LETTER
New Organocatalytic Reduction of Quinolines
1073
(4) (a) Ranu, B. C.; Jana, U.; Sarkar, A. Synth. Commun. 1998,
28, 485. (b) Srikrishna, A.; Reddy, T. J.; Viswajanani, R.
Tetrahedron 1996, 52, 1631. (c) Nose, A.; Kudo, T. Chem.
Pharm. Bull. 1984, 32, 2421.
(5) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T. Synlett
2005, 2367.
ture resulted in longer reaction times and application of
less amount of hydrogen source (1.2 equiv of 2) led to
lower yields of fully reduced tetrahydroquinolines. In the
latter case no formation of 3,4-dihydroquinoline was ob-
served indicating that the first step in the quinoline reduc-
tion, the 1,4-hydrogen addition, is the rate determining
step.
(6) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (b) For a subsequent
optimization of this procedure, see: Hoffmann, S.; Seayad,
A.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424; Angew.
Chem. 2005, 117, 7590. (c) Storer, R. I.; Carrera, D. E.; Ni,
Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
(7) For recent conjugate reductions of a,b-unsaturated
aldehydes, see: (a) Yang, J. W.; Hechavarria Fonseca, M. T.;
List, B. Angew. Chem. Int. Ed. 2004, 43, 6660; Angew.
Chem. 2004, 116, 6829. (b) Yang, J. W.; Hechavarria
Fonseca, M. T.; Vignola, N.; List, B. Angew. Chem. Int. Ed.
2005, 44, 108; Angew. Chem. 2005, 117, 110. (c) Ouellet,
S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 32. (d) Adolfsson, H. Angew. Chem. Int. Ed.
2005, 44, 3340; Angew. Chem. 2005, 117, 3404. (e) Lui, Z.;
Han, B.; Lui, Q.; Zhang, W.; Yang, L.; Lui, Z. L.; Yu, W.
Synlett 2005, 1579. (f) Garden, S. J.; Guimarães, C. R. W.;
Corréa, B.; Oliveira, C. A. F.; Pinto, A. C.; Alencastro, R. B.
J. Org. Chem. 2003, 68, 8815.
Having established the optimal reaction conditions, we
explored the scope of this new metal-free reduction of
quinolines. In general, differently substituted quinolines
with aryl-, heteroaryl- or alkyl- residues as well as func-
tional groups in 2-, 3- or 4-position can be reduced in good
to excellent isolated yields (Table 2).8
In summary, we have developed a new metal-free, effi-
cient, Brønsted acid9 catalyzed hydrogenation of quino-
lines with Hantzsch dihydropyridine as reducing agent.10
The mild reaction conditions, high yields, operational
simplicity and practicability, broad scope, functional
group tolerance, and remarkably low catalyst loading ren-
der this environment friendly process an attractive ap-
proach to multisubstituted 1,2,3,4-tetrahydroquinolines.
(8) General Procedure for the Brønsted Acid Catalyzed
Transfer Hydrogenation of Quinolines.
Acknowledgment
In a typical experiment quinoline (20 mg), diphenyl
phosphate (1 mol%) and Hantzsch dihydropyridine 2 (2.4
equiv) were suspended in benzene (2 mL) in a screw-capped
vial and flushed with argon. The resulting mixture was
allowed to stir at 60 °C for 12 h. The solvent was removed
under reduced pressure and purification of the crude product
by column chromatography on silica gel afforded the pure
1,2,3,4-tetrahydroquinoline. For representative examples,
see:
7-Chloro-1,2,3,4-tetrahydro-4-phenylquinoline (6o): yield
19.3 mg, 94%. IR (KBr): 3412, 3396, 2919, 1604, 1492,
1089, 700 cm–1. 1H NMR (250 MHz, CDCl3): d = 1.88–2.18
(m, 2 H, C-3H), 3.08–3.28 (m, 2 H, C-2H), 3.94 (br s, 1 H,
NH), 4.01 (t, J = 6.1 Hz, 1 H, C-4H), 6.39–6.48 (m, 2 H, Ar),
6.56–6.59 (m, 1 H, Ar), 6.99–7.07 (m, 2 H, Ar), 7.09–7.27
(m, 3 H, Ar). 13C NMR (250 MHz, CDCl3): d = 30.7, 38.9,
42.4, 113.4, 116.8, 121.7, 126.3, 128.4, 128.6, 131.5, 132.6,
145.9, 146.0. MS-ESI: m/z = 243.8 [M+], 245.8 [M+]. Anal.
Calcd for C15H14ClN (243.73): C, 73.92; H, 5.79; N, 5.75.
Found: C, 73.69; H, 5.54; N, 5.74.
1,2,3,4-Tetrahydro-4,7-diphenylquinoline (6p): yield 18.6
mg, 91%. IR (KBr): 3356, 3292, 3024, 2945, 2924, 1562,
1485, 1468, 1319, 758, 698 cm–1. 1H NMR (250 MHz,
CDCl3): d = 1.93–2.27 (m, 2 H, C-3H), 3.13–3.34 (m, 2 H,
C-2H), 3.96 (br s, 1 H, NH), 4.10 (t, J = 6.1 Hz, 1 H, C-4H),
6.69–6.73 (m, 3 H, Ar), 7.10–7.38 (m, 8 H, Ar), 7.45–7.50
(m, 2 H, Ar). 13C NMR (250 MHz, CDCl3): d = 31.2, 39.4,
42.7, 112.7, 116.2, 122.7, 126.2, 127.0, 128.4, 128.6, 128.7,
130.8, 140.4, 141.5, 145.2, 146.5. MS-ESI: m/z = 285.8
[M+]. Anal. Calcd for C21H19N (285.38): C, 88.38; H, 6.71;
N, 4.91. Found: C, 88.11; H, 6.80; N, 4.79.
Financial support by Degussa AG is gratefully acknowledged.
References and Notes
(1) For review, see: Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031.
(2) For examples, see: (a) Jacquemond-Collet, I.; Benoit-Vical,
F.; Mustofa; Valentin, A.; Stanislas, E.; Mallié, M.;
Fourasté, I. Planta Med. 2002, 68, 68. (b) Wallace, O. B.;
Lauwers, K. S.; Jones, S. A.; Dodge, J. A. Bioorg. Med.
Chem. Lett. 2003, 13, 1907. (c) Di Fabio, R.; Tranquillini,
E.; Bertani, B.; Alvaro, G.; Micheli, F.; Sabbatini, F.; Pizzi,
M. D.; Pentassuglia, G.; Pasquarello, A.; Messeri, T.;
Donati, D.; Ratti, E.; Arban, R.; Dal Forno, G.; Reggiani, A.;
Barnaby, R. J. Bioorg. Med. Chem. Lett. 2003, 13, 3863.
(d) Asolkar, R. N.; Schröder, D.; Heckmann, R.; Lang, S.;
Wagner-Döbler, I.; Laatsch, H. J. Antibiot. 2004, 57, 17.
(e) Lombardo, L. J.; Camuso, A.; Clark, J.; Fager, K.; Gullo-
Brown, J.; Hunt, J. T.; Inigo, I.; Kan, D.; Koplowitz, B.; Lee,
F.; McGlinchey, K.; Qian, L. G.; Ricca, C.; Rovnyak, G.;
Traeger, S.; Tokarski, J.; Williams, D. K.; Wu, L. I.; Zhao,
Y. F.; Manne, V.; Bhide, R. S. Bioorg. Med. Chem. Lett.
2005, 15, 1895. (f) Nallan, L.; Bauer, K. D.; Bendale, P.;
Rivas, K.; Yokoyama, K.; Horney, C. P.; Pendyala, P. R.;
Floyd, D.; Lombardo, L. J.; Williams, D. K.; Hamilton, A.;
Sebti, S.; Windsor, W. T.; Weber, P. C.; Buckner, F. S.;
Chakrabarti, D.; Gelb, M. H.; Van Voorhis, W. C. J. Med.
Chem. 2005, 48, 3704.
(3) For some recent publications, see: (a) Fujita, K.;
Yamaguchi, R. Synlett 2005, 560. (b) Lam, K. H.; Xu, L. J.;
Feng, L. C.; Fan, Q. H.; Lam, F. L.; Lo, W. H.; Chan, A. S.
C. Adv. Synth. Catal. 2005, 347, 1755. (c) Xu, L. K.; Lam,
K. H.; Ji, J. X.; Wu, J.; Fan, Q. H.; Lo, W. H.; Chan, A. S. C.
Chem. Commun. 2005, 1390. (d) Lu, S. M.; Han, X. W.;
Zhou, Y. G. Adv. Synth. Catal. 2004, 346, 909. (e) Yang, P.
Y.; Zhou, Y. G. Tetrahedron: Asymmetry 2004, 15, 1145.
(f) Wang, W. B.; Lu, S. M.; Yang, P. Y.; Han, X. W.; Zhou,
Y. G. J. Am. Chem. Soc. 2003, 125, 10536. (g) Michael, J.
P. Nat. Prod. Rep. 2005, 22, 627.
(9) For reviews on chiral Brønsted acid catalysis, see:
(a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(b) Pihko, P. M. Angew. Chem. Int. Ed. 2004, 43, 2062;
Angew. Chem. 2004, 116, 2110. (c) Bolm, C.; Rantanen, T.;
Schiffers, I.; Zani, L. Angew. Chem. Int. Ed. 2005, 44, 1758;
Angew. Chem. 2005, 117, 1788. For the use of chiral
phosphoric acid catalysts, see: (d) Akiyama, T.; Itoh, J.;
Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,
1566; Angew. Chem. 2004, 116, 1592. (e) Uraguchi, D.;
Synlett 2006, No. 7, 1071–1074 © Thieme Stuttgart · New York