Pyridinium ylides, cycloadditions, indolizine

In the reaction of 2-bromo-3,3,3-trifluoropropene with pyridinium ylides cycloaddition occurred readily leading to I-CF3 derivatives of indolizines [21]. Similar reaction took place in the cases of pyridazinium and isoquinolinium ylides. 

Under the amine basic conditions, the subsequently added l-(2-oxoethyl)-pyridinium bromide derivatives 90 are transformed in situ into pyridinium ylides that undergo a [2 + 3] cycloaddition with the alkynone dipolarophiles present in the reaction mixture. The initial cycloadducts instantaneously aromatize to give rise to highly fluorescent indolizine derivatives 91. 

Mechanistically, this sequence can be rationalized by initial alkynone formation upon coupling of acid chloride 7 and aUcyne 4 furnishing the alkynone 8, which now can act as a dipolarophile (Scheme 18). The amount of triethylamine is sufficient to deprotonate the l-(2-oxoethyl)pyridinium bromide 25 giving rise to the zwitter-ionic pyridinium ylide 27, an allyl-type dipole suitable for the subsequent 1,3-dipolar cycloaddition to give the dihydroindolizine 28. Under either aerobic or anaerobic conditions in the final cycloaddition step oxidative aromatization directly furnishes the desired indolizines 26. 

Pyridinium ylides were used to prepare a series of 1-trifluoroacetyl indolizines by cycloaddition with 4-ethoxy-l,l,l-trifluorobut-3-one. After cycloaddition, loss of ethanol and spontaneous aromatization were proposed for the formation of the indolizine. An example of this chemistry is shown in the synthesis of indolizines 77 (Fig. 3.36). Good yields were reported. 

Zhang, X.-c. Huang, W.-y. Cycloaddition reactions of A-(cyanomethyl)pyridinium ylides with 2,2-dihydropolyfluoroalkanoates. J. Fluorine Chem. 1998, 92, 13-16. Zhang, X.-c. Huang, W.-y. A convenient synthesis of polyfluoroalkyl-substituted pyr-azolofl,5-al pyridine, pyrrolo[l,2-6]pyridazine and indolizine derivatives. J. Fluorine Chem. 1998, 87, 57-64. 

Indolizines have been made via carbene addition to 2-vinylpyridine or dipolar addition of pyridinium ylides. 3-substituted indolizines have been obtained in a one step procedure from reaction of chlorocarbenes with 2-vinylpyridine (94CC509). Microwave irradiation has been used in 1,3-dipolar cycloaddition of pyridinium dicyanomethylide with alkynes <94H(38)785>. 

An oxidative one step synthesis of aromatic indolizine (91) by 1,3-dipolar cycloaddition of pyridinium ylides with alkenes was reported (Scheme 51) (93JCS(P1)2487). 

Differently substituted pyrrolidine rings can be obtained by the 1,3-dipolar cycloaddition of pyridinium ylides 42 on SWCNTs that afford indolizine derivatives such as compound 43 (09JA10670,14MI99). 

The effect of solvent nature on the reactions of pyridinium ylides with (E)-l,2-di(alkylsulfonyl)-l,2-dichloroethene has been investigated. It has been found that in aprotic solvents these reactions take place as a 1,3-dipolar cycloaddition followed by double elimination with the formation of substituted l,2-di(alkylsulfonyl)indolizines. 

One of the simplest ways to produce substituted indolizines is by 1,3-dipolar cycloaddition. These procedures allow the use of readily available pyridine rings and simple substrates to construct the fused heterocyclic core in only two steps and, in some cases, one pot. It is important to note that the reactivity profiles of the 1,3-dipolar species and the dipolarophile are greatly dependent on the steric and electronic nature of each reaction component. In general, electron-poor dipolarophiles bearing limited steric encumbrance work best in this reaction paradigm. As some intermediate pyridinium ylides exhibit stability at ambient or cold temperatures, these intermediates can be isolated, which allows rapid generation of substituted indolizines in parallel. An example reaction is described in eq... 

In a similar approach, Huang and coworkers pubhshed a series of papers describing the cycloaddition reactions of fluorinated olefins, generated in situ from fluorinated alkanoates, with pyridinium and other nitrogen-based ylides. The synthesis of the fluorinated indolizine 76 that proceeds by cycloaddition followed by a dehydrochlorination step provides an example of this chemistry (Fig. 3.35). ... 

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