A general synthetic strategy for 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (benzosulfamides)

Article abstract of DOI:10.1016/j.tetlet.2010.07.173

A general route to benzosulfamides is presented, allowing for flexible installation of substituents.

Full text of DOI:10.1016/j.tetlet.2010.07.173

Tetrahedron Letters 51 (2010) 5306–5308
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Tetrahedron Letters
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A general synthetic strategy for 1,3-dihydro-2,1,3-benzothiadiazole
2,2-dioxides (benzosulfamides)
*
Dawn E. Colyer, Andrew Nortcliffe, Simon Wheeler
Sandwich Chemistry, Pfizer Global R and D, 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 general route to benzosulfamides is presented, allowing for flexible installation of substituents.
Received 2 June 2010
Revised 19 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1,3-Dihydro-2,1,3-benzothiadiazole 2,2-dioxides (referred to
herein as benzosulfamides) can be generalised by structure 1.
tion was supplied by the recognition that the nitrile of 2 could be
converted into a variety of other functional groups once fully
substituted benzosulfamides 1 had been prepared. With these stra-
tegic and tactical decisions made we set about reducing our ideas
to practice. Our results are outlined in Scheme 1.
R''
O
S
N
1
R
N
O
R'
Despite their potential for diversity-oriented synthesis, and
consequent attractiveness to the pharmaceutical industry, such
compounds, have, with few exceptions,1 seen only sporadic use
in drug discovery programs. Their use in supramolecular chemistry
has been more extensive but has also been limited to a handful of
publications.2 Such a paucity of work can most likely be explained
by the absence of synthetic routes that allow for independent var-
iation of all R groups indicated in structure 1. The best solution to
this problem disclosed to date relies on the chemoselective mono-
deprotection of bis-carbamate protected benzosulfamides2a and is
thus, in general, limited to materials where the ring is symmetri-
cally substituted. The current Letter advances a new method which
allows for late stage variation of either or both nitrogen substitu-
ents. Previously published chemistry1 has installed one of these
groups, constructed the ring and only then installed the other sub-
stituent, thus considerably reducing the flexibility of the synthesis.
Our general plan for achieving our aim was to prepare a 1,2-
dianiline with one nitrogen bearing a protecting group. Building
the sulfamide ring could be followed by alkylation of the unpro-
tected nitrogen, then deprotection and alkylation of the nitrogen
thereby revealed. We decided to employ p-methoxybenzyl (PMB)
as our protecting group due to its long history in sulfamide chem-
istry.3 Benzonitrile 2 was selected as the starting material for stud-
ies to test our strategy as a very similar compound had previously
been converted into an analogue of dianiline 3.4 Additional motiva-
O2N
Cl
CN
i PMB-NH2 (excess), EtOH, 80 oC
EtOH, 65 oC
80% overall
CN
H2N
HN
ii cat. Pd/C
PMB
2
3
O
H2N
O
S
NH2
diglyme, 160 oC,
up to 59%
R
H
N
first
CN
N
CN
O
O
alkylation
S
S
N
O
N
O
PMB
PMB
4
5
deprotection
R
R
CN
N
O
CN
N
O
second
S
S
N
O
N
alkylation
O
R'
H
1
6
* Corresponding author. Tel.: +44 1304 649173; fax: +44 1304 651987.
E-mail address: simon.wheeler@pfizer.com (S. Wheeler).
Scheme 1. Synthetic route to benzosulfamides 1 (PMB = p-methoxybenzyl).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.173

D. E. Colyer et al. / Tetrahedron Letters 51 (2010) 5306–5308
5307
As expected the initial SNAr reaction proceeded smoothly to
give the PMB-protected nitroaniline. Such compounds are well
known in the chemical literature and it is recognised that similar
intermediates bearing a variety of substituents on the benzene ring
can be prepared by different methods.5 Once such intermediates
are in hand reduction of the nitro group, which can be achieved
with chemoselectivity over most other functional groups, will give
access to the analogues of dianiline 3. At this stage the cyclisation
conditions first disclosed by Teufel6 (which have proven to be gen-
eral, having been applied to a wide variety of substrates7) can be
employed. Thus we reduced the nitro group in 2 using catalytic
hydrogenation to obtain 3 in good yield. We then applied Teufel’s
conditions and added a suspension of dianiline 3 and commercially
available sulfamide to diglyme (diethylene glycol dimethyl ether)
preheated to 160 °C. After 30 min at this temperature benzosulfa-
mide 4 was isolated by pouring the cooled reaction mixture into
diethyl ether and filtering off the precipitated product (Scheme
1). As well as temperature and solvent (pyridine was ineffective
even at 160 °C in a microwave reactor), this reaction was found
to be critically dependent on the purity of the starting dianiline.
Much reduced yields were encountered on running this reaction
with 3 containing even minor levels of impurities. Extensive efforts
to find alternative reaction conditions were made. Sulfuryl chloride
in CH2Cl2 gave no reaction, nor did sulfonyl diimidazole. Forming
the diquaternary salt of sulfonyl diimidazole8 (using methyl io-
dide) and attempting the cyclisation led only to methylation of 3.
No reaction was observed with catechol sulfate9 and only a trace
reaction with the carbamate reagent disclosed by workers at
Lilly.10 Evidence from the literature suggests that the ease of these
cyclisation reactions varies with substituents on the benzene ring
so it is likely that the nitrile group of 3 retards the reaction. It
should be noted that, despite these difficulties, 4 has been rou-
tinely prepared on gram scale.
alkylated with a variety of electrophiles in moderate to good yields.
Thus unfunctionalised alkyl groups could be appended (5a and 5b)
as could groups bearing residues suitable for further manipulation
(5c and 5d). Benzyl groups could also be attached where sites for
continued synthesis were also incorporated (5e and 5f). All these
products were obtained after a few hours in DMF at 80 °C, with
the exception of 5d where reaction at room temperature was used,
otherwise extensive decomposition was observed. For simple alkyl
groups the iodide leaving group was necessary whilst bromide suf-
ficed for more activated electrophiles. The exception to this general
trend was methylation where methyl tosylate was found to be an
effective alkylating agent.
We next attempted the deprotection of 5a to give 6a. This was
found to be successful in neat TFA at reflux (Scheme 3).
Use of milder conditions (room temperature with or without
dilution with CH2Cl2) led to no reaction; alternative deprotection
conditions (DDQ or ceric ammonium nitrate) gave only decompo-
sition of 5a. We also discovered that it was necessary to work up
the reaction using buffer; use of water or aqueous base led to
decomposition.
With access to 6a secure, attention was switched to introducing
a substituent on the second nitrogen. This proved to be possible
using the same conditions as the first alkylation, albeit with gener-
ally lower yields, and is shown in Scheme 4. Alkylations with rep-
resentative alkyl, allyl and benzyl electrophiles were all successful
suggesting that benzosulfamide 6a is likely to undergo alkylation
with a similar range of electrophiles as previous substrate 4. Disap-
pointingly, reaction with ethyl acrylate failed to furnish any prod-
uct despite longer reaction times and multiple equivalents of
electrophile.
Having shown that we could construct benzosulfamides bearing
a variety of substituents we were also interested in their reagent
toleration and set out to explore this by transforming the nitrile
of 5 into a variety of other useful functional groups. The successful
implementation of this plan is shown in Scheme 5. Thus full11 or
partial reduction of the nitrile was possible to give the correspond-
With appreciable quantities of benzosulfamide 4 in hand, we
examined its alkylation. The results of this study are shown in
Scheme 2. As will be readily observed benzosulfamide 4 can be
R
N
S
N
PMB
H
N
CN
R-X, K2CO3, DMF, 80oC
O
CN
CN
O
N
N
O
S
CN
N
S
TFA, reflux, 100%
O
N
PMB
O
O
S
O
N
H
O
PMB
5
4
5a
6a
Scheme 3. Deprotection of benzosulfamide 5a.
CN
CN
CN
N
N
O
N
N
O
O
O
S
S
S
N
O
N
O
CN
N
PMB
O
PMB
PMB
CN
K2CO3, R-X, DMF, 80oC
O
N
S
S
N
H
O
5a, 100%
X=OTs
5b, 54%a
X=I
5c, 61%a
X=Br
N
R
O
6a
5
Br
CO2Me
CO2Et
CN
N
O
CN
N
N
O
CN
N
N
O
CN
S
N
N
S
O
S
CN
N
O
S
N
N
O
O
CN
N
N
O
O
S
O
S
O
PMB
O
PMB
PMB
Cl
5d, 55%
X=Br
5e, 80%
X=Br
5f, 82%
X=Br
1a, 65%
X=Br
1b, 42%a
X=I
1c, 64%
X=Br
Scheme 2. Alkylations of 4, products generated and isolated yields. Standard
conditions: 1 equiv of 4, 1.2 equiv of electrophile, 1.3 equiv of K2CO3: (a) required
2.4 equiv of electrophile.
Scheme 4. Introduction of a substituent onto the second nitrogen atom. Standard
conditions were the same as given in Scheme 2: (a) required 4 equiv of electrophile.

5308
D. E. Colyer et al. / Tetrahedron Letters 51 (2010) 5306–5308
Liu, W.; McGovern, L.; Sebastian, A.; Shen, X.; Shi, X.; Wilk, B.; Varsalona, R.;
N
Zhong, H. Org. Process Res. Dev. 2010, 14, 868.
O
NH2
S
2. (a) Hof, F.; Iovine, P. M.; Johnson, D. W.; Rebek, J., Jr. Org. Lett. 2001, 3, 4247. and
references cited therein; (b) Johnson, D. W.; Hof, F.; Iovine, P. M.; Nuckolls, C.;
Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41, 3793; (c) Johnson, D. W.; Hof, F.;
Palmer, L. C.; Martin, T.; Obst, U.; Rebek, J., Jr. Chem. Commun. 2003, 1638.
3. For some recent applications see: (a) Hannam, J.; Harrison, T.; Heath, F.; Madin,
A.; Merchant, K. Synlett 2006, 833; (b) Dougherty, J. M.; Jimenez, M.; Hanson, P.
R. Tetrahedron 2005, 61, 6218.
LiBH4/TMS-Cl
43%
N
O
R
1e, R=OMe
4. Smits, R. A.; Lim, H. D.; Hanzer, A.; Zuiderveld, O. P.; Guaita, E.; Adami, M.;
Coruzzi, G.; Leurs, R.; de Esch, I. J. P. J. Med. Chem. 2008, 51, 2457.
5. (a) Semple, G.; Skinner, P. J.; Cherrier, M. C.; Webb, P. J.; Sage, C. R.; Tamura, S.
Y.; Chen, R.; Richman, J. G.; Connolly, D. T. J. Med. Chem. 2006, 49, 1227. use p-
methoxybenzylamine to displace the fluorine from 4-fluoro-3-nitrobenzoic
acid; (b) Hubbard, J. W.; Piegols, A. M.; Soederberg, B. C. G. Tetrahedron 2007,
63, 7077. use p-methoxybenzylamine to displace the bromine from 2-
bromonitrobenzene using Pd catalysis; (c) Escande, A.; Guenee, L.; Nozary,
H.; Bernardinelli, G.; Gumy, F.; Aebischer, A.; Buenzli, J.-C. G.; Donnio, B.;
Guillon, D.; Piguet, C. Chem. Eur. J. 2007, 13, 8696. alkylate 4-methoxy-2-
nitroaniline with p-methoxybenzyl bromide; In addition: (d) Rao, C. V. C.;
Veeranagaiah, V.; Reddy, K. K.; Rao, N. V. S. Ind. J. Chem., Sect. B 1979, 17B, 566.
use benzylamine to displace the chlorine from 2-chloro-3-nitrotoluene
indicating that ortho- substituents may be tolerated in the SNAr process.
6. Teufel, H. German patent 1,120, 456, 1959; Chem. Abstr. 1962, 57, 844b.
7. For representative examples consult Refs. 1,2a in adddition to: (a) Goehring, R.
R.; Whitehead, J. F. W.; Brown, K.; Islam, K.; Wen, X.; Zhou, X.; Chen, Z.;
Valenzano, K. J.; Miller, W. S.; Shan, S.; Kyle, D. J. Bioorg. Med. Chem. Lett. 2004,
14, 5045; (b) Bryans, J. S.; Bunnage, M. E.; Johnson, P. S.; Mason, H. J.; Roberts, L.
R.; Ryckmans, T.; Stobie, A.; Underwood, T. J. PCT Int. Appl. WO 2006114706;
Chem Abstr. 2006, 145, 455021.
N
N
CN
O
O
N
N
O
S
S
DIBAL
46%
O
O
R
R
1e, R=H
5
NH
N
O
NH
OH
S
H2N-OH
61%
N
O
R
1f, R=OMe
Scheme 5. Transformation of the nitrile residue into other functional groups.
8. A similar tactic was employed for the synthesis of quarternary sulfonyl ureas
by: Beaudoin, S.; Kinsey, K. E.; Burns, J. F. J. Org. Chem. 2003, 68, 115.
9. To our knowledge this reagent was first used in the synthesis of sulfamides in:
Micklefield, J.; Fettes, K. J. Tetrahedron Lett. 1997, 38, 5387.
10. Borghese, A.; Antoine, L.; Van Hoeck, J. P.; Mockel, A.; Merschaert, A. Org.
Process Res. Dev. 2006, 10, 770.
ing primary amine or the aldehyde, respectively. Preparation of the
amidoxime was also successful. This group is a precursor to
numerous heterocycles either directly or after catalytic hydrogen-
olysis of the N–O bond.12
11. Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl. 1989, 28, 218.
12. Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala, T. E. Synth.
Commun. 1996, 26, 4351.
13. For a recent use of this moiety to protect a sulfonamide see: Chen, L.; Petrelli,
R.; Olesiak, M.; Wilson, D. J.; Labello, N. P.; Pankiewicz, K. W. Bioorg. Med. Chem.
2008, 16, 7462.
14. For a review see: Escoubet, S.; Gastaldi, S.; Bertrand, M. Eur. J. Org. Chem. 2005,
3855–3873.
15. Selected experimental procedures. Cyclisation to benzosulfamide: Diglyme was
deoxygenated by bubbling N2 through it for 10 min. After this time 3 mL of
diglyme was heated to 160 °C (internal temperature). Dianiline 3 (1.533 g,
In summary we have developed a flexible route to a diverse
range of benzosulfamides employing a mono-protected 1,2-diani-
line as the starting material. The key advantage of this method is
that it is possible to add substituents to both nitrogen atoms at a
late stage in the synthesis. Furthermore we have demonstrated
that the sulfamide moiety is resilient to a range of reaction condi-
tions and therefore that further derivatisations are possible. An
obvious weak point of this work is the need to use refluxing TFA
to remove our chosen protecting group. In future it may be possible
to conduct the deprotection under milder conditions by use of the
2,4-dimethoxybenzyl protecting group13 or to use allyl protection
and deprotect using a metal catalyst.14 We anticipate that these
advances will lead to the greater popularity of the benzosulfamide
motif in the pharmaceutical industry.15
6.05 mmol) and sulfamide (698 mg, 7.26 mmol) were then added as
a
suspension in diglyme (6 mL) rinsing in with more diglyme (1 mL). After
30 min at 160 °C the reaction was cooled to room temperature and poured into
Et2O (75 mL) causing 4 to precipitate as an off-white solid (1.135 g, 6.05 mmol,
59%). 1H NMR (400 MHz, methanol-d4): 3.77 (3H, s), 4.78 (2H, s), 6.31 (1H, d,
J = 6.3 Hz), 6.75 (1H, d, J = 2.0 Hz), 6.77 (1H, dd, J = 6.3, 2.0 Hz), 6.87 (2H, d,
J = 9.0 Hz), 7.38 (2H, d, J = 9.0 Hz). 13C NMR (100 MHz, methanol-d4): 45.1, 54.5,
101.1, 105.2, 111.1, 113.8, 120.8, 121.1, 128.3, 128.8, 137.8, 139.5, 159.5. MS
(ESI): m/z 314 [MÀ1]À.
Acknowledgements
Alkylation of benzosulfamide: To a stirred solution of sulfamide 4 (207 mg,
0.66 mmol) in DMF (3 mL) was added K2CO3 (181 mg, 1.32 mmol) followed by
MeOTs (257 mg, 1.38 mmol) and the whole stirred at 80 °C for 2 h. The reaction
was cooled and diluted with H2O (10 mL). EtOAc (5 mL) was added and the
layers separated. The organic layer was washed with H2O (2 Â 20 mL), then
with brine (10 mL), dried over MgSO4 and evaporated to give 5a as a brown
solid (216 mg, 0.66 mmol, 100%). 1H NMR (400 MHz, CDCl3): 3.36 (3H, s), 3.81
(3H, s), 4.88 (2H, s), 6.58 (1H, d, J = 8.2 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.93 (1H, d,
J = 1.6 Hz), 7.18 (1H, dd, J = 8.2, 1.6 Hz), 7.35 (2H, d, J = 8.8 Hz). 13C NMR
(100 MHz, CDCl3): 28.4, 46.2, 55.5, 104.7, 108.6, 110.2, 114.8, 119.0, 125.2,
127.2, 129.1, 130.1, 132.4, 160.0.
Deprotection of the PMB group: Protected sulfamide 5a (500 mg, 1.52 mmol)
was suspended in TFA (5 mL) and heated under reflux for 2 h. The reaction was
then cooled to room temperature and diluted with EtOAc (30 mL). The
resulting solution was washed with pH 7.0 buffer solution (2 Â 30 mL) then
with brine (30 mL). The organic was dried over MgSO4 and evaporated to give a
brown solid. This was triturated with MeOH (5 mL) and the insoluble material
filtered off. Evaporation of the liquors gave 6a as an off-white solid (318 mg,
1.52 mmol, 100%). 1H NMR (400 MHz, methanol-d4): 3.25 (3H, s), 6.93 (1H, d,
J = 8.2 Hz), 7.20 (1H, d, J = 1.6 Hz), 7.31 (1H, dd, J = 8.2, 1.6 Hz). 13C NMR
(100 MHz, methanol-d4): 26.4, 104.5, 110.0, 118.9, 126.0, 126.6, 132.0. MS
(ESI): m/z 208 [MÀ1]À.
We would like to thank Mark Andrews and Adam Stennet for
support and useful discussions.
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