Direct Sulfonamidation of Primary and Secondary Benzylic Alcohols Catalyzed by a Boronic Acid/Oxalic Acid System

Article abstract of DOI:10.1002/ejoc.201700621

The direct sulfonamidation of primary and secondary benzylic alcohols catalyzed by a 2,3,4,5-tetrafluorophenylboronic acid/oxalic acid co-catalytic system was examined. The reaction proceeds under mild conditions with readily available starting materials and has been shown to be gram-scalable without significant decrease of yield. Both primary and secondary benzylic alcohols were evaluated and afforded the desired sulfonamide products with good to excellent yields.

Full text of DOI:10.1002/ejoc.201700621

A Journal of
Accepted Article
Title: Direct Sulfonamidation of Primary and Secondary Benzylic
Alcohols Catalyzed by a Boronic Acid/Oxalic Acid System
Authors: Tristan Verdelet, Robert Ward, and Dennis G. Hall
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.201700621
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700621
Supported by

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
Direct Sulfonamidation of Primary and Secondary Benzylic
Alcohols Catalyzed by a Boronic Acid/Oxalic Acid System
Tristan Verdelet,[a] Robert M. Ward,[a] and Dennis G. Hall*[a]
Abstract: The direct sulfonamidation of primary and secondary
benzylic aclohols catalyzed by a 1,2,3,4-tetrafluorophenylboronic
acid/oxalic acid co-catalytic system has been examined. The
reaction proceeds under mild conditions with readily available
starting materials and has been shown to be gram-scalable without
significant decrease of yield. Both primary and secondary benzylic
alcohols were evaluated and afforded the desired sulfonamide
products with good to excellent yields.
temperatures. Several procedures based on Lewis10 and
Brønsted11 acid activation of benzylic alcohols have also been
reported for the synthesis of N-benzylsulfonamides, however the
substrate scope of these methodologies is often quite limited.
Boronic acid catalysis12 (BAC) has emerged as
a
promising tool for the mild activation and transformation of
carboxylic acids,13 alcohols14 and carbonyls.15 In a practical point
of view, arylboronic acid catalysts exhibit many advantages: they
are usually stable to air and moisture, possess a relatively low
toxicity, are compatible with
a broad range of chemical
functionalities and their properties can be easily tuned via the
introduction or replacement of substituents on the aryl moiety.
Besides, arylboronic acids are now broadly commercially
available at a moderate cost. Herein, by exploiting BAC, we
developed a new carbon-nitrogen bond forming process starting
from readily available benzylic alcohols and sulfonamides.
Introduction
Sulfonamides and their derivatives are versatile
compounds that can be used in various areas of organic and
medicinal chemistry. In organic synthesis, they are often
employed as amine protecting groups1 or as reaction
intermediates.2 In medicinal chemistry, they have been found to
possess interesting properties over a broad variety of diseases
and as a consequence, many important drugs contain a
sulfonamide unit.3 In particular, N-benzyl sulfonamides are a
sub-class of sulfonamides that are commonly employed in drug
discovery4 (Figure 1).
A common general way to access sulfonamides is the
nucleophilic reaction between an amine and a sulfonyl halide
partner.5 The toxicity of the starting materials and the need for a
stoichiometric quantity of a base render this process less
attractive on the point of view of atom-economy and safety.
Consequently, other routes have been widely investigated.6
Among these alternatives, N-alkylation of sulfonamides with
benzylic alcohols has gained great attention from the organic
chemistry community.7-11 A notable advantage of this approach
is that alcohols are broadly available from commercial sources.
In an ideal reaction design, the alcohol would be activated by a
reusable catalyst, avoiding a pre-activation step, and the only
Figure 1. Benzylic sulfonamides in drug discovery.
Results and Discussion
Our reaction optimization study is shown in Table 1. 4-
Bromobenzyl alcohol 1 and para-toluene sulfonamide 2 were
used as model substrates for the catalytic sulfonamidation of
by-product would be a molecule of water. During the last decade, benzylic alcohols. A relatively short reaction time of one hour
considerable efforts have been committed to hydrogen
autotransfer8 or relay race9 strategies for the preparation of
sulfonamides. These elegant approaches, however often suffer
from the need for expensive catalysts and high reaction
was employed in order to obtain a more accurate comparison of
the efficiency of different reaction conditions. We started the
evaluation of boronic acids with tetrafluoroboronic acid BA1
because it was previously reported as an efficient catalyst for the
activation of allylic and benzylic alcohols in Friedel-Crafts
reactions.14g When BA1 (10 mol%) was employed as catalyst
with one equivalent of para-toluene sulfonamide, only trace
quantity of the desired sulfonamide product 3a was obtained
after one hour at 80 °C in a 4:1 mixture of hexafluoroisopropanol
(HFIP) and nitromethane (entry 1). Intrigued by the work of
Moran and co-workers concerning the crucial effect of oxalic
acid as an additive in boronic acid catalyzed Friedel-Crafts
reactions,16 we examined its use in our model reaction. We were
pleased to observe the formation of the desired product with a
yield of 42% when both BA1 and oxalic acid were employed
[a]
Dr. T. Verdelet, R. M. Ward, Prof. D. G. Hall
Department of Chemistry
Centennial Centre for Interdisciplinary Science
University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
E-mail: dennis.hall@ualberta.ca
https://www.ualberta.ca/science/about-us/contact-us/faculty-
directory/dennis-hall
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.201700621
European Journal of Organic Chemistry
FULL PAPER
(entry 2). The use of two equivalents of 2 led to an improved
yield of 65% of product 3a (entry 3). As expected, the absence
of the boronic acid partner only provided trace amount of
product (entry 4). After these initial results, we turned our
attention to the arylboronic acid component of this catalytic
resulting from the reaction of 3a with 1. To disfavor this
undesired side reaction, the number of molar equivalents of
para-toluene sulfonamide was increased from two to five. This
modification led to an improved isolated yield after six hours of
reaction, from 69 to 82% (entry 16). Depending on specific
substrates used, it may be possible to fine tune reaction
conditions and decrease the relative stoichiometry of the
sulfonamide partner.
system (entries
5 to 14). Phenylboronic acid BA2 and
benzoxaborole BA3 were found to be less efficient than BA1,
with only 28% and 11% yield, respectively (entries 5 and 6). Use
of 2-iodo-5-methoxyphenylboronic acid BA4, a known amidation
catalyst,13j,k resulted in 35% of desired product 3a (entry 7).
Electron poor arylboronic acids BA5 and BA6, bearing
respectively a nitro group and a carboxylic acid at the ortho
position of the arylboronic acid, did not demonstrate much
activity for this transformation (entries 8 and 9). Hetero-
arylboronic acids BA7, BA8 and BA9 were also evaluated but
did not afford satisfactory results (entries 10 to 12). Finally,
polyfluorinated arylboronic acids BA10 and BA11 provided
similar results to BA1 with respective yields of 64 and 62%
(entries 13 and 14).
Table 1. Optimization study of the direct sulfonamidation reaction of 1 and 2
(Scheme 1).[a]
Entry
1
Boronic acid
BA1
BA1
BA1
-
Eq. of TsNH2
NMR yield of 3a (%)
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
5
trace[b]
42
2
3
65
4
trace
28
5
BA2
BA3
BA4
BA5
BA6
BA7
BA8
BA9
BA10
BA11
BA1
BA1
6
16
7
35
8
11
9
trace
15
10
11
12
13
14
15
16
trace
trace
64
62
trace[c]
82[d] [e]
Scheme 1. Reaction model used for the optimization study (top) and list of
[a] Reaction conditions: 0.50 mmol of para-bromobenzyl alcohol, para-
toluene sulfonamide, 0.05 mmol of catalyst and 0.05 mmol of oxalic acid
dihydrate were stirred in a mixture of HFIP and nitromethane (4:1, 1.0 mL) at
boronic acids evaluated (bottom).
80 °C in a sealed tube for 1 hour and the crude product was analyzed by 1
H
Having found optimal boronic acid partners, a panel of
different additives bearing carboxylic acids and/or alcohol
functions were evaluated. This study confirmed that oxalic acid
is the best co-catalyst (see SI). Any changes in the solvent
system or in the HFIP/MeNO2 ratio were found to be detrimental
to the product yield (see SI). In order to probe the effect of water,
an experiment was conducted in the presence of molecular
sieves (entry 15). A complete inhibition of the reaction was
observed in these conditions, suggesting that water may play a
crucial role in this sulfonamidation reaction by preventing off-
cycle dehydration of the boronic acid into inactive boronic
anhydrides. A cautious analysis of the crude NMR spectra of the
reaction (entry 2) revealed the presence of a small proportion of
the dibenzylated sulfonamide product 3aa (see SI for structure)
NMR with para-dinitrobenzene as an internal standard. [b] Without oxalic
acid dihydrate. [c] With 500 mg of M.S. 4Å. [d] Isolated yield after a reaction
time of 6 hours. [e] 2.0 mL of solvent.
With the optimal conditions in hand, we investigated the
scope of the direct sulfonamidation of benzylic alcohols, starting
with various primary alcohols (Scheme 2). As indicated above,
para-bromobenzyl alcohol resulted in the formation of the
desired sulfonamide 3a with
a good yield of 82%. The
corresponding chloro- and fluoro- derivatives also provided good
reactivity with 81 and 74% yield, respectively. Benzyl alcohol
afforded product 3d with a moderate yield of 59%. Although a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
nitromethane (4:1, 2.0 mL) at 80 °C in a sealed tube for 6 hours. [b] Reaction
time of 3 hours. [c] Reaction performed at 50°C for 3 hours. [d] 20 mol% of
BA12 and oxalic acid dihydrate A1, 100 °C for 24 h. [e] Reaction time of 24
hours. BA12: ferroceniumboronic acid hexafluoroantimonate.
complete conversion of the starting material was observed, it is
likely that more nucleophilic arenes like benzyl alcohol can
undergo
a Friedel-Crafts self-reaction competing with the
desired sulfonamidation. Consequently, it was not surprising to
observe a moderate yield of 50% of product 3e when para-
methylbenzyl alcohol was subjected to the reaction conditions.
Likewise, no trace of desired product was observed with the
para-methoxy substrate 3f. For the latter, the H NMR spectrum
of the crude product revealed a complete polymerization of the
The direct sulfonamidation of secondary benzylic alcohols
was studied next (Table 3). 1-(4-Bromophenyl)ethanol was
successfully transformed into sulfonamide 5a after 3 hours at
room temperature with an excellent yield of 90%. 1-
Phenylethanol gave the desired sulfonamide 5b with a near
quantitative yield. In contrast with the primary benzylic alcohol
series, electronically enriched 1-(p-tolyl)ethanol led to an
excellent yield of 92% of product 5c after a reaction time of only
10 minutes. In the case of electron poor arenes, an examination
of the crude product by 1H NMR spectroscopy showed the
presence of remaining starting material after 24 hours at room
temperature, consequently the temperature was set at 50 °C for
those substrates. With these slightly modified conditions, 1-(4-
(trifluoromethyl)phenyl)ethanol afforded the desired sulfonamide
1
starting
material.
With
electron
poor
methyl-4-
(hydroxymethyl)benzoate, a very low conversion was observed
when the optimal conditions were applied. However, by using
harsher reaction conditions and a 20 mol% catalyst loading of
the recently described ferrocenium boronic acid14h,i BA12 (see
Scheme 1) with oxalic acid, a moderate yield of 47% of 3g was
obtained. Ortho-bromobenzyl alcohol provided 49% of the
desired benzylsulfonamide 3h while its fluoro analog afforded
61% of product 3i. We were pleased to observe the formation of
products 3j and 3k from the corresponding disubstituted benzylic
alcohols, with 70 and 80% yield, respectively. These
halogenated products are useful toward further derivatization by
cross-coupling chemistry. Unfortunately, methyl- and bromo-
meta-monosubstituted benzyl alcohols 3l and 3m failed to
provide a clean reaction with the expected products.
5d with
a
satisfying yield of 76% and methyl 4-(1-
hydroxyethyl)benzoate provided an excellent yield of 92% of
product 5e. As shown with the high isolated yield of products 5f
and 5g, the position of a bromide substituent had little influence
on the reaction. Finally, an excellent yield of 96% of product 5h
was obtained from diphenylmethanol after a reaction time of just
a few minutes.
Table 2. Substrate scope for primary benzylic alcohols (isolated yields).[a]
Table 3. Substrate scope of secondary benzylic alcohols (isolated yields).[a]
R2
BA1 (10 mol%)
A1 (10 mol%)
O
S
R2
O
S
OH
H2N
+
R1
N
O
O
R1
H
HFIP/MeNO2 (4:1)
c = 0.5 M, r.t.
2
5
O
O
O
S
O
S
S
N
N
N
O
H
O
H
H
Br
Me
5b, 99%
5c, 92%2
5a, 90%
O
O
O
S
O
S
Br
S
N
N
N
O
H
O
H
H
F3C
MeOOC
5d, 76%[b]
5e, 92%[b]
5f, 90%
O
S
Br
O
HN
O
S
N
O
H
5g, 90%
5h, 96%[c]
[a] Reaction conditions : 0.50 mmol of benzylic alcohol, 2.50 mmol of para-
toluene sulfonamide 2, 0.05 mmol of tetrafluorophenylboronic acid BA1 and
0.05 mmol of oxalic acid dihydrate A1 were stirred in a mixture of HFIP and
nitromethane (4:1, 1.0 mL) at room temperature until complete conversion of
[a] Reaction conditions : 0.50 mmol of benzyl alcohol, 2.50 mmol of para-
toluene sulfonamide 2, 0.05 mmol of tetrafluorophenylboronic acid BA1 and
0.05 mmol of oxalic acid dihydrate A1 were stirred in a mixture of HFIP and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
the starting benzylic alcohol (monitored by TLC). [b] Reaction performed at
50 °C. [c] 2 mL of a (4:1) HFIP/nitromethane mixture.
of oxalic acid dihydrate A1 were stirred in a mixture of HFIP and nitromethane
(4:1, 2.0 mL) at 80 °C in a sealed tube for 6 hours. [b] 2 mL of a (4:1)
HFIP/nitromethane mixture were used. [c] Reaction performed at room
temperature. [d] Reaction time of 24 hours. [e] Reaction performed at 100 °C,
20 mol% of BA1 and oxalic acid dihydrate A1.
A
variety of different sulfonamide nucleophiles were
evaluated in the direct sulfonamidation of benzylic alcohols. First,
N-methylated-para-toluenesulfonamide was reacted with 4-
chlorobenzyl alcohol to furnish 6a with an excellent yield of 96%.
A similar yield was obtained when 1-(4-bromophenyl)ethanol
was engaged with the same sulfonamide nucleophile. The
In order to demonstrate that our catalytic system is suitable
with alcohol substrates other than benzylic alcohols, hexen-1-ol,
iso-butanol and 1-adamantanol, were subjected to the reaction
conditions with para-toluenesulfonamide 2. Satisfactorily, all
three alcohols afforded the corresponding sulfonamide products
7a, 7b and 7c with 76%, 47% and 87% yield, respectively. The
successful isolation of products 7b and 7c is remarkable
because the corresponding tertiary alcohol substrates cannot
form π-stabilized carbocations.
electron rich para-methoxy-benzenesulfonamide afforded
a
moderate yield of 62% when reacted with 1. Because of the
convenience of its removal, the o-nosyl group is a widely used
protecting group for primary and secondary amines. The
Fukuyama amine synthesis2 is a well established method for
amination of alcohols, however, it suffers from the drawbacks of
low atom economy associated with the Mitsunobu reaction.
Consequently,
we
attempted
the
reaction
of
2-
Table 5. Versatility of the direct sulfonamidation reaction (isolated yields).[a]
nitrobenzenesulfonamide with primary benzylic alcohol 1.
Although harsher reaction conditions were needed due to the
presence of a nitro group that decreases the nucleophilicity of
the sulfonamide nitrogen, we were pleased to isolate 55% of
desired product 6d after 24 hours at 100 °C and with 20% co-
catalysts loading. Likewise, a good yield of 70% of product 6e
was obtained when N-methyl-2-nitrobenzenesulfonamide was
reacted with (2-bromo-4-fluorophenyl)methanol for 24 hours with
the standard reaction conditions. Disappointing results were
observed when the reactions between secondary benzyl
alcohols with nosylamines were investigated. In contrast, alkyl
sulfonamides provided excellent yields of 72% and 91% of 6f
and 6g, respectively, when subjected to the reaction with
benzylic alcohol 1.
BA1 (10 mol%)
A1 (10 mol%)
O
S
O
S
R1 OH
+
R1HN
H2N
HFIP/MeNO2 (4:1)
c = 0.25 M, r.t.
O
O
2
7
O
S
O
S
O
HN
HN
O
O
S
HN
O
7a, 76%
7b, 47%[b]
7c, 87%
[a] Reaction conditions : 0.50 mmol of alcohol, 2.50 mmol of sulfonamide, 0.05
mmol of tetrafluorophenylboronic acid BA1 and 0.05 mmol of oxalic acid
dihydrate A1 were stirred in a mixture of HFIP and nitromethane (4:1, 2.0 mL)
at room temperature until complete conversion of the starting material
(monitored by TLC).[b] 1 mL of a (4:1) HFIP/nitromethane mixture were used.
Table 4. Substrate scope of sulfonamide reagents (isolated yields).[a]
To further assess the versatility of this sulfonamidation
method, a gram-scale experiment was conducted starting with 5
mmol (935 mg) of 1. We were pleased to obtain a 76% yield of
desired product 3a similar to that obtained when the reaction
was performed on a 0.5 mmol scale (82%). Remarkably, the
unreacted tosylamine 2 was almost quantitatively recovered
during the flash chromatographic purification and could thus be
re-used.
Scheme 1. Gram scale experiment.
[a] Reaction conditions
: 0.50 mmol of benzylic alcohol, 2.50 mmol of
sulfonamide, 0.05 mmol of tetrafluorophenylboronic acid BA1 and 0.05 mmol
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
As described before,14g this BAC system is thought to be
conducive to an SN1 mechanism involving carbocationic
intermediates. This proposal is supported by the reactions of
secondary alcohols (cf. Table 3), which are more facile and
higher yielding compared to the reactions of primary alcohols.
Moreover, sulfonamide partners of sufficient nucleophilicity are
required in order to avoid side-reactions such as the ‘self’
Friedel-Crafts condensation between the transient benzylic
carbocation and the arene unit of the benzylic alcohol substrate.
alcohols were the following ones. Benzylic alcohol derivative (0.50 mmol),
para-toluenesulfonamide
(430
mg,
2.50
mmol),
2,3,4,5-
tetrafluorophenylboronic acid BA1 (10.0 mg, 0.050 mmol) and oxalic acid
dihydrate (6.3 mg, 0.050 mmol) were added to a mixture of HFIP (1.60
mL) and nitromethane (0.40 mL) in a sealed tube equipped with a
magnetic stirring bar. The temperature was set to 80 °C and the reaction
media was stirred at this temperature for 6 hours. The mixture was then
allowed to cool down at room temperature and the solvent was
evaporated. The crude product was purified by flash chromatography on
silica gel using a solid deposit technique (silica).
N-(4-Bromobenzyl)-4-methylbenzenesulfonamide (3a).10f The title
compound was prepared from (4-bromophenyl)methanol (94 mg)
following the general procedure A and was purified with a hexane/DCM
(25:75) eluent to afford an amorphous white solid. 140 mg (82%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.74-7.71 (m, 2 H), 7.40-7.37 (m, 2
H), 7.30-7.28 (m, 2H), 7.08-7.06 (m, 2 H), 4.84 (t, J = 5.0 Hz, 1 H), 4.07
(d, J = 5.0 Hz, 2 H), 2.46 (s, 3 H) ppm; 13C NMR (125 MHz, CDCl3,
25 °C): δ = 143.8, 137.0, 135.5, 131.9, 129.9, 129.7, 127.3, 122.0, 46.8,
21.7 ppm.
Conclusions
In summary, we developed a catalytic method to effect the
direct transformation of primary and secondary benzylic alcohols
into various sulfonamide products using a mixture of 2,3,4,5-
tetrafluorophenylboronic acid and oxalic acid as a co-catalytic
system. The reaction proceeds under mild conditions with
acceptable to excellent yields using relatively benign starting
materials. We showed that the reaction is gram-scalable and the
excess of sulfonamide reagent can be recovered after
purification. Furthermore, we demonstrated that this catalytic
system can potentially be used with other alcohol substrates like
allylic or tertiary alcohols.
N-(4-Fluorobenzyl)-4-methylbenzenesulfonamide (3b).10f The title
compound was prepared from (4-fluorophenyl)methanol (64 mg)
following the general procedure A and was purified with a hexane/DCM
(25:75) eluent to afford an amorphous white solid. 103 mg (74%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.74-7.72 (m, 2 H), 7.29-7.28 (m, 2
H), 7.18-7.15 (m, 2 H), 6.95-6.91 (m, 2 H), 5.27 (t, J = 6.3 Hz, 1 H), 4.08
(d, J = 6.3 Hz, 2 H), 2.44 (s, 3 H) ppm; 13C NMR (125 MHz, CDCl3,
25 °C): δ = 162.4 (JC-F = 246.0 Hz), 143.6, 136.9, 132.3, 129.8, 129.7 (JC-
F = 7.5 Hz), 127.2, 115.5 (JC-F = 21.0 Hz), 46.6, 21.6 ppm.
Experimental Section
N-(4-Chlorobenzyl)-4-methylbenzenesulfonamide (3c).10f The title
compound was prepared from (4-chlorophenyl)methanol (71 mg)
following the general procedure A and was purified with a hexane/DCM
(25:75) eluent to afford an amorphous white solid. 121 mg (82%). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.74-7.72 (m, 2 H), 7.30-7.28 (m, 2
H), 7.23-7.21 (m, 2 H), 7.14-7.12 (m, 2 H), 5.11 (t, J = 6.4 Hz, 1 H), 4.09
(d, J = 6.3 Hz, 2 H), 2.44 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3,
25 °C): δ = 143.8, 136.9, 135.0, 133.8, 129.9, 129.3, 128.9, 127.2, 46.6,
21.6 ppm.
The following materials include representative experimental
procedures and details for the synthesis and isolation of products. Full
characterization of all new compounds and partial characterization of
known compounds presented in the article are described. Unless
otherwise stated, all reactions were performed in capped regular
glassware with no further precautions. Tetrahydrofuran (THF) and
dichloromethane (DCM) were purified using
a cartridge solvent
purification system prior to use. Acetone was dried with magnesium
sulfate before use. All other solvents were purchased as ACS reagents
and used without further purification. Unless otherwise noted, all other
chemicals were purchased from commercial sources and used as
received. Chromatographic separations were performed on silica gel 60
using ACS grade hexanes, ethyl acetate, dichloromethane, diethylether
and toluene as eluents. Thin layer chromatography (TLC) was performed
on silica gel 60 F254 plates, which were visualized under UV light and
with KMnO4 or phosphomolybdic acid (PMA) stains. 1H NMR and 13C
NMR spectra were recorded on 400 MHz or 500 MHz instruments. The
residual solvent protons (1H / CHCl3) or the solvent carbon (13C) were
used as internal references. 1H NMR data is presented as follows:
chemical shifts in ppm downfield from tetramethylsilane (multiplicity,
coupling constant, integration). The following abbreviations are used in
reporting NMR data: s, singlet; br s, broad singlet; d, doublet; t, triplet; q,
quartet; quin, quintet; dd, doublet of doublets; ddd, doublet of doublet of
doublets; td, triplet of doublets; m, multiplet. The error of coupling
constants from high-field 1H NMR spectra is estimated to be 0.3 Hz.
High-resolution mass spectra were recorded on a oaTOF analyzer.
Infrared (IR) spectra frequencies are expressed in cm-1. The resolution of
the IR instrument is 4 wavenumber.
N-Benzyl-4-methylbenzenesulfonamide (3d).10f The title compound
was prepared from benzyl alcohol (54 mg) following the general
procedure A with a reaction time of 3 hours and was purified with a
hexane/DCM (25:75) eluent to afford an amorphous white solid. 77 mg
(59%). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.80-7.77 (m, 2 H), 7.34-
7.32 (m, 2 H), 7.30-7.27 (m, 3 H), 7.23-7.21 (m, 2 H), 7.72 (t, J = 6.2 Hz,
1 H), 4.14 (d, J = 6.2 Hz, 2 H), 2.46 (s, 3 H) ppm; 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 143.5, 136.9, 136.3, 129.8, 128.7, 127.9, 127.9, 127.2,
47.3, 21.6 ppm.
4-Methyl-N-(4-methylbenzyl)benzenesulfonamide (3e).10f The title
compound was prepared from p-tolylmethanol (61 mg) following the
general procedure A. The temperature of the reaction was set to 50 °C
with a reaction time of 3 hours. The crude product was purified with a
hexane/DCM (25:75) eluent to afford an amorphous white solid. 69 mg
(50%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.77-7.74 (m, 2 H), 7.30-
7.28 (m, 2 H), 7.07 (m, 4 H), 4.84 (t, J = 6.0 Hz, 1 H), 4.08 (d, J = 6.4 Hz,
2 H) 2.45 (s, 3 H), 2.42 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 143.4, 137.6, 136.9, 133.3, 129.7, 129.3, 127.9, 127.2, 47.0, 21.5,
21.1 ppm.
General procedure A for the catalytic sulfonamidation of primary
benzylic alcohols: Without any other specification, the reaction
conditions for the direct catalytic sulfonamidation of primary benzylic
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
N-(2-Bromobenzyl)-4-methylbenzenesulfonamide (3h).17 The title
compound was prepared from (2-bromophenyl)methanol (94 mg)
following the general procedure A with a reaction time of 24 hours, and
was purified with a hexane/DCM (25:75) eluent to afford a viscous oil. 83
mg (47%). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.72-7.70 (m, 2 H),
7.47-7.45 (m, 1 H), 7.31-7.29 (m, 1 H), 7.26-7.24 (m, 2 H), 7.23-7.20 (m,
1 H), 7.13-7.09 (m, 1 H), 4.92 (t, J = 6.6 Hz, 1 H), 4.24 (d, J = 6.3 Hz, 2
H), 2.41 (s, 1 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ = 143.4,
136.9, 135.6, 132.7, 130.4, 129.6, 129.4, 127.7, 127.1, 123.4, 47.4, 21.5
ppm.
4.82 (t, J = 6.2 Hz, 1 H), 4.19 (d, J = 6.5 Hz, 2 H), 3.90 (s, 3 H), 2.43 (s, 3
H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 166.7, 143.8, 141.5,
136.8, 130.0, 129.8, 129.7, 127.7, 127.2, 77.3, 77.2, 77.0, 76.8, 52.2,
46.9, 21.6 ppm.
General procedure B for the catalytic sulfonamidation of secondary
benzylic alcohols: without any other specification, the reaction
conditions for the direct catalytic sulfonamidation of secondary benzylic
alcohols were the following ones. benzylic alcohol derivative (0.50 mmol),
para-toluenesulfonamide
(430
mg,
2.50
mmol),
2,3,4,5-
tetrafluorophenylboronic acid BA1 (10.0 mg, 0.050 mmol) and oxalic acid
dihydrate (6.3 mg, 0.050 mmol) were added to a mixture of HFIP (0.8
mL) and nitromethane (0.2 mL) in a sealed tube equipped with a
magnetic stirring bar. The reaction media was stirred at room
temperature until complete conversion of the starting material (monitored
by TLC). The solvent was then evaporated and the crude product was
purified by flash chromatography on silica gel using a solid deposit
technique (silica).
N-(2-fluorobenzyl)-4-methylbenzenesulfonamide
compound was prepared from (2-fluorophenyl)methanol (64 mg)
following the general procedure A and was purified with an hexane/DCM
(3i).
The
title
1
(35:65) eluent to afford a white amorphous solid. 85 mg (61%). H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.75-7.73 (m, 2 H), 7.28-7.22 (m, 4 H),
7.08-7.05 (m, 1 H), 6.99-6.96 (m, 1 H), 4.81 (t, J = 5.0 Hz, 1 H), 4.22 (d, J
= 5.0 Hz, 2 H), 2.43 (s, 3 H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ =
160.7 (JC-F = 246.6 Hz), 143.4, 136.9, 130.1, 129.6, 129.6, 127.1, 124.7,
123.6 (JC-F = 14.5 Hz), 115.3 (JC-F = 21.1 Hz), 41.2, 21.5 ppm; IR (solid)
3253, 1493, 1419, 1346, 1238, 1162, 804, 760 cm-1; HRMS [M–H]– calcd
for C14H13FNO2S 278.0657, found 278.0652.
N-(1-(4-Bromophenyl)ethyl)-4-methylbenzenesulfonamide (5a).18 The
title compound was prepared from 1-(4-bromophenyl)ethanol (102 mg)
following the general procedure B and was purified with an hexane/DCM
(25:75) eluent to afford an amorphous white solid. 160 mg (90%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.55-7.54 (m, 2 H), 7.28-7.26 (m, 2
H), 7.16-7.15 (m, 2 H), 6.96-6.93 (m, 2 H), 4.85 (d, J = 6.9 Hz, 1 H), 4.41
(app quin, J = 6.9 Hz, 1 H), 2.38 (s, 3H), 1.36 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): δ = 143.4, 141.0, 137.5, 131.5, 129.5,
127.9, 127.1, 121.3, 53.1, 23.4, 21.5 ppm.
N-(4-Bromo-3-methylbenzyl)-4-methylbenzenesulfonamide (3j). The
title compound was prepared from (4-bromo-3-methylphenyl)methanol
(101 mg) following the general procedure A and was purified with an
hexane/DCM (25:75) eluent to afford an amorphous white solid. 124 mg
(70%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.74-7.71 (m, 2 H), 7.40 (d,
J = 8.1 Hz, 1 H), 7.30-7.27 (m, 2 H), 7.03 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J
= 8.1, 2.1 Hz, 1 H), 5.06 (t, J = 6.2 Hz, 1 H), 4.05 (d, J = 6.2 Hz, 2 H),
2.45 (s, 3 H), 2.30 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ =
143.6, 138.1, 136.9, 135.6, 132.5, 130.3, 129.7, 127.1, 126.8, 124.2,
46.6, 22.7, 21.5 ppm; IR (cast film, DCM) 3254, 1597, 1444, 1318, 1155,
1090, 1027, 815 cm-1; HRMS (ESI) [M+Na]+ calcd for C15H16BrNNaO2S
375.9983, found 375.9979.
4-Methyl-N-(1-phenylethyl)benzenesulfonamide (5b).18 The title
compound was prepared from 1-phenylethanol (61 mg) following the
general procedure B and was purified with an hexane/DCM (25:75)
1
eluent to afford an amorphous white solid. 137 mg (99%). H NMR (400
MHz, CDCl3, 25 °C): δ = 7.64-7.60 (m, 2 H), 7.20-7.16 (m, 5 H), 7.11-
7.09 (m, 2 H), 4.96 (d, J = 7.0 Hz, 1 H), 4.46 (app quin, J = 6.9 Hz, 1 H),
2.38 (s, 3 H), 1.42 (d, J = 6.9 Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3,
25 °C): δ = 143.1, 142.0, 137.7, 129.4, 128.5, 127.4, 127.1, 126.1, 53.6,
23.5, 21.5 ppm.
N-(2-Bromo-4-fluorobenzyl)-4-methylbenzenesulfonamide (3k). The
title compound was prepared from (2-bromo-4-fluorophenyl)methanol
(102 mg) following the general procedure A and was purified with an
hexane/DCM (25:75) eluent to afford an amorphous white solid. 149 mg
(83%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.73-7.70 (m, 2 H), 7.31
(dd, J = 8.7, 5.9 Hz, 1 H), 7.28-7.26 (m, 2 H), 7.21 (dd, J = 7.9, 2.3 Hz, 1
H), 6.94 (ddd, J = 8.5, 8.0, 2.6 Hz, 1 H), 5.09 (t, J = 6.6 Hz, 1 H), 4.21 (d,
J = 6.6 Hz, 2 H), 2.43 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 161.9 (JC-F = 251.6 Hz), 143.6, 136.9, 131.6 (JC-F = 3.7 Hz), 131.5 (JC-F
= 8.6 Hz), 129.6, 127.1, 123.5 (JC-F = 9.6 Hz), 120.0 (JC-F = 24.6 Hz),
114.7 (JC-F = 21.0 Hz), 46.7, 21.5 ppm; IR (neat) 3263, 1592, 1482, 1325,
1230, 1159, 1053, 778 cm-1; HRMS (ESI) [M+Na]+ calcd for
C14H13BrFNNaO2S 379.9732, found 379.9731.
4-Methyl-N-(1-(p-tolyl)ethyl)benzenesulfonamide (5c).19 The title
compound was prepared from 1-(p-tolyl)ethanol (68 mg) following the
general procedure B with a 2 mL mixture of HFIP and nitromethane (4:1)
as solvent. The crude product was then purified with an hexane/DCM
(25:75) eluent to afford an amorphous white solid. 133 mg (92%). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.64-7.62 (m, 2 H), 7.20-7.17 (m, 2
H), 7.02-6.97 (m, 2 H), 4.91 (d, J = 6.9 Hz, 1 H), 4.41 (app quin, J = 6.9
Hz, 1 H), 1.41 (d, J = 6.8 Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3,
25 °C): δ = 143.0, 139.1, 137.7, 137.2, 129.4, 129.2, 127.1, 126.0, 53.4,
23.5, 21.5, 21.0 ppm.
Methyl
4-((4-methylphenylsulfonamido)methyl)benzoate
(3g).8p
4-Methyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)benzenesulfonamide
(5d).20
The
title
compound
was
prepared
from
1-(4-
Methyl 4-(hydroxymethyl)benzoate (83 mg, 0.50 mmol), para-
toluenesulfonamide (430 mg, 2.50 mmol), ferroceniumboronic acid
hexafluoroantimonate salt BA12 (47 mg, 0.10 mmol) and oxalic acid
dihydrate (12.6 mg, 0.10 mmol) were added to a mixture of HFIP (1.60
mL) and nitromethane (0.40 mL) in a sealed tube equipped with a
magnetic stirring bar. The temperature was set to 100 °C and the
reaction media was stirred at this temperature for 24 hours. The mixture
was then allowed to cool down to room temperature and the solvent was
evaporated. The crude product was purified by flash chromatography on
(trifluoromethyl)phenyl)ethanol (95 mg) following the general procedure B
with a reaction temperature set to 50°C. The crude product was then
purified with a gradient of hexane/DCM eluent (from 50:50 to 25:75) to
afford an amorphous white solid. 131 mg (76%). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 7.55-7.53 (m, 2 H), 7.40-7.38 (m, 2 H), 7.21-7.19 (m,
2H), 7.12-7.11 (m, 2 H), 5.31 (d, J = 7.0 Hz, 1 H), 4.54 (app quin, J = 7.0
Hz, 1 H), 2.36 (s, 3 H), 1.42 (d, J = 6.9 Hz, 3 H) ppm; 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 145.9, 143.4, 137.3, 129.6 (JC-F = 32.8 Hz), 129.4,
127.0, 126.6, 125.3 (JC-F = 4.0 Hz), 124.0 (JC-F = 272.2 Hz), 53.3, 23.5,
21.3 ppm.
silica gel using
a solid deposit technique (silica) and with a
cyclohexane/EtOAc (90:10 to 80:20) eluent to afford the title compound
as an amorphous white solid. 75 mg (47%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.95-7.93 (m, 2 H), 7.76-7.74 (m, 2 H), 7.31-7.27 (m, 4 H),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
Methyl 4-(1-(4-methylphenylsulfonamido)ethyl)benzoate (5e). The
title compound was prepared from methyl 4-(1-hydroxyethyl)benzoate
(90 mg) following the general procedure B with a reaction temperature
set to 50°C. The crude product was then purified with a hexane/EtOAc
eluent (80:20) to afford an amorphous white solid. 153 mg (92%). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.83-7.79 (m, 2 H), 7.60-7.57 (m, 2
H), 7.19-7.16 (m, 2 H), 7.13-7.11 (m, 2 H), 5.67 (d, J = 7.4 Hz, 1 H), 4.49
(app quin, J = 7.0 Hz, 1 H), 3.88 (s, 3 H), 2.34 (s, 3 H), 1.38 (d, J = 7.0
Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ = 166.8, 147.3,
143.3, 137.5, 129.8, 129.5, 129.1, 127.0, 126.2, 53.4, 52.1, 23.5, 21.4
ppm; IR (neat) 3252, 1721, 1432, 1322, 1285, 1153, 1115, 1083 cm-1;
HRMS (ESI) [M+Na]+ calcd for C17H19NNaO4S 356.0932, found 356.0925.
N,4-dimethylbenzenesulfonamide (465 mg) following the general
procedure C and was purified with an hexane/DCM (25:75) eluent to
afford an amorphous white solid. 148 mg (96%). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.73-7.70 (m, 2 H), 7.36-7.34 (m, 2 H), 7.31-7.28 (m,
2 H), 7.26-7.23 (m, 2 H), 4.09 (s, 1 H), 2.57 (s, 1 H), 2.45 (s, 1 H) ppm;
13C NMR (100 MHz, CDCl3, 25 °C): δ = 143.6, 134.3, 134.2, 133.7, 129.8,
129.7, 128.8, 127.5, 53.5, 34.4, 21.6 ppm.
N-(1-(4-Bromophenyl)ethyl)-N,4-dimethylbenzenesulfonamide (6b).
The title compound was prepared from 1-(4-bromophenyl)ethanol (102
mg) and N,4-dimethylbenzenesulfonamide (460 mg) following the
general procedure C. The reaction was performed at room temperature
and monitored by TLC. The crude product was purified with an
hexane/DCM (25:75) eluent to afford an amorphous white solid. 176 mg
(96%). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.76-7.73 (m, 2 H), 7.47-
7.44 (m, 2 H), 7.35-7.33 (m, 2 H), 7.21-7.18 (m, 2 H), 5.25 (q, J = 7.0 Hz,
1 H), 2.58 (s, 3 H), 2.46 (s, 3 H), 1.28 (d, J = 7.0 Hz, 3 H) ppm; 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 143.3, 139.1, 137.0, 131.5, 129.8, 129.0,
127.1, 121.6, 54.3, 28.4, 21.5, 15.1 ppm; IR (solid) 2983, 1485, 1337,
1167, 933, 818, 742, 656 cm-1; HRMS (ESI) [M+Na]+ calcd for
C16H18BrNNaO2S 390.0139, found 390.0132.
N-(1-(3-Bromophenyl)ethyl)-4-methylbenzenesulfonamide (5f). The
title compound was prepared from 1-(3-bromophenyl)ethanol (102 mg)
following the general procedure B and was purified with an hexane/DCM
(25:75) eluent to afford an amorphous white solid. 161 mg (90%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.58-7.56 (m, 2 H), 7.29-7.26 (m, 1
H), 7.18-7.17 (m, 2 H), 7.10 (app s, 1 H), 7.06-7.06 (m, 2 H), 4.84 (d, J =
6.9 Hz, 1 H), 4.45 (app quin, J = 6.9 Hz, 1 H), 2.39 (s, 3 H), 1.40 (d, J =
6.9 Hz, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ = 144.2, 143.4,
137.3, 130.4, 130.0, 129.5, 129.4, 127.0, 124.9, 122.5, 53.2, 23.5, 21.5
ppm; IR (cast film, DCM) 3273, 1597, 1433, 1325, 1160, 1091, 813, 666
cm-1; HRMS (ESI) [M+Na]+ calcd for C15H16BrNNaO2S 375.9983, found
375.9974.
N-(4-Bromobenzyl)-4-methoxybenzenesulfonamide (6c). The title
compound was prepared from (4-bromophenyl)methanol (95 mg) and 4-
methoxybenzenesulfonamide (470 mg) following the general procedure
C and was purified with an hexane/DCM (25:75) eluent to afford an
amorphous white solid. 111 mg (62%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.78-7.75 (m, 2 H), 7.39-7.37 (m, 2 H), 7.08-7.06 (m, 2H),
6.96-6.94 (m, 2 H), 4.89 (t, J = 6.3 Hz, 1 H), 4.06 (d, J = 6.3 Hz, 2 H),
3.87 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ = 163.0, 135.6,
131.6, 131.3, 129.6, 129.2, 121.6, 114.3, 55.7, 46.5 ppm; IR (solid) 3270,
1595, 1577, 1307, 1262, 1155, 1030, 804 cm-1; HRMS (ESI) [M–H]–
calcd for C14H13BrNO3S 353.9805, found 353.9799.
N-(1-(2-Bromophenyl)ethyl)-4-methylbenzenesulfonamide (5g). The
title compound was prepared from 1-(2-bromophenyl)ethanol (102 mg)
following the general procedure B and was purified with an hexane/DCM
(25:75) eluent to afford an amorphous white solid. 159 mg (90%). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.65-7.64 (m, 2 H), 7.37 (dd, J = 8.0,
1.3 Hz, 1 H), 7.24 (dd, J = 7.8, 1.7 Hz, 1 H), 7.14-7.12 (m, 2 H), 7.10 (dd,
J = 7.6, 1.3 Hz, 1 H), 6.98 (td, J = 7.6, 1.7 Hz, 1 H), 5.72 (d, J = 7.4 Hz, 1
H), 4.88 (app quin, J = 7.0 Hz, 1 H), 2.34 (s, 3 H), 1.38 (d, J = 6.9 Hz, 3
H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 143.2, 141.3, 137.1,
132.8, 129.4, 128.5, 127.8, 127.7, 127.1, 122.0, 53.0, 23.0, 21.5 ppm. IR
(cast film, DCM) 3279, 1444, 1324, 1161, 1092, 1024, 958, 756 cm-1;
HRMS (ESI) [M+Na]+ calcd for C15H16BrNNaO2S 375.9983, found
375.9972.
N-(4-Bromobenzyl)-2-nitrobenzenesulfonamide
(6d).
The
title
compound was prepared from (4-bromophenyl)methanol (94 mg) and 2-
nitrobenzenesulfonamide (505 mg) following the general procedure C.
The reaction was performed at 100 °C with a reaction time of 24 hours.
The crude product was purified with an hexane/DCM (50:50 to 75:25)
1
eluent to afford an amorphous white solid. 102 mg (55%). H NMR (500
N-Benzhydryl-4-methylbenzenesulfonamide
(5h).10f
The
title
MHz, CDCl3, 25 °C): δ = 7.97 (dd, J = 7.8, 1.5 Hz, 1 H), 7.83 (dd, J = 7.9,
1.4 Hz, 1 H), 7.71 (td, J = 7.7, 1.5 Hz, 1 H), 7.65 (td, J = 7.7, 1.4 Hz, 1 H),
7.36-7.34 (m, 2 H), 7.11-7.10 (m, 2 H), 5.75 (t, J = 6.5 Hz, 1 H), 4.28 (d, J
= 6.4 Hz, 2 H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 147.8, 134.9,
133.9, 133.5, 132.8, 131.8, 130.9, 129.5, 125.3, 122.0, 47.2 ppm; IR
(solid) 3341, 3100, 1592, 1543, 1487, 1438, 1358, 1204, 1070, 1009, 738
cm-1; HRMS (ESI) [M–H]– calcd for C13H10BrN2O4S 368.9550, found
368.9547.
compound was prepared from diphenylmethanol (benzhydrol) (92 mg)
following the general procedure B with 2 mL of a HFIP/nitromethane (4:1)
solvent. It was then purified with an hexane/DCM (25:75) eluent to afford
an amorphous white solid. 163 mg (96%). 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.58-7.55 (m, 2 H), 7.22-7.19 (m, 6 H), 7.14-7.09 (m, 6 H),
5.57 (d, J = 7.0 Hz, 1 H), 5.10 (d, J = 7.1 Hz, 1 H), 2.38 (s, 3 H) ppm; 13
C
NMR (100 MHz, CDCl3, 25 °C): δ = 143.2, 140.5, 137.4, 129.4, 128.5,
127.6, 127.4, 127.2, 61.3, 21.5 ppm.
N-(2-Bromo-4-fluorobenzyl)-N-methyl-2-nitrobenzenesulfonamide
General procedure C for the catalytic sulfonamidation of benzyl
alcohols with various sulfonamides: Without any other specification,
the reaction conditions for the direct catalytic sulfonamidation of benzylic
alcohols were the following ones. Benzylic alcohol derivative (0.50 mmol),
sulfonamides (2.50 mmol), 2,3,4,5-tetrafluorophenylboronic acid BA1
(10.0 mg, 0.050 mmol) and oxalic acid dihydrate (6.3 mg, 0.050 mmol)
were added to a mixture of HFIP (1.6 mL) and nitromethane (0.4 mL) in a
sealed tube equipped with a magnetic stirring bar. The reaction media
was stirred at 80 °C for 6 hours. The solvent was then evaporated and
the crude product was purified by flash chromatography on silica gel
using a solid deposit technique (silica).
(6e). The title compound was prepared from (2-bromo-4-
fluorophenyl)methanol
(103
mg)
and
N-methyl-2-
nitrobenzenesulfonamide (540 mg) following the general procedure C
with a reaction time of 24 hours. The crude product was then purified with
an hexane/DCM (25:75) eluent to afford an amorphous white solid. 140
mg (70%). 1H NMR (500 MHz, CDCl3, 25 °C): δ = 8.04-8.02 (m, 1 H),
7.76-7.69 (m, 2 H), 7.69-7.67 (m, 1 H), 7.50 (dd, J = 8.7, 5.9 Hz, 1 H),
7.30 (dd, J = 8.1, 2.6 Hz, 1 H), 7.07 (ddd, J = 8.7, 7.9, 2.6 Hz, 1 H), 4.55
(s, 2 H), 2.86 (s, 3 H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 161.9
(JC-F = 251.5 Hz), 148.3 , 133.8 , 132.2 , 131.7 , 131.1 , 130.9 (JC-F = 8.6
Hz), 130.7 (JC-F = 3.5 Hz), 124.3 , 123.6 (JC-F = 9.6 Hz), 120.1 (JC-F
=
24.5 Hz), 115.3 (JC-F = 21.1 Hz), 52.9, 34.7 ppm; IR (cast film, DCM)
3096, 2931, 1589, 1487, 1372, 1168, 925, 763 cm-1; HRMS (ESI)
[M+Na]+ calcd for C14H12BrFN2NaO4S 424.9583, found 424.9583.
N-(4-Chlorobenzyl)-N,4-dimethylbenzenesulfonamide (6a).21 The title
compound was prepared from (4-chlorophenyl)methanol (71 mg) and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
N-(4-Bromobenzyl)methanesulfonamide (6f). The title compound was
(87%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.81-7.79 (m, 2 H), 7.29-
7.27 (m, 2 H), 4.70 (s, 1 H), 2.43 (s, 3 H), 2.02-2.00 (m, 3 H), 1.80-1.79
(m, 6 H), 1.63-1.54 (m, 6 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C): δ =
142.7, 141.1, 129.4, 126.9, 55.1, 43.1, 35.9, 29.5, 21.5 ppm.
prepared
from
(4-bromophenyl)methanol
(94
mg)
and
methanesulfonamide (238 mg) following the general procedure C and
was purified with an hexane/DCM (25:75) eluent to afford an amorphous
white solid. 95 mg (72%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.51-
7.48 (m, 2 H), 7.25-7.21 (m, 2H), 4.78 (bs, 1 H), 4.27 (d, J = 6.2 Hz, 2 H),
2.88 (s, 3 H) ppm; 13C NMR (100 MHz, CDCl3, 25 °C) δ 135.8, 132.0,
129.6, 122.1, 46.5, 41.3 ppm; IR (solid) 3250, 1489, 1452, 1311, 1145,
1083, 810, 758 cm-1; HRMS (ESI) [M–H]– calcd for C8H9BrNO2S
261.9543, found 261.9541.
Acknowledgements
This research was generously funded by the Natural
Science and Engineering Research Council of Canada
(Discovery Grant 203287-2012 to D.G.H.) and the University of
Alberta. The authors thank Mr. Xiaobin Mo and Dr. Timothy
Morgan for help with compound characterization.
2-(4-Bromobenzyl)-1,2-thiazinane 1,1-dioxide (6g). The title compound
was prepared from (4-bromophenyl)methanol (75 mg, 0.40 mmol) and
1,2-thiazinane 1,1-dioxide (270 mg, 2.0 mmol) following the general
procedure C and was purified with an hexane/DCM (25:75) eluent to
afford an amorphous white solid. 111 mg (91%). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 7.49-7.46 (m, 2 H), 7.23-7.21 (m, 2 H), 4.25 (s, 2 H),
3.21-3.19 (m, 2 H), 3.10-307 (m, 2 H), 2.24-2.19 (m, 2 H), 1.64-1.60 (m,
2 H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 135.2, 131.8, 130.2,
121.8, 49.5, 48.9, 48.5, 24.0, 21.9 ppm; IR (solid) 2947, 1487, 1330,
1143, 1094, 1009, 904, 760 cm-1; HRMS (EI) [M]+ calcd for
C11H14BrNO2S 302.9929, found 302.9929.
Keywords: boronic acids • sulfonamides • organocatalysis •
benzylic alcohols • synthetic method
[1]
[2]
[3]
X. Lin, H. Dorr, J. M. Nuss, Tetrahedron Lett. 2000, 41, 3309-3313.
T. Kan, T. Fukuyama, Chem. Commun. 2004, 353-359.
a) A. S. Kalgutkar, R. Jones,
A
Sawant in Metabolism,
Pharmacokinetics and Toxicity of Functional Groups, (Eds.: D. A.
Smith), The Royal Society of Chemistry, Cambridge, 2010, pp 210-274.
a) P. Yang, L. Wang, R. Feng, A. A. Almehizia, Q. Tong, K-Z. Myint, Q.
Ouyang, M. H. Alqarni, L. Wang, X-Q. Xie, J. Med. Chem. 2013, 56,
2045-2058; b) B. P. Fauber, O. René, Y. Deng, J. DeVoss, C.
Eidenschenk, C. Everett, A. Ganguli, A. Gobbi, J. Hawkins, A. R.
Johnson, H. La, J. Lesch, P. Lockey, M. Norman, W. Ouyang, S.
Summerhill, H. Wong, J. Med. Chem. 2015, 58, 5308-5322; c) M.
Lopez, L. F. Bornaghi, A. Innocenti, D. Vullo, S. A. Charman, C. T.
Supuran, S-A. Poulsen J. Med. Chem. 2010, 53, 2913-2926.
General procedure D for the catalytic sulfonamidation of various
alcohols with para-toluenesulfonamide: Without any other
specification, the reaction conditions for the direct catalytic
sulfonamidation of alcohols were the following ones. Alcohol derivative
(0.50 mmol), para-toluenesulfonamide (430 mg, 2.50 mmol), 2,3,4,5-
tetrafluorophenylboronic acid BA1 (10.0 mg, 0.050 mmol) and oxalic acid
dihydrate (6.3 mg, 0.050 mmol) were added to a mixture of HFIP (1.6
mL) and nitromethane (0.4 mL) in a round bottom flask equipped with a
magnetic stirring bar. The reaction media was stirred at room
temperature until completion of the reaction (monitored by TLC). The
solvent was then evaporated and the crude product was purified by flash
chromatography on silica gel using a solid deposit technique (silica).
[4]
[5]
[6]
A. Gioiello, E. Rosatelli, M. Teofrasti, P. Filipponi, R. Pellicciari, ACS
Comb. Sci. 2013, 15, 235-239.
For reviews on the synthesis of sulfonamides, see : a) Y. Chen,
Synthesis, 2016, 48, 2483-2522; b) K. C. Majumdar, S. Mondal, Chem.
Rev. 2011, 111, 7749-7773.
N-(Cyclohex-2-en-1-yl)-4-methylbenzenesulfonamide (7a).19 The title
compound was prepared from cyclohex-2-enol (49 mg, 0.50 mmol)
following the general procedure D with a reaction time of 5 minutes (it
has been noticed that an extension of the reaction time had a detrimental
effect on the reaction yield). The media was then diluted with 20 mL of
DCM and washed successively with water (10 mL) and brine (10 mL).
The organic layer was dried over anhydrous magnesium sulfate, filtered
and evaporated. The crude product was purified with an hexane/DCM
(25:75) eluent to afford an amorphous white solid. 96 mg (76%). 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.78-7.76 (m, 2 H), 7.29-7.27 (m, 2 H),
5.75-5.71 (m, 1 H), 5.36-5.32 (m, 1 H), 4.84 (d, J = 8.5 Hz, 1 H), 3.81-
3.76 (m, 1 H), 2.41 (s, 3 H), 1.97-1.83 (m, 2 H), 1.77-1.69 (m, 1 H), 1.63-
1.48 (m, 3 H) ppm; 13C NMR (125 MHz, CDCl3, 25 °C): δ = 143.2, 138.4,
131.4, 129.7, 127.1, 127.0, 49.0, 30.2, 24.5, 21.5, 19.3 ppm.
[7]
[8]
a) Q-Q. Li, Z-F. Xiao, C-Z. Yao, H-X. Zheng, Y-B. Kang, Org. Lett. 2015,
17, 5328-5331; b) Q. Xu, H. Xie, E-L. Zhang, X. Ma, J. Chen, X-C. Yu,
H. Li, Green Chem. 2016, 18, 3940-3944.
a) S. Kerdphon, X. Quan, V. S. Parihar, P. G. Anderson, J. Org. Chem.
2015, 80, 11529-11537; b) F. Shi, M. K. Tse, S. Zhou, M-M. Pohl, J.
Radnik, S. Hübner, K. Jähnisch, A. Brückner, M. Beller, J. Am. Chem.
Soc. 2009, 131, 1775-1779; c) X. Cui, F. Shi, M. K. Tse, D. Gördes, K.
Thurow, M. Beller, Y. Deng, Adv. Synth. Catal. 2009, 351, 2949-2958;
d) X. Cui, F. Shi, Y. Zhang, Y. Deng, Tetrahedron Lett. 2010, 51, 2048-
2051; e) X. Cui, Y. Zhang, F. Shi, Y. Deng, Chem. Eur. J. 2011, 17,
1021-1028; f) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C.
Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J. Am.
Chem. Soc. 2009, 131, 1766-1774; g) Q. Zou, C. Wang, J. Smith, D.
Xue, J. Xiao, Chem. Eur. J. 2015, 21, 9656-9661; h) S. L. Feng, C. Z.
Liu, X. C. Yu, Q. Xu, Chin. Chem. Lett. 2011, 22, 1021-1024; i) A.
Martinez-Asencio, D. J. Ramon, M. Yus, Tetrahedron Lett. 2010, 51,
325-327; j) A. Martinez-Asencio, D. J. Ramon, M. Yus, Tetrahedron
2011, 67, 3140-3149; k) R. Cano, D. J. Ramon, M. Yus, J. Org. Chem.
2011, 76, 5547-5557; l) F. Shi, M. K. Tse, X. Cui, D. Gördes, D.
Michalik, K. Thurow, Y. Deng, M. Beller, Angew. Chem., Int. Ed., 2009,
48, 5912-5915; m) R. Ramachandran, G. Prakash, M. Nirmala, P.
Viswanathamurthi, J. G. Malecki, J. Organomet. Chem. 2015, 791, 130-
140; n) P. Qu, C. Sun, J. Ma, F. Li, Adv. Synth. Catal. 2014, 356, 447-
459; o) A. Martinez-Asencio, M. Yus, D. J. Ramon, Synthesis, 2011, 22,
3730-3740; p) M. Zhu, K-I. Fujita, R. Yamaguchi, Org. Lett. 2010, 12,
1336-1339; q) A. Mohanty, S. Roy, Tetrahedron Lett. 2016, 57, 2749-
2753.
N-(tert-Butyl)-4-methylbenzenesulfonamide (7b).22 The title compound
was prepared from tert-butanol (38 mg) following the general procedure
D with 2 mL of HFIP/nitromethane (4:1) solvent. It was then purified with
an hexane/DCM (50:50) eluent to afford an amorphous white solid. 53
mg (47%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.81-7.78 (m, 2 H),
7.29-7.27 (m, 2 H), 5.00 (s, 1 H), 2.42 (s, 3 H), 1.21 (s, 9 H) ppm; 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 142.7, 140.6, 129.4, 127.0, 54.5,
30.1, 21.5 ppm.
N-((3s,5s,7s)-Adamantan-1-yl)-4-methylbenzenesulfonamide (7c).23
The title compound was prepared from (3s,5s,7s)-adamantan-1-ol (76
mg) following the general procedure
D and was purified with an
hexane/DCM (75:25) eluent to afford an amorphous white solid. 133 mg
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
[9]
a) Q. Li, S. Fan, Q. Sun, H. Tian, X. Yu, Q. Xu, Org. Biomol. Chem.
2012, 10, 2966-2972; b) X. Yu, L. Jiang, Q. Li, Y. Xie, Q. Xu, Chin. J.
Chem. 2012, 30, 2322-2332; c) C. Liu, S. Liao, Q. Li, S. Feng, Q. Sun,
X. Yu, Q. Xu, J. Org. Chem. 2011, 76, 5759-5773; d) Q. Xu, Q. Li, X.
Zhu, J. Chen, Adv. Synth. Cat. 2013, 355, 73-80.
Int. Ed. 2008, 47, 2876-2879; g) H. Zheng, D. G. Hall, Tetrahedron Lett.
2010, 51, 3561-3564; h) H. Zheng, R. McDonald, D. G. Hall, Chem. Eur.
J. 2010, 16, 5454-5460; i) A. Sakakura, T. Ohkubo, R. Yamashita, M.
Akakura, K. Ishihara, Org. Lett. 2011, 13, 892-895; j) N. Gernigon, R.
Al-Zoubi, D. G. Hall, J. Org. Chem. 2012, 77, 8386-8400; k) S. Fatemi,
N. Gernigon, D. G. Hall, Green Chem. 2015, 17, 4016-4028; l) K.
Ishihara, Y. Lu, Chem. Sci. 2016, 7, 1276-1280; m) E. K. W. Tam, Rita,
L. Y. Liu, A. Chen, Eur. J. Org. Chem. 2015, 1100-1107; n) T. M. E.
Dine, W. Erb, Y. Berhault, J. Rouden, J. Blanchet, J. Org. Chem. 2015,
80, 4532-4544.
[10] a) V. Terrasson, S. Marque, M. Georgy, J-M. Campagne, D. Prim, Adv.
Synth. Catal. 2006, 348, 2063-2067; b) H. Qin, N. Yamagiwa, S.
Matsunaga, M. Shibasaki, Angew. Chem., Int .Ed. 2007, 46, 409-413;
c) Ch. R. Reddy, P. P. Madhavi, A. S. Reddy, Tetrahedron Lett. 2007,
48, 7169-7172; d) B. Sreedhar, P. S. Reddy, M. A. Reddy, B. Neelima,
R. Arundhathi, Tetrahedron Lett. 2007, 48, 8174-8177; e) U. Jana, S.
Maiti, S. Biswas, Tetrahedron Lett. 2008, 49, 858-862; f) J. Pan, J-Q. Li,
R-F. Huang, X-H. Zhang, H. Shen, Y. Xiong, X-M. Zhu, Synthesis 2015,
47, 1101-1108; g) A. K. Maity, P. N. Chatterjee, S. Roy, Tetrahedron
2013, 69, 942-956; h) X. Xu, H. Wu, Z. Li, X. Sun, Z. Wang,
Tetrahedron 2015, 71, 5254-5259; i) L. Li, A. Zhu, Y. Zhang, X. Fan, G.
Zhang, RSC Adv. 2014, 4, 4286-4291; j) M. Noji, T. Ohno, K. Fuji, N.
Futaba, H. Tajima, K. Ishii, J. Org. Chem. 2003, 68, 9340-9347; k) T.
Ohshima, J. Ipposhi, Y. Nakahara, R. Shibuya, K. Mashima, Adv. Synth.
Catal. 2012, 354, 2447-2452; l) P. Trillo, A. Baeza, C. Nájera,
ChemCatChem 2013, 5, 1538-1542; m) L. Li, A. Zhu, H. Yao, Y. Wei, D.
Yang, J. Li, G. Zhang, J. Chem. Res-S. 2010, 34, 511-513.
[14] a) J. A. McCubbin, H. Hosseini, O. V. Krokhin, J. Org. Chem. 2010, 75,
959-962; b) J. A. McCubbin, O. V. Krokhin, Tetrahedron Lett. 2010, 51,
2447-2449; c) J. A. McCubbin, C. Nassar, O. V. Krokhin, Synthesis
2011, 2011, 3152-3160; d) H. Zheng, M. Lejkowski, D. G. Hall, Chem.
Sci. 2011, 2, 1305-1310; e) H. Zheng, S. Ghanbari, S. Nakamura, D. G.
Hall, Angew. Chem., Int. Ed. 2012, 51, 6187-6190; f) H. Zheng, M.
Lejkowski, D. G. Hall, Tetrahedron Lett. 2013, 54, 91-94; g) C. L.
Ricardo, X. Mo, J. A. McCubbin, D. G. Hall, Chem. -Eur. J. 2015, 21,
4218-4223; h) X. Mo, J. Yakiwchuk, J. Dansereau, J. A. McCubbin, D.
G. Hall, J. Am. Chem. Soc. 2015, 137, 9694-9703; i) X. Mo, D. G. Hall,
J. Am. Chem. Soc. 2016, 138, 10762-10765.
[15] a) A. Debache, B. Boumound, M. Amimour, A. Belfaitah, S. Rhouati, B.
Carboni, Tetrahedron Lett. 2006, 47, 5697-5699; b) M. Li, T. Yang, D. J.
Dixon, Chem. Commun. 2010, 46, 2191-2193; c) S. V. Goswami, P. B.
Thorat, S. R. Bhusare, Tetrahedron Lett. 2012, 53, 6771-6774; d) Y. Li,
J. A. Molina de La Torre, K. Grabow, U. Bentrup, K. Junge, S. Zhou, A.
Bruckner, M. Beller, Angew. Chem., Int. Ed. 2013, 52, 11577-11580.
[16] E. Wolf, E. Richmond; J. Moran, Chem. Sci. 2015, 6, 2501-2505.
[17] I. Chatterjee, M. Oestreich, Angew. Chem., Int. Ed. 2015, 54, 1965-
1968.
[11] a) G-W. Wang, Y-B. Shen, X-L. Wu, Eur. J. Org. Chem. 2008, 4367-
4371; b) Z. Q. Qureshi, K. M. Deshmukh, P. J. Tambade, K. P. Dhake,
B. M. Bhanage, Eur. J. Org. Chem. 2010, 6233-6238; c) P. Trillo, A.
Baeza, C. Najera, J. Org. Chem. 2012, 77, 7344-7354; d) R. Sanz, A.
Martinez, J. M. Alvarez-Gutierrez, F. Rodriguez, Eur. J. Org. Chem.
2006, 1383-1386; e) K. Motokura, N. Nakagiri, K. Mori, T. Mizugaki, K.
Ebitani, K. Jitsukawa, K. Kaneda, Org. Lett. 2006, 8, 4617-4620; f) G.
Pallikonda, M. Chakravarty, RSC Adv. 2013, 3, 20503-20511.
[12] For recent reviews on boronic acid organocatalysis: a) I. Georgiou, K.
Ilyashenko, A. Whiting, Acc. Chem. Res. 2009, 42, 756-758; b) E.
Dimitrijevic, M. S. Taylor, ACS Catal. 2013, 3, 945-962; c) H. Zheng, D.
G. Hall, Aldrich. Acta. 2014, 47 (2),41-51.
[18] Z. Wang, Y. Zhang, H. Fu, Y. Jiang, Y. Zhao, Org. Lett. 2008, 10, 1863-
1866.
[19] D. R. Wallach, J. D. Chisholm, J. Org. Chem. 2016, 81, 8035-8042.
[20] T. Nishimura, Y. Yasuhara, T. Hayashi, Org. Lett. 2006, 8, 979-981.
[21] X. Tang, L. Huang, C. Qi, X. Wu, W. Wu, H. Jiang, Chem. Commun.
2013, 49, 6102-6104.
[13] a) K. Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem. 1996, 61, 4196-
4197; b) K. Arnold, B. Davies, R. L. Giles, C. Grosjean, G. E. Smith, A.
Whiting, Adv. Synth. Catal. 2006, 348, 813-820; c) T. Maki, K. Ishihara,
H. Yamamoto, Tetrahedron 2007, 63, 8645-8657; d) K. Arnold, A. S.
Batsanov, B. Davies, A. Whiting, Green Chem. 2008, 10, 124-134; e) K.
Arnold, B. Davies, D. Hérault, A. Whiting, Angew. Chem., Int. Ed., 2008,
47, 2673-2676; f) R. M. Al-Zoubi, O. Marion, D. G. Hall, Angew. Chem.,
[22] K. Born, S. Doye, Eur. J. Org. Chem. 2012, 764-771.
[23] A. Yoshimura, V. N. Nemykin, V. V. Zhdankin, Chem. Eur. J. 2011, 17,
10538-10541.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700621
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
NOTE: the final letter height should
not be less than 2 mm.))
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
FULL PAPER
Direct sulfonamidation*
Tristan Verdelet, Robert M. Ward and
Dennis G. Hall*
Page No. – Page No.
Direct Sulfonamidation of Primary
and Secondary Benzylic Alcohols
Catalyzed by a Boronic Acid/Oxalic
Acid System.
Text for Table of Contents
*one or two words that highlight the emphasis of the paper or the field of the study
TOC Text:
A catalytic method was developed to effect the direct transformation of primary and secondary benzylic
alcohols into various sulfonamide products using a mixture of 2,3,4,5-tetrafluorophenylboronic acid and
oxalic acid as a co-catalytic system. The reaction proceeds under mild conditions affords acceptable to
excellent yields of products using relatively benign starting materials. The reaction is gram-scalable and
the excess of sulfonamide reagent can be recovered after purification.
This article is protected by copyright. All rights reserved.