Reactions of Heterocyclic Ketene Aminals with Baylis-Hillman Acetates: A Novel Synthesis of Tetrahydropyridine-Fused 1,3-Diazaheterocycles

Muhammad Yaqub; Chu-Yi Yu; Yue-Mei Jia; Zhi-Tang Huang

doi:10.1055/s-2008-1072788

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Synlett 2008(9): 1357-1360
DOI: 10.1055/s-2008-1072788

LETTER

Reactions of Heterocyclic Ketene Aminals with Baylis-Hillman Acetates: A Novel Synthesis of Tetrahydropyridine-Fused 1,3-Diazaheterocycles

Muhammad Yaqub, Chu-Yi Yu*, Yue-Mei Jia, Zhi-Tang Huang
Beijing National Laboratory for Molecular Science (BNLMS), Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax: +86(10)62610366; e-Mail: yucy@iccas.ac.cn;

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Publication History

Received 1 February 2008
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

References and Notes

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7

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.