Oxidative reaction of 2-aminopyridine-3-sulfonyl chlorides with tertiary amines

Introduction

The reaction of arenesulfonyl chlorides with amines is known as the Hinsberg reaction or the Hinsberg test that can be used to distinguish primary, secondary and tertiary amines [1]. The reaction of primary and secondary amines with benzenesulfonyl chloride in the presence of base leads to the formation of sulfonamides. Tertiary alkyl amines react with benzenesulfonyl chloride to form N-benzenesulfonyl-N,N,N-trialkylammonium chloride adducts [2], [3] that in the presence of aquatic base (as in the Hinsherg test) undergo hydrolysis into parent amines and benzenesulfonic acid [4].

Recently, Zheng and coworkers have reported a visible-light induced oxidative reaction of arenesulfonyl chlorides 1 with tertiary alkyl amines 2 leading to sulfonylethenamines 3 in the presence of Ru(bpy)₃(PF₆)₂ photoredox catalyst (Scheme 1) [5]. In this paper, we would like to describe a related oxidative reaction of 2-aminopyridine-3-sulfonyl chlorides 4 with tertiary alkyl amines 2 that proceeds in the absence of any catalyst and provides access to sulfonylethenamines 5 (Scheme 1).

Scheme 1

Oxidative reactions of arenesulfonyl chlorides with tertiary alkyl amines.

Results and discussion

This transformation was discovered accidently when the 2-amino-5-methylpyridine-3-sulfonyl chloride 4a was exposed to an excess of triethylamine 2a in the presence of air giving rise to the sulfonylethenamine product 5a. The tentative pathway for the process is outlined on Scheme 2. We believe that 4a and 2a initially react to form the N-2-amino-5-methylpyridinyl-3-sulfonyl-N,N,N-triethylammonium chloride A. Next, the intermediate A undergoes oxidative degradation into the enamine B and 2-amino-5-methylpyridine-3-sulfonic acid 6. Furthermore, A is also responsible for the electrophilic trapping of B that leads to the final sulfonylethenamine 5a [6], [7]. Overall, the conversion of 2 equiv of 2-amino-5-methylpyridine-3-sulfonyl chloride 4a can produce up to 1 equiv of desired sulfonylethenamine 5a consuming in the course of reaction 3 equiv of triethylamine 2a (Scheme 2).

Scheme 2

Tentative reaction pathway.

Importantly, an attempted reaction of tosyl chloride 1a failed to give the sulfonylethenamine product 3a in the absence of Ru(bpy)₃(PF₆)₂, the photoredox catalyst (Scheme 3). However, treating the mixture of 1a and 4a with triethylamine 2a led to the formation of both sulfonylethenamines 3a and 5a in 23% and 22% yields, respectively (Scheme 3). These control experiments confirm the crucial role of 2-aminopyridine-3-sulfonyl chloride 4 as the promotor of the catalyst-free aerobic oxidation.

Scheme 3

Control experiments.

It is worth to note that the oxidations of tertiary amines into iminium cations followed by the reactions with nucleophiles constitute a well-known approach to the α-functionalization of amines [8], [9], [10], [11], [12], [13], [14], [15], [16], [17] while our reaction presumably belongs to a relatively more rare class of complementary processes where the amine is oxidized into enamine with the subsequent trapping by a suitable electrophile [18], [19], [20], [21], [22], [23].

In order to briefly assess the scope of the discovered process, a series of 2-aminopyridine-3-sulfonyl chlorides 4a–d were prepared by reacting appropriate 2-aminopyridines 6a–d with chlorosulfuric acid (Scheme 4) [24], [25]. Next, the reactions of 4a–d with triethylamine (2a) and N,N-diisopropylethylamine (2b) to prepare sulfonylethenamines 5a-e were studied (Scheme 4). At first, we evaluated the reaction of 2-amino-5-methylpyridine-3-sulfonyl chloride (4a) with triethylamine (2a) under various conditions. These trial reactions were run on 0.6 mmol scale in 2 mL of solvent for 1–1.5 h. Treatment of 4a with 2.2 equiv of 2a under the air atmosphere in dioxane as solvent provided sulfonylethenamine 5a in the isolated yield of 31%. The use of 3 equiv of 2a resulted in a slight improvement furnishing 5a in 36% yield.^[1] Importantly, no 5a was formed when the attempted reaction was conducted under the inert atmosphere, which was clearly seen by TLC analysis. Introducing 1 equiv of water in the reaction media as a competitive electrophile impaired the reaction outcome leading to a diminished 25% yield of 5a. The use of THF or DMF instead of dioxane also resulted in the decreased yields of 28% and 25%, respectively.

Scheme 4

Synthesis of 2-aminopyridine-3-sulfonyl chlorides 4 and sulfonylethenamines 5.

The reaction of 2-amino-5-fluoropyridine-3-sulfonyl chloride (4b) with 2a required extended reaction time and delivered sulfonylethenamine 5b in only 17% isolated yield. The analogous transformations involving 2-amino-5-chloropyridine-3-sulfonyl chloride (4c) and 2-amino-5-bromopyridine-3-sulfonyl chloride (4d) proceeded more efficiently yielding sulfonylethenamines 5c and 5d in 44% and 41%, respectively. The structure of (E)-5-chloro-3-[2-(diethylamino)vinylsulfonyl]pyridin-2-amine (5c) was ascertained by X-ray crystallographic analysis (Figure 1, CCDC 1478486 contains the supplementary crystallographic data for this paper and can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html). Finally, the reaction of 2-amino-5-methylpyridine-3-sulfonyl chloride (4a) with a bulky N,N-diisopropylethylamine (2b) furnished sulfonylethenamine 5e in 14% yield.

Figure 1

X-ray crystallographic structure of compound 5c.

Conclusion

A novel catalyst-free process for the oxidative β-functionalization of tertiary amines with 2-aminopyridine-3-sulfonyl chlorides was discovered and documented.

Experimental

¹H and ¹³C NMR spectra were recorded in CDCl₃ at 400 MHz and 100 MHz, respectively, using Bruker Avance III HD instrument. High resolution mass spectra (HR-MS) were obtained on a Bruker micrOTF-Q III instrument. Melting points were measured using an Inesa WRR apparatus. Infrared (FT-IR) spectra were recorded neat on a Bruker Vertex 70 spectrometer. All starting materials and solvents were purchased from commercial sources and used as received.