FULL PAPER DOI: 10.1002/ejoc.201000322 Advancing the Morita–Baylis–Hillman Chemistry of 1-Formyl-β-carbolines for the Synthesis of Indolizino-indole Derivatives [‡] Virender Singh, [a] Samiran Hutait, [a] and Sanjay Batra* [a] Keywords: Nitrogen heterocycles / Alkaloids / Morita–Baylis–Hillman reaction / Harmicine / Homofascaplysin The chemistry of the Morita–Baylis–Hillman adducts of 1- formyl-β-carbolines has been extended for obtaining indoliz- ino-indole derivatives which mimic the harmicine and homo- fascaplysin frameworks. Adducts of N-substituted methyl 1- formyl-9H-β-carboline-3-carboxylate yield indolizino-indole derivatives upon bromination followed by aqueous workup. On the other hand, N-substituted 1-formyl-9H-β-carbolines give rise to similar products in a one-pot DABCO-promoted Introduction We have recently reported on the Morita–Baylis–Hillman (MBH) reactions of 1-formyl-9H-β-carbolines with alkyl acrylates which resulted in one-pot synthesis of unusual canthin-6-ones. [1] Moreover, adducts derived from acryloni- trile were readily transformed into canthine derivatives via base-promoted intramolecular cyclization. Furthermore, in- stalling an alkene or alkyne chain on the indole NH and generating dipolarophile in the form of nitrile oxide, azide or azomethine ylide from the formyl group allowed us to construct a variety of fused β-carboline-based compounds via cycloaddition reactions. [2] In our efforts to expand the repertoire of fused-carbolines which could be synthesized from substituted 1-formyl-β-carbolines, we became inter- ested in investigating the reactivity of substrates substituted at nitrogen by allyl and alkyne groups for 3+2 cycloaddition reaction. In principle, the allyl bromide obtained from the MBH reaction of such N-substituted aldehydes via bromi- nation will lead to an allyl bromide which, under the influ- ence of PPh 3 or PBu 3 may furnish a dipolarophile. This dipolarophile can initiate an intramolecular 3+2 cycload- dition reaction with alkene or alkyne chain on the nitrogen leading to annulated β-carboline (path 1, Figure 1). [3] Alter- natively, the nucleophilicity of the N atom of the C-ring of β-carboline may initiate an intramolecular cyclization re- sulting in an indolizino-indole system (path 2, Figure 1). [‡] CDRI Communication No. 7935. [a] Medicinal and Process Chemistry Division, Central Drug Re- search Institute, CSIR, P. O. Box 173, Lucknow 226001, UP, India Fax: +91-522-2623405 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.201000322. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2010, 3684–3691 3684 reaction of activated alkenes. Alternatively, the DMAP-medi- ated Morita–Baylis–Hillman reaction of N-substituted methyl 1-formyl-9H-β-carboline-3-carboxylate with cycloalkenones yields adducts that cyclize intramolecularly in the presence of PBr 3 to yield compounds with the homofascaplysin frame- work. In contrast, the DMAP-mediated reaction of N-substi- tuted 1-formyl-β-carboline with cyclohexenone directly gives a product with similar framework in a single step. Indeed, the formation of indolizines from 2-pyridinecarbox- aldehyde has been reported to take place following the lat- ter path. [4] More importantly for our study, either pathway would afford new annulated β-carboline system. Investiga- ting this approach, we have discovered that the allyl bro- mide which is generated via bromination of the MBH ad- duct of N-substituted 1-formyl-β-carboline immediately ini- tiates nucleophilic attack of the nitrogen of the C-ring to furnish an indolizino-indole system which represents the aromatized derivative of the alkaloid harmicine (Fig- ure 2). [5] Similar reactions with cycloalkenones give prod- Figure 1. Retrosynthetic pathway. Figure 2. Core structure of alkaloids harmicine and fascaplysin.