A convenient method for reduction dehalogenation of α-halocarbonyl compounds using benzenethiol in K+/CH3CN system

Article abstract of DOI:10.1080/10426507.2016.1138309

Benzenethiol, as a reductive agent for the dehalogenation of various α-halocarbonyl compounds, is investigated in the K⁺/CH₃CN system. The reaction affords the reduced compounds in high yields under mild reaction conditions, especially α-chlorocarbonyl compounds. Furthermore, the reaction performed under ultrasonic irradiation greatly shortens the reaction time.

Full text of DOI:10.1080/10426507.2016.1138309

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A Convenient Method for Reduction
Dehalogenation of α-Halocarbonyl Compounds
Using Benzenethiol in K+/CH3CN System
Wei-Li Dong, Wen-Xi Cai, Rui Wu, Zheng-Ming Li, Wei-Guang Zhao & Xing-Hai
Liu
To cite this article: Wei-Li Dong, Wen-Xi Cai, Rui Wu, Zheng-Ming Li, Wei-Guang Zhao &
Xing-Hai Liu (2016): A Convenient Method for Reduction Dehalogenation of α-Halocarbonyl
Compounds Using Benzenethiol in K+/CH3CN System, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2016.1138309
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1138309
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A Convenient Method for Reduction Dehalogenation of α-Halocarbonyl Compounds Using
Benzenethiol in K+/CH3CN System
3
Wei-Li Dong1,3, Wen-Xi Cai , Rui Wu1, Zheng-Ming Li1, Wei-Guang Zhao1*, Xing-Hai
Liu2*
1. Collaborative Innovation Center of Chemical Science and Engineering, State Key Laboratory
of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
2. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014,
China
3.Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and
Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070,
China
* email: xhliu@zjut.edu.cn or zwg@nankai.edu.cn
Abstract
Benzenethiol, as a reductive agent for the dehalogenation of various α-halocarbonyl compounds,
is investigated in the K+/CH3CN system. The reaction affords the reduced compounds in high
yields under mild reaction conditions, especially α-chlorocarbonyl compounds. Furthermore, the
reaction performed under ultrasonic irradiation greatly shortens the reaction time.
Keywords
Benzenethiol; α-halocarbonyl; dehalogenation; K+/CH3CN
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INTRODUCTION
Dehalogenation has important applications in environmental protection, biochemistry and
organic synthesis, especially in practical organic synthesis[1]. A number of reagents have been
developed for the reductive dehalogenation of α-halocarbonyl compounds, but most of these
reagents have disadvantages in some degree, such as the use of expensive or rare catalysts
(Al-Hg[2], NaI/Me3SiCl3[3], Bi/NH4HF2[4], VCl2[5], TiCl3[6], In[7], NaTeH[8],
Ru(bpy)3Cl2[9]), long reaction time (Na2S2O4[10], Pd[11], phosphines[12], PI3/P2I4[13],
iodotrimethylsilane[14]), high temperature (Zn/NH4Cl[15], Zn/AcOH[16], Al/(NH4)2C2O4[17],
polypropylene[18]), and poor yields (organotinhydrides[19]), especially for the reduction of
α-chlorocarbonyl compounds. It is well known that the ease of reductive hydrodehalogenation of
organic halides follows the general order Br > Cl.
In previous studies, we have introduced a convenient method for the aerobic oxidation of
thiols to disulfides using K+/CH3CN system[20]. As a part of our work on the synthesis of
bioactive lead compounds using ultrasonic or microwave methods[21], we have checked that
α-haloketones and dihalides could also be reduced by the same system (benzenethiol
/K+/CH3CN). The system could be used for the reduction of active halides and sulfides under
acid or alkaline conditions. The method has been published as patents [22] by us.
RESULTS AND DISCUSSION
We found that, in the K2CO3/CH3CN system, the yields of the reduced products 2 varied with
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the reaction time and the amount of thiols used (Table 1). As shown in Table 1, a mixture of the
reductive product 2a (27 %) and the displacement product 3a (56 %) was obtained when the
mole ratios of 5a and K2CO3 to 1a were 1.1 and 1.2, respectively. Compound 2a was obtained in
87 % yield under the same conditions when excess thiol 5a (2.25 equiv) was used, but the yield
of 2a decreased gradually with the extension of reaction time and afforded only 45 % yield after
6 h. In contrast, the yield of 3a increased and gave 80 % yield over 24 h. In the K2CO3/CH3CN
system, the reduction product 2a decreased gradually, and the substitution product sulfide 3a
increased, with prolonged reaction time. And 2a reacted with disulfide 4a under the same
conditions to give the sulfide 3a in high yields. The compound 1a was reduced completely when
the amount of thiol 5a was increased further to 3.0 equiv and 2a was obtained quantitatively.
Besides, the yield of 2a was not affected by the reaction temperature and the H2O content of the
solvent (VH2O/VCH3CN : 0~10 %).
To expand the reaction conditions, the dehalogenation of α-halocarbonyl compound (1a)
using a series of potassium halides was carried out. The results are shown in Table 2. As shown,
the order of the catalytic activity in the reduction was KI>K2CO3>KBr>>KCl~KF. But in the
KBr/CH3CN or KI/CH3CN system, reduction product 2a was obtained in good yield without the
formation of sulfide 3a. Especially with the KI/CH3CN system, the reduction proceeded to give
2a in a high yield after 20 min without the formation 3a using thiol 5a (1 equiv). When the thiol
is omitted, the reaction didn’t occur. The reaction solution became red-brown rapidly in the
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presence of KI, due to the I2 generated in the reaction. The reaction solution changed into blue
when starch was added. It is likely that the Cl2 produced reacted with KI to form I2 and KCl,
which promoted the reaction process. However, in the case of KF and KCl, the reaction
proceeded very slowly, and it just afforded a small amount of sulfide 3a, not the reduction
product, after 6 h. The reaction solution was strongly acidic as checked by pH test paper. We
considered that the acidic medium, derived from Cl2 produced by the reaction, hindered the
process of reduction. In fact, halide 1a was reduced quickly when one equivalent triethylamine
was added. And 2-bromoacetophenone 1j could be debrominated in the presence of KBr to
afford the corresponding ketones in high yields too (entry11, Table 3). The results showed that
bromoacetonitrile detected by GC/MS. Based on these results, the reaction mechanism as shown
in Scheme 1 was proposed.
We applied the K+/CH3CN system with p-tolylthiol (5a) for the reduction of various a-halo
substituted compounds to get dehalogenated products (Table 3). The results indicated that, 1)
dehalogenated products 2 were obtained in good to excellent yields in the K+/CH3CN system; 2)
The reduction of the chlorinated compounds were found to be slower in comparison with those
of the brominated compounds (Table 3, entries 8 and 9); 3) Ultrasonic-assisted organic reactions
have been applied to a wide range of reaction types, the use of ultrasonic irradiation instead of
traditional reducing condition could cut down the reaction time of α-halocarbonyl compound by
about 60~80% (Table 3, entries 1 and 9); 4) We tried to treat 2,2-dichloroacetophenone 1j by
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using KI and p-tolylthiol in acetonitrile under ultrasonic irradiation for 15h, then dehalogenated
acetophenone 2j was obtained in good yield.
It is well known that preparation of alkanes by the reduction of sulfides is a common
methodology in organic synthesis [23]. As shown in Scheme 2, in the K2CO3/CH3CN system,
sulfide 3a (1mmol) was reduced completely with thiol 5a (1.2mmol) to afford 2a and disulfide
4a in a good yield within 20 min. However, 3a appeared again and increased with the extension
of reaction time, and the mixture of 2a, 3a, and 4a was obtained in the end. In the KF, KCl or
KBr/CH3CN system, treatment of 3a with 5a also afforded 2a and 4a in a good yield, without the
formation 3a. For example, 2a was obtained in 99% yield in the presence of KBr. Especially the
catalytic activity of KF is similar with that of K2CO3 in the process, and the reaction catalyzed by
KF was completed within 30 min. But about 24 h was required in the KCl or KBr/CH3CN
system. In the presence of KI, no reaction product was formed under the same conditions, owing
to the acidity of KI.
CONCLUSION
In conclusion, we showed that the reductive dehalogenation of α-halocarbonyl compounds
with benzenethiol as a reductive agent in the K+/CH3CN system. The present procedure is
attractive of its simple reaction conditions, easy product isolation, low cost, high yields and
because the reaction can also proceed under acid or alkaline conditions.
EXPERIMENTAL
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Materials and Methods
Melting points were conducted on a Yanaco MP-500 micro meltingpoint apparatus. 1H NMR
spectra were recorded in CDCl3 as solvent on Bruker AC-300 and Bruker AC-400 instrument
using TMS as an internal standard. Elemental analysis was performed on a Yanaco CHN Corder
MF-3 automatic elemental analyzer. GC analyses of the compounds were performed on an
Agilent Technologies 6890 N Network GC System (with a TCZWAX capillary 30m column).
Synthesis
The a-halocarbony1 compound was prepared according to the literature[24]. To a solution
of 3-oxo-N,3-disubstitutedpropanamide(0.0722mol) in toluene (80 mL), was added sulfuryl
o
dichloride(0.0722mol) at 20 C, then the mixture was stirred for 4h. After the reaction is
completed, the solvent was moved and the solid was recrystallized in PE/EA(v/v =1:1).
A mixture of a-halocarbony1 compound (1.0 mmol), thiol (2.25 mmol), potassium salt (1.2
mmol) in acetonitrile (5 mL) was stirred at room temperature and in the open atmosphere in a
glass reactor. The completion of reaction was monitored by TLC. The reaction mixture was
filtered, and evaporation of the filtrate under reduced pressure followed by preparative thin layer
chromatography on silica gel afforded the pure products. Among them, compounds 2b and 2c are
new.
3-Oxo-N-phenylbutanamide 2a: 1H NMR (DMSO-d6, 400 MHz), δ: 10.08 (s, 1H), 7.57 (dd, J
= 8.6, 1.1 Hz, 2H), 7.36-7.24 (m, 2H), 7.10-6.97 (m, 1H), 3.54 (s, 2H), 2.20 (s, 3H).
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N-phenyl-2-(1,2,3-thiadiazol-4-yl)acetamide 2b: White solid，yield 98%，m.p. 126-128℃; 1H
NMR (CDCl3, 400 MHz), δ: 4.290 (s, 2H, CH2), 7.097-7.536 (m, 5H, Ph), 8.340 (br, 1H, NH),
8.594 (s, 1H, thiadiazole-H); Elem. Anal. for C10H9N3OS: calculated: C, 54.78; H, 4.14; N, 19.16.
found:C, 54.60; H, 4.15; N, 19.29.
1-morpholino-2-(1,2,3-thiadiazol-4-yl)ethan-1-one 2c: White solid ， yield 77%, m.p.
1
126-128℃; H NMR (CDCl3, 400 MHz), δ: 3.671-3.721 (m, 8H, morpholine-H), 4.296 (s, 2H,
CH2), 8.592 (s, 1H, thiadiazole-H); Elem. Anal. for C8H11N3OS calculated: C, 45.06; H, 5.20; N,
19.70. found:C, 45.17; H, 4.98; N, 19.93.
1-Piperidin-1-yl-butane-1,3-dione 2d: Yellow liquid, 1H NMR (CDCl3, 400 MHz), δ: 1.47-1.55
(m, 4H), 1.55-1.64 (m, 2H), 1.90 (s, 0.37H), 2.22 (s, 2.52H), 3.30 (t, J = 4.2 Hz, 2H), 3.36-3.58
(m, 4H), 5.11 (s, 0.12H), 14.7 (s, 0.10H).
N-methyl-3-oxobutanamide 2e: 1H NMR (DMSO-d6, 300 MHz) , δ: 7.5 (s, 1H, NH), 2.25 (s,
3H, CH3), 2.80 (s, 3H, CH3), 3.66 (s, 2H, CH2).
1
1-Morpholinobutane-1,3-dione 2f: pale yellow oil, H NMR (CDCl3, 400 MHz) , δ: 2.24 (s,
3H), 3.38 (t, J = 4.8 Hz, 2H), 3.53 (s, 2H) 3.58-3.60 (m, 2H) , 3.62-3.65 (m, 4H).
1
Acetophenone 2g: H NMR (CDCl3, 300 MHz), δ: 2.60 (s, 3 H), 7.44-7.48 (m, 2 H),7.54-7.58
(m, 1H), 7.95 (d, 2 H, J = 8.2 Hz).
1
Acetophenone 2h: H NMR (CDCl3, 300 MHz), δ: 2.60 (s, 3 H), 7.44-7.48 (m, 2 H),7.54-7.58
(m, 1H), 7.95 (d, 2 H, J = 8.2 Hz).
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1
Ethyl phenylacetate 2i: H NMR (CDCl3, 400 MHz) , δ: 7.40-7.25 (m, 5H), 4.17 (q, J = 8.0
Hz, 2H), 3.63 (s, 2H), 1.27 (t, J = 8.0 Hz, 3H).
Acetophenone 2j: 1H NMR (CDCl3, 300 MHz), δ: 2.62 (s, 3H), 7.45-7.50 (m, 2H), 7.55-7.59 (m,
1H), 8.03 (d, 2H, J = 8.2 Hz).
Characterization data for all the other known compounds is agreement with the literature [25].
Acknowledgment
This study was supported by the China 973 Program (grant No. 2003CB114406), the National
Natural Science Foundation of China (grant No. 20772069 and 21102103), China Postdoctoral
Science Foundation funded project (2014T70222).
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Table 1. Reactions of thiols with active methylene chlorides
SH
O
O
O
O
O
O
5a
N
H
+
+
S
N
N
acetonitrile, K2CO3
S
2
H
H
Cl
r.t.
1a
2a
3a
4a
K2CO3
Yiled(%)
1a
5a
No.
Time
mmol
2a
27
87
3a
56
-
-
40
80
1
2
3
4
5
1
1
1
1
1
1.1
2.25
3.0
2.25
2.25
1.2
1.2
1.2
1.2
1.2
40min
40min
1h
6h
24h
~100
45
-
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Table 2. Reduction of halides in the K+/CH3CN system at room temperature
2a
No.
K+
1a 5a
mmol
Time
Isolated yield (%)
KF
1
2
3
1.0 2.25
1.0 2.25
1.0 2.25
6h
6h
6h
trace
trace
91
(1.2)
KCl
(1.2)
KBr
(1.2)
4
5
1.0 2.25 KI (1.2) 20min
1.0 1.0 KI (1.2) 20min
K2CO3
82
81
6
1.0 2.25
40min
87
(1.2)
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Table 3. Dehalogenation of a-halocarbony1 compounds (halides) in the K+/CH3CN system.
5a
R H
2
R Cl
K+/CH3CN
1
Yiel
d
K+
1
5a
no.
Time
2
(%)a
mmol
1b(1.
0)
1c
(1.0)
1c
(1.0)
1d(1.
0)
1d(1.
0)
1e
(1.0)
1f(1.
0)
1g(1.
0)
4d
2
b
2
c
2
c
2
d
2
d
2
e
1
2.25 KI(0.6)
98
65
(20hc)
K2CO3
2.25
2
24h
24h
(1.2)
3
3.0
2.25
2.25
2.25
1.2
KI(1.2)
77
K2CO3
(1.2)
KBr
(1.2)
K2CO3
(2.4)
4
1.5hb
20h
100
100
100
70
5
6
45minb
16h
7
KI (1.2)
KI (1.2)
2f
2
g
2
h
8
1.2
10min
71
1h(1.
0)
9
1.2
KI (1.2) 7h (3hc)
83
1i(1.
0)
1j(1.
0)
10
11
1.2
KI (1.2)
KI (3.0)
2d
87
2i
2j
3.0
15hc
70
a Isolated yield b by quenching
cUltrasound
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Scheme 1. The proposed mechanism of the redox reaction in the K+/CH3CN system.
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O
O
SH
O
O
N
5a
acetonitrile, K+
S
+
N
H
2
S
H
2a
4a
3a
Scheme 2. Reduction of sulfides in the K+/CH3CN system.
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