Synthesis of Planar Chiral Shvo Catalysts for Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1002/adsc.201501162

A new type of planar chiral Shvo catalysts, where the chirality is based solely on different substitution flanking the C￡O function, was prepared and used for transfer hydrogenation of imines and ketones. The reduction of ketimines represented by N-(1-phe

Full text of DOI:10.1002/adsc.201501162

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DOI: 10.1002/adsc.201501162
Synthesis of Planar Chiral Shvo Catalysts for Asymmetric
Transfer Hydrogenation
Xiaowei Doua and Tamio Hayashia,b,*
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Institute of Materials Research and Engineering, A*STAR, 2 Fusionopolis Way, Singapore 138634, Singapore
b
Fax: (+65)-6779-1691; e-mail: tamioh@imre.a-star.edu.sg or chmtamh@nus.edu.sg
Received: December 23, 2015; Revised: January 15, 2016; Published online: March 8, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501162.
Abstract: A new type of planar chiral Shvo cata-
(Scheme 1).[1] The hydrogenation takes place on com-
À
lysts, where the chirality is based solely on different
plex A by hydride transfer from Ru H and proton
À
À
substitution flanking the C O function, was pre-
transfer from Cp OH leaving complex B, which is
pared and used for transfer hydrogenation of
imines and ketones. The reduction of ketimines rep-
resented by N-(1-phenylethylidene)aniline and pro-
chiral ketones such as phenyl trifluoromethyl
ketone with 2-propanol was efficiently catalyzed by
0.5 mol% of the chiral Shvo catalyst to give high
yields of the corresponding reduction products with
the enantioselectivities in the range 45% to 64% ee.
a key step in the transfer hydrogenation of ketones
and imines. One notable use of the Shvo catalyst
taking advantage of its high activity is as the racemi-
zation catalyst in the dynamic kinetic resolution of
secondary alcohols and amines.[2]
Irrespective of the high catalytic activity, asymmet-
ric reactions with Shvo-type catalysts have not been
well developed, mainly due to lack of a chiral version
of Shvo catalysts with high enantioselectivity. One ra-
tional design of chiral Shvo catalysts is to install two
substituents with different bulks (RL and RS) in close
Keywords: asymmetric catalysis; imine; ketone;
ruthenium complex; Shvoꢀs catalyst; transfer hydro-
genation
À
proximity to the C O function of Shvo catalyst,
which will efficiently differentiate the enantiofaces of
the prochiral substrates at the hydrogen transfer step
[Scheme 2 (A)]. To the best of our knowledge, there
have been only two reports on this type of chiral
Since its discovery in 1985,[1] the Shvo catalyst, which Shvo catalysts,[3] both of which were synthesized
is a cyclopentadienone-ligated dimeric ruthenium through carbonylative cyclization of chiral 1,6-diyne
complex,
{[Ph4(h5-C4CO)]2H}Ru2(CO)4(m-H) precursors as a key step. As a result, they have a ring-
(Scheme 1), has been extensively studied for its appli- fused structure with a chiral carbon center in addition
cation to organic reactions, and it was found to be
one of the most active catalysts for transfer hydroge-
nation of carbonyl and imine compounds and related
reactions.[1] The diruthenium Shvo catalyst is in equi-
librium with two monomeric species in solution, hy-
drido-ruthenium complex A and coordinatively unsa-
turated complex B. They are interconverted through
the gain or loss of “H2” from donors and acceptors,
typically 2-propanol and acetone, respectively
Scheme 2. Chiral Shvo catalyst for asymmetric transfer hy-
drogenation.
Scheme 1. Shvo catalyst and the active monomers
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Synthesis of Planar Chiral Shvo Catalysts and Their Use
to the planar chirality based on the two different sub-
À
stituents flanking to the C O function [Scheme 2
(B)]. Herein, we report a new type of chiral Shvo cat-
alysts, whose structures are very simple only with the
planar chirality, and their application to asymmetric
transfer hydrogenation of imines and ketones.
The cyclopentadienone 1a, which is substituted with
one methyl group at the 2 position and three phenyl
groups at the 3, 4, and 5 positions and is readily ob-
tained by aldol condensation of 1-phenylbutan-2-one
with benzil,[4] was treated with Ru3(CO)12 in methanol
under the conditions reported by Casey[5] to produce
a 70% yield of a racemic mixture of dimeric rutheni-
um complex dl-2a [Scheme 3 (A)]. It is remarkable
that its meso isomer was not observed at all. The race-
mic mixture of dl-2a was separated into enantiomeri-
cally pure components with a chiral HPLC column of
Figure 1. X-ray crystal structure of (1S,1’S)-2a. Thermal el-
lipsoids are drawn at 30% probability. Protons are omitted
for clarity.
preparative size to give us both enantiomers, (1S,1’S)- not always successful for other chiral catalysts while
2a and (1R,1’R)-2a. The absolute configurations were the HPLC separation is efficient for monomers 3.
determined unequivocally by their X-ray crystal struc-
With chiral Shvo catalyst (1S,1’S)-2a in hand, we
ture analyses, the structure of (1S,1’S)-2a being shown examined its reactivity and selectivity in the transfer
in Figure 1.[6] Another route to enantiomerically pure hydrogenation of N-phenyl-(1-phenylethylidene)-
diruthenium complex 2a is by way of separation of amine (4a) (Table 1).[9] Under the reaction conditions
the enantiomers of the monomeric tricarbonyl com- developed by Bäckvall[10] (24 equiv. of 2-propanol in
plex 3a [Scheme 3 (B)]. Thus, the reaction of 1a with toluene at 708C), 4a was all reduced into the corre-
Ru3(CO)12 in toluene gave dl-3a, which was optically sponding amine 5a in the presence of 0.5 mol% of
resolved on a chiral HPLC column. The enantiomeri- (1S,1’S)-2a within 3 h (entry 1). The product 5a was
cally pure (1S)-3a was then subjected to the Hieber determined to be an R isomer of 54% ee by HPLC
base reaction[7] to form the dimer (1S,1’S)-2a.[8] The analysis and its specific rotation. The use of (1R,1’R)-
synthetic route (B) by way of monomeric complex 3a 2a as a catalyst gave (S)-5a with 54% ee (entry 2), the
was found to be more general for the synthesis of same enantioselectivity with the opposite configura-
other chiral Shvo catalysts (vide infra) than the direct tion demonstrating the high reproducibility of the
route (A), because the HPLC resolution of dimer 2 is present asymmetric reaction. In accordance with
Bäckvallꢀs report,[10] the cosolvent plays an important
role in the reactivity of the catalyst. The reduction
was slower in 2-propanol without cosolvent (entry 3)
and it did not take place in DMSO (entry 4). Of the
hydrogen donors examined, cyclopentanol was the
second best to give an 86% yield of (R)-5a with 49%
ee (entry 5). Formic acid did not give the reduction
product in the present system (entry 6). The complex
(1R,1’R)-2a also catalyzed the transfer hydrogenation
of 4-methoxyaniline imine 4b, which gave the corre-
sponding amine with 45% ee (entry 7). The reduction
of the ketimine derived from ortho-substituted aceto-
phenone 4c was slower, although the enantioselectivi-
ty was higher (62% ee) (entry 8).
Enantiomerically pure dimeric complex 2b, where
the methyl group is substituted at the 3 and 3’ posi-
tions in place of the 2 and 2’ positions in 2a, was also
prepared by the two-step method [Scheme 3 (B)] to
examine the effects of the methyl location on the
enantioselectivity. The catalytic activity of 2b was as
high as that of 2a, but the enantioselectivity was very
low (3% ee, entry 9 in Table 1), indicating that the
Scheme 3. Preparation of chiral Shvo catalyst 2a. Reagents
and conditions: (a) Ru3(CO)12, MeOH reflux, 70%; (b) reso-
lution with Chiralpak IA; (c) Ru3(CO)12, toluene reflux,
83%; (d) aqueous Na2CO3, acetone, 59%.
À
chiral environment should be located closer to the C
OH moiety for higher enantiocontrol. To improve the
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Xiaowei Dou and Tamio Hayashi
Table 1. Asymmetric transfer hydrogenation of ketimine 4 catalyzed by chiral Shvo catalysts.[a]
Entry
Catalyst
4
H2 donor/cosolvent
Yield[%][b] of 5
ee [%][c] of 5
1
2
3
4
5
6
7
8
(1S,1’S)-2a
(1R,1’R)-2a
(1S,1’S)-2a
(1S,1’S)-2a
(1S,1’S)-2a
(1S,1’S)-2a
(1R,1’R)-2a
(1R,1’R)-2a
(+)-2b
4a
4a
4a
4a
4a
4a
4b
4c
4a
4a
4a
4a
i-PrOH/toluene
i-PrOH/toluene
i-PrOH/none
99
99
65
0
86
0
99
36
99
99
55
79
54 (R)
54 (S)
47 (R)
–
49 (R)
–
45 (S)
62 (S)
3 (S)
47 (R)
64 (S)
64 (S)
i-PrOH/DMSO
cyclopentanol/toluene
HCO2H/toluene
i-PrOH/toluene
i-PrOH/toluene
i-PrOH/toluene
i-PrOH/toluene
i-PrOH/toluene
i-PrOH/toluene
9
10
11[d]
12[e]
(1S,1’S)-2c
(1R,1’R)-2d
(1R,1’R)-2d
[a]
General conditions: 4 (0.20 mmol), Shvo catalyst (0.5 mol%), hydrogen donor (24 equiv.), cosolvent (1.7”Volhydrogen donor
)
at 708C for 3 h.
Isolated yield.
[b]
[c]
[d]
[e]
Determined by HPLC analysis on a chiral stationary phase column.
Reaction was stopped at 3 h before full conversion of 4a.
1.0 mol% catalyst was used.
enantioselectivity, we have prepared 2c and 2d, which
The catalyst (1R,1’R)-2d was examined for its activ-
are analogous to 2a but substituted with bulkier aro- ity and enantioselectivity in the asymmetric transfer
matic groups at the 5 and 5’ positions, 3,5-dimethyl- hydrogenation of ketones. Preliminary results are
phenyl and 9-anthracenyl, respectively. The (1R,1’R) summarized in Table 2. High catalytic activity was ob-
configuration of 2d was confirmed by X-ray crystallo- served in the reaction of activated ketones, trifluoro-
graphic analysis (Figure 2).[6] The enantioselectivity methyl ketone 6a, a-keto ester 6b, and b,g-unsaturat-
with the catalyst 2c was slightly lower than with cata- ed a-keto ester 6c. They gave a high yield of the cor-
lyst 2a (entry 10), and 2d was found to exhibit highest responding (S)-alcohols 7 with around 50% enantiose-
enantioselectivity (64% ee) of the chiral Shvo type lectivity (entries 1–3). In the reaction of b,g-unsaturat-
catalysts examined here albeit with decreased reactiv- ed a-keto ester 6c, the ketone carbonyl was
ity (entries 11 and 12). It is noted that trisubstituted selectively reduced in the presence of a conjugated
cyclopentadienones, especially for those with hydro- double bond, and isomerization of the resulting allylic
gen next to the carbonyl group, are known to be un- alcohol to ketone was not observed.[11] Unfortunately,
stable,[4] and hence the chiral Shvo type catalysts with the present chiral Shvo catalyst is not applicable for
hydrogens at the 2 and 2’ positions are not readily ac- unactivated ketones like acetophenone 6d. The reac-
cessible by the current method.
tion resulted in low conversion even after a prolonged
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Synthesis of Planar Chiral Shvo Catalysts and Their Use
Scheme 4. Proposed stereochemical pathway for the asym-
metric transfer hydrogenation by catalyst (1R,1’R)-2d. (Car-
bonyls on Ru and Ph rings on Cp are omitted for clarity.)
Figure 2. X-ray crystal structure of (1R,1’R)-2d. Thermal el-
lipsoids are drawn at 30% probability. Protons are omitted
for clarity.
face recognition pathway for the stereochemical out-
come observed in the present study. The proposal in
Scheme 4 is based on an outer-sphere mechanism
model[13] for the Shvo catalyst. The steric repulsions
between the larger substituent of imine or ketone
substrates[14] and the bulky 9-anthracenyl group of
catalyst (1R,1’R)-2d make hydrogen transfer to one of
the enantiofaces less favored, hence accounting for
the observed enantioselectivity.
Table 2. Asymmetric transfer hydrogenation of ketones cata-
lyzed by (1R,1’R)-2d.[a]
In summary, we have developed a new type of
planar chiral Shvo catalysts. It was found that varia-
À
tion of substituents next to the Cp OH moiety is
a promising way to generate chiral Shvo catalysts. In
our study, we found that 9-anthracenyl- and methyl-
substituted catalyst 2d was efficient for asymmetric
transfer hydrogenation reactions of imines and acti-
vated ketones, which showed the highest enantioselec-
tivity achieved by chiral Shvo catalysts reported so
far.
Entry Ketone Catalyst
Yield [%][b]
7
ee [%][c]
7
1
6a
6b
6c
6d
6a
6b
6c
6d
(1R,1’R)-2d 99
56 (S)
53 (S)
46 (S)
4
40 (S)
17 (S)
26 (S)
3
2
(1R,1’R)-2d 91
(1R,1’R)-2d 99
(1R,1’R)-2d 27
(1R,1’R)-2a 99
(1R,1’R)-2a 99
(1R,1’R)-2a 99
(1R,1’R)-2a 80
3
4[d]
5
6
7
8[d]
Experimental Section
[a]
General conditions: ketone 6 (0.30 mmol), (1R,1’R)-2a or
2d (0.5 mol%), 2-propanol (7.2 mmol), and toluene
(0.94 mL) at 708C for 2 h.
General Procedure for Synthesis of Monomeric
Tricarbonyl Complex 3
[b]
[c]
Isolated yield.
A mixture of Ru3(CO)12 (1 equiv.) and 1 (1 equiv. to Ru) in
toluene (0.1M) was stirred at 1108C under N2 for 20–40 h.
After concentration of the mixture, the residue was subject-
ed to column chromatography on silica gel with hexane/
ethyl acetate (2/1) to give the pure complex dl-3 as a solid;
yield: 70–88%. Optical resolution of dl-3 was carried out by
use of a chiral stationary phase column [Chiralpak IA
(2.0 cm I.D.”25 cm)] to give both enantiomers.
Determined by HPLC analysis on a chiral stationary
phase column.
Reaction time was 20 h.
[d]
reaction time and low enantioselectivity (entry 4).
The higher catalytic activity of catalyst 2a than 2d was
also observed in the reaction of ketones 6, but its
enantioselectivity was generally lower (entries 5–8),
as it is expected from the results shown in Table 1.
Although the detailed reaction mechanism for
transfer hydrogenation with the Shvo catalyst is still
General Procedure for Synthesis of Shvo Catalyst 2
from Monomeric Tricarbonyl Complex 3
To
a solution of enantiomerically pure 3 in acetone
under debate,[12] we tentatively propose an enantio- (0.025M) was added saturated aqueous Na2CO3 (Vol=
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Xiaowei Dou and Tamio Hayashi
Volacetone/2) under N2, and the mixture was vigorously stirred
at room temperature for 1–2 h. Water was added to dilute
the reaction, and the mixture was extracted with CH2Cl2.
The combined organic extract was dried over Na2SO4, and
filtered. Evaporation of the solvent followed by flash
column chromatography on silica gel (hexane/CH2Cl2 =1/1)
or GPC purification gave Shvo catalyst 2 as an orange solid;
yield: 59–85%.
iron catalysts with chiral phosphorus ligands, see: c) A.
Berkessel, S. Reichau, A. von der Hçh, N. Leconte, J.-
M. Neudçrfl, Organometallics 2011, 30, 3880–3887.
[4] a) C. F. H. Allen, J. A. VanAllan, J. Am. Chem. Soc.
1950, 72, 5165–5167; b) J. E. Moore, M. York, J. P. A.
Harrity, Synlett 2005, 860–862.
[5] C. P. Casey, S. W. Singer, D. R. Powell, R. K. Hayashi,
M. Kavana, J. Am. Chem. Soc. 2001, 123, 1090–1100.
[6] The details are described in the Supporting Informa-
tion. CCDC 1443812, CCDC 1443813, and CCDC
1443814 contain the supplementary crystallographic
data for (1R,1’R)-2a, (1S,1’S)-2a, and (1R,1’R)-2d, re-
spectively. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for Asymmetric Transfer
Hydrogenation of Ketimine 4
Ketimine 4 (0.20 mol) was placed in an oven-dried Schlenk
tube under nitrogen. Shvo catalyst 2 (0.5 mol%, 1 mmol,
200 mL, 5 mM in toluene) was then added followed by addi-
tion of i-PrOH (367 mL, 4.8 mmol) and toluene (425 mL),
and the solution was stirred at 708C for 3 h. Upon comple-
tion, the solvent was removed on a rotary evaporator, and
the crude product was subjected to silica gel chromatogra-
phy with CH2Cl2/hexane (1/2) to give amine 5.
[7] a) W. Hieber, F. Leutert, Naturwissenschaften 1931, 19,
360–361; b) H. D. Kaesz, R. B. Saillant, Chem. Rev.
1972, 72, 231–281.
[8] Two-steps synthesis of achiral Shvo catalyst, see: N.
Menashe, Y. Shvo, Organometallics 1991, 10, 3885–
3891. Also see ref.[2d]
[9] For a review of Shvo catalyst in hydrogen transfer reac-
tions, see: M. C. Warner, C. P. Casey, J.-E. Bäckvall,
Top. Organomet. Chem. 2011, 37, 85–125.
[10] J. S. M. Samec, J.-E. Bäckvall, Chem. Eur. J. 2002, 8,
2955–2961.
Acknowledgements
We thank Institute of Material Research and Engineering
(IMRE) and National University of Singapore for supporting
this research.
[11] For isomerization of allylic alcohols to ketones in the
presence of Shvo catalyst, see: J.-E. Bäckvall, U. An-
dreasson, Tetrahedron Lett. 1993, 34, 5459–5462.
[12] a) J. S. M. Samec, A. H. Éll, J.-E. Bäckvall, Chem.
Commun. 2004, 2748–2749; b) C. P. Casey, J. B. John-
son, J. Am. Chem. Soc. 2005, 127, 1883–1894; c) C. P.
Casey, G. A. Bikzhanova, Q. Cui, I. A. Guzei, J. Am.
Chem. Soc. 2005, 127, 14062–14071; d) C. P. Casey,
G. A. Bikzhanova, I. A. Guzei, J. Am. Chem. Soc. 2006,
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Šberg, T. Privalov, L. Eriksson, J.-E. Bäckvall, J. Am.
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