Straightforward and Sustainable Synthesis of Sulfonamides in Water under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201800504

Ideally, a sustainable chemical synthesis should involve the use of non-toxic solvents and reactants, easy separations and purification by energy-efficient processes. In this context, reconsidering the synthesis of widely used drugs is especially timely and should allow important benefits to be obtained in terms of environmental impact. Sulfonamides are pertinent as their synthesis generally requires the use of toxic and/or hard-to-remove solvents such as dichloromethane, DMF and DMSO. In addition, toxic and highly reactive sulfur-containing sources such as sulfonyl chloride are often involved and coupled with amines. Moreover, the latter may exhibit some toxicity and are generally difficult to purify. Herein, we disclose the unprecedented and sustainable synthesis of sulfonamides by using sodium sulfinate as a commercial and stable sulfur source and nitroarenes as the nitrogen-containing reactant. In addition, under the optimized conditions only water is used as a “green” solvent and the products are collected by simple filtration.

Full text of DOI:10.1002/ejoc.201800504

A Journal of
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Title: Straightforward and sustainable synthesis of sulfonamides in
water under mild conditions
Authors: Nadim EID, Iyad Karame, and Bruno ANDRIOLETTI
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800504
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10.1002/ejoc.201800504
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Straightforward and sustainable synthesis of sulfonamides in
water under mild conditions
Nadim Eid,[a,b] Iyad Karamé,*[b] and Bruno Andrioletti *[a]
Abstract: Ideally, a sustainable chemical synthesis should involve
the uses of non-toxic solvents and reactants, easy separations and
purifications with energy efficient processes. In this context,
reconsidering the synthesis of widespread drugs is especially timely
and should allow obtaining important benefits in terms of
environmental impact. Sulfonamides are pertinent as their synthesis
requires generally the use of toxic and/or hard to remove solvents
such as dichloromethane, DMF and DMSO. In addition, toxic and
highly reactive sulfur-containing sources such as sulfonyl chloride
are often involved and coupled with amines. Moreover, the latter
may exhibit some toxicity and are generally difficult to purify. Herein,
we disclose the unprecedented and sustainable synthesis of
sulfonamides using sodium sulfinate as a commercial and stable
sulfur source and nitro- arenes as the nitrogen-containing reactant.
In addition, the optimized conditions use water as the only “green”
solvent and the products are collected by simple filtration.
Figure 1. Different bioactive sulfonamides.
Introduction
Another synthetic pathway is the functionalisation of the
sulfonamides. This can be achieved by using a wide variety of
reactants such as aryl nonaflate,[15] aryl halide,[16] alcohols,[17-19]
aldehydes[20] or boronic acids.[21] In addition, all the methods
described in the literature use organic solvents such as
dichloromethane and/or toxic activating agents such as thionyl
chloride for the preparation of the sulfonamides. Hence, low
atom economy was achieved. Furthermore, all the reagents are
prepared by multi synthetic steps and time-consuming
purifications are needed generally.
The unique success of the sulfonamide drug Prontosil[1]
commercialized in 1935 led to intense investigations in the field.
Consequently,
a large number of sulfonamide bioactive
molecules found applications in human[2] and veterinary
medicine,[3-4] but also in agriculture[5] (Figure 1).
Several approaches describing the synthesis of the sulfonamide
function from a wide variety of substrates can be found in the
literature. For instance, a large number of strategies involve
amines as the nitrogen source and sulfonyl chloride[6-7] or a
chlorinating agent with the corresponding sulfurated starting
materials in various oxidation states[8-11] to create the S-N bonds.
Some non-conventional methods using transition metal[12] or
Grignard reagents[13] are also effective (Scheme 1). Of note,
Revankar et al. have prepared a purine based sulfonamide by
oxidation of the sulfenamide analogue.[14]
Scheme 1. Synthesis of sulfonamides from different substrates.
[a]
[b]
Univ Lyon, Université Claude Bernard Lyon 1, ICBMS-UMR 5246,
Campus Lyon-Tech la Doua, Bâtiment Lederer, 1 rue Victor Grignard,
69622 Villeurbanne, France. E-mail: bruno.andrioletti@univ-lyon1.fr
Lebanese University, Faculty of Science I, Laboratory of
Organometallic Catalysis and Coordination Chemistry, Beirut,
Lebanon. E-mail: iyad.karameh@ul.edu.lb
Conversely, sodium sulfinates constitute a promising alternative
to sulfonyl chloride because of their moisture tolerance and easy
synthesis. Indeed, they can be prepared via addition of
organometallic reagents to sulfur dioxide or DABSO.[22] For
instance, sodium sulfinates were used advantageously for
coupling reactions as “arene donors”[23] and for sulfonamide
synthesis via copper catalyzed oxidative coupling with
amines.[24] Recently, Yang et al. described another non-
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800504
European Journal of Organic Chemistry
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catalyzed approach to prepare sulfonamide using sodium
sulfinate and an amine in the presence of iodine as oxidant in
ethanol.[25-26]
with 3 equivalents of sodium bisulfite as the reducing agent at
60°C (Scheme 3).
Nitrogen-containing molecules are usually prepared by reduction
of imine (reductive amination),[27] azide[28] or nitro- group.[29]
However, many amines are toxic[30-31] and their purification is
always challenging. Hence, by-passing the amine function would
afford an advantageous synthetic shortcut for the preparation of
sulfonamides. The nitro- function appears as a promising
alternative to amines. Indeed, nitro-containing molecules are
easy available from simple nitration with nitric acid,[32] Henry
reaction,[33] palladium catalyzed coupling of nitromethane,[34] or
Scheme 3. Our new strategy in sulfonamide synthesis.
Results and Discussion
by functionalizing
a
nitro-containing molecule using
a
hypervalent iodine reagent[35]. The nitro- function is mainly used
as precursor for the preparation of amines by reduction. Due to
their good stability and large availability, nitro- groups constitute
good nitrogen donor. Leimgruber-Batcho[36] indole synthesis is a
remarkable example of the use of a nitro arene in industry at the
expense of the corresponding amines for the preparation of
nitrogen fused rings.
In
a
preliminary screening, we decided to react 2-
nitrobenzaldehyde with sodium p-toluenesulfinate in different
solvents. The choice of 2-nitrobenzaldehyde as a coupling
partner is justified by the fact that the synthesis of sulfonamides
via the amine route is not efficient because of the instability of 2-
aminobenzaldehyde.[40] The reaction did not take place in most
organic solvents (THF, 2-MeTHF, acetone, acetonitrile, ethanol,
ethyl acetate and propylene carbonate, Scheme 4), probably
due to the limited solubility of the sulfinate and bisulfite in these
solvents.
Besides, catalysts play essential roles in sulfonamide synthesis,
as mentioned by Zhang et al., the reaction can proceed without
catalyst in DMSO but with poor yields.[37] Furthermore, metallic
residues resulting from the catalytic process may not be suitable
for uses in the pharmaceutical industry.[38] Zaho et al.[39]
described a sulfonamide synthesis by coupling nitroarenes and
aryl sulfonyl hydrazide in DMF using palladium acetate as the
catalyst in the presence of pyridine and molecular sieves.
Another catalytic system was developed by Zhang et al..[37] It
uses 10% of FeCl2 and trans-N,N′-dimethylcyclohexane-1,2-
diamine as the catalyst, under argon atmosphere in the
presence of an excess of aryl sulfinate salts in DMSO. Using
these conditions, they obtained sulfonamides in good yields
(Scheme 2).
Scheme 4. Solvent determination.
Interestingly, the reaction proceeded in DMSO or water.
However, if the N-(2-formylphenyl)-4-methylbenzenesulfonamide
(Scheme 4) is highly soluble in DMSO, it precipitates in water.
Hence, the low solubility of the sulfonamide in water enables a
facile separation of the product by simple filtration. Accordingly,
we have selected water as solvent for this transformation.
Next, we determined the nature of the optimal reducing agent.
Several sulfur-containing molecules were evaluated (Table 1).
As expected, the reaction does not take place without reducing
agent (Table 1, entry 1) but the screening revealed that sodium
bisulfite efficiently promotes the reaction (Table 1, entries 5-9). If
3 equivalents of sodium bisulfite are used, a full conversion is
observed (Table 1, entry 6).
Table 1. Optimization of the different reaction conditions.
Scheme 2. Nitroaryl as nitrogen donor.
Entry
A
-
eq of A
-
eq of B
1.2
conv (%)[a]
0
Herein, we present a simple strategy for the synthesis of
sulfonamides using water as the only green solvent. This
approach involves nitroarenes as nitrogen donor and sodium
sulfinate salts as the sulfur source in stoichiometric amounts
1
2
3
Na2S2O3
Na2SO3
3
3
1.2
1.2
0
0
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10.1002/ejoc.201800504
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S8
3
1.5
3
1.2
1.2
1.2
1
0
4
5
5
6
+
+
60
75
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
80
100
100
18
6
3
7
8[b]
9[c]
3
1
Conditions: 2.5 mmol nitroarene, sodium p-toluenesulfinate (1 eq), sodium
bisulfite (3 eq), 60 °C, 24h. +: water soluble, -: insoluble in water. Y: yield.
3
1
38
Next, the effect of the relative position of the substituents on the
aromatic ring was investigated. As shown in Table 3,
nitrobenzaldehydes, nitrobenzophenones, and nitrobenzoic
acids were converted to the corresponding sulfonamides in
moderated to good yield. Nitrobenzene shows a moderate
reactivity and gives the corresponding sulfonamide in 33%
isolated yield (Table 3, entry 1) but the formyl- or carboxylic acid
ortho-substituted nitroarenes appeared more reactive as the
expected products were isolated in 73 and 75% isolated yield,
Reaction conditions: 0.375 g 2-nitrobenzaldehyde, sodium p-toluenesulfinate
B, reducing agent A, 60 °C, 3h, [a] determined by 1H NMR related to 2-
nitrobenzaldehyde. [b] 25 °C. [c] 35 °C, conv: conversion.
Interestingly, a complete conversion was observed within 3
hours even when a stoichiometric amount of the sulfinate salt
was used (Table 1, entry 7).
The temperature appears also critical for the reaction. If the
transformation proceeds at room temperature, a limited 18%
conversion was determined (Table 1, entry 8). However, full
consumption of the starting materials was reached when the
temperature was increased from 25 °C to 60 °C (Table 1, entry
7). Consequently, 60 °C was chosen as the optimal reaction
temperature.
respectively (Table 3, entries
2
and 8). However, 2-
nitroacetophenone did not react because of the steric strain
caused by the neighboring methyl group (Table 3, entry 5). The
meta-substituted nitroarenes (Table 3, entries 3 and 6) appeared
moderately reactive (35% and 25% isolated yield, respectively)
but the para-substituted analogues were shown more reactive
(Table 3, entries 4 and 7) at the exception of 4-nitrobenzoic acid
(Table 3, entry 10). Interestingly, bis-nitroarenes were also
converted to sulfonamides, though in moderated yields (20-30%)
(Table 3, entries 11 and 12).
Influence of the substitution on the
nitroarenes
A variety of nitroarenes was successfully converted to the
corresponding sulfonamides in good yield under the optimized
conditions at the exception of water-insoluble or electron-
enriched nitroarenes (Table 2, entries 1 and 2). Hence, soluble
nitroarenes such as nitrobenzene (Table 2, entry 3), 2-
nitrobenzaldehyde (Table 2, entry 4), 4-nitroacetophenone
(Table 2, entry 5) and 2-nitrobenzoic acid (Table 2, entry 6)
afforded the corresponding expected sulfonamides in good
yields under the optimized reaction conditions.
Table 3. Effect of the substitution.
Entry
1
Substrate
Product
T(h)
Y(%)
48
33 [a]
2
3
4
3
4
3
73
35
55
Table 2. Screening of the nitroarenes.
Entry
Substrate
Solubility
Y(%)
1
-
-
2
3
4
+
+
+
-
5
6
48
48
Nd
33
73
25[a]
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10.1002/ejoc.201800504
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N-propylbenzenesulfonamide, but the reaction was little
chemoselective and afforded a variety of sulfurated by-products
resulting from the homo-reaction of sodium p-toluenesulfinate
(Scheme 5). Similar bis-sulfur products were also obtained in
7
24
60
water using
a
cobalt catalyst.[42] Their presence can be
explained to the slow kinetics of this transformation (low
electrophilicity of the nitro group), allowing the competitive
homo-reaction between sulfinates to proceed.
8
9
4
4
75[b]
44[b]
10
11
4
23[b]
24
24
30[c]
Scheme 5. Reaction of nitropropane with sodium p-toluenesulfinate.
Screening of sodium sulfinate salts
12
20[c]
Several sodium sulfinates salts were evaluated. 2-
Nitrobenzaldehyde was chosen as the nitrogen source (Table 4).
Aromatic sodium sulfinates react with 2-nitrobenzaldehyde to
afford the corresponding sulfonamide in good yield. Yet,
substituted aryls with even electron withdrawing (Table 4, entry
3) or electrodonating groups (Table 4, entry 2) appear to be
more reactive than sodium-benzenesulfinate (Table 4, entry 1)
and afforded the expected sulfonamide in 58, 75, and 32% yield,
respectively. Interestingly, the sodium methanesulfinate was
transformed to the corresponding sulfonamide moiety in good
yield 55% (Table 4, entry 4), and the product was crystallized
from water within 48h at room temperature and collected via
filtration. However, sodium triflinate (Table 4, entry 5) was not
reactive under these conditions.
13
14
3
78[d]
2
38
15
16
4
2
40[d]
30
Table 4 Screening of sodium sulfinates.
Conditions: 2.5 mmol nitroarene, sodium p-toluenesulfinate (1eq/ nitro
fonction), sodium bisulfite (3 eq/ nitro fonction), 60 °C, [a] after column
chromatography separation; [b] K2CO3 (1 eq), [c] NaHSO3 (6 eq), sodium p-
toluenesulfinate (2 eq), K2CO3 (1 eq), [d] NaHSO3 (6 eq), sodium p-
toluenesulfinate (2 eq), Nd: not determined. T: reaction time, Y: yield.
Entry
Sulfinate salt
Product
Y(%)
1
32
Highly functionalized sulfonamides were also prepared efficiently
using our one-step methodology (Table 3, entries 13-16) For
example, the 3 synthetic steps (including an oxidation and a
reduction) were required for the preparation of N-(5-bromo-2-
formylphenyl)-4-methylbenzenesulfonamide (Table 3, entry
14).[41] In our case, it could be prepared in a single step 38%
isolated yield.
2
3
75
58
Nitroalkyl such as nitropropane was also converted to 4-methyl-
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10.1002/ejoc.201800504
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monosubstituted sulfonamide even when 1 equivalent of sodium
p-toluenesulfinate per substrate was used. We believe that the
monosulfonamide product 2 is more reactive than the starting
3,5-dinitrobenzoic acid leading to a mixture between mono and
bis substituted aryl carboxylic acid (Scheme 7).
4
5
55
0
Reaction conditions: 0.375 g 2-nitrobenzaldehyde, sodium sulfinate (1 eq),
NaHSO3 (3 eq), 60 °C, 24h, Y: yield.
Scheme 7. Reaction of sodium p-toluenesulfinate with 3.5 dinitrobenzoic acid.
Rationalization
As mentioned above, only electron poor nitroarenes are reactive
under our optimized conditions. This is in agreement with the
mechanism proposed by Zhang et al.[42] Indeed, the key step of
the reaction is the nucleophilic attack of the sulfur atom on the
nitro function to create the S-N bond before the N-O is reduced
by the sodium bisulfite to generate a sulfate ion and the
sulfonamide function. Accordingly, electron poor nitroarenes are
more reactive than the electron rich analogues.
Conversely, aromatic sulfinates seem not to be affected by the
electronic factors. For example, sodium p-toluenesulfinate
(Table 4, entry 2) and sodium p-chlorobenzenesulfinate (Table 4,
entry 3) yielded the expected sulfonamide in 75% and 58% yield,
respectively. At last, electron rich aliphatic sulfonates such as
sodium methanesulfinic acid (Table 4, entry 4) reacted smoothly,
but the less nucleophilic sodium triflinate (Table 4, entry 5) did
not react in our conditions.
This difference in reactivity was further evidenced in the
competitive reaction between sodium p-toluenesulfinate and
sodium methanesulfinic acid using 2-nitrobenzaldehyde as
nitrogen source under optimized conditions. Analysis of the
crude reaction mixture revealed that a 80:20 ratio between 1 and
2 (Scheme 6) was produced. Interestingly, the two products
were isolated separately in pure form without any column
chromatography. Indeed, 1 was isolated by a simple filtration
and 2 via extraction from aqueous phase.
Scalability and solvent purity
In order to explore further the versatility of the transformation, a
large scale reaction using 3 g of 2-nitrobenzaldehyde was
carried out. Even when tap water was used as the solvent, the
expected sulfonamide was collected 67% yield in pure form after
precipitation. The results are comparable with the results
obtained in a 0.37 g batch.
Conclusion
In summary, we have developed a sustainable sulfonamide
preparation from commercially available and non-toxic starting
materials under mild conditions. This method overcomes the
traditional issues of sulfonamide synthesis that involve the use
of toxic, unstable reagents such as thionyl and sulfonyl chloride
or metal catalysis. A very high chemoselectivity was obtained as
only electron poor and water soluble nitroarenes were reactive.
Hence, a wide range of sodium sulfinate was transformed to the
corresponding sulfonamide in good yield, in one step. In addition,
no protecting groups were needed because of the high function
tolerance when using nitro and sulfinate compounds. At last, the
products were collected via simple filtration without using any
organic solvent for extraction or chromatography separation
ensuring a high mass efficiency.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
The authors thank the University Claude Bernard Lyon 1, the
CNRS and the Lebanese University for partial financial support.
Scheme 6. Competitive reaction between aliphatic and aromatic sulfinates.
Next, we investigated the selectivity of the transformation using
a di-nitro reactant. Unfortunately, all the attempts using 2,4-
dinitrobenzoic acid or 3,5-dinitrobenzoic acid failed to afford the
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3
300 MHz): δ (ppm) 10.79 (s, 1H, NH), 9.83 (s, 1H, CHO), 7.77 (d, J
3
3
= 8.2 Hz, 2H, ArH), 7.68 (d, J = 8.4 Hz, 1H, ArH), 7.59 (dd, J =
4
3
7.6, J = 1.5 Hz, 1H, ArH), 7.55 – 7.45 (ddd, J = 7.6 Hz, 3J = 7.6
Hz, 4J = 1.5 Hz 1H, ArH), 7.24 (d, 3J = 8.2 Hz, 2H, ArH), 7.16 (ddd,
3J = 7.5, 3J = 7.5, 4J = 0.9 Hz, 1H, ArH), 2.36 (s, 3H, CH3).13C NMR
(CDCl3, 75 MHz): δ (ppm) 195.1, 144.3, 140.0, 136.2, 135.9, 129.8,
127.4, 123.0, 121.9, 117.8, 21.6.
Experimental Section
1. General information
All reagents were obtained commercially and were used without
further purification. 1H NMR spectra were recorded on a Bruker 300
MHz spectrometer. Samples were prepared in CDCl3 or DMSO-d6
(residual solvent reference: 7.26 ppm for CDCl3, 2.50 ppm for
DMSO-d6) depending on their solubility. 13C NMR spectra were
recorded at 75 MHz in CDCl3 or DMSO-d6 (residual solvent
reference: 77.0 ppm for CDCl3 and 39.52 ppm for DMSO-d6).
N-(3-formylphenyl)-4-methylbenzenesulfonamide (Table 3, entry 3)
(C14H13NO3S): white powder, Yield 35%.1H NMR (CDCl3, 300 MHz): δ
3
(ppm) 9.91 (s, 1H, CHO), 7.70 (d, J = 8.1 Hz, 2H, ArH), 7.64 – 7.54 (m,
3
2H, ArH), 7.42 (m, 3H, ArH), 7.24 (d, J = 8.1 Hz, 2H, ArH), 2.37 (s, 3H,
CH3).13C NMR (CDCl3, 75 MHz): δ (ppm) 191.7, 144.5, 137.9, 137.4,
135.8, 130.2, 130.0, 127.3, 126.8, 126.4, 121.5, 21.6.
N-(4-formylphenyl)-4-methylbenzenesulfonamide (Table 3, entry 4)
2. Synthesis of sulfonamides
1
(C14H13NO3S): white powder, Yield 55%. H NMR (DMSO-d6, 300 MHz):
3
δ (ppm) 10.96 (s, 1H, NH), 9.80 (s, 1H, CHO), 7.75 (br t, J = 8.7 Hz, 4H,
A mixture of sodium sulfinates (0.5 mmol), nitroarenes (0.5 mmol),
NaHSO3 (1.5 mmol) in water (2 mL) were stirred at 60 °C for the
appropriate reaction time (reaction was monitored by TLC (5/1 or
3/1: cyclohexane/ ethyl acetate depending on the substrate
polarity)). After cooling at room temperature, water (8 mL) was
added. The precipitate was collected by filtration and washed with
water to afford the pure product. All sulfonamides could be
crystallized from acetone/water or by slow evaporation of DCM
solutions.
3
ArH), 7.37 (d, 3J = 8.0 Hz, 2H, ArH), 7.28 (d, J = 8.6 Hz, 2H, ArH), 2.32
(s, 3H, CH3).13C NMR (DMSO-d6, 75 MHz): δ (ppm) 191.5, 143.8, 143.5,
136.5.4, 136.2, 131.3, 131.1, 129.9, 126.7, 118.0, 20.9.
N-(3-acetylphenyl)-4-methylbenzenesulfonamide (Table 3, entry 6)
(C15H15NO3S): white powder, Yield 25%.1H NMR (DMSO-d6, 300 MHz): δ
(ppm) 7.67-7.61 (m, 4H, ArH), 7.41-7.31 (m, 4H, ArH), 2.49 (s, 3H, CH3),
2.31 (s, 3H, CH3).13C NMR (DMSO-d6, 75 MHz): δ (ppm) 197.3, 143.4,
138.4, 137.6, 136.5, 129.7, 129.6, 126.7, 124.1, 118.4, 26.6, 20.9.
3. Reaction of sodium p-toluenesulfinate with 3.5
N-(4-acetylphenyl)-4-methylbenzenesulfonamide (Table 3, entry 7)
(C15H15NO3S): white powder, Yield 60%.1H NMR (DMSO-d6, 300 MHz): δ
dinitrobenzoic acid
3
3
(ppm) 10.80 (s, 1H, NH), 7.82 (br d, J = 8.9 Hz, 2H, ArH), 7.72 (br d, J
A mixture of sodium p-toluenesulfinate (0.5 mmol, 0.09g), 3.5-
dinitrobenzoic acid (0.5 mmol, 0.107g, 1 eq), NaHSO3 (1.5 mmol,
0.312g, 3 eq), K2CO3 (0.5 mmol, 0.07g, 1 eq) in water (2 mL) were
stirred at 60 °C for 3 hours. After cooling at room temperature,
water (8 mL) was added. The precipitate was collected by filtration
and washed with water and analyzed by 1H NMR.
3
3
= 8.3 Hz, 2H, ArH), 7.36 (br d, J = 8.5 Hz, 2H, ArH), 7.20 (br d, J = 8.9
Hz, 2H, ArH), 2.45 (s, 3H, CH3), 2.32 (s, 3H, CH3).13C NMR (DMSO-d6,
75 MHz): δ (ppm) 196.2, 143.6, 142.3, 136.2, 131.8, 129.8, 129.7, 126.7,
117.8, 26.3, 20.9.
2-((4-methylphenyl)sulfonamido)benzoic acid (Table 3, entry 8)
(C14H13NO4S): white powder, Yield 75%.1H NMR (DMSO-d6, 300 MHz): δ
(ppm) 11.16 (br s, 1H, COOH), 7.88 (br d, 3J = 8.5 Hz, 1H, ArH), 7.70 (d,
3J = 8.3 Hz, 2H, ArH), 7.59 – 7.47 (m, 2H, ArH), 7.35 (d, 3J = 8.0 Hz, 2H,
4. Competition reaction between sodium p-toluenesulfinate
and sodium methanesulfinic acid
A
mixture of 0.15 g of 2-nitrobenzaldehyde, 0.1 g of sodium
3
3
4
ArH), 7.10 (ddd, J = 8.2 Hz, J = 6.2 Hz, J = 2.2 Hz, 1H, ArH), 2.32 (s,
3H, CH3).13C NMR (DMSO-d6, 75 MHz): δ (ppm) 168.8, 144.2, 139.9,
134.5, 131.5, 129.9, 126.9, 123.2, 118.2, 116.5, 20.9.
methanesulfinic acid (1 eq), 0.17 g of sodium p-toluenesulfinic acid (1 eq),
and 0.312 g of NaHSO3 (3 eq) in water (2 mL) were stirred at 60 °C for
3h. After cooling to room temperature, the precipitate was collected and
analyzed by NMR. Next, the filtrate was extracted with 3 x 5 mL of ethyl
acetate and the organic phase was separated and dried over Na2SO4,
before the solvent was evaporated. The precipitate was mixed with the
organic extract and the mix was analyzed via 1H NMR.
3-((4-methylphenyl)sulfonamido)benzoic acid (Table 3, entry 9)
(C14H13NO4S): white powder, Yield 44%.1H NMR (DMSO-d6, 300 MHz): δ
(ppm) 12.75 (br s, 1H, COOH), 10.43 (br s, 1H, NH), 7.69 (m, 1H, ArH),
7.66-7.63 (dd, 3J = 8.13 Hz, 4J = 1.5 Hz, 2H, ArH), 7.58 (m, 1H, ArH),
7.34 (d, 3J = 6.7 Hz, 4H, ArH), 2.30 (s, 3H, CH3).13C NMR (DMSO-d6, 75
MHz): δ (ppm) 167, 143.7, 138.4, 136.7, 132.2, 130, 126.7, 126.9, 125,
124, 120.6, 21.2.
4-methyl-N-phenylbenzenesulfonamide
(Table
3,
entry
1)
(C13H13NO2S): yellow oil, yield 33%.1H NMR (CDCl3, 300 MHz): δ (ppm)
3
3
7.75 (d, J = 8.3 Hz, 2H, ArH), 7.68 ( br s, 1H, ArH), 7.22 (br d, J = 7.6
3
Hz, 3H, ArH), 7.16 (br d, J = 8.5 Hz, 2H, ArH), 7.12-7.07 (m, 1H, ArH),
4-((4-methylphenyl)sulfonamido)benzoic acid (Table 3, entry 10)
(C14H13NO4S): white powder, Yield 23%.1H NMR (DMSO-d6, 300 MHz): δ
(ppm) 12.72 (br s, 1H, COOH), 10.74 (s, 1H, NH), 7.80 (d, 3J = 8.7 Hz,
2.37 (s, 3H, CH3).13C NMR (CDCl3, 75 MHz): δ (ppm) 166.7, 143.6, 142.0,
136.4, 130.7, 129.8, 126.7, 125.5, 118, 20.9.
3
3
2H, ArH), 7.71 (d, J = 8.3 Hz, 2H, ArH), 7.36 (d, J = 8.0 Hz, 2H, ArH),
7.19 (d, 3J = 8.7 Hz, 2H, ArH), 2.30 (s, 3H, CH3).13C NMR (DMSO-d6, 75
N-(2-formylphenyl)-4-methylbenzenesulfonamide
(Table
3,
entry 2)(C14H13NO3S): white powder, Yield 73%.1H NMR (CDCl3,
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10.1002/ejoc.201800504
European Journal of Organic Chemistry
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MHz): δ (ppm) 166.7, 143.6, 142.0, 136.4, 130.7, 129.8, 126.7, 125.5,
2H), 7.48 (m, 2H), 7.17 (td, 3J = 7.5, 4J = 0.9 Hz, 1H, ArH).13C NMR
(CDCl3, 75 MHz): δ (ppm) 195.1, 136.2, 135.9, 133.3, 129.2, 127.3,
123.2, 117.9.
118.0, 20.9.
3-((4-methylphenyl)sulfonamido)-5-(phenylsulfonamido)benzoic
acid (Table 3, entry 11) (C21H20N2O6S2): white solid, yield 30%.1H NMR
(DMSO-d6, 300 MHz): δ (ppm) 13.08 (s, 1H, COOH), 10.48 (s, 2H, NH),
7.72 (d, 3J = 8.7 Hz, 1H, ArH), 7.69-7.40 (m, 4H, ArH), 7.44 (d, 3J = 2 Hz,
4-chloro-N-(2-formylphenyl)benzenesulfonamide (Table 4, entry 3)
(C13H10NO3SCl):white solid, yield 58%.1H NMR (CDCl3, 300 MHz): δ
(ppm) 10.81 (s, 1H, NH), 9.83 (s, 1H, CHO), 7.86 – 7.77 (m, 2H, ArH),
3
3
3
4
1H, ArH), 7.51-7.40 (m, 4H, ArH), 6.74 (dd, J = 8.7 Hz,4J = 2.1 Hz, 1H,
7.69 (br d, J = 8.4 Hz, 1H, ArH), 7.62 (dd, J = 7.7 Hz, J = 1.5 Hz, 1H,
ArH), 2.33 (s, 6H).13C NMR (DMSO-d6, 75 MHz): δ (ppm) 166.2, 143.4,
ArH), 7.55 (ddd, J = 7.6 Hz, J = 7.6 Hz, 4J = 1.6 Hz, 1H, ArH), 7.46 –
3
3
3
4
138.9, 136.2, 132.3, 129.7, 126.6, 115.2, 20.9.
7.38 (m, 2H, ArH), 7.21 (ddd, J = 7.5 Hz, 3J = 7.5 Hz, J = 1.0 Hz, 1H,
ArH).13C NMR (CDCl3, 75 MHz): δ (ppm) 195.0, 136.3, 136, 129.6, 128.8,
123.4, 118.1.
4-((4-methylphenyl)sulfonamido)-2-(phenylsulfonamido)benzoic
acid (Table 3, entry 12) (C21H20N2O6S2): white solid, yield 20%.1H NMR
(DMSO-d6, 300 MHz): δ (ppm) 11.58 (s, 1H, COOH), 10.90 (s, 2H, NH),
N-(2-formylphenyl)methanesulfonamide
(Table
4,
entry
4)
3
3
7.58 (d, J = 8.1 Hz, 4H, ArH), 7.37-7.35 (m, 1H, ArH), 7.32 (d, J = 8.1
Hz, 4H, ArH), 7.26 (d, 3J = 2 Hz, 2H, ArH), 2.33 (s, 6H).13C NMR (DMSO-
d6, 75 MHz): δ (ppm) 169.4, 143.7, 143.1, 141.5, 136.2, 135.4, 132.7,
129.8, 126.9, 126.7, 112.2, 110.8, 106, 21.
(C8H9NO3S): yellow crystals, yield 55%.1H NMR (DMSO-d6, 300 MHz): δ
3
4
(ppm) 10.25 (s, 1H, NH), 10.07 (s, 1H, CHO), 7.90 (dd, J = 7.7 Hz, J =
1.5 Hz, 1H, ArH), 7.78 – 7.66 (ddd, 3J = 7.8 Hz, 3J = 7.8 Hz, 4J = 1.7 Hz,
1H, ArH), 7.53 (d, 3J = 8.2 Hz, 1H, ArH), 7.38 (ddd, J = 8.3 Hz, J = 8.3
Hz, 4J = 1.7 Hz, 1H, ArH), 3.16 (s, 3H, CH3).13C NMR (DMSO-d6, 75
MHz): δ (ppm) 193.8, 139.4, 135.6, 133, 125.8, 125.6, 124.4, 120.7.
3
3
N-(5-(dimethylamino)-2-formylphenyl)-4-methylbenzenesulfonamide
(Table 3, entry 13) (C16H18N2O3S): orange solid, Yield 78 %.1H NMR
(300 MHz, CDCl3): δ (ppm) 11.27 (s, 1H, NH), 9.48 (s, 1H, CHO), 7.78 (d,
3J = 8.3 Hz, 2H, ArH), 7.29 (d, 3J = 8.8 Hz, 1H, ArH), 7.23 (d, 3J = 8.1 Hz,
3
3
4
2H, ArH), 6.82 (d, J = 2.3 Hz, 1H, ArH), 6.32 (dd, J = 8.8, J = 2.4 Hz,
1H), 3.05 (s, 6H, CH3N), 2.36 (s, 3H, CH3).13C NMR (75 MHz, CDCl3): δ
(ppm) 191.7, 154.7, 143.9, 142.2, 137.9, 129.7, 127.5, 112.2, 106.4, 99.2,
40.3, 21.6.
Keywords: green chemistry• synthesis on water•catalyst free•
purification free•sulfonamides•Sustainable
N-(5-bromo-2-formylphenyl)-4-methylbenzenesulfonamide (table
3
entry 14) (C14H12BrNO3S): white solid, Yield 38%.1H NMR (300 MHz,
DMSO-d6) δ (ppm) 10.67 (s, 1H, NH), 9.94 (s, 1H, CHO), 7.74 (d, 3J =
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3
3
4
8.3 Hz, 1H, ArH), 7.61 (d, J = 8.3 Hz, 2H, ArH), 7.55 (dd, J = 8.3, J =
1.8 Hz, 1H, ArH), 7.39 (d, 3J = 8.0 Hz, 2H, ArH), 7.30 (d, 3J = 1.8 Hz, 1H,
ArH), 2.36 (s, 3H, CH3).13C NMR (75 MHz, DMSO-d6) δ (ppm) 192, 144.5,
139.9, 135.4, 133.4, 130.1, 128.6, 127, 126.5, 125.2, 21.1.
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solid, Yield 40%.1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.93 (s, 1H,
CHO), 10.25 (s, 1H), 10.04 (s, 1H), 7.70 (t, 3J = 8.0 Hz, 1H, ArH), 7.60 (d,
3J = 8.3 Hz, 2H, ArH), 7.53 (d, 3J = 8.2 Hz, 1H, ArH), 7.47 (dd, 3J = 14.6,
4J = 2.6 Hz, 2H, ArH), 7.35 (d, 3J = 8.0 Hz, 2H, ArH), 2.33 (s, 3H,
CH3).13C NMR (75 MHz, DMSO- d6) δ (ppm) 193.2, 153.7, 143.5, 136,
131.8, 130.8, 129.8, 126.7, 123.2, 122.3, 111.8, 20.9.
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2-chloro-5-((4-methylphenyl)sulfonamido)benzoic acid (table 3 entry
16) (C14H12ClNO4S): white solid, Yield 30%.1H NMR (300 MHz, DMSO-
d6) δ (ppm) 13.53 (s, 1H, COOH), 10.56 (s, 1H, NH), 7.65 (d, 3J = 8.3 Hz,
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3
3
1H, ArH), 7.49 (d, J = 2.7 Hz, 1H, ArH), 7.42 (s, 1H, ArH), 7.39 (d, J =
4.6 Hz, 1H, ArH), 7.35 (s, 1H, Ar), 7.24 (dd, 3J = 8.7, 4J = 2.7 Hz, 1H,
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143.6, 136.8, 136.1, 131.5, 129.8, 126.5, 123.2, 121.4, 20.9
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N-(2-formylphenyl)benzenesulfonamide
(Table
4,
entry
1)
(C13H11NO3S):white solid, yield 32%.1H NMR (CDCl3, 300 MHz): δ (ppm)
10.82 (s, 1H, NH), 9.83 (s, 1H, CHO), 7.89 (m, 2H, ArH), 7.70 (d, 3J = 8.4
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Hz, 1H, ArH), 7.60 (dd, J = 7.6, J = 1.5 Hz, 1H, ArH), 7.55 – 7.50 (m,
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10.1002/ejoc.201800504
European Journal of Organic Chemistry
FULL PAPER
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Entry for the Table of Contents (Please choose one layout)
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A green, sustainable and
N. Eid, I. Karamé,* and B. Andrioletti*
chemoselective synthesis of
Page No. – Page No.
sulfonamides using sodium sulfinate
as a commercial and stable sulfur
source and nitro arenes as nitrogen-
containing reactant is described. The
optimized conditions use water as the
solvent and the pure products are
collected by simple filtration. This
method is easily scalable and
Straightforward and sustainable
synthesis of sulfonamides in water
under mild conditions
protecting group free because of the
high functional tolerance.
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