Easy Access to Isomeric 7-Deazapurine–1,2,3-Triazole Conjugates via S_NAr and CuAAC Reactions of 2,6-Diazido-7-deazapurines

Abstract

A simple and efficient synthesis of isomeric 7-deazapurine–1,2,3-triazole conjugates with amino substituents from readily available 9-alkyl-2,6-diazido-7-deazapurines has been developed using consecutive CuAAC and regioselective nucleophilic substitution reactions of ­azido and 1,2,3-triazole groups with amines.

Key words

heterocycles - 7-deazapurines - triazoles - click chemistry - nucleophilic aromatic substitution - regioselectivity

• References and Notes


For recent reviews, see:
• 1a Perlíková P. Hocek M. Med. Res. Rev. 2017; 37: 1429
• 1b De Coen LM. Heugebaert TS. A. García D. Stevens CV. Chem. Rev. 2016; 116: 80
• 1c Tumkevicius S. Dodonova J. Chem. Heterocycl. Compd. 2012; 48: 258

For examples, see:
• 1d Perlíková P. Rylova G. Naus P. Elbert T. Tloustova E. Bourderioux A. Slavetinska LP. Motyka K. Dolezal D. Znojek P. Nova A. Harvanova M. Dzubak P. Siller M. Hlavac J. Hajduch M. Hocek M. Mol. Cancer Ther. 2016; 15: 922
• 1e Bourderioux A. Naus P. Perlíková P. Pohl R. Pichova I. Votruba I. Dzubak P. Konecny P. Hajduch M. Stray KM. Wang T. Ray AS. Feng JY. Birkus G. Cihlar T. Hocek M. J. Med. Chem. 2011; 54: 5498
• 1f Tichy M. Smolen S. Tloustova E. Pohl R. Ozdian T. Hejtmankova K. Liskova B. Gurska S. Dzubak P. Hajduch M. Hocek M. J. Med. Chem. 2017; 60: 2411
• 1g Sugimoto Y. Sawant DB. Fisk HA. Mao L. Li C. Chettiar S. Li P.-K. Darby MV. Brueggemeier RW. Bioorg. Med. Chem. 2017; 25: 2156
• 1h Jiao XY. Kopecky DJ. Liu J. Liu J. Jaen JC. Cardozo MG. Sharma R. Walker N. Wesche H. Li S. Farrelly E. Xiao S.-H. Wang Z. Kayser F. Bioorg. Med. Chem. Lett. 2012; 22: 6212
• 2 Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
• 3 Tornoe CW. Christensen C. Meldal M. J. Org. Chem. 2002; 67: 3057

For a review, see:
• 4a Amblard F. Cho JH. Schinazi RF. Chem. Rev. 2009; 109: 4207

For examples, see:
• 4b Chittepu P. Sirivolu VR. Seela F. Bioorg. Med. Chem. 2008; 16: 8427
• 4c Gierlich J. Burley GA. Gramlich PM. E. Hammond DM. Carell TJ. Org. Lett. 2006; 8: 3639
• 4d Franke R. Dol C. Eichler J. Tetrahedron Lett. 2005; 46: 4479
• 4e Jang H. Farman A. Holub JM. Kirshenbaum KJ. Org. Lett. 2005; 7: 1951
• 4f Holub JM. Jang H. Kirshenbaum K. Org. Biomol. Chem. 2006; 4: 1497
• 4g Kovalovs A. Novosjolova I. Bizdena E. Bizane I. Skardziute L. Kazlauskas K. Jursenas S. Turks M. Tetrahedron Lett. 2013; 54: 850
• 4h Novosjolova I. Bizdena E. Turks M. Tetrahedron Lett. 2013; 54: 6557
• 4i Zayas J. Annoual M. Kumar Das JK. Felty Q. Gonzalez WG. Miksovska J. Sharifai N. Chiba A. Wnuk SF. Bioconjugate Chem. 2015; 26: 1519
• 4j Dyrager C. Borjesson K. Diner P. Elf A. Albinsson BL. Wilhelmsson M. Grøtli M. Eur. J. Org. Chem. 2009; 1515
• 5 Moses JE. Moorhouse AD. Chem. Soc. Rev. 2007; 36: 1249

For review, see:
• 6a Lau YH. Rutledge PJ. Watkinson M. Todd MH. Chem. Soc. Rev. 2011; 40: 2848

For examples, see:
• 6b Collot M. Lasoroski A. Zamaleeva AI. Feltz A. Vuilleumier A. Mallet JM. Tetrahedron Lett. 2013; 69: 10482
• 6c Singh H. Sindhu J. Khurana JM. Sens. Actuators, B 2014; 192: 536
• 6d Cao L. Jiang R. Zhu Y. Wang X. Li Y. Li Y. Eur. J. Org. Chem. 2014; 2687

For reviews, see:
• 7a Tron GC. Pirali T. Billington RA. Canonico PL. Sorba G. Genazzani AA. Med. Res. Rev. 2008; 28: 278
• 7b Sharpless KB. Manetsch R. Expert Opin. Drug Discov. 2006; 1: 525

For examples, see:
• 7c Zhang H. Zhou L. Coats SJ. McBrayer TR. Tharnish PM. Bondada L. Detorio M. Amichai S. Johns MD. Whitaker T. Schinazi RF. Bioorg. Med. Chem. Lett. 2011; 21: 6788
• 7d Agalave SG. Maujan SR. Pore VS. Chem. Asian J. 2011; 6: 2696
• 7e Lauria A. Delisi R. Mingoia F. Terenzi A. Martorana A. Barone G. Almerico AM. Eur. J. Org. Chem. 2014; 3289
• 8a Di Francesco ME. Avolio S. Pompei M. Pesci S. Monteagudo E. Pucci V. Giuliano C. Fiore F. Michael R. Summa V. Bioorg. Med. Chem. 2012; 20: 4801
• 8b Lawson CP. Dierckx A. Miannay F.-A. Wellner E. Wilhelmsson LM. Grøtli M. Org. Biomol. Chem. 2014; 12: 5158
• 8c Ingale SA. Seela F. Tetrahedron 2014; 70: 380
• 8d Kavoosi S. Rayala R. Walsh B. Barrios M. Gonzalez WG. Miksovska J. Mathivathanan L. Raptis RG. Wnuk SF. Tetrahedron Lett. 2016; 57: 4364
• 8e Gehringer M. Forster M. Laufer SA. ACS Comb. Sci. 2015; 17: 5
• 9a Tumkevicius S. Dodonova J. Kazlauskas K. Masevicius V. Skardziute L. Jursenas S. Tetrahedron Lett. 2010; 51: 3902
• 9b Dodonova J. Skardziute L. Kazlauskas K. Jursenas S. Tumkevicius S. Tetrahedron 2012; 68: 329
• 9c Skardziute L. Kazlauskas K. Dodonova J. Bucevicius J. Tumkevicius S. Jursenas S. Tetrahedron 2013; 69: 9566
• 9d Bucevicius J. Skardziute L. Dodonova J. Kazlauskas K. Bagdziunas G. Jursenas S. Tumkevicius S. RSC Adv. 2015; 5: 38610
• 10 Xie H. Zeng L. Zeng S. Lu X. Zhang G. Zhao X. Cheng N. Tu Z. Li Z. Xu H. Yang L. Zhang X. Huang M. Zhao J. Hu W. Eur. J. Med. Chem. 2012; 52: 205
• 11a Seela F. Driller H. Liman U. Liebigs Ann. Chem. 1985; 312
• 11b O’Brien NJ. Brzozowski M. Buskes MJ. Deady LW. Abbot BM. Bioorg. Med. Chem. 2014; 22: 3879
• 11c Chen Z. Venkatesan AM. Dehnhardt CM. Ayral-Kaloustian S. J. Med. Chem. 2010; 53: 3169 (d)
• 12 Bucevicius J. Tumkevicius S. Chemija 2015; 26: 126
• 13 Crystal Data for Compound 4a C₂₀H₂₁N₇, M _w = 359.44, triclinic, space group P-1, Z = 2,  a = 7.934 Å , b = 10.46 Å , c = 11.173 Å,  α = 97.163(2)°,  β = 100.278(2)°,  γ = 90.358(3)°, V = 904.74(8) ų, F(000) = 380, D _x = 1.319 g/cm³. CCDC 1570503 contains the supplementary crystallographic data for the structure 4a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 14 General Procedures for the Synthesis of 9-Alkyl-2-dialkyl-amino-6-(4-substituted 1,2,3-triazol-1-yl)-7-deazapurines 4a–p Method A A mixture of the corresponding diazide 2a–c (0.4 mmol) and secondary amine (1.2 mmol) in CH₃CN (2 mL) was protected from light and stirred for 8–24 h at 40 °C. After completion of the S_NAr reaction (TLC analysis), the reaction mixture was cooled to r.t., and the requisite alkyne (0.52 mmol), DIPEA (70 μL, 0.4 mmol), AcOH (23 μL, 0.4 mmol), and CuI (15 mg, 0.08 mmol) were added, and the reaction mixture was stirred under argon at r.t. for 8–10 h (TLC control). Then the reaction mixture was poured into aq 10% NH₃ solution (25 mL), stirred for 10 min, and extracted with CHCl₃ (3 × 20 mL). The combined organic layers were washed with water (2 × 30 mL), dried over anhydrous Na₂SO₄, and filtered. After removal of the solvent in vacuum, the crude products were purified by silica gel column chromatography (CHCl₃–EtOAc, 6:1) to afford compounds 4a–h,l–p. Method B A mixture of the corresponding diazide 2a–c (0.4 mmol) and amine (1.2 mmol) in DMF (2 mL) was flushed with argon and stirred for 2–4 h at 40 °C in a reaction vessel protected from light. After completion of the S_NAr reaction (TLC analysis), the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 × 20 mL). The organic extracts were combined, washed with water (20 mL), dried over anhydrous Na₂SO₄, and filtered. After removal of the solvent in vacuum, the residue was dissolved in CH₃CN (2 mL), and the requisite alkyne (0.52 mmol), DIPEA (70 μL, 0.4 mmol), AcOH (23 µL, 0.4 mmol), and CuI (15 mg, 0.08 mmol) were added. The reaction mixture was protected from daylight and stirred at r.t. under argon for 8–10 h (TLC analysis). Then the reaction mixture was poured into aq 10% NH₃ solution (25 mL), stirred for 10 min, and extracted with CHCl₃ (3 × 20 mL). The combined organic layers were washed with water (2 × 30 mL), dried over anhydrous Na₂SO₄, and filtered. After removal of the solvent in vacuum, the crude products were purified by silica gel column chromatography (CHCl₃–EtOAc, 6:1) to afford compounds 4a,h–l. Compound 4a Yield 65% (method A), 67% (method B), yellow solid, mp 179–181 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.62–1.79 (6 H, m, piperidine 3 × CH₂), 3.74 (3 H, s, CH₃), 3.91 (4 H, m, piperidine 2 × CH₂), 6.91 (1 H, d, J = 3.6 Hz, 8-H), 7.07 (1 H, d, J = 3.6 Hz, 7-H), 7.39 (1 H, t, J = 7.2 Hz, Ph-H), 7.49 (2 H, d, J = 7.2 Hz, Ph-H), 8.01 (2 H, d, J = 7.2 Hz, Ph-H), 8.85 (1 H, s, triazole-H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.9, 25.7, 30.8, 45.5, 99.8, 101.7, 117.1, 125.9, 127.2, 128.4, 128.8, 130.3, 146.8, 147.1, 156.6, 158.1. ESI-HRMS: m/z [M + H]⁺calcd for C₂₀H₂₂N₇: 360.1931; found: 360.1926. Compound 4e Yield 71% (method A), yellow solid, mp 220 °C (dec.). ¹H NMR (400 MHz, CDCl₃): δ = 2.06 (4 H, m, pyrrolidine 2 × CH₂), 3.71 [(4 H, m, pyrrolidine N(CH₂)₂], 3.75 (3 H, s, CH₃), 6.89 (1 H, d, J = 3.6 Hz, 8-H), 7.08 (1 H, d, J = 3.6 Hz, 7-H), 7.39 (1 H, t, J = 7.2 Hz, Ph-H), 7.49 (2 H, t, J = 7.2 Hz, Ph-H), 8.00 (2 H, d, J = 7.2 Hz, Ph-H), 8.88 (1 H, s, triazole-H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.5, 30.7, 46.9, 99.5, 101.6, 117.1, 125.9, 126.7, 128.3, 128.8, 130.3, 146.8, 146.9, 156.6, 156.8. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₉H₂₀N₇: 346.1775; found: 346.1776
• 15 Preparation of 9-Butyl-2,6-bis(4-substituted 1,2,3-triazol-1-yl)-7-deazapurines 7a,b A mixture of 2b (350 mg, 1.36 mmol), the requisite alkyne (3.4 mmol), CuI (50 mg, 0.26 mmol), DIPEA (227 μL, 1.36 mmol) and AcOH (77 μL, 1.36 mmol) in CH₂Cl₂ (10 mL) was protected from daylight and stirred at r.t. for 24 h. Then the reaction mixture was poured into aq 10% NH₃ solution (25 mL) and extracted with CHCl₃ (3 × 20 mL). The extracts were combined, dried over anhydrous Na₂SO₄, and filtered. After the removal of the solvent, the crude product was purified by silica gel column chromatography (CHCl₃–EtOAc, 2:1) to afford compounds 7a,b. Compound 7a Yield 48%, white solid, mp 226 °C (dec.). ¹H NMR (400 MHZ, CDCl₃): δ = 1.02 (3 H, t, J = 7.2 Hz, CH₃), 1.43 (2 H, sext, J = 7.2 Hz, CH₂), 1.96 (2 H, quin, J = 7.2 Hz, CH₂), 4.43 (2 H, t, J = 7.2Hz, CH₂), 7.39–7.54 (8 H, m, 7-H, 8-H, Ph-H), 8.03 (4 H, t, J = 6.8 Hz, Ph-H), 8.87 (1 H, s, triazole-H), 9.12 (1 H, s, triazole-H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.6, 19.9, 32.1, 44.9, 103.3, 107.1, 117.7, 118.4, 126.1 (× 2 overlapped), 128.6, 128.8, 128.9, 129.0, 129.6, 130.0, 131.3, 147.2, 147.6, 147.7, 147.9, 153.9. ESI-HRMS: m/z [M + H]⁺calcd for C₂₆H₂₄N₉: 462.2149; found: 462.2148. Compound 7b Yield 76%, pale yellow oil. ¹H NMR (400 MHZ, DMSO-d ₆): δ = 0.89–0.95 (9 H, m, 3 × CH₃), 1.23–1.41 (6 H, m, 3 × CH₂), 1.69 (4 H, quin, J = 7.2 Hz, 2 × CH₂), 1.84 (2 H, quin, J = 7.2 Hz, CH₂), 2.72–2.78 (4 H, m, 2 × CH₂), 4.32 (2 H, t, J = 7.2 Hz, CH₂), 7.10 (1 H, d, J = 3.6 Hz, 8-H), 7.85 (1 H, d, J = 3.6 Hz, 7-H), 8.88 (1 H, s, triazole-H), 9.00 (1 H, s, triazole-H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.8, 14.0, 14.1, 19.7, 22.14, 22.19, 24.9, 25.1, 31.2, 31.4, 31.9, 44.6, 102.1, 106.3, 120.4, 121.5, 133.2, 146.9, 147.5, 148.1, 148.3, 154.0. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₂H₃₂N₉: 422.2775; found: 422.2769.
• 16 General Procedure for the Synthesis of 9-Alkyl-6-amino-2-(4-substituted 1,2,3-triazol-1-yl)-7-deazapurines 8a–d A mixture of compound 7a or 7b (0.22 mmol) and requisite amine (1.1 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 100 °C for 24–48 h (TLC analysis). Then the reaction mixture was poured into water and extracted with EtOAc (3 × 20 mL). The organic extracts were combined, washed with water, dried over Na₂SO₄, and filtered. After removal of the solvent in vacuum, the crude products were purified by silica gel column chromatography (CHCl₃–EtOAc, 3:1) to afford compounds 8a–d. Compound 8a Yield 91%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (3 H, t, J = 7.2 Hz, CH₃), 1.38 (2 H, sext, J = 7.2 Hz, CH₂), 1.71–1.81 (6 H, m, piperidine 3 × CH₂), 1.86 (2 H, quin, J = 7.2 Hz, CH₂), 3.94–4.03 (4 H, m, piperidine 2 × CH₂), 4.28 (2 H, t, J = 7.2 Hz, CH₂), 6.55 (1 H, d, J = 3.6 Hz, 7-H), 7.00 (1 H, d, J = 3.6 Hz, 8-H), 7.37 (1 H, t, J = 7.2 Hz, Ph-H), 7.47 (2 H, t, J = 7.2 Hz, Ph-H), 7.99 (2 H, d, J = 7.2 Hz, Ph-H), 8.76 (1 H, s, triazole-H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.7, 19.9, 24.6, 25.9, 32.3, 44.4, 47.0, 101.4, 101.8, 118.6, 123.9, 126.0, 128.1, 128.7, 130.7, 147.0, 148.8, 151.6, 157.1. ESI-HRMS: m/z [M + H]⁺calcd for C₂₃H₂₈N₇: 402.2401; found: 402.2395. Compound 8c Yield 94%, yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (3 H, t, J = 7.2 Hz, CH₃), 0.96 (3 H, t, J = 7.2 Hz, CH₃), 1.35 (2 H, sext, J = 7.2 Hz, CH₂), 1.43 (2 H, sext, J = 7.2 Hz, CH₂), 1.69–1.77 (8 H, m, CH₂ + piperidine 3 × CH₂), 1.83 (2 H, quin, J = 7.2 Hz, CH₂), 2.82 (2 H, t, J = 7.2 Hz, CH₂), 3.91–3.99 (4 H, m, piperidine 2 × CH₂), 4.24 (2 H, t, J = 7.2 Hz, CH₂), 6.52 (1 H, d, J = 3.6 Hz, 7-H), 6.97 (1 H, d, J = 3.6 Hz, 8-H), 8.27 (1 H, s, triazole-H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.6, 13.8, 19.9, 22.3, 24.6, 25.4, 25.9, 31.6, 32.3, 44.3, 47.0, 101.3, 101.7, 119.7, 123.8, 147.7, 148.9, 151.6, 157.1. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₁H₃₂N₇: 382.2714; found: 382.2709.