Pyrrole. (kap 13). Indole. (kap 17). N. Indolizine. (kap 25). NH. Isoindole. (kap 19)
... Protonated pyrroles ≈ iminium ions ... Application in Porphyrine Synthesis. N.
Chapter 13
Pyrroles N H
Pyrrole (kap 13)
NH
N
N H
Indole (kap 17)
Indolizine (kap 25)
Isoindole (kap 19)
Reaction with electrophiles - Protonation H N H H least stable
H
N H
N H
pKA -3.8
H H
H H
N H
H H
most stable
H H
H H
N H
N H
H N H
Protonated pyrroles ≈ iminium ions Reactive intermediates in many react.
H N H
N H
H H
Decomposition
React. under strongly acidic conditions Nu N H
H H
Iminium ion
Reaction with electrophiles - E-fil Ar. Subst. -Halogenation
•Nitration •Sulfonation •Halogenation •FC-acylation •(FC-alkylation)
X
X N R
+
"X " X
N H
X
N H
O
N
Br O
N O Br Br
E
E H
N Si
E
AIBN
N Boc
R=H: Unstable X R=EWG (i.e. Boc): More stable
N O Br (NBS)
N Boc
Br
N Br Boc
E H
N Si
N Si
-H
N Si
Steric hindrance in 2-pos. Br N Si
NBS (1 equiv.)
N Si
NBS (1 equiv.)
Steric hindrance in 2/5-pos.
Br
Br
Br N Si
Br2 N H
EWG ex. -CO2Me deactivating m-directing
N H
EWG
O
-Acylation Ac2O 200 oC
N H
N N Met Met: i.e. Tl Ac2O or AcCl
N H O major prod.
N H minor prod.
N O not formed
N O N O
N PhO2S
O Weak L.A. Weak E+
N O S O Ph EWG Deactivating Lewis acid requir.
N SO2Ph Strong L.A. Strong E+
-Alkylation RX, Lewis acid N R
F.C.-alkyl.
O AcCl AlCl3
Ac2O BF3
Low reactivity, unselective, polymerization etc
O H N H
O
O N H H
N H
Reaction with electrophiles - Condensation with aldehydes / ketones +
H , RCHO N H
N H
R=H, alkyl
OH R H H
±H+
OH2
N H
- H2O
RH
N H
H
Polymer
R red.
N H
2:1 adducts EWG
EWG EWG
R
H+, MeCHO R
N H
R
Reductive trapping sometimes possible
R
N H
Me
N H
EWG
EWG R
H
R
N Me H
N H
With electron rich arylaldehydes N
O NMe2
N H O N H
N H
N H
N N H
N H
N H
N H
N H
Application in Porphyrine Synthesis N
N
N NH
HN N
H
N Mg N
N Met N
O
O H CO2Me H
N
N
Chlorophyll A
O
Vit. B12 N N Fe N CO2H
N
•Hemoglobine •Myoglobine •Cytochromes
Heme CO2H N N Cu
N
N
Copper Phtalocyanin Blue synthetic dye
Application in Porphyrine Synthesis N NH
HN N
React. under acidic conditions OH
+
H , CH2O N H
N H
R=H, alkyl
±H+
OH2
N H
H
Polymer
N H
- H2O
React. under alkaline conditions K2CO3(aq)
±H+
O N
N H
N
H
OH
OH
HO
OH
N H
N H
No highly reactive iminium salts N H HCl (0.15M) HO N NH
HN N
Porphyrin
Chloranil
NH
N H H N
OH N H
HN
Porphyrinogen
BF3 N H
N H
N H
Reaction with electrophiles - Condensation with Imines / Iminum Ions Protonated Aldehyde / Ketone Nu
Aldehyde / Ketone Nu
H
Nu
H
Nu
Nu
Nu
O
NH R
N R
OH
O
Iminium ion Nu
Imine
Nu
N R
OH
NH R
Pyrrole unstable in acidic media H H H
N H Iminium ion
N H H N H
H
N H
H H
H H
H N H H HN
-H
N H H HN Enamine
N H H HN Iminium ions
HCl 6M, 0oC, 30 sec POLYMER
Mannich react. CH2O, R2NH, H+ R N R N H
N H
iminium ion gen. in situ
N
N H
HR N
R
R N
N H
-H
R
Nu
MeX N H
N
N
Nu
N H
H soft Nu (malonate etc.)
Generation of Vilsmeier reagent E-fil Ar. subst. Hydrolysis of iminium salt
Vilsmeier react. (Vilsmeier-Haack): Formylation 1) POCl3, DMF 2) H+/H2O N H
O
O
N H
Cl
P Cl O Cl
Cl
N
Cl
P O Cl
O
N
N
N H
Cl Cl
H+/H2O O
N H
N
N H Cl
N
N Cl H
N -H
H N Cl H
Reaction with nucleophiles Electron rich ring - not very reactive towards Nu O2N
O2N Nu NO2
N H
N H
Nu
Reaction with base and further react. with E-files Base N H pKa 17.5
N
N
N H pKa 44
N
R
R
H
±H N
R-X
N H
R-X
Base N H
+
N Met
N R-X N R
R H
±H+ N H
R
N-alkylation favoured by: -Ionic N-Met bond (Li) -High solvating power of solvent (DMF, DMSO etc., crown ethers, PTC)
C-metallation and further react. SiMe3
N R
TMS-Cl
Stille
Bu3SnCl
BuLi N R
N R
Li
SnBu3
N R
MgX2
N R
B(OMe)3, H3O+
RCOX R-X
N R
ZnX2
N R
RR'CO O N R
OH
R
N R R R
N R
R
N R
Br N R
MgX
B(OH)2
E E
N R
Suzuki
Negishi
ZnX
Li BuLi
NBS
N R
Br
Cyclo Additions N EWG
Pyrrole as diene (4π component) H N N H
N H low yield
R
+
EWG: Less interact. Between Lone pair on N and “diene”
Vinylpyrrole as diene O O
N H PhO2S
O
O O O
N PhO2S
O O O
Pyrrole as dienophile (2π component) A few intramolek. ex. H N
N N
N N
N N H
R
(or alkene)
The less aromatic furane reacts
N SO2Ph
EWG
N-EWG EWG
H N
- N2
N H
N
- H2
N
N
Reaction with carbenes / carbenoids R'
R' R''
N R
Cl
R''
N R
Rearrangements N H
N H
Cl
Cl -HCl
N
Indoles: No cyclopropanes isolated from carben(oid) react.
Pyrrole Carboxylic Acids
Ring synthesis
N R
CO2R1
N R
O O
E
E N R
O
O -CO2
N E R E: H, halogen
Oxypyrroles N O H Major tautomer
N H
OH
N H
N O H NB! sp3 C
N O H NB! sp3 C
N H
O H
O
O
OH N H
O
N H
O
O
N H
N H
R
O R
H O
Aminopyrroles -Amino (not iminoform) - unstable
O
O
O
Synthesis of Pyrroles a
Carbonyl condensations (c.f. chapt. 3) - Pyrroles
X b
X
X
c
X
Strategy a; Paal-Knorr synth.
O
O R
R'
HO R
N R''
OH R'
R, R' = H: - 2 H2O
R
N R' R''
MeO
OH CO2 OH RNH3
Δ - 2 H2O
RNH2 O HO2C
O CO2H
HO HO2C
O
Unstable
Synthons:
NH2R'' R''=H, alkyl, aryl
HO HO2C HO
O
N R''
OH CO2H
O
OMe
- 2 H2O HO2C
HO HO2C HO
OH CO2 OH
N CO2H -2 CO2 R''
BuNH3
N R''
a
Strategy b; Knorr synth.
b X
O
Base
HN R4 R5
R2
Can be removed; hydrol., decarbox.
X
R3
O
X
c
Neccesary for easy enolization RO2C
X
R3
RO2C O
H OH RO2C R3 R2 R4 N HO H R5
O
HN R4 R5
R2
RO2C - 2 H2O
R2, R3 ≠H
R2
Alkyl, aryl
R3 N R4 R5
May be H
If R2=CO2R Can be removed; hydrol., decarbox.
Strategy a and b combined; Hantzsch synth. a/b X
X
R, R4: alkyl, aryl Cl R': H, alkyl, aryl R
CO2R3
CO2R3 R
O NH2 O R4 R'
R4
N R'
May be removed; hydrol, decarbox.
Cl CO2R3
CO2R3 NH2 R'
O R4
HN R'
CO2R3
R4 OH - H2O N R4 R' imin
R taut.
O
CO2R3
CO2R3 HN R4 R' enamin
R4
R - HCl
O
CO2R3 taut.
N R' imin
O HN R' enamin
H H CO2R3
CO2R3 R
N R'
R4
R4
R
- H2O
R HO N R'
R4
a
Strategy c
X b
X
X
c
X R, R2: H, alkyl, aryl R2 R
O
O HN CO2R3 R' glycine der.
R2 O R - H2O HO N R' CO2R3
HN CO2R3 Ts
R
O
R2 Base
N R' CO2R3
R
R2
O N R' CO2R3
R
OH H N CO2R3 - H2O R'
R2 R
CO2R3
N R'
taut. R2
R2 O
R2
R
O
R2
R2 Base
N Ts CO2R3
R
O N Ts CO2R3
R
OH H N CO R - H O 2 3 2 Ts
R2 H R
H N CO R 2 3 Ts
R2 Base
H R
N
CO2R3
Cycloadditions with 1,3-dipoles (c.f. chapt. 3)
b
a
b
c
a
alkene / alkyne 1,3-dipole
X
X
d
c d
e
e
Reaction with isocyanide EWG N C R isocyanate
Base
'R
R
N C
MIC: methyl isocyanate
R=Ts (TsMIC) R=Benzotriazolyl (BetMIC) R=-CO2R
EWG 'R H H H R N
N N N
Bet:
EWG= NO2, COR
Alt. I; van Leusen synth. R: Ts or Bet (Good leaving groups) EWG: -COR COR 'R H H H Ar N
COR 'R H H Ar N
H
R' COR
taut.
'R
N
COR N H
Alt. II; Barton Zard synth. R: -CO2R EWG: -NO2 NO2 'R H H RO2C H N
'R H RO2C
NO2 H N
H RO2C
R' N
taut.
'R
RO2C
N H
Reaction with mesoionic oxido-oxazoliums
R
R3
R3
H N
R4
O
R2
R
R2
N H O
O
R4
R3 HO O
- H2O
N-acylaminoacid
R3
N HR 4 O O
R3
- CO2
R3
O
O
H N
R
R4
H N O
R4 O
R2 N H
R4
Mesoionic: Zwitter ion no uncharged res. form
N H
O Not mesoionic
N H
O
Synthesis from aminoalkynes I I
I
H
R R
HN Ts
Base
EWG
cat. Pd(II) or Cu(II)
R
N Ts
H H EWG
I Base R
H
N EWG Ts
Metn+
N R'
HN 'R
(n-1)+
Met
R
R
R
HN 'R
R: alkyl, alkenyl
R
OH 1) PBr3 2) R'NH2
R HN 'R R: H, Ph, THP
I
H
Spont.
R N R'
R
H N
H
R
EWG
H N H - Metn+ H R'
I
taut
H R
N H
EWG
H taut N H R'
R N R'
