Synthesis of Structurally Diverse Benzotriazoles via Rapid Diazotization and Intramolecular Cyclization of 1,2-Aryldiamines

An operationally simple method has been developed for the preparation of N‐unsubstituted benzotriazoles by diazotization and intramolecular cyclization of a wide range of 1,2‐aryldiamines under mild conditions, using a polymer‐supported nitrite reagent and p‐tosic acid. The functional group tolerance of this approach was further demonstrated with effective activation and cyclization of N‐alkyl, ‐aryl, and ‐acyl ortho‐aminoanilines leading to the synthesis of N1‐substituted benzotriazoles. The synthetic utility of this one‐pot heterocyclization process was exemplified with the preparation of a number of biologically and medicinally important benzotriazole scaffolds, including an α‐amino acid analogue.


Introduction
Benzotriazoles are important heterocyclic scaffolds, widely used in medicinal chemistry, [1] organic synthesis [2] and material science. [3] Application of benzotriazole derivatives in medicinal chemistry is particularly widespread (Figure 1a) due to enzyme inhibition through π-π stacking or hydrogen bonding of the triazole unit. [1a] For example, antifungal benzotriazole derivatives have been discovered that inhibit the growth of fluconazole-insensitive Cryptococcus neoformans, [1b] while halogenated aryloxy-benzotriazoles inhibit isoniazid-resistant Mycobacterium tuberculosis. [1c] In organic synthesis, benzotriazoles have been used as precursors for the preparation of other heterocycles such as indoles, carbazoles as well as pyridoacridines, [4] and seminal work by Katritzky and co-workers demonstrated their application as auxiliaries for alkylation and benzannulation reactions. [2] The general importance of benzotriazoles for a range of scientific applications has resulted in the development of various synthetic methods for the preparation of this benzannulated heterocycle. In recent years, base-mediated "click" type [3+2] cycloaddition reactions of benzynes and azides have allowed the synthesis of N-substituted benzotriazoles under mild conditions ( Figure 1b). [5] A limitation of this approach is the formation of N 1 -and N 3 -benzotriazole regioisomers from unsymmetrically substituted benzynes, although this has been overcome using ortho-ether, boryl, and silyl directing groups. [5a,5e,5f ] Regioselective synthesis of N 1 -aryl-substituted benzotriazoles has been achieved by the transition metal-catalyzed cyclization of 1,3-diaryltriazenes. [6] For example, Ren and co-workers demonstrated such a process via a 1,7-palladium migration-cycliza-tion-dealkylation cascade (Figure 1c). [6b] Palladium-mediated oxidative addition of the aryl C-Br bond was followed by C-H activation and 1,7-palladium migration. Subsequent intramolecular amination and demethylation resulted in the regioselective preparation of a wide range of N 1 -aryl-substituted benzotriazole derivatives. A more traditional approach for the preparation of benzotriazoles involves the diazotization and intramolecular cyclization of 1,2-aryldiamines using sodium nitrite and acidic conditions. [7] This reaction was incorporated into a multistep continuous flow process by Chen and Buchwald for the regioselective synthesis of N 1 -substituted benzotriazoles from ortho-chloronitroarenes (Figure 1d). [8] Base-mediated S N Ar reaction of ortho-chloronitroarenes with amines was followed by reduction of the nitro group and diazotization of the resulting aniline with sodium nitrite and hydrochloric acid. Cyclization gave a range of N 1 -substituted benzotriazoles in high overall yields. The scope of this process was further expanded by using a palladium-catalyzed Buchwald-Hartwig N-arylation reaction as the first step of the continuous flow process.
Despite these advances, there is still a need for a general method that can produce both unsubstituted benzotriazoles and the regioselective preparation of N 1 -substituted benzotriazoles, while avoiding elevated temperatures, harsh acidic conditions and the use of sodium nitrite under these conditions, which can lead to the release of toxic nitrogen oxides. [9] In 2008, Filimonov and co-workers showed that a polymersupported nitrite reagent in combination with less harsh acidic conditions (p-tosic acid) could be used for the preparation of stable aryl diazonium tosylate salts. [10] More recently, we have shown that this safe, mild and operationally simple method for aryl diazonium salt formation can be combined in one-pot multistep processes for (radio)iodination and Heck-Matsuda reactions of anilines. [11,12] We now report a general synthesis of benzotriazoles from 1,2-aryldiamines using a polymer-supported nitrite reagent, under mild conditions ( Figure 1e). As well as exploring the scope of this process for the synthesis of both N-unsubstituted and N 1 -substituted benzotriazoles, we also demonstrate the use of this approach for the facile preparation of pharmaceutically important benzotriazole containing compounds.

Results and Discussion
The study began by investigating whether benzotriazole formation could be achieved by activation and intramolecular cyclization of 1,2-diaminobenzene (1a) with a polymer-supported nitrite reagent and p-tosic acid ( Table 1). The initial aim was to develop an operationally simple process with a short reaction time, that could be performed under mild reaction conditions. Another key objective was to show that the use of a polymersupported nitrite reagent would facilitate work-up and purification of the benzotriazole product. In this study, the polymersupported nitrite reagent was prepared by ion exchange of the tetraalkylammonium functionalized resin, Amberlyst A-26 with an aqueous solution of sodium nitrite. [10][11][12] Following our previous work, [11] diazotization and cyclization of 1a was attempted using 3 equivalents of both the polymer-supported nitrite reagent and p-tosic acid in acetonitrile at 80°C. After a reaction time of 1.5 hours, this gave benzotriazole 2a in 46 % isolated yield (entry 1). Extending the reaction time to 18 hours, led to a more efficient process and a yield of 71 % (entry 2). In an attempt to improve the reaction conditions, the reaction solvent was switched to methanol. Crucially, 1,2-diaminobenzene (1a) was found to have better solubility in methanol, allowing the reaction to progress at much lower temperature. For example, cooling the reaction mixture to 0°C, adding the reagents and warming the mixture to room temperature over 6 hours, gave benzotriazole 2a in 66 % yield (entry 3). Longer reaction times showed no significant improvement in the overall yield (entry 4). Finally, the number of equivalents of reagents required was investigated. Using only 1 equivalent of both the polymer-supported nitrite reagent and p-tosic acid had a detrimental effect on the yield (entry 5), while increasing the number of equivalents to 6 showed no substantial benefit (entry 6). Therefore, the use of 3 equivalents of reagents in methanol at room temperature was deemed the most suitable procedure for this transformation (entry 3). Using these optimized conditions, the substrate scope for the preparation of N-unsubstituted benzotriazoles was explored (Scheme 1). The method was found to be general and efficient for a wide range of commercially available 1,2-aryldiamines bearing both electron-deficient and electron-rich substituents. In addition, for the majority of substrates, the reaction was complete after 1 h, with the benzotriazoles easily isolated by filtration and purification using flash chromatography. As well as benzotriazoles bearing functional groups and a heterocyclic core (e.g. pyridine analogue 2d), the method was applicable for the synthesis of various halogenated compounds (2h-2n). This included the efficient synthesis of antiparasitic agent 2m, a compound that is active against the protozoan parasite Entamoeba histolytica and is more potent than metronidazole, which is used clinically for the treatment of amebiosis. [13] 5-Aryl derived benzotriazoles are excellent substrates for denitrogenative-and carbonylative-Suzuki coupling reactions [4f ] and thus, we wanted to demonstrate that these could be accessed using this approach. 4-Bromo-2-nitroaniline was subjected to a Suzuki-Miyaura reaction with several boronic acids under standard conditions and the resulting 4-aryl analogues were reduced to 1,2-diaminobenzenes 1o-1q using a combination of sodium borohydride and palladium on carbon. [14] The 4-aryl-1,2-diaminobenzenes (1o-1q) were subjected to the one-pot diazotization and intramolecular cyclization and gave the corresponding benzotriazoles (2o-2q), cleanly and in moderate to good yields. Scheme 1. Substrate scope for the synthesis of N-unsubstituted benzotriazoles.
Following the successful synthesis of a wide range of N-unsubstituted benzotriazoles, the general procedure was next investigated for the synthesis of N 1 -substituted derivatives (Scheme 2). Initially, a series of N-benzyl 1,2-aryldiamines 3a-c was prepared by nucleophilic aromatic substitution of 2-nitrofluorobenzene with various benzylamines, followed by chemoselective reduction of the nitro-group with zinc and acetic acid. [14] The resulting N-benzyl aryldiamines were activated and cyclized using the general procedure to give after 1.5 hours, benzotriazoles 4a-c in good yields (75-77 %). It should be noted that acetonitrile was found to be the optimal solvent for the less polar N-substituted 1,2-aryldiamines.
A second series of 1,2-aryldiamines bearing N-alkyl, -acyl or -sulfonyl groups were prepared from 2-nitroaniline by substitution of the amino group, followed by nitro-group reduction. [14] Subsequent treatment with the polymer-supported nitrite reagent and p-tosic acid gave the corresponding N 1 -substituted benzotriazoles 4d-k in good yields (61-77 %). From the range of substrates investigated, only two required modified procedures. N-Tosyl protected 1,2-diaminobenzene 3i, for reasons that are not clear, required both an increase in the amounts of reagents (4.5 equiv.) and a longer reaction time (5 h), while synthesis of benzotriazole 4k, bearing a bulky pseudopelletier-Scheme 2. Substrate scope for the synthesis of N 1 -substituted benzotriazoles.
[a] 4.5 equivalents of reagents were used. ine derived N-substituent, required a reaction time of 3.5 hours. As well as allowing the synthesis of a benzotriazole with an N 1 -alkaloid substituent (e.g. 4k), this method permitted the synthesis of a range of medicinally important compounds. For example, N 1 -nonyl-substituted derivative 4d is an antifungal agent, that can inhibit the growth of the fluconazole-insensitive organism Cryptococcus neoformans, [1b] while N 1 -benzenesulfonyl-benzotriazole (4h) is highly active against the protozoan parasite, Trypanosoma cruzi, which is responsible for Chagas disease. [15] In addition, the 3,4,5-trimethoxybenzoyl derivative 4j has antiproliferative activity against various human cancer cell lines, including stomach carcinoma MKN45. [16] The next stage of this project then demonstrated how the regioselective issues associated with other methods, [5] could be overcome by the synthesis of selectively substituted 1,2-aryldiamines followed by the mild cyclization procedure, allowing the well-defined, efficient preparation of N 1 -functionalized unsymmetrically substituted benzotriazoles (Scheme 3). Initially, a series of N-benzoyl protected 1,2-aryldiamines (5a-c) were prepared by the N-benzoylation of various 2-nitroanilines, followed by tin dichloride reduction. [14] Subsequent treatment with the polymer-supported nitrite reagent and p-tosic acid, under standard conditions completed the synthesis of benzotriazoles 6a-c in good yields (69-77 %). The widespread pharmaceutical properties displayed by unsymmetrical benzotriazoles bearing N-aryl groups, [1,17] has meant that various synthetic strategies for their regioselective synthesis have been reported. [5d-5f,6, 8,18] In this study, an efficient approach for their synthesis has also been developed. Buchwald-Hartwig coupling of various anilines with 4-bromo-3-nitrotoluene using palladium acetate and (S)-BINAP, [19] followed by tin dichloride reduction of the nitrogroup gave N-aryl 3,4-diaminotoluene analogues (5d-f ). [14] These compounds were found to be excellent substrates for the polymer-supported nitrite and p-tosic acid mediated cyclization, giving the target N 1 -aryl benzotriazoles 6d-f in 61-95 % yields.
In the final stage of this project, we wanted to further demonstrate the compatible nature of the mild benzotriazole forming process for the synthesis of functionalized, biologically relevant targets. We have an interest in the development of new synthetic methods for the preparation of novel heterocyclecontaining α-amino acids for biological applications, [20] and so the mild activation and cyclization process was investigated for the synthesis of a benzotriazole-containing α-amino acid (Scheme 4). Initially, the known L-3-aminoalanine derivative 7, [21] was subjected to an S N Ar reaction with 4-fluoro-3-nitrotoluene under basic conditions, which gave coupled product 8 in 62 % yield. [22] Chemoselective reduction of the nitro-group with tin dichloride then gave key intermediate, 1,2-aryldiamine 9. Reaction of 9 with the polymer-supported nitrite reagent and p-tosic acid under the standard conditions was complete after 3 hours and gave benzotriazole 10 in 69 % yield. Finally, removal of the protecting groups under acid-mediated conditions completed the synthesis of novel benzotriazole-containing αamino acid 11.

Conclusions
In summary, a general and efficient process for the conversion of 1,2-aryldiamines to benzotriazoles has been developed. The particularly mild conditions involving a polymer-supported nitrite reagent and p-tosic acid are compatible with a range of substrates and functional groups, allowing easy purification of the targets by filtration and flash chromatography. This method avoids harsh reagents and the safety issues associated with more traditional approaches, as well as the regioselectivity challenges connected with some cycloaddition syntheses of N 1functionalized unsymmetrically substituted benzotriazoles. The general nature of this method has been exemplified with the preparation of various medicinally important benzotriazoles and the synthesis of a new benzotriazole-containing α-amino acid.

Experimental Section
General Information: All reagents and starting materials were obtained from commercial sources and used as received. Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-aminopropanoate (7) was prepared according to the literature. [21] All dry solvents were purified using a PureSolv 500 MD solvent purification system. All reactions were performed under an atmosphere of argon unless otherwise mentioned. Brine refers to a saturated solution of sodium chloride. Flash column chromatography was carried out using Merck Geduran Si 60 (40-63 μm). Merck aluminium-backed plates pre-coated with silica gel 60 (UV 254 ) were used for thin layer chromatography and were visualized under ultraviolet light and by staining with KMnO 4 or ninhydrin. 1 H NMR and 13 C NMR spectra were recorded on a Bruker AVI 400 or AVIII 400 spectrometer with chemical shift values in ppm relative to TMS (δ H = 0.00 and δ C = 0.0), residual chloroform (δ H = 7.26 and δ C = 77.2), methanol (δ H = 3.31 and δ C = 49.0) or dimethyl sulfoxide (δ H = 2.50 and δ C = 39.5) as standard. Assignment of 1 H and 13 C NMR signals are based on two-dimensional COSY, HSQC, and DEPT experiments. TFA was used to facilitate dissolution of various N-unsubstituted benzotriazoles when recording 13 C NMR spectra. Mass spectra were obtained using a JEOL JMS-700 spectrometer or a Bruker microTOFq High Resolution Mass Spectrometer. Infrared spectra were recorded on a Shimadzu FTIR-84005. Melting points were determined on a Gallenkamp melting point apparatus. Optical rotations were determined as solutions irradiating with the sodium D line (λ = 589 nm) using a polarimeter.