Ir- and Ru-catalyzed sequential reactions: Asymmetric α-alkylative reduction of ketones with alcohols

Article abstract of DOI:10.1002/anie.200600677

(Chemical Equation Presented) The compatibility between [{IrCl(cod)} ₂] and ruthenium complex 1 to achieve asymmetric α-alkylative reduction of prochiral ketones with primary alcohols is an essential factor in obtaining optically active alcohols with elongation of the carbon skeleton in good yields with a high enantioselectivity.

Full text of DOI:10.1002/anie.200600677

Angewandte
Chemie
Alkylation
DOI: 10.1002/anie.200600677
Ir- and Ru-Catalyzed Sequential Reactions:
Asymmetric a-Alkylative Reduction of Ketones
with Alcohols**
Gen Onodera, Yoshiaki Nishibayashi,* and
Sakae Uemura
Transition-metal-catalyzed asymmetric reduction of prochiral
ketones is one of the most intensive subjects in organic
synthesis.[1,2] Among a variety of systems for the catalytic
reduction, ruthenium-catalyzed hydrogenation, and transfer
hydrogenation of prochiral ketones have been developed and
used as reliable synthetic methods to
obtain reduced alcohols with a high-
to-excellent enantioselectivity.[1,2] We
have also reported the enantioselec-
tive redox reaction of ketones and
alcohols using ruthenium complex
[RuCl2(PPh3)(ip-foxap[3])] (1) as a
catalyst.[4]
Multiple catalysis in the same
medium to obtain the desired prod-
ucts from simple starting materials is one of the most current
and important topics in synthetic chemistry.[5,6] Such catalysis
[*] Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation
The University of Tokyo
Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax: (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
G. Onodera, Prof. Dr. S. Uemura
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering
Kyoto University
Katsura, Nishikyo-ku, Kyoto, 615-8510 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
for YoungScientists (A; No. 15685006) to Y.N. from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Reactions of acetophenones 2 with alcohols 3 in the presence of
an iridium complex and ruthenium complex 1.[a]
lessens the reaction time and the loss of yield by avoiding the
isolation and purification procedure of intermediates
required in multistep reactions. The sequential reaction
looks easy and simple, but the compatibility between different
transition-metal complexes should be established to achieve
it.
Entry 2, Ar
3, R
Product Yield [%][b] ee [%][c]
During our study on the development of novel catalytic
transformation using chalcogenolate-bridged diruthenium
complexes, we discovered a new type of ruthenium- and
platinum- or gold-catalyzed sequential reaction, in which tri-
and tetrasubstituted furans, pyrroles, oxazoles, and fused
polycyclic products were obtained in good-to-high yields with
excellent selectivities from simple and readily available
starting compounds.[7] These findings prompted us to further
develop useful sequential reactions catalyzed by two different
transition-metal complexes. Toward this end, our attention
was focused on the iridium-catalyzed a-alkylation of ketones
with alcohols[8] and the ruthenium-catalyzed transfer hydro-
genation of prochiral ketones[4] because the combination of
these two catalytic reactions might realize asymmetric a-
alkylative reduction of prochiral ketones with alcohols to
obtain optically active alcohols directly with elongation of the
carbon skeleton.
1
2
3
4
5
6
7
8
9
2a, Ph
2b, 4-MeC6H4
2c, 3-MeC6H4
2d, 2-MeC6H4 3a, nPr
2e, 4-MeOC6H4 3a, nPr
2 f, 4-ClC6H4
2g, 4-FC6H4
2a, Ph
3a, nPr
3a, nPr
3a, nPr
4aa
4ba
4ca
4da
4ea
4 fa
4ga
4ab
4ac
75
72
77
52
57
58
15
51
77
79
0
94 (R)[d]
98
96
97
97 (R)[d]
88
3a, nPr
3a, nPr
3b, iPr
3c, nBu
3d, CH2CHMe2 4ad
3e, Ph 4ae
95
96 (R)[d]
93 (R)[d]
96
2a, Ph
2a, Ph
2a, Ph
10
11
–
[a] All reactions of 2 (2.0 mmol) with 3 (6.0 mmol) were carried out in the
presence of [{IrCl(cod)}2] (1 mol%), PPh3 (4 mol%), and KOH (5 mol%)
at 1008C for 4 h, and the reaction mixture was kept at room temperature
for 2 h by the addition of 1 (1 mol%), iPrONa (4 mol%), and iPrOH
(160 mL). [b] Yield of the isolated product. [c] Determined by HPLC with
a chiral column. [d] The absolute configuration was determined by
comparison of the value of the optical rotation with that reported in the
literature.
Amixture of acetophenone ( 2a) and 1-butanol (3a) in the
presence of a catalytic amount of [{IrCl(cod)}2] (cod = 1,5-
cyclooctadiene; 1 mol%), PPh3 (4 mol%), and KOH
(5 mol%) was heated at 1008C for 4 h and then kept at
room temperature for 2 h after the addition of a catalytic
amount of 1 (1 mol%) and iPrONa (4 mol%) in iPrOH. As a
result, (R)-1-phenyl-1-hexanol (4aa) was obtained in 75%
yield of the isolated product with 94% ee (Scheme 1).
of products were observed without loss of optical purity when
2’-methyl- and 4’-methoxyacetophenones were used as sub-
strates (entries 4 and 5). The presence of an electron-with-
drawing group, such as a chloro moiety, at the para position of
acetophenone slightly decreased both the reactivity and the
enantioselectivity (entry 6). When 4’-fluoroacetophenone was
used as a substrate, only a low yield of product was observed,
even for a prolonged reaction time (entry 7).
Various primary alcohols are available as alkylating
reagents for ketones. Reactions of acetophenone (2a) with
2-methyl-1-propanol, 1-pentanol, and 3-methyl-1-butanol
were carried out in the presence of catalytic amounts of
[{IrCl(cod)}2] (1 mol%) and 1 (1 mol%) to afford the
corresponding a-alkylated alcohols in good yields with a
high enantioselectivity (entries 8–10). However, benzyl alco-
hol could not be employed for this reaction (entry 11).
Although the detailed reaction mechanism is not yet
known, it is considered that a primary alcohol is catalytically
dehydrogenated by the iridium complex to form the corre-
sponding aldehyde, followed by its base-catalyzed aldol
condensation with ketone to afford an a,b-unsaturated
ketone, and then iridium-catalyzed hydrogenation to give an
a-alkylated ketone. Finally, ruthenium-catalyzed enantiose-
lective transfer hydrogenation of the a-alkylated ketone
results in formation of the optically active alcohol with
elongation of the carbon skeleton (Scheme 2).
As described above, it is known that the iridium complex
[{IrCl(cod)}2] catalytically promotes the a-alkylation of
ketones with alcohols.[8] This result indicates that the presence
of the iridium complex, PPh3, and KOH did not interfere with
the final reduction step of the ketone intermediate. It is
noteworthy that the iridium and ruthenium complexes play
their roles independently in each step. The method presented
herein provides a useful synthetic route to obtaining optically
Scheme 1. Asymmetric a-alkylative reduction of a ketone with an
alcohol catalyzed by iridium and ruthenium.
Previously, the ruthenium-catalyzed direct synthesis of elon-
gated secondary alcohols through the a-alkylation of ketones
with primary alcohols had been reported.[9–11] We tried to
develop the enantioselective version of this reaction catalyzed
by using only 1, but a low-to-moderate enantioselectivity was
achieved. When the Noyori complexes,[1,2] such as [RuCl-
(tsdpen)(mesitylene)] (tsdpen = N-(p-toluenesulfonyl)-1,2-
diphenylethanediamine), were used as catalysts in place of
1, the sequential reaction did not proceed effectively. These
results indicate that the compatibility between [{IrCl(cod)}2]
and 1 is an essential factor in directly obtaining optically
active alcohols with elongation of the carbon skeleton.
Next, reactions of other acetophenones with 1-butanol
were investigated by using catalytic amounts of [{IrCl(cod)}2]
(1 mol%) and 1 (1 mol%). Typical results are shown in
Table 1. The introduction of a methyl group at the para or
meta position of acetophenone did not affect the reactivity
and enantioselectivity (entries 2 and 3). Slightly lower yields
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Angewandte
Chemie
with that reported in literature ([a]2D4 = À35.0 (c = 0.88, CHCl3),
92% ee (S)).[12]
Received: February 21, 2006
Published online: May 3, 2006
Keywords: alkylation · homogeneous catalysis · iridium ·
.
reduction · ruthenium
[1] For recent reviews, see: a) R. Noyori, S. Hashiguchi, Acc. Chem.
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2008; d) S. E. Clapham, A. Hadzovic, R. H. Morris, Coord.
Chem. Rev. 2004, 248, 2201.
Scheme 2. Plausible reaction pathway.
[2] For recent examples, see: a) T. Ohkuma, H. Ooka, S. Hashiguchi,
T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 2675; b) S.
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Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 1998, 120, 3817;
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Am. Chem. Soc. 1999, 121, 9580; i) C. J. A. Daley, S. H. Bergens,
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J. Am. Chem. Soc. 2002, 124, 15104; k) R. J. Hamilton, C. G.
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2005, 127, 4152.
active alcohols with elongation of the carbon skeleton directly
from prochiral ketones and alcohols, in contrast to the
conventional asymmetric reduction of prochiral ketones
which only gives the simple reduced alcohols.
In summary, we have disclosed that asymmetric a-
alkylative reduction of prochiral ketones with primary
alcohols catalyzed by both iridium and ruthenium complexes
gave the corresponding optically active alcohols with the
elongation of the carbon skeleton and with a high enantio-
selectivity (up to 98% ee). The compatibility between iridium
and ruthenium complexes is an essential factor in directly
obtaining optically active alcohols with elongation of the
carbon skeleton. Further investigations involving the broad-
ening of the scope of this sequential reaction system are
currently in progress.
[3] a) Since the first preparation of optically active ferrocenylox-
azolinylphosphines (FOXAPs) by us in 1995,[3b] we have
developed many enantioselective reactions catalyzed by various
transition-metal complexes bearing FOXAP as a chiral ligand;
b) Y. Nishibayashi, S. Uemura, Synlett 1995, 79; c) Y. Nishibaya-
shi, K. Segawa, K. Ohe, S. Uemura, Organometallics 1995, 14,
5486; d) Y. Nishibayashi, K. Segawa, H. Takada, K. Ohe, S.
Uemura, Chem. Commun. 1996, 847; e) Y. Nishibayashi, I.
Takei, S. Uemura, M. Hidai, Organometallics 1998, 17, 3420; f) I.
Takei, Y. Nishibayashi, Y. Arikawa, S. Uemura, M. Hidai,
Organometallics 1999, 18, 2271; g) I. Takei, Y. Nishibayashi, Y.
Ishii, Y. Mizobe, S. Uemura, M. Hidai, Chem. Commun. 2001,
2360; h) T. Iwata, Y. Miyake, Y. Nishibayashi, S. Uemura, J.
Chem. Soc. Perkin Trans. 1 2002, 1548; i) the optically active
FOXAP ligand is commercially available from Wako Pure
Chemical Industries (Japan) as ip-FOXAP (065-04331).
[4] a) Y. Nishibayashi, I. Takei, S. Uemura, M. Hidai, Organo-
metallics 1999, 18, 2291; b) Y. Nishibayashi, A. Yamauchi, G.
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Chem. Soc. Rev. 2004, 33, 302; b) J.-C. Wasilke, S. J. Obrey, R. T.
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Experimental Section
Atypical experimental procedure for the reaction of acetophenone
(2a) with 1-butanol (3a) catalyzed by [{IrCl(cod)}2] and [RuCl2-
(PPh3)(ip-foxap)] (1): KOH (5.8 mg, 0.10 mmol), [{IrCl(cod)}2]
(13.1 mg, 0.020 mmol), and PPh3 (21.4 mg, 0.082 mmol) under N2
were place in a 20-mL flask. After the addition of 2a (240.1 mg,
2.0 mmol) and 3a (445.8 mg, 6.0 mmol), the reaction mixture was
kept at 1008C for 4 h. Asolution of iPrOH containing iPrONa
(0.080 mmol) and 1 (18.4 mg, 0.020 mmol) was added to the reaction
mixture, and then the reaction mixture was kept at room temperature
for 2 h. For the workup, aqueous HCl (1n, 0.5 mL) was added to the
reaction mixture. The solvent was concentrated under reduced
pressure, and the residue was extracted with water (50 mL) and
diethyl ether (3 ” 50 mL). The organic solution was dried over
anhydrous MgSO4. For isolation, the extract was concentrated
under reduced pressure by an aspirator, and the residue was purified
by column chromatography on silica gel (EtOAc/n-hexane, 10:90) to
yield 267.7 mg (1.50 mmol, 75%, 94% ee) of (R)-1-phenyl-1-hexanol
(4aa) as a white solid, which was identified by comparison of its
spectroscopic data with that in the literature.[9] [a]D28 = + 35.3 (c = 1.04,
CHCl3); 1H NMR (CDCl3, 270MHz) d = 0.85–0.90 (m, 3H), 1.29–1.43
(m, 6H), 1.71–1.79 (m, 2H), 1.82 (d, 1H, J = 3.3 Hz), 4.64–4.70 (m,
1H), 7.24–7.36 ppm (m, 5H); the ee value was determined by HPLC
analysis with a Chiralcel OD column (eluent: n-hexane/2-propanol,
98:2, flow rate: 0.5 mLminÀ1, column temperature: 308C, retention
time: 34.72 min (R) and 46.60 min (S)); the absolute configuration
was determined by comparison of the value of the optical rotation
[6] For recent examples, see: a) C. J. Kressierer, T. J. J. Mꢀller,
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5997; b) J. Chae, J. Yun, S. L. Buchwald, Org. Lett. 2004, 6, 4809;
c) J. G. Kim, K. M. Waltz, I. F. Garcia, D. Kwiatkowski, P. J.
Walsh, J. Am. Chem. Soc. 2004, 126, 12580; d) H. Lebel, V.
Paquet, J. Am. Chem. Soc. 2004, 126, 11152; e) R. Guo, R. H.
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