Acyl Transfer Catalysis with 1,2,4-Triazole Anion

Abstract

Abstract1,2,4-Triazole anion has been identified as an active acyl transfer catalyst suitable for the aminolysis and transesterification of esters.Neutral nucleophiles (Figure 1), such as 4-dialkylaminopyridines (1), 1 N-alkylimidazoles (2), 2 phosphines (3), 3 imidazolylidene carbenes (4), 4 1,2-diamines (5), 5 and the recently introduced bicyclic amidines (6) and isothioureas (7), 6 have proved to be effective acyl transfer catalysts. As such, they have found a variety of applications in organic synthesis. 7 Their chiral derivatives have demonstrated considerable utility in catalyzing enantioselective transformations. 8 By contrast, the potential of anionic nucleophiles in acyl transfer catalysis remains much less explored.In the course of our studies on enantioselective acyl transfer catalysis we became interested in achieving catalytic acylation of amines using easily accessible achiral acyl donors. 9 Carboxylic esters would be especially attractive in this regard, since their uncatalyzed reaction with amines is typically very slow at ambient temperature. However, the aforementioned neutral Lewis base catalysts, 7 which successfully promote acylations with carboxylic anhydrides (1-3, 6 and 7) or acyl chlorides (5), can attack only highly activated esters. Imidazolylidene carbenes 4, which have gained popularity as transesterification catalysts, 4 have also proved to be ineffective in promoting ester aminolysis. 10 Recently, Mioskowski et al. reported that a variety of unactivated esters undergo efficient aminolysis under solvent-free conditions in the presence of TBD 8 (Figure 2), which was proposed to act as a bifunctional Lewis base catalyst. 11 Its catalytic activity, however, is only moderate, requiring a high catalyst loading (30 mol%). E-mail: birman@wustl.edu. We considered the possibility of catalyzing ester aminolysis with anionic nucleophiles, which might be expected a priori to be more nucleophilic than their neutral counterparts, and therefore better able to attack the ester group. Although the anions of protic nucleophiles 9-12 have been reported in the literature to promote this reaction, their catalytic activities were usually rather modest. 12 NIH Public AccessIn an effort to identify more active anionic acyl transfer catalysts potentially suitable for asymmetric catalyst design, we tested the aforementioned 9-12 and several other commercially available protic nucleophiles (8, 13-21) for their ability to promote the reaction of phenyl acetate with isopropylamine in the presence of stoichiometric amounts of DBU (Table 1). For comparison, we also included DMAP 1, a powerful aprotic Lewis base acylation catalyst. Most compounds tested showed only negligible effect. Among the previously reported catalysts, only catechol and cyanide anions effected significant rate acceleration (entries 6 and 7). The most remarkable results were obtained in the azole series (entries 11-16). 1,2,4-Triazole 18 displayed by far the greatest activity among all the nucleophiles tested. Diminished activity was also foun...

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“…(1) Reaction of benzylamine with isopropenyl acetate (10) in acetonitrile proceeds to N-benzylacetamide (12) in approximately 50% yield in six hours (Figures S9-S11) [26,27]. In the presence of CO2 and 1.1 equivalents of DBU, however, no detectable product was observed during the same time period as analyzed by 13 C NMR.…”

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“…These data indicated that the phenyl ester reacts first (in a rate-limiting step, see Scheme 3) with imidazole to form a highly reactive intermediate (presumably acyl imidazole). Then the intermediate reacts rapidly with Cys through thiol capture [9] or it is destroyed by H 2 O when Cys is absent. To apply the phenyl ester ligation to protein chemical synthesis, we developed a solid-phase method to prepare peptide phenyl esters (Scheme 4).…”

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“…The use of sodium methoxide in toluene for amidation of unactivated esters [35] failed. However, aminolysis of acetonide-ester 3 was successfully performed with 1,2,4-triazole anion as catalyst [36], but in a moderate yield, to provide N-propargylamide derivative of acetonide 4. The acetal deprotection of 4 was carried out with Dowex ® 50 resin in methanol to give the key intermediate 5 in good yield.…”