Synthesis of conformationally restricted sulfonamides via radical cyclisation

Article abstract of DOI:10.1016/j.tetlet.2010.03.089

A convenient synthesis of conformationally restricted sulfonamides such as compounds (12) and (40) with seven- and eight-membered ring structures has been achieved using radical reaction. These compounds and their analogs are expected to serve as important pharmacophores in drug discovery.

Full text of DOI:10.1016/j.tetlet.2010.03.089

Tetrahedron Letters 51 (2010) 2681–2684
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Tetrahedron Letters
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Synthesis of conformationally restricted sulfonamides via radical cyclisation
à
*
D. Biswas , L. Samp , A. K. Ganguly
Department of Chemistry and Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of conformationally restricted sulfonamides such as compounds (12) and (40)
with seven- and eight-membered ring structures has been achieved using radical reaction. These com-
pounds and their analogs are expected to serve as important pharmacophores in drug discovery.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 February 2010
Revised 15 March 2010
Accepted 19 March 2010
Available online 27 March 2010
Keywords:
Radical reactions
Heterocyclic chemistry
There are many drugs, used in human medicine,1 that contain
sulfonamide moiety in their structures. A few representative
examples of sulfonamides that show biological activities against
a variety of disease targets are illustrated below.
It should be noted that several of these drugs contain an acyclic sul-
fonamide chain, and thus they can exist in many conformations
when bound to enzymes or occupying receptors. However, there
are others such as Piroxicam2 and Sulthiame3 that do possess cyclic
sulfonamide structures. We were interested in synthesising con-
formationally restricted sulfonamides, which could serve as impor-
tant pharmacophores in drug discovery, and in this Letter, we
would like to disclose some of our results. Specifically, we were
interested in synthesising compounds represented by the general
structure (1) using radical cyclisation reaction. Katritzky et al.4 syn-
thesised compound (1) wherein, R is a butyl group by Friedel–Craft
cyclisation of compound (1a). The cyclisation to obtain the corre-
sponding eight-membered ring derivative yielded a trace amount
of the desired compound. In this Letter, we wish to disclose a con-
venient synthesis of compounds represented by the structure (1)
wherein the R could be alkyl, aryl and aryl alkyl groups. The ring
size could be either seven or eight.
O
O
O
S
NH
HO
N
O
OCH3
N
N
H
S
H2N
S
O
Sulfathiazole
Antibacterial1
CGS 259661
MMP Inhibitor
O
O
HN
OH
NH
S
O
O
O
N
O
O
S
N
CF3
O
S
OH
TACE Inhibitor1
Tipranavir1
O
S
HIV Protease Inhibitor
O
N
O
N
R
Cl
O
S
O
O
S
N
H
O
S
(1a)
(1)
O
H2N
N
S
N
O
O
OH
O
N
Motherwell5 and co-workers observed that a radical reaction
involving substrate (2) yielded (5) and (6). Thus the initial radical
(3) obtained from (2) cyclised onto the aromatic ring to form (4)
which underwent loss of sulfur dioxide to yield the biphenyl (5)
or rearranged with the loss of hydrogen radical to yield (6) (see
Scheme 1).
Sulthiame3
Anti Epileptic agent
Piroxicam2
Antiinflammatory agent
* Corresponding author. Tel.: +1 201 216 5548; fax: +1 201 216 8240.
E-mail address: akganguly1@aol.com (A.K. Ganguly).
Present address: Merck & Co Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033,
USA.
We further investigated the above-mentioned reaction with (7)
and obtained (8) (see Scheme 2).
à
Present address: Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.089

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D. Biswas et al. / Tetrahedron Letters 51 (2010) 2681–2684
O
S
O
S
N
N
NH2
O
O
AIBN, TBTH
+
Br
Toluene, 110ºC
(6)
(5)
(2)
O
N
O
S
N
S
O
O
(4)
(3)
Scheme 1.
the endocyclic addition products6–8 (12), (13) and (14) as major
products, respectively, along with minor amounts of the corre-
sponding debrominated compounds (15), (16) and (17). In addition
(11) also yielded a smaller amount of (18). Similarly, compound
(19) yielded (20) (see Scheme 3). Thus, the above-mentioned reac-
tions yielded the desired conformationally restricted sulfonamides
represented by the general structure (1).
We believe that the mechanism of the above-mentioned reac-
tion involves direct addition of the phenyl radical (22) to the termi-
nal end of the double bond in an endocyclic sense as shown in the
Scheme 4.
O
S
N
O
O
S
N
AIBN, TBTH
O
Toluene, 110ºC
Br
(8)
(7)
Scheme 2.
To study the scope of the above-mentioned reaction further, we
treated (25) under radical reaction conditions and isolated com-
pounds (26), (27), (28) and (29). (Scheme 5). The major product
in this reaction was formed via benzylic radical (30).
At this point we were interested in studying the radical reaction
of retro sulfonamides such as (9). Thus treatment of compounds
(9), (10) and (11) with AIBN/TBTH in toluene yielded unexpectedly
O
O
O
R
O
O
O
S
S
N
O
N
S
N
O
N
S
AIBN/TBTH
Br
+
Toluene, 110ºC
R
F
R
(15) R=OCH3 (9%)
(18) (5%)
(12) R=OCH3 (71.12%)
(13) R=OC2H5 (73.7%)
(9) R=OCH3
(16)
(17)
R=OC2H5 (12%)
R= F (5%)
(10
(11
) R=OC2H5
) R= F
(14) R=F
(63.6%)
O
O
N
O
S
N
AIBN/TBTH
S
O
Toluene/ 110ºC
Br
(20) (30%)
(19)
Scheme 3.
R
R
R
O
N
O
O
O
O
O
S
S
S
N
N
AIBN/TBTH
(23)
(21)
(22)
Br
R
O
O
S
N
(24)
Scheme 4.

D. Biswas et al. / Tetrahedron Letters 51 (2010) 2681–2684
2683
OC2H5
OC2H5
O
O
O
O
S
S
N
O
N
O
S
AIBN/TBTH
N
O
+
Toluene, 110ºC
+
Br
(25)
OC2H5
(26) (56%)
(27) (11.71%)
O
O
O
OC2H5
S
S
O
N
N
O
S
N
+
OC2H5
(29) (5.55%)
OC2H5
(30)
(28) (9.04%)
Scheme 5.
O
N
O
O
O
O
O
S
S
S
N
AIBN/TBTH
N
+
Br
Toluene/ 110ºC
(31)
(32) (56%)
(33) (3%)
Scheme 6.
When compound (31) was subjected to the radical cyclisation
reaction, it yielded (32) as the major product along with a minor
amount of (33) (see Scheme 6).
with AIBN and TBTH and isolated compound (40), which is a
eight-membered cyclic sulfonamide along with (41) and (42) (see
Scheme 8).
To investigate the competition of phenyl radical addition be-
tween an allyl and a cinnamyl group, we treated compound (34)
with AIBN and TBTH and isolated compounds (35), (36), (37) and
(38). The major product isolated from the reaction was compound
(35) (see Scheme 7).
Upon increasing the length of the carbon chain on nitrogen,
compounds (43), (44) and (45) yielded under radical reaction con-
dition compounds (46), (47) and (48), respectively, along with the
corresponding debrominated compounds (49), (50) and (51)
(Scheme 9).
The origins of (36) and (37) could be traced to the radical de-
rived by the addition of the initial phenyl radical to the allyl double
bond in the endocyclic sense, and (38) is derived from the radical
derived by the addition of the initial phenyl radical to the allyl
double bond in the exocyclic mode.
Thus, when the length of the carbon chain is increased, the dis-
tance of the terminal double bond from the phenyl radical also in-
creases, which makes it difficult to add to the terminal double
bond. Instead, the phenyl radicals take the alternative pathway of
addition to the other aromatic ring followed by rearrangement and
loss of a hydrogen radical to yield the observed products, or the
starting compounds simply underwent debromination.
We then wanted to see the possibility of synthesising com-
pounds of larger ring size, and thus we treated compound (39)
O
N
O
N
O
O
S
S
H
+
H
(35) (37%)
(36) (13%)
O
O
S
AIBN/TBTH
N
O
O
S
Toluene, 110ºC
O
N
N
Br
(34)
O
S
H
+
H
(37) (7%)
(38) (4%)
Scheme 7.

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D. Biswas et al. / Tetrahedron Letters 51 (2010) 2681–2684
O
O
OCH3
O
O
O
O
S
S
S
N
N
N
O
S N
AIBN/TBTH
O
+
Br
Toluene/ 110ºC
+
OCH3
OCH3
OCH3
(42) (10%)
(39)
(41) (27%)
(40) (20%)
Scheme 8.
O
O
O
O
O
S
S
O
N
n
N
S
n
N
n
AIBN/TBTH
Toluene/ 110ºC
+
Br
OCH3
OCH3
OCH3
(43) n=2
(44) n=3
(45) n=4
(46) n = 2, (29%)
(47) n = 3, (23%)
(48) n = 4, (23%)
(49) n = 2 (55%)
(50) n = 3, (40%)
(51) n = 4, (51%)
Scheme 9.
6. In a typical experiment, AIBN (0.09 g, 0.7 mmol) was added to a solution of
compound 10 (0.7 g, 1.8 mmol) in toluene (13 ml) with stirring. TBTH (0.9 ml,
2.9 mmol) was then added dropwise to the above-mentioned solution, which
was then refluxed for around 3 h. At the end of the reaction, it was diluted with
EtOAc and washed with water. The aqueous layer was extracted twice with
EtOAc, and the combined organic extracts were dried over anhydrous Na2SO4,
filtered, concentrated and purified by silica gel column chromatography to
obtain compounds 13 (0.41 g, 73.7%) and 16 (0.069 g, 12%).
Acknowledgement
We would like to thank the Schering Plough Research Institute
for providing MS data presented in this Letter.
References and notes
7. Yields are indicated in parentheses; however, they were not optimised.
Compounds were crystallised from a mixture of dichloromethane and hexane.
Melting points of the crystalline compounds are shown below: 12 (53–54 °C), 13
(57–58 °C), 14 (100–102 °C), 15 (75–77 °C), 16 (68–70 °C), 20 (81–83 °C), 26
(125–126 °C), 27 (169–171 °C), 35 (106–108 °C), 36 (143–144 °C), 37 (98–
100 °C).
1. (a) Supuran, C. T.; Casini, A.; Scozzafava, A. Med. Res. Rev. 2003, 23, 535–558. and
references cited therein; (b) Woessner, J. F.; Nagase, H. Matrix Metalloproteases
and TIMPs; Oxford University Press, 2000. pp 1–223.
2. Rabaseeda, T.; Hopkins, S. J. Drugs Today 1994, 30, 557.
3. Debus, O. M.; Kurlemann, G. Epilepsia 2004, 45, 103.
8. NMR and high resolution mass spectra of all the compounds described in this
Letter were consistent with the assigned structures. Assignments were further
confirmed using 2D NMR experiments.
4. Katritzky, A. R.; Rachwal, J. W. S.; Rachwal, B.; Macomber, D. W.; Smith, T. P. Org.
Prep. Proc. Int. 1992, 24, 463–467. The reviewer pointed out this reference to us.
5. Mata, M. L. E. N. da; Motherwell, W. B.; Ujjainwala, F. Tetrahedron Lett. 1997, 23,
137–140.