PAPER
Synthesis of 8-Substituted 5,6,7,8-Tetrahydroquinolines
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HRMS (CI, isobutene): m/z calcd for C16H19N2: 239.1548 (M+ + H).
Found: 239.1545.
13C NMR (75 MHz): = 15.5, 18.7, 28.2, 28.6, 47.4, 121.9, 132.2,
137.1, 147.1, 156.5.
Anal. Calcd. for C16H18N2: C, 80.63, H, 7.61, N, 11.75. Found: C,
80.47, H, 7.57, N, 11.75.
MS (EI): m/z (%) = 179 (M+, 0.4), 133 (100), 132 (40).
HRMS (EI): m/z calcd for C10H13NS: 179.0769 (M+). Found:
179.0763.
(S)-S-5,6,7,8-Tetrahydroquinolin-8-ylacetate (8)
Rf 0.30 (30% EtOAc in hexane); [ ]D22 –32 (c = 0.18, CHCl3).
Anal. Calcd for C10H13NS: C, 66.99; H, 7.31; N, 7.81. Found: C,
66.25; H, 7.35; N, 7.78.
IR (neat): 1686 cm–1 (C=O).
Chiral-packed column and separation conditions: Daicel AD-RH,
eluent; 30% MeCN in H2O; flow rate; 1.0 mL/min, retention time
for (S)-11a; 12.8 min [(R)-11a; 15.2 min].
1H NMR (300 MHz): = 1.85–2.00 (m, 2 H), 2.10 (m, 1 H), 2.30
(m, 1 H), 2.36 (s, 3 H, CH3), 2.70–2.90 (m, 2 H), 4.99 (t, J = 4.8 Hz,
1 H, H-8), 7.07 (dd, 7.7, 4.8 Hz, 1 H, H-3), 7.38 (d, J = 7.7 Hz, 1 H,
H-4), 8.44 (dd, J = 4.8, 1.1 Hz, 1 H, H-2).
13C NMR (75 MHz): = 19.8, 28.3, 30.4, 30.6, 45.6, 122.1, 133.3,
137.1, 147.7, 154.1, 194.7.
MS (EI): m/z (%) = 207 (M+, 35), 165 (46), 164 (72), 132 (100).
HRMS (EI): m/z calcd for C11H13NOS: 207.0718 (M+). Found:
Methyl (S)-5,6,7,8-Tetrahydroquinolin-8-ylthioacetate (11b)
Rf 0.28 (30% EtOAc in hexane); [ ]D26 –73 (c = 0.70, CHCl3).
IR (neat): 1738 cm–1 (C=O).
1H NMR (300 MHz): = 1.82 (m, 1 H), 2.03–2.23 (m, 3 H), 2.69–
2.90 (m, 2 H), 3.45 (d, J = 15.2 Hz, 1 H, CHH), 3.71 (d, J = 15.2 Hz,
1 H, CHH), 3.74 (s, 3 H, CH3), 4.35 (t, J = 4.4 Hz, 1 H, H-8 ), 7.07
(dd, J = 7.7, 4.6 Hz, 1 H, H-3 ), 7.38 (br d, J = 7.5 Hz, 1 H, H-4 ),
8.38 (br d, J = 4.8 Hz, 1 H, H-2 ).
13C NMR (75 MHz): = 19.0, 28.2, 29.0, 33.7, 45.9, 52.4, 122.1,
131.9, 137.2, 146.9, 156.4, 171.1.
207.0719.
Anal. Calcd for C11H13NOS: C, 63.73; H, 6.32; N, 6.76. Found: C,
63.49; H, 6.51; N, 6.64.
Chiral-packed column and separation conditions: Daicel AD-RH,
eluent; 30% MeCN in H2O; flow rate; 1.0 mL/min, retention time
for (S)-8; 17.1 min [(R)-8; 13.8 min].
MS (EI): m/z (%) = 237 (M+, 2), 206 (4), 164 (5), 133 (100), 132
(40).
Dimethyl (R)-5,6,7,8-Tetrahydroquinolin-8-ylmalonate (9)
Rf 0.53 (20% EtOAc in hexane); [ ]D22 +71 (c = 2.00, CHCl3).
IR (neat): 1735 cm–1 (C=O).
1H NMR (300 MHz): = 1.65–2.10 (m, 4 H), 2.70–2.90 (m, 2 H),
3.65 (m, 1 H, H-8 ), 3.67 (s, 3 H, CH3), 3.78 (s, 3 H, CH3), 4.38 (d,
J = 6.2 Hz, 1 H, 2-H), 7.01 (dd, J = 7.7, 4.8 Hz, 1 H, H-3 ), 7.34 (d,
J = 7.7 Hz, 1 H, H-4 ), 8.29 (d, J = 4.8 Hz, 1 H, H-2 ).
13C NMR (75 MHz): = 21.8, 25.9, 28.8, 41.4, 52.0, 52.3, 54.6,
121.3, 132.5, 136.5, 146.3, 156.5, 169.2, 170.0.
HRMS (EI): m/z calcd for C12H15NO2S: 237.0823 (M+). Found:
237.0821.
Anal. Calcd for C12H15NO2S: C, 60.73; H, 6.37; N, 5.90. Found: C,
60.51; H, 6.66; N, 5.95.
Chiral-packed column and separation conditions: Daicel OJ, eluent;
10% 2-propanol in hexane; flow rate; 1.5 mL/min, retention time
for (S)-11b; 9.3 min [(R)-11b; 10.3 min].
Acknowledgements
MS (EI): m/z (%) = 263 (M+, 22), 232 (11), 204 (100), 172 (55), 132
(16).
The authors are grateful to Professor Y. Ito for his encouragement
and valuable discussions. This work was financially supported by
the Grant-in-Aid for Scientific Research on Priority Areas (A) from
the Ministry of Education, Science, Sports and Culture, Japan, and
a Special Grant for Cooperative Research administered by the Japan
Private School Promotion Foundation.
HRMS (EI) m/z calcd for C14H17NO4: 263.1157 (M+). Found:
263.1152.
Anal. Calcd for C14H17NO4: C, 63.87, H, 6.51, N, 5.32. Found: C,
63.57, H, 6.45, N, 5.40.
Chiral-packed column and separation conditions: Daicel AD-RH,
eluent; 40% MeCN in H2O; flow rate; 1.0 mL/min, retention time
for (R)-8; 7.8 min [(S)-8; 6.5 min].
References
(1) Comprehensive Heterocyclic Chemistry, Vol. 2; Boulton, A.
J.; Mckillop, A., Eds.; Pergamon: Oxford, 1984.
8-Alkylthio-5,6,7,8-tetrahydroquinolines 11
To a solution of (S)-8 (15 mg, 0.07 mmol) in MeOH (1 mL) was
added K2CO3 (53 mg, 0.39 mmol) at 0 °C. The mixture was stirred
at r.t. for 15 min and recooled to 0 °C. To the mixture was added
MeI (5 equiv) or methyl bromoacetate (5 equiv) at the same temper-
ature and the mixture was stirred at r.t. for an additional 30 min.
H2O was added and the mixture was extracted with EtOAc. The ex-
tract was washed with brine and dried (MgSO4). After the solvent
was removed, the residue was purified by flash column chromatog-
raphy on silica gel (15% EtOAc in hexane) to give the correspond-
ing sulfides 11a in 78% yield and 11b in 85% yield as an oil.
(2) (a) Kees, K. L.; Smith, T. M.; McCaleb, M. L.; Prozialeck,
D. H.; Cheeseman, R. S.; Christos, T. E.; Patt, W. C.;
Steiner, K. E. J. Med. Chem. 1992, 35, 944. (b) Beattie, D.
E.; Crossley, R.; Curran, A. C. W.; Hill, D. G.; Lawrence, A.
E. J. Med. Chem. 1977, 20, 718.
(3) (a) Ghera, E.; David, Y. B.; Rapoport, H. J. Org. Chem.
1981, 46, 2059. (b) Uchida, M.; Morita, S.; Chihiro, M.;
Kanbe, T.; Yamasaki, K.; Yabuuchi, Y.; Nakagawa, K.
Chem. Pharm. Bull. 1989, 37, 1517. (c) Yamada, S.; Goto,
T.; Yamaguchi, T.; Aihara, K.; Kogi, K.; Narita, S. Chem.
Pharm. Bull. 1995, 43, 421.
(S)-8-Methylthio-5,6,7,8-tetrahydroquinoline (11a)
(4) (a) Zymalkowski, F.; Kothari, M. Arch. Pharm. (Weinheim.
Ger.) 1970, 303, 667. (b) Beattie, D. E.; Crossley, R.;
Curran, A. C. W.; Dixon, G. T.; Hill, D. G.; Lawrence, A. E.;
Shepherd, R. G. J. Med. Chem. 1977, 20, 714.
Rf 0.52 (30% EtOAc in hexane); [ ]D22 +5 (c = 0.40, CHCl3).
1H NMR (300 MHz): = 2.00–2.15 (m, 4 H), 2.17 (s, 3 H, SCH3),
2.67–2.77 (m, 2 H), 4.20 (t, J = 3.7 Hz, 1 H, H-8), 6.99 (dd, 7.7, 4.6
Hz, 1 H, H-3), 7.30 (d, J = 7.0 Hz, 1 H, H-4), 8.34 (dd, J = 4.8, 0.9
Hz, 1 H, H-2).
(c) Dammertz, W.; Reimann, E. Arch. Pharm. (Weinheim,
Ger.) 1980, 313, 826. (d) Calhoun, W.; Carlson, R. P.;
Crossley, R.; Datko, L. J.; Dietrich, S.; Heatherington, K.;
Synthesis 2002, No. 5, 625–630 ISSN 0039-7881 © Thieme Stuttgart · New York