Iridium-catalyzed synthesis of quinolines from 2-aminobenzyl alcohols with secondary alcohols

Article abstract of DOI:10.1134/S1070363216020298

The quinoline derivatives were synthesized from 2-aminobenzyl alcohols and secondary alcohols by the direct one-step synthesis using the iridium complexes as catalyst. This efficient and easy method is suitable for all kinds of substituted quinolines.

Full text of DOI:10.1134/S1070363216020298

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 2, pp. 376–379. © Pleiades Publishing, Ltd., 2016.
Iridium-Catalyzed Synthesis of Quinolines
from 2-Aminobenzyl Alcohols with Secondary Alcohols1
X. Yu, W. Yao, W. Hu, and D. Wang
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education,
School of Chemical and Material Engineering, Jiangnan University, Jiangsu Province, Wuxi, 214122 China
e-mail: wwangdawei@163.com
Received August 25, 2015
Abstract—The quinoline derivatives were synthesized from 2-aminobenzyl alcohols and secondary alcohols
by the direct one-step synthesis using the iridium complexes as catalyst. This efficient and easy method is
suitable for all kinds of substituted quinolines.
Keywords: iridium, quinolines, secondary alcohols, 2-aminobenzyl alcohols
DOI: 10.1134/S1070363216020298
INTRODUCTION
iridium through carbon, nitrogen, and phosphine atoms
[20, 21]. These complexes, especially the system
benzoxazolyl Ir(III)–CNP complex/AgNTf2, showed
good catalytic activities in the C–N and C–C coupling
reactions via the borrowing hydrogen strategy (Scheme 2)
[22]. Herein, we found that these complexes could also
The quinoline derivatives are typical biologically
active N-heterocyclic compounds widely used in
practice as building block for the synthesis of organic
intermediates and molecules and in the modern
pharmaceutical and agrochemical industries [1–5]. A
straightforward and widely used method of their
synthesis is the Friedländer annulation reaction.
However, most of these reactions proceed at high
temperatures and under harsh conditions [6–9]. In
2003, Cho et al. [10] showed that quinoline derivatives
can be synthesized by ruthenium-catalyzed coupling of
2-aminobenzyl alcohol and secondary alcohols by the
borrowing hydrogen strategy [11–15]. In 2006, Ramón
and Yus also reported RuCl2(DMSO)4-catalyzed
alkylation of secondary alcohols with primary alcohols
to synthesize quinolines [16]. Later, they renewed this
methodology for the synthesis of polysubstituted
quinolines [17]. In 2013, Srimani et al. [18] described
the synthesis of pyridines and quinolines by coupling
of γ-amino-alcohols with secondary alcohols with
liberation of hydrogen in the presence of ruthenium
pincer complexes as catalyst. In 2014, Ruch et al. [19]
found that iridium can also catalyze this transformation
to synthesize quinoline derivatives in moderate to good
yield.
Scheme 1. Several benzoxazolyl Ir(III)-CNP complexes.
Cl
Ir
PR3
O
N
2
1a−1d
R = Ph (a), p-tolyl (b), p-methoxphenyl (c), n-butyl (d).
Scheme 2. Ir-catalyzed coupling of 2-aminobenzyl alcohols
and secondary alcohols.
OH
OH
+
NH2
Recently, we developed several iridium complexes
with the tridentate ligand CNP, which binds with
1, base
solvent
1 The text was submitted by the authors in English.
N
Ph
376

IRIDIUM-CATALYZED SYNTHESIS OF QUINOLINES
Table 1. Screening of reaction conditionsa
377
OH
1/AgNTf2, base
OH
+
Ph2CO, solvent
NH2
N
Ph
4a
3a
Yieldb, % Run no.
2a
Run no. Iridium
Base
Solvent
Toluene
THF
Iridium
1d
Base
Solvent
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Yieldb, %
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
68
61
54
61
66
72
70
68
9
Cs2CO3
NEt3
74
<5
15
8
10
11
12
13
14
15
16
1a
1,4-dioxane
Benzene
DCM
1a
K2CO3
Na2CO3
KOH
1a
1a
47
68
70
<5
Xylene
Xylene
Xylene
1a
t-BuONa
t-BuOK
–
1a
1a
a
Conditions: 2a (1.0 mmol), 3a (1.1 mmol), 1 (1.0 mol %), AgNTf2 (1.2 mol %), base (2.0 mmol), Ph2CO (3.0 mmol), solvent (5 mL),
150°C or reflux, 16 h. b Isolated yield.
be used in the synthesis of quinoline derivatives with
moderate to good yield.
most cases, moderate to good yields were obtained
under the above optimal conditions. The change in the
substituent group on secondary alcohols did not
virtually affect the reaction. The best yield of up to
81% was obtained with the methoxy group in 2-
aminobenzyl alcohols.
RESULTS AND DISCUSSION
Because the system Ir(III)–CNP complex/AgNTf2
has good catalytic activity in the C–N and C–C
coupling reactions [22], we used it to synthesize
heterocyclic compounds. 2-aminobenzyl alcohol and
1-phenylethanol were selected as the model substrates
for the optimization of catalytic activity. The reaction
proceeded in the presence of cesium carbonate as base
and benzophenone as hydride scavenger.
EXPERIMENTAL
Typical procedure for the synthesis of 4a. To a
solution of 2d (1 mol %) in xylene (5 mL), AgNTf2
(1.2 mol %) was added and the mixture was stirred for
5 min. Then, 2-aminobenzyl alcohol (1 mmol), 1-phenyl-
ethanol (1.1 mmol), cesium carbonate (2.0 mmol), and
benzophenone (3 mmol) were added. The mixture was
heated under reflux for 16 h and then cooled to room
temperature. The resulting solution was directly purified
by column chromatography with petroleum ether–ethyl
acetate (5 : 1) as eluent to give the desired product.
The experiment showed that the desired product
was separated in 68% yield (Table 1, run no. 1).
Results obtained in screening the reaction conditions
are summarized in Table 1. It was found in the
experiment that the best solvent is xylene. For all
iridium complexes the results were the same, whereas
complex 1d was somewhat better than the other
complexes. Next, it was found that cesium carbonate is
superior to other bases by yield.
2-Phenylquinoline (4a). 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm: 8.11 m (4H), 7.76 m (2H),
7.62 t (1H, J = 7.8 Hz), 7.51–7.29 m (4H).
With the best reaction conditions in hand, we
studied the reaction scope of all kinds of 2-amino-
benzyl alcohols and secondary alcohols. In general, the
experiments showed that the reaction could carry on
smoothly. The results are summarized in Table 2. In
2-(p-Tolyl)quinoline (4b). 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm: 8.11 t (2H, J = 7.9 Hz),
7.98 d (2H, J = 7.8 Hz), 7.75 d.d (2H, J = 16.2,
8.1 Hz), 7.64 t (1H, J = 7.9 Hz), 7.43 t (1H, J =
7.8 Hz), 7.26 d (2H, J = 8.0 Hz), 2.34 s (3H).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

378
X. YU et al.
Table 2. Substrate expansion experimentsa,b
OH
1d/AgNTf2, Cs2CO3
Ph2CO, xylene
OH
+
Ar
N
Ar
NH2
R
R
2
3
4
Comp.
Formula
no.
Comp.
no.
Yield, %
74
Formula
N
Yield, %
73
MeO
MeO
4a
4f
N
4b
63
4g
62
N
N
N
4c
71
67
4h
4i
53
81
N
4d
MeO
MeO
N
N
CF3
Cl
4e
64
N
a
Conditions: 2 (1.0 mmol), 3 (1.1 mmol), 1d (1.0 mol %), AgNTf2 (1.2 mol %), base (2.0 mmol), Ph2CO (3.0 mmol), xylene (5 mL),
150°C, 16 h. b Isolated yield based on 2.
1
1,2,3,4-Tetrahydroacridine (4c). H NMR spec-
7.75 d (1H, J = 8.0 Hz), 7.68 s (1H), 7.53 d (1H, J =
trum (400 MHz, CDCl3), δ, ppm: 7.91 d (1H, J =
7.8 Hz), 7.71 s (1H), 7.62 d (1H, J = 8.0 Hz), 7.53 t
(1H, J = 7.8 Hz), 7.35 t (1H, J = 7.9 Hz), 3.04 t (2H,
J = 8.0 Hz), 2.89 t (2H, J = 7.8 Hz), 1.93–1.86 m (2H),
1.83–1.78 m (2H).
8.0 Hz), 7.41 m (3H).
1
6,7-Dimethoxy-2-(p-tolyl)quinoline (4f). H NMR
spectrum (400 MHz, CDCl3), δ, ppm: 7.96–7.86 m
(3H), 7.59 d (1H, J = 7.8 Hz), 7.41 s (1H), 7.21 d (2H,
J = 8.0 Hz), 6.92 s (1H), 3.95 s (3H), 3.91 s (3H), 2.33
s (3H).
1
2-[4-(Trifluoromethyl)phenyl]quinoline (4d). H
NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.25–8.07
m (4H), 7.76 t (2H, J = 7.8 Hz), 7.67 t (3H, J =
7.8 Hz), 7.47 t (1H, J = 8.1 Hz).
1
4-Methyl-2-phenylquinoline (4g). H NMR spec-
trum (400 MHz, CDCl3), δ, ppm: 8.09 d.d (3H, J =
12.0, 8.0 Hz), 7.93 d (1H, J = 7.8 Hz), 7.63 d (2H, J =
8.0 Hz), 7.51–7.37 m (4H), 2.68 s (3H).
1
6-Chloro-2-phenylquinoline (4e). H NMR spec-
trum (400 MHz, CDCl3), δ, ppm: 8.12–7.96 m (4H),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016

IRIDIUM-CATALYZED SYNTHESIS OF QUINOLINES
379
1
Commun., 2006, p. 583.
5,6-Dihydrobenzo[c]acridine (4h). H NMR spec-
trum (400 MHz, CDCl3), δ, ppm: 8.49 d (1H, J =
7.8 Hz), 8.04 d (1H, J = 8.0 Hz), 7.78 s (1H), 7.62 d
(1H, J = 7.8 Hz), 7.54 t (1H, J = 8.1 Hz), 7.39–7.24 m
(3H), 7.19–7.14 m (1H), 3.03–2.94 m (2H), 2.93–2.85
m (2H).
5. Yamashkin, S.A. and Oreshkina, E.A., J. Heterocycl.
Chem., 2006, vol. 42, p. 701.
6. Taguchi, K., Sakaguchi, S., and Ishii, Y., Tetrahedron
Lett., 2005, vol. 46, p. 4539.
7. Cho, C.S., Ren, W.X., and Shim, S.C., Tetrahedron
Lett., 2006, vol. 47, p. 6781.
8. Lin, Y., Wu J., Shen, Y., and Zhan, X., J. Food Sci.
Biotechnol., 2012, vol. 31, p. 211.
1
6,7-Dimethoxy-2-phenylquinoline (4i). H NMR
spectrum (400 MHz, CDCl3), δ, ppm: 8.03 d (2H, J =
8.0 Hz), 7.90 d (1H, J = 7.8 Hz), 7.61 d (1H, J =
7.9 Hz), 7.41 t (3H, J = 7.8 Hz), 7.33 t (1H, J = 7.8 Hz,
6.93 s (1H), 3.96 s (3H), 3.91 s (3H).
9. Sun, T., Hu, D., Chen, C., Jiang, Z., and Xie, J., J. Food
Sci. Biotechnol., 2012, vol. 11, p. 1198.
10. Cho, C.C., Kim, B.T., Choi, H.-J., Kim, T.-J., and
Shim, S.C., Tetrahedron, 2003, vol. 59, p. 7997.
11. Colby, D.A., Bergman, R.G., and Ellman, J.A., Chem.
Rev., 2010, vol. 110, p. 624.
12. Mkhalid, I.A.I., Barnard, J.H., Marder, T.B., Murphy, J.M.,
and Hartwig, J.F., Chem. Rev., 2010, vol. 110, p. 890.
13. Beletskaya, I.P. and Ananikov, V.P., Chem. Rev., 2011,
CONCLUSIONS
In conclusion, an efficient method for synthesizing
quinolines from 2-aminobenzyl alcohols and
secondary alcohols was developed. The reaction
proceeds actively in the presence of the system Ir(III)–
CNP complex/AgNTf2 with moderate to good yield.
This methodology provides alternative method to
prepare quinoline derivatives.
vol. 111, p. 1596.
14. Li, B.J. and Shi, Z.J., Chem. Soc. Rev., 2012, vol. 41,
p. 5588.
15. Gulevich, A.V., Dudnik, A.S., Chernyak, N., and Ge-
ACKNOWLEDGMENTS
vorgyan, V., Chem. Rev., 2013, vol. 113, p. 3084.
16. Martínez, R., Ramón, D. J., and Yus, M., Tetrahedron,
2003, vol. 62, p. 8982.
17. Martínez, R., Ramón, D. J., and Yus, M., J. Org. Chem.,
2008, vol. 73, p. 9778.
18. Srimani, D., Ben-David, Y., and Milstein, D., Chem.
Commun., 2013, vol. 49, p. 6632.
The study was financially supported by the National
Natural Science Foundation of China (project 21307042),
the Natural Science Foundation of Jiangsu Province
(project no. BK20130124), and by the China Postdoctoral
Science Foundation (project no. 2014M550262).
19. Ruch, S., Irrgang, T., and Kempe, R., Chem. Eur. J.,
REFERENCES
2014, vol. 20, p. 13279.
20. Wang, D., Zhao, K., Yu, X., Miao, H., and Ding, Y.,
1. Doyle, M. E., and Egan, J. M., Pharmacol. Rev., 2003,
vol. 55, p.105.
RSC Adv., 2014, vol. 4, p. 42924.
21. Wang, D., Ge, B., Li, L., Shan, J., and Ding, Y., J. Org.
Chem., 2014, vol. 79, p. 8607.
2. Benigni, R., Chem. Rev., 2005, vol. 105, p. 1767.
3. Michael, J.P., Nat. Prod. Rep., 2005, vol. 22, p. 627.
4. Ila, H., Baron, O., Wagner, A.J., and Knochel, P., Chem.
22. Wang, D., Zhao, K., Xu, C., Miao, H., and Ding, Y.,
ACS Catal., 2014, vol. 4, p. 3910.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 2 2016