Step-economical synthesis of tetrahydroquinolines by asymmetric relay catalytic Friedlaender condensation/transfer hydrogenation

Article abstract of DOI:10.1002/anie.201106808

Two steps in one reaction: The title relay reaction relies on a combination of an achiral Lewis acid and a chiral Bronsted acid (B-H in the scheme). This one-pot method provides access to tetrahydroquinoline derivatives with multiple continuous stereogeni

Full text of DOI:10.1002/anie.201106808

Angewandte
Chemie
DOI: 10.1002/anie.201106808
Asymmetric Relay Catalysis
Step-Economical Synthesis of Tetrahydroquinolines by Asymmetric
Relay Catalytic Friedlꢀnder Condensation/Transfer Hydrogenation**
Lei Ren, Tao Lei, Jia-Xi Ye, and Liu-Zhu Gong*
Chiral 1,2,3,4-tetrahydroquinoline derivatives have found
widespread application in the preparation of naturally occur-
ring alkaloids and pharmaceutically relevant molecules.[1]
Their great synthetic importance has stimulated a boom in
the development of asymmetric synthetic methods.[2,3] The
most common access to this structural motif is the asymmetric
reduction of quinolines.[3] Although it is straightforward, this
approach requires preformed quinoline derivatives and
thereby suffers from moderate step economy. The direct
and enantioselective conversion of readily available precur-
sors of quinolines into the 1,2,3,4-tetrahydroquinolines would
provide a more elegant approach, but such methods remain
extremely rare. Herein we describe a new relay catalytic
reaction to produce 1,2,3,4-tetrahydroquinolines in high
levels of enantiopurity by using easily accessible 2-amino-
benzaldehydes and enolizable carbonyl-containing com-
pounds as reagents.
chiral phosphoric acids[17] have been excellent catalysts for the
asymmetric transfer hydrogenation of quinolines with
Hantzsch esters.[3a,18] Encouraged by these elegant achieve-
ments, we proposed a sequence consisting of a Friedlꢀnder
condensation and transfer hydrogenation catalyzed by a
combination of an achiral Lewis acid and a chiral Brønsted
acid for the direct conversion of 2-aminobenzaldehydes and
enolizable compounds containing carbonyl groups into highly
optically active 1,2,3,4-tetrahydroquinoline derivatives
(Scheme 1).
Step economy is a preeminent concept in contemporary
organic synthesis.[4] It has been accepted as an ultimate goal to
construct pharmaceutical compounds and complex natural
products. Recently, the combined use of organocatalysts and
metal complexes in relay and cooperative catalysis has led to
the creation of new enantioselective protocols.[5–14] More
significantly, asymmetric relay catalysis (ARC) has been
proven to enable the discovery of unprecedented step-
economical transformations.[5] Successful relay catalysis
relies on the compatibility and more importantly, on the
synergism of metal complexes and organocatalysts. The
binary organo/metal catalyst systems disclosed so far include
the combination of transition-metal complexes based on
Pd,[6,7] Au,[8] Rh,[9,10] Ru,[11,12] and other transition metals[13,14]
with chiral organocatalysts. In contrast, combinations of
Lewis acids and phosphoric acids have rarely found applica-
tion in asymmetric relay catalysis.[15]
Scheme 1. Proposed strategy for the one-pot synthesis of enantiomer-
ically enriched tetrahydroquinolines. LA=Lewis acid, B*–H=chiral
Brønsted acid.
Our initial study began with the reaction of 2-amino-
benzaldehyde (1a) and ethyl acetoacetate (2a) with Hantzsch
ester 3a catalyzed by phosphoric acid 5a (10 mol%) in
toluene at 358C. Encouragingly, the reaction proceeded with
high diastereoselectivity in favor of the anti diastereomer and
with 90% ee for the major product; however, the yield was
poor because the reaction was slow (Table 1, entry 1). The
same reaction went to completion in the presence of 10 mol%
of 5a combined with 10 mol% of Mg(OTf)2,[19] giving the
desired product in 83% yield, and more significantly, the
stereoselectivity remained high (Table 1, entry 2). However,
in the absence of the phosphoric acid, an incomplete Fried-
lꢀnder condensation occurred to give a quinoline derivative of
type I in 41% yield while the desired tetrahydroquinoline 4aa
was not detected (Table 1, entry 3). These results indicated
that the Friedlꢀnder condensation can be catalyzed by either
the phosphoric acid or the Lewis acid while the transfer
hydrogenation is accelerated solely by the chiral Brønsted
acid. We surveyed phosphoric acids 5 (Figure 1) and found
that 5a is the optimal catalyst in terms of enantioselectivity
(Table 1, entries 4–8). The evaluation of Hantzsch esters
revealed that the methyl Hantzsch ester 3b provides the
The Friedlꢀnder condensation has long been recognized
as a reliable and preparatively straightforward route to
quinolines.[16] Either Brønsted or Lewis acids are able to
efficiently promote this transformation. On the other hand,
[*] L. Ren, T. Lei, J. X. Ye, Prof. L. Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
E-mail: gonglz@ustc.edu.cn
Homepage: http://staff.ustc.edu.cn/~gonglz/index.htm
[**] We are grateful for financial support from NSFC (20732006), the
Ministry of Health (2009ZX09501-017), MOST (973 project
2010CB833300), and the Ministry of Education.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106808.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
771

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Communications
Table 1: Optimization of reaction conditions.[a]
Table 2: Generality of the reaction for 2-aminobenzaldehydes and b-keto
esters.[a]
d.r.[c]
ee
Entry
1, R1
2, R2
4
Yield
[%][b]
ee
Entry
5
LA
3
Yield
[%][b]
[%][c,d]
[%][d]
1
2
3
4
5
6
7
1b, 5-AcO
1c, 5-MeO
1d, 5-F
1e, 5-Cl
1 f, 5-Br
1g, 4-Cl
1a, H
1a, H
1a, H
1a, H
1a, H
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2b, n-Pr
2c, Ph
2d, 4-MeC6H4
2e, 4-FC6H4
2 f, 4-ClC6H4
2g, 4-NO2C6H4
2h, 2-Naphthyl
4ba
4ca
4da
4ea
4 fa
4ga
4ab
4ac
4ad
4ae
4af
91
65
65
76
81
55
63
72
71
64
61
67
73
92
92
92
90
90
95
91
91
96
96
97
96
97
1
2
5a
5a
—
5b
5c
5d
5e
5 f
5a
5a
5a
5a
5a
5a
5a
5a
none
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3b
3b
3b
3b
3b
3b
35
83
–
10:1
12:1
–
3.5:1
16:1
3.2:1
6.5:1
7:1
90
90
–
7(6)
88
22(5)
51(18)
86(45)
94
80
89
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Zn(OTf)2
Yb(OTf)3
Mg(ClO4)2
FeCl3
3[e]
4
99
70
97
68
52
76
51
49
64
61
37
17
30
5
6
7
8
8[e]
9[e]
10[e]
11[e]
12[e]
13[e]
9
>20:1
7:1
10
11
12
13
14
15
16
>20:1
>20:1
>20:1
18:1
13:1
17:1
1a, H
1a, H
4ag
4ah
90
94
92
93
[a] The reaction of 1 (0.2 mmol), 2 (1.0 mmol), and 3b (0.46 mmol) was
conducted in toluene (1.0 mL) with 3 ꢀ molecular sieves (200 mg) at
358C. [b] Yield of isolated product. [c] Determined by HPLC on a chiral
stationary phase. [d] d.r. >20:1, determined by 1H NMR analysis of crude
product. [e] 1/2/3b=1:1.2:2.3.
NaAuClO4
Sc(OTf)3
90
[a] The reaction of 1a (0.2 mmol), 2a (1.0 mmol), and 3 (0.46 mmol)
was conducted in toluene (1.0 mL) with 3 ꢀ molecular sieves (200 mg) at
358C for 36 h. [b] Yield of isolated 4aa. [c] Determined by 1H NMR
analysis of the crude product. [d] Major (minor) diastereomer, deter-
mined by HPLC on a chiral stationary phase. [e] Only quinoline (41%
yield) was isolated. Tf=trifluoromethanesulfonyl.
nicely tolerated: the introduction of electron-donating sub-
stituents resulted in high levels of enantioselectivity (92% ee;
Table 2, entries 1 and 2). Halogenated 2-aminobenzaldehydes
participated in the reaction giving the expected product in
high yields and enantioselectivities (Table 2, entries 3–6). In
the reactions of 1e and 1g we found that the position of the
substituent exerts a considerable effect on the enantioselec-
tivity (Table 2, entry 4 versus entry 6). More interestingly, the
reaction conditions were amenable to a wide scope of b-keto
esters and gave high levels of stereochemical control (Table 2,
entries 7–13). In addition to ethyl acetoacetate (2a), other
aliphatic analogues also underwent smooth reaction with high
enantioselectivity as exemplified by ethyl butyrylacetate (2b;
Table 2, entry 7). More significantly, aromatic b-keto esters
proved to be reactive components and provided excellent
levels of enantioselectivity (91–97% ee; Table 2, entries 8–
13). The configuration of 4 fa was assigned by X-ray analysis
(see the Supporting Information).
2,3,4-Trisubstituted tetrahydroquinolines hold great
potential in organic synthesis and show important bioactivi-
ty;[1d] however, only a limited number of enantioselective
catalytic protocols have been available to prepare these
molecules.[23] Thus, a further investigation on the substrate
scope was focused on the 2-aminophenyl ketones. However,
the extension of the optimized reaction conditions to 1-(2-
aminophenyl)ethanone (6a) provided 7aa in moderate yield
and 85% ee (Table 3, entry 1). We therefore re-evaluated the
phosphoric acid catalysts and found that 5 f delivered high
yield and excellent enantioselectivity (98% ee; Table 3,
entry 2). The application of the optimized conditions to 1-
(5-methyl-2-aminophenyl)ethanone (6b) provided 7ab in
90% yield and 96% ee (Table 3, entry 3). More interestingly,
(2-aminophenyl)(aryl)methanones were also successful sub-
Figure 1. Phosphoric acid derivatives surveyed.
highest level of stereoselectivity (> 20:1 d.r., 94% ee; Table 1,
entry 9). A variety of Lewis acids, which have been applied to
the Friedlꢀnder condensation, were examined in combination
with 5a (Table 1, entries 11–16). Basically, the reaction
conversion and diastereoselectivity depend highly on the
Lewis acid co-catalysts while the enanatioselectivity appears
to be less sensitive. The use of either zinc triflate or ytterbium
triflate gave high diastereoselectivities, but both the yield and
enantioselectivity were lower than those obtained with
magnesium triflate (Table 1, entries 11 and 12). Magnesium
perchlorate gave results comparable to those with magnesium
triflate (Table 1, entry 13). However, other Lewis acids that
have shown high catalytic activity for Friedlꢀnder condensa-
tion, including FeCl3,[20] NaAuCl4,[21] and Sc(OTf)3,[22] led to an
incomplete cascade reaction in combination with 5a, although
the stereoselectivity was maintained in most cases (Table 1,
entries 14–16).
We then applied the optimized conditions to the cascade
reaction of various 2-aminobenzaldehydes and b-keto esters
(Table 2). Substitution on the 2-aminobenzaldehyde was
772
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Table 3: The scope of 2-aminophenyl ketones 6.[a]
Entry
6, R1, R2
7
Yield
[%][b]
d.r.[c]
ee
[%][d]
1[e]
2
3
4
5
6
7
8
6a, H, Me
6a, H, Me
7aa
7aa
7ab
7ac
7ad
7ae
7af
64
88
90
96
97
70
72
76
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
85
98
96
95
91
93
95
92
6b, 5-Me, Me
6c, H, Ph
6d,H, 4-MeC6H4
6e, 5-Cl, Ph
6 f, 5-F, Ph
6g, 5-BnO, Ph
7ag
[a] The reaction of 6 (0.1 mmol), 2a (0.5 mmol), and 3b (0.23 mmol)
was conducted in toluene (1.0 mL) with 3 ꢀ molecular sieves (100 mg) at
358C. [b] Yield of isolated product. [c] Determined by 1H NMR analysis of
crude product. [d] Determined by HPLC on a chiral stationary phase.
[e] Phosphoric acid 5a was used.
Figure 2. Course of the Friedlꢁnder condensation catalyzed by 5 mol%
~
*
Mg(OTf)2 and 5 mol% 5a ( ), by 10 mol% Mg(OTf)2 ( ), and by
^
10 mol% 5a ( ).
strates and participated in the relay catalytic reaction to give
the tetrahydroquinoline products in high yields and excellent
levels of enantioselectivity (Table 3, entries 4–8). The pres-
ence of either electron-withdrawing or -donating substituents
on the aryl rings was tolerated, and tetrahydroquinolines
bearing three continuous stereogenic centers were obtained
in high yields and with excellent stereoselectivities (Table 3,
entries 5–8). The configuration of the product was confirmed
by X-ray analysis after derivatization (see the Supporting
Information).
To obtain insight into the reaction process, we investigated
the kinetics of each individual reaction. As shown in Figure 2,
both Mg(OTf)2 and Brønsted acid 5a showed catalytic
activity for the Friedlꢀnder condensation, but Mg(OTf)2 was
somewhat more effective. Interestingly, in the presence of a
mixture of 5a and Mg(OTf)2, the Friedlꢀnder condensation
proceeded even faster, implying a synergistic effect of the
metal complex and Brønsted acid. This type of synergism was
not observed in the transfer hydrogenation, however, because
the reactions catalyzed by 5a and Mg(OTf)2 together and by
5a alone gave similar results (Figure 3). Thus, in this relay
catalytic process, Lewis and Brønsted acids cooperatively
catalyze the Friedlꢀnder condensation while the chiral
Brønsted acid acts as the sole catalyst for the asymmetric
transfer hydrogenation.
Figure 3. Course of the transfer hydrogenation catalyzed by 10 mol%
&
*
Mg(OTf)2 and 10 mol% 5a ( ), and catalyzed by 10 mol% 5a ( ).
bility and synergism of the Lewis acid and chiral Brønsted
acid may provide a new reaction mode potentially amenable
to disclosing other relay catalytic asymmetric transforma-
tions.
Received: September 25, 2011
Published online: December 14, 2011
In conclusion, we have developed a relay reaction
consisting of a catalytic Friedlꢀnder condensation and a
transfer hydrogenation by using a combination of an achiral
Lewis acid and a chiral Brønsted acid. This concise step-
economical protocol provides access to highly substituted
tetrahydroquinoline derivatives with concomitant generation
of multiple stereogenic centers in excellent levels of stereo-
chemical control. In this cascade reaction, the Friedlꢀnder
condensation is catalyzed either by Lewis acid or the chiral
phosphoric acid while the asymmetric transfer hydrogenation
is promoted solely by the chiral Brønsted acid. More
importantly, the synergism of the Lewis acid and the chiral
Brønsted acid occurs in the catalytic process. The compati-
Keywords: Friedlꢁnder condensation · relay catalysis ·
synthetic methods · tetrahydroquinolines ·
transfer hydrogenation
.
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