Highly enantioselective synthesis of polysubstituted tetrahydroquinolines via organocatalytic Michael/Aza-Henry tandem reactions

Article abstract of DOI:10.1021/ol103069d

Highly enantioselective chiral bifunctional thiourea catalyzed asymmetric tandem reactions for synthesis of substituted tetrahydroquinolines are described. Substituted tetrahydroquinolines were given in good yields (up to 98%), high enantioselectivities (

Full text of DOI:10.1021/ol103069d

ORGANIC
LETTERS
2011
Vol. 13, No. 5
832–835
Highly Enantioselective Synthesis of
Polysubstituted Tetrahydroquinolines
via Organocatalytic Michael/Aza-Henry
Tandem Reactions
Zhen-Xin Jia, Yong-Chun Luo, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
xupf@lzu.edu.cn
Received October 11, 2010
ABSTRACT
Highly enantioselective chiral bifunctional thiourea catalyzed asymmetric tandem reactions for synthesis of substituted tetrahydroquinolines are
described. Substituted tetrahydroquinolines were given in good yields (up to 98%), high enantioselectivities (up to >99% ee), and diastereo-
selectivities (up to 20:1 dr).
The tetrahydroquinoline subunit is present in various
natural products, and many tetrahydroquinoline deriva-
tives have shown a wide range of biological activities
as antibiotics and antitumor agents.1 In accordance with
their importance, the development of efficient and sustain-
able procedures toward the synthesis of tetrahydroquino-
line derivatives is an important goal of synthetic organic
chemists. General synthetic methods include the Povarov
reaction, an inverse electron-demand aza Diels-Alder
reaction,2 and various reductions of quinolines.3 These
approaches often facilitate the synthesis of diastereoisome-
rically pure tetrahydroquinolines, but there are few reports
on enantiomerically pure targets.4 Therefore, the develop-
ment of new strategies for the synthesis of these enantio-
merically enriched heterocyclic frameworks still remains
an active field of research.
(1) (a) Johnson, J. V.; Rauckman, S.; Baccanari, P. D.; Roth, B. J.
Med. Chem. 1989, 32, 1942. (b) Omura, S.; Nakagawa, A. Tetrahedron
Lett. 1981, 22, 2199. (c) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.;
VanDuyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715. (d)
Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 48, 15031.
(e) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (f) Kouznetsov, V.;
Palma, A.; Ewert, C.; Varlamov, A. J. Heterocycl. Chem. 1998, 35, 761.
(g) De Kimpe, N.; Keppens, M. Tetrahedron 1996, 52, 3705. (h) Padwa,
A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org. Chem. 1999, 64,
3595. (i) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
52, 15031. (j) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana,
Y.; Kuo, S.- C.; Hamel, E.; Hackl, T.; Lee, K.-H. J. Med. Chem. 1998,
41, 1155. (k) Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.;
Dupassieux, P.; Lenoir, P.; Peck, M. J.; Jasserand, D. J. Med. Chem.
1995, 38, 669.
In the rapidly evolving field of organocatalysis,5 chiral
bifunctional thioureas have become one of the most
(2) For instance, see: (a) Jia, X.; Han, B.; Zhang, W.; Jin, X.; Yang,
L.; Liu, Z.-L. Synthesis 2006, 17, 2831. (b) Keck, D.; Vanderheiden, S.;
Braese, S. Eur. J. Org. Chem. 2006, 4916. (c) Savitha, G.; Perumal, P. T.
Tetrahedron Lett. 2006, 47, 3589. (d) Han, B.; Jia, X.-D.; Jin, X.-L.;
Zhou, Y.-L.; Yang, L.; Liu, Z.-L.; Yu, W. Tetrahedron Lett. 2006, 47,
3545. (e) Gao, K.; Li, Y.; Sun, H.; Fan, R.; Wu, J. Synth. Commun. 2007,
37, 4425. (f) Sridharan, V.; Perumal, P. T.; Avendano, C.; Menendez,
J. C. Org. Biomol. Chem. 2007, 5, 1351. (g) Ramesh, E.; Raghunathan, R.
Tetrahedron Lett. 2008, 49, 2583.
r
10.1021/ol103069d
Published on Web 02/02/2011
2011 American Chemical Society

Table 1. Screenings of the Reaction Conditionsa
entry
cat.
CH3NO2 (equiv)
solvent
timeb (d)
yield (%)c
drd
ee (%)e
1
A
A
B
C
D
E
F
F
F
F
F
F
F
F
F
20
20
20
20
20
20
20
20
20
20
20
20
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
3
7
7
7
7
7
6
6
6
6
6
6
6
6
6
33
78
nd
5:1
4:1
nd
98
98
94
nd
nd
nd
98
94
95
97
nd
nd
90
98
98
2
3
73
4
<20
<20
nr
5
nd
6
nd
7
95
6:1
11:1
10:1
8:1
nd
8
77
9
CH2Cl2
xylene
82
10
11
12
13
14
15
95
THF
<30
44
CH3CN
CH3NO2
toluene
toluene
nd
86
4:1
6:1
6:1
5
77
10
91
a Unless otherwise specified, all reactions were carried out with 1a (0.1 mmol), 2 (2.0 mmol, 20.0 equiv), and organocatalyst (20 mol %) in the
indicated solvent (1.0 mL) at room temperature. b Reaction time was determined by TLC. c Isolated yield after flash chromatography. d Determined by
1H NMR analysis of the crude products. e Determined by chiral-phase HPLC analysis (AD column).
powerful and versatile catalysts for a variety of transfor-
mations. One of the most important reactions catalyzed by
this class of catalysts is the enantioselective Michael reac-
tion, an important carbon-carbon bond forming reaction
for the construction of optically active organic com-
pounds.6 With the development of organic chemistry,
tandem reactions now serve as a powerful tool for the
rapid and efficient assembly of complex structures.7 We
(3) For instance, see: (a) Takamura, M.; Funabashi, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801. (b) Wang, W.-B.; Lu,
S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003,
125, 10536. (c) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 3683. (d) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew.
Chem., Int. Ed. 2008, 47, 759.
(4) (a) Sundararajan, G.; Prabagaran, N.; Varghese, B. Org. Lett.
2001, 3, 1973. (b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem.
Soc. 2006, 128, 13070. (c) Liu, H.; Dagousset, G.; Masson, G.; Retailleau,
P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598. (d) Davies, S. G.; Mujtaba,
N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009, 11, 1959.
(e) Bergonzini, G.; Gramigna, L.; Mazzanti, A.; Fochi, M.; Bernardi, L.;
Ricci, A. Chem. Commun. 2010, 46, 327. (f) Xu, H.; Zuend, S. J.; Woll,
M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986. (g) 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.
(6) For organocatalyst-mediated cross Michael reactions, see: (a)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Enders, D.; Wang, C.;
Liebich, J. X. Chem.;Eur. J. 2009, 15, 11058. (c) Yu, Z.-P; Liu, X.-H.;
Zhou, L.; Lin, L.-L.; Feng, X.-M. Angew. Chem., Int. Ed. 2009, 48, 5195.
(d) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int.
Ed. 2009, 48, 3699. (e) Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura,
S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 8051. (f) Zhang,
X.-S.; Zhang, S.-L.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1481. (g) Li,
H.; Zu, L.; Xie, H.-X.; Wang, J; Jiang, W.; Wang, W. Org. Lett. 2007, 9,
1833. (h) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11, 5654. (i)
Liu, Y.-k.; Ma, C.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Org. Lett. 2009, 11,
2848. (j) Zhou, W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008, 10, 2817. (k)
Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8,
2559.
(7) For recent reviews of tandem reactions, see: (a) Guo, H.-C.; Ma,
J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. (b) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
(c) Pellissier, H. Tetrahedron 2006, 62, 2143. (d) Tietze, L. F.; Rackelmann,
N. Pure Appl. Chem. 2004, 76, 1967. (e) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551. (f) Zhong, C.; Shi, X.-D. Eur. J.
Org. Chem. 2010, 2999.
(5) For reviews on organocatalytic reactions, see: (a) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (b) Enders, D.;
€
Grondal, C.; Huttl, M. R. Angew. Chem., Int. Ed. 2007, 46, 1570. (c)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
Org. Lett., Vol. 13, No. 5, 2011
833

Table 2. Organocatalytic Reaction for the Synthesis of Tetrahydroquinolinesa
entry
R1
Ar
R
product
timeb (d)
yield (%)c
drd
ee (%)e
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
3a
3b
3c
3d
3e
3f
6
6
6
6
6
6
7
7
7
7
7
4
4
4
4
4
4
4
4
6
6
95
94
98
94
96
96
98
95
95
97
95
97
98
96
98
97
98
97
98
94
<20
6:1
8:1
98
98
2
3-CH3C6H4
3-ClC6H4
4-BrC6H4
2-ClC6H4
2-BrC6H4
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-Cl
H
3
4:1
>99
98
4
3:1
5
14:1
20:1
7:1
99
6
>99
98
7
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
3-BrC6H4
Ph
3g
3h
3i
8
2-ClC6H4
2-BrC6H4
3-ClC6H4
4-BrC6H4
Ph
14:1
20:1
7:1
98
9
98
10
11
12
13
14
15
16
17
18
19
20
21
3j
99
3k
3l
7:1
98
3:1
99
3-CH3C6H4
2-ClC6H4
Ph
3m
3n
3o
3p
3q
3r
3s
3t
3:1
99
12:1
5:1
99
99
3-CH3C6H4
3-ClC6H4
2-ClC6H4
3-CH3C6H4
Ph
6:1
98
3:1
99
20:1
3:1
99
98
8:1
98
n.d.f
COOEt
Ph
3u
n.d.
a Unless otherwise specified, all reactions were carried out with 1 (0.1 mmol), 2 (2.0 mmol, 20.0 equiv), and organocatalyst (20 mol %) in the indicated
solvent (1.0 mL) at room temperature. b Reaction time was determined by TLC. c Isolated yield after flash chromatography. d Determined by 1H NMR
analysis of the crude products. e Determined by chiral-phase HPLC analysis (AD column). f Not determined.
wish to report herein the tandem Michael addition and
aza-Henry reaction in the asymmetric synthesis of 2,3,4-
trisubstituted tetrahydroquinolines with high yields and
stereoselectivities from chalcones 1 and nitromethane.8
Our initial study began with the reaction of (E)-3-(2-
((E)-benzylideneamino)phenyl)-1-phenyl prop-2-en-1-one
1a and nitromethane 2. First, several catalysts were
screened for this reaction, and the results are shown in
Table 1. Using catalyst A, we were delighted to obtain
cyclized product 3a with excellent enantioselectivity (98%
ee), but the reaction rate was slow (entries 1 and 2). When
catalyst B was used, the result was basically the same as
that for catalyst A (entry 3). For catalyst C or D, only a
small amount of desired product was given and the reac-
tion rate was still slow (entries 4 and 5). No reaction was
observed using catalyst E (entry 6). Eventually, we found
that catalyst F was the best one for this tandem process
(95% yield, 98% ee).
nonpolar solvents were tested. Toluene proved to be the
best choice for the solvent. Meanwhile, the amount of
nitromethane 2 had a significant effect on the reaction
(entries 14 and 15). For example, when nitromethane
(5 equiv) was used, the reaction yield was only 77% after
7 days. Ultimately, the use of 20 equiv of nitromethane
allowed full conversion of the starting material within a
shorter time and provided a slightly higher yield and high
enantioselectivity.
Under the optimized reaction conditions, the generality
of the reaction was explored (Table 2). The reactions
proceededefficientlywithvariousR,β-unsaturatedketones
in combination with substituted imines. All the reactions
afforded the corresponding tetrahydroquinolines in high
yields and excellent enantioselectivities. For Ar groups, the
reaction went faster with electron-deficient substituents
than with electron-rich substituents (entries 12 to 19 vs
entries 7 to 11). The substitution pattern of Ar1 was obser-
ved to have a significant effect on the diastereoselectivity.
Ortho-substituted R1 groups gave the highest dr values
(entries 5 and 6, 8 and 9, 14, 18). Aliphatic imines were also
reacted with nitromethane, but the yield was low (<20%,
entry 21). In addition to nitromethane, nitroethane as
the nucleophile also reacted with substrates 1a, but no
reaction occurred.
Second, the solvent effect on the reaction was investi-
gated (entries 7 to 13). A variety of polar solvents and
(8) For organocatalyst-mediated cross aza-Henry reactions, see: (a)
Eugenia, M. L.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem.
2009, 2401. (b) Jiang, X.-X.; Zhang, Y.-F.; Wu, L.-P.; Zhang, G.; Liu,
X.; Zhang, H.-L.; Wang, R. Adv. Synth. Catal. 2009, 351, 2096. (c)
Takada, K.; Nagasawa, K. Adv. Synth. Catal. 2009, 351, 345. (d) Wang,
X.; Chen, Y.-F.; Niu, L.-F.; Xu, P.-F. Org. Lett. 2009, 11, 3310.
834
Org. Lett., Vol. 13, No. 5, 2011

Scheme 1. Experiments of Study Mechanism and Postulated
Transition-State Model
Scheme 2. Synthetic Transformation of Product 3a
state. Finally, the absolute (2S,3S,4R)-configuration was
obtained in accordance with X-ray crystal structure ana-
lysis (Scheme 1).
Tetrahydroquinolines 3 are useful synthetic intermedi-
ates because of the potential biological activities exhibited
by their ring-fused derivatives.10 So we decided to perform
a transformation with this multifunctional cycloadduct as
outlined in Scheme 1. The reduction of 3a with Zn/AcOH
followed by reductive amination afforded tricyclic com-
pound 4a in good yield (80%), good diastereoselectivity
(4:1), and high enantioselectivity (>99% ee) (Scheme 2).
The configuration of the product 4a was determined by an
NOE experiment.
In conclusion, we have developed a novel synthetic
method for polysubstituted tetrahydroquinoline deriva-
tives via organocatalytic asymmetric tandem Michael ad-
dition and the aza-Henry reaction, in which easily prepared
chalcone 1 and nitroalkane were employed as the starting
materials. The reaction yields were high (94%-98%), and
highlydiastereo- and enantioenriched tetrahydroquinoline
derivatives with a substantial substitution diversity were
smoothly delivered (up to >99% ee, dr up to 20:1).
Moreover, through a simple transformation, a compound
with a tricyclic core was successfully synthesized. The syn-
thetic applications of this tandem reaction are currently
under investigation.
A series of control experiments were conducted to gain
insight into the mechanism of the transformation. Benzy-
lidene imine 5, enone imine 6, and enol imine 7 reacted with
nitromethane separately, but they did not react. Thus, the
results suggested that this transformation occurred first
Michael reaction, then aza-Henry reaction was occurred.
In the process of the reaction, we did not detect any for-
mation of intermediates through the TLC. The Michael
addition reaction is the rate-determining step in this tan-
dem reaction. When the intermediate of the Michael reac-
tion was generated, the intramolecular aza-Henry reaction
occurred immediately (Scheme 1).
The absolute and relative configurations were unam-
biguously confirmed through X-ray crystal structure ana-
lysis of the compound 3i.9 By single crystal X-ray analysis,
the absolute (2S,3S,4R)-configuration was observed. A
simplistic meachanistic rationale to account for the ob-
served stereoselectivity of this process may be proposed.
Initially, bifunctional catalysts containing hydrogen bond
donors and a tertiary amine moiety activated R,β-unsatu-
rated ketones and nitromethane, and nitromethane at-
tacked R,β-unsaturated ketones from the Si face, thereby
forming intermediate 8. Then, an aza-Henry reaction
proceeded via a six-membered cyclic transition state in
the presence of base, and the intramolecular nucleophi-
lic addition underwent the stable chair form transition
Acknowledgment. We are grateful for the National
Basic Research Program of China (Nos. 2009CB626604,
2010CB833203), the NSFC (20972058, 21032005), and the
“111” program from MOE of P. R. China.
Supporting Information Available. Detailed experimen-
tal procedure, characterization data, NMR spectra for
new compounds, HRMS data for products 3, HPLC
analysis. The information is available free of charge via
the Internet at http://pubs.acs.org.
(10) (a) Staehle, W.; Bruge, D.; Schiemann, K.; Finsinger, D.;
Buchstaller, H.-P.; Zenke, F.; Amendt, C. DE 102005027169, 2006.
(b) Prossnitz, E. R.; Tkatchenko, S. E.; Revankar, C. M.; Sklar, L. A.;
Arterburn, J. B.; Cimino, D. F.; Oprea, T. I.; Bologa, C.-G.; Edwards,
B. S.; Kiselyov, A.; Young, S. M. WO 2007019180, 2007.
(9) CCDC 787334 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.
Org. Lett., Vol. 13, No. 5, 2011
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