Rhodium-catalyzed asymmetric hydrosilylation of ketones employing a new ligand embodying the bis(oxazolinyl)pyridine moiety

Article abstract of DOI:10.1055/s-0029-1219949

A general approach to new ligands embodying bis(oxazolinyl)pyridine has been developed, employing palladium-catalyzed Suzuki coupling and base-mediated cyclization as pivotal steps. A rhodium catalyst derived from the ligand 4-(4-ethylphenyl)-2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine gave excellent enantioselectivity in the asymmetric hydrosilylation of ketones. In addition the electronic effect of remote substituents on the catalytic activity of rhodium catalyst was studied.

Full text of DOI:10.1055/s-0029-1219949

LETTER
1459
Rhodium-Catalyzed Asymmetric Hydrosilylation of Ketones Employing a
New Ligand Embodying the Bis(oxazolinyl)pyridine Moiety
R
hodium-Catalyze
t
d
A
sym
a
m
etric
H
y
n
drosilylation
u
of
K
etones Ghoshal,a,b Asit R. Sarkar,a Govindaswamy Manickam,b R. Senthil Kumaran,b J. Jayashankaran*b
a
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India
Fax +91(33)25828282; E-mail: jjayash@gmail.com
b
Received 25 January 2010
of the remote substituent, that is, located far away from
the catalytic center but connected through an extended p-
conjugation and thereby we envisaged a new ligand class
of type (5a–f, Figure 1).
Abstract: A general approach to new ligands embodying bis(ox-
azolinyl)pyridine has been developed, employing palladium-cata-
lyzed Suzuki coupling and base-mediated cyclization as pivotal
steps. A rhodium catalyst derived from the ligand 4-(4-ethylphe-
nyl)-2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine gave ex-
cellent enantioselectivity in the asymmetric hydrosilylation of
ketones. In addition the electronic effect of remote substituents on
the catalytic activity of rhodium catalyst was studied.
R
Key words: PyBOX, asymmetric hydrosilylation, rhodium cata-
lyst, enantioselectivity, electronic effect
O
O
N
Transition-metal-catalyzed asymmetric synthesis has
emerged as an important tool for the synthesis of chiral
compounds in advanced organic synthesis. Reduction of
ketones by using a chiral catalyst generates a new stereo-
center,1,2 and asymmetric hydrosilylation catalyzed by
rhodium complexes could perform this operation smooth-
ly with high level of enantioselectivity. For this purpose
certain nitrogen-containing chiral molecules have been
synthesized, and they have proved to be efficient chiral in-
ducing ligands in the asymmetric hydrosilyation reac-
tion.3–5
N
N
5a
5b
5c
5d
5e
5f
R = H
R = OMe
R = CN
R = Et
R = Cl
R = COOEt
Figure 1
In this communication, we disclose the syntheses of the
new ligands 5a–f and their influence on the rhodium-cat-
alyzed asymmetric hydrosilylation of ketones.
In 1989, Nishiyama et al. reported the initial finding of py-
box ligand catalytic activity in the rhodium-catalyzed
asymmetric hydrosilylation of ketones.4a Subsequent
studies showed that among the various alkyl substituents
introduced in the oxazolinyl moiety, the isopropyl-con-
taining ligand is much more efficient and thus indicated
the steric influence of the substituent arranged near to the
catalytic center.4a,b Conversely, to understand the elec-
tronic control of the substituent away from the catalytic
center, electron-donating groups such as methoxy and
dimethyl amino groups as well as the chloro electron-
withdrawing group, were installed at the 4-position of py-
ridine moiety. By doing so, the enantioselectivity in-
creased in the case of electron-donating-substituted
ligands whereas for the electron-withdrawing-substituted
ligand the enantioselectivity remained the same as com-
pared to the unsubstituted ligand.4c,6
Our ligand synthesis7a,b commenced from the readily
available chelidamic acid (1) in which the carboxylic ac-
ids were protected as ethyl esters, and then the hydroxyl
group was converted to the corresponding triflate 2. Palla-
dium-mediated Suzuki coupling8a–f of 2 with phenyl bo-
ronic acid in the presence of Pd(PPh3)4 and DIPEA
smoothly afforded the desired product 3a (R = H), thus in-
troducing the extended conjugation at the pyridine 4-posi-
tion. In order to install the oxazolinyl moiety, 3a was
transformed into its acid chloride and further coupling
with optically active (S)-valinol gave the amide 4a. NaH-
mediated cyclization of 4a furnished the ligand 5a
(Scheme 1).9 To introduce the OMe, CN, Et, and Cl
groups at the phenyl ring, the triflate 2 was subjected to
Suzuki coupling with the corresponding boronic acid to
deliver 3b–e which, on further functional-group manipu-
lation and coupling with (S)-valinol, gave 4b–e. Treating
cyano-substituent 5c with ethanolic HCl gave the oxazo-
line ring-cleavage product instead of producing 5f. How-
ever, 4c smoothly produced 4f using ethanolic HCl at
45 °C. Base-mediated cyclization of 4b–f gave the corre-
sponding ligands 5b–f containing electron-donating, elec-
Inspired by this early report of substituent electronic con-
trol in the ligands,4c we were interested to study the effect
SYNLETT 2010, No. 10, pp 1459–1462
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x
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x
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Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1219949; Art ID: D02310ST
© Georg Thieme Verlag Stuttgart · New York

1460
A. Ghoshal et al.
LETTER
R
R
OH
OTf
H
H
N
c
a
b
N
HO
OH
EtO
OEt
N
EtO
OEt
N
N
N
O
O
O
O
O
O
Cl
Cl
O
O
1
4a–e
2
3a–e
d (4c)
a R = H
e
b R = OMe
c R = CN
d R = Et
COOEt
R
R
e R = Cl
f R = COOEt
H
H
f
e
N
N
O
O
O
O
N
N
N
O
O
N
N
N
Rh
Cl
N
Cl
Cl
Cl
Cl
4f
6a–f
5a–f
Scheme 1 Reagents and conditions: (a) i. SOCl2, EtOH, 75 °C; ii. Tf2O, CH2Cl2, 0 °C; (b) RB(OH)2 (R = H, OMe, CN, Et, Cl), DIPEA,
Pd(PPh3)4, DMF, 90 °C; (c) i. LiOH, THF, r.t.; ii. SOCl2, CH2Cl2, 35 °C; iii. (S)-valinol, Et3N, CHCl3, r.t.; iv. SOCl2, 60 °C, (d) ethanolic HCl,
45 °C; (e) NaH, THF, 0 °C; (f) RhCl3, EtOH, 75 °C.
tron-withdrawing, and electron-neutral substituents at the pared to catalyst 6a (Table 1).10 The above screening
phenyl ring9 which are remote from the metal catalytic studies proved that the remote substituents in the catalysts
center.
6b–f have a significant role on controlling the net elec-
tronic environment on the nitrogen and also around the
metal, even though they are far away from the catalytic
center. Encouraged by this outcome, the catalytic activity
of 6d was further explored on substituted acetophenones
and other ketones since it showed best enantioselectivity
among this class of ligands.
The presence of the triflate group in 2 expands the oppor-
tunity to install various kinds of substituents at the pyri-
dine 4-position in ligand type 5. Eventually, based on the
literature procedure,4b the rhodium catalysts 6a–f were
synthesized by refluxing rhodium(III) chloride hydrate in
ethanol with the corresponding ligand 5a–f, to obtain the
products as bright orange solids (Scheme 1).10–12
O
HO
H
Once the catalysts 6a–f were in hand, we focused our at-
tention on studying their catalytic activity in the asymmet-
ric hydrosilylation of ketones. For this purpose, catalyst
6a was initially employed in the hydrosilylation reaction
using acetophenone 8 as a substrate which is considered
a
8
9
as a standard for this kind of investigation. The typical Scheme 2 Reagents and conditions: (a) diphenylsilane, AgBF4,
6a–d (10 mol%), THF, 10 °C, 20 h.
procedure followed for this reaction involved stirring the
acetophenone, diphenylsilane (1.6 equiv), 10 mol% of
Table 1 Screening Results of Catalyst 6a–f on Acetophenone 8
AgBF4 and 10 mol% of the catalyst 6a in THF (1 mL) at
10 °C for 20 hours to give the alcohol (S)-9 in 88% yield
with 90% ee (Scheme 2).13 Under the similar conditions,
the catalyst containing methoxy group, 6b on 8 gave 9 in
78% ee, whereas the catalyst 6c with a cyano substituent
provided 9 with 75% ee. The chloro- and ethyl ester sub-
stituent catalysts gave 9 with ee of 84% and 73%, respec-
tively. Surprisingly, catalyst 6d with the ethyl substituent
gave excellent enantioselectivity, 98% ee with high yield
(94%).14 The enantioselectivity of the reaction decreased
while employing the catalyst 6b containing an electron-
donating group, and it was further decreased for the cata-
lyst 6c possessing an electron-withdrawing group com-
R
Catalyst
6a
Yield (%)
ee (%)
90
H
88
90
96
94
89
78
OMe
CN
Et
6b
78
6c
75
6d
98
Cl
6e
84
COOEt
6f
73
Synlett 2010, No. 10, 1459–1462 © Thieme Stuttgart · New York

LETTER
Rhodium-Catalyzed Asymmetric Hydrosilylation of Ketones
1461
Electron-donating-substituted acetophenone derivatives controlling the net electronic environment at the catalytic
such as 3-methoxyacetophenone 10 gave 11 in 94% ee center. Synthesis and studies of similar ligands and their
whilst electron-withdrawing-substituted acetophenone catalytic activity are in progress and will be communicat-
derivatives such as 3-trifluoromethylacetophenone (12) ed in due course.
furnished 13 in 99% ee. 4-Methoxyacetophenone 14 also
gave 15 in high ee (98%) as shown in Table 2. Similarly
screening other substrates such as 2-phenylethyl methyl
Acknowledgment
A. Ghoshal is grateful to Syngene for providing the necessary faci-
lities to carry out this work. We acknowledge Dr. Goutam Das,
COO, Syngene for his valuable suggestions and kind support. We
also acknowledge K. Kandasamy and D. Anand Raj for their com-
ments during the preparation of the manuscript.
ketone (16) and propiophenone (18) gave 17 and 19, re-
spectively, with >87% ee. Subsequent screening on 1-te-
tralone (20) provided 21 with 98% ee (Table 2).10 All the
substrates studied above using the ligands 5 gave the alco-
hols with S-configuration.
Table 2 Results of Asymmetric Hydrosilylation of Ketones Em-
ploying the Catalyst 6d
References and Notes
(1) (a) Kagan, H. B. Asymmetric Synthesis, Vol. 5; Academic
Press: New York, 1985, 1–39. (b) Brunner, H. Topics in
Stereochemistry, Vol. 18; Interscience: New York, 1988,
129–247.
Entry Substrate
Product
Yield (%)ee (%)
O
HO
H
(2) (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.;
Sayo, N.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem.
Soc. 1987, 109, 5856. (b) Corey, E. J.; Bakshi, R. K.;
Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925.
(3) Bolm, C. Angew. Chem., Int. Ed. Engl. 1991, 30, 542.
(4) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata,
M.; Kondo, M.; Itoh, K. Organometallics 1989, 8, 846.
(b) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K.
Organometallics 1991, 10, 500. (c) Nishiyama, H.;
Yamaguchi, S.; Kondo, M.; Itoh, K. J. Org. Chem. 1992, 57,
4306. (d) Nishiyama, H.; Park, S.-B.; Itoh, K. Tetrahedron:
Asymmetry 1992, 3, 1029. (e) Nishiyama, H.; Yamaguchi,
S.; Park, S.-B.; Itoh, K. Tetrahedron: Asymmetry 1993, 4,
143.
(5) (a) Peyronal, J. F.; Kagan, H. B. Nouv. J. Chim. 1978, 2,
211. (b) Ojima, I.; Kogure, T.; Kumagai, M. J. Org. Chem.
1977, 42, 1671. (c) Brunner, H.; Obermann, U. Chem. Ber.
1989, 122, 499. (d) Brunner, H.; Brandl, P. Tetrahedron:
Asymmetry 1991, 2, 919. (e) Gladiali, S.; Pinna, L.; Delogu,
D. G.; Graf, E.; Brunner, H. Tetrahedron: Asymmetry 1990,
1, 937.
(6) Jacobsen, E. N.; Zhang, W.; Güler, M. L. J. Am. Chem. Soc.
1991, 113, 6703.
(7) (a) Van Staveren, C. J.; Aarts, V. M. L. J.; Grootenhuis,
P. D. J.; Droppers, W. J. H.; Van Eerden, J.; Harkema, S.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1988, 110, 8134.
(b) Hong, F.; Hollenback, D.; Singer, J. W.; Klein, P.
Bioorg. Med. Chem. Lett. 2005, 15, 4703.
(8) (a) Belanger, D. B.; Siddiqui, M. A.; Curran, P. J.; Hamman,
B.; Zhao, L.; Reddy, P. A. P.; Tadikonda, P. K.; Shipps, G.
W. Jr.; Mansoor, U. F. WO 082487 A2, 2008. (b) Oh-e, T.;
Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
(c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(d) Stanforth, S. P. Tetrahedron 1998, 54, 263. (e) Sutton,
A. E.; Clardy, J. Tetrahedron Lett. 2001, 42, 547.
(f) Hovinen, J.; Mukkala, V. M.; Hakala, H.; Peu-Rahlati, J.
WO 058877 A1, 2005.
1
92
94
OMe
11
OMe
10
O
HO
H
2
3
89
85
99
98
CF3
CF3
13
12
O
HO
H
MeO
MeO
15
14
O
HO
H
4
5
93
94
87
95
17
16
18
20
O
O
HO
H
19
HO
H
6
94
98
21
In conclusion, we have envisaged and synthesized a new
class of ligands employing palladium-catalyzed Suzuki
coupling and base-mediated cyclization as pivotal steps.
The ligands were used to synthesize the rhodium catalysts
which were screened for asymmetric hydrosilylation of
ketones. Among these, the catalyst with the electron-neu-
tral ethyl substituent was proved to furnish excellent enan-
tioselectivity with good to high yields and hence it is clear
that the remote substituent has significant influence on
(9) The overall yield of the ligand 5a is 45%. Similarly the
overall yields for ligands 5b,c,d,e,f are 39%, 40%, 38%,
33%, and 28%, respectively.
(10) All compounds were characterized based on 1H NMR and
mass spectrometric analysis. Enantiomeric excesses of
alcohols were determined by chiral HPLC using either
Chiracel or Chiralpak OD-H columns.
(11) 4-(4-Ethylphenyl)-2,6-bis(4-isopropyl-4,5-dihydro-
oxazol-2-yl)pyridine (5d)
Synlett 2010, No. 10, 1459–1462 © Thieme Stuttgart · New York

1462
A. Ghoshal et al.
LETTER
bond of the complex preferably attacks the re face of the
White solid. [a]D22 –44.7 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): d = 8.44 (s, 2 H), 7.72 (dd, J = 1.7, 6.5 Hz, 2
H), 7.33 (d, J = 8.2 Hz, 2 H), 4.57 (d, J = 8.3 Hz, 1 H), 4.55
(d, J = 8.3 Hz, 1 H), 4.28 (d, J = 8.4 Hz, 1 H), 4.24 (d, J = 8.3
Hz, 1 H), 4.15–4.21 (m, 2 H), 2.72 (q, J = 7.6 Hz, 2 H), 1.90
(q, J = 6.6 Hz, 2 H), 1.28 (t, J = 7.6 Hz, 3 H), 1.07 (d, J = 6.7
Hz, 6 H), 0.96 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR (100
MHz, CDCl3): d = 162.5, 149.8, 147.4, 146.2, 134.0, 128.7,
127.2, 123.2, 72.9, 70.9, 32.9, 29.7, 28.6, 19.1, 18.3, 15.4
ppm. HRMS: m/z calcd for C25H31N3O2: 405.2416; found:
405.2437.
ketone to obtain the S-alcohol
(14) Typical Procedure for the Asymmetric Hydrosilylation
of Acetophenone 8: (S)-1-Phenylethanol 9
A suspension of the catalyst 6d (0.0333 mmol) and AgBF4
(0.0333 mmol) in THF (2 mL) was stirred at 10 °C for 1 h,
and acetophenone 8 (0.3329 mmol) was added to the
reaction mixture at the same temperature. Diphenylsilane
(0.5332 mmol) was added at 0 °C and the mixture allowed to
warm up to 10 °C and stirred for a further 20 h. The reaction
was quenched with MeOH (2 mL) followed by the addition
of 1.5 M HCl (2 mL). The mixture was extracted with EtOAc
(3 × 5 mL), and the combined organic layers were washed
with H2O (5 mL), brine (5 mL), dried over Na2SO4, filtered,
and concentrated. The crude product was purified by silica
gel column chromatography using 10% EtOAc in hexane to
obtain 9 (92%). 1H NMR (400 MHz, CDCl3): d = 7.28–7.40
(m, 5 H), 4.93 (q, J = 6.4 Hz, 1 H), 1.52 (d, J = 6.4 Hz, 3 H).
The ee was determined by HPLC with Chiracel OD-H
column, 5% EtOH–hexanes, 0.7 mL/min, 210–400 nm;
tR(major) = 11.7 (98.8%), tR(minor) = 10.1 (1.1%), 98% ee.
(12) Compound 6d
Orange solid. 1H NMR (400 MHz, CDCl3): d = 8.12 (s, 2 H),
7.63 (d, J = 7.8 Hz, 2 H), 7.44 (d, J = 7.7 Hz, 2 H), 4.92–5.03
(m, 4 H), 4.69 (d, J = 7.3 Hz, 2 H), 3.09 (m, 2 H), 2.78 (q,
J = 7.6 Hz, 2 H), 1.31 (t, J = 7.6 Hz, 3 H), 1.03 (d, J = 6.6
Hz, 6 H), 1.0 (d, J = 7.1 Hz, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 166.2, 153.9, 148.8, 146.9, 132.2, 129.6, 127.5,
123.9, 73.2, 68.7, 29.7, 28.7, 28.4, 19.6, 15.2, 15.1 ppm.
(13) Catalyst 6 was activated by AgBF4 followed by treatment
with Ph2SiH2 to form an intermediate complex. The Rh–Si
Synlett 2010, No. 10, 1459–1462 © Thieme Stuttgart · New York

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