RhCl(CO)(PPh3)2 catalyzed α-alkylation of ketones with alcohols

Article abstract of DOI:10.1016/j.jorganchem.2017.05.055

A simple and efficient method for α-alkylation of ketones with primary alcohols catalyzed by RhCl(CO)(PPh₃)₂ without additional additives under mild conditions is developed. It has a wide substrate scope, high atom-efficiency and chemoselectivity. It is an environmentally friendly method to build C[sbnd]C bond because water is the only byproduct.

Full text of DOI:10.1016/j.jorganchem.2017.05.055

Accepted Manuscript
RhCl(CO)(PPh ) catalyzed α-alkylation of ketones with alcohols
3
2
Rui Wang, Lina Huang, Zhengyin Du, Hua Feng
PII:
S0022-328X(17)30370-4
10.1016/j.jorganchem.2017.05.055
JOM 19981
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 14 February 2017
Revised Date: 22 May 2017
Accepted Date: 26 May 2017
Please cite this article as: R. Wang, L. Huang, Z. Du, H. Feng, RhCl(CO)(PPh ) catalyzed α-
3
2
alkylation of ketones with alcohols, Journal of Organometallic Chemistry (2017), doi: 10.1016/
j.jorganchem.2017.05.055.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
3 2
RhCl(CO)(PPh ) catalyzed α-alkylation of ketones with alcohols
Rui Wang, Lina Huang and Zhengyin Du*
A simple and efficient method for α-alkylation of ketones with primary alcohols catalyzed by
RhCl(CO)(PPh ) without additional additives under mildconditions is developed. It has a wide substrate
3
2
scope, a high atom-efficiency and chemoselectivity. It is an environmentally friendly method to build
C-C bond because water is the only byproduct.

Communication
ACCEPTED MANUSCRIPT
RhCl(CO)(PPh ) catalyzed α-alkylation of ketones with
3
2
alcohols
†
†
Rui Wang, Lina Huang, Zhengyin Du* and Hua Feng*
Key Laboratory of Eco-Environment Related Polymer Materials of Ministry of Education, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. China.
*
Phone and Fax: +86-931-7971989; E-mail: clinton_du@126.com
†
They contributed equally to this work.
Abstract. A simple and efficient method for α-alkylation of ketones with primary alcohols catalyzed by RhCl(CO)(PPh3)2
without additional additives under mild conditions is developed. It has a wide substrate scope, high atom-efficiency and
chemoselectivity. It is an environmentally friendly method to build C-C bond because water is the only byproduct.
Keywords: Alkylation; Ketones; Alcohols; Hydrogen transfer; Cross coupling
1
. Introduction
methodology under mild conditions and satisfactory
results were achieved. This cross coupling reaction
α-Alkylation of ketones has been known as a
[15]
can also be catalyzed by iron complex
Fe(OTf)3
and
pivotal method for a carbon-carbon bond formation in
organic synthesis.
[16]
to produce aimed product selectively.
[
1,2]
Transition metal-catalyzed
Besides, metal-free organocatalysis of N-heterocyclic
carbenes and a large number of t-BuOLi were
demonstrated to be efficient for α-alkylation of
cross-coupling reaction between ketones and alcohols
is the most attractive strategy for the α-alkylation of
ketones not only from its high atom efficiency but
also from water as only byproduct, which is in
accordance with sustainable development in views of
economy and environment.
regarded as proceeding via hydrogen transfer strategy
and alcohols are the source of hydrogen, which has
been paid much attention in recent years.
connection with this strategy, many transition metals,
such as ruthenium and iridium complexes have
been successfully used as homogeneous catalysts in
this transformation and good results were obtained.
Supported heterogeneous palladium catalysts, such as
[17]
ketones with primary alcohols. Whatever, this kind
of reaction always suffered from excess base usage,
long reaction time consumption, and innert
atmosphere requirement.
Compared with other heavy metal salts, rhodium
has been proved to be low toxic and rhodium
complexes bearing NHCs have also been widely used
[3,4]
This reaction is
[5]
In
as catalysts for transfer hydrogenation and cross-
[
6]
[7]
[18]
coupling reaction in organic synthesis.
In 2013,
tris(acetylacetonato)rhodium(III) was used as a
catalyst for the α-alkylation of ketones with primary
alcohols followed by transfer hydrogenation to
[8]
[9]
[10]
Pd/C,
Pd(II)/SiO2
Pd NPs/AlO(OH),
Pd NPs/viologen,
furnish reductive coupling products in the presence of
[11]
are also applied for α-alkylation of
[19]
1,4-diazabicyclo[2.2.2]octane (DABCO) as ligand.
ketones with primary alcohols. Most of these catalysts
can be recycled and reused for several times. For
instance, Ni NPs and Ag/Mo oxides are reported
to be good and efficient reusable catalysts for this
reaction. However, harsh reaction temperature of up
to 140 C was required
target products and substrates was often observed.
Also, an additional hydrogen acceptor, 1-dodecene or
Unfortunately, the reaction cannot be stopped on the
stage of alkylated ketone products. In 2014, Donohoe
[12]
[13]
[20]
and coworkers
reported a [Cp*RhCl ] catalyzed
2 2
ketone methylation reaction using methanol as
alkylating reagent to form α-branched products under
mild conditions. Except the above-mentioned
references, few literature in connection with rhodium
catalyst for α-alkylation of ketones was reported.
o
[7a,11]
and over-reduction of
[8]
[8]
1
-decene, must be added to promote the reaction. In
With our continuous interest in transitional metal-
order to overcome these disadvantages and to realize
regioselective α-alkylation of methyl ketone
derivatives with primary alcohols, Yus et al
reported an osmium catalyzed α-alkylation of methyl
[21]
catalyzed efficient cross coupling reaction
and
alkylation reaction with alcohols as green alkylating
[14]
[22]
reagents, we herein report a simple and efficient α-
alkylation coupling reaction of ketones with primary
alcohols catalyzed by RhCl(CO)(PPh3)2 in the
ketones with alcohols through borrowing hydrogen
1

ACCEPTED MANUSCRIPT
presence of KOH as base and 1,4-dioxane as solvent the catalyst and it is found that there was no reaction
o
at 95 C. The corresponding alkylated ketones as took place (Table 1, entry 5). However, when
unique products were obtained in good yields. To the potassium carbonate was replaced by cesium
best of our knowledge, this is the fisrt example of Rh carbonate, 25% yield of 3a was obtained (Table 1,
(
I) complex-catalyzed α-alkylation of ketones with entry 6). When the reaction was catalyzed by
primary alcohols to form alkylated ketones palladium nanoparticles (Pd NPs), in situ generated
[21,23]
o
exclusively.
from palladium chloride in PEG-2000
at 95 C, a
moderate yield of 63% was achieved and there is no
improvement of the yield when increasing the amount
of Pd NPs and the reaction time (Table 1, entry 7). So
we have to screen other transition metal catalysts.
Surprisingly, when the reaction was catalyzed by 2
mol% of RhCl(CO)(PPh ) , a satisfying yield of 81%
2
. Results and discussion
We initiated our studies with the screen of reaction
conditions in the coupling of acetophenone (1a) with
benzyl alcohol (2a), as seen in Table 1.
3
2
was given in the presence of KOH in 1,4-dioxane at
o
a)
95 C (Table 1, entry 8). To investigate the base
Table 1. Optimization of the reaction conditions
influence, potassium tert-butoxide and triethylamine
were also examined and unsatisfactory results were
obtained (Table 1, entries 9 and 10). Subsequently,
we explored the effect of substrates ratio and the
amount of the catalyst and the base. It is found that
the use of 1.5 equivalents of benzyl alcohol and 2
equivalents of KOH resulted in an higher product
yield (91%) in shorter reaction time (Table 1, entry
11). Increasing the amount of the catalyst from 2
mol% to 3 mol% could not improve the product yield
Entry Catalyst
Base
Solvent
Time Yield
(
h)
(%)
1
2
3
FeCl3
NiCl2
CuCl2
Cu NPs
PdCl2
PdCl2
K CO
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PEG-2000
1,4-
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
20
20
20
20
15
18
15
10
—
2
3
3
3
3
3
K CO
16
20
9
—
25
63
81
2
K CO
2
b)
4
K CO
2
5
6
7
8
K CO
2
(
Table 1, entry 12) whereas decreasing the amount of
Cs CO
2
3
3
Pd NPs
RhCl(CO
Cs CO
the base to 1.5 equivalents caused a slight decrease of
3a (Table 1, entry 13). Rhodium (III) chloride hydrate
was also employed as a catalyst for the reaction but
only 36% yield of 3a was gained under the same
reaction conditions (Table 1, entry 14). It is evident
that ligands play a very important role in this reaction.
In comparison with other catalysts, the good catalysis
of RhCl(CO)(PPh ) might be due to the good
2
KOH
)
(PPh3)
2
9
RhCl(CO KOtBu
(PPh3)2
RhCl(CO
(PPh3)2
RhCl(CO
(PPh3)2
RhCl(CO
(PPh3)2
RhCl(CO
(PPh3)2
8
8
56
—
91
91
87
36
)
1
0
Et N
3
)
c)
d)
e)
c)
1
1
1
1
2
3
KOH
KOH
KOH
KOH
9
3
2
)
exchange ability betwween hydrogen atom and ligand
to form rhodium hydride complex which is key active
species in catalytic cycle.
9
)
12
12
)
Under the optimized conditions, we tried to extend
this methodology to a series of ketones and alcohols.
The results are listed in Table 2. It is obvious that our
catalytic system works well for the coupling reactions
of various α-methyl(methylene)ketones with alcohols
to achieve the corresponding α-alkylated ketone
products in moderate to excellent yield. Electron-rich
and electron-deficient acetophenones, such as 4-
methyl-, 4-chloro-, 4-bromo-, 2-methyl-, and 3-
methoxyacetophenone, could react smoothly with
benzyl alcohol, 4-methyl- and 4-fluorobenzyl alcohols
to form a series of α-benzylated acetophenones with
good yields in range of 61-84% (Table 2, entries 2-
1
4
RhCl ·3
3
H O
Dioxane
2
a)
Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol),
o
catalyst (2 mol%), base (1.0 mmol), solvent (3 mL), 95 C.
Yield is isolated yield. Cu NPs (10 mol%). 2a (1.5
mmol), base (2.0 mmol). 2a (1.5 mmol), base (2.0 mmol),
catalyst (3 mol%). 2a (1.5 mmol), base (1.5 mmol).
b)
c)
d)
e)
At first, we chosed different Lewis acids as catalysts
(
2 mol%) and K CO as a base to conduct this
2 3
o
reaction in toluene at 95 C. The results show that
FeCl has no catalytic effect despite extending the
3
reaction time tremendously (Table 1, entry 1) . When
NiCl and CuCl were used as catalysts, 16% and
10). Exchanging the substitution on the aryl ring of
2
2
arylmethylketones and benzyl alcohols has no
significant influence on the yield of aimed products.
To examine the reactivity of aliphatic alcohols, we
used ethanol and 1-butanol as alkylating reagents to
react with acetophenone and 4-methylacetophenone,
respectively, and found that the corresponding
2
0% yields of the aimed product 3a were obtained,
respectively (Table 1, entries 2 and 3). When
replacing CuCl2 with 10 mol% of copper
nanoparticles (Cu NPs), only 9 % yield of 3a was
obtained (Table 1, entry 4). Then PdCl was used as
2
2

ACCEPTED MANUSCRIPT
b)
coupling products 3k and 3l were obtained in the
yield of 56% and 52%, respectively (Table 2, entries
1 and 12). These results proved that the hydrogen
12
52
63
1
3l
transfer reactivity of aliphatic alcohols is inferior to
that of benzyl alcohols. To investigate the scope of
ketones in this reaction, cyclopentanone and
cycohexanone were also studied under the same
reaction conditions to furnish the corresponding α-
alkylation of cycloketones with benzyl alcohol. The
obtained moderate product yields (63% of 3m and
8% of 3n) showed that the reactivity of
arylmethylketones is superior to that of cyclanones.
Table 2, entries 13 and 14). It is need to emphasize
13
3
m
1
4
58
3n
Ketone (1.0 mmol), alcohol (1.5 mmol),
RhCl(CO)(PPh ) (2 mol%), KOH (2.0 mmol), 1,4-dioxane
3 mL) at 95 C for 9 h. Yield is isolated yield. Alcohol
2.0 mmol).
a)
5
3 2
o
b)
(
(
(
that, in all cases, water is the exclusive byproduct and
deeply reductive products, ketals and hemiketals of α-
alkylated ketones were not found.
For the reaction mechanism of α-alkylation of
ketones with primary alcohols, based on previous
[24]
report,
a transitional metal-catalyzed hydrogen
transfer process is proposed with the reaction of
acetophenone and benzyl alcohol as an example, as
seen in Scheme 1. At first, benzyl alcohol is
catalytically dehydrogenated to form benzaldehyde
and the deprived active hydrogens are transferred to
the catalyst to form rhodium hydride complex [RhH2].
Then, the Aldol condensation occurs between
acetophenone and benzaledyde to give chalcone.
Finally, chalcone is further hydrogenated by [RhH2]
species to afford the aimed coupling product. The
detailed mechanism of this reaction is still under
investigation.
Table 2. α-Alkylation of methyl ketone derivatives with
alcohols catalyzed by RhCl(CO)(PPh3)2
a)
Entry
1
Ketone
Alcohol
Product
Yield
%)
91
(
3
a
2
3
4
5
6
84
63
61
74
68
3
b
CHO
O
OH
3
c
[Rh]
Aldol condensation
2
[RhH ]
2
H O
3
d
O
O
3
e
Scheme 1. Mechanism of Rh-catalyzed α-alkylation of
acetophenone with benzyl alcohol.
3
f
3
. Conclusion
7
8
9
66
64
In summary, we have developed a simple and
3
g
efficient method on RhCl(CO)(PPh ) -catalyzed
3
2
α-alkylation of α-methyl(methylene) ketones with
primary alcohols under mild conditions. This
method has been proved to have a wide substrate
scope and broad functional group tolerance. More
importantly, the reaction is highly atom-
economical and chemoselective. There are no
deeply reductive coupling and ketalization
byproducts found in our reaction and completely
no need for the addition of any auxiliary hydrogen
donors, acceptors and additives in this protocol. It
3
h
72
78
56
3
i
1
0
3
j
b)
1
1
3
k
3

ACCEPTED MANUSCRIPT
is a potentially useful method to build C-C bond [7] (a) K. Taguchi, H. Nakagawa, T. Hirabayashi, S.
in organic synthesis.
Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 126 (2004) 72-
4. (b) D. Wang, K. Zhao, P. Ma, C. Xu, Y. Ding,
7
4
. Experimental
Tetrahedron Lett. 55 (2014) 7233-7235; (c) S. Bhat, V.
Sridharan, Chem. Commun. 48 (2012) 4701-4703; (d)
C. Xu, X.-M. Dong, Z.-Q. Wang, X.-Q. Hao, Z. Li,
L.-M. Duan, B.-M. Ji, M.-P. Song, J. Organomet.
Chem. 700 (2012) 214-218; (e) F. Li, J. Ma, N. Wang,
J. Org. Chem. 79 (2014) 10447-10455.
Ketones (1.0 mmol), alcohols (1.5 mmol),
RhCl(CO)(PPh ) (2 mol%) and bases (2.0 mmol)
were added into dioxane (3 mL). The reaction
mixture was stirred at 95 for completion
3
2
℃
monitored by TLC. Then the solution was filtered
by suction and the solvent was evaporated under
reduced pressure. The residue was passed through
flash column chromatography on silica gel to give
[
[
8] C. S. Cho, J. Mol, Catal. A: Chem. 240 (2005) 55-60.
9] M. S. Kwon, N. Kim, S. H. Seo, I. S. Park, R. K.
Cheedrala, J. Park, Angew. Chem. 117 (2005) 7073-
the pure products
.
7
075.
[10] (a) Y. M. A. Yamada, Y. Uozumi, Org. Lett. 8 (2006)
375-1378; (b) Y. M. A. Yamada, Y. Uozumi,
Acknowledgements
1
We gratefully acknowledge the National
Natural Science Foundation of China (20702042,
Tetrahedron 63 (2007) 8492-8498.
[
11] T. T. Dang, S. P. Shan, B. Ramalingam, A. M. Seayad,
RSC Adv. 5 (2015) 42399-42406.
2
1262028) for financial support.
References
[12] (a) M. Yus, P. Rient, F. Alonso, Synlett. 12 (2007)
877-1880; (b) M. Yus, P. Riente, F. Alonso, Eur. J.
1
[
[
[
[
[
[
1] D. Seebach, Angew. Chem. Int. Ed. 29 (1990) 1320-
367.
Org. Chem. 29 (2008) 4908-4914.
1
[
[
[
[
[
13] X. Cui, Y. Zhang, F. Shi, Y. Deng, Chem. Eur. J. 17
2] D. H.Camacho, I. Nakamura, B. H. Oh, S. Saito, Y.
Yamamoto, Tetrahedron Lett. 43 (2002) 2903-2907.
3] J. F. Jenck, F. Agterberg, M. J. Droescher, Green Chem.
(
2011) 1021-1028.
14] M. L. Buil, M. A. Esteruelas, J. Herrero, S. Izquierdo,
I. M. Pastor, M. Yus, ACS Catal. 3 (2013) 2072-2075.
15] S. Elangovan, J. B. Sortais, M. Beller, C. Darcel,
Angew. Chem. Int. Ed. 54 (2015) 14483-14486.
6
(2004) 544-556.
4] G. W. V. Cave, C. L. Raston, J. L. Scott, Chem.
Commun. 21 ( 2001) 2159-2169.
16] X. Pan, M. Li, Y. Gu, Chem. Asian J. 9 (2014) 268-
5] (a) Y. Obora, ACS Catal. 4 (2014) 3972-3981; (b) K.
Shimizu, Catal. Sci. Technol. 5 (2015) 1412-1427.
6] (a) C. S. Cho, B. T. Kim, T. J. Kim, S. C. Shim,
Tetrahedron Lett. 43 (2002) 7987-7989; (b) R.
Martínez, D. J. Ramon, M. Yus, Tetrahedron 62 (2006)
2
74.
17] (a) Y.-F. Liang, X.-F. Zhou, S.-Y. Tang, Y.-B Huang,
Y.-S. Feng, H.-J Xu, RSC Adv. 3 (2013) 7739-7742;
(
(
b)Y. Zhu, C. Cai, G. Lu, Helvetica Chim. Acta. 97
2014) 1666-1671.
8
988-9001; (c) R. Martínez, G. J. Brand, D. J. Ramón,
[
[
18] (a) D. Wang, D. Astruc, Chem. Rev. 115 (2015) 6621-
686; (b) D. A. Colby, R. G. Bergman, J. A. Ellman,
M. Yus, Tetrahedron Lett. 46 (2005) 3683-3686; (d) T.
Kuwahara, T. Fukuyama, I. Ryu, Org. Lett. 14 (2012)
6
Chem. Rev. 110 (2010) 624-655.
4
703-4705; (e) F. X. Yan, M. Zhang, X. T Wang, F.
Xie, M. M. Chen, H. Jiang, Tetrahedron 70
2014)1193-1198; (f) O. O. Kovalenko, H. Lundberg,
D. Hübner, H. Adolfsson, Eur. J. Org. Chem. 30 (2014)
639-6642.
19] (a) P. Satyanarayana, G. M. Reddy, H. Maheswaran,
M. L. Kantam, Adv. Synth. Catal. 355 (2013) 1859-
(
1
867; (b) C. S. Cho, H. J. Seok, S. C. Shim, J.
Heterocycl. Chem. 42 (2005) 1219-1222.
6
[
20] (a) L. K. M. Chan, D. L. Poole, D. Shen, M. P. Healy,
T. J. Donohoe, Angew. Chem. Int. Ed. 53 (2014) 761-
4

ACCEPTED MANUSCRIPT
7
65; (b) X. Yu, Q. Y. Wang, Q. J. Wu, D. W. Wang,
Russ. J. Gen. Chem. 86 (2016) 178-183.
[
21] (a) F. Gang, G. Xu, T. Dong, L. Yang. Z. Du, Chin. J.
Org. Chem. 35 (2015) 1428-1440; (b) G. Xu, Y.
Zhang, K. Wang, Y. Fu, Z. Du, J. Chem. Res. 39
(
2015) 399-402; (c) W. Zhen, Z. Du, X. Li, Chin. J.
Catal. 34 (2013) 679-683; (d) Z. Du, W. Zhou, L. Bai,
F. Wang, J.-X. Wang, Synlett 3 (2011) 369-372; (e) Z.
Du, W. Zhou, F. Wang, Tetrahedron 67 (2011) 4914-
4
918. (f) Z. Du, Y. Li, F. Wang, W. Zhou, J.-X.
Wang, Tetrahedron Lett. 51 (2010) 1745-1747.
22] (a) Z. Du, Y. Yan, Y. Fu, K. Wang, Asian J. Org.
Chem. 5 (2016) 812-818; (b) H. Wu, J. Wu, Z. Du,
[
Chin.
J.
Org.
Chem.
37
(2017),
DOI:10.6023/cjoc201610034; (c) M. Trifonidou, C. G.
Kokotos, Eur. J. Org. Chem. 2012 (2012) 1563-1568.
23] T. M. Razler, Y. Hsiao, F. Qian, R. Fu, R. K. Khan, W.
Doubleday, J. Org. Chem. 74 (2009) 1381-1384.
[
[
24] F. Huang, Z. Liu, Z. Yu, Angew. Chem. Int. Ed. 55
(
2016)
862-875.
5

ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
RhCl(CO)(PPh ) catalyzed α-alkylation of ketones
3
2
with alcohols
†
†
Rui Wang, Lina Huang and Zhengyin Du*
Key Laboratory of Eco-Environment Related Polymer Materials of Ministry of Education, College of
Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. China.
*
Phone and Fax: +86-931-7971989; E-mail: clinton_du@126.com
†
They contributed equally to this work.
Highlights
The first example of Rh(I)-catalyzed α-alkylation of ketones with primary
alcohols.
Aryl methyl ketons, cyclonones, benzyl and aliphatic alcohols are compatible.
Any auxiliary hydrogen donor, acceptor and additive were not needed.
No deeply reductive coupling and ketalization byproducts were found.
It is an environmentally friendly, high atom-efficiency and chemoselective
method.