The synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles was achieved under photochemical conditions. This simple and mild one-step reaction provides regiospecific access to 2,4,5-substituted 1,2,3-triazoles via a nitrile imine intermediate. Syntheses of alkyl and heterocylic derivatives were also investigated

Harris, Robert

Jamieson, Craig

Stewart, Sam

Name not available

Regiospecific synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles via photochemically generated nitrile imine intermediates

University of Strathclyde Institutional Repository

Strathprints Institutional RepositoryStewart, Sam and Harris, Robert and Jamieson, Craig (2014) Regiospecific synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles via photochemically generated nitrile imine intermediates. Synlett, 25 (17). pp. 2480-2484. ISSN 0936-5214 , http://dx.doi.org/10.1055/s-0034-1379010This version is available at http://strathprints.strath.ac.uk/51137/Strathprints is  designed  to  allow  users  to  access  the  research  output  of  the  University  of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may  not  engage  in  further  distribution  of  the  material  for  any  profitmaking  activities  or  any commercial gain. You may freely distribute both the url (http://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge. Any  correspondence  concerning  this  service  should  be  sent  to  Strathprints  administrator: strathprints@strath.ac.ukAbstract: The synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles was achieved under photochemical condi-tions. This simple and mild one step reaction provides regiospecific access to 2,4,5-substituted 1,2,3-triazoles via a nitrile imine intermediate.  Syntheses of alkyl and heterocylic derivatives were also investigated. Key words: Photochemistry, Regioselectivity, Hydrazonyl Chlo-ride, Triazole, Indazole  1,2,3-triazoles are an important class of heterocycles due to a number of useful properties. N2-alkyl and acyl 1,2,3-triazoles act as PPAR agonists1 and as selective CB1 receptor antagonists.2 N2-aryl 1,2,3-triazoles have DSSOLFDWLRQDVȕ3-Adrenergic receptor agonists;3 but more uniquely, have photonic properties which make them suitable as biocompatible UV/blue-light emitting dyes4 and inhibitors of polymer degradation.5 However, issues of regioselectivity between the N1 and N2 position means that the synthesis of N2-substituted 1,2,3-triazoles remains a challenge. Herein, we will focus on synthesis of N2-aryl 1,2,3-triazoles.  Scheme 1 Common routes to N2-aryl 1,2,3-triazoles N2-aryl 1,2,3-triazoles 2 are synthesized via two main pathways: A) arylation of NH-1,2,3-triazoles 1 or B) rearrangement of bis(arylhydrazones) 3 via 1,2,3-triazolium 1-aminides 4 (Scheme 1).  Shi et. al. reported regioselective copper catalysed, or SNAr mediated, N2-arylation utilising bulky ligands or bulky 4,5-substituents.6 Palladium catalysis has also been reported for this application.7 Chen et. al. have demonstrated the regioselective generation of 1,2,3-NH-triazoles followed by subsequent arylation using one-pot multicomponent reactions starting from a variety of mol-ecules.8,9,10 However, the scope of these SNAr reactions was limited to electron poor substrates.  Syntheses from bis(arylhydrazones) 3 can proceed via acid catalysed rearrangement to 1,2,3-triazolium-1-aminides. Subsequent photolysis or reduction with car-bon disulfide11 and hydrogen sulfide12 yield the triazole. Butler et. al. favoured oxidation to 1,2,3-triazolium-1-aminides and subsequent reduction to triazoles using lead oxide and phosphorous trichloride respectively.13 Most recently, Guru et. al. have shown efficient and regiospecific copper catalysed  formation of triaryl 1,2,3- or 1,2,4-triazoles from arylhydrazones under aerobic conditions.14  In an effort to synthesize pyrazoline adducts 8 to serve as probes for the intracellular visualisation of alkene-tagged systems 7, we unexpectedly isolated 2,4,5-triaryl 1,2,3-triazoles 9 from 2,5-diaryl tetrazoles 5 (Scheme 2). Pre-vious accounts had reported the formation of tetrazine 10 from the dimerisation of the nitrile imine intermediate 6, in contrast to the triazoles isolated in the current study.15,16   Scheme 2 Formation of 2,4,5-triaryl 1,2,3-triazoles as a by-product of photochemical pyrazoline synthesis Regiospecific Synthesis of N2-aryl 1,2,3-Triazoles from 2,5-disubstituted Tetrazoles via Photochemically Generated Nitrile Imine Intermediates Sam Stewarta, Robert Harris*a, Craig Jamieson*b. aGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY bUniversity of Strathclyde, Department of Pure and Applied Chemistry, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL E-mail: Robert.M.Harris@gsk.com; Craig.Jamieson@strath.ac.uk  Received: The date will be inserted once the manuscript is accepted. A survey of the literature revealed few examples of con-verting 2,5-diaryl tetrazoles to triazoles under photo-chemical conditions.17,18 Using recently developed methodology for the copper catalysed synthesis of 2,5-diaryl tetrazoles19 we decided to investigate the scope of this reaction. Accordingly, 2,5-diaryl tetrazoles 5a-q were prepared from 5-aryl NH-tetrazoles 11 and aryl boronic acids 12 in 49-93% yield (Table 1) as substrates for the study.19 Table 1 Synthesis of 2,5-diaryl tetrazoles  Entry R R1 Yield/ % Time/ h 5a H H 86 6 5b p-Cl H 64 72 5c m-Cl H 84 24 5d o-Cl H 85 24 5e p-OMe H -a - 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p 5q H H H H H H H H H p-OMe p-Cl p-SO2NMe2 p-Me p-OMe m-OMe o-OMe p-NH2 p-NH(CO)Me p-CO2Et m-CN p-NO2 p-OMe p-OMe p-OMe 93 -a 77 49 -b -c 75 60 55 -a 70 79 6 - 16 16 - - 24 6 24 - 22 16  aCommercially available bSynthesised by reduction of tetrazole 5n (86 %) cSynthesised by acetylation of tetrazole 5j (92%)  With a range of suitably functionalised tetrazole systems in hand, we conducted a solvent screen; a number of which were tolerated in the reaction, including: DCM, MeCN, TBME, 2-MeTHF, EtOAc, toluene and DMF. However, DMSO failed to produce any reaction due to inhibition of nitrile imine formation. Further experimen-tation revealed that a mixture of 2-MeTHF:isopropyl alcohol (1:1 v/v) was a suitable environmentally sustain-able solvent system for the reaction.20    Tetrazoles 5a-q were irradiated with a UVB lamp (270-330 nm) in 2-MeTHF:isopropyl alcohol under atmos-pheric conditions, until all starting material had been consumed. The triazole products were isolated by chro-matography and the results shown in Table 2 provide insight into the effects of substituents on the reaction. Tetrazole 5a was chosen as a baseline for comparison of substituent effects and gave triazole 9a in 19% yield. Initial substituent effects were investigated with C-aryl substitution (Entries 9b-9e). Electron donating substitu-ents appeared to improve yields slightly, relative to elec-tronically neutral 9a. Substitution in the meta and para positions were tolerated; however, o-Cl substitution failed to yield triazole 9d. It was reasoned that this sub-stitution was not tolerated due to steric effects in the nitrile imine intermediate. Table 2 Photochemical synthesis of 2,4,5-triaryl 1,2,3-triazoles  Entry R R1 Yield/ % Time/ h 9a H H 19 24 9b p-Cl H 27 16 9c m-Cl H 28 31 9d o-Cl H 0 26 9e p-OMe H 38 30 9f 9g 9h 9i 9j 9k 9l 9m 9n 9o 9p 9q H H H H H H H H H p-OMe p-Cl p-SO2NMe2 p-Me p-OMe m-OMe o-OMe p-NH2 p-NH(CO)Me p-CO2Et m-CN p-NO2 p-OMe p-OMe p-OMe 47 62 25 33 17 (46)a 41 14 0 0 90 67 0 19 10 35 40 48 (7)a 6 23 24 >100 7 16 6  aIsopropyl alcohol:2-MeTHF solvent (5x volume)   We then investigated the electronic effect of substituents on the N-aryl ring (Entries 9f-9k). In general, addition of electron donating groups favoured formation of the de-sired triazoles in significantly improved yields, particulary in the para position. Interestingly, ortho sub-stitution is also tolerated, albeit in moderate yield.  Sub-stitution with p-NH2 was expected to give excellent reac-tivity; however, triazole 9j could only be isolated in 17% yield. Conducting the reaction under more dilute condi-tions gave an improved yield of 46% due to reduced by-product formation and improved solubility of tetrazole 5j. However, the role of concentration was not explored further in the current study. Instead, the reactive aniline moiety was protected as an acetamide derivative to af-ford triazole 9k in an improved yield of 41%.    As expected, electron deficient N-aryl substituents were poorly tolerated. Of these, only p-CO2Et tetrazole 5l yielded the desired triazole and in a lower yield than for electronically neutral tetrazole 5a. Photo-activation of p-NO2 tetrazole 5n was inefficient, with starting material predominating after irradiaton for 100 hours, and no discernible product evident after this time. Incorporation of a m-CN in tetrazole 5m group did not afford the ex-pected triazole 9m. Instead, isopropyl-N-(3-cyanophenyl) benzo-hydrazonate 13, formed by trapping of the nitrile imine 6m with isopropyl alcohol, was iso-lated as the major product with a yield of 54% (Scheme 3). Such nucleophilic quenching reactions have been reported previously.21,22 Repeating the reaction in ethyl acetate also failed to yield the desired product, presuma-bly due to poor reactivity resulting from the electron withdrawing CN substituent. It should be noted that trapping of the nitrile imine was not observed with the more reactive tetrazole substrates.   Scheme 3 Trapping of nitrile imine 13 by isopropyl alcohol Finally, the observed trends in reactivity were combined when studying triazoles 9o-9q. As predicted, combining an electron rich N-aryl ring with electron donating groups on the C-aryl ring gave significant improvements in yields. However, the electron withdrawing effects of a sulfonamide moiety could not be surmounted. Interestingly, during the synthesis of triazole 9p a precip-itate was formed and, when isolated, Wanzlick dimer 15 was obtained in 57% yield instead of the expected triazole (Scheme 4). Previously, photochemical for-mation of this intermediate had only been observed spectroscopically.17 Further exposure to UV light yielded the desired product by rearrangement to 1,2,3-triazolium-1-aminide 16 and N-N bond cleavage. We suggest that formation of this Wanzlick dimer may occur through the carbenic resonance form 14 of the nitrile imine; which explains the tolerance of o-subtituents on the N-aryl ring, but not the C-aryl ring.23. Based on these observations, we also suggest that the tetrazine by-products previously reported during pyrazoline syntheses15,16 may have been Wanzlick di-mers, as their NMR profile would appear similar. Fur-thermore, we did not observe tetrazine by-products dur-ing our syntheses of pyrazoline adducts.  Having investigated the synthesis of 2,4,5-triaryl 1,2,3-triazoles, we then sought to determine if C-heterocyclic or C-alkyl groups could be tolerated (Scheme 5).   Scheme 4 Mechanism of N2-aryl 1,2,3-triazole formation Commercially available 4-(5-ethyl-2H-tetrazol-2-yl)aniline 17 was irradiated to give triazole 19 in a mod-est 23% yield. In this case, masking the aniline with an acetamide moiety failed to improve the yield, indicating that C-alkyl groups are unfavourable. This could be at-tributed to a less stable carbocation in the nitrile imine intermediate, compared to C-aryl systems, resulting in a complex mixture of products. When irradiating C-morpholine tetrazole 21 we were surprised to observe efficient conversion to 3-morpholine indazole 22. Such transformations have been observed previously using more forcing conditions such as high temperature.25,26  Scheme 5 Synthesis of a N2-aryl 4,5-dialky 1,2,3-triazole and unex-pected formation of substituted indazoles Finally, we wished to investigate if other sources of ni-trile imine intermediates could also yield 2,4,5-trisubtituted 1,2,3-triazoles. Interestingly, formation of tetrazine products via nitrile imine intermediates had been reported by Molteni et. al. from C-acyl, N-Aryl hydrazonyl chlorides.24 To determine if C-aryl substitu-tion would instead yield triazole products we synthesised hydrazonoyl chloride 23 and generated nitrile imine 6f using sodium hydroxide.  Gratifyingly, the main product of the reaction was triazole 9f (29% yield, unoptimised conditions) as confirmed by comparison to the previous-ly obtained product (Scheme 6).   Scheme 6 Synthesis of triazole 9f from 2,5-diaryl tetrazoles or hydrazonyl chlorides In conclusion, we have demonstrated the photochemical  synthesis of a number of 2,4,5-triaryl 1,2,3-triazoles in two steps under mild conditions. Although the reaction shows strong dependence on substituent effects, with electron donating groups giving the best reactivity, we believe the current approach offers efficient access to this useful heterocyclic scaffold. This reaction is there-fore complementary to other synthetic routes and alter-native sources of nitrile imines can also be adopted.  The synthesis of N2-aryl 4,5-dialkyl 1,2,3-triazole and 3-substituted indazole systems was also shown to be possi-ble using this methodology.   Representative Example for the preparation of 2,5-diaryl tetrazoles: 5-phenyl-2-(p-tolyl)-2H-tetrazole (5f) A solution of p-tolyl boronic acid (1.86 g, 13.7 mmol), 5-phenyl tetrazole (1.00 g, 6.84 mmol) and Copper(I) ox-ide (5 mol%, 0.049 g, 0.342 mmol) in DMSO (30 mL) was stirred under O2 (1 atm) at 110 °C for 6 h. The reac-tion mixture was allowed to cool, diluted with ethyl acetate (200 mL) and washed successively with 1M HCL(aq) solution (30 mL) and brine (30 mL) three times. The organic phase was separated, dried, and concentrat-ed in vacuo. Purification by flash column chromatog-raphy (Si, 50 g, 0-10% EtOAc-cyclohexane, 60 mins) gave 5-phenyl-2-(p-tolyl)-2H-tetrazole 5f (1.51 g, 93%) as a white solid. mp 103-104 °C. IR (cm-1): 1507, 1448, 1212, 1012. 1H NMR (400 MHz, CDCl3): įH = 8.26 (dd, J = 2.0, 8.1 Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 7.57 - 7.47 (m, 3 H), 7.38 (d, J = 8.6 Hz, 2 H), 2.46 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): įC = 165.1, 139.9, 134.8, 130.5, 130.2, 128.9, 127.3, 127.0, 120.0, 119.8, 77.3, 77.2, 77.0, 76.7, 21.2 ppm. HRMS (ESI+): m/z calcd for C14H13N4: 237.1135; found 237.1128.   Representative example for the preparation of 2,4,5-trisubstituted 1,2,3-triazoles: 4,5-diphenyl-2-(p-tolyl)-2H-1,2,3-triazole (9f) A solution of 5-phenyl-2-(p-tolyl)-2H-tetrazole 5f (200 mg, 0.85 mmol) in 1:1 Isopropyl alcohol:2-MeTHF (10 mL) was stirred under irradiation with a UVB lamp (270-330 nm) for 19 h. The reaction mixture was con-centrated in vacuo and the residue purified by reverse phase chromatography (Si C18, 50-95% MeCN:H2O, HCO2H modifier, 30 mins) to give 4,5-diphenyl-2-(p-tolyl)-2H-1,2,3-triazole 9f (62 mg, 47%) as a brown gum. IR (cm-1): 1510, 1441, 1268. 1H NMR (400 MHz, CDCl3): įH = 8.10 (d, J = 8.6 Hz, 2 H), 7.72 - 7.65 (m, 4 H), 7.43 (dd, J = 1.9, 4.9 Hz, 6 H), 7.33 (d, J = 8.6 Hz, 2 H), 2.45 (s, 3 H). 13C NMR (101 MHz, CDCl3): įC = 145.7, 137.6, 137.3, 130.9, 129.8, 128.6, 128.6, 128.5, 127.1, 118.7, 21.1. HRMS (ESI+): m/z calcd for C21H18N3: 312.1495; found 312.1496. Acknowledgment We would like to thank The University of Strathclyde and Glax-oSmithKline for the financial support of this project.   References (1) Hadd, M.A.; Nichelson, B.J.; Zhu, Z. WO 2005/000841A1, 2005.  (2) Hou, D.; Alam, S.; Kuan, T.; Ramanathan, M.; Lin, T.; Hung, M. Bioorg. Med. Chem. Lett. 2009, 19, 1022. (3) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; Macintyre, D. E.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 2000, 10, 2111.  (4) Yan, W.; Wang, Q.; Lin, Q.; Li, M.; Petersen, J. 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Helvetica Chimia Acta, 1985, 68, 1283.  (22) Abu Thaher, B.; Zahra, J.; El-Abadelah, M. M.; Voelter, W. Z Naturforsch. 2004, 59b, 930.  (23) Böhm, V. P. W.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 4036±4038. (24) Molteni, G.; Orlandi, M.; Broggini, G. J. Chem. Soc. Per-kin Trans. 1 2000, 3742. (25) Wentrup, C.; Benedikt, J. J. Org. Chem. 1980, 45, 1407±1409.    (26) Wentrup, C.; Damerius, A.; Reichen, W. J. Org. Chem. 1978, 43, 2037±2041.   (27) Patel, H.; Vyas, K.; Pandey, S.; Fernandes, P. Tetrahedron 1996, 52, 661±668.                          6 SYNLETT  Template for SYNLETT and SYNTHESIS © Thieme  Stuttgart ·  New York 2015-01-16 page 6 of 6  Please place the graphical abstract and short title of the article here. The short title will be used as a running header.  Manuscript submission checklist  6WDWHPHQWRIVLJQLILFDQFHRIZRUN  )XOOPDLOLQJDGGUHVVWHOHSKRQHDQGID[QXPEHUVDQGHPDLO address of the corresponding author.  3DSHUVDYHDVD3')ILOH  2ULJLQDO:RUGILOH  2ULJLQDOJUDSKLFILOHV  *UDSKLFDODEVWUDFW             

Robert Harris

Craig Jamieson

Sam Stewart

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Regiospecific Synthesis of N2-Aryl 1,2,3-Triazoles from 2,5-Disubstituted Tetrazoles via Photochemically Generated Nitrile Imine Intermediates

Regiospecific synthesis of N2-aryl 1,2,3-triazoles from 2,5-disubstituted tetrazoles via photochemically generated nitrile imine intermediates

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