Angewandte
Chemie
DOI: 10.1002/anie.201308642
Synthetic Methods
Catalyst-Free Dehydrative a-Alkylation of Ketones with Alcohols:
Green and Selective Autocatalyzed Synthesis of Alcohols and
Ketones**
Qing Xu,* Jianhui Chen, Haiwen Tian, Xueqin Yuan, Shuangyan Li, Chongkuan Zhou, and
Jianping Liu
Abstract: Direct dehydrative a-alkylation reactions of ketones
with alcohols are now realized under simple, practical, and
green conditions without using external catalysts. These
catalyst-free autocatalyzed alkylation methods can efficiently
afford useful alkylated ketone or alcohol products in a one-pot
=
manner and on a large scale by C C bond formation of the in
situ generated intermediates with subsequent controllable and
selective Meerwein–Pondorf–Verley–Oppenauer-type redox
processes.
À
A
mong C C bond construction methods, a-functionaliza-
tion of carbonyl compounds is one of the most fundamental
strategies to synthesize heterocycle-, pharmaceutical-, and
natural-product-directed molecules.[1,2] Conventionally, a-
functionalization of carbonyl compounds was achieved by
reactions of carbonyl compounds and organohalides (Scheme
1a).[1,2] However, these methods require reactive and toxic
organohalides and large amounts of bases, and the concurrent
formation of undesired waste salts is inevitable. Since alcohols
are comparatively greener chemicals, and organohalides are
mostly obtained from alcohols by halogenation, alcohols have
recently been directly used as greener alkylating reagents.[3,4]
Regarding the a-alkylation of ketones to generate alkylated
ketone or alcohol products,[2] several transition-metal (TM)-
catalyzed methods have been achieved by anaerobic dehy-
drogenative alcohol activation (Scheme 1b).[5–7] Despite their
advantages, these TM-catalyzed reactions still have obvious
drawbacks, such as the use of expensive and toxic rare metal
complexes (Ru,[5] Ir,[6] Pd,[7] etc.[7]) or capricious ligands, large
amounts of hydrogen acceptors or bases, and metal contam-
ination in products. Herein we report the catalyst-free
autocatalyzed dehydrative a-alkylation reactions of ketones
with alcohols (Scheme 1c), which selectively afforded useful
alkylated ketone or alcohol products under simple and
practical one-pot conditions. As to known TM-free reactions
of carbonyl compounds and alcohols, they were limited to
simple Meerwein–Pondorf–Verley–Oppenauer (MPV-O)
Scheme 1. Background of the research.
redox reactions (Scheme 1d)[8] without the formation of
À
new C C bonds.
In our studies on alcohol-based TM-catalyzed aerobic
reactions,[4a,9,10] we accidentally observed that aldehydes
efficiently catalyzed dehydrative alkylation reactions of
amides, amines, and secondary alcohols with alcohols by
a TM-free mechanism involving MPV-O-type redox process-
es.[11,12] We thus deduced that ketones may similarly be good
catalysts[13,14] and can lead to new TM-free alkylation
methods. As shown in Scheme 2A, we hypothesized that a-
alkylation of ketones with alcohols may proceed successively
by an MPV-O-type aldehyde formation (step a; Scheme 2B,
X = O),[8] dehydrative aldol condensation (step b), and MPV-
O-type reduction of chalcone intermediates by alcohols to
give alkylated ketones or alcohol products (steps c and d;
Scheme 2B, X = C, O), thus regenerating aldehydes for the
catalytic cycle.[11b] If this process can be realized, it may lead to
advantageous and green catalyst-free autocatalyzed a-alky-
lation reactions because no additional ketones are required.
Consequently, the use of external catalysts can be avoided.
We began our study by investigating the reaction of benzyl
alcohol (1a) and acetophenone (2a) without adding any
external catalysts (Table 1).[15] Thus, directly heating solvent-
free mixtures of 1a and 2a with different bases[16] at 1108C
under air led to the formation of the alkylated ketone 3a and
alcohol 4a in varied yields and ratios. The results showed that
[*] Prof. Dr. Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou, Dr. J. Liu
College of Chemistry and Materials Engineering
Wenzhou University
Wenzhou, Zhejiang 325035 (China)
E-mail: qing-xu@wzu.edu.cn
[**] This research was supported by NNSFC (20902070), SRF for ROCS
of SEM, ZJNSF (Y4100579), and ZJQJTP (QJD0902004).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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