An approach to synthesis of (Z)-2-chloro-1,3-diarylpropen-1-ones by Vilsmeier reagent (bis-(trichloromethyl) carbonate/DMF)

Article abstract of DOI:10.1016/j.cclet.2011.07.006

A series of (Z)-2-chloro-1,3-diarylpropen-l-ones were unexpectedly synthesized in moderate yields by treatment of easily available 2,3-epoxy-l, 3-diarylpropan-1-ones with Vilsmeier reagent, which was derived from bis(trichloromethyl) carbonate (BTC, triph

Full text of DOI:10.1016/j.cclet.2011.07.006

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Chinese Chemical Letters 22 (2011) 1395–1398
www.elsevier.com/locate/cclet
An approach to synthesis of (Z)-2-chloro-1,3-diarylpropen-1-ones
by Vilsmeier reagent (bis-(trichloromethyl) carbonate/DMF)
*
Yi Yi Weng, Jian Jun Li, Wei Ke Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, China
Received 13 April 2011
Available online 12 October 2011
Abstract
A series of (Z)-2-chloro-1,3-diarylpropen-l-ones were unexpectedly synthesized in moderate yields by treatment of easily
available 2,3-epoxy-l, 3-diarylpropan-1-ones with Vilsmeier reagent, which was derived from bis(trichloromethyl) carbonate (BTC,
triphosgene) and DMF. A possible mechanism was also proposed, where sequential ring-opening, halogenation and elimination
reactions were involved.
# 2011 Wei Ke Su. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ring-opening; Halogenation; Vilsmeier reagent; Bis-(trichloromethyl)carbonate; (Z)-2-Chloro-1,3-diaryl-2-enones
Functionalized (Z)-2-chloro-1,3-diarylpropen-l-ones have been used as versatile intermediates in organic synthesis
[1,2]. Extensive studies have brought about many efficient synthetic approaches to such (Z)-2-chloro-1,3-
diarylpropen-l-ones, such as dehydrohalogenation from a,b-dihaloketones [3], and halogenation of a,b-unsaturated
ketones [4]. Most recently, Itoh et al. [5] described an efficient synthesis of a-chloro-a,b-unsaturated aryl ketones
using a-chloro-b-ethoxyalkenyllithiums. However, most of the procedures suffered from their own limitations, such as
harsh conditions, poor substrate scope and selectivity, or not readily available starting materials.
The overwhelming importance of epoxy ketones in organic synthesis has been well recognized for their
‘‘unsaturated’’ character. Marques et al. [6] found that the easily available 2,3-epoxy-l,3-diarylpropan-1-ones showed
promising structural features as novel organic intermediates in ring-opening reactions. To the best of our knowledge,
the route which described the synthesis of (Z)-2-chloro-1,3-diarylpropen-l-ones by treatment of epoxy ketones with
TMSCl/DMSO, followed by Ac2O/DMAP has been reported in the literature [7]. However, this method suffers from
certain limitations such as the necessity for isolation of the intermediates and long reaction periods.
On the other hand, Vilsmeier reagent (halomethylene iminium salts) are electrophilic species which is able to
formylate various electron-rich aromatic, aliphatic and heteroaromatic substrates [8]. Certain novel applications such
as cyclization, halogenation, alkylation (methylation) and haloalkylation have also been exploited in recent years [9].
Practically, Vilsmeier reagents can be easily prepared by reaction of an inorganic acid halide or anhydride (e.g. POCl3,
SOCl2, COCl2, or (CF3SO2)2O) with a N,N-disubstituted formylamide such as DMF at 0–20 8C [10].
* Corresponding author.
E-mail address: pharmlab@zjut.edu.cn (W.K. Su).
1001-8417/$ – see front matter # 2011 Wei Ke Su. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.07.006

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Y.Y. Weng et al. / Chinese Chemical Letters 22 (2011) 1395–1398
Table 1
Effects of reagent, solvent and temperature on the reaction of 1a.
Entry
Ratio of 1a:BTC:DMF
Temperature (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
1:0.33:1
1:0.66:2
1:1:3
80
80
80
80
r.t.
55
80
24
8
20
55
75
73
10
45
–
4
1:1.33:4
1:1:3
4
24
8
1:1:3
1:0:3
24
During the course of our studies on the chemistry of versatile reagent bis-(trichloromethyl) carbonate (BTC,
triphosgene) [11], we found that the easily available reagent BTC is not only a safe substitute for the toxic phosgene
gas, but also associated with such advantages as mild reaction conditions, excellent yields, and avoidance of the
formation of inorganic phosphorus salts.
In continuation of our interest in the use of Vilsmeier reagent derived from BTC/DMF [12], we developed a simple
one-pot protocol for the construction of (Z)-2-chloro-1,3-diarylpropen-l-ones by treatment of a,b-epoxy aryl ketones
with Vilsmeier reagent (BTC/DMF). This method has found wide applicability in preparing such compounds with
more elaborate and flexible substitution patterns.
Initially, 2,3-epoxy-3-(3-nitrophenyl)-1-phenylpropan-1-one 1a was investigated as the model compound to
examine its behavior under different conditions (Scheme 1). The optimization of the reaction conditions, including the
reaction temperature, reaction time and ratio of 1a/BTC/DMF were investigated. When we mixed 1a with Vilsmeier
reagent at room temperature for 24 h, the product 2a was isolated with lower yield (10% yield, Table 1, entry 5).
The ring-opening of epoxy ketone has been reported using the traditional Vilsmeier reagent (POCl3/DMF) [13].
The product was characterized as 3-chloro-3-(3-nitrophenyl)-1-phenylpropen-1-one 3a. Our result was interesting
since it afforded a type of compound (Z)-2-chloro-3-(3-nitrophenyl)-1-phenylpropen-1-one 2a different from that
derived from traditional Vilsmeier reagent. The compound 2a was further confirmed by the X-ray single crystal
analysis [14]. The stereochemistry of 2a indicates that Cl and R4 show a cis relationship. To our delight, the reaction
proceeded smoothly and afforded 75% yield of 2a if elevated the reaction temperature to 80 8C (Table 1, entry 3).
Subsequently, the ratio of 1a/BTC/DMF was also examined under the similar conditions. It is revealed that the ratio
of 1/0.33/1 was ineffective for the complete conversion (20% yield, Table 1, entry 2). When the ratio was changed to 1/
1/3, the reaction proceeded with good efficiency (Table 1, entry 3).
Thus, a variety of 2,3-epoxy-l,3-diarylpropan-1-ones 1, which were readily prepared by oxidation of substituted
chalcones using H2O2 as an oxidant [15], were reacted under the optimized conditions. And the results were
summarized in Table 2. All the substrates employed here (bearing an aryl with either an electron-donating or electron-
withdrawing group on the phenyl ring) could efficiently react with BTC/DMF complex and give the corresponding 2 in
moderate yields. Therefore, it could be concluded that the electronic effects of the substituents on the aryl (–R3, –R4)
have little influence on this reaction (Scheme 2).
Scheme 1. Synthesis of 2a and the structure of 2a by X-ray single crystal analysis.

Y.Y. Weng et al. / Chinese Chemical Letters 22 (2011) 1395–1398
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Table 2
Synthesis of (Z)-2-chloro-1,3-diarylpropen-l-ones 2.
Entry
R3
R4
Time (h)
Product
Yield (%)a
1
C6H5
m-NO2C6H4
C6H5
4
3
2
4
4
3
3
3
2
3
2
3
4
3
2a
2b
2c
2d
2e
2f
75
68
65
63
60
58
54
66
50
55
52
59
70
52
2
C6H5
3
C6H5
m-MeOC6H4
p-ClC6H4
p-FC6H4
4
C6H5
5
C6H5
6
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
2-Furyl
p-FC6H4
7
m-ClC6H4
m-NO2C6H4
m-MeOC6H4
p-ClC6H4
m-MeOC6H4
p-ClC6H4
m-NO2C6H4
C6H5
2g
2h
2i
8
9
10
11
12
13
14
2j
2k
2l
2m
2n
a
Isolated yield.
Scheme 2. Synthesis of (Z)-2-chloro-1,3-diarylpropen-l-ones 2.
Considering that BTC itself is a good chlorinating agent [13a], we performed the reaction in the presence of BTC in
CH2ClCH2Cl at 80 8C for 24 h. However, it was found that no reaction occurred as indicated by TLC (Table 1, entry 7).
This result indicates that the Vilsmeier reagent functions not only as a chlorinating agent but also an activated species,
which may facilitate the ring opening of the epoxy moiety by coordination.
On the basis of the above experimental results together with the related reports [16], a plausible mechanism is
proposed for the formation of (Z)-2-chloro-1,3-diarylpropen-l-ones (Scheme 3).
Firstly, 1/3 equiv. of BTC and 1 equiv. of DMF generated 1 equiv. of halomethylene iminium salts 4, which then
coordinates with 2,3-epoxy-l,3-diarylpropan-1-ones 1 to provide the intermediates oxiranium A. Subsequently, a
chloride anion previously released from the Vilsmeier reagent attacks on the benzyl position of A to give intermediates
B. Further nucleophilic attack of another chloride anion on the a-position of the carbonyl in C leads to the formation of
Scheme 3. Proposed mechanism for the formation of (Z)-2-chloro-1,3-diarylpropen-l-ones 2.

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dichloride D with the regeneration of DMF. Finally, trans-elimination of one molecular of HCl from D affords
products 2.
In summary, we have developed a novel synthesis of (Z)-2-chloro-1,3-diarylpropen-l-ones 2 by treatment of 2,3-
epoxy-l,3-diarylpropan-1-ones 1 with BTC/DMF system, where ring-opening, halogenations and elimination
reactions were sequentially realized in one-pot. Tentative mechanism to rationalize the formation of 2 is proposed. The
advantages of this method including simplicity of manipulation and readily available starting materials make this
synthetic strategy most attractive for both academic research and potential applications.
Typical procedure: In a flask fitted with a thermometer, dropping funnel, condenser and stirrer, the activated
Vilsmeier reagent was prepared by adding a solution of BTC (1 mmol) in CH2ClCH2Cl (7 mL) to DMF (3 mmol) at
0 8C in 15–30 min. Then 2,3-epoxy-3-(3-nitrophenyl)-1-phenylpropan-1-one 1a (1 mmol) was added and the mixture
was heated to 80 8C for 4 h. After completion of the reaction, the mixture was washed with water and brine. The
aqueous phase was extracted with ClCH2CH2Cl (3Â 10 mL). The combined organic layer was dried (Na2SO4) and
evaporated, the product was purified by flash chromatography to provide 2a in 75% yield.
1
(Z)-2-Chloro-3-(3-nitrophenyl)-1-phenylpropen-1-one (2a): White crystal; mp: 95.8–96.8 8C, yield: 75%; H
NMR (400 MHz, CDCl3): d 8.68 (s, 1H), 8.29–8.26 (m, 1H), 8.16 (d, 1H, J = 7.6 Hz), 7.83 (d, 2H, J = 7.2 Hz), 7.67–
7.49 (m, 5H); 13C NMR (100 MHz, CDCl3): d 190.4, 148.3, 135.9, 135.8, 135.7, 134.5, 133.1, 132.9, 129.6, 128.6,
124.9, 124.5; MS (EI) m/z (%): 289 (6, [M+2]+), 287 (17, M+), 252 (22), 105 (100), 77 (60), 51 (9); HRMS Calcd. for
C15H10ClNO3: 287.0349; found: 287.0346.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Nos. 20806073 and 20876147) and the
National Key Technology Research and Development Program (No. 2007BAI34B06) for financial support.
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