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DOI: 10.1055/s-2004-815400
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
Publication History
Publication Date:
12 January 2004 (online)
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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.
Key words
heteroannulation - amines - regioselectivity - condensation - quinolines
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1a
Michael JP. Nat. Prod. Rep. 1997, 14: 605 -
1b
Balasubramaniam M.Keay JG. In Comprehensive Heterocyclic Chemistry II Vol. 5:Katritzky AR.Rees CW.Scriven EFV. Pergamon Press; Oxford: 1996. Chap. 5.06. p.245 -
2a
Spicer JA.Gamage SA.Atwell GJ.Finlay GJ.Baguley BC.Denny WA. J. Med. Chem. 1997, 40: 1919 -
2b
Lyon MA.Lawrence S.William DJ.Jackson YA. J. Chem. Soc., Perkin Trans. 1 1999, 437 - 3
Jones G. In Comprehensive Heterocyclic Chemistry II Vol. 5:Katritzky AR.Rees CW.Scriven EFV. Pergamon Press; Oxford: 1996. Chap. 5.05. p.167 -
4a
Tokuyama H.Sato M.Ueda T.Fukuyama T. Heterocycles 2001, 54: 105 -
4b
Manske RHF.Kulka M. Org. React. 1953, 7: 59 -
5a
Matsugi M.Tabusa F.Minamikawa J-i. Tetrahedron Lett. 2000, 41: 8523 -
5b
Ranu BC.Hajra A.Jana U. Tetrahedron Lett. 2000, 41: 531 -
6a
Schmittel M.Ammon H. Eur. J. Org. Chem. 1998, 785 -
6b
Elderfield RC. In The Chemistry of Heterocyclic Compounds Vol. 4:Elderfield RC. John Wiley and Sons; Chichester: 1952. p.45 -
7a
Ubeda JI.Villacampa M.Avendano C. Synlett 1997, 285 ; and references cited therein -
7b
Chang C.-C.Yan S.-J. Org. React. 1982, 28: 37 - 7c Hsiao Y., Rivera N. R., Yasuda N., Hughes D. L., Reider P. J.; Org. Lett.; 2001, 3: 1101; and references cited therein
- 8
Jones G. In Chemistry of Heterocyclic Compounds Vol. 32:Weissberger A.Taylor EC. Wiley-Interscience; London: 1977. p.181 - For related methods see:
-
9a
Tom NJ.Ruel EM. Synthesis 2001, 1351 -
9b
Baraznenok IL.Nenajdenko VG.Balenkova ES. Eur. J. Org. Chem. 1999, 937 -
9c
Schlosser M.Keller H.Sumida S-i.Yang J. Tetrahedron Lett. 1997, 38: 8523 -
9d
Charpentier P.Lobregat V.Levacher V.Dupas G.Queguiner G.Bourguignon J. Tetrahedron Lett. 1998, 39: 4013 -
9e
Benoit R.Dupas G.Bourguignon J.Queguiner G. Synthesis 1987, 1124 - Reviews:
-
10a
Junjappa H.Ila H.Asokan CV. Tetrahedron 1990, 46: 5423 -
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 -
10c
Dieter RK. Tetrahedron 1986, 42: 3029 -
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 - 16
Kar GK.Karmakar AC.Makur A.Ray JK. Heterocycles 1995, 41: 911 - 18
Zirnstein MA.Staab HA. Angew. Chem., Int. Ed. Engl. 1987, 26: 460
References
All new compounds gave satisfactory spectral and analytical data.
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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; Rf = 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; Rf = 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; Rf = 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%.
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; Rf = 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%.
Data for compound 12: Yield 60%; yellow solid; mp 78 °C; Rf = 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%.
20Data for compound 15a: Yield 88%; white solid; mp 160-161 °C; Rf = 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%.
21Data for compound 17: Yield 80%; white low melting point solid; Rf = 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%.