Convenient one-pot synthesis of sulfonamides from thiols using trichloroisocyanuric acid

Article abstract of DOI:10.1080/00397910701356942

A convenient synthesis of sulfonamides from thiols is described. In situ preparation of sulfonyl chlorides from thiols is accomplished by oxidation with trichloroisocyanuric acid (TCCA), benzyltrimethylammonium chloride and water (2.5 equiv). The sulfonyl chlorides are then further allowed to react with excess amine in the same reaction vessel. Triethylamine can be optionally added as acid scavenger. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701356942

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Convenient One‐Pot Synthesis of
Sulfonamides from Thiols using
Trichloroisocyanuric Acid
Jason D. Bonk a , David T. Amos a & Sarah J. Olson a
a 3M Pharmaceuticals, Chemistry Department, St. Paul, Minnesota, USA
Version of record first published: 22 Jun 2007.
To cite this article: Jason D. Bonk , David T. Amos & Sarah J. Olson (2007): Convenient One‐Pot Synthesis of
Sulfonamides from Thiols using Trichloroisocyanuric Acid, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:12, 2039-2050
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Synthetic Communicationsw, 37: 2039–2050, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701356942
Convenient One-Pot Synthesis of
Sulfonamides from Thiols using
Trichloroisocyanuric Acid
Jason D. Bonk, David T. Amos, and Sarah J. Olson
3M Pharmaceuticals, Chemistry Department, St. Paul, Minnesota, USA
Abstract: A convenient synthesis of sulfonamides from thiols is described. In situ
preparation of sulfonyl chlorides from thiols is accomplished by oxidation with trichloro-
isocyanuric acid (TCCA), benzyltrimethylammonium chloride and water (2.5 equiv).
The sulfonyl chlorides are then further allowed to react with excess amine in the same
reaction vessel. Triethylamine can be optionally added as acid scavenger.
Keywords: oxidation, sulfonamides, thiol, trichloroisocyanuric acid
As a part of our medicinal chemistry program, we wished to synthesize
various imidazoquinoline-based sulfonamides for which existing methods
were largely unsatisfactory. We discovered that the chemistry described
herein suited our needs nicely.[1,2] This communication details our exploration
of the scope and optimization of the method.
Frequently, sulfonamides are formed from a sulfonyl chloride and a
primary or secondary amine. In turn, sulfonyl chlorides can be prepared
from the corresponding thiols using a number of methods, commonly by
bubbling Cl2 gas into aqueous acid or a biphasic mixture containing the
thiol.[3–7] Although this methodology is relatively general, issues associated
with the use of excess oxidant and/or aqueous acid have prompted the devel-
opment of alternative methods.[8,9] We describe an oxidation/substitution
Received in the USA October 27, 2006
Address correspondence to Jason D. Bonk, 3M Pharmaceuticals, Chemistry Depart-
ment, 3M Center, Building 270 4S 02, St. Paul, MN 55144-1000, USA. E-mail:
jbonk@mmm.com
2039

2040
J. D. Bonk, D. T. Amos, and S. J. Olson
sequence that is mild and minimizes both the amount of oxidant required and
the aqueous component.
Initially, we surmised that it might be possible to generate controlled
amounts of Cl2 in nonprotic organic solvents by mixing a tetraalkylammonium
chloride salt with trichloroisocyanuric acid (TCCA).[10] We were pleased to
find that treatment of benzyltrimethyl ammonium chloride (3.4 equiv) with
TCCA (1.1 equiv) in CH2Cl2 (30 min, rt) provided a light yellow solution;
neither of the white solids (TCCA nor BnMe3NCl) are substantially soluble
in CH2Cl2, but within 30 min the suspension became a light yellow solution
(in CH3CN, a small amount of undissolved white solid remained). This
solution, when added to an ice-cooled solution of a thiol containing H2O
(2.5 equiv), provided the corresponding sulfonyl chloride (observable by
liquid chromatography-mass spectrometry (LC-MS)) within 30 min.
Subsequent addition of a primary or secondary amine (6.5 equiv) afforded
the desired sulfonamide (method A).
Ultimately, we found that the reaction could be rendered truly one-pot by
using CH3CN as solvent. Thus, an ice-cooled solution of thiol, H2O, and
BnMe3NCl was treated with TCCA (30 min), followed by the amine
(method B). Optionally, 1.2 equiv of amine can be added, along with 5.5
equiv of Et3N (method C). Standard workup followed by silica gel chromato-
graphy provided the sulfonamides in excellent overall yields.
The stoichiometry of the sulfonyl chloride formation theoretically
requires 3 equiv of oxidant (Cl2) and 2 equiv of water, so the reaction
proceeds cleanly with only a slight excess of each. Also, HCl is evolved,
which necessitates the use of excess amine.
When CH3CN is used as solvent, the scope of the reaction appears to be
fairly general (Table 1). Aryl thiols appeared to be insensitive to substitution.
Both electron withdrawing (entries 11, 12) and electron donating (entries 17,
18) are tolerated, as well as ortho substitution (entries 14–16). 1-Butanethiol
(entry 13) also was oxidized efficiently. In general, there is no significant
difference in yield among the three different procedures (entries 1–3).
We were unable to successfully oxidize heterocyclic thiols (entries
24–26) other than 2-mercaptopyridine, even when keeping the internal
temperature colder than 2258C. In fact, a 70% isolated yield of 2-chlor-
opyrimidine was obtained from thiol 1f. Analysis by LC-MS indicated
that 2-chlorobenzothiazole was formed cleanly from thiol 1g,[11]
although we did observe the transient presence of a small amount of the
sulfonyl chloride.
Yields using CH2Cl2 as solvent are unpredictable using method B
(entries 5, 20, 22) but are good using method A. We attribute this variabil-
ity at least in part to the poor solubility of TCCA in CH2Cl2. In some cases
where yields were poor, we observed formation of the disulfide.[12]
Curiously, using method B and an aged bottle of TCCA, we obtained con-
sistently acceptable yields (.75%). We are currently investigating the
nature of these results.

Table 1. Effect of method and solvent on yield
Entry
1
Thiol (1)
Product (3)
Methoda
A
Solvent
CH3CN
Yield (%)
85
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
3a
3a
3a
3a
3a
3a
B
C
A
B
B
B
CH3CN
CH3CN
CH2Cl2
CH2Cl2
THF
94
91
90
69
67
53
EtOAc
8
1a
B
CH3CN
91
(continued)

Table 1. Continued
Entry
9
Thiol (1)
Product (3)
Methoda
B
Solvent
CH3CN
Yield (%)
88
1a
10
11
1a
Cb
CH3CN
CH3CN
74
89
B

12
13
1b
B
B
CH3CN
CH3CN
93
92
14
15
16
B
B
B
CH3CN
CH3CN
CH3CN
92
82
75
1d
1d
(continued)

Table 1. Continued
Entry
17
Thiol (1)
Product (3)
Methoda
B
Solvent
CH3CN
Yield (%)
94
18
1e
B
CH3CN
93
19
20
21
1e
1e
1e
3l
3l
3l
A
B
B
CH2Cl2
CH2Cl2
THF
92
51
83

22
1e
1e
B
CH2Cl2
0
23
24
3m
3n
B
A
CH3CN
CH3CN
76
0
25
26
1f
B
B
CH3CN
CH3CN
0c
0d
aA: BnMe3NCl and TCCA were premixed (30 min), then added to a solution of thiol and water; after 30 min the amine was added. B: TCCA was
added to a mixture of BnMe3NCl, thiol, and water; after 30 min the amine was added. C: TCCA was added to a mixture of BnMe3NCl, thiol, and
water; after 30 min the amine and Et3N were added.
bUsed 6.5 equiv of Et3N with ethyl 4-aminobutyrate hydrochloride.
cObtained 2-chloropyrimidine at 2258C.
dObserved 2-chlorobenzothiazole at 2258C.

2046
J. D. Bonk, D. T. Amos, and S. J. Olson
We made a number of observations regarding the reaction parameters.
The reaction between BnMe3NCl and TCCA itself (method A) is not
exothermic generating very little pressure if conducted in a capped vial
on a 2-mmol scale. For either procedure A or B, a transient 10–158C temp-
erature increase during the formation of the sulfonyl chloride was observed;
this could be mitigated by portionwise addition of the TCCA over several
min. This phenomenon was true of the amine addition as well.
EXPERIMENTAL
All reactions were conducted open to the atmosphere using commercially
available reagents, which were used as received. NMR analyses were
conducted on a Bruker 300-, 500-, or 700-MHz NMR; the chemical shifts
are referenced to tetramethylsilane at d0.00 ppm. Melting points were
obtained on an OptiMelt automated instrument (Stanford Research
Solutions, Sunnyvale, CA). MS analyses were conducted on a Hewlett
Packard 1100 HPLC system using an electrospray ionization source in
positive ion mode. Elemental analyses were performed by Robertson
Microlit Laboratories (Madison, NJ) and were within 0.4% of the theoretical
values. All final compounds 3a–3m were purified by silica-gel chromato-
graphy using reagent-grade ethyl acetate/hexanes. Reactions performed in
the attempts to synthesize 3n and 3o were conducted at 230 to 2258C
by intermittent cooling in a dry ice/acetone bath, measured with internal
temperature probe.
General Procedures for the Conversion of Thiols to Sulfonamides:
N-Isobutylpyridine-2-sulfonamide (3a).
Method A
To a stirred suspension of BnMe3NCl (1.26 g, 3.4 equiv) in CH3CN (9 mL) at
ambient temperature, trichloroisocyanuric acid (0.51 g, 1.1 equiv) was added
as a solid in one portion. After 30 min, the clear yellow solution was added
dropwise to a stirred 08C solution of 2-mercaptopyridine (0.22 g, 1.0 equiv,
2.0 mmol) and water (90 mL, 2.5 equiv) in CH3CN (9 mL) over about
2 min. After 30 min isobutylamine (1.28 mL, 6.5 equiv) was added to the
mixture over 1–2 min. After 5 min, the ice bath was removed and the
mixture was allowed to stir for 1 h. The mixture was filtered and rinsed
twice with CH3CN (10 mL). The filtrate was evaporated. Column chromato-
graphy on silica gel eluting with ethyl acetate/hexanes provided the product
(85%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) d 8.71
(d, J ¼ 5.0 Hz, 1H), 8.01 (d, J ¼ 7.5 Hz, 1H), 7.91 (td, J ¼ 7.5, 1.9 Hz,
1H), 7.52–7.47 (m, 1H), 5.04 (br t, J ¼ 5.9 Hz, 1H), 2.85 (t, J ¼ 6.5 Hz,

Synthesis of Sulfonamides from Thiols
2047
2H), 1.75 (septet, J ¼ 6.5 Hz, 1H), 0.90 (d, J ¼ 6.9 Hz, 6H); 13C NMR
(125 MHz, CDCl3) d 157.6, 150.0, 138.1, 126.6, 122.3, 51.0, 28.7, 19.8;
MS (ESI) m/z 215 (M þ H)þ; anal. calcd. for C9H14N2O2S: C, 50.45; H,
6.59; N, 13.07. Found: C, 50.56; H, 6.30; N, 13.06.
Method B
To a stirred mixture of 2-mercaptopyridine (0.22 g, 1.0 equiv, 2.0 mmol),
BnMe3NCl (1.26 g, 3.4 equiv), and water (90 mL, 2.5 equiv) in CH3CN
(18 mL) at 08C trichloroisocyanuric acid (0.51 g, 1.1 equiv) was added as a
solid in portions over 1–2 min. After 30 min, isobutylamine (1.28 mL,
6.5 equiv) was added to the mixture over 1–2 min. The reaction was stirred
for 1 h, then processed as in method A to provide the desired product in
94% yield.
Method C
To a stirred mixture of 2-mercaptopyridine (0.22 g, 1.0 equiv, 2.0 mmol),
BnMe3NCl (1.26 g, 3.4 equiv), and water (90 mL, 2.5 equiv) in CH3CN
(18 mL) at 08C trichloroisocyanuric acid (0.51 , 1.1 equiv) was added as a
solid in portions over 1–2 min. After 30 min, triethylamine (1.5 mL,
5.5 equiv) was added followed by isobutylamine (1.28 mL, 6.5 equiv). The
reaction was stirred for 1 h, then processed as in method A to provide the
desired product in 91% yield.
Note: when CH2Cl2 was used as solvent, the reaction was worked up as
follows. The reaction mixture was diluted with CH2Cl2 (100 mL) and
washed twice with H2O (75 mL). The organic phase was dried over
MgSO4, filtered, and evaporated under reduced pressure. The resultant
residue is purified by column chromatography as before.
Data
N-(4-Methoxybenzyl)pyridine-2-sulfonamide (3b). Off-white solid, mp
1
96–978C. H NMR (300 MHz, CDCl3) d 8.65 (d, J ¼ 3.7 Hz, 1H), 7.97
(d, J ¼ 8.1 Hz, 1H), 7.88 (td, J ¼ 7.8, 1.9 Hz, 1H), 7.49–7.44 (m, 1H), 7.16
(d, J ¼ 8.7 Hz, 2H), 6.78 (d, J ¼ 8.7 Hz, 2H), 5.38 (br t, J ¼ 5.9 Hz, 1H),
4.19 (d, J ¼ 5.6 Hz, 2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) d
159.3, 157.7, 150.0, 137.9, 129.4, 128.4, 126.5, 122.2, 114.0, 55.3, 47.3;
MS (ESI) m/z 279 (M þ H)þ; anal. calcd. for C13H14N2O3S: C, 56.10; H,
5.07; N, 10.06. Found: C, 55.94; H, 4.95; N, 9.86.
4-(Pyridin-2-ylsulfonyl)morpholine (3c). White solid, mp 91–928C; 1H
NMR (300 MHz, CDCl3) d 8.75–8.72 (m, 1H), 7.96 (m, 2H), 7.55–7.49
(m, 1H), 3.75 (t, J ¼ 4.7 Hz, 4H), 3.34 (t, J ¼ 5.0 Hz, 4H); 13C NMR

2048
J. D. Bonk, D. T. Amos, and S. J. Olson
(176 MHz, CDCl3) d 156.0, 150.1, 138.0, 126.8, 123.2, 66.4, 46.5;MS (ESI)
m/z 229 (M þ H)þ; anal. calcd. for C9H12N2O3S: C, 47.36; H, 5.30; N,
12.27. Found: C, 47.59; H, 5.22; N, 12.32.
1
Ethyl 4-[(pyridin-2-ylsulfonyl)amino]butanoate (3d). Pale yellow oil. H
NMR (500 MHz, CDCl3) d 8.70 (d, J ¼ 4.7 Hz, 1H), 8.00 (d, J ¼ 7.9 Hz,
1H), 7.91 (td, J ¼ 7.7, 2.2 Hz, 1H), 7.51–7.47 (m, 1H), 5.21 (br t,
J ¼ 5.8 Hz, 1H), 4.10 (q, J ¼ 7.1 Hz, 2H), 3.13 (q, J ¼ 6.6 Hz, 2H), 2.38
(t, J ¼ 7.3 Hz, 2H), 1.84 (pentet, J ¼ 6.9 Hz, 2H), 1.24 (t, J ¼ 7.3 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 173.1, 157.6, 150.0, 138.1, 126.7, 122.2,
60.6, 43.0, 31.2, 25.1, 14.2; anal. calcd. for C11H16N2O4S: C, 48.52; H,
5.92; N, 10.29. Found: C, 48.53; H, 6.24; N, 10.17.
4-Fluoro-N-isobutylbenzenesulfonamide (3e). White solid, mp 85–878C.
1H NMR (500 MHz, CDCl3): d 7.89 (m, 2H), 7.18 (m, 2H), 4.70 (br t,
J ¼ 6.0 Hz, 1H), 2.77 (t, J ¼ 6.6 Hz, 2H), 1.71 (nonet, J ¼ 6.7 Hz, 1H),
0.88 (dd, J ¼ 0.5, 6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 165.0
(d, J ¼ 255 Hz), 136.3, 129.8, 129.7, 116.4, 116.2, 50.6, 28.5, 19.8; MS
(ESI) m/z 232 (M þ H)þ; anal. calcd. for C10H14FNO2S: C, 51.93; H, 6.10;
N, 6.06. Found: C, 52.07; H, 6.19; N, 6.01.
4-Fluoro-N-(4-methoxybenzyl)benzenesulfonamide (3f). White solid, mp
1
93–958C. H NMR (500 MHz, CDCl3): d 7.86 (m, 2H), 7.18 (m, 2H), 7.09
(m, 2H), 6.81 (m, 2H), 4.55 (br t, J ¼ 5.5 Hz, 1H), 4.09 (d, J ¼ 6.0 Hz,
2H), 3.78 (s, 3H); 13C NMR (125 MHz, CDCl3) d 165.0 (d, J ¼ 254 Hz),
159.4, 136.1, 129.9, 129.8, 129.3, 128.0, 116.4, 116.2, 114.1, 55.3, 46.8;
anal. calcd. for C14H14FNO3S: C, 56.94; H, 4.78; N, 4.74. Found: C, 56.87;
H, 4.62; N, 4.63.
N-(4-Methoxybenzyl)butane-1-sulfonamide (3g). White solid, mp 68–
1
708C. H NMR (500 MHz, CDCl3): d 7.26 (m, 2H), 6.88 (m, 2H), 4.49 (br
t, J ¼ 5.9 Hz, 1H), 4.22 (d, J ¼ 6.1 Hz, 2H), 3.80 (s, 3H), 2.90 (m, 2H),
1.73 (m, 2H), 1.38 (sextet, J ¼ 7.4 Hz, 2H), 0.90 (t, J ¼ 7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 159.5, 129.3, 129.0, 114.3, 55.4, 53.1, 46.8,
25.6, 21.5, 13.5; anal. calcd. for C12H19NO3S: C, 56.01; H, 7.44; N, 5.44.
Found: C, 55.94; H, 7.38; N, 5.34.
N-Isobutyl-2-methylbenzenesulfonamide (3h). Colorless oil. 1H NMR
(500 MHz, CDCl3): d 7.96 (m, 1H), 7.45 (ddd, J ¼ 1.4, 7.5, 7.5 Hz, 1H),
7.31 (m, 2H), 4.56 (br, 1H), 2.75 (t, J ¼ 6.6 Hz, 2H), 2.66 (s, 3H), 1.71
(nonet, J ¼ 6.6 Hz, 1H), 0.86 (d, J ¼ 6.7 Hz, 6H); 13C NMR (125 MHz,
CDCl3) d 138.0, 137.0, 132.7, 132.5, 129.5, 126.2, 50.5, 28.5, 20.3, 19.9;
MS (ESI) m/z 228 (M þ H)þ; anal. calcd for C11H17NO2S: C, 58.12; H,
7.54; N, 6.16. Found: C, 58.03; H, 7.82; N, 6.07.

Synthesis of Sulfonamides from Thiols
2049
N-(4-Methoxybenzyl)-2-methylbenzenesulfonamide (3i). Off-white solid,
1
mp 76–778C; H NMR (500 MHz, CDCl3) d 7.99 (d, J ¼ 8.0 Hz, 1H), 7.46
(td, J ¼ 7.6, 1.3 Hz, 1H), 7.34–7.27 (m, 2H), 7.07 (d, J ¼ 8.2 Hz, 2H), 6.79
(d, J ¼ 8.5 Hz, 2H), 4.56 (br t, J ¼ 6.3 Hz, 1H), 4.05 (d, J ¼ 6.0 Hz, 2H),
3.77 (s, 3H), 2.62 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.4, 137.1,
132.8, 132.5, 129.7, 129.3, 128.4, 126.2, 114.2, 55.3, 46.7, 20.3; anal. calcd.
for C15H17NO3S: C, 61.83; H, 5.88; N, 4.81. Found: C, 61.56; H, 5.88; N, 4.79.
N-Benzyl-N,2-dimethylbenzenesulfonamide (3j). Pale yellow oil. 1H NMR
(500 MHz, CDCl3) d 7.93 (d, J ¼ 8.8 Hz, 1H), 7.46 (td, J ¼ 7.6, 1.3 Hz, 1H),
7.36–7.24 (m, 7H), 4.31 (s, 2H), 2.69 (s, 3H), 2.267 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 137.9, 137.2, 135.8, 132.8, 132.7, 129.8, 128.7, 128.4,
127.9, 126.1, 53.5, 33.6, 20.6; MS (ESI) m/z 276 (M þ H)þ; anal. calcd. for
C15H17NO2S: C, 65.43; H, 6.22; N, 5.09. Found: C, 65.47; H, 6.43; N, 5.13.
N-Isobutyl-4-methoxybenzenesulfonamide (3k). White solid, mp 55–568C;
1H NMR (500 MHz, CDCl3) d 7.81 (d, J ¼ 8.8 Hz, 2H), 6.97 (d, J ¼ 8.8 Hz,
2H), 4.79 (t, J ¼ 6.3 Hz, 1H), 3.87 (s, 3H), 2.73 (t, J ¼ 6.6 Hz, 2H), 1.71
(septet, J ¼ 6.6 Hz, 1H), 0.86 (d, J ¼ 6.6 Hz, 6H); 13C NMR (125 MHz,
CDCl3) d 162.8, 131.8, 129.2, 114.2, 55.6, 50.6, 28.4, 19.9; MS (ESI) m/z
244 (M þ H)þ; anal. calcd. for C11H17NO3S: C, 54.30; H, 7.04; N, 5.76.
Found: C, 54.27; H, 6.74; N, 5.66.
4-Methoxy-N-(4-methoxybenzyl)benzenesulfonamide (3l). White solid, mp
1
112–1138C; H NMR (500 MHz, CDCl3) d 7.80 (d, J ¼ 8.8 Hz, 2H), 7.10
(d, J ¼ 8.2 Hz, 2H), 6.97 (d, J ¼ 8.8 Hz, 2H), 6.80 (d, J ¼ 8.5 Hz, 2H),
4.55 (t, J ¼ 6.0 Hz, 1H), 4.05 (d, J ¼ 6.0 Hz, 2H), 3.88 (s, 3H), 3.77
(s, 3H); 13C NMR (125 MHz, CDCl3) d 163.0, 159.4, 131.6, 129.3, 129.3,
128.4, 114.3, 114.1, 55.6, 55.3, 46.8; anal. calcd. for C15H17NO4S: C,
58.61; H, 5.57; N, 4.56. Found: C, 58.64; H, 5.29; N, 4.56.
4-Methoxybenzenesulfonamide (3m). White solid, mp 110–1128C. 1H
NMR (500 MHz, CDCl3): d 7.87 (m, 2H), 6.98 (m, 2H), 4.77 (br s, 2H),
3.87 (s, 3H); 13C NMR (125 Hz, CDCl3) d 163.1, 133.7, 128.7, 114.3, 55.7;
anal. calcd. for C7H9NO3S: C, 44.91; H, 4.85; N, 7.48. Found: C, 45.05; H,
4.89; N, 7.38.
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