Metal-free Br?nsted acid catalyzed transfer hydrogenation - New organocatalytic reduction of quinolines

Article abstract of DOI:10.1055/s-2006-939706

The first metal-free Br?nsted acid catalyzed hydrogenation of quinolines using Hantzsch dihydropyridine as the hydrogen source has been developed. This, so far unprecedented organocatalytic reduction of heteroaromatic compounds provides a variety of differently substituted 1,2,3,4-tetrahydroquinolines in excellent yields under mild reaction conditions using a remarkably low amount of Br?nsted acid catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939706

LETTER
1071
Metal-Free Brønsted Acid Catalyzed Transfer Hydrogenation –
New Organocatalytic Reduction of Quinolines
New
Organocatalytic
R
a
eduction
o
g
f
Q
uinolinesnus Rueping,* Thomas Theissmann, Andrey P. Antonchick
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical Biology, Johann-Wolfgang Goethe University Frankfurtam
Main, Marie-Curie-Str. 11, 60439 Frankfurt, Germany
Fax +49(69)79829248; E-mail: M.Rueping@chemie.uni-frankfurt.de
Received 1 February 2006
fer hydrogenation of heteroaromatic compounds but
Abstract: The first metal-free Brønsted acid catalyzed hydrogena-
would additionally be a mild method to tetrahydroquino-
line derivatives (Scheme 2).
tion of quinolines using Hantzsch dihydropyridine as the hydrogen
source has been developed. This, so far unprecedented organocata-
lytic reduction of heteroaromatic compounds provides a variety of
O
O
differently substituted 1,2,3,4-tetrahydroquinolines in excellent
yields under mild reaction conditions using a remarkably low
amount of Brønsted acid catalyst.
EtO
OEt
R2
R2
N
2
R1
H
R1
Key words: Brønsted acid, Hantzsch dihydropyridine, transfer
hydrogenation, organocatalysis, reduction, 1,2,3,4-tetrahydro-
quinoline
Brønsted acid 1
N
H
N
6
5
Scheme 2 Brønsted acid catalyzed transfer hydrogenation of quino-
lines
1,2,3,4-Tetrahydroquinoline derivatives have attracted
considerable interest due to their importance as synthetic
intermediates, pesticides and pharmaceutical products
with a broad range of physiological and biological proper-
ties.1,2 Although a number of different processes for the
synthesis of tetrahydroquinolines exist, the most direct ap-
proach is the regioselective reduction of quinolines, which
includes heterogeneous or homogeneous metal-catalyzed
hydrogenations, hydroborations and transfer hydrogena-
tions.3,4 However, to date no metal-free transfer hydro-
genation of quinolines has been reported.
Hence, initial experiments focused on the examination of
various Brønsted acids in the transfer hydrogenation of 2-
methyl quinoline (Table 1).
From this survey we found that several Brønsted acids
catalyze the reduction of quinoline 5a using Hantzsch
dihydropyridine5–7 2 as the hydrogen source. In each
instance the reaction was carried out with 2.4 equivalents
Table 1 Survey of Brønsted Acid Catalysts for the Transfer Hydro-
genation of 2-Methylquinoline
Recently, we established the first Brønsted acid catalyzed
transfer hydrogenation of ketimines using a Hantzsch
dihydropyridine as hydrogen source (Scheme 1).5 In this
reaction the imine 3 is activated by catalytic protonation
through Brønsted acid 1, and subsequent hydrogen trans-
fer from the dihydropyridine 2 results in the desired amine
4. Additionally, we were able to demonstrate a catalytic
enantioselective procedure of this transformation by
employing a chiral Brønsted acid as catalyst.6
O
O
EtO
OEt
N
2
H
N
H
N
Brønsted acid 1
5a
6a
Entrya
Brønsted acid 1
CSA
1 (mol%) Time (h) Yield (%)b
1
2
3
4
5
6
7
5
10
10
5
12
12
12
12
18
18
18
79
91
89
90
95
–
This observation encouraged us to extend our procedure
to the organocatalytic hydrogenation of quinolines. This
would not only be the first example of a metal-free trans-
TFA
HBF4
DPPc
O
O
DPP
1
EtO
OEt
PG
R2
PG
R2
N
HN
N
2
MS 4 Å
None
–
∗
H
R1
R1
Brønsted acid 1
3
4
–
–
a All reactions were performed using quinoline 5a (0.28 mmol) and
dihydropyridine 2 (0.67 mmol) at 60 °C in benzene using 1–10 mol%
of acid catalyst.
Scheme 1 Brønsted acid catalyzed transfer hydrogenation of imines
b Isolated yields of tetrahydroquinoline 6a after chromatography.
c Diphenyl phosphate (DPP).
SYNLETT 2006, No. 7, pp 1071–1074
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939706; Art ID: G04706ST
© Georg Thieme Verlag Stuttgart · New York

1072
M. Rueping et al.
LETTER
of 2 in benzene and 1–10 mol% of catalyst 1. Diphenyl Further exploration concentrated on solvent, temperature,
phosphate (DPP), in agreement with the hydrogenation of catalyst loading and concentration. Best results were ob-
imines, appeared to be the best catalyst for this trans- tained when the reaction was carried out with 1 mol%
formation showing the highest rate and best isolated DPP, at 60 °C in benzene using 2.4 equivalents of dihy-
yields of the 1,2,3,4-tetrahydroquinoline 6a (Table 1).
dropyridine 2. Performing the reaction at lower tempera-
Table 2 Brønsted Acid Catalyzed Transfer Hydrogenation of Quinolines
O
O
R2
EtO
OEt
R2
N
H
R1
2
R1
N
H
N
DPP (1 mol%)
5
6
Entrya
Structure
Yield (%)b
85
Entrya
Structure
Yield (%)b
75
6a
6k
OMe
OMe
N
N
H
H
6b
6c
92
88
6l
90
88
N
H
N
H
6m
Ph
F
N
H
N
H
6d
6e
93
95
6n
6o
93
94
N
H
n-Bu
N
H
Ph
N
H
Cl
N
H
6f
92
6p
91
Ph
Cl
N
H
Ph
N
H
6g
6h
92
95
6q
6r
86
91
N
H
Ph
N
H
Ph
n-Pr
F
N
H
N
H
Ph
6i
6j
95
90
6s
6t
82
93
Br
N
H
N
H
CO2Me
O
N
H
N
Ph
H
a All reactions were performed using quinoline 5 Hantzsch dihydropyridine 2 (2.4 quiv) and 1 mol% DPP at 60 °C in 2 mL benzene for 12 h.
b Isolated yield after column chromatography.
Synlett 2006, No. 7, 1071–1074 © Thieme Stuttgart · New York

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.
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Synlett 2006, No. 7, 1071–1074 © Thieme Stuttgart · New York

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M. Rueping et al.
LETTER
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Synlett 2006, No. 7, 1071–1074 © Thieme Stuttgart · New York