An azide and acetylene free synthesis of 1-substituted 1,2,3-triazoles

Abstract

This paper details a simple and efficient 3-component synthesis of 1-substituted 1,2,3-triazoles using a primary amine, 2,2dimethoxyacetaldehyde and tosylhydrazide. The reaction proceeds in good to excel-lent yields using either aliphatic or aromatic amine substrates and is tolerant of a wide range of func-tional groups including electron-rich and deficient aryl groups, terminal alkynes, ketones and highly sterically encumbered amines.

Large-scale synthesis of Notum inhibitor 1-(2,4-dichloro-3-(trifluoromethyl)-phenyl)-1H-1,2,3-triazole (ARUK3001185) employing a modified Sakai reaction as the key step

“…The Sakai reaction was an attractive alternative because of its simplicity through N 1 -aryl specificity of the construction of the 1,2,3-triazole, readily available reagents, precedent for a toleration of wide variety of substituents on the aryl ring, and because it has been used to make representative bioactive molecules on gram scale. 17–19 A pilot reaction with 4 (334 mg) using α,α-dimethoxy tosylhydrazone 2b in MeOH at 75 °C for 16 h following the published conditions 18 gave the required triazole 1 in 65% yield demonstrating the feasibility of this approach. Switching the solvent to THF improved the yield to 76%, whereas the use of DMF as solvent only gave recovered aniline.…”

“…Recently, Clark has reported a convenient and operationally simple modication of the Sakai reaction that produces 1-aryl triazoles with a range of anilines under mildly acidic conditions. 17,18 The one-pot reaction of 2,2-dimethoxyacetaldehyde ((MeO) 2 CHCHO) with p-toluene sulfonylhydrazide (TsNHNH 2 ) in MeOH at RT for 2 h provides the a,a-dimethoxy tosylhydrazone 2b in situ, and then addition of the aniline and AcOH with warming to 75 C for 16 h produces the 1-aryl triazole in good yield. 18 Further modications of the Sakai reaction were presented by Bi using a base-promoted annulation of a,a-diuoro tosylhydrazone 2c with a wide scope of amines under mild conditions.…”

Large-scale synthesis of Notum inhibitor 1-(2,4-dichloro-3-(trifluoromethyl)-phenyl)-1H-1,2,3-triazole (ARUK3001185) employing a modified Sakai reaction as the key step

“…The Sakai reaction was an attractive alternative because of its simplicity through N1-aryl specificity of the construction of the 1,2,3-triazole, readily available reagents, precedent for a toleration of wide variety of substituents on the aryl ring, and because it has been used to make representative bioactive molecules on gram scale. [17][18][19] A pilot reaction with 4 (334 mg) using -dimethoxy tosylhydrazone 2b in MeOH at 75 o C for 16 h following the published conditions 18 gave the required triazole 1 in 65% yield demonstrating the feasibility of this approach. Switching the solvent to THF improved the yield to 76%, whereas the use of DMF as solvent only gave recovered aniline.…”

“…Recently, Clark has reported a convenient and operationally simple modification of the Sakai reaction that produces 1-aryl triazoles with a range of anilines under mildly acidic conditions. 17,18 The one-pot reaction of 2,2dimethoxyacetaldehyde ((MeO)2CHCHO) with p-toluene sulfonylhydrazide (TsNHNH2) in MeOH at RT for 2 h provides the -dimethoxy tosylhydrazone 2b in situ, and then addition of the aniline and AcOH with warming to 75 o C for 16 h produces the 1-aryl triazole in good yield. 18 Further modifications of the Sakai reaction were presented by Bi using a base-promoted annulation of -difluoro tosylhydrazone 2c with a wide scope of amines under mild conditions.…”

“…17,18 The one-pot reaction of 2,2dimethoxyacetaldehyde ((MeO)2CHCHO) with p-toluene sulfonylhydrazide (TsNHNH2) in MeOH at RT for 2 h provides the -dimethoxy tosylhydrazone 2b in situ, and then addition of the aniline and AcOH with warming to 75 o C for 16 h produces the 1-aryl triazole in good yield. 18 Further modifications of the Sakai reaction were presented by Bi using a base-promoted annulation of -difluoro tosylhydrazone 2c with a wide scope of amines under mild conditions. 19 Here, we disclose the application of both a CuAAC method and a modified Sakai reagent for the large-scale synthesis of aryl triazole 1 from aniline 4 (Figure 1).…”