Unsaturated azomethine ylides

Non-stabilized a, p y, 5-unsaturated azomethine ylides (158), generated by the decarboxylation method from 3,3-diarylpropenals (156) and secondary amino acids (157), have been found to undergo [1,7]-electrocyclization followed by a [1,5]-hydrogen shift, to yield 2,3-dihydro-17/-2-benzazepines (159). 

A review of synthesis of azepines by [l,7]-electrocyclization reactions of unsaturated azomethine ylides and azatriene anions has been published. ... 

Azomethine ylides (Section 4.03.6.1.1) have been generated from a wide variety of aziridines using both thermal and photochemical methods. With carbon-carbon unsaturated dipolarophiles, pyrrolines or pyrrolidines are obtained. With hetero double bonds, however, ring systems of interest to this discussion result. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted azomethine ylides have been conducted under microwave irradiation. Oritani reported that a mixture of the aldehyde 137 and N-methyl- or N-benzylglycine ethyl ester (138) on the surface of silica gel, irradiated under microwaves for 15 min, generated azomethine ylides 139 that subsequently underwent in situ intramolecular cycloadditions to afford the corresponding tricyclic compounds 140 in 79 and 81% yield, respectively (Scheme 9.42) [93],... 

A final class of dipole shown to be effective in iminium ion catalysed [3+2] cycloadditions are azomethine ylides derived from 35 [71] (Scheme 12). Vicario showed that 20 mol% of diarylprolinol 33 catalysed the cycloaddition between a,P-unsaturated aldehydes 34 and imines 35 (THE, 4 °C, 72 h) to give the densely... 

The 1,3-dipolar cycloaddition of azomethine yUdes with olefins gives rise to pyrrolidines which represent structural elements of organocatalysts, natural products, and drug candidates. Asymmetric metal-catalyzed variants attracted considerable attention over the last few years [64], Recently, Vicario et al. reported an organo-catalytic [3 -i- 2] cycloaddition of azomethine ylides and a,p-unsaturated aldehydes mediated by a chiral secondary amine [65]. 

This attractive protocol for the asymmetric addition of a, p-unsaturated esters to A-metalated azomethine ylides was further developed using C(2) symmetrical imidazoladine stereodirecting units in an extensive study into the effects of reaction conditions and substituent effects on the facial selectivity of the reaction (36). Both... 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

N-Metalated azomethine ylides (44) are probably the most synthetically useful of these dipoles, since they can be generated from readily available N-alkylide-neamino esters or nitriles through a simple activation method. The resulting 1,3-dipoles show high reactivity with a,p-unsaturated carbonyl acceptors to provide excellent stereo- and regioselectivities. A variety of asymmetric versions have been reported. 

N-Metalated azomethine ylides generated from a-(alkylideneamino) esters can exist as tautomeric forms of the chelated ester enolate (Scheme 11.8). On the basis of the reliable stereochemical and regiochemical selectivities described below, it is clear that the N-metalated tautomeric contributor of these azomethine ylides is important. Simple extension of the above irreversible lithiation method to a-(alkylideneamino) esters is not very effective, and cycloadditions of the resulting lithiated ylides to a,(3-unsaturated carbonyl compounds are not always clean reactions. When the a-(alkylideneamino) esters bear a less bulky methyl ester moiety, or when a,(3-unsaturated carbonyl compounds are sterically less hindered, these species suffer from nucleophihc attack by the organometalhcs, or the metalated cycloadducts undergo further condensation reactions (81-85). 

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. 

Methyl (naphthylideneamino)acetate undergoes dimerization to produce a mixture of two diastereomeric imidazolidines when treated with Mg(C104)2 or C0CI2 (89). Other imines can also be used as acceptor molecules (Scheme 11.12). With the exception of azomethine ylides incorporating sodium and titanium ions, other N-metalated ylides undergo highly endo-selective cycloadditions with a,p-unsaturated... 

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... 

The most commonly applied ot,p-unsaturated ester auxiliary is the menthol group. It is inexpensive and easy to handle. Several different menthyl 2-alkenoates (157), in particular acrylates, have been applied in 1,3-dipolar cycloaddition reactions (Scheme 12.51). The major drawback of the menthyl ester auxiliary in 1,3-dipolar cycloadditions are the poor selectivities often associated with these reactions, except for reactions with azomethine ylides. 

The azomethine ylide derived from 79 has also been used in reactions with chiral ( )-y-alkoxy-cc,p-unsaturated esters 80 (Scheme 12.27). The corresponding tetra-substituted pyrrolidines 81 were obtained with complete regiocontrol in fair to excellent de (125). 

Pyrazolines have also been incorporated as modifying groups by 1,3-addition of azomethine ylides to the carbon-carbon double bond of unsaturated poly(esters) (186 Scheme 89) (68MI11100). Poly(isoxazolines) were prepared in similar fashion by reaction of an unsaturated polymer with a nitrile oxide (75MI11106). 

Commercially available 5-hydroxyethyl-4-methylthiazole has been used in the preparation of the azomethine ylides (588) and (589) (81TL2727). These reacted in good yield with several unsaturated alkenes to provide the adducts (590) which cyclized on silica gel chromatography to (591). The product with X = OEt and Z = C02Et was further transformed into the pyrrole (592) by reaction with methanesulfonic acid in methanol followed by quenching with triethylamine (Scheme 129). 

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