A ruthenium-catalyzed one-pot method for α-alkylation of ketones with aldehydes

Article abstract of DOI:10.1016/j.jorganchem.2006.07.005

Ketones react with an array of aldehydes in dioxane at 80 °C in the presence of a catalytic amount of RuCl₂(PPh₃)₃ along with KOH to give the corresponding α-alkylated ketones in moderate to good yields. A reaction pathway involving base-catalyzed cross-aldol reaction between ketones and aldehydes to form α,β-unsaturated ketones and regioselective reduction of carbon-carbon double bond of α,β-unsaturated ketones is proposed for this catalytic process.

Full text of DOI:10.1016/j.jorganchem.2006.07.005

Journal of Organometallic Chemistry 691 (2006) 4329–4332
www.elsevier.com/locate/jorganchem
Note
A ruthenium-catalyzed one-pot method for a-alkylation of ketones
with aldehydes
Chan Sik Cho a,*, Sang Chul Shim b,
*
a
Research Institute of Industrial Technology, Kyungpook National University, 1370 Sankyuk-dong, Puk-ku, Daegu 702-701, Republic of Korea
b
Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 702-701, Republic of Korea
Received 6 March 2006; received in revised form 26 June 2006; accepted 7 July 2006
Available online 14 July 2006
Abstract
Ketones react with an array of aldehydes in dioxane at 80 ꢀC in the presence of a catalytic amount of RuCl
2
3 3
(PPh ) along with KOH
to give the corresponding a-alkylated ketones in moderate to good yields. A reaction pathway involving base-catalyzed cross-aldol
reaction between ketones and aldehydes to form a,b-unsaturated ketones and regioselective reduction of carbon–carbon double bond
of a,b-unsaturated ketones is proposed for this catalytic process.
ꢁ
2006 Elsevier B.V. All rights reserved.
Keywords: Aldehydes; Aldol reaction; a-alkylation; Ketones; Reduction; Ruthenium catalyst
1
. Introduction
have also reported an iridium-catalyzed a-alkylation of
ketones with primary alcohols [6]. It was suggested by both
groups that the a-alkylation of ketones with primary alco-
hols proceeds via an initial oxidation of the alcohol to alde-
hyde [2,6]. Under these circumstances [7], we have directed
our attention to ruthenium-catalyzed a-alkylation of
ketones with aldehydes [8]. Herein, this report describes a
ruthenium-catalyzed one-pot method for a-alkylation of
ketones with an array of aldehydes [9].
Transition metal-catalyzed carbon–carbon bond form-
ing reaction has been widely explored and used as a prom-
ising tool in synthetic organic chemistry [1]. In connection
with this report, as part of our ongoing studies on ruthe-
nium catalysis, we recently found an unusual type of ruthe-
nium-catalyzed transfer hydrogenation between ketones 1
and primary alcohols 2 accompanied by carbon–carbon
coupling under KOH, in which alkylated ketones 3
(
Scheme 1, route a) [2] or unconventional transfer hydroge-
2. Results and discussion
nated secondary alcohols 4 (Scheme 1, route b) [3] were
preferentially formed according to the molar ratio of pri-
mary alcohols to ketones [4]. It was also disclosed that sec-
ondary alcohols 5 were found to be coupled with primary
alcohols 2 in the presence of a ruthenium catalyst along
with sacrificial hydrogen acceptor to give coupled second-
ary alcohols 4 (Scheme 1, route c) [5]. In closely related
with our report shown in route a of Scheme 1, Ishii et al.
First, several reactions between acetophenone (1a, 1:
R = Ph) and benzaldehyde (6a, 6: R = Ph) were tried to
0
optimize the reaction conditions and elucidate the feature
of the present alkylation (Eq. (1)). When 1a was treated
with equimolar amount of 6a in dioxane at 80 ꢀC for 40 h
in the presence of a catalytic amount of RuCl (PPh )
2
3 3
(2 mol%) along with KOH, the coupled ketone 1,3-diphe-
0
nylpropan-1-one (3a, 3: R = R = Ph) was formed in 71%
isolated yield with concomitant formation of further hydro-
*
Corresponding authors. Tel.: +82 53 950 7318 (C.S. Cho); +82 53 950
genated coupled alcohol 1,3-diphenylpropan-1-ol (4a, 4:
5
586 (S.C. Shim); fax: +82 53 950 6594 (C.S. Cho).
0
R = R = Ph) (2% yield). Performing the reaction for a
E-mail addresses: cscho@knu.ac.kr (C.S. Cho), scshim@knu.ac.kr
(S.C. Shim).
shorter time (26 h) was accompanied by a considerable
0
022-328X/$ - see front matter ꢁ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.07.005

4330
C.S. Cho, S.C. Shim / Journal of Organometallic Chemistry 691 (2006) 4329–4332
Table 1
O
O
a
route a
route c
Ruthenium-catalyzed a-alkylation of ketones 1 with aldehydes 6
+
+
HO
HO
R'
R'
R
R
R
R'
R'
Ketones 1
Aldehydes 6
Products 3
Yield
b
(%)
1
2
2
3
0
O
R
R CHO
O
R
OH
OH
R'
R
0
0
0
5
4
R = Ph (1a)
R = Ph (6a)
3a
71
67
63
64
81
44
48
49
62
76
55
69
68
69
54
54
34
R = 4-MeC
6
H
4
(6b) 3b
(6c) 3c
(6d) 3d
3e
Scheme 1.
R = 4-MeOC
6
H
4
0
0
0
0
R = 4-ClC
6
H
4
R = 2-furyl (6e)
c
R = ferrocenyl (6f) 3f
amount of initial cross-aldol product benzylideneacetophe-
none (12% yield) with lower yield of 3a (36%). Equimolar
amount of both substrates is desirable in atom economy
point of view since the reaction under the molar ratio of
6a]/[1a] = 2 resulted in a slightly increased yield of 3a
79%). As has been shown in our recent report [3], the
reduction of initial benzylideneacetophenone to 3a seems
to be derived from solvent dioxane. Actually, in a separate
experiment, we confirmed that benzylideneacetophenone
was reduced to 3a in 69% yield under RuCl (PPh )
R = heptyl (6g)
3g
3h
3i
R = 2-HOC
R = 2-MeC H (1c)
R = 3-MeC
R = 4-MeC
R = 4-MeOC
6
H
4
(1b)
6a
6a
6a
6a
6
6
6
4
4
4
H
H
(1d)
(1e)
3j
3k
3l
[
(
6 4
H (1f) 6a
R = 4-FC
6
H
4
(1g)
6a
6a
6a
6a
6a
3m
3n
3o
3p
R = 2-thienyl (1h)
R = 2-naphthyl (1i)
R = ferrocenyl (1j)
O
d
O
2
3 3
(
2 mol%)/KOH (1 equivalent)/dioxane (3 ml)/80 ꢀC/40 h.
Ph
Ph
Ph
1
k
3q
This observation also indicates that the olefinic double
bond of benzylideneacetophenone is more susceptible to
reduction than the carbonyl group of that under the
employed conditions.
O
O
6a
6a
O
52
73
Ph
Ph
O
O
OH
2
% RuCl2(PPh3)3
+
R'CHO
+
o
1l
3r
KOH, dioxane, 80 C
ð1Þ
R
R
R'
R
R'
1
6
3
4
Having established reaction conditions, a series of
O
ketones 1 and aldehydes 6 were screened in order to inves-
tigate the reaction scope, and several representative results
are summarized in Table 1. The reaction of 1a with several
aromatic and heteroaromatic aldehydes (6a–6e) proceeds
to give the corresponding coupled ketones 3a–3e in 63–
1m
3s
O
6a
O
trace
8
1% yields with the minimal formation of the further
Ph
Ph
Ph
hydrogenated coupled secondary alcohols 4. The product
yield was not significantly affected by the electronic nature
of the substituent on the aromatic ring of aldehydes. From
the reaction between 1a and ferrocenecarboxaldehyde (6f),
the corresponding coupled ketone (3f) was also produced
in 44% yield with a considerable amount of the initial
cross-aldol product 3-ferrocenyl-1-phenylpropen-1-one
1
n
3
t
O
O
Ph
n
n
(
22%). The reaction proceeds likewise with aliphatic alde-
n = 1 (1o)
n = 2 (1p)
a
6a
6a
3u
3v
45
75
hyde 6g to give the coupled ketone 3g, however, the prod-
uct yield was lower than that when aromatic aldehydes
were used. In the reaction of aryl- and heteroaryl(methyl)
ketones (1b–1i) with 6a, the corresponding coupled ketones
were also obtained in the range of 49–76% yields. As is the
case for the reaction between 1a and 6f, the reaction of
acetylferrocene (1j) with 6a, besides the ususal coupled
ketone 3p (54% yield), resulted in a considerable yield of
the initial aldol product cinnamoylferrocene (20%). With
alkyl(methyl) ketones (1k–1m), the alkylation took place
exclusively at less-hindered methyl position over a-methy-
All reactions were carried out with
(PPh (0.02 mmol), and KOH (1 mmol) in dioxane (3 ml) at 80 ꢀC
for 40 h.
1 (1 mmol), 2 (1 mmol),
RuCl
2
3 3
)
b
Isolated yield.
c
3-Ferrocenyl-1-phenylpropen-1-one was also formed in 22% yield.
Cinnamoylferrocene was also formed in 20% yield.
d
lene and -methine. Similar regioselectivity has been
observed by our recent reports [2,5,10] and others [11]. In
the case of propiophenone (1n) which has only methylene

C.S. Cho, S.C. Shim / Journal of Organometallic Chemistry 691 (2006) 4329–4332
4331
carrier gas. The isolation of pure products was carried out
via column chromatography (silica gel 60, 70–230 mesh,
Merck) and thin layer chromatography (silica gel 60
GF254, Merck). Commercially available organic and inor-
ganic compounds were used without further purification.
O
+
R'CHO
R
R
1
6
base
O
O
4.1. Typical experimental procedure
R'
R
R'
7
3
A mixture of acetophenone (1a) (0.120 g, 1 mmol), benz-
aldehyde (6a) (0.106 g, 1 mmol), RuCl (PPh ) (0.019 g,
2
3 3
0.02 mmol), and KOH (0.056 g, 1 mmol) in dioxane
(3 ml) was placed in a 5 ml screw-capped vial and allowed
to react at 80 ꢀC for 40 h. The reaction mixture was filtered
[Ru]
[Ru]H2
through a short silica gel column (CHCl -ethyl acetate mix-
3
ture) to eliminate inorganic salts. Removal of the solvent
left an oil, which was purified by thin-layer chromatogra-
phy (silica gel, ethyl acetate/hexane = 1/10) to give 1,3-
diphenylpropan-1-one (3a) (0.150 g, 71%).
The compounds 3a [2], 3f [13], 3i–3m [2], 3o [2], and
3r–3v [2] are noted in our recent report and identified by
comparison with the prepared samples.
dioxene
dioxane
Scheme 2.
4
.1.1. 3-(4-Methylphenyl)-1-phenylpropan-1-one (3b) [14]
1
reaction site, the reaction did not proceed at all toward
coupling. However, benzo-fused cyclic ketones such as 1-
indanone (1o) and 1-tetralone (1p) which have only methy-
lene reaction site were readily alkylated with 6a to give the
corresponding alkylated ketones 3u and 3v.
As to the reaction pathway, a,b-unsaturated ketones 7,
initially formed by base-catalyzed cross-aldol reaction
between ketones 1 and aldehydes 6, seem to be reduced
to coupled ketones 3 or coupled secondary alcohols 4 by
Pale yellow oil; H NMR (CDCl ): d 2.31 (s, 3H), 3.02
3
(
(
(
t, J = 7.5 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H), 7.09–7.15
m, 4H), 7.41–7.45 (m, 2H), 7.52–7.56 (m, 1H), 7.93–7.95
m, 2H); C NMR (CDCl ): d 20.9, 29.6, 40.5, 128.0,
1
3
3
128.2, 128.5, 129.1, 133.0, 135.5, 136.8, 138.1, 199.3.
4.1.2. 3-(4-Methoxyphenyl)-1-phenylpropan-1-one (3c)
[14]
1
Pale yellow oil; H NMR (CDCl ): d 3.01 (t, J = 7.5 Hz,
[
(
Ru]H2 derived from ruthenium catalyst and dioxane
Scheme 2). It is known that dioxane has been used as a
3
2H), 3.26 (t, J = 7.5 Hz, 2H), 3.78 (s, 3H), 6.84 (d,
J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.44 (t,
J = 7.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.94–7.96 (m,
hydrogen donor in transition metal-catalyzed transfer
hydrogenation [12].
1
3
2
1
H); C NMR (CDCl ): d 29.7, 41.1, 55.7, 114.3, 128.4,
3
29.0, 129.8, 133.4, 133.7, 137.3, 158.4, 199.8.
3
. Conclusion
In summary, we have demonstrated that ketones react
4.1.3. 3-(4-Chlorophenyl)-1-phenylpropan-1-one (3d) [15]
1
with an array of aldehydes in dioxane in the presence of
a catalytic amount of a ruthenium catalyst together with
KOH to give the corresponding a-alkylated ketones. To
the best of our knowledge, this protocol is the first one-
pot strategy for a-alkyaltion of ketones by aldehydes.
Pale yellow oil; H NMR (CDCl ): d 3.03 (t, J = 7.5 Hz,
3
2H), 3.27 (t, J = 7.5 Hz, 2H), 7.16–7.18 (m, 2H), 7.23–7.26
(m, 2H), 7.43–7.46 (m, 2H), 7.53–7.57 (m, 1H), 7.93–7.95
1
3
(m, 2H); C NMR (CDCl ): d 29.8, 40.5, 128.4, 128.9,
3
129.0, 130.2, 132.3, 133.6, 137.1, 140.1, 199.2.
4
. Experimental
4.1.4. 3-(2-Furanyl)-1-phenylpropan-1-one (3e) [16]
1
Pale yellow oil; H NMR (CDCl ): d 3.09 (t, J = 7.5 Hz,
3
1
13
H and C NMR (400 and 100 MHz) spectra were
2H), 3.33 (t, J = 7.5 Hz, 2H), 6.04 (t, J = 3.0 Hz, 1H), 6.27
(d, J = 3.0 Hz, 1H), 7.25–7.30 (m, 1H), 7P.45 (t,
J = 7.5 Hz, 1H), 7.54–7.57 (m, 1H), 7.95–7.98 (m, 2H);
recorded on a Bruker Avance Digital 400 spectrometer using
TMS as an internal standard. Melting points were deter-
mined on a Thomas–Hoover capillary melting point appara-
tus and were uncorrected. Mass spectra were obtained using
EI ionization at 70 eV. GLC analyses were carried out with a
Shimadzu GC-17 A instrument equipped with a CBP10-
S25-050 column (Shimadzu, fused silica capillary column,
1
3
C NMR (CDCl ): d 22.5, 36.9, 105.3, 110.2, 128.0,
3
128.6, 133.1, 136.7, 141.0, 154.7, 198.6 (C@O).
4.1.5. 1-Phenyldecan-1-one (3g)
This compound is commercially available and identified
by comparison with authentic sample.
0
.33 mm · 25 m, 0.25 lm film thickness) using nitrogen as

4332
C.S. Cho, S.C. Shim / Journal of Organometallic Chemistry 691 (2006) 4329–4332
4
[
.1.6. 1-(2-Hydroxyphenyl)-3-phenylpropan-1-one (3h)
17]
[3] C.S. Cho, B.T. Kim, T.-J. Kim, S.C. Shim, J. Org. Chem. 66 (2001)
020.
[4] For recent reviews on transition metal-catalyzed transfer hydrogen-
tion, see: (a) G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev. 92
9
1
Pale yellow oil; H NMR (CDCl ): d 3.05 (t, J = 7.5 Hz,
3
2
H), 3.30 (t, J = 7.5 Hz, 2H), 6.85 (t, J = 7.5 Hz, 1H), 6.97
(
1992) 1051;
(
d, J = 8.6 Hz, 1H), 7.19–7.31 (m, 5H), 7.41–7.45 (m, 1H),
(b) J.-E. B a¨ ckvall, R.L. Chowdhury, U. Karlsson, G. Wang, in: A.F.
Williams, C. Floriani, A.E. Merbach (Eds.), Perspectives in Coordi-
nation Chemistry, VCH, New York, 1992, pp. 463–486;
1
3
7
2
1
.70–7.72 (m, 1H), 12.30 (s, 1H); C NMR (CDCl ): d
3
9.9, 40.0, 118.5, 118.8, 119.2, 126.2, 128.3, 128.5, 129.8,
36.3, 140.6, 162.4, 205.3 (C@O).
(
(
c) R. Noyori, S. Hashiguchi, S. Acc. Chem. Res. 30 (1997) 97;
d) T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 98 (1998)
2
599;
4
.1.7. 3-Phenyl-1-(2-thienyl)propan-1-one (3n) [18]
1
(e) M. Palmer, M. Wills, Tetrahedron: Asymmetr. 10 (1999) 2045.
[5] C.S. Cho, B.T. Kim, H.-S. Kim, T.-J. Kim, S.C. Shim, Organomet-
allics 22 (2003) 3608.
Pale yellow oil; H NMR (CDCl ): d 3.06 (t, J = 7.8 Hz,
3
2
H), 3.22 (t, J = 7.8 Hz, 2H), 7.08–7.10 (m, 1H), 7.18–7.31
[6] K. Taguchi, H. Nakagawa, T. Hirabayashi, S. Sakaguchi, Y. Ishii, J.
(
m, 5H), 7.60 (dd, J = 5.0 and 1.0 Hz, 1H), 7.67 (dd,
Am. Chem. Soc. 126 (2004) 72–73.
1
3
J = 5.0 and 1.0 Hz, 1H); C NMR (CDCl ): d 30.3, 41.0,
3
[7] These reactions could also be applied to ruthenium-catalyzed
Friedlaender quinoline synthesis by oxidative cyclization of 2-
aminobenzyl alcohol with ketones and secondary alcohols: (a) C.S.
Cho, B.T. Kim, T.-J. Kim, S.C. Shim, Chem. Commun. (2001) 2576;
1
1
26.1, 128.0, 128.4, 128.5, 131.8, 133.5, 140.9, 144.1,
92.1 (C@O).
(
b) C.S. Cho, B.T. Kim, H.-J. Choi, T.-J. Kim, S.C. Shim,
4
.1.8. 1-Ferrocenyl-3-phenylpropan-1-one (3p)
Reddish yellow solid, m.p. 78–79 ꢀC (from hexane) (lit.
Tetrahedron 59 (2003) 7997.
[
8] Conventional a-alkylation of ketone is generally achieved by the
coupling between nucleophilic enolates and electrophilic alkylating
agents: J. d’Angelo, Tetrahedron 32 (1976) 2979.
1
[
19] 79–81 ꢀC); H NMR (CDCl ): d 2.98–3.09 (m, 4H),
3
4
2
6
.07 (s, 5H), 4.47 (t, J = 2.0 Hz, 2H), 4.76 (t, J = 2.0 Hz,
1
3
[9] Although a ruthenium-catalyzed route for a-alkylation of ketones
by primary alcohols reported in Ref. [2] is more useful than this
method using aldehydes instead of primary alcohols as commented
by a reviewer, the present one-pot procedure, in a sense of the
efficiency of reaction, is also superior to conventional a-alkylation of
ketones by aldehydes, which usually proceeds via separate step-by-
step unit transformations such as aldol reaction and regioselective
reduction.
H), 7.19–7.33 (m, 5H); C NMR (CDCl ): d 30.1, 41.5,
3
9.2, 69.6, 72.2, 78.9, 126.1, 128.5, 128.6, 141.6, 203.1
(
C@O).
4
.1.9. 1,5-Diphenylpentan-3-one (3q) [20]
1
Pale yellow oil; H NMR (CDCl ): d 2.69 (t, J = 7.5 Hz,
3
1
3
4
H), 2.87 (t, J = 7.8 Hz, 4H), 7.11–7.31 (m, 10H); C-
[
10] C.S. Cho, B.T. Kim, M.J. Lee, T.-J. Kim, S.C. Shim, Angew. Chem.
NMR (CDCl ): d 29.7, 44.4, 126.0, 128.2, 128.4, 140.9,
2
1
3
Int. Ed. Engl. 40 (2001) 958.
[11] (a) M. Palucki, S.L. Buchwald, J. Am. Chem. Soc. 119 (1997)
11108;
+
09.0 (C@O); MS m/z (relative intensity): 238 (M , 72),
05 (100).
(
b) B.C. Hamann, J.F. Hartwig, J. Am. Chem. Soc. 119 (1997)
2382.
12] (a) T. Nishiguchi, K. Tachi, K. Fukuzumi, J. Am. Chem. Soc. 94
1
Acknowledgements
[
[
(
(
(
1972) 8916;
b) T. Nishiguchi, K. Fukuzumi, J. Am. Chem. Soc. 96 (1974) 1893;
c) H. Imai, T. Nishiguchi, K. Fukuzumi, J. Org. Chem. 41 (1976)
65.
The present work was supported by the Korea Research
Foundation Grant funded by Korea Government
6
(
2
MOEHRD, Basic Research Promotion Fund) (KRF-
005-015-C00264). C.S.C. gratefully acknowledges a Re-
search Professor Grant of Kyungpook National University
2005).
13] C.S. Cho, J.H. Park, B.T. Kim, T.-J. Kim, S.C. Shim, M.C. Kim,
Bull. Korean Chem. Soc. 25 (2004) 423.
[14] V. Calo, A. Nacci, L. Lopez, A. Napola, Tetrahedron Lett. 42 (2001)
701.
15] K. Kokubo, M. Miura, M. Nomura, Organometallics 14 (1995)
521.
[16] P. Canonne, M. Akssira, Tetrahedron Lett. 24 (1983) 5519.
17] C. Cimarelli, G. Palmieri, Tetrahedron 54 (1998) 15711.
4
(
[
4
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