Novel method for the preparation of enantiomerically pure propargylic substituted compounds

Article abstract of DOI:10.1021/om050488i

We have found a novel method for the preparation of enantiomerically pure propargylic alkylated compounds from an achiral propargylic alcohol assisted by a ruthenium complex bearing BINAP as a chiral ligand. It is noteworthy that products bearing completely opposite configurations are obtained with an almost 100% ee.

Full text of DOI:10.1021/om050488i

4106
Organometallics 2005, 24, 4106-4109
Novel Method for the Preparation of Enantiomerically
Pure Propargylic Substituted Compounds
Yoshiaki Nishibayashi,*,† Hiroaki Imajima,‡ Gen Onodera,‡ and Sakae Uemura‡
Institute of Engineering Innovation, The University of Tokyo, Yayoi,
Bunkyo-ku, Tokyo 113-8656, Japan, and Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan
Received June 14, 2005
Summary: We have found a novel method for the prepa-
ration of enantiomerically pure propargylic alkylated
compounds from an achiral propargylic alcohol assisted
by a ruthenium complex bearing BINAP as a chiral
ligand. It is noteworthy that products bearing completely
opposite configurations are obtained with an almost
100% ee.
several diruthenium complexes bearing chiral thiolate-
bridged ligands and applied them as catalysts to the
catalytic enantioselective propargylic alkylation of pro-
pargylic alcohols with acetone, which resulted in the
formation of the propargylic alkylated compounds in
good yields, but with only a moderate enantioselectivity
(up to 35% ee).4
Nicholas and co-workers reported the stereospecific
propargylic alkylation of chiral propargylic alcohols by
using a stoichiometric amount of [Co2(CO)5L] (L )
phosphite), but several reaction steps as well as two
separation procedures of the produced diastereoisomers
were necessary on the way to obtaining the enantio-
merically rich propargylic alkylated compounds.5 As an
alternative Nicholas reaction, Gimeno and co-workers
developed a ruthenium-assisted stoichiometric and step-
wise method for the preparation of propargylic alkylated
compounds from propargylic alcohols via ruthenium-
allenylidene complexes as key intermediates.6 High
diastereoselectivities were achieved in the reactions of
the ruthenium-allenylidene complexes with lithium
enolates.7,8 Independently, Mu¨ller and co-workers re-
ported the highly diastereoselective substitution reac-
tion of propargylic alcohol derivatives with various
nucleophiles via propargyl cations stabilized by a chro-
mium carbonyl arene moiety, (arene)Cr(CO)3.9 Thus,
successful examples of asymmetric propargylic substitu-
In sharp contrast to the enantioselective allylic sub-
stitution reaction of allylic alcohol derivatives with
nucleophiles catalyzed by transition-metal complexes,
which is one of the most successful and reliable methods
in asymmetric synthesis,1 the enantioselective propar-
gylic substitution reaction of propargylic alcohol deriva-
tives catalyzed by transition-metal complexes has not
yet been developed. We have recently disclosed that the
ruthenium-catalyzed propargylic substitution reaction
of propargylic alcohols with a variety of heteroatom- and
carbon-centered nucleophiles afforded the corresponding
functionalized propargylic compounds in high yields
with complete regioselectivity.2 It is noteworthy that the
reactions are catalyzed by thiolate-bridged diruthenium
complexes3 such as [Cp*RuCl(µ2-SR)]2 (Cp* ) η5-C5Me5;
R ) Me, nPr, iPr) and [Cp*RuCl(µ2-SMe)2RuCp*-
(OH2)]OTf (OTf ) OSO2CF3) but not by various monoru-
thenium complexes.2 More recently, we have prepared
* To whom correspondence should be addressed. E-mail: ynishiba@
sogo.t.u-tokyo.ac.jp.
(3) (a) The thiolate-bridged diruthenium complexes were found to
provide a unique bimetallic reaction site for activation and transforma-
tion of various terminal alkynes; see: Nishibayashi, Y.; Yamanashi,
M.; Wakiji, I.; Hidai, M. Angew. Chem., Int. Ed. 2000, 39, 2909 and
references therein. (b) Nishibayashi, Y.; Imajima, H.; Onodera, G.;
Hidai, M.; Uemura, S. Organometallics 2004, 23, 26. (c) Nishibayashi,
Y.; Imajima, H.; Onodera, G.; Inada, Y.; Hidai, M.; Uemura, S.
Organometallics 2004, 23, 5100. (d) The methanethiolate-bridged
diruthenium complexes [Cp*RuCl(µ2-SMe)]2 and [Cp*RuCl(µ2-SMe)2-
RuCp*(OH2)](OTf) are commercially available from Wako Pure Chemi-
cal Industries (Japan) as met-DIRUX (methanethiolate-bridged diru-
thenium complex) (130-14581) and met-DIRUX-OTf (132-14781).
(4) Nishibayashi, Y.; Onodera, G.; Inada, Y.; Hidai, M.; Uemura, S.
Organometallics 2003, 22, 873.
† The University of Tokyo.
‡ Kyoto University.
(1) For recent reviews, see: (a) Tsuji, J. Palladium Reagents and
Catalysts; Wiley: New York, 1995; p 290. (b) Trost, B. M.; Van
Vranken, D. L. Chem. Rev. 1996, 96, 395. (c) Trost, B. M.; Lee, C. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 8E.
(2) (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M. J. Am. Chem. Soc. 2000,
122, 11019. (b) Nishibayashi, Y.; Wakiji, I.; Ishii, Y.; Uemura, S.; Hidai,
M. J. Am. Chem. Soc. 2001, 123, 3393. (c) Nishibayashi, Y.; Inada, Y.;
Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 7900. (d)
Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J.
Am. Chem. Soc. 2002, 124, 11019. (e) Inada, Y.; Nishibayashi, Y.; Hidai,
M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 15172. (f) Nishibayashi,
Y.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 6060.
(g) Nishibayashi, Y.; Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S.
Angew. Chem., Int. Ed. 2003, 42, 1495. (h) Nishibayashi, Y.; Yoshika-
wa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem.,
Int. Ed. 2003, 42, 2681. (i) Nishibayashi, Y.; Yoshikawa, M.; Inada,
Y.; Hidai, M.; Uemura, S. J. Org. Chem. 2004, 69, 3408. (j) Milton, M.
D.; Onodera, G.; Nishibayashi, Y.; Uemura, S. Org. Lett. 2004, 6, 3993.
(k) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem.
Commun. 2004, 2712. (l) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.;
Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2004, 126, 16066. (m)
Nishibayashi, Y.; Milton, M. D.; Inada, Y.; Yoshikawa, M.; Wakiji, I.;
Hidai, M.; Uemura, S. Chem. Eur. J. 2005, 11, 1433. (n) Ammal, S.
C.; Yoshikai, N.; Inada, Y.; Nishibayashi, Y.; Nakamura, E. J. Am.
Chem. Soc. 2005, 127, 9428.
(5) Caffyn, A. J. M.; Nicholas, K. M. J. Am. Chem. Soc. 1993, 115,
6438.
(6) (a) Cadierno, V.; Conejero, S.; D´ıez, J.; Gamasa, M. P.; Gimeno,
J.; Garc´ıa-Granda, S. Chem. Commun. 2003, 840. (b) Cadierno, V.;
Conejero, S.; Gamasa, M. P.; Gimeno, J.; Rodr´ıguez, M. A. Organo-
metallics 2002, 21, 203. (c) Cadieno, V.; Conejero, S.; Gamasa, M. P.;
Gimeno, J.; Pe´rez-Carren˜o, E.; Garc´ıa-Granda, S. Organometallics
2001, 20, 3175.
(7) Cadierno, V.; Conejero, S.; Gamasa, M. P.; Gimeno, J. Dalton
2003, 3060.
(8) (a) Cadierno, V.; Gamasa, M. P.; Gimeno, J.; Pe´rique-Carreno,
E.; Garc´ıa-Granda, S. J. Organomet. Chem. 2003, 670, 75. (b) Cadierno,
V.; Conejero, S.; Gamasa, M. P.; Gimeno, J.; Falvello, L. R.; Llusar, R.
M. Organometallics 2002, 21, 3716. (c) Cadierno, V.; Gamasa, M. P.;
Gimeno, J. Organometallics 1998, 17, 5216.
10.1021/om050488i CCC: $30.25 © 2005 American Chemical Society
Publication on Web 07/15/2005

Communications
Organometallics, Vol. 24, No. 17, 2005 4107
Scheme 1
Scheme 2
carried out at -100 °C. It is noteworthy that the
diastereoisomers of the σ-alkynyl complex ((S)- and (R)-
6a) can be easily separated by using column chroma-
tography on SiO2. As a result, the σ-alkynyl complex
bearing an S configuration on the alkynyl ligand ((S)-
6a) was isolated in 55% yield with >99% de, while the
σ-alkynyl complex bearing an R configuration on the
alkynyl ligand ((R)-6a) was isolated in 28% yield also
with >99% de. This result indicates that each σ-alkynyl
complex can be obtained in diastereomerically pure
form.
Protonation of each of the diastereomerically pure
σ-alkynyl complexes ((S)- and (R)-6a) with HBF4‚Me2O
in diethyl ether at -20 °C for 30 min gave the corre-
sponding vinylidene complexes [Ru{dCdCHC(CH2-
COPh)HPh}(η5-C9H7)((R)-BINAP)]BF4 ((R)- and (S)-7a,
respectively) in high yield and in an enantiomerically
pure form (Scheme 3). Treatment of the vinylidene
complex bearing an R configuration on the vinylidene
ligand ((R)-7a) with acetonitrile at reflux temperature
for 30 min afforded (R)-1,3-diphenyl-4-pentyn-1-one12
((R)-8a) in 89% yield with >99% ee, together with the
formation of [Ru(NtCMe)(η5-C9H7)((R)-BINAP)]BF4 (9)
(Scheme 4). Similarly, transformation of another vi-
nylidene complex bearing an S configuration on the
vinylidene ligand ((S)-7a)) proceeded smoothly to give
(S)-1,3-diphenyl-4-pentyn-1-one ((S)-8a) in enantiomeri-
cally pure form also, together with 9. This stepwise
reaction provides both propargylic alkylated products
in enantiomerically pure form.
When the reactions of the allenylidene complex 3 with
other lithium enolates (4b,c) were investigated under
the same reaction conditions, the corresponding σ-al-
kynyl complexes [Ru{CtCC(CH2COAr)HPh}(η5-C9H7)-
((R)-BINAP)] (6b (Ar ) p-F-C6H4) and 6c (Ar ) 1-naph-
thyl)) were formed as a mixture of two diastereoisomers
quantitatively with only a low diastereoselectivity
(Scheme 5). Fortunately, in both cases, the σ-alkynyl
complexes could be easily separated by column chro-
matography on SiO2 in diastereomerically pure form.
Protonation of the isolated σ-alkynyl complexes ((S)-6b
and (S)-6c) followed by the ligand exchange reaction of
the vinylidene complexes produced ((R)-7b and (R)-7c)
with acetonitrile resulted in the formation of propargylic
tion reactions have only been limited to the diastereo-
selective reactions by using stoichiometric amounts of
transition-metal complexes.
As an extension of our ongoing study on enantiose-
lective propargylic substitution reactions, we have now
found a novel method for the preparation of enantio-
merically pure propargylic alkylated compounds from
an achiral propargylic alcohol assisted by a ruthenium
complex bearing BINAP10 as a chiral ligand. This
methodology is considered to be the first synthetic
approach to the highly enantioselective propargylic
substitution reactions. Preliminary results are described
here.
Treatment of [Ru(η5-C9H7)Cl((R)-BINAP)]11 (1), which
was newly prepared from the reaction of [Ru(η5-C9H7)-
Cl(PPh3)2] with (R)-BINAP in toluene at reflux temper-
ature for 20 h, with racemic 1-phenyl-2-propyn-1-ol (2)
in the presence of NaPF6 in MeOH at room temperature
for 20 h gave the corresponding allenylidene complex
[Ru{dCdCdCHPh}(η5-C9H7)((R)-BINAP)]PF6 (3) in 91%
yield as a single isomer (Scheme 1). The formation of 3
was confirmed by elemental analysis and IR and NMR
(1H, 13C{1H}, and 31P{1H}) spectroscopy.
The reaction of 3 with the lithium enolate 4a, which
was generated in situ from the corresponding silyl enol
ether 5a and MeLi at 0 °C, in tetrahydrofuran (THF)
at -78 °C for 30 min gave the corresponding σ-alkynyl
complex [Ru{CtCC(CH2COPh)HPh}(η5-C9H7)((R)-BI-
NAP)] (6a) as a mixture of two diastereoisomers in
quantitative yield (Scheme 2). Only moderate diaste-
reoselectivity was observed, even when the reaction was
(9) Netz, A.; Polborn, K.; Mu¨ller, T. J. J. J. Am. Chem. Soc. 2001,
123, 3441.
(10) For a recent review, see: Noyori, R. Angew. Chem., Int. Ed.
2002, 41, 2008.
(11) The molecular structure of 1 has been unambiguously clarified
by X-ray analysis. Crystal data for 1:
C53H39ClPRu, Mr ) 874.36,
orthorhombic, space group P212121 (No. 19), a ) 10.7043(9) Å, b )
16.348(1) Å, c ) 23.4626(5) Å, V ) 4105.7(2) Å3, Z ) 4, µ(Mo KR) )
5.62 cm-1, 8788 reflections measured, 6997 unique reflections, which
were used in all calculations. Final R1 ) 0.036 and wR2 ) 0.094 (all
data).
(12) (a) Hydrogenation of (R)-8a afforded (+)-(S)-PhCH(CH2C(O)-
Ph)CH2CH3. (b) Alexakis, A.; Benhaim, C.; Rosset, S.; Human, M. J.
Am. Chem. Soc. 2002, 124, 5262. (c) Shintani, R.; Fu, G. C. Org. Lett.
2002, 4, 3699.

4108 Organometallics, Vol. 24, No. 17, 2005
Communications
Scheme 3
Scheme 5
a Determined by 1H NMR. b After column chromatography.
Scheme 6
Scheme 4
9 can be converted into the original ruthenium-BINAP
complex 1 by ligand exchange. In fact, we confirmed the
quantitative formation of 1 in the reaction of 9 with an
excess amount of KCl in the presence of 18-crown-6.13
Thus, a synthetic cycle for the formation of enantio-
merically pure propargylic alkylated compounds from
an achiral propargylic alcohol has been accomplished
by starting from the ruthenium-BINAP complex 1
(Scheme 7). In this pseudo-catalytic cycle, the ruthe-
nium-BINAP complex can be recovered and reused for
this asymmetric synthetic reaction. The overall process
has the potential to be a general synthetic protocol to
obtain propargylic-substituted compounds with com-
plete enantioselectivity.
In summary, we have found a novel method for the
preparation of enantiomerically pure propargylic alky-
lated compounds from an achiral propargylic alcohol
assisted by a ruthenium complex bearing BINAP as a
chiral ligand. Although four reaction steps and the
column chromatographic separation of two diastereo-
isomers are necessary to obtain the expected com-
alkylated compounds ((R)-8b and (R)-8c) in enantio-
merically pure form (Scheme 6). The ruthenium complex
(13) Morandini, F.; Consiglio, G.; Lucchini, V. Organometallics 1985,
4, 1202.

Communications
Organometallics, Vol. 24, No. 17, 2005 4109
Scheme 7
pounds, this stepwise reaction provides the first syn-
thetic approach to highly enantioselective propargylic
substitution reactions. It is also noteworthy that prod-
ucts bearing completely opposite configurations are
obtained with almost 100% ee. Further work is currently
in progress to improve the diastereoselectivity in the
reaction of the ruthenium allenylidene complexes with
lithium enolates and to broaden the scope of this
enantioselective propargylic substitution reaction by
using other nucleophiles.
(A) (No. 15685006) to Y.N. from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
Supporting Information Available: Text giving experi-
mental procedures and 1H, 13C, and 31P NMR spectral data
for 1, 3‚0.5CH2Cl2, and 6-8 and a table and figure giving
crystallographic details for 1; crystallographic data for 1 are
also available as a CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research for Young Scientists
OM050488I