Chemoselective hydrogenation of imides catalyzed by Cp*Ru(PN) complexes and its application to the asymmetric synthesis of paroxetine

Article abstract of DOI:10.1021/ja067777y

This work represents the first catalytic hydrogenation of imides into amides and primary alcohols, in which the unique chemoselectivity is originated from the bifunctional nature of ruthenium-NH moiety in the catalyst. Copyright

Full text of DOI:10.1021/ja067777y

Published on Web 12/19/2006
Chemoselective Hydrogenation of Imides Catalyzed by Cp*Ru(PN) Complexes
and Its Application to the Asymmetric Synthesis of Paroxetine
Masato Ito, Ayaka Sakaguchi, Chika Kobayashi, and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received October 31, 2006; E-mail: tikariya@apc.titech.ac.jp
Scheme 1. Possible Transition States for the Reductive Cleavage
of C-O Bonds in Ketone or Epoxide
We have been engaged in the development of transition-metal/
NH bifunctional molecular catalysts1 including Cp*Ru(II) com-
plexes bearing protic amine ligands.2 A ternary system of Cp*RuCl-
(cod), Me2N(CH2)2NH2 (1a), and a base (Cp* ) η5-C5Me5, cod )
1,5-cyclooctadiene) provides excellent catalytic activity for the
chemoselective hydrogenation of ketones.2a On the other hand, the
analogous system with Ph2P(CH2)2NH2 (1b) serves as an effective
catalyst not only for the hydrogenation of ketones but also for the
hydrogenolysis of epoxides.2b The difference in their reactivity may
be attributable to the electronic factor of tertiary amino and
phosphino groups in the ligands. We postulated that the Brønsted
acidity of the NH2 group in the possibly active species, Cp*RuH-
[L(CH2)2NH2-κ2-L,N] (L ) NMe2 or PPh2) is responsible for the
range of reducible polar bonds (Scheme 1). Then, to test the
hypothesis, we examined the reactivity of both catalyst systems
for the reduction of imides. We found that the binary catalyst system
of Cp*RuCl[Ph2P(CH2)2NH2-κ2-P,N] (2b) and a base effects an
efficient hydrogenation of imides leading to amides and primary
alcohols. Furthermore, the chiral modification of 2b successfully
leads to the development of the highly enantioselective hydrogena-
tion of prochiral imides via desymmetrization, which is applicable
to the concise synthesis of the antidepressant (-)-paroxetine.
Initial experiments focused on the ligand acceleration effect in
the hydrogenation of N-benzylphthalimide (3a) as a model reaction.
Scheme 2. Cp*Ru(PN)-Catalyzed Hydrogenation of 3a
Table 1. Hydrogenation of Various Imidesa
time
(h)
yield
(%)
time
(h)
yield
(%)
entry
3
entry
3
1
2
3
4
5
6
7b
3b
3c
3d
3e
3f
18
18
18
18
18
18
18
>99
>99
>99
>99
>99
>99
>99
8b
9b
3i
3j
3k
3l
3m
3n
18
18
18
18
2
49
88
>99
>99
>99d
>99e
10b
11b
12b,c
13b
3g
3h
18
a Conditions: PH ) 3 MPa, 80 °C, [3] ) 0.20 M in 2-propanol, 3/2b/
KOt-Bu ) 100:1:1 (21 mol %) unless otherwise noted. b Reaction run using
5 mol %. c [3m] ) 0.04 M in 2-propanol. d The depivaloylated amide was
obtained exclusively. e 4n was obtained exclusively.
We found that the hydrogenation (PH ) 1 MPa) proceeds smoothly
2
in the presence of Cp*RuCl(cod), 1b, and KOt-Bu (3a/Ru/1b/KOt-
Bu ) 100:1:1:1, [3a] ) 0.33 M in 2-propanol) at 80 °C to give
N-benzyl 2-hydroxymethylbenzamide (4a) selectively in >99%
yield after 2 h. In sharp contrast, the use of the diamine 1a resulted
in the complete recovery of the starting material under the same
conditions. Structurally analogous PN ligands with an NH group
(1c-e) also accelerate the reaction (21%, 64%, and 67% yields
after 2 h, respectively), whereas the tertiary amine variant Ph2P(CH2)2-
NMe2 was completely ineffective. These results strongly present
the crucial importance of the NH group in the ligand, which may
exert suitable Brønsted acidity in the transition state. It should be
noted that the binary system of 2b and a base exhibited almost
equal catalytic activity.
As we have reported separately, another notable feature of the
system of 2b and a base is its excellent catalytic activity for the
intramolecular transfer hydrogenation of sec-alcohols, which has
led to our recent development of the racemization of chiral
nonracemic sec-alcohols2c as well as the isomerization of allylic
alcohols.2d Accordingly, it was of interest to clarify the role of
2-propanol used in the hydrogenation of 3a. Although 3a was also
convertible to 4a in 2-propanol containing the same catalyst system
in the absence of H2, its rate was considerably slower (9% yield, 2
h) and the pressurization of H2 dramatically accelerated the reaction.
Furthermore, the reaction also proceeded in non-alcoholic solvents
such as THF or toluene in the presence of H2 albeit less efficiently.
These results led us to conclude that 2-propanol mainly promotes
the reaction by participating in the heterolytic cleavage of H2
possibly through a hydrogen-bonding network as we previously
proposed,2a,b and it hardly serves as a hydrogen source in the present
reaction conditions.
Next, the scope of the hydrogenation with 2b (PH ) 3 MPa)
2
was examined using various imides (Table 1). A variety of
symmetrical cyclic imides (entries 1-11) gave ω-hydroxycarbox-
amides exclusively. Neither of the substituents on the ring system
(entries 4-8) or on the nitrogen (entry 3 vs entries 9-11) interferes
with the catalytic activity. The product distribution in the case of
unsymmetrical imides (entries 12, 13) was delicately influenced
by steric and electronic factors. While the pivaloyl group in 3m
was selectively hydrogenated to give the corresponding amide, the
9
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J. AM. CHEM. SOC. 2007, 129, 290-291
10.1021/ja067777y CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Preparation of (-)-Paroxetinea
Scheme 3. A New Method for the Deprotection of N-Phthaloyl
Amino Acid Derivative
a Reaction conditions: (a) CBr4, PPh3, (b) NaH, (c) CAN.
Table 2. Enantioselective Hydrogenation of Prochiral
Glutarimidesa
of imides into amides and primary alcohols.8 Our system may
provide an alternative method for stoichiometric metal-hydride
reduction because of its unique chemoselectivity and stereoselec-
tivity.
Acknowledgment. Support of this research was provided by
Ministry of Education, Culture, Sports, Science, and Technology
of Japan (Grant Nos. 16750073 and 18065017) and by the Asahi
Glass Foundation (M.I.). We are grateful to Dr. A. Osaku for his
technical assistance on this study.
entry
3
R
yield (%)
ee (%)
confign
1
2
3
4
5
3g
3p
3q
3r
3s
Bn
>99
>99
78
90
>99
64b
75d
85f
(+)c
CH2(1-naphthyl)
(-)c
Phe
(-)c
4-MeOC6H4
(3,4-OCH2O)C6H3
91d
98g
(-)c
R-(-)h
Supporting Information Available: Full experimental details
including spectral data and determination of ee’s. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Conditions: imide/2f/KOt-Bu ) 10:1:1, [imide] ) 0.20 M in 2-propanol
unless otherwise noted. b HPLC analysis using a Daicel Chiralcel OD-H
column. c Not determined. The sign of rotation of the isolated product in
parenthesis. d HPLC analysis using a Daicel Chiralcel OD column. e THF
was used as a cosolvent (2-propanol/THF ) 1:5.6 (v/v)) owing to the low
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plays a key role in the selectivity.3
The present catalysis can be applied for the deprotection of the
primary amine from N-phthalimides.4 For instance, N-(o-hydroxy-
methylbenzoyl)-L-Phe methyl ester (4o), which was cleanly formed
in situ by the hydrogenation of N-phthaloyl-L-Phe methyl ester
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dioxane at 30 °C for 1 h to produce the HCl salt of L-Phe methyl
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catalyst with 1b in the hydrogenation of imides, we next examined
asymmetric hydrogenation of prochiral glutarimides with a well-
defined chiral catalyst precursor Cp*RuCl[(S)-Ph2PCH2CHR′NHR′-
κ2-P,N] (R′ ) -(CH2)3-, 2f). The screening tests of substituents
on nitrogen in 4-(4-fluorophenyl)glutarimides (Table 2) has revealed
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N-alkyl compounds (entries 1, 2 vs entries 3-5).
Lowering the reaction temperature to 60 °C resulted in increased
enantioselectivity and that of 4s reached as high as 99% ee.5,6 As
illustrated in Scheme 4, its further synthetic elaboration including
bromination of OH group, base-induced cyclization, and CAN-
mediated dearylation (Supporting Information) gave the chiral
piperidinone (R)-6s, which constitutes an important synthetic
intermediate for the preparation of the antidepressant (-)-par-
oxetine.7
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with the pro-R carbonyl group preferentially.
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In summary, we have found that the Cp*Ru(PN) system is an
effective catalyst for hydrogenation of imides. This work presents
the first catalytic chemoselective and stereoselective hydrogenation
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