A novel and facile one-pot method for the synthesis of N-substituted sulfamates

Article abstract of DOI:10.1055/s-2008-1067156

A one-pot approach to the formation of N-substituted sulfamates from carboxylic acids using di-tert-butyl dicarbonate, tetrabutylammonium sulfamate, and pyridine under mild conditions is described. A reaction mechanism with two competing pathways is proposed; in reactions with aliphatic and electron-deficient aromatic acid substrates, the desired sulfamate products are formed, in contrast, symmetrical anhydride intermediates are observed with electron-neutral or electron-rich aromatic substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067156

2298
PAPER
A Novel and Facile One-Pot Method for the Synthesis of N-Substituted
Sulfamates
O
ne-Pot Method S
a
ynthesis of
l
N
-Sub
l
stituted
e
Sulfamatesna Rogers,* Guy Humphrey, Anna Chiu, Tao Pei
Department of Process Research, Merck and Co Inc., 126 E. Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA
Fax +1(732)5941499; E-mail: hallena_rogers@merck.com
Received 14 April 2008; revised 29 May 2008
O
O
Abstract: A one-pot approach to the formation of N-substituted
Bu4NSO3NH2
SO3Bu4N
sulfamates from carboxylic acids using di-tert-butyl dicarbonate,
tetrabutylammonium sulfamate, and pyridine under mild conditions
is described. A reaction mechanism with two competing pathways
is proposed; in reactions with aliphatic and electron-deficient aro-
matic acid substrates, the desired sulfamate products are formed, in
contrast, symmetrical anhydride intermediates are observed with
electron-neutral or electron-rich aromatic substrates.
R
OH
R
N
H
Boc2O, pyridine
r.t.
1
2
83–95%
Scheme 1
An efficient method for the direct conversion of a carbox-
ylic acid into a sulfamate under mild conditions was de-
sired for the large-scale preparation of a drug candidate.
We hypothesized that an activated carbonate intermediate
generated in situ from a carboxylic acid and di-tert-butyl
dicarbonate would undergo nucleophilic attack by tetra-
Key words: sulfamates, carboxylic acid, tetrabutylammonium sulf-
amate, carbonate, anhydride
N-Substituted sulfamates are useful synthetic precursors
to monobactams, the only class of b-lactam antibiotic not
known to be hydrolyzed by metallo-b-lactamases.1 Given
the continued growth of drug-resistant bacteria, the devel-
opment of new and efficient routes for the synthesis of
novel antibiotics is critical. N-Substituted sulfamates are
also intermediates along the path to some artificial sweet-
eners.2
Table 1 Bases Screened for Optimum Conversiona
O
O
Bu4NSO3NH2
SO3Bu4N
OH
N
H
Boc2O
base
O2N
O2N
N-Sulfamates have been synthesized from carboxylic ac-
ids in one or two steps, though in poor yields. Cimarusti3
and Epstein4 reported the N,N¢-dicyclohexylcarbodi-
imide-mediated coupling of carboxylic acids and tetra-
butylammonium sulfamate in yields ranging from 37% to
50%. Similarly, Branchini5 reported 1,1¢-carbonyldi-
imidazole-mediated coupling of a carboxylic acid and
2¢,3¢-isopropylidene-5¢-sulfamoyladenosine in 60% yield.
A single example of a reaction between an acid chloride
and sulfamic acid in the presence of triethylamine has also
been reported.6 More commonly sulfamates are produced
from the corresponding amide with chlorosulfonic acid
and 2-picoline.7,8 Not only do these methods involve ini-
tial formation of an activated acid equivalent or an amide,
they also require the use of expensive and harsh reagents.
Entry Base
Temp (°C) Time (h) Conversionb (%)
1
2
pyridine
2,6-lutidine
2,6-lutidine
2-picoline
2-picoline
Et3N
20
20
50
20
50
20
20
20
20
20
20
20
20
20
2
18
18
18
18
2
100
72
99
44
99
2
3
4
5
6
7
Et3N
72
2
36
0
8
i-Pr2NH
i-Pr2NEt
DBU
9
2
0
We have developed a one-pot, high-yielding sulfamation
utilizing di-tert-butyl dicarbonate, pyridine, and tetra-
butylammonium sulfamate to convert carboxylic acids
directly into sulfamates (Scheme 1); isolated yields typi-
cally range from 83% to 95%. In this report, we demon-
strate the versatility of these conditions in efficiently
producing a variety of sulfamates.
10
11
12
13
14
2
0
NaOH
2
0
DMAP
5
0
K2CO3
5
0
KHCO3
5
0
a 4-Nitrobenzoic acid (1.0 equiv), base (1.0 equiv), and Bu4NSO3NH2
(1.8 equiv) were dissolved in THF. A soln of Boc2O (1.5 equiv) in
THF was added over 1 h and the reaction was aged for the times indi-
cated in the table.
SYNTHESIS 2008, No. 14, pp 2298–2302
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1067156; Art ID: M01908SS
x
x.
x
x
.
2
0
0
8
b Determined by HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Method Synthesis of N-Substituted Sulfamates
2299
butylammonium sulfamate to form the desired sulfamate. Table 2 Substrates for Sulfamation under Conditions Aa
To this end, we screened a variety of bases for the reaction
Entry Substrate
Product
Isolated
between 4-nitrobenzoic acid and tetrabutylammonium
sulfamate (Table 1). In general, organic bases (entries 1–
7) performed better than inorganic bases. In particular, ar-
omatic bases such as pyridine resulted in excellent con-
version (entry 1) after two hours at room temperature.
More sterically hindered bases such as 2-picoline and 2,6-
lutidine also provided good conversions, but required
longer reaction times and higher reaction temperatures.
After some optimization, we found that slow addition of
di-tert-butyl dicarbonate to a solution of 4-nitrobenzoic
acid and tetrabutylammonium sulfamate in pyridine pro-
vided optimal yield and reaction profile. The product sulf-
amate was crystalline and could be isolated in high purity
by filtration directly from the reaction mixture.
yield (%)
O
O
SO3Bu4N
1
95
95
OH
N
H
Cbz
N
Cbz
O
O
N
2
NBu4O3S
HO
N
H
OH
O
OH
O
SO3Bu4N
3
89
94
OH
Boc
N
H
HN
OH
HN
Boc
With pyridine having been determined to be the best base
for the transformation, the substrate scope of the reaction
was explored. A variety of aliphatic acids and substituted
aromatic acids were examined (Table 2). In general, ali-
phatic substrates and electron-deficient aromatic acids,
such as 2- and 3-chlorobenzoic acid, 4-nitrobenzoic acid,
and 2-picolinic acid, reacted efficiently to produce the
corresponding sulfamates in high yields (entries 1–5, 7,
8).
O
O
SO3Bu4N
SO3Bu4N
4
5
N
H
Cl
O
Cl
O
N
OH
O
85
H
Cl
Cl
However, reactions with electron-neutral aromatic acids,
such as benzoic acid, and electron-rich aromatic acids,
such as 3-methoxybenzoic acid, resulted in only moderate
yields of the desired sulfamate (Table 2, entries 9, 10). In-
stead, the major byproduct was the symmetrical anhydride
6 resulting from reaction between the activated carbonate
4 and the starting acid 3 (Scheme 2). Aliphatic acids and
electron-deficient carboxylic acids are more likely to react
via path a due to decreased nucleophilicity of the acid
moiety. However, with electron-neutral or electron-rich
aromatic acids, path b, which leads to the formation of the
undesired anhydride 6, becomes a competing pathway.
O
SO3Bu4N
6
7
52
83
OH
N
H
Cl
Cl
O
O
SO3Bu4N
N
OH
H
O2N
O2N
N
H
N
8
9
95
45
OH
N
SO3Bu4N
SO3Bu4N
O
O
O
O
Despite the preferential formation of the symmetrical an-
hydride at room temperature, we were pleased to find that
at higher temperatures, the intermediate anhydride can un-
dergo further reaction with tetrabutylammonium sulfa-
mate to produce the desired sulfamate (Table 3, entry 1).
Hence, by performing the reaction at 50 °C, the sulfamate
salt of benzoic acid, 4-toluic acid, and 3-methoxybenzoic
acid could now be produced in good yield (Table 3, en-
tries 2–4). Unfortunately, very electron-rich substrates,
such as 4-(dimethylamino)benzoic acid (Table 3, entry 5)
still failed to produce the desired sulfamate under these
modified conditions.
N
H
OH
OH
O
O
SO3Bu4N
N
H
10
50
O
O
a Boc2O (1.5 equiv) was added to a soln of carboxylic acid (1.0 equiv)
and 2 M Bu4NSO3NH2 in pyridine (1.8 equiv) at r.t.
In conclusion, we have developed an efficient one-pot
procedure for the preparation of N-substituted sulfamates
from the corresponding carboxylic acids. The use of pyri-
dine or its derivatives was optimal for achieving complete
conversion. A concise mechanistic analysis highlighted
divergent reaction pathways for electron-deficient and
electron-rich aromatic acids.
All reactions were carried out in standard glassware under a nitro-
gen atmosphere. All carboxylic acids and organic solvents were
commercially available and were used without further purification
or drying. All product structures were confirmed by 1H NMR, 13
C
NMR and IR spectroscopy. The NMR spectra samples in CDCl3
were recorded on Bruker Ultra Shield 400-MHz and 500-MHz in-
struments. IR spectra were recorded on a Nicolet Magna-IR 560
spectrometer and samples were prepared on Teflon cards. Assay
Synthesis 2008, No. 14, 2298–2302 © Thieme Stuttgart · New York

2300
H. Rogers et al.
PAPER
O
O
O
O
O
O
O
O
O
O
OH
R
R
pyridine
4
path b
3
3
path a
Bu4NSO3NH2
O
O
O
O
S
Bu4NSO3NH2
N
H
O
O
R
R
R
O
Bu4N
6
5
Scheme 2
Table 3 Electron-Rich Substrates for Sulfamation under Conditions Ba
Entry
Substrate
Product
Time (h)
3
Assay yield (%)
69
O
O
O
O
SO3Bu4N
SO3Bu4N
1
N
H
O
O
2
3
3
70
68
N
H
OH
O
O
SO3Bu4N
15
OH
N
H
O
O
SO3Bu4N
OH
N
H
4
5
3
63
0
O
N
O
N
O
O
SO3Bu4N
b
OH
N
–
H
a Boc2O (1.5 equiv) was added to a hot soln of substrate (1.0 equiv) and 2 M Bu4NSO3NH2 in pyridine (1.8 equiv) at 50 °C.
b Complete conversion into symmetrical anhydride was observed but no further reaction took place.
yields were calculated based on purified standards on an Agilent
1100 HPLC.
soln of Boc2O (1.5 equiv) in pyridine (1 vol) was added slowly to
this hot mixture over 1 h via a syringe pump. The reaction was aged
at 50 °C until the starting acid had been consumed. Upon comple-
tion, the mixture was concentrated in vacuo and the majority of py-
ridine was azeotropically removed using toluene. The crude
sulfamate was purified by column chromatography (3–5% MeOH–
CH2Cl2).
N-Substituted Sulfamates; General Procedure for Conditions A
Carboxylic acid (1.0 equiv) and 2 M Bu4NSO3NH2 in pyridine (1.8
equiv, prepared by combining sulfamic acid (1 equiv) and Bu4NOH
(1 equiv) in pyridine followed by azeotropic removal of H2O) were
charged to a round-bottom flask. A soln of Boc2O (1.5 equiv) in py-
ridine (1 vol) was added slowly to this mixture over 1 h via a syringe
pump at r.t. Upon completion of the addition, the mixture was con-
centrated in vacuo and the majority of pyridine was azeotropically
removed using toluene. The crude sulfamate was purified by col-
umn chromatography (3–5% MeOH–CH2Cl2).
Tetrabutylammonium 3-Chlorobenzoylsulfamate
Mp 168–169 °C.
IR (film): 2921, 1670, 1488, 1455, 1273, 1225, 1046 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (s, 1 H), 7.78 (s, 1 H), 7.63
(d, J = 7.6 Hz, 1 H), 7.42 (t, J = 8 Hz, 1 H), 3.29 (br t, J = 8.4 Hz, 8
H), 1.69–1.61 (m, 8 H), 1.44 (sext, J = 7.2 Hz, 8 H), 0.977 (t, J = 7.2
Hz, 12 H).
N-Substituted Sulfamates; General Procedure for Conditions B
Carboxylic acid (1.0 equiv) and 2 M Bu4NSO3NH2 in pyridine (1.8
equiv) were charged to a round-bottom flask and heated to 50 °C. A
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PAPER
One-Pot Method Synthesis of N-Substituted Sulfamates
2301
13C NMR (100 MHz, CDCl3): d = 204.4, 163.6, 136.5, 134.5, 131.4,
IR (film): 2961, 2920, 2875, 1681, 1524, 1344, 1258, 1042 cm–1.
129.7, 127.8, 125.2, 58.7, 24.0, 19.7, 13.6.
1H NMR (400 MHz, CDCl3): d = 8.16 (br t, J = 7.6 Hz, 4 H), 3.25
(br t, J = 6.4 Hz, 8 H), 1.60–1.56 (m, 8 H), 1.33 (sext, J = 6.0 Hz, 8
H), 0.87 (t, J = 5.6 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 163.2, 149.2, 140.3, 129.2, 123.2,
58.4, 23.8, 19.5, 13.5.
Anal. Calcd for C23H41ClN2O4S: C, 57.90; H, 8.66; Cl, 7.43; N,
5.87; O, 13.41; S, 6.72. Found: C, 57.79; H, 8.72; N, 5.82; O, 13.68;
S, 6.69; Cl, 7.76.
Tetrabutylammonium 4-Chlorobenzoylsulfamate
Mp 55–60 °C.
IR (film): 2961, 2875, 1683, 1463, 1255, 1040 cm–1.
Anal. Calcd for C23H41N3O6S: C, 56.65; H, 8.47; N, 8.62; O, 19.69;
S, 6.58. Found: C, 56.83; H, 8.29; N, 8.70; O, 19.33; S, 6.66.
1H NMR (400 MHz, CDCl3): d = 7.73 (d, J = 1.6 Hz, 2 H), 7.29 (d
J = 8.4 Hz, 2 H), 3.23 (t, J = 8.4 Hz, 8 H), 1.62–1.55 (m, 8 H), 1.38
(sext, J = 7.6 Hz, 8 H), 0.930 (t, J = 7.2 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 137.3, 132.9, 128.8, 128.3, 58.3,
28.1, 23.7, 19.4, 13.4.
Tetrabutylammonium 3-Phenylpropanoylsulfamate
Mp 114–116 °C.
IR (film): 2961, 1694, 1487, 1230, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.18–7.09 (m, 5 H), 3.17 (t, J = 6.4
Hz, 8 H), 2.89 (br s, 2 H), 2.73 (br s, 2 H), 2.41 (br s, 1 H), 1.58–
1.52 (m, 8 H), 1.35 (sext, J = 5.6 Hz, 8 H), 0.92 (t, J = 6.0 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 141.2, 128.1, 127.9, 125.5, 58.2,
23.5, 19.3, 13.3.
Tetrabutylammonium 2-Chlorobenzoylsulfamate
Mp 106 °C.
IR (film): 2875, 1685, 1481, 1255, 1039, 887 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.17 (s, 1 H), 7.57 (d, J = 5.6 Hz,
3 H), 3.24 (t, J = 5.2 Hz, 8 H), 1.60–1.57 (m, 8 H), 1.37 (sext,
J = 6.0, 8 H), 0.93 (t, J = 5.2 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 163.9, 151.5, 134.9, 131.2, 130.4,
130.0, 126.8, 58.3, 28.1, 23.7, 19.4, 13.5.
Anal. Calcd for C25H46N2O4S: C, 63.79; H, 9.85; N, 5.95; O, 13.60;
S, 6.81. Found: C, 62.79; H, 9.93; N, 6.02; O, 14.69; S, 6.61.
Tetrabutylammonium 3-Methoxybenzoylsulfamate
Mp 150–152 °C.
IR (film): 2961, 1694, 1487, 1230, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.69 (s, 1 H), 7.33–7.29 (m, 2 H),
7.20 (t, J = 8 Hz, 1 H), 6.92 (dd, J = 2.4, 8 Hz, 1 H), 3.77 (s, 3 H),
3.21 (m, 8 H), 1.51 (m, 8 H), 1.28 (sext, J = 5.6 Hz, 8 H), 0.85 (t,
J = 7.2 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 164.3, 159.4, 136.0, 129.0, 119.3,
117.6, 112.0, 58.2, 55.3, 23.7, 19.4, 13.4.
Tetrabutylammonium 2-Pyridylcarbonylsulfamate
Mp 114–115 °C.
IR (film): 3380, 2961, 2922, 2875, 1698, 1457, 1258, 1036 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.87 (s, 1 H), 8.44 (d, J = 4.4 Hz,
1 H), 8.07 (dd, J = 7.6 Hz, 1 H), 7.75 (dt, J = 7.6, 1.6 Hz, 1 H), 7.35
(dd, J = 4.8, 1.2 Hz, 1 H), 3.26 (br t, J = 8.4 Hz, 8 H), 1.62–1.54 (m,
8 H), 1.35 (sext, J = 7.6 Hz, 8 H), 0.88 (t, J = 7.4 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 161.6, 150.0, 147.8, 137.0, 126.1,
121.9, 58.4, 23.8, 19.5, 13.5.
Anal. Calcd for C24H44N2O5S: C, 60.98; H, 9.38; N, 5.935. Found:
C, 61.02; H, 9.42; N, 5.88.
Tetrabutylammonium 4-Methylbenzoylsulfamate
Anal. Calcd for C22H41N3O4S: C, 59.56; H, 9.32; N, 9.47; O, 14.43;
S, 7.23. Found: C, 59.12; H, 9.42; N, 9.47; O, 14.87; S, 7.05.
Mp 140–144 °C.
IR (film): 2961, 1694, 1487, 1230, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (s, 1 H), 7.63 (d, J = 8 Hz, 2
H), 7.14 (d, J = 8 Hz, 2 H), 3.24 (m, 8 H), 2.35 (s, 3 H), 1.55 (m, 8
H), 1.32 (sext, J = 7.2 Hz, 8 H), 0.89 (t, J = 7.2 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 164.5, 141.6, 131.7, 128.8, 127.1,
58.3, 23.8, 21.2, 19.5, 13.5.
Tetrabutylammonium (2S,4R)-1-(Benzyloxycarbonyl)-4-hy-
droxypyrrolidin-2-ylcarbonylsulfamate
IR (film): 3389, 2960, 2922, 2875, 1703, 1420, 1255, 1040 cm–1.
1H NMR (400 MHz, MeOD): d = 7.44–7.23 (m, 5 H), 5.17–5.04 (m,
2 H), 4.80 (s, 2 H), 4.41 (br s, 2 H), 3.62 (dd, J = 9.2, 3.6 Hz, 1 H),
3.52 (br d, J = 9.2 Hz, 1 H), 3.22 (br t, J = 4.8 Hz, 8 H), 1.69–1.62
(m, 8 H), 1.41 (sext, J = 6.0 Hz, 8 H), 1.01 (t, J = 6.0 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 156.9, 156.6, 137.9, 129.6, 129.5,
128.8, 71.4, 70.0, 68.31, 59.5, 56.3, 40.5, 24.8, 20.7, 13.9.
Tetrabutylammonium Benzoylsulfamate
Mp 156–159 °C.
1H NMR (400 MHz, CDCl3): d = 8.50 (s, 1 H), 7.74 (d, J = 7.2 Hz,
2 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 2 H), 3.24–3.22
(m, 8 H), 1.57–1.55 (m, 8 H), 1.35 (sext, J = 7.2 Hz, 8 H), 0.88 (t,
J = 7.2 Hz, 12 H).
Anal. Calcd for C29H51N3O7S: C, 59.46; H, 8.78; N, 7.17. Found: C,
59.79; H, 8.82; N, 7.08.
13C NMR (100 MHz, CDCl3): d = 164.6, 134.6, 131.2, 128.2, 127.2,
Tetrabutylammonium (S)-2-(tert-Butoxycarbonylamino)-3-
phenylpropanoylsulfamate
58.4, 23.8, 19.5, 13.5.
[a]D23 –0.234 (c 0.01, CH2Cl2).
Anal. Calcd for C23H42N2O4S: C, 62.41; H, 9.56; N, 6.33. Found: C,
62.30; H, 9.54; N, 6.30.
IR (film): 2963, 2922, 2360, 1695, 1487, 1261, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25–7.12 (m, 5 H), 5.03 (d,
J = 7.6 Hz, 1 H), 3.21 (br t, J = 8.4 Hz, 8 H), 2.92 (br s, 1 H), 2.47
(br s, 1 H), 1.61–1.54 (m, 8 H), 1.37 (sext, J = 7.2 Hz, 8 H), 1.27 (s,
9 H), 0.92 (t, J = 7.2 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 154.8, 149.5, 136.8, 129.5, 128.1,
126.3, 79.2, 77.2, 58.3, 38.4, 28.0, 23.8, 19.5, 13.5.
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Tetrabutylammonium 4-Nitrobenzoylsulfamate
Mp 133–134 °C.
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H. Rogers et al.
PAPER
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