Microwave-assisted dehalogenation of α-haloketones by zinc and ammonium chloride in alcohol

Article abstract of DOI:10.1080/00397910701797889

The treatment of α-haloketones with 1.5 equiv. of Zn and 1 equiv. of NH4Cl in ethanol for 0.5αmin gave the corresponding ketones with excellent yields under microwave irradiation. Vic-dibromides and 2,2-dibromoacetophenone can be efficiently debrominated to alkenes and acetophenones, respectively. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701797889

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Microwave‐Assisted Dehalogenation of
α‐Haloketones by Zinc and Ammonium
Chloride in Alcohol
Jian Li a , Deju Ye a , Hong Liu a , Xiaoming Luo a & Hualiang Jiang a b
a State Key Laboratory of Drug Research, Center for Drug Discovery and
Design, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences , Shanghai, China
b School of Pharmacy, East China University of Science and Technology ,
Shanghai, China
Published online: 27 Feb 2008.
To cite this article: Jian Li , Deju Ye , Hong Liu , Xiaoming Luo & Hualiang Jiang (2008) Microwave‐Assisted
Dehalogenation of α‐Haloketones by Zinc and Ammonium Chloride in Alcohol, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:4, 567-575, DOI:
10.1080/00397910701797889
To link to this article: http://dx.doi.org/10.1080/00397910701797889
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Synthetic Communicationsw, 38: 567–575, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701797889
Microwave-Assisted Dehalogenation
of a-Haloketones by Zinc and Ammonium
Chloride in Alcohol
Jian Li,1 Deju Ye,1 Hong Liu,1 Xiaomin Luo,1
and Hualiang Jiang1,2
1State Key Laboratory of Drug Research, Center for Drug Discovery and
Design, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, Shanghai, China
2School of Pharmacy, East China University of Science and Technology,
Shanghai, China
Abstract: The treatment of a-haloketones with 1.5 equiv. of Zn and 1 equiv. of NH4Cl
in ethanol for 0.5 min gave the corresponding ketones with excellent yields under
microwave irradiation. Vic-dibromides and 2,2-dibromoacetophenone can be effi-
ciently debrominated to alkenes and acetophenones, respectively.
Keywords: dehalogenation, 2,2-dibromoacetophenone, a-haloketones, microwave
irradiation, vic-dibromides
INTRODUCTION
The chemical methods of dehalogenation have been important for degradation
of halogenated compounds, and many reagents have been reported for
effecting this transformation, including (1) reducing agents, such as sodium
dithionate,[1] aluminium in methanol,[2] Bi/NH4F in H2O,[3] organotin
hydrides,[4] and low-valent transition-metal salts;[5,6] (2) nucleophilic
reducing agents, such as iodide ions,[7] phosphines,[8] iodophosphines,[9]
Received in Japan August 7, 2007
Address correspondence to Hong Liu, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park,
Shanghai 201203, China. E-mail: hliu@mail.shcnc.ac.cn
567

568
J. Li et al.
and iodotrimethylsilane;[10] and (3) Pd-catalyzed hydrogenation.[11] However,
many of these reagents suffered from one or more drawbacks: unsatisfactory
yields, high cost or toxicity, necessity of anhydrous conditions, and lack of
selectivity. Therefore, some reagents have been devised to improve the
reaction. Recently, Lee et al.[12] reported an efficient method for this
reaction: a-bromoketone derivatives can be transformed to corresponding
ketones with indium in the presence of acetic acid at room temperature by
stirring for 2 h, giving excellent yields.
Microwave-assisted organic reactions have been applied to a wide range
of reaction types, including aromatic nucleophilic substitution, cycloaddition,
and organometallic reactions.[13,14] Zn/NH4Cl is an efficient reducing agent
for the transformation of aryl acyloin O-alkyl and O-phenyl derivatives to
ketones.[15] To continue our work in the Zn/NH4Cl-mediated reaction, we
applied the reagent to the dehalogenations of a-haloketones under the
microwave irradiation in ethanol at 808C; good to excellent yields of corre-
sponding ketones were afforded in only 0.5 min (Scheme 1). The application
of this reagent is summarized in Table 1. All the a-haloketones were commer-
cially available from Aldrich and Acros companies.
RESULTS AND DISCUSSION
Using 2-bromoacetophenone (1a) as a model compound, we optimized the
reaction conditions by testing several parameters, such as different amounts
of Zn and NH4Cl, as well as different reaction time (Table 2). Compound
1a was separately debrominated with 0, 1, 1.5, and 2 equiv. of Zn and 2
equiv. of NH4Cl at different times (entries 1–6, Table 2). The reactions
with 0 or 1 equiv. of Zn were incomplete after 0.5 min with yields of 0%
and 85%, respectively (entries 5 and 6, Table 2). The conversion rate of 1a
achieved 100% (yields 99%) using 1.5 and 2 equiv. of Zn in ethanol at
808C for 0.5 min. When using 1.5 equiv. of Zn with 0, 0.5, 1.0, 1.5, and 2.0
equiv. of NH4Cl, the yields increased with the amounts of NH4Cl (entries
7–10, Table 2), 1.0 equiv. of which can complete the reaction (yield 99%).
This indicates that the optimization of the dehalogenation conditions by
increasing the amount of Zn and NH4Cl may be useful, and increasing the
amount of NH4Cl may improve the conversion rate. The optimum results
Scheme 1. Transformation of a-haloketones to ketones with Zn/NH4Cl under
microwave irradiation.

Table 1. Examples of transformation from a-haloketones to ketones with Zn/NH4Cl
Compound
Substrate
Compound
Product
Time (min)
Yield (%)a
1a
1b
1c
1d
1e
1f
PhCOCH2Br
2a
2b
2c
2d
2e
2f
PhCOMe
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
99
99
99
94
98
99
99
99
99
99
50
99
50
4-MePhCOCH2Br
4-MeOPhCOCH2Br
4-BrPhCOCH2Br
2,5-(MeO)2-PhCOCH2Br
4-FPhCOCH2Br
4-MePhCOMe
4-MeOPhCOMe
4-BrPhCOMe
2,5-(MeO)2-PhCOMe
4-FPhCOMe
1g
1h
1i
4-CNPhCOCH2Br
4-CF3PhCOCH2Br
2,5-Cl2PhCOCH2Br
PhCOCHBrPh
2g
2h
2i
4-CNPhCOMe
4-CF3PhCOMe
2,5-Cl2PhCOMe
PhCOCH2Ph
1j
2j
1k
1l
PhCOCHBrMe
PhCHBrCOOMe
PhCHClCOOEt
2k
2l
PhCOCH2Me
PhCH2COOMe
PhCH2COOEt
1m
2m
aIsolated yields.

570
J. Li et al.
Table 2. Procedure of optimizing dehalogenation methods of compound 1a under
microwave irradiation
Entry
Zn (equiv.)
NH4Cl (equiv.)
Time (min)
Product (yield, %)
1
2
2
2
2
99
99
99
99
85
0
2
2
1
3
2
2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4
1.5
1.0
0
2
5
2
6
2
7
1.5
1.5
1.5
1.5
1.5
1.0
0.5
0
99
99
80
56
8
9
10
were obtained when 0.5 mM of the starting material was allowed to react with
1.5 equiv. of Zn and 1.0 equiv. of NH4Cl in 2 mL of ethanol at 808C under
microwave irradiation for 0.5 min. The products were obtained by column
chromatography with silica gel.
The debrominations of a variety of a-haloketones under the optimized
conditions, were conducted, and the results are summarized in Table 1. The
results indicated that 2-bromoacetophenones with electron-donating groups
(1b, 1c) or electron-withdrawing groups (1f–h) were debrominated to
afford the corresponding ketones in high yields. Introduction of a phenyl
group to the Ca atom of the 2-bromoacetophenone proceeded to give
similar product yield (1j). However, introduction of a methyl group to the
Ca atom of 2-bromoacetophenone afforded only 50% yield of 2k. The
halogen group substituted at Ca position of ester (1l, 1m) was also dehaloge-
nated. Treatment of ethyl 2-chloro-2-phenylacetate (1m) with Zn and NH4Cl
gave lower product yields than the methyl 2-bromo-2-phenylacetate (1l).
However, the bromo group substituted on the phenyl ring under the same
reaction condition remained intact (1d).
To confirm whether the reagent had an effect on 2,2-dihaloketones, we
tried to apply the reagent to 2,2-dibromoacetophenone (3) by using 1.5
equiv. of Zn and 1 equiv. of NH4Cl in ethanol at 808C under microwave
irradiation for 0.5 min. Acetophenone (4) was obtained in high yield (94%),
and 2-bromoacetophenone was not detected as shown in Scheme 2. The
Scheme 2. Transformation of 2,2-dibromoacetophenone to acetophenone.

Dehalogenation of a-Haloketones
571
results indicate that Zn/NH4Cl may provide a good method for transforming
2,2-dihaloketones to ketones.
The bromination of alkenes and subsequent debromination of the
resulting vic-dibromides offer a means for protection of the carbon–carbon
double bond in synthesis,[16] and a lot of reagents were reported for the deb-
romination, such as Sm,[17] In,[18] Mg,[19] and so on. Here, when we treated
vic-dibromides (1n–r) with 1.5 equiv. of Zn and 1 equiv. of NH4Cl in
ethanol at 808C under microwave irradiation for 0.5 min, alkenes (2n–r)
were obtained with good yields (Scheme 3, Table 3). The results indicate
that using Zn/NH4Cl in the process of transforming vic-dibromides to
alkenes may be an efficient and convenient approach.
We proposed a reaction mechanism (Scheme 4) for the transformation.
Initially, aromatic 2-haloketone gets an electron from a zinc atom to form a
radical anionic species (7), then 7 gets another electron from the zinc atom
to form the zinc enolate (8), which is the same as the intermediate depicted
by Chan et al.[20] The intermediate was confirmed by the 2-deuterioacetophe-
none (9) (55% yield), which was obtained via deuteration of the intermediate
of zinc enolate 8 using D2O instead of NH4Cl (Scheme 5). Finally, the ketone
is produced through neutralization and tautomerization. We used the 2-bro-
moacetophenone to react with benzaldehyde to confirm it, and 3-hydroxy-
1,3-diphenyl-propan-1-one (10) was obtained (42% yield) (Scheme 6).
In conclusion, a convenient and efficient method for microwave-assisted
dehalogenation of aromatic 2-haloketones with Zn/NH4Cl in enthanol at 808C
is described, and its mechanism is proposed. This method can also be efficient
for the transformation of vic-dibromides to alkenes in high yields. In this
article, we also reported a direct way of transforming 2,2-dihaloacetophenone
to acetophenone in high yield.
EXPERIMENTAL
IR spectra were measured with a Perkin-Elmer 598B spectrometer using KBr
pellets. NMR spectra were determined on a Bruker AMX-400 instrument in
CDCl3 MS spectra were recorded on a MAT-95 spectrometer. Microwave
experiments were carried out in the Biotage Initiator. Products are character-
ized by comparison of their spectral data (1H NMR, IR) with that reported in
the literature.
Scheme 3. Transformation of vic-dibromides to alkenes.

Table 3. Examples of transformation from vic-dibromides to alkenes with Zn/NH4Cl
Compound
Substratea
Compound
Productb
Time (min)
Yield (%)c
1n
1o
1p
1q
1r
PhCHBrCHBrCOCH3
PhCCHBrCHBrCOPh
4-MePhCHBrCHBrCOPh
4-FPhCHBrCHBrCOPh
PhCHBrCHBrCOOEt
2n
2o
2p
2q
2r
PhCH55CHCOMe
PhCH55CHCOPh
4-MePhCH55CHCOPh
4-FPhCH55CHCOPh
PhCH55CHCOOEt
0.5
0.5
0.5
0.5
0.5
95
77
70
79
98
aAll dibromides were prepared by bromination of (E)-alkenes with bromine in CCl4 at rt.
1
bThe E or Z form was determined by H NMR spectroscopy.
cIsolated yields.

Dehalogenation of a-Haloketones
573
Scheme 4. Proposed mechanism for the dehalogelation of a-haloketones by
Zn/NH4Cl under microwave irradiation.
Scheme 5. Reaction of 2-bromoacetophenone with benzaldehyde in the presence of
zinc and alcohol under microwave irradiation at 808C.
Scheme 6.
A typical procedure is as follows: 0.5 mmol of each a-haloketone deriva-
tive was dissolved in 2 mL of EtOH in a 3- to 5-mL microwave vial, and
0.75 mmol of Zn and 0.5 mmol of NH4Cl were added. Then the mixture
was stirred for 0.5 min at 808C under microwave irradiation. The reactant
was filtered off; then the reaction solution was concentrated, and 15 mL of
ethyl acetate were added. The solution was washed with water (15 mL Â 3)
and brine and dried over anhydrous magnesium sulfate. Evaporation of the
solvent under vacuum gave the crude reduced product, which was further
purified by column chromatography with silica gel.
2-Bromoacetophenone[21]
1H NMR d (400 MHz, CDCl3): 4.46 (s, 2H), 7.48 (m, 2H), 7.59 (m, 1H), 7.92
(m, 2H).
1,3-Diphenyl-2-propen-1-one[22]
1H NMR d (400 MHz, CDCl3): 7.41 (m, 3H), 7.49 (m, 2H), 7.56 (d, J ¼ 15.8 Hz,
1H), 7.50 (m,1H), 7.71 (m, 2H), 7.83 (d, J ¼ 15.8 Hz, 1H), 8.00 (m, 2H).

574
J. Li et al.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the State Key Program of
Basic Research of China (Grant 2002CB512802, 2005BA711A01), the
National Natural Science Foundation of China (Grants 30672539,
20572117, and 20472094), and the 863 Hi-Tech Program (Grants
2006AA020402 and 2006AA020602).
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