Azomethine ylides Michael additions

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Very recently examples of tandem Michael-azomethine ylide cyclization reactions have been presented.626 Thus, divinyl sulfone reacted with imine (124) in the presence of lithium bromide and tri-ethylamine to give (126) in 40% yield (Scheme 38). Presumably formation of Michael adduct (125), tau-tomerization to an azomethine ylide and ensuing intramolecular [3 + 2] cycloaddition afforded (126). Indeed, (125) could be independently synthesized and converted to (126) under the reaction conditions. The preference for initial Michael addition, rather than cycloaddition, was variable. When (124) and divinyl sulfone were treated with silver acetate and triethylamine in DMSO, intermolecular azomethine cycloaddition occurred giving (127) in 27% yield. 

Treatment of 4-carboxythiazolidine with formaldehyde and methyl propargylate affords thi-azocine (52), apparently via intermediate formation of an azomethine ylide, which then undergoes (3 + 2] cycloaddition with the alkyne, followed by Michael addition to a second equivalent of alkyne and final rearrangement (Scheme 18) <87CC1296>. 

The employment of bifunctional urea-tertiary amine 104 or monothiourea 105 catalysts selectively promotes either the Michael addition or cycloaddition process, respectively, [60]. As depicted in Scheme 2.30, the tertiary amine group would activate the in situ formed a-amino esters to produce azomethine ylides A (or enolates), whereas the nitroalkene counterparts would be activated by the thiourea (urea) moiety through a double H bonding interaction (B). 

Another reaction type involving iminium salts led to pyrrolidines via the trapping of azomethine ylides generated from sarcosine and aqueous formaldehyde (Lubineau et al, 1995). The efficiency of [3+2] cycloaddition was related to the water content. Indeed, adding THF to the reaction medium decreased the rate of the Michael addition, which competed with the desired pyrrolidine synthesis ... 

Lubineau, A. Bouchain, G. Queneau, Y. (1995) Reactivity of the carbonyl group in water. Generation of azomethine ylides from aqueous formaldehyde Michael addition versus dipolar trapping, J. Chem. Soc., Perkin Trans. 1,2433-7. 

MichaeU-Henry Reaction Liu et al. and Xie et al. independently found that tertiary amine-thioureas could stereoselectively promote the addition of diethyl a-aminomalonate-derived azomethine ylides to nitroolefms, affording Michael adducts other than dipolar cycloaddition adducts as the major products. Using monofunctional chiral thioureas 140d instead of tertiary amine-thiourea catalysts, Liu et al. successfully developed a three-component [3-1-2] dipolar cycloaddition of benzaldehydes 3, diethyl a-aminomalonates 45a, and nitrostyrenes 165, resulting directly in the enantioenriched pyrrolidines 208 as the only products (Scheme 2.56) [81a] while Xie et al. efficiently converted the Michael adducts 210 to pyrrolidines 208 in high yield and maintained ee by the use of 30 equiv of 2,2,2-trifluoroethanol as the additive (Scheme 2.56) [81b]. 

The competition between Michael addition and 1,3-dipolar cycloaddition has been investigated for the reaction of alkylidene bisphosphates and alkylidene malonates PhCH=CX2 [X = P(0)(0R)2 or CO2R] with azomethine ylides (generated from PhCH=NCH2C02Me) catalysed by the CuOTf-BiphamPhos complex. ... 

Enantioselective total synthesis of ((47J,5iS)-5-Amino-4-(2,4,5-tri-fluorophenyl) cyclohex- l-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[l, 2,4]tri-azolo[4,3-a]pyrazin-7(877)-yl)methanone ABT-341 (708), a DPP4 (dipeptidyl peptidase IV) inhibitor, has been completed in diphenylprolinol silyl ether (707), in the one-pot, multicomponent, reaction of nitroalkene (704), acetaldehyde (703), vinyl phosphonate (706) and amine (705) (Scheme 178) A novel, catalytic, asymmetric Michael addition of azomethine ylide (710) with p-substituted tetraethyl alkyhdene bisphosphates (709) has been realised in the presence of a chiral copper(I)/TF-Bipham-Phos (712) complex. This system provided enantioenriched unnatural i -amino acid derivatives (711) containing gem-bisphosphonates in high yields with... 

Bifunctional Reagents. Activated a-bromo ketones are smoothly converted into the corresponding silyl enol ethers when treated with a mixture of UBrlRfiSIChlorotrimethylsilane. Aldehydes are converted into the corresponding a,(3-unsaturated esters using Triethyl Phosphonoacetate and Triethylamine in the presence of LiBr (eq 5). Similar conditions were extensively used in the asymmetric cycloaddition and Michael addition reactions of /7-lithiated azomethine ylides (eq 6). ... 

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