Synthesis of 3-Formylbenzenesulfonyl Chloride Derivatives

Article abstract of DOI:10.1055/s-0036-1589015

A synthetic route to 3-formylbenzenesulfonyl chloride derivatives from the corresponding benzaldehydes has been developed. The key step in this procedure is the conversion of aldehyde bisulfite adducts to target compounds via a two-stage reaction in the presence of Na ₂ SO ₄. A series of 3-formylbenzenesulfonyl chloride derivatives were prepared by this method and identified by chemical derivatization method.

Full text of DOI:10.1055/s-0036-1589015

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
X. Bao et al.
Paper
Synthesis
Synthesis of 3-Formylbenzenesulfonyl Chloride Derivatives
Xuefei Bao
CHO
CHO
HOSO2Cl
Ziao Liu
R
R
Xinjie Liang
SO2Cl
Dake Song
Na2SO4
HOSO2Cl
SO3Na
OH
Na2S2O5
Tao Shi
8 derivatives
31–81% yield
Xuan Zhao
R
Changshun Bao
Guoliang Chen*
Key Laboratory of Structure-Based Drug Design & Discovery,
Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, P. R. of China
chenguoliang@syphu.edu.cn
Received: 22.01.2017
Accepted after revision: 01.04.2017
Published online: 05.05.2017
methoxybenzenesulfonyl chloride.4 In this method, benzal-
dehyde was used as the starting material, which was first
reacted with triethyl orthoformate to produce the acetal,
followed by chlorosulfonylation process to provide the tar-
get sulfonyl chloride in a 72% total yield. Zhao et al. report-
ed that salicylaldehyde protected by aniline could afford 3-
formyl-4-hydroxybenzenesulfonyl chloride via chlorosul-
fonation and in situ deprotection during workup.9 In these
two methods, acetal and Schiff base are the synthetic strat-
egies used to mask the reactive aldehyde group. Liu et al.
developed another method for the directly preparation of
4-ethoxy-3-formylbenzenesulfonyl chloride by the reaction
of chlorosulfonic acid with 2-ethoxybenzaldehyde.10 The
problem associated with these methods is the impaired
substrates containing hydroxyl or alkoxy group (Scheme 1).
Besides, commercially available 3-formylbenzenesulfo-
nyl chloride derivatives are rare and most of them are ex-
pensive. And in our previous work,11 we observed that the
reaction of benzaldehyde and chlorosulfonic acid was inef-
ficient for the preparation of 3-formylbenzenesulfonyl
chloride. As shown in Scheme 1, only a small amount of tar-
get compound was obtained because of the generation of
benzal chlorides as reported in literature.12 Several at-
tempts were made to prepare 3-formylbenzenesulfonyl
chloride including acetal and Schiff base, but to no avail.
Therefore, the development of general protocols for the
preparation of 3-formylbenzenesulfonyl chloride deriva-
tives appears to be desirable. In this paper, encouraged by
Lu et al.’s report that potassium sulfate could be conducive
to the preparation of benzenesulfonyl chloride,13 we opti-
mized a reaction of aldehyde bisulfite adducts and chloro-
sulfonic acid to prepare 3-formylbenzenesulfonyl chlorides
and further evaluated the general applicability of this
method.
DOI: 10.1055/s-0036-1589015; Art ID: ss-2017-h1629-op
Abstract A synthetic route to 3-formylbenzenesulfonyl chloride deriv-
atives from the corresponding benzaldehydes has been developed. The
key step in this procedure is the conversion of aldehyde bisulfite ad-
ducts to target compounds via a two-stage reaction in the presence of
Na2SO4. A series of 3-formylbenzenesulfonyl chloride derivatives were
prepared by this method and identified by chemical derivatization
method.
Key words 3-formylbenzenesulfonyl chloride, aldehyde sodium bisul-
fite, chlorosulfonation, two-stage reaction, chemical derivatization
method
3-Formylbenzenesulfonyl chloride derivatives are valu-
able synthetic building blocks for chemical and pharmaceu-
tical industries. They participate in the preparation of many
bioactive compounds, such as anticancer,1 antimalarial,2
antidiabetic,3 antihypertensive,4 anti-inflammatory,5 neu-
rological diseases drugs,6 etc. 3-Formylbenzenesulfonyl
chloride and 4-ethoxy-3-formylbenzenesulfonyl chloride
are key intermediates for the preparation of Belinostat (an-
ticancer drug)7 and Sidenafil (erectile dysfunction drug),8
respectively (Figure 1).
However, only a few synthetic routes to 3-formylben-
zenesulfonyl chloride derivatives are reported. Yamaguchi
et al. disclosed a method for the synthesis of 3-formyl-4-
O
N
N
HN
O
N
N
H
O
O
S
N
N
S
OH
O
N
O
H
O
Belinostat
Sildenafil
Figure 1 Structures of Belinostat and Sildenafil
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
X. Bao et al.
Paper
Synthesis
reaction. Sodium bisulfate, potassium chloride, and sodium
chloride gave results comparable to that obtained with no
additive.
Yamaguchi's work
O
OHC
HC(OEt)3
HOSO2Cl
OHC
MeO
SO2Cl
O
MeO
MeO
Table 1 Optimization of the Reaction Conditions
Zhao's work
NH2
SO3Na
1) HOSO2Cl (1.3 equiv), additive, temp, time
2) HOSO2Cl (4.5 equiv), 30 °C
OHC
SO2Cl
Cl
OHC
HOSO2Cl
OHC
HO
SO2Cl
HO
N
HO
CHCl3
Cl
HO
Entry
Additive (equiv)
Temp ( °C)
Time (h)
Yield (%)a
Liu's work
OHC
OHC
EtO
SO2Cl
1
2
K2SO4 (0.7)
K2SO4 (0.7)
K2SO4 (0.7)
K2SO4 (0.7)
K2SO4 (1)
30
40
50
60
50
50
50
60
50
50
50
50
50
50
50
50
50
50
14
9.5
6
23
28
44
41
49
52
53
47
53
50
50
46
–
HOSO2Cl
OHC
EtO
3
CHCl2
Our previous work
OHC
4
6
SO2Cl Cl2HC
+
SO2Cl
+
HOSO2Cl
5
6
6
K2SO4 (1.3)
K2SO4 (1.5)
K2SO4 (1.5)
Na2SO4 (1.3)
Na2SO4 (1.5)
KH2PO4 (1.3)
KF (1.3)
6
17%
25%
SO2Cl
28%
7
6
8
6
This work
Na2SO4
HOSO2Cl
SO3Na
9
6
OHC
Na2S2O5
OHC
SO2Cl
10
11
12
13b
14b
15
16
17
18
6
HO
6
Scheme 1 Synthetic route of 3-formylbenzenesulfonyl chloride deriva-
tives
6
Na2SO3 (1.3)
Na2CO3 (1.3)
NaHSO4 (1.3)
KCl (1.3)
14
14
6
–
10
9
Aldehyde bisulfite adduct was obtained according to the
literature procedure.14 Then additive, ground in advance,
and the bisulfite adduct were suspended in chloroform and
stirred well. Chlorosulfonic acid (1.3 equiv) was slowly
dropped into the suspension and the mixture was reacted
under appropriate temperature. After no starting material
was detected by TLC, an additional amount of chlorosulfon-
ic acid (4.5 equiv) was slowly added and the mixture was
stirred at 30 °C for 4.5 hours. When the reaction was
deemed complete, the product was isolated by column
chromatography.
As shown in Table 1, we investigated the temperature of
first stage: by raising the temperature, a remarkable in-
crease in yield was observed, but when it rose to 60 °C, no
improvement was observed at higher temperatures (Table
1, entries 1–4). And the reaction with incremental amount
of potassium sulfate afforded a higher yield, and it reached
a maximum (49–53%) when treated with more than 1
equivalent of potassium sulfate (entries 3–7). Meanwhile,
several experiments were performed to investigate the in-
fluence of the type of additives (entries 9–18). Sodium sul-
fate, monopotassium phosphate, and potassium fluoride
gave results similar to those obtained with potassium sul-
fate (46–53%). Almost no target compound was obtained
with sodium sulfite and sodium carbonate, which might be
due to the water generated from these salts retarding the
6
NaCl (1.3)
–
6
8
6
8
a Isolated yield after flash column chromatography.
b Almost no target compound was observed by TLC.
Although a satisfactory result was obtained via the reac-
tion of aldehyde bisulfite adduct and chlorosulfonic acid in
the presence of sodium sulfate, the starting material sodi-
um α-hydroxybenzenemethanesulfonic acid was not com-
mercially available. And in order to better understand the
effect of sodium sulfate, we employed aromatic aldehydes
as starting materials (Scheme 2). Unfortunately, 4-chloro-
benzaldehyde could not be converted into the correspond-
ing 3-formylbenzenesulfonyl chloride at 30 °C, while a
complex mixture of product was formed in the first stage at
50 °C. And the reaction of benzaldehyde also gave an unsat-
isfactory yield, which was equivalent to our previous work.
The poor results indicated that sodium sulfate did not re-
tard the chlorination of the aldehyde.
Based on the above results, a plausible effect of Na2SO4
on the present reaction is outlined in Scheme 3. The buffer-
ing effect of the Na2SO4 prevented deprotection of the alde-
hyde during the sulfonylation stage at a slightly high tem-
perature, and the bisulfate adduct prevented chlorination of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
X. Bao et al.
Paper
Synthesis
1, HOSO2Cl (1.3 equiv), Na2SO4, 50 °C
2, HOSO2Cl (4.5 equiv), 30 °C
CHO
Table 2 Scope of the Present Method for the Formation of 3-Formyl-
benzenesulfonyl Chlorides
CHO
12%
15%
Cl
Cl
CHCl3
R3
SO2Cl
CHO
R3
SO2ONa
OH
1) HOSO2Cl (1.3 equiv), additive, temp
2) HOSO2Cl (4.5 equiv), 30 °C
R2
R1
CHO
R2
R1
1, HOSO2Cl (1.3 equiv), Na2SO4, 50 °C
2, HOSO2Cl (4.5 equiv), 30 °C
CHO
CHCl3
CHCl3
SO2Cl
1
SO2Cl
2
Scheme 2 Aromatic aldehydes employed as starting materials
Product Temp
(°C)
R1
R2
R3
Yield
(%)a
the aldehyde. In detail, bisulfite adduct 1 did not convert to
aldehyde smoothly in the first stage of the reaction, which
might be due to Na2SO4 influencing the acidity of the reac-
tion mixture. After the formation of sulfonic acid 3, it gets
converted into sulfonyl chloride 2 and bisulfite adduct was
converted into aldehyde along with the addition of more
chlorosulfonic acid. And the chlorination reaction rate of
sulfonic acid might be faster than that of aldehyde group.
Thus, 3-formylbenzenesulfonyl chloride 2 was the main
product together with small amounts of benzal chloride.
2a
2b
2c
2d
2e
2f
50
60
30
30
20
20
20
Cl
H
H
53
31
69
74
80
77
81
Cl
H
Cl
H
H
H
H
H
H
H
Me
MeO
MeO
H
H
ClCH2CH2O
2g
OCH2O
SO2ONa
CHO
2h
20
72
S
ClO2S
S
OH
b
2i
60
60
60
H
CHO
NO2
NO2
H
H
H
–
sulfonylation stage
b
2j
H
–
SO2ONa
SO2ONa
OH
b
2k
Me
–
OH
HOSO2Cl
R
a Isolated yield after flash column chromatography.
b No target compound was obtained.
R
Na2SO4
SO2OH
1
3
ses were recorded in an Agilent 1100 Series MSD Trap SL,
the quasi-molecular ion of arylsulfonyl chlorides was not
observed, but quasi-molecular ion of sulfonic acids was
very clear. Then the products were determined to be not
sulfonic acids based on their TLC properties as well as by
comparison with the authentic sulfonic acids. We postulat-
ed that arylsulfonyl chlorides hydrolyzed to the corre-
sponding sulfonic acids when subjected to ESI-MS analyses
(Figure 2).
chlorination stage
Cl
CHO
HOSO2Cl
slow
additional HOSO2Cl
fast
Cl
R
R
SO2Cl
SO2Cl
2
by-product
Scheme 3 Proposed mechanism for the formation of sulfonyl chlorides
1
As shown in Figure 2, the IR spectrum (b) and H NMR
spectrum (c) further confirmed that the product obtained
from this method was not 2-chloro-5-formylbenzenesul-
fonic acid. The sulfonic acid was obtained according to a
modified literature procedure.15 These products were not
stable enough to undergo certain instrumental analysis,
such as mass spectrometry, so we employed chemical deri-
vatization method to confirm the structure. When 2a was
reacted with aqueous ammonia,16 2-chloro-5-formylben-
zenesulfonamide (3a) was obtained as a white solid in high
yield (Scheme 4). This conversion verified indirectly that 2a
was 2-chloro-5-formylbenzenesulfonyl chloride.
The general applicability of this method was further
evaluated for structurally diverse bisulfite adducts (Table
2). The aromatic nucleus with electron-donating substitu-
ents were smoothly converted into the corresponding ben-
zenesulfonyl chlorides in good yields, while the aromatic
nucleus with electron-withdrawing groups had the oppo-
site effect. Isophthalaldehyde, 3-nitrobenzaldehyde, and 4-
methyl-3-nitrobenzaldehyde were also used as substrates,
but no target compound was obtained. As for these sub-
strates, 1.3 equivalents of chlorosulfonic acid could not pro-
duce the intermediate sulfonic acid in the first stage, and
2.5 equivalents chlorosulfonic acid made the reaction mix-
ture more complex.
CHO
CHO
acetone
+
NH4OH
Cl
Cl
The structures of these target compounds were con-
firmed by NMR, IR spectra, and electrospray ionization
mass spectrometry (ESI-MS) analyses. When ESI-MS analy-
SO2NH2
SO2Cl
Scheme 4 Reaction of 2a and aqueous ammonia
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
X. Bao et al.
Paper
Synthesis
Solvents were purchased from commercial suppliers and used with-
out further purification. Melting points were determined with an X-4
apparatus and were uncorrected. NMR spectra were recorded on a
Bruker Ascend 400 or Bruker Avance III 600 using TMS as an internal
standard. Electrospray ionization mass spectrometry (ESI-MS) analy-
ses was recorded in an Agilent 1100 Series MSD Trap SL. The high-
resolution electrospray ionization mass spectrometry (HR-ESI-MS)
analyses were run using a Bruker SolariX 7.0T instrument. All experi-
ments were conducted under an argon atmosphere. Column chroma-
tography and TLC (HG/T2354-92, GF254), which were used to moni-
tor the reactions, were performed on silica gel.
Sodium α-Hydroxybenzenemethanesulfonic Acids 1; General Pro-
cedure
Na2S2O5 (6.3 g, 33 mmol) was dissolved in H2O (15 mL), and a small
amount of insoluble substance was filtered off. Then, the filtrate was
added to a solution of the respective aromatic aldehyde (47 mmol) in
EtOH (30 mL) over 30 min under r.t. and the reaction mixture was
stirred at 45–50 °C under an atmosphere of argon for 13 h. When the
reaction was deemed complete with no aromatic aldehyde detected
by TLC, the heterogeneous reaction mixture was cooled to r.t., stirred
for 4 h, and the product was isolated by vacuum filtration. The prod-
uct cake was washed with EtOH to give the product bisulfite adduct.
3-Formylbenzenesulfonyl Chlorides 2; General Procedure
A suspension of the above corresponding bisulfite adduct (2.0 mmol,
1 equiv) and anhyd Na2SO4 powder (2.6 mmol, 1.3 equiv) in CHCl3
were stirred at 0–5 °C, and HOSO2Cl (2.6 mmol, 1.3 equiv) was added
dropwise to the suspension, and the mixture was allowed to react un-
der appropriate temperature (Table 2). After no starting material was
detected by TLC, the mixture was cooled to 0–5 °C and HOSO2Cl (9.0
mmol, 4.5 equiv) was slowly added dropwise whilst maintaining the
temperature below 30 °C. When the addition was complete, the reac-
tion mixture was stirred at 30 °C. After the completion of the reac-
tion, the mixture was slowly poured into crushed ice. The aqueous
phase was removed, and the organic phase was washed with brine
and dried (anhyd Na2SO4). The Na2SO4 was filtered off and the filtrate
was concentrated under vacuum to afford crude 2, which was puri-
fied by flash column chromatography to afford the desired 3-formyl-
benzenesulfonyl chloride.
2-Chloro-5-formylbenzenesulfonyl Chloride (2a)
Yield: 0.26 g (53%); white solid; mp 51–52 °C; Rf = 0.32 (PE–EtOAc,
5:1).
IR (KBr): 3039, 2928, 2853, 1701, 1592, 1466, 1379, 1175, 1041, 827
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 10.05 (s, 1 H), 8.20 (d, J = 2.0 Hz, 1 H),
7.88 (dd, J = 8.2, 2.0 Hz, 1 H), 7.64 (d, J = 8.2 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 190.6, 141.3, 138.8, 136.1, 135.3,
Figure 2 2-Chloro-5-formylbenzenesulfonyl chloride (2a) hydrolyzed
to 2-chloro-5-formylbenzenesulfonic acid (4a). (a) TLC properties of 2a
and 4a; (b) IR spectrum of 2a and 4a; (c) 1H NMR spectra of 2a and 4a.
131.5, 130.4.
MS (ESI): m/z = 218.7, 220.7 [M – Cl + OH – H]–.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C7H4ClO4S: 218.9523;
found: 218.9524.
In conclusion, we have prepared a class of 3-formylben-
zenesulfonyl chlorides via the two-stage reaction of bisul-
fite adduct and chlorosulfonic acid. This process provides
an alternative protocol to synthesize 3-formylbenzenesul-
fonyl chlorides from benzaldehydes with electron-donating
or weak electron-withdrawing groups. The method has a
relatively wide substrate scope and the presence of Na2SO4
is an important factor in improving the product yield.
2,4-Dichloro-5-formylbenzenesulfonyl Chloride (2b)
Yield: 0.15 g (31%); off-white solid; mp 58–61 °C; Rf = 0.40 (PE–EtOAc,
5:1).
IR (KBr): 3089, 2961, 2875, 1694, 1573, 1442, 1386, 1188, 1081, 928
cm–1
.
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X. Bao et al.
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Synthesis
1H NMR (CDCl3, 400 MHz): δ = 10.43 (s, 1 H), 8.66 (s, 1 H), 7.81 (s, 1
13C NMR (CDCl3, 100 MHz): δ = 190.7, 155.0, 148.2, 130.0, 127.5,
H).
124.9, 111.1, 60.0, 56.3, 41.5.
13C NMR (CDCl3, 100 MHz): δ = 186.0, 144.0, 140.8, 138.6, 134.7,
MS (ESI): m/z = 292.7, 294.7 [M – Cl + OH – H]–.
131.3, 131.2.
MS (ESI): m/z = 252.7, 254.7 [M – Cl + OH – H]–.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C10H10ClO6S: 292.9891;
found: 292.9892.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C7H3Cl2O4S: 252.9132;
found: 252.9134.
6-Formylbenzo[d][1,3]dioxole-4-sulfonyl Chloride (2g)
Yield: 0.40 g (81%); white solid; mp 88–89 °C; Rf = 0.36 (PE–EtOAc,
2:1).
3-Formylbenzenesulfonyl Chloride (2c)
Yield: 0.33 g (69%); light yellow oil; Rf = 0.25 (PE–EtOAc, 5:1).
IR (KBr): 3091, 2929, 2839, 1689, 1595, 1473, 1377, 1257, 1160, 1041,
888 cm–1
.
IR (KBr): 3077, 2846, 2740, 1700, 1596, 1434, 1383, 1204, 1162, 1074,
897 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 9.88 (s, 1 H), 7.89 (d, J = 1.5 Hz, 1 H),
7.61 (d, J = 1.5 Hz, 1 H), 6.41 (s, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 188.1, 151.2, 150.3, 131.6, 125.6,
1H NMR (CDCl3, 400 MHz): δ = 10.13 (s, 1 H), 8.53 (s, 1 H), 8.31–8.26
(m, 2 H), 7.85 (t, J = 8.0 Hz, 1 H).
125.5, 111.5, 105.2.
MS (ESI): m/z = 228.8 [M – Cl + OH – H]–.
13C NMR (CDCl3, 100 MHz): δ = 189.4, 145.4, 137.3, 135.3, 131.9,
130.8, 128.0.
MS (ESI): m/z = 184.7 [M – Cl + OH – H]–.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C8H5O6S: 228.9811;
found: 228.9812.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C7H5O4S: 184.9915;
found: 184.9914.
5-Formylthiophene-2-sulfonyl Chloride (2h)
Yield: 0.35 g (72%); yellow oil; Rf = 0.45 (PE–EtOAc, 5:1).
IR (KBr): 3101, 2855, 2747, 1685, 1519, 1425, 1384, 1169, 1073, 1019,
5-Formyl-2-methylbenzenesulfonyl Chloride (2d)
Yield: 0.36 g (74%); off-white solid; mp 65–67 °C; Rf = 0.36 (PE–EtOAc,
5:1).
818 cm–1
.
IR (KBr): 3066, 2980, 2842, 1704, 1606, 1447, 1368, 1171, 1034, 913
1H NMR (CDCl3, 400 MHz): δ = 10.05 (s, 1 H), 7.94 (d, J = 4.1 Hz, 1 H),
7.79 (d, J = 4.1 Hz, 1 H).
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 10.06 (s, 1 H), 8.56 (d, J = 1.7 Hz, 1 H),
8.14 (dd, J = 7.9, 1.7 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 2.90 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 191.3, 144.6, 142.9, 135.2, 134.6,
130.4, 127.8, 20.0.
MS (ESI): m/z = 198.5 [M – Cl + OH – H]–.
13C NMR (CDCl3, 100 MHz): δ = 182.6, 150.6, 150.0, 134.2, 133.7.
MS (ESI): m/z = 190.7 [M – Cl + OH – H]–.
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C5H3O4S2: 190.9478;
found: 190.9478.
2-Chloro-5-formylbenzenesulfonamide (3a)17
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C8H7O4S: 199.0071;
found: 199.0071.
A solution of 2-chloro-5-formylbenzenesulfonyl chloride (2a; 0.1 g,
0.4 mmol) in acetone (1 mL) was added dropwise to aq ammonia (5
mL, 25%) below 5 °C, then the mixture was stirred at 0–5 °C for 2.5 h.
When TLC analysis indicated the disappearance of 2a, the solid ob-
tained was collected by filtration, washed with H2O (5 mL). The filter
cake was dried in a vacuum oven at 50 °C to afford 3a as an off-white
solid; yield: 0.09 g (97%); mp 167–170 °C; Rf = 0.19 (PE–EtOAc, 2:1).
1H NMR (DMSO-d6, 600 MHz): δ = 10.08 (s, 1 H), 8.46 (d, J = 2.0 Hz, 1
H), 8.12 (dd, J = 8.2, 2.0 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H).
MS (ESI): m/z = 217.8, 219.8 [M – H]–.
5-Formyl-2-methoxybenzenesulfonyl Chloride (2e)
Yield: 0.39 g (80%); white solid; mp 66–68 °C; Rf = 0.21 (PE–EtOAc,
2:1).
IR (KBr): 3111, 2954, 2851, 1699, 1598, 1497, 1369, 1167, 1008, 837
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 9.96 (s, 1 H), 8.48 (d, J = 2.1 Hz, 1 H),
8.25 (dd, J = 8.7, 2.1 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H), 4.18 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 188.6, 161.4, 137.5, 132.3, 132.3,
128.9, 113.8, 57.4.
MS (ESI): m/z = 214.5 [M – Cl + OH – H]–.
2-Chloro-5-formylbenzenesulfonic Acid (4a)18
4-Chlorobenzaldehyde (0.5 g, 3.6 mmol) was added to fuming H2SO4
(2 mL) at r.t. The mixture was stirred and heated at 60 °C for 7.5 h.
After the completion of the reaction as monitored by TLC, the sirupy
liquid was poured slowly with stirring into crushed ice (20 g). The
aqueous solution was extracted with EtOAc (2 × 20 mL). The organic
layers were combined and dried (anhyd Na2SO4). The Na2SO4 was fil-
tered off and the filtrate was concentrated under vacuum to afford
crude 4a, which was recrystallized from EtOH–H2O to afford pure
white crystals of 4a; yield: 0.57 g (73%); mp >300 °C; Rf = 0.35
(CH2Cl2–MeOH–AcOH, 5:1:0.2).
ΗRMS (ESI): m/z [M – Cl + OH – H]– calcd for C8H7O5S: 215.0018;
found: 215.0020.
3-(2-Chloroethoxy)-5-formyl-2-methoxybenzenesulfonyl Chlo-
ride (2f)
Yield: 0.38 g (77%); white solid; mp 79–81 °C; Rf = 0.26 (PE–EtOAc,
2:1).
IR (KBr): 3080, 2963, 2842, 1684, 1595, 1510, 1437, 1361, 1270, 1165,
1020, 865 cm–1
.
IR (KBr): 3441, 1695, 1466, 1434, 1384, 1166, 1067 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 9.93 (s, 1 H), 8.07 (d, J = 1.8 Hz, 1 H),
7.74 (d, J = 1.8 Hz, 1 H), 4.43–4.40 (m, 2 H), 4.29 (s, 3 H), 3.96–3.92 (m,
2 H).
1H NMR (DMSO-d6, 600 MHz): δ = 10.01 (s, 1 H), 8.38 (d, J = 2.1 Hz, 1
H), 7.84 (dd, J = 8.1, 2.1 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
X. Bao et al.
Paper
Synthesis
MS (ESI): m/z = 218.8, 220.8 [M – H]–.
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Funding Information
(5) Lowe, C.; Dyke, H. J.; Hanghan, A. F.; Galvin, F. C. A.; Morgan, T.;
Picken, C. L. Patent PCT Int. Appl. WO 0174786, 2001.
(6) Zimmerman, S. S.; Khatri, A.; Garnier-Amblard, E. C.;
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Traynelis, S. F.; Liotta, D. C. J. Med. Chem. 2014, 57, 2334.
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Discipline Construction Program of Shenyang Pharmaceutical Univer-
sity (52134606)
Natural Science Foundation of Liaoning Province (201602707)
Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589015.
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Primary Data
Primary data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI: 10.4125/pd0093th.
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Patent CN1454892, 2003.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F