Asymmetric sp3 C-H functionalization via a chiral Br?nsted acid-catalyzed redox reaction for the synthesis of cyclic aminals

Article abstract of DOI:10.1016/j.tetlet.2011.10.062

An organocatalytic asymmetric tandem 1,5-hydride transfer/ring closing reaction of o-aminobenzoketones with anilines to give cyclic aminals in fairly good diastereo- and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2011.10.062

Tetrahedron Letters 52 (2011) 7064–7066
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric sp3 C–H functionalization via a chiral Brønsted acid-catalyzed
redox reaction for the synthesis of cyclic aminals
⇑
Yu-Ping He, Yu-Liu Du, Shi-Wei Luo, Liu-Zhu Gong
Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemistry, the University of Science and Technology of China, Hefei 230026, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalytic asymmetric tandem 1,5-hydride transfer/ring closing reaction of o-aminobenzoke-
tones with anilines to give cyclic aminals in fairly good diastereo- and enantioselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 August 2011
Revised 27 September 2011
Accepted 11 October 2011
Available online 17 October 2011
Keywords:
Asymmetric catalysis
1,5-Hydride shift
Brønsted acid
Cyclic aminals
Direct functionalization of relatively inactive C–H bonds has
been a research topic that has been receiving increasing interest
in organic chemistry because it provides a strategically new oppor-
tunity for the creation of structurally complex and diverse organic
molecules.1 In this context, the intramolecular hydride transfer
reaction (intramolecular redox process) proved to be a robust
strategy describing various elegant reaction processes.2 In particu-
lar, the tert-amino effect has attracted much attention triggering a
number of transformations to facilely access synthetically interest-
ing heterocycles under thermal conditions, which involve the func-
tone with aniline in the presence of a chiral Brønsted acid to
generate an iminium species, which is presumably able to undergo
an asymmetric 1,5-hydride shift process and a subsequent ring
closing reaction to give a cyclic aminal (Scheme 1).
The validation of the hypothesis began with a reaction of ethyl
2-oxo-2-(2-(pyrrolidinyl)phenyl)acetate (1a) with 4-methoxyani-
line (2a) conducted in toluene at 115 °C by using phosphoric acid
4a as the catalyst. To our delight, the sequential condensation,
[1,5] hydrogen shift, and 6-endo cyclization underwent smoothly
to furnish an endo-diastereomer 3a in 78% yield and a high diaste-
reoselectivity, albeit with a low ee (Table 1, entry 1). Encouraged
tionalization of an
a
C–H bond to nitrogen.3 However,
enantioselective variants have not been available until Seidel and
Kim established elegant asymmetric tandem 1,5-hydride trans-
fer/ring closing reactions by using either chiral Lewis acid or organ-
ocatalyst, enabling the efficient synthesis of ring-fused
tetrahydroquinolines in high enantiopurity.4 More significantly,
Akiyama established an elegant Brønsted acid-catalyzed 1,5-hy-
dride transfer/ring closure to furnish tetrahydroquinolines in
excellent levels of enantioselectivity.5
Previously, Akiyama and Seidel independently demonstrated
that o-aminobenzaldehydes were able to be transformed into cyc-
lic aminals under the catalysis of Brønsted acids, which proceeded
via a 1,5-hydride shift process, whereas an enantioselective variant
has not been described.6 Herein, we will report an asymmetric syn-
thesis of cyclic aminals via Brønsted acid-catalyzed redox reaction
of o-aminobenzoketones 1 with anilines 2. In principle, this reac-
tion proceeds initially with the condensation of o-aminobenzoke-
CO2R1
O
N
H
*
Ar
CO2R1
R2
B*-H
N
R3
R3
+
H2N Ar
*
N
R2
2
1
R2
R2
-B*-H
3
B*-H
*B
H
Ar
N
N
CO2R1
H
Asymmetric
Ar
*
CO2R1
H
N
1,5-hydride Shift
R3
R3
H
N
R2
R2
R2
B*
R2
I
II
⇑
Scheme 1. Proposed chiral Brønsted acid-catalyzed redox reaction for the synthesis
of cyclic aminals.
Corresponding author.
E-mail address: gonglz@ustc.edu.cn (L.-Z. Gong).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.062

Y.-P. He et al. / Tetrahedron Letters 52 (2011) 7064–7066
7065
Table 1
Screening chiral phosphoric acids and optimizing reaction conditionsa
Table 2
Catalytic enantioselective tandem hydride transfer/ring closing reactiona
CO2Et
NH2
EtO2C
H
CO2Et
NH2
H
EtO2C
PMP
N
5a (10 mol%)
toluene, 115 °C
3d
R2
O
N
N
B*-H (Xmol%)
Solvent, 115
3d
O
N
+
+
R1
N
R1
N
R2
OMe
2a
2
3
1
3a
1a
Entry Product
Yieldb (%) drc
eed (%)
Entry
B⁄-H
X
Solvent
Yieldb (%)
drc
eed (%)
1
2
3
4
4a
4b
4c
5a
5b
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
10
10
10
5
5
5
5
5
5
5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhCl
o-Xylene
m-Xylene
p-Xylene
Toluene
Toluene
Toluene
78
60
66
80
87
Trace
51
72
71
66
78
60
86
77
90
12:1
12:1
7:1
14:1
12:1
—
10:1
13:1
15:1
13:1
8:1
10:1
14:1
7:1
ꢀ11j
ꢀ46j
ꢀ9j
85
27
—
90
89
86
89
EtOOC
H
N
1
3b 81
10:1 74
N
N
5
6e
7f
EtOOC
H
N
8g
9
2
3c
67
11:1 78
10
11
12
13h
14i
15
5
5
5
5
83
82
80
87
OMe
OMe
EtOOC
H
N
3
3d 76
10:1 79
10
14:1
86
N
N
N
a
Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale in
a solvent (1 mL), and the ratio of 1a/2a is 1/1.25.
Cl
Br
b
Combined yield of both diastereomers.
EtOOC
H
N
c
Diastereomeric ratio is determined by 1H NMR spectroscopic analysis.
4
3e 72
8:1
77
d
Enantiomeric excess of major diastereomer is determined by chiral HPLC
analysis.
e
3 Å MS was used.
4 Å MS was used.
5 Å MS was used.
0.5 mL toluene was used.
2 mL toluene was used.
The opposite enantiomer was obtained to 3a.
f
g
EtOOC
H
N
h
5
3f
57
10:1 80
i
j
OMe
EtOOC
H
R
N
6
7
8
9
3g 72
5:1
7:1
72
74
N
O
O
O
P
X
OH
OMe
EtOOC
H
O
P
HO
O
P
OH
Cl
O
O
N
R
3h 44
O
O
4a, R = C6H5
N
5a, X = O
5b, X = S
4b, R = 2,4,6-(i-Pr)3C6H2
4c, R = SiPh3
OMe
EtOOC
H
Figure 1. The catalysts evaluated in this study.
N
3i
3j
32
55
11:1 84
MeO
N
by this preliminary result, a number of chiral phosphoric acids de-
rived from BINOL were evaluated (Fig. 1). It appeared that none of
these catalysts provided satisfactory levels of enantioselectivity,
although they showed good catalytic efficiency (Table 1, entries
1–3). Gratifyingly, the bisphosphoric acid 5a,7 was the most prom-
ising catalyst and provided an excellent yield and a high enantiose-
lectivity of 85% ee (Table 1, entry 4). However, the bisphosphoric
acid 5b with a 3,30-thiobis(methylene) linker offered a poor ee al-
beit in a high yield and diastereomeric ratio (Table 1, entry 5).
With the optimal catalyst 5a in hand, further investigation was
focused on the effect of reaction parameters including solvents,
molecular sieves, and concentrations. The addition of molecular
sieves led to a slight improvement in the enantioselectivity, but
with a considerable erosion of the yield. For instance, the presence
of 3 Å MS almost completely inhibited the reaction (Table 1, entry
6). The use of 4 Å and 5 Å MS as additives gave higher enantiomer-
ical outcomes, but diminished yields were obtained (Table 1,
OMe
EtOOC
H
N
5:1
84
N
a
The reaction was carried out on a 0.1 mmol scale in toluene (1 mL), the ratio of
1/2 is 1/1.25.
b
Combined yield of both diastereomers.
Diastereomeric ratio is determined by 1H NMR spectroscopic analysis.
c
d
Enantiomeric excess of major diastereomer is determined by chiral HPLC
analysis.
entries 7 and 8 vs 4). Screening of solvents found that toluene
was the best media for the reaction in terms of the conversion
and stereoselectivity (Table 1, entries 4, and 9–12). Lowering the
concentration eroded the enantioselectivity while elevating the

7066
Y.-P. He et al. / Tetrahedron Letters 52 (2011) 7064–7066
Acknowledgments
We are grateful for financial support from the NSFC (20732006)
and MOST (973 project 2009CB82530), the Ministry of Education
and the USTC (WK2060190017).
N
N
Ph
COOEt
3b
Supplementary data
Supplementary data (experimental details and characterization
data of new compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.10.062.
Figure 2. X-ray structure of compound 3b.
References and notes
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concentration led to a diminished diastereoselectivity (Table 1, en-
tries 13 and 14). The best result in terms of yield and stereoselec-
tivity was obtained when the reaction was catalyzed by 10 mol %
of 5a (Table 1, entry 15, 90% yield, 86% ee).
The generality of the protocol for different substrates was next
explored (Table 2). A number of anilines were first examined and it
was found that either electronically donating or less withdrawing
substituents on the benzene ring could be tolerated. In these cases,
both diastereo- and enantioselectivities did not show great sensi-
tivity to the substituents. Thus, a good yield and moderate enanti-
oselectivity were obtained when aniline was used (74% ee, Table 2,
entry 1) while either electronically rich anilines (methyl or meth-
oxy) or electron-withdrawing anilines (bromo or chloro) were able
to deliver 3 in good yield ranging from 57% to 76% and with high
diastereomeric ratios ranging from 8/1 to 11/1 and fairly good
enantioselectivities of up to 80% ee (Table 2, entries 2–5). In con-
trast, anilines bearing a strongly electron-withdrawing group pro-
vided a much lower yield and enantioselectivity.8 A variety of ethyl
2-oxo-2-(2-(pyrrolidinyl)-phenyl)acetates 1 were finally exam-
ined. The introduction of electron-donating substituents at 4- or
5-position (Table 2, entries 6, 8, and 9) was well tolerable to give
the desired compounds in high enantioselectivities, but the reac-
tion conversion appeared to be highly dependent on the electronic
feature. For example, a considerably lower yield was obtained in
the reaction of 2-pyrrolidinyl phenyl keto esters bearing an elec-
tron-donating para-substituent (Table 2, entries 8 and 9), probably
because the electron-donating group makes the corresponding
imine functionality in situ formed less reactive toward the 1,5-hy-
dride shift. Again, ethyl 2-(5-chloro-2-(pyrrolidin-1-yl) phenyl)-2-
oxoacetate participated in the reaction in a good enantiomeric ex-
cess, but a moderate yield was offered (Table 2, entry 7). In this
case, the meta-chloro substituent could be considered as an elec-
tron-donating group to make the keto ester electronically richer
and hence a slower reaction was observed.
The absolute configuration of 3b was determined by X-ray crys-
tallographic analysis. After two recrystallizations, the crystalline
3b was obtained in >99% ee. The X-ray structure revealed the abso-
lute configuration of 3b was assigned to be (3R, 5S) (Fig. 2).
In summary, we have disclosed an organocatalytic asymmetric
tandem 1,5-hydride transfer/ring closing reaction of 2-pyrrolidinyl
phenyl keto esters with anilines to give cyclic aminals in fairly
good diastereo- and enantioselectivities. In this reaction, the intra-
molecular transfer hydrogenation (redox reaction) is the stereo-
genic step. This case represents the first example of
organocatalytic asymmetric transfer hydrogenation of imines by
exploiting inactive sp3 C–H hydride donors in view of the fact that
Hantzsch esters and other highly active hydride donors were
exclusively used in the related reactions.9,10 A further investigation
on improving the stereoselectivity and on other related reactions is
underway.
8. The reaction of 4-aminobenzonitrile, 4-nitroaniline, and 2-nitroaniline with
methyl 4-aminobenzoate proceeded in
enantioselectivity.
a
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