Photochemically Mediated Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamides

Article abstract of DOI:10.1021/acs.joc.0c00139

A general method for the N-arylation of sulfamides with aryl bromides is described. The protocol leverages a dual-catalytic system, with [Ir(ppy)2(dtbbpy)]PF6 as a photosensitizer, NiBr2·glyme as a precatalyst, and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)

Full text of DOI:10.1021/acs.joc.0c00139

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Article
Photochemically-mediated nickel-catalyzed
synthesis of N-(hetero)aryl sulfamides
R. Thomas Simons, Georgia E. Scott, Anastasia G. Kanegusuku, and Jennifer L. Roizen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00139 • Publication Date (Web): 20 Apr 2020
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Photochemically-mediated nickel-catalyzed synthesis of N-(hetero)aryl
5
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7
sulfamides
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9
R. Thomas Simons, Georgia E. Scott, Anastasia G. Kanegusuku and Jennifer L. Roizen*
Duke University, Department of Chemistry, Box 90346, Durham, NC, 27708-0354, USA
Corresponding Author - E-mail: j.roizen@duke.edu
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Table of Contents/Abstract Graphic:
(pin)B
S
O
O
O
O
O
O
S
S
S
H2N
N
N
N
N
N
H
H
O
O
O
Ir Ni
F3C
ArBr
tBu
O
O
O
O
O
O
O
O
(hetero)aryl bromide
S
Me
S
Me
S
Me
S
Me
H2N
N
H2N
N
N
N
N
N
Boc
H
H
Boc
Me
Me
readily accessible sulfamides
under mild conditions
broad access to N-(hetero)aryl sulfamides
ABSTRACT: A general method for the N-arylation of sulfamides with aryl bromides is described.
The protocol leverages a dual-catalytic system, with [Ir(ppy)2(dtbbpy)]PF6 as a photosensitizer,
NiBr2•glyme as a precatalyst, and DBU as a base, and proceeds at room temperature under visible
light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through
the reaction untouched. The developed reactions efficiently engage simple bromoarenes and
primary sulfamides in between 66% and quantitative yields. For more challenging substrates, such
as secondary sulfamides, reaction efficiency is documented. Thereby, these methods complement
known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.
INTRODUCTION
N-Aryl sulfamides are critical components of active pharmaceutical1 and agrochemical2
agents (Figure 1).3, 4 In drug discovery, sulfamides can be valuable analogues of sulfamate,
sulfonamide, urea, carbamate, and amide functional groups.1a In reactions, N,N’-disubstituted
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sulfamides are useful as chiral auxiliaries,5 as organocatalysts,6 as reagents to promote
dehydration,7 as precursors to sterically encumbered carbon–carbon bonds8 and as directing
groups for C–H functionalization processes.9 Despite the potential of this valuable functional
group, sulfamides may be underutilized due to limitations in practical methods for their
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preparation.10, 11, 12
Figure 1. N-heteroaryl sulfamides are important FDA-approved drugs and therapeutic targets
To date, approaches to prepare N-(hetero)aryl sulfamides rely on N–S bond-forming
reactions that involve the nucleophilic addition of amines to SO2 sources (not depicted),12, 13 or on
C–N bond-forming strategies (Scheme 1). These direct methods for C–N bond formation have
been primarily limited to nucleophilic substitution reactions (Scheme 1A), copper-mediated Chan-
Lam coupling processes that transform sulfamoyl azides (Scheme 1B),14 and Buchwald-Hartwig
amination conditions that are palladium-mediated (Scheme 1C).15, 16, 17 Herein disclosed is the first
photochemically-mediated, nickel-catalyzed method to access N-(hetero)aryl sulfamides.
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Scheme 1. Recent advances allow for diverse and complementary strategies for the synthesis of N-(hetero)aryl
sulfamides
These investigations are inspired by a pioneering disclosure by Buchwald, MacMillan, and
co-workers, who together have developed a light-driven dual nickel- and iridium-catalyzed
amination reaction18 that has sparked an ongoing revolution in nickel-mediated C–N bond forming
technologies (Scheme 2).19, 20, 21, 22 These approaches have been developed in parallel with recent
innovations in copper-mediated reactions,23 and complement palladium-mediated protocols in
terms of the range of nucleophilic coupling partners engaged and breadth of arenes tolerated.18, 20
Accordingly, we anticipated that the developed photo-driven, nickel-catalyzed processes would
afford an efficient, robust, and complementary strategy to access valuable N-(hetero)aryl
sulfamides. 24
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R1
R1
N
Ni
Ir or Ru
Ar
HN
R2
R2
ArX
nitrogen sources
9
2016
2016
2018
amines
anilines
anilines
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R1
Ar
Ar
HN
H2N
H2N
R2
Oderinde, Johannes
& co-workers
X = I, Br
Buchwald, MacMillan
& co-workers
X = Br, Cl
Key & Vannucci
X = I
2018
sulfonamides
2018
carbamates
O
2018
aryl azides
O
O
Ar
N3
S
R3
OR3
H2N
H2N
Konev, Johannes
& McTeague
X = I, Br, Cl, OTf
MacMillan
& co-workers
X = Br
Reddy
& co-workers
X = Br
2019
2019
2020
sulfamate esters
amines
amines in flow
R1
R1
O
O
HN
HN
S
OR3
R2
H2N
R2
Miyake, Thordarson
& co-workers
X = Br, I
Roizen
& co-workers
X = Br
Buchwald
& co-workers
X = Br
Scheme 2. This research extends the development of light-driven dual catalytic C–N bond-forming technologies, first
pioneered by Buchwald, MacMillan, and co-workers18
Results and Discussion
We20 and othersError! Bookmark not defined.19c have observed that, relative to electron-deficient
arylbromides, electron-rich arylbromides can be more challenging electrophiles when employing
nickel-mediated cross-coupling technologies. Accordingly, we optimized the reactions of
sulfamide 1a with electron-deficient 4-(trifluoromethyl)bromobenzene and electron-rich 4-(tert-
butyl)bromobenzene concurrently (Table 1).
Relying on previously established conditions for the arylation of sulfamate esters,20 in the
presence of light, [Ir(ppy)2(dtbbpy)]PF6 as a photosensitizer, NiBr2•glyme as a precatalyst, and
DBU as a base, sulfamide 1a reacts with 4-(trifluoromethyl)bromobenzene to afford N-aryl
sulfamide 3a in quantitative yield (Table 1, entry 1). This synthetic protocol can transform aryl
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chloride and iodide electrophiles, albeit in diminished yields (entries 2–3). Unsurprisingly,
sulfamide 1a reacts with 4-(tert-butyl)bromobenzene inefficiently (entries 4–5). Consistent with
previous observations,19c, 20 higher turnover numbers can be achieved when 4,4’-di-tert-butyl-2,2’-
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dipyridyl (dtbbpy) is employed as a ligand for nickel (entry 6).
Table 1. Optimization informs distinct conditions for electron-deficient and electron-rich aryl bromidesa
entry
R
X
[Ni]
ligand
solvent
unreacted yield
1a (%)b
(%)b
(mol %)
1
2
3
CF3 Br 5
–
MeCN
0
>98c
79
CF3
I
5
5
–
–
MeCN
MeCN
10
39
CF3 Cl
43
4
5
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8
tBu Br 5
tBu Br 10
tBu Br 10
tBu Br 10
tBu Br 10
–
–
MeCN
MeCN
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22
12
7
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47
89c
90
dtbbpy MeCN
dtbbpy EtOH
dtbbpy 9:1 MeCN:
EtOH
5
9
tBu Br 10
dtbbpy EtOH with H2O
(100 equiv)
72
6
10
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12
13
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15
tBu Br 10
tBu Br 10
tBu Br 10
tBu Br 10
tBu Br 10
tBu Br 10
dtbbpy MeOH
dtbbpy iPrOAc
dtbbpy CH2Cl2
dtbbpy DMSO
dtbbpy acetone
27
50
38
27
46
26
76
7
0
32
35
23
dtbbpy 2-methyl
tetrahydrofuran
16
17
CF3 Br 5
CF3 Br 5
–
–
EtOH
18
12
70
MeOH
81c
18
19
tBu
tBu Cl 10
I
10
dtbbpy EtOH
dtbbpy EtOH
6
81
7
60
a General reaction conditions: sulfamide 1a (1.0 equiv), aryl halide 2 (1.5 equiv), NiBr2•glyme, [Ir(ppy)2(dtbbpy)]PF6
(1 mol %), DBU (3.0 equiv), and ligand (4 mol %) in indicated solvent (0.25 M) with stirring and irradiation between
b
1
two 34 W blue Kessil lamps for 24 h. Yields determined by H NMR using an internal standard of 2,3,5,6–
tetrachloronitrobenzene. c Isolated yield.
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To our surprise, the efficiency of this reaction improves substantially when it is run in
absolute ethanol, or with ethanol as a co-solvent (entries 7–8). Importantly, the solvent and the
aryl bromide do not engage in undesirable C–O coupling processes, as the predicted products of
these processes are not detected. Unfortunately, the reaction efficiency drops in the presence of
100 equiv of water (entry 9).25 When we assessed a single solvent from each of seven solubility
clusters,26 the reaction was less efficient in these other solvents (entries 10–15). The advantages of
ethanol were isolated to reactions engaging this more electron-rich aryl bromide, and did not
translate to the reaction of 4-(trifluoromethyl)bromobenzene (entries 16–17). This synthetic
protocol can be used to transform aryl iodide electrophiles but does not transform electron-rich
aryl chlorides in synthetically useful efficiencies (entries 18–19). Control experiments confirm that
nickel, base, and light are critical to the success of the cross-coupling reaction (see supporting
information for details).
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The design for photocatalyst evaluation was inspired by MacMillan and co-workers’
approach to gathering preliminary data to interrogate their hypothesis about the mechanism of their
sulfonamidation reaction. MacMillan and co-workers correlate photocatalyst efficiency with
catalyst oxidation potentials and triplet state energies (ET). They use these correlations to
interrogate their hypothesis that their light-driven dual catalytic C–N sulfonamidation reaction
productively engages the excited state photocatalyst not to drive electron transfer, but rather to
transfer energy to a reaction intermediate. 19c If an excited state photocatalyst mediates a reaction
based on energy transfer, efficient photocatalysts would be expected to have triplet state energies
that cluster around a narrow range of values. Indeed, this phenomena has been reported in light-
driven dual catalytic C–N bond-forming reactions with sulfonamides,19c and sulfamate esters.20
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Fortunately, many photosensitizers drive the developed sulfamide arylation reactions
(Tables 2 and S8). The optimized reaction conditions rely on [Ir(ppy)2(dtbbpy)]PF6 as a
photosensitizer (Table 1; Table 2, entries 3, 11). More generally, to date, the most efficient
reactions rely on photoexcitable metal complexes with triplet state energies (ET) in the range of
46.2–49.2 kcal/mol (Table 2, entries 3–5, 11–13), which would be expected for reactions mediated
by energy transfer from an excited state photocatalyst to a reaction intermediate. Importantly, these
N-arylation reactions are more efficient in the presence of a photochemical mediator, suggesting
that light-harvesting by the photocatalyst is important to the efficiency of the developed reaction
protocols (Table 2, entries 8, 16). Nevertheless, in ethanol absent photocatalyst, the product yield
is not insignificant (entry 16). Under these conditions, any product that forms may be generated
through a mechanism that involves direct excitation of an intermediate nickel species by light, as
this process can drive nickel-mediated C–N bond-forming reactions,22 and direct photochemical
excitation of a nickel complex cannot be ruled out as a contributing to product formation in ethanol.
While these data are suggestive of processes that rely on energy transfer from an excited state
photocatalysts, these data are not conclusive.
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Indeed, only recently, Miyake and co-workers have disclosed the first studies to provide
unambiguous evidence that a light-driven dual catalytic C–N bond-forming reaction proceeds not
based on electron transfer to the excited state photocatalyst, but instead based on energy transfer
from an excited state photocatalyst.19f Miyake, Thordarson, and co-workers’ investigations rely on
the ability to isolate intermediate nickel amine complexes, and study them spectroscopically. A
thorough and rigorous analysis of the mechanism(s) of the developed reactions is beyond the scope
of this manuscript.
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Table 2. Reaction efficiency is maximized when photocatalyst triplet state energies are within the range of 46.2–
49.2 kcal/mol
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E1/2
ET
(kcal/
mol)
1a
3
entry
R
Photocatalyst
(Pc*/Pc-)
(V vs SCE)
(%)b
(%)b
1a
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
+1.21d
+0.97e
+0.66f
+0.58 g
+0.61 g
+0.74g
+1.37h
–
60.4d
60.1e
49.2e
47.7g
46.3g
39.2g
46.5h
–
78
78
< 5
9
14
12
92
85
81
33
32
< 5
12
26
78
73
71
15
61
13
4b
4c
2 a
3 a
4a
4d
4e
4 a
5 a
9
6 a
57
59
77
78
62
21
21
22
68
30
78
4f
7 a
4g
none
8 a
9 b
+1.21d
+0.97e
+0.66f
+0.58 g
+0.61 g
+0.74g
+1.37h
–
60.4d
60.1e
49.2e
47.7g
46.3g
39.2g
46.5h
–
4b
4c
10 b
11 b
12 b
13 b
14 b
15 b
16 b
4a
4d
4e
4f
4g
none
a General conditions: sulfamide 1a (1.0 equiv, 0.2 mmol scale), 4-bromobenzotrifluoride (1.5 equiv), photocatalyst (1
mol %), NiBr2•glyme (5 mol %), and DBU (3.0 equiv) in MeCN (0.25 M) with stirring between two 34W blue Kessil
lamps for 24 h. General conditions: sulfamide 1a (1.0 equiv, 0.2 mmol scale), bromo-4-(tert-butyl)benzene (1.5
b
equiv), photocatalyst (1 mol %), NiBr2•glyme (10 mol %), DBU (3.0 equiv), and dtbbpy (4 mol %) in EtOH (0.25 M)
with stirring between two 34W blue Kessil lamps for 24 h. c Yields and unreacted starting material determined by 1H
NMR using an internal standard of 2,3,5,6–tetrachloronitrobenzene. d ET in (kcal/mol), E1/2 (V vs SCE) in MeCN27 e
ET in (kcal/mol), E1/2 (V vs SCE) in MeCN 28 f E1/2 (V vs SCE) in MeCN29 g ET in (kcal/mol), E1/2 (V vs SCE) in
19c
MeCN.
h ET in (kcal/mol), E1/2 (V vs SCE) in MeCN 30
The developed dual catalyzed processes offer complementary reactivity profiles to those
available through palladium-mediated Buchwald-Hartwig reactions. We have employed the
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ligand-free protocol to recapitulate palladium-mediated C–N bond-forming reactions to access
arylated 3c and 3d.16a The developed nickel-mediated transformations furnish these products with
increased yields relative to those documented using a known palladium-mediated protocol,16a
suggesting that this nickel-mediated approach is worthy of concurrent investigation in the course
of synthetic campaigns. Given our interest in functionalized pyridines,31 we were pleased to find
that bromopyridines were effective arylating agents using the disclosed protocol. Furthermore, this
dual catalytic reaction manifold can transform aryl bromides, without engaging either C(sp2)–B
(3e) and C(sp2)–Cl (3f-g) bonds to afford products with useful synthetic handles for further
functionalization.
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The ligand-free protocol arylates N,N-disubstituted sulfamides in synthetically useful
yields, to access products that incorporate N-morpholino groups (i.e. 3a–3g), N,N-dimethylated
sulfamides (i.e 3h–3i), and N-carbonyl-N-alkylated sulfamides (i.e. 3j). In this arylation reaction,
such N-carbonyl-N-alkylated sulfamides are appropriate surrogates for N-monosubstituted
sulfamides, which do not react cleanly under the developed reaction conditions.32 Notably, this
protocol does not productively transform a secondary sulfamide substrate unless a modified
procedure is used that employs less base (c.f. 3i). This change in protocol may partially mitigate
base-catalyzed decomposition of sulfamide substrate, a competitive process that has been reported
in some reactions that engage electron-rich, tri-substituted sulfamides.10, 33
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Scheme 3. Photochemically-mediated nickel-catalyzed conditions engage a variety of electron-deficient aryl
5
6
bromides and sulfamides
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9
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a General conditions: sulfamide 1 (1.0 equiv), (hetero)aryl bromide (1.5 equiv), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %),
NiBr2•glyme (5 mol %), and DBU (3.0 equiv unless otherwise specified) in MeCN (0.25 M) with stirring between
two 34W blue Kessil lamps for 24–48 h. b Isolated yield through a palladium-mediated cross-coupling reaction.16a c
Isolated yield when prepared from subjecting morpholinyl sulfamoyl chloride34 following literature conditions.35
d DBU (0.5 equiv).
In general, electron-deficient aryl bromides N-arylate sulfamides in good to excellent
yields (Scheme 3, 3c–3h, 3j). By contrast, in acetonitrile, some electron-rich aryl bromides can be
incorporated into the product with limited efficiency (c.f. Table 1, entry 4). Indeed, 3-bromo
thiophene reacts with a primary sulfamide to furnish sulfamide 3k in limited yield. Nevertheless,
this reaction suggests that this protocol overcomes the common tendency of nickel catalysts to
engage in C–S bond activation36 or to be deactivated upon reaction with sulfur.
Fortunately, with the use of EtOH as a solvent and inclusion of a ligand, the protocol can
transform a similar range of sulfamide substrates and allows the efficient cross-coupling of
electronically-varied (hetero)aryl bromides (Scheme 4). Specifically, para- and meta-substituted
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N-aryl sulfamides 3l and 3m were synthesized with similar or improved yields relative to those
reportedly isolated upon reaction of morpholinyl sulfamyl chloride with anilines. As anticipated,
under these conditions, aryl bromides can react, without engaging either C(sp2)–B and C(sp2)–Cl
bonds, to afford products 3e and 3n with useful synthetic handles for further functionalization.
Furthermore, these conditions can be used to install heteroaryl groups including a pyrimidine (3o).
Unfortunately, the installation of more conjugated benzothiazole, tert-butyl indole-1-carboxylate,
quinoline, and 2-methylnaphthalene moieties has proven less efficient (c.f. 3p–3t). By comparison,
while 13% yield of the quinoline analogue 3r can be isolated under the developed nickel/iridium-
mediated conditions, its preparation has proven more efficient by way of nucleophilic substitution
on sulfur(VI), which proceed in 57% yield.13b
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In EtOH, some variations in sulfamide substitution are well tolerated. The reaction engages
N,N-disubstituted sulfamides in synthetically useful yields, with examples producing N-
morpholino 3e, 3l–3q, N-carbonyl-N-alkylated 3u, and N,N-dimethylated 3v sulfamides. In this
arylation reaction, N-carbonyl-N-alkylated sulfamides, like 3u, are appropriate surrogates for more
sterically accessible sulfamides, such as 3r and 3t, which cannot be efficiently derived directly
from N-monosubstituted sulfamides. Notably, N-monosubstituted sulfamides can be forced to
engage in monoarylation reactions when larger aryl bromide electrophiles are employed, albeit in
low efficiency. Further, this protocol does not provide efficient access to a tetrasubstituted
sulfamide 3w. Ultimately, these protocols are most effective when using primary N,N-disubstituted
sulfamides as substrates.
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Scheme 4. Photochemically-mediated nickel-catalyzed reactions proceed in ethanol
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a General conditions: sulfamide 1 (1.0 equiv), (hetero)aryl bromide (1.5 equiv), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %),
NiBr2•glyme (10 mol %), dtbbpy (4 mol %) and DBU (3.0 equiv) in EtOH (0.25 M) with stirring between two 34 W
b
blue Kessil lamps for 24–96 h. Isolated yield when prepared from N,N-dichlorosulfamide.37 c Isolated yield when
prepared from sulfamic acid.13b
Conclusion
We have developed a new catalytic method for sulfamide N-(hetero)arylation. This
protocol offers several attributes, as it proceeds under mild conditions, and employs a variety of
readily available substrates and reagents that complements the range that may be used under
palladium-mediated Buchwald-Hartwig reaction conditions. The developed photo-driven nickel-
mediated tactics can be employed with (hetero)aryl bromide, iodide, and chloride electrophiles.
Fortunately, owing to the higher reaction efficiency with (hetero)aryl bromides, aryl boronic esters
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and aryl chlorides can be carried through the reaction untouched, so these useful synthetic handles
can be retained for further synthetic manipulation. Owing to these attributes, this method extends
chemists’ ability to use a sulfamide in the most versatile step a medicinal chemistry campaign, the
“production step.”38 Moreover, it broadens the synthetic access to N-(hetero)aryl sulfamides, which
are of increasing pharmacological interest.
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Experimental
General Considerations. Moisture-sensitive reactions were performed using flame-dried
glassware under an atmosphere of dry nitrogen (N2). Air- and water-sensitive manipulations,
where noted, were performed in an MBraun MB200 glove box held under an atmosphere of
nitrogen gas (working pressure 2–6 mbar). Flame-dried equipment was stored in a 130 °C oven
before use and either allowed to cool in a cabinet desiccator 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 or by stainless steel cannula. Chromatographic purification of products was
accomplished by flash column chromatography using Silicycle Silica flash F60 (particle size 40–
63 μm, 230–400 mesh).39 Thin layer chromatography was performed on EMD Millipore silica gel
60 F254 glass-backed plates (layer thickness 250 μm, particle size 10–12 μm, 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,
ninhydrin, or KMnO4 stains followed by heating. Room temperature is 22–23 °C. NMR spectra
were obtained at 20–23 °C on Varian iNOVA spectrometers operating at 400 or 500 MHz for 1H
NMR, 126 MHz for 13C NMR, and 376 or 470 MHz for 19F NMR, and are reported as chemical
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shifts (δ) in parts per million (ppm). Spectra were referenced internally according to residual
solvent signals (1H: CDCl3, 7.26 ppm; CD2Cl2, 5.32 ppm; CD3CN, 1.94 ppm; DMSO-d6, 2.50
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ppm; Acetone-d6, 2.05 ppm. C: CDCl3, 77.2 ppm; CD3CN, 118.3 ppm; DMSO-d6, 39.5 ppm;
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Acetone-d6, 206.3 ppm). Data for NMR spectra use the following abbreviations to describe
multiplicity: s, singlet; br s, broad singlet; d, doublet; t, triplet; dd, doublet of doublets; td, triplet
of doublets; tt, triplet of triplets; app t, apparent triplet; app dd, apparent doublet of doublets; app
td, apparent triplet of doublets; m, multiplet. Coupling constant (J) are reported in units of Hertz
(Hz). IR spectra were obtained on a Nicolet iS50 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, 67–95% 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). Ultraviolet/visible/near-infrared (UV-Vis-NIR) spectra were
obtained on an Agilent Cary 5000 UV−vis−NIR spectrophotometer. Lamps were allowed to warm
up for a minimum of 30 minutes prior to background or spectral data being collected. All visual
representations of data collected were produced in Microsoft Excel under the Duke University
Microsoft Office 365 license. Blue Kessil H150 LED Grow Light LED: 30W High Luminous DEX
2100 LED, emission wavelength range: ca. 400–500 nm, dimensions: 4.49” length x 2.48”
diameter, power supply: 100–240V AC (Input), 24V DC (Output) S4, power usage: 36W (40W
max), http://www.kessil.com/horticulture/H150.php
Preparation of sulfamides via the (tert-butyl)carbamate sulfamoylation of amines:
General Procedure A. Sulfamides were prepared according to modified literature
procedures.40 A flame-dried round bottom flask equipped with a stir bar was evacuated and filled
with nitrogen. The flask was then charged with chlorosulfonyl isocyanate (CSI, 1.5 equiv) in
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diethyl ether (1M) and placed in an ice bath. To this flask was added dropwise neat tert-butanol
(1.49 equiv). Following this addition, the flask was removed to from the ice bath and allowed to
warm to room temperature with continued stirring for 1 hour. At 1 hour of reaction time, the
solution was diluted with hexanes (100% initial volume of diethyl ether) and concentrated under
reduced pressure, without heating, to yield a powdery, white solid. This solid was then dissolved
in acetonitrile (1M), flask was evacuated and filled with nitrogen. A separate flame-dried round
bottom flask was charged with the amine substrate (1.0 equiv), triethylamine (1.5 equiv), and
acetonitrile (1M). Both flasks were then placed in an ice bath and the solution containing the amine
substrate was added dropwise by cannula transfer to the solution of sulfamoyl chloride over the
course of 10–60 minutes. Transfer of the amine solution was made quantitative with additional
acetonitrile (5–10% of initial volume). The reaction mixture was allowed to continue stirring as
the ice bath warmed to room temperature. Upon completion of the reaction, as determined by TLC
analysis, the reaction was quenched by the addition of saturated aqueous NaCl (ca. 10 mL/mmol
of amine substrate). The mixture was transferred to a separatory funnel, and the aqueous layer was
extracted with portions of ethyl acetate (three times ca. 10 mL/mmol of amine substrate). The
organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure to less than 10% initial volume. The resulting concentrate was diluted in
dichloromethane (4M), to which, trifluoroacetic acid (0.66M) was carefully (!) added portion-wise
over 30–60 minutes. Gas evolution was observed upon addition of the acid and care was taken to
avoid foaming or overheated from rapid addition. The reaction was allowed to continue stirring at
room temperature until completion of the reaction, as determined by TLC analysis. The reaction
was concentrated under reduced pressure onto silica gel and purified by silica gel flash
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chromatography using conditions indicated below to isolate pure sulfamide products. The
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preparation and characterization of sulfamides 1b41 and 1e42 have been previously published.
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Preparation of sulfamides via the sulfamoylation of amines:
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General Procedure B. Sulfamides were prepared according to modified literature procedures.43
A flame-dried round bottom flask equipped with a stir bar was evacuated and filled with nitrogen.
The flask was then charged with chlorosulfonyl isocyanate (CSI, 1.5 equiv) and placed in an ice
bath. To this flask was added dropwise neat formic acid (1.5 equiv). During addition, vigorous gas
evolution was observed, and the solution solidified as a white solid. Stirring continued for 5
minutes at 0 C. Next, the solid was dissolved in acetonitrile (1M). The flask was removed from
the ice bath and allowed to warm to room temperature, where it stirred for 12–18 hours. A separate
flame-dried round bottom flask equipped with a stir bar was charged with amine substrate (1.0
equiv), triethylamine (1.5 equiv), and acetonitrile (1M). Both flasks were then placed in an ice bath
and the solution containing amine substrate was added dropwise by cannula transfer to the solution
of sulfamoyl chloride over the course of 10–60 minutes. Transfer of the amine solution was made
quantitative with additional acetonitrile (5–10% of initial volume). The reaction mixture was
allowed to continue stirring, as the ice bath warmed to room temperature. Upon completion of the
reaction, as determined by TLC analysis, the reaction was quenched by the addition of saturated
aqueous NaCl (ca. 10 mL/mmol of amine substrate). The mixture was transferred to a separatory
funnel, and the aqueous layer was extracted with portions of ethyl acetate (three times ca. 10
mL/mmol of amine substrate). The organic phase was separated, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel
flash chromatography using the conditions indicated below to isolate pure sulfamide products. The
characterization of sulfamide 1d has been previously published.44
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Morpholine-4-sulfamide (1a). Prepared from morpholine (3.99 g, 45.0 mmol, 1.0 equiv)
following general procedure A. The product was obtained as a white, amorphous solid (5.444 g,
72% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 4:1 to
1:4). The obtained spectrum matched that reported in the literature.3b 1H NMR (400 MHz, DMSO-
d6) δ 6.83 (s, 2H), 3.65 (t, J = 4.7 Hz, 4H), 2.91 (t, J = 4.7 Hz, 4H) ppm. 13C{1H} NMR (126 MHz,
acetone-d6) δ 66.7 (s), 47.3 (s) ppm. IR (neat) ν 3299 (br), 3177 (br), 3079 (br), 2994 (w), 2929
(w), 2870 (w), 1564 (w), 1472 (w), 1462 (w), 1348 (s), 1330 (m), 1299 (m), 1264 (m), 1219 (w),
1145 (m), 1109 (s), 1071 (s), 1022 (w), 933 (s), 905 (m), 849 (m), 753 (s), 628 (m), 534 (s), 429
(m) cm-1. TLC Rf = 0.18 in 1:1 hexanes:EtOAc.
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N,N-(dimethyl) sulfamide (1b) Prepared from N,N-(dimethyl) sulfamoyl chloride (1.1 mL,
10 mmol, 1.0 equiv) and 30% aqueous ammonium hydroxide (5 mL) according to known literature
procedures.45 The product was obtained as a white, amorphous solid (0.443 g, 37% yield) after
1
extraction by acetone. H NMR (400 MHz, acetone-d6) δ 5.93 (br, 2H), 2.69 (s, 6H). TLC Rf =
0.23 in 1:1 hexanes:EtOAc The obtained spectrum matched that reported in the literature.45
tert-butyl pentyl(sulfamoyl)carbamate (1c). Prepared from tert-butylpentyl carbamate46
(1.87 g, 10 mmol, 1.0 equiv) following general procedure B. The product was obtained as a white,
amorphous solid (0.386 g, 15% yield) after silica gel column chromatography using
acetone:hexanes (gradient elution, 1:19 to acetone:hexanes). 1H NMR (500 MHz, CDCl3) δ 5.33
(br, 2H), 3.66 (t, J = 7.6 Hz, 2H), 1.68 – 1.62 (m, 2H), 1.53 (s, 9H), 1.35 – 1.25 (m, 4H), 0.90 (t, J
= 7.2 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 152.6, 82.3, 47.8, 29.4, 28.9, 28.2, 22.4,
14.1 ppm. IR (neat) ν 3354 (br), 3269 (br), 3120 (w), 2972 (w), 2941 (w), 2859 (w), 1694 (s), 1566
(w), 1456 (w), 1367 (s), 1345 (m), 1330 (m), 1309 (m), 1293 (m), 1284 (m), 1247 (m), 1216 (w),
1186 (m), 1168 (m), 1140 (br), 1031 (w), 1011 (w), 979 (w), 913 (m), 845 (m), 786 (m), 771 (m),
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720 (s), 638 (s), 584 (m), 566 (s), 532 (s), 468 (m), 420 (w), 403 (w) cm-1. TLC Rf = 0.56 in 4:1
hexanes:EtOAc. HRMS (ESI) m/z: [M+Na]+ Calcd for C10H22N2O4S•Na+: 289.1193; Found
289.1197.
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n-Pentyl sulfamide (1d) Prepared from n-pentyl amine (0.701 g, 10 mmol, 1.0 equiv)
following general procedure B. The product was obtained as a white, amorphous solid (0.398 g,
31% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to
1:1). 1H NMR (400 MHz, CDCl3) δ 4.48 (br s, 2H), 4.23 (br s, 1H), 3.13 (q, J = 6.8 Hz, 2H), 1.60
– 1.56 (m, 2 H), 1.32 – 1.36 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). TLC Rf = 0.35 in 1:1 hexanes:EtOAc.
The obtained spectrum matched that reported in the literature.47
N,N,N’-(trimethyl) sulfamide (1e) Prepared from N,N-(dimethyl) sulfamoyl chloride (0.8
mL, 7.5 mmol, 1.0 equiv) and methylamine 2.0 M in THF (7.5 mL, 15.0 mmol, 2.0 equiv)
according to known literature procedures.48 The product was obtained as a clear, yellow oil (1.036
g, ≥98% yield) after silica gel column chromatography using hexanes:acetone (gradient elution,
4:1 to 1:1). 1H NMR (500 MHz, CDCl3) δ 4.41 (br s, 1H), 2.80 (s, 6H), 2.71 (d, J = 5.3 Hz, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 38.1, 29.8. IR (neat) ν 3306 (br), 2924 (w), 1635 (w), 1458
(w), 1415 (w), 1313 (m), 1261 (w), 1185 (w), 1142 (m), 1076 (m), 1051 (m), 952 (m), 834 (m),
697 (m), 590 (m), 511 (m), 426 (m), 406 (m) cm-1. TLC Rf = 0.12 in 3:1 hexanes:acetone HRMS
(ESI) m/z: [M+H]+ Calcd for C3H11N2O2S+: 139.0536; Found 139.0535.
Photochemically driven, nickel-catalyzed N-(hetero)arylation of sulfamides (for electron-
deficient and electron-neutral (hetero)aryl bromides):
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General Procedure C. A 10 mL microwave tube (CG-4920-01) equipped with a stir bar
was charged with [Ir(ppy)2dtbbpy]PF6 (4.7 mg, 0.005 mmol, 0.01 equiv), sulfamide (0.5 mmol,
1.0 equiv), and if solid, (hetero)aryl bromide (0.75 mmol, 1.5 equiv). The vial was then transferred
into a nitrogen-filled glovebox where it was charged with nickel (II) bromide glyme (NiBr2•glyme,
7.7 mg, 0.025 mmol, 0.05 equiv), and partially solubilized upon syringe addition of anhydrous
acetonitrile (2 mL). The mixture turned bright green-blue. The microwave tube was sealed with a
crimp cap containing a Teflon lined septum and removed from the glovebox. If liquid, the
(hetero)aryl bromide (0.75 mmol, 1.5 equiv) was added by syringe to the mixture, followed by
DBU (1.5 mmol, 3.0 equiv). Upon addition, the mixture turned dark yellow. The reaction mixture
was placed in front of two 34W blue LED lamps, approximately 5–10 cm away from each light
source. The reaction mixtures were then stirred at ~1000 rpm with cooling via air circulation for
at least 24 hours (temperatures were found to stay below 30 °C). The reaction mixtures were then
removed from irradiation and the caps were removed. The reaction mixtures were diluted with
ethyl acetate (ca. 25 mL) and transferred to a separatory funnel. The mixture was washed with 1M
aqueous hydrochloric acid (ca. 25 mL). The aqueous phase was then extracted with additional
ethyl acetate (ca. 2 x 10 mL). The combined organic phases were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The resulting residue was then purified by silica
gel flash chromatography eluting with the indicated solvent system. Deviations from the general
procedure are noted below.
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Photochemically driven, nickel-catalyzed N-(hetero)arylation of sulfamides with dtbbpy in
ethanol:
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General Procedure D. A 10 mL microwave tube (CG-4920-01) equipped with a stir bar
was charged with [Ir(ppy)2dtbbpy]PF6 (4.7 mg, 0.005 mmol, 0.01 equiv), sulfamide (0.5 mmol,
1.0 equiv), dtbbpy (5.4 mg, 0.02 mmol, 0.04 equiv), and if solid, (hetero)aryl bromide (0.75 mmol,
1.5 equiv). The vial was then transferred into a nitrogen-filled glovebox where it was charged with
nickel (II) bromide glyme (NiBr2•glyme, 15.6 mg, 0.05 mmol, 0.1 equiv). The microwave tube
was sealed with a crimp cap containing a Teflon lined septum and removed from the glovebox.
The microwave tube was charged with ethanol (200 proof abs., 2.0 mL) by syringe. If liquid, the
(hetero)aryl bromide (0.75 mmol, 1.5 equiv) by syringe to the solution, followed by DBU (1.5
mmol, 3.0 equiv). Upon addition, the solution turned dark yellow in color. The reaction mixture
was placed in front of two 34W blue LED lamps, approximately 5–10 cm away from each light
source. The reaction solution was then stirred at ~1000 rpm with cooling via air circulation for 24
hours (temperatures were found to stay below 30 °C). The reaction solution was then removed
from irradiation and the cap was removed. The reaction solution was diluted with ethyl acetate (ca.
25 mL) and transferred to a separatory funnel. The organic phase was washed with 1M aqueous
hydrochloric acid (ca. 25 mL). The aqueous phase was then extracted with additional ethyl acetate
(ca. 2 x 10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The resulting residue was then purified by silica gel flash
chromatography eluting with the indicated solvent system. Deviations from the general procedure
are noted below.
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N-(4-(trifluoromethyl)phenyl)morpholine-4-sulfamide (3a). Prepared from 1a (0.5 mmol,
1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general procedure C.
The product was obtained as a yellow solid (155 mg, ≥98% yield) after silica gel column
chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). 1H NMR (500 MHz, CDCl3)
δ 7.58 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.28 (t,
J = 4.7 Hz, 4H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 140.4 (s), 124.4 (q, J = 271.6 Hz), 126.8
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(q, J = 3.7 Hz), 126.3 (q, J = 32.5 Hz), 118.9 (s), 66.2 (s), 46.5 (s) ppm. F NMR (376 MHz,
CDCl3) δ –62.20 (s) ppm. IR (neat) ν 3279 (br), 2863 (w), 1617 (w), 1521 (w), 1456 (w), 1404
(w), 1321 (s), 1298 (m), 1263 (m), 1237 (w), 1153 (s), 1107 (s), 1067 (s), 1015 (m), 939 (w), 837
(m), 734 (m), 659 (m), 637 (m), 621 (m), 593 (m), 571 (m), 524 (m), 507 (m), 469 (m) cm-1. TLC
Rf = 0.58 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C11H14F3N2O3S+: 311.0672;
Found 311.0676.
N-(4-(tert-butyl)phenyl)morpholine-4-sulfamide (3b). Prepared from 1a (0.5 mmol, 1.0
equiv) and bromo-4-(tert-butyl)benzene (0.75 mmol, 1.5 equiv) following general procedure D.
The product was obtained as a white solid (133 mg, 89% yield) after silica gel column
chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). Prepared from 1a (1.0 mmol,
1.0 equiv) and bromo-4-(tert-butyl)benzene (1.5 mmol, 1.5 equiv) following general procedure D,
using double the amount of all reagents. The product was obtained as a white solid (243.7 mg,
82% yield) after silica gel column chromatography hexanes:EtOAc (gradient elution 3:2 to 1:4).
1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.8 (s, 1H), 3.66
(t, J = 4.8 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 1.30 (s, 9H) ppm. 13C{1H} NMR (126 MHz, CDCl3)
δ 148.3, 134.3, 126.4, 120.7, 66.3, 46.5, 34.5, 31.5 ppm. IR (neat) ν 3183 (w), 2963 (w), 2917 (w),
2861 (w), 1613 (w), 1512 (m), 1447 (m), 1400 (w), 1364 (m), 1349 (m), 1332 (w), 1331 (w), 1262
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(m), 1239 (w), 1193 (w), 1156 (s), 1127 (m), 1106 (m), 1077 (m), 1068 (m), 1017 (m), 947 (m),
911 (m), 852 (m), 843 (m), 837 (m), 819 (m), 737 (m), 712 (m), 638 (w), 614 (m), 588 (s), 548
(m), 522 (s), 467 (m), 425 (w), 410 (w) cm-1. TLC Rf = 0.66 in 1:1 hexanes:EtOAc. HRMS (ESI)
m/z: [M+H]+ Calcd for C14H23N2O3S+: 299.1424; Found 299.1431.
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N-(4-cyanophenyl)morpholine-4-sulfamide (3c). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 4-bromobenzonitrile (0.75 mmol, 1.5 equiv) following general procedure C. The product was
obtained as a white solid (121 mg, 92% yield) after silica gel column chromatography using
hexanes:EtOAc (gradient elution, 9:1 to 6:4). The obtained spectrum matched that reported in the
literature.16a 1H NMR (400 MHz, DMSO-d6) δ 10.70 (br s, 1H), 7.77 (dd, J = 1.3 Hz, 9.0, 2H),
7.31 (dd, J = 1.3 Hz, 8.9, 2H), 3.55 – 3.48 (m, 4H), 3.10 – 3.05 (m, 4H) ppm. 13C{1H} NMR (126
MHz, DMSO-d6) δ 143.0, 133.6, 118.9, 118.2, 104.7, 65.3, 45.9 ppm. IR (neat) ν 3124 (w), 3061
(w), 2934 (w), 2218 (w), 1603 (w), 1507 (m), 1497 (w), 1454 (w), 1415 (w), 1364 (m), 1338 (w),
1304 (w), 1265 (m), 1240 (w), 1219 (w), 1174 (w), 1159 (m), 1127 (w), 1104 (m), 1071 (m), 943
(m), 931 (w), 904 (m), 849 (m), 837 (m), 818 (m), 803 (w), 726 (m), 642 (m), 619 (w), 581 (m),
544 (m), 526 (m), 502 (m), 425 (w) cm-1. TLC Rf = 0.33 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z:
+
[M+H]+ C11H14N3O3 : 268.0750; Found 268.0753.
N-(2-cyanophenyl)morpholine-4-sulfamide (3d). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 2-bromobenzonitrile (0.75 mmol, 1.5 equiv) following general procedure C. The product was
obtained as a white solid (95 mg, 71% yield) after silica gel column chromatography using
hexanes:EtOAc (gradient elution, 9:1 to 6:4). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz,
1H), 7.66 – 7.55 (m, 2H), 7.23 (t, J = 7.8, 1H), 6.88 (s, 1H), 3.68 (m, 4H), 3.28 (m, 4H) ppm.
13C{1H} NMR (126 MHz, CDCl3) δ 140.2, 134.4, 133.0, 124.9, 121.4 116.2, 103.8, 66.1, 46.6
ppm. IR (neat) ν 3145 (br), 2966 (w), 2921 (w), 2856 (w), 2233 (w), 2098 (w), 1598 (w), 1496
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(w), 1455 (w), 1424 (w), 1392 (w), 1359 (m), 1343 (w), 1332 (w), 1297 (w), 1262 (m), 1236 (w),
1217 (w), 1162 (m), 1122 (w), 1099 (m), 1073 (m), 1064 (m), 1019 (w), 942 (m), 908 (m), 878
(w), 841 (m), 771 (m), 753 (m), 741 (m), 716 (br), 668 (w), 639 (w), 622 (w), 579 (m), 563 (m),
556 (m), 550 (m), 524 (m), 502 (m), 473 (m), 454 (w), 425 (w) cm-1. TLC Rf = 0.44 in 1:1
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+
hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C11H14N3O3 : 268.0756; Found 268.0753.
N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-sulfamide (3e).
Prepared from 1a (0.5 mmol, 1.0 equiv) and 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane49 (0.75 mmol, 1.5 equiv) following general procedure C or D. The product was
obtained as a colorless solid after silica gel column chromatography using hexanes:acetone
(gradient elution, 4:1 to 1:4). The compound was prepared in 75% yield (136 mg) according to
general procedure C for 72 h. The compound was prepared in 86% yield (156 mg) according to
general procedure D for 72 h. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.16 (d, J =
8.2 Hz, 2H), 7.06 (s, 1H), 3.66 – 3.52 (m, 4H), 3.31 – 3.17 (m, 4H), 1.33 (s, 12H). 13C{1H} NMR
(126 MHz, CDCl3) δ 139.7, 136.3, 118.8, 84.0, 66.2, 46.5, 25.0. IR (neat) ν 3266 (br), 2977 (w),
2923 (w), 2861 (w), 1607 (m), 1453 (w), 1391 (m), 1357 (s), 1297 (m), 1262 (m), 1215 (w), 1140
(s), 1114 (m), 1091 (m), 1073 (m), 1019 (w), 941 (m), 857 (m), 828 (m), 735 (m), 719 (m), 673
(m), 656 (m), 634 (w), 622 (w), 571 (s), 522 (m), 468 (s), 450 (s), 415 (s) cm–1. TLC Rf = 0.5 in
4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C16H2610BN2O5S+: 368.1691; Found
368.1692. [M+H]+ Calcd for C16H2611BN2O5S+: 369.1655; Found 369.1666.
N-(3-chlorophenyl)morpholine-4-sulfamide (3f). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 1-bromo-3-chlorobenzene (0.75 mmol, 1.5 equiv) following general procedure C. The product
was obtained as a yellow solid (113 mg, 82% yield) after silica gel column chromatography using
hexanes:EtOAc (gradient elution, 9:1 to 1:1). 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J = 7.9, 8.0
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Hz, 1H), 7.21 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.91 (br s, 1H), 3.67 (t,
J = 4.7 Hz, 4H), 3.27 (t, J = 4.6 Hz, 4H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 138.4, 135.3,
130.6, 125.0, 120.1, 118.1, 66.2, 46.5 ppm. IR (neat) ν 3278 (br), 2977 (w), 2861 (w), 1595 (w),
1509 (w), 1477 (w), 1453 (w), 1399 (w), 1341 (m), 1298 (w), 1261 (m), 1216 (w), 1154 (s), 1113
(m), 1074 (m), 1026 (w), 998 (w), 935 (s), 850 (w), 778 (w), 733 (s), 703 (m), 680 (m), 621 (m),
592 (w), 562 (m), 522 (s), 477 (w), 445 (w), 420 (w) cm-1. TLC Rf = 0.53 in 1:1 hexanes:EtOAc.
HRMS (ESI) m/z: [M+H]+ Calcd for C10H14ClN2O3S+: 277.0408; Found 277.0416.
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N-(6-chloropyridin-2-yl)morpholine-4-sulfamide (3g). Prepared from 1a (0.5 mmol, 1.0
equiv) and (0.75 mmol, 1.5 equiv). The product was obtained as an off-white after silica gel column
chromatography using hexanes:EtOAc (gradient elution, 1:0 to 4:1). The compound was prepared
in 78% yield (108 mg) according to general procedure C (24 h). The compound was prepared in
11% yield (8 mg) according to general procedure D (24 h), and byproduct S1 was obtained in 8%
yield (12 mg). 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 7.8 Hz, 1H), 7.15 (d, J = 8.1 Hz,
1H), 7.04 (d, J = 7.8 Hz, 1H), 3.77 – 3.59 (m, 4H), 3.41 – 3.16 (m, 4H). 13C{1H} NMR (126 MHz,
CDCl3) δ 150.9, 150.0, 141.0, 119.5, 109.9, 66.3, 46.6. IR (neat) ν 3156 (w), 2917 (w), 2861 (w),
1723 (w), 1569 (w), 1464 (w), 1447 (w), 1395 (w), 1345 (w), 1287 (w), 1259 (w), 1163 (w), 1151
(m), 1124 (w), 1104 (m), 1065 (m), 1018 (w), 987 (w), 942 (m), 925 (w), 967 (w), 835 (w), 789
(m), 732 (w), 709 (w), 693 (m), 643 (w), 602 (w), 561 (m), 430 (w), 414 (w) cm-1. TLC Rf = 0.58
in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C9H13ClN3O3S+ 278.0361; Found
278.0364.
Characterization data for byproduct S1: N-(6-(ethoxy)pyridine-2-yl)morpholine-4-
sulfamide. 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.45
(d, J = 8.1 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.77 – 3.54 (m, 4H), 3.40 – 3.17 (m, 4H), 1.37 (t, J
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= 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.3, 148.8, 140.9, 105.9, 103.7, 66.3, 62.2,
46.6, 14.7. IR (neat) ν 3257 (w), 2978 (w), 2860 (w), 1599 (m), 1579 (s), 1440 (s), 1388 (m), 1329
(m), 1299 (m), 1260 (m), 1247 (m), 1224 (w), 1150 (s), 1111 (s), 1072 (m), 1042 (m), 1014 (m),
942 (m), 790 (m), 725 (m), 623 (m), 569 (2), 524 (w) cm-1. TLC Rf = 0.61 in 4:1 hexanes:EtOAc.
HRMS (ESI) m/z: [M+H]+ Calcd for C11H18N3O4S+ 288.1013; Found 288.1013.
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N-(4-(trifluoromethyl)phenyl)-N’,N’-dimethyl sulfamide (3h). Prepared from 1b (0.5
mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general
procedure C. The product was obtained as a pale yellow solid (133 mg, ≥98% yield) after silica
1
gel column chromatography using hexanes:acetone (single eluent, 1:1). H NMR (400 MHz,
CDCl3) δ 9.14 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 2.83 (s, 6H). 13C{1H}
NMR (126 MHz, CDCl3) δ 143.9, 127.6 (q, J = 4.2 Hz), 125.8 (q, J = 270.7 Hz), 125.4 (q, J = 31.8
19
Hz), 119.6, 38.6. F NMR (376 MHz, CDCl3) δ –62.45. IR (neat) ν 3244 (br), 3107 (w), 2962
(br), 2923 (br), 2854 (br), 1694 (w), 1617 (w), 1603 (w), 1590 (w), 1544 (w), 1522 (w), 1467 (m),
1403 (w), 1390 (w), 1369 (w), 1360 (w), 1321 (m), 1298 (m), 1259 (m), 1191 (w), 1141 (s), 1111
(s) 1067 (m), 1016 (m), 954 (m), 922 (m), 856 (m), 836 (m),803 (m), 779 (w), 771 (w), 755 (w),
711 (s), 645 (m), 628 (m), 594 (s), 573 (m), 560 (m), 528 (m), 509 (m), 499 (m), 490 (m), 465 (m),
452 (w), 433 (w), 413 (m), 401 (m) cm-1. TLC Rf = 0.66 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z:
[M+H]+ Calcd for C9H12F3N2O2S+: 269.0566; Found 269.0572.
N-(4-(trifluoromethyl)phenyl)-N,N’,N’-trimethyl sulfamide (3i). Prepared from 1e (0.5
mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following a general
procedure C, using a reduced quantity of DBU (0.25 mmol, 0.5 equiv). The product was
obtained as a bright yellow solid (32 mg, 23% yield) after silica gel column chromatography using
hexanes:EtOAc (single eluent, 4:1). Starting material 1e was recovered as a yellow oil (48 mg,
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70% recovery). Without a reduction in the quantity of DBU, a trace amount of product was
observed by TLC, but was not isolable; the starting material 1e, recovered as a yellow oil (12 mg,
17% recovery), was the only isolable constituent. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4
13
Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 3.31 (s, 3H), 2.82 (s, 6H) ppm. C{1H} NMR (126 MHz,
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CDCl3) δ 146.0, 128.4 (q, J = 32.7 Hz), 126.4 (q, J = 3.6 Hz), 125.3, 124.0 (q, J = 272.1 Hz), 39.1,
38.4 ppm. 19F NMR (376 MHz, CDCl3) δ –62.43 ppm. IR (neat) ν 3307 (br), 2959 (w), 2922 (w),
2852 (w), 1629 (w), 1458 (w), 1415 (w), 1316 (m), 1260 (w), 1185 (w), 1144 (m), 1078 (m), 1053
(m), 953 (m), 835 (m), 699 (m), 579 (w), 513 (m), 428 (w), 403 (w) cm-1.TLC Rf = 0.61 in 1:1
hexanes:acetone. HRMS (ESI) m/z: [M+H]+ Calcd for C10H14F3N2O2S+: 283.0723; Found
283.0723.
tert-butyl pentyl(N-(4-(trifluoromethyl)phenyl)sulfamoyl)carbamate (3j). Prepared from 1c
(0.5 mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general
procedure C. The product was obtained as an off-white solid (164 mg, 80% yield) after silica gel
column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:4). 1H NMR (400 MHz,
acetone-d6) δ 9.25 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 3.60 (t, J = 7.4 Hz,
2H), 1.46 (s, 9H), 1.39 (m, 2H), 1.22 (m, 2H), 1.14 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). C{1H}
13
NMR (126 MHz, acetone-d6) δ 152.1, 141.8, 127.5 (q, J = 3.9 Hz), 127.4 (q, J = 32.9 Hz), 124.4
(q, J = 270.7 Hz), 122.4, 84.5, 49.3, 30.0, 29.4, 28.2, 23.0, 14.3. 19F NMR (376 MHz, acetone-d6)
δ –62.46. IR (neat) ν 3244 (br), 3108 (br), 3041 (br), 2959 (w), 2918 (br), 2852 (w), 2788 (br),
1890 (w), 1616 (w), 1602 (w), 1589 (w), 1544 (m), 1520 (m), 1467 (m), 1451 (m), 1389 (m), 1370
(m), 1360 (m), 1324 (s), 1297 (m), 1288 (m), 1258 (m), 1232 (m), 1191 (m), 1175 (m), 1160 (m),
1141 (s), 1111 (s), 1067 (s), 1018 (m), 987 (w), 953 (m), 930 (m), 921 (m), 859 (m), 833 (m), 803
(m), 779 (m), 771 (m), 713 (s), 686 (m), 644 (s), 627 (m), 595 (s), 570 (m), 560 (m), 528 (m), 508
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(m), 498 (m), 490 (m), 470 (m), 464 (m), 452 (m), 433 (m), 417 (m), 401 (m) cm-1. TLC Rf = 0.56
in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H25F3N2O4S•Na+: 433.1379;
Found 433.1382.
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N-(thiophen-3-yl)morpholine-4-sulfamide (3k). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 3-bromothiophene (0.75 mmol, 1.5 equiv) in ethanol according to general procedure C. The
product was obtained as a purple oil (46 mg, 37% yield) after silica gel column chromatography
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using hexanes:acetone (gradient elution, 4:1 to 1:4). 1a was recovered (36 mg, 43% yield). H
NMR (400 MHz, CDCl3) δ 7.33 – 7.25 (m, 1H), 7.03 (s, 1H), 6.97 (d, J = 5.1 Hz, 1H), 6.39 (s,
1H), 3.68 – 3.49 (m, 4H), 3.28 – 3.10 (m, 4H). 13C{1H} NMR (126 MHz, CDCl3) δ 134.7, 126.1,
123.1, 113.6, 66.4, 46.6. IR (neat) ν 3279 (w), 2922 (w), 1562 (w), 1446 (w), 1350 (m), 1264 (w),
1171 (s), 1108 (w), 1005 (m), 914 (s), 783 (m), 585 (w), 550 (s) cm–1. TLC Rf = 0.35 in 4:1
+
hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C8H12N2O3S2 : 249.0362; Found 249.0361.
N-(3-methoxyphenyl)morpholine-4-sulfamide (3l). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 3-bromoanisole (0.75 mmol, 1.5 equiv) following general procedure D. The product was
obtained as a white solid (95 mg, 70% yield) after silica gel column chromatography using
hexanes:EtOAc (gradient elution, 9:2 to 1:1). 1H NMR (500 MHz, CDCl3) δ 7.21 (dd, J = 7.8, 8.1
Hz, 1H), 7.02 (br s, 1H), 6.70 (s, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 3.79 (s,
1H), 3.65 (t, J = 4.5 Hz, 4H), 3.25 (t, J = 4.5 Hz, 4H). 13C{1H} NMR (126 MHz, CDCl3) δ 160.6,
138.3, 130.3, 112.5, 110.2, 106.4, 66.3, 55.5, 46.5. IR (neat) ν 3202 (br), 2969 (w), 2922 (w), 2857
(w), 1609 (w), 1591 (w), 1507 (w), 1482 (w), 1452 (w), 1410 (w), 1347 (m), 1332 (w), 1300 (w),
1281 (m), 1262 (m), 1216 (w), 1195 (w), 1178 (w), 1168 (w), 1145 (m), 1126 (w), 1106 (m), 1075
(m), 1067 (m), 1053 (m), 998 (w), 944 (m), 930 (m), 868 (w), 854 (m), 841 (m), 768 (m), 716 (m),
685 (m), 642 (w), 617 (w), 574 (m), 549 (m), 524 (m), 456 (w) cm-1. TLC Rf = 0.41 in 1:1
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hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C11H16N2O4S+H+: 273.0904; Found
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273.0909.
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N-(4-methoxyphenyl)morpholine-4-sulfonamide (3m). Prepared from 1a (0.5 mmol, 1.0
equiv) and 4-bromoanisole (0.75 mmol, 1.5 equiv) following general procedure D. The product
was obtained as an yellow solid (88 mg, 66% yield) after silica gel column chromatography using
hexanes:EtOAc (gradient elution, 10:0 to 1:1). 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 8.9 Hz, 2H), 6.43 (br s, 1H), 3.80 (s, 3H), 3.66 – 3.64 (m, 4H), 3.22 – 3.20 (m,
4H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.8, 129.3, 124.7, 114.6, 66.2, 55.5, 46.5. IR (neat) ν
3281 (br), 3015 (w), 2978 (w), 2914 (w), 2859 (w), 1609 (w), 1507 (m), 1469 (w), 1451 (m), 1400
(w), 1343 (m), 1332 (m), 1303 (w), 1292 (w), 1260 (m), 1246 (m), 1214 (m), 1184 (m), 1157 (m),
1109 (m), 1074 (m), 1069 (m), 1027 (m), 934 (m), 927 (m), 912 (m), 856 (w) 850 (m), 819 (m),
768 (w), 732 (m), 629 (m), 592 (m), 545 (m), 518 (m), 478 (m), 450 (m), 424 (w), 410 (w) cm-1.
TLC Rf = 0.41 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C11H17N2O4S+:
273.0904; Found 273.0909.
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N-(6-chloropyridin-3-yl)morpholine-4-sulfamide (3n). Prepared from 1a (0.5 mmol, 1.0
equiv) and 3-bromo-6-chloropyridine (0.75 mmol, 1.5 equiv). The product was obtained as an off-
white solid after silica gel column chromatography using hexanes:EtOAc (gradient elution, 1:0 to
4:1). Prepared in 45% yield (62 mg) according to general procedure C (24 h) and byproduct S2
was obtained in 8% yield. Prepared in 78% yield (108 mg) according to general procedure D (24
h). 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.9 Hz, 1H), 7.61 (dd, J = 8.6, 2.9 Hz, 1H), 7.32 (d,
J = 8.6 Hz, 1H), 6.66 (s, 1H), 3.76 – 3.55 (m, 4H), 3.32 – 3.11 (m, 4H). 13C{1H} NMR (126 MHz,
CDCl3) δ 147.4, 141.7, 133.2, 131.0, 124.8, 66.2, 46.6. IR (neat) ν 3107 (w), 2921 (w), 2860 (w),
1576 (w), 1460 (m), 1376 (w), 1327 (m), 1297 (w), 1262 (m), 1226 (w), 1157 (m), 1111 (m), 1072
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The Journal of Organic Chemistry
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(m), 1020 (w), 938 (m), 835 (m), 720 (w), 637 (m), 579 (m), 527 (m), 480 (w), 440 (w), 418 (w)
cm-1. TLC Rf = 0.37 in 8:2 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C9H13ClN3O3S-
+ 278.0361; Found 278.0366.
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Characterization data for byproduct S2: N-(5-bromopyridine-2-yl)morpholine-4-
sulfamide. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.7, 2.0 Hz, 2H),
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7.24 (s, 1H), 3.86 – 3.57 (m, 4H), 3.39 – 3.19 (m, 4H). C{1H} NMR (126 MHz, CDCl3, –2 x
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C ) δ 150.1, 141.5, 113.8, 66.2, 46.5. IR (neat) ν 3101 (w), 3027 (w), 2964 (w), 1577 (w), 1498
Ar
(w), 1456 (m), 1377 (m), 1339 (m), 1295 (w), 1281 (w), 1262 (m), 1218 (w), 1153 (m), 1140 (m),
1112 (m), 1074 (m), 1013 (w), 942 (m), 824 (w), 717 (w), 684 (w), 645 (w), 620 (m), 578 (m),
527 (w), 515 (w), 471 (w) cm-1. TLC Rf = 0.49 in 8:2 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]+
Calcd for C9H13BrN3O3S+ 321.9856; Found 321.9854.
N-(pyrimidin-5-yl)morpholine-4-sulfamide (3o). Prepared from 1a (0.5 mmol, 1.0 equiv)
and 5-bromopyrimidine (0.75 mmol, 1.5 equiv) following general procedure D. The product was
obtained white solid (93 mg, 77% yield) after silica gel column chromatography using
hexanes:EtOAc (1:4). 1H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.91 (s, 1H), 8.63 (s, 2H),
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3.57 (t, J = 4.6 MHz, 4H), 3.12 (t, J = 4.6 MHz, 4H). C{1H} NMR (126 MHz, DMSO-d6)) δ
153.1, 147.2, 134.2, 65.4, 45.9. IR (neat) ν 3114 (br), 3076 (br), 2959 (w), 2924 (br), 2855 (w),
2664 (w), 1575 (br), 1520 (m), 1453 (w), 1438 (m), 1418 (m), 1362 (m), 1325 (m), 1313 (m), 1300
(m), 1282 (m), 1271 (m), 1264 (m), 1216 (w), 1204 (m), 1159 (m), 1146 (m), 1128 (m), 1117 (m),
1106 (m), 1080 (m), 1071 (m), 1043 (m), 935 (br), 923 (m), 902 (m), 848 (m), 720 (m), 711 (s),
655 (m), 632 (s), 619 (m), 567 (s), 524 (s), 466 (m), 426 (w), 414 (m) cm-1. TLC Rf = 0.20 in 1:4
Hexanes/EtOAc. HRMS (ESI) m/z: [M+H]+ Calcd for C8H13N4O3S+ 245.0703; Found 245.0709.
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