Enantioselective Organocatalytic Transfer Hydrogenation of 1,2-Dihydroquinoline through Formation of Aza-o-xylylene

Article abstract of DOI:10.1021/acs.orglett.5b02025

A new way of forming the aza-o-xylylene with easily accessible 1,2-dihydroquinolines as precursor has been developed. The presence of an electron-donating group at the proper position of 1,2-dihydroquinoline was crucial for protonation of the alkene through dearomatization with a simple Bronsted acid. The in situ forming reactive intermediate was trapped with Hantzsch ester to afford tetrahydroquinolines in excellent yield and enantioselectivity.

Full text of DOI:10.1021/acs.orglett.5b02025

Letter
pubs.acs.org/OrgLett
Enantioselective Organocatalytic Transfer Hydrogenation of 1,2-
Dihydroquinoline through Formation of Aza‑o‑xylylene
Guangxun Li,*,† Hongxin Liu,† Gang Lv,† Yingwei Wang,‡ Qingquan Fu,† and Zhuo Tang*,†
†Natural Products Research Center, Chengdu Institution of Biology Chinese Academy of Science Chendu, Sichuan 610041, China
‡College of Chemical Engineering, Sichuan University, Chendu Sichuan 610041, China
S
* Supporting Information
ABSTRACT: A new way of forming the aza-o-xylylene with
easily accessible 1,2-dihydroquinolines as precursor has been
developed. The presence of an electron-donating group at the
proper position of 1,2-dihydroquinoline was crucial for
protonation of the alkene through dearomatization with a
simple Brønsted acid. The in situ forming reactive
intermediate was trapped with Hantzsch ester to afford tetrahydroquinolines in excellent yield and enantioselectivity.
za-o-xylylene and o-quinone methide imine (AOX)
(Scheme 1a) are highly reactive and unstable species,
However, these precursors were inefficient due to the strict
reaction conditions. Other methods for formation of AOX
under milder reaction conditions such as dehydroxylation with
BF3·Et2O at room temperature (A1) (Scheme 1a),2l fluoride-
induced 1,4-elimination of [o-[(trimethylsilyl)alkylamino]-
benzyl]trimethylammonium iodide (A2) (Scheme 1a),2b and
palladium-mediated decarboxylation (A3) (Scheme 1a)3 were
restricted to special substrates which were difficult to obtain. As
a result, a lack of efficient and mild synthetic methods to
manipulate AOX likely contributed to the paucity of
applications of these species.
A
Scheme 1. Paths for the Formation and Application of AOX
1,2-Dihydroquinoline 1 was quite easy to obtain through the
modified Skraup reaction with simple aromatic amine and
ketone (Scheme 1b).4 Our interest in this underexplored
species stemmed from 1,2-dihydroquinoline 1 that might form
AOX through dearomatization with catalytic Brønsted acid
under mild conditions (Scheme 1b). We reasoned that
increasing the nucleophilicity of the alkene moiety would
allow the substrate to be protonated even by mild Brønsted
acid based on the fact that dihydroquinoline 1 has been used as
electrophile to react with benzene by catalytic AlCl3.5 Adding
an electron-donating group to the aromatic ring of 1 would
easily improve the nucleophilicity of the alkene.
Moreover, a chiral Brønsted acid mediated AOX ion pair
might be used as the electrophile to efficiently prepare chiral
tetrahydroquinolines, which are very important skeletons found
in numerous biologically active natural products and
pharmacologically relevant therapeutic agents5,6 (Figure 1).
Herein, we report a mild strategy for dearomatization of 1,2-
dihydroquinolines to AOX in situ with catalytic amounts of
Brønsted acid, which were then applied as efficient electrophiles
to react with Hantzsch diethyl ester (HEH) to prepare chiral
tetrahydroquinolines.
with the first documented occurrence in 1966.1 Owing to their
high reactivity, they could be trapped with an olefin and
proceed through cycloaddition or electrocyclization reactions to
produce a wide variety of heterocycles.2 These highly unstable
and reactive intermediates are generally formed in situ with
different methods according to the precursor. For example,
pyrolysis or photolysis of various precursors such as o-
aminobenzyl alcohols or their (tert-butoxycarbonyl)amino
derivatives were applied previously (A1) (Scheme 1a),2a,c and
then more and more precursors such as dihydro-l, 3-
benzoxazine-2-one,2g 2,1-benzisothiazoline 2,2-dioxide,2h 2-
azidoindoles,2d and N-phenylbenzoazetine1 were used for
producing these useful intermediates more efficiently.
Received: July 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
HEH to provide chiral 2,2,4-trisubstituted tetrahydroquino-
lines. Therefore, we systematically investigated the asymmetric
reduction of the dihydroquinolines with binol-derived chiral
phosphoric acids 5.
At the beginning, we optimized the reaction by screening
different chiral catalysts with CH2Cl2 as solvent at room
temperature. The reaction results revealed that catalyst 5c was
more efficient considering the enantioselectivity (enties 1−6,
Table 2). We then screened the reaction solvent and found that
Figure 1. Pharmaceutical active tetrahydroquinolines.
As a model reaction to evaluate this concept, we chose the
Hantzsch diethyl ester (HEH) as hydride source to reduce this
active intermediate.7 As a result, several 2,2,4-trimethyldihy-
droquinolines with different substituents on the phenyl ring
were prepared and subjected to HEH with catalytic TsOH in
CHCl3 (Table 1). Neither dihydroquinoline 1a without
Table 2. Optimizing the Reaction Conditions
Table 1. Screening of Appropriate Dihydroquinolines
a
b
c
entry
cat. 5 (mol %)
solvent
temp (°C) ee (%) yield (%)
1
5a (5)
5b (5)
5c (5)
5d (5)
5e (5)
5f (5)
5c (5)
5c (5)
5c (5)
5c (5)
5c (5)
5c (5)
5c (5)
5c (3)
5c (1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
25
25
25
25
25
25
25
25
25
25
0
11
11
68
30
10
40
75
65
68
74
80
88
86
88
86
98
96
95
89
88
92
94
92
85
92
93
95
85
92
80
2
a
b
entry
1, R
1a, R = H
cat.
yield (%)
3
4
1
2
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TFA
5
1b, R = 6-Cl
6
3
1c, R = 6-CF3
7
4
1d, R = 6-Me
8
5
1e, R = 7-OCH3
1f, R = 6-OCH3
1g, R = 6,8-di-OCH3
1e, R = 7-OCH3
1e, R = 7-OCH3
1e, R = 7-OCH3
95
9
TBME
m-xylene
toluene
toluene
toluene
toluene
toluene
6
10
11
12d
7
8
94
93
85
0
9
Yb(OTf)3
MgBr2
d
d
d
13
14
15
−10
0
10
a
Reaction conditions: 0.2 mmol of 1, 0.24 mmol of 2, cat. (5 mol %),
b
0
2 mL of CHCl3 at 25 °C, nitrogen atmosphere. Isolated yield from 1.
a
General conditions: 1 equiv of 1h and 1.2 equiv of 4.
Enatioselectivity was determined by HPLC with chiral AD-H. The
b
c
substituent (Table 1, entry 1) nor dihydroquinolines 1b or
1c with electron-withdrawing groups such as 6-Cl or 6-CF3
(Table 1, entries 2 and 3) could undergo the transfer
hydrogenation to give the corresponding tetrahydroquinolines.
The same results were found for dihydroquinoline 1d with a
weak electron-donating group on the phenyl ring (Table 1,
entry 4).
The above results were ascribed to the failure of formation of
the AOX intermediate. We hypothesized that increasing the
electron density of the phenyl ring by using a stronger electron-
donating group would make the dihydroquinoline substrate
form an AOX intermediate by dearomatization.8 As expected,
dihydroquinoline 1e with a 7-methoxy on the phenyl ring could
be efficiently transformed to the corresponding tetrahydroqui-
noline 3e (Table 1, entry 5). Nevertheless, dihydroquinolines
1f and 1g with 6-methoxy or 6,8-dimethoxy could not afford
the corresponding product (Table 1, entries 6 and 7), which
indicated that the substitution pattern of the electron-donating
group on the proper position of the dihydroquinoline substrate
was crucial for the dearomatization.
reaction yield were determined after purification by flash column; 4 Å
molecular sieves were added.
toluene was more efficient in which the product was obtained
with 75% ee (entries 7−10, Table 2). Decreasing the reaction
temperature to 0 °C could greatly improve the enantioselec-
tivity to 80% (entry 11, Table 2). Finally, addition of 4 Å
molecular sieves could improve the enantioselectivity and yield
(entry 12, Table 2). Further decreasing the reaction temper-
ature to −10 °C did not improve the enantioselectivity but
decreased the enantioselectivity and yield (entry 13, Table 2).
Meanwhile, the catalyst loading was screened, which demon-
strated that 3 mol % was better considering the yield and
enantioselectivity (entries 14−15, Table 2). These preliminary
studies revealed that the best conditions for the transfer
hydrogenation of dihydroquinoline 1h were 1.2 equiv of
dihydropyridine 2 and 3 mol % of catalyst 5c at 0 °C in toluene
for 48 h with 4 Å molecular sieves as additive.
We then continued to investigate the reaction with different
types of catalysts including Brønsted acid TFA (Table 1, entry
8), Strong Lewis acid Yb(OTf)3 (Table 1, entry 9) or mild
Lewis acid MgBr2 (Table 1, entry 10). The results revealed that
all of these catalysts could catalyze the reaction with excellent
yield. Meanwhile, using chiral Brønsted acid as catalyst would
allow the formation of an ionic pair between AOX and an
optically active phosphoric anion,9 which could be trapped with
Under these optimized conditions, we explored the scope of
the Brønsted acid catalyzed transfer hydrogenation of
dihydroquinoline based on the in situ formed AOX (Scheme
2). Tetrahydroquinoline with one methoxy group (3e), two
methoxy groups (3h,i), and three methoxy groups (3j),
tetrahydroquinolines with different 7-alkoxy (3n−r), and even
tetrahydroquinolines with 7-methoxy and different halogens at
C-6 (3k−m) were obtained under the optimal reaction
B
DOI: 10.1021/acs.orglett.5b02025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02025.
Full experimental details and analytical data including
NMR spectra and chiral HPLC analysis (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
ez, G. Chem. Rev. 2007, 107, 1580.
́
́
́
*E-mail: ligx@cib.ac.cn.
*E-mail: tangzhuo@cib.ac.cn.
Notes
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation
of China (Grant No. 21402188).
■
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DOI: 10.1021/acs.orglett.5b02025
Org. Lett. XXXX, XXX, XXX−XXX