Water-Promoted Chlorination of 2-Mercaptobenzothiazoles

Article abstract of DOI:10.1055/s-0036-1591553

Substituted benzothiazoles play an important role in medicinal chemistry due to their pharmacological properties. Their 2-substituted derivatives are often prepared from 2-chlorobenzothiazoles, which in turn can be synthesized from the 2-mercapto precursor using sulfuryl chloride. In practice, this seemingly straightforward and widely used reaction can be impeded by poor reproducibility and low reaction yields. In this communication, we report that the simple addition of water to the reaction leads to remarkable improvements in reaction efficiency. We attribute this effect to the formation of acid through partial hydrolysis of sulfuryl chloride. This hypothesis is supported by the observation that improved yields were also obtained in the presence of some anhydrous acidic additives. The simple combination of sulfuryl chloride and water reproducibly provides excellent yields for a range of chlorinated products.

Full text of DOI:10.1055/s-0036-1591553

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
L. Wimmer et al.
Paper
Synthesis
Water-Promoted Chlorination of 2-Mercaptobenzothiazoles
Laurin Wimmera
Michael Parmentiera
10 SO2Cl2
2 H O
2
+
=
Bernard Rissa
Tobias Kapferera
Chao Yeb
"SO2Cl2/H+"
S
N
S
N
Cl
R
SH
R
3 h, r.t.
Lei Lib
Hongyong Kimb
Jialiang Li*b
• excellent yield • high reproducibility • avoids POCl3
• operational simplicity
a Global Drug Development, Chemical & Analytical Development,
Novartis Pharma AG, Basel, Switzerland
b Global Drug Development, Chemical & Analytical Development,
Suzhou Novartis Pharma Technology Company Limited, Changshu,
Jiangsu 215537, P. R. of China
jialiang.li@novartis.com
Received: 10.11.2017
Accepted after revision: 22.02.2018
Published online: 09.04.2018
Following this literature precedent,4 we prepared a
series of 2-mercaptobenzothiazoles in 73–90% yield
through condensation of 2-haloanilines and potassium O-
ethyl carbonodithioate (Scheme 1).
DOI: 10.1055/s-0036-1591553; Art ID: ss-2017-z0725-op
Abstract Substituted benzothiazoles play an important role in medici-
nal chemistry due to their pharmacological properties. Their 2-substi-
tuted derivatives are often prepared from 2-chlorobenzothiazoles,
which in turn can be synthesized from the 2-mercapto precursor using
sulfuryl chloride. In practice, this seemingly straightforward and widely
used reaction can be impeded by poor reproducibility and low reaction
yields. In this communication, we report that the simple addition of wa-
ter to the reaction leads to remarkable improvements in reaction effi-
ciency. We attribute this effect to the formation of acid through partial
hydrolysis of sulfuryl chloride. This hypothesis is supported by the ob-
servation that improved yields were also obtained in the presence of
some anhydrous acidic additives. The simple combination of sulfuryl
chloride and water reproducibly provides excellent yields for a range of
chlorinated products.
When we first carried out the subsequent chlorination
reaction in the lab we made two observations: (1) The reac-
tion usually did not proceed to completion, and full conver-
sion could not be achieved by prolonging the reaction time,
refluxing the reaction mixture or by the addition of co-sol-
vents. (2) The reproducibility of the reaction outcomes was
poor and results varied widely with the quality of the re-
agents. When anhydrous starting materials were used, the
reaction was sluggish (~50% conversion, 3 h). But surpris-
ingly, when we subjected a wet batch of thiol 4 to the reac-
tion it was cleanly and efficiently converted into the corre-
sponding chloride. This observation prompted us to further
investigate the role of water in this reaction (Table 1).
Key words benzothiazoles, sulfuryl chloride, chlorination, acid-cata-
lyzed, water-promoted
S
S
KS OEt
R
SH
Functionalized benzothiazoles are ubiquitous in drug
discovery owing to their interesting biological and pharma-
cological properties.1 We recently became interested in the
preparation of 2-chlorobenzothiazoles as common and ver-
satile intermediates en route to more complex benzo-
thiazole derivatives. The preparation of chlorinated hetero-
cycles through dehydration of their oxo-precursors using
phosphoryl chloride is a useful and well-established meth-
od on lab scale.2 However, due to the risk associated with
the use of phosphoryl chloride in large-scale applications,
we needed to identify a suitable replacement.3 After a sur-
vey of methods in the literature, we decided to investigate a
procedure4 initially developed by researchers at Bayer: 2-
haloanilines are converted into 2-mercaptobenzothiazoles,
followed by chlorination in the presence of sulfuryl chloride.
Y
X
N
(1.5–1.7 equiv)
1–11
R
DMF, 3–14 h
120–130 °C
F3C
N
NH2
S
SH
X = F, Cl or Br
12
N
Yield R =
n/aa
Yield R =
Yield R =
80% 6-Br
86% 7-F
81% 6-F
73%
H
82% 6-Me
n/aa 6-MeO
74% 6-MeO
87% 7-Cl
1
2
3
4
5
6
7
8
9
81% 6-COOEt
82% 6-CN
10
11
12
90% 4-F-6-COOEt
Scheme 1 Preparation of mercaptobenzothiazoles. a Compound
obtained from a commercial source
Two equivalents5 of water were either premixed with
sulfuryl chloride for 10 minutes before addition of the sub-
strate or water was added to the reaction mixture last.
Interestingly, both procedures led to the same efficient con-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
L. Wimmer et al.
Paper
Synthesis
Table 1 Effects of Additives on the Conversion
the desired reaction. We went on to add a variety of con-
centrated acids to the reaction mixture, and indeed found
considerably improved reaction yields compared to pure
sulfuryl chloride (Table 1, entries 4–7). Interestingly, the re-
action yield does not correlate with the acid strength: the
very strong acids chlorosulfonic acid and methanesulfonic
acid gave yields of 84% and 79%, respectively, but the much
weaker acetic acid promoted the reaction with equal effi-
ciency (82%). On the other hand, sulfuric acid gave a lower
yield of 68%, accompanied by the formation of benzothiazole-
2-sulfonic acid and the desulfurized benzothiazole as side
products. HCl/EtOAc did not promote the reaction (see below).
The hydrolysis reaction of sulfuryl chloride with sub-
stoichiometric amounts of water is likely to produce chloro-
sulfonic acid as the major product. However, this compound
was ruled out as the active chlorinating agent (Table 1, en-
tries 8 and 9). We also wondered if the concentration of
chloride ions in the reaction mixture had an influence on
its success. Neither the addition of tetrabutylammonium
chloride nor of dry HCl in ethyl acetate (Table 1, entries 10
and 12) promoted the reaction compared to pure sulfuryl
chloride (50%, entry 1). The addition of triethylamine hy-
drochloride even led to a diminished yield of 36% (by HPLC)
(Table 1, entry 11).
reagent (10 equiv)
additive (2 equiv)
EtOOC
EtOOC
S
N
S
N
Cl
SH
3 h, 22 °C
4
F
F
16
Entry
Reagent
Additive (2 equiv)
Yielda
1
2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
SO2Cl2
ClSO3H
ClSO3H
SO2Cl2
SO2Cl2
SO2Cl2
–
50%b
90%
90%
84%
79%
68%
82%
n.c.c
n.c.c
46%b
36%b
45%b
H2O (premixed)
H2O (added last)
ClSO3H
3
4
5
MeSO3H
H2SO4
6
7
AcOH
8
–
9
H2O (premixed)
HCl/EtOAc
HCl·NEt3
NBu4Cl
10
11
12
a Yield of isolated product.
b Conversion by HPLC; typically, no starting material remained. The mass
balance after quenching with MeOH is methylsulfinate.
c n.c. = no conversion.
As shown in Scheme 2, addition of water to the reaction
reliably improved the conversion into chlorobenzothiazoles
13–23 and 2-chlorothiazolopyridine 24. The products were
obtained in excellent yields (86–96%) for electron-deficient
or moderately electron-rich substrates. In some cases, the
improvement of reaction efficiency was quite remarkable:
e.g., 86% vs 47% for 17, and even 91% vs 33% in the case of 14.
version of starting material into product (Table 1, entries 2
and 3). We hypothesized that acid, generated through
hydrolysis of sulfuryl chloride, might act as a promoter for
SO2Cl2 (10 equiv)
H2O (2 equiv)
S
N
S
N
R
SH
R
Cl
3 h, 22 °C
1–7
EtOOC
S
N
NC
S
N
EtOOC
S
N
S
N
Cl
Cl
Cl
Cl
F
13, 100% conversion (62%)
14, 98% conversion (33%)
15, 100% conversion (58%)
16, 100% conversion (50%)
90%
91%
90%
90%
X
Cl
Me
S
N
S
MeO
S
N
S
Cl
Cl
Cl
Cl
N
N
Cl
17, 99% conversion (47%)
18, 99% conversion (78%)
19a, X = H, not detected
19b, X = Cl, 51%
20 (ref 4: 53%)
86%
75%
94%
F
Br
F
F3C
N
S
N
S
S
N
S
N
Cl
Cl
N
Cl
Cl
21 (ref 4: 99%)
22 (ref 4: 59%)
23 (ref 4: 99%)
24 (ref 4: 75%)
96%
90%
95%
85%
Scheme 2 Scope of the water-promoted chlorination. Values in brackets represent conversions (HPLC) in the absence of water
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
L. Wimmer et al.
Paper
Synthesis
Compounds 19 (a and b) illustrate the limitation of this
method: The electron-rich starting material 7 was fully
consumed, but over-chlorination of the benzene core led to
the formation of 19b, while 19a could not be detected.
However, it must be mentioned that in the presence of wa-
ter the reaction proceeded in a much cleaner fashion thus
allowing the isolation of 19b, while in the absence of water,
only an intractable mixture of decomposition products was
obtained.
Compared to the water-free chlorination reported in the
literature,4 our modified method delivers high yields with
excellent consistency. Compounds 20–24 are a testament to
the high reliability of the procedure: While near quantita-
tive yields for compounds 21 (96% vs 99%4) and 23 (95% vs
99%4) could be reproduced, excellent results were also ob-
tained for compounds 20 (94% vs 53%4) and 22 (90% vs 59%4),
which performed poorly under water-free conditions.
We next set out to identify some of the intermediates
and by-products of the reaction to gain an understanding of
the underlying mechanism (Scheme 3). Quenching of the
anhydrous reaction mixture with a large excess of metha-
nol or ethanol yielded the corresponding methyl- or ethyl-
sulfinate, along with the chlorinated product and traces of
starting material.
We hypothesize that the thiol undergoes two oxidative
chlorinations to give sulfur(IV) intermediate 25. In the pres-
ence of methanol this compound hydrolyzes to form sulfi-
nate 27 with the incorporation of two 18O-atoms. If
quenched with water, sulfinic acid 26 forms through hydro-
lysis, which in turn rapidly undergoes either further oxida-
tion to 28 or loss6 of SO2 to form 29.
In summary, we have discovered a very simple and con-
venient procedure for the synthesis of 2-chlorobenzothi-
azoles. While electron-rich substrates can undergo further
chlorination of the aromatic core under the reaction condi-
tions, excellent yields are obtained with electron-deficient
to moderately electron-rich substrates. This method offers a
reliable and high-yielding alternative to phosphoryl chlo-
ride that is safer and thus scalable.
2-Mercaptobenzothiazole (1) and 5-chloro-2-mercaptobenzothiazole
(6) were purchased from commercial suppliers. All reactions were
carried out under nitrogen. 1H and 13C NMR spectra were recorded on
a Bruker Avance II 400 MHz spectrometer using tetramethylsilane
(TMS) in DMSO-d6 as the internal standard. 19F NMR spectra were re-
corded on a Bruker Avance III 400 MHz. spectrometer. HRMS spectra
were obtained using an LC-ESI-TOF-MS instrument. Caution! Special
care must be taken when hydrolyzing sulfuryl chloride, especially on
large scale. The hydrolysis reaction is vigorous, exothermic and re-
leases large quantities of HCl.7
EtOOC
EtOOC
S
N
18O
S
18OMe
S
SH
N
2-Mercaptobenzothiazole Starting Materials; General Procedure
+ Me18OH
F
27
F
4
SO2Cl2
S
KS OEt
X
S
N
(1.5–1.7 equiv)
18O
S
18OH
EtOOC
EtOOC
S
S
Cl
R
R
SH
S
DMF, 3–14 h
120–130 °C
NH2
X = Br or F
+ H218O
Cl
N
N
X
25
26
F
F
putative intermediates (not observed)
A round-bottomed flask was charged with 2-bromoaniline or 2-fluoro-
aniline (>3 g, 1.0 equiv) and potassium O-ethyl carbonodithioate
(1.5–1.7 equiv). The mixture was dissolved in DMF (10 volumes) and
heated to 120–130 °C until the aniline was fully consumed (3–14 h).
The reaction mixture was cooled to r.t. and filtered. The filtrate was
diluted with H2O (50 volumes) and the pH was adjusted to 1–2 using
aqueous 2 M HCl. The solid precipitate was collected, washed with
H2O and dried to yield the pure product.
loss of
SO2
EtOOC
S
further
oxidation
H
N
29
F
18O
18O
S
18OH
EtOOC
EtOOC
S
Cl
N
S
N
16
F
F
28
Ethyl 2-Mercaptobenzo[d]thiazole-6-carboxylate (2)
Yield: 1.5 g, 6.16 mmol (81%; from X = F); brown solid; mp 289 °C.
Scheme 3 Observed and putative intermediates and by-products
1H NMR (400 MHz, DMSO-d6): δ = 1.33 (t, J = 7.09 Hz, 3 H), 4.32 (q,
J = 7.09 Hz, 2 H), 7.38 (d, J = 8.56 Hz, 1 H), 7.97 (dd, J = 8.50, 1.65 Hz, 1
H), 8.33 (d, J = 1.47 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.65, 61.41, 112.67, 123.71,
125.99, 128.89, 130.24, 145.17, 165.54, 192.36.
When we repeated this experiment using 18O-methanol,
the fully isotopically labelled sulfinate 27 was formed as
the major product. When the reaction was quenched using
H218O, the fully labelled sulfonic acid 28 was detected by LC-
MS. In some cases, e.g., when methanesulfonic acid was
used as an additive (see the Supporting Information), sig-
nificant amounts of desulfurized compound 29 were found.
HRMS (ESI): m/z [M + H]+ calcd for C10H10NO2S2: 240.0153; found:
240.0125.
2-Mercaptobenzo[d]thiazole-6-carbonitrile (3)
Yield: 5.8 g, 30.0 mmol (82%; from X = F); orange solid; mp 293 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
L. Wimmer et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 7.39 (d, J = 8.31 Hz, 1 H), 7.82 (dd,
J = 8.44, 1.59 Hz, 1 H), 8.22 (d, J = 1.34 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 106.78, 113.46, 119.06, 126.49,
130.72, 131.71, 144.97, 192.17.
HRMS (ESI): m/z [M + H]+ calcd for C8H5N2S2: 192.9894; found:
7-Fluorobenzo[d]thiazole-2-thiol (10)
Yield: 6.2 g, 33.2 mmol (86%; from X = F); brown solid; mp 206 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.11–7.26 (m, 2 H), 7.46 (td,
J = 8.25, 5.62 Hz, 1 H), 14.07 (br s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 109.00 (d, J = 3.4 Hz), 110.21 (d, J =
18.9 Hz), 115.70 (d, J = 23.1 Hz), 129.20 (d, J = 7.5 Hz), 143.56 (d, J =
6.6 Hz), 154.38 (d, J = 244.4 Hz), 289.38.
192.9874.
Ethyl 4-Fluoro-2-mercaptobenzo[d]thiazole-6-carboxylate (4)
HRMS (ESI): m/z [M + H]+ calcd for C7H5FNS2: 185.9847; found:
Yield: 5.76 g, 21.4 mmol (90%; from X = F); off-white solid; mp 266 °C.
185.9865.
1H NMR (400 MHz, DMSO-d6): δ = 1.33 (t, J = 7.15 Hz, 3 H), 4.32 (q,
J = 7.09 Hz, 2 H), 7.74 (dd, J = 10.88, 1.34 Hz, 1 H), 8.17 (d, J = 1.34 Hz,
1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.58, 61.79, 114.31 (d, J = 9.5 Hz),
119.73, 126.82 (d, J = 3.0 Hz), 132.57 (d, J = 2.0 Hz), 133.99, 146.65 (d,
J = 124.7 Hz), 164.72 (d, J = 1.5 Hz), 193.01.
6-Fluorobenzo[d]thiazole-2-thiol (11)
Yield: 5.9 g, 31.9 mmol (81%; from X = F); red-brown solid; mp
255 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.20–7.35 (m, 1 H), 7.22–7.34 (m, 1
H), 7.66 (dd, J = 8.50, 2.14 Hz, 1 H), 13.81 (br s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 108.87 (d, J = 27.5 Hz), 113.37 (d,
J = 8.9 Hz), 114.71 (d, J = 24.8 Hz), 130.75 (d, J = 11.0 Hz), 137.96,
159.11 (d, J = 241.3 Hz), 189.93.
19F NMR (376 MHz, DMSO-d6): δ = –125.50.
HRMS (ESI): m/z [M + H]+ calcd for C10H9FNO2S2: 258.0053; found:
258.0053.
HRMS (ESI): m/z [M + H]+ calcd for C7H5FNS2: 185.9847; found:
6-Methylbenzo[d]thiazole-2-thiol (5)
185.9856.
Yield: 2.50 g, 13.6 mmol (82%; from X = Br); pale brown solid; mp
279 °C.
5-(Trifluoromethyl)thiazolo[5,4-b]pyridine-2-thiol (12)
1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 7.14–7.29 (m, 2 H),
7.40–7.57 (m, 1 H), 7.49 (s, 1 H).
Yield: 3.5 g, 14.1 mmol (73%; from X = Cl); pale brown solid; mp
151 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.77 (d, J = 8.31 Hz, 1 H), 7.91 (d,
J = 8.44 Hz, 1 H), 13.45–14.88 (m, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 21.18, 112.58, 122.03, 128.55,
129.91, 134.28, 139.63, 189.65.
13C NMR (101 MHz, DMSO-d6): δ = 120.07 (q, J = 3.0 Hz), 120.38,
122.03 (q, J = 273.73), 139.49, 142.15 (q, J = 34.7 Hz), 152.62, 190.58.
HRMS (ESI): m/z [M + H]+ calcd for C8H8NS2: 182.0098; found:
182.0080.
HRMS (ESI): m/z [M + H]+ calcd for C7H4F3N2S2: 236.9768; found:
6-Methoxybenzo[d]thiazole-2-thiol (7)
236.9749.
Yield: 1.0 g, 4.97 mmol (74%; from X = Br); brown solid; mp 196 °C.
Chlorination Using Sulfuryl Chloride/Water; General Procedure
1H NMR (400 MHz, DMSO-d6): δ = 3.77 (s, 3 H), 6.99 (dd, J = 8.86, 2.51
Hz, 1 H), 7.22 (d, J = 8.93 Hz, 1 H), 7.35 (d, J = 2.45 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 56.16, 106.39, 113.54, 115.27,
131.15, 135.66, 157.09, 188.82.
HRMS (ESI): m/z [M + H]+ calcd for C8H8NOS2: 198.0047; found:
SO2Cl2 (10 equiv)
H2O (2 equiv)
S
N
S
N
R
SH
R
Cl
3 h, 22 °C
198.0045.
A mixture of the 2-mercaptobenzo[d]thiazole (>1 g, 1 equiv) and sul-
furyl chloride (10 equiv) was stirred at 20–25 °C for 15 min. Next, H2O
(2 equiv) was added and the mixture was stirred at 20–25 °C for an
additional 3 h. A sample was taken, quenched with MeCN/H2O (2:1)
and analyzed by HPLC. After completion of the reaction, the mixture
was diluted with MeCN (5 volumes) and slowly quenched with H2O
(20 volumes). The product precipitated from the aqueous solution.
The solid was collected and washed with H2O. Drying under vacuum
afforded the pure product. In the case of the liquid product 2-chloro-
benzo[d]thiazole (13), the reaction mixture was extracted with
EtOAc. The organic layer was then dried and concentrated to afford
the product as an oil.
7-Chlorobenzo[d]thiazole-2-thiol (8)
Yield: 6.7 g, 33.0 mmol (87%; from X = F); grey solid; mp 261 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.26 (dd, J = 7.58, 1.34 Hz, 1 H),
7.35–7.49 (m, 2 H), 14.04 (br s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 111.78, 124.18, 125.21, 128.64,
129.41, 142.72, 189.54.
HRMS (ESI): m/z [M + H]+ calcd for C7H5ClNS2: 201.9552; found:
201.9561.
6-Bromobenzo[d]thiazole-2-thiol (9)
Yield: 4.0 g, 16.0 mmol (80%; from X = Br); orange solid; mp 299 °C.
2-Chlorobenzo[d]thiazole (13)
1H NMR (400 MHz, DMSO-d6): δ = 7.23 (d, J = 8.68 Hz, 1 H), 7.56 (dd,
J = 8.56, 1.96 Hz, 1 H), 7.98 (d, J = 1.83 Hz, 1 H), 13.89 (br s, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 114.36, 116.83, 124.64, 130.45,
Yield: 3.30 g, 19.5 mmol (90%); yellow oil.
1H NMR (400 MHz, DMSO-d6): δ = 7.45–7.62 (m, 2 H), 7.96 (dd, J =
8.07, 0.73 Hz, 1 H), 8.09 (dd, J = 7.89, 0.92 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 122.81, 122.86, 126.49, 127.47,
136.19, 150.91, 153.23.
131.90, 141.03, 190.53.
HRMS (ESI): m/z [M + H]+ calcd for C7H5BrNS2: 245.9047; found:
245.9041.
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L. Wimmer et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C7H5ClNS: 169.9831; found:
2,7-Dichloro-6-methoxybenzo[d]thiazole (19b)
169.9844.
Monochlorination product 19a was not detected. Instead, dichloride
19b was obtained as the major product. The structure was confirmed
by MS, 1H NMR and 13C NMR.
Ethyl 2-Chlorobenzo[d]thiazole-6-carboxylate (14)
Yield: 0.65 g, 2.66 mmol (91%); off-white solid; mp 106 °C.
Yield: 0.30 g, 1.28 mmol (51%); brown solid; mp 92 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.35 (t, J = 7.09 Hz, 3 H), 4.36 (q,
J = 7.09 Hz, 2 H), 7.96–8.23 (m, 2 H), 8.80 (d, J = 0.86 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 3.97 (s, 3 H), 7.45 (d, J = 8.93 Hz, 1
H), 7.95 (d, J = 8.93 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.64, 61.64, 122.91, 124.93,
13C NMR (101 MHz, DMSO-d6): δ = 57.48, 112.38, 113.55, 122.53,
127.65, 128.01, 136.56, 153.83, 157.43, 165.58.
137.45, 144.79, 150.23, 153.60.
HRMS (ESI): m/z [M + H]+ calcd for C10H9ClNO2S: 242.0043; found:
HRMS (ESI): m/z [M + H]+ calcd for C8H6Cl2NOS: 233.9547; found:
241.9975.
233.9545.
2-Chlorobenzo[d]thiazole-6-carbonitrile (15)
2,7-Dichlorobenzo[d]thiazole (20)
Yield: 0.40 g; 2.06 mmol (90%); off-white solid; mp 171 °C.
Yield: 0.95 g, 4.64 mmol (94%); pale yellow solid; mp 58 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.98 (dd, J = 8.50, 1.65 Hz, 1 H),
8.14 (d, J = 8.44 Hz, 1 H), 8.70 (d, J = 1.47 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.53–7.72 (m, 2 H), 7.89–8.03 (m, 1
H).
13C NMR (101 MHz, DMSO-d6): δ = 108.80, 118.92, 123.87, 128.16,
13C NMR (101 MHz, DMSO-d6): δ = 121.92, 125.54, 126.33, 129.02,
130.74, 136.89, 153.39, 158.37.
135.75, 151.45, 153.36.
HRMS (ESI): m/z [M + H]+ calcd for C8H4ClN2S: 194.9784; found:
HRMS (ESI): m/z [M + H]+ calcd for C7H4Cl2NS: 203.9442; found:
194.9768.
203.9438.
Ethyl 2-Chloro-4-fluorobenzo[d]thiazole-6-carboxylate (16)
6-Bromo-2-chlorobenzo[d]thiazole (21)
Yield: 21.0 g, 80.9 mmol (90%); off-white solid; mp 185 °C.
Yield: 0.98 g, 3.91 mmol (96%); off-white solid; mp 108 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.35 (t, J = 7.09 Hz, 3 H), 4.37 (q,
J = 7.09 Hz, 2 H), 7.84 (dd, J = 11.00, 1.47 Hz, 1 H), 8.64 (d, J = 1.22 Hz,
1 H).
13C NMR (101 MHz, DMSO-d6): δ = 14.56, 62.02, 113.30 (d, J = 10.1
Hz), 121.12 (d, J = 2.0 Hz), 128.81 (d, J = 3.0 Hz), 139.10 (d, J = 1.5 Hz),
142.38 (d, J = 7.0 Hz), 154.00 (d, J = 128.9 Hz), 158.37, 164.70 (d, J = 1.5
Hz).
1H NMR (400 MHz, DMSO-d6): δ = 7.72 (dd, J = 8.68, 2.08 Hz, 1 H),
7.91 (d, J = 8.68 Hz, 1 H), 8.41 (d, J = 1.83 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 119.19, 124.46, 125.46, 130.68,
138.05, 149.93, 154.40.
HRMS (ESI): m/z [M + H]+ calcd for C7H4BrClNS: 247.8936; found:
247.8928.
19F NMR (376 MHz, DMSO-d6): δ = –121.93.
HRMS (ESI): m/z [M + H]+ calcd for C10H8ClFNO2S: 259.9943; found:
2-Chloro-7-fluorobenzo[d]thiazole (22)
Yield: 0.95 g, 4.86 mmol (90%); brown oil.
1H NMR (400 MHz, DMSO-d6): δ = 7.44 (td, J = 8.99, 0.61 Hz, 1 H), 7.62
(td, J = 8.22, 5.69 Hz, 1 H), 7.86 (d, J = 8.19 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 111.93 (d, J = 17.7 Hz), 118.96 (d,
J = 3.6 Hz), 122.34 (d, J = 17.0 Hz), 128.53 (d, J = 7.9 Hz), 152.80 (d, J =
2.9 Hz), 153.25 (d, J = 2.3 Hz), 155.38 (d, J = 247.9 Hz).
259.9942.
2-Chloro-6-methylbenzo[d]thiazole (17)
Yield: 0.64 g, 3.30 mmol (86%); pale brown solid; mp 117 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.39–2.46 (m, 3 H), 7.36 (dd,
J = 8.38, 1.16 Hz, 1 H), 7.79–7.92 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C7H4ClFNS: 187.9737; found:
187.9727.
13C NMR (101 MHz, DMSO-d6): δ = 21.04, 121.77, 121.94, 128.35,
135.76, 135.87, 148.47, 151.40.
HRMS (ESI): m/z [M + H]+ calcd for C8H7ClNS: 183.9988; found:
2-Chloro-6-fluorobenzo[d]thiazole (23)
183.9995.
Yield: 0.96 g, 5.12 mmol (95%); pale yellow solid; mp 98 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.45 (td, J = 9.08, 2.75 Hz, 1 H),
7.94–8.10 (m, 2 H).
2,5-Dichlorobenzo[d]thiazole (18)
Yield: 0.38 g, 2.48 mmol (75%); off-white solid; mp 72 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.58 (dd, J = 8.68, 2.08 Hz, 1 H),
8.09 (d, J = 1.96 Hz, 1 H), 8.16 (d, J = 8.68 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 108.99 (d, J = 27.9 Hz), 115.52 (d,
J = 24.9 Hz), 123.86 (d, J = 9.6 Hz), 136.93 (d, J = 12.2 Hz), 147.26,
152.55 (d, J = 3.0 Hz), 159.92 (d, J = 244.1 Hz).
13C NMR (101 MHz, DMSO-d6): δ = 122.46, 124.46, 126.69, 132.29,
HRMS (ESI): m/z [M + H]+ calcd for C7H4ClFNS:187.9737; found:
134.99, 151.65, 155.65.
187.9747.
HRMS (ESI): m/z [M + H]+ calcd for C7H4Cl2NS: 203.9442; found:
203.9446.
2-Chloro-5-(trifluoromethyl)thiazolo[5,4-b]pyridine (24)
Yield: 0.85 g, 3.56 mmol (85%); off-white solid; mp 102 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.16 (d, J = 8.56 Hz, 1 H), 8.68 (d,
J = 8.44 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
L. Wimmer et al.
Paper
Synthesis
13C NMR (101 MHz, DMSO-d6): δ = 119.75, 121.36 (q, J = 274.1 Hz),
131.99, 143.91 (q, J = 34.8 Hz), 146.46, 157.15, 157.96.
(2) Meier, M. S.; Ruder, S. M.; Malona, J. A.; Frontier, A. J. Phospho-
rus Oxychloride, In e-EROS Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons: Hoboken, 2008.
HRMS (ESI): mass ion not found.
(3) Both SO2Cl2 and POCl3 react with water in a violent, exothermic
reaction with evolution of gas. However, the high density and
limited miscibility of POCl3 with water makes its use particu-
larly hazardous: During the quench with water a delayed onset
of the hydrolysis reaction can occur resulting in a dangerous
accumulation and potential run-away of the reaction.
Acknowledgment
The authors thank Dr. Shangjun Teng and Dr. Fiona Fitzpatrick for
their valuable support.
(4) Zhu, L.; Zhang, M.; Miao, D. J. Heterocycl. Chem. 2005, 42, 727.
(5) The addition of one, two or three equivalents of water led to the
same reaction performance. After these initial experiments, we
decided to use 2 equivalents of water as standard conditions.
(6) The rapid decomposition of heterocyclic sulfinic acids through
loss of SO2 under acidic conditions is well documented. See for
example: Evans, R. M.; Jones, P. G.; Palmer, P. J.; Stephens, F. F.
J. Chem. Soc. 1956, 4106.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591553.
S
u
p
p
ortiInfogrmoaitn
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(7) When quenching excess reagent from a reaction containing 5 g
of mercaptobenzothiazole in 25 g of sulfuryl chloride, 6 liters of
gaseous by-products (mainly hydrogen chloride) were released.
References
(1) Keri, R. S.; Patil, M. R.; Patil, S. A.; Budagumpi, S. Eur. J. Med.
Chem. 2015, 89, 207.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F