Rhodium-catalyzed alkylation of ketones and alcohols with alcohols

Article abstract of DOI:10.1134/S107036321601028X

An efficient method for direct alkylation of ketones and alcohols through the borrowing hydrogen strategy in the presence of rhodium complexes as catalyst was developed. This transformation is tolerant to various functional substrates and is efficient in C-C coupling of primary and secondary alcohols, which provides an alternative method of the synthesis of functional ketones from simple and commercially available materials.

Full text of DOI:10.1134/S107036321601028X

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 1, pp. 178–183. © Pleiades Publishing, Ltd., 2016.
Rhodium-Catalyzed Alkylation of Ketones
and Alcohols with Alcohols1
X. Yu, Q. Y. Wang, Q. J. Wu, and D. W. Wang
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education,
School of Chemical and Material Engineering, Jiangnan University, Jiangsu Province, Wuxi, 214122 China
e-mail: wwangdawei@163.com
Received August 21, 2015
Abstract—An efficient method for direct alkylation of ketones and alcohols through the borrowing hydrogen
strategy in the presence of rhodium complexes as catalyst was developed. This transformation is tolerant to
various functional substrates and is efficient in C–C coupling of primary and secondary alcohols, which
provides an alternative method of the synthesis of functional ketones from simple and commercially available
materials.
Keywords: rhodium, alkylation, alcohols, ketones, borrowing hydrogen
DOI: 10.1134/S107036321601028X
INTRODUCTION
borrowing hydrogen method in our previous studies
[17–20]. In this study, the borrowing hydrogen strategy
is used for rhodium-catalyzed direct alkylation of
primary and secondary alcohols (Scheme 2).
The borrowing hydrogen reaction is considered to
be one of the most valuable achievements of chemistry
during the past ten decades, providing an efficient
method for synthesizing numerous functional amines
and ketones [1–8]. In some cases, the above amines
and ketones are very difficult to synthesize by the
traditional method. Therefore, the borrowing hydrogen
reaction becomes an irreplaceable transformation for
these compounds. Generally, the borrowing hydrogen
strategy has been carried out in the presence of Ru and
Ir complexes as catalyst [9-15]. The catalytic activity
of Ru and Ir catalysts is much better than that of
rhodium catalyst. Although some progress in this area
is achieved, the above reactions commonly proceed at
high temperatures and under harsh conditions.
Therefore, Rh-catalyzed borrowing hydrogen reaction
is still a scientific and challenging issue. In 2014,
Donohoe et al. reported rhodium-catalyzed ketone
methylation using methanol as the alkylating agent and
the hydrogen-borrowing method [16].
RESULTS AND DISCUSSION
Recently, Cowie et al. have synthesized a series of
mono- and binuclear rhodium(I) complexes bearing
ortho-phosphinoanilido and ortho-phosphinoaniline
ligands [21], which were tested as catalysts for styrene
silylation. Here, we found that the rhodium complex
[(P,P-dppe)(P,N-Ph2PAr)Rh] (1) could catalyze the
reaction of alcohols with ketones (Scheme 2).
Although the reaction proceeded with a low yield, it
Scheme 1. C–C bond formation through the borrowing hydrogen
strategy.
O
OH
Ph
Ph
Ph
OH
[M]
Ph
Compared to coupling of amines with alcohols,
coupling of alcohols with ketones, and self-coupling of
alcohols in particular, through the borrowing hydrogen
strategy is more difficult reaction (Scheme 1). Iridium-
catalyzed reactions of C–N and C–C coupling with
moderate to good yield were carried out using the
[M]H2
O
O
R
O
Ph
Ph
Ph
1 The text was submitted by the authors in English.
H2O
178

RHODIUM-CATALYZED ALKYLATION OF KETONES
Table 1. Screening of the reaction conditiona
179
Scheme 2. Rh-catalyzed ketone alkylation.
O
O
OH
HO
O
+
+
2a
3a
1, base
O
solvent
1, base
solvent
Me
4a
Solvent
N
Run no.
Base
Yield, %b
32
(1).
Ph2P Rh PPh2
PPh2
1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
–
Dioxane
CH3CN
DMF
2
68
3
64
compounds in high yields. Electron deficient substrates
were found to be applicable in all cases. For substrates
with an electron withdrawing group, slightly lower
yields were obtained. In general, the yields were
mostly from good to excellent (Table 2).
4
Toluene
Xylene
THF
71
5
76
6
58
7
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
28
Furthermore, we found that this complex is
effective for self-coupling of alcohols. The results are
summarized in Table 3. Generally, the products were
also separated in moderate to good yields (Table 3).
8
NaOH
KOH
63
9
57
10
11
12
13
14
15
K2CO3
Cs2CO3
68
EXPERIMENTAL
91
General experiments. 1H NMR spectra were
measured on a Bruker Avance-400 and Bruker
Avance-300 spectrometers. Chemical shifts (δ, ppm)
are downfield relative to tetramethylsilane. Proton
coupling patterns have peaks due to singlet (s), doublet
(d), triplet (t), and multiplet (m). Thin layer
chromatography (TLC) was performed with
commercial 100-400 mesh silica gel plates GF254 and
the separated components were visualized at the
wavelength 254 nm. All reagents were purchased from
commercial suppliers and used without further
purification.
t-BuONa
t-BuOK
NEt3
85
82
48
84c
Cs2CO3
a
Conditions: 2a (1.2 mmol), 3a (1 mmol), cat. 1 (2 mol %), base
(1.5 mmol), solvent (3 mL), 150oC or reflux, 24 h, N2. b Isolated
yield. c 1 (1 mol%).
was found that this rhodium complex is suitable
catalyst for the reaction (Table 1, run no. 1). To
increase the reaction yield, xylene was chosen as
superior solvent (see Table 1, run nos. 1–6) and
Cs2CO3 as the best base (see Table 1, run nos. 6–12).
Typical procedure for the synthesis of 4a. A
solution of catalyst 1 (2 mol %, 0.01 mmol), aceto-
phenone (1.0 mmol), benzyl alcohol (1.2 mmol),
cesium carbonate (1.5 mmol), and xylene (3 mL) were
stirred in a Schlenk tube in N2 atmosphere. The
mixture was heated under reflux for 24 h and then
cooled to room temperature. The resulting solution was
directly purified by column chromatography with
After screening the reaction conditions, we studied
a series of aryl halides under the optimal conditions of
the reaction. The results are summarized in Table 2. As
seen, all secondary alcohols in a nitrogen atmosphere
are converted into the corresponding carbonyl
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180
YU et al.
Table 2. Ketone alkylation with alcoholsa
O
O
1, Cs2CO3
xylene, reflux
OH
+
R'
R
R'
Product
R'
Run no.
1
R (alcohol)
H
R' (ketone)
H
Yield, %b
91 (4a)
O
O
2
3
4
H
H
2-Cl
4-OMe
H
86 (4b)
83 (4c)
78 (4d)
Cl
O
O
O
OH
N
N
O
5
6
H
86 (4e)
80 (4f)
OH
OH
N
N
N
N
O
4-Cl
Cl
O
7
8
4-Me
4-CF3
86 (4g)
86 (4h)
OH
N
N
O
H
F3C
48 (4i)c
O
9
H
OH
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RHODIUM-CATALYZED ALKYLATION OF KETONES
181
Table 2. (Contd.)
Run no.
10
R (alcohol)
R' (ketone)
H
Product
Yield, %b
57 (4j)c
O
OH
O
O
11
H
68 (4k)
OH
O
a
c
Conditions: 2 (1.2 mmol), 3 (1 mmol), cat. 1 (2 mol %), base (1.5 mmol), xylene (3 mL), reflux, 24 h, N2. b Isolated yield. Primary
alcohol 2 (20 mmol, 20 equiv.).
petroleum ether/ethyl acetate (10 : 1) as eluent to give
the desired product.
1-(4-Chlorophenyl)-3-(pyridin-3-yl)propan-1-one
(4f). H NMR spectrum (400 MHz, CDCl3), δ, ppm:
1
8.45 d (J = 1.8 Hz, 1H), 8.41–8.35 m (1H), 7.86–7.77
m (2H), 7.51–7.46 m (1H), 7.38–7.31 m (2H), 7.15–
7.10 m (1H), 3.21 t (J = 7.4 Hz, 2H), 3.01 t (J =
7.4 Hz, 2H).
1
1,3-Diphenylpropan-1-one (4a). H NMR spec-
trum (400 MHz, CDCl3), δ, ppm: 7.88 d (J = 7.6 Hz,
2H), 7.49 t (J = 7.7 Hz, 1H), 7.39 t (J = 7.6 Hz, 2H),
7.27–7.17 m (4H), 7.14 t (J = 7.1 Hz, 1H), 3.24 t (J =
5.6 Hz, 2H), 3.01 t (J = 5.6 Hz, 2H).
1
3-(Pyridin-3-yl)-1-(p-tolyl)propan-1-one (4g). H
NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.54 d
(J = 1.8 Hz, 1H), 8.43 d.d (J = 5.0, 1.4 Hz, 1H), 7.84 d
(J = 8.2 Hz, 2H), 7.62–7.55 m (1H), 7.24–7.21 m (3H),
3.29 t (J = 7.5, 2H), 3.07 t (J = 7.5 Hz, 2H), 2.42 s
(3H).
3-(2-Chlorophenyl)-1-phenylpropan-1-one (4b).
1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.04–
7.96 m (2H), 7.62–7.57 m (1H), 7.49 t (J = 7.8 Hz,
2H), 7.38 d.d (J = 7.6, 1.7 Hz, 1H), 7.35 d.d (J = 7.4,
1.9 Hz, 1H), 7.21 d.d (J = 7.6, 1.7 Hz, 2H), 3.39–3.32
m (2H), 3.26–3.16 m (2H).
3-Phenyl-1-[4-(trifluoromethyl)phenyl]propan-1-
1
one (4h) H NMR spectrum (400 MHz, CDCl3), δ,
3-(4-Methoxyphenyl)-1-phenylpropan-1-one (4c).
1H NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.05–
7.93 m (2H), 7.59 t (J = 7.4 Hz, 1H), 7.47 t (J =
7.6 Hz, 2H), 7.21 d (J = 8.2 Hz, 2H), 6.91–6.85 m
(2H), 3.81 s (3H), 3.35–3.26 m (2H), 3.11–2.99 m (2H).
ppm: 8.08 d (J = 8.2 Hz, 2H), 7.75 t (J = 7.1 Hz, 2H),
7.37–7.28 m (4H), 7.27 s (1H), 3.39–3.33 m (2H), 3.11
t (J = 7.6 Hz, 2H).
1-Phenylpentan-1-one (4i). 1H NMR spectrum
(400 MHz, CDCl3), δ, ppm: 8.03–7.97 m (2H), 7.61–
7.54 m (1H), 7.53–7.44 m (2H), 3.01 t (J = 7.4 Hz,
2H), 1.83–1.68 m (2H), 0.98–0.84 m (5H).
1-Phenyl-3-(pyridin-3-yl)propan-1-one (4d). 1H
NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.55 s
(1H), 8.46 d (J = 3.8 Hz, 1H), 8.01–7.92 m (2H), 7.63–
7.54 m (2H), 7.48 t (J = 7.5 Hz, 2H), 7.23 d.d (J = 7.6,
4.9 Hz, 1H), 3.34 d.d (J =7.4 Hz, 2H), 3.08 t (J =
7.5 Hz, 2H).
1
1-Phenylheptan-1-one (4j). Yield 62%. H NMR
spectrum (400 MHz, CDCl3), δ, ppm: 8.02–7.96 m
(2H), 7.57 t (J = 7.5 Hz, 1H), 7.49 t (J = 7.6 Hz, 2H),
2.99 t (J = 7.4 Hz, 2H), 1.80–1.70 m (2H), 1.41–1.27
m (4H), 0.97–0.86 m (5H).
1-Phenyl-3-(pyridin-4-yl)propan-1-one (4e). 1H
NMR spectrum (400 MHz, CDCl3), δ, ppm: 8.43 s
(2H), 7.86 d.d (J = 5.4, 3.4 Hz, 2H), 7.53–7.47 m (1H),
7.39 d (J = 8.6 Hz, 2H), 7.11 t (J = 7.0 Hz, 2H), 3.31–
3.20 m (2H), 3.01 t (J = 7.4 Hz, 2H).
3-(Furan-2-yl)-1-phenylpropan-1-one (4k). 1H NMR
spectrum (400 MHz, CDCl3), δ, ppm: 8.05–7.98 m
(2H), 7.59 t (J = 7.4 Hz, 1H), 7.49 t (J = 7.6 Hz, 2H),
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YU et al.
Table 3. The coupling reaction of primary and secondary alcoholsa
O
OH
1, Cs2CO3
OH
R'
xylene, reflux
+
R
R'
R'
2
5
4
Run no.
1
R (compound 2)
R' (compound 5)
Product
Yield, %b
83
H
H
O
2
H
2-Cl
O
76
Cl
O
3
4
H
H
4-OMe
4-CF3
78
72
O
O
F3C
42c
46c
O
5
6
H
H
OH
O
OH
a
Conditions: 2 (1.2 mmol), 5 (1 mmol), cat. 1 (2 mol %), Cs2CO3 (1.5 mmol), xylene (5 mL), reflux, 24 h, N2. b Isolated yield. c Primary
alcohol 2 (20 mmol, 20 equiv.).
7.33 m (1H), 6.33–6.28 m (1H), 6.09 d (J = 3.1 Hz,
1H), 3.35 d.d (J = 9.0, 5.8 Hz, 2H), 3.17–3.11 m (2H).
ACKNOWLEDGMENTS
The study was financially supported by the Natural
Science Foundation of Jiangsu Province (project
BK20130124) and China Postdoctoral Science Foundation
(project 2014M550262).
CONCLUSIONS
In summary, we developed a method of direct
alkylation of ketones with alcohols, primary and
secondary alcohols in particular. This reaction was
carried out through a borrowing hydrogen strategy in
the presence of the rhodium complex as catalyst.
Importantly, the reaction proceeds in good to excellent
yields and is tolerant to various functional substrates.
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