1,3-dipolar indolizine

Pyridazinium and phthalazinium dicyanomethylides give indolizines as primary adducts with 1,2,3-triphenylcyclopropene, either by [4 + 2] cycloaddition or by 1,3-dipolar addition of the ylide to triphenylcyclopropene (81JCS(P1)73). 

The mechanism of attack of 1,3-dipolar reagents on fluoroalkenes can be considered to be either stepwise or concerted. Heteroaromatic N-imines react by a stepwise 1,3 addition to perfluoroalkenes and -alkynes to give fluorinated pyrazolo[l,5-a]pyridines [82JCS(P1)1593]. Pyridinium /-butoxycarbonylmethylide with fluoroalkenes gave pyrrolo[l,2-a]pyri-dines [86JCS(P 1) 1769] and indolizines (22) are obtained with pyridinium phenacylide [91JFC(51)407]. 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

Reaction of the nitrone 4-184 with allenic esters 4-185 as described by Ishar and coworkers led to the benzo[b]indolizines 4-186, together with small quantities of 4-187 (<5%) (Scheme 4.40) [63]. The first transformation is a 1,3-dipolar cycloaddition this is followed by four further steps, including a [4+2] cycloaddition of an intermediate 1-aza-l,3-butadiene. 

The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. 

Bipyridinium ylides 133, generated in situ from 4,4-bipyridinium diquaternary salts 133, undergo 1,3-dipolar cycloaddition with activated alkynes under micro-waves, on KF-alumina in the absence of solvent, to give 7,7-bis-indolizines 134 in 81-93% yield (Scheme 9.40) [91]. The same reactions, when performed using benzene as a solvent under classical heating, yielded 7,7-bis-indolizine derivatives in yields of only 50-60% [92],... 

Another variation of this procedure is provided by the use of iV-(silylmethyl)pyridine analogues 19, which through 1,4-silatropy and subsequent 1,3-dipolar cycloaddition afforded the corresponding indolizines 21 <2003S1398> (Scheme 5). 

The 1,3-dipolar cydoaddition reactions ([3-1-2]) are often used to synthesize five member aza- or azoxaheterocycles. Depending on the nature of the 1,3-dipoles employed in the transformation, different types of heterocycles such as isoxaza-zoles [270], isoxazolines (Scheme 3.22) [110], hydantoins [271], pyrrolidines [272], indolizines [273] or pyrazoles [274] are obtained. 

Treatment of allylpyridinium salts with weak bases gave ylides (152) an intramolecular 1,5-cyclization then yielded dihydroindolizines (153), which are prone to oxidation to (154). More than 90% of (153) is formed if R1 is phenyl and R2 is benzoyl or acetyl. If R is H or p-anisyl the indolizine (154) is the major product. 1,5-Cyclizations of ylides of the type (152) with a different substitution pattern have been investigated. This type of reaction seems to be somewhat unpredictable since the 1,5-cyclization is accompanied by 1,3-dipolar cycloadditions (Section 3.08.6.2.2) to a varying extent (75JCS(Pl)575). 

Indolizines (155) and (156) have been obtained from the appropriate pyridine and diphenylcyclopropenone. A 1,5-dipolar intermediate is possibly involved in this reaction (78S207, 81TL3569). 

Two examples are given for illustration the reaction of (172) with DMAD gave 32% (171) compound (173), on the other hand, has been obtained from the ylide (174) and the enamine (175) in 36% yield. A compilation of 1,3-dipolar cycloadditions which lead to indolizines has been presented (76S209). 

Bora and co-workers44 have developed a microwave-assisted three-component synthesis of indolizines. The reaction involves a 1,3-dipolar cycloaddition reaction between the in situ generated dipole (from the bromoacetophenone and pyridine) and acetylene, Scheme 5.26. The developed method provides fast access to cycloadducts, which otherwise are accessible only through multi-step synthesis. 

In the context of a coupling-1,3-dipolar cycloaddition sequence, Muller and coworkers [89] developed a consecutive one-pot, three-component process to indolizines. Starting from (hetero)arenecarbonyl chlorides 88 and terminal alkynes 89 under Sonogashira conditions, the expected alkynones were formed (Scheme... 

Scheme 5.20 One-pot, three-component coupling-1,3-dipolar cycloaddition synthesis of indolizines.

Dinica, R.M., Druta, I.I., and Rettinari, C. 2000. The synthesis of substituted 7,7 -bis-indolizines via 1,3-dipolar cycloaddition under microwave irradiation. Synlett, 1013-15. 

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. 

Rotaru AV, Dmta ID, Oeser T, Muller TJJ (2005) A novel coupling 1,3-dipolar cycloaddition sequence as a three-component approach to highly fluorescent indolizines. Helv Chim Acta 88 1798-1812... 

Besides processes (1) and (2), the reader should be aware that nucleophilic attacks on alkynes are treated in other chapters of this book, dealing with rearrangements, cyclizations, polyacetylenes, cyclic acetylenes and perhaps others. A number of publications overlap with ours in different ways and at different levels -. They treat individual alkynes or families " , e.g. acetylene, diacetylenes , acetylene dicarboxylic esters haloacetylenes , alkynyl ethers and thioethers > ynamines , fluoro-alkynes ethynyl ketpnes , nitroalkynes , etc. synthetic targets, e.g. pyrazoles , if-l,2,3-triazoles , isothiazoles , indolizines S etc. reagents, e.g. nitrones , lithium aluminium hydride , heterocyclic A -oxides - , azomethine ylids - , tertiary phosphorus compounds , miscellaneous dipolar nucleophiles - , etc. The reader will appreciate that all of these constitute alternate entries into our subject. 

Reviews - Acyl anion equivalents,1 2 crown ethers in synthesis,3 intramolecular 1,3-dipolar additions,11 oxazolines in synthesis,5 oxidation-reduction condensations,6 oxythallation,7 transition metals in synthesis,8 9 and ynamines in synthesis.10 Also reviewed are syntheses of pyridines,11 pyrroles,12 and indolizines.13 Other reviews are in specific sections. 

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

The synthesis of indolizines by 1,5-dipolar cyclization, the reaction of picolinium salts with ketene dithioacetals, the reaction of 2-pyridyl ketene dithioacetals with halogencarbonyls, and a reaction of A7-imines or S-imines with ketene dithioacetals have been reviewed <85YGK669>. 

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