Synthetic methodology for the preparation of N-hydroxysulfamides

Article abstract of DOI:10.1016/j.tetlet.2007.09.037

A convenient synthesis of a variety of substituted N-hydroxysulfamides from chlorosulfonyl isocyanate is reported. Alkyl groups can be introduced selectively on the N-Boc nitrogen of key intermediates 1a or 1b using the Mitsunobu reaction with alcohols. S

Full text of DOI:10.1016/j.tetlet.2007.09.037

Tetrahedron Letters 48 (2007) 8029–8033
Synthetic methodology for the preparation of
N-hydroxysulfamidesI
Krishnaswamy Devanathan, Jennifer A. Bell, Patricia C. Wilkins, Hollie K. Jacobs and
Aravamudan S. Gopalan*
Department of Chemistry and Biochemistry, MSC 3C, New Mexico State University, Las Cruces, NM 88003-8001, United States
Received 17 July 2007; accepted 5 September 2007
Available online 11 September 2007
Abstract—A convenient synthesis of a variety of substituted N-hydroxysulfamides from chlorosulfonyl isocyanate is reported. Alkyl
groups can be introduced selectively on the N-Boc nitrogen of key intermediates 1a or 1b using the Mitsunobu reaction with alco-
hols. Subsequently the nitrogen carrying the silyloxy group can be alkylated under traditional conditions. Deprotection to the
desired N-hydroxysulfamide can be achieved in high yields. Using this method, a number of structurally diverse N-hydroxysulfa-
mides have been prepared. The usefulness of this methodology has further been demonstrated by the synthesis of more complex
targets such as bis-hydroxysulfamide 5, and cyclic hydroxysulfamides 7 and 8.
ꢀ 2007 Elsevier Ltd. All rights reserved.
N-Hydroxysulfamides are a class of compounds that are
structurally similar to N-hydroxyureas,1 N-hydroxysulf-
onamides,2 and sulfamides,3 which exhibit a wide range
of biological activity. However, little research has fo-
cused on the synthesis of N-hydroxysulfamides or their
biological activity. Recently, the synthesis of a few N-al-
kyl, N0-hydroxysulfamides was published.4 These com-
pounds were shown to be potent inhibitors of several
isozymes of carbonic anhydrase establishing the poten-
tial of N-hydroxysulfamides as pharmacophores.5 Supu-
ran et al.6 have recently obtained the X-ray crystal
structure of N-hydroxysulfamide (NH2SO2NHOH) with
an isozyme of CA, which shows it is bound to the Zn
through the ionized primary amino group. They pro-
pose that incorporation of R groups at the N-hydroxy
position could lead to more effective enzyme inhibitors.
Also, some phenylalanine-based N-hydroxysulfamides
have been shown to be inhibitors of carboxypeptidase
A.7 These results prompt us to report our own synthetic
efforts to develop a convenient synthetic methodology
for this class of molecules.
N-hydroxysulfamides have been prepared in low yields
by the direct coupling of a sulfamoyl chloride8 or fluo-
ride9 with hydroxylamine. This method is limited by
poor availability of sulfamoyl chlorides and hydroxyl-
amines. The first attempt to prepare some simple N-
hydroxysulfamides
from
chlorosulfonylisocyanate
(CSI) gave some surprising results. CSI was reacted with
t-BuOH to give the N-Boc-sulfamoyl chloride, which
was then reacted with O-benzylhydroxylamine. How-
ever, attempts to deprotect the N-benzyloxy group using
hydrogenolysis resulted in cleavage of the N–O bond
yielding the corresponding sulfamide and not the desired
N-hydroxysulfamide.10 In one example, direct coupling
with unprotected hydroxylamine did lead to the unsub-
stituted N-hydroxysulfamide. More recently, a limited
study was published that involved the coupling of O-
(t-butyldimethylsilyl)-hydroxylamine with N-Boc sulfa-
moyl chloride.4 Reaction of the resulting sulfamide with
aliphatic alcohols under Mitsunobu conditions gave the
corresponding N-alkyl-N0-hydroxysulfamides after
deprotection with TFA/water 5%. However, this study
was of limited synthetic scope and needed further expan-
sion. We desired a method for the selective preparation
of disubstituted N-hydroxysulfamides (including cyclic
examples) and bis-N-hydroxysulfamides.
q Portions of this work were presented at the 229th American
Chemical Society National Meeting, San Diego, CA, March 13–17,
2005. ORGN 525.
The known N-Boc-sulfamoyl chloride was prepared by
the reaction of t-butanol with CSI and its reaction
with several O-TBDMS protected hydroxylamines was
*
Corresponding author. Tel.: +1 505 646 2589; fax: +1 505 646
2649; e-mail: agopalan@nmsu.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.037

8030
K. Devanathan et al. / Tetrahedron Letters 48 (2007) 8029–8033
by silica gel chromatography. The Mitsunobu reaction
1. t-BuOH, CH Cl
OTBDMS
R
Boc
H
O
S
2
2
OCNSO Cl
proceeded smoothly with selectivity in the case of the
unsubstituted sulfamide 1b, clearly demonstrating the
nitrogen of higher nucleophilicity. The generality of this
method is clearly shown by the examples listed in Table
1.
2
N
N
2. RNHOTBDMS,
Et N, CH Cl rt
O
3
2
2,
R
Yield (%)
1a CH3
1b
1c
71
73
64
H
Bn
1d c-hexyl 60
Because of the time consuming and more difficult isola-
tion of the products from the Mitsunobu reaction, we
also examined the reactions of N-hydroxysulfamides 1
with alkyl halides using standard alkylation conditions
(R1X, K2CO3, CH3CN, reflux-method B14). In the case
of sulfamide 1a, N-alkylation using method B gave good
yields of the desired products, 2a–d, (Table 1, entries 1–
4) after isolation and purification by silica gel chroma-
tography. Alkylation using the more hindered 2-iodo-
propane (Table 1, entry 5) gave a lower yield of the
desired product 2e.
1e t-Bu
35
Scheme 1.
investigated (Scheme 1). In general, a dichloromethane
solution of the N-Boc-sulfamoyl chloride (1 equiv, pre-
pared in situ) was added to a dichloromethane solution
of O-TBDMS protected hydroxylamine (1–1.2 equiv,
prepared in situ) in the presence of triethylamine. After
stirring the mixture overnight, the product was isolated
and purified by flash chromatography. Using this proce-
dure it was possible to prepare protected N-hydrox-
ysulfamides, 1a–d, in good yields (Scheme 1).11,12
However, the yield was lower in the coupling of the
hindered t-butyl hydroxylamine to give 1e.
Alkylation of 1b (R = H) with 1 equiv of ethyl iodide or
benzyl bromide using method B was more complex and
gave mixtures of mono (alkylation at the Boc protected
nitrogen) and dialkylated products (Table 1, entries 6
and 7). It was not possible to selectively effect this alkyl-
ation by variation of the reaction conditions. Though N-
alkylation of the more acidic Boc protected nitrogen was
the faster process, it was somewhat surprising that alkyl-
ation on the hydroxylamine nitrogen also occurred read-
ily. This led us to take advantage of this observation and
exploit it for the one pot preparation of symmetrical
The protected sulfamides 1 provide an excellent starting
material for preparation of derivatives by alkylation. We
first examined the alkylation of the Boc protected nitro-
gen of 1a using Mitsunobu conditions (R1OH, PPh3,
DEAD—method A13). The desired products were ob-
tained in good yields after isolation and purification
Table 1. Alkylation of sulfamides using method A or B
OTBDMS
R
O
S
Boc
Method A
N
N
1 or 2
1
R
Method B
O
2
Entry
1
Substrate
Product
R
R1
Method
Yield (%)
1a
2a
CH3
CH3CH2
Aa
Bb
A
B
A
B
74
75
77
74
66
77
74
2
3
1a
1a
2b
2c
CH3
CH3
Bn
Allyl
4
5
1a
1a
2d
2e
CH3
CH3
A
t-Bu
i-Pr
O
A
B
73
29
6
7
1b
1b
2f
H
H
CH3CH2
Bn
A
B
A
B
78
Mixturec
2g
75
Mixtured
8
9
10
11
12
13
1b
1b
1b
1b
2g
2i
2h
2i
H
H
nBu
Allyl
nBu
Bn
Allyl
i-Pr
nBu
Allyl
Bn
A
A
Be
Be
B
68
77
79
76
77
73
2j
2k
2l
2m
i-Pr
B
a Method A-1, DEAD, PPh3, R1OH, THF, rt.
b Method B-1, R1X (1.2 equiv), K2CO3, CH3CN, reflux: X = I, except in 2b, 2c, 2k, and 2g where X = Br.
c 50:50 Mixture of mono and dialkylated product (based on 1H NMR).
d 40:60 Mixture of mono and dialkylated product (based on 1H NMR).
e 3 equiv of RX.

K. Devanathan et al. / Tetrahedron Letters 48 (2007) 8029–8033
Table 2. Preparation of N-hydroxysulfamides 3
8031
O
S
OH
R
H
1. TFA, CH2Cl2, rt
N
N
1 or 2
2. 15% HCl/MeOH, rt
1
R
O
3
Entry
Substrate
Product
R
R1
Yielda (%)
1
2
3
1c
1d
2a
3a
3b
3c
Bn
c-Hexyl
CH3
H
H
93
90
97
CH3CH2
4
2d
3d
CH3
85
t-Bu
O
a Two-step yield.
dialkylated sulfamides. For example, 2j and 2k were
prepared in good yields using method B with 3 equiv
of butyl iodide or allyl bromide.
CH Br
2
Boc
OTBDMS
N
SO N
2
CH
CH Br
2
3
1a
Boc
K CO , CH CN,
2
3
3
Introduction of different alkyl groups on the two nitro-
gens of 1b was accomplished by a two-step procedure
(Table 1, entries 12 and 13).15 In one example, sulfamide
1b was first reacted with benzyl alcohol under Mitsun-
obu conditions (method A) to give the monoalkylated
product 2g. Subsequent alkylation of 2g using butyl
iodide (method B) gave the unsymmetrical dialkylated
sulfamide 2l. The two-step approach clearly demon-
strates the potential to incorporate the desired alkyl
group at the appropriate nitrogen of 1b.
OTBDMS
N
reflux, 24 h, 79%
SO N
2
4
CH
3
1. 10% TFA/CH Cl rt, 2 h
2. 15% HCl/MeOH, rt, 3 h
78% (2 steps)
2
2
H
OH
N
SO N
2
CH
3
H
N
SO N
OH
CH
Representative sulfamides were deprotected to yield the
corresponding N-hydroxysulfamides 3a–d (Table 2).
The Boc group was first removed by treatment of the
sulfamide with 10% trifluoroacetic acid in dichlorometh-
ane at room temperature. Subsequent removal of the
TBDMS group was accomplished using 15% HCl in
methanol.16
2
5
3
Scheme 2.
1. 1b, K CO ,
CH CN, reflux
2
3
3
3 h,79%
HN
N
O
It is exciting to note that this methodology can be ex-
tended to prepare new classes of previously unreported
N-hydroxysulfamide ligand systems. Treatment of a,a0-
dibromo-m-xylene with 2 equiv of sulfamide 1a in the
presence of potassium carbonate in refluxing acetonitrile
gave the protected sulfamide 4 in 79% yield after purifi-
cation. Removal of the Boc protecting groups with 10%
TFA in dichloromethane followed by treatment with
15% HCl in methanol gave bis-N-hydroxysulfamide 5
in 78% yield (Scheme 2).
S
Br Br
2. 10% TFA/CH Cl ,
2 h, 95%
OTBDMS
2
2
O
6
1. CH I, K CO ,
3
2
3
15% HCl/MeOH,
6 h, 96%
CH CN, reflux,
3
24 h,70%
2. 15% HCl/MeOH
6 h, 98%
HN
N
S
OH
O
N
O
N
O
O
7
S
OH
H C
3
8
This methodology is also useful for the synthesis of cyc-
lic N-hydroxysulfamides (Scheme 3). Alkylation of 1,3-
dibromopropane with 1 equiv of 1b in the presence of
potassium carbonate in refluxing acetonitrile followed
by removal of the Boc protecting group using 10%
TFA in dichloromethane gave the cyclic sulfamide 6.
Removal of the TBDMS protecting group using stan-
dard methods gave the cyclic N-hydroxysulfamide 7 in
excellent yield. Alternatively, sulfamide 6 could be alkyl-
ated with methyl iodide followed by removal of the
TBDMS protecting group to give the cyclic N-methyl,
N0-hydroxysulfamide 8. Cyclic sulfamides have been
shown to inhibit a variety of enzymes.1b
Scheme 3.
In conclusion, we have developed a versatile synthetic
method for the preparation of a wide array of N-
hydroxysulfamides. Further, the methodology has been
shown to be useful for the synthesis of bis-N-hydroxy-
sulfamides as well as cyclic N-hydroxysulfamides. The
present study increases the availability of diverse
substrates for evaluation by researchers in the field of
carbonic anhydrase inhibition, an area of much
biomedical interest.

8032
K. Devanathan et al. / Tetrahedron Letters 48 (2007) 8029–8033
12. Representative procedure for the preparation of sulfa-
mides 1. Preparation of N-(tert-butoxycarbonyl)-N0-
methyl-N0-[(tert-butyldimethyl)silyloxy]-sulfamide
(1a):
Acknowledgment
This work was supported by a grant from the National
Institutes of Health under PHS Grant No. S06
GM08136.
Triethylamine (2.5 mL, 17.9 mmol) was added dropwise
to a suspension of N-methylhydroxylamine hydrochloride
(0.50 g, 6.0 mmol) in anhydrous CH2Cl2 (10 mL) under N2
at 0 ꢁC and stirred at rt for 2 h. The reaction mixture was
cooled to 0 ꢁC and a solution of TBDMSCl (0.90 g,
6.0 mmol) in anhydrous CH2Cl2 (5 mL) was slowly added
at 0 ꢁC. The reaction mixture was then stirred at rt for
20 h. In a separate flask, t-butanol (0.57 mL, 6.0 mmol)
was added dropwise to a solution of chlorosulfonylisocy-
anate (0.51 mL, 6.0 mmol) in anhydrous CH2Cl2(15 mL)
under N2 at 0 ꢁC and stirred at 0 ꢁC for 40 min to give the
t-butoxycarbamoylsulfamoyl chloride. Triethylamine
(2.5 mL, 17.9 mmol) was added to the solution of
protected hydroxylamine at 0 ꢁC. The solution containing
the sulfamoyl chloride was added to the protected
hydroxylamine via syringe. The reaction mixture was
warmed to rt and stirred for 18 h. The solvent was
removed under reduced pressure. The residue was dis-
solved in EtOAc (100 mL) and washed with water
(10 mL), 0.1 M HCl (3 · 10 mL), satd NaHCO3
(3 · 10 mL), brine (15 mL), and dried (Na2SO4). The
crude product was purified by flash silica gel chromatog-
References and notes
1. (a) Lori, F.; Kelly, L. M.; Foli, A.; Lisziewicz, J. Exp.
Opin. Drug Safety 2004, 3, 279; (b) Huang, J.; Zou, Z.;
Kim-Shapiro, D. B.; Ballas, S. K.; King, S. B. J. Med.
Chem. 2003, 46, 3748; (c) King, S. B. Curr. Med. Chem.
2003, 10, 437; (d) Granik, V. G.; Grigor’ev, N. B. Russ.
Chem. Bull. Int. Ed. 2002, 51, 1375; (e) Paz-Ares, L.;
Donehower, R. C. In Cancer Chemotherapy and Biother-
apy—Principles and Practice, 3rd ed.; Chabner, B. A.,
Longo, D. L., Eds.; Lippincott, Williams and Wilkins:
Philadelphia, 2001; pp 315–328, Chapter 11; (f) Frank, I.
J. Biol. Regulat. Homeostat. Agents 1999, 13, 186; (g)
Charache, S.; Barton, F. B.; Moore, R. D.; Terrin, M. L.;
Steinberg, M. H.; Dover, G. J.; Ballas, S. K.; McMahon,
R. P.; Castro, O.; Orringer, E. P. Medicine 1996, 75, 300.
2. (a) Nuti, E.; Orlandini, E.; Nencetti, S.; Rossello, A.;
Innocenti, A.; Scozzafava, A.; Supuran, C. T. Bioorg.
Med. Chem. 2007, 15, 2298; (b) Wilkins, P. C.; Jacobs, H.
K.; Johnson, M. D.; Gopalan, A. S. Inorg. Chem. 2004, 43,
7877–7881; (c) Lee, M. J. C.; Shoeman, D. W.; Goon, D.
J. W.; Nagasawa, H. T. Nitric Oxide—Biol. Chem. 2001, 5,
278; (d) Scozzafava, A.; Supuran, C. T. J. Med. Chem.
2000, 43, 3677; (e) Mincione, F.; Menabuoni, L.; Briganti,
F.; Mincione, G.; Scozzafava, A.; Supuran, C. T. J.
Enzyme Inhib. 1998, 13, 267.
3. (a) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supu-
ran, C. T. Med. Res. Rev. 2006, 26, 767; (b) Winum, J.-Y.;
Scozzafava, A.; Montero, J.-L.; Supuran, C. T. Exp. Opin.
Therap. Patents 2006, 16, 27; (c) Casini, A.; Winum, J.-Y.;
Montero, J.-L.; Scozzafava, A.; Supuran, C. T. Bioorg.
Med. Chem. Lett. 2003, 13, 837; (d) Park, J. D.; Kim, D.
H.; Kim, S.-J.; Woo, J.-R.; Ryu, S. E. J. Med. Chem. 2002,
45, 5295; (e) Tozer, M. J.; Buck, I. M.; Cooke, T.;
Kalindjian, S. B.; McDonald, J. M.; Pether, M. J.; Steel,
K. I. M. Bioorg. Med. Chem. Lett. 1999, 9, 3103.
4. Winum, J.-Y.; Innocenti, A.; Nasr, J.; Montero, J.-L.;
Scozzafava, A.; Vullo, D.; Supuran, C. T. Bioorg. Med.
Chem. Lett. 2005, 15, 2353.
1
raphy to give 1a (1.44 g, 71%) as a white solid. H NMR
(CDCl3, 200 MHz) d 0.22 (s, 6H), 0.94 (s, 9H), 1.51 (s,
9H), 3.09 (s, 3H,) 6.99 (br s, 1H); 13C NMR (CDCl3,
50 MHz) d ꢀ5.1, 17.7, 25.7, 27.8, 42.8, 84.0, 149.1; IR
(KBr) 3192, 2990, 2932, 2859, 1713 cmꢀ1; Anal. Calcd for
C12H28O5N2SSi: C, 42.33; H, 8.29; N, 8.23. Found: C,
42.09; H, 7.98; N, 8.34.
13. Method A—Representative procedure: Preparation of N-
[tert-butoxycarbonyl]-N-(ethyl)-N0-(methyl)-N0-[(tert-butyl-
dimethyl)silyloxy]-sulfamide (2a): To a solution of 1a
(0.350 g, 1.03 mmol) and DEAD (40% in toluene,
0.448 mL, 1.03 mmol) in anhydrous THF (5 mL) under
N2 was added a solution of PPh3 (0.269 g, 1.03 mmol) and
EtOH (0.060 g, 1.24 mmol) in anhydrous THF (3 mL) and
the reaction mixture was stirred at rt for 16 h. The solvent
was removed under reduced pressure and the crude
product was purified by flash silica gel chromatography
1
to give 2a (0.281 g, 74%). H NMR (CDCl3, 200 MHz) d
0.22 (s, 6H), 0.93 (s, 9H), 1.30 (t, 3H), 1.52 (s, 9H), 3.08 (s,
3H), 3.75 (q, 2H); 13C NMR (CDCl3, 50 MHz) d ꢀ5.2,
15.0, 17.7, 25.7, 27.9, 43.0, 46.07, 83.8, 151.0; IR (Neat)
2935, 2860, 1724 cmꢀ1; Anal. Calcd for C14H32O5N2SSi:
C, 45.62; H, 8.75; N, 7.60. Found: C, 45.91; H, 8.40; N,
7.41.
5. For some recent reviews on design of carbonic anhydrase
inhibitors see: (a) Winum, J.-Y.; Scozzafava, A.; Montero,
J.-L.; Supuran, C. T. Curr. Top. Med. Chem. 2007, 7, 835;
(b) Supuran, C. T.; Vullo, D.; Manole, G.; Casini, A.;
Scozzafava, A. Curr. Med. Chem. Cardiovasc. Hematol.
Agents 2004, 2, 49; (c) Supuran, C. T.; Scozzafava, A.;
Casini, A. Med. Res. Rev. 2003, 23, 146.
6. Temperini, C.; Winum, J.-Y.; Montero, J.-L.; Scozzafava,
A.; Supuran, C. T. Bioorg. Med. Chem. Lett. 2007, 17,
2795.
14. Method B—Representative procedure for 2a: To a solu-
tion of 1a (0.150 g, 0.44 mmol) in anhydrous CH3CN
(5 mL) was added anhydrous K2CO3 (0.073 g, 0.53 mmol)
and CH3CH2I (0.082 g, 0.53 mmol) and the reaction
mixture was heated at reflux for 4 h. The solvent was
removed under reduced pressure. The residue was dis-
solved in EtOAc (25 mL) and washed with water
(3 · 10 mL), brine (10 mL), and dried (Na2SO4). The
crude product was purified by flash silica gel chromato-
graphy to give 2a (0.122 g, 75%).
7. Park, J. D.; Kim, D. H. Bioorg. Med. Chem. 2004, 12,
2349.
15. For sequential alkylation on N-Boc protected sulfamides
see: (a) Montero, J.-L.; Dewynter, G.-F.; Agoh, B.;
Delaunay, B.; Imbach, J.-L. Tetrahedron Lett. 1983, 24,
3091; (b) Regainia, Z.; Abdaoui, M.; Aouf, N.; Dewynter,
G.; Montero, J.-L. Tetrahedron 2000, 56, 381.
8. Oettle, J.; Brink, K.; Morawietz, G.; Backhaus, M.;
Boldhaus, M.; Bliefert, C. Z. Naturforsch. 1978, 33b,
1193.
9. Boldhaus, M.; Brink, K.; Bliefert, C. Angew. Chem., Int.
Ed. Engl. 1980, 19, 943.
16. General procedure for deprotection of sulfamides: Prep-
aration of N-(ethyl)-N0-(methyl)-N0-(hydroxy)sulfamide
(3c): To a solution of 2a (0.29 g, 0.79 mmol) in anhydrous
CH2Cl2 (10 mL) was added trifluoroacetic acid (0.9 mL,
3.60 mmol) at rt and the reaction mixture was stirred for
10. Hajri, A.-H.; Dewynter, G.; Criton, M.; Dilda, P.;
Montero, J.-L. Heteroatom Chem. 2001, 12, 1.
11. Spectroscopic (1H, 13C, and IR) and elemental analyses of
all compounds are in agreement with the assigned
structures.

K. Devanathan et al. / Tetrahedron Letters 48 (2007) 8029–8033
8033
1.5 h. The solvent was removed under reduced pressure to
give the Boc deprotected compound (0.21 g, 99%), which
was used without purification. 1H NMR (CDCl3,
200 MHz) d 0.22 (s, 6H), 0.93 (s, 9H), 1.24 (t, 3H), 2.93
(s, 3H), 3.30–3.40 (m, 2H), 4.26 (br s, 1H). The Boc
deprotected compound (0.177 g) was stirred with 15% HCl
in methanol (3 mL) at rt. After 3 h, the solvent was
removed under reduced pressure. The residue was washed
with hexane and dried under vacuum to give N-hydroxy-
sulfamide 3c as a pale yellow oil (0.099 g, 97% two steps).
1H NMR (CDCl3, 200 MHz) d 1.25 (t, 3H), 3.02 (s, 3H),
3.25–3.40 (m, 2H), 4.66 (br s, 1H), 6.26 (br s, 1H); 13C
NMR (CDCl3, 50 MHz) d 15.7, 39.8, 40.4; IR (neat)
3313, 2984, 1435 cmꢀ1; Anal. Calcd for C3H10O3N2S: C,
23.37; H, 6.54; N, 18.17. Found: C, 23.70; H, 6.93; N,
17.78.