Synlett 2018; 29(04): 525-529
DOI: 10.1055/s-0036-1590942
letter
© Georg Thieme Verlag Stuttgart · New York

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

Jonas Bucevicius
a  Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko Str. 24, 03225 Vilnius, Lithuania   Email: [email protected]
,
b  Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, LV-1048 Riga, Latvia
,
Sigitas Tumkevicius*
a  Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko Str. 24, 03225 Vilnius, Lithuania   Email: [email protected]
› Author Affiliations
The research was funded by a Latvian-Lithuanian-Taiwanese co-­project (Lithuania: No. TAP-LLT-01/2015; Latvia: No. W1935//LV-LT-TW/2015/2).
Further Information

Publication History

Received: 02 September 2017

Accepted after revision: 04 October 2017

Publication Date:
14 November 2017 (online)


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.

Supporting Information

 
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  • 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) Å3, 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 2ac (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 SNAr 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 4ah,lp. Method B A mixture of the corresponding diazide 2ac (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 SNAr 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,hl. 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 8ad. 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.