Chemoselective nitration of aromatic sulfonamides with tert-butyl nitrite

Article abstract of DOI:10.1039/c2cc37481a

A methodology for the efficient conversion of aromatic sulfonamides into their mono-nitro derivatives using tert-butyl nitrite is reported. The reaction exhibits a high degree of chemoselectivity for sulfonamide functionalized aryl systems, even in the presence of other sensitive or potentially reactive functionalities.

Full text of DOI:10.1039/c2cc37481a

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Chemoselective nitration of aromatic sulfonamides
with tert-butyl nitrite†
Cite this: Chem. Commun., 2013,
49, 514
Brenden Kilpatrick, Markus Heller and Steve Arns*
Received 13th October 2012,
Accepted 14th November 2012
DOI: 10.1039/c2cc37481a
www.rsc.org/chemcomm
A methodology for the efficient conversion of aromatic sulfon-
Aryl sulfonamides are an important class of compounds that
amides into their mono-nitro derivatives using tert-butyl nitrite is are a fundamental structural unit of a diverse group of pharma-
reported. The reaction exhibits a high degree of chemoselectivity ceuticals, pesticides and other materials.8 Methods by which they
for sulfonamide functionalized aryl systems, even in the presence can be functionalized, particularly in the presence of other reactive
of other sensitive or potentially reactive functionalities.
groups, represents an ongoing challenge for synthetic chemists.
Herein we report a method by which aromatic sulfonamides can
be converted to their nitrated derivatives in near quantitative yield
using tert-butyl nitrite (TBN) as a mild, easily handled and com-
mercially available nitrating reagent. This method exhibits a high
degree of chemoselectivity towards aryl sulfonamides in the
presence of other activating functional groups. To the best of our
knowledge this is the first report of tert-butyl nitrite being used in
the nitration of aromatic sulfonamides. In fact, reports of TBN
being used in any case as a nitrating reagent are limited; it has
been shown TBN is an effective, chemoselective nitrating reagent
for phenols,6 and nitrated byproducts have been periodically
observed in the diazotization reaction of anilines with TBN.9
Our initial observation of a nitration using TBN occurred
during the attempted cyclization of 1 to 2. (Scheme 1) When
compound 1 was treated with TBN in AcOH at 45 1C, an
unexpected nitrated by-product 3 was recovered along with a
trace amount of the target compound 2. Presumably the diazo
cyclization precedes formation of the nitrated product, which
could arise via the direct nitration of the cyclized product, or
the interception of an intermediate in the cyclization process.
Regardless of the process that arrives at the nitrated product,
we recognized the novelty of this reaction and we decided to
further examine the use TBN as a nitrating agent.
The nitration of aromatic compounds has been of interest for over
150 years due to the importance of nitro compounds and their deri-
vatives as synthetic intermediates, pharmaceuticals, dyes, explosives,
plastics, and countless other industrial or commercial products.1
Nitrated aryl compounds can be made with relative ease from unfunc-
tionalized aryl precursors and inexpensive, widely available reagents.
The most ubiquitous and readily identified nitrating reagent is nitric
acid, often used in the presence of another strong acid catalyst.2
These classical nitration methods suffer from a number of
drawbacks, key among them being the high acidity and oxidizing
power of the reagents. Consequently, such reaction conditions are
limited in scope due to a lack of compatibility with easily oxidized
and/or acid sensitive functionalities. In addition, there are also con-
cerns surrounding the spent acid waste generated by such proce-
dures. To overcome these difficulties, a number of techniques have
been developed to perform nitrations under milder conditions.
Some recent advances in this field include the use of nitrate salts,3
the palladium catalyzed nitration of aryl chlorides and triflates,4 and
the nitration of arylboronic acids without the use of a catalyst.5 These
methods are successful in limiting the use of harsh reagents; how-
ever the reagents are often expensive, difficult to prepare and work
with, and/or they are difficult to store. They also do not offer high
degrees of chemoselectivity towards specific aromatic systems within
a substrate. In recent years there have been reports of chemoselective
nitrations; however to date these have been limited to highly
activated electron rich systems such as phenols6 and anilines.7
Center for Drug Research and Development, 2405 Westbrook Mall, Fourth Floor,
Vancouver, BC, Canada, V6T 1Z3. E-mail: sarns@cdrd.ca; Fax: 604-827-1299;
Tel: 604-827-1147
† Electronic supplementary information (ESI) available: For experimental procedures
and spectral data (1H, 13C NMR, MS) of all new compounds, including select
regiochemical assignments (2D NMR). See DOI: 10.1039/c2cc37481a
Scheme 1 Initial observation of nitration using TBN.
c
514 Chem. Commun., 2013, 49, 514--516
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Table 1 Optimization of nitration conditionsa
Table 2 Substrate scope of TBN nitration
Yield (%)
Entry Solvent Temp. (1C) Time (h) AcOH (eq.)
4
5a
5b
1
AcOH
MeOH
MeOH
DMSO
45
0.75
6
24
—
3
3
3
3
3
3
3
3
3
3
1.5
0.5
0
0
51
44
2
45
No reaction
No reaction
3
4
5
6
7
8
9
10
11
12
13
14
15
Reflux
45
6
6
6
6
6
6
6
6
6
6
6
6
84
56
58
41
33
26
11
0
3
0
8
1
7
21
24
27
31
39
45
52
45
47
46
49
5
18
14
26
25
32
39
47
39
36
39
43
Acetone 45
CHCl3
DMF
DCM
THF
EtOAc
ACN
ACN
ACN
ACN
ACN
45
45
45
45
45
45
45
45
45
Reflux
0
a
All reactions were run using 1.5 equivalents of TBN and with a starting
material concentration of 0.1 M.
To investigate this mode of reactivity, N-Ts aniline 4 was
treated with TBN under the same conditions in which the
original nitration was observed. After only 45 minutes, com-
pound 4 was completely converted into a regioisomeric mixture
of nitrated derivatives 5a and 5b in 51% and 44% yields
respectively (Table 1, entry 1). Over-nitrated products were only
observed if the substrate was left under the reaction conditions
until well after the starting material was fully consumed, and
then only in small quantities. The presence of a nitro group in
a
b
Reaction did not run to completion over the indicated time. The starting
c
material was N-Ms aniline. The starting material was N-Ns aniline.
the products was determined by mass spectroscopy and corro- nitration as expected, with reaction rates depending on the overall
borated by reduction of the nitro group to an aniline. electron density of the substrate. Generally, more electron rich
With a preliminary set of conditions in hand we were confident substrates were found to be more reactive, and a variety of
we could modify this protocol to establish a new procedure that common functional groups were well tolerated under the reaction
would be of greater synthetic value by eliminating the use of acetic conditions. In all cases the regioselectivity was seemingly directed
acid as the solvent. To this end a solvent screen was performed, as by the sulfonamide, even in the presence of other powerful
described in Table 1, using acetic acid as an additive. Methanol directing groups such as methoxy (Table 2, entry 1). The regio-
(Table 1, entries 2 and 3) completely inhibited the reaction. To chemical designation of the products was unequivocally proven by
varying extents, the reaction was seen to proceed in all aprotic 2D NMR analysis. Other sulfonamides (Ns and Ms, entries 9
solvents screened. The use of dimethyl sulfoxide, acetone, chloro- and 10) were also successfully nitrated in high yields and in
form, dimethylformamide, or dichloromethane (Table 1, entries reasonable reaction times. Attempts at nitrating tertiary sulfon-
4–8) resulted in incomplete reactions. Though yields of 5a and 5b amides, those without a proton on the nitrogen, were unsuccessful.
were low in these examples, pure unreacted starting material
Efforts to extend this nitration methodology beyond substrates
could be recovered. Conversions were improved significantly by containing a sulfonamide were largely unsuccessful. Attempting the
the use of tetrahydrofuran, ethyl acetate or acetonitrile (Table 1, reaction on unfunctionalized anilines resulted in the generation of
entries 9–11) with combined yields of 5a and 5b exceeding 80% in complex mixtures. Functionalized or protected anilines were
all cases. Ultimately acetonitrile was found to produce the most generally unreactive, with attempted nitrations yielding unreacted
favourable results, with reactions easily running to completion starting material. A range of other functionalized aryl compounds
after 6 hours. Finally, we were pleased to find that reducing or were also found to be resistant to nitration using TBN. One excep-
even eliminating acetic acid had little effect on reaction outcome tion was observed in the case of phenol, which was easily nitrated in
(Table 1, entries 12–15). Running the nitration at reflux had no excellent yield, as has been previously observed (Scheme 2).6
negative effect on the outcome of the reaction while decreasing
reaction time. (Table 1, entry 15).
Perhaps the most remarkable aspect of nitration using TBN
is the high level of selectivity that is displayed for sulfonamides
A summary of the reaction scope are presented in Table 2. over other functional groups. This initially came to light upon
A variety of substituted N-Ts anilines were seen to undergo the nitration of a sulfonamide that also contained a functional
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 514--516 515

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Scheme 2 Nitration of other aryl compounds.
group typically associated as being a strong director of nitration
(Table 2, entry 1), where the nitro group was installed only in an
ortho/para sense relative to the sulfonamide functionality. In
fact, regardless of the other functionalities decorating an aryl
system containing a sulfonamide, the nitro group is always
installed in an ortho/para sense relative to the sulfonamide.
Competition studies show complete selectivity for the nitration
of sulfonamide-containing systems, except in the case of being
compared against phenol (inter- and intramolecular examples)
where the phenol is selectively nitrated (Scheme 3).
In an effort to unravel the mechanism by which this reaction
operates, we doped the typical nitration reaction of N-Ts aniline
with TEMPO, a well known radical scavenger.10 Much to our
surprise, the combined yield of nitrated products dropped from
95% to just 24% on the addition of 2.0 equivalents of TEMPO,
strongly implying a radical based mechanism. TBN is known to
undergo thermal homolysis to liberate an alkoxyl radical and nitric
oxide (NO).11 Abstraction of the sulfonamide N-H proton would
afford a nitrogen-based radical that can be delocalized onto the
aromatic ring. NO2, which is produced by oxidation of NO with
molecular oxygen,12 can intercept the aryl radical to give the
observed nitrated products ortho and para to the sulfonamide
functionality (see Scheme 4 for proposed mechanism). The obser-
vation that running the reaction under an inert atmosphere
significantly impedes the reaction rate while an oxygen atmosphere
offers a slight rate enhancement suggests an oxidation promoted
by oxygen is a crucial feature of the reaction mechanism.13
Scheme 4 Proposed mechanism of nitration.
Alternatively, the sulfonamide radical and NO could be
generated by initial nitrosation of the sulfonamide followed
by thermally induced homolysis of the resulting N–N bond.14 In
either case, this reactivity is analogous to that proposed in the
nitration of phenols using TBN,6 and it effectively explains why
nitration is observed ortho/para with the sulfonamide function-
ality, even in the presence of opposing strong ortho/para
directors that would override the directing ability of the sulfo-
namide were the reaction to proceed via a cationic manifold.
In conclusion, we have developed a novel method by which
sulfonamides can be nitrated selectively in high yield using TBN
as the nitrating agent. This method uses very mild conditions and
generates little waste compared with alternative nitration proto-
cols. This method tolerates a wide variety of functional groups
with no negative effects on reaction outcome, and it exhibits a
high degree of chemoselectivity for sulfonamide functionalized
aryl systems, even in the presence of other potentially reactive
substrates. Preliminary results suggest that the reaction proceeds
through a radical based mechanism. Efforts in further expanding
the scope of the reaction and elucidating the mechanism are
ongoing and will be reported in due course.
Notes and references
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5 G. K. S. Prakesh, C. Panja, T. Mathew, V. Surampudi, N. A. Petasis
and G. A. Olah, Org. Lett., 2004, 6, 2205.
´
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Tetrahedron Lett., 2006, 47, 6879.
8 J. D. Wilden, J. Chem. Res., 2010, 34, 541.
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10 T. Vogler and A. Studer, Synthesis, 2008, 1979.
11 C.-X. Miao, B. Yu and L.-N. He, Green Chem., 2011, 13, 541.
12 B. Galliker, R. Kissner, T. Nauser and W. H. Koppenol, Chem.–Eur. J.,
2009, 15, 6161.
13 Nitration of 4 under 1atm N2 (non-rigourous exclusion of O2) gave
53% 4, 21% 5a and 21% 5b after 6 h. The same reaction under 1 atm
O2 gave 51% 5a and 40% 5b after 4 h.
14 J. Hartung, Chem. Rev., 2009, 109, 4500.
Scheme 3 Competition experiments.
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516 Chem. Commun., 2013, 49, 514--516
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