Indolizine-7-carboxylates

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226 R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition-cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tri-butylphosphine, giving the substituted indolizine-7-carboxylates (228 R2 = OEt, Me R3 = H, Et).265... 

The crystal structure of dimethyl indolizine-l,6-dicarboxylate shows that the indolizine unit is almost planar. The two carboxylate groups are coplanar with the indolizine moiety <2006AX(E)4080>. 

Pyrido[2,3-a]indolizine-3-carboxylate (637) was obtained in 71% yield by the cyclization of (l-indolizinylamino)methylenemalonate (636) in boiling Dowtherm A for 40 min under argon (85JHC817). 

The cyclazine (Iv) was the only product isolated in poor yield from reaction of pyridine and methyl propiolate in acetonitrile. The indolizine derivative (35) may be an intermediate, since it was obtained from a similar reaction in ether.39 2-Acetylpyridine and ethyl pyridine-2-carboxylate reacted similarly.40... 

Indolizine, 1,2,3-trimethyl- H NMR, 4, 453 <66JCS(B)44> Indolizine-2-carboxylic acid HNMR, 4,448 <67M1858)... 

Refluxing 2-acetylpyridine (111) with MP gives a remarkable 29% yield of pyrrolo[2,1,5-< /]indolizine (112), which may be formed by the route (Scheme 5) outlined.296 Ethyl pyridine-2-carboxylate, presumably by a similar mechanism, yields a mixture of three pyrrolo[2,l,5-crf]-indolizines (113,114, and 115).296... 

Indolizine reacts with electrophiles on the five-membered rings by substitution reactions as expected but it has one special reaction that leads dramatically to a more complex aromatic system. It does af cycloaddition with diethyl acetylenedi-carboxylate to give a tricyclic molecule. 

A similar mercaptoacetate addition reaction to 5-acyl-4,7-dioxo-4,7-dihydrobenzo[i]thiophene-2-carboxylates followed by cyclization and oxidation to give benzo[ 1,2-6 5,4-ft ]dithiophene-4,8-dione derivatives 29 has been shown <03H1689>. Nitrogen bridged heterocycles, 3-(benzylthio)thieno[3,4-6]indolizine derivatives 30 have been synthesized and intramolecular arene-arene interactions within these compounds were reported <03CPB75>. The arene-arene interaction leads to significant shifts in the proton NMR signals and red shifts in the absorption maxima. 

A synthesis of a partially reduced indolizine which allows the introduction of a substituent at any of the C-3 to C-6 atoms utilizes an A -acylpiperidine-2-carboxylic acid which is cyclized on heating with ethyl propynate. A lactone intermediate is proposed for this interesting reaction. 

In a reversal of this intramolecularized side-chain reactivity (effecting annulation of a five-membered ring to the N/C-2-position of pyridine) the Baylis-Hillman reaction of pyridine-2-aldehydes with acceptor-substituted alkenes, e.g. acrylates, in the presence of DABCO gives rise to formation of products 74, which can be cyclized to 2-substituted indolizines, e.g. indolizine-2-carboxylates 75 [54]. 

Also the more recently designed 5-HTa receptor antagonists fit the S-HTg receptor antagonist pharmacophore. Some examples (figure 2) are the naphthahmide derivative (compound 1) [218] the 3-methyl-l-indolizine derivative (compoiind 2) [219], the pjnrrolo[2,l-c][l,4]benzoxazine-6-carboxamide derivative (compound 3) [220], the benzopyrano[3,4-c]quinoline derivative (compoimd 4) [221] and the benzimidazole-4-carboxylic acid derivative (compound 5) [222]. 

Pyridine-substituted nicotines, nornicotines, and anabasines are available from a-cyano-amines by a new synthesis. The syntheses of ( )-[l - N]nornicotine and ( )-[l - N]nicotine have been described, from cyclopropyl 3-pyridyl ketone and [ N]formamide. 4-Methylnicotine has been prepared it shows no nicotine-like pharmacological activity. " An investigation into the stereochemical factors involved in the behaviour of nicotine and related compounds in the Menschutkin reaction has been conducted.A bridged nicotine , 1,2,3,5,6,10b-hexahydropyrido[2,3-g]indolizine (44), has been synthesized by carboxylation of the dilithium derivative of 2-methylnornicotine followed by cyclisation and reduction with borane in tetrahydrofuran. Several 5-halogeno-nicotines have been prepared and their pK values and biological activities measured. ... 

Indolizino[l,2-c]quinolines. 60%-Perchloric acid added to a soln. of methyl 2- (2-benzamidophenyl) indolizine-l-carboxylate in glacial acetic acid, and allowed to stand 24 hrs. at room temp. 6-benzoyloxyindolizino[l,2-c]quinoline hydroperchlorate. Y 83%. G. Niederdellmann and F. Krohnke, A. 688, 196 (1965). 

Carboxylic acid selenoamides. Dimethylformamide heated with 2.5 eqs. 2 M PhP(Se)Cl2 in xylene at 95-100° for 3 h - dimethylselenoformamide. Y 84%. Added NEt3 may improve the yield. F.e. incl. indolizine-3-selenaldehydes and l,2-dithiole-3-selenones s. J.P. Michael et al., J. Chem. Soc. Chem. Commun. 1988, 1494—6. 

Indole-2-carboxylic acids. A soln. of startg. indolizine in 50% ethanol treated with aq. alcoholic KOH at room temp. - product. Y 85%. F.e.s. E.V. Babaev et al., Khim. Geterotsikl. Soedin. 1988, 1570. 

Indolizines, formation from pyridine acetates, 355-357 formation from pyridine side-chain carboxylic acids, 355-357, 481-488 5-methyl, synthesis, 352 N-(2- (3-Indolyl)ethyl]-2-halo (or ethoxy) pyridinium bromide, hydrolysis, 787 ring closure by fusion, 787... 

The 3-diazoniumtetrafluoroborates 64 were obtained in good yields via nitrosation of 3-aminoquinolizines 63. Treatment of 64 with anhydrous alcohol afforded a mixture of alkyl indolizine-3-carboxylates 67 and the 3-unsubstituted 4/f-quinolizin-4-ones 68. The product selectivity of this reaction depends upon the alcohol. The formation of indolizine 67 has been regarded as an aza Wolff rearrangement through ring contraction via 65 and... 

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