1.3- Dipolar cycloadditions indolizine

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). 

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). 

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... 

Using DMF as a solvent to facilitate solubility of fluorocarbons and thus ease conditions of the reaction, Wu and Chen prepared indolizines and 4//-pyrrolo[ 1,2-a] benzimidazoles in good yields by 1,3-dipolar cycloaddition of fluoroalkenes to N-ylides, exemplified below by the synthesis of indolizine 75 (Fig. 3.34). ... 

Wu, K. Chen, Q.-Y. S3mthesis of fluorinated indolizines and 4//-pyrrolo[l,2-fl]henzi-midazoles via 1,3-dipolar cycloaddition of fluoroalkenes to iV-ylides. Synthesis 2003, 35 0. 

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 ethanol, with excess Et3N and heating, the reactions of substituted pyridinium salts with ( )-l,2-di(alkylsulfonyl)-l,2-dichloroethenes take place simultaneously as a 1,3-dipolar cycloaddition and as an addition-elimination and lead to the formation of l,2-di(alkylsulfonyl)indolizines and 4,5-di(alkylsulfonyl)furans. 

Acceptor-CH-substituted pyridinium-N-betaines 15 (accessible in situ by deprotonation of the corresponding N-alkylpyridinium salts 14) undergo 1,3-dipolar cycloaddition with activated alkynes and alkenes as dipolarophiles. With alkynes, the cycloadducts (16/19) dehydrogenate spontaneously to indolizines, which are either of the 1,2,3-trisubstituted type 17 or (indicating a regioselective cycloaddition) of the 1,3-disubstituted type 18. With olefinic substrates, the presence of an oxidant for additional dehydrogenation of the primary cycloadduct (20 -> 17) is required [219] ... 

The first example of a stable pyridinium yhde of type 80 is the pyridinium phenacylide (80, A = CH2COPh), obtained from the N-phenacylpyridinium ion (79, A = CH2COPh) by deprotonation with Na2C03 [97]- The reactivity of the pyridinium betaines is determined by their electron distribution (80a-c). Thus, they can be smoothly alkylated or acylated at the N-substituent ( 81) as 1,3-dipoles, they undergo dipolar cycloadditions with activated alkynes or alkenes [98] for example, the sequence 80 —> 82 83 establishes an efficient principle of indolizine synthesis (cf. p. 154). 

Although the position 3 in the indolizine ring is the most reactive toward electrophilic attack, no direct fluorination of indolizines have been reported. Instead, in the recent work [2] 1,3-dipolar cycloaddition was studied to difluoro-substituted pyri-dinium ylides. 

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... 

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). 

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