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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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R
SCHEME 7.1
54
7 CATEGORY Пас CYCLIZATIONS
7.1 FISCHER INDOLE SYNTHESIS
Retrosynthesis a in Scheme 7.1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischcr cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves oft/ro-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia.
The Fischer cyclization is usually carried out with a protic or Lewis acid which functions both to facilitate the formation of the enchydrazine by tautomerization and also to assist the N N bond breakage. The mechanistic basis of the Fischer cyclization has been discussed in recent reviews[l,2].
The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition.
7.1.1 Reaction mechanism and catalysts
The mechanism of the Fischer cyclization outlined in equation 7.1 has been supported by spectroscopic observation of various intermediates[4] and by isolation of examples of intermediates in specialized structures[5]. In particular, it has been possible to isolate enehydrazines under neutral conditions and to demonstrate their conversion to indoles under the influence of acid catalysts^].
Sigmatropic rearrangements are normally classified as concerted processes with relatively nonpolar transition states. However, the Fischer cyclization involves rearrangement of a charged intermediate and ring substituents have a significant effect on the rate of the rearrangement. The overall cyclization rate
7.1 TISCHER INDOLE SYNTHESIS
55
is accelerated by ER substituents in the benzene ring[2,7]. The acceleration provided by acid catalysis is in the range 103-106[6,8], This catalytic effect is due at least in part to acceleration of the sigmatropic rearrangement of intermediate. Both protic and Lewis acids have been shown to accelerate related sigmatropic reactions involving rupture of nitrogen-carbon bonds[9].
A variety of both protic and Lewis acids have been used to effect Fischer cyclizations. Hydrochloric acid or sulfuric acid in aqueous, alcohol or acetic acid solution are frequently used. Polyphosphoric acid and BF3 in acetic acid have also been employed[10]. Zinc chloride is the most frequently used of the common Lewis acids. This choice is supported by comparative studies with FeCl3, A1C13, CoCl2 and NiCl2, which found ZnCl2 to be the most effective catalyst[l 1]. Zinc chloride can be used either as a solid mixture with the hydrazone reactant or in ethanol or acetic acid solution[12],
Fischer indolization can also be carried out under thermal conditions without a catalyst in solvents such as ethylene glycol[13], diethylene glycol[14], sulfolane[15] or pyridine (using the hydrazone hydrochloride)[16]. High temperature (275-350°C) heterogeneous cyclizations of arylhydazones to indoles have also been developed with special emphasis on the cyclization of acetaldehyde phenylhydrazone, a reaction which is difficult to achieve in solution. Vapour phase cyclization occurs using A1203, MgO and Mg0/Si02[17]. Yields of 85% have been achieved using an alumina-MgF2 catalyst[18]. This catalyst has also been used successfully to make substituted indoles. An acidic aluminium orthophosphate catalyst has been used to prepare several alkyl-indoles[19].
References
1. D. L. Hughes, Org. Prep. Proved. Int. 25, 609 (1993).
2. N. M. Przhevai'ski, L. Yu. Kostromina and I. I. Grandberg, Chem. Heterocycl. Cmpds., Engl. 'Iransl. 24, 709 (1988).
3. R. Robinson. The Fischer Indole Synthesis, John Wiley and Sons, New York, 1982.
4. Л. W. Douglas, J. Am. Chem. Soc. 100, 6463 (1978); A. W. Douglas. J. Am. Chem. Soc. 101, 5676 (1979); D. L. Hughes and D. Zhao, J. Org. Chem. 58, 228 (1993).
5. K. Mills, I К. A1 Khawaja. F. S. Al-Saleh and J. A. Joule, J. Chem. Soc., Perkin Trans. ! 636
(1981); F P. Robinson and R. K. Brown, Can. J. Chem. 42, 1940 (1964); P. L. Southwick and D. S. Sullivan, III, Syntfifsi's 731 (1986); М. K. Eberle and L. Brzechffa, J. Org. Chem. 41, 3775 (1976); G. Kollenz, Monatsh. Chem. 109, 249 (1978); G. P. Tokmakov, T. G. Zemlyanova and
I. I. Grandberg, Chem. Heterocycl. Cmpds.. Engl. Transl. 22, 1345 (1986).
6. P. Schiess and A. (Jrieder, Tetrahedron Lett. 2097 (1969); P. Schiess and A. Grieder, Hetv. Chim. Acta 57, 2643 (1974); P. Schiess and E. Seni, Helv. Chim. Acta 61, 1364 (1978).
7. Y. B. Vystoskii. N. M. Prsheval'skii, B. P. Zemskii, 1. I. Grandberg and L. Y. Koblromina, Chem. Heterocycl. Cmpds., Engl. Transl. 22, 713 (1986).
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