Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Although 2‐imino‐1H‐imidazol‐5(2H)‐ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as “privileged scaffolds” in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper‐catalyzed domino reactions for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones and quinoxalines involving C?C bond‐cleavage with a 1,3‐dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones includes aza‐Michael addition, intramolecular cyclization, C?C bond‐cleavage, 1,2‐rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza‐Michael addition, intramolecular cyclization, elimination reaction, and C?C bond‐cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.     

Aza‐Michael addition reaction: Post‐polymerization modification and preparation of PEI/PEG‐based polyester hydrogels from enzymatically synthesized reactive polymers

The utility of aza‐Michael addition chemistry for post‐polymerization functionalization of enzymatically prepared polyesters is established. For this, itaconate ester and oligoethylene glycol are selected as monomers. A Candida Antarctica lipase B catalyzed polycondensation reaction between the two monomers provides the polyesters, which carry an activated carbon‐carbon double bond in the polymer backbone. These electron deficient alkenes represent suitable aza‐Michael acceptors and can be engaged in a nucleophilic addition reaction with small molecular mono‐amines (aza‐Michael donors) to yield functionalized linear polyesters. Employing a poly‐amine as the aza‐Michael donor, on the other hand, results in the formation of hydrophilic polymer networks. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 745–749     

KOtBu‐Catalyzed Michael Addition Reactions Under Mild and Solvent‐Free Conditions

Designed transition metal complexes predominantly catalyze Michael addition reactions. Inorganic and organic base‐catalyzed Michael addition reactions have been reported. However, known base‐catalyzed reactions suffer from the requirement of solvents, additives, high pressure and also side‐reactions. Herein, we demonstrate a mild and environmentally friendly strategy of readily available KO^tBu‐catalyzed Michael addition reactions. This simple inorganic base efficiently catalyzes the Michael addition of underexplored acrylonitriles, esters and amides with (oxa‐, aza‐, and thia‐) heteroatom nucleophiles. This catalytic process proceeds under solvent‐free conditions and at room temperature. Notably, this protocol offers an easy operational procedure, broad substrate scope with excellent selectivity, reaction scalability and excellent TON (>9900). Preliminary mechanistic studies revealed that the reaction follows an ionic mechanism. Formal synthesis of promazine is demonstrated using this catalytic protocol.     

2,2‐Bis(methoxy‐NNO‐azoxy)ethyl Derivatives of 4,8‐Dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine: The Synthesis and X‐ray Investigation

The first synthesis of 4,8‐dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine bearing 2,2‐bis(methoxy‐NNO‐azoxy)ethyl groups has been developed. These compounds are obtained by aza‐Michael reaction of 1,1‐bis(methoxy‐NNO‐azoxy)ethene or its equivalents, such as 2,2‐bis(methoxy‐NNO‐azoxy)ethanol derivatives, with 4,8‐dihydro‐bis‐furazano[3,4‐b:3′4′‐e]pyrazine.     

过无溶剂、无催化的aza-Michael加成反应合成b氨基酸衍生物

本文报道一种安全,环境有好,经济实用的合成b氨基酸衍生物的新方法。利用α,β不饱和化合物和脂肪族胺,通过无溶剂、无催化的aza-Michael加成反应,高产率的合成b氨基酸衍生物。     

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

Modular One‐Step Three‐Component Synthesis of Tetrahydroisoquinolines Using a Catellani Strategy

Reported is a modular one‐step three‐component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza‐Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2‐alkyl‐ and 2‐aryl‐substituted aziridines to access 1,3‐cis‐substituted and 1,4‐cis‐substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.     

Multicomponent Synthesis of Isoindolinone Frameworks via RhIII‐Catalysed in situ Directing Group‐Assisted Tandem Oxidative Olefination/Michael Addition

A Rh^III‐catalysed three‐component synthesis of isoindolinone frameworks via direct assembly of benzoyl chlorides, o‐aminophenols and activated alkenes has been developed. The process involves in situ generation of o‐aminophenol (OAP)‐based bidentate directing group (DG), Rh^III‐catalysed tandem ortho C?H olefination and subsequent cyclization via aza‐Michael addition. This protocol exhibits good chemoselectivity and functional group tolerance. Computational studies showed that the presence of hydroxyl group on the N‐aryl ring could enhance the chemoselectivity of the reaction.     

Switchable Stereocontrolled Divergent Synthesis Induced by aza‐Michael Addition of Deactivated Primary Amines under Acid Catalysis

Switchable tandem intramolecular aza‐Michael/Michael and double aza‐Michael reactions allow the oriented synthesis of highly functionalised cyclic skeletons. Conjugate addition of deactivated anilines triggers chemo‐ and stereo‐divergent ring‐closure reaction pathways with a striking selectivity depending on reaction conditions.     

N‐tert‐butoxycarbonyl‐N‐substituted hydrazines in SNAr displacements. Synthetic pathways to N‐1‐substituted anthrapyrazoles,aza‐anthrapyrazoles and aza‐benzothiopyranoindazoles

The synthesis of several N‐tert‐butoxycarbonyl(Boc)‐protected‐N‐substituted hydrazines has been accomplished. The use of these protected hydrazines in S_NAr substitutions leads to products in which the most nucleophilic nitrogen displaces the leaving group. Treatment of these compounds with trifluoroacetic acid readily removes the Boc‐protecting group and the intermediates readily undergo cyclizations to yield N‐1‐substituted aza‐benzothiopyranoindazoles, anthrapyrazoles and aza‐anthrapyrazoles. Side chain buildup was employed in the synthesis of several aza‐anthrapyrazoles.     

Steric and Electronic Requirements in the Synthesis of 2,3‐Dihydro‐4(1H)‐quinolinones by the Tandem Michael‐SNAr Reaction

The steric and electronic requirements have been investigated for the synthesis of 2,3‐dihydro‐4(1H)‐quinolinones by the tandem Michael‐S_NAr reaction. Substrates bearing a single methyl group at the β‐enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X═H or NO₂. Substrates with β,β‐dimethyl substitution at the Michael terminus gave low yields of heterocyclic products in molecules having monoactivated S_NAr aromatic acceptor rings (X═H) and very good yields for diactivated systems (X═NO₂). For these hindered substrates, success in the final cyclization hinges on the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct before this intermediate can revert to starting materials.     

Flame retardant high oleic sunflower oil‐based thermosetting resins through aza‐ and phospha‐michael additions

Phosphorus‐containing thermosetting resins derived from high oleic sunflower oil were prepared through phospha‐Michael addition of a difunctional secondary phosphine oxide, the 1,3‐bis(phenylphosphino)propane dioxide on the α,β‐unsaturated ketone derived from high oleic acid (ETR). The aim of this approach was to introduce phosphorus and to crosslink the material in one single step. Materials with increasing aromatic content were also prepared by addition 4,4′‐diaminodiphenylmethane and co‐crosslinking through aza‐Michael addition. The kinetics of the phospha and aza‐Michael additions was investigated using the enone derivative of methyl oleate (EO) in presence of BF₃·Et₂O as catalyst and in absence of catalyst at different temperatures. Competitive experiments showed that phospha‐Michael addition proceeds faster than the aza‐Michael addition. The new triglyceride‐based thermosets containing up to 4.2% of P, were characterized and their thermal and flame retardant properties evaluated. Limiting oxygen index values increase from 21.5 for the phosphorus free material up to 38.0 for the final material with 4.2% P content. These results demonstrate that the flame retardant properties of vegetable oil‐based thermosets can be significantly improved by adding covalently bonded phosphorus to the polymer. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Efficient Synthesis of 1,2,3‐Triazoles by Copper‐Mediated CN and NN Bond Formation Starting From N‐Tosylhydrazones and Amines

An effective copper‐mediated synthesis of 1,5‐dialkyl‐4‐aryl‐1,2,3‐triazoles and 1,4‐dialkyl‐5‐aryl‐1,2,3‐triazoles has been achieved by the use of different N‐tosylhydrazones and alkyl amines. The scope of the substrates could be extended from anilines to aliphatic amines when 30 mol % amino acid is added into the reaction mixture. This methodology exhibits many notable features, such as broad substrates scope, high efficiency, and good regioselectivity. Preliminary mechanistic studies indicated that the reaction probably proceeded through a 1‐tosyl‐2‐vinyldiazene intermediate and subsequent aza‐Michael addition and N?N bond formation process.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.     

Chiral Ammonium Betaine‐Catalyzed Highly Stereoselective Aza‐Henry Reaction of α‐Aryl Nitromethanes with Aromatic N‐Boc Imines

A highly stereoselective aza‐Henry reaction of α‐aryl nitromethanes with aromatic N‐Boc imines was established by using C₁‐symmetric chiral ammonium betaine as a bifunctional organic base catalyst. Various substituted aryl groups for both imines and nitromethanes were tolerated in the reaction, and a series of precursors for the synthesis of unsymmetrical anti‐1,2‐diaryl ethylenediamines was provided.     

Nickel‐Catalyzed Mizoroki–Heck‐ versus Michael‐Type Addition of Organoboronic Acids to α,β‐Unsaturated Alkenes through Fine‐Tuning of Ligands

Various arylboronic acids reacted with activated alkenes in the presence of [Ni(dppe)Br₂], ZnCl₂, and H₂O in CH₃CN at 80 °C to give the corresponding Mizoroki–Heck‐type addition products in good to excellent yields. Furthermore, 1 equivalent of the hydrogenation product of the activated alkene was also produced. By tuning the ligands of the nickel complexes and the reaction conditions, Michael‐type addition was achieved in a very selective manner. Thus, various p‐ and o‐substituted arylboronic acids or alkenylboronic acid reacted smoothly with activated alkenes in CH₃CN at 80 °C for 12 h catalyzed by Ni(acac)₂, P(o‐anisyl)₃, and K₂CO₃ to give the corresponding Michael‐type addition products in excellent yields. However, for m‐substituted arylboronic acids, the yields of Michael‐type addition products are very low. The cause of this unusual meta‐substitution effect is not clear. By altering the solvent or phosphine ligand, the product yields for m‐substituted arylboronic acids were greatly improved. In contrast to previous results in the literature, the present catalytic reactions required water for Mizoroki–Heck‐type products and dry reaction conditions for Michael‐type addition products. Possible mechanistic pathways for both addition reactions are proposed.     

Synthetic and DFT Studies Towards a Unified Approach to Phlegmarine Alkaloids: Aza‐Michael Intramolecular Processes Leading to 5‐Oxodecahydroquinolines

A diastereoselective synthesis of cis‐5‐oxodecahydroquinolines is described in which three stereocenters are generated in a one‐pot reaction. The reaction involves a lithium hydroxide‐promoted Robinson annulation/intramolecular aza‐Michael domino process from an achiral acyclic tosylamine‐tethered β‐keto ester. The development and scope of this reaction was facilitated through the use of DFT‐based mechanistic studies, which enabled the observed diastereodivergent course of the azacyclization to be rationalized. The varying stereochemistry and stability of the resulting decahydroquinolines was found to depend on whether a β‐keto ester or ketone were embedded in the substrates undergoing aminocyclization. This synthetic approach gave access not only to both diastereomeric cis‐decahydroquinolines from the same precursor, but also to the corresponding trans isomers, through an epimerization processes of the corresponding N‐unsubstituted cis‐5‐oxodecahydroquinolines. The described methodology provides advanced building‐blocks with the three relative stereochemistries required for the total synthesis of phlegmarine alkaloids.     

NH2SO3H–SiO2 as a new water‐compatible,recyclable heterogeneous catalyst for the synthesis of novel (α,β‐unsaturated) β‐amino ketones via aza‐Michael reaction

NH₂SO₃H–SiO₂/water as a novel catalytic system was used for the synthesis of (α,β‐unsaturated) β‐amino ketones via aza‐Michael reaction at reflux conditions. The methodology was of general applicability and the catalyst exhibited activity up to five cycles. The catalyst was characterized for the first time using FT‐IR, X‐ray diffraction and scanning electron microscopic–energy dispersion analytical X‐ray. The stability of the catalyst was evaluated by differential scanning calorimetry and TGA/differential thermal analysis. High efficiency of the catalyst along with its recycling ability and the rather low loading demonstrated in reactions are the merits of the presented protocol. Copyright © 2013 John Wiley & Sons, Ltd.