Cyclization of o-Alkynylisocyanobenzenes with 1,3-Dicarbonyl Compounds

Abstract

A facile and convenient reaction of o-alkynylisocyanobenzenes with various active-methylene compounds, including 1,3-diesters, 1,3-diketones, β-keto esters, and β-keto amides, under Brønsted basic conditions, has been developed. Diethyl malonate reacted smoothly with a collection of o-alkynylisocyanobenzenes to provide the corresponding 2-quinolin-2-yl malonates in excellent yields. Acetylacetone gave a mixture of quinolin-4-yl and quinolin-2-yl derivatives. Acetoacetate esters and acetoacetyl amide derivative initially gave 2-quinolin-2-yl adducts that underwent partial deacetylation under the reaction conditions.

Key words

alkynylisocyanobenzenes - isonitriles - dicarbonyl compounds - Brønsted bases - quinolines

Publication History

Received: 26 December 2021

Accepted after revision: 01 March 2022

Accepted Manuscript online:
01 March 2022

Article published online:
21 March 2022

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• 14 Diethyl 2-(Quinolin-2-yl)malonates 4aa–qa; General Procedure Step I: POCl₃ (0.07 mL, 0.75 mmol, 1.5 equiv) was added dropwise to a mixture of the appropriate formamide 1 (0.5 mmol) and (i-Pr)₂NEt (0.70 mL, 4.0 mmol, 8.0 equiv) in CH₂Cl₂ (4.0 mL, 0.125 M) at 0 °C under argon, and the mixture was stirred at 0 °C for 1 h. The reaction was then quenched with sat. aq NaHCO₃ (5 mL), and the resulting mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated (aspirator). The crude product was filtered through a short-path layer of aluminum oxide (Type E), with elution by EtOAc, to provide the corresponding o-alkynylisocyanobenzene 2, which was used in Step II without further purification. Step II: Diethyl malonate (3a) (0.23 mL, 1.5 mmol, 3 equiv) was added to a suspension of Cs₂CO₃ (488.7 mg, 1.5 mmol, 3 equiv) in DMF (2.0 mL) at rt, and the mixture was stirred for 10 min. The freshly prepared solution of o-alkynylisocyanobenzene 2 in DMF (2.0 mL) from Step I was added at rt, and mixture was stirred at rt for 6 h. The mixture was then diluted with H₂O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated (aspirator). The crude product was purified by column chromatography (silica gel). Diethyl 2-(3-Phenylquinolin-2-yl)malonate (4aa) Prepared from 1-isocyano-2-(phenylethynyl)benzene (2a) [freshly prepared from 1a (110.6 mg, 0.5 mmol)], and purified by column chromatography [silica gel, CH₂Cl₂–EtOAc–hexane (0.5:1:8.5)] as a yellow solid; yield: 157.7 mg (86%); mp 73.9–75.9 °C. IR (ATR): 2981.94, 1727.23, 1443.17, 1143.86, 754.46, 699.77 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 6.8 Hz, 1 H), 8.03 (s, 1 H), 7.81 (d, J = 6.4 Hz, 1 H), 7.71 (dd, J = 6.4, 6.4 Hz, 1 H), 7.55 (dd, J = 6.0, 6.0 Hz, 1 H), 7.48–7.42 (m, 3 H), 7.38–7.36 (m, 2 H), 5.16 (s, 1 H), 4.24–4.18 (m, 4 H), 1.23 (t, J = 5.6 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.49, 152.23, 146.94, 138.37, 136.69, 135.32, 129.57, 129.37, 129.27, 128.52, 128.01, 127.28, 127.16, 127.02, 61.64, 58.77, 13.95. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₂H₂₁NNaO₄: 386.1363; found: 386.1362. 3-(3-Phenylquinolin-2-yl)pentane-2,4-dione [5ab(keto)]; (3E)-4-Hydroxy-3-(3-phenylquinolin-2-yl)pent-3-en-2-one [5ab(enol)], and 3-(3-Phenylquinolin-4-yl)pentane-2,4-dione [6ab(keto)]; Typical Procedure Step I: A solution of the isocyanide 2a was prepared as described above. Step II: Acetylacetone (3b) (0.09 mL, 0.9 mmol, 3 equiv) was added to a suspension of Cs₂CO₃ (293.2 mg, 0.9 mmol, 3 equiv) in DMF (1.4 mL) at rt, and the mixture was stirred for 10 min. To this mixture was added the freshly prepared solution of 2a in DMF (1.0 mL) at rt, and the mixture was stirred at rt for 16 h. The mixture was then diluted with H₂O (3 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (15 mL), dried (Na₂SO₄), filtered, and concentrated (aspirator). The crude product mixture was purified by column chromatography [silica gel, acetone–hexane (1:9)] to give 5ab(keto) and a mixture of 5ab(enol) and 6ab(keto); these were separated by preparative TLC (acetone–hexane, 1:9) and repeated column chromatography (silica gel, EtOAc–hexane, 1:19). 5ab(keto) White solid; yield: 30.4 mg (20%); mp 94.4–95.5 °C. IR (ATR): 2919.52, 1690.99, 1613.53, 1409.36, 1135.51, 697.74 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.21 (s, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.72 (dd, J = 8.0, 7.5 Hz, 1 H), 7.58 (d, J = 7.0 Hz, 2 H), 7.54 (dd, J = 8.0, 7.0 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 1 H), 5.82 (s, 1 H), 2.43 (s, 3 H), 2.10 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 197.48, 168.01, 156.45, 139.81, 135.73, 130.07, 129.09, 128.51, 128.23, 127.88, 127.82, 127.51, 126.92, 126.22, 110.10, 32.08, 18.87. DEPT-135 (125 MHz, CDCl₃): δ = 139.81, 130.07, 129.09, 128.51, 128.23, 127.87, 127.51, 126.21, 110.10, 32.08, 18.86. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₇NNaO₂: 326.1151; found: 326.1152. 5ab(enol) Yellow solid; yield: 86.5 mg (57%); mp 106.3–108.9 °C. IR (ATR): 2920.94, 1658.01, 1553.07, 1197.82, 699.49 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 16.64 (s, 1 H), 8.21 (s, 1 H), 8.16 (d, J = 10.5 Hz, 1 H), 7.91 (d, J = 10.5 Hz, 1 H), 7.78 (ddd, J = 10.5, 8.8, 1.8 Hz, 1 H), 7.62 (ddd, J = 10.1, 8.6, 1.4 Hz, 1 H), 7.44–7.35 (m, 3 H), 7.33–7.30 (m, 2 H), 1.83 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 191.00, 155.12, 147.24, 138.93, 137.50, 136.59, 129.96, 129.26, 129.11, 129.04, 128.56, 127.83, 127.56, 127.48, 127.33, 115.00, 24.06. DEPT-135 (125 MHz, CDCl₃): δ = 137.50, 129.95, 129.23, 129.07, 128.55, 127.81, 127.54, 127.32, 24.06. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₇NNaO₂: 326.1151; found: 326.1160. 6ab(keto) Pale-yellow viscous liquid; yield: 21.3 mg (14%). IR (ATR): 2920.90, 1697.04, 1660.75, 1409.25, 1194.27, 697.85 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.16 (s, 1 H), 7.91 (d, J = 10.5 Hz, 1 H), 7.83 (dd, J = 10.0, 1.5 Hz, 1 H), 7.70–7.64 (m, 3 H), 7.51–7.43 (m, 4 H), 5.75 (s, 1 H), 2.23 (s, 3 H), 2.16 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 197.25, 161.50, 156.55, 145.54, 139.37, 135.85, 129.91, 129.41, 128.43, 128.13, 127.52, 127.48, 126.33, 125.56, 117.66, 30.72, 21.19. DEPT-135 (125 MHz, CDCl₃): δ = 139.37, 129.90, 129.40, 128.42, 128.12, 127.51, 127.46, 125.56, 117.65, 30.72, 21.18. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₇NNaO₂: 326.1151; found: 326.1152. 3-Phenylquinolines 7a, 7d–g; General Procedure Step I: A solution of the isocyanide 2a was prepared as described above. Step II: The appropriate β-keto esters or β-keto amide 3 (1.5 mmol, 3 equiv) was added to a suspension of Cs₂CO₃ (488.7 mg, 1.5 mmol, 3 equiv) in DMF (2.0 mL) at rt, and the mixture was stirred for 10 min. The freshly prepared solution of 2a in DMF (2.0 mL) was then added at rt, and the mixture was stirred at rt for 6 h. The mixture was diluted with H₂O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated (aspirator). The crude product was purified by column chromatography (silica gel). Methyl 3-Oxo-2-(3-phenylquinolin-2-yl)butanoate (7ac) Prepared by the reaction of methyl acetoacetate (3c) (0.16 mL, 1.50 mmol) with freshly prepared 1-isocyano-2-(phenylethynyl)benzene (2a), and purified by column chromatography [silica gel, acetone–hexane (1:9)] and repeated column chromatography [silica gel, EtOAc–hexane (1:19)] as a yellow oil; yield: 70.4 mg (44%). IR (ATR): 2921.74, 1715.97, 1410.51, 1196.71, 1122.45, 757.66 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.19 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.85 (dd, J = 8.0, 0.8 Hz, 1 H), 7.70 (ddd, J = 8.4, 7.0, 1.4 Hz, 1 H), 7.60–7.58 (m, 2 H), 7.55–7.42 (m, 4 H), 5.42 (s, 1 H), 3.66 (s, 3 H), 2.47 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.07, 167.42, 156.47, 145.65, 135.74, 130.00, 129.49, 129.13, 128.47, 128.17, 127.87, 127.73, 127.47, 126.88, 126.14, 102.63, 51.08, 18.38. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₁₇NNaO₃: 342.1101; found: 342.1103.
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