Synthesis and transformations of 2-phenylhydroxymethyl)cyclohexylamines Pe Âter Csomo Âs, a Ga Âbor Berna Âth, a,b Pa Âl Soha Âr, c Antal Csa Âmpai, c Norbert De Kimpe d and Ferenc Fu Èlo Èp a,p a Institute of Pharmaceutical Chemistry, University of Szeged, P.O. Box 121, H-6720 Szeged, Hungary b Research Group for Heterocyclic Chemistry of the Hungarian Academy of Sciences, P.O. Box 121, H-6720 Szeged, Hungary c Department of General and Inorganic Chemistry, Eo Ètvo Ès Lora Ând University, P.O. Box 32, H-1518 Budapest, Hungary d Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Gent University, Coupure Links 653, B-9000 Gent, Belgium Received 15 November 2000; revised 15 January 2001; accepted 1 February 2001 Abstract ÐDiastereomeric 2-phenylhydroxymethyl)cyclohexylamines were synthesised by reduction of 2-benzoylcyclohexylamines. 1S p ,2R p )-2-Benzoylcyclohexylamine can be reduced diastereoselectively to the corresponding g-amino alcohol with sodium borohydride; for the trans counterpart 1R p ,2R p )-2-benzoylcyclohexylamine, lithium aluminium hydride was found to be a selective reducing agent. In both cases, high syn selectivities were observed. The amino alcohols were transformed to the corresponding cyclohexane-fused tetrahydro- 1,3-oxazin-2-ones and -2-thiones. The g-amino alcohols reacted with arylimidates to afford 4,5-dihydro-6H-1,3-oxazines. Their cyclization with phenyl isothiocyanate yielded 2-phenyliminotetrahydro-1,3-oxazines. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The stereocontrolled synthesis of 1,3-amino alcohols has attracted much attention recently because of their pharmacological properties and their utility as building blocks for the preparation of potential pharmacons. 1±6 Alicyclic amino alcohol derivatives have also been intro- duced into therapy. For example, ciramadol and tramadol are used as analgesics. 7 The methods most generally applied for the preparation of stereoisomeric 1,3-amino alcohols involve reduction reac- tions. 8 These include mainly the reductions of the corre- sponding b-amino carbonyl derivatives or the cleavage of N,O-heterocycles. 9 The alicyclic amino alcohols can also be obtained via these two procedures. However, various methods can be used for the stereoselective preparation of alicyclic 1,2-disubstituted 1,3-amino alcohols possessing two stereogenic centres. 10±12 The preparation of the corre- sponding stereohomogeneous alicyclic amino alcohols possessing three stereogenic centres is more dif®cult and is dependent on the selectivity of the reduction reaction. On the other hand, as the number of possible stereoisomers increases, only some of them can be prepared with good stereoselectivity. The literature syntheses of alicyclic amino alcohols containing three stereogenic centres commonly involve the reductions of b-amino ketones, 13±15 enaminones 16±18 or isoxazolines. 19,20 In recent years, the synthesis of cycloalkane-fused hetero- cycles has been one of our main research topics. A number of alicycle-condensed oxazines, thiazines and pyrimidines have been prepared by ring closure of the corresponding 1,3-difunctional compounds. The chemistry and stereo- chemistry of the partially saturated heterocycles obtained has been widely investigated. 21 As a continuation of our earlier investigations, our present aim was the diastereo- selective synthesis of hydroxymethylcyclohexylamines containing a phenyl substituent on the carbon atom adjacent to the anellation. The synthesised amino alcohols were transformed to different alicycle-condensed 1,3-oxazines for further conformational studies. 2. Synthesis For the preparation of amino alcohols 3 and 6, amino ketones 2 and 5 were chosen as key intermediates. N-Substi- tuted derivatives of 2 and 5 were earlier prepared for pharmacological studies of their analgesic activity. 17 The partially unsaturated derivative of 2, 1R p ,2S p )-N-tert- butoxycarbonyl)-2-[3 0 ,4 0 -methylenedioxy)benzyl]-4-cyclo- hexenylamide was used as a building block in the synthesis of montanine-type Amaryllidaceae alkaloids. 22,23 To obtain Tetrahedron 57 2001) 3175±3183 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-402001)00176-4 Keywords: amino alcohols; 1,3-oxazines; 1,3-benzoxazines. p Corresponding author. Tel.: 136-62-545-564; fax: 136-62-545-705; e-mail: fulop@pharma.szote.u-szeged.hu