Aza-Michael

The direct aziridinadon of nitroalkanes has been repotted for the first dme. Treatment of nitroalkene with an excess of CaO and NsONHCO-.Et fNs =4-nitroben2enesulfonyl gives the ct-nitroaziridine in good yields fEq. 10.70. ° The reaction proceeds via aza-Michael reaction followed by a ring closure. 

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

Rare earth-Li-binaphthooxides Aza-Michael reaction on chalcone High (+)-NLE 55... 

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). 

The imidazolium-based ionic liquid [bmim][BF ] has been used as a catalyst in the aza-Michael reaction of various aliphatic amines to unsaturated compounds with different electron withdrawing groups in good yields as shown in Scheme 76. Water was used as the solvent in order to obtain up to 98% yield in 7 h. In the presented example, 95% yield in 7 h was achieved [198], The ionic liquid could be recovered and reused five times without loss of activity. 

Scheme 76 Ionic liquid catalyzed aza-Michael reaction...

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Andreana and Santra have investigated the influence of the solvent on the generation of molecular diversity arising from a set of MCR substrates under microwave irradiation [36]. They have found that by using water as solvent, both 2,5-DKPs and 2-azaspiro[4.5]deca-6,9-diene-3,8-diones were obtained through aza-Michael reaction and 5-exo Michael cyclization, respectively. Nevertheless,... 

Scheme 12 Synthesis of nitrogen-containing hi- and tricyclic heterocycles by a Knoevenagel-aza-Michael sequence...

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) [293]. Ricci and co-workers explained the outcome of their aza-Michael reaction with the mechanistic picture visualized in Scheme 6.140 C9-epi-QN -derived thiourea 121 displayed a bifunctional mode of catalysis, which simultaneously activated both the chalcone Michael acceptor and the donor O-benzylhydroxylamine through explicit hydrogen bonding. 

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

Thiourea catalyst 139 was also screened in the asymmetric Friedel-Crafts reaction between 2-naphthol trans-nitrostyrene (73% yield 0% ee 18 h in toluene at -20 °C and 10 mol%) [277], in the asymmetric aza-Michael reaction of O-benzyl-hydroxylamine to chalcone (72% conv. 19% ee 72 h in toluene at 20 °C and 20mol% catalyst loading) [293], and in the asymmetric Morita-BayUs-HiUman [176, 177] reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (20% yield 31% ee 46 h at rt and 20mol% DABCO and 139) [310]. In aU these transformations, thiourea 139 proved to be not competitive to the organocatalysts probed for these transformations under identical screening conditions and thus was not employed in the optimized protocols. 

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]. 

Hydroamination of Alkenes Kobayashi et at. found that several transition metal salts displayed high catalytic activity in aza-Michael reactions of enones with carbamates, while conventional Lewis acids (BF3-OEt2, A1C13, TiCl4...) were much less active. 

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]. 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

Conjugate additions of carbamates to a, P-unsaturated enones require - apart from metal halide - TMSC1 as a stoichiometric additive [96]. The addition of ethyl carbamate to cyclohexenone (41h) requires only 50mol% TMSC1, which was an exceptionally low amount compared with other Michael acceptors. With 10 mol% of the catalyst, the yield of 3-aminocyclohexenone derivative 66 was good (93%) [97], Aza-Michael reactions also proceed in aqueous media with good results if Co(II),... 

Scheme 8.30 Aza-Michael reactions of carbamates in aqueous media.

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... 

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