Direct α-alkylation of ketones with primary alcohols catalyzed by iridium-CNP complex

Article abstract of DOI:10.1016/j.tetlet.2014.11.034

The α-alkylation of ketones with primary alcohols was realized by CC cross-coupling with iridium-CNP complexes as catalyst. This reaction proceeds via dehydrogenation reactions, aldol condensation, and hydrogenation using the borrowed hydrogen atoms from alcohols. The pyridyl methanols and other heterocyclic substituted methanols, especially alkyl alcohols, were also suitable for this transformation.

Full text of DOI:10.1016/j.tetlet.2014.11.034

Tetrahedron Letters 55 (2014) 7233–7235
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct
a-alkylation of ketones with primary alcohols catalyzed
by iridium–CNP complex
⇑
⇑
Dawei Wang , Keyan Zhao, Piming Ma, Chongying Xu, Yuqiang Ding
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The a-alkylation of ketones with primary alcohols was realized by CAC cross-coupling with iridium–CNP
Received 22 August 2014
Revised 4 November 2014
Accepted 9 November 2014
Available online 15 November 2014
complexes as catalyst. This reaction proceeds via dehydrogenation reactions, aldol condensation, and
hydrogenation using the borrowed hydrogen atoms from alcohols. The pyridyl methanols and other het-
erocyclic substituted methanols, especially alkyl alcohols, were also suitable for this transformation.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Alkylation
Solvent-free
CAC coupling
Iridium complexes
Dehydrogenation aldol condensation
Introduction
ing agents sounds reasonable and interesting.6 However, an often
overlooked fact is that transfer hydrogenation is an important
The direct
a
-alkylation of ketones with alcohols has been
competitive reaction. It is a famous, well-studied reaction, but it
drastically limits the development of alkylation (Scheme 2).2i,5a,7
Despite the aforementioned shortcomings, scientists have put in
a lot of efforts into this area. Hitherto, Ru and Ir have proved to
receiving much attention as an efficient method to form CAC
bonds.1 Compared to alkylation using alkyl halides as coupling
reagents, the use of alcohols is an atom-economical process and
green chemistry solution in which water is the only byproduct.2,3
The reaction proceeds through: (1) oxidation of alcohols to the cor-
responding carbonyl compounds; (2) alkylation of ketones to form
unsaturated carbonyl compounds; and (3) reduction of the CAC
bonds using the borrowed hydrogen atoms from alcohols
(Scheme 1).4,5 Therefore, the use of alcohols as alternative alkylat-
be the most effective catalysts for the
a-alkylation of ketones with
alcohols.8
Our interest in developing new catalysts to adjust transition
metal reactivity9,10 has led to the recent discovery of CNP iridium
complexes. We have synthesized the CNP iridium complexes with
phosphine ligand and non-coordinating anion (Scheme 3).11 Here
we reported that
a-alkylation of ketones with alcohols was real-
ized by using iridium–CNP complexes as catalysts through borrow-
ing hydrogen reaction with good yields. Compared to the
literatures (especially Zhang’s work with [RuCl2(p-Cymene)]2 as
catalyst), this method does not need the expensive Xantphos as
ligand but slightly enhanced yields obtained. Also, the experiments
showed that no transfer hydrogenation product was detected and
iridium–CNP complexes are effective catalysts for borrowing
hydrogen reaction without any interference from transfer
hydrogenation.
O
R1
OH
R2
R1
[M]
[M]H2
O
Alkylation
O
R1
O
R2
R1
R2
Given such considerations, the reaction of acetophenone with
benzyl alcohol was chosen as a model reaction by which to evaluate
the influence of various benzothienyl skeleton phosphine ligand
iridium(III) catalysts. First we examined the iridium complexes with
toluene as a solvent. The results showed that the yield of the product
with catalyst 2b was slightly higher than other cationic iridium(III)
compounds, but the yield was not satisfactory in toluene (Table 1,
Scheme 1.
strategy.
a-Alkylation of ketones with alcohols using the borrowing hydrogen
⇑
Corresponding authors. Tel./fax: +86 510 85917763.
E-mail addresses: wangdw@jiangnan.edu.cn (D. Wang), yding@jiangnan.edu.cn
(Y. Ding).
http://dx.doi.org/10.1016/j.tetlet.2014.11.034
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

7234
D. Wang et al. / Tetrahedron Letters 55 (2014) 7233–7235
Table 2
R3
OH
Transfer
hydrogenation
Alkylation of acetophenonea,b
+
R2
R3
O
O
R3
R1
O
R2
OH
+
O
R1
2b
1 mol%, Cs2CO3
O
R1
Alkylation
R1 OH
+
t-amyl alcohol, 120 o
C
R1
R2
5
4
3
Scheme 2. Transfer hydrogenation versus
a-alkylation of ketones with alcohols.
O
O
O
O
N
Cl
5a, 92%
5b, 98%
5c, 81%
X
Cl
1a
: R = PPh3
O
O
O
Ir
Ir
1b: R = n-Bu
2a
PR3
PR3
S
N
N
O
S
N
: R = PPh3, X = OTf
2b: R = n-Bu, X = OTf
2c: R = n-Bu, X = BF4
N
2
2
2d
: R = n-Bu, X = SbF6
5d, 81%
5e, 86%
5f, 83%
1
2
O
O
O
S
Scheme 3. Benzothienyl skeleton Ir(III)–CNP complexes.
c
c
5g
5h
5i,
,78%
, 76%
63%
Table 1
Screening of optimized reaction conditions for acetophenone with benzyl alcohola
O
O
O
O
O
[Ir], Cs2CO3
solvent, 120 o
OH
+
c
c
5j,
5k,
5l,
49%
42%
61%
C
a
3a
4a
5a
Reagents and conditions: 3 (1.0 mmol), 4 (1.1 mmol), 2b loading (1 mol %),
Cs2CO3 (1.0 mmol), tert-amyl alcohol (2 mL), 120 °C, 24 h, N2.
b
Entry
Catalyst
None
Solvent
Yieldb (%)
Isolated yield.
c 4 (3.0 mmol).
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
Trace
17
42
51
69
79
77
76
32
51
92
85
87
88
92
[Ir⁄(Bt)2Cl]2
1a
1b
2a
2b
2c
2d
2b
2b
2b
2a
2c
2d
2b
Table 3
Alkylation of ketonesa,b
O
O
2b
1 mol%, Cs2CO3
OH
+
t-amyl alcohol, 120 o
C
9
R2
R2
R1
R1
10
11
12
13
14
15c
1,4-Dioxane
3
4
5
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
O
O
O
N
N
N
Cl
O
5m, 75%
5n, 87%
5o, 84%
a
Reagents and conditions: acetophenone (1.0 mmol), benzyl alcohol (1.1 mmol),
Cat [Ir] loading (1 mol %), Cs2CO3 (1.0 mmol), solvent (2 mL), 120 °C, 24 h, N2.
O
O
O
b
Isolated yield.
Cat [Ir] loading (2 mol %).
c
N
N
F3C
O
5p, 83%
5q, 81%
5r, 57%
entries 3–8). Other solvents, such as DMSO, 1,4-dioxane were found
to have no promise, but fortunately the yield was increased while
tert-amyl alcohol added to the reaction (Table 1, entries 9–11). It
should be noted that nearly all the catalysts with coordination anion
gave excellent yields (Table 1, entries 12–14).
Encouraged by the promising results, we further employed the
above methods to acetophenone and various alcohols. The
obtained results are summarized in Table 2. The effect of substitu-
ents on the aromatic ring of alcohol has also been explored, and
acetophenone with benzyl alcohols with an electron-donating or
an electron-withdrawing substituent proceeded in moderate to
good yield (Table 2, see 5a–c). It was found that the substitution
patterns of pyridyl methanol substrates have little influence on
the formation of desired products (Table 2, see 5d–f). And furyl-,
thienyl-heterocyclic alcohols could react under the optimal reac-
tion conditions with gratifying yield (Table 2, see 5g–h).
O
O
O
N
O
N
O
N
O
Cl
5s
, 69%
5u,
73%
O
5t
, 63%
O
O
5v
5w
, 83%
5x
, 81%
, 68%
a
Reagents and conditions: 3 (1.0 mmol), 4 (1.1 mmol), 2b loading (1 mol %),
Cs2CO3 (1.0 mmol), tert-amyl alcohol (2 mL), 120 °C, 24 h, N2.
b
Isolated yield.
The corresponding target products were all separated smoothly,
while the yields were significantly lower than those of aromatic
alcohol. It should be noted that excess aliphatic alcohols are usu-
ally needed in the reaction, which is probably caused by their easy
volatility.
In addition to the aromatic alcohol employed, linear and
branched chain aliphatic alcohols were also employed for the
a-
alkylation reactions. We have chosen iso-octyl alcohol, isobutanol,
1-pentanol, and n-propanol as representatives (Table 2, see 5i–5l).

D. Wang et al. / Tetrahedron Letters 55 (2014) 7233–7235
7235
Table 4
References and notes
The alkylation of acetophenone with alcohol under solvent-free conditionsa,b
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O
O
2b
(1 mol%)
R1
+
R1
OH
Cs2CO3, reflux
5
4
3
2. For some recent examples, see (a) Hamid, M. H. S. A.; Slatford, P. A.;
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O
O
O
O
5g
, 74%
5a, 86%
5i,
65%
O
O
O
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5j,
5k,
5l,
73%
61%
52%
a
Reagents and conditions: 3 (1.0 mmol), 4 (2 mL), 2b loading (1 mol %), Cs2CO3
(1.0 mmol), reflux, 24 h, N2.
b
Isolated yield.
The reaction of different substituted aromatic ketones with aro-
matic alcohols was studied (Table 3). The results showed that dif-
ferent alkylated ketones were obtained in good yields by using the
catalyst 2b. The reaction had good substituent tolerance. The sub-
stituents having different electronic properties on the aryl ring of
acetophenones significantly affected the reaction yields. Generally,
acetophenones possessing electron-donating groups gave the cor-
responding products in higher yields (Table 3, see 5n, 5o, 5p, 5q,
and 5u) as compared to electron-poor ones (Table 2, see 5m, and
5t). Notably benzyl alcohol with 1-[4-(trifluoromethyl)phenyl]eth-
anol afforded only 57% yield of the desired product. We attributed
this result to the trifluoromethyl strong electron withdrawal
(Table 3, see 5r). A similar trend was also observed by Zhang
group,8g and they figured out that it was due to the decomposition
of ketone starting materials.
Moreover, the borrowing hydrogen reaction of acetophenone
with alcohols was also examined under solvent-free conditions.
To our surprise, all the acetophenones were converted to their cor-
responding ketones with moderate to good yields (Table 4). This
reaction under solvent-free conditions provides an effective, green
method for the alkylation of ketones with alcohols.
Conclusions
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G.; Li, Q.; Feng, J.; Liu, Q.; Zhang, Z.; Wang, X.; Zhang, X.; Mu, X.
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In conclusion, a highly efficient CAC bond formation was devel-
oped through the
a-alkylation of ketones with primary alcohols.
The corresponding functionalized ketones were obtained with irid-
ium–CNP complex as a catalyst through borrowing hydrogen reac-
tion, and the substrate scope was wide. The pyridyl methanols and
other heterocyclic substituted methanols, especially alkyl alcohols,
were also suitable for this transformation. The present methodol-
ogy provides an easy alternative route to aldol reaction derivatives.
9. (a) Yang, W.; Fu, H.; Song, Q.; Zhang, M.; Ding, Y. Organometallics 2011, 30, 77;
(b) Yang, W.; Wang, D.; Song, Q.; Zhang, S.; Wang, Q.; Ding, Y. Organometallics
2013, 32, 4130.
10. For selected recent papers in our group, see: (a) Zhao, K.; Wang, D.; Wang, H.;
Zhu, Z.; Ding, Y. Inorg. Chem. Commun. 2014, 47, 131; (b) Wang, D.; Zhao, K.; Xu,
C.; Miao, H.; Ding, Y. ACS Catal. 2014, 4, 3910; (c) Li, L.; Wu, F.; Zhang, S.; Wang,
D.; Ding, Y.; Zhu, Z. Dalton Trans. 2013, 42, 4539; (d) Liu, X.; Zhang, S.; Ding, Y.
Dalton Trans. 2012, 41, 5897; (e) Zhang, S.; Ding, Y. Organometallics 2011, 30,
633.
Acknowledgments
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (21401080,
21371080), the Natural Science Foundation of Jiangsu Province of
China (BK20130125), China Postdoctoral Science Foundation
(2014M550262) and MOE & SAFEA for the 111 Project (B13025).
11. Wang, D.; Zhao, K.; Yu, X.; Miao, H.; Ding, Y. RSC Adv. 2014, 4, 42924.
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.034.