One-pot synthesis of N-substituted benzannulated triazoles via stable arene diazonium salts†

A mild and effective one-pot synthesis of 1,2,3-benzotriazin-4(3H)-ones and benzothiatriazine-1,1(2H)dioxide analogues has been developed. The method involves the diazotisation and subsequent cyclisation of 2-aminobenzamides and 2-aminobenzenesulfonamides via stable diazonium salts, prepared using a polymer-supported nitrite reagent and p-tosic acid. The transformation was compatible with a wide range of aryl functional groups and amide/sulfonamide-substituents and was used for the synthesis of pharmaceutically important targets. The synthetic utility of the one-pot diazotisaton–cyclisation process was further demonstrated with the preparation of an α-amino acid containing 1,2,3-benzotriazin-4(3H)-one.

The importance of 1,2,3-benzotriazin-4(3H)-ones and 1,2,3benzothiatriazine-1,1(2H)-dioxides have resulted in the development of a wide range of methods for their synthesis. 1 Traditionally, these compounds were prepared from 2-aminobenzamides or 2-aminobenzenesulfonamides by reaction with sodium nitrite and hydrochloric acid (Scheme 1a). 2b,12 Due to the harsh acidic conditions that limits substrate scope, unstable diazonium salts and the use of sodium nitrite that can lead to the release of toxic nitrogen oxides, milder reagents and reaction conditions for this transformation have been reported. 13 In addition, new approaches have been developed for the preparation of 1,2,3-benzotriazin-4(3H)-ones and 1,2,3-benzothiatriazine-1,1(2H)-dioxides. 14 For example, Chandrasekhar and Sankararaman reported the preparation of N-substituted 1,2,3-benzotriazin-4(3H)-ones via the palladium(0)catalysed carbonylation of 1,3-diaryltriazenes (Scheme 1b), 15 while Cui and co-workers prepared both series of compounds by a redox cyclisation of amides and sulfonamides with nitrous oxide (Scheme 1c). 16 The Song group have reported the preparation of 1,2,3-benzotriazin-4(3H)-ones by the oxidative rearrangement of 3-aminoindazoles. 17 Despite the wide range of approaches now developed for the synthesis of these heterocycles, there is still a need for a mild and general approach from readily available starting materials, that avoids the requirement of harsh acidic or strongly oxidising conditions and precious transition metal catalysis. In recent years, issues associated with standard diazonium salt formation (NaNO 2 , HCl) of aromatic compounds have been overcome with the use of polymer-supported nitrite reagents and milder acids. 18 For example, Filimonov and co-workers demonstrated that aryl diazonium tosylate salts could be prepared using nitrite supported on a tetraalkylammonium functionalised resin, such as Amberlyst A-26, in the presence of p-tosic acid. 18c,d As well as the mild reaction conditions, the aryl diazonium tosylate salts were found to have high thermal and aging stability. Our group have exploited this safe and mild approach for aryl diazonium salt formation in one-pot processes for (radio)iodination, 19 Heck-Matsuda reactions, 20 and the synthesis of benzotriazoles. 21 We now report the one-pot synthesis of 1,2,3-benzotriazin-4 (3H)-ones and 1,2,3-benzothiatriazine-1,1(2H)-dioxides via stable aryl diazonium salts, by reaction of readily available 2-aminobenzamides and 2-aminobenzenesulfonamides with a polymer-supported nitrite reagent and p-tosic acid (Scheme 1d). As well as demonstrating the scope of these processes, we describe the application of this transformation for the synthesis of various biologically active compounds, including the synthesis of an α-amino acid containing 1,2,3benzotriazin-4(3H)-one.

Results and discussion
The study began with the optimisation of a one-pot diazotisation and cyclisation of 2-aminobenzamide (6a) for the preparation of 1,2,3-benzotriazin-4(3H)-one (7a) ( Table 1). Following our previous work, 19-21 a polymer-supported nitrite reagent, readily prepared by the ion exchange of Amberlyst A-26 with an aqueous solution of sodium nitrite, was used in combination with p-tosic acid. 18c,d The reaction was initially trialled using one equivalent of both reagents and methanol as the reaction solvent (entry 1). While the transformation proceeded at room temperature, a reaction time of 48 hours was required for completion and gave 7a in 39% yield (entry 1). Using three equivalents of both reagents led to a substantial improvement, generating 7a in 87% yield after 2 hours (entry 2). A further increase in the number of equivalent of reagents resulted in a faster, but less efficient process (entry 3). A solvent screen was also performed (entries 4-6), and while these reactions gave 7a in good yields, methanol was deemed the optimal solvent. It should be noted that as well as avoiding toxic reagents and harsh conditions, an advantage of this process is the simple work-up procedure and purification of products. On reaction completion, the polymer resin is removed by filtration (and recycled), and the product then purified by flash column Scheme 1 Methods for the synthesis of benzotriazin-4(3H)-ones and benzothiatriazine-1,1(2H)-dioxides. chromatography. By comparison, if the polymer-supported nitrite reagent is replaced with sodium nitrite in this process, while the reaction is completed in a similar time, the requirement of performing a work-up involving aqueous washes to remove p-TsOH, results in the isolation of 7a in 56% yield (entry 7). Following optimisation, the scope of the reaction was explored for the preparation of other N-unsubstituted 1,2,3benzotriazin-4(3H)-ones (Scheme 2). 2-Aminobenzamides 6a-6k bearing a range of o-, m-and p-substituted functional groups were found to be substrates for the reaction, providing the corresponding 1,2,3-benzotriazin-4(3H)-ones 7a-7k in 53-91% yields. For the majority of the 2-aminobenzamides, the transformation proceeded at room temperature in reaction times of 2-4.5 h. Only methoxy-substituted 2-aminobenzamide 6i required both elevated temperatures (65°C) and a long reaction time (76 h). This is likely due to the reduced electrophilic nature of the diazo intermediate prior to cyclisation.
The next stage of the project investigated the application of the one-pot method for the synthesis of N-substituted 1,2,3benzotriazin-4(3H)-ones (Scheme 2). Unlike most of the simple 2-aminobenzamides used in the first part of this study that were commercially available, many of the N-alkyl and N-aryl substituted benzamides required synthesis. These were prepared in one-step by the reaction of isatoic anhydride with various amines. 22,23 Reaction of N-alkyl benzamides with polymer-supported nitrite reagent and p-tosic acid, under optimised conditions gave the corresponding N-alkyl 1,2,3-benzotriazin-4(3H)-ones 7l-7p in 54-89% yields. With these compounds, it was found that cyclisation of more sterically hindered secondary amides required more forcing conditions. For example, N-cyclohexyl benzamide 6n required a reaction time of 49 hours and a reaction temperature of 65°C, while a t-butyl analogue demonstrated the limitation of this approach with no reaction observed. N-Aryl benzamides also required slightly elevated temperatures (40°C) but all substrates investigated were converted to the corresponding N-aryl 1,2,3-benzotriazin-4(3H)-ones (7q-7x). The process was efficient for the preparation of 1,2,3-benzotriazin-4(3H)-ones bearing both electron-rich and electron-deficient N-aryl substituents and was also compatible with N-heterocyclic moieties (e.g. 7x). The synthesis of 7r demonstrates that ortho-substituted N-aryl groups are also tolerated during the cyclisation step.
The research programme then examined the scope of the one-pot diazotisation and cyclisation for the preparation of N-substituted 1,2,3-benzothiatriazine-1,1(2H)-dioxides 9 (Scheme 3). The N-substituted benzenesulfonamides 8 were prepared in two steps by reaction of 2-nitrobenzenesulfonyl chloride with an amine, under basic conditions, followed by reduction of the nitro-group with tin dichloride. 23 The N-substituted 2-aminobenzenesulfonamides 8 were found to be more reactive to diazotisation and cyclisation than the corresponding benzamides 6. Reactions proceeded at 0°C or room temperature and with relatively short reaction times (2-4.5 h). For 2-amino-N-methylbenzenesulfonamide (8a) and N-ethyl analogue 8b, room temperature reactions led to denitrogenation of the diazo intermediates and isolation of the deaminated N-alkylbenzenesulfonamides as the major products. However, performing these reactions at 0°C, allowed clean transformations and the isolation of 8a and 8b in 51% and 75% yields, respectively. Reaction of the other N-alkylbenzenesulfonamides proceeded smoothly at room temperature and gave 1,2,3-benzothiatriazine-1,1(2H)-dioxides 9c-9f, in 60-85% yields. A demonstration of the increased reactivity of this class of compound was the synthesis of t-butyl analogue 9d. While the corresponding 2-aminobenzamide gave no product, 9d was isolated in 60% yield. Similarly, the reaction of 2-amino-N-arylbenzenesulfonamides also proceeded at 0°C or room temperature and gave the corresponding N-aryl 1,2,3-benzothiatriazine-1,1(2H)-dioxides 9g-9k in 59-71% yields. Several of the compounds prepared in this part of the study are used for the production of materials. For example, 9a, 9d and 9g are blowing agents for the formation of cellular rubber, 24 while 9a and 9g are also used as catalysts for free-radical polymerisation. 25 We next examined the application of the one-pot process for the synthesis of biologically active benzannulated triazoles. Initially, the optimised conditions for diazotisation and cyclisation (Table 1, entry 2) were used for the gram scale synthesis of 1,2,3-benzotriazin-4(3H)-one (7a). This gave 7a in 64% yield (Scheme 4). Copper(II)-catalysed N-arylation of 7a with naphthalene-2-boronic acid under basic conditions completed the two-step synthesis of chorismate mutase inhibitor 10. 26 1,2,3-Benzotriazin-4(3H)-one (7a) was also used for the threestep synthesis of anaesthetic compound 3, which has similar activity to lidocaine. 2c N-Alkylation of 7a with ethyl bromoacetate, followed by aminolysis with N,N-diethylethylenediamine gave 3 in good overall yield. As well as the synthesis of biologically active 1,2,3-benzotriazin-4(3H)-ones, the one-pot method was also used for a new synthesis of benzothiatriazine-1,1(2H)dioxide 5, a compound with nematicidal activity and a poten-tial pesticide with low-toxicity. 2e Initially, amine 12 was prepared in two steps. 23 N-Benzoylpiperazine was alkylated with N-(2-bromoethyl)phthalimide and this was followed by removal of the phthalimide protecting group with hydrazine. Reaction of 12 with 2-nitrobenzenesulfonyl chloride and nitrogroup reduction with zinc/acetic acid gave sulfonamide 14 in high yields. Application of the one-pot diazotisation and cyclisation method with 14, proceeded at room temperature and after a reaction time of 2 hours, gave nematicidal agent 5 in 72% yield.
We have an interest in the development of novel α-amino acids that can be used as biological probes. 27 Thus, as a proofof-concept experiment, we were interested in exploring whether the one-pot diazotisation and cyclisation procedure could be used for the preparation of an α-amino acid bearing a 1,2,3-benzotriazin-4(3H)-one side-chain. Key intermediate 16 was prepared by the reaction of known L-3-aminoalanine derivative 15 28 with isatoic anhydride (Scheme 5). Diazotisation and cyclisation of 16 was complete in 3 hours and gave 1,2,3-benzotriazin-4(3H)-one 17 in 87% yield. Despite the use of p-tosic acid, no Boc-group deprotection was observed under the mild diazotisation reaction conditions. Scheme 3 Reaction scope for the synthesis of 1,2,3-benzothiatriazine-1,1(2H)-dioxides.
Ester hydrolysis with caesium carbonate at room temperature, followed by acid-mediated removal of the Boc-protecting group gave parent amino acid 18.

Conclusions
In summary, a mild and general one-pot process has been developed for the synthesis of both 1,2,3-benzotriazin-4(3H)ones and 1,2,3-benzothiatriazine-1,1(2H)-dioxides via stable aryl diazonium tosylate salts. The use of a polymersupported nitrite reagent and p-tosic acid facilitated the rapid diazotisation and cyclisation of 2-aminobenzamides and 2-aminobenzenesulfonamides, yielding the target compounds in good yields. The process was found to be compatible for a wide range of substrates, 29 bearing N-aryl or N-alkyl substituted amides or sulfonamides. The mild nature of this transformation allowed the preparation of various agents for rubber and polymer production, as well as the synthesis of medicinally important compounds. The use of this process for the preparation of a benzotriazin-4(3H)-one derived amino acid serves as a platform for future work and the synthesis of more complex analogues for chemical biology applications.

Experimental
All reagents and starting materials were obtained from commercial sources and used as received. All dry solvents were purified using a PureSolv 500 MD solvent purification system. Brine refers to a saturated aqueous solution of sodium chloride. Flash column chromatography was performed using Merck Geduran Si 60 (35-70 µm) silica gel. Merck aluminiumbacked plates pre-coated with silica gel 60F 254 were used for thin layer chromatography and were visualised with a UV lamp or by staining with KMnO 4 or ninhydrin. 1 H NMR spectra were recorded on a Bruker DPX spectrometer at either 400 or 500 MHz and data are reported as follows: chemical shift in ppm relative to tetramethylsilane as the internal standard, multiplicity (integration, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non-equivalent resonances). 13 C NMR spectra were recorded on a Bruker DPX spectrometer at either 101 or 126 MHz and data are reported as follows: chemical shift in ppm relative to tetramethylsilane or the solvent as internal standard (CDCl 3 : δ 77.0 ppm, CD 3 OD: δ 49.0 ppm, DMSO-d 6 : δ 39.5 ppm), multiplicity with respect to hydrogen (deduced from DEPT experiments, C, CH, CH 2 or CH 3 ). Infrared spectra were recorded on a Shimadzu FTIR-84005 spectrometer; wavenumbers are indicated in cm −1 . Mass spectra were recorded using a JEOL JMS-700 Spectrometer or a Bruker microTOFq High Resolution Mass Spectrometer. Melting points were determined on a Gallenkamp melting point apparatus and are reported uncorrected.
General procedure for preparation of polymer supported nitrite resin To a stirred solution of sodium nitrite (5.50 g, 80.0 mmol) in water (200 mL) was added Amberlyst A26 hydroxide form resin (10.0 g, 40.0 mmol). The reaction mixture was stirred at rt for 1 h. The polymer-supported resin was filtered and washed with water until the filtrate was of neutral pH. The content of the polymer-supported nitrite was 3.5 mmol of NO 2 per g. 18

General Procedure for synthesis of 1H-benzotriazinones
To a stirred solution of the 2-aminobenzamides (1 equiv.) in methanol (10 mL mmol −1 ) at 0°C was added polymer-supported nitrite (containing 3.0 equiv. of NO 2 ) and p-toluenesulfonic acid monohydrate (3 equiv.). The reaction mixture was stirred for 1 h at 0°C. The reaction mixture was then warmed to room temperature and stirred until completion. The resin was filtered and washed with methanol (20 mL mmol −1 ). The reaction mixture was concentrated in vacuo. Purification by flash column chromatography gave the 1H-benzotriazinones.