DOI: 10.1002/ajoc.201300142 Synthesis of 3,5-Disubstituted Cyclohex-2-en-1-one via a Five-Step Domino Reaction Catalyzed by Secondary Amines: Formation of (E)-a,b-Unsaturated Methyl Ketones Manas K. Ghorai,* Sauvik Samanta, and Subhomoy Das [a] Abstract: A simple strategy for the synthesis of 5-substitut- ed-3-methylcyclohex-2-en-1-ones by proline-catalyzed five- step domino reactions of acetone and aromatic aldehydes is reported. The starting materials are stirred in the presence of l-proline for 24 h then heated to 45 8C for a further 4- 6 h. The method can also be changed to exclusively form a,b-unsaturated methyl ketones with > 99 % E-selectivity by heating the mixture to 80 8C in the second stage. Cyclohexenones are of considerable research interest in organic synthesis because of their versatile utility as build- ing blocks for a wide range of natural products and other useful compounds. [1] The intramolecular aldol reaction (Robinson-type annulation) is one of the best routes to- wards the formation of a cyclohexenone skeleton. [2] In this regard, pioneering work was reported by Agami et al., [3] who used amino acid l-proline as the catalyst. The develop- ment of the Hajos–Parrish–Eder–Sauer–Wiechert reaction [4] was a crucial event for the synthesis of chiral cyclohexe- none moieties, though a racemic synthesis was reported ear- lier by Wieland and Miescher. [5] In recent years, a few inter- esting syntheses of enantioenriched substituted cyclohexe- none derivatives from 2,6-diones have been reported. [6] Syn- thesis of 3,5-disubstituted 2-cyclohexenones has also been performed by using different two/multicomponent intermo- lecular reactions. [7] The formation of 3,5-disubstituted-2-cy- clohexenone derivatives in very poor yields as byproducts from reactions starting directly from aldehydes and ketones was reported earlier. [8] We envisioned that cyclohexenone derivatives could be synthesized easily as the major product from acetone and aldehydes by a five-step domino aldol-de- hydration-Michael-aldol-dehydration sequence under suita- ble reaction conditions, that is, with proper choice of an amine catalyst, solvent and temperature and so on. (Scheme 1). In continuation of our research activities in enolate chemistry and domino reactions, [9] we have developed a simple strategy for the synthesis of 5-substituted-3-meth- ylcyclohex-2-en-1-one derivatives 4 from easily available starting materials such as acetone (1) and aromatic alde- hydes 2 by using l-proline as the catalyst. Moreover, our protocol provides a simple route for the synthesis of a,b-un- saturated methyl ketones 3 (E/Z > 99:1) as the only product under appropriate reaction conditions. a,b-Unsaturated methyl ketones have been used as important building blocks for many organic transformations [10] and a number of methods are known for the synthesis of such a,b-unsatu- rated ketones. [11] Herein, we report our preliminary results. To test the viability of our approach initially we per- formed the domino reaction by using acetone (2.5 equiv.) and benzaldehyde (2a, 1.0 equiv.) in the presence of pyrro- lidine (A) as the secondary amine catalyst in different polar solvents, such as CH 2 Cl 2 , CH 3 CN, and dimethyl sulfoxide (DMSO). After 24 h stirring at room temperature, the reac- tion mixture was heated to 45 8C for 6 h and the a,b-unsatu- rated methyl ketone 3a was obtained as the only product in up to 36% yield (Table 1, entries 1–3). Under these reac- tion conditions, the cyclic product 4a was not formed. Upon increasing the amount of acetone to up to ten equiva- lents had no significant effect in terms of yield of 3 and 4. When the amount of acetone was increased to 50.0 equiva- lents, interestingly the cyclohexenone 4a was obtained in poor yields of up to 34 % along with the acyclic product 3a (Table 1, entries 6–8). By using acetone as the solvent the yield of the cyclic product 4a was increased to 60 % and the acyclic ketone 3a was produced as the minor product in 25% yield (Table 1, entry 9). [a] M. K. Ghorai, S. Samanta, S. Das Department of Chemistry Indian Institute of Technology Kanpur Kanpur-208016, Uttar Pradesh (India) Fax: (+ 91) 512-259-7518 E-mail : mkghorai@iitk.ac.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201300142. Scheme 1. Five-step domino reaction sequence for the synthesis of 5- substituted-3-methylcyclohex-2-en-1-one. Asian J. Org. Chem. 2013, 2, 1026 – 1030  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1026 COMMUNICATION