The Preparation of 1,2,3‐Trisubstituted Guanidines

Abstract

Submitted to honor the 85th birthday of Rolf Huisgen: inspiring chemist and good friend An operationally straightforward and efficient benzotriazole-based method for the guanylation of diverse amines by use of the new reagent classes (bis-benzotriazol-1-yl-methylene)amines 13a ± 13f and benzotriazole-1-carboxamidines 17a ± 17i is described. The preparation is described for a variety of both acyclic and cyclic 1,2,3-trisubstituted guanidines in high yields.Introduction. ± A wide variety of structurally diverse molecules that incorporate guanidine units have been isolated from many microorganisms and higher plants [1]. Guanidines are core features of many therapeutically active compounds [2 ± 7], and guanidine alkaloids exhibit antiviral, antifungal, and antitumor activities [1]. Thus, procedures for the preparation of guanidines [8] are of great interest in medicinal chemistry, and much effort has been directed towards efficient syntheses of these compounds (see, e.g., [9]).The synthesis of guanidines 3 is complicated by their high basicity and nucleophilicity. Many syntheses utilize intermediates with easily removed protective groups. Common methods for the preparation of guanidines 3 involve attack of an amine 1 on various activated guanidinylating reagents 2a ± 2j (Scheme 1). Primary amines react smoothly and efficiently with these reagents, whereas sterically more demanding secondary or electronically deactivated aromatic amines face various difficulties.Methods for the preparation of guanidines 3 (Scheme 1) include: i) reaction of various ureas 2a with phosgene then treating the resultant Vilsmeier salt with amines 1 [10]; ii) using triflicguanidines 2b as guanidinylating reagents [11], or iii) guanylpyrazole 2c as guanidinylating reagents [12]. Several common routes to 3 involve the treatment of amines with electrophilic species 2d ± 2i generated from thioureas: iv) sulfonic acids 2d derived from N-alkyl-substituted thioureas

The Use of Chloroformamidine Hydrochloride as a Reagent for the Synthesis of Guanidines from Electron Deficient Aromatic Amines

“…Guanidines are of great importance in the pharmaceutical industry due to their many synthetic applications, often being utilized as heterocyclic precursors, strong bases and catalysts, and their alkaloids have exhibited a broad range of antimicrobial and antitumor activities . For these reasons, much effort has gone into the development of facile, efficient guanylating reagents.…”

“…For these reasons, much effort has gone into the development of facile, efficient guanylating reagents. Many methods for the synthesis of substituted guanidines reported in the literature often perform well with electron‐rich amines, but only modestly, if at all, with electron‐deficient aromatic amines . This paper reports a clean, convenient one‐pot synthesis of guanidines from electron‐deficient aromatic amines using chloroformamidine hydrochloride as the guanylating reagent.…”

Bis(benzotriazolyl)methanethione

“…8 (F) The Diels-Alder addition of bis(benzotriazole-1-yl)methanethione to cyclopentadiene provides the moisture-stable crystalline adduct. 9 (G) Katritzki et al have reported the synthesis of acyclic and cyclic 1,2,3-trisubstituted guanidines 10 in high yield with a convenient method for the guanylation of various primary and secondary amines by the use of (bisbenzotriazol-1-yl-methylene)amines and benzotriazole-1-carboxamidines. These reagents are prepared by bis(benzotriazole-1-yl)methanethione.…”

The chemistry and biology of organic guanidine derivatives

“…192 An optimised method for the production and purification of microsystin-LR (75) has been reported, describing conditions for M. aeruginosa PCC7806 growth, extraction, purification in two steps and storage in MeOH. 193 Both microcystin-LR and nodularin (76) are degraded in a similar way by hydrolases of an unidentified bacterial strain B-9, which promote sequential hydrolysis, first at the Arg-Adda junction, then at the Ala-Leu peptide bond and finally at the Adda-Glu connection (Scheme 18). The products and intermediates formed during this degradation process have been identified by LC-ITMS (ion trap mass spectrometry).…”

“…73,74 Concomitantly, new methods for guanidine synthesis have been reported in the literature. These include new guanylating agents such as N,N 0 ,N 00 -tri-Boc-guanidine, which reacts with amines to give di-Boc-protected guanidines and mono-Boc-protected amidinoureas (Scheme 1), 75 the use of (bis-benzotriazole-1-yl-methylene)amines or benzotriazole-1-carboxamidines for the preparation of 1,2,3-trisubstituted guanidines (Scheme 2), 76 use of hexamethyldisilazane (HMDS) and acylthioureas to prepare acylguanidines, 77 or HMDS as a catalyst in the reaction of disubstituted carbodiimides with aromatic amines to yield di-substituted aromatic guanidines, 78 use of a solvent-free, microwave-assisted, KF-Al 2 O 3 -catalyzed reaction between an acylthiourea and an amine, 79 a one-pot reaction for the preparation of N G -hydroxyguanidines using a primary amine, carboxybenzylisothiocyanate and tetrahydropiranylhydroxylamine (Scheme 3), 80 the use of a vanadium-based catalyst for the guanylation of aromatic amines with carbodiimides (Scheme 4), 81 a remarkable method employing rare-earth (Y, Yb and Lu) alkyl complexes as efficient catalysts within the coupling reaction between carbodiimides and amines to give substituted guanidines (Scheme 5), 82,83 related to a similar procedure using a titanocarborane amide complex (Scheme 6), 84 the preparation of chiral guanidines from chiral homoallyl amines, 85 synthesis of trichloroethoxysulfonyl-protected guanidines and subsequent oxidative cyclisation using a rhodium-based catalyst, 86 as well as rather classical guanidine preparations using either BrCN 87 or substituted thioureas and BiI 3 /NaBiO 3 as catalyst. 88 The use of O-methylisourea for the preparation of homoarginines from lysine residues has proven to be useful in proteomics.…”