N-Acyl-1,2,3-triazoles – key intermediates in denitrogenative transformations

Direct N-acylation of 1,2,3-NH-triazoles aimed at obtaining elusive N-acyl-1,2,3-triazoles was investigated. A preference for the formation of thermodynamically favoured N2 isomers was established and an influence of the hard/soft character of the electrophile on the regioselectivity of acylation was found. Although N-acylated 1,2,3-triazoles are hydrolytically unstable compounds, they were isolated and fully characterized, including crystal structure determination of examples of N1 and N2 acylated products by X-ray difraction. N1-and N2-acyltriazoles interconvert in the presence of Brønsted or Lewis acids, which explained the efficiency of triazole cleavage transformations proceeding via N1-acylated triazoles. Efficient synthesis of enamido triflates from NH-triazoles proceeding via the intermediacy of N2-acyl-1,2,3-triazoles was developed.

1,2,3-Triazoles are important heterocyclic compounds with various biological activities and high synthetic value. 1 There are two general synthetic routes to N-substituted 1,2,3-triazolescycloaddition reactions of azides with alkynes, 2 activated ketones 3 , or nitroalkenes, 4 and nitrogen functionalization of NH-1,2,3-triazoles with electrophiles. 5 Whereas the cycloaddition reaction is widely investigated and established as an efficient and robust method, functionalization of NH-1,2,3-triazoles containing three nucleophilic nitrogen atoms is considered problematic because of unpredictable regioselectivity.1a,5 However, NH-1,2,3-triazoles are available starting materials that can be efficiently prepared from inexpensive azide sources, such as NaN3 6 or TMSN3 7 and alkynes, or NaN3 and commercially available aldehydes and nitroalkanes via tandem Henry reaction/[3+2] cycloaddition. 8Recently, a number of regioselective protocols for the synthesis of either N2 9 or N1substituted 10 isomers of 1,2,3-triazoles have been developed.] It is important to note that sulfonylation of NH-1,2,3-triazoles, which would be a tempting route to synthetically useful N1-sulfonyl-1,2,3-triazoles, is not regioselective (Scheme 1B), 11 and only regioselective N2sulfonylation via radical reaction is known. 12n contrast to a broad variety of known N-alkyl-, Nfluoroalkyl, N-aryl-and N-sulfonyl-1,2,3-triazoles (Scheme 1A), N-acyl-1,2,3-triazoles are almost unexplored, and only rare and scattered examples have been reported. 13Indeed, a click reaction with acyl azide is not a viable route because of the low stability of acyl azides in the presence of a Cu(I) catalyst, resulting in nitrene formation. 14N-Carbamoylation of NH-1,2,3triazoles was studied and the formation of a mixture of N1-and N2-isomers was observed. 15These compounds possess significant application potential in biological studies.For example, 2-carbamoyl-4-aryl-1,2,3-triazole derivatives were used for site-selective incorporation into proteins, 15c as selective chemical probes of endocannabinoid biosynthesis enzymes such as diacylglycerol lipase and ABHD6.15d,e Very recently, the first example of selective formation of N2alkoxycarbonyl-1,2,3-triazoles was observed in prolinecatalyzed click reaction of carbamoyl azides with alkynes followed by spontaneous carbamoyl group migration to N2position. 16The resulting N2-carbamoyl triazoles were highly sensitive to hydrolysis to NH-triazoles (Scheme 1C).
1,2,3-Triazoles bearing an electron-withdrawing group at position N1 are useful starting materials in denitrogenative ring opening transformations. 1, 17Among them, N-sulfonyl-1,2,3triazoles are the most widely explored in denitrogenative transformations, which are possible under metal catalysis 17 or by the action of Lewis or Brønsted acids (Scheme 2A). 18The transannulation process was recently extended by us to Nfluoroalkylated triazoles to give access to a number of Nfluoroalkylated nitrogen heterocycles. 19Moreover, there has been one report about denitrogenative cleavage of N-(1,2,4triazolyl)-1,2,3-triazoles. 20However, it is remarkable that Nacyltriazoles have never been used as substrates in denitrogenative transformations.This can be attributed to the low stability of these compounds and their sensitivity to Please do not adjust margins Please do not adjust margins moisture, as their hydrolysis results in deacylation to NHtriazoles. 16Also, it has been reported that reactions of Nacylbenzotriazoles with nucleophiles (amines, alcohols) result in deacylation as well. 21Thus, N-acylbenzotriazoles have been used as mild acylation reagents with limited applicability in ring transformations.Only recently, the first reports of efficient monocyclic 1,2,3-triazole ring cleavage starting from NHtriazoles via in situ acylation were published by us (Scheme 2B) 22 and Li's group (Scheme 2C). 23The formation of unstable Nacyltriazoles as intermediates in these processes has been proposed.Indeed, the utilization of readily available NHtriazoles is more atom-economical compared to N-sulfonyl-and N-fluoroalkyl-triazoles.However, the formation, stability and reactivity of N-acyl-1,2,3-triazoles remains unexplored.A high efficiency of NH-triazole ring cleavage transformations could support the hypothesis of regioselective N1-acylation, 23 while it is well-established that in reactions of NH-triazoles with electrophiles the formation of N2-substituted isomers is preferred.9h-l We hypothesized that a rapid interconversion between N1 and N2-acyltriazoles in the presence of an excess of acylation agent might enable the conversion of N-acyltriazole into ring cleavage products.Herein we report on our systematic study on N-acylation of 1,2,3-NH-triazoles and their regioselectivity, as well as on our study of ring cleavage reactions of N-acyltriazoles with Brønsted and Lewis acids.
We initiated our study of the acylation of the model 1,2,3triazole 1a with different acylating agents in the presence of stoichiometric amount of base (Et3N).Acylation of 1a proceeded quickly at ambient temperature, with nearly quantitative yields (Table 1).In the case of benzoyl chloride or benzoic anhydride, mostly N2-acylated triazole 3a formed (entries 1 and 2).The more electron-deficient 4-nitrobenzoyl chloride led to the exclusive formation of N2-substituted acyl triazole 3b (entry 3), while 4-methoxybenzoylchloride, by contrast, showed a preference for N1-isomer 2c (entry 4).The presence of halogen atoms in ortho-positions, exerting steric hindrance, also favoured the formation of N1-isomers (entries 5-6).Acetic anhydride and fluorinated acid anhydrides afforded almost exclusively N2-isomers (entries 7-9).However, electronrich electrophile ethyl chloroformate gave a nearly 1:1 mixture of isomers (entry 10).Thus, the general observation is that N2acylation is favoured and that only soft, weak and bulky acylating reagents favour N1-acylation.Solvent effects and effects of substituents at position 4 affect only slightly the reaction outcome, compared to the remarkable effect of acylating agents (see the SI for full details).X-ray diffraction analysis of N1-isomer 2c and N2-isomer 3f confirmed their structure (Figure 1).Surprisingly, acylated triazoles 2 and 3 are stable enough to be isolated by solvent extraction using aqueous workup and to be fully characterized spectroscopically.Products 3b, 3g and 3h were found to be hydrolytically very unstable and aqueous workup could not be used.All acylated triazoles underwent partial or full decomposition during silica gel column chromatography.Please do not adjust margins
N1-and N2-isomers of acylated triazoles convert to one another.N1-to N2-acyltriazole interconversion (Scheme 3) can be driven by thermodynamics, as in the case of the slow conversion of 2c to 3c at ambient temperature, or by the formation of a crystal lattice during crystallization, which is likely the case for sterically hindered N2-isomer 3e (Scheme 3).By contrast, we succeeded in isolating pure N1-isomer 2c by recrystallization of a 2c/3c mixture.The process of N1-to N2interconversion can depend on solvent system, the concentration and even the reaction scale, which complicated its detailed study.
Nevertheless, denitrogenative triazole ring cleavage can only take place from N1 isomers.We have demonstrated that the reverse process of N2-to N1-acyltriazole interconversion is crucial for the success of N-acyltriazole cleavage with the of N2-isomers in denitrogenative transformations.In situ formed N2-acylated triazoles 3 react efficiently with triflic acid to produce enamido triflates 4 (Scheme 4).Previously, trifluoroacetylated enamido triflates were prepared by the reaction of N-perfluoroalkyl-1,2,3-triazoles with triflic acid, 19e but the present methodology benefits from the use of readily available NH-triazoles and trifluoroacetic anhydride.The reaction was found to be applicable for the synthesis of products 4, bearing neutral aryl substituents (4a, 4b, 4d) or a bromine atom (4c), in good yields.Electron-withdrawing substituents on the aryl ring (CO2Me, NO2, CF3) were also tolerated (compounds 4e-4g), while a longer reaction time was required for complete conversion.A sterically hindered orthobromo-substituted compound (4h) was synthesized in good yield as well.Importantly, the method broadens the scope of enamido triflates to compounds with other fluoroalkyl groups than trifluoromethyl (CF2Cl, CF2CF3, CF2H; compounds 4j-4l).Whereas in the first two cases, acyltriazoles afforded triflates 4 as the sole products after treatment with TfOH, in the case of N-difluoroacetyl-1,2,3-triazole, a 33% yield was obtained, due to competitive cyclization to 2-difluoroacetyloxazole, which was observed as a side-product.Similarly, enamido triflate 4m bearing a trichloroacetyl group was obtained from trichloroacetic anhydride.In conclusion, N-acylation of 1,2,3-NH-triazoles was investigated and N2-acyltriazoles were found to be the main products; however, electron-rich and bulky acylating reagents induced the formation of a mixture of N1-and N2-acylatated triazoles.Interconversion between regioisomers of Nacyltriazoles under thermodynamic conditions, during crystal formation, or in the presence of Brønsted or Lewis acids was observed.Triazole denitrogenative ring cleavage starting from N2-acyltriazoles is reported for the first time.Efficient synthetic access to valuable β-trifluoroacetylamido triflates from NHtriazoles was developed.