Efficient synthesis of unsymmetrical sulfamides from sulfamic acid salts by activation with triphenylphosphine ditriflate

Article abstract of DOI:10.1016/j.tet.2019.02.063

A general approach to prepare unsymmetrical sulfamides is described. This method relies on the activation of sulfamic acid salts with triphenylphosphine ditriflate, and subsequent trapping by a nucleophilic amine. This strategy improves access to N-octade

Full text of DOI:10.1016/j.tet.2019.02.063

Accepted Manuscript
Efficient synthesis of unsymmetrical sulfamides from sulfamic acid salts by activation
with triphenylphosphine ditriflate
Mina F. Shehata, Melanie A. Short, Matthew A. Sanders, Jennifer L. Roizen
PII:
S0040-4020(19)30258-3
https://doi.org/10.1016/j.tet.2019.02.063
TET 30186
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 January 2019
Revised Date: 23 February 2019
Accepted Date: 28 February 2019
Please cite this article as: Shehata MF, Short MA, Sanders MA, Roizen JL, Efficient synthesis of
unsymmetrical sulfamides from sulfamic acid salts by activation with triphenylphosphine ditriflate,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.02.063.
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Efficient synthesis of unsymmetrical
sulfamides from sulfamic acid salts by
activation with triphenylphosphine ditriflate
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Mina F. Shehata, Melanie A. Short, Matthew A. Sanders, Jennifer L. Roizen
Duke University, Department of Chemistry, Box 90346, Durham, North Carolina 27708-0354, United States.

1
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Tetrahedron
journal homepage: www.elsevier.com
Efficient synthesis of unsymmetrical sulfamides from sulfamic acid salts by activation
with triphenylphosphine ditriflate
Mina F. Shehata,† Melanie A. Short,† Matthew A. Sanders, and Jennifer L. Roizen
Duke University, Department of Chemistry, Box 90346, Durham, North Carolina 27708-0354, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general approach to prepare unsymmetrical sulfamides is described. This method relies on the
activation of sulfamic acid salts with triphenylphosphine ditriflate, and subsequent trapping by a
nucleophilic amine. This strategy improves access to N-octadecyl-N’-propylsulfamide, a feeding
suppressant.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
sulfamide
triphenylphosphine ditriflate
sulfamic acid salt
Hendrickson reagent
sulfamoylation
1. Introduction
sulfamides can be prepared by sequential addition of two
alkylamines to sulfuryl chloride (Scheme 2B),7
a
Sulfamides are valuable synthetic targets.1 They can be
thought of as bioisosteres for amides, ureas, carbamates, and
sulfonamides.2 Unsymmetrical acyclic N,N’-dialkyl sulfamides
are employed clinically (Scheme 1A) and serve as powerful
synthetic intermediates as precursors to sterically encumbered
carbon–carbon bonds (Scheme 1B).3 Additionally, sulfamides
incorporate hydrogen-bonding motifs that are critical to chiral
auxiliaries4 and organocatalysts.5
sulfuryldiimidazole analogue (Scheme 2C),8 or catechol sulfate
(not depicted).9
Scheme 1. Sulfamides are useful
Owing to these applications, chemists have developed a few
methods to access sulfamides. An efficient and operationally
straightforward Mitsunobu reaction sequence furnishes
unsymmetrical dialkyl sulfamides from primary or secondary
alcohol precursors (Scheme 2A);6 however, access to dialkyl
sulfamides from amines can be challenging. Some N,N’-dialkyl
———
Corresponding author.
E-mail address: j.roizen@duke.edu (J.L. Roizen).
†Authors with equal contributions
Scheme 2. Few tactics provide access to unsymmetrical N,N’-dialkyl
sulfamides

2
Tetrahedron
Unfortunately, these protocols do not provide synthetically
Unfortunately, this protocol proved fickle when sulfamides
ACCEPTED MANUSCRIPT
useful yields of many dialkyl sulfamides, a challenge that is
exacerbated when the involved nucleophiles are sterically
hindered or electron deficient amines. We recently reported the
preparation of sulfamate esters from the inexpensive and broadly
available solid, SO3•pyridine, by way of sulfamic acid salts based
on activation with triphenylphosphine ditriflate (Scheme 2D).10
Herein described is research to extend this reaction platform to be
a broadly effective protocol to access unsymmetrical dialkyl
sulfamides.
were constructed from two electronically similar amines. For
example, application of the published procedure to access N-tert-
butyl-N’-pentylsulfamide
butyl)sulfamide (3a) as
symmetrical 3a was not readily separable from desired
unsymmetrical 2m, presumably because both sulfamides
incorporate amines of similar polarity.
(2m),
furnished
N,N’-di(tert-
a
byproduct (Scheme 4). Sadly,
2. Results and discussion
Previously, the disclosed protocol had been applied to access
three unsymmetrical sulfamides (i.e. 2a–2c), demonstrating the
ability of primary, secondary, and sterically encumbered primary
amines to serve as nucleophiles in their preparation (Scheme
3).10a Without significant modifications, this technology also
transforms sterically encumbered secondary amines (2d) and
cyclic amines (2e). Amines react even when they are
incorporated into scaffolds that present other functional groups,
such as esters, arenes, heterocycles, and even N-
aminophthalimide (2f–2i). Given our interest in 2-functionalized
pyridines,11 we were delighted to find that 2-aminopyridine
proved a competent nucleophile to furnish 2-pyridyl-sulfamide
2i. Furthermore, the reaction conditions activate electronically
and sterically varied sulfamic acid salts to access differentially
substituted 2j–2l.
Scheme 4. Previously reported conditions generate mixture of desired
sulfamide and N,N’-di(tert-butyl)sulfamide 3a
To circumvent this challenge, the protocol was adjusted to
employ sulfamic acid salt as limiting reagent, and to enable
careful control of the reaction temperature. Specifically, the
reaction of tert-butylsulfamic acid salt with triphenylphosphine
ditriflate in dichloromethane was cooled to –78 °C prior to the
addition to triethylamine. Additionally, while the ultimate
reaction concentration was maintained, the salt was activated at a
lower concentration in an effort to limit formation of symmetrical
N,N’-di(tert-butyl)sulfamide (3a).
Owing to these operational changes, two electronically similar
amines could be incorporated into unsymmetrical sulfamides
cleanly (Table 1, entry 1). We anticipated that some amine
nucleophiles would not be amenable to reaction in
dichloromethane, owing to their insolubility. To surmount this
foreseen challenge, we assessed a single solvent from each of
seven solubility clusters for the addition of the amine nucleophile
(Table 1, entries 2–8).12 Within a given cluster, the evaluated
solvent is more likely to be accepted at some production sites13
based on safety, health, environmental, and legal constraints. To
our delight, this range of solvents proved effective in sulfamide
formation from pentylamine, though with diminished yields.
Table 1. Solvent variations are tolerated
Entrya
Solvent
CH2Cl2
MeCN
heptane
PhMe
2-MeTHF
DMF
MTBE
DMSO
Yield [%]b
1
2
3
4
5
6
7
8
79
47
48
63
61
57
52
36
a
General reaction conditions: 1.65 equiv of Ph3PO, CH2Cl2 (0.15 M with
respect to amine), 1.5 equiv of Tf2O, 1.0 equiv of sulfamic acid salt (1d) in
CH2Cl2 (1.25 M with respect to amine), 3.0 equiv of Et3N in CH2Cl2 (0.36 M
with respect to amine), 1.0 equiv of H2NC5H11 in solvent (1.25 M), –78 → 22
°C.b Isolated yields.
Scheme 3. Application of sulfamate ester preparation protocol to access
sulfamides

3
3. Conclusion
As a testament to the synthetic utility of these operational
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changes, several sulfamides that could not be accessed in high
purity under the original protocol can now be prepared. This
improved protocol is effective with primary and secondary
amines to yield sulfamides 2m and 2n. The reaction converts
pendant acyclic, cyclic, and sterically encumbered alkyl amines
to furnish 2o–2p and 2s. Furthermore, primary amines at
secondary centers are readily incorporated into sulfamides 2q– 2r
and 2t, even tolerating a pendant methyl ester to furnish leucine-
derived sulfamide 2r. Additionally, electron deficient amines and
8-aminoquinoline are effective nucleophiles providing access to
sulfamides 2c and 2u. This improved protocol is also successful
when activating N-aryl sulfamic acid salts, yielding N-aryl
sulfamides 2u and 2v.
The disclosed reaction conditions enable preparation of a
series of sulfamides. Importantly, these reaction conditions
minimize the formation of N,N’-di(tert-butyl)sulfamide as a
byproduct, and is robust across a range of solvents. These
conditions improve access to the potential feeding suppressant N-
octadecyl-N’-propylsulfamide.
4. Experimental section
4.1. General methods
Moisture-sensitive reactions were performed using flame-
dried glassware under an atmosphere of dry nitrogen (N2).
Flame-dried equipment was stored in a 130 °C oven before use
and either allowed to cool in a cabinet dessicator or assembled
hot and allowed to cool under an inert atmosphere. Air- and
moisture-sensitive liquids and solutions were transferred via
plastic or glass syringe. Chromatographic purification of products
was accomplished by flash column chromatography using
Silicycle Silica flash F60 (particle size 40–63 µm, 230–400
mesh) or by Teledyne Isco CombiFlashRf system using 12–220 g
Redi Sep Rf normal phase silica columns (particle size 40–63 µm
irregular, 230–400 mesh). Thin layer chromatography was
performed on EMD Millipore silica gel 60 F254 glass-backed
plates (layer thickness 250 µm, particle size 10–12 ꢀm,
impregnated with a fluorescent indicator). Visualization of the
developed chromatogram was accomplished by fluorescence
quenching under shortwave UV light and/or by staining with p-
anisaldehyde or KMnO4 stains. Unless otherwise noted, room
temperature is 22 ºC.
NMR spectra were obtained on Varian iNOVA spectrometers
1
operating at 400 or 500 MHz for H NMR, 101 or 126 MHz for
13C NMR, and 376 MHz for 19F NMR at 23–25 °C, or on a
Bruker Neo spectrometer operating at 500 MHz for 1H NMR and
126 MHz for 13C NMR at 23–25 °C, and are reported as chemical
shifts (δ) in parts per million (ppm). Spectra were referenced
internally according to residual solvent signals (1H: CDCl3, 7.26
ppm; 13C: CDCl3, 77.0 ppm; CD3CN, 1.3, 118.3 ppm). Data for
NMR spectra use the following abbreviations to describe
multiplicity: s, singlet; br s, broad singlet; d, doublet; t, triplet; q,
quartet; dd, doublet of doublets; dt, doublet of triplets; ddd,
doublet of doublet of doublets; qd, quartet of doublets; m,
multiplet. Coupling constant (J) are reported in units of Hertz
(Hz). IR spectra were obtained on a Nicolet 6700 FT-IR system.
Peaks are reported in cm–1 with indicated relative intensities: s
(strong, 0–33% T); m (medium, 34–66% T); w (weak, 67–100%
T); and br (broad). High resolution mass spectra (HRMS, m/z)
were recorded on an Agilent LCMS-TOF-DART spectrometer
using electrospray ionization (ESI, Duke University Department
of Chemistry Instrumentation Center).
Scheme 5. Modified conditions results in formation of only desired
sulfamides. General conditions : 1.65 equiv of Ph3PO, CH2Cl2 (0.15 M with
respect to amine), 1.5 equiv of Tf2O, 1.0 equiv of tert-butyl sulfamic acid
salt (1d) in CH2Cl2 (1.25 M with respect to amine), 3.0 equiv of Et3N in
CH2Cl2 (0.36 M with respect to amine), 1.0 equiv of amine in CH2Cl2 (1.25
M), –78 → 22 °C. a Isolated yields. b Prepared from pentyl sulfamic acid salt
c
and 8-aminoquinoline. Prepared from quinolin-8-yl sulfamic acid salt and
d
pentylamine. Prepared from 4-(tert-butyl)phenyl sulfamic acid salt and
e
pentylamine.
Prepared from crude propyl sulfamic acid salt and
octadecylamine added as a solution in toluene.
We wanted to improve access to the potential hypolipidemic
All reagents and chemicals were obtained commercially and
used without further purification or prepared according to
previously reported procedures. Anhydrous dichloromethane
(CH2Cl2), and diethyl ether (Et2O) were obtained from Sigma
Aldrich and were purified, dried, and degassed by passage
through two columns of neutral, activated alumina under N2
using an Innovative Technologies solvent purification system.
Anhydrous toluene was purified, dried, and degassed by passage
through a column containing copper followed by a column of
neutral, activated alumina under N2 using an Innovative
Technologies solvent purification system. Triethylamine (Et3N)
was distilled from CaH2 and stored in a Schlenk flask for future
use.
compound
and
feeding
suppressant
N-octadecyl-N’-
propylsulfamide (2w; CAS 925892-74-3).14 It has been generated
previously in up to 31% yield through the patented reaction of
octadecylamine and N-propylsulfamoyl chloride (CAS 10305-42-
16
7).15,
As N-octadecylamine is insoluble in CH2Cl2, an
alternative solvent was required to affect the addition of this
nucleophile. Through preparation of propyl sulfamic acid salt and
addition of N-octadecylamine as a solution in toluene, N-
octadecyl-N’-propylsulfamide (2w) was isolated in 42% yield
over 2 steps. This constitutes a marked improvement over the
previously reported routes to the desired compound from
commodity chemicals following a single purification.

4
Tetrahedron
8:2 hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd for
4.2. General Procedure A: Preparation of sulfamides using
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previously disclosed procedure (Schemes 3 and 4)
C13H23N2O2S 279.2106; Found 279.2097.
4.2.2. N-(4-(Pyridin-2-yl)piperazin-1-yl)-N’-(2,2,2-
trifluoroethyl)sulfamide (2e)
A flame-dried round bottom flask equipped with magnetic stir
bar was charged with triphenylphosphine oxide (1.65 equiv) and
fitted with a rubber septum. The flask was evacuated and
backfilled with N2. Anhydrous CH2Cl2 (0.22 M with respect to
amine) was added and the flask was cooled at 0 °C in an ice
water bath. Trifluoromethanesulfonic anhydride (1.5 equiv) that
had been freshly removed from the glovebox was then added to
the cooled solution dropwise via syringe. The reaction was
allowed to stir at 0 °C in an ice water bath for 15 minutes. This
suspension was treated with a solution of sulfamic acid salt (1.50
or 1.65 equiv as noted below) in CH2Cl2 (1.25 M with respect to
amine) that had been cooled at 0 °C via cannula transfer. The
flask containing sulfamate salt solution was rinsed with CH2Cl2
(ca. 5.0 M with respect to amine) to achieve quantitative transfer.
The resulting yellow solution was stirred for 15 minutes at 0 °C.
During this time, a clean, flame-dried round bottom flask
equipped with stir bar was fitted with a rubber septum and
subsequently evacuated and backfilled with N2. This process was
repeated two more times. The flask was then charged with Et3N
(3.0 equiv) and CH2Cl2 (0.22 M with respect to amine) and the
Prepared
from
triethylammonium
N-(2,2,2-
trifluoroethyl)sulfamate (2.31 g, 8.25 mmol, 1.65 equiv) and 1-
(2-pyridyl)piperazine (0.76 mL, 5.00 mmol) according to general
procedure A. The product was isolated as a white solid (1.37 g,
85% yield) after purification on a Teledyne Isco CombiFlashRf
system using a Redi Sep Rf normal phase silica gel column
(65:35 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3) δ 8.21 (dd,
J = 5.0, 2.1 Hz, 1H), 7.54–7.50 (m, 1H), 6.71–6.66 (m, 2H), 4.56
(t, J = 6.8 Hz, 1H), 3.72 (qd, J = 8.8, 7.1 Hz, 2H), 3.64 (dd, J =
6.6, 4.9 Hz, 4H), 3.35 (dd, J = 6.6, 5.2 Hz, 4H). 13C NMR (101
MHz, CD3CN) δ 160.0, 148.7, 138.6, 125.1 (q, J = 277.6 Hz),
114.7, 108.3, 46.6, 45.3, 45.3 (q, J = 34.6 Hz). 19F NMR (376
MHz, CDCl3) δ –72.55 (t, J = 8.7 Hz). IR (neat) ν 3324 (br),
2975 (w), 2853 (w), 1597 (m), 1566 (w), 1477 (m), 1459 (m),
1436 (m), 1394 (m), 1365 (w), 1346 (m), 1333 (m), 1313 (m),
1291 (m), 1275 (m), 1242 (m), 1153 (s), 1119 (s), 1105 (s), 1068
(m), 983 (m), 946 (s), 918 (m), 828 (m), 778 (s), 751 (m), 729
(s), 659 (m), 622 (m), 553 (s), 529 (m) cm–1. TLC Rf = 0.31 in
6:4 hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd for
C11H16F3N4O2S 325.0946; Found 325.0950.
i
mixture was cooled at –78 °C in an PrOH/dry ice bath. The
sulfamate salt solution was transferred dropwise to the Et3N
solution via cannula (during which time a yellow to intense red
color often developed), rinsing the flask with CH2Cl2 (ca. 2.0 M
with respect to amine) to achieve quantitative transfer. The
resultant solution was stirred at –78 °C for 15 minutes. A solution
of the amine ((R2)(R3)–NH, 1.0 equiv) in CH2Cl2 (1.25 M) that
had been precooled at 0 °C was then added to the triethylamine
solution via cannula. The amine-containing flask was rinsed with
CH2Cl2 (ca. 5.0 M with respect to amine) to achieve quantitative
transfer. Without removing the cooling bath, the reaction was
then stirred overnight, during which time no additional dry ice
was added to the bath and the mixture gradually warmed to room
temperature.
4.2.3. N’-tert-Butyl-N-(methyl hexano-6-
yl)sulfamide (2f)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
4.19 g, 16.5 mmol, 1.65 equiv) and methyl 6-aminohexanoate
hydrochloride (1.82 g, 10.0 mmol) according to general
procedure A. The product was isolated as a colorless oil (1.68 g,
60% yield) after purification on a Teledyne Isco CombiFlashRf
system using a Redi Sep Rf normal phase silica gel column (6:4
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 4.03 (br s, 2H),
3.67 (s, 3H), 3.05 (dt, J = 6.8, 6.8 Hz, 2H), 2.32 (t, J = 7.4 Hz,
2H), 1.70–1.52 (m, 4H), 1.42–1.38 (m, 2H), 1.35 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 173.9, 53.6, 51.3, 42.8, 33.6, 29.5,
28.8, 26.0, 24.2. IR (neat) ν 3283 (br), 2940 (w), 2868 (w), 1723
(m), 1434 (m), 1391 (m), 1366 (m), 1303 (m), 1205 (m), 1136
(s), 1094 (m), 1041 (w), 992 (m), 930 (w), 892 (m), 734 (w), 607
(m) cm–1. TLC Rf = 0.28 in 8:2 hexanes/EtOAc. HRMS (ESI)
m/z: [M – H]– Calcd for C11H23N2O4S 279.1378; Found
279.1382.
After stirring overnight, the reaction was diluted with 1 M
HCl (ca. 5 mL/mmol of sulfamide) and H2O (ca. 5 mL/mmol of
sulfamide). The biphasic mixture was transferred to a separatory
funnel, rinsing the flask with CH2Cl2 to achieve quantitative
transfer. The organic phase was separated and the aqueous phase
was extracted twice more with CH2Cl2 (ca. ½ reaction volume).
The combined organic phases were dried with MgSO4, filtered,
and concentrated under reduced pressure. The crude reaction
mixtures were then purified by silica gel flash chromatography
by dry loading the samples and eluting with a hexanes:EtOAc
solvent system as noted below.
4.2.4. N-tert-Butyl-N’-(3-phenylprop-1-yl)sulfamide
(2g)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
3.05 g, 12.0 mmol, 1.50 equiv) and 3-phenylpropylamine (1.1
mL, 8.00 mmol) according to general procedure A. The product
was isolated as a white solid (1.56 g, 72% yield) after
purification on a Teledyne Isco CombiFlashRf system using a
Redi Sep Rf normal phase silica gel column (9:1
4.2.1. N-tert-Butyl-N’-tert-butyl-N-pentylsulfamide
(2d)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
839 mg, 3.30 mmol, 1.65 equiv) and N-tert-butyl-N-pentylamine
(S2, 286 mg, 2.00 mmol) according to general procedure A. The
product was isolated as a white solid (317 mg, 57% yield) after
purification on a Teledyne Isco CombiFlashRf system using a
Redi Sep Rf normal phase silica gel column (9:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.4
Hz, 2H), 7.22–7.17 (m, 3H), 4.03 (br s, 2H), 3.07 (dt, J = 6.8, 6.8
Hz, 2H), 2.69 (m, 2H), 1.94–1.86 (m, 2H), 1.33 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 141.0, 128.4, 128.3, 126.0, 53.9,
42.8, 33.0, 31.0, 29.7. IR (neat) ν 3282 (br), 3027 (w), 2975 (w),
1601 (w), 1494 (w), 1477 (w), 1453 (w), 1427 (w), 1390 (w),
1365 (w), 1339 (w), 1297 (m), 1230 (w), 1208 (w), 1137 (m),
1082 (m), 1062 (m), 1044 (m), 1031 (w), 1005 (m), 921 (m), 749
(m), 698 (m), 613 (m), 576 (m) cm–1. TLC Rf = 0.17 in 8:2
hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd for
C13H23N2O2S 271.1480; Found 271.1480.
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 3.68 (br s, 1H),
3.18 (dd, J = 8.1, 10.7 Hz, 2H), 1.71–1.63 (m, 2H), 1.43 (s, 9H),
1.34 (s, 9H), 1.25–1.17 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 58.6, 54.5, 47.3, 31.7, 30.1, 29.7,
29.3, 22.4, 14.1. IR (neat) ν 3276 (br), 2960 (m), 2931(w), 2872
(w), 1469 (w), 1391 (m), 1365 (m), 1308 (m), 1217 (m), 1189
(m), 1129 (s), 1040 (w), 992 (m), 916 (m), 864 (m), 836 (w), 797
(w), 766 (w), 726 (w), 680 (m), 588 (m) cm–1. TLC Rf = 0.49 in
4.2.5. N’-Pentyl-N-(phthalimid-2-yl)sulfamide (2h)

5
A flame-dried round bottom flask equipped with magnetic stir
bar was charged with triphenylphosphine oxide (2.755 g, 9.90
mmol, 1.65 equiv) and fitted with a rubber septum. The flask was
evacuated and backfilled with N2. Anhydrous CH2Cl2 (50 mL,
0.12 M with respect to amine) was added and the flask was
cooled at 0 °C in an ice water bath. Trifluoromethanesulfonic
anhydride (1.51 mL, 8.99 mmol, 1.5 equiv) that had been freshly
removed from the glovebox was then added to the cooled
solution dropwise via syringe. The reaction was allowed to stir at
0 °C in an ice water bath for 15 minutes. This suspension was
treated with a solution of triethylammonium N-pentylsulfamate
(2.42 g, 9.00 mmol, 1.50 equiv) in CH2Cl2 (9 mL, 0.67 M with
respect to amine) via cannula transfer. The flask containing
sulfamate salt solution was rinsed with CH2Cl2 (1.2 mL, ca. 5.0
M with respect to amine) to achieve quantitative transfer. The
resulting yellow solution was stirred for 15 minutes at 0 °C.
During this time, a clean, flame-dried round bottom flask
equipped with stir bar was fitted with a rubber septum and
subsequently evacuated and backfilled with N2. This process was
repeated two more times. The flask was then charged with Et3N
(2.5 mL, 18.0 mmol, 3.0 equiv) and CH2Cl2 (72 mL, 0.08 M with
respect to amine) and the mixture was cooled at –78 °C in an
iPrOH/dry ice bath. The sulfamate salt solution was transferred
dropwise to the Et3N solution via cannula (during which time a
yellow to intense red color often developed), rinsing the flask
with CH2Cl2 (0.33 mL, ca. 2.0 M with respect to amine) to
achieve quantitative transfer. The resultant solution was stirred at
–78 °C for 15 minutes. During this time, a flame-dried round
bottom flask equipped with a stir bar was charged with N-
aminophthalimide. (973 mg, 6.00 mmol, 1.00 equiv) and CH2Cl2
(6.0 mL, 1.0 M) and chilled to –78 ºC in a dry ice/ iPrOH bath.
After 15 minutes, the Et3N solution was cannula transferred to
the solution of the amine. The triethylamine-containing flask was
rinsed with CH2Cl2 (ca. 5.0 M with respect to amine) to achieve
quantitative transfer. Without removing the cooling bath, the
reaction was then stirred overnight, during which time no
additional dry ice was added to the bath and the mixture
gradually warmed to room temperature.
evacuated and backfilled with N2. Anhydrous CH2Cl2 (23 mL,
ACCEPTED MANUSCRIPT
0.22 M with respect to amine) was added and the flask was
cooled at 0 °C in an ice water bath. Trifluoromethanesulfonic
anhydride (1.26 mL, 7.50 mmol, 1.5 equiv) that had been freshly
removed from the glovebox was then added to the cooled
solution dropwise via syringe. The reaction was allowed to stir at
0 °C in an ice water bath for 15 minutes. This suspension was
treated with
a
solution of triethylammonium N-(2,2,2-
trifluoroethyl)sulfamate (2.31 g, 8.25 mmol, 1.65 equiv) in
CH2Cl2 (6.6 mL, 1.25 M with respect to amine) that had been
cooled at 0 °C via cannula transfer. The flask containing
sulfamate salt solution was rinsed with CH2Cl2 (1 mL, ca. 5.0 M
with respect to amine) to achieve quantitative transfer. The
resulting yellow solution was stirred for 15 minutes at 0 °C.
During this time, a clean, flame-dried round bottom flask
equipped with stir bar was fitted with a rubber septum and
subsequently evacuated and backfilled with N2. This process was
repeated two more times. The flask was then charged with Et3N
(2.1 mL, 15.0 mmol, 3.0 equiv) and CH2Cl2 (23 mL, 0.22 M with
respect to amine) and the mixture was cooled at –78 °C in an
iPrOH/dry ice bath. The sulfamate salt solution was transferred
dropwise to the Et3N solution via cannula (during which time an
intense red color developed), rinsing the flask with CH2Cl2 (2.5
mL, ca. 2.0 M with respect to amine) to achieve quantitative
transfer. The resultant solution was stirred at –78 °C for 15
minutes. A solution of 2-aminopyridine (471 mg, 5.00 mmol, 1.0
equiv) in CH2Cl2 (4 mL, 1.25 M) that had been precooled at 0 °C
was then added to the triethylamine solution via cannula. The
amine-containing flask was rinsed with CH2Cl2 (1 mL, ca. 5.0 M
with respect to amine) to achieve quantitative transfer. Without
removing the cooling bath, the reaction was then stirred
overnight, during which time no additional dry ice was added to
the bath and the mixture gradually warmed to room temperature.
After stirring overnight, the suspension was filtered. The solid
was suspended in a 4:1 mixture of EtOAc/hexanes (50 mL) and
the suspension was vigorously stirred in an oil bath held at 100
ºC for 15 minutes. After 15 minutes, the suspension was vacuum
filtered hot and the white solid was rinsed with hexanes to afford
1
After stirring overnight, the reaction was diluted with 1 M
HCl (ca. 10 mL/mmol of sulfamide) and H2O (ca. 10 mL/mmol
of sulfamide). The biphasic mixture was transferred to a
separatory funnel, rinsing the flask with CH2Cl2 to achieve
quantitative transfer. The organic phase was separated and the
aqueous phase was extracted twice more with CH2Cl2 (ca. ½
reaction volume). The combined organic phases were dried with
MgSO4, filtered, and concentrated under reduced pressure. The
product was isolated as a white solid (1.25 g, 67% yield) after
purification on a Teledyne Isco CombiFlashRf system using a
Redi Sep Rf normal phase silica gel column (7:3
the pure product as a white powder (804 mg, 63% yield). H
NMR (400 MHz, CD3OD) δ 8.14 (dd, J = 5.4, 2.0 Hz, 1H), 7.74
(ddd, J = 8.4, 7.0, 2.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H),
6.97 (ddd, J = 7.0, 5.4, 2.0 Hz, 1H), 3.68 (q, J = 9.2 Hz, 2H).13C
NMR (126 MHz, (CD3)2SO) δ 152.7, 145.7, 139.0, 124.6 (q, J =
279.1 Hz), 116.6, 112.4, 44.0 (q, J = 33.8 Hz). 19F NMR (376
MHz, (CD3)2SO) δ –71.01 (t, J = 9.7 Hz). IR (neat) ν 3274 (br),
2996 (w), 2736 (w), 1637 (m), 1615 (m), 1535 (m), 1468 (w),
1449 (w), 1426 (w), 1394 (m), 1357 (m), 1301 (m), 1291 (m),
1281 (m), 1257 (m), 1176 (w), 1135 (s), 1100 (m), 1040 (m),
1015 (m), 991 (m), 972 (m), 939 (m), 867 (w), 821 (m), 771 (s),
726 (m), 678 (m), 661 (m), 642 (m), 617 (m), 578 (m), 555 (s)
cm–1.
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 7.92 (dd, J =
5.4, 3.1 Hz, 2H), 7.81 (dd, J = 5.6, 3.0 Hz, 2H), 6.78 (br s, 1H),
4.45 (t, J = 5.8 Hz, 1H), 3.33 (dt, J = 6.8, 6.8 Hz, 2H), 1.66–1.58
(m, 2H), 1.38–1.34 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 164.9, 134.8, 129.6, 124.0, 43.9, 29.1, 28.6,
22.1, 13.9. IR (neat) ν 3276 (br), 3165 (br), 2929 (m), 2865 (m),
1791 (m), 1726 (s), 1609 (m), 1426 (m), 1379 (m), 1341 (s),
1200 (m), 1153 (s), 1111 (m), 1080 (s), 1021 (m), 993 (m), 923
(m), 879 (s), 788 (m), 719 (s), 706 (s), 656 (s), 584 (s) cm–1. TLC
Rf = 0.28 in 6:4 hexanes/EtOAc. HRMS (ESI) m/z: [M – H]–
Calcd for C13H16N3O4S 310.0861; Found 310.0863.
4.2.7. N-(2,2,2-Trifluoroethyl)-N’-pentylsulfamide
(2j)
Prepared
from
triethylammonium
N-(2,2,2-
trifluoroethyl)sulfamate (947 mg, 3.40 mmol, 1.65 equiv) and
pentylamine (0.24 mL, 2.00 mmol) according to general
procedure A. The product was isolated as a white solid (484 mg,
94% yield) after purification on a Teledyne Isco CombiFlashRf
system using a Redi Sep Rf normal phase silica gel column (8:2
hexanes/EtOAc).1H NMR (400 MHz, CDCl3) δ 4.75 (br s, 1H),
4.30 (br s, 1H), 3.72–3.63 (m, 2H), 3.06 (q, J = 6.8 Hz, 2H),
1.60–1.53 (m, 2H), 1.35–1.30 (m, 4H), 0.90 (t, J = 6.7 Hz, 3H).
13C NMR (126 MHz, CD3CN) δ 125.3 (q, J = 277.4 Hz), 44.8 (q,
J = 34.8 Hz), 43.7, 29.6, 29.5, 22.9, 14.2. 19F NMR (376 MHz,
CDCl3) δ –72.57 (t, J = 8.9 Hz). IR (neat) ν 3273 (br), 2962 (w),
4.2.6. N-(2-Pyridyl)-N’-(2,2,2-
trifluoroethyl)sulfamide (2i)
A flame-dried round bottom flask equipped with magnetic stir
bar was charged with triphenylphosphine oxide (2.29 g, 8.25
mmol, 1.65 equiv) and fitted with a rubber septum. The flask was

6
Tetrahedron
2938 (w), 2865 (w), 1466 (m), 1426 (m), 1394 (m), 1325 (s),
times. The flask was then charged with Et3N (3.0 equiv) and
ACCEPTED MANUSCRIPT
1291 (s), 1267 (s), 1160 (s), 1138 (s), 1124 (s), 1109 (s), 1058
(s), 1040 (m), 1015 (m), 964 (s), 910 (s), 890 (m), 856 (m), 835
(m), 731 (m), 657 (s), 573 (s), 545 (s) cm–1. TLC Rf = 0.19 in 8:2
hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd for
C7H16F3N2O2S 249.0884; Found 249.0882.
CH2Cl2 (0.36 M with respect to amine) and the mixture was
i
cooled at –78 °C in an PrOH/dry ice bath. The sulfamate salt
solution was transferred dropwise to the Et3N solution via
cannula (during which time a yellow to intense red color often
developed), rinsing the flask with CH2Cl2 (ca. 2.0 M with respect
to amine) to achieve quantitative transfer. The resultant solution
was stirred at –78 °C for 15 minutes. The amine ((R2)(R3)–NH,
1.0 equiv) was then added as a solution in solvent 1 (1.25 M) to
the triethylamine solution via cannula. The amine-containing
flask was rinsed with solvent 1 (ca. 5.0 M with respect to amine)
to achieve quantitative transfer. Without removing the cooling
bath, the reaction was then stirred overnight, during which time
no additional dry ice was added to the bath and the mixture
gradually warmed to room temperature. Unless otherwise noted,
solvent 1 = CH2Cl2.
4.2.8. N-(2-Methyl-1,1,1-trifluoroprop-2-yl)-N’-
pentylsulfamide (2k)
Prepared from triethylammonium N-pentylsulfamate (3.37 g,
12.5
mmol,
1.65
equiv)
and
1,1-dimethyl-2,2,2-
trifluoroethylamine hydrochloride (1.24 g, 7.60 mmol) according
to general procedure A. The product was isolated as a white solid
(1.51 g, 72% yield) after purification on a Teledyne Isco
CombiFlashRf system using a Redi Sep Rf normal phase silica
gel column (Gradient: 100% hexanes → 7:3 hexanes/EtOAc). 1H
NMR (400 MHz, CDCl3) δ 4.41 (br s, 1H), 4.12 (br s, 1H), 3.07
(q, J = 7.4 Hz, 2H), 1.60–1.53 (m, 2H), 1.56 (s, 6H), 1.36–1.30
(m, 4H), 0.91 (t, J = 6.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
126.0 (q, J = 284.3 Hz), 58.1 (q, J = 28.9 Hz), 43.0, 28.7, 28.7,
22.1, 20.7, 13.7. 19F NMR (376 MHz, CDCl3) δ –82.30. IR (neat)
ν 3303 (br), 2959 (w), 2933 (w), 2874 (w), 1442 (m), 1399 (w),
1378 (w), 1318 (m), 1233 (m), 1206 (m), 1151 (s), 1119 (s), 1078
(s), 1036 (m), 1012 (m), 933 (m), 842 (m), 728 (w), 654 (w), 589
(m), 556 (m) cm–1. TLC Rf = 0.33 in 8:2 hexanes/EtOAc. HRMS
(ESI) m/z: [M – H]– Calcd for C9H18F3N2O2S 275.1041; Found
275.1047.
After stirring overnight, the reaction was diluted with 1 M
HCl (ca. 5 mL/mmol of sulfamide) and H2O (ca. 5 mL/mmol of
sulfamide). The biphasic mixture was transferred to a separatory
funnel, rinsing the flask with CH2Cl2 to achieve quantitative
transfer. The organic phase was separated and the aqueous phase
was extracted twice more with CH2Cl2 (ca. ½ reaction volume).
The combined organic phases were dried with MgSO4, filtered,
and concentrated under reduced pressure. The crude reaction
mixtures were then purified by silica gel flash chromatography
by dry loading the samples and eluting with a hexanes:EtOAc
solvent system as noted below.
4.2.9. N-Cyclohexyl-N’-pentylsulfamide (2l)
4.3.1. N-tert-Butyl-N’-pentylsulfamide (2m)
Prepared from triethylammonium N-cyclohexylsulfamate
(3.05 g, 12.0 mmol, 1.5 equiv) and pentylamine (0.93 mL, 8.00
mmol) according to general procedure A. The product was
isolated as a white solid (993.3 mg, 50% yield) after purification
Prepared from triethylammonium N-tert-butylsulfamate (1d,
5.09 g, 20.0 mmol) and pentylamine (2.4 mL, 20.0 mmol)
according to general procedure B. The product was isolated as a
white solid (3.54 g, 79% yield) after silica gel column
chromatography (9:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3) δ 4.23 (br s, 1H), 4.16 (br s, 1H), 3.02 (dt, J = 6.9, 6.9
Hz, 2H), 1.59–1.52 (m, 2H), 1.33–1.30 (m, 4H), 1.34 (s, 9H),
0.90 (t, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 53.9,
43.3, 29.8, 29.1, 28.9, 22.3, 13.9. IR (neat) ν 3278 (br), 2958 (w),
2931 (w), 2871 (w), 1427 (w), 1392 (m), 1367 (m), 1298 (m),
1230 (m), 1208 (w), 1136 (s), 1092 (m), 1041 (m), 996 (m), 930
(m), 907 (m), 808 (m), 719 (m) 607 (m), 568 (m) cm–1. TLC Rf =
0.23 in 8:2 hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd
for C9H23N2O2S 223.1480; Found 223.1475.
1
by silica gel column chromatography (9:1 hexanes/EtOAc). H
NMR (400 MHz, CDCl3) δ 4.24–4.20 (m, 2H), 3.24–3.12 (m,
1H), 3.01 (dt, J = 6.8, 6.8 Hz, 2H), 2.01–1.95 (m, 2H), 1.75–1.68
(m, 2H), 1.60–1.52 (m, 3H), 1.37–1.12 (m, 9H), 0.90 (t, J = 6.8
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 52.6, 43.2, 34.0, 29.2,
28.9, 25.3, 24.8, 22.2, 13.9. IR (neat) ν 3291 (br), 2927 (m), 2855
(m), 1468 (w), 1454 (m), 1377 (w), 1321 (m), 1301 (m), 1257
(w), 1242 (w), 1192 (w), 1135 (s), 1080 (m), 1070 (s), 1032 (m),
1012 (w), 992 (m), 928 (m), 916 (m), 887 (m), 840 (m), 822 (m),
759 (m), 727 (w), 664 (m), 582 (m), 558 (m) cm–1. TLC Rf = 0.17
in 8:2 hexanes/EtOAc. HRMS (ESI) m/z: [M – H]– Calcd for
C11H23N2O2S 247.1480; Found 247.1489.
4.3.2. N’-tert-Butyl-N-methyl-N-pentylsulfamide
(2n)
4.3. General Procedure B: Preparation of sulfamides using
modified conditions (Table 1 and Scheme 5)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
2.54 g, 10.0 mmol) and N-methylpentylamine (1.0 g, 10.0 mmol)
according to general procedure B. The product was isolated as a
colorless oil (1.33 g, 56% yield) after silica gel column
A flame-dried round bottom flask equipped with magnetic stir
bar was charged with triphenylphosphine oxide (1.65 equiv) and
fitted with a rubber septum. The flask was evacuated and
backfilled with N2. CH2Cl2 (0.15 M with respect to amine) was
added and the flask was cooled at 0 °C in an ice water bath.
Trifluoromethanesulfonic anhydride (1.5 equiv) that had been
freshly removed from the glovebox was then added to the cooled
solution dropwise via syringe. The reaction was allowed to stir at
0 °C in an ice water bath for 15 minutes. This suspension was
treated with a solution of sulfamic acid salt (1.0 equiv) in CH2Cl2
(1.25 M with respect to amine) via cannula transfer. The flask
containing sulfamate salt solution was rinsed with CH2Cl2 (ca.
5.0 M with respect to amine) to achieve quantitative transfer. The
resulting yellow solution was stirred for 5 minutes at 0 °C and
chromatography (Gradient: 20:1 hexanes/EtOAc
→
9:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 3.89 (br s, 1H),
3.09 (dd, J = 7.8, 9.5 Hz, 2H), 2.75 (s, 3H), 1.6–1.53 (m, 2H),
1.35–1.24 (m, 4H), 1.30 (s, 9H), 0.88 (t, J = 7.0 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 53.9, 50.2, 34.4, 29.8, 28.8, 27.2,
22.3, 13.9. IR (neat) ν 3277 (br), 2958 (w), 2931 (w), 2870 (w),
1466 (w), 1391 (w), 1366 (w), 1309 (m), 1229 (m), 1206 (m),
1135 (s), 1090 (w), 1039 (w), 996 (m), 948 (m), 893 (m), 866
(m), 766 (w), 719 (m), 606 (m), 566 (m) cm–1. TLC Rf = 0.36 in
8:2 hexanes/EtOAc. HRMS (ESI) m/z: [M + H]+ Calcd for
C10H25N2O2S 237.1636; Found 237.1633.
i
4.3.3. N-tert-Butyl-N’-(2-
cyclopentylethyl)sulfamide (2o)
A flame-dried flask with stir bar and fitted with a reflux
condenser was charged with lithium aluminum hydride (LiAlH4,
was then cooled at –78 °C in an PrOH/dry ice bath. During this
time, a clean, flame-dried round bottom flask equipped with stir
bar was fitted with a rubber septum and subsequently evacuated
and backfilled with N2. This process was repeated two more

7
797 mg, 21.0 mmol, 2.1 equiv). The flask was fitted with a
rubber septum and evacuated and back-filled with N2. Anhydrous
Et2O (45 mL, 0.2 M) was added and the reaction flask was
cooled at 0 °C in an ice/water bath. 2-Cyclopropylacetamide (S1,
1.27 g, 10.0 mmol, 1.0 equiv) was carefully added portion-wise
as a solid (ca. 3 portions) by briefly removing the reflux
condenser and then replacing it. Once all amide had been added,
the ice/water bath was replaced with an oil bath and the reaction
flask was heated at reflux and stirred overnight.
(m), 1424 (m), 1391 (m), 1367 (m), 1323 (m), 1303 (m), 1292
ACCEPTED MANUSCRIPT
(m), 1225 (w), 1209 (w), 1195 (m), 1125 (s), 1039 (m), 992 (s),
981 (s), 953 (m), 932 (m), 860 (m), 812 (w), 766 (w), 661 (m),
609 (s) cm-1. TLC Rf = 0.50 in 4:1 hexanes:EtOAc. HRMS (ESI)
m/z: [M – H]– Calcd for C14H30N2O2S 289.1955; Found
289.1947.
4.3.6. N’-tert-Butyl-N-((2R)-methyl 4-
methylpentano-2-yl)sulfamide (2r)
A flame-dried round bottom flask equipped with magnetic stir
bar was charged with triphenylphosphine oxide (2.29 g, 8.25
mmol, 1.65 equiv) and fitted with a rubber septum. The flask was
evacuated and backfilled with N2. CH2Cl2 (33 mL, 0.15 M with
respect to amine) was added and the flask was cooled at 0 °C in
an ice water bath. Trifluoromethanesulfonic anhydride (1.25 mL,
7.5 mmol, 1.5 equiv) that had been freshly removed from the
glovebox was then added to the cooled solution dropwise via
syringe. The reaction was allowed to stir at 0 °C in an ice water
bath for 15 minutes. This suspension was treated with a solution
of triethylammonium tert-butylsulfamate (1d, 1.27 g, 5.00 mmol,
1.0 equiv) in CH2Cl2 (4.0 mL, 1.25 M with respect to amine) via
cannula transfer. The flask containing sulfamate salt solution was
rinsed with CH2Cl2 (1.0 mL, ca. 5.0 M with respect to amine) to
achieve quantitative transfer. The resulting yellow solution was
stirred for 5 minutes at 0 °C and was then cooled at –78 °C in an
iPrOH/dry ice bath. During this time, a clean, flame-dried round
bottom flask equipped with stir bar was fitted with a rubber
septum and subsequently evacuated and backfilled with N2. This
process was repeated two more times. The flask was then charged
with Et3N (2.1 mL, 15.0 mmol, 3.0 equiv) and CH2Cl2 (13.6 mL,
0.36 M with respect to amine) and the mixture was cooled at –78
After refluxing overnight, the reaction was removed from the
heat and allowed to cool to room temperature and then further
cooled at 0 °C in an ice/water bath. The reaction was then
carefully quenched by dropwise, sequential addition of deionized
H2O (0.8 mL), 15% w/v aq. NaOH (0.8 mL), and deionized H2O
(0.8 mL). The quenched reaction was left stirring at 0 °C for ca.
30 minutes to ensure complete quenching of remaining LiAlH4.
Once fully quenched, the reaction was filtered through a pad of
celite in a glass-fritted funnel by vacuum filtration eluting with
Et2O (ca. ½ reaction volume). The filtrate was then concentrated
under reduced pressure. The concentrated crude material used
directly in the preparation of sulfamide 2o. Sulfamide 2o was
prepared from triethylammonium N-tert-butylsulfamate (1d, 2.54
g, 10.0 mmol) and crude 2-cyclopentylethyl amine following
general procedure B. The product was obtained as a white solid
(1.27 g, 51% yield,
2 steps) after silica gel column
chromatography (9:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3) δ 4.13 (br s, 1H), 4.07 (br s, 1H), 3.04 (dt, J = 6.4, 6.4
Hz, 2H), 1.85–1.74 (m, 3H), 1.63–1.51 (m, 6H), 1.35 (s, 9H),
1.14–1.05 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 53.7, 42.6,
37.4, 35.6, 32.4, 29.6, 25.0. IR (neat) ν 2866 (m), 1470 (w), 1446
(m), 1430 (m), 1391 (m), 1364 (m), 1305 (s), 1211 (m), 1133 (s),
1068 (m), 1042 (m), 1004 (s), 946 (m), 898 (m), 618 (s), 580
(s) cm-1. TLC Rf = 0.33 in 4:1 hexanes:EtOAc. HRMS (ESI)
m/z: [M + H]+ Calcd for C11H24N2O2S 249.1631; Found
249.1631.
i
°C in an PrOH/dry ice bath. The sulfamate salt solution was
transferred dropwise to the Et3N solution via cannula (during
which time a yellow to intense red color often developed),
rinsing the flask with CH2Cl2 (1.0 mL, ca. 2.0 M with respect to
amine) to achieve quantitative transfer. The resultant solution
was stirred at –78 °C for 15 minutes. (2R)-methyl-2-amino-4-
methylpentanoate hydrochloride (908.3 mg, 5.00 mmol, 1.00
equiv) in CH2Cl2 (4.0 mL, 1.25 M) chilled at 0 ºC was treated
with Et3N (0.70 mL, 5.0 mmol, 1.0 equiv). The cooled solution of
(2R)-methyl-2-amino-4-methylpentanoate hydrochloride and
Et3N was added to the solution of Et3N and activated sulfamic
acid salt via cannula. The flask was rinsed with CH2Cl2 (1.0 mL,
ca. 5.0 M with respect to amine) to achieve quantitative transfer.
Without removing the cooling bath, the reaction was then stirred
overnight, during which time no additional dry ice was added to
the bath and the mixture gradually warmed to room temperature.
4.3.4. N-tert-Butyl-N’-neopentylsulfamide (2p)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
2.54 g, 10.0 mmol) and neopentylamine (872 mg, 10.0 mmol)
following general procedure B. The product was obtained as a
white solid (1.31 g, 59% yield) after silica gel column
chromatography (9:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3) δ 4.16 (br s, 1H), 4.13 (t, J = 6.7 Hz, 1H), 2.78 (d, J = 6.7
Hz, 2H), 1.35 (s, 9H), 0.94 (s, 9H). 13C NMR (101 MHz, CDCl3)
δ 54.9, 53.8, 31.0, 29.7, 27.3. IR (neat) ν 3287 (br m), 2956 (m),
2912 (w), 2870 (w), 1475 (m), 1456 (m), 1431 (m), 1392 (m),
1367 (m), 1323 (s) 1296 (s), 1209 (m), 1147 (s), 1080 (s), 1055
(m), 1039 (m), 1029 (m), 990 (s), 947 (m), 930 (m), 863 (s), 817
(m), 613 (s), 568 (s) cm-1. TLC Rf = 0.33 in 4:1 hexanes:EtOAc.
HRMS (ESI) m/z: [M – H]– Calcd for C9H22N2O2S 221.1329;
Found 221.1323.
After stirring overnight, the reaction was subjected to an
aqueous workup as described in general procedure B. The
product was isolated as a colorless oil (1.16 g, 83% yield) after
purification on a Teledyne Isco CombiFlashRf system using a
Redi Sep Rf normal phase silica gel column (8:2
4.3.5. N-tert-Butyl-N-((1S, 2S, 5R)-2-isopropyl-5-
methylcylcohexyl)sulfamide (2q)
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 4.78 (d, J = 9.9
Hz, 1H), 4.11 (br s, 1H), 3.99 (ddd, J = 9.9, 8.0, 6.6 Hz, 1H),
3.77 (s, 3H), 1.80 (septet, J = 6.7 Hz, 1H), 1.56–1.52 (m, 2H),
1.34 (s, 9H), 0.95 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 174.2, 54.5, 52.3, 41.9, 29.7,
24.4, 22.6, 21.7. IR (neat) ν 3279 (br), 2958 (w), 2871 (w), 1732
(m), 1433 (w), 1392 (w), 1367 (w), 1310 (w), 1274 (w), 1232
(m), 1202 (m), 1136 (s), 1091 (w), 1042 (w), 993 (m), 908 (m),
861 (w), 817 (w), 731 (m), 614 (m) cm–1. TLC Rf = 0.56 in 6:4
hexanes/EtOAc. HRMS (ESI) m/z: [M – H]– Calcd for
C11H23N2O4S 279.1378; Found 279.1377.
Prepared from triethylammonium N-tert-butylsulfamate (1d,
1.20 g, 4.73 mmol) and (1S, 2S, 5R)-2-isopropyl-5-
methylcyclohexan-1-amine (735 mg, 4.73 mmol) following
general procedure B. The product was obtained as a white solid
(617 mg, 45% yield) after silica gel column chromatography
(Gradient: 20:1 hexanes/EtOAc → 9:1 hexanes/EtOAc). 1H NMR
(400 MHz, CDCl3) δ 4.14 (br s, 1H), 4.03 (br s, 1H), 3.81–3.79
(m, 1H), 2.21–2.17 (m, 1H), 1.79–1.71 (m, 2H), 1.60–1.47 (m,
4H), 1.42–1.26 (m, 2H), 1.36 (s, 9H), 0.99 (d, J = 6.6 Hz, 3H),
0.89 (d, J = 6.5 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 54.3,
51.1, 47.7, 39.8, 34.6, 29.8, 28.5, 26.1, 24.6, 22.1, 21.0, 20.9. IR
(neat) ν 3327 (br), 3275 (br), 2947 (m), 2867 (w), 2844 (w), 1452
4.3.7. N-tert-Butyl-N’-hexylsulfamide (2s)

8
Tetrahedron
Prepared from triethylammonium N-tert-butylsulfamate (1d,
(s), 732 (s), 635 (m), 567 (s) cm-1. TLC Rf = 0.36 in 2:1
ACCEPTED MANUSCRIPT
1.27 g, 5.0 mmol) and hexylamine (0.66 mL, 5.0 mmol)
following general procedure B. The product was obtained as a
white solid (1.68 g, 71% yield) after silica gel column
chromatography (10:1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3) δ 4.20 (br s, 1H), 4.13 (t, J = 6.8 Hz, 1H), 3.02 (dt, J =
6.8, 6.8 Hz, 2H), 1.58–1.51 (m, 2H), 1.34 (s, 9H), 1.32–1.26 (m,
6H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
53.8, 43.3, 31.3, 29.7, 29.3, 26.4, 22.5, 13.9. IR (neat) ν 3275 (br
m), 2968 (w), 2928 (m), 2853 (m), 1481 (w), 1467 (w), 1427
(m), 1391 (m), 1368 (m), 1341 (w), 1300 (s), 1233 (m), 1206
(m), 1240 (s), 1084 (m), 1041 (m), 997 (s), 918 (m), 762 (w), 728
(m), 609 (s) cm-1. TLC Rf = 0.36 in 4:1 hexanes:EtOAc. HRMS
(ESI) m/z: [M – H]– Calcd for C10H24N2O2S 235.1486; Found
235.1482.
hexanes:acetone. HRMS (ESI) m/z: [M – H]– Calcd for
C14H19N3O2S 292.1125; Found 292.1117.
4.3.11. N-((4-tert-Butyl)phenyl)-N’-pentylsulfamide
(2v)
Prepared
from
triethylammonium
N-((4-tert-
butyl)phenyl)sulfamate (1.65 g, 5.0 mmol) and pentylamine (0.58
mL, 5.0 mmol) following general procedure B. The product was
obtained as an orange oil (857 mg, 58% yield) after silica gel
column chromatography (Gradient: 9:1 hexanes/EtOAc → 4:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.6
Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.71 (br s, 1H), 4.55 (t, J = 5.8
Hz, 1H), 3.05 (dt, J = 7.0, 7.0 Hz, 2H), 1.50–1.43 (m, 2H), 1.29
(s, 9H), 1.24–1.19 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 147.7, 134.3, 126.3, 120.0, 43.3, 34.3, 31.3,
29.0, 28.6, 22.1, 13.9. IR (neat) ν 3273 (br), 2957 (m), 2865 (w),
1613 (w), 1515 (m), 1457 (m), 1394 (m), 1363 (m), 1323 (m),
1300 (m), 1268 (m), 1235 (w), 1202 (w), 1150 (s), 1083 (m),
1017 (m), 934 (m), 830 (m), 734 (m), 702 (m), 640 (m), 595 (s),
535 (s) cm-1. TLC Rf = 0.42 in 4:1 hexanes:EtOAc. HRMS (ESI)
m/z: [M – H]– Calcd for C15H26N2O2S 297.1642; Found
297.1635.
4.3.8. N-tert-Butyl-N’-(6-methylhept-2-yl)sulfamide
(2t)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
2.54 g, 10.0 mmol) and 2-amino-6-methylheptane (1.7 mL, 10.0
mmol) following general procedure B. The product was obtained
as a white solid (2.04 g, 77% yield) after silica gel column
chromatography (Gradient: 20:1 hexanes/EtOAc
→
9:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 4.12 (br s, 1H),
3.97 (d, J = 7.6 Hz, 1H), 3.46–3.36 (m, 1H), 1.57–1.50 (m, 2H),
1.42–1.38 (m, 2H), 1.35 (s, 9H), 1.33–1.29 (m, 2H), 1.22 (d, J =
6.5 Hz, 3H), 1.19–1.16 (m, 1H), 0.87 (d, J = 6.5 Hz, 6H). 13C
NMR (126 MHz, CDCl3) δ 53.8, 49.8, 38.6, 37.4, 29.7, 27.7,
23.3, 22.5, 22.4, 21.0. IR (neat) ν 3283 (m, br), 2953 (w), 1464
(w), 1430 (m), 1392 (w), 1365 (w), 1299 (m), 1208 (w), 1127 (s),
1085 (w), 1041 (m), 998 (m), 931 (w), 907 (m), 736 (w), 619
4.3.12. N-Octadecyl-N’-propylsulfamide (2w)
A round bottom flask equipped with magnetic stir bar was
charged with sulfur trioxide pyridine complex (SO3•pyr, 318 mg,
2.0 mmol 1.0 equiv). Acetonitrile (6 mL, 0.33 M) was then added
in a single portion without taking any precautions to exclude air
or moisture. The suspension was stirred at 22 °C until all of the
SO3•pyr had dissolved. Upon complete dissolution, the reaction
flask was cooled at 0 °C in an ice water bath and capped with a
rubber septum containing a nitrogen inlet. Propylamine (0.164
mL, 2.0 mmol, 1.0 equiv) was then added dropwise via Hamilton
syringe. Following complete addition of amine, Et3N (0.31 mL,
2.2 mmol, 1.1 equiv) was added dropwise. The reaction was
removed from the ice bath and stirred for 0.5 h. Upon
completion, the solvent was removed under reduced pressure to
give triethylammonium N-propylsulfamate, which was further
dried on the high vacuum and used directly in the preaparation of
sulfamide 2w. Sulfamide 2w was prepared from crude
triethylammonium N-propylsulfamate and octadecylamine (539
mg, 2.0 mmol) added as a solution in PhMe (9 mL, 0.2 M)
following general procedure B (solvent 1 = PhMe). The product
was obtained as an off-white solid (330 mg, 42% yield, 2 steps)
after silica gel column chromatography (Gradient: 9:1
hexanes/EtOAc → 4:1 hexanes/EtOAc). The characterization
data for this compound were in agreement with previously
published information.15a
(m), 590 (m), 548 (m) cm-1. TLC Rf
= 0.32 in 4:1
hexanes:EtOAc. HRMS (ESI) m/z: [M – H]– Calcd for
C12H28N2O2S 263.1799; Found 263.1801.
4.3.9. N-tert-Butyl-N’-(2,2,2-
trifluoroethyl)sulfamide (2c)
Prepared from triethylammonium N-tert-butylsulfamate (1d,
2.54 g, 10.0 mmol) and 2,2,2-trifluoroethylamine (1.7 mL, 10.0
mmol) following general procedure B. The product was obtained
as a white solid (1.77 g, 76% yield) after silica gel column
chromatography (Gradient: 9:1 hexanes/EtOAc
→
4:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3) δ 4.62 (t, J = 6.3
Hz, 1H), 4.24 (br s, 1H), 3.71–3.62 (m, 2H), 1.37 (s, 9H). The
characterization data for this compound were in agreement with
previously published information.10
4.3.10. N-Pentyl-N’-(quinolin-8-yl)sulfamide (2u)
Prepared from triethylammonium N-pentylsulfamate (1.34 g,
5.0 mmol) and 8-aminoquinoline (721 mg, 5.0 mmol) following
general procedure B. The product was obtained as a brown oil
(838 mg, 57% yield) after silica gel column chromatography
(Gradient: 20:1 hexanes/acetone → 4:1 hexanes/acetone).
4.3.13. N,N’-Di(tert-butyl)sulfamide (3a)
Isolated as a byproduct when attempting to prepare sulfamide
2n following general procedure A. 1H NMR (400 MHz, CDCl3) δ
3.98 (br s, 2H), 1.34 (s, 18H). 13C NMR (126 MHz, CDCl3) δ
53.8, 29.7. IR (neat) ν 3304 (br), 2981 (w), 1476 (w), 1432 (w),
1417 (w), 1392 (m), 1369 (m), 1304 (m), 1227 (w), 1198 (m),
1130 (m), 1044 (m), 993 (s), 931 (m), 884 (m), 771 (w), 735 (w),
623 (m), 593 (m), 535 (m) cm-1. TLC Rf = 0.33 in 4:1
hexanes:EtOAc. HRMS (ESI) m/z: [M – H]– Calcd for
C8H19N2O2S 207.1167; Found 207.1173.
Sulfamide 2u was obtained in 43% yield (628 mg) from
triethylammonium N-(quinolin-8-yl)sulfamate (1.63 g, 5.0 mmol)
and pentylamine (0.58 mL, 5.0 mmol) following general
procedure B. 1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 8.81
(dd, J = 4.2, 1.6 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), 7.77–
7.75 (m, 1H), 7.52–7.51 (m, 2H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H),
4.63 (br s, 1H), 3.00 (dt, J = 6.7 Hz, 2H), 1.38–1.31 (m, 2H),
1.08–1.04 (m, 4H), 0.69 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 148.7, 138.4, 136.3, 134.4, 128.2, 127.0, 122.0, 121.6,
114.2, 43.2, 28.8, 28.5, 21.9, 13.7. IR (neat) ν 3292 (br), 2955
(w), 2930 (w), 2859 (w), 1621 (w), 1579 (w), 1504 (s), 1471 (m),
1410 (m), 1363 (m), 1331 (m), 1308 (s), 1235 (w), 1153 (s), 1086
(s), 1058 (m), 1027 (m), 918 (s), 845 (m), 823 (s), 780 (s), 756
Acknowledgements
This project was funded by Duke University. M.F.S. was
supported in part by the U.S. Department of Education GAANN
Fellowship, Award Num: P200A150114. M.A.S. was supported
in part as a Burroughs Wellcome Fellow. Characterization data

9
Palomo Nicolau, F. E.; Palomo Coll, A. L. Preparation of
Pure Sulfamide. Spanish Patent 2,006,778, Apr 7, 1989.
10. (a) Blackburn, J. M.; Short, M. A.; Castanheiro, T.; Ayer, S. K.;
Muellers, T. D.; Roizen, J. L. Org. Lett. 2017, 19, 6012. In
relation to nucleophilic addition to SO3 reagents, for seminal
reports, see: (b) O’Connell, J. F.; Rapoport, H. J. Org. Chem.
were obtained on instrumentation secured by funding from the
ACCEPTED MANUSCRIPT
NSF (CHE-0923097, ESI-MS, George Dubay, the Duke Dept. of
Chemistry Instrument Center), or the NSF, the NIH, HHMI, the
North Carolina Biotechnology Center and Duke (Duke Magnetic
Resonance Spectroscopy Center).
1992, 57, 4775; (c) Ingram, L. I.; Taylor, S. D. Angew. Chem. Int.
Ed. 2006, 45, 3503. For select recent advances, see: (d) Ingram, L.
J.; Desoky, A.; Ali, A. M.; Taylor, S. D. J. Org. Chem. 2009, 74,
6479; (e) Desoky, A. Y.; Hendel, J.; Ingram, L.; Taylor, S. D.
Tetrahedron 2011, 67, 1281. For a review, see: (f) Abdoli, M;
Saeidian, H.; J. Sulfur Chem. 2015, 36, 556–582. For a seminal
report focused on the activating agent, see: (g) Hendrickson, J. B.;
Schwartzman, S. M. Tetrahedron Lett. 1975, 16, 277. For
sulfonamide preparation using the Hendrickson reagent, see: (h)
Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004,
126, 1024.
Conflicts of Interest
There are no conflicts to declare.
Appendix A. Supplementary data
Supplementary data to this article can be found online at XX.
Notes and References
11. (a) Laulhé, S.; Blackburn, J. M.; Roizen, J. L. Org. Lett. 2016, 18,
4440; (b) Laulhé, S.; Blackburn, J. M.; Roizen, J. L. Chem.
Commun. 2017, 53, 7270.
12. Qiu, J.; Albrecht, J. Org. Process Res. Dev. 2018, 22, 829.
13. Prat, D.; Pardigon, O.; Fleming, H.-W.; Letestu, S.; Ducandas, V.;
Isnard, P.; Guntum, E.; Senac, T.; Ruisseau, S.; Cruciani, P.;
Hosek, P. Org. Process Res. Dev. 2013, 17, 1517.
1. Spillane, W. Chem. Rev. 2014, 114, 2507.
2. Reitz, A. B.; Smith, G. R.; Parker, M. H. Expert Opinion on
Therapeutic Patents, 2009, 19, 1449.
3. (a) Movassaghi, M.; Ahmad, O. K.; Lathrop, S. P. J. Am. Chem.
Soc. 2011, 133, 13002; (b) Lathrop, S. P.; Movassaghi, M. Chem.
Sci. 2014, 5, 333; (c) Kim, J.; Movassaghi, M. Acc. Chem. Res.
2015, 48, 1159.
4. Ahn, K. H.; Yoo, D. J.; Kim, J. S. Tetrahedron Lett. 1992, 33,
6661.
5. Zhang, X.-J.; Liu, S.-P.; Li, X.-M.; Yan, M.; Chan, A. S. C. Chem.
Commun. 2009, 833.
6. Iso, Y.; Irie, T.; Iwaki, T.; Ku, M.; Sendo, Y.; Motokawa, K.;
Nishitani, Y. J. Antibiotics, 1996, 49, 478.
7. Vandi, A.; Moeller, T.; Audrieth, L. F. J. Org. Chem. 1961, 26,
1136.
8. For a recent example, see: Beaudoin, S.; Kinsey, K. E.; Burns, J.
F. J. Org. Chem. 2003, 68, 115.
9. (a) Lee, C.-H.; Lee, M. S.; Lee, Y.-H.; Chung, B. Y. Bull.
14. This is an expensive compound, yet appears to be commercially
available: As of December 1, 2018, the list price on
emolecules.com for N-octadecyl-N’-propylsulfamide is $651/50
mg at Cayman Chemicals.
15. (a) Cano, C.; Pavón, J.; Serrano, A.; Goya, P.; Paez, J. A.;
Rodriguez de Fonseca, F.; Macias-Gonzalez, M. J. Med. Chem.
2007, 50, 389; (b) Rodrigues de Fonseca, F. A.; Gonzalez, M. M.;
Pavon Moron, J.; Goya-Laza, M. P.; Paez Prosper, J. A.; Cano
Ramos, C. Acyclic Sulfamide Derivatives. May 29, 2012. US
8,188,312 B2.
16. This is an expensive intermediate: As of December 1, 2018, the
list price on emolecules.com for propyl sulfamoyl chloride is
$1,134/5 g at Princeton Biomolecular Research BB.
Korean Chem. Soc. 1992, 13, 357; (b) Ballester Rodes, M.;