Job/Unit: O20107 /KAP1 Date: 17-04-12 15:20:07 Pages: 11 FULL PAPER DOI: 10.1002/ejoc.201200107 Versatile Synthesis of 2-(Substituted phenyl)-6,7-dihydro-1H-indol-4(5H)-ones from Morita–Baylis–Hillman Acetates of 2-Oxo-2-(substituted phenyl)acetaldehyde [‡] Harikrishna Batchu [a] and Sanjay Batra* [a] Keywords: Nitrogen heterocycles / Synthetic methods / Indole Derivatives / Morita–Baylis–Hillman A versatile synthesis of 2-(substituted phenyl)-6,7-dihydro- 1H-indol-4(5H)-ones from adducts of the Morita–Baylis–Hill- man reaction between 2-oxo-2-(substituted phenyl)acetalde- Introduction 6,7-Dihydro-1H-indole-4(5H)-one is an important struc- tural motif because it serves as the starting material for con- struction of several indole-based compounds. [1] In addition, derivatives bearing this core are of considerable pharmaco- logical interest and possess an array of biological activities including HSP90 inhibition, [2] soluble guanylate cyclase in- hibition, [3] kv 1.5 blocking, [4] anti-psychotic, [5] GABAA-α5 receptor ligands, [6] antiproliferation and aurora kinase inhi- bition. [7] Furthermore 4-oxo-4,5,6,7-tetrahydroindole is a sub-structural unit of the biologically important alkaloids, mitomycins, [8] and several elegant syntheses of this struc- tural unit have been reported. The first synthesis, reported in 1962 by Stetter and Lauterbach, involved treatment of 1,3-cyclohexadiones with α-haloketones leading to triones that upon reaction with ammonia or primary amines af- forded substituted 4-oxo-4,5,6,7-tetrahydroindoles. [9] A variant to the procedure included alkylation of cyclohexa- 1,3-dione with ethyl bromopyruvate to generate 4-oxote- trahydrobenzofuran-3-carboxylic acid that reacted with am- monia at high temperature to give the product. [10] In an- other strategy electro-oxidative coupling of cyclohexa-1,3- dione with ethyl vinyl ether followed by aminolysis was re- ported. [11] Heravi et al. disclosed that a potassium hydrogen sulfate catalyzed Ugi reaction between cyclohexylisocy- anide, an aldehyde, a cyclic 1,3-dicarbonyl compound and ammonium acetate in acetonitrile produced 2,3-disubsti- tuted 6,7-dihydro-1H-indole-4(5H)-ones. [12] Aoyagi et al. generated the same core through Pd-catalyzed oxidation of [‡] CDRI Communication No. 8223 [a] Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, PO Box 173, Lucknow 226 001, India Fax: +91-522-2623405, 2623938 E-mail: batra_san@yahoo.co.uk s_batra@cdri.res.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201200107. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 hydes and cyclohex-2-enone under mild conditions is de- scribed. hydroxy-enamines. [13] Recently, during studies towards de- velopment of new anticancer agents, Huang’s group synthe- sized this scaffold from 1,3-cyclohexanedione and 5-amino- levulinic acid hydrochloride. [14] More recently, Li’s group re- ported a multi-component approach for this moiety through a microwave-promoted reaction between differently substituted enamines, phenylglyoxal monohydrate and acetic acid. [15,16] The Morita–Baylis–Hillman (MBH) reaction has been used extensively in heterocyclic synthesis during the last decade. [17] In one of our research programs we have been exploring the synthetic potential of MBH derivatives for realizing aza-heterocycles. [18] We envisaged the synthesis of 6,7-dihydro-1H-indole-4(5H)-ones from the adduct of the MBH reaction between 2-oxo-2-phenylacetaldehyde and cy- clohex-2-enone (Figure 1). A S N 2' reaction of a primary amine on the double bond of the cycloalkene unit of the MBH acetate followed by intramolecular cyclization involv- ing the keto group is anticipated to afford the desired prod- uct. Here, we have developed a facile synthesis of substi- tuted 6,7-dihydro-1H-indole-4(5H)-ones. The advantage of this method is that it is versatile and a wide range of pri- mary amines can be used to give the N-substituted 6,7-dihy- dro-1H-indole-4(5H)-one unit. Figure 1. Retrosynthetic plan for the formation of 6,7-dihydro-1H- indole-4(5H)-one from the MBH adduct of 2-oxo-2-phenylacetal- dehyde.