A facile synthesis of 1,3-thiazole-4-sulfonyl chlorides

Article abstract of DOI:10.1080/00397911.2011.571356

(Chemical Equation Presented) A four-step preparative-scale synthesis of eight 2-alkyl- and arylsubstituted thiazole-4-sulfonyl chlorides from chloralamides is reported. Good yields and easy availability of starting materials are valuable advantages of the procedure that gives access to formerly unattainable building blocks. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.571356

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A Facile Synthesis of 1,3-Thiazole-4-
sulfonyl Chlorides
Bogdan A. Demydchuk a , Kostyantyn M. Kondratyuk a , Andrey N.
Korniyenko a , Vladimir S. Brovarets a , Roman Y. Vasylyshyn b ,
Andrey Tolmachev b & Oleg Lukin b
a Institute of Bioorganic Chemistry and Petrochemistry, National
Academy of Sciences of Ukraine, Kyiv, Ukraine
b National Taras Shevchenko University, ChemBioCenter, Kyiv,
Ukraine
Available online: 02 Jan 2012
To cite this article: Bogdan A. Demydchuk, Kostyantyn M. Kondratyuk, Andrey N. Korniyenko, Vladimir
S. Brovarets, Roman Y. Vasylyshyn, Andrey Tolmachev & Oleg Lukin (2012): A Facile Synthesis of
1,3-Thiazole-4-sulfonyl Chlorides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:19, 2866-2875
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Synthetic Communications1, 42: 2866–2875, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.571356
A FACILE SYNTHESIS OF 1,3-THIAZOLE-4-SULFONYL
CHLORIDES
Bogdan A. Demydchuk,1 Kostyantyn M. Kondratyuk,1
Andrey N. Korniyenko,1 Vladimir S. Brovarets,1
Roman Y. Vasylyshyn,2 Andrey Tolmachev,2 and Oleg Lukin2
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of
Sciences of Ukraine, Kyiv, Ukraine
2National Taras Shevchenko University, ChemBioCenter, Kyiv, Ukraine
GRAPHICAL ABSTRACT
Abstract A four-step preparative-scale synthesis of eight 2-alkyl- and arylsubstituted
thiazole-4-sulfonyl chlorides from chloralamides is reported. Good yields and easy avail-
ability of starting materials are valuable advantages of the procedure that gives access to
formerly unattainable building blocks.
Keywords Chloralamides; sulfonyl chlorides; thiazole
INTRODUCTION
The thiazole structural unit is found in many natural products and synthetic
compounds with a broad spectrum of biological activities.[1–3] In this context the
development of reliable methods for preparation of building blocks with the thiazole
scaffold is of significance in drug discovery and agrochemistry. Integration of the
thiazole subunit into biologically potent species is most frequently carried out by
acylation of 2-amino-1,3-thiazoles.[3] Alternative methods for introduction of the
thiazole fragment include the use of halogenated thiazoles and thiazole acyl- or sul-
fonyl chlorides.[4] The latter are especially useful synthetic building blocks because a
biologically relevant sulfo-group is introduced along with the valuable thiazole frag-
ment. There are many reports on the preparation and the use of diverse thiazole-2-
and 5-sulfonyl chlorides in the synthesis of pharmacologically active compounds,[4]
Received February 9, 2011.
Address correspondence to Oleg Lukin, National Taras Shevchenko University, ChemBioCenter,
Volodymyrska St. 62, 01033 Kiev, Ukraine. E-mail: oleg.lukin@univ.kiev.ua
2866

SYNTHESIS OF THIAZOLE-4-SULFONYL CHLORIDES
2867
whereas, to our knowledge, there are only two articles describing thiazole-4-sulfonyl
chlorides.[5,6] In both reports, the thiazole-4-sulfonyl chlorides were prepared by sul-
fonylation of 2,5-substituted thiazole derivatives. Presently no suitable procedure
allowing a straightforward preparation of parent or monosubstituted thiazole-4-
sulfonyl chlorides is available. Given the potential of thiazole sulfonyl chlorides in
high-throughput synthesis of screening compounds for early drug discovery pro-
grams, it seems important to have access to all of their isomeric forms. In this work,
we describe a simple and efficient synthetic route to 2-substituted thiazole-4-sulfonyl
chlorides.
RESULTS AND DISCUSSION
The synthetic route to thiazole-4-sulfonyl chlorides is outlined in Scheme 1.
Starting chloralamides 3 were prepared in nearly quantitative yields from chloral 1
and amides 2 by the classical procedure of Jacobsen.[7] The chloralamides were
efficiently transformed into N-(2,2,-dichlorovinyl)amides 4.[8] Compounds 4 are
known to undergo the addition reaction with alkylamines[9] and thiophenoles.[10]
By analogy with the latter procedure, we carried out reactions of 4 with benzyl thiol.
Compounds 4 were reactive enough to allow the addition of benzyl thiol under mild
basic conditions, giving rise to amidosulfides 5. Thionation of compounds 5 with
2,4-bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide (so-called Lawesson
reagent)[11] followed by in situ treatment of thioamide intermediates with sodium
hydroxide resulted in thiazole-4-benzylsulfides 6. Notably, the latter reaction step
is a completely new approach to functionalized thiazoles.[12] The oxidative cleavage
Scheme 1. Preparation of 2-substituted thiazole-4-sulfonyl chlorides (LR stands for Lawesson reagent).

2868
B. A. DEMYDCHUK ET AL.
of sulfides 6 with chlorine[13] gave rise to corresponding thiazole-4-sulfonyl chlorides
in good to excellent yields.
CONCLUSIONS
The described approach allows a straightforward preparation of hitherto un-
available thiazole-4-sulfonyl chlorides bearing 2-alkyl or aryl substituent. The pre-
pared sulfonyl chlorides are promising building blocks for medicinal chemistry
and high-throughput synthesis of screening compounds.
EXPERIMENTAL
1H (500-MHz) and 13C (125-MHz) NMR spectra were recorded on a Bruker
Avance DRX 500 spectrometer in DMSO-d6 solution with tetramethylsilane (TMS)
as an internal standard. Melting points were measured with a Buchi melting-point
¨
apparatus and are uncorrected. Elemental analysis was carried out by the Analytical
Laboratory of Institute of Bioorganic Chemistry and Petrochemistry of National
Academy of Sciences of Ukraine (NAS). Preparation and characterization of com-
pounds 3a;[7] 3b, 3d, 3f;[14] 3c;[15] 3h;[16] 4a;[17] 4b, 4d, 4e;[14] and 4f[18] are available
from the literature.
Preparation of Compounds 3e and 3g
General procedure. A stirred mixture of amide (0.2 mol), chloral (21.5 mL,
0.22 mol), and concentrated sulfuric acid (1 mL) was heated at 100–110 ꢀC for 1 h.
The reaction mixture crystallized upon cooling. The mixture was triturated with
deionized water, filtered, washed with a large amount of water, and recrystallized
from ethanol.
N-(2,2,2-Trichloro-1-hydroxyethyl)-4-fluorobenzamide
from 27.8 g of 2e. Yield 52.7 g (92%). Colorless crystals; mp 130–131 ꢀC. H NMR
(3e). Prepared
1
3
3
(500 MHz, DMSO-d6): d ¼ 6.03 (d, JHH ¼ 9 Hz, 1 H, CH), 7.32 (t, JHH ¼ 9 Hz,
3
2 H, ArH), 7.87 (b.s., 1 H, NH), 7.98–8.01 (m, 2 H, ArH), 9.17 (d, JHH ¼ 9 Hz,
1 H, OH). 13C NMR (125 MHz, DMSO-d6): d ¼ 81.92, 103.08, 115.61, 115.78,
130.36, 131.12, 131.20, 163.74, 165.73, 166.25. 19F NMR (470 MHz, DMSO-d6):
d ¼ ꢁ54.13. Calcd (%) for C9H7Cl3FNO2: C, 37.73; H, 2.46; Cl, 37.12; N, 4.89.
Found: C, 37.66; H, 2.51; Cl, 36.96; N, 4.82.
N-(2,2,2-Trichloro-1-hydroxyethyl)-3-bromobenzamide (3g). Prepared
1
from 40 g of 2g. Yield 65.3 g (94%). Colorless crystals; mp 145–146 ꢀC. H NMR
3
3
(500 MHz, DMSO-d6): d ¼ 6.03 (d, JHH ¼ 8.5 Hz, 1 H, CH), 7.46 (t, JHH ¼ 9 Hz,
3
1 H, ArH), 7.78 (d, 7.87 JHH ¼ 9 Hz, 1 H, ArH), 7.90 (m, 2 H, ArH, NH), 8.10 (s,
1 H, ArH), 9.33 (d, JHH ¼ 8.5 Hz, 1 H, OH). 13C NMR (125 MHz, DMSO-d6):
3
81.94, 102.92, 122.04, 127.56, 130.96, 131.02, 135.07, 136.05, 165.92. Calcd. (%)
for C9H7BrCl3NO2: C, 31.11; H, 2.03; Br, 23.00; Cl, 30.61; N, 4.03. Found: C,
31.20; H, 2.09; Br, 23.05; Cl, 30.76; N, 3.98.

SYNTHESIS OF THIAZOLE-4-SULFONYL CHLORIDES
2869
Preparation of Compounds 4e, 4g, and 4h
General procedure. Zinc dust (13.1 g, 0.2 mol) was gradually added to a
stirred suspension of 3 (0.1 mol) in glacial acetic acid (50 mL) over a period of 3 h.
During the zinc addition the temperature of the reaction mixture was kept below
40 ꢀC. The reaction mixture was then stirred at room temperature for 24 h. Then
the precipitated zinc salt was filtered off and washed with glacial acetic acid. The
acetic acid was removed under reduced pressure. The solid residue was triturated
with deionized water and recrystallized.
N-(2,2-Dichloroethenyl)-3-methylbenzamide (4e). Prepared from 28.2 g
of 3c and recrystallized from n-hexane. Yield 12.6 g (55%). Colorless crystals; mp
1
57–58ꢀC. H NMR (500 MHz, DMSO-d6): d ¼ 2.39 (s, 3 H, CH3), 7.40–7.43 (m,
3
3 H, CH, ArH), 7.69–7.73 (m, 2 H, ArH), 10.02 (d, JHH ¼ 9 Hz, 1 H, NH). 13C
NMR (125 MHz, DMSO-d6): d ¼ 21.34, 106.79, 124.14, 125.89, 128.73, 129.13,
132.96, 133.38, 138.19, 165.52. Calcd. (%) for C10H9Cl2NO: C, 52.20; H, 3.94; Cl,
30.82; N, 6.09. Found: C, 52.12; H, 4.02; Cl, 30.86; N, 6.02.
N-(2,2-Dichloroethenyl)-3-bromobenzamide (4g). Prepared from 34.7 g of
3g and recrystallized from 2-propanol. Yield 23.6 g (80%). Colorless crystals; mp
3
92–93 ꢀC. 1H NMR (500 MHz, DMSO-d6): d ¼ 7.41 (d, JHH ¼ 9 Hz, 1 H, CH),
3
3
7.49 (t, JHH ¼ 7.5 Hz, 1 H, ArH), 7.82 (d, JHH ¼ 7.5 Hz, 1 H, ArH), 7.89 (d,
3JHH ¼ 7.5 Hz, 1 H, ArH), 10.25 (d, JHH ¼ 9 Hz, 1 H, NH). 13C NMR (125 MHz,
3
DMSO-d6): d ¼ 107.51, 122.00, 124.01, 127.92, 131.03, 131.28, 135.19, 135.45,
164.17. Calcd. (%) for C9H6BrCl2NO: C, 36.65; H, 2.05; Br, 27.09; Cl, 24.04; N,
4.75. Found: C, 36.60; H, 2.02; Br, 27.12; Cl, 24.16; N, 4.68.
N-(2,2-Dichloroethenyl)-4-bromobenzamide (4h). Prepared from 34.7 g of
3h and recrystallized from 2-propanol. Yield 21 g (72%). Colorless crystals; mp
1
3
113–114 ꢀC. H NMR (500 MHz, DMSO-d6): d ¼ 7.41 (d, JHH ¼ 9 Hz, 1 H, CH),
3
3
7.73 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 7.86 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 10.17 (d,
3JHH ¼ 9 Hz, 1 H, NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 107.30, 124.04,
126.66, 130.83, 131.86, 132.11, 164.67. Calcd. (%) for C9H6BrCl2FNO: C, 36.65;
H, 2.05; Br, 27.09; Cl, 24.04; N, 4.75. Found: C, 36.58; H, 1.98; Br, 27.16; Cl,
24.16; N, 4.67.
Preparation of Compounds 5
General procedure. Benzylthiol (1.2 mL, 0.01 mol) and triethylamine
(1.4 mL, 0.01 mol) were added to a stirred solution of compound 4 (0.01 mol) in
2-propanol (50 mL). The reaction mixture was stirred at room temperature for
48 h. Then the solvent was removed under reduced pressure and the residue was tri-
turated with water, resulting in a crystalline solid. The crude product was purified by
recrystallization from either 2-propanol or ethanol.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)acetamide (5a). Prepared from
1.54 g of 4a. Yield 2.25 g (81%). Colorless crystals; mp 108–109 ꢀC. 1H NMR
2
(500 MHz, DMSO-d6): d ¼ 1.94 (s, 3 H, CH3), 3.83 (d, JHH ¼ 13.5 Hz, 1 H, CH2),
2
3
3
3.91 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 5.41 (dd, JHH ¼ 3 Hz, JHH ¼ 9.5 Hz, 1 H,

2870
B. A. DEMYDCHUK ET AL.
3
CH), 6.41 (d, JHH ¼ 3 Hz, 1 H, CH), 7.25–7.33 (m, 5 H, ArH), 8.71 (d,
3JHH ¼ 9.5 Hz, 1 H, NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 22.78, 35.12,
60.83, 75.30, 127.57, 128.92, 129.34, 138.23, 170.17. Calcd. (%) for C11H13Cl2NOS:
C, 47.49; H, 4.71; Cl, 25.49; N, 5.03; S, 11.53. Found: C, 47.51; H, 4.76; Cl, 25.38; N,
4.96; S, 11.67.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)benzamide (5b). Prepared from
2 g of 4b. Yield 2.24 g (66%). Colorless crystals; mp 118–120 ꢀC. 1H NMR
3
(500 MHz, DMSO-d6): d ¼ 3.96 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 4.06 (d,
2
2
2JHH ¼ 13.5 Hz, 1 H, CH2), 5.80 (d, JHH ¼ 9 Hz, 1 H, CH), 6.73 (d, JHH ¼ 9 Hz,
1 H, CH), 7.27–7.65 (m, 10 H, ArH), 8.23 (d, J ¼ 9 Hz, 1 H, NH). 13C NMR
(125 MHz, DMSO-d6): d ¼ 35.52, 62.06, 75.00, 127.60, 128.28, 128.78, 128.94,
129.39, 132.31, 133.79, 138.14, 167.06. Calcd. (%) for C16H15Cl2NOS: C, 56.48; H,
4.44; Cl, 20.84; N, 4.12; S, 9.42. Found: C, 56.55; H, 4.33; Cl, 20.76; N, 4.09; S, 9.36.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-3-methylbenzamide
pared from 2.30 g of 4c. Yield 2.90 g (82%). Colorless crystals; mp 87–89 ꢀC. H
(5c). Pre-
1
2
NMR (500 MHz, DMSO-d6): d ¼ 2.38 (s, 3 H, CH3), 3.91 (d, JHH ¼ 13.5 Hz, 1 H,
2
3
3
CH2), 3.98 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 5.60 (dd, JHH ¼ 4.5 Hz, JHH ¼ 9 Hz,
3
1 H, CH), 6.44 (d, JHH ¼ 4.5 Hz, 1 H, CH), 7.23–7.71 (m, 9 H, ArH), 9.13 (d,
3JHH ¼ 9 Hz, 1 H, NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 21.38, 35.50, 62.03,
74.99, 125.44, 127.58, 128.68, 128.72, 128.93, 129.38, 132.85, 133.75, 138.09,
138.17, 167.12. Calcd. (%) for C17H17Cl2NOS: C, 57.63; H, 4.84; Cl, 20.01; N,
3.95; S, 9.05. Found: C, 57.66; H, 4.82; Cl, 19.96; N, 3.93; S, 9.12.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-4-methylbenzamide (5d). Pre-
1
pared from 2.30 g of 4d. Yield 2.37 g (67%). Colorless crystals; mp 107–108 ꢀC. H
2
NMR (500 MHz, DMSO-d6): d ¼ 2.39 (s, 3 H, CH3), 3.91 (d, JHH ¼ 13.5 Hz, 1 H,
2
3
3
CH2), 3.98 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 5.56 (dd, JHH ¼ 4.5 Hz, JHH ¼ 9 Hz,
3
1 H, CH), 6.28 (d, JHH ¼ 4.5 Hz, 1 H, CH), 7.21–7.80 (m, 9 H, ArH), 8.96 (d,
3JHH ¼ 9 Hz, 1 H, NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 21.52, 35.52, 62.08,
75.01, 127.58, 128.31, 128.93, 129.31, 129.38, 130.96, 138.15, 142.34, 166.86. Calcd.
(%) for C17H17Cl2NOS: C, 57.63; H, 4.84; Cl, 20.01; N, 3.95; S, 9.05. Found: C,
57.56; H, 4.90; Cl, 19.99; N, 4.21; S, 9.40.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-4-fluorobenzamide
pared from 2.34 g of 4e. Yield 3.33 g (93%). Colorless crystals; mp 92–93 ꢀC. H
(5e). Pre-
1
2
NMR (500 MHz, DMSO-d6): d ¼ 3.92 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 3.98 (d,
3
3
2JHH ¼ 13.5 Hz, 1 H, CH2), 5.59 (dd, JHH ¼ 5 Hz, JHH ¼ 9 Hz, 1 H, CH), 6.45 (d,
J ¼ 5 Hz, 1 H, CH), 7.24-7.98 (m, 9 H, ArH), 9.23 (d, J ¼ 9 Hz, 1 H, NH). 13C
NMR (125 MHz, DMSO-d6): d ¼ 35.52, 62.11, 74.99, 115.64, 115.81, 127.58,
128.92, 129.37, 130.22, 131.00, 131.08, 138.13, 163.72, 165.70, 166.00. 19F NMR
(470 MHz, DMSO-d6): d ¼ -54.18. Calcd. (%) for C16H14Cl2FNOS: C, 53.64; H,
3.94; Cl, 19.79; N, 3.91; S, 8.95. Found: C, 53.72; H, 4.02; Cl, 19.73; N, 3.82; S, 8.79.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-4-chlorobenzamide
pared from 2.50 g of 4f. Yield 2.92 g (78%). Colorless crystals; mp 114–115 ꢀC. H
(5f). Pre-
1
2
NMR (500 MHz, DMSO-d6): d ¼ 3.92 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 4.02 (d,
3
3
2JHH ¼ 13.5 Hz, 1 H, CH2), 5.73 (dd, JHH ¼ 2.5 Hz, JHH ¼ 9 Hz, 1 H, CH), 5.95

SYNTHESIS OF THIAZOLE-4-SULFONYL CHLORIDES
2871
3
3
(d, JHH ¼ 2.5 Hz, 1 H, CH), 6.59 (d, JHH ¼ 9 Hz, 1 H, NH), 7.23-7.70 (m, 9 H,
ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 35.54, 62.11, 74.96, 127.59, 128.86,
128.92, 129.37, 130.24, 132.50, 137.16, 138.10, 166.08. Calcd. (%) for
C16H14Cl3NOS: C, 51.29; H, 3.77; Cl, 28.38; N, 3.74; S, 8.56. Found: C, 51.23; H,
3.72; Cl, 28.42; N, 3.69; S, 8.73.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-3-bromobenzamide
(5g). Pre-
1
pared from 2.95 g of 4g. Yield 4.02 g (96%). Colorless crystals; mp 81–83 ꢀC. H
NMR (500 MHz, DMSO-d6): d ¼ 3.99 (m, 2 H, CH2), 5.61 (m, 1 H, CH), 6.42 (d,
3JHH ¼ 5 Hz, 1 H, CH), 7.25–7.88 (m, 8 H, ArH) 8.04 (s, 1 H, ArH), 9.23 (s, 1 H,
NH). 13C NMR (125 MHz, DMSO-d6): d ¼ 35.50, 62.10, 74.93, 122.03, 127.50,
127.58, 128.92, 129.36, 130.87, 131.03, 135.00, 135.88, 138.14, 165.63. Calcd. (%)
for C16H14BrCl2NOS: C, 45.85; H, 3.37; Br, 19.09; Cl, 16.92; N, 3.34; S, 7.65. Found:
C, 45.88; H, 3.44; Br, 19.03; Cl, 17.12; N, 3.28; S, 7.73.
N-(1-Benzylsulfanyl-2,2-dichloroethyl)-4-bromobenzamide
pared from 2.95 g of 4h. Yield 3.56 g (85%). Colorless crystals; mp 120–121 ꢀC. H
(5h). Pre-
1
2
NMR (500 MHz, DMSO-d6): d ¼ 3.93 (d, JHH ¼ 13.5 Hz, 1 H, CH2), 3.99 (d,
3
3
2JHH ¼ 13.5 Hz, 1 H, CH2), 5.59 (dd, JHH ¼ 5 Hz, JHH ¼ 9 Hz, 1 H, CH), 6.46 (d,
3JHH ¼ 5 Hz, 1 H, CH), 7.23–7.37 (m, 5 H, ArH) 7.72 (d, JHH ¼ 8.5 Hz, 2 H,
3
ArH), 7.83 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 9.31 (d, JHH ¼ 9 Hz, 1 H, NH). 13C
NMR (125 MHz, DMSO-d6): d ¼ 35.55, 62.12, 74.95, 126.10, 127.59, 128.92,
129.36, 130.40, 131.80, 132.90, 138.10, 166.21. Calcd. (%) for C16H14BrCl2NOS:
C, 45.85; H, 3.37; Br, 19.09; Cl, 16.92; N, 3.34; S, 7.65. Found: C, 45.74; H, 3.41;
Br, 19.12; Cl, 17.03; N, 3.26; S, 7.71.
3
3
Preparation of Compounds 6
General procedure. Lawesson reagent (2.22 g, 5.5 mmol) was added to a stir-
red solution of compound 5 (5 mmol) in 1,4-dioxane (30 mL). The reaction mixture
was refluxed for 8 h, and then the solvent was removed under reduced pressure. The
residue was triturated with 10% aqueous NaOH, adjusting to pH 9. The raw product
was filtered, dried, and recrystallized from 2-propanol. Liquid products were
extracted with dichloromethane. The organic layer was dried over magnesium sulfate
and evaporated, and the product was purified by distillation in vacuo for 6a.
4-Benzylsulfanyl-2-methyl-1,3-thiazole (6a). Prepared from 13.91 g of 5a.
1
Yield 8.63 g (78%). Colorless liquid; bp 146–148 ꢀC (5 mbar). H NMR (500 MHz,
DMSO-d6): d ¼ 2.59 (s, 3 H, CH3), 4.04 (s, 2 H, CH2), 7.20–7.33 (m, 5 H, ArH),
7.44 (s, 1H, ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 19.71, 43.25, 127.50,
128.47, 128.55, 129.00, 137.17, 148.06, 170.21. Calcd. (%) for C11H11NS2: C,
59.69; H, 5.07; N, 6.33; S, 28.97. Found: C, 59.71; H, 5.07; N, 6.27; S, 29.03.
4-Benzylsulfanyl-2-phenyl-1,3-thiazole (6b). Prepared from 1.70 g of 5b.
Yield 1.12 g (79%). Colorless crystals; mp 54–55 ꢀC. 1H NMR (500 MHz,
DMSO-d6): d ¼ 4.08 (s, 2 H, CH2), 7.21–7.84 (m, 10 H, ArH), 7.61 (s, 1 H, ArH).
13C NMR (125 MHz, DMSO-d6): d ¼ 42.37, 126.50, 127.87, 128.91, 129.49, 129.75,
131.06, 133.29, 137.67, 148.95, 170.56. Calcd. (%) for C16H13NS2: C, 67.81; H,
4.62; N, 4.94; S, 22.63. Found: C, 67.61; H, 4.72; N, 5.33; S, 22.28.

2872
B. A. DEMYDCHUK ET AL.
4-Benzylsulfanyl-2-(3-methylphenyl)-1,3-thiazole (6c). Prepared from
1.77 g of 5c. Yield 1.15 g (77%). Yellow oil. 1H NMR (500 MHz, DMSO-d6):
d ¼ 2.36 (s, 3 H, CH3), 4.13 (s, 2 H, CH2), 7.24–7.32 (m, 6 H, ArH), 7.36 (d,
3
3JHH ¼ 8 Hz, 1 H, ArH), 7.64 (d, JHH ¼ 8 Hz, 1 H, ArH), 7.68 (s, 1 H, ArH), 7.70
(s, 1 H, ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 21.36, 42.43, 123.75, 126.91,
127.85, 128.89, 129.28, 129.46, 129.59, 131.71, 133.29, 137.66, 139.10, 148.90,
170.75. Calcd. (%) for C17H15NS2: C, 68.65; H, 5.08; N, 4.71; S, 21.56. Found: C,
68.61; H, 5.10; N, 4.67; S, 21.60.
4-Benzylsulfanyl-2-(4-methylphenyl)-1,3-thiazole (6d). Prepared from
1.77 g of 5d. Yield 1.31 g (88%). Colorless crystals; mp 84–85 ꢀC. 1H NMR
(500 MHz, DMSO-d6): d ¼ 2.36 (s, 3 H, CH3), 4.07 (s, 2 H, CH2), 7.21–7.78 (m,
9 H, ArH), 7.95 (s, 1 H, ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 21.46, 42.38,
126.44, 127.85, 128.90, 129.09, 129.48, 130.28, 130.74, 137.71, 141.01, 148.89,
170.77. Calcd. (%) for C17H15NS2: C, 68.65; H, 5.08; N, 4.71; S, 21.56. Found: C,
68.66; H, 5.11; N, 4.69; S, 21.63.
4-Benzylsulfanyl-2-(4-fluorophenyl)-1,3-thiazole (6e). Prepared from
1.79 g of 5e. Yield 1.07 g (71%). Colorless crystals; mp 85–87 ꢀC. 1H NMR
(500 MHz, DMSO-d6): d ¼ 4.14 (s, 2 H, CH2), 7.24–7.92 (m, 9 H, ArH), 7.70 (s, 1
H, ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 42.34, 116.74, 116.91, 127.88,
127.88, 128.79, 128.92, 129.48, 129.93, 129.96, 137.66, 148.95, 162.86, 164.84,
169.34. 19F NMR (470 MHz, DMSO-d6): d ¼ ꢁ55.69. Calcd. (%) for C16H12FNS2:
C, 63.76; H, 4.01; N, 4.65; S, 21.28. Found: C, 63.67; H, 3.98; N, 4.57; S, 21.34.
4-Benzylsulfanyl-2-(4-chlorophenyl)-1,3-thiazole (6f). Prepared from
1.87 g of 5f. Yield 1.06 g (67%). Colorless crystals; mp 99–100 ꢀC. 1H NMR
(500 MHz, CDCl3): d ¼ 3.40 (s, 2 H, CH2), 7.21–7.42 (m, 5H, ArH), 7.41 (d,
3
3JHH ¼ 8.5 Hz, 2 H, ArH), 7.58 (s, 1 H, ArH), 7.81 (d, JHH ¼ 8.5 Hz, 2 H, ArH).
13C NMR (125 MHz, DMSO-d6): d ¼ 42.30, 127.89, 128.14, 128.92, 129.48, 129.83,
130.44, 132.05, 135.64, 137.61, 148.94, 169.04. Calcd. (%) for C16H12ClNS2: C,
60.46; H, 3.81; Cl, 11.15; N, 4.41; S, 20.17. Found: C, 60.51; H, 3.86; Cl, 11.28;
N, 4.36; S, 20.19.
4-Benzylsulfanyl-2-(3-bromophenyl)-1,3-thiazole (6g). Prepared from
2.09 g of 5g. Yield 1.41 g (78%). Colorless crystals; mp 53–54 ꢀC. 1H NMR
(500 MHz, DMSO-d6): d ¼1H NMR (DMSO-d6): d ¼ 4.17 (s, 2 H, CH2),
3
3
7.25–7.31 (m, 5 H, ArH), 7.46 (t, JHH ¼ 8 Hz, 1 H, ArH), 7.69 (d, JHH ¼ 8.5 Hz,
3
1 H, ArH), 7.76 (s, 1 H, ArH), 7.84 (d, JHH ¼ 8 Hz, 1 H, ArH), 8.02 (s, 1 H,
ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 42.27, 122.99, 125.65, 127.91, 128.58,
128.94, 129.49, 130.97, 131.95, 133.64, 135.24, 137.58, 148.88, 168.35. Calcd. (%)
for C16H12BrNS2: C, 53.04; H, 3.34; Br, 22.05; N, 3.87; S, 17.70. Found: C, 53.03;
H, 3.37; Br, 22.07; N, 3.85; S, 17.72.
4-Benzylsulfanyl-2-(4-bromophenyl)-1,3-thiazole (6h). Prepared from
2.09 g of 5h. Yield 1.37 g (76%). Colorless crystals; mp 101–102 ꢀC. 1H NMR
(500 MHz, DMSO-d6): d ¼1H NMR (DMSO-d6): d ¼ 4.16 (s, 2 H, CH2),
3
7.27–7.32 (m, 5 H, ArH), 7.70 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 7.74 (s, 1 H, ArH),
3
7.80 (d, JHH ¼ 8.5 Hz, 2 H, ArH). 13C NMR (125 MHz, DMSO-d6): d ¼ 42.28,

SYNTHESIS OF THIAZOLE-4-SULFONYL CHLORIDES
2873
123.68, 128.53, 128.93, 129.49, 130.95, 131.44, 133.05, 135.28, 137.59, 148.90, 168.49.
Calcd. (%) for C16H12BrNS2: C, 53.04; H, 3.34; Br, 22.05; N, 3.87; S, 17.70. Found:
C, 53.13; H, 3.27; Br, 22.08; N, 3.81; S, 17.63.
Preparation of 1,3-Thiazole-4-sulfonyl Chlorides (7)
General procedure. Compound 6 (5 mmol) was dissolved in a mixture of gla-
cial acetic acid (50 mL) and deionized water (5 mL). The chlorine was bubbled slowly
into the stirred reaction mixture at a temperature below 20 ꢀC for 30 min. Then the
reaction mixture was poured onto ice. The precipitated crude product was filtered,
washed with water, dried in vacuum, and recrystallized from n-hexanes. In the case
of liquid products, the crude product was extracted with dichloromethane. The
organic layer was dried over magnesium sulfate and evaporated, and the product
was purified by distillation in vacuo for 7a.
2-Methyl-1,3-thiazole-4-sulfonyl chloride (7a). Prepared from 7.96 g of 6a.
1
Yield 2.37 g (24%). Colorless liquid; bp 75–80 ꢀC (5 mbar). H NMR (500 MHz,
CDCl3): d ¼ 2.85 (s, 3 H, CH3), 8.31 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3):
d ¼ 19.86, 126.83, 150.01, 171.54. Calcd. (%) for C4H4ClNO2S2: C, 24.31; H, 2.04;
Cl, 17.94; N, 7.09; S, 32.44. Found: C, 24.27; H, 2.09; Cl, 18.02; N, 7.06; S, 32.38.
2-Phenyl-1,3-thiazole-4-sulfonyl chloride (7b). Prepared from 1.42 g of 6b.
1
Yield 0.86 g (66%). Colorless crystals; mp 89–90 ꢀC. H NMR (500 MHz, CDCl3):
d ¼ 7.50–8.00 (m, 5 H, ArH), 8.46 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3):
d ¼ 127.36, 129.52, 131.61, 132.72, 139.23, 149.68, 176.71. Calcd. (%) for
C9H6ClNO2S2: C, 41.62; H, 2.33; Cl, 13.65; N, 5.39; S, 24.69. Found: C, 41.58; H,
2.38; Cl, 13.70; N, 5.36; S, 24.76.
2-(3-Methylphenyl)-1,3-thiazole-4-sulfonyl chloride (7c). Prepared from
1.49 g of 6c. Yield 0.81 g (59%). Colorless crystals; mp 74–75 ꢀC. 1H NMR
(500 MHz, CDCl3): d ¼ 2.46 (s, 3 H, CH3), 7.42 (m, 2 H, ArH), 7.79 (d, 3JHH ¼ 8 Hz,
Hz, 2 H, ArH), 7.83 (s, 1 H, ArH), 8.46 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3):
d ¼ 21.34, 124.59, 127.85, 129.40, 131.54, 133.56, 139.06, 139.51, 149.62, 177.01.
Calcd. (%) for C10H8ClNO2S2: C, 43.87; H, 2.95; Cl, 12.95; N, 5.12; S, 23.42. Found:
C, 43.89; H, 2.98; Cl, 12.92; N, 5.13; S, 23.45.
2-(4-Methylphenyl)-1,3-thiazole-4-sulfonyl chloride (7d). Prepared from
1.49 g of 6d. Yield 1.08 g (79%). Colorless crystals; mp 104–105 ꢀC. 1H NMR
3
(500 MHz, CDCl3): d ¼ 2.45 (s, 3 H, CH3), 7.33 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 7.88
3
(d, JHH ¼ 8.5 Hz, 2 H, ArH), 8.45 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3):
d ¼ 21.69, 127.31, 129.02, 130.19, 138.64, 143.64, 149.69, 176.97. Calcd. (%) for
C10H8ClNO2S2: C, 43.87; H, 2.95; Cl, 12.95; N, 5.12; S, 23.42. Found: C, 43.91;
H, 2.87; Cl, 12.91; N, 5.03; S, 23.49.
2-(4-Fluorophenyl)-1,3-thiazole-4-sulfonyl chloride (7e). Prepared from
1.51 g of 6e. Yield 0.94 g (68%). Colorless crystals; mp 81–82 ꢀC. 1H NMR
(500 MHz, CDCl3): d ¼ 7.21–8.04 (m, 4 H, ArH), 8.46 (s, 1 H, ArH). 13C NMR
(125 MHz, CDCl3): d ¼ 116.74, 116.92, 128.01, 129.62, 139.30, 149.65, 164.39,
166.42, 175.28. 19F NMR (470 MHz, DMSO-d6): d ¼ ꢁ52.04. Calcd. (%) for

2874
B. A. DEMYDCHUK ET AL.
C9H5ClFNO2S2: C, 38.92; H, 1.80; Cl, 12.77; N, 5.04; S, 23.09. Found: C, 38.87; H,
1.86; Cl, 12.72; N, 5.04; S, 23.11.
2-(4-Chlorophenyl)-1,3-thiazole-4-sulfonyl chloride (7f). Prepared from
1.59 g of 6f. Yield 0.98 g (67%). Colorless crystals; mp 98–99 ꢀC. 1H NMR
3
3
(500 MHz, CDCl3): d ¼ 7.51 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 7.95 (d, JHH ¼ 8.5 Hz,
2 H, ArH), 8.47 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3): d ¼ 128.52, 129.84,
130.05, 139.04, 139.52, 149.66, 175.15. Calcd. (%) for C9H5Cl2NO2S2: C, 36.75; H,
1.71; Cl, 24.10; N, 4.76; S, 21.80. Found: C, 36.71; H, 1.75; Cl, 24.12; N, 4.69; S,
21.75.
2-(3-Bromophenyl)-1,3-thiazole-4-sulfonyl chloride (7g). Prepared from
1.81 g of 6g. Yield 1.2 g (71%). Colorless crystals; mp 95–96 ꢀC. 1H NMR
3
3
(500 MHz, CDCl3): d ¼ 7.42 (t, JHH ¼ 8 Hz, 1 H, ArH), 7.72 (d, JHH ¼ 8 Hz, 1 H,
ArH), 7.92 (d, JHH ¼ 8 Hz, 1 H, ArH), 8.20 (s, 1H, ArH), 8.49 (s, 1H, ArH). 13C
3
NMR (125 MHz, DMSO-d6): d ¼ 123.63, 125.88, 130.13, 130.96, 133.33, 135.48,
139.94, 149.57, 174.56. Calcd. (%) for C9H5BrClNO2S2: C, 31.92; H, 1.49; Br,
23.60; Cl, 10.47; N, 4.14; S, 18.94. Found: C, 31.90; H, 1.50; Br, 23.58; Cl, 10.49;
N, 4.12; S, 18.91.
2-(4-Bromophenyl)-1,3-thiazole-4-sulfonyl chloride (7h). Prepared from
1.81 g of 6h. Yield 1.42 g (84%). Colorless crystals; mp 117–119 ꢀC. 1H NMR
3
3
(500 MHz, CDCl3): d ¼ 7.68 (d, JHH ¼ 8.5 Hz, 2 H, ArH), 7.88 (d, JHH ¼ 8.5 Hz,
2 H, ArH), 8.46 (s, 1 H, ArH). 13C NMR (125 MHz, CDCl3): d ¼ 127.51, 128.62,
130.50, 132.81, 139.57, 149.66, 175.23. Calcd. (%) for C9H5BrClNO2S2: C, 31.92;
H, 1.49; Br, 23.60; Cl, 10.47; N, 4.14; S, 18.94. Found: C, 31.87; H, 1.52; Br,
23.64; Cl, 10.42; N, 4.08; S, 18.87.
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