Pyridinium ylides, indolizine

The reaction of 196 with phenyl chlorocarbene 198 illustrates the synthesis of indolizines by cyclization of pyridinium ylides (Scheme 7). Cyclization of ylide rotamer 199 generates the intermediate product 200, which undergoes elimination of chloride to provide compound 201 <2005EJ01532>. 

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. 

The high reactivity of iV-substituted pyridincs (review (1870]) is exemplified in the mild conditions needed to cyclize the A -allyiic side-chain of the pyridinium salt (42.1). Evidence for the participation of pyridinium ylides in this reaction is provided by adding ethyl propynoate and carbonate to the pyridinium salt [2469, 2471, 2518]. The pyridinium salt (42.2, R = Et) reacts with ketene dithioacetals (review [3712]) to give 3-substituted indolizines [2881] the behav-... 

Dipolar °f pyridinium ylides have been used to prepare indolizines. 

Rhodium(II) catalyzed reaction of a-diazoazetophenone in the presence of 2-(methylthio)pyridine and DMAD gave 3-benzoyl-l,2-dicarbomethoxy-5-(methylthio)indolizine. The formation of the product proceeds via a pyridinium ylide formed by attack of the nitrogen lone pair on the electrophilic keto carbenoid <93JOCll44>. 

Nitrogen Systems.—Monoaza-compounds. Treatment of the azapentalene anion (745) with dichloromethane and butyl-lithium yields a mixture of indolizine (746 R = H) and compound (747) it has been established that the latter is not a precursor of indolizine.3-Diethylaminoindolizine (746 R = NEt2) is formed by the reaction of 2-bromopyridine with propargyl alcohol and diethylamine in the presence of bis(triphenylphosphine)palladium(ll) dichloride and copper(i) iodide. The pyridinium ylide (748) undergoes 1,5-dipolar cyclization to the tran -dihydroindolizine (749). As in previous years, there have been several reports on the synthesis of the indolizine ring system from pyridinium ylides the methide (750 R = H, R = Ph) adds benzylideneacetophenone to form the tetrahydroindolizine (751), the action of phenyl vinyl sulphoxide. 

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. 

FIGURE 3.36 Pyridinium ylides as precursors of fluorinated indolizines. 

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. 

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. 

The reaction of 3-COCF3 pyridinium ylide with 1,1,1-trifluoropropyne proceeded similarly giving I-CF3 indolizine in low yield [4], Similarly behaved other pyridinium ylides with benzoyl and ester groups [22],... 

Pyridinium ylides reacted with 4-ethoxy-l,l,l-trifluorobut-3-en-2-one to give the corresponding 1-trilluoroacetyl-substituted indolizines [23], Isoquinolinium ylides behaved similarly. 

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... 

A pyridinium ylide bearing a pendant o, /3-unsaturated ketone is capable of cyclizing directly to the indolizine core without the need of an exogenous dipolarophile. As exemplified in eq 7, treatment of an appropriate bromoenone with various substituted pyridines and subsequent exposure to base can facilitate the ring-forming reaction in one pot. 

In another example of heterocyclic ring synthesis, pyridinium salts 816 require only Et3N for deprotonation, the resulting ylides 817 add to esters of 2-bromo-2-alkenecarboxylic acids or analogous benzonitriles to give intermediate betaines 818 which, via intramolecular nucleophilic attack, give indolizines 819 (Scheme 174) <1999JOC7618>. 

Woi sel et al reported reaction of bipyridinium ylides with an electron deficient propynamido-P-cydodextrin forming the pyridinoindolizine- 3-cyclodextrin conjugates <04TL1557>. Moreover, Wu has reported the reaction of pyridinium halides with 2,2-difluorovinyl tosylate in the presence of base to yield monofluorinated indolizines <04T5487> as shown in Scheme 24. When unsymmetrical pyridinium halides were used, a mixture of isomers represented by 52 and 53 was obtained. 

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). ... 

Dipolar addition reactions of iV-ylides with 2,2-difluorovinyl tosylate provides a convenient route to moderate yields of monofluorinated indolizines and related structures. A -Ylides derived from pyridinium, isoquinolinium, and bezimidazolium salts were generated in situ from halide salts (Fig. 3.31)7 ... 

In acetonitrile, the nitrogen ylides (152) react with DMAD but the usual indolizinic products formed in other solvents are not observed. Instead the products are formulated as the ylides (153) and are obtained by a mechanism which is believed to involve an unusual 1,3-shift of the CO2R group.i s An analogous 1,3-ethoxycarbonyl migration accounts for the formation of (154) from the ylide (155) and DMAD. A-Vinyliminopyridinium ylides, (155), are readily available from pyridinium A-imines and activated vinyl halides... 

Similarly, the reaction of ylide formed from N-CH2COCF3 pyridinium salt and dimethyl acetylenedicarboxylate or perfluorobut-2-yne gave rise to 3-COCF3-indolizines 3 [4],... 

In the presence of K2CO3 and EtsN, pyridinium N-ylides, generated in situ from their halides, reacted with gaseous fluoroalkenes CF2=CFX (X=C1, Br) in DMF under atmospheric pressure in normal glassware at 70 °C to give the corresponding 1,2-fluorinated indolizines. Similar results were obtained with tetrafluoroethene in an autoclave [30],... 

Earlier work has demonstrated that pyridinium 7V-ylides and keten thioacetals and related compounds yield allyl ylides and indolizines/ " The extension of this reaction to pyridinium JV-imines provides a useful synthesis of pyrazolo-[l,5-a]pyridines (95), as shown in Scheme 21. ... 

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