An Efficient Cyanide-Free Approach towards 1-(2-Pyridyl)isoquinoline-3-carbonitriles via the Reaction of 5-Phenacyl-1,2,4-triazines with 1,2-Dehydrobenzene in the Presence of Alkyl Nitrites

Abstract

A cyanide-free method for the preparation of 1-(2-pyridyl)isoquinoline-3-carbonitriles (3-cyanoisoquinolines) was developed. The interaction of 5-phenacyl-3-(2-pyridyl)-1,2,4-triazines with 1,2-dehydrobenzene generated in situ from anthranilic acid and an excess of amyl nitrites afforded the target compounds in good yields. The proposed mechanism involves the in situ transformation of the 5-phenacyl group into the 5-cyano group under the action of alkyl nitrite and the following inverse demand aza-Diels–Alder reaction of thus formed 5-cyano-1,2,4-triazines with 1,2-dehydrobenzene affording the target products. The presence of the 5-phenacyl substituent is a key for the reaction, as in case of 5-styryl- or 5-phenylethynyl-3-(2-pyridyl)-1,2,4-triazines the formation of the 1,2,4-triazine ring-transformation products was observed

Key words

1-(2-pyridyl)isoquinoline-3-carbonitriles - cyanide-free - aryne - inverse demand aza-Diels–Alder reaction - alkyl nitrites

• References and Notes

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• 24 Representative Synthetic Procedure for 4-Arylisoquinoline-3-carbonitriles 6 Corresponding 1,2,4-triazines 1, 4, or 9d (1.0 mmol) were suspended in dry toluene (60 mL). iso-Amyl nitrite or n-amyl nitrite (0.47 mL, 3.5 mmol) was added at once. The resulting mixture was stirred under reflux while the solution of anthranilic acid (3.5 mmol) in dry 1,4-dioxane (15 mL) was added dropwise for 30 min. The reaction mixture was heated under reflux for an additional hour and then cooled to room temperature. After that the reaction mixture was washed with 3 M aq KOH solution (3 × 50 mL), dried with anhydrous Na₂SO₄. After the filtration and evaporation of the solvents under reduced pressure the obtained residue was purified by column chromatography (silica gel) using the corresponding eluent. 1-(Pyridin-2-yl)-4-phenylisoquinoline-3-carbonitrile (6a) Eluent: DCM/EtOAc (3:1); R_f = 0.4; yield 230 mg (75%); mp 171–173 °С. ¹Н NMR (400 MHz, DMSO-d ₆): δ = 7.53–7.60 (m, 3 H, Ph), 7.62–7.69 (m, 3 H, Ph, H-5 (py)), 7.72–7.76 (m, 1 H, isoquin.), 7.82–7.87 (m, 2 H, isoquin.), 8.06 (ddd, 1 Н, J = 7.8, 7.8, 2.0 Hz, Н-4 (py)), 8.12 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (py)), 8.80 (dd, 1 Н, J = 4.8, 2.0 Hz, Н-6 (py)), 8.90–8.94 (m, 1 H, isoquin.). ¹³C NMR (100 MHz, CDCl₃): δ = 117.6, 123.9, 125.4, 125.6, 126.5, 127.5, 128.6, 128.9, 129.4, 130.1, 130.2, 131.4, 133.8, 135.9, 137.3, 140.5, 148.7, 157.0. IR (neat): 2227 cm^–1 (CN). MS (ESI): m/z [M + H]⁺ calcd for С₂₁Н₁₄N₃ ⁺: 308.12; found: 308.12. Anal. Calcd (%) for C₂₁H₁₃N₃: C, 82.07; H, 4.26; N, 13.67. Found: C, 81.88; H, 4.03; N, 13.32. 4-(4-Methoxyphenyl)-1-(pyridine-2-yl)isoquinoline-3-carbonitrile (6b) Eluent: DCM/EtOAc (3:1); R_f = 0.5; yield 246 mg (73%); mp 175–177 °С. ¹Н NMR (400 MHz, CDCl₃): δ = 3.93 (s, 3 Н, ОМе), 7.13 (m, 2 Н, 4-MeOPh), 7.48 (m, 3 Н, 4-MeOPh, Н-5 (pу)), 7.75 (m, 2 Н, isoquin.), 7.85 (m, 1 Н, isoquin.), 7.97 (ddd, 1 Н, J = 7.8, 7.8, 2.0 Hz, Н-4 (pу)), 8.13 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (pу)), 8.82 (m, 2 Н, Н-6 (pу), isoquin.). IR (neat): 2228 cm^–1 (CN). MS (ESI): m/z [M + H]⁺ calcd for С₂₂Н₁₆N₃O⁺: 387.10; found: 387.10. Anal. Calcd (%) for C₂₂H₁₅N₃O: C, 78.32; H, 4.48; N, 12.46. Found: C, 78.08; H, 4.24; N, 12.16. 4-(4-Chlorophenyl)-1-(pyridine-2-yl)isoquinoline-3-carbonitrile (6c) Eluent: DCM/EtOAc (3:1); R_f = 0.4; yield 252 mg (74%); mp 180–182 °С. ¹Н NMR (400 MHz, CDCl₃): δ = 7.45–7.51 (m, 3 H, H-5 (py), 4-chlorophenyl), 7.59 (m, 2 H, 4-chlorophenyl), 7.72–7.82 (m, 3 H, isoquin.), 7.97 (ddd, 1 Н, J = 7.8, 7.8, 2.0 Hz, Н-4 (py)), 8.13 (dd, 1 Н, J = 7.8, 0.8 Hz, Н-3 (py)), 8.81 (dd, 1 Н, J = 4.8, 2.0 Hz, Н-6 (py)), 8.87 (m, 1 H, isoquin.). IR (neat): 2226 cm^–1 (CN). MS (ESI): m/z [M + H]⁺ calcd for С₂₁Н₁₃ClN₃ ⁺: 342.08; found: 342.08. Anal. Calcd (%) for C₂₁H₁₂ClN₃: C, 73.79; H, 3.54; N, 12.29. Found: C, 73.62; H, 3.38; N, 12.38.
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