Cycloaddition of N-sulfonyl and N-sulfamoyl azides with alkynes in aqueous media for the selective synthesis of 1,2,3-triazoles

Abstract

The cycloaddition of N-sulfonyl and N-sulfamoyl azides with terminal alkynes generally produces amide derivatives via ketenimine intermediates. We herein delineate a Cu(I) catalyzed method using a prolinamide ligand that selectively generate N-sulfonyl and sulfamoyltriazoles in aqueous media by inhibiting the cleavage of the N¹-N² bond of 5-cuprated triazole intermediates. The present method is mild and tolerant to air, moisture and a wide range of functional groups thereby providing an easy access to a variety of triazole products.

Introduction

The Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC)^1-2 has been used to access an array of 1,4-disubstituted-1,2,3-triazoles³ from a range of alkyl and aryl azides. However, the cycloaddition of electron deficient azides (such as N-sulfonyl,^4,5 N-sulfamoyl⁶ and N-carbonyl⁷ azides) with terminal alkynes to obtain 1,4-triazoles remain largely unexplored. This is largely because the stability of intermediate A (Scheme 1), produced by CuAAC, is considerably reduced in the presence of electron withdrawing substituents (sulfonyl, sulfamoyl) in the triazole ring. As a result, CuAAC of sulfonyl and sulfamoyl azides does not usually provide the desired 1,2,3-triazole derivatives (Scheme 1, pathway a). Mostly, a ketenimine species C is produced via the intermediate B due to facile cleavage of the N1-N2 bond of 5-cuprated triazole intermediate A. The intermediate C upon reaction with amines, alcohols, or water, leads to the formation of amidines, imidates or amides respectively (Scheme 1, pathway b).⁸

Scheme 1. Synthesis of N-sulfonyl and sulfamoyl-1,2,3-triazoles.

Till date, only a few studies report the exclusive formation of N-sulfonyltriazoles using CuAAC approach. Fokin and Chang first used CuI/2,6-lutidine to obtain the N-sulfonyltriazoles, in the presence of anhydrous chloroform at low temperature.^4a Zhao et al. reported a green synthetic protocol for the cycloaddition of sulfonyl azides with alkynes at room temperature using Cu(I)/PhSMe catalyst system.^4b Pérez and coworkers used a cationic complex [Tpm*,BrCu(NCMe)]BF₄ (Tpm*, Br = tris(3,5-dimethyl-4-bromo-pyrazolyl)methane) for the synthesis of N-sulfonyl-triazoles in high yields.^4c Fokin et al. explored the cycloaddition for the synthesis of N-sulfonyl-1,2,3-triazoles in the presence of a CuTC complex at room temperature.^4d Hu and coworkers studied the cycloaddition of sulfonyl azides and alkynes in the presence of a combination of Cu(OAc)₂·H₂O/2-aminophenol, leading to the formation of the triazole products.^4e Chandak and coworkers demonstrated that the cycloaddition can also be performed using the classical CuAAC method in aqueous media.^4f Recently, Moses et al. developed a click-inspired approach to synthesize 1-substituted-1,2,3-triazoles from organic azides and acetylene-surrogate, ethenesulfonyl fluoride.⁵ On the other hand, there is a single report of CuAAC for the synthesis of N-sulfamoyltriazoles using a CuTC catalyst by Fokin et al..⁶ Therefore, selective synthesis of the sulfonyl and sulfamoyl triazoles via cycloaddition using a simple catalyst system is worth exploring.

In this context, we herein report a robust CuI/prolinamide catalytic system⁹ that promotes the cycloaddition of both sulfonyl and sulfamoyl azides with terminal alkynes in aqueous media at room temperature.

Results and discussion

Initially, the CuAAC of tosyl azide (1a) and phenylacetylene (2a) was studied at rt in the presence of Pro-1 in aqueous media (Table 1 and Table S1, see supporting information, S.I.). To our delight, the reaction proceeded satisfactorily providing the desired product 3a in excellent yield (entry 1). Encouraged by the result, various reaction conditions were investigated, by varying ligand, catalyst, solvent and time. The detailed optimization study has been discussed in the supporting information (Table S1 and S2, S.I.). When the reaction was carried out in the absence of CuI or Pro-1, no product was obtained (Table 1, entries 2 and 3), indicating that both CuI and Pro-1 play significant roles in accelerating the cycloaddition. Next, we evaluated the effect of various ligands on this reaction such as DMEDA, phenanthroline, L-proline and chiral prolinamide derivatives Pro-1 to Pro-3 (entries 4-8). The prolinamide ligands were synthesized from readily available starting materials following reported methods (Schemes S1-S5, see supporting information, S.I.). Pro-1 was found to be the optimal ligand for the cycloaddition, suggesting that the conformation of this ligand is critical for attaining high reactivity (entry 1). Subsequent screening of the reaction with different copper catalysts suggested that copper salts like CuBr, Cu(OAc)₂, CuO, as well as Cu(0) were less effective in promoting the reaction as compared to CuI (entries 9-12).

Table 1. Optimization of reaction conditions^a.

entry	ligand	Catalyst	solvent	time (h)	yield (%)b
1	Pro-1	CuI	H2O	3.5	95
2	-	CuI	H2O	24	20
3	Pro-1	-	H2O	24	n.r
4	DMEDA	CuI	H2O	3.5	40
5	Phenanthroli ne	CuI	H2O	3.5	51
6	L-Proline	CuI	H2O	3.5	65
7	Pro-2	CuI	H2O	3.5	68
8	Pro-3	CuI	H2O	3.5	40
9	Pro-1	Cu(OAc)2	H2O	3.5	21
10	Pro-1	CuO	H2O	3.5	-
11	Pro-1	CuBr	H2O	3.5	57
12	Pro-1	Cu(0)	H2O	3.5	-

^aReaction conditions: 1a (1.0 mmol), 2a (1.50 mmol), CuI (0.05 mmol), Pro-1 (0.1 mmol), in 2 mL water

^byield refers to the isolated yield without chromatographic purification.

Having established the optimal reaction conditions for cycloaddition of tosyl azide 1a with phenylacetylene 2a (5 mol% CuI, 10 mol% Pro-1, in 0.1 M water at rt, Table 1, entry 1), the scope and generality was explored using a variety of sulfonyl azides with terminal alkynes. We were pleased to find that a series of alkynes reacted efficiently with tosyl azide 1a to provide the triazole products 3a-3q in excellent yields (Scheme 2). Aryl acetylenes bearing electron-rich substituents such as methyl, tert-butyl, n-pentyl and methoxy underwent smooth cycloaddition to produce the corresponding triazoles 3a-3h (67-94% yields). Electron-deficient aryl alkynes (fluoro, bromo, and trifluromethyl) also reacted well under the optimized conditions giving access to N-sulfonyltriazole products in excellent yields (3i-3k, Scheme 2). Both 6-methoxy-ethynylnaphthalene and 3-ethynylthiophene were found to be compatible with cycloaddition affording the triazole products (3l and 3m) in high yields. Aliphatic alkynes also provided the corresponding triazoles under the reaction conditions in good yields (3n-3r, Scheme 2).

Scheme 2. Cycloaddition of N-sulfonyl azides and alkynes.^a,b.

It is worth mentioning that electron rich alkynes e.g 3-methoxyprop-1-yne and ethoxyethyne were found to be suitable substrates to obtain the triazole products (3s and 3t) in good yields. Next, a variety of sulfonyl azides were used for cycloaddition with phenylacetylene 2a under the reaction conditions. Sulfonyl azides containing different aryl substituents (e.g. Me, I, OCF₃, CH₂Br) provided the corresponding N-sulfonyltriazole products 3u-3x. Naphthalene sulfonyl azide, dihydrobenzodioxine azide and heterocyclic azide (i.e. thiophene sulfonyl azide) underwent cycloaddition with phenylacetylene to give the corresponding triazoles 3y, 3z and 3aa in good yields. Notably, alkyl sulfonyl azides were found to be compatible under the developed conditions to provide the triazole derivatives 3ab-3af in high yields (Scheme 2). The structure of N-sulfonyltriazole 3x was confirmed by single crystal X-ray analysis (Scheme 2, CCDC 2090344; Figure S1, S.I.).¹⁰ Gram scale experiment using 1 g of 1a was found to be successful, affording the corresponding sulfonyltriazole product 3a in good yield (Scheme 2, for details see experimental section). However, N-sulfonyl azides containing trifluromethyl and nitro groups in the aromatic ring did not undergo cycloaddition with phenyl acetylene under the optimized reaction conditions.

The viability of this protocol was next expanded using sulfamoyl azides in the presence of various alkynes under the obtained optimized reaction conditions (5 mol% CuI, 10 mol% Pro-1, in 0.1 M water at rt, Table 1). The cycloaddition of sulfamoyl azides 4 with alkynes 2 proceeded faster in comparison to the sulfonyl azides and completed within 45 minutes, providing the desired triazole products. A series of alkynes bearing different electron-donating moieties underwent cycloaddition with N,N-dimethylsulfamoyl azide 4a to provide the corresponding triazoles 5a-5k in high yields (Scheme 3). Aryl alkynes containing halo (fluoro, bromo) and trifluoromethoxy substituents reacted smoothly under the optimal conditions affording the desired N-sulfamoyltriazole products 5l-5n (Scheme 3). Aryl alkynes containing halo (fluoro, bromo) and trifluoromethoxy substituents reacted smoothly under the optimal conditions affording the desired triazole products 5l-5n (Scheme 3).

Scheme 3. Cycloaddition of N-sulfamoyl azides and alkynes.^a,b.

These observations suggested that the electronic variation of the alkynes did not alter the efficiency of the reaction. Intriguingly, polyaromatic and heteroaryl alkynes provided the triazole products 5o-5q in good yields (Scheme 3). The aliphatic alkynes also underwent smooth cycloaddition with azide 4a providing the triazoles 5r-5t in good yields.

We have also performed the cycloaddition of piperidine sulfamoyl azide 4b with phenylacetylene to obtain the corresponding triazole derivative 5u in high yield. However, the cycloaddition of N,N-dimethylsulfamoyl azide 4a did not proceed in the presence of 2-ethynyl pyridine, ethyl propiolate and prop-2-yn-1-ol under the optimal conditions. The structure of 5f was confirmed by X-ray crystal analysis (Scheme 3, CCDC 2090346, Fig. S2, S.I.).¹⁰ Gram scale experiments with 1 g of 4a was performed to obtain the N-sulfamoyltriazole 5a in excellent yields (Scheme 3, for details see experimental section).

We next demonstrated the synthetic potential of the method by the preparation of free 1,2,3-triazoles. 1,2,3-Triazoles are important class of heterocycles that exhibit a wide range of biological activities and are used in pharmaceuticals and agrochemicals.^11,12 The deprotection of sulfonyl and sulfamoyl moieties of N-sulfonyl and N-sulfamoyltriazoles were carried out as shown in Scheme 2. Sulfonyl triazoles 3 was simply refluxed in MeOH to produce free triazoles 6.¹³

We performed the deprotection of the sulfamoyl group of 5 under similar reaction conditions as the deprotection of N-sulfonyl moiety and obtained compound 6 in high yields. No method for the deprotection of sulfamoyl group has been reported so far. The free triazole derivatives 6a-6e were synthesized in excellent yields starting from 3 or 5 via the deprotection of sulfonyl and sulfamoyl groups respectively (Scheme 4). Synthesis of these free triazoles 6 will be useful for further synthetic transformations.

Scheme 4. Deprotection of sulfonyl and sulfamoyl moiety.

Conclusions

In summary, we have developed a simple and efficient synthetic protocol for the cycloaddition of sulfonyl and sulfamoyl azides with terminal acetylenes in the presence of water at room temperature, using CuI and an easily synthesizable prolinamide ligand. Further, the deprotection of sulfonyl and sulfamoyl functional group provided free triazole derivatives. The salient features of this method are mild reaction conditions, shorter reaction time, broad substrate scope and robustness of the CuI-Pro-1 catalyst system. The corresponding triazoles were obtained exclusively in excellent yields rendering the method general, expeditious and efficient for the convenient and practical synthesis of N-sulfonyl and N-sulfamoyltriazole derivatives. The detailed mechanistic aspect of this reaction is currently under investigation in our laboratory.