Abstracl: 2-Cyano-3-(2-pyrtdyI)methylacrylates form substttuted mdolumes upon electrochemical reduction m the presence of chlorotrlmethylsllane. All indohzmes prepared by this procedure show mtense fluorescence in solutlon and m the crystallmc state Copyright 0 1996 Elsevier Science Ltd Indolizine (pyrrolo-[ IJ-alpyridine) is isomeric to indole and isoindole and is found in many natural products, 1.2,3 mainly in its hydrogenated state Indolizines were mostly prepared from substituted pyridines and the five membered ring is formed in several steps '.'-"
We found a short and efficient access to substituted indolizines from 2-cyano-3-pyridylacrylates 1, which can easily be prepared from 2-acylpyridines and cyanoacetate '2,'3.'J The electrochemical reduction of 1 in dry acetonitrile and in the presence of chlorotrimethylsilane leads in one step to the indolizine 2. The overall reaction is shown in scheme 1 1
Scheme 1 2a 2b
Comparable with the electrochemical reaction is the reduction of 1 with diisobutyl-aluminumhydride, which leads to the amino derivative 2b (R=H, R'=Et) in 45% yield. I5 The electrochemical procedure showed to be a more general and versatile method for the synthesis of indolizines allowing a variety of substituents in 1.
Compounds 1 are electrochemically reduced at potentials between -1 2 V and -1 7 V ( vs. SCE ) The anion radicals are fairly stable in acetonitrile (peak current ratio &ii,= < 0.5 -1 0) and the second reduction peak (dianion) lies very close at -1 3 V to -1 7 V When R is an aryl group the reversibility of the reduction steps is much enhanced (&ii, close to I), indicating a dimerization at this position as a possible side reaction to the formation of the indolizines A plausible mechanism for the formation of 2a is given in scheme 2 Transfer of an electron, silylation at the ester enolate centre and transfer of a second electron leads to the anion 1'. The nitrogen atom of the pyridine ring now attacks the adjacent cyano group This cyclization reaction is fixed by silylation at the exocyclic nitrogen atom A final 1,5-sigmatropic migration of a silyl group leads to T. TROLL etal. 2a After aqueous workup 2a and sometimes also the desilylated product 2b are isolated The structure of 2a was proved by an X-ray analysis. I6 Me0 0 N OSiMe 3 c + CISiMeg Gf OMe . oFCozMe Me,Si OSiMe, Me,Si /Nx SiMe 3 2a Me? OSiMe, Meq l CO,Me NH* 2b Scheme 2 Some examples for the synthesis of indolizine derivatives are given in table 1 Substituents in 3-position decrease the rate of dimerization at the radical anion state and therefor increase the yield of indolizine. The cyclization to the indolizine fails with only a few exceptions (4 and 5) after replacing the cyano group by an ester function. Starting from quinohne and isoquinoline derivatives of 1 benzo anellated indolizines can also be prepared in good yields (5-8). The pyrazine and the quinoxaline derivative of 1 lead to the azaindolizines 9b and lob. Cyclization could also be achieved with benzthiazole derivatives of 1 leading to the heterocycles 11 and 12. These indolizines are electron rich aromatic compounds which can be oxidized at potentials between 0 5 V and 1.0 V (vs SCE, table 1) The oxidation wave is only reversible, if there is a substituent at C-l, indicating a dimerization of the cation radical at this position Oxidative dimerizations of indolizines at C-3 are known. ", I*. I9 Electrochemical synthesis of substituted indolizines Table 1: Yields, absorption and fluorescence spectra and oxidation potentials of indolizines 2a -12b compound yield [%] L aX (*bs 1 [ml a) km,,,;; EN [V] b, E[dm3mol-'cm-']