Additions aza-Michael

Scettri et al. reported the aza-Michael addition of aniline to chalcones under solvent-free conditions, promoted by cinchonine. The corresponding products were obtained in good yield but with poor ee (11-58%). The enantioselectivity was improved up to 99% by the addition of an achiral silicon-based Lewis acid catalyst such as trimethylsilyl iodide (TMSI).  

Chalchones were recently also used as substrates for addition of indolines catalysed by quinine-derived squaramides and for addition of pyrazole catalysed by 9-epi-QA in combination with l-hydro)y-2-naphthoic acid additive. 

Fustero et al. described an intramolecular aza-Michael reaction of enone carbamates catalysed by 9-amino-9-deoxy-epi-hydroquinine (9-epi-DHQA) with pentafluoropropionic acid (PFP) as cocatalyst affording a series of piperidines, pyrrolidines and the corresponding benzofused derivatives with up to 98% ee. Reaction times can be significantly reduced by performing the reaction under microwave irradiation at 60 °C without any loss of yield or enantioselectivity. At the same time, Fan et al. described the same reaction to produce functionalised 2-substituted piperidines with up to 98% ee, but using a combination of 9-epi-DHQA and trifluoroacetic acid.  

The straightforward reaction of carbonyls with an oxidant is a very well-known route towards the widely present a-hydro y-carbonyl structural motive and several types of organometallic or organocatalytic asymmetric protocols have been developed. The reaction is generally accepted as a variant of Rubottom oxidation (oxidation with peracids), with a mechanism proceeding via an epoxide intermediate obtained from an enol. The first catal5Aic asymmetric reaction was developed in 1988 using a quaternised Cinchona alkaloid. (See Chapter 16). 

Jorgensen et al. used similar p-ketoesters as substrates and cumyl hydroperoxide instead TBHP. Among various alkaloids and solvents, the best results were obtained with 20 mol% dihydroquinine in dibromomethane (up to 98% yield and 73% ee). 

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The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

In an equally distinguished example, Langer et al. demonstrated the synthesis of a 140-membered library of degradable polymers from diacrylate and amine monomers (compare Fig. 6) that were polymerized via aza-Michael addition chemistry [80],... 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

In the presence of thiourea 121 (20mol% in toluene at 4°C/20°C), the aza-Michael addition [149-152] of 0-benzylhyroxylamine to numerous frans-chalcones bearing electron-rich and electron-deficient (hetero)aromahc subshtuents as well as aliphatic side chains provided the respective P-keto hydroxylamines 1-8 in moderate to very good yields (35-94%) and low to moderate (30-60%) ee values... 

Scheme 6.139 Typical products of the aza-Michael addition of O-benzylhydroxylamine to frans-chalcones under bifunctional 121 -catalysis.

Xu et al reported using [bmim][OH] as a basic IL for the Aza-Michael addition reaction between various amines and a,(3-unsaturated carbonyl compounds and nitriles. The products were obtained in high yields and the IL could be recycled eight times without significant change in the product yields. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Scheme 1.1.6 Tandem aza-Michael addition/a-ester enolate alkylation or aldol reaction.

Sulfones have become increasingly important in organic synthesis in recent years and a, P-unsaturated sulfones especially are known to be excellent Michael acceptors. Following our concept of using SAMP derivatives as chiral equivalents of ammonia, the enantioselective aza-Michael addition has been investigated in order to provide a new method for the synthesis of P-aminosulfones [15]. 

In 2008 Yang and coworkers have reported an efficient synthesis of substituted a-alkilidene-fi-lactams via aNaOH- promoted intramolecular aza-Michael addition of a-carbamoyl, a-(l-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution reaction in alcoholic media (Scheme 90), [198]. 

Cerium(IV) ammonium nitrate (CAN) has been reported to catalyse a facile and efficient aza-Michael addition of aromatic and aliphatic amines to a -unsaturated esters in the absence of solvent under ultrasound irradiation.136 a,/l-Unsaturated ketones react in aqueous solutions under these conditions but only with aliphatic (not aromatic) amines.137... 

The basic ionic liquid [BmimJOH has been introduced as a catalyst for the aza-Michael addition of aromatic amines and A-heterocycles to cyclic or acyclic ketones under solvent-free conditions.138... 

A double aza-Michael addition was enforced by high pressure in the reaction of primary amines with the ,/l-unsaluraled bis ester (92) to afford the azanorbomyl derivatives (93).141... 

Ying A-G, Liu L, Wu G-F et al (2009) Aza-Michael addition of aliphatic or aromatic amines to [alpha], [beta]-unsaturated compounds catalyzed by a DBU-derived ionic liquid under solvent-free conditions. Tetrahedron Lett 50(14) 1653-1657... 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

Michael additions to conjugated carbonyls can be catalyzed by gold species. Among them, arene additions are the most studied area but other nucleophiles can attack the gold-coordinated enones as well. In fact, the intermolecular aza-Michael additions of carbamates to enones was reported in 2002 with both Au(I) and Au(III) salts, and in 2007 an intramolecular aUcoxide and amide conjugate addition has been developed and applied to the synthesis of (+)-andrachcinidine (equation 132). In the latter case, the enones are formed as intermediates in a previous gold-catalyzed step that is the hydration of an alkyne and methanol loss. Then the cyclization takes place to give piperidines. 

Polshettiwar V, Varma RS (2010) Nano-organocatalyst magnetically retrievable ferrite-anchored glutathione for microwave-assisted Paal-Knorr reaction, aza-Michael addition, and pyrazole synthesis. Tetrahedron 66 1091-1097... 

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

The high-pressure aza-Michael addition of mono- and diamines on a,p-unsaturated diesters provide a practical route for preparing some p-aminoesters and novel bridged p-aminodiesters. ... 

The aza-Michael addition is an important class of carbon-nitrogen bondforming reactions, and has been demonstrated to be a powerful tool in organic synthesis. EiScient aza-Michael addition reactions of alkyl amine (Scheme 8.34)... 

Scheme 3.20 One pot synthesis of enantioenriched isoindolines based on chiral Bronsted acid catalyzed F C reaction/base catalyzed aza Michael addition reaction sequence.

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