CuAAC reactions of sterically hindered azides

Abstract

The regularities of the CuAAC reactions due to the structure of the substituent were determined and basic requirements for the choice of the catalytic system in the case of azides or alkynes with bulky substituents, and azides containing fragments able to effectively act on Cu(I) ions were shown. The insufficiently known types of the Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC) were studied. The choice of a catalyst for such reactions of sterically hindered azides, whose behavior in “click”-reactions is poorly studied, was discussed. The scope and major disadvantages or limitations of most commonly used Cu-catalytic systems were shown on a number of examples. The methods of synthesis were developed and for the first time a series of sterically hindered azides: ((2-azido-5-methyl-1,3-phenylene)bis (methanetriyl))tetrabenzene, 2-azido-1,3,5-trimethylbenzene, 2-azido-1,3-diisopropylbenzene, 1-(azidomethyl)naphthalene, 1,3-bis(azidomethyl)-5-(tert-butyl)benzene were obtained and studied in the CuAAC reactions. Examples of their use in the synthesis of 1,2,3-triazoles were demonstrated. A series of new 1,4-disubstituted 1,2,3-triazoles were obtained by cyclization of the synthesized azides to terminal alkynes. The protocol for CuI-catalytic cycloaddition of the highly sterically hindered ((2-azido-5-methyl-1,3-phenylene)bis(methanetriyl))tetrabenzene to highly reactive alkyne: methyl propiolate was optimized via replacement of the Et 3 N with N,N-diisopropylethylamine (DIPEA) base and using DMSO as the solvent. Further hydrolysis of methyl 1-(2,6-dibenzhydryl-4-methylphenyl)-1 H -1,2,3-triazole-4-carboxylate without isolation allowed to obtain 1-(2,6-dibenzhydryl-4-methylphenyl)-1 H -1,2,3-triazole-4-carboxylic acid in good yield. For the number of azides with less bulky substituents (e.g. 2-azido-1,3,5-trimethylbenzene, 2-azido-1,3-diisopropylbenzene, (1-azido-2-bromoethyl)benzene, 1-(azidomethyl)naphthalene) another catalytic system: CuSO4•5H 2 O / Na-ascorbate was applied, where Cu (I) is generated in situ . This catalytic system has proven to be effective for the use of sterically hindered azides as well as for sterically hindered acetylene. Hence, 1,1-diphenylprop-2-yn-1-ol readily reacted with mesitylazide to form (1-mesityl-1 H -1,2,3-triazol-4-yl)diphenylmethanol in a high yield. Successful usage of the CuSO 4 •5H 2 O / Na-ascorbate system was also performed while treatment of a norbornyl containing propargylamide with benzyl azide or mesityl azide. The mentioned alkyne was obtained from commercially available endo-endo-5-norbornene-2,3-dicarboxylic acid anhydride by the reaction with propagylamine. Such 5-norbornene containing amides are attractive structural blocks for the synthesis of polymers variety via click reactions. Target 1,2,3-triazoles with norbornyl residue were obtained in a good yields. It was considered that catalytic system: CuSO 4 •5H 2 O / Na-ascorbate is the most affordable and relatively effective for the sterically hindered reaction partners in AAC reactions. Thus, some features of application of two frequently used catalytic systems (CuI and CuSO 4 / Na-ascorbate) for AAC reaction of azides to terminal acetylenes were studied. On a number of examples, including the reactions of sterically hindered azides, the main drawbacks and limitations in the use of these catalytic systems are shown. The possibility of introducing new types of reagents into the click-reaction was discussed. Keywords : azides, alkynes, 1,3-dipolar cycloaddition, CuAAC, click chemistry, sterically hindered azides, 1 H -1,2,3-triazoles.