A Novel Method for Preparation of 2-Chloro Enesulfonamides

Article abstract of DOI:10.1002/cjoc.201700114

A novel method for the synthesis of 2-chloro enesulfonamides via the one-pot addition-elimination of N-chloro-N-fluorobenzenesulfonamides (CFBSA) to styrenes in the presence of Et₃N is described. A total of 20 examples are presented to illustrate this concept including various of styrenes.

Full text of DOI:10.1002/cjoc.201700114

FULL PAPER
DOI: 10.1002/cjoc.201700114
A Novel Method for Preparation of 2-Chloro Enesulfonamides
Haiyong Zhao,†,a Xiaoqiu Pu,†,a and Xianjin Yang*,a,b
a Key Laboratory for Advanced Materials & Institute of Fine Chemicals, School of Chemistry & Molecular
Engineering, East China University of Science and Technology, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
A novel method for the synthesis of 2-chloro enesulfonamides via the one-pot addition-elimination of
N-chloro-N-fluorobenzenesulfonamides (CFBSA) to styrenes in the presence of Et3N is described. A total of 20
examples are presented to illustrate this concept including various of styrenes.
Keywords 2-chloro enesulfonamides, styrenes, CFBSA, addition-elimination, one-pot
Introduction
2-chloro enesulfonamides via the addition of CFBSA to
styrenes and Et3N-promoted elimination of HF (Scheme
1). As far as we know, it is the first protocol to generate
2-chloro enesulfonamides from styrenes without metal
catalyst.
Enesulfonamides are valuable synthetic intermedi-
ates in asymmetric addition reactions and those com-
pounds play a great role in metal-catalyzed reactions.[1]
Generally, enesulfonamides are synthesized from the
corresponding ketones via the N-sulfonylimine interme-
diates.[1a] In the past several years, aminohalogenation
has been reported to construct enesulfonamides from
alkynes and alkenes.[2-8] Li and co-workers demonstrat-
ed a one-pot reaction to synthesize enesulfonamides.[9]
The synthesis of 2-chloro enesulfonamides has received
wide attention due to important values of C－Cl bond in
transformation reactions.[10] Recently, Liu’s group re-
ported a copper-catalyzed aminochlorination of al-
kynes.[7a] However, most of these previous methods
need metal catalysts to complete aminohalogenation
reactions.[11-14] Hence, a novel strategy for the synthesis
of 2-chloro enesulfonamides is still a sustained topic in
synthetic chemistry.
Scheme 1 The strategies for constructing 2-chloro enesulfona-
mides
Previous work
O
(1) CuOTf (10 mol %)
O
CH3CN, r.t
Ar
R
+4-TsNCl2
R
(a)
Ar
(2) Base
NHTs
R = Alkyl, Aryl or Alkoxy
H
N
Cl
R2
Ts
Cu Catalyst
R1
+
(b)
N
R2
R1
Cl
Ts
Our previous work
SO2Ph
F
N
The reactivity of the N－F bond has been studied for
many years in our group and many research results have
been achieved.[15,16] Very recently, we developed a novel
catalyst-free aminochlorination of alkenes by the direct
addition of N-chloro-N-fluorobenzenesulfonamides
(CFBSA) to alkenes. The reaction produced N-(2-chlo-
ro-2-phenylethyl)-N-fluorobenzenesulfonamide and N-
(2-chloro-1-phenylethyl)-N-fluorobezenesulfonamide (3
and 4 in Scheme 1) in 1,2-dichloroethane under reflux
and dichloromethane at room temperature, respective-
ly.[17] Due to the strong electronegativity of fluorine in
adducts, we explored the reactivity of the N－F bond in
these compounds.
Cl
CFBSA
R
R
DCM, r.t.
4
1
CFBSA
DCE, 85 oC
F
Cl
N
SO2Ph
R
3
This work
R
Cl
H
N
(1) CFBSA (1.2 equiv.)
DCE, 85 oC
SO2Ph
R
(2) Et3N (1.2 equiv.)
DCE, r.t.
5
Herein, we reported a one-pot method to construct
*
E-mail: yxj@ecust.edu.cn; † These authors contributed equally to this work.
Received February 11, 2017; accepted March 29, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700114 or from the author.
Chin. J. Chem. 2017, XX, 1—5
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Zhao, Pu & Yang
Table 1 Optimization of the reaction conditions
FULL PAPER
Experimental
All raw materials were commercially available and
used without further purification. Chlorinating reagent
CFBSA were purchased from Shanghai Science
Bio-pharmaceutical Co. Ltd. Substrates were purchased
from Energy Chemical Co. Ltd. and Damas-beta Co.
Ltd. Flash column chromatography was performed us-
ing silica gel (300－400 mesh). Digital melting point
apparatus (WRS-1B) was used produced by Inesa Ana-
Entry Solvent
Base/equiv.
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (0.8)
Et3N (1.0)
Et3N (1.5)
Et3N (3.0)
KOH (1.2)
NaHCO3 (1.2)
K2CO3 (1.2)
Benzylmine (1.2)
Et2NH (1.2)
Timea/h Yieldsb/%
1
2
EA
DCMc
Hexane
Dioxane
Toluene
DCE
THF
3/0.5
3/0.5
3/0.5
3/0.5
3/0.5
3/0.5
3/0.5
3/0.5
3/1
trace
40
1
lytical Instrument Co. Ltd. All H NMR spectra were
recorded on a Bruker spectrometer at 400 MHz. The 19F
NMR spectra were recorded on a Bruker spectrometer at
376 MHz. The 13C NMR spectra were recorded on a
Bruker spectrometer at 100 MHz. Chemical shifts (δ
value) were reported down field from internal tetrame-
thylsilane (TMS). J values are reported in Hz. IR spec-
trum (Film) is recorded on a Nicolet 6700 spectropho-
tometer in the range of 400－4000 cm1. HRMS (EI)
Spectra were recorded on a Waters GCT Premier
ms-spectrometer with electron impact (70 eV).
3
28
4
45
5
52
6
65
7
40
8
MeCN
DCE
53
9
30
10
11
12
13
14
15
16
17
DCE
3/1
53
A mixture of styrenes (1.0 mmol) and CFBSA (1.2
equiv.) was stirred in 1,2-dichloroethane at 85 ℃ for 3
h or dichloromethane at room temperature for 12 h.
When styrenes were completely consumed, Et3N (1.2
equiv.) was dropped into the system at room tempera-
ture and stirred for 1 h. After the reaction was complet-
ed, evaporated by vacuo, the residues were purified on
silica [V(ethyl acetate)/V(petroleum ether)＝1/20] to
give 5a－5r and 6a－6b.
DCE
3/0.5
3/0.5
3/1
29
DCE
25
DCE
n.dd
n.dd
n.dd
43
DCE
3/1
DCE
3/1
DCE
3/1
DCE
3/1
50
Reaction conditions: For the first step, a mixture of 1 (1.0 mmol),
2 (1.2 equiv.), solvent (5 mL), stirred at 85 ℃; For the second
step, Et3N was added to the system, stirred at ambient tempera-
ture. a The reaction time of each step. b Isolated yield after column
chromatography. c The reaction proceeded in a pressure glass tube.
d No desired product was detected as determined by 1H NMR
analysis.
Results and Discussion
The addition reaction of CFBSA to styrene was car-
ried out refering to our previous report.[17] After the ad-
dition went completion, Et3N was directly dropped into
the mixed system and stirred at room temperature for 1
h, obtaining product 5a in 65% yield (entry 6 in Table 1).
The investigation of various solvents demonstrated that
1,2-dichloroethane (DCE) was the preferential solvent
(entries 1－8 in Table 1). As shown in Table 1, inorgan-
ic bases such as KOH, NaHCO3, K2CO3 gave no desired
products (entries 13－15). Among the organic bases
screened, Et3N was found to be the most efficient. (en-
tries 6, 16 and 17). By contrasting experiments, we
found that 1.2 equiv. of Et3N was an excellent choice
(entries 9－12).
Therefore, the optimal reaction conditions were de-
termined as follows: styrene (1.0 equiv.), CFBSA (1.2
equiv.), DCE, at 85 ℃ then Et3N (1.2 equiv.) at room
temperature.
With the optimized conditions in hand, various sub-
stituted-styrenes were surveyed. The results were illus-
trated in Table 2. It was found that both the position and
electronic nature of the substituents on the aromatic ring
have a negligible effect on the reaction efficiency of this
process.
sponding compounds 5b, 5c and 5f in 55%, 40% and
50% yields, respectively. When p-nitrostyrene was se-
lected as the substrate, which exhibits strong electron-
withdrawing effect to the double-bond in optimal condi-
tions, 5g was obtained in 15% yield.
For styrenes with electron-donating groups (such as
p-Me and p-t-Bu), products 5d and 5e were furnished in
56% and 57% yields, respectively. Meanwhile, sub-
strates with o-chloro, o-bromo, m-chloro, m-fluoro and
m-bromo groups were also examined, affording prod-
ucts 5h, 5i, 5j, 5k and 5l in 67%, 35%, 45%, 38% and
63% yields, respectively. For substrates with steric hin-
drance (such as chloromethyl and bromomethyl group),
compounds 5m and 5n were obtained in 66% and 58%
yields. 1-Methoxy-4-vinylbenzene and (E)-1-methoxy-
4-(prop-1-en-1-yl) benzene, interestingly, worked
smoothly in DCM at room temperature, delivering the
other type of compounds 6a and 6b in 48% and 78%
yields. Notably substrates such as (E)-stilbene and
(E,E)-(C6H5CH＝CH)2 were also tolerated in the
Substrates with electron-withdrawing groups (such
as p-fluoro, p-bromo and p-chloro) gave the corre-
2
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A Novel Method for Preparation of 2-Chloro Enesulfonamides
Table 2 The reaction scope of styrenes with CFBSA
Cl
NHSO2Ph
Cl
R2
NHSO2Ph
Conditions
R1
R1
+ CFBSA
or R1
R2
R2
5
6
Cl
H
Cl
Cl
H
Cl
H
H
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
F
Br
5da 56%
5ca 40%
5aa 65%c
5ba 55%
Cl
Cl
Cl
Cl
Cl
H
H
N
H
N
H
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
Cl
O2N
5ha 67%
5ga 15%
5ea 57%
5fa 50%
Cl
Cl
Cl
Br Cl
H
H
H
N
H
N
Cl
N
F
N
Br
SO2Ph
SO2Ph
SO2Ph
SO2Ph
5ia 35%
5la 63%
5ka 38%
5ja 45%
Cl
Cl
Cl
Cl
H
H
N
N
SO2Ph
SO2Ph
HN
HN
SO2Ph
Br
SO2Ph
Cl
5ma 66%
5pa 65%
5na 58%
5oa 81%
Cl
HN SO2Ph
SO2Ph
Cl
SO2Ph
HN
O
HN
H
Cl
Cl
H
SO2Ph
N
N
H
Cl
5ra 10%
O
O
O
6ab 48%
6bb 78%
5qa 25%
5sa 38%
a Condition: for the first step, a mixture of substrate (1.0 mmol), CFBSA (1.2 equiv.), in DCE (5 mL), stirred at 85 ℃; for the second step,
b
Et3N (1.2 equiv.) was added to the system, stirred at ambient temperature (less than 35 ℃). Condition: for the first step, a mixture of
substrate (1.0 mmol), CFBSA (1.2 equiv.), in DCM (5 mL), stirred at ambient temperature; for the second step, Et3N (1.2 equiv.) was
added to the system, stirred at ambient temperature. c Isolated yields by column chromatography for all compounds.
reaction, thus resulting in the desired products (5o and
5p) in 81% and 65% yields under the standard reaction
conditions. It is worthy to note that 2-chloro-1-(4-
methoxy-pheny-l) ethanone 5s was got as a byproduct in
38% yield in the process of the formation of 6a. We
speculated that the formation of 5s was a result of the
hydrolysis of imine 8 (shown in Table 2). Meanwhile,
when we tried to use aliphatic olefins (such as allylben-
zene and vinylcyclohexane), identical product benzsul-
famides were got in 50% and 64% yields owing to the
strong hydrolysis of unstable imide intermediates.
acenaphthylene and 2-vinylpyridine.
In order to explore the possible mechanism, contrast
experiment was carried out as described in Scheme 2.
When compound 9 was treated with the standard condi-
tions, we received 10 instead of the corresponding
elimination product. This experiment result illustrated
the particularity of N－F bond compared with N－Cl
bond.
Scheme 2 Contrast experiment
Additionally, acenaphthylene and 2-vinylpyridine
were transformed into 5q and 5r in 25% and 10% yields,
respectively. We envisioned that it is the poor reactivity
of 2-vinylpyridine and the steric effect of acenaph-
thylene that reduced the efficiency of the addition pro-
cess. In fact, corresponding adducts were obtained in
only 50%－55% yields in the addition reaction of
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Zhao, Pu & Yang
FULL PAPER
Scheme 3 The plausible mechanism
Although the detailed mechanism remains unclear, a
plausible mechanism is proposed on the basis of the
above results and is shown in Scheme 3. Adducts 3 and
4 were generated under condition A and condition B,
respectively (shown in Scheme 3). Then HF was re-
moved in the presence of Et3N and the hydrogen bond-
ing interaction of fluorine atoms with water molecules,
providing intermediates 7 and 8 smoothly. Finally, the
corresponding products were received by the tautomer-
ization of 7 and 8. According to the previous research[18]
and the fact that 5s was detected, we suspect that the
hydrolysis of imines may be promoted by HF or Et3N.
This could be utilized to explain the moderate yields.
Foundation of China (No. 21372077) for financial sup-
port. This work was supported by “the Fundamental
Research Funds for the Central Universities (No.
222201717003).
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Chin. J. Chem. 2017, XX, 1—5

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