(η5-triphenylindenyl)Ru(CO)2Cl: A new ruthenium catalyst for the highly efficient racemization of chiral 1-phenylethanol at room temperature

Article abstract of DOI:10.1055/s-2006-939038

A new ruthenium complex, (η⁵-triphenylindenyl)Ru(CO) ₂Cl, was synthesized and successfully applied in the racemization of (S)-1-phenylethanol at room temperature. Instead of potassium tert-butoxide, stronger bases such as sodium hydr

Full text of DOI:10.1055/s-2006-939038

LETTER
5
945
(
h -Triphenylindenyl)Ru(CO) Cl: A New Ruthenium Catalyst for the Highly
2
Efficient Racemization of Chiral 1-Phenylethanol at Room Temperature
a
N
Q
ew
R
uthenium
C
i
atalyst
a
for Racemi
n
zation of Ch
g
iral 1-Phenylethano
X
l
i,a,b Weicheng Zhang, Xumu Zhang*a
a
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
b
School of Chemical Engineering and Pharmacy, Wuhan Institute of Chemical Technology, Wuhan, P. R. of China
Fax +1(814)8653932; E-mail: xumu@chem.psu.edu
Received 7 December 2005
pentadiene ligand in various associative substitution reac-
tions (‘indenyl effect’),7 we envisioned that a new
ruthenium complex 4 bearing a triphenylindenyl moiety
5
Abstract: A new ruthenium complex, (h -triphenylinde-
nyl)Ru(CO) Cl, was synthesized and successfully applied in the ra-
cemization of (S)-1-phenylethanol at room temperature. Instead of
2
potassium tert-butoxide, stronger bases such as sodium hydride and will racemize alcohols more effectively.
n-butyllithium were used to activate the precatalyst. In situ NMR
The designed complex 4 can be easily synthesized from
experiments revealed the presence of ruthenium hydride as a key in-
termediate in the catalytic cycle.
8
9
2
,3-diphenylindenone (5) in two steps (Scheme 1). X-
ray diffraction analysis of a single crystal of 4 confirms
Key words: organometallic reagents, ruthenium, complexes, catal-
the expected structure (Figure 2). All five Ru–Cp carbon
ysis, racemization
5
bond lengths are similar, supporting the h -coordination
of the indenyl ligand to the ruthenium atom.
Chemoenzymatic dynamic kinetic resolution (DKR) com-
bines an enzymatic kinetic resolution with continuous in
situ racemization of substrates by transition-metal cata-
O
Ph
Ph
1
. PhMgBr
1. n-BuLi
Ph
Ph
4
1
2
2. LiAlH4
2. [Ru(CO)3Cl2]2
lysts. Pioneered by Williams’ work, a number of highly
efficient DKR systems have been established (Figure 1).
For example, Bäckvall et al. reported the use of Shvo’s
Ph
5
6
3
catalyst 1 in combination with immobilized lipase for the
Scheme 1
4
DKR of various functionalized secondary alcohols. Since
high temperature is required to activate this dimeric com-
plex, the choice of available biocatalysts has been limited
to those thermal stable species. To overcome this draw-
back, Park and co-workers developed a highly active ru-
thenium catalyst 2, which can completely racemize
With the new complex in hand, we started to test its
catalytic performance in the racemization of (S)-1-phenyl-
ethanol [(S)-7] at room temperature (Scheme 2). For com-
6b
parison, 3 was synthesized according to literature. In the
3
-mediated racemization of (S)-7, a Ru tert-butoxide
5
alcohols within 30 minutes at room temperature. Howev-
species generated from the preliminary mixing of 3 and
potassium tert-butoxide (t-BuOK) was identified as a key
er, extended reaction time is necessary when it works in
the presence of lipase. In searching of a mild and more ef-
ficient catalyst, Bäckvall et al. recently developed ruthe-
nium complex 3, demonstrating broad substrate scope as
6
intermediate. Following this method, the Ru-tert-butox-
ide corresponding to 4 was prepared by stirring 4 (0.5
mol%, 2.5 mM) and t-BuOK (1.0 mol%, 5.0 mM) in tolu-
ene (5 mL) for 10 minutes. The reaction mixture changed
its color from yellow to dark red during this period, in-
dicative of the formation of Ru-alkoxide. Then (S)-7 was
6
well as excellent biocompatibility. Although the detailed
racemization mechanism remains to be elucidated, an as-
sociative ligand substitution pathway was proposed in-
5
3
6b
volving a h → h ring slippage. Because an indenyl
10
added and the racemization process was monitored with
ligand can achieve large rate enhancement over a cyclo-
chiral GC. Although the exact kinetics remain to be estab-
Ph
Ph
O
O
NH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph Ph
H
Ph
Ph
Ph
Ph
Ph
OC
Ru
Ru
Ru
CO
2
Ru
CO
3
Ru
CO
Cl
Cl
Cl
OC
OC
OC
CO
CO OC
1
4
Figure 1
SYNLETT 2006, No. 6, pp 0945–0947
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939038; Art ID: S12005ST
Georg Thieme Verlag Stuttgart · New York
©

9
46
Q. Xi et al.
LETTER
To our surprise, faster racemization was achieved when 4
was activated with other bases such as sodium hydride
(
NaH) and n-butyllithium (n-BuLi). We found that in the
absence of t-BuOK, 4 can still be activated by treatment
of (S)-7 with catalytic amount of NaH (0.5 mol%), pro-
ducing sodium alkoxide 8 quantitatively. Once mixed
with 4 (0.5 mol%), 8 readily converts into Ru-alkoxide 9
showing characteristic dark red color in toluene
(
Scheme 3). Kinetic studies show a significant rate en-
6
hancement compared with the literature method using t-
BuOK (Figure 4, t1/2 = 13.3 min vs. t1/2 = 31.3 min). Sim-
ilarly, n-BuLi (0.5 mol%) was used with a t1/2 of 15.5 min-
utes. Increasing the amount of n-BuLi (2.5 mol%) further
accelerates racemization (t1/2 = 6.0 min) so that (S)-7 is
completely racemized within 30 minutes (Figure 4). A
possible explanation of the observed counterion effect is
the different solubilities of the produced KCl, LiCl, and
NaCl.
Figure 2 X-ray single crystal structure of 4 at 50% probability for
the ORTEP drawing of thermal ellipsoids. Hydrogen atoms are omit-
ted for clarity. Selected bond lengths (Å): Ru(1)–C(22): 1.913,
Ru(1)–C(23): 1.848, Ru(1)–Cl(1): 2.408, Ru(1)–C(18): 2.344,
Ru(1)–C(13): 2.341, Ru(1)–C(19): 2.246, Ru(1)–C(20): 2.242,
Ru(1)–C(21): 2.200. Space group: P2(1)2(1)2(1). Z: 4.
–
+
O M
Ph
Ph
base
(0.5 mol%)
4
(0.5 mol%)
Ph
OC
(S)-7
Ru
CO
lished, the half time of racemization (t ) offers an ap-
O
1
/2
6
proximate estimation of racemization rate. As shown in
Figure 3, pretreatment of 4 with t-BuOK led to effective
racemization of (S)-7 at room temperature with an esti-
mated half time (t ) of 31.3 minutes. Unfortunately, this
Ph
8 (M = Na or Li)
9
Scheme 3
1
/2
is much slower than that achieved by using 3 under the
same reaction conditions (t1/2 = 2.1 min). This result dem-
onstrates that in addition to ring slippage, there are some
other factors such as steric bulkiness of the precatalyst,
which could alter stabilities of some intermediates, con-
tributing to the overall racemization rate.
Figure 4
To gain insight into the racemization mechanism, the ac-
tivation reaction was studied with in situ NMR spectros-
copy. Thus freshly prepared lithium alkoxide 8 in d6-
benzene was added into 4 (1 equiv) in an NMR tube and
shaken vigorously. A dark red color immediately ap-
peared with simultaneous precipitation of LiCl. A new
proton resonance at d = –11.2 ppm was detected. It is not-
ed that so far no direct experimental evidence has been
provided regarding the existence of ruthenium hydride
Figure 3
OH
OH
Ru catalyst
base, toluene, r.t.
1
1
(S)-7
(rac)-7
during racemization. Our result identifies the ruthenium
hydride 10 as a key intermediate. Therefore, a general
mechanism is proposed in Scheme 4. The first step is the
activation of precatalyst 4 by 8 with the formation of ru-
Scheme 2
5
3
thenium alkoxide 9. Ring slippage from h to h facilitates
Synlett 2006, No. 6, 945–947 © Thieme Stuttgart · New York

LETTER
New Ruthenium Catalyst for Racemization of Chiral 1-Phenylethanol
947
1
2
b-hydride elimination, generating ruthenium hydride 10
Larsson, A. L. E.; Le Ray, M.; Bäckvall, J.-E. J. Am. Chem.
Soc. 1999, 121, 1645.
5) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-
J.; Park, J. Angew. Chem. Int. Ed. 2002, 41, 2373. (b) Choi,
J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim,
M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972.
6) (a) Martin-Matute, B.; Edin, M.; Bogar, K.; Bäckvall, J.-E.
Angew. Chem. Int. Ed. 2004, 43, 6535. (b) Martin-Matute,
B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Bäckvall, J.-E. J.
Am. Chem. Soc. 2005, 127, 8817.
(7) (a) Hart-Davis, A. J.; White, C.; Mawby, R. J. Inorg. Chim.
Acta 1970, 4, 441. (b) Rerek, M. E.; Ji, L.-N.; Basolo, F. J.
Chem. Soc., Chem. Commun. 1983, 1208. (c) Rerek, M. E.;
Basolo, F. J. Am. Chem. Soc. 1984, 106, 5908.
as revealed by proton NMR. The following migratory in-
sertion of the coordinating ketone into Ru–H bond leads
to racemized (rac)-9. Finally, ligand exchange reaction
regenerates 9 with the release of a racemized substrate
(
(
rac)-7.
(
Ph
Ph
Ph
OC
Ru
CO
Cl
4
OLi
OH
n-BuLi
(
8) 1,2,3-Triphenyl-1H-indene (5)
Ph
Ph
(S)-7
To a freshly prepared PhMgBr solution (5.68 mmol in 20 mL
THF) was added dropwise a solution of 2,3-diphenyl-
indenone (3.54 mmol, 1.0 g) in 10 mL THF at 0 °C. Then the
reaction mixture was stirred at 50 °C for 12 h. When it was
8
LiCl
Ph
Ph
cooled to r.t., LiAlH (26.3 mmol, 1.0 g) was added in
4
OH
portions and then stirred for 6 h. The reaction mixture was
Ph
OC
Ru
quenched with sat. aq NH Cl solution, filtered, and extracted
Ph
(
4
O
rac)-7
with CH Cl . The organic phase was separated, washed with
2
2
CO
Ph
brine and then dried with Na SO . After evaporation of the
2 4
9
OH
solvent, flash chromatography (EtOAc–hexane = 1:15) on
silica gel afforded the product as white powder (0.81 g,
Ph
1
(S)-7
66%). H NMR (300 MHz, CD Cl ): d = 5.18 (s, 1 H), 7.09–
2
2
1
3
7
.28 (m, 14 H), 7.44–7.45 (m, 5 H). C NMR (75 MHz,
Ph
Ph
Ph
CD Cl ): d = 58.19, 120.82, 124.14, 126.04, 127.05, 127.11,
2 2
Ph
H
127.28, 127.88, 128.21, 128.46, 129.93, 129.07, 129.73,
29.86, 135.89, 135.93, 140.30, 141.23, 145.35, 146.08,
148.70. HRMS: m/z calcd: 344.1565; found: 344.1570.
Ph
Ph
1
Ru
Ru
O
OC
OC
10
OC
O
5
CO
rac)-9
(
9) (h -1,2,3-Triphenylindenyl)Ru(CO) Cl (4)
Ph
2
(
Toward the THF (10 mL) solution of 6 (440 mg, 1.28 mmol)
was added n-BuLi (0.46 mL, 1.32 mmol) at –78 °C. Then it
was allowed to warm to r.t. in 10 min. Then, [Ru(CO) Cl ]
Ph
3
2 2
(
327 mg, 0.64 mmol) was added into the solution, and stirred
Scheme 4
for 10 min. Afterwards, silica gel was added and the solvent
was removed by evaporation. Flash chromatography
(
EtOAc–hexane, 1:10) on silica gel afforded the product as
In summary, a new ruthenium complex has been synthe-
sized for the racemization of (S)-1-phenylethanol at room
temperature. An effective method to activate this precata-
lyst was developed using strong bases such as NaH and n-
BuLi instead of t-BuOK. NMR experiment identifies ru-
thenium hydride as a key intermediate during racemiza-
tion. Further mechanistic studies, as well as its
combination with biocatalysts for DKR of alcohols, will
be reported in due course.
1
an air-stable yellow powder (150 mg, 44%). H NMR (300
MHz, CD Cl ): d = 7.00–7.11 (m, 4 H), 7.17–7.20 (m, 1 H),
2
2
7
.38–7.42 (m, 6 H), 7.49–7.57 (m, 6 H), 7.61–7.65 (m, 2 H).
1
3
C NMR (75 MHz, CD Cl ): d = 92.01, 111.73, 116.78,
2
2
124.57, 128.16, 128.96, 129.03, 129.28, 130.94, 131.00,
131.71, 132.35, 197.19. HRMS [M – Cl + MeOH]: m/z
calcd: 533.0691; found: 533.0690. FT-IR (KBr): 2042, 1986
cm .
–
–
1
(
10) Racemization Experiments
The racemization of (S)-7 was carried out in a 5-mL Schlenk
tube at r.t. The two methods to activate 4 are described in this
paper. When the racemization started, the reaction mixture
was sampled regularly to determine the ee (chiral GC, b-dex
Acknowledgment
Financial support from NIH-GM is appreciated. The X-ray diffrac-
tion experiment (NSF grant CHE-0131112) was carried out by Dr.
Yennawar.
325 capillary column, 120 °C isothermal, t
= 8.50 min).
R
= 8.31 min,
t
S
(11) Previously, only 13C NMR was used to study the formation
of Ru tert-butoxide. Moreover, the long induction time
observed in the attempt to racemize (S)-7 with ruthenium
hydride and corresponding ketone gives no convincing
evidence in support of the existence of ruthenium hydride
during racemization (see ref. 6).
References and Notes
(
1) For a recent review on DKR, see: Pamies, O.; Bäckvall, J.-
E. Chem. Rev. 2003, 103, 3247; and references cited therein.
2) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M.
J.; Harris, W. Tetrahedron Lett. 1996, 37, 7623.
(
12) Previous crossover experiments with 3 indicate that the
ketone generated from b-hydride elimination stays within
the coordination sphere of the Ru atom during racemization
(
(
(
3) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885.
4) (a) Larsson, A. L. E.; Persson, B. A.; Bäckvall, J.-E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.;
(see ref. 6b).
Synlett 2006, No. 6, 945–947 © Thieme Stuttgart · New York