A novel transition metal free [bis-(trifluoroacetoxy)iodo]benzene (PIFA) mediated oxidative ipso nitration of organoboronic acids

Article abstract of DOI:10.1039/c5ob00337g

A mild, convenient and transition metal free methodology for oxidative ipso nitration of diversely functionalized organoboronic acids, including heteroaryl- and alkylboronic acids, has been developed at ambient temperature using a combination of [bis-(trifluoroacetoxy)]iodobenzene (PIFA) - N-bromosuccinimide (NBS) and sodium nitrite as the nitro source. It is anticipated that the reaction proceeds through in situ generation of NO₂ and O-centred organoboronic acid radicals followed by the formation of an O-N bond via combination of the said radicals. Finally transfer of the NO₂ group to the aryl moiety occurs through 1,3-aryl migration to provide the nitroarenes.

Full text of DOI:10.1039/c5ob00337g

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A novel transition metal free [bis-(trifluoroacetoxy)-
iodo]benzene (PIFA) mediated oxidative ipso
nitration of organoboronic acids†
Cite this: DOI: 10.1039/c5ob00337g
Received 18th February 2015,
Accepted 13th March 2015
Nachiketa Chatterjee, Divya Bhatt and Avijit Goswami*
DOI: 10.1039/c5ob00337g
www.rsc.org/obc
A mild, convenient and transition metal free methodology for oxi- opment of mechanistic concepts.2,3 Therefore, developing
dative ipso nitration of diversely functionalized organoboronic novel methodologies to access variedly functionalized nitro-
acids, including heteroaryl- and alkylboronic acids, has been arenes always have a great research importance.
developed at ambient temperature using a combination of [bis-
The traditional approach of synthesizing nitroarenes is the
(trifluoroacetoxy)]iodobenzene (PIFA) N-bromosuccinimide direct electrophilic nitration of the arenes. Such electrophilic
–
(NBS) and sodium nitrite as the nitro source. It is anticipated that nitration methods usually require the use of excess mixed
the reaction proceeds through in situ generation of NO2 and acids (c.HNO3–c.H2SO4) or a mixture of conc. HNO3 and di-
O-centred organoboronic acid radicals followed by the formation nitrogen pentoxide as the nitrating agent.3 However, these
of an O–N bond via combination of the said radicals. Finally trans- approaches suffer from several drawbacks, such as limited sub-
fer of the NO2 group to the aryl moiety occurs through 1,3-aryl strate scope, poor regioselectivity and formation of various
migration to provide the nitroarenes.
undesired by-products.4 To overcome these difficulties, some
notable efforts have been made towards regioselective synth-
eses of nitroarenes under mild reaction conditions.5
Over the last century nitroarenes have been considered as ver-
satile structural motifs because of their wide range of appli-
cations in pharmaceuticals, pesticides, dyes, agrochemicals
and polymers (Fig. 1).1 They also play a vital role in the devel-
Recently, our group has reported a novel methodology for
ipso hydroxylation of organoboronic acids/esters mediated by
PhI(OAc)2.6 Likewise, ipso nitration of the arylboronic acids
can be considered as a useful alternative methodology for
synthesizing nitroarenes as it completely circumvents the
regioselectivity problem and very often can be performed
under mild reaction conditions. First transition metal free
ipso nitration of arylboronic acids was achieved using a rela-
tively strong oxidant the Crivello reagent.7 Later, several other
transition metal free methodologies for ipso nitration of the
arylboronic acids have been developed using a chlorotrimethyl-
silane–nitrate salt,8 tert-butyl nitrite (TBN),9 and bismuth
nitrate–perdisulphate10 (Scheme 1). However, despite their
noticeable advancements, these protocols suffer from long
reaction time, higher reaction temperature and the use of
hazardous reagents. Furthermore, it could also be mentioned
that none of the literature so far reported, has documented
the ipso nitration of the alkylboronic acids and very few
have reported the ipso nitration with heteroaryl boronic
compounds.
Fig. 1 Selected biologically active nitro compounds.
Over the last two decades, organic hypervalent iodine has
been widely utilized as a green and potential oxidant in
various fields of organic synthesis including functionalization
of different organic compounds,11 but much less attention has
been devoted to generate nitro radicals through 1 electron
oxidation of simple sodium or potassium nitrite12 utilizing
Department of Chemistry, Indian Institute of Technology, Ropar (IIT Ropar), Nangal
Road, Rupnagar, Punjab 140001, India. E-mail: agoswami@iitrpr.ac.in;
Tel: +91-1881-242121
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00337g
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Table 1 Optimization of reaction conditionsa
Eq. of
PIFA
Eq. of the
additive
Yieldc
(%)
Entry
Additive
Solvent
1
2
3
4
5
6
7
8
2.0
4.0
—
2.0
3.0
3.0
3.0
3.0
—
—
—
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
n.rd
n.rd
n.re
52
NBS
NBS
NBS
NBS
NBS
NBS
2.1
1.1
1.1
2.1
2.1
2.1
64
Scheme 1 ipso Nitration of organoboronic acids under various reaction
conditions.
93 f
92g
76
a Optimized reaction conditions: 1a (0.5 mmol, 1.0 eq.), PhI(OCOCF3)2
(1.5 mmol, 3.0 eq.), NaNO2 (1.5 mmol, 3.0 eq.), NBS (1.05 mmol, 2.1
eq.), CH3CN (5 mL), rt, 3 h, open air. b All optimization reactions were
carried out with 3.0 equiv. of NaNO2. c Isolated yield. d No nitration
took place either by stirring the reaction mixture for 24 h at room
temperature or on heating at 60 °C for 6 h. e No nitration was observed
either by stirring the reaction mixture for 24 h at room temperature or
on heating at 60 °C for 6 h, however, bromination took place on
heating the mixture at 60 °C for 6 h. f These reaction conditions were
taken as optimized reaction conditions. g The reaction was carried out
under an argon atmosphere.
the hypervalent iodine reagents. Recently, Kloeckner et al.
reported an efficient [bis-(trifluoroacetoxy)]iodobenzene (PIFA)
mediated generation of a nitro radical through 1 electron oxi-
dation from NaNO2.13
Taking this lead, we herein report a highly efficient PIFA
mediated oxidative regioselective nitration of aryl-, alkyl- and
heteroarylboronic acids which are expected to have biological
importance. This is not only an efficient alternative to other
ipso nitrations of the organoboronic acids but also to the best
of our knowledge, the first example of using PIFA–NBS–NaNO2
combination to generate nitroarenes under transition metal
free conditions.
To start the initial investigation, 3-methylphenylboronic
acid (1b) was chosen as the model substrate for obtaining
3-nitrotoluene (2b). An initial screening of the organoiodine(III)
species revealed that the reagents I, II and III failed to provide
the desired nitroarenes irrespective of the presence or absence
of any additive, whereas, with IV, the ipso nitration of the
organoboronic acids was successfully achieved in the presence
of NBS as an additive (Fig. 2).
essential for nitration to happen but also the amount of the
additive is important for better conversion of the organoboro-
nic acids to the nitroarenes (entries 1–6). Keeping the amount
of NBS fixed (1.1 eq.), increase in the amount of PIFA from 2.0
eq. to 3.0 eq. enhances the yield of the reaction a bit (entries 4
and 5) while increasing the amount of NBS from 1.1 eq. to 2.1
eq. (PIFA 3.0 eq.) resulted in almost quantitative nitration of
the m-tolylboronic acid (entries 5 and 6). However, changing
the solvent from acetonitrile to dichloromethane resulted in a
comparatively lower yield probably owing to the lower solubility
of NaNO2 in dichloromethane (entry 8). In this context it could
be mentioned that performing the reaction in an inert environ-
ment did not change the reaction outcome by any extent
(entry 7).
Table 1 summarizes the optimization results of PIFA
mediated ipso nitration of organoboronic acids in open air and
at ambient temperature.
It was observed that, for the reaction to be successful, the
presence of both PIFA and NBS are essential; in the absence of
any one of the reagents, the reaction could not be made possi-
ble (entries 1–3). The presence of an additive (NBS) is not only
Having optimized the reaction conditions, the investi-
gations were conducted in other substrates in order to outline
the substrate scope of this PIFA mediated nitration methodo-
logy and the results are summarized in Scheme 2.
Successful nitrations of diversely substituted arylboronic
acids demonstrated the excellent functional group (e.g. halide,
nitro, aldehyde, keto and nitrile) compatibility of the protocol
developed in the present work. The nitrations of the ortho-sub-
stituted arylboronic acids to the corresponding nitroarenes
(2c, 2d, 2j and 2n) indicated that the steric effect plays a negli-
gible role in the reaction outcome. It is noteworthy that the
nitration process developed herein works equally well with
arylboronic acids, having either an electron donating or with-
drawing group. It is important to mention that arylboronic
acids with an oxidation sensitive functional group such as
Fig. 2 Different organoiodine(III) reagents employed. a No nitration took
place with these reagents. b Isolated yield.
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Scheme 3 PIFA mediated ipso nitration of heteroarylboronic acids.
Reaction conditions: 3 (0.5 mmol), PhI(OCOCF3)2 (1.5 mmol), NaNO2
(1.5 mmol), NBS (1.05 mmol), CH3CN (5 mL), rt, 3 h, open air. a The
reported yield is along with the impurity associated with the compound.
The radical scavenging experiment with TEMPO confirms
the radical mechanistic pathway of the nitration reactions pres-
ented in this work.14 On the other side, the reaction between
arylboronic acids and PIFA–NBS (Scheme 4) did not afford any
biaryl compounds which clearly suggests that the aryl radical
is not getting formed during the course of the reaction. Hence
the combination of aryl radical and nitro radical to generate
nitroarenes might not be the probable mechanism.
Another possibility could be such that in the presence of
PIFA, NBS could readily react with the nitro radical to form
N-nitrosuccinimide which then reacts with arylboronic acids in
the same fashion as proposed by Petasis et al. for the bromina-
tion of organoboronic acids/esters by NBS.15
Scheme 2 PIFA mediated ipso-nitration of aryl- and alkylboronic acids.
a Reaction conditions: 1 (0.5 mmol), PhI(OCOCF3)2 (1.5 mmol), NaNO2
(1.5 mmol), NBS (1.05 mmol), CH3CN (5 mL), rt, 3 h, open air. b The reac-
tion with 1p was carried out on the 2.0 mmol scale.
However, the reaction between m-tolylboronic acid (1b) and
N-nitrosuccinimide, synthesized separately following the
reported literature procedure,16 did not afford the corres-
ponding m-nitrotoluene (2b) (Scheme 5). Also we did not
observe the formation of N-nitrosuccinimide in GCMS when
we performed a separate reaction between NBS and NaNO2 in
the presence of PIFA.
As the reaction proceeds through the radical pathway
(already confirmed through the TEMPO experiment) and the
reaction occurs at ambient temperature which is much faster
aldehyde (2j) also endured the reaction conditions employed,
without undergoing over-oxidation. The smooth transform-
ation of halide-substituted arylboronic acids to the corres-
ponding halo substituted nitroarenes (2m and 2n), synthons
for further functionalization, makes this protocol further
versatile.
Encouraged by these results, the alkylboronic acids were
also employed for nitration reactions to judge the spectrum of
this methodology (Scheme 2). Surprisingly, there is no docu-
mentation so far on the synthesis of nitroalkanes through ipso
substitution of the alkylboronic acids/esters. Greatly, through
this newly developed protocol, both primary and secondary
nitroalkanes (2o and 2p) were successfully synthesized in high
yields. On the other hand, organoboronates could not be trans-
formed to their corresponding nitro compounds through this
protocol.
Equally stimulating was the observation that the methodo-
logy developed herein, can conveniently nitrate the hetero-
arylboronic acids in excellent yields, which were otherwise in
general hard to achieve (Scheme 3). However, compound 4c Scheme 4 Attempted synthesis of biphenyl derivatives.
was always obtained with an inseparable impurity associated
with it.
There could be several possible mechanistic rationales for
this regioselective nitration of the organoboronic acids. As it is
known that PIFA reacts with NaNO2 to generate the nitro
radical,12,13 the choice of NBS was made with this consider-
ation that if the combination of PIFA–NBS, with arylboronic
acids could generate an aryl radical, then these two radicals
may combine to provide nitroarenes in a single pot.
Scheme 5 Synthesis of N-nitrosuccinimide and its reaction with 1b.
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Scheme 6 Proposed reaction mechanism.
compared to other ipso nitrations, an intramolecular nitro
transfer along with a radical pathway seems logical for the
reaction to proceed.
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be proposed that organoboronic acids in the presence of NBS
and PIFA generate O-centred radicals which react readily
with the nitro radical, generated through one electron oxi-
dation of NaNO2 in the presence of PIFA, to form the meta-
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(Scheme 6).
In conclusion, we have developed a novel method for ipso
nitration of organoboronic acids using a combination of PIFA–
NBS and NaNO2. The method is applicable for aryl-, hetero-
aryl-, and alkylboronic acids and provides nitro compounds at
ambient temperature in a significantly less reaction time exhi-
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Acknowledgements
We are grateful to CSIR, New Delhi, India for their generous
financial support and IIT Ropar for infrastructural facilities.
NC and DB would like to thank IIT Ropar and UGC, New
Delhi, respectively, for their fellowship.
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