Asymmetric transfer hydrogenation of ketimines by indoline as recyclable hydrogen donor

Article abstract of DOI:10.1021/ol502486f

(Chemical Equation Presented) The chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of various ketimines was achieved by the use of 2-aryl indoline as the hydrogen donor. Corresponding chiral amines were obtained in good chemical yi

Full text of DOI:10.1021/ol502486f

Letter
pubs.acs.org/OrgLett
Asymmetric Transfer Hydrogenation of Ketimines by Indoline as
Recyclable Hydrogen Donor
Kodai Saito, Hiromitsu Miyashita, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
S
* Supporting Information
ABSTRACT: The chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of various ketimines was achieved by
the use of 2-aryl indoline as the hydrogen donor. Corresponding chiral amines were obtained in good chemical yields with
excellent enantioselectivities.
he demand for enantiomerically pure compounds has been
steadily increasing in the fields of biochemistry and
T
pharmaceutical chemistry in recent years. Chiral amines, in
particular, are important building blocks in those fields, and it is
thus imperative to develop synthetic methods for the
construction of stereogenic centers bearing nitrogen. The
asymmetric reduction of the CN bond is one of the most
straightforward approaches to afford the chiral amines.1
Although a range of methods for the reduction of ketimines
by means of chiral transition metal catalysts have been
developed,2 drawbacks persist, including the limited substrate
scope and the danger of handling high-pressure hydrogen gas.
Inspired by the manner by which nature conducts reduction
using NAD(P)H, an asymmetric transfer hydrogenation was
developed, which employs hydrogen donors in the presence of
chiral organocatalysts.3,4 Whereas Hantzsch ester 1 is well-
known and the most frequently used hydrogen donor,5 we
recently developed an asymmetric transfer hydrogenation that
uses benzothiazoline 2 as the hydrogen donor and chiral
phosphoric acid (Figure 1).6 Benzothiazoline can be used for a
range of reduction reactions to furnish chiral amines with high
optical purity. Benzothiazoline has an S,N-acetal structure; thus,
the hydrolysis of benzothiazoline proceeds in the presence of
water. Although we have recently developed oxidative kinetic
resolutions of indoline 3 derivatives involving hydrogen transfer
to aromatic imines, the transfer hydrogenation of various imines
was not fully examined.7 As the sulfur atom of benzothiazoline is
substituted by a carbon atom in the molecular structure of
indoline, we can expect that indoline 3 would have higher
stability than benzothiazoline and would be a more useful
hydrogen donor.8 However, another problem persisted: it was
difficult to regenerate 2 by the reduction of benzothiazole due to
the high stability of benzothiazole. We envisioned that the
indole would be cleanly recovered after the hydrogenation
Figure 1. Molecular structures of hydrogen donors and their oxidized
structures (Hantzsch ester, benzothiazoline, and indoline).
reaction and be easily regenerated to the corresponding indoline
by a simple reduction method.9 We wish to report herein the
phosphoric acid catalyzed transfer hydrogenation of aromatic
ketimines and the reductive amination of aliphatic ketones using
indoline as the hydrogen donor.
An initial attempt to perform the proposed transfer
hydrogenation was carried out by using aromatic imine 5a and
an excess amount of racemic 2-phenylindoline 3a in the
presence of a catalytic amount of chiral phosphoric acid 410 (10
mol %) and molecular sieves 5 Å (5 Å MS) at 50 °C (Scheme 1).
When 1.4 equiv of rac-3a was employed for the transfer
hydrogenation, target product 6a was obtained in 71% yield with
85% ee and the remaining indoline 3a was recovered in 62%
yield with 91% ee. From this result, it was found that one
enantiomer of indoline preferentially participated in the
hydrogen transfer to imine 5a.7 The use of 2.0 equiv of rac-3a
Received: August 22, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
With the optimum reaction conditions in hand, we examined
the substrate scope of this asymmetric transfer hydrogenation of
aromatic imines (Scheme 2). The reaction was found to tolerate
Scheme 1. Effect of Hydrogen Donor Loading
Scheme 2. Substrate Scope of Chiral Phosphoric Acid
Catalyzed Asymmetric Transfer Hydrogenation Using
a
,b,c
Indoline
resulted in an 87% yield with 93% ee, and the hydrogen donor
loading of 2.5 equiv produced the best result (quant, 95% ee).
Next, we examined the effect of a substituent of indoline.
When indoline 3b and alkyl-substituted indoline 3c were used
for the transfer hydrogenation, 6a was obtained in 18% and 49%
yields with 63% ee and 76% ee, respectively. The use of 2-aryl
indolines 3d−3h improved both chemical yields and enantio-
selectivities, and indoline 3h bearing a 3,5-xylyl group at the 2-
position was the best choice for this transfer hydrogenation. To
our delight, changing the solvent from benzene to mesitylene
further enhanced both yield and enantioselectivity (entry 8,
Table 1). In addition, 6a was obtained in a quantitative yield
without loss of enantioselectivity despite the lower catalyst
loading (entry 9, Table 1). Finally, the optimum reaction
conditions were established as follows: 5 mol % (R)-4, imine 5
(1.0 equiv), and 2-(3,5-xylyl)indoline 3h (2.5 equiv) in the
presence of 5 Å MS in benzene at 50 °C.
a
Conditions: Reactions were carried out on a 0.1 mmol scale with
starting material 5 (0.1 mmol), 3h (0.25 mmol), (R)-4 (5 mol %), and
5 Å MS (50 mg) in mesitylene (0.1 M) at 50 °C for 3 days (details in
b
c
Supporting Information). Isolated yields. Determined by chiral
HPLC analysis. PMP = p-methoxyphenyl. TMP = 3,4,5-trimethoxy-
phenyl.
electron-withdrawing halo and nitro compounds, albeit with
slightly lower yields in the latter. Ketimine 5e having a sterically
hindered 2-naphthyl group was also employed for this reaction,
and 6e was obtained in 91% yield with 98% ee. Corresponding
amines 6f−6h were also obtained in high to excellent yields with
>99% ee’s. Ketimines 5i, 5j, and 5k bearing a 3,4,5-trimethoxy-
phenyl group on nitrogen11 also proved to be suitable substrates
(>99% ee). Ketimine 5l could also be converted to the
corresponding amine 6l with 97% ee.
a
Table 1. Effect of Substituent at 2-Position of Indoline
Next, we compared the reactivity of two hydrogen donors,
benzothiazoline and indoline (Scheme 3).12 Whereas the
transfer hydrogenation that used benzothiazoline 2a resulted
in good yield with 97% ee, the chemical yield and
enantioselectivity of 6a were further improved to >99% with
>99% ee when indoline 3h was used. These results indicate that
indoline 3h is the effective reagent for the asymmetric transfer
hydrogenation catalyzed by chiral phosphoric acid.
To further test the flexibility of this methodology, we
performed the enantioselective reductive amination of aliphatic
ketones.6e Using 5 mol % (R)-4 and 2.5 equiv of 3h in
mesitylene (80 °C) gave desired product 7a in a quantitative
yield with 95% ee. It is worth noting that the use of
benzothiazoline 2a resulted in a much lower yield due to the
low stability of 2a under the reaction conditions employed
(Scheme 4).
b
c
entry
R
yield (%)
ee (% ee)
1
2
3
4
5
6
7
H (3b)
18
63
76
Me (3c)
49
p-FC6H4 (3d)
p-MeOC6H4 (3e)
m-MeOC6H4 (3f)
2-naphthyl (3g)
3,5-xylyl (3h)
3,5-xylyl (3h)
3,5-xylyl (3h)
92
94
99
93
92
98
81
98
quant
quant
quant
99
d
8
de
,
>99
>99
9
a
Conditions: Reactions were carried out on a 0.1 mmol scale with
starting material 5a (0.1 mmol), 3 (0.25 mmol), (R)-4 (10 mol %),
and 5 Å MS (50 mg) in benzene (0.1 M) at 50 °C for 3 days. Isolated
yields. Determined by chiral HPLC analysis. Mesitylene was used as
b
c
d
e
solvent. (R)-4 (5 mol %) was used.
B
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Scheme 3. Comparison of Reactivity and Selectivity between
Indoline and Benzothiazoline
Scheme 5. Regeneration of Indoline and Indole
a
,b,c
In conclusion, we have developed an asymmetric transfer
hydrogenation of aromatic ketimines and a reductive amination
of aliphatic ketones catalyzed by chiral phosphoric acid in the
presence of indoline as the hydrogen donor. Various chiral
amines were obtained in good yields with excellent
enantioselectivities. Indoline proved to be an efficient hydrogen
donor. The salient features are as follows: (1) Asymmetric
transfer hydrogenation of aryl and aliphatic ketimines proceeded
with high enantioselectivity. (2) 2-Aryl indoline could be
regenerated by the reduction of 2-aryl indole after asymmetric
transfer hydrogenation. (3) 2-Aryl indoline exhibited higher
stability than benzothiazoline as a hydrogen donor in
phosphoric acid catalyzed transfer hydrogenation.
a
Conditions: Ractions were carried out on a 0.1 mmol scale with
starting material 5 (0.1 mmol), 3 or 2a (0.25 mmol), (R)-4 (10 mol
%), and 5 Å MS (50 mg) in mesitylene (0.1 M) at 50 °C for 3 days
(details in Supporting Information). b Isolated yields. c Determined by
chiral HPLC analysis.
Scheme 4. Substrate Scope of Enantioselective Reductive
Amination Using Indoline
a
,b,c
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, analytical data for all new compounds,
NMR spectra for the products, HPLC charts. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: takahiko.akiyama@gakushuin.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Trans-
formation by Organocatalysis” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and a Grant-in-
Aid for Scientific Research from the Japan Society for the
Promotion of Science.
a
Conditions: Reactions were carried out on a 0.1 mmol scale with
amine (0.1 mmol), ketone (0.15 mmol), 3h (0.25 mmol), (R)-4 (5
mol %), and 5 Å MS (50 mg) in benzene (0.1 M) at 80 °C for 3 days
(details in Supporting Information). b Isolated yields. c Determined by
chiral HPLC analysis.
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