Ramaraju Korivi,Kanagaraj Madasamy,Popuri Sureshbabu,Subramaniyan Mannathan
Convenient Synthesis of Salicylanilide Sulfonates from 1,2,3-Benzotriazin-4(3H)-ones and Organosulfonic Acids via Denitrogenative Cross-Coupling
An efficient and straightforward approach to synthesize salicylanilide aryl and alkyl sulfonates from 1,2,3-benzotriazin-4(3H)-ones and organosulfonic acids is described. This protocol is operationally simple and scalable, exhibits a broad substrate scope with high functional group tolerance, and affords the desired products in good to high yield. Application of the reaction is also demonstrated by converting the desired product to synthetically useful salicylamides in high yields.
Convenient Synthesis of Salicylanilide Sulfonates from 1,2,3-Benzotriazin-4(3H)-ones and Organosulfonic Acids via Denitrogenative Cross-Coupling

An efficient and straightforward approach to synthesize salicylanilide aryl and alkyl sulfonates from 1,2,3-benzotriazin-4(3H)-ones and organosulfonic acids is described. This protocol is operationally simple and scalable, exhibits a broad substrate scope with high functional group tolerance, and affords the desired products in good to high yield. Application of the reaction is also demonstrated by converting the desired product to synthetically useful salicylamides in high yields.

Sulfonate ester is one of the key functional groups that received paramount attention owing to their diverse applications in various fields like synthetic chemistry, material science, and pharmaceutical chemistry. They have also been explored as synthetic auxiliaries, intermediates, protecting groups, and activating groups. Furthermore, sulfonate ester derivatives have been utilized as the bifunctional DNA alkylating agents (such as busulfan and treosulfan), monoamine oxidase A inhibitors, P2X7 receptor antagonist, phospho-STAT3 inhibitor, and antimicrotubule agents with antibacterial and antifungal properties (e.g., secnidazole sulfonate) as shown in Figure 1, in clinical settings. As a result, the creation of these bioactive molecules containing sulfonate esters is in great demand. In recent years, metal-catalyzed denitrogenative annulation and cross-coupling reactions of 1,2,3-benzotriazin-4(3H)-ones have emerged as an effective protocol to prepare heterocycles and ortho-substituted benzamide derivatives. Conversely, such types of reactions in the absence of metal catalysts are hardly studied. Literature report reveals that acid-mediated denitrogenative cross-coupling reactions of 1,2,3-benzotriazin-4(3H)-ones in the absence of metal catalysts have been reported but remain underdeveloped. For instance, Raffa’s research group reported the acetic acid-mediated synthesis of 2-iodobenzamides in the presence of potassium iodide. Subsequently, Kishore and colleagues discovered the formation of 2-azido benzamide intermediates during the synthesis of 4H-tetrazolo[1,5-a][1,4]benzodiazepin-6-ones. Tang et al. demonstrated an organic-dye catalyzed denitrogenative phosphorylation of 1,2,3-benzotriazin-4(3H)-ones. Meanwhile, we also described trifluoroacetic acid-mediated ortho-hydroxylated benzamide synthesis from 1,2,3-benzotriazin-4(3H)-ones. More recently, acid-mediated heteroannulation of benzotriazinones using sodium sulfide to synthesize benzo[c][1,2]dithiol-3-ones was reported by the research group of Zhou. In the past few years, we have been investigating denitrogenative cross-coupling reactions of 1,2,3-benzotriazin-4(3H)-ones to prepare ortho-substituted benzamides. During our studies on the synthesis of ortho-hydroxylated benzamides, we discovered that the reaction of 1,2,3-benzotriazin-4(3H)-one (1a) with para-toluenesulfonic acid (p-TSA) (2a) yields (phenylcarbamoyl)phenyl 4-methyl benzenesulfonate 3a in a 65% yield. This result is noteworthy because the metal-free approaches toward the direct arylation of organosulfonic acids are scarcely studied, particularly the synthesis of ortho-sulfonylated benzamides from 1,2,3-benzotriazin-4(3H)-ones has not been reported. Representative examples include a metal-free arylation of oxygen nucleophiles using diaryliodonium salts in the presence of a base by the research group of Olofsson (Scheme 1a) and an efficient iodobenzene-catalyzed synthesis of aryl sulfonate esters from aminoquinolines by Shen and co-workers (Scheme 1b). Given the significance of sulfonate esters in bioactive molecules and the utility of 1,2,3-benzotriazin-4(3H)-ones in the acid-mediated cross-coupling reactions, we have investigated the synthesis of ortho-sulfonylated benzamides. It’s worth mentioning that this reaction has a broad substrate scope and gives the desired products in good to high yields under mild conditions.

We continued our investigation on the denitrogenative ortho-sulfonylation reaction of 1,2,3-benzotriazin-4(3H)-one 1a using p-TSA 2a as the coupling partner (Table 1). We initially screened the reaction of 1a and 2a with different solvents at 80 °C for 12 h (entries 2–6). Among the solvents that we tested, 1,4-dioxane gave 3a in 72% yield, while the remaining solvents such as toluene, tetrahydrofuran (THF), 1,2-dichloroethane (DCE), and xylene furnished the desired product in moderate yields. Finally, upon increasing the reaction temperature to 100 °C and the p-TSA equivalent to 1.5, the reaction yielded 3a in high yield (98%; entry 8). It is important to mention that a minor amount (7–11%) of ortho-hydroxylated benzamide 4a was also observed while carrying out the reaction using toluene, DCE, and xylene as solvents (entries 2, 4, and 5, respectively). With the optimal conditions in hand (entry 8, Table 1), we then explored the scope of this metal-free denitrogenative ortho-sulfonation reaction (Scheme 2). The present protocol is highly general and works well with a wide range of substituted benzotriazin-4(3H)-ones. To our delight, electron-donating groups (4-OMe, 4-Me), halogens (4-F, 4-Cl, 4-Br, and 4-I), and electron-withdrawing groups (4-CF3) at the para-position of N-aryl-substituted 1,2,3-benzotriazin-4(3H)-ones gave corresponding products in high yields (3b–3h, 88–93%). The structure of the ortho-sulfonylated product 3e was unambiguously confirmed by single-crystal X-ray analysis. Additionally, meta-substituted (3-Cl and 3-Me) 1,2,3-benzotriazin-4(3H)-ones also delivered the desired products 3i and 3j in 85% and 88% yields, respectively. Interestingly, sterically hindered ortho-substituted 1,2,3-benzotriazin-4(3H)-ones (1k and 1l) were also well-tolerated under these reaction conditions and offered ortho-sulfonylated benzamides 3k and 3l in good yields. On the other hand, N-alkyl-substituted 1,2,3-benzotriazin-4(3H)-ones such as benzyl- (1m), n-hexyl- (1n), cyclohexyl- (1o), and allyl- (1p) efficiently participated in the reaction, yielding the corresponding products 3m–3p in good to high yields (80–93%). It is also noteworthy that other substituted 1,2,3-benzotriazin-4(3H)-ones, such as 6,7-dimethoxy-1,2,3-benzotriazin-4(3H)-one (1q) and 7-methylester-1,2,3-benzotriazin-4(3H)-one (1r) and methyl-1,2,3-benzotriazin-4(3H)-one (1s), reacted well with p-TSA under the standard reaction conditions, yielding the desired products 3q–3s in 83–90% yields (Scheme 2). Surprisingly, unsubstituted 1,2,3-benzotriazin-4(3H)-one (1a–H) failed to give the desired product 3. To demonstrate the versatility of the developed methodology, we examined the reactivity of various organosulfonic acids (2b–2f) with 1,2,3-benzotriazin-4(3H)-one (1a) under the optimized reaction conditions (Scheme 3). Unsubstituted, ortho-chlorinated, and 2,4-dimethyl-substituted benzene sulfonic acids delivered the ortho-sulfonated benzamides 3t–3v in 85–92% yields. Notably, trifluoromethanesulfonic acid (CF3SO3H) and methanesulfonic acid (CH3SO3H) gave the corresponding products 3w and 3x in 85 and 88% yields, respectively. We also tested the practicality of this protocol by performing a reaction on a gram scale (Scheme 4). Under the optimized conditions, the gram-scale denitrogenative ortho-sulfonylation reaction of 1a with 2a proceeded smoothly, and the desired product 3a was obtained in a comparable yield (3.1 g, 85%). To demonstrate the utility of the present reaction, a series of biologically significant salicylamide derivatives were successfully synthesized (Scheme 5). Gratifyingly, N-aryl and N-alkyl salicylanilide sulfonates underwent hydrolysis and provided the corresponding salicylamides (4a–4d) in good to high yields. A plausible mechanism for metal-free ortho-sulfonation of 1,2,3-benzotriazin-4(3H)-one is provided in Scheme 6. Initially, the reaction proceeds through a reversible ring opening of 1,2,3-benzotriazinone (1a) in the presence of sulfonic acid generating the benzene diazonium intermediate A. Subsequent nucleophilic attack of the sulfonate ion on the diazonium intermediate (A) results in ortho-sulfonylated benzamide (salicylanilide sulfonate) 3 with the extrusion of molecular nitrogen as a sole byproduct.

In summary, we have successfully developed a metal-free denitrogenative sulfonylation reaction of 1,2,3-benzotriazin-4(3H)-ones using p-TSA as an efficient sulfonylating agent. This protocol is simple to execute, has a broad substrate scope and good functional group tolerance, and affords the desired salicylanilide aryl and alkyl sulfonates in good to high yields. Moreover, the present methodology provides a promising alternative for the synthesis of salicylamides in high yields.

All experiments were carried out in oven-dried glassware. Flash column chromatography was performed on 100–200 mesh silica gel. 1H and 13C NMR spectroscopy was performed on a Bruker BBFO (400 MHz and 500 MHz) spectrometer. Chemical shifts were determined relative to the residual solvent peaks (CDCl3, δ = 7.26 ppm for 1H NMR, δ = 77.0 ppm for 13C NMR). The mass spectra (ESI-MS) were recorded on an Agilent 6200 Series Q-TOF LC/MS spectrometer. The starting materials 1,2,3-benzotriazin-4(3H)-ones (1a–s) were prepared according to the literature procedure. All the reactions were conducted under an air atmosphere unless otherwise stated.

A sealed tube containing 1,2,3-benzotriazin-4(3H)-ones (1) (0.4 mmol), organosulfonic acid (0.6 mmol), and 1,4-dioxane (3 mL) was stirred at room temperature for 2 min. The sealed tube was placed in a preheated oil bath at 100 °C and stirred for 12 h. After completion of the reaction, the mixture was allowed to cool and then diluted with ethyl acetate (10 mL). The reaction mixture was washed three times with 10 mL of water, and the organic layer was separated. The separated organic layer was then dried over MgSO4 and concentrated under a vacuum to remove the solvent. The residue was purified by silica gel column chromatography using a suitable eluent (hexane/ethyl acetate) to afford the desired pure product 3.

To a sealed tube containing 3-phenylbenzo[d][1,2,3] triazin-4(3H)-one (1a) (2.23 g, 10 mmol), p-TSA (2.6 g, 15 mmol) and 1,4-dioxane (30 mL) were added, and the mixture was stirred at room temperature for 2 min. The sealed tube was then placed in a preheated oil bath at 100 °C for 12 h. After completion of the reaction, the mixture was cooled and diluted with ethyl acetate (100 mL). The reaction mixture was then poured into 100 mL of water and shaken well. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a vacuum. The resulting residue was purified by silica gel column chromatography using a suitable eluent (hexane/ethylacetate; 8:2) to afford the desired pure product 2-(phenylcarbamoyl)phenyl 4-methylbenzenesulfonate (3a) in 85% (3.1 g) yield.

To a sealed tube containing 0.2 mmol of compound 3, 3 mL of a 9:1 mixture of dichloromethane and methanolic sodium hydroxide solution was added. The resulting mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the solvent was removed under reduced pressure, and the remaining mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a vacuum. The resulting residue was purified using silica gel column chromatography with a suitable eluent to obtain the desired pure product 4.