Highly enantioselective synthesis of tetrahydroquinolines via cobalt(II)-catalyzed tandem 1,5-hydride transfer/cyclization

Article abstract of DOI:10.1021/ol1028282

A chiral catalyst prepared from N,N′-dioxide and Co(BF ₄)₂·6H₂O was applied in the asymmetric hydride transfer initiated cyclization reaction, giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.

Full text of DOI:10.1021/ol1028282

ORGANIC
LETTERS
2011
Vol. 13, No. 4
600–603
Highly Enantioselective Synthesis of
Tetrahydroquinolines via Cobalt(II)-
Catalyzed Tandem 1,5-Hydride
Transfer/Cyclization
Weidi Cao, Xiaohua Liu, Wentao Wang, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
xmfeng@scu.edu.cn
Received November 22, 2010
ABSTRACT
A chiral catalyst prepared from N,N0-dioxide and Co(BF4)2 6H2O was applied in the asymmetric hydride transfer initiated cyclization reaction,
3
giving optically active tetrahydroquinolines in good yields with high enantioselectivities under mild reaction conditions. Meanwhile, in light of the
absolute configuration of the product, a possible working model was proposed to explain the origin of the activation and asymmetric induction.
Optically pure tetrahydroquinoline derivatives are widely
used in organic synthesis and pharmaceutical chemistry due
to their significant building blocks and intriguing biological
activities.1 Traditional methodologies for the formation of
these lichipins mainly include the Povarov reaction2 and
reduction of quinolines.3 As an alternative straightforward
approach to afford tetrahydroquinolines, the intramolecu-
lar tandem hydride transfer/cyclization4 process (Scheme 1),
which undergoes a zwitterionic intermediate formed by a
1,5-hydride transfer, has been developed in recent years.
To the best of our knowledge, only two asymmetric exam-
ples have been described subsequently by the Seidel group
and Kim group. Bis(oxazoline)-Mg(OTf)2 catalyst5 and
(1) (a) Barton, D. H.; Nakanishi, K.; Meth-Cohn, O. Comprehensive
Natural Chemistry; Elsevier: Oxford, 1999; Vols. 1-9. (b) Katritzky, A. R.;
Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031.
(2) (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070. (b) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2008,
77, 137. (c) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721. (d) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. P. J. Am. Chem. Soc. 2009,
131, 4598. (e) Bergonzini, G.; Gramigna, L.; Mazzanti, A.; Fochi, M.;
Bernardi, L.; Ricci, A. Chem. Commun. 2010, 46, 327.
(4) For racemic examples: (a) Verboom, W.; Reinhoudt, D. N.; Visser,
R.; Harkema, S. J. Org. Chem. 1984, 49, 269. (b) Nijhuis, W. H. N.; Verboom,
W.; Reinhoudt, D. N.; Harkema, S. J. Am. Chem. Soc. 1987, 109, 3136–3138.
(c) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127,
12180. (d) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7, 5429. (e) Tobisu, M.;
Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (f) Zhang, C.; De, C. K.;
Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416. (g) McQuaid, K. M.;
Sames, D. J. Am. Chem. Soc. 2009, 131, 402. (h) Shikanai, D.; Murase, H.;
Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166. (i) Murarka, S.; Zhang,
C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129. (j) McQuaid,
K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972. (k) Zhang, C.; Murarka,
S.; Seidel, D. J. Org. Chem. 2009, 74, 419. (l) Mori, K.; Kawasaki, T.; Sueoka,
S.; Akiyama, T. Org. Lett. 2010, 12, 1732.
(3) (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 3683. (b) Zhou, Y. G. Acc. Chem. Res. 2007,
ꢀ ꢁ
40, 1357. (c) Mrsic, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa,
B. L.; de Vries, J. G. Adv. Synth. Catal. 2008, 350, 1081. (d) Guo, Q. S.; Du,
D. M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759. (e) Wang, X. B.; Zhou,
Y. G. J. Org. Chem. 2008, 73, 5640. (f) O'Byrne, A.; Evans, P. Tetrahedron
2008, 64, 8067.
(5) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc.
2009, 131, 13226.
r
10.1021/ol1028282
Published on Web 01/10/2011
2011 American Chemical Society

Scheme 1. Mechanistic Concept for the R-Alkylation of Amines
via 1,5-Hydride Transfer/Cyclization
Figure 1. Chiral ligands used in this study.
Table 1. Evaluation of Reaction Parametersa
organocatalyst6 were used to promote the intramolecular
asymmetric tandem 1,5-hydride transfer/cyclization with
excellent enantioselectivities. However, high temperature
(80 °C) or a long reaction time (4-12 days) was involved
in these cases. Thus, searching for new catalyst systems that
could achieve high reactvity and enantioselectivity under
mild reaction conditions and extending the substrate scope
are still challenging and desirable. Herein, we wish to report
a highly enantioselective intramolecular tandem hydride
transfer/cyclization of o-dialkylamino-substituted alkyl-
idene malonates, which could be tolerated under a chiral
N,N0-dioxide-Co(II) complex catalyst system, delivering the
corresponding optically active tetrahydroquinolines in ex-
cellent yields (up to 99%) with high enantioselectivities (up
to 90% ee).
In view of the requirement of effective activation as well
as the proper stereoinduction of the substrate by coordi-
nating with a chiral N,N0-dioxide-metal complex,7,8 alkyl-
idene malonate derivative 1a was selected as a model
substrate which could bind to the central metal with
dicarbonyl groups. Initiatlly, various metal salts such as
MgII, FeII, NiII, and CoII chelated with L-proline-derived
N,N0-dioxide L1 (Figure 1) were used to catalyze this
tandem 1,5-hydride transfer cyclization (Table 1, entries
1-4). Gratifyingly, moderate enantioselectivity (51% ee)
and high yield were obtained using cobalt(II) as the central
metal. Then, the influence of counterions was investigated
(Table 1, entries 5-7), and a better result was obtained
yield
(%)b
ee
entry
ligand
metal
Mg(OTf)2
(%)c
1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L6
86
35
-
50
51
-
2
Fe(BF4)2 6H2O
NRe
63
3
3
Ni(ClO4)2 6H2O
3
4
Co(ClO4)2 6H2O
92
3
5
Co(AcAc)2
Co(OAc)2
NRe
NRe
95
6
-
7
Co(BF4)2 6H2O
57
20
37
39
7
3
8
Co(BF4)2 6H2O
87
3
9
Co(BF4)2 6H2O
80
3
10
11
12
13d
Co(BF4)2 6H2O
90
3
Co(BF4)2 6H2O
93
3
Co(BF4)2 6H2O
99
87
90
3
Co(BF4)2 6H2O
35
3
a Unless otherwise noted, reactions were carried out with ligand
(10 mol %), metal (10 mol %), and 1a (0.1 mmol) in CH2Cl2 (0.2 mL) at
35 °C for 30 h. b Isolated yield. c Determined by HPLC using chiral IC
column. d Reaction was performed at 20 °C. e NR = No reaction.
with Co(BF4)2 6H2O (Table 1, entry 7). Next, a series of
3
N,N0-dioxides were examined (Figure 1). It was found that
the chiral backbone strongly affected both yield and
enantioselectivity. L-Proline derived L1 could achieve bet-
ter results than L-pipecolic acid derived L2 and L-ramipril
derived L3 (Table 1, entry 7 vs 8 and 9). Moreover, the
steric effect of the amide moiety played a crucial role;
bulkier groups at the o-position of aniline were superior to
smaller ones (Table 1, entries 7 and 10-12). High enantio-
(6) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132,
11847.
(7) (a) Wang, L. J.; Liu, X. H.; Dong, Z. H.; Fu, X.; Feng, X. M.
Angew. Chem., Int. Ed. 2008, 47, 8670. (b) Liu, Y. L.; Shang, D. J.; Zhou,
X.; Liu, X. H.; Feng, X. M. Chem.;Eur. J. 2009, 15, 2055. (c) Chen, D. H.;
Chen, Z. L.; Xiao, X.; Yang, Z. G.; Lin, L. L.; Liu, X. H.; Feng, X. M.
Chem.;Eur. J. 2009, 15, 6807.
(8) (a) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc.
2008, 130, 15770. (b) Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng,
X. M. Angew. Chem., Int. Ed. 2008, 47, 1308. (c) Wang, W. T.; Liu, X. H.;
Cao, W. D.; Wang, J.; Lin, L. L.; Feng, X. M. Chem.;Eur. J. 2010, 16, 1664.
(d) Shen, K.; Liu, X. H.; Zheng, K.; Li, W.; Hu, X. L.; Lin, L. L.; Feng, X. M.
Chem.;Eur. J. 2010, 16, 3736. (e) Li, W.; Wang, J.; Hu, X. L.; Shen, K.;
Wang, W. T.; Chu, Y. Y.; Lin, L. L.; Liu, X. H.; Feng, X. M. J. Am. Chem.
Soc. 2010, 132, 8532. (f) Xie, M. S.; Chen, X. H.; Zhu, Y.; Gao, B.; Lin, L. L.;
Liu, X. H.; Feng, X. M. Angew. Chem., Int. Ed. 2010, 49, 3799. (g) Hui,
Y. H.; Jiang, J.; Wang, W. T.; Chen, W. L.; Cai, Y. F.; Lin, L. L.; Liu, X. H.;
Feng, X. M. Angew. Chem., Int. Ed. 2010, 49, 4290. (h) Cai, Y. F.; Liu,
X. H.; Hui, Y. H.; Jiang, J.; Wang, W. T.; Chen, W. L.; Lin, L. L.; Feng, X. M.
Angew. Chem., Int. Ed. 2010, 49, 6160.
selectivity (87% ee) was achieved using the L6-Co(BF4)2
3
6H2O complex (Table 1, entry 12). Lowering the reaction
temperature to 20 °C further enhanced the enantioselec-
tivity to 90% ee but led to an obvious loss in yield (Table 1,
entry 13). Therefore, the optimal conditions were as fol-
lows: the L6-Co(BF4)2 6H2O complex (10 mol %; molar
3
ratio L6/Co(BF4)2 6H2O = 1/1), alkylidene malonate (0.1
mmol) in CH2Cl2 (0.2 mL) at 35 °C.
3
Org. Lett., Vol. 13, No. 4, 2011
601

Table 2. Substrate Scope for the Catalytic Asymmetric
Intramolecular 1,5-Hydride Transfer/Cyclization of Acyclic
Compoundsa
Table 3. Substrate Scope for the Catalytic Asymmetric Intra-
molecular 1,5-Hydride Transfer/Cyclization of Polycyclic
Compoundsa
time
(h)
yield
(%)b
ee
(%)c
entry
R2
R3
prod.
1
Ph
Ph
Ph
Me
Et
3a
3b
3c
3d
3e
3f
30
48
24
32
48
40
24
28
40
24
48
48
48
40
24
20
48
99
60
93
95
83
84
97
95
85
96
86
81
73
89
97
97
90
87
2
84
86
90
87
83
82
82
85
83
86
86
84
83
87(S)
86
79
3
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-FC6H4
5
6
7
3g
3g
3h
3i
8d
9
10
11
12
13
14
15e
16
17
3j
4-ClC6H4
3k
3l
4-BrC6H4
2,3-(MeO)2C6H3
1-naphthyl
2-naphthyl
2-thienyl
3m
3n
3o
3p
a Reactions were carried out with L1 (10 mol %), Co(BF4)2 6H2O
3
(10 mol %), and 1 (0.1 mmol) in CH2Cl2 (1.0 mL) at 0 °C for 48 h.
b Isolated yield. c Determined by HPLC using chiral OJ-H column.
a Unless otherwise noted, reactions were carried out with L6 (10 mol
%), Co(BF4)2 6H2O (10 mol %), and 1 (0.1 mmol) in CH2Cl2 (0.2 mL)
3
at 35 °C. b Isolated yield. c Determined by HPLC using chiral IC column.
d 2 mol % catalyst was used. e The absolute configuration was deter-
mined to be S by X-ray crystallographic analysis.
Under the optimized reaction conditions, a series of
substrates (1a-p) were investigated. As summarized in
Table 2, the ester group of malonate derivatives had little
influence on the enantioselectivity (Table 2, entries 1-3).
Regardless of the electronic properties or steric hindrance
of the substituents on the aromatic ring, the corresponding
ring-fused tetrahydroquinolines were obtained in good
yields (73-99%) with high enantioselectivities (82-90%
ee; Table 2, entries 4-7 and 9-13) within less than 48 h.
The electrodonating groups on aromatic substrates exhib-
ited higher reactivity (Table 2, entries 4-10 vs 11-13), and
for the o-methoxy substrate 1g, the enantioselectivity was
still maintained even as the catalyst loading was decreased
to 2 mol % (Table 2, entry 8). Furthermore, disubstituted,
condensed-ring, and heteroaromatic substrates were also
well tolerated (Table 2, entries 14-17).
To extend the application of this protocol, further
examination of the substrates was focused on forming
polycyclic compounds. Under the same reaction condi-
tions (Table 2, entry 1), the desired product 3q was
obtained in 70% ee. To our delight, after a slight modifica-
tion of ligand, by altering the ligand L6 to L1 and
decreasing the reaction temperature to 0 °C, a higher ee
value (88% ee) of 3q was obtained (Table 3, entry 1).
Moreover, products incorporating five- and six-membered
Figure 2. Proposed transition-state model and the absolute con-
figuration of 3n determined by X-ray crystallographic analysis.
azacycles were also gained with promising yields and
enantioselectivities (Table 3, entries 2-3).
To gain insight into the mechanism, the relationship
between the enantiomeric excess of the product 3q and
N,N0-dioxide L1 was studied under the optimal condi-
tions (Table 3). A linear effect9 was observed, which mani-
fested that the monomeric catalyst may be the main
catalytically active species.10 On the basis of the absolute
configuration of product 3n,11 a possible transition-state
(9) Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew. Chem.,
Int. Ed. 2009, 48, 456.
(10) See Supporting Information for more details.
(11) CCDC-798879 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
602
Org. Lett., Vol. 13, No. 4, 2011

model was proposed (Figure 2), in which the oxygens of N,
N0-dioxide, amide oxygens, and the alkylidene malonate
coordinated to cobalt(II) in a hexadentate manner. The
carbanion prefers to attack the Re face rather than the
Si face of the imine because the latter is strongly shielded
by the nearby anthracenyl ring, which results in the
S-configured product.
In summary, we have developed a highly enantioselective
intramolecular 1,5-hydride transfer/cyclization of o-dialkyl-
amino-substituted alkylidene malonates using a 10 mol %
N,N0-dioxide-Co(II) complex, which facilitated the asym-
metric synthesis of biologically interesting tetrahydroqui-
nolines. Various tetrahydroquinolines were obtained in
good yields with high enantioselectivities (up to 90% ee)
under mild conditions. Meanwhile, a transition-state
model was proposed to explain the origin of the asym-
metric induction. This catalyst system may provide a
new entry for other asymmetric hydride transfer cycli-
zation reactions. Further application of the current
method is currently underway.
Acknowledgment. We appreciate the National Natural
Science Foundation of China (Nos. 20732003 and 21021001)
and the Basic Research Program of China (973 Program:
2010CB833300) for financial support. We also thank Sichuan
University Analytical & Testing Center for NMR and X-ray
analysis.
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
603