Azaindolizines. 3. Formylation studies on 6-azaindolizines

Buchan, Robert; Fraser, M.; Shand, C. A.

doi:10.1021/jo00864a036

Cited by 13 publications

(13 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results prompted us to explore their further conversions into the corresponding pyrrolo [2,1,5-cd]indolizines. By survey of literature, the procedure for the preparation of pyrrolo[2,1,5-cd]-5-azaindolizine (2) [8] draw our attention because its third ring can be constructed in a single step from 5-methyl-6-azaindolizine (1) under Vilsmeier conditions, even though with very low yields (Scheme 1). Following that procedure, a mixture of 5-methylindolizine-1-carbonitrile (4a) and phosphorus oxychloride in N,N-dimethylformamide was stirred at room temperature overnight.…”

Section: (Chart 1)mentioning

confidence: 99%

Preparation of pyrrolo[2,1,5‐cd]indolizine Derivatives by intramolecular condensation of 3‐acyl‐5‐methylindolizines

Feng¹,

Hu²,

Zhang³

et al. 2001

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

An efficient two step route has been developed to synthesize pyrrolo[2,1,5-cd]indolizine derivatives. The reaction sequence proceeds via preparation of 3-acyl-5-methylindolizines followed by an intramolecular condensation. The procedures were carried out under convenient conditions and gave the products in high yields. It could be expected to be used to prepare a broad range of potentially interesting pyrrolo [2,1,5-cd] A number of methods have been developed for the preparation of pyrrolo[2,1,5-cd]indolizines [1,5]. Over recent years, the [8+2]-cycloaddition of indolizine with an electron-deficient acetylene has been frequently employed for this purpose. But it bears two significant drawbacks arising from inaccessible electron-deficient acetylenes and the requirment for 3-cyano-or 3-unsubstituted indolizines without electron-withdrawing substitutents on C1 and C2 [6]. These drawbacks have seriously limited the range of C1-C4 functionalized pyrrolo[2,1,5-cd]indolizines that can be prepared by this method. So, there remains a need for a more efficient and practical route for the synthesis of pyrrolo[2,1,5-cd]indolizines. Herein we report an efficient route that proceeds via preparation of 3-acyl-5-methylindolizine followed by an intramolecular condensation and overcomes some of the limitation of published procedures.In our previous work, a general and convenient method has been developed for the preparation of 3-unsubstituted and 3-acylindolizines [7]. These results prompted us to explore their further conversions into the corresponding pyrrolo[2,1,5-cd]indolizines. By survey of literature, the procedure for the preparation of pyrrolo[2,1,5-cd]-5-azaindolizine (2) [8] draw our attention because its third ring can be constructed in a single step from 5-methyl-6-azaindolizine (1) under Vilsmeier conditions, even though with very low yields (Scheme 1). Following that procedure, a mixture of 5-methylindolizine-1-carbonitrile (4a) and phosphorus oxychloride in N,N-dimethylformamide was stirred at room temperature overnight. After normal workup, a white solid was obtained by recrystallization. Unfortunately, it was not the expected product 1-cyanopyrrolo[2,1,5-cd]indolizine-4-carboxaldehyde (5) and its structure was assigned as 1-cyano-5-methylindolizine-3-carboxaldehyde (6a) by its ir, 1 H nmr and mass spectroscopy. This result may reason the fact that 5-Me in compound 4a is much less active than that of compound 1. By optimizing conditions, the formylation of 4a was completed at 40-50 °C within 2 hours and yielded 6a in 91% yield. Intramolecular condensation of 3-acyl-5-methylindolizine can be used for the preparation of pyrrolo-[2,1,5-cd]indolizine. But this convenient method has almost been ignored because it suffered seriously from very low yields under several conditions [5h,8]. However, when 6a was treated with potassium hydroxide in N,N-dimethylformide at 160 °C for 10 minutes, the condensation occurred and yielded the desired pyrrolo[2,1,5-cd]indolizine-1-carbonitrile (7a) in 94% yield (Scheme 2).

show abstract

Section: (Chart 1)mentioning

confidence: 99%

Preparation of pyrrolo[2,1,5‐cd]indolizine Derivatives by intramolecular condensation of 3‐acyl‐5‐methylindolizines

Feng¹,

Hu²,

Zhang³

et al. 2001

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

“…Refluxing 5-chloro-7-methyl-2-phenyl-6-azaindolizine (2) with phosphoryl chloride gave a dark red product whose mass spectrum showed a molecular ion at m/e 412 corresponding to the m/e value expected for a molecule constructed from two units of the percursor 2 less two molecules of hydrogen chloride. The NMR spectrum of this dark red compound was simple and apart from methyl and phenyl absorptions at 1.93 and 7.20-7.88 showed only two other singlets at 5.96 and 6.08.…”

mentioning

confidence: 99%

“…Although nucleophilic displacement from pyrimide and other -deficient1 heteroaromatic systems is common, even hydride ion displacement being possible,6 no instances of successful nucleophilic displacement from the indolizine nucleus have been reported, and of the seven possible azaindolizines only the 1-azaindolizine system has been shown to undergo nucleophilic displacement of chlorine. [7][8][9] In this paper we describe the reactivity of the chlorine in 5-chloro-7methyl-2-phenyl-6-azaindolizine (2) and 7-chloro-2-phenyl- 8-azaindolizine (5). Attempts to effect direct nucleophilic subtitution on 7-methyl-2-phenyl-6-azaindolizine (1) by treatment with sod amide or sodium methoxide at temperatures up to 180 °C merely resulted in decomposition or at lower temperatures in the recovery of starting material.…”

mentioning

confidence: 99%

Azaindolizines. 5. Nucleophilic substitution on chloro-6- and -8-azaindolizines

Buchan¹,

Fraser²,

Shand³

1978

J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

“…Had 2,5-dimethyl-8-azaindolizine (12) been isolated from the reaction between bromoacetone and 2,4-dimethylpyrimidine its formylation product could in no way show a peri shift by formylation at C-l or C-3; had the 6-azaindolizine 15 been isolated formylation would be expected to yield a 5-azacycl[3.2.2]azine structure. 4 The low yields (0.2-5.6%) obtained for simple 8-azaindolizines compared with the yields (6.0-89%) obtained in the Chichi bahin synthesis of 6-azaindolizines from 4-methylpy-rimidines4'8*9-and the preferential formation of 6-azaindolizines from the reaction between 2,4,6-trimethylpyrimidine and bromoacetone or phenacyl bromide4 suggest that the 2methyl group is less reactive than the 4-methyl group in methyl substituted pyrimidines.10 Since a 4-methoxy group would be expected to increase the reactivity of the 2-methyl group, it was hoped that improved yields of 8-azaindolizines would be obtained from the reaction of 4-methoxy-2methylpyrimidine and an a-halo ketone. Quaternization of 4-methoxy-2-methylpyrimidine with phenacyl bromide at room temperature followed by cyclization gave in fact 7methoxy-2-phenyl-8-azaindolizine (8) in 27% yield.…”

mentioning

confidence: 99%

“…Chemical Shifts (A) in the 100-MHz 'H NMR Spectra of the 8-Azaindolizines(1)(2)(3)(4)(5)(6)(7)(8)(9)(10) in CDCb0…”

mentioning

confidence: 99%