Highly efficient one-pot synthesis of N-alkyl sulfonamides from alcohols using N-(p-toluenesulfonyl) imidazole (Tsim)

Article abstract of DOI:10.1080/10426507.2013.829828

A facile and efficient method for one-pot synthesis of N-alkyl sulfonamides from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this protocol, treatment of various potassium sulfonylamide salts and alcohols in the presence of TsIm and triethylamine in refluxing DMF furnishes the corresponding N-alkyl sulfonamides in good to excellent yields. This methodology is highly efficient for reaction of various structurally diverse primary and secondary alcohols as well as potassium sulfonylamides. Also, the density functional theoretical calculations are employed to mechanistically study this protocol. [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text and figures.]

Full text of DOI:10.1080/10426507.2013.829828

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Highly Efficient One-Pot Synthesis of N-
Alkyl Sulfonamides from Alcohols Using
N-(p-Toluenesulfonyl) Imidazole (Tsim)
a
a
Mohammad Navid Soltani Rad , Somayeh Behrouz & Abdo-Reza
a
Nekoei
a
Department of Chemistry , Shiraz University of Technology ,
Shiraz , Iran
Accepted author version posted online: 12 Sep 2013.Published
online: 12 Mar 2014.
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To cite this article: Mohammad Navid Soltani Rad , Somayeh Behrouz & Abdo-Reza Nekoei (2014)
Highly Efficient One-Pot Synthesis of N-Alkyl Sulfonamides from Alcohols Using N-(p-Toluenesulfonyl)
Imidazole (Tsim), Phosphorus, Sulfur, and Silicon and the Related Elements, 189:4, 465-476, DOI:
10.1080/10426507.2013.829828
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Phosphorus, Sulfur, and Silicon, 189:465–476, 2014
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.829828
HIGHLY EFFICIENT ONE-POT SYNTHESIS OF N-ALKYL
SULFONAMIDES FROM ALCOHOLS USING
N-(p-TOLUENESULFONYL) IMIDAZOLE (TSIM)
Mohammad Navid Soltani Rad, Somayeh Behrouz,
and Abdo-Reza Nekoei
Department of Chemistry, Shiraz University of Technology, Shiraz, Iran
GRAPHICAL ABSTRACT
TsIm/TEA
RSO NHK + R' OH
RSO NHR'
2
2
DMF, reflux
O
N
TsIm:
H
3
C
S
N
O
R = alkyl, aryl
R' = alkyl, allyl, benzyl, ...
Abstract A facile and efficient method for one-pot synthesis of N-alkyl sulfonamides from
alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this protocol, treatment
of various potassium sulfonylamide salts and alcohols in the presence of TsIm and triethylamine
in refluxing DMF furnishes the corresponding N-alkyl sulfonamides in good to excellent yields.
This methodology is highly efficient for reaction of various structurally diverse primary and
secondary alcohols as well as potassium sulfonylamides. Also, the density functional theoretical
calculations are employed to mechanistically study this protocol.
[
Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
files: Additional text and figures.]
Keywords Alcohol; N-alkylation; potassium sulfonylamide salt; TsIm; triethylamine (TEA);
DFT study
INTRODUCTION
The N-alkylated sulfonamides are an important class of compounds in medicinal and
agrochemical chemistry.1 N-Alkyl sulfonamides are known to exhibit a wide spectrum of
biological activities such as antibacterial, antiviral, anti-HIV, anticancer, diuretic, antihy-
–4
3
,5–7
pertensive, anti-inflammatory, antiallergic, antimigraine, and anticonvulsant activities.
Received 23 March 2013; accepted 22 July 2013.
The authors wish to thank Shiraz University of Technology Research Council for financial support of this
work.
Address correspondence to Dr. Navid Soltani Rad, Ph.D., Department of Chemistry, Shiraz University of
Technology, Modaress BLVD, Shiraz 71555-313, Islamic Republic of Iran. E-mail: soltani@sutech.ac.ir
4
65

466
M. N. S. RAD ET AL.
Many famous drugs such as ambuside, droxicam, mefruside, piroxicam, probenecid, sul-
tiame, sumatriptan, and tenoxicam which demonstrating the different chemotherapeutic
3
activities contain N-alkyl sulfonamide residue in their scaffolds. In addition, sulfonamides
8
have been used as protecting groups and also for the synthesis of primary amines.
The most common route to access N-alkyl sulfonamides involves the condensation of
9
,10
amines with sulfonyl chlorides. Other known methods, such as hydroamination of olefins
with sulfonamides,1
1–14
reductive amination of aldehydes and nucleophilic substitutions of
1
5,16
1
alkyl halides or sulfonates with sulfonamides,
the reaction of sulfonamides with inactive ethers, allylic and benzylic hydrocarbons,
and one-pot oxidative reaction of methyl sulfinates with amines have also been reported
have also been employed. Additionally,
7
18,19
20
for preparing N-alkyl sulfonamides.
In the light of wide diversity and readily availability of alcohols, lower toxicity, and
ease of handling in comparison with alkyl halides, the one-pot reaction of sulfonamides
with alcohols seems to be a suitable and attractive strategy. In this context, methods based
on Mitsunobu reaction,2
1–24
hydrogen borrowing methods,
25–32
and acid-catalyzed direct
3
3–39
N-alkylation of sulfonamides with alcohols via a carbocation mechanism
have been
developed. Although these protocols are normally employed to obtain the N-alkylated
adducts, however, they suffer from several disadvantages. As an instance the use of the
expensive as well explosive reagent such as diethyl azodicarboxylate and its related reagents
in Mitsunobu condition has limited its applicability in large scale synthesis. Furthermore,
the generated triphenyl phosphine oxide with products in Mitsunobu condition makes a
cumbersome separation process. On the other hand, since the application of oxidants in
hydrogen borrowing methods and also the use of strong acids in acid-catalyzed direct N-
alkylation of sulfonamides with alcohols, the sensitive functional groups in molecules can
be annihilated. Because of ease of handling, higher nucleophilicity, and cleaner reaction
of sulfonylamide salts compare to sulfonamides, the reaction of sulfonylamide salts with
alcohols is usually preferred. Previously, we have demonstrated that N-(p-toluenesulfonyl)
imidazole (TsIm) is a highly efficient, cheap, neutral, and stable reagent for many organic
transformations.4
0–45
In continuation of our ongoing research on sulfonamide chemistry46,47
and also our interest in use of TsIm in organic transformations hereby, we report the one-pot
N-alkylation of potassium sulfonylamide salts with alcohols using TsIm in the presence of
triethylamine (TEA) in refluxing DMF (Scheme 1).
Scheme 1 N-alkylation of potassium sulfonylamide salts with alcohols using TsIm.
RESULTS AND DISCUSSION
To recognize the optimal conditions for the reaction, a model reaction consisting of
2-phenylethanol, potassium phenylsulfonylamide, freshly prepared TsIm, and TEA was
considered.

ONE-POT SYNTHESIS OF N-ALKYL SULFONAMIDES
467
Initially, the effect of various solvents on the model reaction was studied. The results
are depicted in Table 1. In the absence of solvent (solvent free condition) the reaction
was examined; however, low yield of product was obtained (Table 1, entry1). Among the
examined solvents, DMF (entry 5) demonstrated the best result and hence it was the used
solvent for all reactions. Using DMSO, HMPA, and NMP (Table 1, entries 2–4) afforded
the corresponding product in reasonable yields. Recently, applications of ionic liquids in
organic transformations have demonstrated many advantageous from different aspects. In
this context, regarding to polar nature of reactants in our reaction, we have tested the
reaction in several room temperature imidazolium-ionic liquids (Table 1, entries 10–13).
Unexpectedly, none of the examined ionic liquids were useful in progress of reaction.
Other solvents were inefficient even if the reaction time was prolonged.
It is critically important to choose the proper base for activating alcohols to react
with TsIm. In this case, we tested the potency of several organic and inorganic bases on
the model reaction (Table 2). In Table 2, Et3N (entry 5) is the most efficient base for the
progress of reaction. The use of DBU and DMAP (Table 2, entries 7 and 8) also afforded
satisfactory results. However, Et3N was preferred because of higher yield, favorable reaction
rate, lower cost, and ready availability. Other examined bases afforded lower yields of the
corresponding sulfonamide.
Table 1 Effect of solvent variation on model reaction
O O
S
O O
S
TsIm/TEA
N
NHK
Solvent, reflux
H
HO
b
Entry
Solvent
Time (h)
Yield (%)
1a
2
3
4
5
6
7
8
—
18
5
5
7
4
14
18
18
20
24
24
24
24
12
80
76
64
91
35
NR
NR
24
NR
DMSO
HMPA
NMP
DMF
MeCN
Toluene
H2O
Acetone
[bmim]Br
[bmim]I
[hmim]Brf
[omim]Br
c
c
9
h
d
c
1
1
1
1
0
1
2
3
h
h
h
e
c
NR
NR
NR
c
g
c
a
◦
The reaction was carried out in sealed tube on an oil-bath at 100 C.
Isolated yield.
No reaction.
b
c
d
1-butyl-3-methylimidazolium bromide.
e
1-butyl-3-metylimidazolium iodide.
f
1-hexyl-3-methylimidazolium bromide.
g
h
1
-octyl-3-methylimidazolium bromide.
◦
The reactions were attempted at 80 C.

468
M. N. S. RAD ET AL.
Table 2 Effect of base variation on model reaction
b
Entry
Base
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
NaH
Cs2CO3
K2CO3
MgO
Et3N
Al2O3a
DBU
10
8
8
20
4
12
6
31
62
54
c
NR
91
36
87
84
DMAP
6
a
Basic alumina.
Isolated yield.
No reaction.
b
c
The optimized amount of TsIm was found to be 1.2 equiv. per an equiv. of alcohol. We
also investigated other TsIm analogues and also some N-tosyl-N-heterocyclic compounds
(Table 3). As shown in Table 3, using TsIm (Table 3, entry 3), the reaction rate and yield
are remarkably increased in comparison with other sulfonyl analogues.
Replacing the tolyl group in TsIm with methyl, trifluoromethyl, and phenyl did not
afford the satisfactory results (Table 3, entries 1, 2, and 4). Other azole analogues of TsIm
were not as effective as imidazole (Table 3, entries 5, 6, and 10). The N-tosyl imides such
as N-tosylphthalimide and N1-tosyl uracil (Table 3, entries 7 and 13) were inactive for the
conversion even after refluxing for 48 h.
The N-benzene sulfonyl derivatives of benzimidazole, indole, and pyyrole (Table 3,
entries 8, 9, and 11) were also examined as the reagent similar to TsIm for progress of
the reaction; however, unsatisfactory yields of product were attained. In addition, using
sulfonamide of some cyclic amines including N-tosyl morpholine and/or N1-tosyl-N4-
phenylpiperazine (Table 3, entries 12 and 14) instead of TsIm, gave no product; nevertheless,
the reaction time was prolonged to 48 h.
We also investigated the role of various phase transfer catalysts (PTC) on the model
reaction, since it was expected that the use of PTC can help in further dissolving of
sulfonamide salt in DMF and hence accelerates the reaction rate. Therefore, tetra-n-
butylammonium halides (TBAX; X = F, Cl, Br, and I) were employed. In contrary, using
PTC has no distinguishable effect on the reaction progress.
Applying sulfonamides instead of the corresponded potassium salts under the opti-
mized conditions (included two equivs. of TEA) afforded lower yields of the desired N-alkyl
sulfonamides even after prolonging the reaction times. As an example, the N-alkylation of
benzenesulfonamide with 2-phenylethanol was carried out in 55% yield after 9 h.
Various sulfonyl chlorides were also examined instead of TsIm to attain the N-
phenethylbenzenesulfonamide (Table 4). However, unfavorable yields for N-alkyl product
were obtained using these sulfonating reagents. This may be attributed to the high reactivity
and hence low selectivity of sulfonyl chlorides in reaction with alcohols.

ONE-POT SYNTHESIS OF N-ALKYL SULFONAMIDES
469
Table 3 Effect of reagent variation on model reaction
a
Entry
1
Reagent
Time (h)
6
Yield (%)
70
2
3
4
5
6
7
6
4
77
91
7
74
10
10
48
63
65
NRb
8
9
12
14
45
14
10
11
12
13
8
35
21
10
48
48
NRb
NRb
14
48
NRb
aIsolated yield.
b
No reaction.

470
M. N. S. RAD ET AL.
Table 4 Effect of various sulfonyl chlorides on model reaction
a
Entry
1
RSO2Cl
Time (h)
10
Yield (%)
48
45
57
53
50
59
2
3
4
5
6
10
10
10
10
10
aIsolated yield.
To explore the scope of this method, the optimized reaction conditions were screened
to diverse potassium sulfonylamide salts and alcohols (Table 5).
It is clear that this method is highly efficient and useful for benzylic (3a–d, 3f, 3m, 3n,
and 3q), propargylic (3k), aliphatic (3e, 3g, 3o, and 3p), and alicyclic (3h and 3i) alcohols.
This method is also suitable for various structurally diverse primary and secondary alcohols;
however, the tertiary alcohol was inactive in this protocol (3l). To further elucidate the
utility of this method, the N-alkylation of different potassium sulfonylamide salts bearing
various functional groups on the aromatic ring were also studied (Table 5). Excellent
results were obtained for potassium sulfonylamide salts with either electron-donating or
electron-withdrawing substituents on the aryl ring (3o and 3p).
Lower yields of the N-alkylated products were obtained for ortho-substituted benzyl
alcohols and potassium sulfonylamide salts which is attributed to the steric hindrance
present at ortho position (3a and 3n). Furthermore, the aliphatic sulfonamide derivative
such as potassium methylsulfonylamide also gave the desired alkylated product in good
yield (3q).
To investigate the applicability of this protocol in preparative scale, the reaction of
model substrates was carried out at a 100-mmol scale under optimized conditions. Indeed,
the reaction proceeded efficiently comparable to smaller scale synthesis (Table 5, compound
3j). 83% yield of 3j was attained after 4h when the reaction was conducted in a larger
scale.
The selectivity of this method was demonstrated via a competitive reaction of a
mixture consisting of 1-octanol, i-PrOH, TsIm, TEA, and potassium tosylamide in the
respective molar ratio of (1.5:1.5:1.8:2:1.5) under the optimal conditions (Table 6). The

ONE-POT SYNTHESIS OF N-ALKYL SULFONAMIDES
471
Table 5 One-pot N-alkylation of potassium sulfonylamide salts via alcohols using TsIm/TEA in refluxing DMF
ꢁ
Compound
R
R
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
Tolyl
Tolyl
Tolyl
Tolyl
Tolyl
Tolyl
Tolyl
Tolyl
2-Chlorobenzyl
3-Methoxybenzyl
3-Fluorobenzyl
4-Bromobenzyl
Octyl
f
1-Phenylethyl
Isopropyl
g
h
i
j
k
l
m
n
o
p
q
Cyclohexyl
Cyclohexyl
2-Phenylethyl
Propargyl
t-Butyl
Benzyl
Benzyl
Butyl
Butyl
Tolyl
Ph
Ph
Ph
2-Naphthyl
2-Chlorophenyl
4-Methoxyphenyl
4-Nitrophenyl
Me
Benzyl
Compounda
Time (h)
Yield (%)
b
Ref.
25,29
27
25
25,29
29
29
19
29
29
20
51
—
25
27
17
17
25,29
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
6
5
5
4
5
6
6
6
6
4
3
18
4
6
5
4
5
80
88
89
90
87
82
80
79
78
91
93
f
g
h
i
j
k
l
m
n
o
p
q
c
NR
90
79
88
91
88
a
All products were characterized by H and 13C-NMR, IR, CHN, and MS analysis.
1
b
c
Isolated yield.
No reaction.
results in Table 6 demonstrate the selectivity between primary and secondary alcohols
entry 1). There is high selectivity for N-alkylation of potassium sulfonylamide salts using
(
the primary alcohols rather than the secondary analogs.
The same result was observed when a mixture of 1-octanol and cyclohexanol was
investigated in competitive N-alkylation reaction with potassium tosylamide (Table 6,
entry 2).

472
M. N. S. RAD ET AL.
Table 6 Comparative N-alkylation of potassium tosylamide with primary/secondary alcohols using TsIm/TEA
in refluxing DMF
a
Entry
1
Alcohol mixture
Product
Time (h)
6
Yield (%)
79
5
82
4
2
6
aIsolated yield.
Mechanistically, as shown in Scheme 2, in the presence of alcohol (C1), sulfonylamide
anion (C2), and TsIm (C3) in a flask, three possible reactions may occur for the presented
one-pot N-alkylation of sulfonamide (Scheme 2).
Scheme 2 Three possible reactions in the present of alcohol, sulfonylamide anion, and TsIm compounds.
48
As it is well-known in organic synthesis, normal alcohols are not good electrophiles
expect to be attacked by a nucleophiles such as sulfonylamide anion (first reaction). In this
one-pot protocol, the TsIm has the activating role for alcohol which converts the alcohol
into a good electrophile (second reaction). However, TsIm itself is a good electrophile, and
due to third reaction, it can be attacked by sulfonylamide anion (that is a good nucleophile)
to produce C5. If this is the case, C5 then must be attacked by C1 (that is not a good
ꢁ
nucleophile) which leads to production of two different N-alkyl sulfonamides, RSO2NHR

ONE-POT SYNTHESIS OF N-ALKYL SULFONAMIDES
473
ꢁ
Figure 1 The optimized structures for C1–C5 molecules in Scheme 2 with R=Ph and R =CH2CH2Ph. (Color
figure available online).
ꢁ
and MePhSO2NHR . Our investigation on the reaction products showed that this does not
take place.
In other word, among the three possible reactions mentioned above, the second
reaction is the first step, and its product (C4) then will be attacked by C2 to produce the
ꢁ
desire N-alkyl sulfonamides, RSO2NHR .
In order to theoretically investigate and recognize why the second reaction is preferred
to the third one, nevertheless C2 is much better nucleophile than C1, quantum mechanical
calculations have been carried out on the reactants and the products of these reactions.
Gaussian 03W program49 has been used for all calculations, employing DFT method at
B3LYP/6-311+G(d) level of theory. The reaction of a mixture of 2-phenylethanol, phenyl-
ꢁ
sulfonylamide anion (i.e., R = –Ph and R = CH2CH2Ph in Scheme 2) and TsIm, which
was designated before for optimizing the reaction conditions, have also been considered
for this theoretical study. The optimized structures of C1–C5 are shown in Figure 1, using
GaussView 5.0 program.50 The frequency calculations have been performed at B3LYP/6-
3
11+G(d) level to investigate the optimized structures and their thermodynamic proper-
ties. The calculated changes in enthalpy and Gibbs free energy, besides some other energy
changes, for the second and third reactions are given in Table 7. Thermodynamically, as it
Table 7 Theoretical changes in some energies and enthalpy of the studied reactions (all
∗
in kcal/mol, calculated at B3LYP/6-311+G level of theory)
Parameter
Second reaction
Third reaction
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Ea
−11.28
−10.73
−10.78
−10.78
−11.2
6.65
7.04
7.09
7.09
8.11
b
EZPE
ETher.c
H
G
a
Changes in calculated absolute energy.
Changes in calculated absolute energy including zero point energy correction.
Changes in calculated absolute energy including thermal energy corrections.
b
c

474
M. N. S. RAD ET AL.
is obvious from Table 7, the energy and enthalpy changes of the second reaction have the
negative values, while the third one is an endothermic reaction.
Also, comparing the calculated changes in the Gibbs free energy of both reactions
shows that, in spite of the third one which is unfavorable, the second reaction is a spon-
taneous reaction. Therefore, according to the theoretical prediction, the second reaction
should dominate the third one, in the best agreement with the experiment.
In the kinetic point of view, also the second reaction is more proper than the third
one. This is because of much more steric hindrance of the transition state (see optimized
structures of C2, C3, and C5 in Figure 1) and higher activation energy in the third reaction
than those in the second one. Even if the third reaction have a little percent to take place,
the product C5 has a little chance to be attacked by C1, because of high steric hindrance in
its likely intermediate (see optimized structures of C1 and C5 in Figure 1).
CONCLUSIONS
In summary, a mild, simple, and efficient protocol has been established for the syn-
thesis of N-alkyl sulfonamides which are present in many drugs and bioactive compounds.
In this method, one-pot N-alkylation of different potassium sulfonylamide salts with var-
ious structurally diverse alcohols has been achieved using TsIm/TEA in refluxing DMF
affording good to excellent yields of N-alkyl sulfonamides. The theoretical predictions are
well supported by the experimental outcomes.
EXPERIMENTAL
General: All preliminary chemicals were purchased from Fluka, Merck, and/or
Sigma-Aldrich. The fresh TsIm, was prepared according to published methods.40 Sol-
vents were purified and dried by standard procedures, and stored over 3 Å molecular
sieves. Reactions were followed by TLC using SILG/UV 254 silica gel plates. Column
chromatography was performed on silica gel 60 (0.063–0.200 mm, 70–230 mesh, ASTM).
Melting points were measured using a B u¨ chi-510 apparatus in open capillaries and are
uncorrected. IR spectra were obtained using a Shimadzu FT-IR-8300 spectrophotometer.
1
13
H and C NMR spectra were obtained using a Br u¨ ker Avance-DPX-250 spectrometer
operating at 250/ 62.5 MHz, respectively (d in parts per million, J in hertz). GC/MS were
performed on a Shimadzu GC/MS-QP 1000-EX apparatus (m/z, rel%). Elemental analyses
were conducted on a Perkin-Elmer 240-B micro-analyzer. Complete characterizations of
1
13
products and sample H and C NMR (Figures S1–S4) are located in the Supplemental
Materials.
General Procedure for One-Pot N-alkylation of Potassium
Sulfonylamide Salts with Alcohols Using TsIm
To a double-necked round bottom flask (25 mL) equipped with a condenser was added
a mixture of alcohol (1.0 mmol), TsIm (1.2 mmol), TEA (1.5 mmol), and RSO2NHK
(1 mmol) in DMF (10 mL). The mixture was refluxed, and in most cases, darkening
occurred. Reflux was continued until TLC monitoring indicated no further improvement
in the conversion (Table 5). The solvent was evaporated under vacuum (Note) and the
remaining foam was dissolved in CHCl3 (50 mL) and subsequently washed with water

ONE-POT SYNTHESIS OF N-ALKYL SULFONAMIDES
475
(
2 × 50 mL). The organic layer was dried (Na2SO4) and evaporated. The crude product was
purified by column chromatography on silica gel eluting with a mixture of n-hexane/EtOAc.
◦
(
Note: DMF (b.p. 153 C) can be evaporated in rotary evaporator if the efficient unit’s
vacuum system is capable of sufficiently low pressure. For instance, DMF can be boiled
◦
below 80 C if the vacuum is reduced to 5 torr or less. However, if the efficient vacuum
pump is not available, then the surrogate procedure can be employed in which the reaction
mixture is diluted in water (100 mL). Then, CHCl3 (100 mL) is added and the organic phase
is separated. The separated CHCl3 is washed subsequently with water (3 × 100 mL). The
CHCl3 is evaporated to obtain the crude product.)
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2
. Northley, E. H. The Sulfonamides and Related Compounds; Reinhold: NewYork, 1948.
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S. A. J. Med. Chem. 2010, 53, 2913-2926.
3. Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances, 3rd ed.; Thieme:
Stuttgart, 1999.
4
. Wilson, C. O.; Gisvold, O.; Block, J. H. In: J. H. Block, J. M. Beale, (Eds.)., Wilson and Gisvold’s
Textbook of Organic Medicinal and Pharmaceutical Chemistry, 11th ed., Lippincott Williams &
Wilkins: Philadelphia, 2004.
5. Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med. Chem. 2003, 10, 925-953,
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