Recyclable palladium catalyst for highly selective α alkylation of ketones with alcohols

Article abstract of DOI:10.1002/anie.200502422

(Chemical Equation Presented) An air-stable, heterogeneous, and recyclable catalyst composed of palladium nanoparticles entrapped in aluminum hydroxide was applied to a highly selective α alkylation. A wide range of aliphatic and aromatic ketones and primary alcohols were coupled to prepare enones in an O₂ atmosphere and ketones in an argon atmosphere (see scheme).

Full text of DOI:10.1002/anie.200502422

Angewandte
Chemie
Synthetic Methods
a alkylation of ketones with primary alcohols as it is able to
produce aldehydes from primary alcohols and hydrogenate
intermediate enones formed from the coupling of aldehydes
and ketones in the presence of a base.[2d] In fact, 1,3-
diphenylpropan-1-one was obtained in 97% yield in the
reaction of acetophenone with 1.2 equivalents of benzyl
alcohol in the presence of 1 (0.2 mol% of Pd) and K3PO4
(3 equiv) for 8 h at 808C under argon. Notably, the same
reaction under 1 atm O2 produced chalcone in 95% yield
after 20 h.
DOI: 10.1002/anie.200502422
Recyclable Palladium Catalyst for Highly
Selective a Alkylation of Ketones with Alcohols**
Min Serk Kwon, Namdu Kim, Seong Hyeok Seo,
In Soo Park, Ravi Kumar Cheedrala, and Jaiwook Park*
The reaction conditions were optimized for the alkylation
of acetophenone with benzyl alcohol through variation of the
base, temperature, and solvent. Among the bases tested,
K3PO4 was found to be the best. Strong bases such as KOH,
NaOH, and CaH2 dissolved the aluminum hydroxide matrix,
whereas the alkylation product was not detected in reactions
with weak bases, such as K2HPO4, K2CO3, Na2CO3, and
triethylamine. The reaction rate was affected by the amount
of K3PO4;[5] thus, three equivalents were needed to complete
the reaction within 8 h at 808C. The temperature was also an
important factor for the reaction rate: as the temperature was
raised to 1108C, the alkylation was completed in 2.5 h. Studies
on the effect of the solvent revealed that toluene is more
effective than trifluorotoluene, n-heptane, 1,4-dioxane, or
water.
The high efficiency of 1 for the coupling of acetophenone
and benzyl alcohol relative to commercially available cata-
lysts and the a-alkylation catalysts reported previously was
shown clearly (Table 1). Low selectivities (< 71%) and yields
(< 55%) of 1,3-diphenylpropan-1-one (2) were observed for
the reactions with commercially available heterogeneous
palladium catalysts (entries 2–4). The reaction with [RuCl2-
(PPh3)3] requires the addition of 1-dodecene to increase the
selectivity.[2c] The production of 1,3-diphenylpropane-1-ol
increases as the amount of benzyl alcohol is increased for
the reactions with [RuCl2(PPh3)3] and [Ru(dmso)4]Cl2
(dmso = dimethyl sulfoxide),[2f] and phosphine ligands were
needed with [{IrCl(cod)}2] (cod = cyclooctadiene).[2e] The
ruthenium-grafted hydrotalcite is a notable catalyst for
a alkylation in the absence of a base, although a long reaction
time at high temperature is required.[3]
À
Carbon carbon bond-forming reactions are fundamental in
organic synthesis. The a alkylation of enolates derived from
ketones with electrophiles such as alkyl halides is the
conventional method to form C C bonds. The metal-
[1]
À
catalyzed a alkylation of ketones with alcohols is attracting
much attention because of its critical advantage over the
conventional a-alkylation method, which suffers from prob-
lems with waste salts. Recently, several groups have reported
the use of homogeneous catalysts for the a alkylation of
ketones with alcohols.[2] However, these catalytic systems
often suffer from low yield, low product selectivity, and/or the
À
need for additives and strong bases. As a related C C
coupling reaction, Kaneda and co-workers developed an
a alkylation of nitriles with primary alcohols using a Ru-
grafted hydrotalcite as the catalyst.[3] Herein, we report a
heterogeneous and recyclable palladium catalyst, which does
not require ligands or additives, for the a alkylation of
ketones with primary alcohols. Furthermore, our catalyst is
active in the presence of oxygen and can produce enones
selectively under 1 atm O2, whereas ketones are the major
product under argon (Scheme 1).
Scheme 1. Palladium-catalyzed coupling of acetophenone and benzyl
alcohol.
The main advantage of 1, besides its selectivity, is its
recyclability—it can be recovered by filtration or decantation
(Table 2). To the best of our knowledge, 1 is the first
recyclable catalyst for the a alkylation of ketones with
alcohols.[9] When the recovered catalyst was used without
any treatment, the reaction rate decreased considerably
(entry 2), whereas the addition of K3PO4 lead to resumption
of the rate. Therefore, for each successive use, one equivalent
of K3PO4 relative to acetophenone was added. Catalyst 1
retained its activity even during its sixth use, as 2 was
prepared in 96% yield after 20 h.
With suitable reaction conditions established, a series of
ketones and alcohols were employed to investigate the scope
of the reaction (Table 3). Our catalytic system was effective
for a wide combination of ketones and alcohols that produced
the corresponding a-alkylated products under anaerobic
conditions. It was also effective for the selective production
of trans enones under 1 atm O2, although the reaction rates
Recently, we reported a heterogeneous palladium cata-
lyst, Pd/AlO(OH) (1), that is composed of palladium nano-
particles entrapped in aluminum hydroxide[4] and is highly
active for both alkene hydrogenation and aerobic alcohol
oxidation. We envisioned that 1 would be applicable to the
[*] M. S. Kwon, N. Kim, S. H. Seo, I. S. Park, R. K. Cheedrala, Prof. J. Park
Center for Integrated Molecular Systems
Department of Chemistry
Division of Molecular and Life Sciences
Pohang University of Science and Technology (POSTECH)
San 31 Hyoja Dong, Pohang 790-784 (Korea)
Fax: (+82)54-279-3399
E-mail: pjw@postech.ac.kr
[**] This work was supported by the SRC/ERC program of MOST/
KOSEF (R11-2000-070-05003-0).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Table 1: Catalytic activity comparison.[a]
were relatively slow (entries 5, 11, and 13).
The alkylation of 4’-(trifluoromethyl)aceto-
phenone was somewhat less selective, as the
expected ketone was obtained in 87% yield
along with the corresponding alcohol in 6%
yield (entry 6).[6] Indanone was alkylated
successfully at the a-methylene position
(entry 7). Acetophenone was also alkylated
by aliphatic alcohols in high yield (entries 8
and 9). Furthermore, aliphatic ketones were
alkylated by an aliphatic alcohol as well as
by aromatic alcohols in high yields and with
high selectivities (entries 10–15). Alkylation
occurred almost exclusively at the methyl
positions, and the coupling of acetone with
1-butanol produced undecan-6-one in 92%
yield (entry 16). The reactions of aliphatic
primary alcohols were slower than those of
Entry Catalyst
Metal [mol%] Base (equiv) T [8C] t [h] Conv. [%][b] Product yield [%][c]
2
3
4
1
2
3
4
5
6
7
8
1
0.2
0.2
0.2
0.2
2.0
K3PO4 (3)
K3PO4 (3)
K3PO4 (3)
K3PO4 (3)
KOH (1)
KOH (1)
KOH (0.1)
none
80
80
80
80
80
80
100
180
8
8
8
>99
78
47
97
55
21
11
82
72
86
85
2
4
2
0
2
0
5% Pd/C[d]
5% Pd/Al2O3
10
17
12
[e]
[e]
[e]
[e]
[d]
[d]
5% Pd/BaCO3
[RuCl2(PPh3)3]
[Ru(dmso)4]Cl2 2.0
[{Ir(cod)Cl}2]
Ru/HT
8
30
20
84
[e]
[e]
[e]
[f]
1.0
0.75
4
20
10
[e]
85
[a] A solution of acetophenone (1.0 mmol) and benzyl alcohol (1.2 mmol) in toluene (2 mL) was heated
under argon. [b] Conversion of acetophenone. [c] Determined by GC. [d] Commercially available
catalysts. [e] No report. HT=hydrotalcite.
aryl methanol derivatives. In particular, the coupling between
an aliphatic ketone and an aliphatic alcohol required a
reaction time about eight times longer than for the coupling
between aryl methyl ketones and aryl methanol derivatives
(entry 15). A noticeable example is the coupling of 5-
pregnen-3b-ol-20-one with benzyl alcohol,[7] as the secondary
Table 2: Recycling 1 for the coupling of acetophenone and benzyl
alcohol.[a,b]
Use
T [8C]
t [h]
Yield [%][c]
1
2
3
4
5
6
80
80
80
80
80
80
8
8
8
8
8
97
30[d]
97
=
hydroxy group and the C C bond are compatible with the
92
87
96
coupling conditions (entry 17). Furthermore, the epimeriza-
tion at C17 was negligible.[8]
20
In summary, we have demonstrated a highly efficient
a alkylation of ketones with primary alcohols by the use of a
recyclable palladium catalyst that is easily prepared from
readily available reagents. We are currently investigating
[a] A solution of acetophenone (1.0 mmol) and benzyl alcohol
(1.2 mmol) in toluene (2 mL) was heated at 808C in the presence of 1
(0.2 mol% of Pd) under argon. [b] K3PO4 (1 equiv) was added for the
reuse of 1. [c] Determined by GC. [d] Without the addition of K3PO4.
Table 3: a Alkylation of ketones with primary alcohols.[a]
Entry
Ketone
Alcohol
t [h]
Product
Yield [%][b]
97(92)[c]
1
2.5
2
3
4
2.5
2.5
2.5
96
96
98(90)[c]
5
6
20[d]
87(80)[c]
87[e]
3
7
8
3
97
12[f]
95(88)[c]
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Angewandte
Chemie
Table 3: (Continued)
Entry
Ketone
Alcohol
t [h]
Product
Yield [%][b]
95
9
14[f]
10
11
12
13
14
3
20[d]
3
97(90)[c]
85[c]
97
20[d]
82[c]
3
98(94)[c]
15
16
20
94
92
48[f]
17
5
84[c]
[a] A solution of ketone (1.0 mmol) and alcohol (1.2 mmol) in toluene (2 mL) was heated in the presence of 1 (0.2 mol% of Pd) and K3PO4 (3 mmol) at
1108C under argon. [b] Determined by GC. [c] Yield of isolated product. [d] Under 1 atm O2. [e] 3-Phenyl-1-(4-trifluoromethyl)phenylpropanol was
formed in 6% yield. [f] Excess 1-butanol (4 mmol) was used.
2001, 66, 9020 – 9022; c) C. S. Cho, B. T. Kim, T.-J. Kim, S. C.
Shim, Tetrahedron Lett. 2002, 43, 7987 – 7989; d) C. S. Cho, B. T.
Kim, H.-S. Kim, T.-J. Kim, S. C. Shim, Organometallics 2003, 22,
3609 – 3610; e) K. Taguchi, H. Nakagawa, T. Hirabayashi, S.
Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 2004, 126, 72 – 73; f) R .
Martínez, G.-J. Brand, D.-J. Ramón, M. Yus, Tetrahedron Lett.
2005, 46, 3683 – 3686.
other one-pot multicatalytic reactions based on the versatile
activity of the palladium catalyst.
Experimental Section
Coupling of acetophenone and benzyl alcohol: Acetophenone
(120 mg, 1.00 mmol), benzyl alcohol (130 mg, 1.20 mmol), 1 (24 mg,
0.2 mol% of Pd), K3PO4 (636 mg, 3.00 mmol), and toluene (2 mL)
were placed in a 20-mL flask under argon at 808C for 8 h. The catalyst
was separated by filtration, and the filtrate was purified by column
chromatography (ethyl acetate/hexane 1:9) to give 1,3-diphenylpro-
pan-1-one (193 mg) in 92% yield.[10]
[3] K. Motokura, D. Nishimura, K. Mori, T. Mizugaki, K. Ebitani, K.
Kaneda, J. Am. Chem. Soc. 2004, 126, 5662 – 5663.
[4] M. S. Kwon, N. Kim, C. M. Park, J. S. Lee, K. Y. Kang, J. Park,
Org. Lett. 2005, 7, 1077 – 1079.
[5] The coupling reaction was completed in 16 h (10 h) when one
equivalent (2 equiv) of K3PO4 was used.
[6] The major product is the corresponding alcohol when [Ru-
(dmso)4]Cl2 is used as the catalyst; see ref. [2f].
Received: July 12, 2005
Published online: October 5, 2005
[7] Pregnenolone is a main precursor of steroid hormones: K.
Tsutsui, H. Sakamoto, K. Ukena, J. Steroid Biochem. Mol. Biol.
2003, 85, 311 – 321.
À
Keywords: alkylation · aluminum · C C coupling ·
.
1
[8] According to H NMRspectroscopic analysis, no diastereomer
heterogeneous catalysis · palladium
of the major coupling product was formed in significant yield.
[9] Palladium was not detected in the filtrate with inductively
coupled plasma (ICP) analysis.
[1] a) D. Caine in Comprehensive Organic Synthesis, Vol. 3 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 1 – 63;
b) S. Carrettin, J. Guzman, A. Corma, Angew. Chem. 2005, 117,
2282 – 2285; Angew. Chem. Int. Ed. 2005, 44, 2242 – 2245;
c) Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH,
Weinheim, 2000.
[10] The NMRspectroscopic data for the coupling products shown in
Table 3 and the experimental procedures for the preparation of
1, E-1,3-diphenyl-2-propen-1-one, and 21-benzylpregnenolone
are contained in the Supporting Information.
[2] a) C. S. Cho, B. T. Kim, M. J. Lee, T.-J. Kim, S. C. Shim, Angew.
Chem. 2001, 113, 984 – 986; Angew. Chem. Int. Ed. 2001, 40, 958 –
960; b) C. S. Cho, B. T. Kim, T.-J. Kim, S. C. Shim, J. Org. Chem.
Angew. Chem. Int. Ed. 2005, 44, 6913 –6915
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