Sulfonyl Azides as Precursors in Ligand-Free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides

Article abstract of DOI:10.1021/acs.joc.5b02755

(Chemical Equation Presented). An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl₂, and CO gas, released ex situ from Mo(CO)₆, were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.

Full text of DOI:10.1021/acs.joc.5b02755

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Featured Article
Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis
of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides
Shiao Y Chow, Marc Y. Stevens, and Luke R. Odell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02755 • Publication Date (Web): 11 Mar 2016
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Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl
Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides
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Shiao Y. Chow,a Marc Y. Stevens,a Luke R. Odella*
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Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
To whom correspondence should be addressed. Luke Odell, Phone: +46ꢀ18ꢀ4714297, Fax: +46ꢀ18ꢀ
4714474. Eꢀmail: luke.odell@orgfarm.uu.se
Graphical Abstract
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Abstract
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An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a
palladiumꢀcatalyzed carbonylation protocol has been developed. Using a twoꢀchamber system,
sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)6, were assembled to generate
sulfonyl isocyanates in situ and alcohols and aryl amines were exploited as nucleophiles to afford a
broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of
substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also
developed.
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Introduction
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Sulfonylꢀcontaining moieties (sulfonamides, sulfonyl carbamates, and sulfonyl ureas) are an important
class of functional group, particularly in pharmaceuticals due to their hydrogen bonding capabilities,
structural rigidity and potential role as nonꢀcleavable amide surrogates (Figure 1).1 Conventionally,
sulfonyl carbamates (also useful Nꢀnucleophiles for the Mitsunobu reaction)2 are synthesized via Nꢀ
acylation of a sulfonamide with a preꢀactivated carbonic acid derivative (chloroformate or anhydride)
in the presence of a strong base, or in milder conditions using an acylating catalyst (i.e. DMAP).3
Very recently, the preparation of sulfonyl carbamates from sulfamoyl inner salts and organometallic
nucleophiles was reported.4 Sulfonyl ureas are commonly synthesized from the condensation of aryl
sulfonamides with phenoxycarbamates5 or isocyanates6 or alternatively by aminolysis of sulfonyl
carbamates with alkyl7 or (hetero)arylamines.8
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Figure 1. Biologically active sulfonyl group containing compounds
An alternate and arguably more divergent synthesis of sulfonamides, sulfonyl carbamates and sulfonyl
ureas is via the reaction of a sulfonyl isocyanate intermediate with an appropriate nucleophile
(Scheme 1).9 Unfortunately, the utility of this synthetic manifold is currently hampered by the limited
commercial availability of sulfonyl isocyanates and a paucity of simple, effective and environmentally
friendly methods for their preparation. Sulfonyl isocyanates are typically prepared by reacting
sulfonyl ureas or sulfonamides and alkyl isocyanates with phosgene10 or oxalyl chloride followed by
heating in oꢀdichlorobenzene [Eq. (1)].9a Recently, Jiao et al. reported a mild and facile palladiumꢀ
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catalyzed synthesis of aryl carbamates via aryl isocyanate intermediates by assembling inexpensive
aryl azides, carbon monoxide (CO), and alcohols without the use of costly and environmentally
unfriendly reagents [Eq. (2)].11 Accordingly, we proposed that sulfonyl isocyanates could also be
generated in situ from sulfonyl azides and CO via palladiumꢀcatalyzed carbonylation12 in a oneꢀpot,
cascade reaction with amines or alcohols to afford sulfonyl ureas and sulfonyl carbamates.
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Scheme 1. Synthesis of sulfonamides, sulfonyl carbamates and sulfonyl ureas.
The sulfonyl azide functional group has been the subject of intense research over the past decade and
has been reported to undergo a wealth of diverse and unique transformations13 (e.g cycloaddition,
amidation, amination) to form sulfonylꢀcontaining pharmacophores, such as 1,2,3ꢀtriazoles, amidates,
amidines and amides.13b,14 More importantly, they can be readily accessed from primary sulfonamides
via a diazotransfer process or by treatment of sulfonyl chlorides with sodium azide.13a The conversion
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of sulfonyl azides to sulfonyl ureas via a carbonylative process15 has been reported by Långström et
al., but this method requires the use of expensive rhodium catalysts and specialized high pressure
equipment, limiting its synthetic utility. In addition, the carbonylative synthesis of sulfonyl
carbamates from sulfonyl azides has, to the best of our knowledge, not yet been reported. We report
herein a practical, divergent and environmentally benign ligandꢀfree palladiumꢀcatalyzed synthesis of
sulfonyl carbamates and sulfonyl ureas from sulfonyl azides via in situ generation of sulfonyl
isocyanates and subsequent nucleophilic attack by alcohols or aryl amines [Eq. (3)]. A modified twoꢀ
chamber vialꢀsystem16 originally disclosed by Skrydstrup et al.17 was employed, using Mo(CO)6 as an
ex situ CO releasing source (Chamber A) for the carbonylative transformations (Chamber B). We also
report an unexpected direct synthesis of substituted sulfonamides from sulfonyl azides and alkyl
amine nucleophiles [Eq. (3)].
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Results and Discussion
The initial study commenced with the treatment of p-tolyl sulfonyl azide (1a) with butylamine (2
equiv), 5 mol% PdCl2, and MoCO6 as the ex situ CO generating source. Formation of desired sulfonyl
urea 2a’ was not observed (ESIꢀMS analysis), and unexpectedly, the substituted sulfonamide 2a was
obtained in 54% yield (Scheme 2). To delineate the mechanism of the unexpected reaction, 1a and
butylamine were subjected to a oneꢀpot reaction in the absence of metal catalyst and carbon monoxide
(Scheme 2, Table 1, Entry 1), furnishing 2a in 50% yield. It was hypothesized that 2a was the product
of a direct nucleophilic attack on 1a by butylamine, analogous to the formation of amides from acyl
azides and aminea via Nꢀacylation18 employing a substitution mechanism similar to that observed for
the reaction of sulfonyl chlorides.
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Scheme 2. Unexpected formation of substituted sulfonamide 2a.
The synthesis of substituted sulfonamides using sulfonyl azides as precursors has been previously
reported by Chang and coꢀworkers, however the preparation involved a multiꢀcomponent copperꢀ
catalyzed hydrative reaction between sulfonyl azides, terminal alkynes and water in the presence of an
amine base to afford the resulting sulfonamides.19 Cyclic sulfonamides (benzosultams) have also been
prepared via intramolecular nitrene insertion of CꢀH bonds with sulfonyl azides using cobalt (II)
catalysts.20 In previous reports, sulfonyl azides have also been used as diazotransfer agents in the
presence of amines (and other CHꢀacid compounds such as activated esters, betaꢀketoesters and
ketosulfones), and formation of sulfonamides was not observed.21 Indeed, amineꢀcontaining substrates
led to decreased yields in diazotransfer reactions between sulfonamides and an imidazoleꢀ1ꢀsulfonyl
azide salt, possibly due to nitrogen interaction with the S(VI) center.13a The catalystꢀfree direct
nucleophilic substitution reaction between sulfonyl azides and amines represents an attractive and
simple preparation of substituted sulfonamides and there are only a few rare examples of this type of
reaction reported in the literature.22 Notably, this method has great potential for the selective lateꢀstage
functionalization of primary sulfonamide derivatives, which can be readily transformed into sulfonyl
azides via diazotransfer.13a,14b,22d Subsequent optimization studies were then carried out (Table 1) and
it was discovered that the reaction proceeded smoothly at ambient temperature, polar solvents (DMA
> MeCN > THF > MeOH > toluene) were favored and the addition of TEA as base afforded a drastic
improvement in efficiency and 2a was isolated in 84% yield.
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Table 1. Optimization of the direct synthesis of 2a
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entry
solvent
temp (oC)
yielda
1
2
3
4
5
DMA
DMA
THF
MeCN
MeOH
Toluene
ꢀ
75
rt
rt
rt
rt
rt
rt
rt
50%
55%
35%
37%
31%
28%
21%
84%
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8b
DMA
aIsolated yield. b1 equiv TEA was added.
Using the optimized protocol, the substrate scope in respect to the amine component was investigated
(Table 2). The reaction performed well with primary and unhindered secondary amines affording
moderate to excellent yields of sulfonamides 2b–2d. Hindered secondary amines were found to react
less efficiently and returned decreased yields due to unfavorable steric effects resulting in the
competing decomposition of the azide starting material (2e, 2f, 33–36%). Notably, good
chemoselectivity was observed with allylamine and propargylamine with no traces of sideꢀproducts
being observed by ESIꢀMS analysis (2g, 2h). Heterocyclic and benzylic amines reacted smoothly to
give the desired sulfonamide in moderate yields (2i, 2j). However, amino acids performed poorly as
substrates, with a low yield obtained for glycine methyl ester (2k) and only traces of product were
observed for bulkier amino acids (2l, 2m). This is most likely due to reduced nucleophilicity as a
result of the electronꢀwithdrawing character of the adjacent αꢀcarboxyl group. However, this effect
was offset by the addition of a methylene group, demonstrated by a substantial increase in isolated
yield (61%) for the βꢀalanineꢀderivative 2n. Additionally, no reaction was observed when employing
poorly nucleophilic aniline as a substrate (2o).
Next, the reaction scope was extended to include different sulfonyl azides and substrates carrying
electronꢀdonating or electronꢀwithdrawing groups in the paraꢀposition were found to be wellꢀtolerated
(2p–2r). The lower yield observed in 2r was due to instability of the sulfonyl azide precursor, despite
the reaction being carried out at room temperature. The presence of an ortho substituent was also
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compatible with the reaction and 59% of desired product 2s was obtained. Interestingly, no reaction
was observed for alkyl sulfonyl azide substrates, indicating a requirement for an aryl group on the
sulfur atom (2t, 2u). Electronꢀrich heterocyclic azides afforded moderate yields of the desired
products (2v, 2w) and the diuretic furosemide was chemoselectively transformed into sulfonamide
analogue 2x in modest yield.
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Table 2: Synthesis of various sulfonamides from different sulfonyl azides and aminesa
2a, 84%
2e, 36%b
2i, 64%
2b, 86%
2d, 90%
2h, 58%
2c, 45%
2g, 59%
2f, 33%b
2j, 64%
2k, 19%c
2l, tracec
2p, 70%
2o, no reaction
2m, tracec
2q, 85%
2n, 61%
2t, no reaction
2s, 59%
2r, 41%(93%)d
2v, 49%
2w, 52%
2u, no reaction
2x, 23%
aIsolated yield. Reaction conditions: Sulfonyl azide (0.25 mmol, 1.0 equiv), amine (0.50 mmol, 2 equiv) and Et3N (0.25
b
c
mmol, 1.0 equiv) in DMA (1 mL). 4 equiv amine, 6 equiv Et3N for 5 days. 4 equiv amine, 6 equiv Et3N for 4 days.
dReaction run without Et3N.
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Table 3. Optimization of the carbonylative synthesis of 3a
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entry PdCl2 [mol%]
aniline [equiv]
yielda
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3
5%
5%
2%
2
1
1
73%
76%
74%
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aIsolated yield
Based on the lack of formation of sulfonamide 2o from 1a and aniline, we hypothesized that the
palladiumꢀcatalyzed carbonylative transformation to corresponding sulfonyl urea 3a would not be
hampered by the competing nucleophilic substitution reaction. Accordingly, the synthesis of 3a was
explored using 1a, excess aniline, 5 mol% PdCl2, and MoCO6 as the CO source (Table 3).
Gratifyingly, the reaction afforded 3a in an isolated yield of 73%. Significant formation of
diphenylurea from aniline and CO was also observed and this was circumvented by using a
stoichiometric amount of aniline. The amount of catalyst was also reduced to 2 mol% without
concomitant reduction in yield. In addition, the product was purified as the TEA salt as sulfonyl ureas
are prone to undergo acidꢀ or selfꢀcatalyzed hydrolysis.23 With these conditions in hand, we next
studied the scope and limitations of the reaction (Table 4). Paraꢀ and orthoꢀsubstituted anilines
carrying electronꢀdonating or electronꢀwithdrawing substituents gave the corresponding urea products
in moderate to excellent yields (3b–3h). Notably, this methodology enables the isocyanateꢀfree
preparation of antitumor agent 3d.1d Arylsulfonyl azides with electronꢀdonating or electronꢀ
withdrawing paraꢀsubstituents also performed well and returned excellent yields (3i, 3j, 90% and
87%, respectively). Heteroarylsulfonyl azides underwent smooth conversion to the corresponding
sulfonyl ureas, albeit in slightly decreased yields (3k–3l). Finally, due to the observed formation of
primary sulfonamide sideꢀproducts, resulting from thermal decomposition of arylsulfonyl azide
substrates, the sulfonyl isocyanate intermediates or the sulfonyl urea products, lower reaction
temperatures (30–50 oC) were employed in the preparation of sulfonyl ureas 3e, 3f and 3i–3l.
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Table 4: Synthesis of sulfonyl ureas from different sulfonyl azides and aryl aminesa
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3b, 87%b
3c, 67%
3g, 45%
3d, 54%
3h, 31%
3l, 72%d
3a, 74%
3e, 62%b
3i, 90%c
3f, 50%b
3j, 87%c
3k, 78%c
aIsolated yield. Reaction conditions: Chamber A: Mo(CO)6 (0.15 mmol, 0.6 equiv) and DBU (0.38 mmol, 1.5 equiv) in
DMA (2 mL). Chamber B: Sulfonyl azide (0.25 mmol, 1.0 equiv), amine (0.25 mmol, 1.0 equiv), PdCl2 (0.006 mmol,
0.02 equiv) in DMA (2 mL).b40 oC. c50 oC. d30 oC.
Encouraged by the above results, we next set about exploring the use of alcohols as nucleophiles to
generate sulfonyl carbamates from sulfonyl azides. Our studies commenced with the reaction between
1a, excess butanol, 5 mol% PdCl2, and MoCO6 at 75 °C for 20 h (Table 5). Rewardingly, the reaction
proceeded smoothly to afford the desired sulfonyl carbamate 4a in 82% isolated yield. The catalyst
loading could again be reduced to 2 mol% without affecting the reaction outcome, although lowering
the temperature to 50 °C led to a twoꢀfold decrease in yield.
Table 5. Optimization of the carbonylative synthesis of 4a
entry
PdCl2
[mol%]
5%
5%
2%
BuOH
[equiv]
temp [oC]
yielda
1
2
3
4
2
1
2
2
75
75
75
50
82%
45%
80%
44%
2%
aIsolated yield
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Using the optimized protocol, the alcohol substrate scope was then investigated. Primary,
secondary and tertiary alcohols were all found to be compatible substrates, affording fair to good
yields of the desired products (4b–4e, 52–76%). In the case of 4c, a oneꢀpot experiment was
attempted, but no product could be detected. The presence of an electronꢀwithdrawing trifluoromethyl
substituent gave a reduction in yield, as did an sp or sp2 carbon β to the alcohol moiety, presumably
due to decreased nucleophilicity (4f–4l). Disappointingly, no traces of the desired product were
observed when phenol was used as the nucleophile (4m) even with the addition of excess Et3N. The
substrate scope was also extended to include different sulfonyl azides. In line with the above results,
paraꢀsubstituted arylsulfonyl azides with electronꢀdonating or electronꢀwithdrawing substituents were
well tolerated, giving moderate to good yields of the desired products (4n–4p, 45–78%). The presence
of an ortho substituent led to a reduced yield due to steric effects (4q). The reaction was also found to
be compatible with heteroarylsulfonyl azides and the corresponding sulfonyl carbamates were
obtained in good yields (4r–4t). Finally, benzylsulfonyl azide reacted smoothly to give the desired
sulfonyl carbamate in 80% isolated yield (4u). This is in contrast to the sulfonamide formation
reaction, where the presence of a sp2 center adjacent to the sulfur atom was found to be essential for
the reaction to proceed.
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Table 6: Synthesis of sulfonyl carbamates from various sulfonyl azides and alcohols.a
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4a, 80%
4c, 73%/no reactionb
4d, 62%
4h, 45%c
4l, 42%
4b, 65%
4f, 36%
4g, 24%
4e, 76%
4i, 19%
4j, 59%
4k, 33%
4m, no reactiond
4n, 50%
4r, 63%c
4p, 78%
4t, 54%c
4o, 45%
4s, 78%c
4q, 37%
4u, 80%
aIsolated yield. Reaction conditions: Chamber A: Mo(CO)6 (0.15 mmol, 0.6 equiv) and DBU (0.38 mmol, 1.5 equiv) in
DMA (2 mL). Chamber B: Sulfonyl azide (0.25 mmol, 1.0 equiv), alcohol (0.50 mmol, 2.0 equiv), PdCl2 (0.006 mmol,
0.02 equiv) in DMA (2 mL). bOneꢀpot experiment. c50 oC. d2 equiv of Et3N added.
To investigate the mechanism of the sulfonamide formation and carbonylation reactions, isotope
labeling experiments were carried out using pꢀtolyl sulfonyl azideꢀ1ꢀ15N (15N1ꢀ1a).13a Thus, 15N1ꢀ1a
was treated with butylamine using the optimized conditions from Scheme 3. The resulting
sulfonamide product 2a (71% yield) lacked the characteristic M+1 ion expected upon incorporation of
the 15N atom. This suggests that the reaction proceeds via a direct nucleophilic substitution at the S(VI)
center with the azide anion serving as the leaving group. Moreover, the isotopic ratio was similar to
that obtained from the reaction in Table 2, indicating limited competition from potential azide
exchange or tetrazine formation processes.24 As mentioned above, the reaction of amines with
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sulfonyl azides has previously been reported to result in diazotransfer to the amine and the
development of a new and generally applicable deazidation substitution process is of significant
importance. This opens up a potentially powerful alternative synthetic route to this valuable class of
compounds from stable and readily available primary sulfonamides via selective lateꢀstage
diazotransfer13a,14b and subsequent functionalization of the sulfonyl azide intermediates.
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O
O
Et3N, DMA
S
Bu
N
Ref. 13a
H
BuNH2
71%
2a
O
O
N
S
N
N
Mo(CO)6
DBU, PdCl2
DMA
O
O
O
S
Bu
N
O
15H
15N1-labelled 1a
N = 15
BuOH
69%
N
15N1-4a
Scheme 3. Mechanistic investigation using 15N1ꢀlabeled 1a
15
In contrast, the reaction of N1ꢀ1a with butanol under the alkoxycarbonylation conditions in Table
6 resulted in the exclusive formation of the 15N1ꢀlabeled sulfonyl carbamate 15N1ꢀ4a in 69% yield.
This is consistent with a reaction mechanism involving the extrusion of N2 from the azide substrate.
This suggests the reaction may proceed either via a Pd(0)/Pd(II) cycle similar to other alkoxyꢀ or
aminocarbonylation reactions,25 or an oxidative Pd(II)/Pd(0) process analogous to that reported for the
synthesis of carbamates and ureas from amines.26 The latter reaction mode would require the addition
of an external oxidant to facilitate palladium reoxidation and should also lead to product formation
from a primary sulfonamide precursor. Considering that the carbonylation reaction does not require an
external oxidant and no product was observed in a control reaction using tosyl amide we believe that
the reaction operates within a Pd(0)/Pd(II) manifold. This is further supported by the successful use of
the Pd(0) catalyst Pd(PPh3)4, which afforded 4a in 59% yield using the conditions from Table 6.
Based on these results, we suggest that the palladiumꢀcatalyzed carbonylation of sulfonyl azides
occurs via the mechanism outlined in Scheme 4. Reduction of the preꢀcatalyst, by either CO or an
alcohol or amine, to an active Pd(0) species followed by addition to the sulfonyl azide generates the
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nitreneꢀpalladium complex A.27 Subsequent CO coordination and insertion gives an acyl palladium
intermediate followed by reductive elimination to afford a sulfonyl isocyanate species (B), the identity
of which was confirmed by EIꢀMS analysis. Finally, nucleophilic attack on the sulfonyl isocyanate by
an alcohol or amine nucleophile gives the sulfonyl carbamate (3) or sulfonyl urea (4) products.
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PdCl2
3 or 4
1a
Pd(0)Ln
R-OH or
ArNH2
N2
O
O
S
O
C
N
S
LnPd
N
O
O
PdLn
B
A
CO
O
C
O
L Pd
N
S
O
Scheme 4. Mechanistic proposal for the formation of 3 and 4.
Conclusion
In conclusion, we have developed a facile synthesis of sulfonamides, sulfonyl carbamates and sulfonyl
ureas using organic sulfonyl azides as versatile building blocks. We have successfully applied a
ligandꢀfree palladiumꢀcatalyzed carbonylation procedure to transform sulfonyl azides into sulfonyl
isocyanate intermediates, in which further derivatizations with alcohol or aryl amine nucleophiles
allow the robust generation of a broad range sulfonyl carbamates and sulfonyl ureas. In addition, a
direct synthesis of substituted sulfonamides from aryl sulfonyl azides and a variety of amines was
developed, providing a versatile synthetic platform for the preparation of substituted sulfonamides.
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Experimental Section
General methods
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All reagents were purchased at the highest commercial quality and used without further purification.
Solvents used for extraction and silica gel chromatography (EtOAc, hexane, nꢀpentane,
dichloromethane, methanol and Et3N) were used without purification or removal of water. Yields are
for isolated, homogenous and spectroscopically pure material. Silica gel chromatography was carried
out using E. Merck silica gel (60 Å pore size, particle size 40ꢀ63 nm). 1H NMR spectra were recorded
at 400 MHz, 13C NMR spectra at 100 MHz and 15N NMR spectra at 40 MHz. The chemical shifts for
1H NMR and 13C NMR were referenced to tetramethylsilane via residual solvent signals (1H, CDCl3 at
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7.26 ppm; C, CDCl3 at 77.16 ppm; H, DMSO-d6 at 2.45 ppm; C, DMSO-d6 at 39.43 ppm, H,
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CD3OD at 3.31 ppm; C, CD3OD at 49.0 ppm). LC/MS was performed on an instrument equipped
with a CPꢀSil 8 CB capillary column (50 x 3.0 mm, particle size 2.6 ꢁm, pore size 100 Å) running at
an ionization potential of 70 eV with a CH3CN/H2O gradient (0.05% HCOOH). Accurate mass values
were determined by electrospray ionization with a 7ꢀT hybrid ion trap and a TOF detector running in
positive or negative mode.
Preparation of sulfonyl azides. Sulfonyl azides were prepared either from the corresponding sulfonyl
chloride28 or the sulfonamide13a following the literature procedures. Warning! Sulfonyl azides are
potentially explosive and all reactions should be carried out behind blast shields. The authors
recommend the use of plastic spatulas for the handling of solid material.
6-(Trifluoromethyl)pyridine-3-sulfonyl azide (1j) for use in stability study (see Supporting
1
Information). Prepared from the corresponding sulfonyl chloride. White solid (44 mg, 76%); H
NMR (400 MHz, CDCl3) δ 9.29–9.22 (m, 1H), 8.51–8.39 (m, 1H), 7.96 (dd, J = 8.3, 0.9 Hz, 1H); 13C
2
3
NMR (100 MHz, CDCl3) δ 152.8 (q, JCF = 35.9 Hz), 148.3, 138.0, 137.0, 121.3 (q, JCF = 2.6 Hz),
1
120.8 (q, JCF = 275.1 Hz); IR (neat) 2155 cmꢀ1; MS (ESI) calc’d for C6H4F3N4O2S ([M+H]+) m/z
253.XXXX, found m/z 253.XXXX.
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General procedure for the synthesis of sulfonamides 2a–2x, exemplified by N-butyl-4-
methylbenzenesulfonamide (CAS 1907-65-9) (2a).29 To a stirred solution of 1a (50 mg, 0.25 mmol)
in DMA (2 mL) at ambient temperature were added butylamine (50 µL, 50 mmol) and triethylamine
(35 µL, 0.25 mmol). The resulting mixture was stirred for 20 h, after which it was loaded on a silica
column and eluted with 10% EtOAc in n-pentane to obtain the title compound as a colorless liquid (49
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mg, 0.21 mmol, 84%); H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 7.8, 0.8
Hz, 2H), 4.78 (s, 1H), 2.87 (t, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.46–1.32 (m, 2H), 1.29–1.16 (m, 2H),
13
0.79 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ 143.4, 137.1, 129.8, 127.2, 43.0, 31.7, 21.6,
20.0, 13.6.
General procedure for the synthesis of sulfonyl ureas 3a–3m, exemplified by 4-methyl-N-
(phenylcarbamoyl)benzenesulfonamide (CAS 13909-63-2) (3a).30 Chamber A of an Hꢀtube
reactor16 was charged with 1a (100 mg, 0.51 mmol) and PdCl2 (2 mg, 0.01 mmol). The chamber was
capped and anhydrous DMA (1.5 mL) and aniline (47 mg, 0.51 mmol) were added through the
septum. Chamber B was charged with Mo(CO)6 (670 mg, 0.3 mmol) and capped.16b Anhydrous DMA
(1.5 mL) and DBU (116 mg, 0.76 mmol) were added through the septum and the assembly was stirred
for 20 h at 75 ºC, after which the contents of chamber A were loaded onto a silica gel column. The
title compound was obtained as a colorless liquid (109 mg, 74%), eluting with 10% EtOAc in nꢀ
pentane with 1% Et3N as a stabilizer (see below). Spectral data were in agreement with literature
1
values. H NMR (400 MHz, CD3OD) δ 7.94–7.86 (m, 2H), 7.43–7.37 (m, 2H), 7.34–7.29 (m, 2H),
13
7.28–7.22 (m, 1H), 7.07–7.00 (m, 1H), 2.43 (s, 3H); C NMR (101 MHz, CDCl3) δ 149.2, 145.3,
136.6, 136.3, 130.2, 129.2, 126.9, 124.9, 120.3, 21.6.
General procedure for the synthesis of sulfonyl carbamates 4a–4u, exemplified by butyl
tosylcarbamate (CAS 31224-37-0) (4a).31 Chamber A of an Hꢀtube reactor was charged with 1a (50
mg, 0.25 mmol) and PdCl2 (2 mg, 0.01 mmol). The chamber was capped and anhydrous DMA (1.5
mL) and nꢀbutanol (38 mg, 0.51 mmol) were added through the septum. Chamber B was charged with
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Mo(CO)6 (40 mg, 0.15 mmol) and capped. Anhydrous DMA (1.5 mL) and DBU (58 mg, 0.38 mmol)
were added through the septum and the assembly was stirred for 20 h at 75 ºC, after which the
contents of chamber A loaded onto a silica gel column. The title compound was obtained as a
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colorless liquid (57 mg, 82%), eluting with 10% EtOAc in nꢀpentane. H NMR (400 MHz, CDCl3) δ
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8.51 (s, 1H), 7.95–7.76 (m, 2H), 7.23 (dd, J = 8.3, 2.1 Hz, 2H), 3.97 (td, J = 6.7, 2.3 Hz, 2H), 2.33 (s,
3H), 1.60–1.29 (m, 2H), 1.17 (m, 2H), 0.76 (td, J = 7.1, 2.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
150.3, 144.2, 134.9, 128.8, 127.5, 66.1, 29.6, 20.9, 18.0, 12.8.
Stability issues with sulfonyl ureas (3a–3l) and sulfonyl carbamates (4l, 4n, 4o, 4r and 4s). These
compounds were observed to degrade to the corresponding sulfonamide in acidic environments such
as silica gel or CDCl3. For this reason, the authors recommend the use of 1% Et3N as a
chromatography additive, enabling target compounds to be isolated as their triethylammonium salts.
These are stable for up to a month at ꢀ21 °C.
N-Hexyl-4-methylbenzenesulfonamide (CAS 1143-01-7) (2b).28,29a Spectral data were in agreement
1
with literature values. Colorless liquid (56 mg, 86%); H NMR (400 MHz, CDCl3) δ 7.83–7.67 (m,
2H), 7.40–7.26 (m, 2H), 4.76–4.53 (m, 1H), 3.05–2.79 (m, 2H), 2.43 (s, 3H), 1.53–1.36 (m, 2H),
1.32–1.12 (m, 6H), 0.92–0.67 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 143.4, 137.1, 129.8, 127.2,
43.3, 31.3, 29.6, 26.3, 22.6, 21.6, 14.1.
N-Cyclohexyl-4-methylbenzenesulfonamide (CAS 80-30-8) (2c).29b,33 Spectral data were in
agreement with literature values. Colorless liquid (29 mg, 45%); 1H NMR (400 MHz, CDCl3) δ 7.00–
6.91 (m, 2H), 6.51–6.46 (m, 2H), 3.99–3.38 (m, 1H), 2.31 (td, J = 6.3, 3.0 Hz, 1H), 1.61 (s, 3H),
0.98–0.89 (m, 2H), 0.86–0.77 (m, 2H), 0.73–0.66 (m, 1H), 0.47–0.26 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 143.2, 138.6, 129.7, 127.1, 52.7, 34.1, 25.3, 24.7, 21.6.
1-Tosylpiperidine (CAS 4703-22-4) (2d).29b,34 Spectral data were in agreement with literature
1
values. Colorless liquid (55 mg, 90%); H NMR (400 MHz, CDCl3) δ 7.67–7.60 (m, 2H), 7.35–7.29
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(m, 2H), 3.08–2.89 (m, 4H), 2.43 (s, 3H), 1.68–1.59 (m, 4H), 1.45–1.37 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 143.4, 133.4, 129.7, 127.9, 47.1, 25.3, 23.7, 21.7.
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N,N-diethyl-4-methylbenzenesulfonamide (CAS 649-15-0) (2e).29b,35 Spectral data were in
agreement with literature values. 4 equiv. diethylamine, 6 equiv. Et3N, 120 h. Colorless liquid (21 mg,
36%); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.0 Hz, 2H), 3.22 (q, J =
7.2 Hz, 4H), 2.41 (s, 3H), 1.12 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 142.9, 137.4, 129.6,
127.0, 41.9, 21.5, 14.1.
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N,N-dipropyl-4-methylbenzenesulfonamide (CAS 723-42-2) (2f).29b,36 Spectral data were in
agreement with literature values. 4 equiv. dipropylamine, 6 equiv. Et3N, 120 h. Colorless liquid (21
mg, 33%); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 3.09–3.01
13
(m, 4H), 2.41 (s, 3H), 1.62–1.44 (m, 4H), 0.89–0.85 (m, 6H); C NMR (100 MHz, CDCl3) δ 142.6,
136.9, 129.3, 126.8, 49.8, 21.8, 21.3, 11.0.
N-Allyl-4-methylbenzenesulfonamide (CAS 50487-71-3) (2g).37 Spectral data were in agreement
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with literature values. Colorless liquid (32 mg, 59%); H NMR (400 MHz, CDCl3) δ 7.78–7.71 (m,
2H), 7.34–7.30 (m, 2H), 5.72 (ddt, J = 17.1, 10.2, 5.8 Hz, 1H), 5.21–5.14 (m, 1H), 5.10 (dd, J = 10.2,
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1.3 Hz, 1H), 4.54 (s, 1H), 3.59 (tt, J = 6.2, 1.5 Hz, 2H), 2.43 (s, 3H); C NMR (100 MHz, CDCl3) δ
143.6, 137.1, 133.1, 129.9, 127.3, 117.8, 45.9, 21.7.
4-Methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (CAS 55022-46-3) (2h).38 Spectral data were in
agreement with literature values. Colorless liquid (31 mg, 58%); 1H NMR (400 MHz, CDCl3) δ 8.11–
7.93 (m, 2H), 7.65–7.51 (m, 2H), 5.12–4.82 (m, 1H), 4.26–3.80 (m, 2H), 2.66 (s, 3H), 2.43–2.23 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 143.9, 136.6, 129.8, 127.5, 78.1, 73.1, 33.0, 21.7.
4-Methyl-N-(thiophen-2-ylmethyl)benzenesulfonamide (CAS 545358-50-7) (2i).39 Spectral data
were in agreement with literature values. Colorless liquid (43 mg, 64%); 1H NMR (400 MHz, CDCl3)
δ 8.17–7.95 (m, 2H), 7.61–7.55 (m, 2H), 7.45 (dd, J = 5.0, 1.2 Hz, 1H), 7.14 (dd, J = 5.0, 3.5 Hz, 1H),
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7.12–7.10 (m, 1H), 5.07–4.92 (m, 1H), 4.59 (d, J = 6.1 Hz, 2H), 2.70 (s, 3H); C NMR (100 MHz,
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5
CDCl3) δ 143.6, 138.9, 136.8, 129.7, 127.2, 126.8, 126.5, 125.8, 42.1, 21.5.
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N-Benzyl-4-methylbenzenesulfonamide (CAS 1576-37-0) (2j).29b,40 Spectral data were in agreement
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with literature values. Colorless liquid (42 mg, 64%); H NMR (400 MHz, CDCl3) δ 7.80–7.67 (m,
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2H), 7.33–7.29 (m, 2H), 7.29–7.24 (m, 3H), 7.22–7.18 (m, 2H), 4.79 (t, J = 6.2 Hz, 1H), 4.12 (d, J =
13
6.2 Hz, 2H), 2.44 (s, 3H); C NMR (100 MHz, CDCl3) δ 143.6, 137.0, 136.4, 129.8, 128.8, 128.13,
128.11, 127.3, 47.4, 21.7.
Methyl toluenesulfonylglycinate (CAS 2645-02-5) (2k).41 Spectral data were in agreement with
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literature values. Colorless liquid (12 mg, 19%); H NMR (400 MHz, CDCl3) δ 7.78–7.69 (m, 2H),
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7.39–7.27 (m, 2H), 5.00 (s, 1H), 3.78 (d, J = 5.3 Hz, 2H), 3.64 (s, 3H), 2.43 (s, 3H); C NMR (100
MHz, CDCl3) δ 169.2, 143.8, 136.1, 129.7, 127.2, 52.6, 44.0, 21.5.
Methyl 3-((4-methylphenyl)sulfonamido)propanoate (62456-75-1) (2n).42 Spectral data were in
agreement with literature values. Colorless liquid (42 mg, 61%); 1H NMR (400 MHz, CDCl3) δ 7.86–
7.62 (m, 2H), 7.36–7.26 (m, 2H), 5.31 (br s, 1H), 3.65 (s, 3H), 3.18 (t, J = 5.9 Hz, 2H), 2.68–2.48 (m,
13
2H), 2.41 (s, 3H); C NMR (100 MHz, CDCl3) δ 172.1, 143.2, 136.6, 129.4, 126.7, 51.6, 38.4, 33.6,
21.2.
N-butyl-4-methoxybenzenesulfonamide (CAS 35088-85-8) (2p).43 Spectral data were in agreement
with literature values. Colorless liquid (45 mg, 70%); 1H NMR (400 MHz, CDCl3) 8.17–7.64 (m, 2H),
7.20–6.90 (m, 2H), 4.50 (s, 1H), 3.97 (s, 3H), 3.15–2.91 (m, 2H), 1.62–1.46 (m, 2H), 1.45–1.30 (m,
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2H), 1.08–0.84 (m, 3H); C NMR (100 MHz, CDCl3) δ 162.9, 131.7, 129.3, 114.3, 55.7, 43.0, 31.7,
19.8, 13.7.
N-butyl-4-bromobenzenesulfonamide (CAS 1984-28-7) (2q).43 Spectral data were in agreement
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with literature values. Colorless liquid (62 mg, 85%); H NMR (400 MHz, CDCl3) δ 7.76–7.70 (m,
2H), 7.68–7.64 (m, 2H), 4.54 (br s, 1H), 3.17–2.84 (m, 2H), 1.51–1.39 (m, 2H), 1.37–1.19 (m, 2H),
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0.86 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.2, 132.5, 128.7, 127.6, 43.1, 31.7, 19.8,
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13.6.
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4-acetyl-N-butylbenzenesulfonamide (CAS 733031-17-9) (2r). Colorless liquid (31 mg, 41%); H
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NMR (400 MHz, CDCl3) δ 8.19–8.03 (m, 2H), 8.01–7.82 (m, 2H), 4.39 (s, 1H), 2.99 (d, J = 6.9 Hz,
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2H), 2.66 (s, 3H), 1.50–1.39 (m, 2H), 1.32–1.25 (m, 4H), 0.91–0.81 (m, 3H); C NMR (100 MHz,
CDCl3) δ 196.9, 144.2, 140.1, 129.1, 127.5, 43.2, 31.8, 27.0, 19.8, 13.6.
N-butyl-2-bromobenzenesulfonamide (CAS 951885-17-9) (2s).44 Spectral data were in agreement
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with literature values. Colorless liquid (43 mg, 59%); H NMR (400 MHz, CD3OD) δ 8.22–7.92 (m,
1H), 7.96–7.72 (m, 1H), 7.57–7.51 (m, 1H), 7.48 (td, J = 7.6, 1.9 Hz, 1H), 2.90 (t, J = 7.0 Hz, 2H),
1.48–1.36 (m, 2H), 1.35–1.25 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ
141.2, 136.5, 134.7, 132.3, 128.9, 120.9, 43.7, 32.8, 20.7, 13.9.
1
N-butylthiophene-2-sulfonamide (CAS 741728-91-6) (2v). Colorless liquid (26 mg, 49%); H
NMR (400 MHz, CDCl3) δ 7.81–7.45 (m, 2H), 7.16–6.98 (m, 1H), 4.39 (s, 1H), 3.18–2.98 (m, 2H),
1.51–1.44 (m, 2H), 1.36–1.29 (m, 2H), 0.88 (d, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 132.2,
131.9, 127.5, 43.4, 31.6, 19.8, 13.8; MS (ESI) calc’d for C8H14NO2S2 ([M+H]+) m/z 220.0466, found
m/z 220.0469.
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N-butylbenzo[b]thiophene-3-sulfonamide (2w). Colorless liquid (35 mg, 52%); H NMR (400
MHz, CDCl3) δ 8.27 (s, 1H), 8.24–8.16 (m, 1H), 7.94 (dd, J = 7.9, 1.4 Hz, 1H), 7.57–7.48 (m, 2H),
4.63 (t, J = 6.2 Hz, 1H), 3.08–2.97 (m, 2H), 1.48–1.38 (m, 2H), 1.35–1.20 (m, 2H), 0.83 (t, J = 7.3
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Hz, 3H); C NMR (100 MHz, CDCl3) δ 132.2, 131.9, 127.5, 43.4, 31.6, 19.9, 13.7; MS (ESI) calc’d
for C12H16NO2S2 ([M+H]+) m/z 270,0622 found m/z 270.0633.
5-(N-butylsulfamoyl)-4-chloro-2-((furan-2-ylmethyl)amino)benzoic acid (CAS 207866-32-8)
(2x).45 Colorless liquid (12 mg, 23%); H NMR (400 MHz, (CD3)2CO) δ 8.54 (s, 1H), 7.57–7.35 (m,
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1H), 7.03 (s, 1H), 6.45–6.19 (m, 2H), 4.57 (s, 2H), 2.84 (t, J = 7.0 Hz, 2H), 1.48–1.34 (m, 2H), 1.30–
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1.21 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 169.3, 154.2, 152.3, 143.6,
138.2, 136.7, 124.5, 114.6, 111.4, 109.3, 108.6, 43.5, 40.4, 32.5, 20.5, 14.0; MS (ESI) calc’d for
C16H20ClN2O5S ([M+H]+) m/z 387.0771, found m/z 387.0781.
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Triethylammonium
N-((4-methoxyphenyl)carbamoyl)-4-methylbenzenesulfonamide
(CAS
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92580-79-5, free urea) (3b).46 Reaction run at 40 ºC on 0.25 mmol scale. Tan solid (93 mg, 87%); 1H
NMR (400 MHz, (CD3)2CO) δ 8.66 (s, 1H), 8.00–7.64 (m, 2H), 7.58–7.35 (m, 2H), 7.26–7.08 (m,
2H), 6.86–6.61 (m, 2H), 3.65 (s, 3H), 3.01 (d, J = 7.2 Hz, 6H), 2.30 (s, 3H), 1.15 (t, J = 7.2 Hz, 9H);
13C NMR (100 MHz, (CD3)2CO) δ 158.0, 155.9, 155.9, 143.5, 142.3, 134.9, 129.9, 127.7, 121.2,
121.1, 114.7, 55.8, 46.9, 21.6, 9.8.
Triethylammonium N-((4-bromophenyl)carbamoyl)-4-methylbenzenesulfonamide (CAS 100716-
1
09-4, free urea) (3c).1d 0.62 mmol scale. Colorless liquid (140 mg, 67%); H NMR (400 MHz,
(CD3)2CO) δ 8.72 (s, 1H), 7.88–7.67 (m, 2H), 7.45–7.32 (m, 2H), 7.25–7.18 (m, 2H), 7.17–7.13 (m,
2H), 3.07 (q, J = 7.3 Hz, 7H), 2.25 (s, 3H), 1.14 (t, J = 7.3 Hz, 8H); 13C NMR (100 MHz, (CD3)2CO)
δ 158.1, 143.34, 142.0, 141.2, 132.1, 129.6, 127.4, 120.9, 113.7, 46.7, 21.35, 9.2.
Triethylammonium N-((4-chlorophenyl)carbamoyl)-4-methylbenzenesulfonamide (CAS 3955-
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50-8, free urea) (3d).15,47 0.25 mmol scale. Colorless liquid (58 mg, 54%); H NMR (400 MHz,
(CD3)2CO) δ 8.84 (s, 1H), 8.04–7.78 (m, 2H), 7.73–7.56 (m, 2H), 7.35–7.29 (m, 2H), 7.28–7.24 (m,
1H), 3.19 (t, J = 7.2 Hz, 6H), 1.32 (t, J = 7.3 Hz, 9H); 13C NMR (100 MHz, (CD3)2CO) δ 159.5,
145.1, 143.4, 142.2, 131.1, 130.6, 128.9, 127.7, 122.0, 48.3, 22.8, 10.9.
Triethylammonium N-((4-cyanophenyl)carbamoyl)-4-methylbenzenesulfonamide (CAS 51594-
96-8, free urea) (3e).46a Reaction run at 40 ºC on 0.25 mmol scale. Colorless liquid (65 mg, 62%); 1H
NMR (400 MHz, (CD3)2CO) δ 9.01 (s, 1H), 7.93–7.81 (m, 2H), 7.76–7.65 (m, 2H), 7.60–7.42 (m,
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2H), 7.36–7.15 (m, 2H), 3.27 (q, J = 7.3 Hz, 6H), 2.36 (s, 3H), 1.30 (t, J = 7.3 Hz, 9H); C NMR
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(100 MHz, (CD3)2CO) δ 157.6, 146.5, 146.4, 143.2, 143.1, 142.5, 142.5, 133.9, 129.9, 127.8, 127.8,
120.2, 119.2, 119.1, 104.7, 104.6, 47.2, 21.6, 9.3.
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Triethylammonium methyl 4-(3-tosylureido)benzoate (CAS 404905-23-3, free urea) (3f).48
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Reaction run at 40 ºC on 0.62 mmol scale. Colorless liquid (141 mg, 50%); H NMR (400 MHz,
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(CD3)2CO) δ 8.91 (s, 1H), 7.89–7.73 (m, 4H), 7.73–7.45 (m, 2H), 7.39–7.09 (m, 2H), 3.81 (s, 3H),
3.20 (q, J = 7.4 Hz, 6H), 2.35 (s, 3H), 1.26 (d, J = 7.4 Hz, 9H); 13C NMR (100 MHz, (CD3)2CO) δ
157.9, 146.5, 143.4, 141.9, 131.1, 129.6, 127.4, 123.4, 118.1, 51.8, 46.8, 21.3, 9.2.
Triethylammonium 4-methyl-N-(o-tolylcarbamoyl)benzenesulfonamide (CAS 53855-77-9, free
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urea) (3g).1d 0.62 mmol scale. Colorless liquid (115 mg, 45%); H NMR (400 MHz, (CD3)2CO) δ
8.64 (s, 1H), 8.11–7.74 (m, 3H), 7.42–7.34 (m, 2H), 7.21–7.17 (m, 1H), 7.17–7.13 (m, 1H), 7.01–6.95
(m, 1H), 3.37–3.13 (m, 4H), 2.45 (s, 3H), 2.29 (s, 6H), 1.44–1.26 (m, 9H); 13C NMR (100 MHz,
(CD3)2CO) δ 155.3, 142.8, 142.3, 138.7, 130.9, 129.9, 128.6, 127.5, 126.9, 123.7, 122.2, 46.4, 21.3,
18.2, 8.9.
Triethylammonium N-((2-chlorophenyl)carbamoyl)-4-methylbenzenesulfonamide (CAS 53855-
1
79-1. free urea) (3h).1d,49 0.62 mmol scale. Colorless liquid (82 mg, 31%); H NMR (400 MHz,
(CD3)2CO) δ 8.92 (s, 1H), 8.28 (dd, J = 8.6, 1.6 Hz, 1H), 7.99–7.76 (m, 2H), 7.35 (dd, J = 8.1, 1.5 Hz,
1H), 7.31–7.25 (m, 3H), 7.19 (ddd, J = 8.6, 7.3, 1.5 Hz, 2H), 6.94 (td, J = 8.1, 7.3, 1.5 Hz, 1H), 3.26
(q, J = 7.2 Hz, 6H), 2.35 (s, 3H), 1.29 (d, J = 7.2 Hz, 9H); 13C NMR (100 MHz, (CD3)2CO) δ 155.6,
142.7, 142.5, 137.7, 129.8, 129.7, 128.1, 127.4, 123.5, 122.7, 121.8, 46.4, 21.3, 8.8.
Triethylammonium 4-methoxy-N-(phenylcarbamoyl)benzenesulfonamide (CAS 51327-24-3, free
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urea) (3i).50 Reaction run at 50 ºC on a 0.19 mmol scale. Colorless liquid (69 mg; 90%); H NMR
(400 MHz, (CD3)2CO) δ 8.79 (s, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.54 (dd, J = 8.6, 1.2 Hz, 2H), 7.21 (m,
J = 8.6, 7.3 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.94 – 6.89 (m, 1H), 3.86 (s, 4H), 3.04 (q, J = 7.2 Hz,
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6H), 1.22 (t, J = 7.2 Hz, 9H). 13C NMR (100 MHz, (CD3)2CO) δ 162.6, 157.4, 141.7, 138.0, 129.4,
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129.3, 122.3, 119.3, 114.2, 55.8, 46.7, 9.9.
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urea) (3j).51 Reaction run at 50 ºC on a 0.19 mmol scale. Colorless liquid, (68 mg, 87%); H NMR
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(400 MHz, (CD3)2CO) δ 8.37 (s, 1H), 8.07–8.01 (m, 2H), 8.01–7.96 (m, 2H), 7.52 (dd, J = 8.5, 1.3
Hz, 2H), 7.16 (dd, J = 8.5, 7.3 Hz, 2H), 6.85 (td, J = 7.3, 1.3 Hz, 1H), 3.00 (q, J = 7.3 Hz, 9H), 2.58
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(s, 3H), 1.18 (t, J = 7.3 Hz, 12H); C NMR (100 MHz, (CD3)2CO) δ 197.4, 159.7, 151.3, 142.1,
139.2, 129.2, 128.9, 127.3, 121.9, 119.2, 46.8, 26.9, 10.0.
Triethylammonium 5-chloro-N-(phenylcarbamoyl)thiophene-2-sulfonamide (3k). Reaction run at
50 ºC on a 0.25 mmol scale. Colorless liquid (82 mg, 78%); 1H NMR (400 MHz, (CD3)2CO) δ 8.30 (s,
1H), 7.61–7.57 (m, 2H), 7.41 (d, J = 3.9 Hz, 1H), 7.36–7.12 (m, 2H), 6.96 (d, J = 4.0 Hz, 1H), 6.94–
6.89 (m, 1H), 3.28 (q, J = 7.3 Hz, 6H), 1.33 (t, J = 7.3 Hz, 9H); 13C NMR (100 MHz, (CD3)2CO) δ
158.8, 146.9, 140.8, 131.5, 128.2, 127.6, 125.7, 121.0, 118.2, 45.7, 7.9; MS (ESI) calc’d for
C11H10ClN2O3S2 ([M+H]+) m/z 316.9821, found m/z 316.9835.
Triethylammonium N-(phenylcarbamoyl)benzo[b]thiophene-3-sulfonamide (3l). Reaction run at
30 ºC on a 0.25 mmol scale. Colorless liquid (78 mg, 72%); 1H NMR (400 MHz, (CD3)2CO) δ 8.54 (s,
1H), 8.51–8.47 (m, 1H), 8.33 (s, 1H), 8.02–7.92 (m, 1H), 7.63–7.51 (m, 2H), 7.50–7.40 (m, 2H), 7.18
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(dd, J = 8.5, 7.3 Hz, 2H), 6.98–6.84 (m, 1H), 3.19 (q, J = 7.3 Hz, 6H), 1.25 (t, J = 7.3 Hz, 9H); C
NMR (100 MHz, (CD3)2CO) δ 159.1, 141.8, 141.2, 140.7, 136.0, 130.9, 129.2, 125.7, 125.5, 125.2,
123.4, 122.1, 119.3, 46.7, 9.1; MS (ESI) calc’d for C15H13N2O3S2 ([M+H]+) m/z 333.0372, found m/z
333.0377.
Methyl tosylcarbamate (CAS 14437-03-7) (4b).52 Spectral data were in agreement with literature
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values. Colorless liquid (38 mg, 65%); H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.33–8.08 (m,
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2H), 7.66–7.57 (m, 2H), 5.50–4.48 (m, 1H), 2.72 (s, 3H), 1.47 (d, J = 6.3 Hz, 6H);13C NMR (100
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MHz, CDCl3) δ 151.1, 145.3, 135.5, 129.8, 128.5, 53.7, 21.8.
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Isopropyl tosylcarbamate (CAS 18303-02-1) (4c).53 Colorless liquid (48 mg, 73%); H NMR (400
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MHz, CDCl3) δ 8.18 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 4.87 (hept, J = 6.3 Hz,
1H), 2.41 (s, 3H), 1.16 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.4, 144.9, 135.8, 129.5,
129.5, 128.4, 71.5, 21.7, 21.6.
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tert-Butyl tosylcarbamate (CAS 18303-04-3) (4d).54 Spectral data were in agreement with literature
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values. Colorless liquid (43 mg, 62%); H NMR (400 MHz, CDCl3) δ 8.07–7.74 (m, 2H), 7.81 (s,
1H), 7.41–7.15 (m, 2H), 2.43 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 149.4, 144.8,
136.1, 129.6, 128.3, 84.1, 27.9, 21.7.
Cyclohexyl tosylcarbamate (CAS 18303-08-7) (4e).55 Colorless liquid (58 mg, 76%); 1H NMR (400
MHz, CDCl3) δ 8.10 (s, 1H), 7.99–7.83 (m, 2H), 7.40–7.27 (m, 2H), 4.63 (tt, J = 9.0, 3.7 Hz, 1H),
2.42 (s, 3H), 1.80–1.71 (m, 2H), 1.69–1.57 (m, 2H), 1.50–1.43 (m, 1H), 1.41 – 1.17 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 150.3, 144.9, 135.8, 129.6, 128.4, 76.2, 31.4, 25.2, 23.5, 21.7.
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4,4,4-trifluorobutyl tosylcarbamate (4f). 0.50 mmol scale. Colorless liquid (59 mg, 36%); H NMR
(400 MHz, CDCl3) δ 7.96 (s, 1H), 7.94–7.87 (m, 2H), 7.39–7.33 (m, 2H), 4.14 (t, J = 6.2 Hz, 2H),
2.44 (s, 3H), 2.10–1.95 (m, 2H), 1.89–1.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.5, 145.5,
135.5, 129.7, 128.4, 126.8 (q, 1JCF = 276.2 Hz), 65.3, 30.4 (q, 2JCF = 29.5 Hz), 21.8, 21.8 (q, 3JCF = 3.1
Hz); MS (ESI) calc’d for C12H13F3NO4S ([MꢀH]ꢀ) m/z 324.0517, found m/z 324.0513.
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Prop-2-yn-1-yl tosylcarbamate (CAS 63924-66-3) (4g).56 Colorless liquid (16 mg, 24%); H NMR
(400 MHz, CDCl3) δ 8.11–7.93 (m, 2H), 7.55–7.31 (m, 2H), 5.52 (s, 1H), 4.85–4.65 (m, 2H), 4.52 (s,
1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 148.0, 136.7, 135.9, 131.7, 129.9, 92.5, 68.8,
31.4, 23.5.
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Thiophen-2-ylmethyl tosylcarbamate (4h). Reaction run at 50 °C. Colorless liquid (36 mg, 45%);
1H NMR (400 MHz, CDCl3) δ 8.08–7.66 (m, 2H), 7.30–7.19 (m, 3H), 7.03–6.96 (m, 1H), 6.91 (dd, J
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= 5.1, 3.5 Hz, 1H), 5.19 (s, 2H), 2.39 (s, 3H); C NMR (100 MHz, CDCl3) δ 150.3, 145.0, 136.0,
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([M+MeCN+Na]+) m/z 375.0449, found m/z 375.0456.
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2,3-Dihydro-1H-inden-1-yl tosylcarbamate (4i). Colorless liquid (16 mg, 19%); H NMR (400
MHz, CDCl3) δ 7.86–7.72 (m, 2H), 7.61 (s, 1H), 7.32–7.20 (m, 5H), 7.18–7.11 (m, 1H), 6.06 (dd, J =
6.8, 3.1 Hz, 1H), 3.07–2.90 (m, 1H), 2.81 (ddd, J = 16.2, 8.6, 4.2 Hz, 1H), 2.41 (s, 3H), 2.45–2.31 (m,
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1H), 2.05 (dddd, J = 14.3, 8.3, 4.2, 3.1 Hz, 1H); C NMR (100 MHz, CDCl3) δ 150.5, 145.0, 144.7,
139.6, 135.6, 129.6, 129.5, 128.5, 126.9, 125.8, 124.9, 81.6, 32.1, 30.2, 21.8; MS (ESI) calc’d for
C19H20N2O4SNa ([M+MeCN+Na]+) m/z 395.1041, found m/z 395.1038.
Benzyl tosylcarbamate (CAS 18303-10-1) (4j).52b Spectral data were in agreement with literature
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values. Colorless liquid (46 mg, 59%); H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.87–7.69 (m,
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2H), 7.66–6.66 (m, 8H), 5.03 (s, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3) δ 150.5, 145.1,
135.5, 134.5, 129.7, 128.8, 128.7, 128.49, 128.48, 68.7, 21.8.
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Pyridin-3-ylmethyl tosylcarbamate (4k). Colorless liquid (26 mg, 33%); H NMR (400 MHz,
(CD3)2CO) δ 8.55–8.52 (m, 2H), 7.93–7.81 (m, 2H), 7.72–7.66 (m, 1H), 7.46–7.38 (m, 2H), 7.34
(ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 5.14 (s, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 150.94,
150.87, 146.0, 137.7, 137.4, 137.0, 132.5, 130.8, 129.3, 124.6, 66.4, 21.9; MS (ESI) calc’d for
C14H13N2O4S ([MꢀH]ꢀ) m/z 305.0596, found m/z 305.0600.
Triethylammonium ((cinnamyloxy)carbonyl)(tosyl)amide (CAS 159259-78-6, free carbamate)
(4l).57 Colorless liquid (46 mg, 42%); 1H NMR (400 MHz, DMSOꢀd6) δ 7.68–7.61 (m, 2H), 7.43–7.35
(m, 2H), 7.35–7.27 (m, 2H), 7.28–7.23 (m, 1H), 7.23–7.17 (m, 2H), 6.55 – 6.45 (m, 1H), 6.25 (dt, J =
16.0, 5.8 Hz, 1H), 4.42 (dd, J = 5.8, 1.5 Hz, 2H), 3.09 (q, J = 7.3 Hz, 6H), 2.32 (s, 3H), 1.17 (t, J = 7.3
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Hz, 9H); 13C NMR (100 MHz, CD3OD 158.9, 143.2, 141.2, 137.8, 133.7, 129.7, 129.3, 128.6, 128.1,
127.3, 125.2, 66.2, 47.5, 21.2, 8.9.
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carbamate) (4n).58 Colorless liquid (49 mg, 50%); H NMR (400 MHz, (CD3)2CO) δ 8.00–7.92 (m,
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2H), 7.15–7.04 (m, 2H), 3.99 (t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 3.02 (q, J = 7.2 Hz, 5H), 1.64–1.52 (m,
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2H), 1.42–1.34 (m, 3H), 1.29 (t, J = 7.2 Hz, 9H), 0.95 (t, J = 7.4 Hz, 3H); C NMR (100 MHz,
CD3OD) δ 163.4, 153.5, 131.9, 129.6, 113.6, 65.4, 54.9, 46.4, 30.4, 18.5, 12.5, 7.8.
Butyl ((4-acetylphenyl)sulfonyl)carbamate (2: 1 mixture with Et3N) (4o). Colorless liquid (45 mg,
45%); 1H NMR (400 MHz, CD3OD) δ 8.15–8.09 (m, 2H), 8.07–8.01 (m, 2H), 3.94 (t, J = 6.5 Hz, 2H),
3.23 (q, J = 7.3 Hz, 3H), 2.65 (s, 3H), 1.58–1.45 (m, 2H), 1.42–1.21 (m, 7H), 0.88 (t, J = 7.4 Hz, 3H);
13C NMR (100 CD3OD) δ 199.2, 156.0, 139.5, 128.1, 127.5, 65.0, 46.4, 30.6, 25.6, 18.6, 12.6, 7.8;
MS (ESI) calc’d for C13H16NO5S ([MꢀH]ꢀ) m/z 298.0749, found m/z 298.0753.
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Butyl ((4-bromophenyl)sulfonyl)carbamate (4p). Colorless liquid (66 mg, 78%); H NMR (400
MHz, CDCl3) δ 7.22–7.02 (m, 2H), 6.92–6.81 (m, 2H), 3.30 (td, J = 6.7, 0.9 Hz, 2H), 0.86–0.64 (m,
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2H), 0.57–0.39 (m, 2H), 0.08 (td, J = 7.4, 1.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 149.7, 136.8,
131.7, 129.2, 128.6, 66.6, 29.8, 18.2, 12.9; MS (ESI) calc’d for C11H13BrNO4S ([MꢀH]ꢀ) m/z
333.9749, found m/z 333.9753.
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Butyl ((2-bromophenyl)sulfonyl)carbamate (4q). Colorless liquid (31 mg, 37%); H NMR (400
MHz, (CD3)2CO) δ 10.7 (s, 1H), 8.24 (ddd, J = 7.4, 1.9, 0.7 Hz, 1H), 7.87 (ddd, J = 7.0, 1.9, 0.7 Hz,
1H), 7.69–7.59 (m, 2H), 4.02 (td, J = 6.5, 0.7 Hz, 3H), 1.48 (ddt, J = 8.4, 7.0, 6.0 Hz, 2H), 1.30–1.18
(m, 3H), 0.84 (td, J = 7.4, 0.6 Hz, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 153.0, 140.9, 137.8, 137.3,
135.4, 130.3, 122.0, 68.4, 32.8, 21.0, 15.4; MS (ESI) calc’d for C11H13BrNO4S ([MꢀH]ꢀ) m/z
333.9749, found m/z 333.9740.
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Triethylammonium (butoxycarbonyl)(thiophen-2-ylsulfonyl)amide (CAS 14437-09-3, free
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carbamate) (4r).59 Reaction run at 50 °C. Colorless liquid (57 mg, 63%); H NMR (400 MHz,
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(CD3)2CO) δ 7.75 (dd, J = 5.0, 1.4 Hz, 1H), 7.68 (dd, J = 3.7, 1.4 Hz, 1H), 7.10 (dd, J = 5.0, 3.7 Hz,
1H), 3.97 (t, J = 6.7 Hz, 2H), 3.27 (q, J = 7.3, Hz, 6H), 1.59–1.47 (m, 2H), 1.41–1.25 (m, 10H), 0.88
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(t, J = 7.4 Hz, 3H); C NMR ((CD3)2CO) δ 154.7, 131.8, 131.0, 126.6, 64.6, 45.1, 30.8, 18.8, 13.1,
7.7.
Butyl ((5-chlorothiophen-2-yl)sulfonyl)carbamate (4s). Reaction run at 50 ºC. Colorless liquid (54
mg, 731H NMR (400 MHz, (CD3)2CO) δ 7.42 (d, J = 4.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 3.93 (t, J
= 6.7 Hz, 2H), 3.28 (q, J = 7.4 Hz, 6H), 1.58–1.48 (m, 2H), 1.39–1.27 (m, 11H), 0.89 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, (CD3)2CO)) δ 157.9, 145.4, 133.9, 130.6, 126.9, 64.9, 46.1, 31.9, 19.8,
14.0, 8.6; MS (ESI) calc’d for C9H11ClNO4S2 ([MꢀH]ꢀ) m/z 295.9823, found m/z 295.9824.
Butyl (benzo[b]thiophen-3-ylsulfonyl)carbamate (2:1 mixture with Et3N) (4t). Reaction run at 50
°C. Colorless liquid (56 mg, 54%); 1H NMR (400 MHz, (CD3)2CO) δ 8.48 (s, 1H), 8.44–8.20 (m, 1H),
8.19–7.90 (m, 1H), 7.71–7.25 (m, 2H), 3.92 (td, J = 6.6, 0.7 Hz, 2H), 3.33 (q, J = 7.3 Hz, 3H), 1.51–
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1.41 (m, 2H), 1.37 (t, J = 7.3 Hz, 4H), 1.29–1.15 (m, 2H), 0.90–0.74 (m, 3H); C NMR (100 MHz,
(CD3)2CO)) δ 156.4, 141.3, 137.9, 137.5, 136.7, 127.6, 127.5, 126.4, 126.3, 124.7, 124.1, 66.0, 47.6,
31.8, 19.9, 14.2, 9.0; MS (ESI) calc’d for C13H14NO4S2 ([MꢀH]ꢀ) m/z 312.0369, found m/z 312.0368.
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Butyl (benzylsulfonyl)carbamate (4u). Colorless liquid (55 mg, 80%); H NMR (400 MHz, CDCl3)
δ 7.45–7.32 (m, 5H), 7.02 (s, 1H), 4.63 (s, 2H), 4.23 (t, J = 6.6 Hz, 2H), 1.73–1.61 (m, 2H), 1.45–1.34
(m, 2H), 1.02–0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 151.2, 130.8, 129.4, 129.1, 128.1, 67.4,
58.6, 30.7, 19.0, 13.7; MS (ESI) calc’d for C12H16NO4S ([MꢀH]ꢀ) m/z 270.0800, found m/z 270.0791.
Isotopic labelling studies
Starting from ammoniumꢀ15N chloride (CAS 39466ꢀ62ꢀ1), 15N1ꢀ1a was prepared in 7% total yield
following the literature procedure.13a Spectral data were in agreement with literature values.
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Azide displacement study, 14N-butyl-4-methylbenzenesulfonamide (2a). Following the general
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procedure (starting from 0.05 mmol N1ꢀ1a), the title compound was obtained as a colorless liquid
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(11 mg, 71%). Mass spectrometry and 15N NMR confirmed its identity as the title compound.
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Butyl tosylcarbamate-15N (15N-4a). Following the general procedure (starting from 0.05 mmol 15N1ꢀ
1a), the title compound was isolated as a colorless liquid (8 mg, 69%); 1H NMR (400 MHz, CDCl3) δ
7.98–7.53 (m, 2H), 7.34–7.27 (m, 2H), 4.55 (s, 1H), 3.03–2.79 (m, 2H), 2.42 (s, 3H), 1.43 (s, 2H),
1.35–1.22 (m, 2H), 0.84 (dd, J = 7.8, 6.8 Hz, 3H); 15N NMR (40 MHz) δ ꢀ241.2. MS (ESI) calc’d for
C12H1815NO4S ([M+H]+) m/z 273.0927, found m/z 273.0936.
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Control reaction
Following the general procedure for formation of sulfonyl carbamates but with tosyl amide (43 mg,
0.25 mmol), no product could be observed. Using 1a (50 mg, 0.25 mmol) and Pd(PPh3)4 (6 mg, 5
µmol), 4a was isolated in 59% yield.
Acknowledgements
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The authors thank Prof. Adolf Gogoll for assistance with N NMR studies and Dr. Lisa Haigh for
assistance with accurate mass determination. Financial support from the Knut and Alice Wallenberg
foundation and the Carl Tryggers Stiftelse för Vetenskaplig Forskning (CTS) is gratefully
acknowledged.
Associated Content
Supporting information
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13
Twoꢀchamber, experimental apparatus for carbonylation, stability studies, H and C spectra for all
products and 15N spectra for 15N-4a. This material is available free of charge via the Internet at
http://pubs.acs.org/.
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