Lithium tert-butoxide mediated α-alkylation of ketones with primary alcohols under transition-metal-free conditions

Article abstract of DOI:10.1039/c3ra23221b

LiOtBu was found to efficiently promote the α-alkylation reaction of ketones with primary alcohols, without the addition of any transition metal catalyst.

Full text of DOI:10.1039/c3ra23221b

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Lithium tert-butoxide mediated a-alkylation of ketones
with primary alcohols under transition-metal-free
conditions3
Cite this: RSC Advances, 2013, 3, 7739
Received 7th December 2012,
Accepted 3rd April 2013
a
a
b
b
a
Yu-Feng Liang, Xin-Feng Zhou, Shi-Ya Tang, Yao-Bing Huang, Yi-Si Feng
DOI: 10.1039/c3ra23221b
a
and Hua-Jian Xu*
www.rsc.org/advances
LiOtBu was found to efficiently promote the a-alkylation reaction
of ketones with primary alcohols, without the addition of any
transition metal catalyst.
a-alkylation of acetophenone (1a) with benzyl alcohol (2a)
(Table 1). Although we indeed observed the expected alkylation
with the copper catalysts, we were surprised to find that the
alkylation reaction can take place more efficiently without any
copper catalyst (entry 3, Table 1). Thus, in the present work we
wish to report an unprecedented and unexpected transition-metal-
free a-alkylation reaction of ketones with primary alcohols (eqn
(1)).
Carbon–carbon bond forming reactions are of fundamental
importance in synthetic organic chemistry. The a-alkylation of
ketones with electrophiles such as alkyl halides is an important
1
tool for the construction of C–C bonds. In recent years, alcohols
have attracted increasing attention as electrophilic alkylating
agents because they do not generate any side products other than
2
water in the reaction. In this context, several groups have reported
3
4
5
the use of transition metals, such as ruthenium, iridium,
6
7
8
9
palladium, nickel, titanium, and silver as catalysts for the
a-alkylation reaction of ketones with alcohols. For example, Cho
et al. showed that ketones can be a-alkylated with primary alcohols
Table 1 a-Alkylation of acetophenone with benzyl alcohol under various
a
conditions
4
3 3
a
6a
with both RuCl (PPh ) and Pd/C catalysts in the presence of a
2
sacrificial hydrogen acceptor (1-dodecene or 1-decene). The
5a
iridium complex [Ir(cod)Cl]2 assisted by PPh was reported to
3
be active for ketone alkylation. Yus et al. reported the a-alkylation
of ketones with benzylic alcohols using the phosphine free catalyst
b
Entry
Cat.
Solvent
Base
Yield [%]
4
b–d
c
RuCl
2
(DMSO)
4
.
Very recently, Ryu disclosed that
could be an efficient catalyst with Cs CO as
the base. The heterogeneous Pd/AlO(OH), Pd-NPs (nanoparti-
1
Cu(OAc)
2
dioxane
toluene
toluene
dioxane
benzene
xylene
DMSO
DMF
NMP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
KOH
33
RuHCl(CO)(PPh
3
)
3
2
3
2
3
CuCl
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
2
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
87(84)
92(90)
49
4e
6b
c
4
6
c–d
7
8
9a
c
cles)/viologen,
Ni-NPs, mesoporous TiO
2
, and Ag/Mo were
5
38
6
7
8
9
1
1
1
85(84)
trace
trace
trace
37
also successful catalysts in ketone–alcohol coupling. The instances
above show that transition-metal catalysts are essential in the
a-alkylation of ketones with alcohols.
0
1
2
The successes of the above noble metal-catalyzed reactions
prompted us to examine the possibility of achieving a-alkylation
reaction of ketones with alcohols by using inexpensive metal
catalysts. Considering the good availability of copper catalysts and
the recent studies on copper-catalyzed reactions of amines with
7
Li
2
CO
3
trace
trace
41
13
LiOAc
LiOMe
LiOEt
1
1
1
17
1
4
5
6
53
LiOH
trace
83(80)
82(80)
92(90)
10
d
e
f
primary alcohols, we carried out research on copper-catalyzed
LiOtBu
LiOtBu
LiOtBu
8
a
19
School of Medical Engineering, Hefei University of Technology, Hefei 230009, P. R.
China. E-mail: hjxu@hfut.edu.cn; Fax: +86-551-2904405; Tel: +86-551-2904353
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst (0.05
mmol), base (1.0 mmol), solvent (2 mL), 110 uC, for 12 h, under
b
Department of Chemistry, University of Science and Technology of China, Hefei
b
2
30026, P. R. China
argon. The yields were determined by GC (average of two GC runs),
c
3
Electronic supplementary information (ESI) available: Experimental details and
values in parenthesis are isolated yields. At reflux temperature.
d
e
f
For 6 h. At 80 uC. Use of LiOtBu purified by sublimation.
spectral data. See DOI: 10.1039/c3ra23221b
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with LiOH as the base (entry 16). The above results indicate that
the base and solvent are key factors in promoting the reaction
3
(also see ESI ). A Lower yield was obtained with a shorter reaction
time or a lower reaction temperature (entries 17 and 18). Finally,
we used LiOtBu purified by sublimation to avoid the involvement
of other metals, and the reaction provided the same yield with the
Our initial efforts focused on the copper-catalyzed a-alkylation
of ketones with alcohols. As shown in Table 1, only 33% yield of
the expected product 1,3-diphenylpropan-1-one (3aa) was formed
11
analytically pure (99.9% purity) LiOtBu (entry 19).
To test the scope of this method, we next examined a variety of
substrates under the optimal reaction conditions (Table 2).
Coupling reactions between aryl methyl ketones and benzylic
primary alcohols with different substituents mostly gave the
expected products in good yields (3aa–3ra). The ketones bearing
when 1a and 2a were treated with Cu(OAc) , dioxane, and KOH
2
(
entry 1). We were pleased to find that when using CuCl
2
as the
catalyst in toluene with LiOtBu as a base which has not been
4–9
studied in this type of reaction, the system generated 3aa in
7% yield (entry 2). To our surprise, when LiOtBu was employed
8
electron-withdrawing groups, such as CF
with 2a to give 3da. However, the reactions of the substrates with
an NO group (3ad and 3ea) were inhibited. It is noteworthy that
3
, can also be alkylated
without a Cu catalyst, 3aa was also obtained in 92% yield (entry 3).
We then surveyed the effect of different solvents. The reaction gave
low yields in dioxane, benzene and xylene (entries 4–6). The use of
polar solvent such as DMSO, DMF, and NMP gave no products
2
aryl–X (X = F, Cl, Br, I) bonds (in products 3ae–3ag, and 3fa–3ia)
were well tolerated, thus leading to halo-substituted products,
which could be used for further transformations. Substituted
acetyl naphthalenes were also tolerated in this transformation
(entries 7–9). Toluene, a nonpolar solvent, was proven to be the
most effective for this coupling reaction. The yield was moderate
when NaOtBu was used, and a low yield was observed for KOtBu,
whereas the alkylation product was not detected with weaker bases
such as Li CO and LiOAc (entries 10–13). When LiOMe or LiOEt
2 3
were used, the product was obtained in 41 and 53% yields,
respectively (entries 14 and 15). However, no product was formed
(
3ma, 3na). Moreover, naphthalenone and indanone were
alkylated successfully at the a-methylene position, thus generating
oa and 3pa in 92% and 72% yields, respectively. The reaction was
3
also applicable to heteroaromatic methyl ketones, giving in these
a
Table 2 Scope of the coupling reaction of ketones with alcohols mediated by LiOtBu
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), LiOtBu (1 mmol), toluene (2 mL), 110 uC, for 12 h, under argon. Isolated yield based on 1.
b
c
3
-phenyl-1-(pyridin-2-yl) propan-1-ol as the product. 1.5 mmol of 2a was used.
7
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12–17
a
function to an aldehyde.
The position of the substituent on
Table 3 Synthesis of quinolines from (2-aminophenyl)methanol and ketones
the aromatic ring of the aryl methyl ketones (para-, meta-, and
ortho-positions) had no effect on the quinoline yield. It should be
noted that the reaction result of 2-acetylpyridine was similar to
other ketones (Table 2). In the case of alkyl methyl ketones, the
corresponding quinolines were formed as a regioisomeric mixture,
favoring cyclisation at a less-hindered position over a-methylene or
a-methine.
18,19
The mechanism of this transformation is not clear, yet.
Two eq. (based on LiOtBu) of 12-crown-4, a common lithium
chelator, were added to trap the Li cation during the transforma-
tion, and a significantly lower yield (19%) was observed. This
result shows that the Li cation plays a crucial role in this reaction.
More detailed studies are needed to understand the mechanism.
In summary, we disclosed a novel approach for the a-alkylation
of ketones with primary alcohols promoted by LiOtBu without a
transition-metal catalyst. Many ketones were successfully alkylated
with benzylic, aliphatic, and allylic alcohols, where water is the
only by-product. In addition, a wide variety of quinolines could be
prepared by using 2-aminobenzyl alcohol as the alkylating agent.
The method does not need the catalysis of any transition metal,
and consequently avoids contamination of the products by toxic
metals. This feature will make it a reaction of choice for the
pharmaceutical and chemical industries.
Acknowledgements
a
Financial support from the National Natural Science
Foundation of China (No. 21272050, 21072040, 21071040)
and the Program for New Century Excellent Talents in
University of the Chinese Ministry of Education (NCET-11-
Reaction conditions: 2n (0.5 mmol), 1 (1.0 mmol), LiOtBu (1
mmol), toluene (2 mL), 110 uC, for 12 h, under argon. Isolated yield
based on 2n. 1 (0.5 mmol), 2n (0.75 mmol), isolated yield based on
1
b
c
d
e
. For 24 h. At 80 uC for 36 h. 2 mmol of acetone was used.
0627) are greatly appreciated.
cases different results depending on the nature of the heteroaro-
matic system. Thus, the reaction with 2-acetylthiophene gave the
expected ketones 3qa with excellent yields, while a moderate yield
of 3ra was obtained for 2-acetylfuran. In the reaction of
Notes and references
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2-acetylpyridine, instead of the expected ketone 3sa, 4sa was
obtained (44%), possibly from the expected alkylation process
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should be pointed out that the further hydrogenated products 4 in
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2
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sources of LiOtBu were used with new glassware, almost the
same results were obtained. These results amply indicated that
this ketone–alcohol coupling is promoted by LiOtBu itself
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742 | RSC Adv., 2013, 3, 7739–7742
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