Auto-Tandem Catalysis in Ionic Liquids: Synthesis

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Auto-Tandem Catalysis in Ionic Liquids: Synthesis of 2-Oxazolidinones by Palladium-Catalyzed Oxidative Carbonylation of Propargylic Amines in EmimEtSO4 Raffaella Mancuso 1, *, Asif Maner 1 , Ida Ziccarelli 1 , Christian Pomelli 2 , Cinzia Chiappe 2 , Nicola Della Ca’ 3 , Lucia Veltri 1 and Bartolo Gabriele 1, * 1

2 3

*

Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci 12/C, Article 87036 Arcavacata di Rende (CS), Italy; [email protected] (A.M.); [email protected] (I.Z.); Auto-Tandem Catalysis in Ionic Liquids: Synthesis of [email protected] (L.V.) Department of Pharmacy, Universityby of Pisa, Via Bonanno 33, 56126 Pisa, Italy; 2-Oxazolidinones Palladium-Catalyzed Oxidative [email protected] (C.P.); [email protected] (C.C.) Carbonylation of Propargylic Amines in EmimEtSO4 Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy; [email protected] Raffaella Mancuso 1,*, Asif Maner 1, Ida Ziccarelli 1, Christian Pomelli 2, Cinzia Chiappe 2, 1,* Nicola Della Ca’ 3, Lucia Veltri 1 and Bartolo(R.M.); Gabriele Correspondence: [email protected] [email protected] (B.G.); 1 Laboratory of Industrial and Synthetic Organic Chemistry Tel.: +39-0984-49-2816 (R.M.); +39-0984-49-2815 (B.G.) (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci 12/C,

87036 Arcavacata di Rende (CS), Italy; [email protected] (A.M.); [email protected] (I.Z.); Academic Editor: Derek J. McPhee [email protected] (L.V.)5 July 2016; Published: 8 July 2016 Received: 16 June 2016; Accepted: 2

Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy; [email protected] (C.P.); [email protected] (C.C.) carbonylative approach to 2-oxazolidinone derivatives carried out using an Abstract: A 3convenient Department of Chemistry, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy; [email protected] ionic liquid (1-ethyl-3-methylimidazolium ethyl sulfate, EmimEtSO4 ) as the solvent is presented. It is * Correspondence: [email protected] (R.M.); [email protected] (B.G.); based on the sequential concatenation of two catalytic cycles, both catalyzed by the same metal species Tel.: +39-0984-49-2816 (R.M.); +39-0984-49-2815 (B.G.)

(auto-tandem catalysis): the first cycle corresponds to the oxidative monoaminocarbonylation of the Academic Editor: Derek J. McPhee Received: 16 June 2016; Accepted: 5 July 2016; date triple bond of propargylic amines to give the Published: corresponding 2-ynamide intermediates, while the second one involvesAbstract: the cyclocarbonylation of the latter to yield 2-(2-oxooxazolidin-5-ylidene)-acetamides. A convenient carbonylative approach to 2-oxazolidinone derivatives carried out using an Reactions areionic carried out using a simple catalytic consisting ofthePdI with an excess 4) as solvent is presented. It is liquid (1-ethyl-3-methylimidazolium ethylsystem sulfate, EmimEtSO 2 in conjunction on the sequential system concatenation of two catalytic cycles, both catalyzed by the same metal speciesloss of activity of KI, and thebased catalyst/solvent could be recycled several times without appreciable (auto-tandem catalysis): the first cycle corresponds to the oxidative monoaminocarbonylation of the after extraction of the organic product with Et O. triple bond of propargylic amines to give 2the corresponding 2-ynamide intermediates, while the second one involves the cyclocarbonylation of the latter to yield 2-(2-oxooxazolidin-5-ylidene)acetamides. Reactions are carried out using aoxazolidinones; simple catalytic system consisting of PdI2 in conjunction Keywords: carbonylation; cascade catalysis; palladium with an excess of KI, and the catalyst/solvent system could be recycled several times without appreciable loss of activity after extraction of the organic product with Et2O. Keywords: carbonylation; cascade catalysis; oxazolidinones; palladium

1. Introduction Cascade catalysis, in which a catalytic cycle is concatenated to another eventually leading to the 1. Introduction final product, is one of the most exciting areas of modern catalysis [1–10]. Although rather frequent Cascade catalysis, in which a catalytic cycle is concatenated to another eventually leading to the in biological systems [11], where processes may be sequentially catalyzed by different enzymes, it is final product, is one of the most exciting areas of modern catalysis [1–10]. Although rather frequent still relatively rare in chemical transformations, they usually two concatenated cycles. in biological systems [11], where processes maywhere be sequentially catalyzed involve by different enzymes, it is stillinteresting relatively rare case, in chemical transformations, where usually involve two concatenated A particularly commonly referred asthey “auto-tandem catalysis” [9],cycles. occurs when the A particularly interesting case, commonly referred as “auto-tandem catalysis” [9], occurs when the same catalytic system is able to catalyze both the concatenated cycles, as shown in Scheme 1. same catalytic system is able to catalyze both the concatenated cycles, as shown in Scheme 1.

substrate

catalyst

catalyst intermediate

product

Scheme 1. The concept of “auto-tandem catalysis; the same catalyst promotes the two concatenated

Scheme 1. The concept of “auto-tandem catalysis; the same catalyst promotes the two concatenated catalytic cycles. catalytic cycles. Molecules 2016, 21, 897; doi:10.3390/molecules21070897

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In this work, we report on the direct synthesis of 2-oxazolidinone derivatives through an Molecules 2016, 21, 897 process consisting of the concatenation of two carbonylative catalytic 2 ofcycles, 8 auto-tandem catalysis both catalyzed by the same catalytic system (PdI2 in conjunction with an excess of KI), performed in In this work, we report on the direct synthesis of 2-oxazolidinone derivatives through an autothe ionic liquid 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4 ) as an unconventional solvent. tandem catalysis process consisting of the concatenation of two carbonylative catalytic cycles, both catalyzed by the same catalytic system (PdI2 in conjunction with an excess of KI), performed in the 2. Result and Discussion ionic liquid 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4) as an unconventional solvent.

Some years ago, we reported a novel method for the synthesis of 2-(2-oxooxazolidin2. Result and Discussion 5-ylidene)acetamides 3 based on the PdI2 /KI-catalyzed oxidative carbonylation [12–19] of substituted propargylic amines 1, carried out ina the presence of the a secondary 2 as external nucleophile, Some years ago, we reported novel method for synthesis ofamine 2-(2-oxooxazolidin-5-ylidene) 3 based and on themolecular PdI2/KI-catalyzed oxidative carbonylation [12–19] of substituted wateracetamides as a promoter, oxygen as oxidant [20]. The process, carriedpropargylic out at 100 ˝ C ˝ amines 1, carried out in(DME) the presence of asolvent secondary amine20 2 as external nucleophile, water as a promoter, in 1,2-dimethoxyethane as the under atm (at 25 C) of a 4:1 mixture of CO/air, and molecular oxygen as oxidant [20]. The process, carried out at 100 °C in 1,2-dimethoxyethane (DME) led to the formation of a Z/E mixture of 3 through the concatenation of two catalytic cycles, both as the by solvent (at 25 °C) of aan 4:1 example mixture of of CO/air, led to the formation a Z/Efirst mixture catalyzed PdI2under /KI, 20 so atm it represented auto-tandem catalysis.of The process of 3 through the concatenation of two catalytic cycles, both catalyzed by PdI2/KI, so it represented an corresponded to the oxidative aminocarbonylation of the triple bond [21] of 1 with 2, CO, and O2 , example of auto-tandem catalysis. The first process corresponded to the oxidative aminocarbonylation to give 2-ynamide intermediates I, while the second process corresponded to the water-promoted of the triple bond [21] of 1 with 2, CO, and O2, to give 2-ynamide intermediates I, while the second oxidative cyclocarbonylation of water-promoted I to give the final products (Scheme 2; anionic ligands process corresponded to the oxidative cyclocarbonylation of I toiodide give the final are omitted for clarity) [20]. products (Scheme 2; anionic iodide ligands are omitted for clarity) [20]. R2

R3 R2

R1HN 1

R3

PdI2

CO

PdI

R1HN

R2

HI

R3

O

1

R HN

PdI

H2O Pd(0)+HI

R2NH 2

(1/2) O2

R2

R3

1

R HN

O NR2

I

R2

R3

O

1

NR PdI PdI2

CO

NR2

HI

R2

H2O

R3

O

NR1 PdI

(1/2) O2

O

Pd(0)+HI

O R2

O R

2

R3

R1 N

CHCNR2

NR2

R3

R1 N HO

CHCNR2 O

H2O

PdI

O O

3

Scheme 2. Auto-tandem catalysis leading to oxazolidinones 3 by sequential PdI2/KI-catalyzed oxidative

Scheme 2. Auto-tandem catalysis leading to oxazolidinones 3 by sequential PdI2 /KI-catalyzed monoaminocarbonylation of propargylic amines 1 to give 2-ynamide intermediates I followed by oxidative monoaminocarbonylation of propargylic 1 to give 2-ynamide intermediates I followed PdI2/KI-catalyzed and water-promoted oxidative amines cyclocarbonylation of I (anionic iodide ligands are by PdI /KI-catalyzed and water-promoted oxidative cyclocarbonylation of I (anionic iodide ligands omitted for clarity). 2 are omitted for clarity). Considering the importance of the class of products obtained, which are known to possess important pharmacological activities [22–25], the currentobtained, attention devoted to the possibility to Considering the importance of the class and of products which are known to possess

important pharmacological activities [22–25], and the current attention devoted to the possibility to

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carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we Molecules 2016, 333of Molecules 2016,21, 21,897 897 Molecules 2016, 21, 897 ofof8system, 88 with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic we Molecules 2016,21, 21,897 897 of88 Molecules 2016, 33of have herein explored the possibility to perform our process in the ionic liquid EmimEtSO Molecules 2016, 21, 897 897 of 88 4 . Molecules 2016, 21, 33 of have herein the possibility to perform our process in the ionic liquid EmimEtSO Molecules 2016,explored 21,897 897 of848. Molecules 2016, 21, 33of Molecules 2016, 21,897 897processes Molecules 2016, 21, 33ofof88 carry catalytic carryout out catalytic processesin inionic ionicliquids liquids(ILs) (ILs)as assafer saferand andmore moreenvironmentally environmentallyfriendly friendlysolvents solvents carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents Molecules 2016, 21, 3 3ofof8 8 Molecules 2016, 21,897 897processes carryout out catalytic processesin inionic ionicliquids liquids(ILs) (ILs)as assafer saferand andmore moreenvironmentally environmentallyfriendly friendlysolvents solvents carry catalytic Molecules 2016, 21, 897 Molecules 2016, 21, 897 33we ofof 88 carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we with respect to 897 classical [26–30], coupled the possibility recycle catalytic system, Table 1.catalytic Synthesis ofVOCs 2-(2-oxooxazolidin-5-ylidene)acetamides (3) bythe PdI oxidative Molecules 21, 3we of 8 2 /KI-catalyzed carry out2016, catalytic processes inionic ionic liquids (ILs)to as safer andmore moreto environmentally friendly solvents carry out processes in liquids (ILs) as safer and environmentally friendly solvents with respect to897 classical VOCs [26–30], coupled to the possibility possibility to recycle the catalytic system, we with respect to classical VOCs [26–30], coupled to the to recycle catalytic system, we Table 1.21, Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) bythe PdI 2/KI-catalyzed oxidative Molecules 2016, 21, 897 of8 8 Molecules 2016, 3 3of carry out catalytic processes inionic ionic liquids (ILs) assafer safer and more environmentally friendly solvents carry out catalytic processes in liquids (ILs) as and more environmentally friendly solvents with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we have herein explored the possibility to perform our process in the ionic liquid EmimEtSO 4 . have herein explored the possibility to perform our process in the ionic liquid EmimEtSO 4 . have herein explored the possibility to perform our process in the ionic liquid EmimEtSO 4 . carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents carry out catalytic processes in ionic liquids (ILs) as safer and more environmentally friendly solvents carbonylation of propargylic amines (1) with CO, O , and secondary amines (2) in EmimEtSO with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we with respect to classical VOCs [26–30], coupled to the possibility to recycle theEmimEtSO catalytic system, we 4 and 2 in 4 and have herein explored the possibility toperform perform our process in the ionic liquid EmimEtSO 4.. have herein explored the possibility to our process the ionic liquid 4EmimEtSO carry outcatalytic catalytic processes inionic ionic liquids (ILs) asthe safer and more environmentally friendly solvents carry out processes in liquids (ILs) as safer and more environmentally friendly 2, and secondary amines (2) insystem, carbonylation of propargylic amines (1) with CO, O with respect toclassical classical VOCs [26–30], coupled to the possibility to recycle the catalytic we with respect to VOCs [26–30], coupled to possibility to recycle the catalytic we have herein explored the to perform perform our process in the ionic liquid EmimEtSO 4.. solvents have herein explored the possibility to our process the ionic liquid EmimEtSO 4system, apossibility carry out catalytic processes ionic liquids (ILs)to asthe safer andin more environmentally friendly with respect to VOCs possibility recycle the catalytic system, we with respect toclassical classical VOCs [26–30], coupled to the possibility recycle the catalytic system, we have herein explored the possibility to coupled perform our process in thetoto ionic liquid EmimEtSO 4. solvents recycling experiments . in[26–30],

have herein explored theVOCs possibility to perform our process in theto ionic liquid EmimEtSO 4. solvents a.in carry outcatalytic catalytic processes inionic ionic liquids (ILs)our assafer safer andin more environmentally friendly carry out processes liquids (ILs) as and more environmentally friendly with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic we with respect to classical [26–30], coupled to the possibility recycle the catalytic system, we have herein explored the possibility toperform perform our process in the ionic liquid EmimEtSO have herein explored the possibility to process the ionic liquid EmimEtSO 4system, .4. solvents recycling experiments Table 1.1. Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI 22/KI-catalyzed oxidative Table Synthesis ofpossibility 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI 2/KI-catalyzed oxidative Table Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI /KI-catalyzed oxidative with respect to classical VOCs [26–30], coupledour to process the possibility to recycle the catalytic we have explored the to ininthe ionic liquid EmimEtSO 4.system, haveherein herein1. explored the possibility toperform perform our process the ionic liquid EmimEtSO 4. Table 1. Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI /KI-catalyzed oxidative Table 1. Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI 22/KI-catalyzed oxidative with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we with respect to classical VOCs [26–30], coupled to the possibility to recycle the catalytic system, we O havecarbonylation herein explored the possibility to perform our process in the ionic liquid EmimEtSO 4 . have herein explored the possibility to perform our process in the ionic liquid EmimEtSO 4 . Table 1. Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI 2 /KI-catalyzed oxidative 2 , and secondary amines (2) in EmimEtSO 4 and of propargylic amines (1) with CO, O Table 1. Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by PdI 2 /KI-catalyzed oxidative 2 , and secondary amines (2) in EmimEtSO 4 and carbonylation of propargylic amines (1) with CO, O , and secondary amines (2) in EmimEtSO4.4 and of propargylic amines (1) with CO, O2process havecarbonylation herein explored the possibility to perform our in the ionic liquid EmimEtSO Table 1. Synthesis Synthesis of 2-(2-oxooxazolidin-5-ylidene)acetamides 2-(2-oxooxazolidin-5-ylidene)acetamides (3) by by PdIR /KI-catalyzed oxidative Table 1. of (3) PdI 22/KI-catalyzed oxidative and secondary secondary amines (2) in in EmimEtSO EmimEtSO and carbonylation of propargylic propargylic amines (1) with CO, CO, Oprocess 3(2) 22, , and amines 44 and carbonylation of amines (1) with a2-(2-oxooxazolidin-5-ylidene)acetamides haverecycling herein explored the perform ourO the ionic EmimEtSO a.2-(2-oxooxazolidin-5-ylidene)acetamides have herein explored the totoperform our process ininthe liquid EmimEtSO 4.4.44 and Table Synthesis (3)ionic by PdI 2/KI-catalyzed oxidative Table 1.1. Synthesis ofofapossibility (3) by PdI 2/KI-catalyzed 2liquid and secondary secondary amines (2)CHCNR in EmimEtSO and carbonylation of propargylic propargylic amines (1) with CO, CO, O 22,, and amines (2) in EmimEtSO carbonylation of (1) with O experiments 2 oxidative recycling experiments . recycling experiments .possibility 3amines

R Table 1.1.Synthesis ofofa2-(2-oxooxazolidin-5-ylidene)acetamides (3) PdI 2/KI-catalyzed oxidative a2-(2-oxooxazolidin-5-ylidene)acetamides Table Synthesis (3)by by PdI 2/KI-catalyzed oxidative and secondary secondary amines (2) in in EmimEtSO EmimEtSO and carbonylation of propargylic propargylic amines (1) (1) with with CO, CO, O O22,, and amines (2) 44 and carbonylation of amines recycling experiments recycling experiments ..R2 R amines O PdI a2-(2-oxooxazolidin-5-ylidene)acetamides O2O/KI-catalyzed Table Synthesis (3) by by PdI 2/KI-catalyzed oxidative Table 1.1. Synthesis ofofa2-(2-oxooxazolidin-5-ylidene)acetamides (3) PdI oxidative andsecondary secondary amines (2)ininEmimEtSO EmimEtSO and carbonylation propargylic amines(1) (1)with withCO, CO,OO2,2,and 2/KI amines (2) 4 4and carbonylation ofofpropargylic recycling experiments . recycling experiments O2/KI-catalyzed Table 1. experiments Synthesis ofaa...2-(2-oxooxazolidin-5-ylidene)acetamides (3)RRR PdI oxidative 2,O amines (2) in EmimEtSO 4 4and carbonylation ofofpropargylic amines (1) with CO, O O 33by 2,and andsecondary secondary (2) in EmimEtSO and carbonylation propargylic amines (1) with CO, O 3amines + 2 CO + R NH + recycling experiments recycling 2 2 1 N O inEmimEtSO CHCNR CHCNR CHCNR O 222 by O Table Synthesis (3) by PdI 2/KI-catalyzed oxidative Table 1.1.Synthesis ofofaa2-(2-oxooxazolidin-5-ylidene)acetamides (3) PdI 2/KI-catalyzed oxidative 2 and secondary (2) EmimEtSO and carbonylation propargylic amines(1) (1)with withCO, CO,OO2,2,and 22 in secondary amines (2) 4 4and carbonylation ofofpropargylic 3amines R recycling experiments .HN 333 amines 3 recycling experiments .aa12-(2-oxooxazolidin-5-ylidene)acetamides EmimEtSO R R R R 4 R R R R R CHCNR O CHCNR O 2 2 , and secondary amines (2) in EmimEtSO 4 and carbonylation of propargylic amines (1) with CO, O 2 recycling .aR 2.22 33 1 recyclingexperiments experimentsR 22 PdI PdI R22 R /KI R333 amines 22/KI 2/KI R amines aR CHCNR CHCNR OO (2) H2OR ,and and secondary (2) in3EmimEtSO EmimEtSO4 4and and carbonylation propargylic amines (1) secondary carbonylation ofofpropargylic (1) CO, OO2,2PdI 22 in recyclingexperiments experiments recycling .aR.22R PdI /KI R122N +++222CO +++with R ++CO, R33amines PdI CO R +O CO Rwith NH OO OO O 22NH 222 CHCNR R3333 2NH 22/KI R 1R 2NR 1R N O OCHCNR 3O recycling experiments11aR 22 PdI22/KI /KI 444 R RR PdI R R 1aR.22 R R + 2 CO + R NH + O EmimEtSO EmimEtSO EmimEtSO + 2 CO + R NH + O R CHCNR R O CHCNR 2 2 O 3 2 2 2 1 2 R HN N O 3 R HN R HN 2 1R N OCHCNR2 22 recyclingexperiments experiments1R 2 ++ O recycling .R.22RR31311 ++ 22 CO R PdI /KI R R PdI /KI 1 CHCNR R CO + R NH O + R NH EmimEtSO 2 2 O 2 EmimEtSO 2 2 2 2 2 2 1 2N H O N3 3Yield O 333 of 32 (%) b (Z/E ratio) c HN O HH OO 44 R RR1R 2 2 3 311 R PdI 2NH ++ O PdI R11R R CO ++ RR22NH O22 EmimEtSO 1HN R 22/KI ++ 22 CO EmimEtSO 222/KI O CHCNR O3OO O 12 2N NR OCHCNR 2 2RR 2 2 b (Z/E ratio) c O 44 RR HN R HN H2H PdI /KI 33O3 (%) 2 ++OO PdI /KI R R RO Entry 1 2R1R1HN 3++RR2NH 222O of CO NH R ++22CO EmimEtSO R3 311 222 2 2 EmimEtSO 2Yield 1N NR 1R OOCHCNR 44 RR HN 3 3O H O Run H 2 2R 311 33b3b b 2 Run 4cc c Run 5 Entry 2NH+ +OO PdI /KI + +2 2CO + +RR NH 2O 2/KI PdI 1 2RRR 3 CO Run 1 2 Run Run 6 Run 7 d 1R R 1 EmimEtSO 2 2 2 R EmimEtSO R 2 2 2 1 CHCNR N O CHCNR O O 4 1 N O 4 2 2 of R HN Yield 333(%) H222O O 2 2 ratio) 2 31 Yield of (%) (Z/E ratio) Yield of (%) (Z/E ratio) 3 (Z/E H 2 3 R 2 31 PdI /KI 1 HN R EmimEtSO R 1 + 2 CO + R NH + O R + 2 CO + R NH + O EmimEtSO 4 22 O3O RR1 22 2 2 1 HHO 42Yield O N O bb(Z/E c cRun 5 1 1 NRun Entry 111 22R2R1HN 3 HN Entry 3 O Entry 3 3 Yield of 3 (%) (Z/E ratio) Run Run 3 Run 4 Run 6 3 2 O Run 7 d 2 of (%) ratio) 2 2 R PdI /KI 1 R PdI /KI + 2 CO + R NH + O EmimEtSO R1R 2 2 4 4 Run 2 H2 O 1 3NOO Run Run21 EmimEtSO Run Run 5 cc Run 6 Run 7 ddd O b4b 3 3 4(Z/E Run11 EmimEtSO Run Run 3of 33Run Run 4(Z/ERun Run Run66 Run Run77 Run Run 55 Run HN 11 H Entry 2RHN 3 ++RRNH 2 2O22 Yield Yield (%) ratio) Entry 11 2R 3CO (%) ratio) 22 +Run R1 3of 1 2 +Run OO Me O3O 2 2 11 CHCN2 2NH Me Run Run 3O Run 4(Z/ERun Run Run66 Run Run77dd HN 1 ++2 1 NN H2O H Entry Yield ofO 3O (%) ratio) Run Run 3of Run 55cc Run Entry 11 22R 33OCO 33 bb4(Z/E 2 ORun (%) ratio) 2O22 4 Yield OO R R 1 1NH EmimEtSO 70Run 71 74 74 55cc c Run 7166 Run H2O224 4Yield Run11EmimEtSO Run Run 3O Run 4(Z/ERun Run Run Run 770 7 dd Entry Me 11 2R Run Run 3 Run HN 1 1 Me 33 OO O 2R 3bb b4 HN Yield of 3 (%) ratio) of 3 (%) (Z/E ratio) Entry 2 2 Me MeCHCN Me O 1Entry Me Me 3 3(%) CHCN OO Run11 Run Runof Run Run Run66 Run Run77ddd 1Me 3 OO Yield (%) ratio) Entry 1Me 22 3CHCN Run Run 33ofO Run 44(Z/Eratio) Run 55 c Run H HRun O 3 bb(Z/E 3 74 2O22 Yield 271 Me Me Me Me Me1Me Me 70 71 74 74 71 70 70 Me O 70 71 74 71 70 70 b4(Z/E c c Run N O 70 74 74 71 70 70 O Entry 2 3 O NH (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) O NH Run 1 Run 2 Run 3 Run 4 Run 5 Run 6 Run 7d CHCN O O NH Entry BnHN 1Me 2 3 Run 1 Run 2 Run 3 Run Run 5 6 Run 7 Yield of 3 (%) (Z/E ratio) CHCN O Yield of 3 (%) ratio) Bn 2a Me Me Me1Me c Run Run 1 1 Run Run 3 3of(2.9) Run 7 7d d 111 70 712 2(3.2) (3.4) (3.2) 70 (3.4) Me 3 70(3.1) 7474 744b474 715 5 71 706 6 Run 70 Me Me Run Run Run Run Run Run Run NH 70 71 74 74 71 70 70 CHCN O Entry 11a 3OOO Me Yield 3Run (%) (Z/E ratio) Entry OO 22 NH O 3aaO N O OCHCN (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) MeNNMe Me BnHN (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN BnHN dd Me Me MeO Bn Me b(Z/E Bn 11 b4 c c Run 70 71 74 74 71 70 70 Bn 70 71 74 74 71 70 70 1a Run 1 Run 2 Run 3 Run 4 Run 5 Run 6 Run 7 CHCN O 2a 2a 1a Me Entry 1 2 3 Run 1 Run 2 Run 3 Run Run 5 6 Run 7 O2a NH 1a O NH CHCN O Yield of 3 (%) (Z/E ratio) Yield of 3 (%) ratio) O O O Me NMe OO Me N (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN Me1 (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN 11 Me 70 1 71 2 74 3 74 4 71 5 Run 70 6 Run 70 7 d Me Bn Run Run Run Run Run 70 71 74 74 71 70 70 NH 1a CHCN OO Bn Me OO 2a Entry 1Me1a 2 NH 33aa Entry 22a 3OCHCN 3aa O OO O3aa MeMe Me NMe N O (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) O (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN MeMe O BnHN d O Me CHCN 70 71 74 74 71 70 70 11 70 71 74 74 71 70 70 Bn CHCN O Bn O NH Me O NH Run 1 Run 2 Run 3 Run 4 Run 5 Run 6 Run 7 2a 1a Run 1 Run 2 Run 3 Run 4 Run 5 Run 6 Run 7 d 2a 1a 3aa Me 3aa O MeN NMe OCHCN Me (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN 70 71 74 74 71 70 70 MeMe (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) 11 BnHN 70 71 74 74 71 70 70 OO 2a Me Bn OOO NH O Me Bn 2aNH CHCN OO 1a O 1a 3aa 3aa MeNNMe OO OCHCN O Me 11 CHCNO (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN Me Me Me OOMe 70 71 74 74 71 70 70 O Bn 70 71 74 74 71 70 70 Bn O2a2aNH NH 1a O O 1a O Me 3aa Me 3aa N O Me Me (3.1) (2.9) (3.4) (3.2) (3.4) MeMe CHCN NMe O BnHN CHCN CHCN 74(3.2) 75 73 75 74 (3.2) 73 (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN MeMe NH BnMe 11 70 71 74 74 71 70 70 Bn 1a1a OOCHCN O2a2a NH CHCN Me OO MeN Me OO 3aa 3aa 74 75 73 75 74 73 74 Me 74 75 73 75 74 73 74 74 75 73 75 74 73 74 Me NH N Me CHCN NH Me (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) 2 2212 BnHN (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN CHCN OOO Me1a O Me Bn 70 71 74 74 71 70 70 Bn 70 74 74 71 70 70 2aNH NH O 1a1a OO2a NH 3aa MeNMe O 1a 3aa Me 1a 1a Me 74 (3.1)71 75 (3.4) 73 75 74 73 74 O O NH 74 75 73 75 74 73 74 (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) O CHCN (3.2) (3.0) (3.3) (3.2) BnHN CHCN NH ON Bn Bn 2a 1a O NNMe O 2b O N O O Me (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) Me (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) 3aa 1a 3aa Me 1a Bn 21212 1a 74 (3.1) 75 (3.4) 73 (3.2) 75 (3.0) 74 (3.3) 73 (3.2) Bn 74 75 73 75 74 73 74 Bn 74 75 73 75 74 73 74 2b CHCN 2bNH 2b N NOOOO NH (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) (3.1) (3.2) (2.9) (3.4) (3.2) (3.4) (3.2) BnHN 1a1a BnHN O3aa BnBn O 3ab 2a Me 2a NMe OCHCN O Me (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) N 1a 1a (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) 22 Me 74 75 73 75 74 73 74 Bn 74 75 73 75 74 73 74 CHCN NH 2bNH Bn O CHCN 2b 3ab 3ab 3ab O O O MeMe Me NNMe 1a (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) O 3aa (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) 3aa OOOOCHCN 1a 74 75 73 75 74 73 74 22 74 75 73 75 74 73 74 Bn Bn NH 2bNH 2b 3ab OO CHCN Me 3ab O MeN N OCHCN (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) O 74 75 73 75 74 73 74 1a1a (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) O Me 22 74 75 73 75 74 73 74 NH Me Bn O O O NH Bn O 2b CHCN O 2b 3ab 3ab Me O 1a1a N O O Me N O 22 (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) Me 74 75 73 75 74 73 74 OO CHCN Bn Me 74 75 73 75 74 73 74 Bn NH 2bNH O 2b O 3ab 3ab Me N O Me Me (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) Me CHCN N O CHCN CHCN (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) 1a1a BnBn 22 74 75 73 75 74 73 74 Me 2b2b NH OOCHCN Me Me CHCN Me OCHCN Me O 3ab 3ab 75 75 74 76 76 75 75 Me 75 75(3.4) 75 74 76 76 75 7575 75 75 74 76 76 75 75 NH NMe MeNMe NH CHCN NH Me (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) 1a 75(3.2) 74 76 76 (3.1) (3.0) (3.3) (3.2) (3.3) 2 OOOCHCN O NH Bn 74 75 73 75 74 73 74 Bn 74 75 73 75 74 73 74 2bNH NH 2b MeNMe 3ab OO 1a 3ab Me 1a 1a 75 75 74 76 76 75 75 OCHCN NH 75 75 74 76 76 75 75 OMe 1a (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) CHCN 3 233233 NH 1a OO 1a Bn 2b OO N O O MeNN (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) Me (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 3ab 1a 3ab 2c Me 1a Bn 2cNH 2c Bn 3 75 75 74 76 76 75 75 Bn Me 75 75 74 76 76 75 75 CHCN N O N O NH N O CHCN (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) (3.3) (4.0) (3.9) (3.9) (4.0) (3.9) (3.3) (3.7) (3.1) (3.4) (3.2) (3.0) (3.3) (3.2) OO OO O 2c BnBn Bn O 2b Me 2b N Me 3ab (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) N 1a 1a (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) Me 3 3 Me 75 75 74 76 76 75 75 2c Bn 3 1a 75 75 (3.9) 7474 (3.9)76 76 (4.0) 75 75 (3.7) 75(4.0) 75 76 76 (3.9) 75 CHCN NH 2c NH Bn O CHCN 3ac 3ac O O3ac MeMe Me OCHCN NNMe 1a O (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 3ab (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 3ab OOO 1a 75 75 74 76 76 75 75 33 75 75 74 76 76 75 75 2c Bn 2c NH Bn NH 3ac OO CHCN Me O 3ac MeN N OCHCN O3ac (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 75 75 74 76 76 75 75 1a1a (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) Me 33 NH 75 75 74 76 76 75 75 Me 2c Bn OOO NH O 2c Bn CHCN O O 3ac 3ac MeNNMe O 1a1a O Me 33 (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) OOOCHCN 75 75 74 76 76 75 75 O Bn 75 75 74 76 76 75 75 2c2c Bn NH NH OO O 3ac NMe OCHCN 3ac Me Me Me (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) N O CHCN CHCN (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 2c2c NH 1a1a Bn 33 75 75 74 76 76 75 75 Me Bn OOCHCN Me Me CHCN Me Me OO 3ac 3ac Et 70 71 71 70 70 69 71 Me EtEt NH 70 71 71 70 70 69 71 70 71 71 70 70 69 71 O Me 22c Me Me NN CHCN Me 2NH 2NH (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 1a (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 3 CHCN OO CHCN O Bn 2c 75 75 74 76 76 75 75 Bn 75 75 74 76 76 75 75 NH O NH 3ac Me O 1a 3ac Me 4 1a 1a 4 Me Et Me 70 70 (3.9) 71 71 70 70 69 7169 Me N O Et NH 70 71 71 70 69 71 O (4.0) (3.9) (4.0) (3.9) (3.7) (3.8) 22NH CHCN CHCN Et NH OO 71(3.1) 71 70 70 22d 1a1a 2d 2c 343 Bn 2d O NNMe O N O O Me (3.1) (2.9) (3.4) (3.4) (3.0) (3.1) Me (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 3ac 1a 3ac Me Bn 1a Et NH Bn Et NH 70 71 71 70 70 69 71 Bn 70 71 71 70 70 69 71 N O CHCN N O 2 1a (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) 2 CHCN (4.0) (3.9) (3.9) (4.0) (3.9) (3.7) (3.8) O 4 4444 O 2d O3ac 2c2d 2c BnBn O MeN NMe OO Me (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 1a 1a (3.1) (3.1) (3.4) (3.4) (3.0) (3.1) Et2d NH Me 70 (3.1)(2.9) 71 (2.9) 71 70 70 69 71 Bn Et 70 71 71 70 70 69 71 CHCN 2NH CHCN Bn O ONO 22d 3ad (3.1) (3.4) (3.4) (3.0) 3ad 3ad 2d O Bn O Me Me OCHCN NNMe Me (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 1a O 3ac (3.1) (3.4) (3.4) 3ac O 1a 70(3.1) (2.9) 71 7171 (3.1) 70 70 (3.4) 70 70 (3.0) 69 71 EtEt NH 70 71 71 70 70 69 71 444 1a 70 71 (2.9) (3.1) (3.4) 69(3.1) (3.0) Bn Bn 2NH 22d OOCHCN 3ad 2d Me 3ad O MeN NO OCHCN (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) EtEt 70 71 71 70 70 69 71 1a1a (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) Me 44 70 71 71 70 70 69 71 Me 2NH Bn OOO O 2NH Bn 3ad CHCN O O 2d 3ad 2d 3ad MeNNMe 1a1a Me OOCHCN 44 OOOO (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) NH O 70 71 71 70 70 69 71 O EtEt Bn 70 71 71 70 70 69 71 Bn 2 2NH 2d 2d 3ad O Et 3ad NEtN O Et (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) Me OO Et CHCN (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) CHCN OO Et 1a Et 1a Bn Et2d NH 44 70 71 71 70 70 69 71 Me Bn OOCHCN Me Me CHCN O Me O Me 3adO O 3ad 2d2 Me Me Et Me 75 75 74 75 76 74 74 Et 75 75 74 75 76 74 74 75 75 74 75 76 74 74 NOOO OCHCN MeN Et Me CHCN (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 1a (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) Et 4 CHCN NH Bn EtEt NH 70 71 71 70 70 69 71 Bn 70 71 71 70 70 69 71 22a 22a Me OO3ad OO 2d 2a Me Me1a1a Et 75 75 74 75 76 74 74 NOO O3ad Et Me (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 75 75 74 75 76 74 74 Et CHCN CHCN O Et Et 455455 Bn CHCN O Et O O N O N O Me N O (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) Me 3ad BnHN (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) 2d 2a BnHN BnHN 2d Et Me Et 2a Me Me Bn 5 75 75 74 75 76 74 74 Bn 75 75 74 75 76 74 74 Bn NOOO OO3ad CHCN O NEt 1b Et1b (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) 1b (3.1) (2.9) (3.1) (3.4) (3.4) (3.0) (3.1) CHCN O Me 75 75 74 75 76 Bn Bn O MeN NEt O OCHCN 3ad OO Me (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) BnHN 2a Me EtEt1b 2a (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) Et BnHN 75 75 74 75 76 74 7474 Me Bn 75 75 74 75 76 74 74 1b Bn OCHCN 2a 3ba 5 5555 3ba 3ba O O MeEt Me OCHCN NNEt O 3ad OO 2a (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) 3ad (2.9) (3.3) (3.0) (3.1) (3.1) (3.2) O MeEtEt1b BnHN BnHN Me 2a CHCN O 75 (2.9)(3.4) 75 (3.4) 74 75 76 74 74 75 75 74 75 76 74 74 Bn Bn 1b NO O OO (3.3) (3.0) (3.1) (3.1) 3ba BnHN Me O 3ba Me N O Me Bn (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) N O 2a 75 75 74 75 76 74 74 BnHN Me 2a 1b 5 (2.9) (3.0) (3.1) BnHNEtEt1b 75(2.9) (3.4) 75 7474 (3.3) 75 75 (3.0) 76 76 (3.1) 74 74 555 2a 75 75 (3.4) (3.3) (3.1) 74(3.2) (3.1) Bn EtEt OOCHCN CHCN OO O 1b Bn O O 3ba 3ba O MeNNEt O 2a2a Me (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) BnHN 5 Me Et BnHN Me 75 75 74 75 76 74 74 OOOCHCN O 75 75 74 75 76 74 74 Bn O Bn 1b 1b O 3ba O 3ba NEt OCHCN 3ba Me (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) NEt OO BnHN O (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) CHCN O CHCN OO BnHN MeEtEt 2a2a BnBn 55 75 75 74 75 76 74 74 1b1b OOCHCN CHCN O O O 3ba 3ba 71 74 72 74 73 75 74 71 74 72 74 73 75 74 71 74 72 74 73 75 74 MeNNOOOO Me (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) CHCN 2a (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) BnHN 5 BnHN CHCN Me 1b Me 75 75 74 75 76 74 74 Bn 75 75 74 75 76 74 74 Bn 1b O O OO 3ba O 2a 3ba 2a 2a 71 74 72 74 73 75 74 (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) O OO 71 74 72 74 73 75 74 BnHN 1b CHCN O O 2a 2a 566566 Bn NNN O O3ba N OO O OCHCN (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) BnHN 2a 3ba BnHN BnHN 2a Bn BnNN 6 71 74 72 74 73 75 74 Bn 71 74 72 74 73 75 74 CHCN (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) (2.9) (3.4) (3.3) (3.0) (3.1) (3.1) (3.2) CHCN OO BnHN BnHN OO O O CHCN O Bn Bn O 1b 1b N O 3ba (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) 2a BnHN 2a 1c (6.1) (6.4) (7.1) (7.3) (7.3) 66 1c 1c 71 71 (7.2) 74 72 74 73 7573 7475 BnHN Bn N OO 71 74 72 74 73 75 74 CHCN CHCN OO Bn 3ca 3ca 3ca 74(6.9) 72 74 O O3ba OCHCN O 2a O (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) 3ba OCHCN OO 2a BnHN1c OO BnHN 71 74 72 74 73 75 74 1c 71 74 72 74 73 75 74 Bn NNO Bn 2a 3ca 6 6666 3ca O OCHCN (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) O 71 74 72 74 73 75 74 2a2a BnHN1c (6.1) (6.9) (6.4) (7.1) (7.3) (7.3) 71 (6.1)(7.2) 74 (7.2) 72 74 73 75 74 BnHN 1c Bn NN OO O Bn CHCN OO O O N O 3ca 3ca (6.9) (6.4) (7.1) (7.3) BnHN O 2a N O O N O 6 (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) Bn 2a (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) BnHN1c BnHN O CHCN 71 74 72 74 73 75 74 1c 66 2a 71 (6.1) 74 (7.2) 72 (6.9) 74 (6.4) 73 (7.1) 75 (7.3) BnNEt O 71 74 72 74 73 75 74 Bn O O O 3ca O 3ca Et EtOO CHCN (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) N OCHCN O BnHN Et O (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) CHCN EtEt 2a2a BnHN 1c Bn 66 71 74 72 74 73 75 74 1c Bn 1c CHCN Me CHCN OOO O 3ca Me O Me 3ca 3ca Me Me1c Me EtOO 69 70 70 71 72 69 72 69 70 70 71 72 69 72 69 70 70 71 72 69 72 O Et NN CHCN O (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) 2a (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) Et 6 BnHN CHCN O O BnHN O 1c Et Bn 71 74 72 74 73 75 74 Bn 71 74 72 74 73 75 74 O 3ca Me N O 3ca 2a Me 2a 2a Me Et EtO O 69 70 70 71 72 69 72 Et Me O (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) 69 70 70 71 72 69 72 CHCN O CHCN BnHN Et 2a 2a 1c 677677 Bn 1c O O O O3ca NEt O Me N (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) OO Me (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) BuHN (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) 3ca 2a BuHN BuHN Et Me Et 2a Me Bu 7 69 70 70 71 72 69 72 Bu Bu 69 70 70 71 72 69 72 NNN 1d CHCN 1d Et (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) 1d (6.1) (7.2) (6.9) (6.4) (7.1) (7.3) (7.3) CHCN OO OOOO BnHN 1c BnHN O3ca Bn Bn O MeN NEt OCHCN Me (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) BuHN O 2a Me EtEt1d 2a (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) Et 77 BuHN 69 70 70 71 72 69 72 Me Bu O 69 70 70 71 72 69 72 CHCN O 1d Bu O Et 3da 1c 3da 1c 3da CHCN O O O3ca O EtEt MeEt Me OCHCN NNEt O (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) 2a 3ca (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) O MeEt BuHN BuHN OCHCN Me 2a OO 69 70 70 71 72 69 72 77 69 70 70 71 72 69 72 O Bu Bu 1d 1d Me 3da Me O 70(6.0) 70 71 3da MeMe NO OCHCN Me (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) N 69 70 70 71 72 69 72 BuHN MeEtEt1d 2a2a (5.3) (5.5) (5.0) (5.9) (5.6) Et Et BuHN 69 69 (5.4) 70 70 71 72 6972 7269 Bu OOO CHCN O Bu 1d OO OO 2a 3da 3da 7 7777 O MeNNEt O 2a2a Me OOCHCN (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) BuHN Me Et BuHN Me 69 (5.3) 70 (5.4) 70 71 72 69 72 O O 69 70 70 71 72 69 72 Bu O Bu 1d 1d O O 3da N O N O Et 3da (6.0) (5.5) (5.0) (5.9) Me (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) Et Et BuHN N O BuHN CHCN (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) CHCN OO 2a BuHN CHCN MeEtEt 2a Bu BuBu 69(5.3) 76 70 7070 (6.0)75 71 71 (5.5) 72 72 (5.0) 69 72 777 2a 69 70 (5.4) 76 6974 (5.9) EtEt 1d 1d OOCHCN 1d CHCN Me Me OO Me 3da 3da 74 75 74 Et 76 76 75 74 75 74 74 Me 76 76 75 74 75 74 74 Me NNO (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) Et 2a (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) CHCN BuHN 7 BuHN OOOCHCN Me 1d Me 69 70 70 71 72 69 72 Bu 69 70 70 71 72 69 72 Bu 3da MeNO OO 3da 3da 1d 2d Me 1d1d 2d 1d 2d O Et 76 76 75 74 75 74 74 Et (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) BuHN 76 76 75 74 75 74 74 CHCN 2a CHCN 2a O 788788 OO Bu e e e e e e e OO O Me N (6.0) (6.3) (6.2) (6.4) NEt O 3da Me (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 3da (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 1d 1d 2d Et 1d 2d Bu 8 76 e e 76 e e 75 e e 74 e e (6.1) 75 e e (6.0) 74 e e 74 e e (5.9) N Bu 76 76 75 74 75 74 74 Bu NN CHCN (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) (5.3) (5.4) (6.0) (5.5) (5.0) (5.9) (5.6) BuHN OOOCHCN BuHN O OO O Bu Bu 1d1d MeN NEt OCHCN 3da Me (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 1d 2d 1d 2d (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 88 Et 76 eeee 76 eeee 75 eeee 74 eeee 75 eeee 74 eeee 74 eeee Bu 76 76 75 74 75 74 74 CHCN O O Bu 3dd 3dd O O3dd MeEt Me NNEt OO 3da 1d 2d (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 3da (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) O 1d 2d OOCHCN 76 76 75 74 75 74 74 88 76 76 75 74 75 74 74 CHCN Bu Bu O O Et 3dd Me OCHCN 3dd MeN NEt OCHCN (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 1d 2d 7676 eee 7676 eee 7575 eee 7474 eee 7575 eee 7474 eee 7474 eee 1d 2d (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 88 Et Bu OOO CHCN O Bu Me O O 3dd e e 3dd 76 75 O MeN 1d1d 2d2d O Me NEt 88 (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 76ee e 76 76ee e 75ee e 74ee e (6.1) 7574 74e75 74ee e 74(5.9) 76 76 75 74 75 74 74 OOOOCHCN Bu Bu O e e e 3dd O NEt O 1d 2d 3dd (6.0) (6.3) (6.2) (6.0) (6.4) Me 8 88 NEt OO (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) CHCN 1d 2d CHCN OO 1d 2d BuBu 76 76 75 74 75 74 74 OOCHCN 74 (6.4) 76 (5.9) 76 (6.0) 75 (6.3) 74 (6.2) 75 (6.1) CHCN CHCN e e e e e O O 3dd e e e e e e 3dd e e e e e e ee e N 69 72 71 71 72 72 70 (6.0) (6.3) (6.2) (6.1) 69 (6.4) 72 (5.9) 71 71 72 72 70 O O 69 72 71 71 72 72 70 Me Me NNOO O (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) 2d CHCN O (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) CHCN O Bu 89989 1d1d 2d 76 76 75 74 75 74 74 Bu 76 76 75 74 75 74 74 Bu O 3dd ee e (6.2) e72 e e ee e e e e e 2a 2a 2a NOOCHCN O O3dd O 69 72 71 71 72 72 70 (5.9) (6.0) (6.3) (6.1) (6.0) (6.4) 69 72 71 71 72 70 CHCN O 2d 1d1d 2d 8 89 Bu O O NNN O O O (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 3dd 3dd (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 3dd BuHN 2a BuHN BuHN 2a Bu 9 69e e (5.9) 72e e 71e e 71e e 72e e (6.1) 72e e 70e e Bu OO Bu 69 72 71 71 72 72 70 O CHCN (5.9) (6.0) (6.3) (6.2) (6.1) (6.0) (6.4) (6.0) (6.3) (6.2) (6.0) (6.4) CHCN OO Bu NNOO Bu O OCHCN 3dd OO (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) O 2a BuHN 2a (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 1e 99 1e 1e 69 72 71 71 72 72 70 BuHN Bu NN O 69 72 71 71 72 72 70 CHCN Bu 3ea 3ea 3ea O O OCHCN O 3ddO OO (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 2a 3dd (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) BuHN1e OO 2a CHCN O BuHN 69 72 71 71 72 72 70 1e 99 69 72 71 71 72 72 70 Bu NNO Bu O 3ea O 3ea OCHCN (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 69 72 71 71 72 72 70 2a2a BuHN1e (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 99 69 72 71 71 72 72 70 BuHN 1e Bu NN OOO CHCN OO Bu 3ea 3ea O O 2a Othe CHCN Oof NN 9 9aa aAll (4.3) (4.5) (4.9) (4.5) (4.5) (4.8) 2a (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) BuHN BuHN 69 72and 71 72 72 70 reactions were carried out in the presence PdI 22,,2KI, 271 O °C 20 (at 25 OO 1e O 69 72 71 72 72 70 AllBuHN reactions were carriedBu out in presence of PdI ,(4.5) KI, andH H 271 Oat 100 °Cunder under 20atm atm (at 25°C) °C) Bu All reactions were carried out in the presence of PdI KI, and H 2(4.5) O atat100 100 °C under 20 atm (at 25 °C) CHCN O 1e 3ea N O 3ea (4.3) (4.5) (4.9) (4.5) (4.5) (4.8) a N O 69 72 71 71 72 (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) a 2a BuHN 99 All OCHCN 69PdI 72and 71 71 72 72 7072 1e1e Bu O Allreactions reactions were2acarried carriedBuout out in the presence of PdI22,,KI, KI, andH H(4.5) Oat at100 100(4.9) °Cunder under 20atm atm(4.5) (at25 25°C) °C) CHCN OO were in the presence of 22O °C 20 (at 3ea 3ea 2a O NNin 9 9of aa All (4.3) (4.5) (4.5) (4.8) 2a (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) 1e BuHN BuHN OOthe 1e O 72and 71 71 72 72 70 Bu 69 72 71 71 72 72 70 Bu reactions were carried out in the of69PdI PdI , KI, KI, and H O at at 100 100 °Cof under 20 atm atm 25mL °C) 44presence for aa(4.3) concentration 0.5 mmol of 1(at aaa4:1 mixture CO/air, in reactions were carried out of 22,substrate H 22O °C under 20 25 °C) 4presence for24 24hhhwith with asubstrate concentration of 0.5 mmol of 1per per mL ofAll 4:1 mixture CO/air, inEmimEtSO EmimEtSO for 24 with substrate concentration of 0.5 mmol of 1(at per mL of 4:1 mixture CO/air, in EmimEtSO 3ea 3ea N O a All NOin O (4.5) (4.5) (4.9) (4.5) (4.5) (4.3) (4.5) (4.5) (4.9) (4.5) (4.5) (4.8) BuHN BuHN 2a 2a O 1e 1e Bu 99aaof 2a 69 (4.3) 72 (4.5) 71 (4.5) 71 (4.9) 72 (4.5) 72 (4.5) reactions were carried out the presence of PdI 2 , KI, and H 2 O at 100 °C under 20 atm (at 25 °C) Bu All reactions were carried outNNinOthe of PdI , (4.5) KI, and concentration H 2O at 100 °C of under 20 atm 25 mL °C) 4for for24 24hhwith with substrate concentration of0.5 0.5 mmol of(at 1per per mL 4:1 mixture CO/air, inEmimEtSO EmimEtSO 4presence aa2substrate mmol of 1(at aa4:1 mixture CO/air, in 3ea 3ea aof O (4.3) (4.5) (4.9) (4.5) (4.8) (4.3) (4.5) (4.9) (4.5) (4.5) (4.8) BuHN BuHN O All reactions were carried outin the of250:250:50:10:1. PdI 2,KI, KI, andH H 2Oat at100 100 °C 20 atm 25 °C) All reactions were carried out the of PdI ,substrate and 2(4.5) O °C under 20 atm (at 25 °C) 1e1e Bu Bu of 4:1 mixture CO/air, in EmimEtSO EmimEtSO 4presence for 24was with concentration of 0.5 mmol of(4.5) per mL 22O:2:1:KI:PdI 2in ratio Conversion of 11under quantitative in all of ionic liquid. The H 4presence for 24 hhwas with aa2substrate concentration of 0.5 mmol of 11 per mL aaionic 4:1 mixture CO/air, in 2O:2:1:KI:PdI 2molar molar ratio 250:250:50:10:1. Conversion 1was was quantitative all of liquid. The O:2:1:KI:PdI 2Omolar ratio was 250:250:50:10:1. Conversion ofof was quantitative inin all of ionic liquid. The HH 3ea

70 (3.2) 70 (3.2)

74 (3.3) 74 (3.3)

75 (3.8) 75 (3.8)

71 (3.1) 71 (3.1)

74 (3.2) 74 (3.2)

74 74 (7.3) (7.3)

72 72 (5.6) (5.6)

74 74 (6.0) (6.0) ee

70 70 (4.8) (4.8)

3ea All reactions were carried out presence of PdI ,substrate 2Conversion O under 20 2525 °C) Othe All reactions were carried outinin the of250:250:50:10:1. PdI 2KI, , KI,and andH H 2Oatat100 100°C °C under 20atm atm °C) 1e1e O3ea of 4:1 mixture CO/air, inEmimEtSO EmimEtSO for 24h hwas with concentration of 0.5 mmol of(at 1per per mL 44presence for 24 with aa2substrate concentration of mmol of 1(at mL of aaionic 4:1 mixture CO/air, in O:2:1:KI:PdI molar ratio 250:250:50:10:1. of was quantitative in all liquid. The H 3ea 22O:2:1:KI:PdI 22molar ratio was Conversion of 110.5 was quantitative in all ionic liquid. The H bb bmixture cof Oin All reactions were outin the presence of PdI ,KI, KI,and and H 2Oat at100 100 °C under 20 atm 25 °C) cDetermined cwith All reactions were carried out the PdI 2,2substrate H 2Conversion O °C under 20 atm 25 °C) 4for for 241. h1.with concentration of 0.5 mmol 1per per mL of a4:1 4:1 mixture CO/air, EmimEtSO of aionic CO/air, ininEmimEtSO 4presence 24 hwas aasubstrate concentration of 0.5 mmol ofof(at 1(at mL 2(Z+E) O:2:1:KI:PdI 2on molar ratio was 250:250:50:10:1. of 1pure was quantitative in all ionic liquid. The H cases. Isolated yield based starting by isolation of the diastereoisomers. 2carried O:2:1:KI:PdI 2O molar ratio 250:250:50:10:1. Conversion of 1pure was quantitative in all of liquid. The H cases. Isolated yield (Z+E) based on starting Determined by isolation the pure diastereoisomers. cases. Isolated yield (Z+E) based on starting Determined by isolation ofof the diastereoisomers. All reactions were carried out in the presence PdI 2, KI, and H 2O at 100 °C under 20 atm 25 °C) of a 4:1 mixture CO/air, in EmimEtSO 4 for 24 with aof concentration ofof 0.5 ofof1(at mL cof areactions 4:1 mixture CO/air, in EmimEtSO 4 for 24h1. h asubstrate substrate concentration 0.5mmol mmol 1per per mL bbliquid. cwith O:2:1:KI:PdI molar ratio was 250:250:50:10:1. Conversion of 1100 was quantitative in all (at 25 °C) of ionic liquid. The H22O:2:1:KI:PdI 22on molar ratio was 250:250:50:10:1. Conversion of 1 was quantitative in all of ionic The H cases. Isolated yield (Z+E) based on starting 1. Determined by isolation of the pure diastereoisomers. All were carried out in the presence PdI 2 , KI, and H 2 O at °C under 20 atm cases. Isolated yield (Z+E) based starting 1. Determined by isolation of the pure diastereoisomers. All reactions were carried out in the presence PdI 2,KI, KI, and H 2Oat at 100 °C 20atm 25 °C) All reactions were carried out in the presence of PdI 2substrate ,substrate and 2Conversion O 100 °C under 20 25 °C) ccof eeatm 4for for 24 h with aruns concentration of 0.5 mmol of(at 1per per mL of a4:1 4:1 mixture CO/air, inEmimEtSO EmimEtSO ˝ eDetermined of aRun CO/air, in 4starting 24 h with aruns concentration of 0.5 mmol of 1(at mL 2(Z+E) O:2:1:KI:PdI molar ratio was 250:250:50:10:1. of 1pure was quantitative all ˝ C) of a 4:1 ionic liquid. The 2to O:2:1:KI:PdI 2 2molar ratio was 250:250:50:10:1. Conversion of 1under was quantitative inin all ionic liquid. The HH cases. Isolated yield (Z+E) based on 1. Determined byH isolation of the pure diastereoisomers. cases. Isolated yield based on starting 1. Determined by isolation of the diastereoisomers. Run 1b1bbbliquid. corresponds the experiment, the next runs recycles. text for details. Determined 1mixture corresponds to the 1st experiment, the next to recycles. See text for details. Determined Run corresponds to the 1st experiment, the next to recycles. See text for details. All were out the of PdI KI, and H O at 100 under 20 (at 25 2 ,to 2See c 250:250:50:10:1. 4 presence for 24 h a substrate 0.5 mmol ofatm 1 per mL of a reactions 4:1 mixture CO/air, in 1st EmimEtSO 2carried O:2:1:KI:PdI 2in molar ratio was Conversion of 1of1C was quantitative in of ionic The HH cwith 2(Z+E) O:2:1:KI:PdI 2on molar ratio was 250:250:50:10:1. Conversion of was quantitative inall all ionic liquid. The cases. Isolated yield (Z+E) based on starting 1. Determined byconcentration isolation of the pure diastereoisomers. cases. Isolated yield based starting 1. by isolation of the pure diastereoisomers. Run 1mixture corresponds to the 1st experiment, the next runs recycles. See text for details. Determined corresponds to the 1st experiment, the next runs to recycles. See text for details. Determined c Determined of aRun 4:1 mixture CO/air, EmimEtSO 424 for 24 h250:250:50:10:1. ato substrate concentration ofeeee1of 0.5 ofionic 1 per mL b1b cwith 4for for 24 h astate substrate concentration of 0.5 mmol of per mL of aGLC. 4:1 mixture CO/air, inin EmimEtSO 4starting h1. with awith substrate concentration of 0.5 mmol 11mmol per mL of aRun 4:1 CO/air, in EmimEtSO 2to O:2:1:KI:PdI 2isolated molar ratio was Conversion of 1 was quantitative in all ionic liquid. The H 2O:2:1:KI:PdI 2isolated molar ratio was 250:250:50:10:1. Conversion of 1 was quantitative in all ionic liquid. The H cases. Isolated yield (Z+E) based on 1. Determined by isolation of the pure diastereoisomers. cases. Isolated yield (Z+E) based on starting Determined by isolation of the pure diastereoisomers. mixture CO/air, in EmimEtSO for 24 h with a substrate concentration 0.5 mmol of per mL of liquid. 1 corresponds to the 1st experiment, next runs to recycles. See text for details. Determined by GLC. The E isomer could be isolated at the pure state after column chromatography, while the Z Run 1 corresponds the 1st experiment, next runs to recycles. See text for details. Determined by GLC. The E isomer could be at the pure state after column chromatography, while the by The E isomer could be at the pure after column chromatography, while the ZZ 4 b c cDetermined 2to O:2:1:KI:PdI 2 on molar ratio was 250:250:50:10:1. Conversion of 1pure wasdiastereoisomers. quantitative in all of ionic liquid. The H(Z+E) cases. yield on starting 1.1. by of pure ee Determined cases. Isolated yield (Z+E) based starting Determined byisolation isolation ofthe the diastereoisomers. Run corresponds thebased 1st experiment, the next runs to recycles. Seechromatography, text for details. Determined Run 11bbIsolated corresponds to the 1st experiment, the next runs to recycles. See text for details. by GLC. The E isomer could be isolated at the state after column chromatography, while the Z by GLC. The E isomer could be isolated at pure state after column while the Z cpure b b c e e 2 O:2:1:KI:PdI 2 molar ratio was 250:250:50:10:1. Conversion of 1 was quantitative in all of ionic liquid. The H 2 O:2:1:KI:PdI 2 molar ratio was 250:250:50:10:1. Conversion of 1 was quantitative in all of ionic liquid. The H cases. Isolated yield (Z+E) based on starting 1. Determined by isolation of the pure diastereoisomers. 2to O:2:1:KI:PdI 2 ca. molar ratio was 250:250:50:10:1. Conversion of 1edetails. was quantitative in all of ionic H cases. Isolated yield (Z+E) based on starting 1. Determined byExperimental isolation of the pure diastereoisomers. Run 1liquid. corresponds the 1st experiment, next runs recycles. See text for details. Determined The H molar ratio was 250:250:50:10:1. Conversion of 1chromatography, was quantitative in all cases. Isolated Run 1O:2:1:KI:PdI corresponds to the experiment, next runs toto recycles. See text for details. Determined by GLC. The isomer could be isolated atthe the state after column chromatography, while the isomer isolated aa1st purity of 60% (by GLC). See the Section for by GLC. The EEThe isomer could be isolated at the pure state after column while the ZZ 2with isomer was isolated with a1st purity of ca. 60% (by GLC). See the Experimental Section for details. isomer was isolated with purity of ca. 60% (by GLC). See the Section for cpure e details. cases. Isolated yield (Z+E) based on starting 1. Determined byExperimental isolation of the pure diastereoisomers. Run 12 b1was corresponds to the experiment, next runs to recycles. See text for details. Determined Run corresponds to the 1st experiment, next runs to recycles. Seechromatography, text for details. Determined by GLC. The isomer could be isolated atthe the state after column chromatography, while the the ZZ by GLC. The EEyield isomer could be at the state after column while isomer was isolated with purity ofstarting ca.60% 60% (by GLC). See the Experimental Section for details. isomer was isolated with aa1st purity of ca. GLC). See the Experimental Section for cisolated d cpure c pure e edetails. bb1b1 cruns cases. Isolated yield (Z+E) based on starting 1. Determined by isolation ofthe the pure diastereoisomers. cases. Isolated (Z+E) based on 1.(by Determined by isolation of pure diastereoisomers. Run corresponds to the 1st experiment, the next recycles. See text for details. Determined yield (Z+E) based onto starting 1. Determined by isolation of the pure diastereoisomers. Run 1 corresponds to Run corresponds the experiment, next runs toto recycles. See text for details. Determined by GLC. The isomer could be isolated atthe the pure state after column chromatography, while the by GLC. The EEisomer could be isolated at the pure state after column chromatography, while the ZZ cases. Isolated yield (Z+E) based on starting 1. Determined by isolation of the pure diastereoisomers. isomer was isolated with a purity of ca. 60% (by GLC). See the Experimental Section for details. isomer was isolated with a purity of ca. 60% (by GLC). See the Experimental Section for details. e 1was corresponds tocould the 1st experiment, the next runs to recycles. See text for details. Determined by GLC. The EEisomer be isolated at pure state after column chromatography, while byRun GLC. The isomer could be isolated atthe the pure state after column chromatography, whilethe theZZ isomer was isolated with purity ofrecycles. ca. 60% 60% (by GLC). See the Experimental Section for details. e Determined isomer isolated with aa1st purity of ca. (by GLC). See the Experimental Section for details. e eDetermined 1st experiment, the next runs to See text for details. by GLC. The Ethe isomer could be Run 1 corresponds to the 1st experiment, the next runs to recycles. See text for details. Determined Run 1 corresponds to the experiment, the next runs to recycles. See text for details. by GLC. The E isomer could be isolated at the pure state after column chromatography, while the Z by GLC. The E isomer could be isolated at the pure state after column chromatography, while Z isomer was isolated with a purity of ca. 60% (by GLC). See the Experimental Section for details. dthe e isomer was isolated with a purity of ca. 60% (by GLC). See the Experimental Section for details. Run 1 was corresponds tocould the 1st the next runs to recycles. See text for fordetails. details. by GLC. The E isomer be experiment, isolated at the pure state after column chromatography, while the Determined Z isomer isolated with aafter ofofca. (by GLC). See the Section isomer was isolated with apurity purity ca.60% 60% (by GLC). See theExperimental Experimental Section details. isolated at the state chromatography, while the Zchromatography, isomer was for isolated with by GLC. The isomer could becolumn isolated atthe the pure state after column chromatography, while theZaZpurity of ca. by GLC. The EEpure isomer could be isolated at pure state after while the isomer was isolated with purity ca.60% 60% (by GLC). See thecolumn Experimental Section fordetails. details. isomer was isolated with aapurity ofofca. (by GLC). See the Experimental Section for by GLC. Theisolated ESee isomer could be of isolated pure after columnSection chromatography, while the Z isomer with a purity ca. 60%at (by GLC). Seestate the Experimental for details. 60% (by was GLC). the Experimental Section forthe details. isomerwas wasisolated isolatedwith withaapurity purityofofca. ca.60% 60%(by (byGLC). GLC).See Seethe theExperimental ExperimentalSection Sectionfor fordetails. details. isomer aa aa a a aaddad dd dd dd dd dd dd d dd

isomer was isolated with a purity of ca. 60% (by GLC). See the Experimental Section for details.

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Our first experiment was carried out using N-benzyl-2-methylbut-3-yn-2-amine (1a) as the substrate. This compound was allowed to react with CO, morpholine (2a), O2 , and water in the presence of the catalytic system PdI2 /KI under the following conditions: PdI2 /KI/1a/2a/H2 O molar ratio = 1:10:50:250:250, T = 100 ˝ C, P(CO) = 16 atm, P(air) = 4 atm, EmimEtSO4 as the solvent (0.5 mmol of 1a per mL of solvent) (Table 1, entry 1, run 1). After 24 h, the reaction crude was extracted several times with diethyl ether and the collected ethereal phases analyzed by TLC, GLC and GC-MS, who revealed the formation of two products whose MS spectra were compatible with the expected isomeric oxazolidinone products 3aa-Z and 3aa-E. The two isomers were isolated by column chromatography and their structure confirmed by IR, 1 H-NMR and 13 C-NMR spectroscopies (Z/E ratio = 3.1:1, total yield = 70%). The yield turned out to be lower using only 2 equiv of 2a instead of 5 (total yield = 55%). These results confirmed the possibility to carry out the auto-tandem catalysis process leading to oxazolidinones 3 in an ionic liquid (IL) as unconventional solvent. We accordingly verified the possibility to recycle the catalyst/solvent system. Thus, the residue obtained after product extraction with diethyl ether (still containing the catalyst dissolved in the IL), after drying under vacuum (to eliminate the residual diethyl ether), was used again by adding to it fresh propargylamine 1a and morpholine (2a) (1:5 ratio). After stirring at 100 ˝ C for 24 h, 3aa was obtained again as a 3.2:1 Z/E mixture in 71% total isolated yield (Table 1, entry 1, run 2), after extraction with diethyl ether. The recycling procedure was then successfully repeated up to six times. In order to assess the generality of the method, the reaction was then performed using different combinations of propargylic amines 1a–e and secondary amines 2a–d, with the results shown in Table 1, entries 2–9. As can be seen from Table 1, the method could be successfully applied to propargylic amines bearing various alkyl groups α to the triple bond, including simple alkyl groups (such as methyl and ethyl (1a, 1b, and 1d) and a cyclic chain such as –(CH2 )4 , (1c)), different groups on nitrogen (such as benzyl (1a–c) and butyl (1e, 1f)), and different nucleophilic secondary amines, both cyclic (as in the case of morpholine (2a), piperidine (2b), and pyrrolidine (2c)) and acyclic (as in the case of diethylamine (2d)). In all cases, good yields of the corresponding 2-(2-oxooxazolidin-5-ylidene)acetamides 3 were obtained (69%–76%), and the PdI2 /KI/EmimEtSO4 system could be conveniently recycled up to six times without loss of activity. 3. Experimental Section 3.1. General Information Chemicals were purchased from Sigma-Aldrich Italia (Milano, Italy) and were used as such without further purification. Melting points were taken on a Reichert Thermovar apparatus and are uncorrected. 1 H-NMR and 13 C-NMR spectra were recorded at 25 ˝ C in CDCl3 solutions with a Bruker DPX Avance 300 spectrometer (Bruker Italia, Milano, Italy) operating at 300 MHz and 75 MHz, respectively, with Me4 Si as internal standard. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy). Mass spectra were obtained using a Shimadzu QP-2010 GC-MS apparatus (Shimadzu Italia, Milano, Italy) at 70 eV ionization voltage. Microanalyses were carried out with a Thermo-Fischer Elemental Analyzer Flash 2000 (Fischer Scientific Italia, Rodani, Milano, Italy). All reactions were analyzed by TLC (Merck Italy, Vimodrone, Milano, Italy) on silica gel 60 F254 (Merck Italy) or on neutral alumina (Merck Italy) and by GLC using a Shimadzu GC-2010 gas chromatograph (Shimadzu Italia) and capillary columns with polymethylsilicone + 5% polyphenylsilicone as the stationary phase (HP-5). Column chromatography was performed on neutral alumina 90 (Merck Italy, 70–230 mesh). Evaporation refers to the removal of solvent under reduced pressure. 3.2. Preparation of Substrates Starting propargylic amines 1a–e were prepared and characterized as already described [20].

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3.3. Preparation of EmimEtSO4 Ionic liquid 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4 ) was prepared as previously described [31]. 3.4. General Procedure for the PdI2 /KI-Catalyzed Oxidative Carbonylation of Propargylic Amines (1) with CO, O2 , and Secondary Amines (2) in EmimEtSO4 and Recycling Experiments A 35 mL stainless steel autoclave was charged with PdI2 (8.3 mg, 0.023 mmol), KI (38.3 mg, 0.23 mmol), the starting propargylic amine 1 (1a, 199.0 mg; 1b, 215.0 mg; 1c, 245.0 mg; 1d, 176.0 mg; 1e, 206.0 mg; 1.15 mmol) and the amine 2 (2a, 501.0 mg; 2b, 490.0 mg; 2c, 409.0 mg; 2d, 420.6 mg; 5.75 mmol) in EmimEtSO4 (2.3 mL). Water (103.5 µL, 5.75 mmol) was then added and the autoclave was sealed, and pressurized at 20 atm (16 atm CO and 4 atm Air). After stirring at 100 ˝ C for 24 h, the autoclave was cooled and degassed. The mixture was then extracted with Et2 O (6 ˆ 4 mL), and the residue (still containing the catalyst and water dissolved in the ionic liquid) was used as such for the next recycle (see below). The collected ethereal phases were concentrated and the products purified by column chromatography on neutral alumina using as the eluent hexane:AcOEt from 95:5 to 6:4 (the E isomers were eluted first in all cases). (3aa-E, 64.8 mg, 17%; 3aa-Z, 201.4 mg, 53%; 3ab-E, 68.0 mg, 18%; 3ab-Z, 211.5 mg, 56%; 3ac-E, 54.5 mg, 15%; 3ac-Z, 216.7 mg, 60%; 3ad-E, 61.9 mg, 17%; 3ad-Z, 192.8 mg, 53%; 3ba-E, 75.2 mg, 19%; 3ba-Z, 221.8 mg, 56%; 3ca-E, 42.6 mg, 10%; 3ca-Z, 259.9, 61% mg; 3da-E, 39.3 mg, 11%; 3da-Z, 207.0 mg, 58%; 3dd-E, 34.1 mg, 10%; 3ea-E, 50.3 mg, 13%; 3ea-Z, 216.7 mg, 56%). Note: Product 3dd-Z could not be isolated at the pure state by column chromatography, and the GLC analysis evidenced a purity of ca. 60%. The GLC-MS analysis was compatible with the proposed structure and 1 H-NMR spectrum of the crude product evidenced a peak at 5.19, compatible with a Z stereochemistry. For testing recycling of the catalyst, after removal of Et2 O under vacuum, the residue obtained as described above, still containing the catalyst dissolved in the ionic liquid, was transferred into the autoclave. The starting material 1 (1.15 mmol), the amine 2 (5.75 mmol) and H2 O (103.5 µL, 5.75 mmol) was added, and then the same procedure described above was followed. 3.5. Characterization of Products Oxazolidinones 3aa-Z, 3aa-E, 3ab-Z, 3ab-E, 3ad-Z, 3ad-E, 3ba-Z, 3ba-E, 3ca-Z, 3ca-E, 3da-Z, 3da-E, 3ea-Z, 3ea-E, were characterized by comparison with the characterization data already reported by us [20]. All the other products were fully characterized by MS spectrometry, IR, 1 H-NMR and 13 C-NMR spectroscopies, and elemental analysis, as reported below. Copies of 1 H-NMR and 13 C-NMR spectra for all products are given in the Supplementary Materials. (E)-3-Benzyl-4,4-dimethyl-5-(2-oxo-2-pyrrolidin-1-ylethylidene)-oxazolidin-2-one (3ac-E). White solid, m.p. = 124–125 ˝ C. IR (KBr): ν = 1779 (s), 1664 (m), 1611 (m), 1404 (m), 1346 (w), 1194 (w), 709 (w) cm´1 ; 1 H-NMR (CDCl ): δ = 7.38–7.26 (m, 5 H, aromatic), 5.83 (s, 1 H, =CH), 4.47 (s, 2H, CH Ph), 3.51–3.40 3 2 (m, 4H, pyrrolidine ring), 2.02–1.82 (m, 4H, pyrrolidine ring), 1.64 (s, 6H, 2Me); 13 C-NMR (CDCl3 ): δ = 165.4, 162.9, 153.6, 137.3, 128.7, 127.8, 96.8, 64.4, 47.2, 45.7, 43.8, 26.2, 24.4, 23.9; GC-MS m/z = 314 (11) [M+ ], 299 (5), 286 (2), 255 (1), 244 (2), 223 (13), 216 (2), 181 (2), 166 (4), 146 (2), 140 (8), 132 (2), 112 (2), 98 (9), 91 (100); anal. calcd for C18 H22 N2 O3 (314.38): C, 68.77; H, 7.05; N, 8.91; found C, 68.75; H, 7.04; N, 8.89. (Z)-3-Benzyl-4,4-dimethyl-5-(2-oxo-2-pyrrolidin-1-ylethylidene)-oxazolidin-2-one (3ac-Z). Yellow solid, m.p. = 105–106 ˝ C. IR (KBr): ν = 1780 (s), 1685 (s), 1616 (m), 1438 (m), 1401 (m), 1225 (w), 1036 (m), 754 (w) cm´ 1 ; 1 H-NMR (CDCl3 ): δ = 7.48–7.22 (m, 5H, aromatic), 5.21 (s, 1H, =CH), 4.48 (s, 2H, CH2 Ph), 3.59–3.43 (m, 4H, pyrrolidine ring), 2.03–1.84 (m, 4H, pyrrolidine ring), 1.35 (s, 6H, 2Me); 13 C-NMR (CDCl ): δ = 162.7, 160.5, 153.8, 137.1, 128.8, 128.0, 127.8, 94.6, 62.4, 47.1, 45.7, 44.2, 27.5, 25.9, 3 24.4; GC-MS m/z = 314 (8) [M+ ], 299 (4), 286 (1), 255 (1), 243 (3), 223 (11), 216 (1), 181 (2), 166 (2), 147 (4), 140 (6), 132 (1), 112 (2), 98 (7), 91 (100); anal. calcd for C18 H22 N2 O3 (314.38): C, 68.77; H, 7.05; N, 8.91; found C, 68.78; H, 7.03; N, 8.92.

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(E)-2-(3-Butyl-4-ethyl-4-methyl-2-oxooxazolidin-5-ylidene)-N,N-diethylacetamide (3dd-E). Yellow oil. IR (film): ν = 1786 (s), 1687 (m), 1618 (m), 1401 (w), 1052 (m), 1082 (m) cm´1 ; 1 H-NMR (CDCl3 ): δ = 5.92 (s, 1H, =CH), 3.46–3.30 (m, 4H, 2NCH2 ), 3.29–3.16 (m, 1H, CHH), 3.06–2.93 (m, 1H, CHH), 2.76–2.60 (m, 1H, CHH), 1.70–1.53 (m, 3H, CH2 + CHH), 1.42–1.30 (m, 2H, CH2 ), 1.66 (s, 3H, Me), 1.19 (t, J = 7.2, 3H, Me), 1.14 (t, J = 7.1, 3H, Me), 0.95 (t, J = 7.4, 3H, Me), 0.79 (t, J = 7.4, 3H, Me); 13 C-NMR (CDCl3 ): δ = 164.1, 163.5, 153.8, 96.7, 68.0, 43.0, 40.5, 40.0, 31.1, 28.5, 23.7, 20.3, 14.5, 13.7, 13.1, 8.2; GC-MS m/z = 296 (25) [M+ ], 281 (15), 267 (100), 224 (8), 180 (15), 168 (98), 140 (15), 124 (19), 112 (9), 100 (54), 72 (71); anal. calcd for C16 H28 N2 O3 (296.41): C, 64.83; H, 9.52; N, 9.45; found C, 64.80; H, 9.54; N, 9.42. (Z)-2-(3-Butyl-4-ethyl-4-methyl-2-oxooxazolidin-5-ylidene)-N,N-diethylacetamide (3dd-Z). Yellow oil, purity: ca. 60% (by GLC). GC-MS m/z =296 (26) [M+ ], 281 (11), 267 (100), 224 (13), 197 (8), 180 (26), 168 (74), 138 (13), 124 (33), 112 (14), 100 (37), 72 (89). 4. Conclusions In conclusion, we have shown that it is possible to successfully perform the PdI2 /KI-catalyzed auto-tandem catalysis oxidative carbonylative process leading to oxazolidone derivatives 3 in an ionic liquid, such as EmimEtSO4 , as unconventional solvent, and that the catalyst/solvent system can be easily recycled several times without loss of activity. Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/ 21/7/897/s1. Acknowledgments: This research work was partially supported by MIUR PON R&C 2007-2013 Project “DIRECT FOOD” cod. PON01_00878 (research grant to R.M.). Author Contributions: All authors contributed equally to this work. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript: DME EmimEtSO4 Et2 O GC GC-MS GLC GLC-MS ILs TLC MS NMR VOCs

1,2-dimethoxyethane 1-ethyl-3-methylimidazolium ethyl sulfate diethyl ether gas chromatograph gas chromatograph/mass spectrometer gas-liquid chromatography gas-liquid chromatography/mass spectrometry Ionic Liquids thin layer chromatography mass nuclear magnetic resonance Volatile Organic Compounds

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Sample Availability: Samples of the compounds 3 are available from the authors. © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).