!(ESI+)!found!396.16249![M+H]+,!C23H26O3NS+!requires!396.16279.! ! "tertLButyl' 2L(4Lcyanophenyl)L5L[2L(methylthio)phenyl]L1HLpyrroleL1L carboxylate,'4f' Me

S N Boc

CN

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! ! (19! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! [1>(4> cyanophenyl)prop>2>yn>1>yl]carbamate! 2g)' (50.0! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(81! µL,!1!M).!After!stirring!for!2!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and! p>TSA! (29.0! mg,! 0.150! mmol,! 1.0! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 16! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4f' as! colourless!oil!(44.6!mg,!76%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.69>7.66! (2H,! m,! Ar>H),! 7.54>7.51! (2H,! m,! Ar>H),! 3

!

S35!

7.40!(1H,!ddd,!J!8.0,!7.5,!2.0,!Ar>H),!7.31>7.29!(1H,!m,!Ar>H),!7.26!(1H,!d,!J!7.0,!Ar> H),!7.22!(1H,!app!td,!J!7.5,!2.0,!Ar>H),!6.40!(1H,!d,!J!3.5,!NCCH),!6.25!(1H,!d,!J!3.5,! NCCH),!2.41!(3H,!s,!SCH3),!1.15!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ! 148.9,!139.8,!138.8,!135.2,!134.1,!133.4,!131.6,!130.5,!129.0,!128.8,!124.5,!124.4,! 119.1,!114.5,!113.4,!110.3,!84.0,!27.1,!15.3;!IR:!νmax!(neat)/cm>1!2980,!2226,!1745,! 1607,! 1454,! 1301,! 1255,! 1146,! 909;! LRMS! (ESI+):! m/z! 391! ([M+H]+,! 20%),! 413! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 413.12903! [M+Na]+,! C23H22O2N2SNa+! requires!413.12942.! ! tertLButyl' 3LhexylL2L[2L(methylthio)phenyl]L5LphenylL1HLpyrroleL1L carboxylate,'4g" Me

Me

S N Boc

Ph

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a!(19! µL,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(tert>butyl!(1>phenylnon>2> yn>1>yl)carbamate!2p)!(61.5!mg,!0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,! 5!mol%)!and!dppm!(2.9!mg,!5!mol%)!in!acetone!(70!µL,!1!M).!After!stirring!for!4! hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and!p>TSA!(28.5!mg,!0.150!mmol,! 1.0!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further!4!hrs.!The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)!to!afford!pyrrole!4g'as!colourless!oil!(57!mg,!85%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.44!(2H,!dd,!J!8.5,!1.5,!Ar>H),!7.41>7.37!(3H,!m,!Ar> 3 H),! 7.34>7.31! (1H,! m,! Ar>H),! 7.29>7.20! (3H,! m,! Ar>H),! 6.26! (1H,! s,! NCCH),! 2.31> 2.16! (2H,! m,! CH3(CH2)4CH2),! 1.55! (2H,! dd,! J! 7.0,! 3.5,! CH3(CH2)3CH2),! 1.31>1.24! (6H,! m,! CH3(CH2)3),! 1.13! (9H,! s,! CO2C(CH3)3),! 0.88! (3H,! t,! J! 7.0,! CH3(CH2)5);! 13C! NMR!(101!MHz,!CDCl3):!δ!149.4,!140.8,!135.3,!134.6,!132.9,!131.3,!129.5,!128.5,! 128.4,!127.7,!126.8,!126.2,!124.12,!124.08,!113.9,!82.7,!31.7,!30.2,!29.1,!27.1,!25.7,! 22.6,!15.1,!14.1;!IR:!νmax!(neat)/cm>1!3061,!2968,!2855,!1744,!1606,!1484,!1361,! 1254,! 1074,! 991;! LRMS! (ESI+):! m/z! 450! ([M+H]+,! 100%),! 472! ([M+Na]+,! 30%);! HRMS!(ESI+)!found!472.22689![M+Na]+,!C28H35O2NSNa+!requires!472.22807.! ! " "

!

S36!

tertLButyl' 5LcyclopropylL3LhexylL2L[2L(methylthio)phenyl]L1HLpyrroleL1L carboxylate,'4h' ' Me

Me

S N Boc

' Prepared! according! to! general! procedure! G! using! 2>(methylthio)benzaldehyde! 1a! (63! µL,! 0.49! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! (1> cyclopropyldec>2>yn>1>yl)carbamate! 2q)! (178! mg,! 0.640! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4!(9.35!mg,!5!mol%)!and!dppm!(9.61!mg,!5!mol%)!in!acetone!(0.3! mL,!1!M).!After!stirring!for!16!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and! p>TSA! (93.0! mg,! 0.49! mmol,! 1.0! equiv.)! were! added! and! stirred! at! room! temperature!for!a!further!2!hrs.!The!crude!product!was!purified!by!flash!column! chromatography! ! (10%! Et2O! in! petrol)! to! afford! pyrrole) 4h' as! colourless! oil! (178.3!mg,!88%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.32!(1H,!ddd,!J!8.0,!5.0,!3.5,!Ar>H),!7.19!(1H,!d,!J!8.0,! 3 Ar>H),!7.17>7.15!(2H,!m,!Ar>H),!5.85!(1H,!s,!NC(CH(CH2)2)CH),!2.35!(3H,!s,!SCH3),! 2.33>2.29!(1H,!m,!NC(CH(CH2)2)CH),!2.18>2.07!(2H,!m,!CH3(CH2)4CH2),!1.46>1.25! (6H,! m,! CH3CH2(CH2)3CH2),! 1.20! (9H,! s,! CO2C(CH3)3),! 0.94>0.83! (6H,! m,! CH3CH2(CH2)4! and! NCCH(CHaHbCHaHb),! 0.75>0.72! (1H,! m,! NCCH(CHaHbCHaHb),! 0.64>0.58!(1H,!m,!NCCH(CHaHbCHaHb),!0.49>0.44!(1H,!m,!NCCH(CHaHbCHaHb);!13C! NMR!(101!MHz,!CDCl3):!δ!149.8,!145.1,!140.4,!138.4,!133.9,!131.0,!127.8,!127.6,! 125.5,!124.0,!109.0,!82.2,!31.6,!30.2,!29.0,!27.4,!25.7,!22.6,!15.0,!14.1,!9.8,!7.2,!6.9;! IR:!νmax!(neat)/cm>1!3085,!2926,!1736,!1590,!1477,!1335,!1158,!1047,!830;!LRMS! (ESI+):! m/z! 414! ([M+H]+,! 100%),! 436! ([M+Na]+,! 75%);! HRMS! (ESI+)! found! 436.22792![M+H]+,!C25H35O2NSNa+!requires!436.22830.! " " "

!

S37!

tertLButyl' 2L[4,5LdimethoxyL2L(methylthio)phenyl]L3LhexylL5LphenylL1HL pyrroleL1Lcarboxylate,'4i' Me

Me

S N Boc

MeO

Ph

OMe

! Prepared! according! to! general! procedure! G! using! 4,5>dimethoxy>2> (methylthio)benzaldehyde4! 1f! (31.9! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine!(tert>butyl!(1>phenylnon>2>yn>1>yl)carbamate!2p)!(61.5!mg,!0.195!mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)! and! dppm! (2.9! mg,! 5! mol%)! in! acetone!(80!µL,!0.9!M).!After!stirring!for!16!hrs!at!room!temperature,!acetonitrile! (1.5!mL)!and!p>TSA!(29.0!mg,!0.15!mmol,!1.0!equiv.)!were!added!and!stirred!at! room! temperature! for! a! further! 2! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! EtOAc! in! petrol)! to! afford! pyrrole) 4i! as! colourless!oil!(65.8!mg,!86%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.43>7.36! (4H,! m,! Ar>H),! 7.32>7.28! (1H,! m,! Ar>H),! 3 6.92!(1H,!s,!Ar>H),!6.84!(1H,!s,!Ar>H),!6.23!(1H,!s,!NCCH),!3.97!(3H,!s,!OCH3),!3.89! (3H,!s,!OCH3),!2.35!(3H,!s,!SCH3),!2.31>2.14!(2H,!m,!CH3(CH2)4CH2),!1.56>1.48!(2H,! m,! CH3(CH2)3CH2),! 1.31>1.24! (6H,! m,! CH3(CH2)3),! 1.15! (9H,! s,! CO2C(CH3)3),! 0.87! (3H,!t,!J!7.0,!CH3(CH2)5);! 13C!NMR!(101!MHz,!CDCl3):!δ!149.5,!148.9,!146.8,!135.0,! 134.7,! 131.0,! 129.8,! 128.4,! 127.7,! 126.8,! 126.7,! 126.1,! 114.9,! 113.6,! 111.2,! 82.8,! 56.1,!31.7,!30.3,!29.7,!29.2,!27.2,!25.9,!22.6,!17.1,!14.1;!IR:!νmax!(neat)/cm>1!2928,! 1742,!1497,!1369,!1247,!1207,!1151,!1070,!908;!LRMS!(ESI+):!m/z!510!([M+H]+,! 100%),!532!([M+Na]+,!45%);!HRMS!(ESI+)!found!510.26648![M+H]+,!C30H40O4NS+! requires!510.26726.! ! tertLButyl' 2L[3LmethoxyL2L(methylthio)phenyl]L5L[4L (methoxycarbonyl)phenyl]L1HLpyrroleL1Lcarboxylate,'4j' Me MeO

S N Boc

CO2Me

! Prepared! according! to! general! procedure! G! using! 3>methoxy>2> (methylthio)benzaldehyde! 1i! (24.3! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (methyl! 4>{1>[(tert>butoxycarbonyl)amino]prop>2>yn>1>yl}benzoate! 2l)! (56.4!mg,!0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (66! µL,! 1! M).! After! stirring! for! 2! hrs! at! room! !

S38!

temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 16! hrs.! The! crude! product!was!purified!by!flash!column!chromatography!!(5>10%!Et2O!in!petrol)!to! afford!pyrrole!4j!as!colourless!oil!(52.7!mg,!77%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 8.07! (2H,! d,! J! 8.5,! Ar>H),! 7.50! (2H,! d,! J! 8.5,! Ar>H),! 3 7.33!(1H,!dd,!J!8.0,!7.5,!Ar>H),!7.04>6.97!(2H,!m,!Ar>H),!6.36!(1H,!d,!J!3.5,!NCCH),! 6.18!(1H,!d,!J!3.5,!NCCH),!3.98!(3H,!s,!CO2CH3),!3.96!(3H,!s,!ArOCH3),!2.26!(3H,!s,! SCH3),! 1.16! (9H,! s,! CO2C(CH3)3));! 13C! NMR! (101! MHz,! CDCl3):! δ! 159.6,! 140.1,! 139.2,!134.4,!130.4,!130.0,!129.7,!129.1,!128.3,!128.2,!123.4,!123.0,!120.8,!113.7,! 112.7,!110.8,!83.9,!56.0,!52.1,!27.2,!17.9;!IR:!νmax!(neat)/cm>1!2979,!2838,!1607,! 1275,! 1111,! 994;! LRMS! (ESI+):! m/z! 454! ([M+H]+,! 10%),! 476! ([M+Na]+,! 100%);! HRMS!(ESI+)!found!454.13187![M+H]+,!C25H28O5NS+!requires!454.16827.! ' 2LMethoxyL6L{5L[2L(methylthio)L5L(trifluoromethyl)phenyl]L1HLpyrrolL2L yl}pyridine,'4k' Me

S N H

N OMe

CF3

' Prepared! according! to! general! procedure! G! using! 2>(methylthio)>5> (trifluoromethyl)benzaldehyde!1n!(33.0!mg,!0.15!mmol,!1.0!equiv.),!propargylic! amine!(tert>butyl![1>(6>methoxypyridin>2>yl)prop>2>yn>1>yl]carbamate!2m)!(59! mg,!0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(4.1!mg,!7.5!mol%)!and!PNP(Cy)!(5.2! mg,! 7.5! mol%)! in! acetone! (60! µL,! 1! M).! After! stirring! for! 16! hrs! at! room! temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 4! hrs.! The! crude! product!was!purified!by!flash!column!chromatography!!(5>10%!Et2O!in!petrol)!to! afford!pyrrole!4k'as!pale!brown!oil!(41.0!mg,!74%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!10.42!(1H,!br!s,!NH),!7.76!(1H,!td,!J!1.5,!0.5,!Ar>H),! 3 7.59! (1H,! dd,! J! 8.0,! 7.5,! Ar>H),! 7.50>7.48! (1H,! m,! Ar>H),! 7.44! (1H,! d,! J! 8.5,! Ar>H),! 7.21!(1H,!dd,!J!7.5,!0.5,!Ar>H),!6.79!(1H,!dd,!J!4.0,!2.5,!NCCH),!6.66!(1H,!dd,!J!=!4.0,! 2.5,!NCCH),!6.58!(1H,!dd,!J!8.0,!0.5,!Ar>H),!4.03!(3H,!s,!OCH3),!2.52!(3H,!s,!SCH3);! 13C! NMR! (101! MHz,! CDCl ):! δ! 163.5,! 147.6,! 139.6,! 139.3,! 132.6,! 132.0,! 130.2,! 3 2 127.9! (q,! JCF! 32.5),! 127.7,! 125.3! (q,! 3JCF! 3.5),! 124.1(q,! 1JCF! 272.0),! 123.5! (q,! 3JCF! 3.5),!112.0,!110.8,!108.0,!107.6,!53.3,!16.5;!19F!NMR!(377!MHz,!CDCl3):!δ!>62.5;!IR:! νmax! (neat)/cm>1! 3429,! 2923,! 1573,! 1471,! 1423,! 1374,! 1328,! 1260,1096,! 907;! LRMS! (ESI+):! m/z! 365! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 365.09313! [M+H]+,! C18H16ON2F3S+!requires!365.09299.! !

!

S39!

tertLButyl' 2L[2LfluoroL6L(methylthio)phenyl]L3LhexylL5LphenylL1HLpyrroleL 1Lcarboxylate,'4l! Me

Me

S

F

N Boc

Ph

! Prepared! according! to! general! procedure! G! using! 2>fluoro>6> (methylthio)benzaldehyde! 1j! (25.5! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! (1>phenylnon>2>yn>1>yl)carbamate! 2p)! (70.9! mg,! 0.23! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)! and! dppm! (2.9! mg,! 5! mol%)! in! acetone! (55! µL,! 1! M).! After! stirring! for! 2! hrs! at! room! temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (43! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 4! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (10%! Et2O! in! petrol)! to! afford! the! pyrrole! 4l! as! colourless!oil!(34.0!mg,!50%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.46>7.43! (2H,! m,! Ar>H),! 7.41>7.35! (3H,! m,! Ar>H),! 3 7.34>7.30!(1H,!m,!Ar>H),!7.02!(1H,!d,!J!8.0,!Ar>H),!6.94!(1H,!app!td,!J!8.5,!1.0,!Ar>H),! 6.29!(1H,!s,!NCCH),!2.42!(3H,!s,!SCH3),!2.28>2.18!(2H,!m,!CH3(CH2)4CH2),!1.56>1.49! (2H,!m,!CH3(CH2)3CH2),!1.25!(6H,!app!td,!J!10.5,!5.5,!CH3(CH2)3(CH2)2),!1.15!(9H,!s,! CO2C(CH3)3),! 0.87! (3H,! t,! J! 7.0,! CH3(CH2)5);! 13C! NMR! (101! MHz,! CDCl3):! δ! 162.2,! 159.7,!149.1,!143.6,!135.4!(d,! 1JCF!190.0),!129.7!(d,! 2JCF!19.5),!128.5,!127.7,!126.8,! 122.3,!120.5!(d,!2JCF!19.0),!119.2!(d,!3JCF!8.5),!118.2,!114.2,!111.2!(d,!3JCF!8.5),!82.8,! 31.6,!29.8,!29.0,!27.1,!25.9,!22.6,!15.3,!14.1;! 19F!NMR!(377!MHz,!CDCl3):!δ!>112.3;! IR:!νmax!(neat)/cm>1!2925,!1743,!1605,!1482,!1306,!1153,!989;!LRMS!(ESI+):!m/z! 468! ([M+H]+,! 100%),! 490! ([M+Na]+,! 50%);! HRMS! (ESI+)! found! 468.23627! [M+H]+,!C28H35O2NFS+!requires!468.23670.! ! tertLButylL2L(4LBromophenyl)L5L[2L(methylthio)L5L(trifluoromethyl)L phenyl]L1HLpyrroleL1Lcarboxylate,'4m' Me

S N Boc

Br

CF3

! Prepared! according! to! general! procedure! G! using! 2>(methylthio)>5> (trifluoromethyl)benzaldehyde' 1n' (33! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>Butyl! [1>(4>bromophenyl)prop>2>yn>1>yl]carbamate! 2k)! (60.5! mg,! 0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!

!

S40!

mol%)! in! acetone! (57! µL,! 1! M).! After! stirring! for! 2! mins! at! room! temperature,! acetonitrile!(1.5!mL)!and!p>TSA!(51.0!mg,!0.30!mmol,!2.0!equiv.)!were!added!and! stirred!at!room!temperature!for!a!further!3!hrs.!The!crude!product!was!purified! by!flash!column!chromatography!!(5>10%!Et2O!in!petrol)!to!afford!pyrrole!4m'as! a!waxy!white!sold!(50.1!mg,!81%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.62!(1H,!ddd,!J!8.5,!2.0,!0.5,!Ar>H),!7.54>7.51!(3H,!m,! 3 Ar>H),!7.30!(3H,!app!dq,!J!9.0,!3.0,!Ar>H),!6.32!(1H,!d,!J!3.5,!NCCH),!6.27!(1H,!d,!J! 3.5,! NCCH),! 2.45! (3H,! s,! SCH3),! 1.14! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):!δ!148.7,!145.3,!135.5,!133.7,!133.0,!132.1,!130.9,!130.4,!127.1!(q,!3JCF!3.5),! 126.3! (q,! 2JCF! 33.0),! 125.1! (q,! 3JCF! 3.5),! 124.1! (q,! 3JCF! 262.0),! 123.4,! 121.4,! 113.7,! 113.3,!83.9,!27.1,!14.9;! 19F!NMR!(377!MHz,!CDCl3):!δ!>62.1;!IR:!νmax!(neat)/cm>1! 2943,! 1749,! 1609,! 1475,! 1369,! 1171,! 1121,! 991,! 792;! LRMS! (ESI+):! m/z! 512! ([79Br]![M+H]+,!40%),!514!([81Br]![M+H]+,!50%),!534!([79Br]![M+Na]+,!90%),!536! ([81Br]! [M+Na]+,! 100%);! HRMS! (ESI+)! found! 534.03119! [[79Br]! M+Na]+,! 536.02904! [[81Br]! M+Na]+,! C23H2179BrNO2F3SNa+! requires! 534.03207,! C23H2181BrNO2SF3Na+!requires!536.03002;!mp:!88>89!°C!(Et2O/petrol).! " tertLButyl' 2L[4LbromoL2L(methylthio)phenyl]L5L(thiophenL2Lyl)L1HL pyrroleL1Lcarboxylate,'4n' Me

Br

S N S Boc

! Prepared! according! to! general! procedure! G! using! 3 4>bromo>2>(methylthio)benzaldehyde ! 1e! (34.7! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! [1>(thiophen>2>yl)prop>2>yn>1>yl]carbamate! 2i)! (46.3!mg,!0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (69! µL,! 1! M).! After! stirring! for! 2! hrs! at! room! temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 12! hrs.! The! crude! product!was!purified!by!flash!column!chromatography!!(5>10%!Et2O!in!petrol)!to! afford!pyrrole!4n!as!white!solid!(49.2!mg,!73%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.36>7.32! (3H,! m,! Ar>H),! 7.16>7.13! (2H,! m,! Ar>H),! 3 7.07!(1H,!dd,!J!5.0,!3.5,!SCHCH),!6.40!(1H,!d,!J!3.5,!NCCH),!6.21!(1H,!d,!J!3.5,!NCCH),! 2.41!(3H,!s,!SCH3),!1.21!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!148.8,! 142.2,!134.9,!132.7,!132.4,!131.7,!128.4,!127.5,!127.2,!126.7,!126.6,!125.5,!122.5,! 114.6,!113.3,!83.8,!27.2,!15.3;!IR:!νmax!(neat)/cm>1!2978,!1747,!1453,!1368,!1299,! 1145,! 1080,! 791;! LRMS! (ESI+):! m/z! 472! ([79Br]! [M+Na]+,! 95%),! 474! ([81Br]! [M+Na]+,!100%);!HRMS!(ESI+)!found!450.01863![[79Br]!M+H]+,!452.01656![[81Br]!

!

S41!

M+H]+,! C20H2179BrNO2S2+! requires! 450.01916,! C20H2181BrNO2S2+! requires! 452.01711;!mp:!85>86!°C!(Et2O/petrol).! ! tertLButyl'2L[4LbromoL2L(methylthio)phenyl]L1HLpyrroleL1Lcarboxylate,'4o' Me

S N Boc

Br

! Prepared! according! to! general! procedure! G! using! 3 4>bromo>2>(methylthio)benzaldehyde ! 1e! (34.6! mg,! 0.15! mmol,! 1.0! equiv.),! N> Boc>propargyl! amine! 2a! (30.2! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)! and! PNP(Cy)! (3.2! mg,! 5! mol%)! in! acetone! (80! µL! ,! 1! M).! After! stirring! for! 16! hrs! at! room! temperature,! acetonitrile! (1.5! mL)! and! p>TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further!3!hrs.!The!crude!product!was!purified!by!flash!column!chromatography!! (5>10%!Et2O!in!petrol)!to!afford!pyrrole)4o!as!an!off>white!solid!(42.6!mg,!80%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.43!(1H,!dd,!J,!3.5,!2.0,!NCH),!7.31>7.30!(2H,!m,!Ar> 3 H),!7.1!(1H,!d,!J)8.5,!Ar>H),!6.30!(1H,!app!t,!J!3.5,!NCCH),!6.17!(1H,!dd,!J!3.5,!2.0,! NCHCH),!2.39!(3H,!s,!SCH3),!1.33!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):! δ!148.9,!142.6,!132.6,!131.5,!127.1,!126.8,!126.3,!122.4,!122.0,!114.9,!110.7,!83.5,! 27.5,!15.4;!IR:!νmax!(neat)/cm>1!2923,!1740,!1493,!1449,!1399,!1370,!1338,!1312,! 1257,! 1150,! 1082;! LRMS! (ESI+):! m/z! 368! ([79Br]! [M+H]+,! 25%),! 370! ([81Br]! [M+H]+,! 30%),! 390! ([79Br]! [M+Na]+,! 95%),! 392! ([81Br]! [M+H]+,! 100%);! HRMS! (ESI+)! found! 390.0131! [[79Br]! [M+Na]+],! 392.0110! [[81Br]! [M+Na]+],! C16H1879BrNO2SNa+! requires! 390.0134,! C16H1881BrNO2SNa+! requires! 392.0114;! mp:!84>90!°C!(Et2O/petrol).! ! tertLButyl' 2L[4LbromoL2L(methylthio)phenyl]L5LcyclopropylL3L (hydroxymethyl)L1HLpyrroleL1Lcarboxylate,'4p' OH Me

Br

S N Boc

' Prepared! according! to! general! procedure! G! using! 3 4>bromo>2>(methylthio)benzaldehyde ! 1e! (27.7! mg,! 0.12! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! [3>(benzyloxy)>1>cyclopropylprop>2>yn>1> yl]carbamate! 2r)! (48.3! mg,! 0.15! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.2! mg,! 5! mol%)!and!dppm!(2.3!mg,!5!mol%)!in!acetone!(44! µL,!1!M).!After!stirring!for!16! hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and!p>TSA!(46.0!mg,!0.24!mmol,! !

S42!

2.0!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further!3!hrs.!The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)!to!afford!pyrrole!4p!as!colourless!oil!(32.0!mg,!61%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.54!(1H,!d,!J!2.0,!Ar>H),!7.26!(1H,!dd,!J!8.5,!2.0,!Ar> 3 H),!6.99!(1H,!d,!J!8.5,!Ar>H),!5.77!(1H,!s,!NCCH),!3.66!(2H,!s,!NCCCH2OH),!2.14!(1H,! ttd,!J!8.5,!5.5,!1.0,!NC(CH(CH2)2)),!1.58!(3H,!s,!SCH3),!1.56!(9H,!s,!CO2C(CH3)3),!0.91! (1H,!dt,!J!!5.5,!2.0,! NC(CHCH2CH2)),!0.69>0.65!(2H,!m,!NCCH(CH2CH2));! 13C!NMR! (101!MHz,!CDCl3):!δ!150.3,!141.0,!132.5,!130.9,!129.0,!128.1,!127.2,!125.4,!123.2,! 118.5,!106.9,!84.5,!29.7,!27.7,!25.6,!9.3,!6.9;!IR:!νmax!(neat)/cm>1!3285!(br),!2922,! 1688,! 1557,! 1433,! 1323,! 1156,! 1093;! LRMS! (ESI+):! m/z! 460! ([79Br]! [M+Na]+,! 80%),! 462! ([81Br]! [M+Na]+,! 75%),! 492! ([79Br]! [M+MeOH+Na]+,! 100%),! 494! ([81Br]! [M+MeOH+Na]+,! 90%);! HRMS! (ESI+)! found! 492.00881! [[79Br]! [M+MeOH+Na]+],! 494.00654! [[81Br]! [M+MeOH+Na]+],! C21H2879BrNO4SNa+! requires!492.00815,!C21H2881BrNO4SNa+!requires!494.00794.! " tertLButyl'2L[2L(methylthio)ethyl]L5LphenylL1HLpyrroleL1Lcarboxylate,'4q' Me

S N Boc

Ph

' Prepared! according! to! general! procedure! G! using! 3> (methylthio)propionaldehyde! 1b! (15! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine!(tert>butyl!(1>phenylprop>2>yn>1>yl)carbamate!2d)!(45.1!mg,!0.195!mmol,! 1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!!mg,!5!mol%)!in! acetone!(75! µL,!1!M).!After!stirring!for!16!hrs!at!room!temperature,!acetonitrile! (1.5!mL)!and!p>TSA!(43.0!mg,!0.23!mmol,!1.5!equiv.)!were!added!and!stirred!at! room! temperature! for! a! further! 6! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole) 4q! as! colourless!oil!(39.9!mg,!84%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.40>7.36! (2H,! m,! Ar>H),! 7.34>7.30! (3H,! m,! Ar>H),! 3 6.15! (1H,! d,! J! 3.5,! NC(Ph)CH),! 6.10! (1H,! dt,! J! 3.5,! 1.0,! NC(CH2CH2SCH3)CH),! 3.20! (2H,! t,! J! 7.5,! NCCH2),! 2.88>2.84! (2H,! m,! SCH2),! 2.20! (3H,! s,! SCH3),! 1.28! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 150.0,! 135.5,! 135.4,! 135.3,! 128.4,! 127.8,!126.7,!112.2,!110.4,!83.6,!33.9,!29.1,!27.3,!15.6;!IR:!νmax!(neat)/cm>1!2979,! 1606,!1526,!1444,!1369,!1144,!908;!LRMS!(ESI+):!m/z!!318!([M+H]+,!40%),!340! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 340.13413! [M+Na]+,! C18H23O2NSNa+! requires!340.13417.! ! " "

!

S43!

tertLButyl' 2L(2Lbromophenyl)L5L[2L(methylthio)ethyl]L1HLpyrroleL1L carboxylate,'4r' Me

Br S N Boc

! Prepared! according! to! general! procedure! G! using! 3> (methylthio)propionaldehyde! 1b! (15! µL,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! [1>(2>bromophenyl)prop>2>yn>1>yl]carbamate! 2j)! (60.5! mg,! 0.195!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5! mol%)! in! acetone! (75! µL,! 1! M).! After! stirring! for! 16! hrs! at! room! temperature,! acetonitrile!(1.5!mL)!and!p>TSA!(51.0!mg,!0.30!mmol,!2.0!equiv.)!were!added!and! stirred!at!room!temperature!for!a!further!5!hrs.!The!crude!product!was!purified! by!flash!column!chromatography!!(5>10%!Et2O!in!petrol)!to!afford!pyrrole!4r!as! colourless!oil!(46.2!mg,!78%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.61>7.58! (1H,! m,! Ar>H),! 7.36>7.31! (2H,! m,! Ar>H),! 3 7.21!(1H,!ddd,!J!8.0,!6.5,!3.0,!Ar>H),!6.12!(1H,!dt,!J!3.5,!1.0,!NC(CH2CH2SCH3)CH),! 6.07!(1H,!d,!J!!3.5,!NCCH),!3.23!(2H,!t,!J!7.5,!NCCH2),!2.85!(2H,!t,!J!7.5,!SCH2),!2.19! (3H,!s,!SCH3),!1.23!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!149.4,!137.5,! 135.4,!133.1,!131.9,!131.4,!128.8,!126.9,!125.1,!112.8,!110.5,!83.3,!33.8,!29.6,!27.3,! 15.7;!IR:!νmax!(neat)/cm>1!2921,!1742,!1369,!1312,!1148,!908;!LRMS!(ESI+):!m/z! 418! ([79Br]! [M+Na]+,! 100%),! 420! ([81Br]! [M+Na]+,! 60%);! HRMS! (ESI+)! found! 418.04401! [[79Br]! M+Na]+,! 420.04180! [[81Br]! M+Na]+,! C18H2279BrNO2SNa+! requires!418.0.4468,!C18H2281BrNO2SNa+!requires!420.04100.! ! tertLButyl' 2L[4L(methoxycarbonyl)phenyl]L5L[2L(methylthio)propyl]L1HL pyrroleL1Lcarboxylate','4s' Me Me

S N Boc

CO2Me

' Prepared!according!to!general!procedure!G!using!3>(methylthio)butanal!1c' (18! µL,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(tert>butyl!(1>phenylprop>2>yn>1> yl)carbamate! 2l)! (56.0! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(76!µL,!1!M).!After!stirring!for!4! hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and!p>TSA!(42.8!mg,!0.23!mmol,! 1.5!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further!4!hrs.!The! crude! product! was! purified! by! flash! column! chromatography! (5>10%! Et2O! in! petrol)!to!afford!pyrrole)4s!as!colourless!oil!(44.0!mg,!75%).! !

!

S44!

1H! NMR! (400! MHz,! CDCl

3):! δ! 8.05>8.03! (2H,! m,! Ar>H),! 7.38>7.36! (2H,! m,! Ar>H),!

6.22!(1H,!d,!J!3.5,!NCCH),!6.10!(1H,!d,!J!3.5,!NCCH),!3.96!(3H,!s,!CO2CH3),!3.25!(1H,! dd,!J!14.5,!6.0,!SCH(CH3)CHaHb),!3.10>3.02!(1H,!m,!SCH(CH3)),!2.93!(1H,!dd,!J!14.5,! 8.0,!SCH(CH3)CHaHb),!2.14!(3H,!s,!SCH3),!1.33!(3H,!d,!J!7.0,!SCH(CH3)),!1.28!(9H,!s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 167.4,! 150.3,! 140.2,! 136.2,! 134.6,! 129.6,!128.4,!128.3,!113.8,!112.5,!84.6,!52.5,!41.3,!36.4,!27.7,!20.9,!14.0;!IR:!νmax! (neat)/cm>1! 2923,! 1721,! 1609,! 1453,! 1308,! 1276,! 1144,! 909;! LRMS! (ESI+):! m/z! 412! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 390.17340! [M+H]+,! C21H28O4NS+! requires!390.17336.! " tertLButyl' 3LhexylL2L[2L(methylthio)cyclohexL1LenL1Lyl]L5LphenylL1HL pyrroleL1Lcarboxylate,'4t' Me

Me

S N Boc

Ph

' Prepared! according! to! general! procedure! G! using! 2>(methylthio)cyclohex>1> enecarbaldehyde,2!1d!(23.5!mg,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(tert> butyl!(1>phenylnon>2>yn>1>yl)carbamate!2p)!(71.0!mg,!0.195!mmol,!1.3!equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!dppm!(2.9!mg,!5!mol%)!in!acetone!(56! µL,! 1.0!M).!After!stirring!for!4!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and!p> TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 16! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4t! as! colourless!oil!(42.8!mg,!63%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.37>7.32! (4H,! m,! Ar>H),! 7.28>7.25! (1H,! m,! Ar>H),! 3 6.14!(1H,!s,!NCCH),!2.40!(2H,!app!d,!J!3.0,!CH2(CH2)4CH3),!2.30!(2H,!ddd,!J!8.5,!7.0,! 3.0,!SCCH2),!2.14!(3H,!s,!SCH3),!1.93>1.88!(2H,!m,!CH2(CH2)3CH3),!1.78>1.75!(2H,! m,!SCCCH2),!1.63>1.46!(4H,!m,!SCCH2(CH2)2),!1.39>1.32!(6H,!m,!(CH2)3CH3),!1.31! (9H,!s,!CO2C(CH3)3),!0.91!(3H,!t,!J!7.0,!CH3(CH2)5);! 13C!NMR!(101!MHz,!CDCl3):!δ! 149.6,! 135.1,! 134.3,! 133.0,! 132.5,! 128.4,! 128.2,! 127.6,! 126.4,! 123.6,! 113.6,! 82.6,! 32.8,! 31.8,! 30.1,! 29.4,! 29.3,! 27.4,! 25.9,! 23.4,! 22.7,! 22.6,! 22.5,! 14.2;! IR:! νmax! (neat)/cm>1!2927,!1742,!1601,!1488,!1467,!1304,!1259,!1155,!729;!LRMS!(ESI+):! m/z! 454! ([M+H]+,! 100%),! 476! ([M+Na]+,! 90%);! HRMS! (ESI+)! found! 476.25847! [M+Na]+,!C28H39O2NSNa+!requires!476.25937.! " " "

!

S45!

tertLButyl' 2LcyclopropylL5L[3L(methylthio)thiophenL2Lyl]L1HLpyrroleL1L carboxylate,'4u' Me S

S

N Boc

' Prepared! according! to! general! procedure! G! using! 3>(methylthio)thiophene>2> carbaldehyde' 1m' (16.3! mg,! 0.103! mmol,! 1.0! equiv.),! propargylic! amine! (tert> butyl! (1>cyclopropylprop>2>yn>1>yl)carbamate! 2n)! (26.2! mg,! 0.134! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (1.9! mg,! 5! mol%)! and! PNP(Cy)! (2.2! mg,! 5! mol%)! in! acetone!(61! µL,!1!M).!After!stirring!for!16!hrs!at!room!temperature,!acetonitrile! (1.5!mL)!and!p>TSA!(!mg,!0.15!mmol,!1.0!equiv.)!were!added!and!stirred!at!room! temperature!for!a!further!4!hrs.!The!crude!product!was!purified!by!flash!column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole) 4u! as! colourless! oil! (28.8!mg,!79%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.29!(1H,!d,!J!5.5,!SCH),!7.02!(1H,!d,!J!5.5,!SCH CCH),! 3 3 6.18!(1H,!d,!J!3.5,!NCCH),!5.92!(1H,!dd,!J!3.5,!1.0,!NC(CH(CH2)2)CH),!2.32!(3H,!s,! SCH3),!2.29>2.25!(1H,!m,!NC(CH(CH2CH2))),!1.40!(9H,!s,!CO2C(CH3)3),!0.90!(2H,!dt,! J! 6.5,! 2.0,! NC(CH(CH2CH2))),! 0.69>0.67! (2H,! m,! NC(CH(CH2CH2)));! 13C! NMR! (101! MHz,!CDCl3):!δ!149.5,!140.4,!132.7,!132.0,!128.6,!124.5,!124.2,!115.0,!108.1,!83.2,! 27.5,!17.9,!9.9,!7.0;!IR:!νmax!(neat)/cm>1!3086,!1742,!1369,!1297,!1135,!1090,!971;! LRMS!(ESI+):!m/z!336!([M+H]+,!100%),!358!([M+Na]+,!90%);!HRMS!(ESI+)!found! 358.09025![M+Na]+,!C17H21O2NS2Na+!requires!358.09059.! ! tertLButyl' 2L(furanL2Lyl)L5L[3L(methylthio)thiophenL2Lyl]L1HLpyrroleL1L carboxylate,'4v' Me S

S

N Boc

O

! Prepared! according! to! general! procedure! G! using! 3>(methylthio)thiophene>2> carbaldehyde!1m!(23.7!mg,!0.15!mmol,!1.0!equiv.),!propargylic!amine!(tert>butyl! [1>(furan>2>yl)prop>2>yn>1>yl]carbamate! 2f)! (43.1! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(83! µL,!1!M).!After!stirring!for!3!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and! p>TSA! (42.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further! 16! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! Et2O! in! petrol)! to! afford! pyrrole! 4v! as! a! light! brown!oil!(32.4!mg,!60%).' !

S46!

! 1H! NMR! (400! MHz,! CDCl

3):! δ! 7.49! (1H,! dd,! J! 2.0,! 1.0,! OCH),! 7.36! (1H,! d,! J! 5.5,!

(CH3)SCCH),!7.06!(1H,!d,!J!5.5,!SCH),!6.55!(1H,!dd,!J!3.5,!1.0,!OCHCH),!6.48!(1H,!d,!J! 3.5,! NC(CS)CH),! 6.47! (1H,! d,! J! 3.5,! OCCH)! 6.36! (1H,! d,! J! 3.5,! NC(CO)CH),! 2.36! (s,! SCH3),!1.32!(9H,!s,!CO2C(CH3)3);!13C!NMR!(101!MHz,!CDCl3):!δ!148.7,!146.8,!141.9,! 133.3,! 131.0,! 128.6,! 126.8,! 126.4,! 125.4,! 115.5,! 113.6,! 111.0,! 108.7,! 83.9,! 27.3,! 18.0! ;! IR:! νmax! (neat)/cm>1! 2923,! 2853,! 1752,! 1458,! 1393,! 1328,! 1258,! 1104,! 1011,! 843,! 684;! LRMS! (ESI+):! m/z! 362! ([M+H]+,! 75%),! 384! ([M+Na]+,! 100%);! HRMS!(ESI+)!found!362.08800![M+H]+,!C18H20O3NS+!requires!362.08791.! " tertLButyl' 2L[2L(dimethylamino)phenyl]L5LmethylL1HLpyrroleL1L carboxylate,'4w' Me

N

Me N Boc

Me

! Prepared! according! to! general! procedure! G! using! 2> (dimethylamino)benzaldehyde5!1g!(22.4!mg,!0.15!mmol,!1.0!equiv.),!propargylic! amine!(tert>butyl!but>3>yn>2>ylcarbamate!2b)!(33.0!mg,!0.195!mmol,!1.3!equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(95! µL,!1!M).!After!stirring!for!3!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and! p>TSA! (142.6! mg,! 0.75! mmol,! 5.0! equiv.)! were! added! and! stirred! at! room! temperature!for!a!further!2!hrs.!The!crude!product!was!purified!by!flash!column! chromatography!!(5>10%!Et2O!in!petrol)!to!afford!pyrrole!4w!as!pale!yellow!oil! (33.1!mg,!73%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.28!(1H,!d,!J!10.0,!Ar>H),!7.25>7.23!(1H,!m,!Ar>H),! 3 6.96!(1H,!app!td,!J!7.5,!1.0,!Ar>H),!6.91!(1H,!dd,!J!8.5,!1.0,!Ar>H),!6.06!(1H,!d,!J!3.0,! NC(Ar)CH),!5.99!(1H,!dt,!J!3.0,!1.0,!NC(CH3)CH),!2.51!(6H,!s,!N(CH3)2),!2.48!(3H,!d,! J!1.0,!NC(CH3)CH),!1.29!(9H,!s,!CO2C(CH3)3);! 13C!NMR!(101!MHz,!CDCl3):!δ!150.0,! 133.2,! 132.1,! 130.6,! 130.4,! 128.0,! 127.9,! 120.8,! 116.5,! 111.4,! 110.1,! 82.5,! 42.5,! 27.5,!15.4;!IR:!νmax!(neat)/cm>1!2922,!2870,!1677,!1599,!1478,!1450,!1260,!1162,! 751;! LRMS! (ESI+):! m/z! 301! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 301.19044! [M+H]+,!C18H25O2N2+!requires!301.19105.! ! " "

!

S47!

tertLButyl' carboxylate,'4x'

2LmethylL5L(2L(pyrrolidinL1Lyl)phenyl)L1HLpyrroleL1L

N N Boc

Ph

' Prepared! according! to! general! procedure! G! using! 2>(pyrrolidin>1> yl)benzaldehyde5! 1h! (26.3! mg,! 0.15! mmol,! 1.0! equiv.),! propargylic! amine! (tert> butyl!(1>phenylprop>2>yn>1>yl)carbamate!2d)!(45.1!mg,!0.195!mmol,!1.3!equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(79! µL,!1!M).!After!stirring!for!16!hrs!at!room!temperature,!acetonitrile!(1.5!mL)!and! p>TSA! (43.8! mg,! 0.23! mmol,! 1.5! equiv.)! were! added! and! stirred! at! room! temperature!for!a!further!3!hrs.!The!crude!product!was!purified!by!flash!column! chromatography! ! (10%! Et2O! in! petrol)! to! afford! pyrrole! 4x' as! pale! yellow! oil! (40.2!mg,!69%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.40>7.36! (4H,! m,! Ar>H),! 7.35>7.30! (1H,! m,! Ar>H),! 3 7.28>7.24!(2H,!m,!Ar>H),!6.83!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!6.76!(1H,!d,!J!8.0,!Ar>H),! 6.27! (1H,! d,! J! 3.5,! NC(Ar)CH),! 6.18! (1H,! d,! J! 3.5,! NC(Ar)CH),! 2.95! (4H,! t,! J! 6.0,! > CH2NCH2>),! 1.81>1.78! (4H,! t,! J! 6.0,! >CH2CH2NCH2CH2>),! 1.14! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl ):! δ! 149.5,! 148.5,! 135.3,! 134.9,! 134.2,! 132.1,! 128.6,! 3 128.5,! 127.8,! 126.9,! 122.1,! 117.4,! 114.0,! 112.3,! 112.0,! 83.0,! 49.4,! 31.0,! 27.0;! IR:! νmax! (neat)/cm>1! 2924,! 2853,! 1599,! 1484,! 1366,! 1303,! 1180,! 1027,! 978;! LRMS! (ESI+):! m/z! 389! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 389.22244! [M+H]+,! C25H29O2N2+!requires!389.22235.' '

8.'Functionalising'existing'pyrroles! ! tertLButyl' 3LbromoL2LcyclopropylL4LhexylL5L[2L(methylthio)phenyl]L1HL pyrroleL1Lcarboxylate,'5a! Me

Me

Br S N Boc

! Pyrrole! (tert>butyl! 5>cyclopropyl>3>hexyl>2>[2>(methylthio)phenyl]>1H>pyrrole> 1>carboxylate!4h)!(62.0!mg,!0.15!mmol,!1.0!equiv.),!was!dissolved!in!THF!(1!mL)! and!cooled!to!>78!°C.!N>Bromosuccinimide!(53.4!mg,!0.3!mmol,!2.0!equiv.)!in!THF! (1.2! mL)! was! added! dropwise! to! the! stirring! solution! of! pyrrole.! The! reaction! !

S48!

mixture!was!allowed!to!warm!to!room!temperature!for!16!hrs.!After!which,!sat.! NaHCO3!(aq)!(2!mL)!was!added!at!room!temperature.!The!product!was!extracted! with! EtOAc! (3! ×! 5! mL)! and! washed! with! brine! (10! mL).! The! organic! layer! was! dried!over!MgSO4,!filtered!and!concentrated!under!reduced!pressure.!The!crude! product!was!purified!by!flash!column!chromatography!!(5%!EtOAc!in!petrol)!to! yield!brominated!pyrrole!5a!as!an!off>white!oil!(64.0!mg,!87%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.38>7.34! (1H,! m,! Ar>H),! 7.20! (1H,! d,! J! 8.0,! Ar>H),! 3 7.18>7.16! (2H,! m,! Ar>H),! 2.37! (3H,! s,! SCH3),! 2.26>2.09! (2H,! m,! CH3(CH2)4CH2),! 2.02>1.95! (1H,! m,! NCCH),! 1.44>1.37! (2H,! m,! CH3(CH2)3CH2),! 1.23! (9H,! s,! CO2C(CH3)3),!1.21>1.16!(6H,!m,!CH3(CH2)3),!1.04>0.92!(3H,!m,!NCCH(CH2CHaHb)),! 0.84!(3H,!t,!J!7.0,!CH3(CH2)5),!0.73>0.67!(1H,!m,!NCCH(CH2CHaHb));! 13C!NMR!(101! MHz,! CDCl3):! δ! 148.7,! 140.5,! 132.1,! 131.2,! 128.4,! 127.0,! 124.4,! 124.1,! 124.0,! 123.9,! 104.5,! 82.8,! 31.4,! 29.6,! 29.1,! 27.2,! 25.2,! 22.5,! 15.0,! 14.1,! 8.6,! 7.8,! 7.3;! IR:! νmax! (neat)/cm>1! 2925,! 1744,! 1577,! 1459,! 1335,! 1155,! 1078,! 965;! LRMS! (ESI+):! m/z!492!([79Br]![M+H]+,!95%),!494!([81Br]![M+H]+,!100%),!514!([79Br]![M+Na]+,! 48%),!516!([81Br]![M+H]+,!50%);!HRMS!(ESI+)!found!514.13841![[79Br]!M+Na]+,! 516.13630! [[81Br]! M+Na]+,! C25H3479BrNO2SNa+! requires! 514.13858,! C25H3481BrNO2SNa+!requires!516.13654;'mp:!99>101!°C!(DCM/hexane).! ! 1L[2LCyclopropylL4LhexylL5L(2L(methylthio)phenyl]L1HLpyrrolL3Lyl)ethanL 1Lone,'5b' ' Me

O Me Me

S N H

' Prepared! according! to! a! procedure! adapted! from! Frost! et.! al.15! Pyrrole! (tert> butyl! 5>cyclopropyl>3>hexyl>2>[2>(methylthio)phenyl]>1H>pyrrole>1>carboxylate! 4h)! (124! mg,! 0.30! mmol,! 1.0! equiv.)! in! nitromethane! (0.7! mL)! was! ! added! dropwise!to!a!solution!of!indium!(III)!trifluoromethanesulfonate!(16.9!mg,!0.03! mmol,! 10! mol%)! and! lithium! perchlorate! (31.9! mg,! 0.30! mmol,! 1.0! equiv.)! in! nitromethane!(0.1!mL)!at!50!°C,!followed!by!the!addition!of!acetic!anhydride!(43! µL,!0.45!mmol,!1.5!equiv.).!The!reaction!mixture!was!stirred!at!50!°C!for!16!hrs! and!then!quenched!by!the!addition!of!water!(2!mL).!The!product!was!extracted! with! DCM! (3! ×! 5! mL)! and! washed! with! brine! (10! mL).! The! organic! layer! was! dried!over!MgSO4,!filtered!and!concentrated!under!reduced!pressure.!The!crude! product!was!purified!by!flash!column!chromatography!!(5>10%!EtOAc!in!petrol)! to!yield!acylated!pyrrole!5b!as!a!white!solid!(84.0!mg,!79%).! ! !

S49!

1H!NMR!(400!MHz,!CDCl

3):!δ!8.17!(1H,!br!s,!NH),!7.35!(1H,!ddd,!J!8.0,!7.0,!1.5,!Ar>

H),!7.28>7.25!(2H,!m,!Ar>H),!7.20!(1H,!app!td,!J!7.5,!1.5,!Ar>H),!2.62!(3H,!s,!COCH3),! 2.35!(3H,!s,!SCH3),!2.30!(1H,!app!dt,!J!10.0,!4.0,!NHCCH),!1.48!(2H,!app!ddd,!J!10.0,! 5.0,! 2.0,! CH3(CH2)4CH2),! 1.26>1.20! (8H,! m,! CH3(CH2)4),! 1.10>1.05! (2H,! m,! NCCH(CH2CH2)),!0.85>0.81!(5H,!m,!CH3(CH2)5!and!NCCH(CH2CH2);! 13C!NMR!(101! MHz,! CDCl3):! δ! 195.2,! 139.0,! 138.5,! 131.5,! 130.7,! 128.5,! 125.5,! 125.07,! 125.03,! 124.7,! 122.1,! 31.6,! 31.3,! 31.1,! 29.4,! 25.7,! 22.7,! 15.3,! 14.1,! 10.3,! 7.4;! IR:! νmax! (neat)/cm>1!3249!(br),!2954,!2854,!1622,!1444,!1361,!908;!LRMS!(ESI+):!m/z!356! ([M+H]+,!100%);!HRMS!(ESI+)!found!356.20450![M+H]+,!C22H30OSNNa+!requires! 356.20426;!mp:!88>89!°C!(DCM/hexane).! ' 3LHexylL2L[2L(methylthio)phenyl]L5LphenylL1HLpyrrole,'5c' Me

Me

S N H

Ph

! Pyrrole! (tert>butyl! 3>hexyl>2>[2>(methylthio)phenyl]>5>phenyl>1H>pyrrole>1> carboxylate!4g)!(30.6!mg,!0.07!mmol,!1.0!equiv.)!was!dissolved!in!DCM!(2!mL).! Trifluoroacetic! acid! (0.6! mL,! 8.4! µmol,! 0.12! equiv.)! was! added! to! the! pyrrole! dropwise! and! stirred! at! room! temperature! for! 2! hrs.! The! reaction!mixture! was! diluted! with! DCM! (5! mL)! and! neutralised! with! sat.! NaHCO3! (aq.).! The! aqueous! layer! was! extracted! with! DCM! (3! ×! 5! mL)! and! the! combined! organic! extracts! were! washed! with! brine! (10! mL),! dried! over! MgSO4,! filtered! and! concentrated! under! reduced! pressure.! The! crude! product! required! no! further! purifications! and!afforded!deprotected!5c!pyrrole!as!a!colourless!oil!(23.3!mg,!98%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!8.62!(1H,!br!s,!NH),!7.55>7.52!(2H,!m,!Ar>H),!7.41> 3 7.34! (5H,! m,! Ar>H),! 7.26>7.20! (2H,! m,! Ar>H),! 6.55! (1H,! app! d,! J! 3.0,! NCCH),! 2.51! (2H,! t,! J! 8.0,! CH3(CH2)4CH2),! 2.38! (3H,! s,! SCH3),! 1.63! (2H,! app! t,! J! 7.5,! CH3(CH2)3CH2),! 1.37>1.25! (6H,! m,! CH3(CH2)3),! 0.90! (3H,! t,! J! 7.0,! CH3(CH2)5);! 13C! NMR!(101!MHz,!CDCl3):!δ!138.2,!132.7,!131.9,!131.3,!131.1,!128.8,!128.0,!127.4,! 126.1,!126.0,!124.9,!124.8,!123.5,!106.9,!31.7,!31.1,!29.2,!26.3,!22.7,!15.6,!14.1;!IR:! νmax!(neat)/cm>1!3430!(br),!3057,!2954,!2854,!1606,!1377,!1201,!907;!HRMS!(FI+)! found!349.1862![M]+,!C23H27SN+!requires!349.1864.!

' !

!

'

S50!

9.'Synthesis'of'pyrroles'via'a'telescoped'hydroacylationLSuzukiL cyclisation! ! General' procedure' H' for' the' three' component' coupling' synthesis' of' pyrroles' as' exemplified' by' the' formation' of' tertLbutyl' 2L[4'LacetylL4L (trifluoromethyl)L(1,1'Lbiphenyl)L2Lyl]L5LphenylL1HLpyrroleL1Lcarboxylate,' 6a' O

Me

N Boc

Ph

CF3

' ! An! oven>dried! microwave! vial! was! charged! with! [Rh(nbd)2BF4]! (7.5! mg,! 10! mol%),! PNP(Cy)! (4.2! mg,! 5! mol%)! and! dcpm! (4.1! mg,! 5! mol%).! Once! under! an! inert! atmosphere,! they! were! dissolved! in! acetone! (1! mL).! Hydrogen! gas! was! bubbled! through! the! solution! at! room! temperature! for! 1>2! mins! in! order! to! generate!the!active!catalyst!species.!The!hydrogen!gas!was!purged!using!nitrogen! gas,!and!this!was!bubbled!through!the!catalyst!to!dryness.!The!dry!catalyst!was! dissolved! in! acetone! (96! µL,! 1.0! M! with! respect! to! aldehyde)! and! this! was! transferred! to! a! nitrogen>filled! microwave! vial! containing! 2>(methylthio)>5> (trifluoromethyl)benzaldehyde! 1n! (44! mg,! 0.20! mmol,! 1.0! equiv.)! and! propargylic!amine!(tert>butyl!(1>phenylprop>2>yn>1>yl)carbamate!2d)!(60.1!mg,! 0.26!mmol,!1.3!equiv.).!The!reaction!mixture!was!then!stirred!at!55!°C!for!5!mins.! It! was! then! transferred! to! an! oven>dried! microwave! vial! charged! with! silver! carbonate!(55.2!mg,!0.20!mmol,!1.0!equiv.)!and!4>acetylphenylboronic!acid!(49.2! mg,! 0.30! mmol,! 1.5! equiv.)! using! acetone! (0.47! mL,! 0.3! M! with! respect! to! aldehyde!minus!starting!materials).!The!vessel!was!heated!at!55!°C!for!a!further! 5!hrs,!after!which!it!was!cooled!to!room!temperature,!opened!to!air,!and!filtered! through!a!plug!of!silica!with!DCM!(3!mL).!p>TSA!(76.1!mg,!0.40!mmol,!2.0!equiv)! was!added!to!the!solution!and!stirred!at!room!temperature!until!complete.!After! 6!hrs!the!solution!was!diluted!with!DCM!(5!mL)!and!neutralised!by!the!addition! of! sat.! NaHCO3! (aq)! (10! mL)! in! a! separatory! funnel.! The! aqueous! mixture! was! extracted!with!DCM!(3!×!5!mL)!and!the!combined!organic!extracts!were!washed! with!brine!(10!mL)!and!dried!over!MgSO4.!The!solvent!was!removed!in)vacuo!to! obtain!the!crude!product!and!this!was!purified!by!flash!column!chromatography!! (5>10%!EtOAc!in!petrol)!to!afford!title!pyrrole!6a'as!a!light!brown!solid!(51.0!mg,! 50%).! !

!

S51!

1H! NMR! (400! MHz,! CDCl

3):! δ! 7.96>7.93! (2H,! m,! Ar>H),! 7.75>7.71! (2H,! m,! Ar>H),!

7.58!(1H,!d,!J!8.0,!Ar>H),!7.40>7.37!(2H,!m,!Ar>H),!7.33>7.32!(3H,!m,!Ar>H),!7.21> 7.19!(2H,!m,!Ar>H),!6.17!(1H,!d,!J!3.5,!NCCH),!6.14!(1H,!d,!J!3.5,!NCCH),!2.64!(3H,!s,! COCH3),! 1.01! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 197.7,! 148.7,! 145.0,!143.6,!136.8,!135.8,!134.3,!134.2,!133.1,!129.9,!129.8!(q,! 2JCF!31.5)!129.2,! 129.0,! 128.1,! 127.7,! 127.3,! 127.2! (q,! 3JCF! 3.5),! 124.3! (q,! 3JCF! 3.5),! 123.9! (q,! 1JCF! 252.0),!114.7,!113.0,!83.8,!27.1,!26.7;! 19F!NMR!(377!MHz,!CDCl3):!δ!>62.3;!IR:!νmax! (neat)/cm>1! 2974,! 2361,! 2169,! 1746,! 1684,! 1397;! LRMS! (ESI+):! m/z! 528! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 528.17477! [M+Na]+,! C30H26O3F3NNa+! requires!528.17570;!mp:!146>147!°C!(EtOAc/petrol).! ! tertLButyl' 2L[5LbromoL4'LmethoxyL(1,1'Lbiphenyl)L2Lyl]L5LmethylL1HL pyrroleL1Lcarboxylate,'6b' OMe

Br

N Boc

Me

! Prepared! according! to! general! procedure! H! using! 3 4>bromo>2>(methylthio)benzaldehyde ! 1e! (58! mg,! 0.25! mmol,! 1.0! equiv.),! propargylic! amine! (tert>butyl! but>3>yn>2>ylcarbamate! 2b)! (56! mg,! 0.33! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (9.3! mg,! 10! mol%)! ,! ! PNP(Cy)! (5.3! mg,! 5! mol%)! and! dcpm!(5.1!mg,!5!mol%)!in!acetone!(0.14!mL,!1!M).!After!5!mins!at!55!°C!it!was! transferred! to! silver! carbonate! (69! mg,! 0.25! mmol,! 1.0! equiv.)! and! 4> methoxyphenylboronic!acid!(50!mg,!0.33!mmol,!1.5!equiv.)!using!acetone!(0.46! mL).! After! stirring! for! 4! hrs! at! 55! °C! the! reaction! was! filtered! and! stirred! with! DCM!(4!mL)!and!p>TSA!(48!mg,!0.25!mmol,!1.0!equiv.)!at!room!temperature!for!a! further!3!hrs.!The!crude!product!was!purified!by!flash!column!chromatography!! (10>40%! DCM! in! petrol)! to! afford! pyrrole! 6b! as! an! off>white! solid! (43.8! mg,! 43%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.54!(1H,!d,!J!2.0,!Ar>H),!7.45!(1H,!dd,!J!8.0,!2.0,!Ar> 3 H),!7.21!(1H,!d,!J!8.0,!Ar>H),!7.12>7.10!(2H,!m,!Ar>H),!6.83>6.81!(2H,!m,!Ar>H),!5.91! (2H,! app! s,! (NCCH)2),! 3.82! (3H,! s,! OCH3),! 2.36! (3H,! s,! NCCH3),! 1.26! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 158.8,! 149.4,! 142.3,! 133.1,! 132.5,! 132.4,! 132.3,! 132.2,! 131.8,! 129.8,! 129.2,! 121.3,! 113.6,! 113.4,! 110.6,! 83.2,! 55.3,! 27.6,!16.0;!IR:!νmax!(neat)/cm>1!2979,!1739,!1610,!1513,!1250,!1177,!1093,!983;! LRMS! (ESI+):! m/z! 442! ([79Br]! [M+H]+,! 95%),! 444! ([81Br]! [M+H]+,! 100%),! 464! ([79Br]! [M+Na]+,! 80%),! 466! ([81Br]! [M+Na]+,! 70%);! HRMS! (ESI+)! found! 464.08330! [[79Br]! [M+Na]+],! 466.8122! [[81Br]! [M+Na]+],! C23H2479BrNO3Na+!

!

S52!

requires! 464.08318,! C23H2481BrNO3Na+! requires! 466.08113;! mp:! 133>134! °C! (DCM/petrol).! ' tertLButyl' 2L[4L(methoxycarbonyl)phenyl]L5L[4'LmethylL4L (trifluoromethyl)L(1,1'Lbiphenyl)L2Lyl]L1HLpyrroleL1Lcarboxylate,'6c! ! Me

N Boc

CO2Me

CF3

! Prepared! according! to! general! procedure! H! using! 2>(methylthio)>5> (trifluoromethyl)benzaldehyde! 1n! (44! mg,! 0.20! mmol,! 1.0! equiv.),! propargylic! amine! (methyl! 4>{1>[(tert>butoxycarbonyl)amino]prop>2>yn>1>yl}benzoate)! (75! mg,!0.26!mmol,!1.3!equiv.),![Rh(nbd2)]BF4!(7.5!mg,!10!mol%)!,!!PNP(Cy)!(4.2!mg,! 5!mol%)!and!dcpm!(4.1!mg,!5!mol%)!in!acetone!(81! µL,!1!M).!After!5!mins!at!55! °C! it! was! transferred! to! silver! carbonate! (55! mg,! 0.20! mmol,! 1.0! equiv.)! and! 4> tolylboronic!acid!(41!mg,!0.30!mmol,!1.5!equiv.)!using!acetone!(0.45!mL).!After! stirring!for!6!hrs!at!55!°C!the!reaction!was!filtered!and!stirred!with!DCM!(3!mL)! and! p>TSA! (38! mg,! 0.20! mmol,! 1.0! equiv.)! at! room! temperature! for! a! further! 3! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (5>10%! EtOAc!in!petrol)!to!afford!pyrrole!6c'as!a!pale!brown!solid!(51.3!mg,!55%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 8.03>8.00! (2H,! m,! Ar>H),! 7.71>7.68! (2H,! m,! Ar>H),! 3 7.56!(1H,!d,!J!8.5,!Ar>H),!7.29!(2H,!app!td,!J!4.0,!2.0,!Ar>H),!7.15!(4H,!br!s,!Ar>H),! 6.24!(1H,!d,!J!3.5,!NCCH),!6.16!(1H,!d,!J!3.5,!NCCH),!3.95!(3H,!s,!CO2CH3),!2.40!(3H,! s,! ArCH3),! 1.04! (9H,! s,! CO2C(CH3)3);! 13C! NMR! (101! MHz,! CDCl3):! δ! 166.9,! 148.5,! 144.9,!139.0,!137.2,!137.0,!135.5,!134.9,!133.8,!129.9,!129.0,!128.9!(q,! 2JCF!32.5),! 128.8,! 128.7,! 128.6,! 128.5,! 127.0! (q,! 3JCF! 3.5),! 124.8! (q,! 3JCF! 3.5),! 124.0! (q,! 1JCF! 270.0),!114.6,!114.0,!84.0,!52.1,!27.1,!21.1;!19F!NMR!(377!MHz,!CDCl3):!δ!>62.3;!IR:! νmax!(neat)/cm>1!2931,!1747,!1720,!1611,!1396,!1327,!1169,!1045;!LRMS!(ESI+):! m/z! 536! ([M+H]+,! 75%),! 558! ([M+Na]+,! 100%);! HRMS! (ESI+)! found! 536.20435! [M+H]+,!C31H29O4F3N+!requires!536.20432;!mp:!128>129!°C!(EtOAc/petrol).!

' '

!

'

S53!

10.'OneLpot'synthesis'of'dihydropyrroles' ' General'procedure'I'for'the'synthesis'of'dihydropyrroles'as'exemplified'by' the' synthesis' of' 5L[2L(methylthio)phenyl]L2LphenylL3,4LdihydroL2HL pyrrole,'7a' Me

S N

Ph

! An! oven>dried! microwave! vial! was! charged! with! [Rh(nbd)2BF4]! (11.2! mg,! 5! mol%)! and! PNP(Cy)! (12.7! mg,! 5! mol%).! Once! under! an! inert! atmosphere,! they! were! dissolved! in! acetone! (1! mL).! Hydrogen! gas! was! bubbled! through! the! solution! at! room! temperature! for! 1>2! mins! in! order! to! generate! the! active! catalyst!species.!The!hydrogen!gas!was!purged!using!nitrogen!gas,!and!this!was! bubbled! through! the! catalyst! to! dryness.! The! dry! catalyst! was! dissolved! in! acetone!(0.34!mL,!1.0!M!with!respect!to!aldehyde!minus!starting!materials)!and! this! was! transferred! to! a! nitrogen>filled! microwave! vial! containing! 2> (methylthio)benzaldehyde! 1a! (77! µL,! 0.60! mmol,! 1.0! equiv.)! and! tert>butyl! (1> phenylallyl)carbamate7! 10a! (182! mg,! 0.78! mmol,! 1.3! equiv.).! The! reaction! mixture,! once! homogenous! (on! occasion,! sonication! was! required),! was! then! stirred!at!55!°C!and!monitored!by!TLC!until!complete.!After!10!mins,!the!reaction! vessel!was!opened!to!air!followed!by!the!addition!of!acetonitrile!(3!mL)!and!p> TSA! (114! mg,! 0.6! mmol,! 1.0! equiv.).! The! reaction! mixture! was! further! stirred! until! complete.! After! 16! hrs,! the! solution! was! diluted! with! acetonitrile! (5! mL)! and! neutralised! by! the! addition! of! sat.! NaHCO3! (aq)! (10! mL)! in! a! separatory! funnel.! The! aqueous! mixture! was! extracted! with! EtOAc! (3! ×! 10! mL)! and! the! combined! organic! extracts! were! washed! with! brine! (20! mL)! and! dried! over! MgSO4.!The!solvent!was!removed!in)vacuo!to!obtain!the!crude!product!and!this! was! purified! by! flash! column! chromatography! ! (10%! Et2O! in! petrol)! to! afford! title!dihydropyrrole!7a!as!a!pale!yellow!solid!(134!mg,!84%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.59!(1H,!dd,!J!7.5,!1.5,!Ar>H),!7.52>7.49!(2H,!m,!Ar> 3 H),!7.45>7.36!(4H,!m,!Ar>H),!7.32>7.28!(1H,!m,!Ar>H),!7.24!(1H,!ddd,!J!7.5,!7.0,!1.5,! Ar>H),!5.47!(1H,!tt,!J!8.0,!2.0,!NCH),!3.23>3.08!(2H,!m,!NCCH2),!2.68>2.60!(1H,!m,! NCHCHaHb),!2.50!(3H,!s,!SCH3),!1.90!(1H,!ddd,!J!9.5,!9.0,!8.0,!NCHCHaHb);!13C!NMR! (101!MHz,!CDCl3):!δ!174.2,!144.7,!140.1,!132.9,!129.9,!129.8,!128.4,!126.6,!126.5,! 125.2,!123.8,!76.7,!37.9,!32.6,!16.5;!IR:!νmax!(neat)/cm>1!3059,!2918,!1612,!1557,! 1470,! 1329,! 1084;! LRMS! (ESI+):! m/z! 268! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 268.11560![M+H]+,!C17H18NS+!requires!268.11545;!mp:!52>53!°C!(DCM/hexane).' ' ' '

!

S54!

2LMethylL5L[2L(methylthio)phenyl]L3,4LdihydroL2HLpyrrole,'7b' Me

S N

Me

! Prepared!according!to!general!procedure!I!using!2>(methylthio)benzaldehyde!1a! (19! µL,! 0.15! mmol,! 1.0! equiv.),! allylic! amine! (tert>butyl! but>3>en>2>ylcarbamate! 10b)! (33.4! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (2.8! mg,! 5! mol%)! and! PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(98! µL,!1!M).!After!stirring!for!3!hrs!at!55! °C,!acetonitrile!(1.5!mL)!and!p>TSA!(30.0!mg,!0.15!mmol,!1.0!equiv.)!were!added! and! stirred! at! room! temperature! for! a! further! 3! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (10>50%! Et2O! in! petrol)! to! afford! dihydropyrrole!7b!as!a!colourless!oil!(18.4!mg,!60%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.49>7.46! (1H,! m,! Ar>H),! 7.37>7.35! (1H,! m,! Ar>H),! 3 7.31! (1H,! dd,! J! 8.0,! 1.5,! Ar>H),! 7.20>7.17! (1H,! m,! Ar>H),! 4.47>4.38! (1H,! m,! NCH),! 3.11!(1H,!dddd,!J!17.0,!9.5,!5.0,!2.0,!NCHCHaHb),!3.00>2.91!(1H,!m,!NCCHaHb),!2.46! (3H,!s,!SCH3),!2.25!(1H,!dddd,!J!12.5,!9.5,!7.5,!5.0,!NCHCHaHb),!1.61>1.56!(1H,!m,! NCCHaHb),!1.43>1.42!(3H,!d!J!6.5,!NCHCH3);! 13C!NMR!(101!MHz,!CDCl3):!δ!172.4,! 139.3,! 133.5,! 130.2,! 129.5,! 125.3,! 124.0,! 69.0,! 37.7,! 31.0,! 22.2,! 16.4;! IR:! νmax! (neat)/cm>1! 2962,! 2924,! 1613,! 1559,! 1470,! 1290,! 908;! LRMS! (ESI+):! m/z! 206! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 206.09988! [M+H]+,! C12H16NS+! requires! 206.09980.! ! 5L[4LBromoL2L(methylthio)phenyl]L2L(thiophenL3Lyl)L3,4LdihydroL2HL pyrrole,'7c' Me

S N

S

Br

! Prepared! according! to! general! procedure! I! using! 3 4>bromo>2>(methylthio)benzaldehyde ! 1e! (45.8! mg,! 0.20! mmol,! 1.0! equiv.),! allylic! amine! (tert>butyl! [1>(thiophen>2>yl)allyl]carbamate! 10c)! (62.2! mg,! 0.26! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (3.7! mg,! 5! mol%)! and! PNP(Cy)! (4.2! mg,! 5! mol%)!in!acetone!(89! µL,!1!M).!After!stirring!for!16!hrs!at!55!°C,!acetonitrile!(2! mL)!and!p>TSA!(152!mg,!0.80!mmol,!4.0!equiv.)!were!added!and!stirred!at!room! temperature!for!a!further!6!hrs.!The!crude!product!was!purified!by!flash!column! chromatography! ! (10>50%! Et2O! in! petrol)! to! afford! dihydropyrrole! 7c! as! an! off! white!solid!(58!mg,!82%).! !

!

S55!

1H! NMR! (400! MHz,! CDCl

3):! δ! 7.43! (1H,! d,! J! 2.0,! Ar>H),! 7.40! (1H,! d,! J! 8.0,! Ar>H),!

7.34>7.29! (3H,! m,! Ar>H),! 7.15! (1H,! dd,! J! 5.0,! 1.5,! Ar>H),! 5.50! (1H,! t,! J! 7.5,! NCH),! 3.11>3.06!(2H,!m,!NCCH2),!2.61>2.53!(1H,!m,!NCHCHaHb),!2.48!(3H,!s,!SCH3),!1.98> 1.90!(1H,!m,!NCHCHaHb);!13C!NMR!(101!MHz,!CDCl3):!δ!172.7,!145.2,!142.9,!131.3,! 131.0,! 127.4,! 126.7,! 126.5,! 125.8,! 124.5,! 120.2,! 73.2,! 37.4,! 31.2,! 16.6;! IR:! νmax! (neat)/cm>1! 2918,! 1573,! 1466,! 1330,! 1273,! 1081,! 988;! LRMS! (ESI+):! m/z! 352! ([79Br]![M+H]+,!95%),!354!([81Br]![M+H]+,!100%);!HRMS!(ESI+)!found!351.98270! [[79Br]! M+H]+],! 353.98037! [[81Br]! M+Na]+],! C15H1579BrNS2+! requires! 351.98238,! C15H1581BrNS2+!requires!352.98033;!mp:!59>61!°C!(Et2O/petrol).! ' 2LCyclopropylL5L[4LmethoxyL2L(methylthio)phenyl]L3,4LdihydroL2HL pyrrole,'7d' Me

S N

MeO

! Prepared! according! to! general! procedure! I! using! 4>methoxy>2> (methylthio)benzaldehyde! 1k! (36.5! mg,! 0.20! mmol,! 1.0! equiv.),! allylic! amine! (tert>butyl!(1>cyclopropylallyl)carbamate!10f)!(51.3!mg,!0.26!mmol,!1.3!equiv.),! [Rh(nbd2)]BF4!(3.7!mg,!5!mol%)!and!PNP(Cy)!(4.2!mg,!5!mol%)!in!acetone!(110! µL,!1!M).!After!stirring!for!16!hrs!at!55!°C,!acetonitrile!(2!mL)!and!p>TSA!(38!mg,! 0.20!mmol,!1.0!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further! 3! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (10> 50%! Et2O! in! petrol)! to! afford! dihydropyrrole! 7d! as! a! colourless! oil! (25.1! mg,! 48%).! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.44! (1H,! d,! J! 8.5,! Ar>H),! 6.82! (1H,! d,! J! 2.5,! Ar>H),! 3 6.68! (1H,! dd,! J! 8.5,! 2.5,! Ar>H),! 4.02>3.97! (1H,! m,! NCH),! 3.87! (3H,! s,! OCH3),! 3.01! (1H,! dddd,! J! 12.0,! 9.5,! 4.5,! 2.0,! NCHCHaHb),! 2.91! (1H,! dddd,! J! 16.5,! 9.5,! 8.0,! 1.5,! NHCHCHaHb),!2.43!(3H,!s,!SCH3),!2.21>2.18!(1H,!m,!NCHCH(CH2)2),!1.74!(1H,!app! d,!J!8.5,!NCCHaHb),!1.04>1.02!(1H,!m,!NCCHaHb),!0.55>0.45!(4H,!m,!NCHCH(CH2)2);! 13C!NMR!(101!MHz,!CDCl ):!δ!172.2,!160.4,!142.0,!131.3,!125.9,!111.4,!108.1,!55.3,! 3 37.2,! 30.9,! 28.8,! 16.7,! 16.4,! 2.5;! IR:! νmax! (neat)/cm>1! 3078,! 2959,! 1593,! 1556,! 1435,! 1332,! 1247,! 1229,! 1045,! 907;! LRMS! (ESI+):! m/z! 262! ([M+H]+,! 100%);! HRMS!(ESI+)!found!262.12549![M+H]+,!C15H20NOS+!requires!262.12601.! ' ' '

!

S56!

5L[2,4LBis(methylthio)phenyl]L2LphenylL3,4LdihydroL2HLpyrrole,'7e! Me

S Ph

N

Me

S

! Prepared! according! to! general! procedure! I! using! 2,4> bis(methylthio)benzaldehyde' 1l' (29.7! mg,! 0.15! mmol,! 1.0! equiv.),! allylic! amine! (tert>butyl! (1>phenylallyl)carbamate7! 10a)! (45.5! mg,! 0.195! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4!(2.8!mg,!5!mol%)!and!PNP(Cy)!(3.2!mg,!5!mol%)!in!acetone!(70! µL,!1!M).!After!stirring!for!1!hr!at!55!°C,!acetonitrile!(1.5!mL)!and!p>TSA!(57.2!mg,! 0.30!mmol,!2.0!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further! 2! hrs.! The! crude! product! was! purified! by! flash! column! chromatography! ! (10> 20%! Et2O! in! petrol)! to! afford! dihydropyrrole! 7e! as! an! off>white! solid! (40.9! mg,! 87%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.51! (1H,! d,! J! 8.0,! Ar>H),! 7.47>7.45! (2H,! m,! Ar>H),! 3 7.40>7.36! (2H,! m,! Ar>H),! 7.28>7.25! (1H,! m,! Ar>H),! 7.19! (1H,! d,! J! 2.0,! Ar>H),! 7.06! (1H,!dd,!J!8.0,!2.0,!Ar>H),!5.45!(1H,!t,!J!8.0,!NCH),!3.15>3.07!(2H,!m,!NCCH2),!2.65> 2.58!(1H,!m,!NCHCHaHb),!2.56!(3H,!s,!SCH3),!2.49!(3H,!s,!SCH3),!1.90>1.81!(1H,!m,! NCHCHaHb);! 13C! NMR! (101! MHz,! CDCl3):! δ! 173.4,! 144.8,! 141.2,! 141.1,! 130.4,! 129.1,! 128.4,! 126.58,! 126.50,! 122.1,! 120.9,! 76.6,! 37.6,! 32.4,! 16.4,! 15.4;! IR:! νmax! (neat)/cm>1! 2919,! 1493,! 1473,! 1331,! 1269,! 1114,! 1085,! 968;! LRMS! (ESI+):! m/z! 314!([M+H]+,!100%);!HRMS!(ESI+)!found!314.10234![M+H]+,!C18H20NS2+!requires! 314.10317;!mp:!73>74!°C!(DCM/hexane).! ! 5L[3L(Methylthio)thiophenL2Lyl]L2LphenylL3,4LdihydroL2HLpyrrole,'7f! Me

S N

Ph

S

! Prepared! according! to! general! procedure! I! using! 3>(methylthio)thiophene>2> carbaldehyde' 1m' (31.6!mg,!0.20!mmol,!1.0!equiv.),!allylic!amine!(tert>butyl!(1> phenylallyl)carbamate7! 10a)! (60.6! mg,! 0.26! mmol,! 1.3! equiv.),! [Rh(nbd2)]BF4! (3.7!mg,!5!mol%)!and!PNP(Cy)!(4.2!mg,!5!mol%)!in!acetone!(100! µL,!1!M).!After! stirring!for!16!hrs!at!55!°C,!acetonitrile!(3.0!mL)!and!p>TSA!(57.2!mg,!0.30!mmol,! 2.0!equiv.)!were!added!and!stirred!at!room!temperature!for!a!further!3!hrs.!The! crude! product! was! purified! by! flash! column! chromatography! ! (10>20%! Et2O! in! petrol)!to!afford!dihydropyrrole!7f!as!an!off>white!solid!(41.6!mg,!76%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.45! (1H,! d,! J! 5.5,! Ar>H),! 7.37>7.33! (4H,! m,! Ar>H),! 3 7.28>7.25! (1H,! m,! Ar>H),! 7.07! (1H,! d,! J! 5.5,! Ar>H),! 5.40>5.35! (1H,! m,! NCH),! 3.23! (1H,!dddd,!J!14.5,!9.5,!4.5,!2.5,!NCCHaHb),!3.14>3.05!(1H,!m,!NCCHaHb),!2.66>2.59!

!

S57!

(1H,! m,! NCHCHaHb),! 2.58! (3H,! s,! SCH3),! 1.91! (1H,! dddd,! J! 12.5,! 9.5,! 8.0,! 7.5,! NCHCHaHb);! 13C! NMR! (101! MHz,! CDCl3):! δ! 168.1,! 144.8,! 137.6,! 130.1,! 128.4,! 127.9,!127.3,!126.6,!126.5,!75.5,!37.8,!33.0,!17.4;!IR:!νmax!(neat)/cm>1!2921,!1659,! 1590,! 1494,! 1426,! 1319,! 1260,! 1051;! LRMS! (ESI+):! m/z! 274! ([M+H]+,! 100%);! HRMS!(ESI+)!found!274.07187![M+H]+,!C15H16NS2+!requires!274.07187;!mp:!57> 58!°C!(Et2O/petrol).! ! 2L(4LMethoxyphenyl)L5L[3L(methylthio)thiophenL2Lyl]L3,4LdihydroL2HL pyrrole,'7g' Me

S N

OMe

S

' Prepared! according! to! general! procedure! I! using! 3>(methylthio)thiophene>2> carbaldehyde' 1m' (31.6! mg,! 0.20! mmol,! 1.0! equiv.),! allylic! amine! (tert>butyl! [1> (4>methoxyphenyl)allyl]carbamate! 10d)! (79! mg,! 0.26! mmol,! 1.5! equiv.),! [Rh(nbd2)]BF4!(3.7!mg,!5!mol%)!and!PNP(Cy)!(4.2!mg,!5!mol%)!in!acetone!(89! µL,!1!M).!After!stirring!for!16!hrs!at!55!°C,!acetonitrile!(3.0!mL)!and!p>TSA!(57.2! mg,! 0.30! mmol,! 2.0! equiv.)! were! added! and! stirred! at! room! temperature! for! a! further!2!hrs.!The!crude!product!was!purified!by!flash!column!chromatography!! (10>20%! Et2O! in! petrol)! to! afford! dihydopyrrole! 7g' as! a! very! pale! yellow! solid! (54.6!mg,!90%).' ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.45! (1H,! d,! J! 5.5,! Ar>H),! 7.29>7.27! (2H,! m,! Ar>H),! 3 7.07! (1H,! d,! J! 5.5,! Ar>H),! 6.92>6.88! (2H,! m,! Ar>H),! 5.34>5.30! (1H,! m,! NCH),! 3.82! (3H,! s,! OCH3),! 3.22! (1H,! dddd,! J! 16.5,! 9.5,! 4.5,! 2.0,! NCCHaHb),! 3.12>3.03! (1H,! m,! NCCHaHb),! 2.61>2.56! (1H,! m,! NCHCHaHb),! 2.58! (3H,! s,! SCH3)! 1.88! (1H,! dddd,! J! 12.5,!9.5,!8.0,!7.5,!NCHCHaHb);! 13C!NMR!(101!MHz,!CDCl3):!δ!167.8,!137.6,!137.0,! 130.2,! 129.1,! 127.9,! 127.5,! 127.3,! 113.8,! 74.9,! 55.3,! 37.8,! 33.1,! 17.4;! IR:! νmax! (neat)/cm>1!2953,!2833,!1612,!1511,!1464,!1351,!1319,!1244,!1035;!LRMS!(ESI+):! m/z! 304! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 304.08220! [M+H]+,! C16H18NOS2+! requires!304.08243;!mp:!79>80!°C!(Et2O/petrol).! ! 5L[4LBromoL2L(methylthio)phenyl]L2L[4L(trifluoromethyl)phenyl]L3,4L dihydroL2HLpyrrole,'7h' Me

S N

CF3

Br

! Prepared! according! to! general! procedure! I! using! 3 4>bromo>2>(methylthio)benzaldehyde '1e'(46!mg,!0.20!mmol,!1.0!equiv.),!allylic! amine! (tert>butyl! {1>[4>(trifluoromethyl)phenyl]allyl}carbamate)! (90! mg,! 0.3!

!

S58!

mmol,! 1.5! equiv.),! [Rh(nbd2)]BF4! (3.7! mg,! 5! mol%)! and! PNP(Cy)! (4.2! mg,! 5! mol%)!in!acetone!(64!µL,!1!M).!After!stirring!for!16!hrs!at!55!°C,!acetonitrile!(3.0! mL)!and!p>TSA!(57.2!mg,!0.30!mmol,!2.0!equiv.)!were!added!and!stirred!at!room! temperature!for!a!further!3!hrs.!The!crude!product!was!purified!by!flash!column! chromatography!!(10>20%!Et2O!in!petrol)!to!afford!dihydropyrrole!7h' as!a!very! pale!yellow!solid!(69.6!mg,!84%).' ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.62!(4H,!app!q,!J!11.5,!Ar>H),!7.45>7.42!(2H,!m,!Ar> 3 H),! 7.34! (1H,! dd,! J! 8.5,! 2.0,! Ar>H),! 5.47! (1H,! t,! J! 8.0,! NCH),! 3.15>3.10! (2H,! m,! NCCH2),! 2.66! (1H,! dtd,! J! 12.5,! 8.0,! 4.5,! NCHCHaHb),! 2.49! (3H,! s,! SCH3),! 1.83! (1H,! app!dq,!J!12.5,!9.0,!NCHCHaHb);! 13C!NMR!(101!MHz,!CDCl3):!δ!173.7,!148.5,!143.1,! 131.4,!130.6,!128.9!(q,! 2JCF!32.5),!127.4,!126.8,!126.7,!126.1!(q,! 1JCF!205.5),!125.4! (q,! 3JCF!3.5),!124.7,!76.3,!37.7,!32.2,!16.5;! 19F!NMR!(377!MHz,!CDCl3):!δ!>62.3;!IR:! νmax! (neat)/cm>1! 2360,! 1618,! 1574,! 1540,! 1325,! 1122,! 1106;! LRMS! (ESI+):! m/z! 414! ([79Br]! [M+H]+,! 95%),! 416! ([81Br]! [M+H]+,! 100%);! HRMS! (ESI+)! found! 435.9951! [[79Br]! M+Na]+],! 437.9929! [[81Br]! M+Na]+],! C18H1579BrNF3SNa+! requires! 435.9953,! C18H1581BrNF3SNa+! requires! 437.9926;! mp:! 80>82! °C! (Et2O/petrol).! ! 11.'Reduction'of'dihydropyrrole'products! ' General'procedure'J'for'the'synthesis'of'cisLpyrrolidines'as'exemplified'by' the'synthesis'of'2L[2L(methylthio)phenyl]L5Lphenylpyrrolidine,'8a' Me

S N H H H

Ph

NOE

! Dihydropyrrole!(5>[2>(methylthio)phenyl]>2>phenyl>3,4>dihydro>2H>pyrrole!7a)! (17.0!mg,!0.06!mmol,!1.0!equiv.),!was!dissolved!in!toluene!(0.2!mL)!and!cooled!to! >78! °C.! Diisobutylaluminium! hydride! solution! (0.18! mL,! 1.0! M! in! toluene,! 0.18! mmol,!3.0!equiv.)!was!added!dropwise!and!the!solution!was!stirred!at!>78!°C!for! 1!hr.!The!reaction!was!then!quenched!by!the!addition!of!sat.!NH4Cl! (aq)!(0.16!mL)! and!warmed!to!room!temperature.!The!reaction!mixture!was!diluted!with!DCM,! dried!over!MgSO4,!filtered!and!concentrated!in)vacuo.!The!reaction!gave!the!cis> diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(5%!EtOAc!in! petrol)!to!yield!title)pyrrolidine!8a'as!a!colourless!oil!(15.6!mg,!96%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 8.00>7.98! (1H,! m,! Ar>H),! 7.61! (2H,! d,! J! 7.5,! Ar>H),! 3 7.41!(2H,!app!t,!J!7.5,!Ar>H),!7.33>7.25!(4H,!m,!Ar>H),!4.78!(1H,!t,!J!7.5,!NHCH(Ar> SCH3)),! 4.40! (1H,! t,! J! 7.5,! NHCH(Ph)),! 2.54! (3H,! s,! SCH3),! 2.49>2.44! (1H,! m,!

!

S59!

NHCH(Ar>SCH3)CHaHb),! 2.36>2.25! (2H,! m,! NH! and! NHCH(Ph)CHaHb),! 1.89>1.81! (1H,!m,!NHCH(Ph)CHaHb),!1.75!(1H,!tdd,!J!11.5,!5.5,!2.5,! NHCH(Ar>SCH3)CHaHb);! 13C! NMR! (101! MHz,! CDCl ):! δ! 145.2,! 143.4,! 136.2,! 128.3,! 127.2,! 126.9,! 126.8,! 3 126.3,!125.4,!125.2,!62.2,!58.4,!34.5,!32.8,!16.1;!IR:!νmax!(neat)/cm>1!3329,!3059,! 3026,!2867,!1603,!1491,!1460,!1394,!1124,!907;!LRMS!(ESI+):!m/z!270!([M+H]+,! 100%);!HRMS!(ESI+)!found!270.13096![M+H]+,!C17H20NS+!requires!270.13110.! ! Cis>selectivity! from! a! DIBAL>H! reduction! was! confirmed! by! NOE! experiments,! which!displayed!in>space!interactions!between!the!two!hydrogen!atoms!shown.!!

! 2L[3L(Methylthio)thiophenL2Lyl]L5Lphenylpyrrolidine,'8b! Me

S

S

N H

Ph

! Prepared! according! to! general! procedure! J! using! dihydropyrrole! (5>[3> (methylthio)thiophen>2>yl]>2>phenyl>3,4>dihydro>2H>pyrrole! 7f),! (15! mg,! 0.06! mmol,! 1.0! equiv.),! diisobutylaluminium! hydride! solution! (0.18! mL,! 1.0! M! in! toluene,!0.18!mmol,!3.0!equiv.)!in!toluene!(0.2!mL).!After!stirring!for!2!hrs!at!>78! °C! sat.! NH4Cl! (aq)! (0.16! mL)! was! added! and! the! reaction! gave! the! cis> diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(15%!Et2O!in! petrol)!to!yield!pyrrolidine!8b!as!a!colourless!oil!(14.9!mg,!90%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.58>7.56!(2H!m,!Ar>H),!7.38!(2H,!dd,!J!8.0,!7.0,!Ar> 3 H),!7.29!(1H,!app!dt,!J!7.5,!1.5,!Ar>H),!7.23!(1H,!d,!J!5.0,!Ar>H),!7.04!(1H,!d,!J!5.0,!Ar>

!

S60!

H),!4.91>4.87!(1H,!m,!NHCHCS),!4.37!(1H,!t,!J!7.5,!NHCH(Ph)),!2.45!(3H,!s,!SCH3),! 2.40>2.34! (1H,! m,! NHCH(CS)CHaHb),! 2.29>2.22! (1H,! m,! NHCH(Ph)CHaHb),! 1.86! (2H,! tdt,! J! 7.5,! 3.5,! 2.80,! NHCH(CS)CHaHb! and! NHCH(Ph)CHaHb),! 1.29! (1H,! br! s,! NH);!13C!NMR!(101!MHz,!CDCl3):!δ!150.0,!145.1,!129.7,!129.5,!128.3,!126.9,!126.7,! 123.2,! 62.3,! 56.3,! 34.7,! 34.4,! 19.1;! IR:! νmax! (neat)/cm>1! 2920,! 1491,! 1452,! 1319,! 1246,! 1099,! 908;! LRMS! (ESI+):! m/z! 276! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 276.08766![M+H]+,!C15H18NS2+!requires!276.08752.! ! 2L(4LMethoxyphenyl)L5L[3L(methylthio)thiophenL2Lyl]pyrrolidine,'8c' Me

S

OMe

N H

S

! Prepared! according! to! general! procedure! J! using! dihydropyrrole! (2>(4> methoxyphenyl)>5>[3>(methylthio)thiophen>2>yl]>3,4>dihydro>2H>pyrrole! 7g),! (40!mg,!0.13!mmol,!1.0!equiv.),!diisobutylaluminium!hydride!solution!(0.39!mL,! 1.0!M!in!toluene,!0.39!mmol,!3.0!equiv.)!in!toluene!(0.8!mL).!After!stirring!for!1!hr! at! >78! °C! sat.! NH4Cl! (aq)! (0.35! mL)! was! added! and! the! reaction! gave! the! cis> diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(15%!Et2O!in! petrol)!to!yield!pyrrolidine!8c'as!a!colourless!oil!(35.6!mg,!90%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.50>7.47! (2H,! m,! Ar>H),! 7.22! (1H,! d,! J! 5.0,! Ar>H),! 3 7.03! (1H,! d,! J! 5.0,! Ar>H),! 6.94>6.90! (2H,! m,! Ar>H),! 4.86! (1H,! dd,! J! 8.0,! 6.0,! NHCH(CS)),!4.31!(1H,!t,!J!7.5,!NHCH(Ar>OCH3)),!3.84!(3H,!s,!OCH3),!2.52!(1H,!br!s,! NH),! 2.44! (3H,! s,! SCH3),! 2.39>2.34! (1H,! m,! NHCH(CS)CHaHb),! 2.23>2.16! (1H,! m,! NHCH(Ar>OCH3)CHaHb),! 1.88>1.80! (2H,! m,! NHCH(CS)CHaHb! and! NHCH(Ar> OCH3)CHaHb);! 13C! NMR! (101! MHz,! CDCl3):! δ! 158.6,! 150.1,! 137.1,! 129.7,! 127.7,! 123.2,! 123.0,! 113.6,! 61.8,! 56.1,! 55.3,! 34.7,! 34.4,! 19.1;! IR:! νmax! (neat)/cm>1! 2965,! 2833,! 1611,! 1584,! 1511,! 1440,! 1244,! 1035;! LRMS! (ESI+):! m/z! 306! ([M+H]+,! 100%);!HRMS!(ESI+)!found!306.09800![M+H]+,!C16H20NOS2+!requires!306.09808.! ! 2L[4LBromoL2L(methylthio)phenyl]L5L(thiophenL3Lyl)pyrrolidine,'8d! Me

S N H

S

Br

! Prepared!according!to!general!procedure!J!using!dihydropyrrole!(5>[4>bromo>2> (methylthio)phenyl]>2>(thiophen>3>yl)>3,4>dihydro>2H>pyrrole!7c)!(40!mg,!0.11! mmol,! 1.0! equiv.),! diisobutylaluminium! hydride! solution! (0.33! mL,! 1.0! M! in! toluene,!0.33!mmol,!3.0!equiv.)!in!toluene!(0.5!mL).!After!stirring!for!2!hrs!at!>78! °C! sat.! NH4Cl! (aq)! (0.3! mL)! was! added! and! the! reaction! gave! the! cis>

!

S61!

diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(15%!Et2O!in! petrol)!to!yield!pyrrolidine!8d!as!a!colourless!oil!(31.1!mg,!77%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.76!(1H,!d,!J!8.0,!Ar>H),!7.34!(1H,!dd,!J!5.0,!3.0,!Ar> 3 H),!7.32>7.28!(3H,!m,!Ar>H),!7.21!(1H,!dd,!J!5.0,!1.5,!Ar>H),!4.63!(1H,!app!t,!J!7.5,! NHCH(CCHS)),!4.46!(1H,!t,!J!8.0,!NHCH(Ar>Br)),!2.51!(3H,!s,!SCH3),!2.41!(1H,!dtd,!J! 12.5,!8.0,!7.5,!NHCH(CCHS)CHaHb),!2.25>2.19!(1H,!m,!NHCH(Ar>Br)CHaHb),!1.86> 1.77! (1H,! m,! NHCH(Ar>Br)CHaHb),! 1.65! (1H,! dddd,! J! 12.0,! 9.5,! 7.5,! 5.0,! NHCH(CCHS)CHaHb),! 1.49! (1H,! br! s,! NH);! 13C! NMR! (101! MHz,! CDCl3):! δ! 146.6,! 142.2,!127.8,!127.7,!127.1,!126.6,!125.7,!120.9,!120.1,!58.1,!57.7,!33.3,!32.6,!28.4,! 15.8;!IR:!νmax!(neat)/cm>1!2969,!2920,!1575,!1552,!1492,!1327,!1084,!907;!LRMS! (ESI+):!m/z!354!([79Br]![M+H]+,!95%),!356!([81Br]![M+H]+,!100%);!HRMS!(ESI+)! found! 353.99802! [[79Br]! M+H]+],! 355.99585! [[81Br]! M+H]+],! C15H1779BrS2+! requires!353.99803,!C15H1781BrNS2+!requires!355.99598.! ! 2L[4LBromoL2L(methylthio)phenyl]L5L[4L(trifluoromethyl)Lphenyl]L pyrrolidine,'8e' Me

S N H

CF3

Br

! Prepared!according!to!general!procedure!J!using!dihydropyrrole!(5>[4>bromo>2> (methylthio)phenyl]>2>[4>(trifluoromethyl)phenyl]>3,4>dihydro>2H>pyrrole! 7h)! (46!mg,!0.11!mmol,!1.0!equiv.),!diisobutylaluminium!hydride!solution!(0.33!mL,! 1.0!M!in!toluene,!0.33!mmol,!3.0!equiv.)!in!toluene!(0.6!mL).!After!stirring!for!1!hr! at! >78! °C! sat.! NH4Cl! (aq)! (0.3! mL)! was! added! and! the! reaction! gave! the! cis> diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(15%!Et2O!in! petrol)!to!yield!pyrrolidine!8e!as!a!colourless!oil!(42.1!mg,!92%).!! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.82!(1H,!d,!J!8.0,!Ar>H),!7.66!(4H,!app!q,!J!9.0,!Ar>H),! 3 7.35>7.29! (2H,! m,! Ar>H),! 4.68! (1H,! t,! J! 7.5,! NHCH(Ar>Br)),! 4.42! (1H,! t,! J! 8.0,! NHCH(Ar>CF3)),!2.52!(3H,!s,!SCH3),!2.49>2.40!(1H,!m,!NHCH(Ar>Br)CHaHb),!2.33> 2.26! (1H,! m,! NHCH(Ar>CF3)CHaHb),! 2.13! (1H,! br! s,! NH),! 1.80>1.70! (1H,! m,! NHCH(Ar>CF3)CHaHb),! 1.70>1.61! (1H,! m,! NHCH(Ar>Br)CHaHb);! 13C! NMR! (101! MHz,!CDCl3):!δ!149.4,!141.9,!138.6,!129.1!(q,!2JCF!32.0),!127.8,!127.7,!127.1,!127.0,! 125.2!(q,!3JCF!3.5),!124.2!(q,!1JCF!247.5),!121.0,!61.5,!57.9,!34.4,!32.5,!15.8;!19F!NMR! (377! MHz,! CDCl3):! δ! >62.3;! IR:! νmax! (neat)/cm>1! 2943,! 1619,! 1575,! 1460,! 1324,! 1163,! 1066;! LRMS! (ESI+):! m/z! 416! ([79Br]! [M+H]+,! 95%),! 418! ([81Br]! [M+H]+,! 100%);! HRMS! (ESI+)! found! 416.0304! [[79Br]! M+H]+],! 418.0282! [[81Br]! M+H]+],! C18H1879BrF3S+!requires!416.0289,!C18H1881BrNF3S+!requires!418.0312.! !

S62!

! 2LCyclopropylL5L[4LmethoxyL2L(methylthio)phenyl]pyrrolidine,'8f' Me

S N H

MeO

! Prepared!according!to!general!procedure!J!using!dihydropyrrole!(2>cyclopropyl> 5>[4>methoxy>2>(methylthio)phenyl]>3,4>dihydro>2H>pyrrole! 7d)! (20! mg,! 0.08! mmol,! 1.0! equiv.),! diisobutylaluminium! hydride! solution! (0.24! mL,! 1.0! M! in! toluene,!0.24!mmol,!3.0!equiv.)!in!toluene!(0.2!mL).!After!stirring!for!2!hrs!at!>78! °C! sat.! NH4Cl! (aq)! (0.22! mL)! was! added! and! the! reaction! gave! the! cis> diastereoisomer)as! the! only! isomer! detectable! by! crude! 1H! NMR! spectroscopy.! The!crude!product!was!purified!by!flash!column!chromatography!!(15%!Et2O!in! petrol)!to!yield!pyrrolidine!8f!as!a!colourless!oil!(18.1!mg,!88%).!! ! 1H! NMR! (400! MHz,! CDCl ):! δ! 7.62! (1H,! d,! J! 8.5,! Ar>H),! 6.77! (1H,! d,! J! 2.5,! Ar>H),! 3 6.72! (1H,! dd,! J! 8.5,! 2.5,! Ar>H),! 4.46! (1H,! t,! J! 7.5,! NHCH(Ar)),! 3.83! (3H,! s,! OCH3),! 2.61! (1H,! app! q,! J! 7.5,! NHCH(CH(CH2)2)),! 2.48! (3H,! s,! SCH3),! 2.24>2.17! (1H,! m,! NHCH(Ar)CHaHb),! 2.02>1.94! (2H,! m,! NH! and! NHCH(CH(CH2)2)CHaHb),! 1.75>1.66! (1H,! m,! NHCH(CH(CH2)2)CHaHb),! 1.66>1.57! (1H,! m,! NHCH(Ar)CHaHb),! 0.96>0.91! (1H,!m,!NHCH(CH(CH2)2)),!0.53>0.46!(2H,!m,!NHCH(CH(CH2)(CHaHb)),!0.31>0.27! (1H,! m,! NHCH(CH(CH2)(CHaHb)),! 0.24>0.19! (1H,! m,! NHCH(CH(CH2)(CHaHb));! 13C! NMR! (101! MHz,! CDCl3):! δ! 158.6,! 137.6,! 135.1,! 127.1,! 111.7,! 109.7,! 63.7,! 57.9,! 55.3,!32.5,!30.7,!16.2,!16.0,!3.1,!2.0;!IR:!νmax!(neat)/cm>1!2999,!2832,!1597,!1571,! 1484,! 1436,! 1290,! 1242,! 1053;! LRMS! (ESI+):! m/z! 264! ([M+H]+,! 100%);! HRMS! (ESI+)!found!264.14158![M+H]+,!C15H22NOS+!requires!264.14166.! ' 2L(2L(Methylthio)phenyl)L5Lphenylpyrrolidine,'8g! Me

S N H

Ph

! Dihydropyrrole!(5>[2>(methylthio)phenyl]>2>phenyl>3,4>dihydro>2H>pyrrole!7a)! (120!mg,!0.45!mmol,!1.0!equiv.),!was!dissolved!in!acetic!acid!(2.25!mL).!Sodium! borohydride! (42! mg,! 1.13! mmol,! 2.5! equiv.)! was! added! and! the! solution! was! stirred! at! room! temperature! for! 1! hr.! The! reaction! was! then! quenched! by! the! addition! of! water! (10! mL)! and! potassium! carbonate! (0.1! g).! The! aqueous! layer! was! extracted! with! EtOAc! (3! ×! 10! mL)! and! the! combined! organic! layers! with! washed!with!brine!(20!mL),!dried!over!MgSO4!and!concentrated!under!reduced! pressure.! The! reaction! gave! the! transJ! to! cis>diastereoisomers! in! a! ratio! of! 3:1! (trans:cis)!and!they!were!separated!by!column!chromatography!!(5>20%!Et2O!in!

!

S63!

petrol)!to!yield!transJpyrrolidine!8g!as!the!major!diastereoisomer!as!a!colourless! oil!(83!mg,!68%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.64!(1H,!dd,!J!8.5,!1.0,!Ar>H),!7.48>7.45!(2H,!m,!Ar> 3 H),!7.39!(2H,!dd,!J!8.5,!7.0,!Ar>H),!7.31>7.28!(1H,!m,!Ar>H),!7.27>7.21!(3H,!m,!Ar> H),!5.00!(1H,!t,!J!7.0,!NHCH(Ar>SCH3)CH2),!4.57!(1H,!t,!J!7.0,!NHCH(Ph)CH2),!2.56> 2.50! (1H,! m,! NHCH(Ar>SCH3)CHaHb),! 2.53! (3H,! s,! SCH3),! 2.46>2.38! (1H,! m,! NHCH(Ph)CHaHb),!2.09!(1H,!br!s,!NH),!1.98>1.91!(1H,!m,!NHCH(Ph)CHaHb),!1.83! (1H,!app!ddt,!J!12.0,!9.0,!7.0,!NHCH(Ar>SCH3)CHaHb);! 13C!NMR!(101!MHz,!CDCl3):! δ! 145.9,! 143.7,! 136.4,! 128.5,! 127.2,! 126.8,! 126.4,! 125.6,! 125.36,! 125.17,! 62.3,! 58.8,!35.4,!33.6,!16.1;!IR:! νmax!(neat)/cm>1!2920,!1612,!1586,!1492,!1436,!1272,! 1060;! LRMS! (ESI+):! m/z! 270! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 270.13023! [M+H]+,!C15H22NOS+!requires!270.13110.! ! trans>selectivity! from! a! sodium! borohydride! reduction! was! confirmed! by! NOE! experiments,! which! displayed! a! lack! of! in>space! interactions! between! the! two! hydrogen!atoms!shown!in!comaparison!to!the!cis>pyrrolidine.!! !

! 2LAllylL2L[2L(methylthio)phenyl]L5Lphenylpyrrolidine,'8h' Me

S N H

Ph

! Dihydropyrrole!(5>[2>(methylthio)phenyl]>2>phenyl>3,4>dihydro>2H>pyrrole!7a)! (50!mg,!0.19!mmol,!1.0!equiv.)!was!dissolved!in!THF!(1.9!mL)!and!cooled!to!0!°C.! !

S64!

Allylmagnesium! bromide! (0.36! mL,! 0.8! M! in! THF,! 0.29! mmol,! 1.5! equiv.)! was! added! dropwise! and! the! solution! was! warmed! to! room! temperature! over! 30! mins.! The! reaction! was! then! quenched! by! the! addition! of! sat.! NH4Cl(aq)! (3! mL)! and! the! aqueous! layer! was! extracted! with! EtOAc! (3! ×! 5! mL)! and! the! combined! organic! layers! were! washed! with! brine! (10! mL),! dried! over! MgSO4! and! concentrated! under! reduced! pressure.! The! reaction! gave! the! cisJ! to! trans> diastereoisomers! in! a! ratio! of! 25:1! (cis:trans)! and! they! were! separated! by! column!chromatography!!(20%!Et2O!in!petrol)!to!yield!title)cisJpyrrolidine!8h!as! a!colourless!oil!(53.6!mg,!91%).! ! 1H!NMR!(400!MHz,!CDCl ):!δ!7.97>7.95!(1H,!m,!Ar>H),!7.53!(2H,!dd,!J!8.0,!1.0,!Ar> 3 H),!7.39>7.34!(3H,!m,!Ar>H),!7.29>7.20!(3H,!m,!Ar>H),!5.37!(1H,!dddd,!J!17.0,!10.0,! 9.0,! 5.5,! NHCCH2CHCH2),! 5.09>4.99! (2H,! m,! NHCCH2CHCH2),! 4.44! (1H,! dd,! J! 9.0,! 6.5,!NHCH),!3.37!(1H,!dd,!J!14.0,!5.5,!NHCCHaHbCHCH2),!2.65!(1H,!dd,!J!14.0,!9.0,! NHCCHaHbCHCH2),! 2.54! (3H,! s,! SCH3),! 2.48>2.38! (3H,! m,! NH! and! NCH(Ph)CH2),! 2.25!(1H,!dddd,!J!12.0,!7.5,!6.5,!4.5,!NCCHaHbCH2CH(Ph)),!1.69!(1H,!app!dq,!J!12.0,! 9.0,! NCCHaHbCH2CH(Ph));! 13C! NMR! (101! MHz,! CDCl3):! δ! 146.9,! 145.7,! 135.4,! 135.2,!128.5,!128.4,!128.2,!126.9,!126.8,!126.7,!124.9,!118.0,!66.6,!60.4,!43.8,!38.1,! 35.2,!18.0;!IR:!νmax!(neat)/cm>1!2975,!2922,!1637,!1584,!1435,!1256,!1049;!LRMS! (ESI+):! m/z! 310! ([M+H]+,! 100%);! HRMS! (ESI+)! found! 310.16204! [M+H]+,! C20H24NS+!requires!310.16240.! ! Cis>selectivity! from! allylmagnesium! bromide! addition! was! confirmed! by! NOE! experiments,! which! displayed! in>space! interactions! between! the! two! hydrogen! atoms!shown.!

!

S65!

11.'References' 1. I.! Pernik,! J.! F.! Hooper,! A.! B.! Chaplin,! A.! S.! Weller,! M.! C.! Willis,! ACS)Catal.,! 2012,!2,!2779>2786.! 2. C.! González>Rodríguez,! R.! J.! Pawley,! A.! B.! Chaplin,! A.! L.! Thompson,! A.! S.! Weller,!M.!C.!Willis,)Angew.)Chem.)Int.)Ed.,!2011,!50,!5134>5138.! 3. M.!Arambasic,!J.!F.!Hooper,!M.!C.!Willis,!Org.)Lett.,!2013,!15,!5162>5165.! 4. S>J.!Poingdestre,!J.!D.!Goodacre,!A.!S.!Weller,!M.!C.!Willis,!Chem.)Commun.,! 2012,!48,!6354>6356.! 5. M.!Castaing,!S.!L,!Wason,!B.!Estepa,!J.!F.!Hooper,!M.!C.!Willis,!Angew.)Chem.) Int.)Ed.,!2013,!52,!13280>13283.! 6. E.!Hernando,!R.!Gomez!Arryas,!J.!C.!Carretero,!Chem.)Commun.,!2012,!48,! 9622>9624.! 7. T.!Mecozzi,!M.!Petrini,!J.)Org.)Chem.,!1999,!64,!8970>8972.! 8. L.!Huang,!W.!D.!Wulff.!!J.)Am.)Chem.)Soc.,!2011,!133,!8892>8895.! 9. C.!G.!Goodman,!D.!T.!Do,!J.!S.!Johnson,!Org.)Lett.,!2013,!15,!2446>2449.! 10. S.! A.! Tsai,! M.! E.! Tauchert,! R.! G.! Bergman,! J.! A.! Ellman,! J.) Am.) Chem.) Soc.,! 2011,!133,!1248>1250.! 11. G.!C.!Tsui,!F.!Menard,!M.!Lautens,!Org.)Lett.,!2010,!12,!2456>2459.! 12. J.! F.! Teichert,! S.! Zhang,! A.! W.! Van! Zijl,! J.! W.! Slaa,! A.! J.! Minnaard,! B.! L.! Feringa,!Org.)Lett.,!2010,!12,!4658>4660.!! 13. E.!S.!Lee,!H.!S.!Yeom,!J.!H.!Hwang,!S.!Shin,!Eur.)J.)Org.)Chem.,!2007,!3503> 3507.! 14. D.!J.!Wiex,!D.!Marković,!M.!Ueda,!J.!F.!Hartwig,!Org.)Lett.,!2009,!11,!2944> 2947.!! 15. K.!K.!Chauhan,!C.!G.!Frost,!!J.)Chem.)Soc.)Perkin)Trans.)1,!2000,!3015.! ! !

!

S66!

Aldehyde'1i:'1H$NMR$(400$MHz,$CDCl3)$ S

MeO

O

1 0.916 0.916 ppm-1

1

3.16 3.16

1.09 1.09

1.081.08 1011-20.019

910

2.433

7.539 7.536 7.520 7.517 7.432 7.410 7.392 7.150 7.147 7.129 7.127

10.801

H

3.983

Me

89

3.1 3.1 78

67

56

45

34

23

12

01

-10

ppm0

$

200-258.727

180200

160180

140160

120140

100120

80100

6080

18.862

56.254

115.823

120.164

129.354 128.655

138.465

160.368

192.629

Aldehyde'1i:'13C$NMR$(101$MHz,$CDCl3)$ $ Me $ S O MeO $ H $ $

4060

2040

020

$

S65$ S67

1 0.765 0.765 ppm-1

1

2.478

7.092 7.071 6.935 6.913 6.891

7.524 7.517 7.504 7.496

10.508

Aldehyde'1j:'1H!NMR!(400!MHz,!CDCl3)! ! Me ! S O ! H ! F !

0.918 0.918

3.56 3.56

1.12 1.12 1011-20.019

910

89

78

67

56

ppm0

!

200-258.727

180200

160180

140160

120140

34

23

12

!

01

-10

15.355

110.937 110.720

120.683 120.604 119.800 119.769

135.006 134.897

146.053

167.939 165.364

187.194

! Aldehyde'1j:'13C!NMR!(101!MHz,!CDCl3)! ! Me ! S O ! H ! F !

45

100120

80100

6080

4060

2040

020

!

S66! ! S68

-120.333

Aldehyde'1j:'19F!NMR!(377!MHz,!CDCl3)! ! Me ! S O ! H ! F !

ppm-180

! ! ! !

80100-301.749

6080

4060

2040

-020

-20-0

-40-20

-60-40

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

!

S67! !S69

3.06 3.06

0.884 0.884 ppm-1

1011-20.019

910

89

78

67

56

ppm0

200-258.727

180200

160180

140160

45

34

23

120140

12

100120

80100

6080

$

01

55.576

111.043 109.059

126.478

136.156

145.716

163.964

189.713

$ $ Aldehyde'1k:'13C$NMR$(101$MHz,$CDCl3)$ $ Me S O $ H $ MeO $

$ $ $

3 3

1.911.91

-10

15.135

0.9740.974

2.495

3.925

6.816 6.811 6.802 6.796 6.781 6.775

7.789 7.768

10.106

Aldehyde'1k:'1H$NMR$(400$MHz,$CDCl3)$ $ Me S O $ H $ MeO $

4060

2040

020

$

S68$ S70

Aldehyde'1l:'1H$NMR$(400$MHz,$CDCl3)$ Me

S

O H

Me

S

0.958 0.84 0.84 ppm-1

0.958

2.557 2.499

7.710 7.708 7.689 7.687 7.342 7.341 7.322 7.321 7.311 7.284 7.283 7.281 7.249 7.225 7.083 7.063

10.150

$

3 3

0.917 0.917

0.938 0.938

1011-24.987

910

89

$

3.12 3.12

78

67

56

45

34

23

12

01

-10

Aldehyde'1l:'13C$NMR$(101$MHz,$CDCl3)$ Me

S

O H

Me

S

ppm0

200-238.855

180200

160180

140160

120140

15.406 14.667

121.287 120.492

129.505

133.546

143.818

147.653

190.242

$

100120

80100

6080

4060

2040

020

$

S69$ S71

Aldehyde 1m: 1H NMR (400 MHz, CDCl3) Me S

O H S

1

2.606 3.3 3.3

1

0.909 0.909 ppm-1

7.127 7.114

7.752 7.750 7.739 7.737

10.056

$

$

1.07 1.07

1011-20.019

910

89

78

67

56

45

34

23

12

01

-10

Aldehyde 1m: 13C NMR (101 MHz, CDCl3) Me S

O H S

ppm0

200-258.727

180200

160180

140160

17.140

128.059

135.173 134.590

146.007

181.483

$

120140

100120

80100

6080

4060

2040

020

$

S70$ S72

Aldehyde 1n: 1H NMR (400 MHz, CDCl3) Me

S

O H

0.928 0.928 0.8810.881 ppm-1

1

2.574

7.469 7.448

7.782 7.778 7.761 7.757

8.069 8.065

10.279

CF3

1

3.15 3.15

0.93 0.93

1011-20.019

910

89

78

67

56

45

34

23

12

$

01

-10

Aldehyde 1n: 13C NMR (126 MHz, CDCl3) Me

S

O H

CF3

ppm0

200-248.384

180200

160180

140160

120140

15.159

132.324 130.209 130.179 130.150 130.120 129.930 129.905 129.875 129.847 126.994 126.888 126.723 126.456 126.189 125.144 124.728 122.567 120.407

148.355

189.963

$

100120

80100

6080

4060

2040

020

$

S71$ S73

! Aldehyde 1n: 19F NMR (377 MHz, CDCl3) Me

S

O H

CF3 -62.548

!

ppm-200

80100-301.749

6080

4060

2040

-020

-20-0

-40-20

-60-40

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

!

-200-180

S72! S74

α!Amido'sulfone'9j: 1H NMR (400 MHz, CDCl3): $ O

" " "

O

NH S N O

O

OMe

α!Amido'sulfone'9j: 13C NMR (101 MHz, CDCl3): O O

NH S N O

O

OMe

S73$ S75

!α!Amido'sulfone'9k:'1H NMR (400 MHz, CD2Cl2)

O O

NH S

0.985 2.98 0.985 2.98 1.02 1.02 2 2 ppm-1

1011-20.019

910

89

1.13 1.08 1.131.08

1

1.311

5.895 5.868

O 7.982 7.963 7.705 7.687 7.669 7.653 7.652 7.633 7.606 7.592 7.591 7.575 7.564 7.556 7.467 7.464 7.448 7.445 7.429 7.426 7.334 7.330 7.314 7.311 7.296 7.289 6.675 6.648

O Br

1

8.93 8.93

0.789 0.789 78

67

56

45

!α!Amido'sulfone'9k:'13C NMR (101 MHz, CD2Cl2)

34

23

12

01

-10

O O

NH S

ppm0

200-238.897

180200

160180

140160

120140

100120

80100

27.718

72.442

81.174

137.212 134.197 133.902 133.162 131.205 130.998 129.358 129.227 127.975 125.827

O 153.346

O Br

6080

4060

2040

020

S74$ S76

a!Amido'Sulfone'9l:'1H$NMR$(400$MHz,$CDCl3)$ O O

NH S

3.13 3.13

1011-20.025

910

1.154 1.134

9.47 9.47

1.16 1.16

2.172.17 ppm-1

4.856 4.828

5.213 5.184

6.954 6.950 6.936 6.924

O 7.891 7.887 7.874 7.868

O

1.191.19

89

78

67

56

9 45

34

23

9 12

01

-10

a!Amido'Sulfone'9l:'13C$NMR$(101$MHz,$CDCl3)$ O O

NH S

ppm0

200-238.897

180200

160180

140160

120140

100120

80100

6080

4060

28.330 27.379 25.339

36.746

80.594

129.072 128.807

133.402

139.303

O 153.871

O

2040

020

S75$ S77

ppm0

200-238.897

180200

160180 78

140160 67

120140 56

100120 3.063.06 1.081.08

45

80100 34

6080 9.02 9.02

23 12

4060

2040

4.167 1.995

NH 89 0.977 0.977

8.986

O 910 0.9330.933

21.292

1011-20.019 2.08

27.683

2 2

74.306

ppm-1

80.491

2.08

129.598 129.231

5.140 5.113 4.393 4.369 4.345 2.442 1.387 1.386 1.385 1.384 1.376 1.371 1.365 1.361 1.355 1.343 1.338 1.335 1.334 1.323 1.322 1.322 1.321 1.277 0.858 0.844 0.837 0.830 0.823 0.816 0.809 0.803 0.801 0.788 0.727 0.714 0.712 0.706 0.699 0.692 0.684 0.679 0.672 0.669 0.657 0.652 0.628 0.616 0.610 0.605 0.597 0.591 0.591 0.470 0.470 0.469 0.468 0.467 0.458 0.457 0.456 0.444 0.434 0.433 0.421 0.413 0.412 0.412 0.410 0.409 0.409 0.408

O

134.500

O NH

7.359 7.339

7.829 7.808

O

144.976

153.754

a!Amido'Sulfone'9m:'1H$NMR$(400$MHz,$CDCl3)$ O Me

S O

1.14 1.14 1.091.09 1.12 1.18 1.18 1.12 01 -10

a!Amido'Sulfone'9m:'13C$NMR$(101$MHz,$CDCl3)$

O Me

S O

020

S76$ S78

Propargylic+Amine+2b:+1H#NMR#(400#MHz,#CDCl3)# O HN

O

1.479 1.438 1.421

2.286 2.280

4.511

4.728

Me

1.03 1.03 0.726 0.726 ppm-1

1011-20.019

910

89

78

67

9.03 9.03 3 3

0.876 0.876

56

45

34

23

12

01

-10

Propargylic+Amine+2b:+13C#NMR#(101#MHz,#CDCl3)# O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

22.542

28.352

38.240

70.119

79.909

84.552

154.605

Me

2040

020

S77# S79

! Propargylic+Amine+2c:+1H!NMR!(400!MHz,!CDCl3)! O HN

1

1

1011-20.019

910

89

78

67

56

1.011

9.399.39

1.111.11 ppm-1

1.476

2.279 2.273

4.276 4.255

4.730 4.710

O

0.923 0.923 45

34

9.74 9.74

23

12

01

-10

Propargylic+Amine+2c:+13C!NMR!(101!MHz,!CDCl3)! O

ppm0

200-248.384

180200

160180

120140

100120

80100

6080

4060

25.775

28.376

35.418

52.166

71.703

82.488 140160

79.815

O

155.284

HN

2040

020

S78! S80

Propargylic+Amine+2d:+1H$NMR$(400$MHz,$CDCl3)$ O HN

3.07

3.07

1011-20.019

910

0.98 0.98

89

1.488

2.526 2.520

9.46 9.46

1.07

2.24 2.24 ppm-1

5.244

5.719 5.703

7.543 7.525 7.402 7.399 7.394 7.385 7.382 7.377 7.366 7.347 7.343 7.340 7.335 7.329 7.311 7.308

O

78

67

1 56

45

34

1 23

12

01

-10

Propargylic+Amine+2d:+13C$NMR$(101$MHz,$CDCl3)$ O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.369

46.149

73.015

82.201 80.257

128.676 128.106 126.873

138.790

O

154.763

HN

4060

2040

020

S79$ S81

Propargylic+Amine+2e:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

2.04

2.04

1011-20.019

910

89

67

1.483

0.846 0.846

0.852 0.852 78

2.511 2.505

3.828

0.848 0.848

2 2 ppm-1

5.048

5.638 5.624

6.919 6.897

7.461 7.439

OMe

9.25 9.25

3.11 3.11 56

45

34

23

12

01

-10

Propargylic+Amine+2e:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.358

45.656

55.324

72.710

82.422 80.215

114.005

128.139

130.933

154.699

159.422

OMe

4060

2040

020

S80$ S82

! Propargylic+Amine+2f:+1H!NMR!(400!MHz,!CDCl3)! O HN

O

1.13 1.13 1.021.02 ppm-1

1011-20.019

910

89

1.03 1.03

1.15 1.15 78

1

1.471

2.445 2.439

5.189

5.721 5.705

6.394 6.392 6.386 6.384 6.343 6.338 6.335 6.330

7.394 7.392 7.390 7.387

O

1

9.31 9.31

1.13 1.13

67

56

45

34

23

12

01

-10

Propargylic+Amine+2f:+13C!NMR!(101!MHz,!CDCl3)! O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

28.302

40.498

71.922

80.466 80.037

107.446

110.373

142.777

150.803

154.459

O

2040

020

S81! S83

Propargylic+Amine+2g:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

1.03 1.03 4.4 ppm-1

1011-20.019

910

4.4

89

1

1.481

2.579 2.573

5.147

5.741 5.723

7.701 7.696 7.685 7.680 7.660 7.639

CN

1

9.14 9.14

1 78

67

56

45

34

23

12

01

-10

Propargylic+Amine+2g:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.289

45.896

74.186

80.900 80.702

112.048

118.507

127.585

132.510

144.107

154.654

CN

4060

2040

020

S82$ S84

Propargylic+Amine+2h:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

0.9470.947 4.4 ppm-1

1011-20.019

910

4.4

89

1

1.459

2.552 2.545

5.438

5.754

7.651 7.629 7.622 7.600

CF3

1

9.15 9.15

1.14 1.14 78

67

56

45

Propargylic+Amine+2h:+13C$NMR$(101$MHz,$CDCl3)$

34

23

12

01

-10

O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.236

45.763

73.718

81.255 80.582

130.744 130.415 130.096 129.776 128.043 127.177 125.625 125.549 125.516 125.331 122.627 119.927

142.927

154.772

CF3

4060

2040

020

S83$ S85

-62.593

Propargylic Amine 2h: 19F NMR (377 MHz, CDCl3) $ O $ HN O $ $ CF3 $

ppm-200

80100-301.749 6080

4060

2040

-020

-20-0

-40-20

-60-40

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

$

-200-180

S84$ S86

Propargylic+Amine+2i:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

1.09 1.09

1011-20.019

910

89

1

1.492

2.534 2.528

0.9880.988

1.081.08 1.17 1.17 ppm-1

5.264

5.899

7.274 7.271 7.261 7.258 7.193 7.190 7.182 7.179 6.978 6.970 6.966 6.957

S

1

9.32 9.32

1.04 1.04

78

67

56

45

+ Propargylic+Amine+2i:+13C$NMR$(101$MHz,$CDCl3)$

34

23

12

01

-10

O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

28.337

42.100

72.453

81.536 80.527

126.733 125.707

142.557

154.450

S

2040

020

S85$ S87

Propargylic+Amine+2j:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

1.13 1.131.19 1.19

1011-20.019

910

89

1.434

2.487 2.481

9.02 9.02

1.22 1.22

1.161.161.231.23 ppm-1

5.367

5.865

7.650 7.646 7.631 7.627 7.565 7.562 7.545 7.542 7.337 7.334 7.319 7.315 7.300 7.296 7.183 7.179 7.163 7.144 7.140

Br

1.021.02

78

67

1 56

45

+ Propargylic+Amine+2j:+13C$NMR$(101$MHz,$CDCl3)$

34

1 23

12

01

-10

O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.337

46.631

73.160

81.442 80.294

123.087

129.733 128.749 127.777

133.333

137.750

154.254

Br

4060

2040

020

S86$ S88

Propargylic+Amine+2k:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

2.02 2.02

1011-20.019

910

89

1.476

2.533 2.527

9.28 9.28

1.03 1.03

2.382.38 ppm-1

5.130

5.649

7.521 7.515 7.510 7.499 7.494 7.488 7.480 7.413 7.392

Br

1 1 78

67

1 56

45

34

1 23

12

01

-10

Propargylic+Amine+2k:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.332

45.662

73.421

81.538 80.530

122.121

128.584

131.755

137.961

154.661

Br

4060

2040

020

S87$ S89

Propargylic Amine 2l: 1H NMR (400 MHz, CDCl3) O HN

O

2.18

2.18

1011-20.019

910

1

0.947 0.947

89

78

67

1.466

2.547 2.541

3.925

1 1

2.262.26 ppm-1

5.251

5.737

7.595 7.574

8.049 8.044 8.040 8.028 8.023 8.019

CO2Me

1

9.01 9.01

3.01 3.01 56

45

34

23

12

01

-10

Propargylic Amine 2l:13C NMR (101 MHz, CDCl3) O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.305

45.920

52.166

73.600

81.398 80.558

129.970 129.875 126.812

143.760

154.720

166.654

CO2Me

4060

2040

020

S88# S90

Propargylic+Amine+2m:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

N

0.985 0.985 1 ppm-1

1011-20.019

910

1

0.835 0.835

0.9270.927

89

78

9.19 9.19

3.033.03

1.031.03 67

1.495

2.427 2.421

3.981

5.668 5.584

6.717 6.696

7.026 7.008

7.615 7.597 7.595 7.576

OMe

0.840.84 56

45

34

23

12

01

-10

Propargylic+Amine+2m:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

N

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.368

46.972

53.474

71.945

82.342

110.261

113.890

139.478

154.871 153.988

163.921

OMe

4060

2040

020

S89$ S91

Propargylic+Amine+2n:+1H$NMR$(400$MHz,$CDCl3)$ O

1.437 1.155 1.139 1.122 1.106 1.103 1.088 1.074 0.492 0.486 0.475 0.466 0.450 0.438 0.426

2.212 2.206

4.388

O

4.928

HN

1.1 1.1

ppm-1

1011-20.019

910

89

78

67

56

4.36 4.36

9.269.26

1.11.1

1 45

34

1

1.251.25

23

12

01

-10

++ Propargylic+Amine+2n:+13C$NMR$(101$MHz,$CDCl3)$ O

ppm0

200-258.727

180200

160180

120140

100120

80100

6080

4060

2040

2.724 1.552

15.087

28.320

45.454

81.176

140160

71.084

O

154.764

HN

020

S90$ S92

Propargylic+Amine+2o:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

2.186 2.181 2.169 2.164 2.151 2.146 1.528 1.526 1.510 1.491 1.465 1.395 1.390 1.379 1.362 1.340 1.338 1.334 1.330 1.319 1.314 1.309 1.305 1.304 1.300 1.295 1.293 1.284 1.278 1.268 0.926 0.909 0.891

4.691

4.468

Me

Me

0.974 0.974

2.24 9.15 2.24 9.15

0.8180.818 ppm-1

1011-20.019

910

89

78

67

56

2.01 2.01 45

34

9.3 9.3

23

3 3 12

01

-10

Propargylic+Amine+2o:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

2040

14.046

18.585

82.581 80.667

154.696 ppm0

31.322 28.872 28.636 28.481 28.384 27.970 23.257 22.533

Me

Me

020

S91$ S93

ppm0

200-258.727

180200

160180

140160 67

120140

100120 2.182.18 2.052.05

56 45

80100 34

6080 8.72 4.05 8.72 4.05

23

4060

2040

14.045

HN 78 2.02 2.02

18.767

89 0.763 0.763

22.541

910 0.769 0.769

31.319 29.443 28.558 28.369

1.85 1.85

46.495

1.82 1.82 0.771 0.771

79.930 78.317

1011-20.019

85.515

ppm-1

128.502 127.734 126.845

2.285 2.280 2.268 2.262 2.250 2.244 1.592 1.576 1.557 1.538 1.520 1.480 1.439 1.435 1.430 1.423 1.421 1.417 1.409 1.401 1.384 1.351 1.347 1.342 1.334 1.327 1.318 1.309 1.301 1.291 0.936 0.919 0.902

5.028

5.661

7.532 7.513 7.394 7.391 7.387 7.374 7.370 7.358 7.355 7.331 7.328 7.324 7.316 7.310

HN

140.250

154.788

Propargylic+Amine+2p:+1H$NMR$(400$MHz,$CDCl3)$ O O

Me

12

3 3 01 -10

Propargylic+Amine+2p:+13C$NMR$(101$MHz,$CDCl3)$

O O

Me

020

S92$ S94

ppm0

200-258.727

180200

160180

140160

120140

100120 11.1 11.1 0.993 0.993

56 45

80100 34 23

6080 12

4060

2040

2.587 1.235

67 2

10.350

HN 78 2

15.450 14.043

1.18

18.564

0.8820.882

22.540

89

31.292 28.651 28.383

910

69.757

1011-20.019

79.563

ppm-1

2.183 2.177 2.165 2.160 2.148 2.142 1.505 1.479 1.466 1.451 1.413 1.401 1.395 1.391 1.388 1.379 1.375 1.364 1.356 1.341 1.323 1.318 1.310 1.307 1.302 1.297 1.295 1.288 1.285 1.280 1.270 1.264 1.260 1.257 1.152 1.148 1.133 1.127 1.119 1.114 1.105 1.100 0.931 0.914 0.896 0.506 0.501 0.488 0.477 0.474 0.469 0.464 0.457 0.454 0.449 0.442 0.441 0.437 0.431 0.418

4.481

4.778

HN

83.669

154.872

Propargylic+Amine+2q:+1H$NMR$(400$MHz,$CDCl3)$ O O

Me

6.18 6.182.992.99

4.13 4.13

01 -10

Propargylic+Amine+2q:+13C$NMR$(101$MHz,$CDCl3)$

O O

Me

020

S93$ S95

Propargylic+Amine+2r:+1H$NMR$(400$MHz,$CDCl3)$ O HN

O

0.924

0.924

1011-20.019

910

89

1.488 1.194 1.192 1.189 1.182 1.179 1.174 1.167 1.159 1.156 1.147 1.142 0.540 0.528 0.520 0.513 0.497 0.485 0.478 0.472

4.191 4.186

2.07 2.071.87 1.87

4.17 4.17 ppm-1

4.599 4.496

4.837

7.394 7.387 7.385 7.382 7.380 7.375 7.364 7.361 7.358 7.348 7.340 7.338 7.336 7.326

O

1.071.07

0.946 0.946 1.041.04 78

67

9

56

45

34

9

23

4.24 4.24

12

01

-10

Propargylic+Amine+2r:+13C$NMR$(101$MHz,$CDCl3)$ O HN

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

2040

2.827 1.710

15.371

28.371

45.742

57.328

71.479

78.838

83.956

128.438 128.153 127.887

137.394

154.828

O

020

S94$ S96

Allylic&Amine&10b:&1H$NMR$(400$MHz,$CDCl3)$ H N

2.07 2.07 1.13 1.13 ppm-1

1011-20.019

910

89

78

67

3 3

1.04 1.04 0.9780.978

56

1.243 1.226

1.471

4.244

4.485

O 5.880 5.867 5.854 5.841 5.838 5.825 5.811 5.799 5.191 5.187 5.183 5.147 5.144 5.094 5.091 5.088 5.068 5.065 5.062

Me

O

99 45

34

23

12

01

-10

Allylic&Amine&10b:&13C$NMR$(101$MHz,$CDCl3)$ H N

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

20.709

28.415

48.170

79.469

113.574

116.377

O 140.166

Me

O

2040

020

S95$ S97

Allylic&Amine&10c:&1H$NMR$(400$MHz,$CDCl3)& H N

O

0.902 0.902

1

1

0.9960.996 1 1 ppm-1

1011-24.987

910

89

1.460

5.359 5.273 5.270 5.230 5.228 5.208 5.205 5.202 4.996

7.297 7.291 7.290 7.284 7.279 7.277 7.272 7.121 7.119 7.116 7.023 7.020 7.011 7.008 7.005

6.057 6.043 6.032 6.015 6.000 5.989 5.975

O

S

9.34 9.34

2.32 2.32 0.949 0.949 1.021.02

78

67

56

45

34

23

12

01

-10

Allylic&Amine&10c:&13C$NMR$(101$MHz,$CDCl3)$ H N

O

200-238.855

180200

160180

140160

120140

100120

80100

6080

28.403

52.549

79.651

115.350

121.550

126.723 126.193

137.566

155.042

ppm0

142.208

O

S

4060

2040

020

S96$ S98

Allylic&Amine&10d:&1H$NMR$(400$MHz,$CDCl3)& H N

O O

2.03

2.03

2 2 ppm-1

1011-20.019

910

89

67

1.459

3.803

3.03 3.03 0.9350.935

78

5.276 5.248 5.244 5.238 5.234 5.209 5.206 4.936

6.036 6.023 6.011 5.997 5.993 5.980 5.968 5.955

7.238 7.233 7.221 7.216 6.903 6.895 6.890 6.879 6.873 6.866

OMe

3.123.12

9.14 9.14

0.904 0.904 56

45

34

23

12

01

-10

Allylic&Amine&10d:&13C$NMR$(101$MHz,$CDCl3)$ H N

O O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.396

56.043 55.245

79.547

115.073 113.989

128.236

133.216

138.199

155.031

158.931

OMe

4060

2040

020

S97$ S99

Allylic Amine 10e: 1H NMR (400 MHz, CDCl3) H N

O O

2.1 2.1

1011-20.019

910

89

1.453

0.9020.902 1.061.06

2.122.12 ppm-1

5.363 5.281 5.256 5.241 5.198 5.111 5.093

6.018 6.004 5.992 5.976 5.961 5.949 5.935

7.622 7.601 7.442 7.422

CF3

1 1 78

67

9.01 9.01

2.262.26 56

45

34

23

12

01

-10

Allylic Amine 10e: 13C NMR (101 MHz, CDCl3) H N

O O

ppm0

!

200-258.727

180200

160180

140160

120140

100120

80100

6080

28.294

56.356

80.014

137.122 130.128 129.802 129.480 129.164 128.151 127.253 125.562 125.520 125.489 122.738 120.038 116.641

145.246

154.981

CF3

4060

2040

020

SS98! 100

Allylic Amine 10e: 19F NMR (377 MHz, CDCl3) H N

O O

-62.504

CF3

ppm-180

!

80100-301.749

6080

4060

2040

-020

-20-0

-40-20

-60-40

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

SS99! 101

ppm0

200-258.727

180200 89

160180 78

140160 67 56

120140

100120 1.01 1.01 9.469.46

45

80100 34 23

6080 12

4060

2040 2.673

H N 910 0.9440.944

15.560

2.11 2.11

28.352

1 1

56.319

1011-20.019

79.172

ppm-1

114.367

1.431 0.894 0.882 0.874 0.870 0.862 0.854 0.849 0.841 0.833 0.829 0.821 0.809 0.526 0.518 0.508 0.504 0.496 0.491 0.487 0.483 0.479 0.475 0.471 0.468 0.462 0.459 0.448 0.426 0.397 0.385 0.375 0.363 0.351 0.273 0.260 0.250 0.237 0.228 0.224 0.216

3.577

5.838 5.825 5.812 5.799 5.795 5.782 5.769 5.756 5.211 5.207 5.203 5.168 5.164 5.160 5.090 5.086 5.082 5.064 5.060 5.056 4.701

H N

137.869

155.319

Allylic Amine 10f: 1H NMR (400 MHz, CDCl3) O

O

1.051.05 1.311.31 1.15 2.16 2.16 1.15 01 -10

Allylic Amine 10f: 13C NMR (101 MHz, CDCl3)

O

O

020

SS100$ 102

γ!Amino'enone'3a:'1H$NMR$(400$MHz,$CDCl3)$ Me

S

O

H N

O

1.01 1.01 1.04 1.04 1 1 1.011.01 ppm-1

1011-20.019

910

89

0.911 0.911

1.89 1.89

78

3

S

O

H N

3

9.01 9.01

2.09 2.09 67

56

45

" γ!Amino'enone'3a:'13C$NMR$(101$MHz,$CDCl3)$ Me

1.482

2.459

4.021

4.828

7.641 7.624 7.490 7.469 7.451 7.375 7.355 7.234 7.215 7.196 6.862 6.860 6.853 6.852 6.849 6.848 6.845 6.844 6.822 6.813 6.803 6.762

O

34

23

12

01

-10

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

16.350

28.353

41.776

79.937

131.645 129.706 127.912 126.073 123.966

136.305

140.849

145.563

155.596

182.051

O

2040

020

S103 S101$

γ-Amino enone 3a’: 1H NMR (400 MHz, CDCl3) O

1.94

1.94

1.061.06

1 10.982 0.982 ppm-1

1011-20.019

910

89

0.799 0.799 1.08 1.08

78

67

1.469

2.453

4.145 4.130

O

7.473 7.469 7.455 7.453 7.451 7.449 7.435 7.431 7.401 7.399 7.381 7.239 7.236 7.221 7.218 7.202 7.199

N H

5.109

O

5.689

S

6.125

Me

2.982.98

9.15 9.15

2.162.16 56

45

34

23

12

01

-10

γ-Amino enone 3a’: 13C NMR (101 MHz, CDCl3) O

ppm0

200-258.727

180200

160180

140160

100120

80100

6080

4060

17.029

28.384

79.409 120140

41.504

O

155.898

198.043

N H

130.979 129.321 129.273 127.520 124.565

O

138.376 137.874

S

145.378

Me

2040

020

S104 S102%

γ-Amino enone 3a-CBz: 1H NMR (400 MHz, CDCl3) Me

S

O

H N

O

1.02 1.02 1.03 1.03 0.9670.967 5.725.72 ppm-1

1011-20.019

910

89

2.448

4.100 4.091 4.086 4.077

5.156

7.623 7.604 7.492 7.489 7.472 7.470 7.469 7.454 7.450 7.381 7.372 7.352 7.222 7.204 7.185 6.875 6.865 6.836 6.826 6.815 6.776

O

3 3

3 3

1.96 1.96

1.96 1.96

78

67

56

45

34

23

12

01

-10

γ-Amino enone 3a-CBz: 13C NMR (101 MHz, CDCl3) Me

S

O

H N

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

16.318

42.192

67.069

136.275 136.115 131.742 129.797 128.581 128.262 128.192 127.910 126.006 123.964

140.984

144.861

156.222

192.270

O

4060

2040

020

S105 xx"

γ-Amino enone 3a’-CBz: 1H NMR (400 MHz, CDCl3) O

7.16 7.16

1

1

1.19 1.19 1.25 1.25 1011-20.019

910

89

78

67

2.427

4.225 4.209

0.979 0.979 1.05 1.05

2.262.26

3.07 3.07

2.112.11 56

45

γ-Amino enone 3a’-CBz: 13C NMR (101 MHz, CDCl3)

01

-10

180200

160180

140160

120140

100120

80100

6080

4060

17.098

O

156.410

200-258.727

12

O N H

ppm0

23

66.760

O

138.231 137.835 136.494 130.982 129.923 129.875 129.084 128.516 128.105 128.043 127.658 124.647

S

144.954

Me

34

41.913

ppm-1

5.146

O

7.471 7.468 7.451 7.448 7.433 7.430 7.396 7.388 7.377 7.356 7.349 7.234 7.216 7.198

N H

5.386 5.374 5.360

O

5.712

S

6.158

Me

2040

020

S106 xx"

! γ-Amino enone 3a-Ts: 1H NMR (500 MHz, CDCl3) Me H N

S O

7.796 7.780 7.571 7.556 7.499 7.484 7.468 7.369 7.353 7.344 7.327 7.222 7.207 7.192 6.855 6.824 6.745 6.736 6.726 6.715 6.705 6.695

O

1.1 1.1 3.023.02

1.141.14

2.072.07 1.121.12 1.151.15 ppm-1

910-20.649

89

2.459 2.436

O

3.902 3.892 3.882

S

4.695 4.683 4.670

Me

1.07 1.07

1.231.23

3 3 3.04 3.04

2.1 2.1

78

67

56

45

34

23

12

01

-10

γ-Amino enone 3a-Ts: 13C NMR (125 MHz, CDCl3) Me S

ppm0

200-248.384

143.922 142.441 141.419

O

191.434

O

180200

160180

140160

120140

100120

80100

6080

4060

16.281

H N

21.563

O

44.287

S

136.751 135.597 131.967 129.915 129.719 128.694 127.146 125.891 123.908

Me

2040

020

S107 xx!

γ-Amino enone 3a’-Ts: 1H NMR (400 MHz, CDCl3) Me

S

O

O N H

O S

0.991.91 0.99 1.03 1.91 1.03 1.88 1.88 1.05 1.05 0.853 0.853 ppm-1

1011-20.019

910

89

78

1.01 1.01 1

1 67

2.458 2.433

4.010 3.994

5.193 5.177 5.161

5.684

7.804 7.799 7.787 7.783 7.463 7.458 7.445 7.442 7.441 7.438 7.425 7.421 7.377 7.359 7.345 7.343 7.324 7.322 7.186 7.183 7.167 7.164 7.149 7.146 7.134 7.129 7.115 7.114 7.110 6.153

Me

3.02 3.02

2.042.04 0.994 0.994 56

3.093.09 45

34

23

12

01

-10

γ-Amino enone 3a’-Ts: 13C NMR (101 MHz, CDCl3) Me

S

O

O N H

O S Me

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

16.950

21.550

44.237

139.398 138.503 137.171 137.058 131.213 131.172 129.780 129.133 127.459 127.206 124.426

143.498

197.636

"

2040

020

S108 xx"

γ!Amino'enone'3b:'1H%NMR%(400%MHz,%CDCl3)% H N O 7.652 7.649 7.633 7.629 7.479 7.476 7.459 7.456 7.441 7.437 7.366 7.346 7.223 7.220 7.204 7.201 7.185 7.182 6.813 6.774 6.767 6.728

Me

O

1.01 1.01 1.06 1.06 1 1 1.011.01 ppm-1

1011-20.019

910

89

0.8560.856

2.01 2.01

78

1.467 1.325 1.307

O

2.448

S

4.651 4.488 4.487 4.486 4.485 4.473 4.468

Me

3.06 3.06

3.063.06

1.091.09 67

56

9.159.15 45

34

23

12

01

-10

γ!Amino'enone'3b:'13C%NMR%(101%MHz,%CDCl3)% H N

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

16.350

20.369

28.369 27.307

47.464

126.591 126.022 123.933

131.666 129.828

O 154.947

192.726

Me

O

136.333

O

140.930

S

149.892

Me

2040

020

S109 S103%

ppm0

200-258.727

O

180200 89

H N

160180 78

140160 0.916 0.916 0.957 0.957

67

120140 56

100120 45

80100 34 23

6080

4060

16.382

910 1

30.325 28.361

2.092.09 1.07 1.07 0.9860.986

55.883

1011-20.019

80.179

1.04 1.04 5.095.091

131.746 129.885 129.021 128.169 127.286 126.092 123.984

S 1.482

2.455

5.028 5.017

H N

136.237

ppm-1

O

141.059 139.286

Me S

147.403

7.678 7.674 7.659 7.655 7.516 7.492 7.488 7.471 7.470 7.468 7.463 7.453 7.450 7.391 7.387 7.382 7.375 7.370 7.368 7.357 7.355 7.349 7.346 7.333 7.328 7.317 7.313 7.234 7.232 7.215 7.213 7.197 7.194 7.016 7.003 6.977 6.964 6.889 6.885 6.850 6.847 5.550

Me

154.825

192.423

!

γ-Amino enone 3c: 1H NMR (400 MHz, CDCl3) O

O

3.033.03 9.11 9.11

12 01

2040

-10

γ-Amino enone 3c: 13C NMR (101 MHz, CDCl3)

O

O

020

S110 S104!

γ-Amino enone 3d: 1H NMR (400 MHz, CDCl3) Me

S

O

H N

O

1.02 1.02 1 1 1 ppm-1

1011-20.019

910

0.9850.985

78

9.219.21

1.01 1.01 67

56

3.093.09 45

0.986

1.479

2.467

0.936 0.936

1 0.999 0.999 1.01 1.01

89

4.207 4.176

4.697 4.672

7.689 7.686 7.670 7.667 7.501 7.497 7.481 7.479 7.463 7.459 7.384 7.365 7.247 7.244 7.228 7.226 7.210 7.207 6.935 6.921 6.897 6.882 6.849 6.847 6.811 6.808

O

34

23

9.04 9.04 12

01

-10

γ-Amino enone 3d: 13C NMR (101 MHz, CDCl3) Me

S

O

H N

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

16.367

28.385 26.473 25.354

35.048

60.506

79.699

131.700 129.828 128.637 126.003 123.937

141.100

146.505

155.423

192.251

O

2040

020

S111 S105%

ppm0

200-258.727

180200

160180

140160

67

120140

1.11.1

56

100120

2.182.18 3.12 3.12

45

80100

34 23

6080

4060

2040

14.112

Hex Me 1.021.02

16.887

H N 78 1

22.635 21.009

O 89 1

31.668 29.646 29.172 28.368 26.553

1.06 1.02 1.06 1.02

45.082

1.04 1.04 1.061.06

68.556

910

99.982

1011-20.019

124.460

2.561 2.559 2.546 2.531 2.524 2.509 2.502 2.501 2.500 2.492 2.442 1.612 1.599 1.594 1.583 1.578 1.574 1.570 1.568 1.562 1.561 1.560 1.554 1.539 1.505 1.502 1.502 1.491 1.482 1.479 1.456 1.405 1.390 1.372 1.353 1.339 1.330 1.322 1.305 1.247 1.230 0.925 0.908 0.891

4.469

4.609

5.868 5.846

Hex Me

130.443 129.290 127.151

S

H N

138.797

ppm-1

O

141.905

Me S

146.707

7.440 7.436 7.422 7.420 7.418 7.416 7.402 7.398 7.366 7.364 7.347 7.344 7.324 7.307 7.206 7.203 7.188 7.185 7.169 7.166

Me

167.824

198.838

γ!Amino'enone'3e:'1H%NMR%(400%MHz,%CDCl3)% O

O

3.07 1.981.98 6.196.19 3.07 9.53 9.53 3.123.12 12 01 -10

γ!Amino'enone'3e:'13C%NMR%(101%MHz,%CDCl3)%%

O

O

020

S112 S106%

γ!Amino'enone'3f:'1H%NMR%(400%MHz,%CDCl3)% Me

S

O

H N

O

1.09 1.09

1.05 1.05 1 1 ppm-1

1011-20.019

910

89

3

1.479

2.456

0.936 0.936

0.9080.908 78

4.017

7.527 7.507 7.443 7.439 7.342 7.338 7.322 7.317 6.877 6.867 6.855 6.838 6.828 6.818 6.779 6.740

1.02 1.02

4.844

O

Br

3

9.28 9.28

2.14 2.14 67

56

45

34

23

12

01

-10

γ!Amino'enone'3f:'13C%NMR%(101%MHz,%CDCl3)% Me

S

O

H N

180200

160180

140160

120140

100120

80100

6080

4060

16.255

28.354 27.421

41.789

79.974

131.068 128.249 127.262 126.827

134.384

155.602

191.321

200-258.727

145.972 143.837

O

Br

ppm0

O

2040

020

S113 S107%

γ!Amino'enone'3g:'1H%NMR%(400%MHz,%CDCl3)% Me

O

S

H N

O

1

1

1.05 1.05 ppm-1

1011-20.019

910

89

78

2.07 2.07 0.959 0.959

67

56

1.464

2.130

2.904 2.901 2.884 2.867 2.793 2.775 2.758 2.755

3.959

4.841

6.236 6.196

6.840 6.828 6.816 6.800 6.788 6.776

O

2.982.98 4.084.08

45

34

23

9.14 9.14 12

01

-10

γ!Amino'enone'3g:'13C%NMR%(101%MHz,%CDCl3)% Me

S

O

H N

O

ppm0

200-248.384

180200

160180

140160

120140

100120

80100

6080

4060

15.877

41.530 40.113

80.057

129.232

143.436

155.629

198.057

O

2040

020

S114 S108%

γ!Amino'enone'3h:'1H%NMR%(400%MHz,%CDCl3)% Me

S

O

H N

O

1

1

1011-20.019

910

89

2.491 2.476 2.461 2.424 2.409 2.394 2.256 1.760 1.756 1.755 1.746 1.741 1.724 1.712 1.710 1.705 1.696 1.695 1.690 1.478

2.042.04

11 ppm-1

3.971

4.722

6.834 6.821 6.809 6.795 6.783 6.770 6.561 6.522

O

2.172.17

0.968 0.968

78

67

56

2.08 2.08 3.023.02 45

34

4.094.09 9.14 9.14

23

12

01

-10

γ!Amino'enone'3h:'13C%NMR%(101%MHz,%CDCl3)% Me

S

O

H N

O

ppm0

200-248.384

180200

160180

140160

120140

100120

80100

6080

4060

2040

14.976

23.035 21.918

29.893 28.398 28.258

41.831

79.808

127.886

132.452

142.772

145.175

155.624

192.798

O

020

S115 S109%

γ!Amino'enone'3i:'1H$NMR$(400$MHz,$CDCl3)$ S

O

H N

S

O

1.08 1.08 1.01 1.01 1 1 ppm-1

1011-20.019

910

0.931 0.931

78

1.491

2.563

9.24 9.24

2.162.16

1.061.06

89

4.023

4.841

7.608 7.595

O 7.086 7.073 7.064 7.051 7.026 7.014 7.001 6.815 6.810 6.773

Me

67

3.123.12

56

45

34

23

12

01

-10

γ!Amino'enone'3i:'13C$NMR$(101$MHz,$CDCl3)$ O

H N

S

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

16.699

23.851

28.386

83.541

110.516

128.611 126.386 125.045

131.330

O 180.925

ppm0

O

143.687

S

155.649

Me

2040

020

S116 S110$

γ!Amino'enone'3j:'1H#NMR#(400#MHz,#CDCl3)# Me

N

Me O

H N

O

1.14 1.14 1.03 1.04 1.03 1.04 1 1 ppm-1

1011-20.019

910

78

1.469

2.798

9.03 9.03

2.21 2.21

1.17 1.17 1.141.14

89

3.982

4.808

7.472 7.468 7.453 7.449 7.403 7.399 7.385 7.382 7.380 7.378 7.364 7.360 7.001 6.999 6.980 6.979 6.946 6.943 6.927 6.925 6.887 6.875 6.864 6.844 6.841 6.838 6.805 6.802 6.799

O

1.16 1.16 67

56

6.3 6.3 45

34

23

12

01

-10

γ!Amino'enone'3j:'13C#NMR#(101#MHz,#CDCl3)# Me

N

Me O

H N

O

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

2040

14.202

21.057

28.376

41.616

44.244

79.691

116.719

119.768

131.976 130.508 128.951

142.669

152.140

194.673

O

020

S117 S111#

ppm0

200-258.727

180200

160180

140160 0.926 0.926

67 56

120140

100120 45

80100 34 23

6080

4060

15.485

78

27.436

89

83.101

910 1.03 1.03

110.521

Me 1011-20.019 1 1 2.072.07

114.353

1.11 1.02 1.111.02

124.743 124.322 121.664

ppm-1

134.120 131.944 130.334 128.331

1.283

2.377

Me

139.887

149.142

7.451 7.447 7.443 7.439 7.373 7.369 7.354 7.353 7.351 7.349 7.334 7.331 7.262 7.259 7.258 7.250 7.247 7.244 7.240 7.240 7.231 7.228 7.202 7.199 7.183 7.180 7.165 7.162 6.316 6.308 6.300 6.190 6.186 6.182 6.178

Pyrrole'4a:'1H$NMR$(400$MHz,$CDCl3)$ S N Boc

3.053.05 9.02 9.02

12 01

2040 -10

Pyrrole'4a:'13C$NMR$(101$MHz,$CDCl3)$

S N Boc

020

S118 S112$

ppm0

200-258.727

910

N Boc

180200

89

160180

140160

0.996 0.996

78 1

120140

3.183.18

67 56

100120

45

80100

34 23

6080

4060

15.767 15.277

Me 1011-20.019 1

27.326

2.19 2.19

82.786

1.09 1.09 1.07 1.07

112.663 110.531

ppm-1

124.301 124.254

1.221

2.532 2.530 2.375

N Boc

135.038 132.846 131.802 130.227 127.928

Me

139.429

149.821

7.352 7.348 7.334 7.332 7.329 7.328 7.314 7.310 7.246 7.245 7.242 7.241 7.226 7.223 7.222 7.220 7.202 7.200 7.188 7.185 7.170 7.167 7.152 7.148 6.073 6.065 6.048 6.046 6.043 6.041 6.038 6.035 6.033

Pyrrole 4b: 1H NMR (400 MHz, CDCl3) S Me

3.083.08

9.26 9.26

12 01

2040

-10

Pyrrole 4b: 13C NMR (101 MHz, CDCl3)

S Me

020

S11 9 S113$

Pyrrole'4c:'1H$NMR$(400$MHz,$CDCl3)$ Me

S tBu

ppm-1

1011-20.019

910

0.988 1.01 1.01 0.988

0.893 0.893

1.071.07 0.992 0.992

1

89

78

1

9.129.12 9.19 9.19

3.063.06

67

56

45

34

1.147

1.475

2.362

7.348 7.344 7.330 7.328 7.326 7.324 7.310 7.306 7.252 7.251 7.248 7.247 7.232 7.229 7.215 7.213 7.195 7.193 7.169 7.166 7.150 7.147 7.132 7.129 6.112 6.103 6.096 6.087

N Boc

23

12

01

-10

Pyrrole'4c:'13C$NMR$(101$MHz,$CDCl3)$ Me

S tBu

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

15.245

26.977

30.358

33.089

83.070

107.435

111.005

124.142 124.050

127.997

130.586

134.184

139.621

147.025 144.879

151.274

N Boc

2040

020

S1 20 S114$

ppm0

200-258.727 910

N Boc

180200 89 2.04 2.04 2.04 1.07 2.04 1.07 3.053.05 1.071.07

160180 78

140160 1

0.973 0.973 1

67

120140 56

100120 45

80100 34 3.083.08

23

6080

4060

15.419

Me 1011-20.019

27.116

ppm-1

83.243

1.164

2.420

N Boc

112.887 112.615

Me

139.846 136.034 134.471 133.874 133.634 130.633 128.770 128.461 127.744 127.017 124.552 124.330

149.207

7.475 7.471 7.466 7.457 7.454 7.451 7.446 7.434 7.431 7.418 7.413 7.409 7.398 7.395 7.394 7.376 7.371 7.367 7.363 7.359 7.356 7.349 7.340 7.336 7.287 7.284 7.267 7.264 7.252 7.249 7.234 7.230 7.215 7.212 6.335 6.327 6.255 6.247

Pyrrole 4d: 1H NMR (400 MHz, CDCl3) S Ph

9.08 9.08 12 01

2040 -10

Pyrrole 4d: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 21 S115$

Pyrrole'4e:'1H$NMR$(400$MHz,$CDCl3)$ S

ppm-1

1011-20.019

910

89

1

1

9.19 9.19

3.163.16

1.011.01

78

1.150

2.404

7.393 7.386 7.370 7.365 7.355 7.351 7.330 7.326 7.311 7.308 7.261 7.242 7.227 7.209 7.190 6.955 6.934 1.08 1.12 1.08 1.12 3.163.16 1.121.12 2.13 2.13

3.871

OMe

N Boc

6.258 6.250 6.219 6.211

Me

3.043.04

67

56

45

34

23

12

01

-10

Pyrrole'4e:'13C$NMR$(101$MHz,$CDCl3)$ S

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

15.372

27.136

55.276

83.101

113.184 112.850 112.144

135.923 134.073 133.160 130.570 130.049 128.327 126.954 124.459 124.271

139.777

OMe

158.794

N Boc

149.283

Me

2040

020

S1 22 S116$

ppm0

200-258.727

N Boc

180200

89

160180

140160

0.942 0.942

78 67 3

56

120140

100120

45

80100

34 23

6080

4060

15.324

910

27.104

Me 1011-20.019 0.9810.981

84.002

2.02 2.02 1.05 1.02 1.05 1.02

110.262

ppm-1 1.971.97 1.031.03 1.021.02

114.521 113.389

1.149

2.408

N Boc

119.091

Me

139.840 138.846 135.229 134.140 133.372 131.565 130.508 129.008 128.755 124.460 124.349

148.922

7.691 7.687 7.686 7.682 7.670 7.665 7.661 7.544 7.540 7.535 7.523 7.520 7.519 7.514 7.419 7.415 7.401 7.399 7.397 7.395 7.381 7.377 7.313 7.309 7.294 7.264 7.247 7.239 7.236 7.220 7.217 7.202 7.199 6.402 6.394 6.252 6.244

Pyrrole 4f: 1H NMR (400 MHz, CDCl3) S CN

3 9.09 9.09

12 01

2040

-10

Pyrrole 4f: 13C NMR (101 MHz, CDCl3)

S CN

020

S1 23 S117$

ppm0

200-258.727

N Boc

180200

89

160180

140160

0.9170.917 2.182.18

78 67

120140

56

100120

45

80100

34

6080

6.2 6.2

23

4060

15.118 14.124

3.15 3.04 3.153.04

22.604

910

31.668 30.231 29.064 27.107 25.731

1011-20.019

82.691

2.062.06 1.051.05

113.879

ppm-1

135.261 134.645 132.939 131.313 129.481 128.468 128.377 127.696 126.754 126.181 124.124 124.081

2.310 2.292 2.289 2.286 2.280 2.274 2.257 2.253 2.236 2.222 2.218 2.212 2.200 2.197 2.179 2.163 1.565 1.557 1.548 1.539 1.310 1.294 1.291 1.277 1.274 1.258 1.249 1.241 1.127 0.898 0.881 0.863

N Boc

140.807

149.363

7.454 7.451 7.433 7.430 7.409 7.407 7.405 7.396 7.394 7.389 7.387 7.383 7.376 7.372 7.369 7.368 7.367 7.336 7.332 7.328 7.314 7.291 7.286 7.285 7.282 7.281 7.267 7.263 7.247 7.246 7.244 7.239 7.236 7.222 7.218 7.203 7.200 6.256

Pyrrole'4g:'1H$NMR$(400$MHz,$CDCl3)$ Me Hex S Ph

2.232.23 9.04 9.04

3 3

12 01

2040

-10

Pyrrole'4g:'13C$NMR$(101$MHz,$CDCl3)$

Me Hex S Ph

020

S1 24 S118$

ppm0

200-258.727

180200

160180

140160

120140 56

100120 45

80100 34 3.09 3.09 2.2 2.2

1.061.06

23

6080 12

4060

2040

9.813 7.224 6.906

1 1

15.007 14.077

1.06 1.06 1.99 1.99

22.557

67

31.620 30.199 29.030 27.357 25.731

1.08 1.08

82.170

78

108.982

89

130.978 127.812 127.556 125.506 123.987

910

133.855

1011-20.019

140.380 138.389

ppm-1

145.147

149.763

2.348 2.329 2.327 2.316 2.314 2.303 2.300 2.295 2.293 2.181 2.179 2.170 2.164 2.152 2.147 2.142 2.125 2.112 2.094 2.091 2.073 1.461 1.448 1.447 1.446 1.443 1.429 1.409 1.270 1.254 1.247 1.246 1.204 0.935 0.934 0.919 0.911 0.906 0.899 0.893 0.890 0.885 0.880 0.872 0.867 0.850 0.832 0.753 0.744 0.740 0.735 0.731 0.727 0.725 0.721 0.717 0.639 0.633 0.628 0.625 0.623 0.620 0.615 0.610 0.605 0.597 0.592 0.583 0.493 0.481 0.478 0.474 0.458 0.454 0.441

5.851

7.342 7.332 7.329 7.322 7.320 7.313 7.309 7.300 7.203 7.183 7.173 7.165 7.163 7.156 7.155 7.152 7.150

Pyrrole 4h: 1H NMR (400 MHz, CDCl3) Me Hex S N Boc

6.16.1 6.036.03 1.1 1.1 0.843 9.02 9.02 1.121.12 0.843 01 -10

Pyrrole 4h: 13C NMR (101 MHz, CDCl3)

Me Hex S N Boc

020

S1 25 S119$

ppm0

N Boc

200-258.727

180200 89

160180 78

140160 3.033.03

67 56

120140

100120 3

45

80100 3.02 3.02 2.182.18

34 23

6080

4060

2040

14.093

MeO 910 3

17.085

1011-20.019 0.985 0.985

31.715 30.310 29.711 29.189 27.215 25.873 22.604

1.08 1.08 1.01 1.01

56.081

ppm-1 1.041.04

82.770

4.064.06

114.884 113.565 111.154

2.348 2.312 2.303 2.295 2.291 2.276 2.260 2.255 2.238 2.219 2.201 2.198 2.180 2.164 2.144 1.564 1.547 1.545 1.530 1.527 1.520 1.514 1.511 1.506 1.502 1.498 1.490 1.481 1.311 1.304 1.288 1.277 1.271 1.257 1.249 1.244 1.239 1.227 1.154 0.891 0.874 0.856

3.975 3.886

6.227

MeO N Boc

134.962 134.724 130.979 129.766 128.407 127.712 126.837 126.733 126.086

149.457 148.935 146.818

7.431 7.427 7.410 7.406 7.402 7.394 7.392 7.374 7.370 7.359 7.355 7.324 7.320 7.316 7.309 7.302 7.296 7.289 7.285 6.921 6.836

Pyrrole'4i:'1H%NMR%(400%MHz,%CDCl3)% Me Hex S Ph

OMe

2.082.08 9.079.07 3.08 6.366.36 3.08 12 01 -10

Pyrrole'4i:'13C%NMR%(101%MHz,%CDCl3)%

Me Hex S Ph

OMe

020

S1 26 S120%

Pyrrole'4j:'1H$NMR$(400$MHz,$CDCl3)$ S

ppm-1

1011-20.019

910

1.311.31

89

0.970.97 1

1.162 9.12 9.12

3.193.19

1

78

2.257

8.078 8.057

2.01 2.01 2.01 2.01 2.04 2.04

3.976 3.956

CO2Me

N Boc

6.361 6.352 6.184 6.176

MeO

7.508 7.487 7.354 7.335 7.334 7.314 7.291 7.043 7.040 7.024 7.021 6.987 6.984 6.966

Me

3.243.24 67

56

45

2.972.97 34

23

12

01

-10

Pyrrole'4j:'13C$NMR$(101$MHz,$CDCl3)$ S

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

17.866

27.215

52.073

56.042

83.857

113.674 112.730 110.782

134.422 130.428 130.002 129.686 129.101 128.344 128.217 123.373 122.978 120.779

CO2Me

N Boc 159.594

MeO

140.074 139.240

Me

2040

020

S1 27 S121$

ppm0

200-248.384 910

N H

180200 89 1.08 1.081.071.07 1.04 1.04

1.12 1.04 1.121.04

160180 78 1

140160 1.03 1.03

0.964 1 0.964 67

120140 56 3.043.04

100120 45

80100 34

6080 16.506

Me 1011-20.019

53.280

1.13 1.13

2.517

4.027

N H

139.648 139.276 132.610 131.991 130.232 128.296 128.034 127.776 127.685 127.517 127.327 125.309 125.279 125.250 125.164 123.591 123.561 123.531 123.502 123.001 120.840 111.955 110.812 107.961 107.561

ppm-1

7.764 7.762 7.761 7.759 7.757 7.756 7.610 7.591 7.590 7.571 7.503 7.501 7.498 7.496 7.482 7.481 7.479 7.477 7.476 7.446 7.425 7.222 7.220 7.203 7.201 6.797 6.791 6.788 6.781 6.672 6.665 6.663 6.656 6.593 6.591 6.572 6.570

Me

147.573

163.540

10.420

Pyrrole'4k:'1H$NMR$(400$MHz,$CDCl3)$ S N OMe

CF3

3.07 3.07 23 12

4060 01

2040

-10

Pyrrole'4k:'13C$NMR$(101$MHz,$CDCl3)$

S N OMe

CF3

020

S1 28 S122$

Pyrrole'4k:'19F%NMR%(377%MHz,%CDCl3)% Me

S N H

N OMe

CF3 -62.496

%

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

%

S1 29 S123%

ppm0

200-258.727

180200

160180

140160 1 3.13 3.13

2.052.05

67

120140 56

100120 45

80100 34 23

6080

4060 15.292 14.124

2.06 1.13 2.06 1.13 1.03 1.03

22.588

78

31.634 29.757 28.995 27.104 25.873

N Boc 89 1

82.769

3.09 3.09 1.071.07

114.162 111.336 111.114

F 910

129.701 129.607 128.485 127.676 126.843 122.274 120.556 120.367 119.217 118.175

1011-20.019

136.428 134.565

' Pyrrole'4l:'13C%NMR%(101%MHz,%CDCl3)% ppm-1

143.600

1.556 1.542 1.539 1.529 1.522 1.511 1.490 1.301 1.287 1.269 1.252 1.243 1.234 1.217 1.207 1.148 0.892 0.875 0.856

7.457 7.453 7.448 7.439 7.436 7.433 7.406 7.403 7.399 7.390 7.385 7.382 7.376 7.370 7.366 7.355 7.349 7.337 7.335 7.333 7.329 7.321 7.315 7.309 7.297 7.289 7.033 7.014 6.965 6.963 6.944 6.942 6.923 6.921 6.288

F N Boc

149.114

162.176 159.737

Pyrrole'4l:'1H%NMR%(400%MHz,%CDCl3)% Me Hex S Ph

2.162.16 9.169.16

3.27 6.236.233.27

12 01

2040 -10

Me Hex S Ph

020

S1 30 S124%

Pyrrole'4l:%19F%NMR%(377%MHz,%CDCl3)% % Me Hex S Ph

-112.317

F

N Boc

ppm-200

80100-301.749 6080

4060

2040

-020

-20-0

-40-20

-60-40

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

%

-200-180

S1 31 S125%

ppm0

200-248.384

910

N Boc

180200

89 1 1 3.08 3.08 2.93 2.93

160180

78 0.9370.937

140160

0.912 0.912

67

120140

56

100120

45

80100

34 2.952.95

23

6080

4060

14.923

Me 1011-20.019

27.082

ppm-1

1.144

2.455

N Boc

6.321 6.312 6.271 6.262

Me

83.902

148.789 145.311 135.461 133.688 133.043 132.111 130.915 130.419 127.843 127.450 127.160 127.131 127.101 127.072 126.724 126.464 126.205 125.943 125.359 125.290 125.089 125.058 125.027 124.978 123.391 121.371 113.728 113.283

7.630 7.628 7.625 7.623 7.609 7.608 7.604 7.603 7.542 7.537 7.525 7.520 7.514 7.325 7.319 7.314 7.302 7.297 7.289 7.282

Pyrrole'4m:'1H%NMR%(400%MHz,%CDCl3)% S Br

CF3

9.12 9.12 12 01

2040

-10

Pyrrole'4m:'13C%NMR%(101%MHz,%CDCl3)%

S Br

CF3

020

S1 32 S126%

Pyrrole 4m: 19F NMR (377 MHz, CDCl3) Me

S N Boc

Br

-62.141

CF3

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

%

S1 33 S127%

Pyrrole'4n:'1H%NMR%(400%MHz,%CDCl3)% Me

S

2.07 2.07 3.073.07 1.04 1.04 ppm-1

1011-20.019

910

89

1

1

1.207

7.356 7.353 7.343 7.340 7.329 7.325 7.323 7.163 7.142 7.139 7.133 7.130 7.077 7.068 7.064 7.055 6.409 6.400 6.217 6.209

Br

2.412

N S Boc

3.043.04

9.02 9.02

1.021.02

78

67

56

45

34

23

12

01

-10

Pyrrole'4n:'13C%NMR%(101%MHz,%CDCl3)% Me

S

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

15.327

27.182

83.798

114.573 113.253

134.897 132.737 132.368 131.669 128.390 127.466 127.210 126.736 126.562 125.550 122.546

148.758

Br

142.191

N S Boc

2040

020

S1 34 S128%

Pyrrole'4o:'1H%NMR%(400%MHz,%CDCl3)% Me

S

2.02 2.02

1

0.9340.934 11 ppm-1

1011-20.019

910

89

1

3.163.16

78

67

56

45

34

23

12

01

-10

S

180200

160180

140160

120140

100120

80100

6080

4060

15.383

27.497

83.481

110.657

114.685

127.145 126.795 126.307 122.406 121.996

132.639 131.534

148.903 200-258.727

142.556

N Boc

Br

ppm0

9.11 9.11

0.944 0.944

' Pyrrole'4o:'13C%NMR%(101%MHz,%CDCl3)% Me

1.331

2.390

7.439 7.434 7.430 7.426 7.318 7.313 7.312 7.307 7.297 7.292 7.111 7.104 7.096 7.090

Br

6.308 6.300 6.291 6.179 6.175 6.171 6.167

N Boc

2040

020

S1 35 S129%

ppm0

Me

Br

200-248.384 910

180200 89

160180 1.13 1.13

140160 11

78 2

67

120140 56

100120 45

80100 2 1.181.18 3.133.13

34

6080 9.039.03

23

4060 9.261 6.924

1011-20.019

29.740 27.652 25.628

ppm-1

84.512

1.12 1.12

106.877

0.9490.949

118.472

2.179 2.176 2.165 2.163 2.158 2.155 2.152 2.150 2.145 2.142 2.137 2.135 2.131 2.129 2.124 2.121 2.111 2.108 1.583 1.561 0.922 0.917 0.912 0.906 0.901 0.896 0.885 0.692 0.682 0.677 0.669 0.666 0.664 0.653

3.656

5.773

Br

132.472 130.917 129.019 128.103 127.246 125.447 123.186

7.540 7.535 7.277 7.271 7.256 7.250 7.000 6.979

Me

140.964

150.313

Pyrrole'4p:'1H%NMR%(400%MHz,%CDCl3)% OH

S N Boc

2.132.13

2.18 2.18

12 01

2040 -10

Pyrrole'4p:'13C%NMR%(101%MHz,%CDCl3)%

OH

S N Boc

020

S1 36 S130%

ppm0

200-258.727 910

N Boc

180200 89

160180 78

140160 1

120140 2.142.14 2.17 2.17

67 56

100120 45

80100 34

6080 3 23

4060 15.640

Me 1011-20.019 1.041.04

29.079 27.278

ppm-1 1

33.942

3.06 3.06

83.622

2.092.09

112.174 110.359

1.284

2.203

3.222 3.204 3.183 2.883 2.867 2.863 2.862 2.845

N Boc

128.391 127.791 126.749

Me

135.513 135.358 135.260

150.047

7.400 7.384 7.382 7.378 7.371 7.364 7.362 7.341 7.337 7.336 7.334 7.329 7.322 7.321 7.319 7.315 7.307 7.302 7.298 6.158 6.150 6.103 6.101 6.099 6.095 6.093 6.091

Pyrrole'4q:'1H$NMR$(400$MHz,$CDCl3)$ S Ph

3 9.01 9.01

' Pyrrole'4q:'13C$NMR$(101$MHz,$CDCl3)$ 12 01

2040 -10

S Ph

020

S1 37 S131$

1.011.01 1.01 1.01 2.04 2.04

ppm0

200-248.384

180200

160180

78

140160

1

0.963 0.963

67 1

120140

56

100120

45 2.092.09

80100

34 2.032.03

2.872.87

23

6080

4060

15.709

% 89

29.563 27.286

Me 910

33.760

% Pyrrole'4r:'13C%NMR%(101%MHz,%CDCl3)% 1011-20.019

83.326

ppm-1

112.812 110.477

1.235

2.187

2.870 2.850 2.832

3.249 3.230 3.211

Me

137.484 135.415 133.142 131.944 131.392 128.755 126.865 125.137

149.385

7.607 7.606 7.603 7.586 7.584 7.583 7.356 7.344 7.342 7.339 7.338 7.328 7.325 7.309 7.306 7.227 7.220 7.211 7.207 7.204 7.201 7.191 7.184 6.122 6.120 6.118 6.114 6.112 6.110 6.076 6.068

Pyrrole'4r:'1H%NMR%(400%MHz,%CDCl3)% S Br

N Boc

9.06 9.06 12 01

2040

-10

S Br

N Boc

020

S1 38 S132%

Pyrrole'4s:'1H$NMR$(400$MHz,$CDCl3)$ S

2.05

1011-20.019

910

78

67

1.336 1.319 1.277

2.142

1.081.08 1.081.08

0.9760.976

89

3.276 3.261 3.240 3.225 3.105 3.088 3.085 3.071 3.068 3.056 3.053 3.052 3.036 3.020 2.959 2.938 2.922 2.903

0.994 0.994

2 2 ppm-1

3.957

8.053 8.048 8.036 8.031

2.05

6.229 6.221 6.109 6.101

CO2Me

N Boc

Me

7.385 7.380 7.368 7.363

Me

3.063.06 56

45

1.071.07

3.033.03

34

23

3.163.16 9.28 9.28 12

01

-10

' Pyrrole'4s:'13C$NMR$(101$MHz,$CDCl3)$ S

200-240.939

180200

160180

140160

120140

100120

80100

6080

4060

2040

13.978

20.878

27.729

36.384

41.276

52.537

84.611

113.803 112.524

129.588 128.442 128.300

136.171 134.596

167.413

ppm0

140.185

CO2Me

N Boc

Me

150.295

Me

020

S1 39 S133$

ppm0

200-258.727

0.993 0.993

N Boc

180200

89

160180

78

140160

1

67

120140

56

100120

45

80100

34 23

6080

4060

2040

14.156

910

32.817 31.779 30.121 29.411 29.363 27.436 25.858 23.412 22.732 22.636 22.608

1011-20.019 1

82.610

ppm-1

113.563

4.13 4.13

2.419 2.411 2.409 2.403 2.396 2.327 2.320 2.311 2.305 2.303 2.299 2.288 2.281 1.925 1.924 1.911 1.905 1.904 1.897 1.890 1.885 1.884 1.881 1.880 1.779 1.776 1.773 1.769 1.764 1.758 1.757 1.750 1.629 1.628 1.625 1.611 1.610 1.609 1.592 1.579 1.573 1.561 1.557 1.550 1.545 1.540 1.530 1.529 1.528 1.523 1.464 1.386 1.367 1.359 1.353 1.350 1.345 1.335 1.328 1.321 1.308 0.932 0.915 0.897

6.142

N Boc

135.055 134.330 132.971 132.546 128.414 128.170 127.618 126.371 123.556

149.568

7.370 7.368 7.364 7.355 7.349 7.347 7.341 7.339 7.325 7.322 7.319 7.284 7.278 7.270 7.267 7.264 7.262 7.257 7.254 7.247 7.246

Pyrrole'4t:'1H%NMR%(400%MHz,%CDCl3)% Me Hex S Ph

3.12 2.142.14 3.33 3.33 2.26 2.26 6.086.08 3.12 2.112.111.931.93 3.92 3.92 9.049.04 12 01 -10

Pyrrole'4t:'13C%NMR%(101%MHz,%CDCl3)%

Me Hex S Ph

020

S1 40 S134%

Pyrrole 4u: 1H NMR (400 MHz, CDCl3) Me S

1.02 1.02

1.071.07

1.131.13 ppm-1

1011-20.019

910

89

1

78

0.915 0.910 0.905 0.900 0.894 0.889 0.690 0.685 0.677 0.674 0.672

1.399

2.320 2.294 2.294 2.292 2.287 2.284 2.273 2.271 2.260 2.258 2.253 2.250

6.181 6.173 5.921 5.919 5.913 5.910

7.031 7.017

N Boc 7.295 7.282

S

1.051.05

1

3.123.12

67

56

45

34

9.039.03

23

2.152.15 2.06 2.06

12

01

-10

Pyrrole 4u: 13C NMR (101 MHz, CDCl3) Me S

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

2040

6.955

9.892

17.930

27.531

83.243

108.131

114.968

124.459 124.245

128.612

132.653 131.991

140.377

N Boc 149.521

S

020

S1 41 S135%

Pyrrole 4v: 1H NMR (400 MHz, CDCl3) Me S

1.03 1.03 1 1 ppm-1

1011-20.019

910

1.322

9.16 9.16

1.01 0.989 1.010.989

1.08 1.08

89

2.362

O 6.554 6.552 6.545 6.543 6.482 6.478 6.474 6.469 6.360 6.351

N Boc

7.497 7.495 7.493 7.490 7.370 7.357 7.068 7.055

S

2.02 2.02

78

3.043.04 67

56

45

34

23

12

01

-10

Pyrrole 4v: 13C NMR (101 MHz, CDCl3) Me S

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

18.042

27.294

83.907

110.974 108.668

115.490 113.643

133.289 130.995 128.629 126.781 126.435 125.407

O 141.878

N Boc

148.701 146.835

S

2040

020

S1 42 S136%

Pyrrole'4w:'1H%NMR%(400%MHz,%CDCl3)% Me Me

7.290 7.266 7.247 7.243 7.230 6.983 6.980 6.965 6.962 6.946 6.943 6.927 6.924 6.905 6.902 6.065 6.057 5.996 5.994 5.991 5.988 5.986 5.984

N Boc

1.06 1.06 1.1 1.1 1 1 ppm-1

1011-20.019

910

89

1.09 1.09

1.021.02 1

78

1.288

N

2.510 2.479 2.477

Me

3.033.03

1

9.13 9.13

6.046.04

67

56

45

34

23

12

01

-10

Pyrrole'4w:'13C%NMR%(101%MHz,%CDCl3)% Me

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

15.390

27.533

42.454

82.472

111.447 110.136

116.469

Me

150.025

N Boc

120.844

N

133.192 132.149 130.562 130.381 128.045 127.934

Me

2040

020

S1 43 S137%

ppm0200-248.384

180200

160180 78

140160 1 4.114.11

67

120140 56

100120 45

80100 34

6080 23

4060

26.998

89 0.9710.971

30.955

N Boc 910

49.351

1011-20.019 1

83.030

ppm-1 0.992 0.992

113.965 112.320 112.025

1.08 1.08 1.04 1.04

117.421

4.01 1.87 4.011.87

122.115

1.141

1.813 1.813 1.798

2.969 2.953 2.938

7.388 7.377 7.364 7.355 7.347 7.337 7.328 7.316 7.313 7.306 7.304 7.303 7.290 7.283 7.268 7.264 7.243 7.239 6.849 6.846 6.830 6.828 6.812 6.809 6.776 6.756 6.275 6.267 6.191 6.182

N Boc

135.302 134.858 134.242 132.110 128.619 128.563 127.799 126.918

149.483 148.492

Pyrrole'4x:'1H%NMR%(400%MHz,%CDCl3)% N Ph

4.05 4.05 9.1 9.1

% Pyrrole'4x:'13C%NMR%(101%MHz,%CDCl3)% 12 01

2040 -10

%%

N Ph

%% %

020

%

S1 28 S138%

ppm0

200-258.727

180200

160180

140160 3 2.252.25

78 67

120140 56

100120 45

80100 34

6080 3 1.051.05

23

4060

9

12

2040 8.597 7.808 7.296

1.22 1.22

14.961 14.075

1.081.08 2.12 2.12

22.524

89

31.415 29.631 29.063 27.246 25.240

Me Hex S 910

82.833

1011-20.019

104.467

ppm-1

132.087 131.185 128.438 127.049 124.366 124.032 123.985 123.905

2.367 2.283 2.269 2.259 2.249 2.244 2.235 2.224 2.210 2.151 2.135 2.126 2.117 2.111 2.101 2.092 2.077 2.015 2.002 1.995 1.988 1.981 1.967 1.960 1.947 1.445 1.439 1.436 1.435 1.430 1.421 1.413 1.405 1.389 1.381 1.372 1.365 1.232 1.218 1.215 1.210 1.202 1.192 1.186 1.179 1.171 1.164 1.156 1.044 1.040 1.037 1.034 1.029 1.023 1.019 1.008 0.998 0.988 0.979 0.974 0.967 0.964 0.958 0.953 0.945 0.943 0.941 0.933 0.932 0.927 0.925 0.921 0.856 0.839 0.821 0.725 0.716 0.712 0.707 0.702 0.690 0.688 0.680 0.674

7.380 7.370 7.368 7.360 7.358 7.349 7.338 7.210 7.190 7.176 7.173 7.171 7.163 7.161

Me Hex S

140.504

148.683

Pyrrole'5a:'1H%NMR%(400%MHz,%CDCl3)% Br

N Boc

2.03 2.036.09 6.093.273.27

1.12 3.11 9 3.11 1.12

01 -10

Pyrrole'5a:'13C%NMR%(101%MHz,%CDCl3)%

Br

N Boc

020

S1 45 S139%

ppm0

200-258.727

180200

160180 78

140160 67

120140 56

100120 45

80100 34 3.393.39 1.021.02 3.113.11

23

6080 12

4060

2040 7.444

2.182.18

10.334

1.12 1.05 1.12 1.05

15.309 14.094

Me Hex S 89

22.684

1.02 1.02

25.731

910

31.574 31.335 31.086 29.426

1011-20.019

2.622 2.353 2.317 2.309 2.296 2.282 2.275 1.501 1.493 1.487 1.482 1.474 1.469 1.463 1.458 1.264 1.090 1.085 1.084 1.080 1.074 1.069 1.064 0.849 0.832 0.823 0.819 0.814 0.811 0.809 0.805

8.173 7.376 7.371 7.358 7.356 7.353 7.351 7.338 7.334 7.283 7.280 7.272 7.271 7.268 7.267 7.263 7.260 7.253 7.252 7.249 7.221 7.218 7.203 7.200 7.185 7.181

Me Hex S

131.534 130.714 128.550 125.454 125.075 125.028 124.712 122.107

ppm-1

138.987 138.481

195.248

Pyrrole 5b: 1H NMR (400 MHz, CDCl3) O Me

N H

2.132.13 2.012.01 5.09 88 5.09 01 -10

Pyrrole 5b: 13C NMR (101 MHz, CDCl3)

O Me

N H

020

S1 46 S140%

ppm0

200-258.727 910

N H

180200 89

160180 78

140160 1 2.05 2.05 3

67

120140 56

100120 45

80100 34

6080 3 2.26 2.26

23

4060

15.607 14.140

1011-20.019 1

22.683

2.16 2.16 2.1 2.1

26.331

ppm-1 5.07 5.07

31.747 31.067 29.221

1.02 1.02

2.525 2.506 2.487 2.380 1.666 1.648 1.629 1.610 1.590 1.372 1.368 1.353 1.341 1.334 1.325 1.319 1.316 1.313 1.305 1.298 1.291 1.281 1.274 1.272 1.254 0.913 0.896 0.879

N H

106.947

138.245 132.738 131.879 131.251 131.133 128.818 127.996 127.364 126.105 125.958 124.885 124.774 123.541

8.618 7.545 7.542 7.541 7.527 7.524 7.521 7.408 7.392 7.389 7.388 7.387 7.385 7.382 7.380 7.379 7.377 7.373 7.369 7.362 7.362 7.359 7.355 7.352 7.350 7.344 7.342 7.259 7.251 7.245 7.240 7.238 7.235 7.227 7.222 7.220 7.218 7.201 6.550 6.543

Pyrrole 5c: 1H NMR (400 MHz, CDCl3) Me Hex S Ph

6.26.2

3.2 3.2

12 01

2040 -10

Pyrrole 5c: 13C NMR (101 MHz, CDCl3)

Me Hex S Ph

020

S128 S141$

197.724

2.1 2.12.21 2.06 2.21 2.06

ppm-1

O

ppm0 1011-20.019

200-248.384 910

N Boc

180200 89

160180 78

140160 1

67

120140 56

100120 27.090 26.701

2.172.17 1.15 1.15 3.093.09

83.841

N Boc

148.740 144.999 143.575 136.834 135.810 134.317 134.228 133.105 130.238 129.979 129.852 129.718 129.497 129.147 128.973 128.092 127.691 127.327 127.274 127.245 126.619 125.099 124.766 124.738 124.709 124.681 122.933 120.770 114.692 112.950 11 45

80100 34

6080

1.014

2.644

O

7.960 7.955 7.950 7.938 7.933 7.929 7.753 7.752 7.750 7.749 7.741 7.739 7.736 7.721 7.719 7.716 7.714 7.585 7.565 7.404 7.399 7.394 7.382 7.377 7.373 7.332 7.328 7.323 7.319 7.317 7.213 7.208 7.207 7.203 7.200 7.198 7.194 7.190 6.175 6.167 6.144 6.136

Pyrrole'6a:'1H%NMR%(400%MHz,%CDCl3)% Me

Ph

CF3

1 3.043.04 9.08 9.08

23 12

4060 01

2040 -10

Pyrrole'6a:'13C%NMR%(101%MHz,%CDCl3)%

Me

Ph

CF3

020

S1 48 S142%

Pyrrole 6a: 19F NMR (377 MHz, CDCl3) O

Me

N Boc

Ph

CF3 -62.257

% % % % % % %

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

%

S1 49 S143%

Pyrrole 6b: 1H NMR (400 MHz, CDCl3) OMe

1.04 1.04 2.082.08

2

2

1011-20.019

910

89

1.261

3.093.09

1.02 1.021.021.022.09 2.09 ppm-1

2.363

3.824

7.547 7.542 7.466 7.460 7.445 7.440 7.220 7.199 7.121 7.115 7.104 7.099 6.831 6.825 6.814 6.809

Br

Me

5.906

N Boc

9.16 9.16

3.063.06

78

67

56

45

34

23

12

01

-10

Pyrrole 6b: 13C NMR (101 MHz, CDCl3) OMe

ppm0

200-258.727

180200

160180

140160

120140

100120

80100

6080

4060

15.968

27.610

55.262

83.212

113.641 113.423 110.583

121.285

133.144 132.545 132.434 132.276 132.198 131.802 129.844 129.214

142.256

158.764

Br

Me

149.410

N Boc

2040

020

S1 50 S144$

Pyrrole 6c: 1H NMR (400 MHz, CDCl3) Me

CO2Me

N Boc

2.052.05 2.33 2.33 2.092.09 ppm-1

1011-20.019

910

1.2 1.2

89

11

44

1 78

1.037

2.396

3.953

6.247 6.238 6.162 6.153

8.034 8.030 8.025 8.013 8.009 8.004 7.706 7.705 7.688 7.687 7.684 7.682 7.567 7.548 7.301 7.296 7.290 7.284 7.279 7.150

CF3

9 9

3.023.02 1 67

Pyrrole 6c: 13C NMR (101 MHz, CDCl3)

3.04 3.04 56

45

34

23

12

01

-10

Me

N Boc

CO2Me

CF3

S1 51 S145%

Pyrrole 6c: 19F NMR (377 MHz, CDCl3) Me

CO2Me

N Boc

-62.320

CF3

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

%

S1 52 S146%

ppm0

200-258.727 910

N

180200 89

160180 78

140160 67

120140 1 2.162.16 1.091.09

56

100120 45 34

80100 23

6080

4060 16.537

Me 1011-20.019 1

32.553

1.07 1.07 4.04 4.04 11

37.938

2 21.02 1.02

76.705

ppm-1

132.913 129.939 129.781 128.391 126.638 126.575 125.183 123.843

N

140.110

Me

144.735

174.155

7.605 7.602 7.586 7.582 7.519 7.517 7.516 7.514 7.511 7.501 7.498 7.496 7.495 7.493 7.451 7.448 7.434 7.431 7.428 7.422 7.413 7.410 7.408 7.405 7.393 7.388 7.385 7.368 7.365 7.323 7.319 7.317 7.316 7.306 7.301 7.296 7.286 7.283 7.283 7.256 7.252 7.238 7.236 7.234 7.233 7.219 7.215 5.499 5.494 5.490 5.479 5.475 5.470 5.459 5.455 5.450 3.228 3.224 3.215 3.210 3.204 3.200 3.197 3.193 3.187 3.182 3.173 3.169 3.163 3.158 3.141 3.135 3.121 3.119 3.116 3.113 3.099 3.093 3.077 2.683 2.672 2.663 2.660 2.651 2.640 2.630 2.629 2.621 2.618 2.609 2.598 2.502 1.945 1.925 1.924 1.921 1.914 1.904 1.901 1.899 1.894 1.892 1.890 1.880 1.872 1.870 1.868 1.848

Dihydropyrrole 7a: 1H NMR (400 MHz, CDCl3) S Ph

3.083.08

1.15 1.15

12 01

2040

-10

Dihydropyrrole 7a: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 53 S147%

7.486 7.483 7.467 7.467 7.464 7.392 7.388 7.374 7.372 7.368 7.354 7.350 7.323 7.320 7.303 7.300 7.205 7.201 7.187 7.186 7.183 7.182 7.168 4.466 4.454 4.449 4.444 4.442 4.437 4.432 4.428 4.426 4.418 4.413 4.409 4.401 4.397 4.392 4.385 4.380 3.149 3.144 3.136 3.131 3.124 3.119 3.112 3.107 3.101 3.094 3.089 3.082 3.077 3.070 3.064 3.001 2.997 2.982 2.977 2.973 2.958 2.954 2.940 2.935 2.931 2.923 2.916 2.912 2.458 2.289 2.276 2.270 2.265 2.257 2.252 2.245 2.238 2.233 2.226 2.221 2.214 2.202 1.619 1.617 1.614 1.611 1.606 1.599 1.595 1.590 1.587 1.583 1.580 1.575 1.571 1.564 1.558 1.556 1.435 1.421 1.418

Dihydropyrrole 7b: 1H NMR (400 MHz, CDCl3) Me

Me S N

ppm-1 1011-20.019

N

Me

910 89 1.03 1.03 1.061.06 1.09 1.09 1.09 1.09

78 67 56 1 1 45 1.031.03

1.121.12

34 3.02 3.02 1.2 1.2 23

1.191.19 3.06 3.06 12 01 -10

Dihydropyrrole 7b: 13C NMR (101 MHz, CDCl3)

S Me

S154 S148%

ppm0

1.05 1.05 1.02 1.02

1 31 3

200-258.727

180200

160180

78

140160

67 1

120140

1 56

100120

45 2.03 2.03

80100

34 1.2 1.2

6080

3.173.17

23

4060

16.556

N 89

31.163

Me 910

37.417

1011-20.019

73.185

ppm-1

120.243

3.114 3.110 3.106 3.100 3.095 3.090 3.086 3.076 3.071 3.069 3.064 2.610 2.595 2.590 2.578 2.575 2.570 2.564 2.558 2.556 2.544 2.538 2.533 2.526 2.478 1.981 1.962 1.959 1.957 1.949 1.941 1.939 1.936 1.930 1.927 1.918 1.909 1.905

5.516 5.497 5.478

N

131.250 130.996 127.379 126.654 126.543 125.756 124.459

7.430 7.425 7.413 7.393 7.344 7.337 7.332 7.325 7.316 7.312 7.312 7.309 7.305 7.302 7.289

Me

145.177 142.935

172.654

Dihydropyrrole 7c: 1H NMR (400 MHz, CDCl3) S S

Br

1.07 1.07 12 01

2040

-10

Dihydropyrrole 7c: 13C NMR (101 MHz, CDCl3)

S S

Br

020

S155 S149%

ppm0

200-258.727

180200

160180

140160

78 3.033.03

67

120140

56

100120

45

80100

1.011.01

1.021.02

6080

3.033.03

34 1.311.31

1.08 1.08

23 12

4060

2040

2.519

0.955 0.955

16.682 16.414

1

30.942 28.779

0.9640.964

37.180

89

55.298

Me 910

108.051

1011-20.019

111.352

1

125.880

0.967 0.967

131.332

ppm-1

141.989

4.018 4.005 4.001 3.983 3.978 3.965 3.865 3.049 3.044 3.036 3.031 3.024 3.019 3.014 3.007 3.002 2.994 2.990 2.983 2.978 2.952 2.948 2.932 2.928 2.924 2.911 2.909 2.906 2.904 2.891 2.887 2.883 2.867 2.863 2.425 2.208 2.196 2.193 2.184

6.820 6.814 6.694 6.687 6.672 6.666

7.455 7.433

Me

160.385

172.165

Dihydropyrrole 7d: 1H NMR (400 MHz, CDCl3) S N

MeO

0.995 0.995 4.01 4.01

01 -10

Dihydropyrrole 7d: 13C NMR (101 MHz, CDCl3)

S N

MeO

020

S1 56 S150%

Me

ppm0

200-258.727

180200

910

N 89

160180

78

140160

67

120140

1 2.16 2.16

56

100120

45

80100

3.053.05

34 23

6080

4060

16.443 15.388

Me 1011-20.019 1

32.426

1.98 1.98 1.12 1.12 11

37.606

1.072.02 1.072.02 1.01 1.01

76.625

ppm-1

122.136 120.878

3.151 3.146 3.140 3.135 3.127 3.122 3.118 3.116 3.111 3.102 3.096 3.080 3.075 2.654 2.643 2.634 2.632 2.622 2.612 2.601 2.591 2.589 2.580 2.564 2.486 1.903 1.881 1.879 1.862 1.859 1.858 1.852 1.850 1.848 1.830 1.828 1.806

5.467 5.447 5.427

Me

130.444 129.088 128.360 126.578 126.496

N

141.166 141.136

7.519 7.498 7.472 7.470 7.468 7.467 7.463 7.454 7.451 7.449 7.447 7.446 7.398 7.394 7.390 7.376 7.372 7.360 7.356 7.277 7.276 7.272 7.267 7.266 7.254 7.253 7.190 7.185 7.072 7.067 7.051 7.047

Me

144.751

173.365

Dihydropyrrole 7e: 1H NMR (400 MHz, CDCl3) S Ph

S

1.11 3.08 1.113.08

1.11 1.11

12 01

2040

-10

Dihydropyrrole 7e: 13C NMR (101 MHz, CDCl3)

S Ph

S

020

S1 57 S151$

ppm0

200-258.727

910

N

180200

89

160180

1

78

140160

67

120140

1 1.051.05 1.06 1.06

56

100120

45

80100

1.1 1.1

34 23

6080

4060

17.409

4.05 4.05 11

33.011

0.971 0.971 1.03 1.03

37.827

Me 1011-20.019

75.461

ppm-1

130.127 128.376 127.949 127.285 126.639 126.449

5.398 5.393 5.388 5.374 5.359 5.355 5.350 3.266 3.259 3.255 3.247 3.242 3.235 3.229 3.224 3.217 3.213 3.205 3.200 3.193 3.188 3.139 3.134 3.119 3.115 3.114 3.110 3.095 3.090 3.077 3.073 3.072 3.068 3.053 3.048 2.660 2.649 2.640 2.637 2.628 2.625 2.616 2.614 2.608 2.605 2.596 2.593 2.581 1.954 1.936 1.934 1.930 1.922 1.916 1.912 1.910 1.904 1.903 1.898 1.892 1.884 1.880 1.878 1.860

N

137.646

7.460 7.447 7.370 7.363 7.356 7.354 7.349 7.340 7.334 7.282 7.276 7.268 7.266 7.261 7.252 7.246 7.081 7.068

Me

144.762

168.058

Dihydropyrrole 7f: 1H NMR (400 MHz, CDCl3) S Ph

S

3.083.08

1.08 1.08

12 01

2040

-10

Dihydropyrrole 7f: 13C NMR (101 MHz, CDCl3)

S Ph

S

020

S1 58 S152%

ppm0

200-258.727

180200 89

N

160180 78

140160 3.033.03

67

120140 1.051.05

56

100120 45

80100 1.071.07

34 23

6080

4060

17.408

910 1

33.090

Me 1011-20.019 1

37.811

ppm-1 2.2 2.01 2.01

55.293

0.931 0.9310.959 0.959

74.941

2.2

113.769

5.343 5.338 5.334 5.319 5.304 5.300 5.295 3.822 3.817 3.262 3.257 3.251 3.246 3.238 3.233 3.226 3.220 3.215 3.209 3.204 3.196 3.191 3.185 3.180 3.122 3.117 3.102 3.098 3.097 3.093 3.079 3.074 3.060 3.056 3.055 3.051 3.037 3.032 2.614 2.599 2.590 2.575 2.567 2.559 1.924 1.906 1.904 1.899 1.892 1.886 1.882 1.880 1.874 1.872 1.868 1.862 1.854 1.850 1.848 1.830

N

130.191 129.088 127.902 127.523 127.270

7.452 7.439 7.295 7.293 7.289 7.278 7.277 7.273 7.271 7.074 7.061 6.916 6.909 6.903 6.892 6.887 6.879

Me

137.552 136.999

167.776

Dihydropyrrole 7g: 1H NMR (400 MHz, CDCl3) S

OMe

S

4.084.08 1.11 1.11

12 01

2040

-10

Dihydropyrrole 7g: 13C NMR (101 MHz, CDCl3)

S

OMe

S

020

S1 59 S153%

ppm0

Me

200-258.727 910

180200 89

N

160180 78

140160 67

120140 1 2.122.12 1.081.08

56

100120 45 34

80100 23

6080

4060 16.513

1011-20.019 1

32.201

4.044.04 0.986 0.986

37.717

ppm-1 2.03

76.327

2.03

131.358 130.617 129.419 129.101 128.775 128.454 128.170 127.366 127.068 126.803 126.685 125.689 125.437 125.359 125.329 124.728 122.989

3.155 3.148 3.143 3.139 3.126 3.122 3.120 3.115 3.105 3.099 2.706 2.695 2.687 2.675 2.664 2.655 2.643 2.635 2.623 2.493 1.876 1.852 1.844 1.831 1.821 1.808 1.799 1.776

5.493 5.473 5.452

N

143.076

7.655 7.634 7.599 7.578 7.450 7.446 7.439 7.419 7.357 7.353 7.337 7.332

Me

148.460

173.696

Dihydropyrrole 7h: 1H NMR (400 MHz, CDCl3) S

CF3

Br

3.163.16

1.06 1.06

12 01

2040

-10

Dihydropyrrole 7h: 13C NMR (101 MHz, CDCl3)

S

CF3

Br

020

S1 60 S154%

Dihydropyrrole 7h: 19F NMR (377 MHz, CDCl3) Me

S N

CF3

-62.283

Br

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

$

S1 61 S155$

ppm0

200-258.727

N H

180200 89 1.99 1.99 4.04 4.04

160180 1.99 1.99 78

140160 67

120140 56 0.994 0.994 11

100120 45

80100 34 3.01 2.03 3.01 2.03

1.06 1.06

23

6080

4060

16.100

0.9730.973

34.463 32.757

910

58.378

Me 1011-20.019

62.193

ppm-1

2.541 2.511 2.495 2.491 2.482 2.474 2.471 2.468 2.466 2.461 2.453 2.444 2.440 2.423 2.364 2.329 2.317 2.311 2.307 2.299 2.287 2.281 2.278 2.269 2.266 2.260 2.249

4.421 4.402 4.382

4.797 4.778 4.759

N H

128.312 127.193 126.859 126.796 126.259 125.415 125.157

Me

136.191

145.240 143.423

7.999 7.982 7.978 7.620 7.602 7.433 7.415 7.395 7.335 7.332 7.329 7.318 7.314 7.298 7.294 7.290 7.284 7.279 7.277 7.267 7.260 7.254

!

Pyrrolidine 7a: 1H NMR (400 MHz, CDCl3) S Ph

0.962 0.962 1.15 1.15 12 01

2040

-10

Pyrrolidine 7a: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 62 S156!

S

ppm0

200-258.727

910

N H

180200

89

160180

78

140160

1 1 1.02 1.02

67

120140

56

100120

2.91 2.91 1.051.05

45

80100

34 23

6080

4060

19.065

2 0.849 2 0.849

34.653 34.433

1.93 1.931.05 0.892 1.05 0.892

56.255

Me 1011-20.019

62.272

ppm-1 4.906 4.902 4.894 4.891 4.886 4.881 4.871 4.389 4.370 4.351 2.451 2.410 2.404 2.402 2.401 2.400 2.397 2.395 2.392 2.389 2.387 2.384 2.378 2.372 2.364 2.352 2.346 2.345 2.338 2.291 2.287 2.281 2.268 2.264 2.261 2.258 2.253 2.249 2.246 2.243 2.239 2.226 2.223 2.220 1.890 1.886 1.882 1.877 1.873 1.867 1.862 1.859 1.855 1.850 1.845 1.841 1.834 1.289

S N H

129.717 129.483 128.265 126.859 126.717 123.211

7.582 7.566 7.564 7.562 7.398 7.380 7.377 7.361 7.302 7.299 7.296 7.286 7.281 7.275 7.232 7.219 7.043 7.030

Me

145.098

150.010

Pyrrolidine 8b: 1H NMR (400 MHz, CDCl3) S Ph

1.141.14 2.06 2.06

1.1 1.1

12 01

2040

-10

Pyrrolidine 8b: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 63 S157%

ppm0

200-258.727

180200

N H

160180

140160 1

78 67

120140

100120 1 1.051.05

56 3.06 3.06 0.959 0.959 1.131.13

45

80100 34 23

6080

4060

19.051

89 1.021.02

34.652 34.446

1.05 1.05 2.12 2.12

56.130 55.308

S 910

61.830

Me 1011-20.019

113.642

ppm-1

123.163 123.037

2.07 2.07

129.717 127.743

2.523 2.443 2.389 2.387 2.378 2.369 2.361 2.357 2.349 2.337 2.228 2.217 2.214 2.210 2.204 2.201 2.190 2.183 2.180 2.172 2.161 1.875 1.868 1.858 1.852 1.850 1.845 1.842 1.840 1.835 1.831 1.829 1.825 1.817 1.813 1.802 1.796

3.840

4.331 4.312 4.294

4.877 4.863 4.857 4.842

S N H

137.108

7.501 7.494 7.490 7.477 7.473 7.466 7.223 7.210 7.035 7.022 6.938 6.931 6.926 6.914 6.909 6.902

Me

150.119

158.568

Pyrrolidine 8c: 1H NMR (400 MHz, CDCl3) S

OMe

2.91 2.91 1.151.15

2.18 2.18

12 01

2040

-10

Pyrrolidine 8c: 13C NMR (101 MHz, CDCl3)

S

OMe

020

S1 64 S158%

ppm0

Me

200-258.727

910

N H

180200

89

160180

78

140160

1 0.991 0.991

67

120140

56

100120

1 3.043.04 1.091.09

1.131.13

45

80100

34 23

6080

4060

15.777

1011-20.019 3.04 3.04

28.399

1.13 0.932 1.13 0.932

33.310 32.567

ppm-1

58.102 57.692

1.02 1.02

4.648 4.629 4.611 4.476 4.457 4.437 2.514 2.452 2.434 2.432 2.421 2.414 2.412 2.403 2.401 2.393 2.383 2.381 2.362 2.261 2.248 2.243 2.240 2.230 2.228 2.222 2.218 2.212 2.210 2.206 2.200 2.197 2.192 2.179 1.864 1.846 1.841 1.834 1.823 1.819 1.816 1.810 1.801 1.794 1.792 1.789 1.770 1.688 1.675 1.670 1.664 1.657 1.651 1.645 1.639 1.634 1.627 1.621 1.616 1.603 1.488

N H

127.791 127.760 127.056 126.576 125.691 120.859 120.053

Me

142.195

146.551

7.772 7.752 7.351 7.343 7.338 7.331 7.315 7.314 7.310 7.309 7.305 7.303 7.302 7.300 7.297 7.295 7.294 7.290 7.284 7.217 7.214 7.204 7.201

Pyrrolidine 8d: 1H NMR (400 MHz, CDCl3) S S

Br

1.16 1.161.161.16 1.161.16 12 01

2040

-10

Pyrrolidine 8d: 13C NMR (101 MHz, CDCl3)

S S

Br

020

S165 S159%

ppm0

Me

200-248.384

910

180200

89

N H

160180

11

78

140160

67

120140

56

100120

45

80100

34 23

6080

4060

15.765

1011-20.019 11

34.433 32.469

4.034.03

57.856

ppm-1

61.517

0.977 0.977 2.06 2.06

2.523 2.487 2.468 2.458 2.451 2.448 2.443 2.437 2.430 2.420 2.418 2.400 2.331 2.318 2.312 2.310 2.300 2.288 2.280 2.269 2.261 2.250 2.130 1.796 1.778 1.772 1.766 1.755 1.751 1.742 1.734 1.729 1.725 1.721 1.705 1.696 1.685 1.680 1.667 1.661 1.655 1.650 1.643 1.637 1.631 1.626 1.613

N H

4.700 4.681 4.663 4.443 4.424 4.405

7.835 7.815 7.690 7.669 7.646 7.625 7.349 7.344 7.328 7.323 7.307 7.303 7.290

Me

141.920 138.608 129.467 129.214 128.958 128.700 127.821 127.655 127.148 126.962 126.806 125.419 125.284 125.255 125.226 125.196 123.259 121.098 121.005

149.407

Pyrrolidine 8e: 1H NMR (400 MHz, CDCl3) S

CF3

Br

2.99 1.15 2.99 1.15 1.151.15 1.12 1.181.18 1.06 1.06 1.12 12 01

2040

-10

Pyrrolidine 8e: 13C NMR (101 MHz, CDCl3)

S

CF3

Br

020

S1 66 S160%

Pyrrolidine 8e: 19F NMR (377 MHz, CDCl3) Me

S N H

CF3

-62.345

Br

ppm-240

-60-199.174

-80-60

-100-80

-120-100

-140-120

-160-140

-180-160

-200-180

-220-200

-240-220

$

S1 67 S161$

ppm0

200-258.727

180200

160180

140160 67

120140 56

100120 1.051.05 1.231.23

45

80100 3.113.11 2.162.16 1.171.17

34

6080 1.161.16

4060

1.141.14

23 12

2040

3.099 1.992

78 3.063.06

16.221 15.956

89 1 1

32.455 30.749

Me 910 1.03 1.03

55.326

1.03 1.03

57.886

1011-20.019

63.657

ppm-1

111.683 109.662

1 1

127.065

7.629 7.607 6.769 6.763 6.734 6.728 6.713 6.707 4.479 4.459 4.441 3.833 2.640 2.621 2.602 2.583 2.479 2.241 2.237 2.235 2.226 2.222 2.220 2.216 2.207 2.204 2.202 2.192 2.189 2.185 2.170 2.019 2.004 2.001 1.996 1.988 1.983 1.978 1.974 1.970 1.966 1.960 1.956 1.953 1.949 1.936 1.752 1.737 1.732 1.727 1.721 1.717 1.712 1.707 1.702 1.696 1.693 1.682 1.677 1.664 1.656 1.644 1.638 1.628 1.624 1.619 1.613 1.608 1.603 1.600 1.594 1.589 1.584 1.569 0.968 0.960 0.948 0.940 0.936 0.928 0.920 0.916 0.908 0.529 0.521 0.517 0.509 0.501 0.498 0.489 0.479 0.470 0.468 0.459 0.314 0.301 0.290 0.281 0.278 0.269 0.266 0.239 0.236 0.227 0.224 0.215 0.204 0.191

Me

137.551 135.136

158.649

Pyrrolidine 8f: 1H NMR (400 MHz, CDCl3) S N H

MeO

1.061.06 1.06 2.162.16 1.06 01 -10

Pyrrolidine 8f: 13C NMR (101 MHz, CDCl3)

S N H

MeO

020

S1 68 S162%

ppm0

200-258.727 910

N H

180200 89

160180 78

140160 67

120140 1 1.021.02

56

100120 45

80100 34 1.11 1.11 23

6080

4060

16.145

Me 1011-20.019 1

35.411 33.642

1.02 1.02 2.07 3.06 2.07 3.06

58.813

2.052.05 1.071.07

62.312

ppm-1 2.559 2.551 2.541 2.539 2.532 2.524 2.510 2.503 2.502 2.496 2.492 2.453 2.442 2.435 2.424 2.406 2.404 2.395 2.386 2.378 2.018 1.963 1.959 1.940 1.932 1.928 1.921 1.909 1.873 1.855 1.843 1.837 1.832 1.825 1.820 1.806 1.802

4.592 4.574 4.556

5.014 4.996 4.978

N H

128.504 127.175 126.844 126.354 125.647 125.358 125.165

Me

136.400

145.873 143.693

7.654 7.653 7.634 7.631 7.477 7.476 7.472 7.456 7.454 7.453 7.405 7.387 7.384 7.367 7.307 7.304 7.300 7.286 7.280 7.272 7.269 7.268 7.260 7.258 7.257 7.251 7.241 7.222 7.212

Pyrrolidine 8g: 1H NMR (400 MHz, CDCl3) S Ph

1.08 4.254.25 1.05 1.08 1.05 1.141.14 12 01

2040

-10

Pyrrolidine 8g: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 69 S163%

ppm0

200-258.727

N H

180200 89

160180 78

140160 67

120140 56

100120 1.061.06 1.04 1.04 1.06 1.06 3.083.08

45

80100 3.07 3.07 1.191.19

34 23

6080

4060

18.038

910 2.152.15

35.227

Me 1011-20.019 0.989 0.989

38.110

ppm-1 3.083.08

43.795

2.07 2.07 3.18 3.18

60.361

1 1

66.632

N H

118.001

Me

135.356 135.230 128.515 128.454 128.202 126.875 126.781 126.722 124.870

146.929 145.652

7.973 7.954 7.949 7.542 7.538 7.521 7.519 7.391 7.387 7.379 7.377 7.372 7.368 7.359 7.356 7.344 7.340 7.290 7.286 7.282 7.272 7.269 7.265 7.250 7.245 7.239 7.235 7.220 7.216 7.202 7.198 5.422 5.408 5.398 5.397 5.385 5.383 5.379 5.374 5.365 5.360 5.356 5.354 5.342 5.340 5.331 5.317 5.087 5.085 5.081 5.079 5.077 5.075 5.042 5.040 5.038 5.036 5.034 5.032 5.027 5.025 5.022 5.021 5.019 5.001 5.000 4.997 4.996 4.994 4.455 4.439 4.432 4.416 3.402 3.398 3.395 3.388 3.385 3.381 3.367 3.364 3.360 3.354 3.350 3.347 2.679 2.656 2.644 2.621 2.544 2.479 2.468 2.456 2.450 2.445 2.431 2.429 2.418 2.409 2.399 2.396 2.377 2.284 2.274 2.268 2.265 2.257 2.254 2.249 2.243 2.238 2.235 2.227 2.224 2.218 2.207 1.739 1.717 1.709 1.694 1.686 1.671 1.664 1.641

Pyrrolidine 8h: 1H NMR (400 MHz, CDCl3) S Ph

1.18 1.18 12 01

2040

-10

Pyrrolidine 8h: 13C NMR (101 MHz, CDCl3)

S Ph

020

S1 70 S164%