Kinetic resolution of indolines through reductive amination of aldehydes by chiral Br?nsted acid

Article abstract of DOI:10.1016/j.tetlet.2017.06.057

We have developed a highly efficient and practical strategy for the kinetic resolution of indoline derivatives, involving a chiral Br?nsted acid-catalyzed iminium ion formation and asymmetric transfer hydrogenation cascade process. The kinetic resolution allows the synthesis of 2-substituted N-benzylindolines in good yields with moderate to excellent enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2017.06.057

Accepted Manuscript
Kinetic Resolution of Indolines through Reductive Amination of Aldehydes by
Chiral Brønsted Acid
Yingwei Wang, Guangxun Li, Hongxin Liu, Zhuo Tang, Yuan Cao, Gang Zhao
PII:
S0040-4039(17)30788-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.057
TETL 49049
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 May 2017
16 June 2017
19 June 2017
Please cite this article as: Wang, Y., Li, G., Liu, H., Tang, Z., Cao, Y., Zhao, G., Kinetic Resolution of Indolines
through Reductive Amination of Aldehydes by Chiral Brønsted Acid, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.06.057
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Graphical Abstract

Kinetic Resolution of Indolines through Reductive Amination of Aldehydes by Chiral Brønsted
Acid
Yingwei Wang,a, b Guangxun Li,b Hongxin Liu,b Zhuo Tang,*b Yuan Cao,a Gang Zhao*a
aDepartment of Pharmaceutical & Biological Engineering, School of Chemical Engineering, Sichuan
University, Chengdu, Sichuan 610065, China
E-mail: gzhao@scu.edu.cn
bNatural Products Research Center Chengdu Institution of Biology Chinese Academy of Science,
Chengdu, Sichuan 610041, China
E-mail: tangzhuo@cib.ac.cn
Abstract: We have developed a highly efficient and practical strategy for the kinetic resolution of
indoline derivatives, involving a chiral Brønsted acid-catalyzed iminium ion formation and asymmetric
transfer hydrogenation cascade process. The kinetic resolution allows the synthesis of 2-substituted
N-benzylindolines in good yields with moderate to excellent enantioselectivities.
Keywords: Kinetic resolution, indolines, Chiral Brønsted acid, Hydride donor, Transfer hydrogenation
Optically active tertiary amines are important chiral building blocks in preparation of
pharmaceuticals and agrochemicals. Thus, the design and research of new strategies for
enantioselective construction of carbon-nitrogen skeletons has captured the attention of organic
chemists.1 Over the past several decades, N-alkyl indolines have been found in a range of nature
products,2 as well as a variety of biologically active products.3 For example, Vindoline4 acting as an
important anti-tumor agent in clinical practice is one of many alkaloids extracted from Aspidosperma
genus. The alkaloid (+)-ajmaline5 which has antiarrhythmic and anti-sympathomimetic effect was
isolated from the roots of R. serpentina in 1931. The indoline alkaloid (+)-physostigmine6 was
separated out from physostigmine and is a reversible cholinesterase inhibitor for the treatment of
glaucoma (Figure 1). Although asymmetric synthesis of chiral indolines has been achieved by a few
methods, including asymmetric hydrogenation,7 asymmetric cyclization8 and kinetic resolution (KR),9
the specialized researches for asymmetric synthesis of N-alkyl indolines, to the best of our knowledge,
have not been reported.
Figure 1． Examples of natural N-alkyl indolines
The development of KR of racemic starting materials has been attracting considerable attention
of many organic chemists, as the KR has been one of the most powerful and efficient methods for the
synthesis of chiral compounds.10 As we all know, a number of organic scientists have developed
available and reliable catalytic nonenzymatic methodologies for KR of alcohol derivatives.11 However,
there are only a few examples of the catalytic synthesis of indolines that use KR to achieve high
enantioselectivities, especially for construction of N-functionalized indolines. In 2006, Fu’s group9a
firstly reported the KR of indolines to achieve 2-alkyl indolines in high enantioselectivities. N-allyated

products up to 52-92% ee were obtained by the kinetic resolution of indolines through Pd-catalyzed
asymmetric allylic amination by Hou’s group.9b Recently, Seidel utilized the KR of 2-subtituded
indolines to realize the rapid synthesis of polycyclic amines through Povarov reactions.12 Akiyama’s
group9c firstly reported oxidative KR of indolines based on asymmetric hydrogenation of aromatic
imine catalysed with chiral phosphoric acid. And subsequently, they developed KR of indolines based
on a self-redox reaction,13 which was catalyzed by chiral phosphoric acid without synthesizing,
isolating and using excess of resolving reagent. Although the KR of 2-substituted indolines proceeded
in excellent enantioseletivities, N-benzyl indolines were obtained with no more than 78% ee.
Furthermore, the results in fact demonstrated that the reaction proceed by the resolution of the
starting materials that serve as reductant (Scheme 1a).
Scheme 1. General strategies for creating chiral N-benzyl indoline derivatives
Organocatalytic asymmetric transfer hydrogenation with different organic hydride donors14 has
been developed as a useful tool for the construction of C-N bond by reduction of imines in the
presence of Brønsted acids. We envisioned that an organocatalytic KR through a phosphoric acid
catalyzed15 iminium ion formation and transfer hydrogenation cascade process could potentially be a
competitive and general approach toward chiral N-benzyl indoline derivatives. Herein we provided an
efficient protocol for obtaining the N-benzyl indolines through KR of aldiminium intermediate, which is
a significant complement to Akiyama’ work (Scheme 1b).
Scheme 2. Initial attempts with different hydride donors
To validate the feasibility of the proposed process, we selected 2-phenylindoline rac-1a as the
model substrate. We initiated our studies by examining the reaction between rac-1a and 1.2 equiv of
2-nitrobenzaldehyde 2a using 5 mol% of chiral phosphoric acid 4a as catalyst and hantzsch ester (HEH)

5 as hydride donor in toluene at 10 ℃ for 12 h. Emotionally, the reaction proceeded smoothly but
only gave the desired product N-benzylindoline 3a in > 90% yield with 0% ee.16 However, we were
surprised to find that using benzothiazoline 6a as hydride donor, the reaction proceeded better to give
(S)-3a in 34% yield with 70% ee accompanied by (R)-1a in 23% yield with 25% ee (Scheme 2). As a
result, a detailed optimization study was done. We synthesized and screened a variety of chiral
phosphoric acid catalysts for the KR of indoline rac-1a in the presence of aldehyde 2a and thiazoline
6a (Table 1, entries 1-8). In the presence of the catalyst with phenyl group on the 3,3’-positions (Table
1, entry 2), the ee of product 3a was very low and after calculation, a selectivity factor (abbreviated as
s)17 of 1.3 was obtained. The catalysts with 4-substituted phenyl group on the 3,3’- positions (Table 1,
entries 3-5) were capable of inducing KR, however, they produced N-benzylindoline (S)-3a with low ee
(= 2%-6%) and low s (= 1.2-1.3). It was interesting to find that when the triisopropyl phenyl catalyst 4f
(Table 1, Entry 6) was examined, (S)-3a was found to have an ee of 28% and a yield of only 13%, giving
a selectivity factor of 1.9. Gratifyingly, when the aromaticity of 3, 3’-substituted group of the catalysts
enhanced gradually, the ee and s of 3a had prominent improvement (Table 1, entries 1 and 7-8).
According to the results of catalyst screening, the catalyst 4h appeared to be the best catalyst which
showed satisfactory result (s=10.7) for the KR of rac-1a. Subsequently we further examined a range of
benzothiazolines in the KR reaction by means of phosphoric acid 4h (Table 1, 8-12). To our delight, ee
and s could be respectively increased to 84% and 25.2 by using benzothiazoline 6c bearing a
p-nitrophenyl group (entry 10). Next, we investigated the effects of the 3 Å and 4 Å molecular sieves
as additives which were often used to remove water to reduce reaction time and increase ee.
Lamentedly, the diminished ee and s of 3a were observed (Table 1, entries 13-14). Further screening18
for the reaction conditions revealed that the exposure of indoline rac-1a to 2.0 equiv of
2-nitrobenzaldehyde 2a and 1.0 of equiv benzothiazoline 6c in the presence of 10 mol% 4h in 1mL
toluene at -30 ℃ for 56 h provided the product (S)-3a in 43% yield with 92% ee, giving a selectivity
factor of 49.4.
Table 1. Screening results of reaction conditionsa
sd
Entry
Cat.
Thiazoline
3a
yieldb/%
eec/%
1
4a
4b
4c
4d
4e
4f
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
47
71
64
69
68
13
52
40
50
42
58
7
6.8
2
1.3
3
2
1.2
4
6
1.3
5
5
1.2
6
28
41
74
79
84
1.9-
3.7
7
4g
4h
4h
4h
8
10.7
20.6
25.2
9
10

11
4h
4h
4h
4h
4h
6d
6e
6c
6c
6c
60
55
>95
73
43
53
62
5
8.9
12.2
-
12
13e
14f
15g
31
92
5.2
49.4
a The reactions were carried out with rac-1a (0.1 mmol), 2-nitrobenzaldehyde 2a
(1.2 equiv), thiazoline 6 (1.4 equiv) and catalyst 4 (5 mol%) in 1 mL toluene at 10
b
c
℃ under N2. Yield of isolated product. Determined by chiral phase HPLC
d
analysis.
The
selectivity
factor
was
calculated
as
s=In[(1-C)(1-ee(1a))]/In[(1-C)(1+ee(1a))], C=ee(1a)/(ee(3a)+ee(1a)). e50 mg 3 Å MS
was added. 50 mg 4 Å MS was added. g The reaction was performed with 2.0
f
equiv of 2-nitrobenzaldehyde, 1.0 equiv of thiazoline and 10 mol% catalyst at -30
℃ for 56 h.
With the optimal reaction conditions in hand, we set out to explore the substrate generality of
this procedure. As shown in Table 2, the racemic indolines 1b and 1c bearing electron-withdrawing
groups at the 5-position were suitable substrates, affording the corresponding chiral
N-(2-nitrobenzyl)indolines 3b and 3c in moderate yields with excellent enantioselectivities (s= 46 and
52; respectively). Indoline 1d bearing electron-donating group at the 5-position was unsuitable under
the optimal reaction conditions with low selectivity factor (s=3.7). For indolines 1e with and p-tolyl
group and 1f with m-tolyl group at 2-position, the chiral products 3e and 3f were afforded in moderate
yield and ee (s = 35 and 44, respectively). But due to steric hindrance, the 2-(o-tolyl)indoline 1g was
transformed into the product 3g with decreasing ee and s (s = 10). In spite of electronic effect and
steric hindrance, the indolines 1h-k reacted smoothly to steric hindrance, the indolines 1h-k reacted
smoothly to give the corresponding chiral N-(2-nitrobenzyl)indolines 3h-k in moderate or high yields
with excellent enantioselectivities (s=10-165). In addition, indoline 1l bearing cyclohexyl group at 3-
position was also an appropriate substrate, giving the product 3l with 73% ee in 40% yield (s=11). In
consideration of the generality of methodology, electronically different aldehydes have been partially
studied. Those results demonstrated that the high enantiomeric ratios and best yields were obtained
while using hindered and electron-deficient o-nitrobenzaldehyde.

Table 2. Reaction scope for the kinetic resolution of indolinesa,b,c
a The reactions were carried out with rac-1 (0.1 mmol), 2-nitrobenzaldehyde 2a (2.0 equiv), thiazoline 6c (1.0 equiv) and catalyst 4h (10
mol%) in 1 mL toluene at -30 ℃ under N2. b Yield of isolated product. c Determined by chiral phase HPLC analysis.
In analogy to the previously reported results by Akiyama’s group,14h we speculated a
ten-membered transition state in which the ion pair is formed by (S)-aldimiun and chiral phosphate
anion while the benzothiazoline coordinates with the Lewis basic oxygen atom. The hydride is then
transferred to the (S)-aldiminium. (Figure 2)
Figure 2. Proposed transition state
In conclusion, we have developed a highly efficient and practical strategy for the kinetic
resolution of indolines derivatives, involving a chiral Brønsted acid-catalyzed iminium ion formation
and asymmetric transfer hydrogenation cascade process. The KR allows the synthesis of 2-substituted
N-benzylindolines in good yields with moderate to excellent enantioselectivities. The method features
a mild KR through transfer hydrogenation with extra benzothiazoline as hydride sources. The reaction
proceed through the KR of in situ formed aldiminium ion, which was good complementary to
Akiyama’s work for obtaining chiral indolines via KR of starting material. Further application of this

strategy toward the kinetic resolution of similar chiral compounds are currently under active
investigation.
This work was financially supported by the National Natural Science Foundation of China (NSFC)
(grant numbers 21402188, 21402189 and 21322208).
Supplementary data. Supplementary data (experimental procedure, optimization of reaction
conditions and characterisation data of all products listed in the tables) associated with this article are
provided as a separate file and can be found in online version
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Highlights
1. The method provided a concise methodology for the synthesis of chiral indolines.
2. An external hydride transfer agent was used for the KR of racemic indolines.
3. The reaction was good complementary to Akiyama’s work.