Microwave solvent-free synthesis of nitrocyclohexanols Olivier Correc, a Karine Guillou, a Jack Hamelin, a Ludovic Paquin, a Franc ßoise Texier-Boullet a, * and Lo € ıc Toupet b a Synth ese et Electrosynth ese Organiques 3, UMR 6510, CNRS et Universit e de Rennes I, Campus de Beaulieu, 35042 Rennes, France b Groupe Mati ere Condens ee et Mat eriaux, UMR C66-26, Universit e de Rennes I, Campus de Beaulieu, 35042 Rennes, France Received 28 May 2003; revised 22 October 2003; accepted 24 October 2003 Abstract—New nitrocyclohexanols 3a–f are synthesized by a clean and original method from nitromethane 1 and unsaturated ketones 2a–f in the presence of solid potassium fluoride–alumina under solvent-free conditions coupled with microwave irradiation. The reaction involves a double and diastereoselective Michael addition followed by ring closure. Another diastereomer 3 0 , which differs by the configuration of C-4, is obtained in the presence of piperidine and EtOH at room temperature. Ó 2003 Elsevier Ltd. All rights reserved. 1. Introduction The reactivity of primary nitroalkanes especially nitro- methane 1 with electrophilic gem-disubstituted alkenes, has been largely studied in our laboratory under solvent- free conditions coupled with microwave irradiation, with supported reagents on various mineral oxides 2–4 in some cases. As part of our program to develop the synthesis of carbocycles after Michael additions in this environmentally benign process, we studied the reaction of nitromethane 1 with alkenes bearing one electron- withdrawing group such as unsaturated a,b-enones 2a–f and we report here our preliminary results. 2. Results and discussion For example, by mixing nitromethane 1 (0.32 g, 5.2 mmol) and chalcone 2a (1 g, 4.8 mmol) without sol- vent in the presence of a mixture, in an unusual ratio, of neutral Alumina 60 Merck (2 g) and a potassium fluoride (3 g)––the molar ratio of KF and Al 2 O 3 was carefully optimized––we obtained the new nitrocyclo- hexanol 3a (60% yield) after 20 min under microwave irradiation in a monomode reactor Synthewave 402 â Prolabo at 90 °C (monitored temperature 5 ) reached after 5 min and maintained 15 min (Scheme 1). 3a Was iso- lated after cooling to room temperature, addition of boiling acetonitrile, elimination of solids by filtration and acetonitrile evaporation. The reaction is highly diastereoselective: only one isomer (A) was detected by 1 H NMR spectroscopy of the crude product. The rela- tive configuration of the carbons of isomer A has been established by X-ray analysis 6;7 (Fig. 1). The pure product is obtained after crystallization in the appropriate solvent (see Table 1). Classical activation of the reaction in an oil bath with the same temperature profile, does not allow the formation of cyclohexanol. Obviously, this is an evidence for a specific microwave reactivity. If the reaction is realized in EtOH 95% (anhydrous EtOH or diethyl oxide are inefficient), with piperidine in excess (1.5 equiv), after 4 days at room temperature, the 1 H NMR spectrum of the crude reac- tion mixture exhibits signals for four products: the well- known monoadduct 5a (34%), 10 the bis-adduct 6a (24%), 8–12 the heteroadduct 4a (15%) (Scheme 2) and another isomeric cyclohexanol 3 0 a (isomer B: 24% Keywords: nitrocyclohexanols; a,b-enones; Michael additions; alu- mina–potassium fluoride; solvent-free reactions; microwave activation. * Corresponding author. Tel.: +33-2-23-23-57-82; fax: +33-2-23-23-63- 74; e-mail: francoise.texier@univ-rennes1.fr 2 PhCH=CHCOPh CH 3 NO 2 Ph O 2 N Ph COPh Ph OH 1 2 3 4 5 6 2a 1 3a Scheme 1. 0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2003.10.148 Tetrahedron Letters 45 (2004) 391–395 Tetrahedron Letters