Click Variations on the Synthesis of 2-Nitrophenyl-4-aryl-1,2,3-triazoles without Isolation of 2-Nitrophenyl Azides

Published as part of the ISySyCat2019 Special Issue

Abstract

We report a series of efficient procedures to prepare 2-nitrophenyl-4-aryl-1,2,3-triazoles avoiding the isolation of potentially hazardous 2-nitrophenyl azides. An organocatalyzed azide-enolate variant allows efficient access to the target compounds while it was shown that a metal-catalyzed azide-alkyne procedure involving a preliminary ­Sonogashira coupling was feasible starting from electron-deficient aryl iodides.

Key words

click chemistry - azides - alkynes - enolates - triazoles - ­organocatalysis

• References

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• 12 General Procedure (DMSO): 2-Nitroaryl fluoride reagent was dissolved in DMSO (ca. 1 mL per mmol), then NaN₃ (1.1 equiv) was added. The solution was either heated or stirred at room temperature until completion of the aromatic nucleophilic substitution (either followed by TLC or ¹H NMR). After cooling to room temperature, phenylacetaldehyde (0.9 equiv) and DBU (0.09 equiv) were subsequently added. The mixture was stirred either at room temperature or heated until completion of the reaction (followed by TLC). CH₂Cl₂ was then added to the solution, and the organic phase was washed with a saturated aqueous solution of NH₄Cl. The aqueous phase was then extracted with CH₂Cl₂ and the combined organic phases were washed with water, brine, dried over MgSO₄, and the solvent was evaporated under reduced pressure. Recrystallization with EtOH gave the desired product. Analytical data for a representative compound obtained by this procedure: 1-(5-Chloro-2-nitrophenyl)-4-phenyl-1H-1,2,3-triazole. ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.36–7.44 (m, 1 H, H_Ar), 7.51 (t, J = 7.5 Hz, 2 H, H_Ar), 7.93 (d, J = 7.5 Hz, 2 H, H_Ar), 8.02 (d, J = 8.5 Hz, 1 H, H_Ar), 8.10 (dd, J = 8.5, 2.2 Hz, 1 H, H_Ar), 8.43 (d, J = 2.2 Hz, 1 H, H_Ar), 9.18 (s, 1 H, H_triazole). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 122.7 (CH_Ar), 125.4 (CH_Ar), 125.6 (CH_Ar), 127.8 (Cq_Ar), 128.5 (CH_Ar), 128.7 (CH_Ar), 129.1 (CH_Ar), 129.7 (Cq_Ar), 134.2 (CH_Ar), 135.1 (Cq_Ar), 144.3 (Cq_triazole), 147.2 (Cq_Ar). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₀ClN₄O₂: 301.0487; found: 301.0482.
• 13 General procedure (acetonitrile): 2-Nitroaryl fluoride reagent was dissolved in MeCN (ca. 1 mL per mmol), then NaN₃ (1.1 equiv) and tetrabutylammonium hydrogensulfate (0.1 g per gram of starting material) were added. The solution was either heated or stirred at room temperature until completion of the aromatic nucleophilic substitution (either followed by TLC or ¹H NMR). After cooling to room temperature, phenylacetaldehyde (0.9 equiv) and DBU (0.09 equiv) were added. The mixture was stirred either at room temperature or heated to 80 °C until completion of the reaction (followed by TLC). Either work-up 1 or 2 were used. Work-up 1 (gram-scale): as described in reference 12. Work-up 2 (Table 1, entries 6, 10; 10–30 g scale): a massive precipitate was observed. The solid was isolated by filtration and washed with a minimal amount of cold (0 °C) acetonitrile and several times with water. After desiccation, the solid was obtained in pure form. Analytical data for a representative compound obtained by this procedure: 1-(4-Iodo-2-nitrophenyl)-4-phenyl-1H-1,2,3-triazole. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.35–7.45 (m, 1 H, H_ar), 7.46–7.55 (m, 2 H, H_ar), 7.74 (d, J = 8.3 Hz, 1 H, H_ar), 7.93 (d, J = 7.2 Hz, 2 H, H_ar), 8.36 (dd, J = 8.3, 1.7 Hz, 1 H, H_ar), 8.58 (d, J = 1.6 Hz, 1 H, H_ar), 9.17 (s, 1 H, H_triazole).¹³C NMR (100 MHz, DMSO-d ₆): δ = 96.4 (Cq_ar-I), 122.5 (CH_ar), 125.4 (CH_triazole), 128.4 (CH_ar), 128.5 (Cq_ar), 128.5 (Cq_ar), 129.1 (CH_ar), 129.7 (Cq_ar), 133.5 (CH_ar), 142.8 (CH_ar), 144.1 (Cq_triazole), 147.2 (CH_ar). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₀IN₄O₂: 392.9843; found: 392.9840.
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• 15 Previously reported (61% yield) in reference 8c.
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• 17 As evidenced by a dangerous massive gaseous evolution we observed while performing an experiment related to entry 7 under the conditions described by Ramana et al. in reference 8c.
• 18 General procedure (Sonogashira click): In a first round-bottom flask, iodophenyl starting material was dissolved in THF (10 mL per 4 mmol). Ethynyltrimethylsilane (1.1 equiv), triethylamine (4 equiv), PdCl₂(PPh₃)₂ (0.4 mol%), and CuI (0.4 mol%) were then added, and the mixture was stirred at 50 °C until completion of the Sonogashira reaction. In a second round-bottom flask, fluoronitrobenzene starting material (1.05 equiv) was dissolved in MeCN (10 mL per 4 mmol). Sodium azide (1.15 equiv) and tetrabutylammonium hydrogensulfate (0.05 equiv) were then added and the mixture was stirred at 50 °C until completion of the aromatic nucleophilic substitution reaction. The first round-bottom flask was then filtrated, and the filtrate was poured into the second round-bottom flask. CuI (8 mol%) was finally added, and the resulting mixture was stirred at 60 °C until completion of both the deprotection and click reaction. The resulting solution was then filtered over Celite, and the filtrate was evaporated under reduced pressure. Recrystallization with EtOH was performed to obtain the desired product. Analytical data for a representative compound obtained by this procedure: Methyl 4-[1-(5-chloro-2-nitrophenyl)-1H-1,2,3-triazol-4-yl]benzoate: ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.88 (s., 3 H, CH₃), 7.85–8.08 (overlapping signals, 5 H, H_Ar), 8.18–8.39 (overlapping signals, 2 H, H_Ar), 9.36 (s, 1 H, H_triazole). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 52.0 (CH₃), 124.0 (CH, C_Ar), 125.3 (CH, C_Ar), 127.2 (CH, C_Ar), 127.2 (CH, C_Ar), 129.1 (Cq, C_Ar), 129.8 (Cq, C_Ar), 129.9 (CH, C_Ar), 131.0 (CH, C_Ar), 134.0 (Cq, C_Ar), 138.4 (Cq, C_Ar), 142.4 (Cq, C_triazole), 145.8 (Cq, C_Ar), 165.7 (Cq, C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₂N₄O₄Cl: 359.0542; found: 359.0532.
• 19 Shashank AB, Karthik S, Madhavachary R, Ramachary DB. Chem. Eur. J. 2014; 16877