Unprecedented observation of sulfonamides in the transesterification of N-unsubstituted carbamates with sulfonyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2003.10.139

Sulfonamides have been identified as by-products in the base-mediated transesterification of N-unsubstituted carbamates with sulfonyl chlorides to give the corresponding sulfonates. A proposed mechanism and the synthesis of hindered 2,6-disubstituted arylsulfonates via this method are also reported.

Full text of DOI:10.1016/j.tetlet.2003.10.139

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 43–47
Unprecedented observation of sulfonamides in the transesterification
of N-unsubstituted carbamates with sulfonyl chlorides
*
ꢀ ^
Jerome Dauvergne, Kevin Wellington and Kelly Chibale
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Received 23 June 2003; revised 13 October 2003; accepted 23 October 2003
Abstract—Sulfonamides have been identified as by-products in the base-mediated transesterification of N-unsubstituted carbamates
with sulfonyl chlorides to give the corresponding sulfonates. A proposed mechanism and the synthesis of hindered 2,6-disubstituted
arylsulfonates via this method are also reported.
Ó 2003 Elsevier Ltd. All rights reserved.
In a program aimed at developing methodology for the
synthesis of diverse arrays of arenesulfonyl ureas, we
considered the possibility of reacting arenesulfonyl
chlorides with phenyl carbamate to produce arene-
sulfonyl phenyl carbamates. We envisaged that these
intermediates could then be reacted with an array of
amines to give the target arenesulfonyl ureas with phe-
nol as a by-product (Scheme 1).
tion conducted in N,N-dimethylformamide (DMF)
afforded 3 and the N-sulfonylamidine 6.
A literature search subsequently revealed a publication
in 1987 by Latif and co-workers concerning the trans-
esterification reaction of p-toluenesulfonyl chloride with
N-unsubstituted aryl carbamates bearing a nitroethenyl
side chain using 1,4-dioxane as a solvent in the presence
of Et3N.1 The corresponding sulfonates were reported as
the only products. No accompanying sulfonamides were
reported in this publication. Accordingly we decided to
investigate further the reaction of benzenesulfonyl
chloride 1 with substituted phenylcarbamates under the
reported conditions. For this purpose substituted phe-
nylcarbamates were synthesized following a literature
procedure in which substituted phenols 7–11 were re-
acted with chlorosulfonyl isocyanate (CSI) followed by
When benzenesulfonyl chloride 1 (1.3 equiv) was reacted
with phenylcarbamate 2 in 1,4-dioxane in the presence
of triethylamine (Et3N), the reaction afforded benzene-
sulfonic acid phenyl ester 3 and benzenesulfonamide 4
(Scheme 2). The envisaged carbamate 5 was not
observed. Similarly, the reaction conducted in tetra-
hydrofuran (THF) in the presence of sodium hydride
(NaH) also afforded products 3 and 4. The same reac-
R
R
O
S
O
R
O
O
Cl
O
S
O
O
S
O
R'R"NH
+
R' N
R"
N
H
OH
O
N
H
+
O
O
NH2
Scheme 1.
Keywords: carbamates; transesterification; arylsulfonates; sulfonamides.
* Corresponding author. Tel.: +27-21-650-2553; fax: +27-21-689-7499; e-mail: chibale@science.uct.ac.za
Present address: Peakdale Molecular Ltd., Sheffield Road, Chapel-en-le-Frith SK23 0PG, UK. E-mail: jerome.dauvergne@peakdale.co.uk
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.139

44
J. Dauvergne et al. / Tetrahedron Letters 45 (2004) 43–47
O
S Cl
O
O
S O
O
O
O
O
N S
H
O
3
1
5
Et3N
+
+
O
S N
O
O
N
O
O
NH2
S NH2
O
6
2
4
Scheme 2.
Table 1. Preparation of the substituted phenylcarbamates 12–16
starting from phenols 7–11
R3
R4
R1
R3
R4
R1
1. CSI
CH2Cl2/CHCl3
O
R2
OH
Entry Phenol R1
R2
R3
R4
Product
(% yield)
R2
O
NH2
2. H2O
1
2
3
4
5
7
8
CH3
CH3
CH3
H
CH3
H
H
H
12 (49)
13 (71)
14 (83)
15 (96)
16 (77)
CH3
H
H
7-11
12-16
9
H
CH3
H
10
11
CH3
O
H
H CH
Scheme 3.
H
H
3
water hydrolysis of the resulting intermediate (Scheme
3).2–4
R3
R4
R1
O
O S
R2
The substituted phenylcarbamates 12–16 were obtained
in good yields (Table 1) and high purity as judged from
the respective 1H NMR spectra. No further purification
was required. These carbamates were then reacted with
benzenesulfonyl chloride 1 in the presence of Et3N at
90–95 °C (Scheme 4). The results of these reactions are
summarized in Table 2.
1
O
(1.3 eq)
17-21
Et3N
+
R4
+
Dioxane
90-95oC
R3
O
O
R2
O
NH2
S
NH2
O
R1
From the results in Table 2, it is evident that most of the
reactions yielded mixtures of both the sulfonic acid
phenyl esters and benzenesulfonamide. It is noteworthy
that the reaction involving 4-methoxy-phenylcarbamate
16 afforded higher yields of both products in a relatively
short time (entry 5). The longest reaction time (74 h) was
that involving 2,6-dimethylphenylcarbamate 14 (entry
3). This is presumably due to the steric crowding
imparted by the methyl groups at both ortho positions.
4
12-16
Scheme 4.
Phenylcarbamate presumably reacts with the arene-
sulfonyl chloride to give the expected arenesulfonyl
phenyl carbamate. This species is subsequently deprot-
onated in situ, and the anionic intermediate collapses to
form an arenesulfonyl isocyanate and a phenoxide
anion. The former is hydrolyzed during the work-up to
yield an arenesulfonamide, while the latter reacts with a
In order to account for the formation of both the sul-
fonates and benzenesulfonamide in these reactions, a
proposed mechanism is depicted in Scheme 5.
Table 2. Reactions of benzenesulfonyl chloride 1 with carbamates 12–16 at 90–95°C
Entry
Carbamate
R1
R2
R3
R4
Reaction
time (h)
Product A
(% yield)
Product B
(% yield)
1
2
3
4
5
12
13
14
15
16
CH3
CH3
CH3
H
CH3
H
H
H
48
48
74
1
17 (36)
18 (18)
19 (14)
20 (37)
21 (50)
4 (30)
4 (36)
CH3
H
H
H
CH3
H
4 (41)
No product
4 (50)
CH3
O
H
CHH
H
H
1
3
A ¼ sulfonic acid phenyl ester.
B ¼ benzenesulfonamide.

J. Dauvergne et al. / Tetrahedron Letters 45 (2004) 43–47
45
O
O
O
O O
S
O O
S
O O
S
Base
+
Ar'O
NH2
Cl
Ar
Ar'O
N
Ar
Ar'O
N
Ar
H
12-16
O O
S
O
O O
S
O O
S
H2O
- CO2
O
H2N
Ar
HO
N
Ar
Ar
N
O
O O
S
H
Ar'O
N
Ar
O O
O O
S
S
Ar'O
Cl
OAr'
Ar
Ar
+
17-21
Scheme 5.
second molecule of arenesulfonyl chloride to yield an
arenesulfonic phenyl ester.
other sulfonyl chlorides (Scheme 7). Initial attempts to
react 14 with sulfonyl chlorides 22–25 in the presence of
Et3N at various temperatures (room temperature and
90–95 °C) in 1,4-dioxane and at 60–65 °C in THF were
unsuccessful. We reasoned that the substrates and/or
products decomposed at high temperature or that the
reactions were taking too long to occur as was the case
previously. As a result, we resorted to the use of NaH in
THF and lower temperatures. The reactions proceeded
within 4–5 h; the results are shown in Table 3. From the
results in Table 3, it is evident that various sulfonamides
and sulfonic acid esters can be obtained (albeit in low
yields) utilizing this reaction in the presence of sodium
hydride.7
When DMF is used as the solvent, the intermediate
sulfonyl isocyanate formed reacts further with DMF to
produce 6 (Scheme 6). Presumably, the adduct formed
between the arylsulfonyl isocyanate and DMF is not
thermally stable, and its decarboxylation product is
observed.
A similar phenomenon was previously
described with chloroformates.5;6
The long reaction time and low yield for the sulfonic
acid phenyl ester 19 prompted us to investigate further
the reaction of 2,6-dimethylphenylcarbamate 14 with
O
O
O
S N
O
O
S N
O
-CO2
S N C O
O
O
6
NMe2
NMe2
O
H
NMe2
Scheme 6.
O
O
O
O
S
R
O
NH2
O
S
R
O
O
NaH
NaH
26-29
14
+
26-29
THF
rt
+
THF
+
40-45oC
O
O
O
R S NH2
O
Cl S R
O
R
S
O
NH2
31-33
30-33
22-25
22, 26, 23, 27, 24, 28, 25, 29,
30 31 32 33
Compound
R
NO2
Cl
Scheme 7.

46
J. Dauvergne et al. / Tetrahedron Letters 45 (2004) 43–47
Table 3. Reactions of carbamate 14 with sulfonyl chlorides in THF using NaH as the base
Entry
Sulfonyl chloride
Reaction time (h)
Reaction temperature (°C)
Product A (% yield)
Product B (% yield)
1
2
3
4
5
6
7
8
22
23
24
25
22
23
24
25
4
4
40–45
40–45
40–45
40–45
rt
26 (39)
27 (16)
28 (32)
29 (21)
26 (46)
27 (28)
28 (41)
29 (30)
30 (10)
31 (26)
32 (13)
33 (29)
No product
31 (14)
32 (27)
33 (29)
4
5
14
14
15
14
rt
rt
rt
A ¼ sulfonic acid ester.
B ¼ sulfonamide.
R1
R1
R1
R1
O
O
O
NH2
O S R
O
1, 3,
22, 34, 25, 35,
2 : R1 = H
3, 34, 35 : R1 = H
Compound
36, 4
26, 30
29, 33
14 : R1 = CH3
36, 26, 29 : R1 = CH3
NaH
+
+
THF
R
O
O
45oC
R
S
NH2
Cl
R
S Cl
O
O
1, 22, 25
4, 30, 33
Scheme 8.
Table 4. Reactions of carbamates 14 with sulfonyl chlorides (2 equiv) at rt in THF using NaH as the base
Entry
Sulfonyl chloride
Carbamate
Reaction time (h)
Product A (% yield)
Product B (% yield)
1
2
3
4
5
8
1
22
25
1
2
2
16
16
16
16
16
16
3 (44)
34 (90)
35 (26)
36 (90)
26 (99)
29 (55)
4 (17)
30 (69)
33 (12)
4 (61)
2
14
14
14
22
25
30 (29)
33 (22)
A ¼ sulfonic acid ester.
B ¼ sulfonamide.
Product yields are based on phenylcarbamates.
In the light of these results, we became interested in
optimizing the yields of arenesulfonic acid esters, espe-
cially in the case of hindered arylsulfonates. Following
the mechanism given in Scheme 5, this could be easily
achieved by using 2 equiv of arenesulfonyl chloride with
respect to the phenylcarbamate. A last series of experi-
ments was carried out at 45 °C in THF, using NaH as a
base (Scheme 8).8 The results listed in Table 4 show the
expected noticeable increase in yields of arenesulfonic
acid ester.
synthesis of sulfonamides9–14 and hindered arylsulfo-
nates.15;16 Work in this regard will be reported in a
future full paper.
Acknowledgements
We thank GlaxoSmithKline (UK) for financial support
under the Action TB programme. Additional support
through the Technology and Human Resources for
Industry Programme (THRIP) of the Department of
Trade and Industry (South Africa) is gratefully
acknowledged. We thank Dr. Brian Cox (GlaxoSmith-
Kline) for useful discussions and Mr Freddy Muganza
Munyololo (University of Cape Town) for assistance
with some of the experiments. Last but not least we wish
to thank the referee for constructive criticisms and
helpful suggestions.
In summary, we have shown that sulfonamides can be
obtained from the transesterification reaction of N-un-
substituted carbamates with sulfonyl chlorides. More-
over, this procedure has potential for the efficient
synthesis of hindered sulfonates exemplified by 2,6-di-
substituted arylsulfonates. Although a number of these
reactions give low yields, there is scope for optimization
studies aimed at making this a synthetically useful pro-
tocol to compliment existing methodologies for the

J. Dauvergne et al. / Tetrahedron Letters 45 (2004) 43–47
47
Hexane, 1:4) and upon completion (16 h), the mixture was
concentrated under an air blast. The crude mixture was
purified by preparative thin layer chromatography to
afford benzenesulfonic acid 2,6-dimethylphenyl ester 36
(0.043 g, 90%) and benzenesulfonamide 4 (0.017 g, 61%).
9. Anderson, K. K. In Comprehensive Organic Chemistry;
Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3,
pp 345–349.
References and Notes
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408.
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Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3,
pp 339–341.
11. Scully, F. E.; Bowdring, K. J. Org. Chem. 1981, 46, 5077–
5081.
12. Graham, S. L.; Scholz, T. H. Synthesis 1986, 1031–1032.
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7. All compounds were fully characterized and gave spec-
troscopic data consistent with the structures.
8. Typical procedure. 2,6-Dimethylphenylcarbamate 14
(0.03 g, 0.18 mmol) was added portionwise to a suspension
of 95% sodium hydride (0.012 g, 0.48 mmol) in dry THF
(2 mL). Benzenesulfonyl chloride 1 (0.089 mL, 0.36 mmol)
was added to the resulting mixture, which was then heated
at 40–45 °C. The reaction was monitored by TLC (EtOAc–
15. OÕConnell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57,
4775–4777.
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1994, 24, 205–216.