Regioselective Synthesis of γ‐Amino Esters, Nitriles, Sulfones, and Pyrrolidinones by Nickel‐Catalyzed Reductive Coupling of Aldimines and Activated Alkenes

Abstract

The transition-metal-catalyzed regioselective coupling of two organic p components via a five-membered metallacycle intermediate is one method for the construction of CÀC bonds and the synthesis of molecules with multiple functional groups. Among these reactions, the reductive coupling of alkyne/alkyne [1a] alkene/alkyne, [1b,c,i,j] and alkene/alkene [1a] couples has been widely explored by us and others. Similarly, the coupling of alkene/carbonyl [1d] and alkyne/carbonyl [1e-h] couples catalyzed by metal complexes has more recently also attracted attention. In comparison, the use of an imine derivative as one of the p components has only rarely been explored. [2,3] Rhodium- [2a-c] and organo-catalyzed [2d,e] coupling reactions of conjugated alkenes with activated imines were found to give Baylis-Hillman-type products in which a CÀC bond was formed between the a-carbon atom of the alkene and the carbon atom of the imine. There is no report of an analogous metal-catalyzed coupling reaction occurring at the b-carbon atom of the alkene.[3] Our efforts to develop methods for the reductive coupling of two p components [1b,c, 4a] prompted us to investigate the coupling reaction of conjugated alkenes and imines. Herein, we report an efficient eneimine reductive coupling reaction catalyzed by a nickel-1,10-phenanthroline complex to give various substituted g-amino esters, [5i,j] g-aminonitriles, [5k,l] g-aminosulfones, and pyrrolidinones.[5] These products are all g-aminobutyric acid (GABA) derivatives, which are known to exhibit a wide range of biological properties [6] and have found various industrial applications.[6] In contrast to the base- [2d] and metal-catalyzed reactions, our ene-imine coupling reaction yields saturated products in which a C À C bond is formed at the b-carbon atom of conjugated alkenes.The success of the reductive ene-imine coupling reaction depends greatly on the choice of the ligand and metal. When 4-fluorobenzaldimine 1 a was treated with ethyl acrylate in acetonitrile in the presence of [CoI 2 (dppe)] (dppe = 1,2-bis(diphenyphosphanyl)ethane) or [NiBr 2 (dppe)], Zn, and H 2 O at 808C, only a trace of the reductive coupling product 3 a was observed. Fortunately, when we changed the catalyst to [NiI 2 (phen)], [NiBr 2 (bipy)], [NiCl 2 (bipy)], or [NiBr 2 -(phen)] (phen = 1,10-phenanthroline, bipy = 2,2'-bipyridine), the expected product 3 a was formed in yields of 55, 75, 37, or 99 %, respectively. The yields of 3 a were determined by integration of the 1 H NMR signals, using mesitylene as the internal standard. The nickel complex [NiBr 2 (tmeda)] (tmeda = tetramethylethylenediamine), which has an electron-rich nitrogen ligand, did not give the desired product. Also, phenanthroline or zinc alone did not catalyze the reaction. Surprisingly, these studies show that phosphines are not suitable ligands in the present catalytic reaction, but that bipyridine-type ligands, particularly phen, are essential.

Π–Π Stacking Complex Induces Three‐Component Coupling Reactions To Synthesize Functionalized Amines

“…To our delight, various electron‐rich and electron‐poor aniline derivatives ( 5 a – 5 e ) reacted smoothly, providing the desired products in moderate to good yields. It is worth noting that the products formed by electron‐rich substituted anilines and n ‐butyl acrylate were not stable; instead, they readily formed the substituted pyrrolidones via intramolecular cyclization [29a, 34] . To avoid this cyclization reaction, acrylonitrile was selected as model olefin to investigate the scope further.…”

Catalytic transformations of alkenes via nickelacycles

“…Cheng and co-workers reported a nickel-catalysed reductive coupling of activated alkenes with imines in 2008 (Scheme 10). 49 The reaction is suitable for aryl imines and alkenes bearing ester, cyano, or sulfonyl groups. This method efficiently yields γ-amino esters, nitriles, and sulfonyl derivatives with excellent regio-selectivity.…”

Cobalt‐Catalyzed Regioselective Synthesis of Indenamine from o‐Iodobenzaldimine and Alkyne: Intriguing Difference to the Nickel‐Catalyzed Reaction

“…Generally, the alkyne insertion takes place in such a way that the electron-deficient carbon atom is near the metal. [8] Alternatively, intermediate It is worth noting that both cobalt and nickel complexes can catalyze the cyclization reaction of 2-iodobenzaldimine 1 with alkyne 4, but the products, as shown in Scheme 4, are different. These two reactions are likely all through a fivemembered azametalacycle A followed by insertion of alkyne into A to give B.…”