Indolizines, cycloaddition

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). 

Indolizine, 1 -cyano-2-(methylthio)-synthesis, 4, 465 Indolizine, 3,5-dialkyl-synthesis, 4, 475 Indolizine, dihydrosynthesis, 4, 467, 468 Indolizine, dimethyl-mass spectrometry, 4, 187 Indolizine, 1,2-dimethyl-oxidative dimerization, 4, 458 Indolizine, 2,6-dimethyl-cycloaddition reaction, 4, 460 reduction, 4, 459... 

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. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

Synthetic routes to the various classes of azacycl[3.2.2]azines generally follow along very similar lines to the above. For example, l-azacycl[3.2.2]azines (imida/o[ 5,1,2-tv/] indolizines), 356, may be obtained by the [8+2] cycloaddition... 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

Electron-rich heterocyclic systems such as indolizines react readily with DEAZD (and PTAD) to give substitution products (Eq. 16).141 None of the formal [8 + 2] cycloaddition products (e.g., 89) are observed. This is in direct contrast to the reaction of indolizines with electrophilic acetylenes which gives high yields of cycloaddition products, presumably via a stepwise mechanism, in the presence of palladium on charcoal.142 This example of... 

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],... 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

Using benzotriazole methodology, it was possible to obtain indolizine compounds by cycloaddition of benzotria-zole-substituted /V-ylidcs to bromoalkenes and acetylene derivatives <1999JOC7618>. 

This cycloaddition has found application in the combinatorial synthesis of indolizines on solid support <1999TL8741 2005BML453> and on soluble support as poly(ethyleneglycol) <2004SL1231>. 

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). 

Cycloaddition reactions of indolizines such as 547 can generally be performed with moderately electron-poor alkenes only, because alkenes with strong acceptor substituents predominantly give Michael adducts. The cycloaddition of 2-methylindolizine... 

Cyclic amino acids 139, when heated in acetic anhydride, probably form initially mesoionic oxazolium 5-oxides (munchnones) subsequent 1,3-dip olar cycloaddition of 1,2-dicyanocyclobutene, loss of carbon dioxide, and opening of the cyclobutane ring lead to dinitriles 140 (80JHC1593). Pyridone 141 is the by-product (together with an indolizine) of the mono-cyclic pyridone dicarboxylate and acrylic ester (73JHC77). 

The intramolecular cyclization of oximes with alkene substituents to dihydropyrroles in the presence of radical initiator or by heating was also describedThus, oxime 83 underwent a tandem 1,2-prototropy-cycloaddition sequence and gave an unstable cycloadduct 84, which on treatment with NaOH afforded indolizine 85 (equation 36). ... 

It seems useful to compare the chemical properties of indolizines with those of pyrroles, indoles and isoindoles. There is however one important exception, namely that cycloadditions involve the entire 7r-system of indolizines. 

No cycloaddition has been found to occur in the reaction of several indolizines with tetracyanoethylene, substitution occurring instead in the 1- and 3-positions (78JHC1471). Similar products have been formed in the reactions of 2-methylindolizine with nitroethane, yielding (86) (79JPS321), and of indolizines with dialkyl azodicarboxylates, which gave a mixture of (87) and (88) (80TL3673, 79H(12)787>. 

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). 

Most of the methods of formation of [2.2.3]cyclazines have been described already the intramolecular condensation of indolizines in Sections 3.08.1 and 3.08.4, the cycloaddition to indolizines in Section 3.08.3.5, the cycloaddition to methylenepyrrolizines in Section 3.08.6.2.1 and a multistep synthesis from 2-formylpyrrole and l,2-bis(hetero) substituted ethylenes in Section 3.08.6.3.1. 

Cycloaddition of ylide 90, formed from 3-oxopyrido[2,l-6][l,3]thiazin-5-ium iodide (89) on the action of triethylamine, with acrylonitrile or methyl acrylate gave [l,3]thiazino[4,3,2-cd]indolizines (91), which were subsequently aromatized by treatment with chloranil (80CL947). 

A novel microwave-mediated three-component coupling of a-acyl bromides, pyridine and internal alkynes was carried out in the absence of a solvent on activated basic alumina to provide a collection of indolizines (Scheme 3.5)7. It was proposed that the reaction proceeded via in situ generation of a dipole from an N-acyl pyridinium salt, followed by a [3+2] cycloaddition reaction. A dedicated laboratory microwave system was... 

The indolizines constitute the core structure of many naturally occurring alkaloids, such as (-)-slaframine, (-)- dendroprimine, indalozin 167B and coniceine. There are a number of different routes to the synthesis of indolizines and they are most commonly synthesised by sequential N-quaternisation, intramolecular cyclocondensation reactions or the cycloaddition reaction of /V-acyl/alkyl pyridinium salts. 

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. 

Cycl[3,2,2]azines are also obtained from cycloaddition of indolizines with DMAD.60,201 This is illustrated by the reaction of 2-phenylindoli-zine with DMAD which gives 135. Hydrolysis with methanolic potassium hydroxide gives the corresponding acid, which can be decarboxy-lated using copper chromite. 

Substituted indolizines have been shown to undergo cycloadditions with suitably substituted alkenes to give pyrroloindolizines.202 Thus, 2,6-dimethylindolizine with methyl acrylate gives 136. The reactions presumably involve [8 + 2] cycloadditions, with subsequent 1,5-proton shifts. 

The only reaction reported between 3//-pyrrolizine (1) and a carbene (or carbenoid) is that involving n-butyllithium and dichloromethane.135 One of the products is formed by cycloaddition (Section III,B,6), one by ring opening (Section III,B,7), and the third according to Eq. (4). The latter two products are viewed as derived from the carbenoid 272, and the proposed route to indolizine (273) is shown in Eq. (4). 

Keywords 4,4 -bipyridinium diquaternary salts, acetylenedicarboxylate, 1,3-di-polar cycloaddition, microwave irradiation, 7,7 -bis-indolizine... 

---