An efficient synthesis of sulfamides

Article abstract of DOI:10.1016/j.tetlet.2010.03.106

Here we report an efficient synthesis of sulfamides. 3,5-Lutidine was found to be an optimal solvent and catalyst for the reaction. The method was developed during our efforts to synthesize a series of novel FKBP-12 inhibitors in which the known ketoamide linker was replaced with sulfamide.

Full text of DOI:10.1016/j.tetlet.2010.03.106

Tetrahedron Letters 51 (2010) 2909–2913
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Tetrahedron Letters
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An efficient synthesis of sulfamides
*
Chuangxing Guo , Liming Dong, Susan Kephart, Xinjun Hou
Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report an efficient synthesis of sulfamides. 3,5-Lutidine was found to be an optimal solvent and
catalyst for the reaction. The method was developed during our efforts to synthesize a series of novel
FKBP-12 inhibitors in which the known ketoamide linker was replaced with sulfamide.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 20 February 2010
Revised 24 March 2010
Accepted 25 March 2010
Available online 30 March 2010
The sulfamide functional group (R2NSO2NR2)1 can be found in a
number of marketed and investigational drugs intended to treat a
wide variety of conditions, examples of which are shown in
Table 1. In recent years, molecules containing sulfamides have also
been investigated as inhibitors of ATP-sensitive potassium chan-
these reagents are somewhat unstable. The more stable N-(tert-
butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydro-
pyridin-1-ylsulfonyl]azanide24 is also employed in the synthesis of
BOC-protected primary sulfamides.
Sulfamides with a higher degree of substitution are commonly
synthesized by the reaction of a substituted sulfamoyl chloride
with an amine in the presence of a base such as triethyl amine or
pyridine.8,18,23 Sterically hindered or less reactive amines, how-
ever, may be sluggish to these conditions, leading to side products
and decomposition of the sulfamoyl chloride. Activating/stabilizing
groups such as oxazolidinone25 and imidazolium triflates26,19 have
been employed to improve the efficiency of difficult reactions. This
Letter describes a difficult sulfamide synthesis we encountered,
and how mechanistic investigation of the side product led to our
use of 3,5-lutidine as a novel solvent/base/activating group.
In our neuroimmunophilin project, we sought to design and
synthesize novel FKBP (FK506 Binding Protein) inhibitors with bet-
ter metabolic stability and physical properties. As a substitute for a
potentially reactive and metabolically unstable ketoamide, a sulf-
amide linker was proposed. The sulfamides with a general struc-
ture 11a/b shown in Scheme 1 were targets of synthetic efforts.
The amine core (8a/b) can be readily synthesized in 2–3 steps.
The alkyl esters (7a/b) of proline and pipecolinic acid were pre-
pared from N-CBz amino acids (6a/b). The CBz group was removed
under standard hydrogenation conditions to give the free amines
(8a/b).
nels,2 carbonic anhydrase,3 carboxypeptidase A,4 -secretase,5 gly-
c
cosidase,6 HCV polymerase (NS5B),7 HIV-1 integrase,8 HIV-1
protease,9 histone deacetylase,10 human chymase,11 human leuko-
cyte elastase,12 kinesin spindle protein,13 monoamine reuptake,14
plasma cell membrane protein-1,15 and thrombin;16 as agonists
of androgen receptor,17 b3-andrenergic receptor,18 and PPAR;19
and as antagonists of CXCR2.20
The widespread pharmaceutical use of sulfamides may be
attributed to their unique chemical and structural features, as well
as their ability to confer desirable physical properties. A tetrahe-
dral sulfur atom and multiple vectors for substitution off the nitro-
gen atoms lead to conformational and structural diversity.
Depending on the degree of substitution, the number of hydro-
gen-bond donors and acceptors can be varied, and the lipophilicity
tuned. Sulfamides can be used as a bioisosteres of amides, ureas,
carbamates, ketoamides, esters, sulfonamides, or sulfamates. Like
ureas, sulfamides may be less prone to acidic, basic, or enzyme-cat-
alyzed hydrolysis than other isosteres. Compared to the more com-
monly used sulfonamide, the extra nitrogen of the sulfamide
provides more hydrogen-bonding potential, as well as different
physical properties such as log P and solubility.
Primary sulfamides (R1R2NSO2NH2) can be made from sulfamide
itself, either by heating with an amine23 or by reductive amination of
an aldehyde.21 Amines can also be acylated by unsubstituted sulfa-
moyl chloride, which is often generated in situ by the reaction of
chlorosulfonyl isocyanate with formic acid16 or water.13 BOC- or
CBZ-protected sulfamoyl chlorides can be generated in situ by the
reaction of chlorosulfonyl isocyanate with tert-butyl alcohol24,10 or
benzyl alcohol,4 allowing selective further functionalization, though
To form the sulfamide moiety, several known protocols for sul-
famoyl chloride formation were tested. At room temperature, the
mixture of sulfuryl chloride and the amine (8a/b) showed no
reaction even with addition of Lewis acids. Higher temperatures
only led to decomposition. The more reactive thionyl chloride
was proposed as a substitute for sulfuryl chloride, though the
products would require oxidation at a later stage. Unfortunately,
the addition of amines (NH2R) to thionyl chloride gave a complex
mixture. Next we decided to test sulfamide formation via substi-
tuted sulfamoyl chloride prepared from the amine (8a/b). The
amine (8a/b) was treated with chlorosulfonic acid and triethyl-
* Corresponding author. Tel.: +1 18586225927.
E-mail address: alex.guo@pfizer.com (C. Guo).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.106

2910
C. Guo et al. / Tetrahedron Letters 51 (2010) 2909–2913
Table 1
Examples of sulfamide-containing drugs
O
OH
S
H
N
O
H
N
NH2
O
N
S
O
N
O
S
H
N
O
S
H
H
N
H
HO
O
S
H
N
H
NH2
OH
O
Quinagolide (2)
Doripenem (1)
JNJ-26990990 (3)
H
N
N
O
N
O
S
O
N
O
S
O
N
N
NH2
S
O
H
NH2
N
S
Br
H2N
NH2
N
N
Macitentan (4)
Famotidine (5)
Br
Compound
Indication
Stage
On market
Company
Doripenem (1)
Quinagolide (2)
JNJ-26990990 (3)
Macitentan (4)
Famotidine (5)
Broad-spectrum antibiotic
Hyperprolactinaemia
Broad-spectrum Anticonvulsant
Pulmonary arterial hypertension
Gastroesophageal reflux disease
Shinogi/Johnson & Johnson
Ferring Pharmaceuticals
Johnson & Johnson
Actelion
Johnson & Johnson/Merck
Marketed outside US/Japan
Ph I21
Ph III22
On market
1) SO2Cl2
n
n
n
MeOH
H2/Pd-C
No Reaction
(first step)
COOH
COOR
COOR
N
N
N
H
2) HNR1R2
SOCl2
~90%
90-95%
70-85%
8a/b
7a/b
Cbz
Cbz
1) ClSO2OH, -30oC
2) PCl5, benzene, reflux
n=1 6a
n=2 6b
or ROH/EDC/DIEA
n
COOR
Imidazole
n
n
HNR1R2
HNR1R2
COOR
N
No Reaction
COOR
N
SO2
N
~65%
Et3N, CHCl 3
SO2Cl
SO2
N
N
R2
R1
9a/b
Sulfamide 11a/b
Not observed
10a/b
N
Scheme 1.
amine at À30 °C to give a sulfamoic acid, which was heated with
phosphorous pentachloride to give the sulfamoyl chloride (9a/b)
in good isolated yield (50–90%).27 However, our attempts to dis-
place the chlorine of the sulfamoyl chloride (9a/b) by amines in
the presence of triethylamine gave none of the desired sulfamide
(11a/b). At low temperature (À78 °C to À30 °C) as suggested in
the literature, no reaction was observed. Heating at ambient or
higher temperatures (25–50 °C) resulted in decomposition. To in-
crease stability, the sulfamoyl chloride was converted to sulfa-
moyl imidazole (10a/b), but this intermediate was not reactive
toward amines, even with large excess of the amines and at a
higher temperature (70 °C).
n
n
RNH2
COOMe
COOMe
N
N
base
solvent
SO2
NHR
SO2Cl
11
not observed
n=1-2 (9)
Base tested: Et3N, DIEA or morpholine
Solvent tested: CH2Cl2, CHCl3, benzene, THF, Et2O or DMF
n
n
n
RNH2
COOMe
COOMe
COOMe
+ red tar
(polymer?)
+
N
N
N
pyridine
SO2
SO2Cl
9
SO2
NH2
11
12
30-50%
NHR 5-25%
Scheme 2.

C. Guo et al. / Tetrahedron Letters 51 (2010) 2909–2913
15N labeled experiments:
2911
Ph15NH2
N
PhNH2
N15
N
COOMe
N
COOMe
N
COOMe
N
COOMe
SO2
SO2
SO2Cl
SO2Cl
15NH2
15
14
NMR, MS consistent with 14N
NH2
13
confirmed by NMR
(1H and 15N), MS
Proposed Mechanism:
N
I
e
SO2
y
n
n
a
o
18
f
l
w
u
h
t
N
t
t
s
a
a
(desired sulfamide product)
k
p
c
NHR
a
N
RNH2
-
N
O2S
Cl
a
a
t
N+
SO2Cl
t
a
h
H+
c
p
k
N
N
O2S
NH
t
α
-
c
w
N
16
a
a
rb
y
O2S
I
o
I
O2S
NH2
21
NHR
NHR
N
17
20
19
Scheme 3.
Table 2
Sulfamides prepared by following above-mentioned general procedure
N
(3,5-lutidine)
XSO2Y
XSO2Cl
+
Y (amine)
CH2Cl2
Compound
X
Y
Isolated yield (%)
72
N
HN
HN
N
O
O
22
OBn
OBn
OBn
OMe
O
N
N
N
N
N
N
N
O
O
O
O
O
O
O
N
23
24
25
26
27
28
89
99
88
95
70
2
N
O
OMe
HN
N
OMe
OMe
OMe
Ph
4
H
N
O
Ph
O
N
H
N
H
4
O
N
HN
O
Ph
S
4
(continued on next page)

2912
C. Guo et al. / Tetrahedron Letters 51 (2010) 2909–2913
Table 2 (continued)
Compound
X
Y
Isolated yield (%)
90
HN N
29
30
31
32
33
34
35
36
37
O
O
O
O
O
O
O
O
Ph
N
N
N
N
N
N
N
4
O
O
O
O
O
O
O
O
HN
N
O
15
Ph
4
C(O)NH2
N
75
Ph
4
N
HN
Cl
96
Ph
4
CH(OMe)2
N
N
94 (10:1 regioisomers)
Ph
4
F
F
HN
HN
46
69
55
25
Ph
4
F
N
Ph
4
N
Ph
4
HO
N
MeO
H
NH
NH
MeO
MeO
MeO
MeO
N
Ph
4
N
O
H
N
N
38
67
O
O
MeO
N
N
HN
HN
OBn
39
40
99
83
N
O
S
N
OMe
OMe
OMe
OMe
O
OMe
OMe
O
HN
41
42
43
Bn
Bn
Ph
87
45
75
N
N
N
N
N
OMe
O
N
N
N
OMe
HN
OMe
OMe
O
4
O
To investigate the reaction between the sulfamoyl chloride (9a/
b) and the amines, we screened a number of solvent (CH2Cl2,
CHCl3, benzene, THF, Et2O, DMF) and base (Et3N, DIEA, morpholine)
combinations (Scheme 2), but found that only pyridine as both

C. Guo et al. / Tetrahedron Letters 51 (2010) 2909–2913
2913
solvent and base gave the desired product sulfamides (11)
References and notes
although in a very low yield (5–25%). A detailed characterization
of the side products in the reaction mixture revealed that the pri-
mary sulfamide (12) was the main product formed (50–60%). The
finding is surprising because there is no ammonia or its equivalent
in the reaction.
1. This functional group is occasionally referred to as a ‘sulfonylurea’ (see Refs.
2,26), though care should be taken not to confuse it with the sulfonylurea class
of antidiabetic drugs having the structure ArSO2NHCONHR.
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‘Piperidinesulfonylureas and Thioureas, Their Preparation, Their Use and
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To identify the source of the terminal NH2 and to understand
the mechanism that produced this side product (12), 15N-labeled
aniline and 15N-labeled pyridine were used in two different runs
of this reaction (Scheme 3). When 15N-labeled aniline was used,
the primary sulfamide (14) was isolated without measurable
enrichment of 15N.28 With 15N-labeled pyridine as a solvent, 15N-
labeled 15 was isolated.29 These results suggested that the termi-
nal NH2 of 12 came from pyridine. We propose a reaction mecha-
nism (Scheme 3) in which the sulfamoyl chloride is first activated
by the formation of pyridinium salt. Nucleophilic addition of ani-
line to the sulfone, with pyridine as a leaving group, leads to the
desired sulfamide product 18. Alternatively, nucleophilic attack
of the aniline on the activated ortho or para positions of the pyrid-
inium ring,30 followed by ring opening hydrolysis results in the
undesired primary sulfamide side product 21. Based on the ob-
served product ratio, pathway II is favored under our reaction
conditions.
According to the proposed mechanism, pyridine plays three key
roles in the reaction—(1) co-solvent with a favorable dipole envi-
ronment; (2) catalyst to activate the sulfamoyl chloride; (3) base.
To facilitate the formation of desired sulfamide via pathway I, luti-
dines were substituted for pyridine as base/co-solvent. The steric
bulk of the extra methyl groups might impede nucleophilic addi-
tion to the pyridinium ring, thus disfavoring pathway II. The reac-
tion in 2,6-lutidine was found to be sluggish. Almost 95% of the
sulfamoyl chloride remained even after 24 h. The basic nitrogen
of 2,6-lutidine may be too hindered to activate the sulfonyl chlo-
ride via formation of a pyridinium salt, which seems to be critical
for the reaction. On the other hand, the reaction was faster and
cleaner with 3,5-lutidine as the base, affording the desired sulfam-
ide in a substantially improved yield (up to 90% yield). Only a min-
imal amount (<5%) of the primary sulfamide side product was
observed. 3,5-Lutidine not only provides the desirable dipole envi-
ronment, base, and catalytic effect of pyridine but also minimizes
the formation of the undesired side product by slowing down
nucleophilic addition of the amine to the pyridinium ring. Using
3,5-lutidine as the solvent/base, a large number of sulfamides with
diverse structures were prepared, as shown in Table 2.31
Typical conditions for sulfamide formation: To a 3,5-lutidine
solution (1 mL) of 3,4,5-trimethoxyaniline (176 mg, 0.96 mmol)
was added (S)-methyl 1-(chlorosulfonyl)piperidine-2-carboxylate
(compound 25X, 116 mg, 0.481 mmol) in CH2Cl2 (1 mL) at 25 °C.
After 20 hours, the mixture was diluted with EtOAc (40 mL) and
washed with 5% HCl solution (ice-cold, 25 mL) and brine (25 mL).
The organic layer was dried over MgSO4 and concentrated. The res-
idue was purified by column chromatography (25–30% EtOAc in
hexanes) to provide 165 mg (88%) of sulfamide 25 as a white solid.
In summary, new sulfamide formation conditions have been
established by studying the mechanism of the side product forma-
tion. As a result, wewere able tosynthesize a newclass of FKBP inhib-
itors. The new sulfamide formation protocol provides medicinal
chemists an additional effective method for synthesizing sulfamides,
which potentially have more favorable pharmaceutical properties.
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27. Preparation of various sulfamoyl chlorides have been previously reported in
following patent publication. Guo, C.; Dong, L.; Hou, X.; Vanderpool, D. L.;
Villafranca, J. E. PCT Int. Appl. WO 01/40185 A1, 2001.
28. Compound 14 was found to have a parent MS ion [MS(M+H+): 223] and 1H
NMR (broad singlet on peak for NH2 in deuterated DMSO) consistent with
unlabeled product.
29. Compound 15 was found to have a parent MS ion [MS(M+H+): 224], 1H NMR
(doublet peak for NH2 in deuterated DMSO) and 15N NMR (triplet peak for NH2)
consistent with 15N-labeled product.
Supplementary data
30. Nucleophilic addition to either ortho or para position of the pyridinium ring can
lead to the same terminal sulfamide side product (21). Ortho addition is shown
as an example in the proposed mechanism.
31. Syntheticprocedure andanalytical dataof allcompounds listed herein have been
previously reported in following patent publication. Guo, C.; Dong, L.; Hou, X.;
Vanderpool, D. L.; Villafranca, J. E. PCT Int. Appl. WO 01/40185 A1, 2001.
Supplementary data (analytical data (spectroscopic and physical
characterization) for new sulfamides reported in this work is in-
cluded as Supplementary data) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.03.106.