Aza-enamine reaction

Scheme 5. Br0nsted acid catalyzed imino aza-enamine reaction...

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

In a recent study of the 3-aza-Cope reaction, Murahashi and coworkershave found that Af- 2-butenylJ-enamine 90 undergo [l,3]-sigmatropic rearrangement rather than [3,3]-rearrangement in the presence of Pd(0) and CFjCOjH. Thus, y,<5-unsaturated aldehyde 92 is formed in 60% yield from 90 (R = Me, Ph) through rearrangement and hydrolysis reactions (equation 17). 

Both symmetrical and unsymmetrical ketones have been utilized in synthetic applications of the aza-annulation reaction of enamine derivatives with acrylamides. The most efficient use of this methodology involved generation of the enamine from the symmetrical ketone 21 (eq. 5).11 Aza-annulation with this enamine led to the formation of 22 as an 85 15 mixture of the regioisomeric tetra- and trisubstituted alkenes (b and a), respectively, which were then oxidized to the corresponding pyridone 23. Formation of intermediate 23 was a key to the synthesis of the... 

Regioselective aza-annulation reactions have been achieved through the use of aryl substituted keto enamine substrates. Aryl substitution at the a-position of the enamine provides for regioselective imine-enamine tautomerization at the non aryl (i carbon. Early studies in this area compared the utility of pyrrolidine enamine versus benzyl imine derivatives of a-tetralone.8 In the absence of solvent, aza-annulation of 75 with acrylamide led to the formation of 76, but use of imine derivative 77 resulted in significantly higher yield of 76 (eq. 19).8 Similar reactions were observed between an aryl ethyl ketone and acrylamide (72% yield, dioxane, 70 °C) or acrylonitrile when catalyzed by AICI3 at 25 °C.33... 

Methyl acrylate (37) was used as a reagent for annulation with the phenyl imine derivative of acetophenone. For example, phenyl imine 78 was converted to 79 by treatment with 37 in the presence of AICI3 (eq. 20).34 The enamine formed from acetophenone (80) and NH4OAC was converted to 82 by combination with 81 (eq. 21).17 In the case of 81, the aryl substituent provided a steric and electronic hindrance to the aza-annulation reaction, but the reactivity of the reagent was enhanced by the combined effects of the C02Et and CN functionality. Due to the nature of the substituents on the intermediate dihydropyridone, dehydrogenation occurred to form pyridone 82. 

Development in the area of asymmetric aza-annulation reactions paralleled achievements in the analogous area of asymmetric Michael addition reactions with chiral imines.111 Induction of asymmetry has been primarily controlled through substitution at the nitrogen of the imine or enamine that becomes incorporated into the heterocycle. Restricted rotation of this asymmetric substituent led to preferred conformational isomers, which provided stereofacial bias for carbon-carbon bond formation. 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

The axially chiral dicarbo>g7lic acids 63 proved to be effective catalysts also in other classes of reactions. They were successfully used in the asymmetric addition of simple aza-enamines or vinylogous aza-enamines to imines (Scheme 24.22). In both cases, the optimisation of experimental parameters allowed products to be obtained with good yields and high ee values. Furthermore, the possibility to transform reaction products 70 and 73 respectively into a-aminoketones and y-amino a,p-unsaturated nitriles easily and without loss in ee gave additional value to the methodologies. 

In 2011 the same research group described another efficient application of dicarbo Q lic acids 63 in the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition (lED 1,3-DC) of C//-cyclic azomethine imines with t-butyl vinyl ether or vinylogous aza-enamines (synthesized from enals) (Scheme 24.23). This latter reaction, carried out without exclusion of moisture and air, gave cycloadducts regioisomeric to the products observed in the normal-electron-demand 1,3-dipolar cycloaddition (NED 1,3-DC) catalysed by Ti/binolate starting from the enals and for this reason the authors introduced the concept of lED umpolung 1,3-DC. 

A new catalyst incorporating chiral thiourea and nucleophilic Lewis base showed efficiency in the asymmetric BH reactions. The use of a binaphthyl-based amino-thiourea catalyst 63 synthesized by Wang et al. [ 114] resulted in good yields and enantioselectivities in the reaction of cyclohexenone and aldehydes. Another amino-thiourea 12 was demonstrated as an efficient bifunctional catalyst for the enantio-selective aza-BH reaction of (3-methyl-nitrostyrene and iV-tosyl-aldimines, affording P-nitro-y-enamines in modest to excellent enantioselectivities and diastereoselec-tivities (Scheme 9.32). It was found that no reaction occurred in the absence of the methyl group of nitroalkene [115]. A similar phophine-thiourea catalyst 64 was reported in 2008 by Wu and co-workers [116] and turned out to be efficient in the asymmetric BH reaction of MVK and aldehydes, providing fast reaction rate, good yields, and excellent enantioselectivities (87-94% ee). More recently, aL-threonine-derived phosphine-thiourea catalyst 65 was readily synthesized by Lu and coworkers [117] and applied in the enantioselective BH reaction of aryl aldehyde with methyl acrylate. 

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