Indolizines cycl azines

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). 

The most frequently used synthetic route to cycl[3.2.2]azines involves the reaction of an indolizine with a dienophile, for example, DMAD, in the presence of a dehydrogenating agent such as palladium-on-carbon (Scheme 85), although the scope of the reaction is limited by the presence of substituents in one or both of the reactants, and/or the reaction conditions. If C-3 and C-5 of the indolizine are unsubstituted, the cyclazine is the main product a 3,4-dihydrocyclazine may sometimes be isolated as a by-product (see below). 

A third method for the synthesis of cycl[3.2.2]azines, from iV-(aroylmethyl)pyridinium salts via indolizines, involves intramolecular (reductive) McMurry coupling of the latter. For example, 3,5-dibenzoylindolizines, obtained from 2-benzoyl-iV-phenacylpyridinium bromide as shown (Scheme 91), are cyclized using zinc and titanium(iv) chloride to give the 3,4-diphenylcyclazines 352 in high yield (>90%). The reaction cannot be applied, however, to... 

Most of the methods of forming cycl[3,2,2]azine derivatives involve indolizines. Other precursors are 3//-pyrrolizines and pyridines. 

Better yields may be obtained from vinylpyridines and alkyl propiolates, as can be seen from the conversion of 36 to the cycl[3,2,2]-azine (lw).41 Reaction of a-(bismethylthio)methylene-2-pyridineaceto-nitrile and ethyl bromoacetate using triethylamine afforded the indolizine derivative (37). Dimethyl l-carbamoyl-2-methylthiocycl-[3,2,2]azine-3,4-dicarboxylate (Iz) was synthesized by allowing dimethyl acetylenedicarboxylate to react with indolizine derivative 38, which was obtained by decarboxylation of 37 using sulfuric acid in presence of palladium-on-charcoal as catalyst [Eq. (6)].42... 

Cyclazines are an interesting class of compounds that can be synthesized by intramolecular cyclization to the 3-position of the indolizine ring.200 The reactivity of the methyl group in 5-methylindolizine is similar to that in 2-picoline, and this provides the means of preparing cycl[3,2,2]azines. Thus, the reaction of 5-methyl-2-phenylindolizine with butyl lithium followed by JV,JV-dimethylbenzamide yielded the 5-(phenacyl) derivative, which could be ring-closed to 133 by heating... 

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. 

The formation of cycl[3,2,2]azines from indolizines has its parallel in the saturated system with a reaction reported by Japanese workers.275 The indolizidinone ester 238 gives the tricyclic compound 239 on distillation with soda lime. This reaction is of potential importance in view of the number of alkaloids containing fused systems similar to 239. 

Partial rate factors of hydrogen exchange of azulene, cycl(2.2.3)azine, indolizine, A-methyl-isoindole, and indole have been compared <87JCS(P2)591>. 

Reactions of indolizines with electron deficient alkenes and alkynes were studied. Cycloaddition reactions with dimethyl alkynedicarboxylate yield cycl(2.2.3)azine derivatives (22)-(24), adducts (25), and (2.3.4)cyclazines (26) <84H(22)705>. 

Indolizine (37) has been transformed into cycl(2.3.3)azine (38) by an intramolecular condensation reaction (Equation (1)) <81JCS(P1)3150>. 

There is some resemblance to the two-step formation of cycl[3.2.2]azines (184) when indolizines (182) were treated with butyllithium followed by A,A-dimethylamides to give, after hydrolysis, ketones (183), which were cyclodehydrated by glacial acetic acid (58JA2020 59JA1459) as shown in Scheme 41. 

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