Chiral Phosphoric Acid Catalyzed Kinetic Resolution of Indolines Based on a Self-Redox Reaction

Article abstract of DOI:10.1002/anie.201510692

A strategy for oxidative kinetic resolution of racemic indolines was developed, employing salicylaldehyde derivative as the pre-resolving reagent and chiral phosphoric acid as the catalyst. The iminium intermediate, formed by the condensation reaction of an enantiomer of indoline with salicylaldehyde derivative, was hydrogenated by the same enantiomer of indoline to afford another enantiomer of indoline by a self-redox mechanism. The oxidative kinetic resolution of 2-aryl-substituted indolines proceeded to give enantiomers in good yields with excellent enantioselectivities.

Full text of DOI:10.1002/anie.201510692

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International Edition: DOI: 10.1002/anie.201510692
German Edition: DOI: 10.1002/ange.201510692
Kinetic Resolution
Chiral Phosphoric Acid Catalyzed Kinetic Resolution of Indolines
Based on a Self-Redox Reaction
Kodai Saito and Takahiko Akiyama*
Abstract: A strategy for oxidative kinetic resolution of racemic
indolines was developed, employing salicylaldehyde derivative
as the pre-resolving reagent and chiral phosphoric acid as the
catalyst. The iminium intermediate, formed by the condensa-
tion reaction of an enantiomer of indoline with salicylaldehyde
derivative, was hydrogenated by the same enantiomer of
indoline to afford another enantiomer of indoline by a self-
redox mechanism. The oxidative kinetic resolution of 2-aryl-
substituted indolines proceeded to give enantiomers in good
yields with excellent enantioselectivities.
T
he development of new methods for the asymmetric
synthesis of chiral skeletons has captured the attention of
synthetic organic chemists.[1] Kinetic resolution (KR) of
racemic substrates is one of the most important methods for
obtaining chiral compounds.[2] Although efficient KR of
alcohol derivatives has been achieved by many research
groups using catalytic nonenzymatic methods, KR of amines
is little investigated because of the high reactivity and
coordinating ability of amines. KR of amines and alcohols is
generally carried out in the presence of a chiral catalyst using
more than half an equivalent of resolving reagent R’X or
chiral resolving reagent R’*X (Scheme 1, N-functionaliza-
tion).
Scheme 1. Approaches for kinetic resolution of racemic amines.
the Brønsted acid catalyzed redox amination reaction of
cyclic amines with aldehyde (operating via an intramolecular
hydride transfer step) has undergone extensive study by many
research groups. The organocatalyzed asymmetric intermo-
lecular redox amination (reductive amination) is also well-
known,[10] but requires addition of terminal reductants, such
as Hantzsch ester. As an interesting example, the groups of
Pan and Seidel independently reported the benzoic acid
catalyzed self-redox amination reaction of indolines.[9i,j] Their
reports describe efficient intermolecular hydride transfer
from starting material (A-H) to iminium intermediate (BA-
H, which is generated by reacting starting material with
aldehyde (B)), to give oxidized (A) and reduced (H-BA-H)
products (Scheme 1). Zhou and Fan et al. reported an
asymmetric disproportionation reaction of achiral dihydro-
quinoxaline using chiral phosphoric acid, wherein two mol-
ecules of dihydroquinoxaline reacted to afford quinoxaline
and tetrahydroquinoxaline with excellent enantioselectivity
by a self-transfer hydrogenation reaction.[11] Nevertheless, to
the best of our knowledge the asymmetric self-redox reaction
of racemic substrates has not been reported. Our strategy for
KR of amines is based on the self-redox reaction of a chiral
starting material to form a chiral iminium intermediate, which
is generated by condensation of the racemic starting amine
and aldehyde. Two working hypotheses were required to
realize the proposed KR: 1) the reduction of one enantiomer
of racemic iminium intermediates (enantiomers are in
equilibrium) is faster than that of the other enantiomer
(in situ generated chiral resolving reagent is required); 2) one
Over the last decades, indolines have attracted consid-
erable attention in the pharmaceutical as well as agrochemical
sciences.[3] Nevertheless, there are few reports on the catalytic
synthesis of indolines that use KR to achieve high enantio-
selectivity. Fu and Hou independently developed KR of
indolines derived from functionalization of the nitrogen atom
of indoline.[4,5] On the other hand, we recently reported
oxidative KR of indolines based on an asymmetric hydrogen
transfer reaction to aromatic ketimine by means of chiral
phosphoric acid.[6] Although that was the first report on KR of
secondary amines that employed a dehydrogenation reaction
without oxidation of the nitrogen atom,[7,8] we still had to
synthesize, isolate, and use an excess of the resolving reagent
(ketimine).
The redox amination reaction has received much atten-
[9]
À
tion as a powerful tool for C N bond formation. Recently,
[*] Dr. K. Saito, Prof. Dr. T. Akiyama
Department of Chemistry, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
E-mail: takahiko.akiyama@gakushuin.ac.jp
Dr. K. Saito
Present address: Department of Chemistry, Keio University
Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510692.
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Table 1: Screening of aldehydes for catalytic kinetic resolution.
enantiomer of the racemic starting material preferentially
donates a hydride to the iminium intermediate, thereby
resulting in an enantiomerically enriched starting material
and a chiral reductive amination product.
At the outset, we chose racemic 2-phenylindoline (rac-2a)
as the model substrate and treated it with 0.3 equiv of 4-
bromobenzaldehyde (3a) in the presence of a catalytic
amount of phosphoric acid (R)-1a[12,13] at room temperature
(Scheme 2). An intermolecular hydride transfer reaction
2a
4
Entry Aldehyde
Yield [%] ee [%] Yield [%] ee [%]
1[a]
2[b]
3
3b
3b
3b
43
36
41
49
91
90
20
27
31
51
4
5
3c
3d
no reaction
40
45
6
7
8
3e
3 f
3g
53
36
45
83
86
96
20
29
24
58
50
78
Yields of isolated products reported, ee determined by chiral phase HPLC
analysis. [a] (R)-1a (5 mol%) was used. [b] (R)-1b (5 mol%) was used.
Scheme 2. First attempt at kinetic resolution of indoles and a proposed
reaction mechanism.
proceeded to give (S)-2a in 43% yield with 4% ee, 4a
(27% yield), and 5 (30% yield). On the other hand, use of
0.3 equiv of salicylaldehyde (3b) resulted in the formation of
(R)-2a in 43% yield with 49% ee accompanied by 4b and 5.[14]
A plausible reaction mechanism for describing the phosphoric
acid catalyzed KR is proposed in Scheme 2. When 3b was
employed, intermolecular hydride transfer from (S)-2a to
iminium intermediate 6b occurred with moderate ee.[9h,15]
Importantly, to achieve a highly enantioselective KR by the
self-redox method, equivalent enantiomers of 2a have to
cooperate to form an iminium intermediate 6b and prefer-
entially supply a hydride to 6b.
We examined the effect of the 3,3’-substituents of
phosphoric acid on selectivity (Table 1). The connection of
the substituents at the ortho and para positions of the
aromatic ring to the 3,3’-positions of the BINOL backbone
played an important role in the enantiocontrol of KR.
Introduction of the 9-anthryl group ((R)-1b) gave the highest
ee of 91% (entry 2), and the loading of (R)-1b could be
reduced to 2 mol% without any deleterious effect on
enantioselectivity (entry 3). Subsequently, we tried to opti-
mize the resolving reagent for KR using (R)-1b. Resolving
reagents bearing a substituent at the position ortho to the
hydroxyl and formyl groups induced no conversion (entry 4)
and lowered the enantioselectivity (entry 5). Introduction of
a substituent para with respect to the hydroxy group had
a significant impact on enantioselectivity; in particular, an
electron-donating group had a positive effect on enantiose-
lectivity (entries 6–8). Finally, we found that commercially
available 5-methoxysalicylaldehyde (3g) was the aldehyde of
choice for this reaction (entry 8).
To examine the scope of the KR method, a series of 2-
substituted indolines 2a–2u were subjected to the optimized
reaction conditions (Table 2). All of the racemic indolines
reacted smoothly to give the corresponding chiral indolines in
high yields with good to excellent enantioselectivities. Indo-
lines 2m–2t bearing electron-donating or -withdrawing
groups at the 4-, 5-, and 6-positions were also suitable
substrates, affording the corresponding chiral indolines in
high yields with excellent enantioselectivities. Substrate 2u
bearing a 7-methyl group participated in oxidative KR with
a high selectivity factor (s = 49). It is noted that the 2-aryl-
substituted indolines bearing no protecting group on the
nitrogen atom are inaccessible by the previously reported
asymmetric hydrogenation approaches.[5,16] Moreover, it
should also be noted that the recovered 2a had an opposite
absolute configuration compared to the previous oxidative
kinetic resolution (OKR) product when ketimine 7 was used
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Table 2: Scope of catalytic kinetic resolution of indolines.
Table 2: (Continued)
Entry
Indoline
Yield [%]
52
ee [%]
20
2t
93
Entry
1
Indoline
Yield [%]
45
ee [%]
21
2u
77 (56[a])
33 (72[a])
2a
96
Yields of isolated products reported, ee determined by chiral phase HPLC
analysis. [a] 3g (0.05 mmol) was used.
2
3
4
5
2b
2c
2d
2e
49
44
41
44
98
93
98
97
as the resolving reagent in conjunction with catalyst (R)-1b.[6]
In this manner, an enantiodivergent synthesis of 2-substituted
indoline could be achieved with identical catalyst simply by
changing the resolving reagent. To confirm the utility of this
method, we compared the reactivity and selectivity of the
present KR procedure with that of the previous method
(Scheme 3).[6] Both enantiomers of 2p and 2m were obtained
with excellent enantioselectivity after an appropriate choice
of resolving agent was made. The present method proved to
be superior for 2s, whereas the previous OKR approach was
superior for 2u in terms of conversion.[17]
6
7
2 f
42
40
97
97
2g
In conclusion, we have developed a highly efficient
method for kinetic resolution of indoline derivatives, which
involves an asymmetric intermolecular hydride transfer from
indoline to iminium intermediate, which is generated by
reacting aldehyde with indoline. KR enabled synthesis of 2-
aryl-substituted indolines in high yields with excellent enan-
tioselectivities. The method features mild OKR using a hy-
dride transfer reaction and a small amount of resolving
reagent. Investigations into mechanistic function, and appli-
cations that extend to the synthesis of more complex
molecules, are under way.
8
9
2h
2i
41
50
96
87
10
11
12
2j
2k
2l
38
46
43
89
93
94
13
14
2m
2n
40
41
95
95
15
2o
39
96
Scheme 3. Enantiodivergent synthesis of 2-substituted indolines.
Yields of isolated products reported, ee determined by chiral phase
HPLC analysis. [a] Resolutions were carried out on a 0.1 mmol scale
with racemic 2 (0.1 mmol), 3g (0.03 mmol), (R)-1b (2 mol%), and 5 Š
M.S. (50 mg) in benzene (0.1 m) at room temperature for 22 h.
[b] Resolutions were carried out on a 0.1 mmol scale with racemic 2
(0.1 mmol), 7 (0.06 mmol), (R)-1b (5 mol%), and 5 Š M.S. (50 mg) in
benzene (0.1 m) at 508C for 19 h.
16
17
2p
2q
41
43
99
97
18
19
2r
40
47
98
92
2s
Experimental Section
A typical procedure for the reaction of rac-2a: A magnetic stirrer bar
and 5 Š M.S. (50 mg) were placed in a test tube (10 mL) under
a nitrogen atmosphere. The 5 Š M.S. were then dried with a heat gun
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2a (19.6 mg, 0.100 mmol), phosphoric acid (R)-1b (2.0 mg, 2 mmol),
and aldehyde 3g (4.5 mg, 0.030 mmol) were added to the test tube
successively, under nitrogen atmosphere, and at room temperature.
Benzene degassed by sonication under reduced pressure (1 mL) was
added to the test tube. After stirring for 22 h at room temperature, the
mixture was filtered through a Celite pad (previously washed with
CH2Cl2), the filtrate concentrated under reduced pressure, and the
residue purified by preparative thin layer chromatography on silica
gel (AcOEt/hexanes = 1:5) to give 8.8 mg (0.045 mmol, 45%) of (R)-
2a as an amorphous solid.
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Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Trans-
formation by Organocatalysis” from MEXT, Japan.
Keywords: asymmetric synthesis · heterocycles ·
hydrogen transfer · kinetic resolution · organocatalyst
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(S)-4b (28%, > 99% ee). This result indicates that racemization
of the 2-position of 2a by intramolecular 1,3-hydrogen shift did
not occur during this process.
[16] The reaction of 2-alkyl substituted indolines resulted in lower
conversions and selectivities (in the case of racemic 2-methyl-
indoline, 62% yield with 24% ee). Additionally, 2,3-disubsti-
tuted indolines were not converted efficiently. These substrates
were successfully kinetically resolved by our previous method
(Ref. [6]).
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[14] The absolute configuration of the recovered enantio-enriched 2a
was determined by comparison of retention times using chiral
phase HPLC analysis and the sign of optical rotation derived
from our previous report (ref. [6]).
[17] In our previous report (Ref. [6]), the effect of substituents on the
aromatic ring of indoline was not fully examined.
[15] The reaction of (S)-2a (> 99% ee) and 3b in the presence of
a catalytic amount of (R)-1b gave (S)-2a (40%, > 99% ee) and
Received: November 18, 2015
Published online: January 28, 2016
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