Yongming Deng

Synergistic–cooperative combination of enamine catalysis with transition metal catalysis

Synergistic-cooperative combination of enamine catalysis with transition metal catalysis is an emerging and exciting field aiming to achieve organic transformations that cannot be accomplished by individual catalysis. The biggest obstacle in this field lies in the catalyst incompatibility arising from Lewis acid-Lewis base interactions. Several strategies including soft/hard combination of a Lewis acid and a Lewis base, the utilization of a chelating ligand, and mixing an ammonium salt with a Lewis acid have been developed to solve the incompatibility problem. A number of new reactions and new reaction modes have been discovered using these strategies. In this review article, we aim to highlight these new discoveries found in the literature.

Arylamine-catalyzed enamine formation: Cooperative catalysis with arylamines and acids

The explosive growth of organocatalysis has had a huge impact on asymmetric catalysis in the past decade. Transition-metal catalysis, on the other hand, has been established for a long time as one of the most powerful methods in organic synthesis. Aminocatalysis is a major field in organocatalysis. The combination of organocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to achieve organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently. Although it promises huge potential, this research area has grown only slowly. The major challenge lies in the incompatibility of the catalysts, in particular, the combination of enamine catalysis with harder metal Lewis acid is very difficult. The circumvention of this problem would represent an important breakthrough, given the huge number of substrates that can be activated by the large variety of metal Lewis acids. Herein, we present the solution to this longstanding problem by using arylamines as the catalysts in enamine catalysis. Very importantly, we demonstrate that arylamines can serve as efficient amine catalysts in direct asymmetric aldol reactions. Furthermore, we have developed a highly chemoand enantioselective three-component azaDiels–Alder reaction by combining arylamines with metal Lewis acids. The combination of enamine catalysis with metal Lewis acid catalysis was first reported by Ibrahem and Codava in 2006. Since then, considerable progress has been made in this area, leading to a series of exciting discoveries. However, these combinations were limited to soft metals, such as Cu, Ag, Au, Ir, and Pd or Pd, activating either p-allyl electrophiles or alkynes (Scheme 1,A and B). Combining enamine catalysis with harder metal Lewis acid (Scheme 1, C) turned out to be very challenging because of acid–base self-quenching reactions, which render the catalysts inactive. In asymmetric aminocatalysis involving either an enamine or an iminium intermediate, a chiral aliphatic secondary or primary amine serves as the catalyst. Aliphatic amines are hard bases, and thus likely to be compatible with softer metals based on the soft/hard approach, but less likely to be compatible with harder metals. We hoped to find an amine catalyst that is compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine/ metal Lewis acid catalysis, and to facilitate the development of a new research area of iminium/metal Lewis acid catalysis. We considered to use arylamines, such as aniline, because they have a much lower pKa value (4–6) than aliphatic amines (9–11), and should be much softer because of the delocalization of the lone pair to the aromatic p system. It appeared to us that arylamines are ideal candidates for combination with harder metal Lewis acids. Despite their ubiquity in organic chemistry, arylamines have never been used in enamine catalysis. This may be mainly due to the general understanding that the nucleophilicity of arylamines is much lower compared to aliphatic amines. However, List and co-workers suggested the formation of enamine intermediates from arylamines as a step in organocatalytic cascade reactions. In a recent report, Gong and co-workers also suggested that an achiral arylamine played a crucial role in controlling the stereochemistry of a Friedl nder condensation by forming an enamine intermediate. We speculate that arylamines might be suitable to serve as an efficient amine catalyst in enamine catalysis in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid. The asymmetric aza-Diels–Alder reaction (ADAR) is the most convenient and powerful method to form nitrogencontaining heterocycles, which are one of the most important structural motifs in natural products, pharmaceuticals, and biosystems. While the recent progress on normal-electrondemand ADARs based on dienamines and imine dienophiles Scheme 1. Combination of enamine catalysis with metal catalysis.

Sc(OTf)3-catalyzed three-component cyclization of arylamines, β,γ-unsaturated α-ketoesters, and 1,3-dicarbonyl compounds for the synthesis of highly substituted 1,4-dihydropyridines and tetrahydropyridines

A Sc(OTf)3-catalyzed three-component cyclization reaction of arylamines, β,γ-unsaturated α-ketoesters and 1,3-dicarbonyl compounds was developed to synthesize highly substituted 1,4-dihydropyridines and fused bicyclic tetrahydropyridines carrying a quaternary all-carbon center.

Highly Regio- and Enantioselective Formal [3 + 2]-Annulation of Indoles with Electrophilic Enol Carbene Intermediates

Chiral cyclopentane-fused indolines are synthesized with high regio- and enantiocontrol by formal [3 + 2]-annulation reactions of indoles and electrophilic enol carbenes. High enantioselectivity and exclusive regiocontrol occurred with enoldiazoacetamides using a less sterically encumbered prolinate-ligated dirhodium(II) catalyst in reactions with N-substituted indoles without substituents at the 2- or 3-positions via a selective vinylogous addition process. In this transformation, donor-acceptor cyclopropenes generated from enoldiazoacetamides serve as the carbene precursors to form metal carbene intermediates.

Catalytic Asymmetric [3+1]-Cycloaddition Reaction of Ylides with Electrophilic Metallo-enolcarbene Intermediates

The first asymmetric [3+1]-cycloaddition was successfully achieved by copper(I) triflate/double-sidearmed bisoxazoline complex catalyzed reactions of β-triisopropylsilyl-substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio- and diastereoselectivities (up to 99 % ee, and >20:1 d.r.). Additionally, the [3+1]-cycloaddition of catalytically generated metallo-enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex.

Catalytic Asymmetric Synthesis of Cyclopentyl β‐Amino Esters by [3+2] Cycloaddition of Enecarbamates with Electrophilic Metalloenolcarbene Intermediates

Chiral cyclopentyl β-amino esters are formed catalytically by [3+2] cycloaddition reactions of enecarbamates with electrophilic metalloenolcarbenes in high yield with up to 98 % ee and excellent diastereocontrol. Use of β-silyl-substituted enoldiazoacetates with a chiral dirhodium catalyst and trans-β-arylvinylcarbamates are optimal for this transformation, which occurs with hydrogen-bond association between the vinylcarbamate and the intermediate metalloenolcarbene. Reductive conversion of the protected amino esters forms highly functionalized cyclopentyl β-amino acids and 3-aminocyclopentanones.

Hg(OTf)2 Catalyzed Intramolecular 1,4-Addition of Donor-Acceptor Cyclopropenes to Arenes

A Hg(OTf)2 catalyzed intramolecular arene 1,4-addition reaction of N-benzyl donor-acceptor cyclopropenecarboxamides was developed to synthesize a series of [3.2.2]nonatriene derivatives. This novel reaction is also observed with silver(I) catalysts known to form metal carbene intermediates in competition with the Buchner reaction.

Catalytic Divergent [3+3]‐ and [3+2]‐Cycloaddition by Discrimination Between Diazo Compounds

Highly selective divergent cycloaddition reactions of enoldiazo compounds and α-diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2-a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]-cycloaddition of a carbonyl ylide. Use of Rh2 (pfb)4 or Rh2 (esp)2 directs the reactants to regioselective [3+2]-cycloaddition generating cyclopenta[2,3]pyrrolo[2,1-b]oxazoles with good yields and excellent diastereoselectivities.

In situ fabrication and electrochemical behavior of amino acid polyoxometalate nanoparticles-embedded microcapsules

Amino acid polyoxometalate nanoparticles-embedded microcapsules were in situ fabricated by layer-by-layer (LbL) self-assembly method [polyoxometalate, H3PMo12O40·nH2O (PMo12); amino acid, glycine (Gly)]. The morphology of the obtained microcapsules was characterized by transmission electron microscopy and scanning electron microscopy. The electrochemical behavior of the amino acid polyoxometalate nanoparticles-embedded microcapsules was studied by cyclic voltammetry. The microcapsules show the pH-dependent properties, indicating that the pH of solution plays an important role in the electrochemical behavior of heteropolyanions.

Chiral Bimetallic Catalysts Derived from Chiral Metal Phosphates: Enantioselective Three-Component Asymmetric Aza-Diels-Alder Reactions of Cyclic Ketones

A new type of chiral bimetallic catalyst is disclosed. These chiral bimetallic catalysts are easily formed through mixing a metal Lewis acid and a metal binaphthyl phosphate (MLA/M[P]3) in solution. (1)H and (31)P NMR spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, and X-ray crystallographic analysis reveal a bimetallic structure of the Y(Yb)(III)/Y[P]3 complexes with bridging binaphthyl phosphate ligands. The Lewis acidity of these chiral bimetallic catalysts is readily tuned by changing either the metal Lewis acid or the chiral metal phosphate. Through cooperative metal Lewis acid-enamine catalysis, asymmetric three-component aza-Diels-Alder reactions of 5-, 6-, and 7-membered cyclic ketones, unsaturated ketoesters, and arylamines were successfully achieved to afford fused bicyclic dihydropyridines in high yields (up to 94%) with high enantioselectivity (up to 99% enantiomeric excess) and excellent chemoselectivity.