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DOI: 10.1055/s-2008-1072788
Reactions of Heterocyclic Ketene Aminals with Baylis-Hillman Acetates: A Novel Synthesis of Tetrahydropyridine-Fused 1,3-Diazaheterocycles
Publication History
Publication Date:
07 May 2008 (online)
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Abstract
A novel method for the synthesis of tetrahydropyridine-fused 1,3-diazaheterocycles was developed via the reaction of heterocyclic ketene aminals (HKAs) with Baylis-Hillman acetates (B-H acetates).
Key words
synthesis - tetrahydropyridine-fused 1,3-diazaheterocycles - heterocyclic ketene aminals - Baylis-Hillman acetates
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References and Notes
The crystal structure of 5a has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number: CCDC 674283.
8
General Method for the Synthesis of 5a, 6, and 7
Baylis-Hillman acetate 3 or 4 (0.47 mmol) and HKAs 1 or 2 (0.47 mmol) were stirred in CH2Cl2 (20 mL) at 0 °C for 1 h and then stirred at r.t. for further 6 h. Solvents were evaporated in vacuo and the residue was passed through a short silica gel chromatographic column, eluting with EtOAc-PE (1:1) to afford the desired products 5a, 6, or 7. When the reaction was carried out in THF or DMF at r.t., as mentioned in the main text, compound 5b was isolated together with 5a.
Compound 5a: light yellow solid; mp 194-195 °C. 1H NMR (300 MHz, CDCl3): δ = 2.03 (m, 2 H), 2.60 (dd, J = 16.08, 3.82 Hz, 1 H), 3.05 (ddd, J = 16.11, 3.77, 1.91 Hz, 1 H), 3.25-3.37 (m, 4 H), 4.51 (m, 1 H), 5.06 (s, 1 H), 7.26-7.43 (m, 10 H, Ar), 12.48 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.88, 24.84, 37.99, 46.57, 63.22, 79.44, 82.65, 126.44, 126.55, 127.88, 128.08, 128.94, 129.50, 137.00, 142.75, 156.95, 186.88 (C=O). FT-IR (KBr): 3050, 2861, 1590, 1558, 1451, 1409, 1325, 1242, 701 cm-1. ESI-MS:
m/z = 363 [M+]. ESI-HRMS: m/z calcd for C21H21N3O3 [M+]: 363.1583; found: 363.1588.
Compound 5b: light yellow solid; mp 196-197 °C. 1H NMR (300 MHz, CDCl3): δ = 2.02 (m, 2 H), 3.14 (dd, J = 14.06, 3.31 Hz, 1 H), 3.24-3.42 (m, 4 H), 3.05 (dt, J = 14.07, 1.80 Hz, 1 H), 4.50 (m, 2 H), 6.84-7.41 (m, 10 H), 12.29 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.85, 37.76, 43.58, 46.11, 47.30, 82.26, 82.41, 125.78, 127.25, 127.49, 127.69, 127.73, 128.90, 142.35, 142.58, 156.75, 188.17 (C=O). IR (KBr): 3053, 2933, 1585, 1513, 1451, 1411, 1321, 1187, 698 cm-1. ESI-MS: m/z 363 [M+]. ESI-HRMS: m/z calcd for C21H21N3O3 [M+]: 363.1583; found: 363.1587.
Compound 6a: light yellow solid; mp 168-169 °C. 1H NMR (300 MHz, CDCl3): δ = 2.90 (dd, J = 15.51, 4.02 Hz, 1 H), 3.23 (dd, J = 15.53, 5.00 Hz, 1 H), 3.49-3.75 (m, 4 H), 4.87 (dd, J = 8.63, 3.95 Hz, 1 H), 5.14 (d, J = 3.31 Hz, 1 H), 6.35 (s, 2 H, furan ring), 7.27-7.42 (m, 6 H, Ph and furan ring), 9.39 (br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 26.37, 42.34, 47.58, 54.33, 78.85, 81.27, 109.48, 110.71, 126.92, 128.02, 128.74, 141.55, 143.73, 148.76, 156.48, 187.01 (C=O). IR (KBr): 3288, 2887, 1604, 1540, 1523, 1478, 1406, 1335, 1293, 1155, 1005, 735, 702 cm-1. ESI-MS:
m/z = 339 [M+]. HRMS (EI): m/z calcd for C18H17N3O4: 339.1219 [M+]; found: 339.1222 [M+].
Compound 6b: light yellow solid; mp 166-167 °C. 1H NMR (300 MHz, CDCl3): δ = 2.88 (dd, J = 15.52, 3.79 Hz, 1 H), 3.22 (ddd, J = 15.51, 4.81, 1.02 Hz, 1 H), 3.49-3.82 (m, 4 H), 4.85 (dd, J = 6.34, 3.76 Hz, 1 H), 5.16 (d, J = 2.96 Hz, 1 H), 6.37-6.40 (m, 2 H, furan ring), 7.32 (s, 4 H, Ph), 7.44 (s, 1 H, furan ring), 9.37 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 26.15, 42.35, 47.65, 54.29, 78.67, 81.10, 109.45, 110.79, 128.25, 128.43, 134.57, 139.99, 143.78, 148.71, 159.88, 187.55 (C=O). IR (KBr): 3286, 2888, 1604, 1549, 1523, 1479, 1409, 1335, 1293, 1086, 1002, 760 cm-1. ESI-MS: m/z = 373 [M+]. HRMS (EI): m/z calcd for C18H16N3O4Cl [M+]: 373.0829; found: 373.0834.
Compound 6c: light yellow solid; mp 145-146 °C. 1H NMR (300 MHz, CDCl3): δ = 2.89 (dd, J = 15.51, 3.95 Hz, 1 H), 3.24 (ddd, J = 15.52, 4.94, 1.24 Hz, 1 H), 3.51-3.78 (m, 4 H), 4.86 (dd, J = 7.60, 4.74 Hz, 1 H), 5.16 (d, J = 2.78 Hz, 1 H), 6.39 (m, 2 H, furan ring), 7.03 (t, J = 8.79 Hz, 2 H), 7.38 (dd, J = 8.76, 5.55 Hz, 2 H), 7.43 (dd, J = 1.62, 0.96 Hz, 1 H, furan ring), 9.37 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 26.31, 42.32, 47.63, 54.30, 78.60, 81.17, 109.43, 110.76, 114.89 (d, J
C-F = 21.31 Hz), 128.99 (d, J
C-F = 8.33 Hz), 137.78 (d, J
C-F = 3.23 Hz), 143.73, 148.77, 159.87, 162.88 (d, J
C-F = 246.15 Hz), 187.55 (C=O). IR (KBr): 3288, 2889, 1599, 1550, 1524, 1479, 1411, 1335, 1293, 1153, 1004, 764, 738 cm-1. ESI-MS: m/z = 357 [M+]. HRMS (EI): m/z calcd for C18H16N3O4F [M+]: 357.1125; found: 357.1129.
Compound 6d: light yellow solid; mp 134-135 °C. 1H NMR (300 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3), 2.92 (dd, J = 15.44, 4.09 Hz, 1 H), 3.28 (dd, J = 15.45, 5.12 Hz, 1 H), 3.54 (m, 2 H), 3.69 (m, 2 H), 4.82 (dd, J = 9.06, 3.97 Hz, 1 H), 5.13 (d, J = 3.29 Hz, 1 H), 6.38 (s, 2 H, furan ring), 7.25 (d, J = 7.80 Hz, 2 H, Ar), 7.29 (d, J = 7.98 Hz, 2 H, Ar), 7.43 (s, 1 H, furan ring), 9.40 (br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 21.35, 26.61, 42.34, 47.58, 54.41, 78.86, 81.35, 109.51, 110.76, 126.97, 128.68, 128.68, 138.74, 143.72, 148.82, 159.78, 187.11 (C=O). IR (KBr): 3286, 2921, 1602, 1550, 1520, 1478, 1409, 1334, 1266, 1172, 1004, 757 cm-1. ESI-MS: m/z = 353 [M+]. HRMS (EI): m/z calcd for C19H19N3O4 [M+]: 353.1376; found: 353.1379.
Compound 7a: light yellow solid; mp 184-185 °C. 1H NMR (300 MHz, CDCl3): δ = 2.00-2.07 (m, 2 H), 2.74 (dd, J = 15.92, 3.89 Hz, 1 H), 3.12 (ddd, J = 15.93, 3.96, 1.89 Hz, 1 H), 3.34-3.43 (m, 4 H), 4.70 (dd, J = 6.69, 3.92 Hz, 1 H), 5.09 (s, 1 H), 6.36-6.40 (m, 2 H, furan ring), 7.26-7.33 (m, 5 H, Ar), 7.42 (dd, J = 1.74, 0.78 Hz, 1 H, furan ring), 12.51 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.89, 25.96, 37.96, 46.59, 57.94, 79.39, 80.10, 109.07, 110.83, 126.53, 127.89, 128.05, 142.75, 143.61, 149.39, 156.48, 187.01 (C=O). IR (KBr): 3134, 2944, 1590, 1556, 1441, 1406, 1321, 1240, 1171, 732, 704 cm-1. ESI-MS: m/z = 353 [M+]. HRMS (EI): m/z calcd for C19H19N3O4 [M+]: 353.1376; found: 353.1379.
Compound 7b: light yellow solid; mp 164-165 °C. 1H NMR (300 MHz, CDCl3): δ = 2.04 (m, 2 H), 2.73 (dd, J = 15.90, 3.79 Hz, 1 H), 3.09 (ddd, J = 15.90, 3.78, 1.88 Hz, 1 H), 3.33-3.41 (m, 4 H), 4.71 (dd, J = 6.34, 3.76 Hz, 1 H), 5.11 (s, 1 H), 6.35-6.41 (m, 2 H, furan ring), 7.23 (d, J = 8.40 Hz, 2 H, Ar), 7.30 (d, J = 8.52 Hz, 2 H, Ar), 7.43 (m, 1 H, furan ring), 12.44 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.79, 25.81, 37.97, 46.60, 57.85, 79.45, 79.93, 109.11, 110.86, 128.15, 128.86, 133.68, 141.10, 143.70, 149.20, 156.50, 185.31 (C=O). IR (KBr): 3121, 2944, 1591, 1556, 1443, 1411, 1321, 1243, 1163, 840, 735 cm-1. ESI-MS:
m/z = 387 [M+]. HRMS (EI): m/z calcd for C19H18N3O4Cl [M+]: 387.0986; found: 387.0990.
Compound 7c: light yellow solid; mp 171-172 °C. 1H NMR (300 MHz, CDCl3): δ = 2.03 (m, 2 H), 2.74 (dd, J = 15.89, 3.88 Hz, 1 H), 3.11 (ddd, J = 15.89, 3.92, 1.91 Hz, 1 H), 3.36-3.43 (m, 4 H), 4.72 (dd, J = 6.54, 3.86 Hz, 1 H), 5.11 (s, 1 H), 6.36 (d, J = 3.28, 1 H), 6.40 (dd, J = 1.86, 3.82 Hz, 1 H), 7.00 (dd, J = 8.79, 6.66 Hz, 2 H, Ar), 7.28 (dd, J = 8.79, 5.43 Hz, 2 H, Ar), 7.43 (m, 1 H, furan ring), 12.47 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.82, 25.94, 37.96, 46.60, 57.89, 79.40, 80.01, 109.08, 110.83, 114.87 (d, J
C-F = 21.15 Hz), 128.57 (d, J
C-F = 8.18 Hz), 138.86 (d,
J
C-F = 3.3 Hz), 143.65, 149.29, 156.53, 162.38, (d, J
C-F = 244.95 Hz), 185.31 (C=O). IR (KBr): 3117, 2963, 1595, 1557, 1409, 1321, 1240, 1155, 740 cm-1. ESI-MS: m/z = 371 [M+]. HRMS (EI): m/z calcd for C19H18N3O4F [M+]: 371.1281; found: 371.1287.
Compound 7d: light yellow solid; mp 141-142 °C. 1H NMR (300 MHz, CDCl3): δ = 1.96-2.09 (m, 2 H), 2.33 (s, 3 H, CH3), 2.75 (dd, J = 15.89, 3.94 Hz, 1 H), 3.12 (ddd, J = 15.90, 3.99, 1.80 Hz, 1 H), 3.31-3.42 (m, 4 H), 4.71 (dd, J = 6.79, 3.93 Hz, 1 H), 5.08 (s, 1 H), 6.35-6.40 (m, 2 H, furan ring), 7.11 (d, J = 7.99 Hz, 2 H, Ar), 7.19 (d, J = 8.05 Hz, 2 H, Ar), 7.42 (d, J = 0.91 Hz, 1 H, furan ring), 12.51 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 20.88, 21.28, 26.10, 37.96, 46.59, 57.94, 79.52, 80.13, 109.09, 110.82, 126.61, 128.63, 137.69, 139.81, 143.60, 149.39, 156.48, 187.01 (C=O). IR (KBr): 3041, 2864, 1591, 1553, 1442, 1411, 1321, 1241, 1176, 737 cm-1. ESI-MS: m/z = 367 [M+]. HRMS (EI): m/z calcd for C20H21N3O4 [M+]: 367.1532; found: 367.1536.