Reactions of Indolizines

Indolizine is an electron-rich system and its reactions are mainly electrophilic substitutions, which occur about as readily as for indole, and go preferentially at C-3, but may also take place at C-1. Consistent with their similarity to pyrroles, rather than pyridines, indolizines are not attacked by nucleophiles, nor are there examples of nucleophilic displacement of halide. 

Indolizine, p/faH 3.9, is much more basic than indole (p/faH -3.5) and the implied relative stability of the cation makes it less reactive, and thus indolizines are resistant to acid-catalysed polymerisation (cf. 20.1.1.9). Indolizine protonates at C-3, but 3-methylindolizine protonates mainly (79%) at C-1 the delicacy of the balance is further illustrated by 1,2,3-trimethyl- and 3,5-dimethylindolizines, each of which protonate 

Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-1, presumably via attack on the indolizinium cation. 

Indolizine and its simple alkyl derivatives are sensitive to light and to aerial oxidation, which lead to destruction of the ring system. Catalytic reduction in acidic solution (reduction of the indolizinium cation) selectively saturates the pyrrole ring, giving a pyridinium salt complete saturation, affording indolizidines, results from reductions over platinum.  

Despite its 10-electron aromatic 7t-system, indolizine apparently participates as an 8-electron system in its reaction with diethyl acetylenedicarboxylate, though the process may be stepwise and not concerted. By carrying out the reaction in the presence of a noble metal as catalyst, the initial adduct is converted into an aromatic cyclazine (28.5).  

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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). 

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... 

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... 

A vinylogous indole derivative like 264 reacts with DMAD to give a phenanthridone derivative (267) (Scheme 42). An interesting case of the reaction of an enamine system is observed in the case of the 2H-pyrrolizine (268), which gives a mixture of the azepino[2,l,7-crflpyrrolizine derivative (271) and the 1 1 adduct (275) (Scheme 43) 164,165 reaction of 3-ethoxycarbonylmethylene-3 -pyrrolizine, on the other hand, yields a pyrrolo[2,l,5-croom temperature, the primary adduct (278) is isolated and undergoes thermal cyclization to 281 (Scheme 44). ... 

The reaction of indolizines with dialkyl acetylenedicarboxylates in the presence of a dehydrogenating catalyst leads to 1,2-dicarbalkoxycycl-[3,2,2]azines.22 23 Methyl phenylpropiolate may be used instead, although attempts to effect reaction between indolizine and certain other dienophiles including diphenylacetylene, diethyl azodicarboxylate, and 1,3-cyclohexadiene were unsuccessful. Hydrolysis of the diesters yielded the corresponding acids. Subsequent decarboxylation proceeded in high yield using copper chromite in quinoline [Eq. (5)]. 

The experimental evidence supports the considerations presented virtually all electrophilic substitution reactions of indolizines and azaindolizines that have been reported occur at the 3- or 1-positions or at the 1,3-positions simultaneously. 

Azo derivatives of indolizines are readily prepared since the arenediazonium ion is a good electrophile. Compounds of this type are sometimes used as dyes (73AC(R)95>. Another method of preparing azobisindolizines is by reaction of indolizines with tosyl or picryl azides thus compound (33) has been obtained from 2-methylindolizine by this route. Redox characteristics of such compounds have been studied (71LA(752)182, 71LA(752)196). 

The reaction of indolizines with aldehydes and ketones in the presence of acids yields coloured salts, two of which (43 and 44) are given here for illustration. The salts (45) and (46) have been obtained from the reaction of the pertinent indolizines with formaldehyde and glyoxal respectively. Polymethine dyes, some of which have found application in photography, have been prepared from indolizines and malondialdehyde derivatives or vinylogous dialdehydes (47) was prepared from 1,2-dimethylindolizine and /3-ethoxy-acrolein diethyl acetal (48). 

The indolizine derivatives (57) and (58) were obtained from a reaction of indolizines with the a-oxohydroximoyl chloride (59) in the presence of triethylamine. It has been assumed that (59) is first converted into a nitrile oxide which is the effective reagent. Cyclization of the 3-(2-oxohydroximyl)indolizines (58) to yield the [2.3.3]cyclazine derivatives (60) was brought about by treatment with potassium r-butoxide (81JCS(P1)3150). 

Cyclazines (76) were obtained from the reaction of indolizines with DMAD or methyl phenylpropiolate in the presence of a dehydrogenating catalyst (Scheme 8) (78AHC(22)32l). Theoretical considerations concerning the mechanism of the reaction have been presented (61JA453) which has been assumed to be of a concerted [W8S + 2S] type on the basis of resonance energy differences between the pericyclic transition state and the reactants (78BCJ1788). 

The reaction has been applied to 5,6,7,8-tetrahydroindolizines151,152 the length of the methine chain and the position of attachment to the rings have been varied, and a different heterocyclic system used for the second nucleus.151,153 155 Other types of dyes, e.g., 101 and 102, were produced by reaction of indolizines with aromatic aldehydes or ketones.156-158... 

The reaction of indolizine with V.W-dimethylformamide and phosphorus oxychloride gave almost exclusively indolizine-3-aldehyde.166 The Vilsmeier formylation of 6-ethoxycarbonyl-2-methylindolizine gave the 1,3-dialdehyde, but with the corresponding 2-phenyl compound the product was almost totally the 3-aldehyde.167... 

Imidazo[l,5-fl]pyridine, on reaction with aqueous HNO2 gave 3-(pyridin-2-yl)-l,2,4-oxadiazole. Suggest a mechanism. What product would be obtained by reaction of indolizine with nitrous acid ... 

Addition reaction of indolizines with tropone yielded (11) and (12) <81H(16)1697>. 

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>. 

Electrophilic nature of 3-COCF3 group is displayed by the reaction of indolizine 14 with hydrazine forming pyridazinone derivative 19 in the yield 79 % [11]. 

Mirek J, Haas A (1982) The reaction of indolizines and acetyUndolizines with trifluoro-methylsulfenyl chloride. J Fluor Chem 19 67-70... 

Cycloaddition Reactions of Indolizine. Indolizine is known to participate in [2+2] photocyclization reactions. Interestingly, the 5,6-7T-bond is the most reactive toward stilbene under pho-tolytic activation. The product itself can further undergo a second [2+2] photocyclization with the 7,8-jr system (eq 8). ... 

A Heck-type CDC reaction of indolizines with electron-deficient alkenes produces 3-alkenyl-substituted indolizines. The reaction took place selectively at the 3-position through palladium(II)-catalysed C-H activation, following a Heck-type cross-coupling reaction under mild and ligand-free conditions. The results of the H/D exchange experiments confirmed that the C-H activation was catalysed by palladium(II) acetate (Scheme 8). ... 

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