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Synlett 2011(15): 2237-2241  
DOI: 10.1055/s-0030-1261182
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Studies of Functionally Substituted Enamines: A New, One-Step Method for the Formation of Tetrahydroquinolinone and Nicotinonitrile Derivatives

Moustafa Sherief Moustafa, Saleh Mohammed Al-Mousawi*, Mohamed Hilmy Elnagdi*
Department of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 12613, Safat 13060, Kuwait
Fax: +96524816482; e-Mail: salehalmousawi@hotmail.com; e-Mail: shelmy1941@yahoo.com;
Further Information

Publication History

Received 19 May 2011
Publication Date:
12 August 2011 (online)

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Abstract

Novel rearrangement reactions leading to the formation of 2-piperidinyl-tetrahydroquinolinones were observed to occur ­in reactions of enaminonitrile with the 1,3-cyclohexanedione derivatives. In contrast, 2-phenyl-3-(piperidin-1-yl)acrylonitrile was observed to react with 5,5-dimethyl-1,3-cyclohexanedione to yield 7,7-di­methyl-3-phenyl-7,8-dihydroquinoline-2,5(1H,6H)-dione. While not participating in reaction with 5,5-dimethyl-1,3-cyclohexanedione, 2-benzoyl-3-(dimethylamino)acrylonitrile reacted with 3-oxo-3-phenylpropanenitrile to yield 2-benzoyl-4-[hydroxy(phenyl)­-methylene]pent-2-enedinitrile and 5-benzoyl-6-hydroxy-2-phenyl­nicotinonitrile. The structure of 2-benzoyl-4-[hydroxy(phenyl)methylene]pent-2-enedinitrile along with other substances prepared in this effort were determined by X-ray crystallographic analysis.

Key words

enamines - quinolinones - Michael addition - enamino ketones - tetrahydroquinolindione

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CCDC 811998 contains the supplementary crystallographic data for compound 11a. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

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CCDC 822858 contains the supplementary crystallographic data for compound 11c. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

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Procedure for the Synthesis of 11a-c Separate solutions of 3-(piperidin-1-yl)acrylonitrile (1a) or 3-morpholinoacrylonitrile (1b, 0.01 mol) and dimedone (2a) or 1,3-cyclohexanedione (0.01 mol) in EtOH (15 mL) were treated with piperidine (5 drops). The reaction mixture was stirred at reflux for 3-4 h [reaction progress monitored by using TLC with EtOAc-PE (1:1) as eluent]. The solid, obtained by pouring the reaction mixture into H2O, was collected by filtration and crystallized from EtOH to give the product as colorless crystals. 7,7-Dimethyl-2-(piperidin-1-yl)-7,8-dihydroquinolin-5-(6 H )-one (11a)
Yield 97%; mp 145-147 ˚C. Anal. Calcd for C16H22N2O (258.36): C, 74.38; H, 8.58; N, 10.84. Found: C, 74.46; H, 8.58; N; 10.75. IR (KBr): 1653 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 0.99 (s, 6 H, 2 CH3), 1.53-1.63 (m, 6 H, pip-H), 2.34 (s, 2 H, CH2), 2.70 (s, 2 H, CH2), 3.67 (br, 2 H, pip-H), 6.73 (d, 1 H, J = 8 Hz, CH), 7.82 (d, 1 H, J = 8 Hz, CH). ¹³C NMR (100 MHz, DMSO): δ = 194.95 (CO), 162.73, 159.52, 135.24, 116.20, 104.58, 51.07, 46.11, 44.97 (2 C), 32.48, 27.93 (2 C), 25.29 (2 C), 24.19. MS: m/z (%) = 258 (100) [M+], 229 (90), 215 (45), 203 (40), 175 (55), 145 (10), 119 (10), 91 (15), 84 (35).
2-(Piperidin-1-yl)-7,8-dihydroquinolin-5(6 H )-one (11b) Yield 95%; mp 70-72 ˚C. Anal. Calcd for C14H18N2O (230.31): C, 73.01; H, 7.88; N, 12.16. Found: C, 73.21; H, 7.77; N; 12.32. IR (KBr): 1660 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 1.51-1.55 (m, 4 H, 2 CH2), 1.63-1.65 (m, 2 H, CH2), 1.97-2.00 (m, 2 H, CH2), 2.44-2.47 (m, 2 H, CH2), 2.79-2.82 (m, 2 H, CH2), 3.67-3.69 (m, 2 H, CH2), 6.75 (d, 1 H, J = 12 Hz, CH), 7.83 (d, 1 H, J = 12 Hz, CH). ¹³C NMR (100 MHz, DMSO): δ = 195.13 (CO), 164.21, 159.08, 135.63, 117.28, 104.80, 54.86 (2 C), 37.59, 32.43, 25.25 (2 C), 24.17, 21.71. MS: m/z (%) = 230 (100) [M+], 215 (10), 201 (95), 187 (45), 147 (60), 117 (10), 91 (20), 84 (40).
7,7-Dimethyl-2-morpholino-7,8-dihydroquinolin-5(6 H )-one (11c) Yield 96%; mp 130-31 ˚C. Anal. Calcd for C15H20N2O2 (260.34): C, 69.20; H, 7.74; N, 10.76. Found: C, 69.26; H, 7.82; N; 10.75. IR (KBr): 1655 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 1.00 (s, 6 H, 2 CH3), 2.37 (s, 2 H, CH2), 2.74 (s, 2 H, CH2), 3.64-3.69 (m, 8 H, morpholin-H), 6.77 (d, 1 H, J = 8 Hz, CH), 7.88 (d, 1 H, J = 8 Hz, CH). ¹³C NMR (100 MHz, DMSO): δ = 195.23 (CO), 162.50, 159.88, 135.35, 117.17, 104.80, 65.86 (2 C), 51.06, 46.00, 44.32 (2 C), 32.48, 27.87 (2 C). MS: m/z (%) = 260 (65) [M+], 229 (100), 203 (75), 175 (45), 146 (15), 119 (10), 91 (15), 77 (5).

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Synthesis of 2-(Dimethylamino)-6-(4-hydroxy-6-methyl-2-oxo-2 H -pyran-3-yl)nicotinonitrile (17)
A solution of malononitrile (0.66 g, 0.01 mol) and 3-[3-(dimethylamino)acryloyl]-4-hydroxy-6-methyl-2H-pyran-2-one (13, 2.23 g, 0.01 mol) in EtOH (15 mL) was treated with piperidine (5 drops). The reaction mixture was stirred at reflux for 3-4 h [reaction progress monitored by using TLC with EtOAc-PE (1:1) as eluent]. The solid obtained by pouring the reaction mixtures into H2O was collected by filtration and crystallized from benzene to give yellow crystals; yield 50%; mp 275-76 ˚C. Anal. Calcd for C14H13N3O3 (271.28): C, 61.99; H, 4.83; N, 15.49. Found: C, 62.01; H, 4.89; N; 15.56. IR (KBr): 3429 (OH), 2209 (CN), 1698 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 2.09 (s, 6 H, 2 CH3), 2.19 (s, 3 H, CH3), 6.02 (br, 1 H, OH), 7.91 (d, 1 H, J = 8 Hz, CH), 8.11 (d, 1 H, J = 8 Hz, CH). ¹³C NMR (100 MHz, DMSO): δ = 206.57 (CO), 179.81, 164.13, 155.31, 147.55, 118.07, 108.23, 91.95, 87.03, 79.01, 40.79, 30.72 (2 C), 19.46. MS: m/z (%) = 271 (100) [M+], 242 (100), 228 (15), 186 (10), 172 (30), 158 (45), 144 (15), 117 (15), 90 (5), 85 (15), 69 (5).

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CCDC 821560 contains the supplementary crystallographic data for compound 17. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

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Synthesis of 7,7-Dimethyl-3-phenyl-7,8-dihydro-quinoline-2,5(1 H ,6 H )-dione (18) A solution of 2-phenyl-3-(piperidin-1-yl)acrylonitrile (1c, 2.12 g, 0.01 mol) and dimedone (2a, 1.40 g, 0.01 mol) in EtOH (15 mL) was treated with piperidine (5 drops). The reaction mixture was stirred at reflux for 3-4 h [reaction progress monitored by using TLC with EtOAc-PE (1:1) as eluent], and the solid, obtained by pouring the reaction mixture into H2O, was collected by filtration and crystallized from EtOH to give colorless crystals; yield 85%; mp 157-58 ˚C. Anal. Calcd for C17H17NO2 (267.33): C, 76.38; H, 6.41; N, 5.24. Found: C, 76.29; H, 6.42; N; 5.18. IR (KBr): 3450 (NH), 1672 (CO),16636 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 1.05 (s, 6 H, 2 CH3), 2.38 (s, 2 H, CH2), 2.75 (s, 2 H, CH2), 7.32-7.68 (m, 5 H, PhH), 7.88 (s, 1 H, CH), 12.36 (s, 1 H, NH, D2O exchangeable). ¹³C NMR (100 MHz, DMSO): δ = 206.54 (CO), 193.34 (CO), 162.09, 154.88, 135.83, 133.69, 128.38 (2 C), 128.13 (2 C), 111.88, 50.10, 32.72 (2 C), 30.70, 27.76 (2 C). MS: m/z (%) = 267 (100) [M+], 224 (5), 211 (40), 183 (20), 183 (20), 154 (25), 128 (20), 115 (10), 77 (10).

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CCDC 821559 contains the supplementary crystallographic data for compound 18. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

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Synthesis of 2-Benzoyl-4-[hydroxy(phenyl)methylene]-pent-2-enedinitrile (23)
A solution of 2-benzoyl-3-(dimethylamino)acrylonitrile (1d, 2.00 g, 0.01 mol) and 3-oxo-3-phenylpropanenitrile (19, 1.45 g, 0.01 mol) in EtOH (15 mL) was treated with piperidine (5 drops). The mixture was stirred at reflux for 20 h [reaction progress monitored by using TLC with EtOAc-PE (1:1) as eluent]. The solid, obtained by pouring the reaction mixture into H2O, was collected by filtration and crystallized from EtOH to give yellow crystals; yield 75%; mp 163-65 ˚C. Anal. Calcd for C19H12N2O2 (300.32): C, 75.99; H, 4.03; N, 9.33. Found: C, 76.02; H, 4.12; N; 9.42. IR (KBr): 3431 (OH), 2209 (CN), 2196 (CN), 1611 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 7.38-7.51 (m, 10 H, Ph-H), 8.02 (s, 1 H, CH), 8.21 (s, 1 H, OH). ¹³C NMR (100 MHz, DMSO): δ = 190.11 (CO), 152.56, 139.80, 130.27 (2 C), 128.27 (4 C), 127.80 (4 C), 118.65, 86.73, 83.26, 54.48, 54.44, 54.40. MS: m/z (%) = 300(70) [M+], 271 (30), 255 (10), 223 (30), 195 (5), 140 (10), 105 (50), 84 (100), 77 (30).

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Synthesis of 5-Benzoyl-6-hydroxy-2-phenylnico-tinonitrile (25)
A solution of 2-benzoyl-3-(dimethylamino)acrylonitrile (1d, 2.00 g, 0.01 mol), 3-oxo-3-phenylpropanenitrile (19, 1.45 g, 0.01 mol) and NH4OAc (1 g) in AcOH (15 mL) was stirred at reflux for 3-4 h [reaction progress monitored by using TLC with EtOAc-PE (1:1) as eluent]. The solid, obtained by pouring the reaction mixture into H2O, was collected by filtration and crystallized from EtOH to give colorless crystals; yield 70%; mp 272-74 ˚C. Anal. Calcd for C19H12N2O2 (300.32): C, 75.99; H, 4.03; N, 9.33. Found: C, 75.85; H, 4.09; N; 9.49. IR (KBr): 3448 (OH), 2220 (CN), 1657 (CO) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 7.50-7.97 (m, 10 H, PhH), 8.17 (br, 1 H, OH), 8.53 (s, 1 H, CH). ¹³C NMR (100 MHz, DMSO): δ = 168.76, 159.79, 158.16, 142.56, 138.52, 137.26, 131.22, 130.85, 130.28, 129.37 (2 C), 129.31 (2 C), 129.15 (2 C), 128.79 (2 C), 117.87, 104.85. MS: m/z (%) = 299 (100) [M - 1], 283 (25), 255 (35), 227 (15), 201 (5), 177 (5), 151 (10), 127 (10), 77 (15).

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CCDC 821551 contains the supplementary crystallographic data for compound 23. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.