Ruthenium-catalyzed asymmetric propargylic substitution reactions of propargylic alcohols with acetone

Article abstract of DOI:10.1002/anie.200502981

Enantioselective propargylic substitution reactions of propargylic alcohols with acetone catalyzed by a diruthenium complex gives the propargylic alkylated products in good yields with up to 82% ee. A π-π interaction of phenyl rings between the ligand and

Full text of DOI:10.1002/anie.200502981

Angewandte
Chemie
OSO2CF3), but not by various monoruthenium complexes,[2]
and they proceeded via allenylidene complexes[4] as key
intermediates under the synergistic effect of the two ruthe-
nium atoms in the diruthenium complexes.[2]
More recently, we have prepared several diruthenium
complexes bearing chiral thiolate bridging ligands and
applied them as catalysts in the catalytic enantioselective
propargylic alkylation of propargylic alcohols with acetone,
which resulted in the formation of the propargylic alkylated
compounds in good yields, but only with moderate enantio-
selectivity (up to 35% ee).[5] To achieve higher enantioselec-
tivity, a different concept than steric repulsion between
substrates and chiral ligands, which was considered in our
previous system,[5] would be needed. Therefore, we envisaged
a new type of chiral ligands with a phenyl ring that might
interact with a phenyl ring of ruthenium–allenylidene com-
plexes by p–p interaction.[6] In this system, nucleophilic attack
of nucleophiles at the Cg atom of the allenylidene ligand
should occur from the side that is not blocked by the chiral
ligand (Scheme 1). Indeed, high enantioselectivity was
observed in catalytic propargylic alkylation with the second-
generation catalyst (up to 82% ee). Preliminary results are
described here.
Synthetic Methods
DOI: 10.1002/anie.200502981
Ruthenium-Catalyzed Asymmetric Propargylic
Substitution Reactions of Propargylic Alcohols
with Acetone**
Youichi Inada, Yoshiaki Nishibayashi,* and
Sakae Uemura
In sharp contrast to enantioselective allylic substitution
reactions of allylic alcohol derivatives with nucleophiles
catalyzed by transition metal complexes,[1] its propargylic
version has not yet been developed. We recently disclosed
that ruthenium-catalyzed propargylic substitution reactions
of propargylic alcohols with a variety of heteroatom- and
carbon-centered nucleophiles affords the corresponding
functionalized propargylic compounds in high yields with
complete regioselectivity.[2] The reactions were catalyzed only
by thiolate-bridged diruthenium complexes[3] such as
[{Cp*RuCl(m2-SR)}2] (Cp* = h5-C5Me5; R = Me, nPr, iPr)
Scheme 1. Nucleophilic attack of acetone on the Cg atom of the
allenylidene complex.
A new class of chiral disulfides was prepared from the
corresponding aldehydes (Scheme 2).[7] Treatment of 1-
phenyl-2-propyn-1-ol (2a) with acetone in the presence of a
catalytic amount of chiral thiolate-bridged diruthenium com-
and
[Cp*RuCl(m2-SMe)2RuCp*(OH2)]OTf
(OTf =
[*] Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation
The University of Tokyo
Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax: (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Y. Inada, Prof. Dr. S. Uemura
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering
Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
for Young Scientists (A) (No.15685006) to Y.N. from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan. Y.I. is a
recipient of the JSPS Predoctoral Fellowships for Young Scientists.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Preparation of chiral disulfides.
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Communications
plexes, which were prepared in situ from the tetranuclear
p-tert-butylphenyl group on the phenyl ring of a chiral
disulfide (1i and 1j) did not improve the enantioselectivity.
The use of 1h as chiral ligand at lower reaction temperature
did not influence the enantioselectivity. Other additives such
as NH4PF6 did not affect the enantioselectivity. In the absence
of additives such as NH4BF4 and NH4PF6, no reaction
occurred. When other simple ketones such as 2-butanone
and 3-methyl-2-butanone were used in place of acetone, the
catalytic reactions did not proceed smoothly.
ruthenium(ii) complex and the corresponding chiral disulfides
in THF at room temperature for 12h, [3,5] and NH4BF4 at
reflux temperature for 6 h afforded the propargylic alkylated
product 4-phenyl-5-hexyn-2-one (3a) in moderate yields with
complete regioselectivity (Scheme 3). The enantiomeric
excess of the product was determined by GLC on a chiral
capillary column. Compared with our previous result,[5] the
introduction of a phenyl group in the meta position of the
phenyl ring of a chiral disulfide (1a) increased the enantio-
selectivity from 11 to 37% ee. Interestingly, introduction of a
further phenyl group into the phenyl ring (1 f and 1g) greatly
increased the enantioselectivity to 43 and 64% ee, respec-
tively, but the enantioselectivity decreased when the positions
of the phenyl rings were not appropriate (1b–1e). Finally, the
use of a chiral disulfide (1h) bearing three phenyl groups on a
phenyl ring achieved the highest enantioselectivity (74%
ee).[7] Unfortunately, the introduction of a p-methylphenyl or
Next, the catalytic alkylation of propargylic alcohols 2 was
investigated using 1h as chiral ligand. Typical results for
various alcohols 2 are shown in Table 1. The presence of
Table 1: Ruthenium-catalyzed asymmetric propargylic alkylation of prop-
argylic alcohols (2) with acetone.[a]
Entry
2, Ar
3, yield [%][b]
ee of 3 [%][c]
1
2
3
4
5
6
7
8
2a, P h
3a, 56
3b, 61
3c, 14
3d, 57
3e, 42
3 f, 50
3g, 50
3h, 58
74
72
2b, o-MeC6H4
2c, p-MeOC6H4
2d, p-ClC6H4
2e, 1-naphthyl
2 f, 2-napthyl
2g, p-PhC6H4
2h, 3,5-Ph2C6H3
68[d]
68[d]
70
70
70
82
[a] All reactions of 2 (0.300 mmol) with acetone were carried out in the
presence of ruthenium complex (0.015 mmol, generated in situ from
[{Cp*RuCl}4] and 1h) and NH4BF4 (0.030 mmol) in acetone (4.5 mL) at
608C for 6 h. [b] Yield of isolated product. [c] Determined by HPLC.
[d] Determined by GLC.
substituents such as methyl, methoxy, and chloro in the
benzene ring of the propargylic alcohols did not greatly affect
the enantioselectivity for the products (Table 1, entries 2–4).
Enantioselectivity at the same level was observed in the
reactions of 1-naphthyl-2-propyn-1-ols (2e and 2 f) with
acetone under the same reaction conditions (Table 1, entries 5
and 6). Although the reaction of propargylic alcohol bearing a
phenyl group in the benzene ring (2g) with acetone gave the
same enantioselectivity (Table 1, entry 7), the introduction of
two phenyl groups at the meta positions of the benzene ring of
the propargylic alcohols further increased the enantioselec-
tivity to 82% ee (Table 1, entry 8).
To obtain more information on the propargylic alkylation,
the stereochemistry of the alkylated product 3a in the
reaction with 1h as a chiral ligand was determined. Hydro-
genation of the alkylated product in the presence of a catalytic
amount of Pd/C under 1 atm of H2 at room temperature for
20 h gave (S)-4-phenyl-2-hexanone (4a)[7,8] quantitatively
(Scheme 4), that is, the original alkylated product 3a has an
R absolute configuration. This result is consistent with our
proposed reaction pathway (Scheme 1), and the p–p inter-
action[6] of phenyl rings between the ligand and allenylidene
moieties might be considered to be one of the reasons for
achievement of high enantioselectivity.
Scheme 3. Reactions of 1-phenyl-2-propyn-1-ol (2a) with acetone in the
presence of chiral thiolate-bridged diruthenium complexes generated
in situ from [{Cp*RuCl}4] and chiral disulfides.
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[3] The thiolate-bridged diruthenium complexes have been found to
provide unique bimetallic reaction sites for activation and
transformation of various terminal alkynes: a) Y. Nishibayashi,
M. Yamanashi, I. Wakiji, M. Hidai, Angew. Chem. 2000, 112,
3031; Angew. Chem. Int. Ed. 2000, 39, 2909, and references
therein; b) Y. Nishibayashi, H. Imajima, G. Onodera, M. Hidai,
S. Uemura, Organometallics 2004, 23, 26; c) Y. Nishibayashi, H.
Imajima, G. Onodera, Y. Inada, M. Hidai, S. Uemura, Organo-
metallics 2004, 23, 5100.
Scheme 4. Palladium-catalyzed hydrogenation of 3a.
In summary, we have developed a diruthenium complex-
catalyzed, highly enantioselective propargylic substitution
reaction of propargylic alcohols with acetone to give the
propargylic alkylated products with up to 82% ee. Here, p–p
interaction of phenyl rings between the ligand and allenyli-
dene moieties is considered to play a crucial role in achieving
such a high selectivity. The method presented is in sharp
contrast to the so-far-known highly diastereoselective and
enantioselective propargylic substitution reactions, which use
a stoichiometric amount of transition metal complexes.[9]
Further work is currently in progress to improve the
enantioselectivity and to broaden the scope of this enantio-
selective propargylic substitution reaction by using other
nucleophiles.[10]
[4] For recent examples of catalytic reactions via allenylidene
complexes, see a) B. M. Trost, J. A. Flygare, J. Am. Chem. Soc.
1992, 114, 5476; b) S. M. Maddock, M. G. Finn, Angew. Chem.
2001, 113, 2196; Angew. Chem. Int. Ed. 2001, 40, 2138; c) K.-L.
Yeh, B. Liu, C.-Y. Lo, H.-L. Huang, R.-S. Liu, J. Am. Chem. Soc.
2002, 124, 6510; d) S. Datta, C.-L. Chang, K.-L. Yeh, R.-S. Liu, J.
Am. Chem. Soc. 2003, 125, 9294.
[5] Y. Nishibayashi, G. Onodera, Y. Inada, M. Hidai, S. Uemura,
Organometallics 2003, 22, 873.
[6] For a review, see E. A. Meyer, R. K. Castellano, F. Diederich,
Angew. Chem. 2003, 115, 1244; Angew. Chem. Int. Ed. 2003, 42,
1210.
[7] See Supporting Information for experimental details.
[8] M.-J. Brienne, C. Ouannes, J. Jacques, Bull. Soc. Chim. Fr. 1967,
613.
[9] a) A. J. M. Caffyn, K. M. Nicholas, J. Am. Chem. Soc. 1993, 115,
6438; b) V. Cadierno, S. Conejero, M. P. Gamasa, J. Gimeno,
Dalton Trans. 2003, 3060; c) Y. Nishibayashi, H. Imajima, G.
Onodera, S. Uemura, Organometallics 2005, 24, 4106.
[10] We have already investigated the reaction of 2a with p-
chloroaniline in the presence of our second generation catalyst,
but good enantioselectivity was not observed.
Experimental Section
Typical experimental procedure for the reaction of 2a with acetone:
[{Cp*RuCl}4] (8.2mg, 0.0075 mmol) and 1h (11.4 mg, 0.015 mmol)
were placed in a 20 mL round-bottomed flask under N2. Anhydrous
THF (1.0 mL) was added, and then the mixture was magnetically
stirred for 12h at room temperature. The solvent was evaporated in
vacuo. NH4BF4 (3.1 mg, 0.030 mmol) and anhydrous acetone
(4.5 mL) were added under N2, and then the mixture was magnetically
stirred at room temperature. After the addition of 2a (39.7 mg,
0.30 mmol), the reaction flask was kept at 608C for 6 h. The solvent
was concentrated under reduced pressure by an aspirator, and then
the residue was purified by column chromatography (SiO2) with
hexane and AcOEt to give 3a as a pale yellow oil (30.3 mg,
0.18 mmol, 56% yield, 74% ee); 1H NMR (270 MHz, CDCl3): d =
2.13 (s, 3H), 2.26 (s, 1H), 2.80 (dd, 1H, J = 16, 5.2Hz), 3.00 (dd, 1H,
J = 16, 8.4 Hz), 4.20 (br, 1H), 7.22–7.39 ppm (m, 5H); 13C NMR
(67.5 MHz, CDCl3): d = 30.4, 32.4, 51.5, 71.0, 84.8, 127.1, 127.2, 128.6,
140.1, 205.4 ppm. The optical purity of 3a was determined by HPLC
analysis (column: Daicel, OD; eluent: hexane/2-propanol 97:3).
Received: August 22, 2005
Published online: October 27, 2005
Keywords: asymmetric catalysis · nucleophilic substitution ·
.
ruthenium · S ligands · synthetic methods
[1] For recent reviews, see a) J. Tsuji, Palladium and Catalysts,
Wiley, New York, 1995, p. 290; b) B. M. Trost, D. L. VanV-
ranken, Chem. Rev. 1996, 96, 395; c) B. M. Trost, C. Lee in
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-VCH,
New York, 2000, chap. 8E.
[2] a) Y. Nishibayashi, I. Wakiji, M. Hidai, J. Am. Chem. Soc. 2000,
122, 11019; b) Y. Nishibayashi, I. Wakiji, Y. Ishii, S. Uemura, M.
Hidai, J. Am. Chem. Soc. 2001, 123, 3393; c) Y. Nishibayashi, M.
Yoshikawa, Y. Inada, M. Hidai, S. Uemura, J. Am. Chem. Soc.
2002, 124, 11846; d) Y. Nishibayashi, M. D. Milton, Y. Inada, M.
Yoshikawa, I. Wakiji, M. Hidai, S. Uemura, Chem. Eur. J. 2005,
11, 1433; e) S. C. Ammal, N. Yoshikai, Y. Inada, Y. Nishibayashi,
E. Nakamura, J. Am. Chem. Soc. 2005, 127, 9428.
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