An efficient synthetic method for the preparation of disubstituted guanidines is described. Primary and secondary alcohols were treated with guanylating agents under Mitsunobu conditions and their subsequent reactions with amines provided disubstituted guanidines.During the course of our investigation in the area of anticoagulation, 1 we required a facile synthetic method for the preparation of N,N'-unsymmetrical disubstituted guanidines 1 (Scheme), which is applicable to solid phase synthesis. 2
Scheme 1Although there are a variety of synthetic methods available to prepare monosubstituted guanidines, 3,4 few methods have been developed for the synthesis of disubstituted guanidines. 5,6 One general approach toward this type of compound involves the alkylation of the monoalkylated guanidine 3 which, in turn, is prepared from the reaction of amines with the guanylating agents 2a and 2b (Route a of Scheme). 5 The known procedure appears unattractive to apply to solid phase synthesis due to the harsh reaction conditions. We envisioned that alcohols (R'OH) could be used as the alkylating source to prepare the guanylating agent 4 by use of the Mitsunobu conditions 3 and subsequent reaction with amines under mild conditions to afford the disubstituted guanidines 1 (Route b in Scheme). In order to test this approach, commercially available bisBoc-thiopseudourea 2b was treated with benzyl alcohol in the presence of PPh 3 and DEAD (Table). 7 The desired alkylated thiopseudourea 4a was isolated in 87 % yield within a few hours (Entry 1). Based upon this encouraging result, we prepared thiopseudoureas 4b, 4c, and 4d (Entry 2, 3 and 4) by using thiourea, 2b, or pyrazole derivative 4e (Entry 5) by using 2a 4 from several different alcohols i.e. m-nitrobenzyl, m,m'-dinitrobenzyl, and allyl alcohol in good to excellent yields.Additionally, we investigated secondary alcohols. Several secondary alcohols including (S)-methyllactate were used for this purpose. The expected thioureas 4f (Entry 6), 4i (Entry 9) and pyrazole derivatives 4g (Entry 7), 4j (Entry 10) were obtained in moderate yields, presumably due to steric interaction.b-Amino alcohols were reacted with 2a or 2b under the same reaction conditions to provide cyclic guanidine derivatives 5a (Entry 11) and 5b (Entry 12) presumably via the mono-alkylated 4k and 4l (Eq. 1). However, when NBoc-N-methyl aminoethanol was treated with 2b under the same reaction conditions, the desired 4m was obtained in 92% yield (Entry 13 and Eq. 2).
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