Alkylation of ethylenethiourea with alcohols: a convenient synthesis of S-alkyl-isothioureas without toxic alkylating agents Michael K. Denk * and Xuan Ye Guelph-Waterloo Center for Graduate Studies in Chemistry, Guelph, Ontario, Canada N1G 2W1 Received 14 June 2005; revised 23 August 2005; accepted 25 August 2005 Available online 13 September 2005 Abstract—The alkylation of ethylenethiourea with alcohols and aqueous acids (HCl, HBr, and HI) allows the synthesis of the respective S-alkyl-isothioureas in high yield and purity. Consistently high yields (91–98%) were obtained with 56% HI, the yields for 48% HBr (48–93%) and 37% HCl (36–85%) were lower and varied with the type of alcohol. The method is a convenient low- cost alternative to the use of alkyl iodides and an easy access to the S-tert-butyl isothiourea. Ó 2005 Elsevier Ltd. All rights reserved. 1. Introduction S-Alkyl-isothiouronium salts 1 1 and S-alkyl-isothioureas 2 2 are starting materials for the synthesis of guanidines and heterocyclic systems. 3 In the last decade, it has been recognized that they can also serve as remarkably potent inhibitors for a whole range of enzyme systems. 4–7 Inhi- bition of nitric oxide synthase (NOS) has led to their use in the treatment of a range of life threatening conditions including septic shock, acute kidney failure, and organ rejection after transplantation surgery. 4 Clobenpropit Ò , a potent histamine H3 antagonist, 5 finds use as an anti- convulsant, while Dimaprit Ò is used as histamine H2 inhibitor as well as NOS antagonist. 6 The capability of 1 and 2 to block the heart muscles Na + /Ca 2+ exchange system (NCX) has become a promis- ing approach for the treatment of conditions leading to acute heart failure. 7 Preceding these exciting new find- ings are older studies that demonstrated the ability of 1 and 2 to protect DNA against radiation damage both in vivo and in vitro. 8 S-Alkyl-isothioureas 2 (Scheme 1) are typically obtained by reaction of thioureas 9 with alkyl halides or other alkylating agents via the S-alkyl-isothiouronium salts (1). Tertiary alkyl derivatives is not readily accessible in this way, as solvolysis and elimination become the main reaction. 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.08.150 Keywords: Alkylation; Thiourea; S-Alkyl-isothiourea. * Corresponding author. E-mail addresses: mdenk@uoguelph.ca; michaeldenk@mac.com NH N H S Cl N H N Clobenpropit ® H 2 N H 2 N S R H 2 N H 2 N S RX X HN H 2 N S R 1 2 + HX - HX NH H 2 N S NMe 2 Dimaprit ® Scheme 1. Synthesis and use S-alkyl-isothioureas. Tetrahedron Letters 46 (2005) 7597–7599 Tetrahedron Letters