Russian Chemical Bulletin, International Edition, Vol. 57, No. 10, pp. 2220—2222, October, 2008 2220 Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2178—2180, October, 2008. 1066-5285/08/5710-2220 © 2008 Springer Science+Business Media, Inc. One-step synthesis of 2-indolylalkylamines* E. S. Balenkova, E. P. Zakurdaev, and V. G. Nenajdenko Department of Chemistry, M. V. Lomonosov Moscow State University, 1 Leninskie Gory, 119992 Moscow, Russian Federation. Fax: +7 (495) 932 8846. E-mail: nen@acylium.chem.msu.ru An efficient one-step synthesis of 2-indolylalkylamines was proposed. The synthesis involves the Fischer reaction of phenylhydrazine with cyclic imines containing a CH 2 group in the α-position or with amino ketones containing two CH 2 groups in the α-position with respect to the C=O group. Key words: indole, the Fischer reaction, cyclic imines, regiochemistry, indolylalkylamines. the indolization pathway, we employed cyclic imine 1 and amino ketones 2a and 2b. A reaction of imine 1 with phenylhydrazine afforded compound 3, which is a first representative of a novel class of 3-arylisohomotryptamines. A thorough examination of the reaction products revealed no formation of the second isomer. As with cyclic imine 1, reactions of aminohexanones 2a and 2b with phenylhydrazine mainly involve the shorter aliphatic chain, so we obtained for the first time iso- homotryptamines 4a and 4b. A 1 H NMR study of the reaction mixture revealed the formation of isomeric dihomotryptamines 5a and 5b as minor products. The ratios of the products 4a : 5a and 4b : 5b are 17 : 1 and 5 : 1, respectively. The higher selectivity of the Fischer reaction in the former case can be attributed to conjuga- tion of the double bond of intermediate ene hydrazine with the aromatic ring in the context of the Fischer reac- tion mechanism. To sum up, we developed an efficient one-step method for the synthesis of not easily accessible 2-indolyl- alkylamines via the Fischer reaction of cyclic imines (or amino ketones) containing a CH 2 group in the α-position with respect to the imino (or carbonyl) group. * Dedicated to Academician B. A. Trofimov on the occasion of his 70th birthday. Heterocyclic compounds containing an aminoalkyl fragment occupy a special place among aromatic com- pounds because of a variety of their biological activity. Indolylalkylamines are the most striking examples. They are an essential part of most known indole alkaloids and are components of many biologically active substances and drugs. 1,2 Among these compounds, 2-substituted 3-indolylalkylamines (tryptamines) attract much atten- tion because they are highly selective toward serotonin and melatonin receptors and receptors controlling the secretion of gonadotropin. 3—5 The most convenient routes to indolylalkylamines include the Fischer, 6 Grandberg, 7 and Japp—Klingemann reactions. 8 In recent years, the synthetic scope of the Fischer reaction for five—seven- membered cyclic imines and their synthetic acyclic analogs (amino ketones) has been extensively studied. This approach can be effected in one step without using protecting groups. 9—11 In contrast to 3-indolylalkylamines, which can be syn- thesized in well-developed ways, 2-indolylalkylamines (isotryptamines) are studied much more poorly for lack of accessible synthetic methods. Acylamides of 2-indolyl- alkylamines (isomelatonins) have been obtained in many steps by acylation of prepared isotryptamines. 12 For the synthesis of these compounds, we successfully used the Fischer reaction of arylhydrazines with amido ketones. 13 Here we proposed a one-step synthesis of 3-substi- tuted 2-indolylalkylamines from cyclic imines containing a CH 2 group bound to the N atom or from amino ketones containing two CH 2 groups in the α-position with respect to the carbonyl group. 13 According to the concept of the mechanism of the Fischer rearrangement, cyclization of the above compounds can follow two pathways. To study