Iodine-catalyzed expeditious synthesis of sulfonamides from sulfonyl hydrazides and amines

Article abstract of DOI:10.1039/c5ob02075a

A new synthesis of sulfonamides has been developed via an iodine-catalyzed sulfonylation of amines with arylsulfonyl hydrazides. This metal-free strategy employs readily accessible and easy to handle starting materials, catalysts and oxidants, and can be easily conducted under mild conditions, providing a convenient access to a wide range of sulfonamides in moderate to excellent yields within a short reaction time.

Full text of DOI:10.1039/c5ob02075a

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DOI: 10.1039/C5OB02075A
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Iodine-Catalyzed Expeditious Synthesis of Sulfonamides from
Sulfonyl Hydrazides and Amines
Sirilata Yotphan*, Ladawan Sumunnee, Danupat Beukeaw, Chonchanok Buathongjan and Vichai
Reutrakul
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A new synthesis of sulfonamides has been developed via an iodine-catalyzed sulfonylation of amines with arylsulfonyl
hydrazides. This metal-free strategy employs readily accessible and easy to handle starting materials, catalyst and oxidant,
and can be easily conducted under mild conditions, providing a convenient access to a wide range of sulfonamides in
moderate to excellent yields within a short reaction time.
www.rsc.org/
Introduction
The traditional method for the sulfonamide formation
involves a reaction of amines with sulfonyl chlorides in the
Sulfonamides are prominent structural motifs found in
numerous bioactive molecules, pharmaceuticals, and natural
products. They exhibit a broad spectrum of biological activities
and are employed extensively in various medicinal and
pharmaceutical applications, for example as antibacterials,
anticonvulsants, HIV protease inhibitors, antitumor and
antifungal agents.1 Pharmaceutically important examples of
sulfonamides include the analgesic celecoxib, sildenafil for
erectile dysfunction and the HIV protease inhibitors darunavir
and amprenavir (Fig. 1).2 In addition, sulfonamides are
important functional groups with a wide utility in herbicides,
dyes and organic materials.3 They are also used as amine
protecting groups with an easy removability under mild
conditions.4
presence of a base.5 Other examples for the synthesis of
sulfonamides include
a transition metal-catalyzed cross-
coupling of N-unsubstituted/N-monosubstituted sulfonamides
with organohalides or boronic acids,6 a copper-catalyzed Chan-
Lam type coupling using sulfonyl azides and boronic acids,7 an
oxidation reaction of sulfenamides/sulfinamides,8 and an
oxidative coupling reaction of sulfinate salts with amines.9
Although many of these available methods can form
sulfonamides successfully, they are still limited by some
drawbacks such as using non-stable, hazardous and mutagenic
starting materials (e.g. sulfonyl chlorides and organic azides),
generating a large quantity of toxic waste, difficulty in handling
and storing, poor functional group tolerance, and requirement
of harsh conditions and prolonged reaction time. Therefore, an
alternative and facile catalytic methodology to construct
sulfonamides efficiently is highly desirable for a synthetic
viewpoint.
Fig.1 Examples of important sulfonamide drugs.
Center of Exellence for Innovation in Chemistry (PERCH-CIC),
Department of Chemistry, Faculty of Science, Mahidol University,
Bangkok 10400, Thailand.
Scheme 1 Approaches for the synthesis of sulfonamides.
E-mail: sirilata.yot@mahidol.ac.th
† Electronic Supplementary Information (ESI) available.
See DOI: 10.1039/x0xx00000x
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During the past few years, molecular iodine and its salts alternative to DCE (entry 6; 80%). Other polar or non-polar
View Article Online
DOI: 10.1039/C5OB02075A
have emerged as efficient catalysts in modern synthetic solvents were less efficient (entries 7–14). Further attempts to
chemistry because of the ease of handling, commercial drive the reaction to completion by increasing the temperature
availability, low toxicity, mild reactivity and versatile nature of were unsuccessful; there was no improvement in yield through
the reagents. A number of studies have demonstrated our efforts and a slight decrease in product yield was found as
impressive advancements of iodine- and iodide-catalyzed temperature increased (entries 15−17).16 Screening a range of
carbon−carbon and carbon−heteroatom bonds formation.10 additives (acid, base, etc) and oxidants such as H2O2, di-tert
Our group are also interested in exploring a metal-free catalytic butyl peroxide (DTBP) revealed that other reagents were
approach for the synthesis of biologically active nitrogen- ineffective for this transformation.16 In addition, no reaction
containing compounds.11 We recently reported a convenient was observed in the absence of I2 catalyst (entry 18), and only
synthesis of sulfonamides via an iodine-catalyzed oxidative trace amount of product was obtained when TBHP was omitted
coupling reaction of sodium sulfonates and amines.9c The from the reaction (entry 19). These results highlighted the
combination of catalytic amount of iodine and tert-butyl importance of both I2 catalyst and TBHP for this catalytic
hydroperoxide (TBHP) or hydrogen peroxide (H2O2) has reaction.
provided an expedient liaison for our successful
transformations.
Recently, the readily accessible sulfonyl hydrazides have
received considerable attention as an excellent synthon for
many organic transformations. They have been used as
odourless and easy to handle sulfonyl sources,12 sulfenylating
reagents (aryl thiol surrogates),13 and arylating precursors.14
Depending upon the nature of the reaction conditions, sulfonyl
hydrazides can act as nucleophiles or electrophiles. Comparing
to other sulfur reagents, sulfonyl hydrazides are not sensitive to
air and moisture, exhibit high reactivity and versatility under
relatively mild conditions, and give eco-friendly byproducts
(water and N2). However, to the best of our knowledge, the
formation of sulfonamides from sulfonyl hydrazides and amines
has not been explored so far. With our continuing efforts
towards the development of improved catalytic methods for
sulfonamide preparation, herein, we wish to report a new route
to synthesize sulfonamides via iodine-catalyzed sulfonylation of
amines with arylsulfonyl hydrazides. The present method is
metal-free, features simple experiment procedure,
accommodates a broad scope of substrates, generates clean by-
products, and can be a good synthetic tool to access a number
of sulfonamide products in reasonable to excellent yields at
room temperature within a short reaction time.
Entry
1
2
3
4
5
6
7
8
Catalyst
Solvent
DCE
DCE
DCE
DCE
T (°C)
rt
rt
rt
rt
rt
rt
rt
rt
rt
Yieldb (%)
67
36
64
45
85
80
49
46
NIS
KI
NH4I
TBAI
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
DCE
CH2Cl2
Toluene
MeCN
MeOH
H2O
DMSO
DMF
THF
1,4-Dioxane
DCE
DCE
DCE
DCE
9
20
10
11
12
13
14
15
16
17
18
19
rt
rt
rt
rt
trace
trace
trace
73
70
80
rt
40
60
80
rt
80
76
-
I2
0
DCE
rt
tracec
a Conditions: 1a (0.5 mmol), 2a (1.5 mmol), TBHP in decane (1.5 mmol),
catalyst (0.1 mmol; 20 mol%), solvent (4 mL), 1 h. b Isolated yield. c No
TBHP added.
Results and discussion
To evaluate the feasibility of sulfonamide formation via a
catalytic sulfonylation of amines from sulfonyl hydrazide
precursors, we initiated our investigation by studying a coupling
Overall, the optimal conditions for I2-catalyzed sulfonylation
of amines were established (Table 1, entry 5; 1 equiv. of sulfonyl
hydrazide, 3 equiv. of amine, 20 mol% of I2, 3 equiv. of TBHP,
DCE, rt, 1 h). With these conditions in hand, we sought to
expand the substrate scope that is applicable for the current
reaction. Therefore, the sulfonylation reaction between p-
toluenesulfonyl hydrazide (1a) and different types of amines
were tested under the established conditions and the results
reaction between p-toluenesulfonyl hydrazide
(1a) and
diethylamine (2a) as a model reaction. After screening several
combinations of catalysts (metals and non-metals) and oxidants
(see Supporting Information), the reaction proceeded in high
yield when 20 mol% of molecular iodine (I2) was employed in
combination with TBHP (3.0 equiv.) in 1,2-dichloroethane (DCE)
solvent at room temperature. Moreover, the reaction was
essentially complete after 1 hour15 and gave the corresponding
sulfonamide product 3a in 85% yield (Table 1, entry 5). The
combination of TBHP with other forms of iodine or iodide salts
showed lower catalytic activities (entries 1−4). Encouraged by
these results, various solvents were screened and
dichloromethane (CH2Cl2) could also be used as a viable
were summarized in Table 2 (3a−3i). A range of secondary
aliphatic amines, including acyclic and cyclic amines, were
suitable for this I2-catalyzed sulfonylation reaction and they
delivered the expected products in good to excellent yields
(3a−3f). Additional oxygen or sulfur heteroatom in the amine
was tolerated, as shown by the successful sulfonylation
reactions with morpholine or thiomorpholine in this
transformation (3c1 and 3c2). Delightfully, 1-methyl piperazine
and 1-boc-piperazine exhibit relatively high reactivity toward
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sulfonylation reaction and the sulfonamide products 3d1 and transformation, leading to a formation of productVsie4waA4rtaicnledOn4liane5
3d2 were achieved in excellent quantities (87 and 90%, in decent yields. Notably, arylsulfonyDl OhI:y1d0.r1a0z3i9d/eCs5ObB0e2a0r7in5Ag
respectively). Benzyl protecting groups on nitrogen were also substitutents at ortho position (o-CH3 and o-Br) could be
compatible with the standard conditions, affording good to high converted to their corresponding sulfonamide products 4b1 and
yields of desired products 3e1 and 3e2. In case of diallylamine, 4b2 in very high yields (90 and 84%, respectively). Additionally,
the sulfonamide product 3f could be collected in moderate mesitylenesulfonyl hydrazide substrate was effective substrate
quantity (48 %). We next turned our attention to reactions of for this reaction, furnishing the product 4c in 82% yield.
primary amines in which sulfonylation reactions also proceeded Remarkably, the heteroarylsulfonyl hydrazides were also
readily and yielded only single products under the optimal tolerated under these conditions as exemplified by the
conditions (3g1−3g3). Moreover, modest to good amounts of successful reaction using 2-thiophene- and 8-quinolinesulfonyl
sulfonamide products (3h and 3i) were obtained upon hydrazide substrates (4d and 4e). Nevertheless, none or trace
examining sulfonylation reactions of heterocyclic amines amount of the desired product was obtained when aliphatic
(pyrazole, and triazole). On the other hand, we observed no sulfonyl hydrazides such as butylsufonyl hydrazide and
reaction when less nucleophilic aromatic amines were benzylsulfonyl hydrazide were employed. In this regard, it could
employed under these conditions. These results suggested that be due to an instability of reaction intermediates generated
nucleophilic character of amine could play a crucial role on a from alkylsulfonyl hydrazide substrates.
product formation.
a Conditions:
1 (1.0 mmol), morpholine (3.0 mmol), TBHP in decane (3.0
mmol), I2 (0.2 mmol, 20 mol%), DCE (8 mL), rt, 1 h. Isolated yield.
It is noteworthy that the synthesis of sulfonamide via this
iodine-catalyzed sulfonylation of amine could be effectively
scaled up to the gram scale (10 mmol) with a similar efficacy
(Scheme 2). As shown below, p-toluenesulfonyl hydrazide (1a
)
and morpholine were reacted with each other under the
standard conditions and generated sulfonamide 3c1 in 84% yield
(2.0 gram), which might suggest a potential application in
industry.
a Conditions: 1a (1.0 mmol),
2 (3.0 mmol), TBHP in decane (3.0 mmol),
I2 (0.2 mmol; 20 mol%), DCE (8 mL), rt, 1 h. Isolated yield.
The scope of this reaction with a variety of sulfonyl
hydrazides was also investigated as illustrated in Table 3.
Various types of arylsulfonyl hydrazides are compatible with
standard conditions, affording the desired sulfonamide
Scheme 2 Gram scale reaction
products
(4a−4e) in moderate to excellent quantities.
Arylsulfonyl hydrazides with halogen-substituents (Cl and Br)
could serve as practical substrates for the I2-catalyzed
sulfonylation reaction and the sulfonamide products 4a2 and
4a3 were obtained in 80% and 86% yields. The electron-rich
(methoxy) and electron-deficient (nitro) substituents on the aryl
ring of arylsulfonyl hydrazides also underwent a successful
The utility of this protocol was further extended to the
sulfonylation of amine hydrochloride salt. Unfortunately, trace
amount of product was detected. Thus, we added
a
stoichiometric amount of Na2CO3 base for neutralization and
increasing a solubility of amine salt. In the presence of added
base, sulfonylation reactions of diethylamine hydrochloride and
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t-butylamine hydrochloride gave the sulfonamide products in radical scavenger; thus, the reaction pathway is likVeielywtAorticinlevOonllvinee
DOI: 10.1039/C5OB02075A
comparable yields to those from the reactions of normal amine a radical process.
substrates (Table 4, entries 1−2). Interestingly, when
To understand the role of iodine, this reaction was carried
ammonium chloride (NH4Cl) was applied as an amine source, out in the absence of TBHP. Upon subjecting 1 equivalent of I2,
the corresponding product 3k was produced in 66% yield.
small amount of product was observed at 1 h and 24 h (Scheme
3b). This outcome implies that I2 does not react with substrates
directly in this transformation. The I2 precatalyst, therefore, is
likely to be converted to another intermediate in the presence
of TBHP prior to reacting with sulfonyl hydrazide or amine.
Scheme 3 Control experiments
a Conditions: 1a (1.0 mmol),
2 (3.0 mmol), Na2CO3 (3.0 mmol), TBHP
in decane (3.0 mmol), I2 (0.2 mmol; 20 mol%), DCE (8 mL), rt, 1 h.
b Isolated yield.
c Isolated yield after 16 h.
d Product 3k was obtained in 30% yield after 1 h of reaction.
In comparison to previous approaches using other synthetic
precursors (e.g. sulfonyl chloride, sulfonyl azide, sodium
sulfinate), sulfonyl hydrazides have proven to be particularly
useful and attractive substrates for the preparation of
sulfonamides due to their commercial availability and synthetic
accessibility, their stability to air and moisture at ambient
temperature, their good solubility in organic solvents, and their
high reactivity under I2/TBHP-catalyzed reaction. Therefore, this
method greatly enriches current N−S bond formation chemistry
with several advantages including metal-free catalysis, mild
conditions, simple experimental procedure, using easy to
handle and readily available reagents, generating clean by-
products, and can be carried out at room temperature within a
short reaction time with reliable scalability as well as broad
substrates scope, which make this synthetic strategy highly
valuable for future applications.
Scheme 4 Possible mechanism
To elucidate the reaction mechanism of the sulfonamide
formation, several control experiments were conducted
(Scheme 3).16 A reaction of sulfonyl hydrazide 1a and amine 2a
in the presence of radical scavenger under the standard
conditions resulted in a decrease in product yield. Sulfonamide
3a was obtained in 39%, 2% and 0% in the presence of TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl), BHT (2,6-di-tert-butyl-
4-methylphenol), and hydroquinone, respectively (Scheme 3a).
These results indicated that the reaction was inhibited by a
Based on the aforementioned results and relevant
literature,10,17 a plausible mechanism for the I2-catalyzed
sulfonylation of amine is proposed in Scheme 4. This
transformation presumably involves an initial reaction of I2 and
TBHP to form a reactive iodine radical species through a radical
process.17c Then, the sequential N−H abstraction by iodine
radical would lead to a formation of sulfonyl radical (I). This
resulting sulfonyl radical could subsequently combine with
iodine radical and yield a sulfonyl iodide (II). A direct
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displacement of the sulfonyl iodide (II) by amine would furnish Na2SO4, and concentrated in vacuo. The crude product was purified
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the sulfonamide product and release HI species. Further by SiO2 column chromatography to affordDaOId: 1e0s.i1r0e3d9/sCu5lOfoBn0a2m07id5Ae
transformation of HI under standard conditions could product.
regenerate I2 to resume the catalytic cycle.16,18
N,N-diethyl-4-methylbenzenesulfonamide (3a).9c White solid (
192 mg, 85% yield); H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.2 Hz,
1
2H), 7.24 (d, J = 8.2 Hz, 2H), 3.18 (q, J = 7.0 Hz, 4H), 2.37 (s, 3H), 1.11
(t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 142.8, 137.3, 129.5,
126.9, 41.9, 21.4, 14.1; HRMS (ESI): calcd for C11H17NO2SNa [M+Na]+
250.0872, found 250.0871.
Conclusions
In summary, we have developed a new protocol for the
synthesis of sulfonamides via an iodine-catalyzed sulfonylation
of amines with sulfonyl hydrazides. In this work, for the first
time sulfonyl hydrazides were applied to the preparation of a
variety of sulfonamides at room temperature and provided
moderate to excellent yields of products within a short reaction
time. This method utilizes cheap and readily available reagents,
features simple experimental procedure, generates non-toxic
by-products, demonstrates good functional group compatibility
and proves to be versatile for a range of arylsulfonyl hydrazides
and various types of amines such as primary and secondary
aliphatic amines, heteroaromatic amines and amine
hydrochloride salts. Further mechanistic investigation and
expansion of the synthetic application of this chemistry are
currently under exploration in our laboratory.
1-tosylpyrrolidine (3b1).9c White solid (194 mg, 86% yield); 1H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz,
2H), 3.22–3.18 (m, 4H), 2.40 (s, 3H), 1.73–1.70 (m, 4H); 13C NMR (100
MHz, CDCl3): δ 143.3, 133.8, 129.6, 127.5, 47.9, 25.2, 21.5; HRMS
(ESI): calcd for C11H15NO2SNa [M+Na]+ 248.0716, found 248.0729.
1-tosylpiperidine (3b2).9c White solid (206 mg, 86% yield); 1H
NMR (400 MHz, CDCl3): δ 7.61–7.59 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H),
2.92 (t, J = 5.6 Hz, 4H), 2.39 (s, 3H), 1.62–1.57 (m, 4H), 1.40–1.34 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 143.2, 133.1, 129.5, 127.6, 46.9,
25.1, 23.4, 21.4; HRMS (ESI): calcd for C12H17NO2SNa [M+Na]+
262.0872, found 262.0877.
1-tosylazepane (3b3).9c White solid (215 mg, 85% yield); 1H NMR
(400 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H),
3.21 (t, J = 5.8 Hz, 4H), 2.38 (s, 3H), 1.68–1.66 (m, 4H), 1.55–1.52 (m,
4H); 13C NMR (100 MHz, CDCl3): δ 142.8, 136.5, 129.5, 126.9, 48.1,
29.0, 26.8, 21.4; HRMS (ESI): calcd for C13H19NO2SNa [M+Na]+
276.1029, found 276.1032.
Experimental section
General Information
Unless otherwise noted, all reagents were obtained from commercial
suppliers and used without further purification. All experiments were
carried out under air atmosphere, and oven-dried glassware was
1
4-tosylmorpholine (3c1).9c White solid (211 mg, 87% yield); H
NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz,
used in all cases. Column chromatography was performed over silica 2H), 3.70 (t, J = 4.8 Hz, 4H), 2.94 (t, J = 4.8 Hz, 4H), 2.41 (s, 3H); 13C
gel (SiO2; 60 Å silica gel, Merck Grade, 70–230 Mesh). GC
experiments were carried out with an Agilent 6890N GC-FID on
chromatograph equipped with an Agilent column (HP-1,
polysiloxane, 24.5 m × 0.32 mm ID × 0.17 µm). 1H and 13C NMR
spectra were recorded on Bruker-AV400 spectrometers in CDCl3
solution, at 400 and 100 MHz, respectively. NMR chemical shifts are
reported in ppm, and were measured relative to CHCl3 (7.24 ppm for
1H and 77.00 ppm for 13C). IR spectra were recorded on Bruker FT-IR
Spectrometer Model ALPHA by neat method, and only partial data
are listed. Melting points were determined on Buchi Melting Point
M-565 apparatus. High resolution mass spectroscopy (HRMS) data
were analysed by a high-resolution micrOTOF instrument with
electrospray ionization (ESI). The structures of known compounds
NMR (100 MHz, CDCl3): δ 143.9, 131.9, 129.7, 127.8, 66.0, 45.9, 21.5;
HRMS (ESI): calcd for C11H15NO3SNa [M+Na]+ 264.0665, found
264.0679.
4-tosylthiomorpholine (3c2).9c White solid (213 mg, 83% yield);
1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0
Hz, 2H), 3.28–3.26 (m, 4H), 2.67–2.64 (m, 4H), 2.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 143.7, 133.6, 129.7, 127.3, 47.7, 27.2, 21.4;
HRMS (ESI): calcd for C11H15NO2S2Na [M+Na]+ 280.0436, found
280.0442.
1-methyl-4-tosylpiperazine (3d1).9c White solid (221 mg, 87%
yield); 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 2H), 7.27 (d, J
= 8.0 Hz, 2H), 2.96 (br, 4H), 2.43–2.41 (m, 4H), 2.37 (s, 3H), 2.21 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 143.6, 132.1, 129.5, 127.8, 53.9,
45.9, 45.6, 21.4; HRMS (ESI): calcd for C12H19N2O2S [M+H]+ 255.1162,
found 255.1167.
tert-butyl 4-tosylpiperazine-1-carboxylate (3d2).9c White solid
(307 mg, 90% yield); 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.4 Hz,
2H), 7.30 (d, J = 8.4 Hz, 2H), 3.46 (t, J = 5.0 Hz, 4H), 2.91 (t, J = 5.0 Hz,
4H), 2.40 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 154.1,
143.9, 132.3, 129.7, 127.7, 80.3, 45.8, 43.2, 28.2, 21.5; HRMS (ESI):
calcd for C16H24N2O4SNa [M+Na]+ 363.1349, found 363.1352.
N,N-dibenzyl-4-methylbenzenesulfonamide (3e1).9c White solid
(245 mg, 70% yield); 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22–7.18 (m, 6H), 7.05–7.02 (m, 4H),
4.29 (s, 4H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.2, 137.7,
1
were corroborated by comparing their H NMR, 13C NMR data with
those of literature.
Typical procedure for the synthesis of sulfonamides 3a–3i, 3k and
4a1–4e.
To a 20 ml oven-dried scintillation vial equipped with a magnetic stir
bar, sulfonylhydrazide substrate (1.00 mmol, 1.00 equiv.), iodine (I2)
(51 mg, 0.20 mmol, 0.20 equiv.), 1,2-dichloroethane (DCE) (8.00 mL),
amine (3.00 mmol, 3.00 equiv.), and TBHP in decane (3.00 mmol,
3.00 equiv.) were added. The reaction mixture was stirred at room
temperature for 1 h. Upon completion, distilled deionized H2O (10
mL) and saturated Na2S2O3 (10 mL) were added, and the mixture was
extracted with ethyl acetate (EtOAc) (2 × 20 mL). The combined
organic layer was washed with saturated NaCl, dried over anhydrous
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135.6, 129.7, 128.5, 128.4, 127.6, 127.2, 50.4, 21.5; HRMS (ESI): calcd HRMS (ESI): calcd for C10H13NO3SNa [M+Na]+ 250.0508, found
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for C21H21NO2SNa [M+Na]+ 374.1185, found 374.1191.
250.0514.
DOI: 10.1039/C5OB02075A
N-benzyl-N,4-dimethylbenzenesulfonamide (3e2).9c White solid
4-((4-chlorophenyl)sulfonyl)morpholine (4a2).9b White solid
(246 mg, 89% yield); 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, (210 mg, 80% yield); 1H NMR (400 MHz, CDCl3): δ 7.66 (dt, J = 8.8, 2.4
2H), 7.35–7.25 (m, 7H), 4.10 (s, 2H), 2.56 (s, 3H), 2.43 (s, 3H); 13C NMR Hz, 2H), 7.50 (dt, J = 8.8, 2.4 Hz, 2H), 3.71 (t, J = 4.8 Hz, 4H), 2.96 (t, J
(100 MHz, CDCl3): δ 143.4, 135.6, 134.2, 129.7, 128.6, 128.3, 127.8, = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 139.6, 135.6, 129.4, 129.2,
127.4, 54.1, 34.3, 21.5; HRMS (ESI): calcd for C15H17NO2SNa [M+Na]+ 66.0, 45.9; HRMS (ESI): calcd for C10H12ClNO3SNa [M+Na]+ 284.0119,
298.0872, found 298.0878.
found 284.0125.
N,N-diallyl-4-methylbenzenesulfonamide (3f).19 Colorless oil
4-((4-bromophenyl)sulfonyl)morpholine (4a3).9e White solid
(121 mg, 48% yield); 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz, (263 mg, 86% yield); 1H NMR (400 MHz, CDCl3): δ 7.68–7.65 (m, 2H),
2H), 7.27 (d, J = 8.0 Hz, 2H), 5.63–5.53 (m, 2H), 5.14–5.09 (m, 4H), 7.60–7.56 (m, 2H), 3.70 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 4.8 Hz, 4H); 13
C
3.77 (d, J = 6.4 Hz, 4H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ NMR (100 MHz, CDCl3): δ 134.1, 132.4, 129.2, 128.1, 65.9, 45.8;
143.2, 137.3, 132.6, 129.6, 127.1, 118.9, 49.3, 21.5; HRMS (ESI): HRMS (ESI): calcd for C10H12BrNO3SNa [M+Na]+ 327.9613, found
calcd for C13H17NO2SNa [M+Na]+ 274.0872, found 274.0880.
327.9617.
4-((4-methoxyphenyl)sulfonyl)morpholine (4a4).9e White solid
N-cyclohexyl-4-methylbenzenesulfonamide (3g1).9c Dark yellow
solid (213 mg, 84% yield); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 (229 mg, 89% yield); 1H NMR (400 MHz, CDCl3): δ 7.65 (dt, J = 9.6, 2.4
Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 4.97–4.96 (m, 1H), 3.08–3.06 (m, 1H), Hz, 2H), 6.97 (dt, J = 9.6, 2.4 Hz, 2H), 3.84 (s, 3H), 3.69 (t, J = 4.8 Hz,
2.39 (s, 3H), 1.71–1.68 (m, 2H), 1.60–1.56 (m, 2H), 1.47–1.43 (m, 1H), 4H), 2.93 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 163.1, 129.9,
1.19–1.07 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 143.0, 138.4, 129.5, 126.4, 114.2, 66.0, 55.6, 45.9; HRMS (ESI): calcd for C11H15NO4SNa
126.9, 52.5, 33.7, 25.1, 24.5, 21.4; HRMS (ESI): calcd for [M+Na]+ 280.0614, found 280.0619.
C13H19NO2SNa [M+Na]+ 276.1029, found 276.1037.
4-((4-nitrophenyl)sulfonyl)morpholine (4a5).9e Yellow solid (236
N-butyl-4-methylbenzenesulfonamide (3g2).9c Colorless oil (180 mg, 87% yield); 1H NMR (400 MHz, CDCl3): δ 8.37 (dt, J = 9.2, 2.0 Hz,
mg, 79% yield); 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 2H), 7.92 (d, J = 9.2, 2.0 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 3.02 (t, J = 4.8
7.25 (d, J = 8.4 Hz, 2H), 5.10 (br s, 1H), 2.88–2.83 (m, 2H), 2.37 (s, 3H), Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 150.3, 141.2, 128.9, 124.4, 65.9,
1.40–1.35 (m, 2H), 1.26–1.20 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR 45.8; HRMS (ESI): calcd for C10H12N2O5SNa [M+Na]+ 295.0359, found
(100 MHz, CDCl3): δ 143.1, 136.8, 129.5, 127.0, 42.8, 31.4, 21.4, 19.6, 295.0365.
13.4; HRMS (ESI): calcd for C11H17NO2SNa [M+Na]+ 250.0878, found
250.0878.
4-(o-tolylsulfonyl)morpholine (4b1). White solid (218 mg, 90%
yield); m.p. 79.8 – 89.1 °C; 1H NMR (400 MHz, CDCl3): δ 7.86–7.84 (m,
N-(tert-butyl)-4-methylbenzenesulfonamide (3g3).9c White solid 1H), 7.44 (td, J = 7.2, 0.8 Hz, 1H), 7.32–7.28 (m, 2H), 3.68 (t, J = 4.8
(131 mg, 58% yield); 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, Hz, 4H), 3.11 (t, J = 4.8 Hz, 4H), 2.61 (s, 3H); 13C NMR (100 MHz,
2H), 7.24 (d, J = 8.0 Hz, 2H), 5.02 (br, 1H), 2.38 (s, 3H), 1.17 (s, 9H); CDCl3): δ 138.1, 134.8, 133.0, 132.8, 130.3, 126.1, 66.2, 45.2, 20.8; IR
13C NMR (100 MHz, CDCl3): δ 142.7, 140.5, 129.4, 126.9, 54.4, 30.1, (neat, cm-1): ν 2860, 1447, 1337, 1261, 1158, 1114, 942, 728; HRMS
21.4; HRMS (ESI): calcd for C11H17NO2SNa [M+Na]+ 250.0878, found (ESI): calcd for C11H15NO3SNa [M+Na]+ 264.0665, found 264.0670.
250.0894.
4-((2-bromophenyl)sulfonyl)morpholine (4b2). White solid (256
1-tosyl-1H-pyrazole (3h).9c White solid (173 mg, 78% yield); H mg, 84% yield); m.p. 127.2 – 128.4 °C; H NMR (400 MHz, CDCl3): δ
NMR (400 MHz, CDCl3): δ 8.08–8.07 (m, 1H), 7.86 (d, J = 8.0 Hz, 2H), 8.05–8.02 (m, 1H), 7.73 (dd, J = 7.6, 1.2 Hz, 1H), 7.45–7.36 (m, 2H),
7.69–7.68 (m, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.36–6.35 (m, 1H), 2.38 (s, 3.70–3.67 (m, 4H), 3.26–3.24 (m, 4H); 13C NMR (100 MHz, CDCl3): δ
3H); 13C NMR (100 MHz, CDCl3): δ 145.8, 145.1, 133.9, 131.0, 130.0, 137.0, 135.8, 133.8, 132.3, 127.5, 120.4, 66.3, 45.6; IR (neat, cm-1): ν
128.0, 108.7, 21.6; HRMS (ESI): calcd for C10H10N2O2SNa [M+Na]+ 2860, 1573, 1344, 1262, 1166, 1113, 942, 761, 532; HRMS (ESI): calcd
1
1
245.0355; found 245.0365.
for C10H12BrNO3SNa [M+Na]+ 327.9613, found 327.9618.
1-tosyl-1H-1,2,4-triazole (3i).20 White solid (131 mg, 59% yield);
4-(mesitylsulfonyl)morpholine (4c).21 White solid (220 mg, 82%
1H NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.6 yield); H NMR (400 MHz, CDCl3): δ 6.93 (s, 2H), 3.67–3.65 (m, 4H),
Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, 3.13–3.10 (m, 4H), 2.60 (s, 6H), 2.27 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 154.1, 147.2, 144.4, 132.6, 130.3, 128.6, 21.8; HRMS (ESI): CDCl3): δ 142.9, 140.6, 131.9, 130.7, 66.1, 44.3, 22.9, 20.9; HRMS
1
calcd for C9H9N3O2SNa [M+Na]+ 246.0313; found 223.0323.
(ESI): calcd for C13H19NO3SNa [M+Na]+ 292.0978, found 292.0985.
4-methylbenzenesulfonamide (3k).9c White solid (113 mg, 66%
4-(thiophen-2-ylsulfonyl)morpholine (4d).22 White solid (106
yield); 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.29 (d, J mg, 41% yield); 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J = 4.8, 1.2 Hz,
= 8.0 Hz, 2H), 4.92 (s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 1H), 7.51 (dd, J = 4.0, 1.2 Hz, 1H), 7.14 (dd, J = 4.8, 4.0 Hz, 1H), 3.74
143.6, 139.0, 129.7, 126.4, 21.5; HRMS (ESI): calcd for C7H9NO2SNa (t, J = 4.8 Hz, 4H), 3.03–3.00 (m, 4H); 13C NMR (100 MHz, CDCl3): δ
[M+Na]+ 194.0246, found 194.0252.
135.1, 132.7, 132.5, 127.7, 65.9, 45.9; HRMS (ESI): calcd for
4-(phenylsulfonyl)morpholine (4a1).9e White solid (187 mg, 82% C8H11NO3S2Na [M+Na]+ 256.0073, found 256.0081.
yield); 1H NMR (400 MHz, CDCl3): δ 7.73–7.70 (m, 2H), 7.61–7.57 (m,
4-(quinolin-8-ylsulfonyl)morpholine (4e).9e White solid (208 mg,
1H), 7.54–7.50 (m, 2H), 3.69 (t, J = 4.8 Hz, 4H), 2.95 (t, J = 4.8 Hz, 4H); 75% yield); 1H NMR (400 MHz, CDCl3): δ 9.03 (dd, J = 4.0, 1.6 Hz, 1H),
13C NMR (100 MHz, CDCl3): δ 134.9, 133.0, 129.0, 127.7, 66.0, 45.9; 8.44 (dd, J = 7.6, 1.2 Hz, 1H), 8.22 (dd, J = 8.4, 1.6 Hz, 1H), 8.02 (dd, J
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
Ranyanil, G. Balan and N. L. Calkins, J. Org. Chem., 2007, 72
,
= 8.4, 1.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.52–7.49 (m, 1H), 3.68 (t, J
= 4.8 Hz, 4H), 3.41 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ
151.2, 144.1, 136.4, 136.3, 133.6, 133.3, 128.9, 125.4, 122.0, 66.8,
46.3; HRMS (ESI): calcd for C13H14N2O3SNa [M+Na]+ 301.0617, found
301.0620.
View Article Online
683; (e) R. Sridhar, B. Srinivas, V. P. Kumar, M. Narender and
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Acknowledgements
The authors gratefully acknowledge financial support from
Thailand Research Fund (TRF) Grant TRG5780148, Faculty of
Science, Mahidol University, the Office of the Higher Education
Commission and Mahidol University under the National
Research Universities Initiative and the Center of Excellence for
Innovation in Chemistry (PERCH-CIC). The authors also thank
Department of Chemistry and the Center of Instrumental
Facility (CIF), Faculty of Science, Mahidol University for
providing research facilities.
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Page 8 of 8
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15 We observed the iodine-catalyzed sulfonylation of
diethylamine (2a) completed after 10 minutes and afforded
sulfonamide 3a in 85% yield (monitoring by GC). At longer
reaction time (1 or 24 hours), we did not observe the product
decomposition. Thus, we chose 1 hour of reaction time for
further evaluation of other reaction variables and
investigation of substrate scope.
16 See the ESI† for details.
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18 Due to the difficulty in isolating a reaction intermediate and
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8 | J. Name., 2012, 00, 1-3
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