Piperidine and Azetidine Formation by Direct Cyclization of Diols with N-Nonsubstituted Sulfonamide under the Mitsunobu Conditions Utilizing (Cyanomethylene)tributylphosphorane (CMBP) and Its Application to the Synthesis of Lupinine

Cyanomethylene)tributylphosphorane (CMBP) can promote the Mitsunobu reaction of 1,3-and 1,5-diols with N-nonsubstituted sulfonamides, such as tosylamide (TsNH 2 ) and 3,3-dimethoxypropylsulfonamide (DimpsNH 2 ), to prepare azetidine and piperidine ring systems directly.Utilizing this methodology, lupinine, a biologically active piperidine alkaloid, was synthesized.The synthesis of cyclic amines possessing a wide variety of interesting biological activities has attracted much attention and has been accomplished with the development of efficient synthetic methods. 1 In the course of our studies on the Mitsunobu chemistry, diethyl azodicarboxylate (DEAD)-PPh 3 and our new azodicarboxamide reagents, e.g., N,N,N',N'-tetramethylazodicarboxamide 2 (TMAD)-PBu 3 could not promote alkylation of N-nonsubstituted sulfonamides such as TsNH 2 , because the amide reacted with PPh 3 or PBu 3 to form triphenyl-or tributylphosphine tosylimide (TsN=PR 3 ) under the reaction conditions. 3,4Furthermore, the same is true with (cyanomethylene)trimethylphosphorane (CMMP), our new phosphorane-type reagent. 5,6By contrast, the alkylation was accomplished utilizing (cyanomethylene)tributylphosphorane (CMBP) 7 with primary or secondary alcohols to give the desired N-monosubstituted sulfonamide in excellent yields. 4In addition, CMBP could promote the Mitsunobu reaction of 1-phenyl-1,5-pentanediol with TsNH 2 to provide the 2-phenylpiperidine ring system directly (Scheme 1). 4