B(C6F5)3-catalyzed metal-free hydrogenations of 2-quinolinecarboxylates

Article abstract of DOI:10.1016/j.tetlet.2018.02.057

A metal-free hydrogenation of 2-quinolinecarboxylates has been realized by using 5 mol% of B(C₆F₅)₃ as catalyst. A variety of tetrahydroquinolines were obtained in 57–99% yields. An attempt for the asymmetric hydrogenation with chiral boron Lewis acids generated from chiral dienes afforded very low ee's.

Full text of DOI:10.1016/j.tetlet.2018.02.057

Accepted Manuscript
B(C6F5)3-catalyzed metal-free hydrogenations of 2-quinolinecarboxylates
Caifang Han, E Zhang, Xiangqing Feng, Shoufeng Wang, Haifeng Du
PII:
S0040-4039(18)30262-4
https://doi.org/10.1016/j.tetlet.2018.02.057
TETL 49742
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
12 January 2018
22 February 2018
23 February 2018
Please cite this article as: Han, C., Zhang, E., Feng, X., Wang, S., Du, H., B(C6F5)3-catalyzed metal-free
hydrogenations of 2-quinolinecarboxylates, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.02.057
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B(C6F5)3-catalyzed metal-free
hydrogenations of 2-quinolinecarboxylates
Caifang Hana,b , E Zhangc , Xiangqing Fenga,d, * , Shoufeng Wangc, * and Haifeng Dua,d,
*

1
Tetrahedron Letters
B(C6F5)3-catalyzed metal-free hydrogenations of 2-quinolinecarboxylates
Caifang Hana,b , E Zhangc , Xiangqing Fenga,d, * , Shoufeng Wangc, * and Haifeng Dua,d,
*
aBeijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China.
bCollege of Chemistry and Material Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, P. R. China
cCollege of Chemistry and Chemical Engineering, Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, University of Jinan,
Jinan 250022, P. R. China.
d University of Chinese Academy of Sciences, Beijing 100049, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free hydrogenation of 2-quinolinecarboxylates has been realized by using 5 mol % of
B(C6F5)3 as catalyst. A variety of tetrahydroquinolines were obtained in 57−99% yields. An
attempt for the asymmetric hydrogenation with chiral boron Lewis acids generated from chiral
dienes afforded very low ee’s.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Quinolinecarboxylates
Metal-free hydrogenation
Tetrahydroquinolines
Frustrated Lewis pairs
Tetrahydroquinoline derivatives are ubiquitous building
blocks in both synthetic and medicinal chemistry.1 Catalytic
hydrogenations of quinolines undoubtedly belong to one of the
most efficient approaches to these important compounds.
Significant advances including the great success of asymmetric
hydrogenations have been achieved in the past several decades.2,3
Generally, simple aryl and alkyl substituents of quinolines were
well studied for the hydrogenation. In contrast, carboxyl ester
substituents (2-quinolinecarboxylates 1) have far less been
investigated, which could produce highly desirable cyclic α-
amino acid derivatives 2 (Scheme 1).4,5 For the heterogeneous
hydrogenation, only scattered examples with Pd/C or PtO2 as
catalysts have been reported. For example, McEachern and co-
development of novel FLP catalysts,8d,13 recently, we have
realized
a
highly enantioselective hydrogenation of
polysubstituted quinolines14 using chiral boron Lewis acid
catalysts derived in situ from chiral dienes15 and Piers’ borane16.
As a strong electron-withdrawing group, ester substituents are
likely to diminish the reactivity of 2-quinolinecarboxylates.
Herein, we wish to report our efforts on the metal-free
hydrogenation of 2-quinolinecarboxylates.
workers described
a PtO2-catalyzed hydrogenation of 2-
quinolinecarboxylates to give a mixture of products 2 and 2’.4d
Recently, Agbossou-Niedercorn and co-workers employed a
homogeneous iridium-catalyst for the asymmetric hydrogenation
of 2-quinolinecarboxylates 1 to give the corresponding 1,2,3,4-
tetrahydro-quinolines 2 in high yields and ee’s (Scheme 1).5a,b
Very recently, Beller and co-workers reported a cobalt-catalyzed
hydrogenation of methyl quinoline-2-carboxylate.5c Despite these
advances, to the best of our knowledge, metal-free
hydrogenations of 2-quinolinecarboxylates 1 have rarely been
reported.
Scheme 1. Catalytic hydrogenations of 2-quinolinecarboxylates.
With an extremely rapid growth in the past decade, the
chemistry of frustrated Lewis pairs (FLPs) has become the most
powerful approach for the metal-free hydrogenations.6-8 A broad
range of unsaturated compounds including quinolines were
suitable substrates for the FLP catalysis.7,8 As shown in Figure 1,
both alkyl and aryl substituted quinolines have been successfully
employed as substrates for the metal-free hydrogenation with
diverse types of catalysts.9-12 As our on-going interest in the
Figure 1. FLPs-catalyzed metal-free hydrogenations of quinolines.
 Corresponding author. Tel: +86-10-62652117; fax: +86-10-62554449; e-mail: fxq@iccas.ac.cn, chmˍwangsf@ujn.edu.cn,
haifengdu@iccas.ac.cn.

2
Tetrahedron
Table 2. Hydrogenation of 2-quinolinecarboxylatesa
The initial study on the hydrogenation of quinoline 1a was
carried out by using 10 mol % of B(C6F5)3 (3a) as catalyst under
H2 (40 atm) in toluene at 110 °C for 12 h (Scheme 2). This
reaction proceeded smoothly and cleanly to give the desired
1,2,3,4-tetrahydroquinoline 2a in a quantitative conversion. The
in situ generated boron Lewis acid 3b from Piers’ borane
HB(C6F5)2 and pentafluorostyrene exhibited a similar catalytic
activity, which provides a possibility for the asymmetric
hydrogenation with chiral diene-derived boron Lewis acids.
Entry
Substrate (1)
Product (2)
Yield b (%)
1
2
1a: R = H
2a
2b
2c
2d
2e
94
94
98
99
82
1b: R = Cl
1c: R = Br
1d: R = CH3
1e: R = OCH3
3
4c
5d
Scheme 2. Metal-free hydrogenation of 2-quinolinecarboxylate 1a.
6
7
1f: R = F
2f
2g
2h
2i
99
99
85
99
96
Further studies suggested that the hydrogenation can be
completed rapidly under a more mild reaction condition with 5
mol % of B(C6F5)3 at 50 °C (Table 1, entry 1 vs 2). A shorter
reaction time (1 h) only gave a 44% conversion (Table 1, entry 3).
Reducing the hydrogen pressure from 40 to 20 atm resulted in an
obvious lower conversion (Table 1, entry 4). Lowering the
temperature or the catalyst loading led a dramatic drop of
reactivity (Table 1, entries 5-7). Solvents had a large influence on
this reaction, and toluene was the optimal one (Table 1, entries 2
and 8−12).
1g: R = Cl
1h: R = Br
1i: R = I
8
9
10c
1j: R = CH3
2j
1k
1l
11
2k
2l
80
92
Table 1. Optimization of reaction conditionsa
12c
Entry
B(C6F5)3
(mol %)
Solvent
Temp.
(°C)
Time
(h)
Conv.
(%)b
1
2
10
5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
n-Hexane
CH2Cl2
C6H5Cl
THF
110
50
50
50
25
50
80
50
50
50
50
50
12
4
>99
>99
44
2m
57
13d
3
5
1
4c
5
4
63
1m
5
5
4
13
6
2.5
2.5
5
12
12
4
29
2m’
22
99
7
59
8
43
9
5
4
18
10
11
12
5
4
54
14e
1n
2n
5
4
n.r. d
n.r. d
5
Et2O
4
a With 1a (0.10 mmol) in a solvent (0.5 mL) with a 40 atm H2 pressure unless
15
16
2o
2p
<10% conv. f
<10% conv.
1o: R = 6-CF3
1p: R = 8-CF3
otherwise noted.
b Determined by crude 1H NMR.
c Under H2 (20 atm).
d No reaction.
a With 2-quinolinecarboxylates 1 (0.40 mmol) and B(C6F5)3 3a (0.02 mmol)
in toluene (1.5 mL) with H2 (40 atm) at 50 °C for 4 h unless otherwise noted.
b Determined by crude 1H NMR.
c At 80 °C for 8 h.
d 3a (10 mol %) at 110 °C for 12 h.
e At 110 °C for 12 h.
f Determined by crude 1H NMR.

3
15031-15070; (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669-1730; (c) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444-463; (d)
Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Chem. Rev. 2011,
111, 7157-7259.
A
variety of 2-quinolinecarboxylates 1a-m were next
subjected to the metal-free hydrogenation under the optimal
reaction conditions. As shown in Table 2, all these reactions went
well to give tetrahydroquinolines 2a-n in 57-99% yields. Both
steric and electronic factors of substituents on the 6 or 8-positions
2. For early examples, see: (a) Jardine, I.; McQuillin, F. J. Chem. Commun.
1970, 626-626; (b) Fish, R. H.; Thormodsen, A. D.; Cremer, G. A. J. Am.
Chem. Soc. 1982, 104, 5234-5237.
3. For selected reviews, see: (a) Glorius, F. Org. Biomol. Chem. 2005, 3,
4171-4175; (b) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357-1366; (c)
Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem. Rev. 2012,
112, 2557-2590.
of 2-quinolinecarboxylates
reactivities (Table 2, entries 1-10). Much harsher conditions were
needed for 2-quinoline-carboxylates bearing methyl or
1 are likely to influence the
1
methoxyl substituents to give satisfactory yields (Table 2, entries
4,5,10). Methyl 7,8-difluoroquinoline-2-carboxylate (1l) was also
an effective substrate for this reaction to give the corresponding
product in 92% yield (Table 2, entry 12). In contrast, 5,6,7,8-
tetrafluoroquinoline-2-carboxylate 1m was less reactive to afford
a mixture of dihydro- and tetrahydroquinolines 2m and 2m’
(Table 2, entry 13). Isopropyl quinolone-2-carboxylate 1n was a
suitable substrate to afford the desired product 2n in 99% yield
(Table 2, entry 14). However, 2-quinolinecarboxylates 1o-p with
trifluoromethyl groups were inert under the current reaction
conditions (Table 2, entries 15 and 16).
4. (a) Vecchietiti, V.; Clarke, G. D.; Colle, R.; Giardina, G.; Petrone, G.;
Sbacchi, M. J. Med. Chem. 1991, 34, 2624-2633; (b) Carling, R. W.;
Leeson, P. D.; Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood, S.;
Kemp, J. A.; Marshall, G. R. J. Med. Chem. 1992, 35, 1942-1953; (c)
Nicolaou, K. C.; Safina, B. S.; Funke, C.; Zak, M.; Zécri, F. J. Angew.
Chem., Int. Ed. 2002, 41, 1937-1940; (d) Skupinska, V. K. A.;
McEachern, E. J.; Skerlj, R. T.; Bridger, G. J. J. Org. Chem. 2002, 67,
7890-7893; (e) Kannenberg, A.; Rost, D.; Eibauer, S.; Tiede, S.;
Blechert, S. Angew. Chem., Int. Ed. 2011, 50, 3299-3302; (f) Chan, B.
K.; Ciufolini, M. A. J. Org. Chem. 2007, 72, 8489-8495.
5. (a) Maj, A. M.; Suisse, I.; Méliet, C.; Hardouin, C.; Agbossou-
Niedercorn, F. Tetrahedron Lett. 2012, 53, 4747-4750; (b) Maj, A. M.;
Suisse, I.; Hardouin, C.; Agbossou-Niedercorn, F. Tetrahedron 2013, 69,
9322-9328; (c) Adam, R.; Cabrero-Antonino, J. R.; Spannenberg, A.;
Junge, K.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed. 2017, 56,
3216-3220.
With these results in hand, we subsequently examined the
possibility for the asymmetric hydrogenation with chiral boron
Lewis acids as catalysts. Chiral diene 4-derived Lewis acid was
effective for the hydrogenation of 2-quinolinecarboxylate 1a to
give a quantitative conversion (Scheme 3). Unfortunately,
racemic product 2a was obtained. When Cy3P was subjected as a
Lewis base in this reaction, 2a was obtained in 82% conversion
with 14% ee. A vast number of chiral dienes and Lewis bases
were evaluated for this reaction. Regrettably, the
enantioselectivity cannot be further improved.
6. For a seminal work, see: Welch, G. C.; San Juan, R. R.; Masuda, J. D.;
Stephan, D. W. Science 2006, 314, 1124-1126.
7. For leading reviews, see: (a) Kenward, A. L.; Piers, W. E. Angew. Chem.,
Int. Ed. 2008, 47, 38-41; (b) Stephan, D. W.; Erker, G. Angew. Chem.,
Int. Ed. 2010, 49, 46-76; (c) Soós, T. Pure Appl. Chem. 2011, 83, 667-
675; (d) Paradies, J. Angew. Chem., Int. Ed. 2014, 53, 3552-3557; (e)
Stephan, D. W. Erker, G. Angew. Chem., Int. Ed. 2015, 54, 6400-6441;
(f) Stephan, D. W. J. Am. Chem. Soc. 2015, 137, 10018-10032; (g)
Stephan, D. W. Acc. Chem. Res. 2015, 48, 306-316; (h) Stephan, D. W.
Science 2016, 354, aaf7229-aaf7229.
8. For leading reviews on asymmetric hydrogenations, see: selected
examples, see: (a) Liu, Y.; Du, H. Huaxue Xuebao 2014, 72, 771-777; (b)
Feng, X.; Du, H. Tetrahedron Lett. 2014, 55, 6959-6964; (c) Shi, L.;
Zhou, Y.-G. ChemCatChem 2015, 7, 54-56; (d) Meng, W.; Feng, X.; Du,
H. Acc. Chem. Res. 2018, 51, 191-201.
9. (a) Geier, S. J.; Chase, P. A.; Stephan, D. W. Chem. Commun. 2010, 46,
4884-4886; (b) Farrell, J. M.; Hatnean, J. A.; Stephan, D. W. J. Am.
Chem. Soc. 2012, 134, 15728-15731; (c) Mahdi, T.; del Castillo, J. N.;
Stephan, D. W. Organometallics 2013, 32, 1971-1978.
10. Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.;
Repo, T. Adv. Synth. Catal. 2011, 353, 2093-2110.
11. Erős, G.; Nagy, K.; Mehdi, H.; Pápai, I.; Nagy, P.; Király, P.; Tárkányi,
G.; Soós, T. Chem. Eur. J. 2012, 18, 574-585.
12. Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C. M. Angew.
Chem., Int. Ed. 2015, 54, 2467-2471.
Scheme 3. Asymmetric hydrogenation of 2-quinolinecarboxylate 1a.
13. For selected examples, see: (a) Liu, Y.; Du, H. J. Am. Chem. Soc. 2013,
135, 12968-12971; (b) Liu, Y.; Du, H. J. Am. Chem. Soc. 2013, 135,
6810-6813; (c) Wei, S.; Du, H. J. Am. Chem. Soc. 2014, 136, 12261-
12264; (d) Zhang, Z.; Du, H. Angew. Chem., Int. Ed. 2015, 54, 623-626;
(e) Ren, X.; Du, H. J. Am. Chem. Soc. 2016, 138, 810-813.
14. (a) Zhang, Z.; Du, H. Org. Lett. 2015, 17, 2816-2819; (b) Zhang, Z.; Du,
H. Org. Lett. 2015, 17, 6266-6269.
15. Feng, X.; Du, H. Asian J. Org. Chem. 2012, 1, 204-213.
16. (a) Parks, D. J.; von H. Spence, R. E.; Piers, W. E. Angew. Chem., Int.
Ed. Engl. 1995, 34, 809-811; (b) Parks, D. J.; Piers, W. E.; Yap, G. P. A.
Organometallics 1998, 17, 5492-5503.
In summary,
a
metal-free hydrogenation of 2-
quinolinecarboxylates was successfully realized for the first time
by using 5 mol % of B(C6F5)3 as catalyst to furnish a wide range
of cyclic α-amino ester derivatives in 57−99% yields. An attempt
for the asymmetric hydrogenation with the frustrated Lewis pair
of Cy3P and chiral boron Lewis acid generated in situ from chiral
diene gave the desired product with 14% ee. Further efforts on
searching for more effective chiral catalysts as well as expanding
the substrate scope are underway in our laboratory.
Supplementary Material
Acknowledgments
Supplementary data (the procedures for the metal-free
We are grateful for the financial support by the National
Natural Science Foundation of China (21572231, and 21521002)
and Key Research and Development Plan of Shandong Province
(2017GSF218061).
hydrogenation
of
2-substituted
quinolines,
and the
characterization and data for the determination of ee’s along with
NMR spectra) associated with this article can be found, in the
online version.
References and notes
1. (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52,

4
Tetrahedron
Graphical Abstract
A metal-free hydrogenation of 2-
quinolinecarboxylates was realized for the first time
to furnish the desired products in high yields.

5
Highlights
1. Hydrogenations of quinolinecarboxylates were
realized in a frustrated Lewis pair manner.
2. A variety of cyclic α-amino acid derivatives
were obtained in high yields.
3. The asymmetric hydrogenation only gave a low
ee.