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Synlett 2022; 33(14): 1411-1418
DOI: 10.1055/a-1784-2513
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Organic Chemistry in Thailand

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

Kannika La-ongthong
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Natthapat Sawekteeratana
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Jasarin Klaysuk
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Darunee Soorukram
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Pawaret Leowanawat
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Vichai Reutrakul 
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
,
Sucheewin Krobthong
b   Center for Neuroscience and Central Instrument Facility, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
,
Patompon Wongtrakoongate
c   Center for Neuroscience and Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
,
Chutima Kuhakarn  ∗
a   Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
› Author AffiliationsWe thank the Thailand Research Fund (TRF), National Research Council of Thailand (NRCT), Mahidol University (BRG6180005 and IRN58W0005), and the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher Education, Science, Research and Innovation for financial support. We also thank the Institute for the Promotion of Teaching Science and Technology and Science Achievement Scholarship of Thailand (SAST) for financial support through student scholarship to K.L. P.W. was supported by the Office of National Higher Education Science Research and Innovation Policy Council by Program Management Unit for Human Resources and Institutional Development, Research and Innovation (PMU-B; B05F640047)
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1784-2513.
  • Supporting Information


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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  • References and Notes

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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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