A general and mild two-step procedure for the synthesis of aryl and heteroaryl sulfonamides from the corresponding iodides

Article abstract of DOI:10.1016/j.tetlet.2010.12.050

A mild two-step preparation of aryl and heteroaryl sulfonyl chlorides and sulfonamides from their corresponding iodides is developed. Acid labile functionalities are shown to be stable under both the copper-catalysed coupling and the subsequent oxidative chlorination.

Full text of DOI:10.1016/j.tetlet.2010.12.050

Tetrahedron Letters 52 (2011) 820–823
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Tetrahedron Letters
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A general and mild two-step procedure for the synthesis of aryl
and heteroaryl sulfonamides from the corresponding iodides
⇑
Danny K. H. Ho , Lily Chan, Alice Hooper, Paul E. Brennan
Pfizer Worldwide Medicinal Chemistry, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild two-step preparation of aryl and heteroaryl sulfonyl chlorides and sulfonamides from their corre-
sponding iodides is developed. Acid labile functionalities are shown to be stable under both the copper-
catalysed coupling and the subsequent oxidative chlorination.
Received 5 November 2010
Revised 26 November 2010
Accepted 10 December 2010
Available online 16 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Sulfonamides
Acid labile groups
Oxidative chlorination
Thiobenzoates
Sulfonamides are important functional groups in medicinal
chemistry as they have many desirable properties such as their
ability to act as H-bond donors and acceptors. They are the basis
of some of the early antibiotics such as the sulfanilamides. They
are widespread in other classes of pharmaceuticals such as the
anti-inflammatory agent celecoxib (1) and sildenafil (2) for erectile
dysfunction (Fig. 1).
Commonly, sulfonamides are prepared from sulfonyl chlorides
and amines. Aryl sulfonyl chlorides are typically prepared via: (1)
electrophilic aromatic substitution using an excess of chlorosul-
fonic acid, or (2) oxidative chlorination of sulfur compounds, such
as thiols, sulfides, thioacetates and thiocarbamates, with aqueous
chlorine.1 Although these reactions are very effective for synthesis-
ing sulfonyl chlorides, they do suffer from some drawbacks. Regi-
oselectivity of the electrophilic aromatic substitution is dictated
by substituents on the aryl ring and the strongly acidic conditions
can limit substrate scope. With oxidative chlorination, the use of
chlorine gas is not desirable as it is hazardous and requires careful
handling. Other oxidising agents, such as H2O2/SOCl2,2 NCS/HCl3
and trichloroisocyanuric acid (TCCA)/BnMe3NCl4 have been used
which allow for milder reaction conditions, but are still too acidic
for acid-sensitive functionalities to withstand. This approach also
requires the sulfur to be already incorporated in the molecule,
which either relies on the commercial availability of thiols or on
the effective methods for forming C–S bonds. Barrett’s group has
reported a one-pot sulfonamide formation from aryl or heteroaryl
halides, which involves the use of Grignard reagents with sulfur
dioxide, sulfuryl chloride and an amine (Scheme 1).5 However, this
method requires the use of reactive organometallics, which can be
incompatible with polar functionalities and the use of hazardous
SO2 gas is not desirable.
MgBr
X
SO2Cl
1) SO2
RMgBr
O
2) SO2Cl2
N
R
R
R
N
HN
O
F
N
N
S
N
N
N
H
F
O
HNR1R2
R1
F
OEt
H2N
S
O
O
1
2
O
N
S
R2
Figure 1. Examples of drugs with a sulfonamide functionality.
O
R
⇑
Corresponding author.
E-mail address: danny.kh.ho@pfizer.com (D.K.H. Ho).
Scheme 1. Barrett’s one-pot sulfonamide formation from aryl/heteroaryl halides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.050

D. K. H. Ho et al. / Tetrahedron Letters 52 (2011) 820–823
821
Willis and coworkers have demonstrated recently that efficient
aminosulfonylation of aryl halides can be achieved with the more
attractive DABCOÁ(SO2)2 complex and hydrazines.6
aryl iodides coupled just as effectively in most cases (entries 7–
10).8
With the scope of the copper-catalysed coupling established,
our focus was switched to the oxidative chlorination. Phenyl thi-
obenzoate was chosen as a model substrate for optimisation of
the oxidative chlorination reaction (Table 2). Under the reaction
conditions described by Nishiguchi (NCS/HCl), the desired sulfonyl
chloride was obtained in 67% yield. Even though the reaction was
Despite the recent progress in this field, there is still a need to
develop general and mild methods for the synthesis of aryl and
heteroaryl sulfonyl chlorides/sulfonamides from simple amines,
especially in the presence of acid labile functionalities. Herein,
we report a mild and general two-step procedure for the prepara-
tion of aryl/heteroaryl sulfonyl chlorides (and sulfonamides) from
the corresponding iodides. This procedure is tolerant of acid labile
groups such as Boc and Trityl (Tr), and it does not require the use of
strongly basic organometallic reagents or hazardous SO2 gas.
Nishiguchi reported that thioacetates can be oxidised to sulfo-
nyl chlorides using N-chlorosuccinimide (NCS);3 however, there
is a lack of general methods for converting halides into thioace-
tates. We envisaged that oxidative chlorination of aryl/heteroaryl
thiobenzoates could be achieved in the same way as thioacetates.
Aryl/heteroaryl thiobenzoates can be easily prepared from their
corresponding iodides via copper-catalysed coupling,7 although
examples with heteroaryl iodides are limited. In the first stage of
our study we focused on expanding the scope of the copper-cata-
lysed coupling, especially with respect to heteroaryls and also in
the presence of acid/heat sensitive groups. The results from this
investigation are summarised in Table 1.
Table 2
Optimisation of the oxidative chlorination of S-phenyl thiobenzoate
O
Cl
S
Ph
Chlorinating agent
S
O
Additives
O
MeCN, 0 oC, 20 min
Entry Chlorinating
agent (equiv)
Additives (equiv)
pH
Yielda (%)
1
2
3
NCS (2)
NCS (2)
NCS (2)
2 M HCl (0.5)
NaCl (0.5)
2 M HCl (0.5), phosphate
buffer
0
7
7
67
0
0
4
5
6
7
NCS (2)
NCS (2)
TCCA (1.2)
TCCA (1.2)
NH4Cl (0.5), H2O (2.5)
NEt3HCl (0.5), H2O (0.5)
BnMe3NCl (3.4), H2O (2.5)
BnMe3NCl (3.4), H2O (2.5),
NEt3 (1)
2–0
8
2–0
9
100
0
90
0
A range of aryl iodides were coupled effectively to yield the de-
sired thiobenzoates (entries 1, 2 and 4–6). Substrates which con-
tain heat/acid labile groups were stable under the reaction
condition (entries 4–6 and 10), except for the TBS-protected phe-
nol (entry 3), which was deprotected during the reaction. Hetero-
8
9
10
TCCA (1.2)
TCCA (1.2)
TCCA (1.2)
BnMe3NCl (3.4), 1 M Na2CO3 (1) 6–5 87
BnMe3NCl (3.4), 1 M K2CO3 (1)
BnMe3NCl (3.4), H2O (2.5),
NaOAc (1)
5–4 100b
1
100b
11
12
HOCl (3)
HOCl (3)
None
NaOAc (2)
0
8
<5
<5
a
Isolated yield after column chromatography.
Crude yield.
Table 1
b
Copper-catalysed coupling of thiobenzoic acid and various aryl or heteroaryl iodides
CuI (10 mol%)
1,10-phen (20 mol%)
O
O
Table 3
Ar/Het
I
Ph
+
i-Pr2NEt (2 eq.)
toluene
reflux, 16 h
HS
Ph
Oxidative chlorination with various aryl or heteroaryl thiobenzoates
Ar/Het
S
TCCA (1.2 equiv)
BnMe3NCl (3.4 equiv)
O
S
O
Yielda (%)
Ar/het
Ar/het
Cl
Entry
Het/Ar-I
S
Ph
1M Na2CO3 (1 equiv)
MeCN, 0 oC,
20 min
O
1
2
Ph-I
78
83
4-MeOC6H4I
I
Entry
1
Product
Yielda (%)
81
3
0
O
S
O
TBSO
MeO
Cl
I
O
S
O
4
56
Cl
2
3
89 [43]b
92 [<5]b
BocHN
BocHN
NHBoc
I
O
S
O
Cl
5
6
80
88
BocHN
I
O
S
O
Cl
4
5
46 [<5]b
80 [35]b
NHBoc
NHBoc
I
O
S
O
7
8
3-IC5H4N
4-IC5H4N
89
79
N
Cl
N
Tr
N
N
9
94
O
0 [0]b
0 [0]b
S
O
O
S
Cl
6
7
N
N
I
N
N
Cl
10
72
N
O
Tr
a
Isolated yield.
Yield without Na2CO3.
b
a
Isolated yield after column chromatography.

822
D. K. H. Ho et al. / Tetrahedron Letters 52 (2011) 820–823
successful, the reaction conditions were deemed too acidic (pH 0)
for any acid labile groups present in the molecule.9 Since this reac-
tion is believed to proceed via in situ generation of chlorine,3 it was
thought the reaction conditions could be made milder by using a
different chloride source. When NaCl was used instead of HCl
(pH 7), no reaction occurred (entry 2). The reaction was also unsuc-
cessful when carried out in a phosphate buffer (entry 3) or using a
milder HCl source (entry 5). The only other success was with
NH4Cl, which gave an almost quantitative yield although the reac-
tion was still too acidic (pH 2–0, entry 4). Alternative chlorinating
agents were investigated at this point. Oxidative chlorination with
bleach was attempted but gave little reaction (entries 11–12). A
mixture of trichloroisocyanuric acid (TCCA) and benzyltrimethy-
lammonium chloride (BnMe3NCl) has been reported recently in
effecting oxidation of thiophenols to sulfonyl chlorides.4 Under
these reaction conditions, the desired sulfonyl chloride was ob-
tained in 90% yield, although the pH was still low (entry 6). A range
of bases were investigated as buffering agents (entries 7–10) and
Na2CO3 (entry 8) was found to be the most effective in terms of
pH and yields.
To evaluate the generality of the oxidative chlorination, a vari-
ety of aryl/heteroaryl thiobenzoates, some with acid labile func-
tionalities, were subjected to the optimised reaction conditions
(Table 3).
Gratifyingly, acid labile functionalities were well tolerated un-
der the reaction conditions (entries 2–5), affording good yields of
products in most cases. The oxidative chlorination reaction was
sensitive to steric hindrance, as exemplified by the low yields
Table 4
One-pot sulfonamide formation
TCCA (1.2 equiv)
BnMe3NCl (3.4 equiv)
O
S
O
O
R1
R2
O
S
O
HNR1R2 (1.2 equiv)
Ar/Het
N
Ar/Het
Cl
Ar/Het
S
Ph
1M Na2CO3 (2 equiv)
MeCN, 0 oC,
20 min
Entry
1
Sulfonamide
Yielda (%)
81
O
S
N
O
O
O
S
O
O
S
H
N
2
3
4
5
6
7
8
15
49
70
85
<5
87
87
hexyl
H
N
Ph
O
O
MeO
S
N
O
O
O
S
O
O
S
N
O
BocHN
H
N
hexyl
O
BocHN
BocHN
O
O
S
O
O
S
N
H
N
BocHN
Ph
O
O
S
N
O
9
31
O
NHBoc
O
S
O
N
N
N
O
10
11
84
59
Tr
Tr
O
S
O
N
N
NH
hexyl
O
N
S
O
O
S
O
O
S
N
O
12
13
14
74
59b
0
N
N
O
O
N
N
N
O
a
Isolated yield.
b
Yield estimated from the NMR spectrum, a mixture of product and benzamide side-product was obtained.

D. K. H. Ho et al. / Tetrahedron Letters 52 (2011) 820–823
823
O
obenzoates can be oxidised under near neutral conditions to give
sulfonyl chlorides or further transformed into sulfonamides in
one-pot by the addition of an amine. The one-pot procedure allows
access to heteroaryl sulfonamides which are derived from unstable
sulfonyl chlorides.
R1
Ph
N
R2
Figure 2. The benzamide side-product.
Acknowledgement
obtained with o-N-Boc-phenylsulfonyl chloride (entry 4). Control
experiments (without Na2CO3) demonstrated the importance of
base in buffering the reaction; in its absence, the yields were signif-
icantly reduced (entries 2–5). Unsurprisingly, 3-pyridyl- and 5-
pyrimidyl-sulfonyl chlorides could not be isolated as they are
known to be unstable at room temperature (entries 6 and 7).
The mechanism of the oxidative chlorination is believed to be
similar to that of oxidation of thioacetates under the Nishiguchi
conditions. Molecular chlorine generated from TCCA and
BnMe3NCl effects the oxidative chlorination. It is possible that
the reaction goes via thiophenol as an intermediate, but this spe-
cies was not observed when the reaction was monitored closely
by LCMS.10
Next, we investigated the possibility of forming sulfonamides
from the corresponding thiobenzoates by adding amines directly
to the reactions. This would circumvent the problems with sulfonyl
chlorides which are unstable and/or difficult to handle. A brief
optimisation study showed that addition of 2 equiv of Na2CO3 at
the beginning of the reaction alleviated the need for a base to be
added when the amine is introduced. Using the optimised condi-
tions, the generality of this reaction was examined. The results,
summarised in Table 4, indicate that reactions with the secondary
amine, morpholine proceeded efficiently and the desired sulfona-
mides were obtained in moderate to good yields. In fact, morpho-
line was more efficient than primary and electron-deficient
amines. For a given amine, the yields are sensitive to the electronic
nature of the aryls or heteroaryls where higher yields were ob-
tained from more reactive sulfonyl chlorides (entries 1, 4, 7 and
10). As hoped, the desired sulfonamides were obtained from sub-
strates where the corresponding sulfonyl chlorides are known to
be unstable (entries 12 and 13) and which failed to yield any iso-
lable sulfonyl chlorides (Table 3, entry 6). Surprisingly, 5-pyrimidyl
thiobenzoate gave none of the desired sulfonamide, suggesting
decomposition of the preceding sulfonyl chloride occurs too rap-
idly (entry 14). The main side products isolated from these reac-
tions, especially for primary and electron-deficient amines, are
the corresponding benzamides (Fig. 2). The benzamide is presum-
ably formed from reaction of the amine with the benzoyl chloride
(or other activated benzoyl moiety) generated as a by-product
from the oxidative chlorination.
We thank Pete Wilson for helpful discussions.
References and notes
1. (a) Watson, R. J.; Batty, D.; Baxter, A. D.; Hannah, D. R.; Owen, D. A.; Montana, J.
G. Tetrahedron Lett. 2002, 43, 683; (b) Percec, V.; Bera, T. K.; De, B. B.; Sanai, Y.;
Smith, J.; Holerca, M. N.; Barboiu, B.; Grubbs, B. B. B.; Fréchet, J. M. J. J. Org.
Chem. 2001, 66, 2104.
2. Bahrami, K.; Khodaei, M. M.; Soheilizad, M. J. Org. Chem. 2009, 74, 9287.
3. Nishiguchi, A.; Maeda, K.; Miki, S. Synthesis 2006, 4131.
4. Bonk, J. D.; Amos, D. T.; Olson, S. J. Synth. Commun. 2007, 37, 2039.
5. Pandya, R.; Murashima, T.; Tedeschi, L.; Barrett, A. G. M. J. Org. Chem. 2003, 68,
8274.
6. Nguyen, B.; Emmett, E. J.; Willis, M. C. J. Am. Chem. Soc. 2010, 132, 16372.
7. Sawada, N.; Itoh, T.; Yasuda, N. Tetrahedron Lett. 2000, 47, 6595.
8. All thiobenzoates were synthesised following the procedure reported in Ref. 7.
9. pH was used as a guide to determine whether acid labile groups are likely to be
stable under the reaction conditions.
10. In some cases, a small amount of benzoic anhydride was detected by LCMS
during the oxidative chlorination step.
Typical procedures for the oxidative chlorination (Table 3, entry 1):
(4-Chlorosulfonyl-phenyl)-carbamic acid tert-butyl ester
To a stirred suspension of BnMe3NCl (192 mg, 1.03 mmol) in MeCN (2 ml) was
added TCCA (78 mg, 0.34 mmol) and the mixture was left to stir for 30 min. The
clear yellow solution obtained was added dropwise to a stirred solution of p-N-
Boc-phenylthiobenzoate (100 mg, 0.30 mmol) in MeCN (2 ml) over 2 min at
0 °C. To this mixture was added a 1 M solution of Na2CO3 (0.30 ml, 0.30 mmol)
and the reaction was allowed to proceed at this temperature for 20 min. At the
end of the reaction, the mixture was partitioned between EtOAc (10 ml) and
satd Na2CO3 (10 ml). The EtOAc layer was washed with brine (10 ml), dried and
concentrated in vacuo. The crude residue was purified by flash column
chromatography, eluting with 0–10% EtOAc/heptane, yielding 82 mg (92%
yield) of pure sulfonyl chloride as an off-white solid.
LC–MS ELSD 100% (ESI) m/z 290 [35Cl MÀH]À; 292 [37Cl MÀH]À
Anal. Calcd for C11H14ClNO4S: C, 45.29; H, 4.84; N, 4.80. Found: C, 45.42; H,
4.74; N, 4.91.
1H NMR (400 MHz, CDCl3) d 7.94 (d, J = 12 Hz, 2H), 7.60 (d, J = 12 Hz, 2H), 6.85
(br s, 1H), 1.56 (s, 9H).
Typical procedure for the one-pot sulfonamide formation (Table 4, entry 10):
4-(1-Trityl-1H-pyrazole-3-sulfonyl)-morpholine
To a stirred suspension of BnMe3NCl (142 mg, 0.76 mmol) in MeCN (2 ml) was
added TCCA (57 mg, 0.25 mmol) and the mixture was left to stir for 30 min. The
clear yellow solution obtained was added dropwise to a stirred 0 °C solution of
the N1-tritylpyrazol-4-yl thiobenzoate (100 mg, 0.22 mmol) in MeCN (2 ml)
over 2 min. To this mixture was added a 1 M solution of Na2CO3 (0.45 ml,
0.45 mmol) and the reaction was allowed to proceed at this temperature for
20 min. Morpholine (23 ll, 0.27 mmol) was added and mixture stirred for
20 min whilst warming to room temperature. At the end of the reaction, the
mixture was partitioned between EtOAc (10 ml) and sat. Na2CO3 (10 ml). The
EtOAc layer was washed with brine (10 ml), dried and concentrated in vacuo.
The crude residue was purified by flash column chromatography, eluting with
0–20% EtOAc/heptane, yielding 86 mg (84% yield) of pure sulfonamide as a
white solid.
In conclusion, we have developed a general and mild two-step
approach for the synthesis of aryl and heteroaryl sulfonyl chlorides
and sulfonamides which tolerates the presence of acid labile func-
tionalities. Copper-catalysed coupling of aryl/heteroaryl iodides
with thiobenzoic acid allows the preparation of thiobenzoates
without the need for strongly acidic or basic conditions. The thi-
LC–MS ELSD 100% (ESI) m/z 243 [Tr]+
Anal. Calcd for C26H25N3O3S: C, 67.95; H, 5.48; N, 9.14. Found: C, 68.03; H, 5.54;
N, 9.01.
1H NMR (400 MHz, CDCl3) d 7.71 (s, 1H), 7.51 (s, 1H), 7.39–7.31 (m, 9H), 7.19–