Mild hypervalent iodine mediated oxidative nitration of N-aryl sulfonamides

Article abstract of DOI:10.1039/c4cc04738a

An oxidative and acid-free method for the nitration of N-aryl sulfonamides has been developed using a combination of sodium nitrite as cheap and easy to handle NO₂-source and the hypervalent iodine reagent PIFA as stoichiometric oxidant. Under

Full text of DOI:10.1039/c4cc04738a

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Mild hypervalent iodine mediated oxidative
nitration of N-aryl sulfonamides†
Cite this: Chem. Commun., 2014,
50, 10485
Ulrich Kloeckner and Boris J. Nachtsheim*
Received 22nd June 2014,
Accepted 19th July 2014
DOI: 10.1039/c4cc04738a
www.rsc.org/chemcomm
An oxidative and acid-free method for the nitration of N-aryl its known highly exothermic decomposition (1200 J gÀ1) at
sulfonamides has been developed using a combination of sodium elevated temperatures (above 110 1C).15
nitrite as cheap and easy to handle NO2-source and the hypervalent
A so far neglected way to generate nitronium cations under
iodine reagent PIFA as stoichiometric oxidant. Under very mild non-acidic conditions would be a direct 1- or 2-electron oxidation
reaction conditions, the desired mononitrated aryl sulfonamides of sodium nitrite.16 In this communication we want to describe
were isolated in up to 87% yield. This is the first example of an such a reaction mediated by aryl-l3-iodanes as mild and safe
iodane-mediated oxidative nitration.
oxidants and atom transfer reagents.17–25 Aryl-l3-iodanes of type
ArIX2 readily undergo ligand exchange reactions to substitute one
Nitroarenes are versatile structural motifs since they have been or both ligands X against external anions or neutral nucleophiles
widely utilized as important precursors for the synthesis of (Scheme 1). We proposed that ligand exchange with sodium
pharmaceuticals and biological active compounds. Further- nitrite should give the highly reactive key intermediate A which
more, nitrated arenes and heteroarenes can be found in a should subsequently decompose in a 2-electron transfer process
variety of drugs, pesticides and explosives.1 The most common to generate phenyl iodide and a nitronium cation (Scheme 1a). As
approach to synthesize nitroarenes is the direct electrophilic an alternative, a radical mechanism can be proposed through
nitration of arenes. Traditionally, this transformation requires generation of NO2 (Scheme 1b). However, herein we want to report
harsh reaction conditions such as concentrated nitric acid or the development of such an oxidative transformation, which is
mixtures of nitric acid and sulphuric acid in order to generate not only a remarkable mild alternative to classical nitration
the reactive nitronium cation (NO2+) through dehydration of reactions, but is also, to the best of our knowledge, the first
nitric acid.2 As an alternative, stoichiometric amounts of metal example of a hypervalent iodine mediated oxidative nitration.
nitrates such as Bi(NO)3 or expensive nitronium salts can be
To start our investigations, we chose to use N-phenyl sulfon-
applied.3 Even though these methods turned out to be mild amide 1a as a comparatively unreactive arene. We were pleased
alternatives to classical nitration conditions, they are usually to find that our first attempt using a combination of the aryl-l3-
restricted to reactive, electron rich arenes and unfortunately, iodane PIFA (phenyl iodine bis(trifluoroacetate)) and NaNO2 in
stoichiometric amounts of metal oxides are generated as undesired DMSO at room temperature already resulted in formation of
side products. Recently, tert-butyl nitrite (TBN) was found by the desired nitrated N-phenyl sulfonamide 2a in 55% yield with
Savinov and co-workers to be a mild nitration reagent for a 1 : 1.4 mixture of the ortho and para isomers (Table 1, entry 1).
phenols.4–6 Subsequently, this reagent was used extensively for
oxidative radical nitrations of alkenes and nitration cascade
reactions.7–13 In 2013 Arns reported an elegant chemoselective
nitration of N-aryl sulfonamides using tert-butyl nitrite.14
Despite its great versatility, TBN is potential hazardous due to
¨
¨
Institute of Organic Chemistry, Eberhard Karls Universitat Tubingen,
¨
72076 Tubingen, Germany. E-mail: boris.nachtsheim@uni-tuebingen.de;
Fax: +49 7071 29 5897
Scheme 1 Proposed oxidative generation of nitronium ions (a) or NO2
(b) using aryl-l3-iodanes.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04738a
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Table 1 Optimization of the reaction conditionsa
Entry Solvent [O]
Time (h) Temp. (1C) Ratio (o : p) Yield (%)
1
2
3
4
5
6
7
DMSO PIFA
EtOAc PIFA
2
5
5
4
rt
rt
rt
rt
rt
0
50
1 : 1.4
1 : 1.1
1 : 1.4
1 : 1.1
1 : 1.1
1 : 1.6
1 : 1.6
55
72
85
87
47
59
52
DMF
PIFA
MeCN PIFA
MeCN PIDA
MeCN PIFA 32
MeCN PIFA
3.5
4
a
Reaction conditions: 0.2 mmol 1a, 0.24 mmol NaNO2, 0.24 mmol PIFA
or PIDA in acetonitrile at rt.
Addition of more than 1.2 equivalents of either PIFA or NaNO2
did not result in improved yields or regioselectivities (data not
shown). Therefore, we concentrated our further optimization
on solvent and temperature. In ethyl acetate and DMF the
yields could be further improved to 85% (Table 1, entries 2
and 3). Finally, acetonitrile turned out to be the solvent of
choice giving 2a in 87% yield. However, it has to be mentioned
that o/p selectivity dropped slightly (Table 1, entry 4).
Changing the aryl-l3-iodane from PIFA to PIDA (phenyl
iodine diacetate) resulted in a significant lower yield of 47%
(Table 1, entry 5). This observation is in good agreement with
our proposal including a ligand-exchange as the initiating step
since ligand exchange to generate A should be much faster with
a less coordinating anion. Finally, lowering or increasing the
temperature to 0 1C or 50 1C did also not result in improved
product yields (Table 1, entries 6 and 7). Therefore, we decided
to use the almost optimal reaction conditions described in
entry 4 for our further systematic investigation of the substrate
scope (Scheme 2). Electron-rich N-aryl sulfonamides bearing
additional methoxy or alkyl substituents reacted well and in
perfect regioselectivity. p-Methoxy and p-methyl derivatives 1b
and 1d gave the corresponding o-nitro derivatives 2b and 2d in
62% and 67% yield whereas the o-methoxy substituted derivative 1c
gave para selective nitration to yield 2c in 48%. Nitration of the
3,5-dimethyl substituted sulfonamide 1e resulted in formation
of 2e in 60% yield. Interestingly, when phenyl substituted
sulfonamide 1f was used, exclusive nitration of the N-aryl group
Scheme 2 Substrate scope. Reaction conditions: 0.2 mmol 1a, 0.24 mmol
NaNO2, 0.24 mmol PIFA in acetonitrile at rt. Reaction time: 1–48 h.
of the sulfonamide was observed in 74% yield (2f). N-(1-Naphthyl) desired nitro-substituted pyridine derivative 2r in 56% yield.
sulfonamide gave 2g in 66% yield in an almost 1 : 1 mixture of o/p Finally, it is worth mentioning that N-unprotected aniline, N-methyl
regioisomers. Next, we investigated halogenated N-aryl sulfon- aniline and N,N-dimethylaniline gave messy reaction mixtures
amides. Chlorinated- and fluorinated derivatives reacted smoothly under similar reaction conditions.
to give the desired products 2h–j in 66–79% yield. However, an
To prove our initial proposal presented in Scheme 1, in
additional iodine-substituent had a negative influence on reactivity particular the generation of a nitronium ion (Scheme 1a), a
resulting in formation of 2k in only 42% yield. Very electron-poor replacement experiment was performed (Scheme 3). When a
nitro-, cyano-, and ester-containing sulfonamides could be nitrated mixture of 1a was treated with PIFA and NaNO2 in the presence
as well to give the desired products 2l–2p in 66–82% yield. of a slight excess of mesitylene 3, formation of 2a was observed
Cyano- and chloro substituted sulfonamide 1q gave 2q in poor exclusively in 59%. If a nitronium ion would be the active
isolated yield of 24%. N-(3-Pyridyl) sulfonamide yielded the species in this transformation, the more electron-rich arene 3
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cheap and easy to handle nitro source and the aryl-l3-iodane
PIFA as a mild oxidant the desired nitro (hetero)arenes could
be isolated in up to 87% yield. This novel nitration method is
acid free and subsequently tolerates a variety of additional
functional groups on the (hetero)arene moiety. Based on these
initial results we want to use the combination of a hypervalent
iodine reagent and nitrite salts in the near future to introduce
nitro functionalities into other, less reactive substrates in an
oxidative manner.
Scheme 3 Replacement experiment.
We gratefully acknowledge the DFG (NA 955/1-1) and the
Fonds der Chemischen Industrie (Sachkostenzuschuss) for
financial support.
Notes and references
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