Hypervalent Iodine Mediated Sulfonamide Synthesis

Article abstract of DOI:10.1002/ejoc.201900259

A new metal-free sulfonylation reaction is described. The method takes advantage of the Umpolung reactivity and group-transfer properties of iodine(III) compounds, combining hypervalent iodine reagents and sulfinate salts to deliver a clean and mild transfer of sulfonyl groups to amines and anilines. A total of 25 sulfonamides was synthesised in up to 99 % yield, even on gram-scale. The reaction mechanism was investigated by ESI-MS and DFT calculations.

Full text of DOI:10.1002/ejoc.201900259

A Journal of
Accepted Article
Title: Hypervalent Iodine mediated sulfonamide synthesis
Authors: Diogo Poeira, João Macara, Hélio Faustino, Jaime Coelho,
Pedro Goís, and Maria M Marques
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900259
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900259
Supported by

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
Hypervalent Iodine mediated sulfonamide synthesis
Diogo L. Poeira,a,₸ João Macara,a,₸ Hélio Faustino,b Jaime A. S. Coelho,b Pedro M. P. Gois,b and M.
Manuel B. Marquesa,*
Abstract: A new metal-free sulfonylation reaction is described. The
method takes advantage of the umpolung reactivity and group transfer
properties of iodine(III) compounds, combining hypervalent iodine
reagents and sulfinate salts to deliver a clean and mild transfer of
sulfonyl groups to amines and anilines. A total of 25 sulfonamides
were synthesised in up to 99% yield, even in a gram-scale. The
reaction mechanism was investigated by ESI-MS and DFT
calculations.
The classic method for the synthesis of sulfonamides involves
the reaction between an amine and a sulfonyl chloride, in the
presence of a base (Scheme 2A).[3] Other methods include
metal-catalysed reactions of unsubstituted or mono-
substituted sulfonamides,[4] oxidation of sulfonamides or
sulfinimides,[5] oxidative coupling reactions between sulfinate
salts and amines (Scheme 2B).[6-8] These methods either use
harsh conditions, non-environmentally friendly reagents or
are limited in scope. Recently, DABSO (a complex of 1,4-
diazabicyclo[2.2.2]octane with two molecules of SO2) has
been widely explored on sulfonylation reactions as a SO2
surrogate (Scheme 2C).[9] DABSO can be applied to
sulfonamide synthesis from amines however, it requires the
use of metal catalysts and/or organometallic reagents.[10]
Introduction
The sulfonyl group is present in many compounds, such as
natural products, marketed therapeutics and materials.[1] In
particular, the sulfonamide pharmacophore is present in many
pharmaceutical agents, e.g. antimicrobial, anti-inflammatory,
[2] or anti-hypertensive drugs. Its medicinal significance can be
traced to the 30´s with the discovery of the so called “sulfa
drugs” (Scheme 1).[1]
(A) Traditional method
O
O
O
O
R2
R3
Base
S
S
R2
R1
N
R3
S
+
N
R1
Cl
H
(B) Sulfinate oxidation method
O
O
O
R2
R3
Ox.
R2
R1
N
+
N
S
R1
ONa
H
R3
(C) SO2 surrogate DABSO method
SO2
O
O
N
OH
R2
R3
[Cu]
S
S
R2
R1
N
R3
+
N
+
B
R1
OH
H
N
SO2
(D) This work
O
O
O
R2
R3
Cl
I
O
R2
N
+
+
R1
N
R3
H
S
R1
ONa
O
Scheme 2 Current methods for sulfonamide synthesis.
Scheme 1 Examples of “sulfa drugs” currently in the pharmaceutical market.
Despite the progress in this field, there is a still room for
improvement in a metal-free, versatile and fast methodology
towards sulfonamides compatible with the use of amines.
The exceptional properties of benziodoxolone-derived
reagents have attracted the attention of the scientific
community for both carbon and hetero-atom transfer
reactions.[11, 12]
[a]
D. L. Poeira, J. Macara, Prof. M. M. B. Marques
LAQV@REQUIMTE, Departamento de Química
Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa
Campus de Caparica, 2829-516 Caparica, Portugal
E-mail: msbm@fct.unl.pt: https://docentes.fct.unl.pt/msbm/
These authors have contributed equally
₸
[b]
Dr. H Faustino, Dr. J. A. S. Coelho, Prof. P. M. P. Gois
Research Institute for Medicines (iMed.ULisboa)
Faculty of Pharmacy, Universidade de Lisboa
Benziodoxolone-derived
iodine(III)
compounds
are
characterized by the presence of an endocyclic iodine, which
confers stability, while inverting the polarity of an attached
moiety, proving conditions for an umpolung reaction.
Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
Recently, the use of these reagents on heteroatom transfer presence of TBAI is crucial for the outcome of the reaction,
reactions became a major field of study.[12-14]
with the iodine anion possibly playing a role in the reaction’s
Herein, we describe a novel fundamental oxidative process for mechanism.
preparing sulfonamides. The method involves the sulfonyl
Table 1. Optimization of the reaction conditions.
group transfer from hypervalent iodine adducts to amines.
This strategy circumvents the use of metal catalysts and
sulfonyl chlorides and allows the development of an
environmentally friendly alternative (Scheme 2D). In addition,
similar works have been reported for the formation of
sulfonates[15] and sulfones.[16]
O
S
Ph
ONa
1)
2a
O
O
I
O
Cl
I
O
DCM or MeCN
S
+
Ph
N
O
N
HN
O
2)
O
O
1
3aa
4
Results and Discussion
Entry[a]
Solvent
Additive
(equiv)
T
(°C)
Time[b]
1)/2) (h)
Yield[c] 3a/4
(%)
We initiated our studies with the synthesis of the chlorine-
1
MeCN
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
DCM
--
82
1/16
40/NO
28/NO
61/38
53/40
60/32
62/3
bearing benziodoxolone
protocol, where oxidation and chlorination of
acid is performed in one step.[13] In order to produce a
sulfonyl-transfer reagent, benziodoxolone was mixed with
1
in quantitative yield using Togni’s
2
-iodobenzoic
2[d]
3
--
82
1/16
TBAI (1.5)
TBAI (1.5)
TBAI (1.5)
TBAI (1.5)
TBAI (0.5)
TBAI (0.2)
TBAI (0.2)
--
40
0.5/16
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
0.25/2
1
sodium phenylsulfonate 2a. Attempts to isolate a stable
product failed, however, in situ addition of morpholine to the
reaction medium resulted in the formation of sulfonamide 3aa
4
40
5
RT
-40
-40
-40
RT
-40
RT
-40
RT
-40
in 40% yield (Table 1, entry 1). Benziodoxolone
1, sodium
6
phenylsulfonate and morpholine were used as the standard
2
7
84/NO
98/NO
56/43
59/NO
68/NO
96/NO
54/31
55/NO
reagents for the optimization of the reaction conditions (Table
1). It was shown that lowering the amount of 2a from 1.5 to
1.0 equiv resulted in a decreased yield of the desired product
3aa (40 vs 28%, entry 2). Due to the low reagents’ solubility,
1.5 equiv of tetrabutylammonium iodide (TBAI) was added and
the solvent changed to dichloromethane.[14] This resulted in an
improved 61% yield of 3aa, along with formation of an
8
9
10
11
12
13
14
--
undesired amide product 4 (entry 3).
TBAI (0.2)
TBAI (0.2)
TBAC (0.2)
Next, the reaction time and temperature’s effects were
studied. The reaction time was reduced from 30 min to 15 min
and 16 h to 2 h, for steps 1) and 2) respectively, with no
significantly change in the yields of 3aa and
Reduction of the reaction temperature to RT and -40 °C
resulted in decreased yields of (32 and 3%, respectively)
while maintaining similar yields of 3aa (entries 5 and 6). With
these results in mind, lower amounts of TBAI were tested.
Gratifyingly, sulfonamide 3aa was isolated in higher yields (84
and 98% with 0.5 and 0.2 equiv of TBAI, respectively) and no
4 (entry 4).
[a] All experiments were carried out under the following conditions: 1) 0.18 mmol of
chlorobenziodoxolone (1) with 0.28 mmol of sodium benzenesulfinate (2a, 1.5
equiv) in 1 mL of DCM or MeCN; 2) 0.28 mmol of morpholine (1.5 equiv) was added
to the reaction mixture; [b] 1) refers to the time of the first step, 2) refers to the time
of the second step (after the addition of morpholine); [c] Isolated yields. NO – Not
Observed; [c] 0.18 mmol of 2a (1 equiv) was used.
4
With the optimized conditions in hand,
a large-scale
trace of
experiments were carried out to further understand the
mechanism of the reaction. It was shown that amide is only
obtained in the presence of TBAI at RT (entry 9). While was
4 (entries 7 and 8) was observed. Several control
experiment (using 10.6 mmol of ) was performed, resulting in
1
a quantitative yield of 3aa (Scheme 3).
4
O
4
not observed in the absence of TBAI, either at RT or -40 °C
(entries 10 and 11), yields of 3aa decreased. These results
S
Ph
ONa
Cl
I
O
1)
O
O
2a
S
suggest that TBAI has a role in the formation of amide 4, while
DCM, TBAI, 15 min
O
Ph
N
being important in the enhancement of sulfonamide 3aa
formation. Performing the reaction in MeCN with TBAI gave
similar results (entries 12 and 13). Furthermore, replacing TBAI
by TBAC (tetrabutylammonium chloride) gave only 55% of 3aa
(entry 14), comparable with the 59% yield of 3aa obtained in
the absence of any additive (entry 10). This suggests that the
O
HN
2)
1
3aa 99%
(2.4 g)
O
(3 g)
2h
Scheme 3 Gram scale synthesis of 3aa.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
Further studies were performed to investigate a possible mechanism, as when the reaction was carried out in the
radical mechanism and the influence of the temperature in presence of TEMPO, there were no significant changes in the
both steps (see SI). On the basis of these studies, it was yields of both sulfonamide 3aa and amide
4
.
concluded that the reaction does not undergo a radical
Table 2. Synthesis of sulfonamides from sulfinate salts and amines or anilines.
We next studied the scope of the reaction (Table 2). For the
sulfinate salt 2a, secondary aliphatic amines offered higher
A
1) K2S2O5, HCO2Na,
Pd(OAc)2, PPh3, phen,
TBAC, DMF, 70 °C
O
O
I
yields than primary amines (3aa
, 3ab, 3ac, 3ad, 3ae, up to 98%
S
N
yield vs 3af 3ah 3ai up to 68% yield).
,
,
MeO
HN
2)
Distinctly, the bifunctional secondary aliphatic amine –
piperazine – gave product 3ag in 33% yield (with 1 equiv of
piperazine). The use of anilines resulted in lower overall yields,
e.g. sulfonamide 3aj (50%), 3ak (51%), 3al (53%), 3am (20%)
and 3an (33%). Salt 2a was also tested with benzotriazole, and
compound 3ao was obtained in 57% yield. Comparing the
MeO
53%
NBS, DMF/THF,
0 to 23 °C
B
SO2Na
1)
2)
three sulfinate salts 2a
,
2b and 2c, the corresponding
3be and 3ac 3ce, were generally
MeO
Cl
I
O
sulfonamides 3aa 3ae 3ba
-
,
-
-
O
O
2c
obtained in higher yields when the sodium p-methoxybenzene
sulfinate 2c was used, possibly due to a p-MeO group
activation.
S
DCM, TBAI, 15 min, -40 °C
HN
O
N
MeO
Between the sodium benzene sulfinate 2a and the sodium p-
methylbenzene sulfonate 2b, the results are similar. In
addition, sulfonamide 3cb was prepared in 82% yield by this
method. The same sulfonamide was prepared by Pfizer in 53%,
using a one-pot two step procedure where an aryl halogen is
1
3cb 82%
2h
Scheme 4 Comparison of Pfizer’s method and the herein reported method for
the synthesis of 3cb.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
sulfonylated using K2S2O5 as SO2 source and an amine (Scheme sulfonylation method into drug optimization and drug
4).[17]The reaction mechanism was then investigated by a discovery processes, avoiding harsh conditions, the use of
combination of ESI-MS analysis and density functional theory sulfonyl chlorides and metal catalysts as used in alternative
(DFT) calculations (Scheme 5). Reaction of
1 with sodium approaches.
benzenesulfinate 2a in the absence of morpholine revealed a
mass signal of 411 m/z by ESI-MS analysis. This mass was
Experimental Section
tentatively attributed to I, which could be a reaction
intermediate formed through displacement of the halide atom
of the benziodoxolone by the benzenesulfinate. In this
context, the role of TBAI in the reaction could be attributed to
the formation of iodine-bearing benziodoxolone via reaction
of iodine atom of TBAI with 1. DFT analysis of I suggest that
sulfur is the most electrophilic center (see natural charges
depicted in Scheme 5).
Synthesis of 1-chloro-1,2-benziodoxol-3-(1H)-one (1)[13]
A round-bottom flask was charged with 2-iodobenzoic acid (500 mg, 2
mmol) and dissolved in 4 mL of acetonitrile. The mixture stirred at 82 °C
until full dissolution was observed. A solution of TCICA (155 mg, 0.67
mmol) in a 1 ml of hot acetonitrile was then added to the mixture. The
resulting mixture was stirred at 82 °C for 10 min and, while still hot, filtered
through a hot Hirsch funnel and washed with hot acetonitrile. The resulting
solution was concentrated under vacuum, affording 1-chloro-1,2-
benziodoxol-3-(1H)-one (1) as a white solid in 98% yield. 1H NMR (400
MHz, CDCl3) δH = 8.26 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.99
(t, J = 7.2 Hz, 1H), 7.80 (t, J = 7.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δC
= 167.3, 136.8, 133.6, 132.0, 128.8, 127.0, 117.2.
Thus, a possible reaction mechanism including intermediate
I
involves the addition of amine into the sulfur center. DFT
calculations suggested an energy barrier of 20.6 kcal mol-1 (via
calculated proposed TS structure) for the consequent
concerted sulfur oxidation/iodine reduction to yield the
corresponding sulfonamide product and 2-iodobenzoic acid.
General procedure for sulfinate salts synthesis
A round-bottom flask was charged with a sulfonyl chloride (11 mmol),
sodium sulfite (24 mmol), sodium hydrogencarbonate (22 mmol) and
dissolved in 40 mL of water. The mixture stirred at 100 °C for 4 h. After
cooled to room temperature, the water was evaporated and the mixture
was extracted three times with hot ethanol. The resulting product was
recrystallized from ethanol and filtered.
Ph
O
O
S
O
S
X
I
O
Natural charges:
Ph
ONa
NaX
I
O
S = 1.36
I = 1.35
O
O
CCOO = 0.83
X = Cl (1), I
ESI-MS [M+Na]+ 411 m/z
O
Sodium 4-methylbenzenesulfinate (2b)
I
Prepared according to the general procedure and obtained as a white solid
in 74% yield. 1H NMR (400 MHz, DMSO) δH = 7.37 (d, J = 7.6 Hz, 2H),
7.12 (d, J = 7.7 Hz, 2H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO) δC
‡
=
156.9, 136.8, 128.2 (2C), 124.3 (2C), 20.8.
N
H
Sodium 4-methoxybenzenesulfinate (2c)
O
O
I
O
Prepared according to the general procedure and obtained as a white solid
S
in 66% yield. 1H NMR (400 MHz, DMSO) δH = 7.40 (d, J = 8.3 Hz, 2H),
Ph
N
OH
+
6.86 (d, J = 8.3 Hz, 2H), 3.74 (s, 3H). 13C NMR (101 MHz, DMSO) δC
=
Proposed TS (M06-2X/LANL2DZ)
G‡ = 26.4 kcal/mol
O
159.0, 152.1, 125.7 (2C), 112.9 (2C), 55.1.
isolated
ESI-MS 228 m/z
isolated
G‡ (DCM) = 21.7 kcal/mol

G‡ (MeCN) = 20.6 kcal/mol
General procedure for sulfonamide synthesis.
A round-bottom flask was charged with chlorobenziodoxolone (50 mg,
0.18 mmol), the sulfinate salt (0.27 mmol, 1.5 equiv.) and
tetrabutylammonium iodine (41.4 µmol, 0.2 equiv.). To the solids, 1 mL of
dichloromethane was added and the reaction was stirred at -40 °C for 15
min. The amine (0.28mmol, 1.5 equiv.) was then added and the reaction
was stirred at -40 °C for 2 h. When completed, the reaction was allowed to
warm up to room temperature, washed with water, saturated sodium
hydrogencarbonate solution and brine. The resulting organic phase was
dried with sodium sulfate, filtered and concentrated under vacuum. The
crude was purified using preparative thin layer chromatography or flash
chromatography with ethyl acetate/hexane.
Scheme 5 Proposed reaction mechanism.
Conclusions
In conclusion, a new sulfonylation method was developed
relying on the use of a hypervalent iodine reagent. The
established protocol, a reaction between a sulfinate salt and a
benziodoxolone-derived reagent, followed by in situ addition
of an amine, proved to be versatile and compatible with both
aliphatic and aromatic amines. The corresponding
sulfonamides were obtained in moderate to excellent yields,
also in a highly efficient gram scale.
A plausible mechanism for this transformation was proposed
on the basis of ESI-MS data and DFT calculations. The results
suggested the formation of a reactive intermediate, that
delivers the final sulfonamide. The protocol herein described
consists on a versatile platform for implementation of the
4-(phenylsulfonyl)morpholine (3aa)[18]
Prepared according to the general procedure. Freshly distilled morpholine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a white solid in 98% yield. 1H NMR (400 MHz, CDCl3) δH = 7.76 (d, J = 7.4
Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 3.74 (t, J = 4.6
Hz, 4H), 3.00 (t, J = 4.5 Hz, 4H). 13C NMR (101 MHz, CDCl3) δC = 135.3,
133.2, 129.3 (2C), 128.0 (2C), 66.2 (2C), 46.1 (2C).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
4-tosylmorpholine (3ba)[8]
Prepared according to the general procedure. Freshly distilled
diethylamine stored under 3 Å molecular sieves was used. Purification by
flash chromatography using ethyl acetate/hexane (1:3) gave the title
Prepared according to the general procedure. Freshly distilled morpholine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a light-yellow solid in 77% yield. 1H NMR (400 MHz, CDCl3) δH = 7.61 (d,
J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.70 (t, J = 4.7, 4H), 2.95 (t, J =
4.6, 4H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 144.0, 132.1, 129.8
(2C), 127.9 (2C), 66.1 (2C), 46.0 (2C), 21.6.
product as a light-yellow oil in 78% yield. 1H NMR (400 MHz, CDCl3) δH
=
7.65 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.19 (q, J = 7.1 Hz, 4H),
2.37 (s, 3H), 1.09 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz, CDCl3) δC
=
143.0, 137.4, 129.6 (2C), 127.0 (2C), 42.0 (2C), 21.5, 14.2 (2C).
N,N-diethyl-4-methoxybenzenesulfonamide (3cd)[18]
4-[(4-methoxyphenyl)sulfonyl]morpholine (3ca)[8]
Prepared according to the general procedure. Freshly distilled
diethylamine stored under 3 Å molecular sieves was used. Purification by
flash chromatography using ethyl acetate/hexane (1:3) gave the title
product as a colourless oil in 73% yield. 1H NMR (400 MHz, CDCl3) δH
7.72 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 3.20 (q, J =
7.1 Hz, 4H), 1.10 (t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δC
Prepared according to the general procedure. Freshly distilled morpholine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (4:6) gave the title product as
a light-yellow solid in 99% yield. 1H NMR (400 MHz, CDCl3) δH = 7.69 (d,
J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.77 – 3.70 (m, 4H),
2.97 (t, J = 4.5 Hz, 4H). 13C NMR (101 MHz, CDCl3) δC = 163.4, 130.1 (2C),
126.8, 114.4 (2C), 66.2 (2C), 55.8, 46.1 (2C).
=
=
162.7 (s), 132.2 (s), 129.1 (2C), 114.2 (2C), 55.7 (s), 42.0 (2C), 14.2 (2C).
N-benzyl-N-methylbenzenesulfonamide (3ae)[21]
1-(phenylsulfonyl)piperidine (3ab)[18]
Prepared according to the general procedure. Purification by flash
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a white solid in 87% yield. 1H NMR (400 MHz, CDCl3) δH = 7.85 (d, J = 7.4
Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.4 Hz, 2H), 7.37 – 7.28 (m,
5H), 4.15 (s, 2H), 2.61 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 137.5,
135.7, 132.8, 129.3 (2C), 128.8 (2C), 128.5 (2C), 128.0, 127.5 (2C), 54.2,
34.4.
Prepared according to the general procedure. Freshly distilled piperidine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a yellow solid in 95% yield. 1H NMR (400 MHz, CDCl3) δH = 7.75 (d, 2H, J
= 7.7 Hz), 7.59 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 5.5,
4H), 1.67 – 1.60 (m, 4H), 1.45 – 1.37 (m, 2H). 13C NMR (101 MHz, CDCl3)
δC = 136.4, 132.7, 129.0 (2C), 127.7 (2C), 47.0 (2C), 25.3 (2C), 23.6.
N-benzyl-N,4-dimethylbenzenesulfonamide (3be)[6]
1-tosylpiperidine (3bb)[19]
Prepared according to the general procedure. Purification by flash
chromatography using ethyl acetate/hexane (1:4) gave the title product as
a white solid in 95% yield. 1H NMR (400 MHz, CDCl3) δH = 7.73 (d, J = 8.1
Hz, 2H), 7.40 – 7.26 (m, 7H), 4.12 (s, 2H), 2.58 (s, 3H), 2.46 (s, 3H). 13
NMR (101 MHz, CDCl3) δC = 143.6, 135.8, 134.5, 129.9 (2C), 128.8 (2C),
128.5 (2C), 128.0, 127.7 (2C), 54.3, 34.5, 21.7.
Prepared according to the general procedure. Freshly distilled piperidine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:4) gave the title product as
a light-yellow solid in 67% yield. 1H NMR (400 MHz, CDCl3) δH = 7.63 (d,
J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.96 (t, J = 5.4, 4H), 2.42 (s, 3H),
C
1.67 – 1.58 (m, 4H), 1.45 – 1.36 (m, 2H). 13C NMR (101 MHz, CDCl3) δC
143.4, 133.4, 129.7 (2C), 127.8 (2C), 47.1 (2C), 25.3 (2C), 23.6, 21.6.
=
N-benzyl-4-methoxy-N-methylbenzenesulfonamide (3ce)[22]
Prepared according to the general procedure. Purification by flash
chromatography using ethyl acetate/hexane (1:4) gave the title product as
a white solid in 99% yield. 1H NMR (400 MHz, CDCl3) δH = 7.78 (d, J = 8.8
Hz, 2H), 7.36 – 7.28 (m, 5H), 7.03 (d, J = 8.8 Hz, 2H), 4.12 (s, 2H), 3.89
(s, 3H), 2.58 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 163.1, 135.8, 129.7
(2C), 129.1, 128.8 (2C), 128.5 (2C), 128.0, 114.4 (2C), 55.8, 54.3 (s), 34.5.
1-[(4-methoxyphenyl)sulfonyl]piperidine (3cb)[17]
Prepared according to the general procedure. Freshly distilled piperidine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:8) gave the title product as
a white solid in 82% yield. 1H NMR (400 MHz, CDCl3) δH = 7.68 (d, J = 8.7
Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.95 (t, J = 5.4 Hz, 4H), 1.66
– 1.60 (m, 4H), 1.44 – 1.36 (m, 2H). 13C NMR (101 MHz, CDCl3) δC = 163.0,
129.9 (2C), 128.1, 114.2 (2C), 55.7, 47.1 (2C), 25.3 (2C), 23.7.
N-benzylbenzenesulfonamide (3af)[8]
Prepared according to the general procedure. Freshly distilled
benzylamine stored under 3 Å molecular sieves was used. Purification by
thin layer chromatography using ethyl acetate/hexane (1:3) gave the title
product as a white solid in 65% yield. 1H NMR (400 MHz, CDCl3) δH =
7.86 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H),
7.30 – 7.13 (m, 5H), 5.02 (s, 1H), 4.14 (d, J = 6.0 Hz, 2H). 13C NMR (101
MHz, CDCl3) δC = 139.98, 136.33, 132.76, 129.20 (2C), 128.73 (2C),
127.94 (2C), 127.16 (2C), 47.30.
1-[(4-methoxyphenyl)sulfonyl]pyrrolidine (3cc)[20]
Prepared according to the general procedure. Freshly distilled pyrrolidine
stored under 3 Å molecular sieves was used. Purification by flash
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a white solid in 76% yield. 1H NMR (400 MHz, CDCl3) δH = 7.76 (d, J = 8.7
Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.21 (t, J = 6.6 Hz, 4H), 1.74
(t, J = 6.6 Hz, 4H). 13C NMR (101 MHz, CDCl3) δC = 163.0, 129.7 (2C),
128.7, 114.2 (2C), 55.7, 48.0 (2C), 25.3 (2C).
1-(phenylsulfonyl)piperazine (3ag)[23]
Prepared according to the general procedure. Purification by thin layer
chromatography using ethyl acetate/hexane (1:1) gave the title product as
a yellow oil in 33% yield. 1H NMR (400 MHz, CDCl3) δH = 7.74 (d, J = 7.6
Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 3.35 – 3.15 (m,
2H), 3.11 – 2.93 (m, 7H). 13C NMR (101 MHz, CDCl3) δC = 135.6, 133.1,
129.3 (2C), 127.9 (2C), 46.2 (2C), 44.0 (2C).
N,N-diethylbenzenesulfonamide (3ad)[18]
Prepared according to the general procedure. Freshly distilled
diethylamine stored under 3 Å molecular sieves was used. Purification by
flash chromatography using ethyl acetate/hexane (1:3) gave the title
product as a light-yellow solid in 88% yield. 1H NMR (400 MHz, CDCl3) δH
= 7.78 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.3 Hz, 2H),
3.22 (q, J = 7.1 Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δC = 140.5, 132.3, 129.1 (2C), 127.1 (2C), 42.1 (2C), 14.2 (2C).
N-allylbenzenesulfonamide (3ah)[24]
Prepared according to the general procedure. Freshly distilled allylamine
stored under 3 Å molecular sieves was used. Purification by thin layer
chromatography using ethyl acetate/hexane (1:1) gave the title product as
a white oil in 68% yield. 1H NMR (400 MHz, CDCl3) δH = 7.88 (d, J = 7.8
N,N-diethyl-4-methylbenzenesulfonamide (3bd)[6]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
Hz, 2H), 7.59 (t, J = 7.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 5.72 (dq, J = 10.7,
5.8 Hz, 1H), 5.09-5.19 (m, 2H), 4.52 (s, 1H), 3.64-3.59 (m, 2H). 13C NMR
(101 MHz, CDCl3) δC = 140.1, 133.0, 132.9, 129.3 (2C), 127.2 (2C), 118.0,
45.9.
1-(phenylsulfonyl)-1H-benzo[d][1,2,3]triazole (3ao)[29]
Prepared according to the general procedure. Purification by thin layer
chromatography using ethyl acetate/hexane (1:1) gave the title product as
a light-brown solid in 57% yield. 1H NMR (400 MHz, CDCl3) δH = 8.18 –
8.04 (m, 4H), 7.66 (dd, J = 13.9, 6.9 Hz, 2H), 7.58 – 7.43 (m, 3H). 13C NMR
(101 MHz, CDCl3) δC = 145.5, 137.2, 135.3, 131.8, 130.5, 129.8 (2C),
128.0 (2C), 126.0, 120.7, 112.1.
N-cyclohexylbenzenesulf0onamide (3ai)[25]
Prepared according to the general procedure. Freshly distilled
ciclohexilamine stored under 3 Å molecular sieves was used. Purification
by thin layer chromatography using ethyl acetate/hexane (1:29) gave the
Computational methods
title product as a yellow oil in 38% yield. 1H NMR (400 MHz, CDCl3) δH
=
7.89 (d, J = 7.4 Hz, 2H), 7.59 – 7.54 (m, 1H), 7.50 (t, J = 7.3 Hz, 2H), 4.61
(d, J = 6.5 Hz, 1H), 3.21 – 3.07 (m, 1H), 1.78 – 1.70 (m, 2H), 1.66 – 1.59
(m, 2H), 1.54 – 1.47 (m, 1H), 1.24 – 1.04 (m, 5H). 13C NMR (101 MHz,
CDCl3) δC = 141.6, 132.5, 129.2 (2C), 127.0 (2C), 52.8, 34.1 (2C), 25.3,
24.7 (2C).
DFT calculations were performed using the Gaussian 09 software
package[30] and structural representations were generated with
CYLview.[31] All the geometry optimizations were carried out at the M06
level of theory with the LANL2DZ basis set (Los Alamos National
Laboratory 2 double ζ). All of the optimized geometries were verified by
frequency computations as minima (zero imaginary frequencies) or
transition states (a single imaginary frequency corresponding to the
desired reaction coordinate). Single-point energy calculations on the
optimized geometries were then evaluated using the functional M06-2X
and the same basis set, with solvent effects (dichloromethane or
acetonitrile) calculated by means of the Polarizable Continuum Model
(PCM) initially devised by Tomasi and coworkers,[32] with radii and non-
electrostatic terms of the SMD solvation model, developed by Truhler and
co-workers.[33] The free energy values presented along the manuscript
were derived from the electronic energy values obtained at the
M06-2X/LANL2DZ//M06/LANL2DZ level, including solvent effects, and
corrected by using the thermal and entropic corrections based on structural
and vibration frequency data calculated at the M06/LANL2DZ level.
N-methyl-N-phenylbenzenesulfonamide (3aj)[8]
Prepared according to the general procedure. Freshly distilled N-
methylaniline stored under 3 Å molecular sieves was used. Purification by
thin layer chromatography using ethyl acetate/hexane (1:3) gave the title
product as a brown solid in 50% yield. 1H NMR (400 MHz, CDCl3) δH
=
7.62 – 7.53 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.33 – 7.23 (m, 3H), 7.09 (d,
J = 6.8 Hz, 2H), 3.18 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 141.6, 136.6,
132.9, 129.0 (2C), 128.9 (2C), 128.0 (2C), 127.5, 126.8 (2C), 38.3.
1-(phenylsulfonyl)indoline (3ak)[26]
Prepared according to the general procedure. Indoline stored under 3 Å
molecular sieves was used. Purification by thin layer chromatography
using ethyl acetate/hexane (1:3) gave the title product as a light-brown
solid in 51% yield. 1H NMR (400 MHz, CDCl3) δH = 7.79 (d, J = 7.7 Hz, 2H),
7.65 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H),
7.20 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H),
3.93 (t, J = 8.4 Hz, 2H), 2.88 (t, J = 8.4 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δC = 142.0, 137.1, 133.3, 131.9, 129.1 (2C), 127.8, 127.4 (2C), 125.3,
124.0, 115.1, 50.1, 28.0.
Acknowledgments
We thank to the FC&T for fellowships PD/BD/142864/2018 and
N-(4-methoxyphenyl)benzenesulfonamide (3al)[8]
SFRH/BD/116322/2016,
SFRH/BPD/100433/2014,
Prepared according to the general procedure. p-Anisidine was
recrystalized before being used. Purification by thin layer chromatography
using ethyl acetate/hexane (1:2) gave the title product as a black solid in
54% yield. 1H NMR (400 MHz, CDCl3) δH = 7.69 (d, J = 7.9 Hz, 2H), 7.53
(t, J = 7.1 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.75
(d, J = 8.6 Hz, 2H), 3.75 (s, 3H). 13C NMR (101 MHz, CDCl3) δC = 158.3,
139.1, 133.0, 129.1 (2C), 128.8, 127.4 (2C), 125.9 (2C), 114.6 (2C), 55.6.
SFRH/BPD/102296/2014 and PTDC/QUI-QOR/29967/2017,
iMed.ULisboa grant UID/DTP/04138/2013). This work was
supported by the Associated Laboratory for Sustainable Chem-
istry-Clean Pro-cesses and Technologies- LAQV which is
financed by national funds from FCT/MEC (UID/QUI/50006/2013)
and cofinanced by the ERDF under the PT2020 Partnership
Agreement
(POCI-01-0145-FEDER-007265).
The
NMR
N-(2,4-dimethylphenyl)benzenesulfonamide (3am)[27]
spectrometers are part of The National NMR Facility, supported
by FC&T (RECI/BBB-BQB/0230/2012).
Prepared according to the general procedure. Purification by thin layer
chromatography using ethyl acetate/hexane (1:3) gave the title product as
a light-brown solid in 20% yield.1H NMR (400 MHz, CDCl3) δH = 7.71 (d, J
= 8.0 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.12 (d, J =
8.0 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.18 (s, 1H), 2.26 (s, 3H), 1.93 (s, 3H).
13C NMR (101 MHz, CDCl3) δC = 139.9, 136.7, 133.0, 132.3, 131.6, 129.1
(2C), 127.7, 127.3 (2C), 125.5, 21.0, 17.6.
Keywords: Sulfonamides • Hypervalent iodine • Umpolung
reaction • Computational chemistry • Mass spectrometry
[1]
[2]
J. Drews, Science 2000, 287, 1960-1964.
L. C. R. Carvalho, D. Ribeiro, R. S. G. R. Seixas, A. M. S. Silva, M. Nave,
A. C. Martins, S. Erhardt, E. Fernandes, E. J. Cabrita, M. M. B. Marques,
RSC Adv. 2015, 5, 49098-49109; M. S. Estevao, L. C. R. Carvalho, M.
Freitas, A. Gomes, A. Viegas, J. Manso, S. Erhardt, E. Fernandes, E. J.
Cabrita, M. M. B. Marques, Eur. J. Med. Chem. 2012, 54, 823-833.
T. J. De Boer, H. J. Backer, Org. Synth. 1954, 34, 96; R. Sridhar, B.
Srinivas, V. P. Kumar, M. Narender, K. R. Rao, Adv. Synth. Catal. 2007,
349, 1873-1876.
N-(3-fluorophenyl)benzenesulfonamide (3an)[28]
Prepared according to the general procedure. Purification by thin layer
chromatography using ethyl acetate/hexane (1:9) gave the title product as
a light-brown solid in 33% yield. 1H NMR (400 MHz, CDCl3) δH = 7.82 (d,
J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.18 (dd,
J = 14.7, 8.1 Hz, 1H), 6.96 (s, 1H), 6.90 (dt, J = 10.1, 1.9 Hz, 1H), 6.85 –
6.76 (m, 2H). 13C NMR (101 MHz, CDCl3) δC = 163.2 (d, J = 246.9 Hz),
138.9, 138.2 (d, J = 10.3 Hz), 133.5, 130.7 (d, J = 9.3 Hz), 129.3 (2C),
127.4 (2C), 116.6 (d, J = 3.1 Hz), 112.3 (d, J = 21.2 Hz), 108.5 (d, J = 25.3
Hz).
[3]
[4]
F. Shi, M. K. Tse, S. L. Zhou, M. M. Pohl, J. Radnik, S. Hubner, K.
Jahnisch, A. Bruckner, M. Beller, J. Am. Chem. Soc. 2009, 131, 1775-
1779; G. Burton, P. Cao, G. Li, R. Rivero, Org. Lett. 2003, 5, 4373-4376;
J. J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 6043-6048; B.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
R. Rosen, J. C. Ruble, T. J. Beauchamp, A. Navarro, Org. Lett. 2011, 13,
[20] J. L. G. Ruano, A. Parra, L. Marzo, F. Yuste, V. M. Mastranzo,
Tetrahedron 2011, 67, 2905-2910.
2564-2567.
[5]
J. L. G. Ruano, A. Parra, F. Yuste, V. M. Mastranzo, Synthesis 2008,
311-319; X. Huang, J. C. Wang, Z. Q. Ni, S. C. Wang, Y. J. Pan, Chem.
Commun. 2014, 50, 4582-4584.
[21] H. B. Zhu, Y. J. Shen, Q. Y. Deng, T. Tu, Chem. Commun. 2015, 51,
16573-16576.
[22] D. A. Powell, H. Fan, J. Org. Chem. 2010, 75, 2726-2729.
[23] B. J. Henderson, D. J. Carper, T. F. Gonzalez-Cestari, B. Yi, K.
Mahasenan, R. E. Pavlovicz, M. L. Dalefield, R. S. Coleman, C. L. Li, D.
B. McKay, J. Med. Chem. 2011, 54, 8681-8692.
[6]
[7]
X. D. Tang, L. B. Huang, C. R. Qi, X. Wu, W. Q. Wu, H. F. Jiang, Chem.
Commun. 2013, 49, 6102-6104.
J. W. Zhao, J. X. Xu, J. X. Chen, X. Q. Wang, M. H. He, RSC Adv. 2014,
4, 64698-64701; C. Buathongjan, D. Beukeaw, S. Yotphan, Eur. J. Org.
Chem. 2015, 1575-1582; W. Wei, C. L. Liu, D. S. Yang, J. W. Wen, J. M.
You, H. Wang, Adv. Synth. Catal. 2015, 357, 987-992.
[24] L. De Luca, G. Giacomelli, J. Org. Chem. 2008, 73, 3967-3969.
[25] K. Moriyama, Y. Nakamura, H. Togo, Org. Lett. 2014, 16, 3812-3815.
[26] E. Wagner, H. J. Wittmann, S. Elz, A. Strasser, Bioorg. Med. Chem. Lett.
2011, 21, 6274-6280.
[8]
[9]
K. Yang, M. L. Ke, Y. G. Lin, Q. L. Song, Green Chem. 2015, 17, 1395-
1399.
[27] S. Z. Siddiqui, A. Sarwar, M. A. Abbasi, R. Aziz ur, M. Hussain, I. Ahmad,
S. A. A. Shah, J. Chem. Soc. Pak. 2016, 38, 1151-1158.
[28] T. Kim, S. J. McCarver, C. Lee, D. W. C. MacMillan, Angew. Chem., Int.
Ed. 2018, 57, 3488-3492.
H. Woolven, C. Gonzalez-Rodriguez, I. Marco, A. L. Thompson, M. C.
Willis, Org. Lett. 2011, 13, 4876-4878; A. S. Deeming, C. J. Russell, M.
C. Willis, Angew. Chem., Int. Ed. 2015, 54, 1168-1171; B. N. Du, Y. Wang,
W. X. Sha, P. Qian, H. B. Mei, J. L. Han, Y. Pan, Asian J. Org. Chem.
2017, 6, 153-156; F. Zhang, D. Q. Zheng, L. F. Lai, J. Cheng, J. T. Sun,
J. Wu, Org. Lett. 2018, 20, 1167-1170; Y. Chen, P. R. D. Murray, A. T.
Davies, M. C. Willis, J. Am. Chem. Soc. 2018, 140 8781–8787.
[29] S. X. Wu, Y. K. Zhang, J. Yan, Synth. Commun. 2016, 46, 1432-1437.
[30] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino,
G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T.
Vreven, J. A. M. Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M.
Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma,
V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich,
A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J.
Fox, GAUSSIAN 09 (Revision D.01), Gaussian, Inc., Wallingford CT,
2009.
[10] C. Waldmann, O. Schober, G. Haufe, K. Kopka, Org. Lett. 2013, 15,
2954-2957.
[11] V. V. Zhdankin, Curr. Org. Synth. 2005, 2, 121-145.
[12] J. Charpentier, N. Frueh, A. Togni, Chem. Rev. 2015, 115, 650-682; A.
Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328-3435.
[13] V. Matousek, E. Pietrasiak, R. Schwenk, A. Togni, J. Org. Chem. 2013,
78, 6763-6768.
[14] H. Egami, T. Yoneda, M. Uku, T. Ide, Y. Kawato, Y. Hamashima, J. Org.
Chem. 2016, 81, 4020-4030.
[15] J. Gao, X. J. Pan, J. Liu, J. Y. Lai, L. M. Chang, G. Q. Yuan, RSC Adv.
2015, 5, 27439-27442; E. Deruer, V. Hamel, S. Blais, S. Canesi, Beilstein
J. Org. Chem. 2018, 14, 1203-1207.
[16] Y. J. Guo, S. Lu, L. L. Tian, E. L. Huang, X. Q. Hao, X. J. Zhu, T. Shao,
M. P. Song, J. Org. Chem. 2018, 83, 338-349.
[31] D. J. Aitken, H. Eijsberg, A. Frongia, J. Ollivier, P. P. Piras, Synthesis
2014, 46, 1-24.
[17] A. Shavnya, S. B. Coffey, A. C. Smith, V. Mascitti, Org. Lett. 2013, 15,
6226-6229.
[32] E. Cances, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107, 3032-
3041.
[18] R. Pandya, T. Murashima, L. Tedeschi, A. G. M. Barrett, J. Org. Chem.
2003, 68, 8274-8276.
[33] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378-6396.
[19] N. Takasu, K. Oisaki, M. Kanai, Org. Lett. 2013, 15, 1918-1921.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900259
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Sulfonamide Synthesis
Diogo L. Poeira, João C. Macara, Hélio
Faustino, Jaime A. S. Coelho, Pedro M.
P. Gois and M. Manuel B. Marques*
Page No. – Page No.
Hypervalent Iodine mediated
sulfonamide synthesis
The method describes a clean and mild transfer of sulfonyl groups to amines and
anilines, mediated by a hypervalent iodine reagent. With this reaction a total of 25
sulfonamides were synthesised in up to 99% yield, even in a gram-scale. The
reaction mechanism was investigated by ESI-MS and DFT calculations.
This article is protected by copyright. All rights reserved.