Practical approach for preparation of unsymmetric benzils from β-ketoaldehydes

Article abstract of DOI:10.1021/ol403762e

An efficient and practical method for the synthesis of unsymmetric benzils from readily available β-ketoaldehydes has been developed. Various unsymmetric 1,2-diaryldiketones bearing functional groups have been obtained in good to excellent yields under mild reaction conditions. A plausible mechanism was proposed, and α,α-dichloroketone was considered as the key intermediate. The generation of α,α-dichloroketones from β-ketoaldehydes may undergo the following steps: (1) oxidation by sodium hypochlorite, (2) decarboxylation, and (3) chlorination by Cl₂ generated from sodium hypochlorite.

Full text of DOI:10.1021/ol403762e

Letter
pubs.acs.org/OrgLett
Practical Approach for Preparation of Unsymmetric Benzils from
β‑Ketoaldehydes
Libo Ruan, Min Shi, Nian Li, Xu Ding, Fan Yang,* and Jie Tang*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University,
Shanghai 200062, China
S
* Supporting Information
ABSTRACT: An efficient and practical method for the synthesis of unsymmetric
benzils from readily available β-ketoaldehydes has been developed. Various
unsymmetric 1,2-diaryldiketones bearing functional groups have been obtained in
good to excellent yields under mild reaction conditions. A plausible mechanism was
proposed, and α,α-dichloroketone was considered as the key intermediate. The
generation of α,α-dichloroketones from β-ketoaldehydes may undergo the following steps: (1) oxidation by sodium hypochlorite,
(2) decarboxylation, and (3) chlorination by Cl2 generated from sodium hypochlorite.
a
enzil derivatives have attracted a great deal of attention
Table 1. Optimization of the Reaction Conditions
B
due to their rich applications across many fields of
science.1 Their wide applications have motivated efforts toward
the synthesis of these compounds. Traditionally, benzils are
prepared via benzoin condensation followed by oxidation of the
obtained α-hydroxycarbonyls.2 Although this method showed
high efficiency, it was also limited to the preparation of
symmetric benzils. The synthesis of unsymmetrically sub-
stituted benzils was proven to be more difficult to achieve due
to lack of regiochemical control in the cross-benzoin reaction of
two different aldehydes. Therefore, efficient synthesis of
unsymmetric benzils has recently drawn significant attention.
Over the past decade, several synthetic strategies for the
preparation of unsymmetric benzils have been reported
including the oxidation of alkynes, alkenes,3 or α-methylene
ketones,4 decarboxylation of 1,3-diketones,5 and some
others.1b,g,6 Herein, we reported a new practical synthetic
route for the preparation of unsymmetric benzils from β-
ketoaldehydes which can be obtained conveniently from Lewis
acid catalyzed Meinwald rearrangement7 of chalcone epoxides,
and this method has been demonstrated to be of excellent
substrate scope.
b
b
b
c
entry x equiv NaClO
solvent
DCM
temp (°C) time (h) yield (%)
1
2
3
4
5
6
4
5
rt
rt
rt
rt
rt
rt
rt
rt
40
0
4
4
80
84
84
84
84
81
72
84
84
84
DCM
DCM
DCM
CH3CN
THF
6
4
10
5
2.5
4
5
4
7
d
5
1,4-dioxane
DCM
4
8
5
4
9
5
DCM
3.5
6
10
5
DCM
a
Reaction conditions: β-ketoaldehyde (1 mmol), solvent (5 mL), x
equiv of 5.2% (w/v) NaClO solution was added dropwise; the reaction
mixture was stirred at room temperature until TLC indicated
completion. After extraction and concentration in vacuo, the crude
intermediate was obtained, then it was dissolved in 5 mL of 30%
AcOH solution, and the reaction mixture was stirred at 60 °C,
b
monitored by TLC. The reaction in the presence of aqueous NaClO.
Isolated yield. Tetrabutylammonium bromide (10 mol %) was
added.
c
d
It was found that the oxidation of 3-oxo-2,3-diphenyl-
propionaldehyde with aqueous sodium hypochlorite in
dichloromethane followed by hydrolysis with acid gave a
product 1,2-diphenylethane-1,2-dione (benzil). To explore the
reaction carefully and optimize the oxidation reaction
conditions, we examined solvent, temperature, amount of the
oxidant, as well as reaction time (Table 1). Most of the
attempts afforded good results. When 5−6 equiv of sodium
hypochlorite was employed, the yield improved to 84% (Table
1, entries 2 and 3). Solvent has no obvious impact on the
reaction except for 1,4-dioxane (Table 1, entry 7). Higher
temperatures accelerated the reaction to some extent (Table 1,
entry 9). Thus, the optimum oxidation conditions were
established as using 5 equiv of aqueous NaClO as the oxidant
as well as the source of the chlorine and carrying out the
reaction in DCM at room temperature.
With the optimum conditions in hand, the substrate scope
was then examined. As shown in Table 2, benzil derivatives
were obtained in good to excellent yields for most substrates.
There was no significant difference in reactivities between 3-
oxo-2,3-diphenylpropanal (Table 2, entry 1) and its derivatives
containing electron-donating groups (Table 2, entries 2−5 and
12−14) or electron-withdrawing/donating groups (Table 2,
entries 6−11 and 15). In addition, the reaction was not
sensitive to steric hindrance. For the substrates where methyl
Received: December 29, 2013
Published: January 29, 2014
© 2014 American Chemical Society
733
dx.doi.org/10.1021/ol403762e | Org. Lett. 2014, 16, 733−735

Organic Letters
Letter
a
Table 2. Conversion of β-Ketoaldehydes to 1,2-Dicarbonyl Compounds
a
All reactions were run under the same conditions: 2 mmol β-ketoaldehyde was dissolved in 10 mLof CH2Cl2; 13.6 mL of 5.2% (w/v) NaClO
solution was added dropwise, and the reaction mixture was stirred at room temperature. After chlorination, reaction was complete, and the crude
dichloroketone was obtained by extraction and concentration. Then it was dissolved in 5 mL of 30% AcOH solution, and the reaction mixture was
b
stirred at 60 °C, monitored by TLC. Isolated yield.
and methoxy groups are substituted at the ortho position of the
aromatic ring Ar1, satisfactory yields of the products were
successfully obtained (Table 2, entries 2, 3, and 7−17). It was
noteworthy that when Ar2 was altered with heterocyclic groups
(Table 2, entries 16 and 17), the corresponding heteroaromatic
products 3p and 3q were also obtained in excellent yields
(92%).
To clarify the reaction mechanism, we attempted to trap
reaction intermediates. To our delight, when 3-oxo-2,3-
diphenylpropionaldehyde was treated with 5 equiv of aqueous
sodium hypochlorite in DCM, 1,2-diphenylethanone (III, when
R1 = R2 = Ph), 2-chloro-1,2-diphenylethanone (IV, when R1 =
R2 = Ph), and 2,2-dichloro-1,2-diphenylethanone (V, when R1
= R2 = Ph) were isolated from the reaction mixture by
quenching the reaction at 0.5 h. While being treated 3-oxo-2,3-
diphenylpropionaldehyde with 3 equiv of sodium hypochlorite
solution in dichloromethane for 4 h, 2-chloro-1,2-diphenyl-
ethanone (IV when R1 = R2 = Ph, 21%) and 2,2-dichloro-1,2-
diphenylethanone (V when R1 = R2 = Ph, 71%) were obtained.
On the basis of the above facts, we proposed a pathway for the
aqueous sodium hypochlorite mediated transformation of β-
ketoaldehydes to benzils (Scheme 1). Oxidation of β-
ketoaldehydes by sodium hypochlorite gave the corresponding
3-oxo-2,3-diarylpropanoic acids (I), and then decarboxylation
of I provided deoxybenzoins (III); chlorination of III by
chlorine, released from the decomposition of NaClO in water,
Scheme 1. Possible Reaction Pathway
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dx.doi.org/10.1021/ol403762e | Org. Lett. 2014, 16, 733−735

Organic Letters
Letter
(l) Campillo, N.; García, C.; Goya, P.; Pae
́
z, J. A.; Carrasco, E.; Grau,
produced α,α-dichloroketones (V) which were hydrolyzed in
the presence of acetic acid and finally afforded the desired
benzils.
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In conclusion, we have developed an efficient and practical
method for the synthesis of unsymmetric benzils from readily
available and inexpensive β-ketoaldehydes. Various unsymmet-
ric 1,2-diaryldiketones bearing functional groups have been
obtained in high to excellent yields under mild reaction
conditions. Notably, the products which have halogen
substituents at aromatic rings allow further functionalization
via transition-metal-catalyzed cross-coupling reactions and thus
the accessibility of unsymmetric diketone derivatives. Fur-
thermore, due to easy access to a variety of β-ketoaldehyde
substrates by Meinwald rearrangement of chalcone epoxides,
this work provides a very convenient and straightforward
protocol to construct useful unsymmetric 1,2-dicarbonyls from
simple starting materials. Further studies of other related
applications of this protocol are currently ongoing in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, 1H and 13CNMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fyang@chem.ecnu.edu.cn.
*E-mail: jtang@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Shanghai Science and
Technology Council (Nos. 12142200802 and 13142200902).
We also thank Laboratory of Organic Functional Molecules and
the SINO-FRENCH INSTITUTE OF ECNU for support.
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