Desilylation azomethine ylide generation

The feasibility of azomethine ylide generation from 7 and intramolecular dipolar cycloaddition was examined under a variety of conditions. For example, activation of vinylogous amide 71 with BzOTf [41] followed by desilylation with TBAT led to complex mixtures of products. Likewise, using MeOTf as the activating agent yielded similar results. Significantly, none of these protocols furnished the desired pyrrolidine 73. Only decomposition of the silylpyridinone to form unidentified products was observed, despite the fact that quantitative O-methylation of the... 

Finally, the LDA deprotonation of amine N-oxides has been reported to generate azomethine ylides that can be trapped in [2 + 3] cycloadditions with simple alkenes.126 For example, N-methylpyrrolidine N-oxide (137) reacts with LDA in the presence of cyclopentene to give adduct (139 Scheme 31). A variety of other N-oxides behave similarly. Interestingly, there are no examples published to date where nonstabilized azomethine ylides generated by the desilylation procedure can be trapped by simple, unactivated alkenes. It is not clear whether these discrepancies are due to some fundamental difference in the reactive intermediate being generated, or whether the differences in environment are responsible for differing behavior. Further work is needed to establish this point. 

The A -unsubstituted nonstabilized azomethine ylides generated from the desilylation of A -[(trimethylsilyl)methyl]-iminium triflates [1384, R = H, R = Ph R R = (CH2)s, (CH2)20(CH2)2] cycloadd to strongly polarized sulfonyl-imines 1385 (Ar = Ph, 4-CIC6H4, 4-O2NG6H4) to produce the corresponding A -imidazolines, for example, 1387, together with the initial cycloadducts 1386 (Scheme 358) <2001H(55)243>. 

Although structural modification is quite limited, the azomethine ylides generated by the N-oxide route are complementary in their applications in organic synthesis to the identical ylides generated by other methods [e.g., the decarboxylation route (Section II,E) and the desilylation route (Section II,B)]. When the origin of the enhanced reactivity is solved, a new field will be open in the chemistry of azomethine ylide 1,3-dipoles. 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

The desilylation methodology for the generation of 1,3-dipoles, developed by Vedejs and West (29) with regard to azomethine ylides, was successfully applied by Achiwa and co-workers (30) to the field of thiocarbonyl ylides. This approach allowed the generation of the parent thioformaldehyde (5)-methylide (la) and its use for preparative purposes (31,32). Generation of la in the presence of C=C dipolarophiles led to tetrahydrothiophenes (19) in high yield (Scheme 5.4). 

Alkynyl azomethine ylides containing an aryl bridge have been shown to undergo cyclization. Thus, tautomerization of imine (137) afforded an azomethine ylide which cyclized to give two diastereomeric dihydropyrroles and traces of aromatized product (Scheme 42).56 The activated cyclic ylide (138), generated via the desilylation route, underwent cyclization to afford dihydropyrrole (139) in 42% yield.67b The structure of (139) is closely related to erythramine. The structurally related non-stabilized azomethine ylide (140) did not cyclize, tautomerizing to the corresponding enamine instead. 

The generation of nonstabilized azomethine ylide 256 via PET-initiated sequential double desilylation and [3 + 2]-cycloaddition reaction with various dipolarophiles to generate five-membered heterocycles 257, has also been established by Pandey et al., as shown in Table 8.5 [110]. 

The efficient desilylation from amine radical cation in media favouring SSIP formation has also been used [104] for the sequential double desilylation reaction of amine 110 to generate azomethine ylide 111 which upon cycloaddition with a different dipolarophile gives a stereoselective pyrrolidine ring system 112 as depicted in Scheme 20. 

Cycloaddition of thiazolium azomethine ylides with dialkyl acetylenedicarboxylates 61 provides another approach to pyrrolo[2,1 -bjthiazoles 64 <070L4099>. Quatemization of 2-methylthiothiazole with trimethylsilylmethyl trifluoromethanesulfonate (TMSChkOTf) and subsequent fluoride-induced desilylation of the resulting (trimethylsilyl)methylammonium salt generate the acyclic azomethine ylide 62. This ylide readily participates in 1,3-dipolar cycloadditions with acetylene derivatives 61 to give adducts 63, which undergo spontaneous elimination of methylmercaptan to give the A-fuse cl thiazoles 64. ... 

Use of trimethylsilylmethyl triflate enables the effective formation of intermediate iminium salts in the reaction mixture because the counteranion, triflate ion, is nonnucleophilic both to carbon and silicon atoms. N-Silyl-methylation can also be performed with other alkylating agents, such as silymethyl chloride, bromide, and iodide. However, the resulting iminium salts desilylate immediately after they are formed by the attack of the halide counteranions, leading to a serious decomposition of the requisite iminium intermediates. The final step of desilylation generating azomethine ylides is effected by a fluoride anion which is selectively nucleophilic to a silicon atom. 

Though a sequence of N-alkylation of imines and subsequent deprotonation at the (X position, instead of N-silylmethylation and desilylation, would seem to be an even more useful and general method for the generation of azomethine ylides, both the N-alkylation and the selective deprotonation are tricky processes (75JOC2048). The difficulty involved in the alkylation and deprotonation method discussed previously (86CRV941) increases the synthetic importance of the silylmethylation and desilylation method. 

N-Silylation with trimethylsilyl triflate forms N-silylated iminium triflates, which are subsequently desilylated in situ with fluoride ion to generate N-silylated azomethine ylides (82TL2589 84CL2041 85CPB1975). 

In general S-alkylation of thioamides occurs much more readily and selectively than O-alkylation of amides. Thus, N-silylmethylthioamides obtained by the reaction of N-silylmethylamides with Lawesson s reagent (83JOC4773) are treated with methyl triflate to give C-methylthioiminium triflate ylide precursors. Their desilylation with cesium fluoride generates C-hetero-substituted azomethine ylides 35 (83JOC4773 85JOC2170). 

N-Alkoxymethyl(trimethylsilyImethyl)amines are convenient precursors for C-unsubstituted azomethine ylides 43 since the N-alkoxymethyl(trimeth-ylsilylmethyl)amines are readily available by the reaction of N-alkylated silylmethylamines with formaldehyde in alcohol solvents (84CL1117). Treatment of the amines with trimethylsilyl triflate in acetonitrile or tetrahy-drofuran brings about the elimination of alkoxy group R O to form N-silylmethyliminium trifiates 42. The subsequent desilylation with cesium fluoride generates C-unsubstituted azomethine ylides 43 (84CL1117). Both steps of the alkoxy elimination and subsequent desilylation of 42 are induced by trifluoroacetic acid (85CPB896, 85CPB2762), tetrabutylammonium... 

Table II summarizes the azomethine ylide 1,3-dipoles generated by the desilylation route.

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