Heteroannulation of 3-Bis(methylthio)acrolein with Aromatic Amines -
A Convenient Highly Regioselective Synthesis of 2-(Methylthio)quinolines and their Benzo/Hetero Fused Analogs - A Modified Skraup Quinoline Synthesis

Abstract

A simple and efficient synthesis of 2-(methylthio)quinolines and their condensed analogs has been developed through acid-induced cyclocondensation of their respective anilines or aromatic diamines with 3-bis(methylthio)acrolein. The 2-(methylthio) functionality in these quinolines could be either dethiomethylated or ­replaced by various nitrogen and carbon nucleophiles to afford 2-substituted quinolines.

heteroannulation - amines - regioselectivity - condensation - quinolines

References

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Reviews:

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10b Ila H. Junjappa H. Mohanta PK. Progress in Heterocyclic Chemistry   Vol. 13:  Gribble GW. Gilchrist TL. Pergamon; New York: 2001.  Chap. 1. p.1 

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11a Syam Kumar UK. Ila H. Junjappa H. Org. Lett.  2001,  3:  4193 

11b Panda K. Suresh JR. Ila H. Junjappa H. J. Org. Chem.  2003,  68:  3498 

11c Mahata PK. Syam Kumar UK. Sriram V. Tetrahedron  2003,  59:  2631 

12 Mahata PK. Barun O. Ila H. Junjappa H. Synlett  2000,  1345 

13 For our recent quinoline synthesis see: Mahata PK. Venkatesh C. Syam Kumar UK. Ila H. Junjappa H.
J. Org. Chem.  2003,  68:  3966 

14

All new compounds gave satisfactory spectral and analytical data.

15

General Procedure for the Synthesis of Substituted and Fused Quinolines 3a-e, 6, 8, 10: Method A: A solution of 3-bis(methylthio)acrolein (1, 2.0 mmol, 0.3 g) and the appropriate anilines (2.2 mmol) or aryldiamines (1.1 mmol) in glacial HOAc (30 mL) was heated under reflux for 8-10 h (monitored by TLC). It was then cooled, quenched with sat. NaHCO₃ solution, extracted with CHCl₃ (3 × 30 mL), the combined organic layer was washed with H₂O (50 mL) and dried over Na₂SO₄. Removal of solvent gave crude products, which were purified by column chromatography over silica gel using hexane-EtOAc (9:1) as eluent. Data for compound 3a: Yield 78%; light yellow solid; mp 43-44 °C; R_f = 0.4 (hexane-EtOAc, 9:1). IR (KBr): 2999, 2924, 1593 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.69 (s, 3 H, SMe), 3.94 (s, 3 H, OMe), 7.07 (dd, J = 2.4, 8.8 Hz, 1 H, ArH), 7.10 (d, J = 8.5 Hz, 1 H, ArH), 7.30 (d, J = 2.4 Hz, 1 H, ArH), 7.58 (d, J = 8.8 Hz, 1 H, ArH), 7.80 (d, J = 8.5 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 12.98, 55.45, 106.62, 117.74, 118.15, 120.73, 128.58, 134.89, 149.96, 160.17, 160.88. MS (EI): m/z (%) = 205 (100) [M⁺], 159 (42.8). Anal. Calcd for C₁₁H₁₁NOS (205.28): C, 64.36; H, 5.40; N, 6.82%. Found: C, 64.30; H, 5.45; N, 6.75%.
Data for compound 6: Yield 67%; white solid; mp 125-126 °C; R_f = 0.7 (hexane-EtOAc, 9:1). IR (KBr): 2919, 1611, 1593 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.77 (s, 3 H, SMe), 2.80 (s, 3 H, SMe), 7.36 (d, J = 8.5 Hz, 1 H, ArH), 7.44 (d, J = 8.5 Hz, 1 H, ArH), 7.83 (d, J = 9.0 Hz, 1 H, ArH), 7.93 (d, J = 8.2 Hz, 2 H, ArH), 9.25 (d, J = 8.5 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 13.17, 13.31, 120.42, 120.93, 122.47, 123.06, 125.77, 129.32, 132.43, 135.24, 145.41, 148.99, 159.80, 161.44. MS (EI): m/z (%) = 273 (100) [M⁺ + 1], 258 (10). Anal. Calcd for C₁₄H₁₂N₂S₂ (272.40): C, 61.73; H, 4.44; N, 10.28%. Found: C, 61.50; H, 4.35; N, 10.42%.
Data for compound 8: Yield 65%; white solid; mp 225-226 °C; R_f = 0.7 (hexane-EtOAc, 9:1). IR (KBr): 3748, 3621, 2924, 1579 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.86 (s, 6 H, 2 × SMe), 7.41 (d, J = 8.6 Hz, 2 H, ArH), 7.87 (d, J = 8.8 Hz, 2 H, ArH), 8.03 (d, J = 8.6 Hz, 2 H, ArH), 9.25 (d, J = 8.8 Hz, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 13.26, 121.25, 121.77, 124.56, 125.66, 131.18, 135.49, 145.45, 158.96. MS (EI): m/z (%) = 323 (40) [M⁺ + 1], 273 (10). Anal. Calcd for C₁₈H₁₄N₂S₂ (322.46): C, 67.05; H, 4.38; N, 8.69%. Found: C, 67.10; H, 4.25; N, 8.42%.

16 Kar GK. Karmakar AC. Makur A. Ray JK. Heterocycles  1995,  41:  911 

17

General Procedure for the Synthesis of Substituted and Fused Quinolines 3f-m, 12: Method B: To a solution of 3-bis(methylthio)acrolein (1, 2.0 mmol, 0.3 g) and respective anilines 2f-m (4.4 mmol) or o-phenylenediamine (11, 3.0 mmol) in CH₂Cl₂ (20 mL), TFA (6.0 mmol, 0.46 mL) was added at r.t. and the reaction mixture was left for stirring at the same temperature for 5-6 h (monitored by TLC). It was then quenched with sat. NaHCO₃ solution (2 × 25 mL), extracted with CH₂Cl₂ (2 × 25 mL), dried over Na₂SO₄.The organic layer was distilled off under reduced pressure to give crude iminoenamines which were used as such for further reactions whereas few of the iminoenamines were purified by column chromatography over silica gel using hexane-EtOAc (9:1) as eluent for characterization. The crude iminoenamine (5 mmol) obtained was dissolved in PPA (20 mL) and the reaction mixture was heated with stirring at 90 °C for 6 h (monitored by TLC). It was then cooled, poured into ice-cold H₂O (50 mL), extracted with CHCl₃ (3 × 50 mL), the combined organic layer was washed with H₂O (3 × 50 mL) and dried over Na₂SO₄.The solvent was distilled off to give crude product, which was purified by column chromatography over silica gel using hexane-EtOAc (9:1) as eluent.
Data for compound 3m: Yield 60%; yellow liquid; R_f = 0.8 (hexane-EtOAc, 8:2). IR (KBr): 2928, 2359, 1723, 1618 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.66 (s, 3 H, SMe), 3.96 (s, 3 H, OMe), 6.93 (dd, J = 1.4, 8.0 Hz, 1 H, ArH), 7.15-7.26 (m, 3 H, ArH), 7.76 (d, J = 8.8 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 12.91, 56.12, 108.80, 119.57, 120.90, 125.15, 126.82, 135.26, 139.94, 154.19, 159.04. MS (EI): m/z (%) = 206 (100) [M⁺ + 1], 191 (20). Anal. Calcd for C₁₁H₁₁NOS (205.28): C, 64.36; H, 5.40; N, 6.82%. Found: C, 64.58; H, 5.32; N, 6.60%.

18 Zirnstein MA. Staab HA. Angew. Chem., Int. Ed. Engl.  1987,  26:  460 

19

Data for compound 12: Yield 60%; yellow solid; mp 78 °C; R_f = 0.7 (hexane-EtOAc, 8:2). IR (KBr): 3371, 2925, 1628, 1597 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.51 (s, 6 H, 2 × SMe), 7.25 (d, J = 8.3 Hz, 2 H, ArH), 7.52 (s, 2 H, ArH), 7.70 (d, J = 8.3 Hz, 2 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.71, 126.21, 127.20, 127.38, 129.90, 133.87, 135.40. MS (EI): m/z (%) = 273 (70) [M⁺ + 1], 225 (30). Anal. Calcd for C₁₄H₁₂N₂S₂ (272.40): C, 61.73; H, 4.44; N, 10.28%. Found: C, 61.58; H, 4.32; N, 10.40%.

20

Data for compound 15a: Yield 88%; white solid; mp 160-161 °C; R_f = 0.5 (hexane-EtOAc, 8:2). IR (KBr): 3015, 2927, 1620, 1302 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 3.26 (s, 3 H, OMe), 3.89 (s, 3 H, SO₂Me), 7.26 (dd, J = 2.7, 9.0 Hz, 1 H, ArH), 7.40 (d, J = 2.7 Hz, 1 H, ArH), 7.71 (d, J = 9.0 Hz, 1 H, ArH), 7.89 (d, J = 8.3 Hz, 1 H, ArH), 8.24 (d, J = 8.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 39.99, 55.68, 107.38, 114.16, 122.89, 124.68, 128.72, 138.25, 149.02, 157.51, 161.93. MS (EI): m/z (%) = 238 (100) [M⁺ + 1], 206 (30). Anal. Calcd for C₁₁H₁₁NO₃S (237.28): C, 55.68; H, 4.67; N, 5.90%. Found: C, 55.60 H, 4.75; N, 5.85%.

21

Data for compound 17: Yield 80%; white low melting point solid; R_f = 0.6 (hexane-EtOAc, 8:2). IR (KBr): 3232, 2998, 2930, 1613 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 3.88 (s, 3 H, OMe), 4.69 (d, J = 5.1 Hz, 2 H, CH₂), 5.16 (br s, 1 H, NH), 6.47 (d, J = 8.6 Hz, 1 H, ArH), 6.86 (dd, J = 2.4, 8.6 Hz, 1 H, ArH), 7.08 (d, J = 2.4 Hz, 1 H, ArH), 7.27 (t, J = 7.0 Hz, 1 H, ArH), 7.33 (t, J = 7.0 Hz, 2 H, ArH), 7.39 (d, J = 7.0 Hz, 2 H, ArH), 7.45 (d, J = 8.8 Hz, 1 H, ArH), 7.72 (d, J = 8.8 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 45.89, 55.33, 105.40, 108.35, 114.23, 118.22, 127.28, 127.63, 128.44, 128.63, 137.21, 139.21, 149.48, 157.20, 161.10. MS (EI): m/z (%) = 265 (100) [M⁺ + 1]. Anal. Calcd for C₁₇H₁₆N₂O (264.33): C, 77.25; H, 6.10; N, 10.60%. Found: C, 77.15; H, 6.20; N, 10.65%.