Indolizines, formylation

Very few reactions of carbenes with heterocyclic systems containing more than one hetero atom have been studied. They are confined to variants of the Reimer-Tiemann formylation of thiazoles, pyra-zoles, iminazoles, and indolizines/ and ring expansion does not appear to have been observed. 

Decroix and co-workers synthesized thieno[2,3(3,2)-/]indolizine 117 by polyphosphoric acid (PPA) catalyzed cyclization of 2-formyl+V-(thiophenyl)methylpyrazole 116 (Equation 26) <1995TL83>. 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

Cyclohydrocarbonylation of 1-allylpyrroles 74a-d catalyzed by Rh4(CO)i2 gave the corresponding 5,6-dihydro-indolizines 77a-d in good yield and excellent regioselectivity (Scheme 12)." This reaction proceeded through a cascade hydroformylation-cyclization-dehydration sequence (Scheme 12). Exclusive introduction of a formyl group... 

Vilsmeier formylation of indolizine and 2-phenylindolizine gave almost exclusively the indolizine-3-aldehydes. 6-Ethoxycarbonyl-2-methylindolizine gave the 1,3-dialdehyde (52) (75JHC379). Thioaldehydes (53) have been obtained by solvolysis of the intermediate Vilsmeier salts with sodium hydrogen sulfide <70JCS(C)145>. 

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... 

Formyl-l,4-dihydropyridines 131 can be converted to either indolizines 132 or bis-l,4-dihydropyridines 133 with benzoylacetonitrile or 3-aminocrotononitrile, respectively (Scheme 35) <2002T5747>. Broadening of the signals in both the H and 13C NMR spectra showed that bis-l,4-dihydropyridine 133 exists in a restricted conformation with very slow rotation about the bond between the two 1,4-dihydropyridine rings. 

Indolizine is formylated almost exclusively at the 1-position (75JHC379), and with ethyl benzoylacetate (PhC0CH2C02Et), 2-methylindolizine gives a 70% yield of the 3-ketone (62JGU1515). The higher reactivity of the 3-position is here aided by the greater activation by 2-methyl across the 2,3- compared to the 2,1-bond. 

Pyrrolo[l,2-ci]quinoline is a benzo derivative of indolizine and its 2,7-dimethyl derivative (8.65) is nitrosated, acetylated. diazo coupled, and formylated in the expected 1-position in 90, 40, 90, and 70% yields, respectively (79JHC393). Nitration also goes in the 1-position if the conditions are not strongly acidic, in which case it goes in the 6-position. This... 

The preferential 1-substitution in some of the compounds just discussed compared to preferential 3-formylation in indolizine (8.61) led Fuentes and Paudler to suggest that the electrophile coordinates with the bridgehead nitrogen of indolizine (75JHC379). However, this postulate is both... 

Electrophilic substitution on indolizine takes place at C-3, such as acylation (e.g., AC2O/ACOH), ViLSMEiER formylation (DMF/POCI3), or diazo coupling (Ar — N ). 

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