Metal and H2O2 free aerobic oxidative aromatic halogenation with [RNH3+] [NO3-]/HX and [BMIM(SO3H)][NO3)x(X)y] (X = Br, Cl) as multifunctional ionic liquids

Article abstract of DOI:10.1021/ol4001476

Novel multifunctional ionic liquids (ILs) are generated by addition of HBr or HCl to alkylammonium nitrates ([RNH₃⁺] [NO ₃^-]) and to 3-methyl-1-(butyl-4-sulfonyl)imidazolium nitrate ([BMIM(SO₃H)][NO₃]). The resulting [RNH ₃⁺] [NO₃^-]/HX and mono (3-methyl-1-(butyl-4-sulfonyl)imidazolium) monohalogenide mononitrate ([BMIM(SO₃H)][NO₃)_x(X)_y] (X = Br, Cl)) systems act as solvent and promoter for aerobic oxidative halogenation of arenes under mild conditions in high yields that can be repeated over several cycles.

Full text of DOI:10.1021/ol4001476

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Metal and H O Free Aerobic Oxidative
2
2
þ
000–000
Aromatic Halogenation with [RNH ]
3
ꢀ
[
NO ]/HX and [BMIM(SO H)][NO ) (X) ]
3
3
3 x y
(
X = Br, Cl) as Multifunctional Ionic Liquids
,†
†
,‡,§
,‡
Kenneth K. Laali,* and Stojan Stavber*
Rok Prebil,
Department of Physical and Organic Chemistry, “Jo zꢀ ef Stefan” Institut, Jamova
3
1
9,1000 Ljubljana, Slovenia, and Department of Chemistry, University of North Florida,
UNF Drive, Jacksonville, Florida 32224, United States
Kenneth.Laali@UNF.edu; Stojan.Stavber@ijs.si
Received February 28, 2013
ABSTRACT
3þ
3ꢀ
Novel multifunctional ionic liquids (ILs) are generated by addition of HBr or HCl to alkylammonium nitrates ([RNH ] [NO ]) and to 3-methyl-
þ
ꢀ
1
-(butyl-4-sulfonyl)imidazolium nitrate ([BMIM(SO
3
H)][NO
3
]). The resulting [RNH ]/HX and mono (3-methyl-1-(butyl-4-sulfonyl)-
imidazolium) monohalogenide mononitrate ([BMIM(SO H)][NO ) (X) ] (X = Br, Cl)) systems act as solvent and promoter for aerobic oxidative
3
] [NO
3
3
3 x
y
halogenation of arenes under mild conditions in high yields that can be repeated over several cycles.
Haloarenes are highly versatile synthetic intermediates
and building blocks that are extensively employed in cross-
coupling reactions and in nucleophilic substitutions and
utilized as precursors to organometallic reagents. Bromo-
and chloroarenes are widely used as building blocks of fine
chemicals, pharmaceuticals and agrochemicals and are
routinely elaborated in the synthesis of natural products
and materials. Given the worldwide demand for these
compounds, there is ever increasing need to synthesize
them under environmentally more acceptable green con-
ditions while at the same time achieving atom economy,
selectivity, and high yields. It is therefore logical to devise
alternative strategies to the conventional methods of
bromide and chloride ions are converted in situ to electro-
philic reagents. The large majority of the systems studied
earlier employ metal catalysts as well as Brønsted or Lewis
acids and typically use hydrogen peroxide as oxidant or
1ꢀ6
workunder aerobic conditions. The system KBr/HNO3
(65%) in Ac O as solvent was used by a Norwegian group
2
7
for mild ring bromination of representative activated arenes.
The use of green media such as supercritical CO , water, and
2
ionic liquids (ILs) have also met with some success but left
much room for improvement particularly with regard to
3
,6
8
selectivity. A notable report by Chiappe and co-workers
utilized the Brønsted acidic 3-methylimidazolium nitrate
halogenations that employ molecular halogen X and
2
(2) Kikushima, K.; Moriuchi, T.; Hirao, T. Tetrahedron Lett. 2010,
51, 340.
N-halosuccinimides NXS and to also avoid the use of
halogenated solvents. In this context, there is active on-
going interest in oxidative halogenation of arenes in which
(
3) Review: Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem. Int.
Ed. 2009, 48, 8424.
4) Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron
009, 65, 4429.
5) Wang, J. A.; Wang, W.; Li, J. H. Green Chem. 2010, 12, 2124.
(6) Pavlinac, J.; Zupan, M.; Laali, K. K.; Stavber, S. Tetrahedron
(
2
(
†
“
Jo ꢀz ef Stefan” Institut
‡
§
University of North Florida
Visiting PhD student at UNF
2009, 65, 5625.
(7) Tsoukala, A.; Liguori, L.; Occhipinti, G.; Bjorsvika, H. R. Tetra-
(1) Kikushima, K.; Moriuchi, T.; Hirao, T. Tetrahedron 2010, 66,
hedron Lett. 2009, 50, 831.
6906.
(8) Chiappe, C.; Leandri, E.; Tebano, M. Green Chem. 2006, 8, 742.
1
0.1021/ol4001476 r XXXX American Chemical Society

(
[HMIM][NO ]) as cosolvent and promoter in oxidative
3
chlorination of alkylbenzenes and representative aromatic
aldehydes and ketones using aqueous HCl. Depending on
the substrate structure, ring halogenation, side chain hal-
ogenation or oxidation were observed. By comparison,
Table 1. Bromination of Activated and Deactivated Aromatics
in EAN/HBr
a
the [HMIM][NO ]-HBr system proved less effective for
3
bromination.
In the context of projects focusing on electrophilic
9
chemistry in ILs, and our continuing joint studies on
1
0ꢀ12
halofunctionalization of aromatic compounds in ILs,
we report here on the generation of novel multifunctional ionic
þ
ꢀ
liquids (ILs) alkylammonium nitrates [RNH ] [NO ]/HX
3
3
and mono(3-methyl-1-(butyl-4-sulfonyl)imidazolium) mono-
halogenide mononitrate ([BMIM(SO H)][(NO ) (X) ] (X=
3
3 x
y
Br, Cl)) and their utility as solvent and promoter for aerobic
oxidative ring bromination and chlorination of arenes
under mild conditions in high yields with repeated recy-
cling and reuse. The multifunctional ILs are readily formed
by addition of HBr or HCl to ethyl- or propylammonium
nitrates (EAN or PAN) and to 3-methyl-1-(butyl-4-sulfonyl)-
imidazolium nitrate ([BMIM(SO H)][NO ]).
3
3
Table 1 summarizes the bromination outcomes for acti-
ꢀ
þ
vated and deactivated arenes with the [EtNH ] [NO ]/
3
3
HBr system formed by addition of HBr to the readily
available EAN ionic liquid. The reactions were carried out
at 30ꢀ50 °C, except for p-nitroanisole which was per-
formed at 80 °C. It is noteworthy that anisole (entry 1)
gives only the para isomer 2a whereas both ortho and para
isomers were formed with toluene (entry 6) and ethylben-
zene (entry 7), with para isomers predominating. Ring
substitution products were regioselectively formed with
cumene (entry 8). No meta halogenated isomers (entries
6
ꢀ8) were detected. Bromination of phenol (entry 9) was
strongly para selective with the ortho isomer also present.
Whereas p-bromoanisole (entry 10) could be brominated
to 2,4-dibromo-1-methoxybenzene (2i) in good yield, further
deactivation of aromatic ring as in p-nitroanisole (entry 11)
resulted in low conversion to 2-bromo-4-nitroanisole (2j).
Electron-rich arenes such as 1,3-dimethoxybenzene (entry 3),
1
(
2
,3,5-trimethylbenzene (entry 4) or 1,2,4,5-tetramethylbenzene
entry 5) gave regioselectively monobrominated products 2b,
c, or 2d, respectively. Only in the case of 1,2,4,5-
tetramethylbenzene (entry 4) small amounts of dibromi-
nated product was formed. Using only 1.1 mmol of HBr
(
48%) in EAN, anisole (entry 2) was quantitatively con-
a
Reaction conditions: Arene (1 mmol), EAN (3 mmol), HBr
aqueous 48% solution, 1.8 mmol), 30ꢀ80 °C, 35 minꢀ24 h, air balloon.
verted and 89% of pure p-bromoanisole 2a was isolated.
As a representative case, 2-acetylthiophene was regiose-
lectively ring brominated to 2-acetyl-5-bromothiophene
after two hours at r.t. in 64% yield. The need for the
presence of the nitrate ion was shown in a control experiment
(
b
1
Conversions and isomer distribution were determined by H NMR and
c
d
GC-MS spectroscopy of crude reaction mixture. Isolated yield. Arene
1 mmol), EAN (3 mmol), HBr (aqueous 48% solution, 1.1 mmol), air
(
balloon. 5% of 1,4-dibromo-2,3,5,6-tetramethylbenzene (2d ).
e
0
(
0, 7347. (b) Kumar, G. G. K. S. N.; Aridoss, G.; Laali, K. K.
Tetrahedron Lett. 2012, 53, 3066. (c) Aridoss, G.; Laali, K. K. J. Org.
Chem. 2011, 76, 8088. (d) Aridoss, G.; Laali, K. K. Tetrahedron Lett.
9) (a) Kumar, G. G. K. S. N.; Laali, K. K. Org. Biomol. Chem. 2012,
by replacing EAN/HBr with 3-methyl-1-(butyl-4-sulfonyl)-
imidazolium hexafluorophosphate(V)/HBr in a reaction
with anisole, where no reaction was observed.
The recycling and reuse aspect of EAN/HBr in aerobic
oxidative bromination of anisole was explored for five
consecutive runs with quantitative yields for 4-bromoani-
sole formation (see Supporting Information, SI). Under
similar reaction conditions there is a slightly higher tendency
1
2
9
2
1
011, 52, 6859.
10) Hubbard, A.; Okazaki, T.; Laali, K. K. Aust. J. Chem. 2007, 60,
23.
(
(
11) Pavlinac, J.; Laali, K. K.; Zupan, M.; Stavber, S. Aust. J. Chem.
008, 61, 946.
(12) Vrazic, D.; Jereb, M.; Laali, K. K.; Stavber, S. Molecules 2012,
7, 74.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Chlorination of Activated Aromatic Substrates in
EAN/HCl
Table 3. Chlorination of Activated Aromatic Substrates in
[BMIM][SO H][NO ]/HCl
3 3
a
a
a
3 3
Reaction conditions: Arene (1 mmol), [BMIM(SO H)][NO ]
b
(
between were determined by NMR and GC-MS. Isolated yield. 1.1
2 mmol), 30ꢀ60 °C, 21 h, air balloon. Conversions and product ratios
c
d
e
mmol of added HCl (aqueous 37% solution). 2.5 mmol of added HCl
f
0
(
2
aqueous 37% solution). 9% of 1-chloro-2-methoxybenzene (3a ) and
4% of 4-chloro-2-methoxybenzene were formed.
a
Reaction conditions: Arene (1 mmol), EAN (3 mmol), HCl
(
aqueous 37% solution, 1.8 mmol), 60ꢀ80 °C, 1ꢀ24 h, air baloon.
x and y (see SI), and the best chemoselectivity for mono-
halogenation and quantitative conversion was reached
with x:y = 1 (see SI).
b
1
Conversions and isomer distribution were determined by H NMR and
c
GC-MS spectroscopy of crude reaction mixture. Isolated yield. 24%
of 1-chloro-2,4-dimethoxybenzene (3b) was formed.
d
The multifunctional IL mono(3-methyl-1-(butyl-4-sul-
fonyl)imidazolium) monochloride mononitrate ([BMIM-
for dibromination of 1,3-dimethoxybenzene and durene in
PAN as compared to EAN (see SI).
Focusing on the [EtNH3 ] [NO ]/HCl system, anisole
3
(SO H)][(NO ) (Cl)0.5]) prepared by addition of 37%
aqueous HCl and 65% aqueous HNO to the zwitterion
3 3 0.5
3
þ
ꢀ
(
(
entry 1), 1,3-dimethoxybenzene (entry 2) and mesitylene
entry 3) were chlorinated under mild conditions in high
Table 4. Chlorination of Activated Aromatic Substrates in
yields (Table 2). In the case of 1,3-dimethoxybenzene
competing dichlorination was observed as the main pro-
cess, while anisole (entry 1) was transformed to the para 3a
and ortho 3a products in 2.4:1 relative ratio.
We hadpreviouslyused the Brønsted acidicIL3-methyl-
a,c
3
[BMIM][SO H][(NO3)0.5(Cl)0.5]
0
1
solvent for aromatic chlorination with trichloroisocyanuric
-(butyl-4-sulfonyl)imidazolium triflate as catalyst and
1
0
acid (TfOH). In the present study [BMIM(SO H)][NO ]
3
3
was prepared by adding HNO instead of trifluorometh-
3
anesulfonic acid (TfOH) to 3-methyl-1-(butyl-4-sulfonate)-
ꢀ
imidazolium [BMIM(SO )] zwitterion. The system [BMIM-
3
(SO H)][NO ]/HCl proved very effective for aerobic
3 3
chlorination of anisole in test experiments as indicated
in Table 3. In the presence of slight molar excess of HCl
0
(
entry 1) 4-chloro- (3a) and 2-chloroanisole (3a ) were
formed in 2.7:1 relative ratio, while higher concentration
of HCl (entry 2) caused the formation of considerable
00
amounts of 2,4-dichloroanisole 3a .
Subsequent studies showed that isolation of [BMIM-
(
SO H)][NO ] is unnecessary and multifunctional [BMIM-
3 3
a
(
temperature by addition of HNO and HX to the zwitterion
SO H)][(NO ) (X) ] ILs can be prepared directly at room
3
3 x
y
Reaction conditions: Arene (1 mmol), EAN (3 mmol), HCl
(aqueous 37% solution, 1.8 mmol), 60ꢀ80 °C, 1ꢀ24 h, air balloon.
3
b
1
Determined by H NMR and GC-MS spectroscopy of crude reaction
without the need to dry [BMIM(SO H)][NO ].
3
c
d
mixture. Isolated yield. 12% of 2,4-dichloro-1,3,5-trimethylbenzene
3
Optimization reactions were performed for chlorination
of anisole with the [BMIM(SO H)][(NO ) (Cl) ] by varying
0
e
3c ) was formed. [BMIM][SO
(
3
H][(NO3)0.5(Cl)0.5] contained water.
3
3 x
y
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 5. Bromination of Aromatic Substrates in
[
Scheme 1. Bromination of Acetophenone (4a) and
1-(4-Methoxyphenyl)ethanone (4b)
a,b
3 3
BMIM][SO H][(NO )0.5(Br)0.5]
In summary, we have devleoped novel metal-free and
peroxide-free multifucntional IL systems for mild and
green aerobic oxidative bromination and chlorination of
activated arenes from the readily available alkylammo-
nium nitrate and HX with the possibility of recycling and
reusing over several cycles. The imidazolium-based sys-
tems prepared by direct addition of HX and HNO to
3
ꢀ
[
BMIM(SO )], without drying or any additional steps,
3
offer greater promise as multifunctional ILs for aerobic
oxidative halogenation of arenes. Protocols for the regen-
eration and reuse of these multifunctional ionic liquids,
insight into the role of nitrate anion in the reported oxi-
dativehalogenations, and the larger scopeof thischemistry
are under current investigation.
a
Reaction conditions: Arene (1 mmol), EAN (3 mmol), HBr (aqueous
b
4
8% solution, 1.8 mmol), 60ꢀ80 °C, 1ꢀ23 h, air baloon. Determined by
1
c
H NMR and GC-MS of crude reaction mixture. Isolated yield. 38% of
d
0
1
,5-dibromo-2,4-dimethoxybenzene (2b ) was formed and 20% was iso-
3
lated. [BMIM][SO H][(NO3)0.5(Br)0.5] contained water.
Acknowledgment. The authors are grateful to the
Slovenian Research Agency (contracts: Programme
P1-0134, Young Researchers Fellowship PR-03767-1,
USA/SI bilateral project BI-US/12-13-004), Human
Resources Development and Scholarship fund (contract:
4-Month research fellowship #11012-1712012-7), European
Regional Development Found (OP 13.1.1.02.0005), and
UNF for financial support.
was used directly (without drying) for aerobic chlorina-
tion of arenes (Table 4). This highly practical method
þ
ꢀ
proved superior to those when the [EtNH ] [NO ]/HCl
3
3
was used.
In a subsequent step the mono(3-methyl-1-(butyl-4-
sulfonyl)imidazolium) monobromide mononitrate ([BMIM-
(
SO H)][NO ) (Br) ]) was prepared in a similar manner
3 3 0.5 0.5
Note Added after ASAP Publication. We regret having
missed the reference Earl, M. J.; Katdare, S. P.; Seddon,
K. R. Paradigm Confirmed: The First Use of Ionic Liquids
to Dramatically Influence the Outcome of Chemical Reac-
tions. Org. Lett. 2004, 6, 707ꢀ710. This paper reposted on
April 12, 2013.
and employed in aerobic bromination of representative
aromatics in high yields under very mild conditions (Table 5).
Finally, the selectivity of halofunctionalization was ex-
amined by using acetophenone (4a) and 1-(4-methoxy-
phenyl)ethanone (4b) as model compounds bearing two
potentially reactive sites. Bromination of acetophenone
in EAN/HBr mixture gave only 2-bromo-1-phenylethanone
in 90% yield (5a, Scheme 1), while 1-(4-methoxyphenyl)-
ethanone was ring brominated to give 3-bromo-4-methoxy
acetophenone (5b, Scheme 1) in 80% yield (see SI). Chlori-
nation of these compounds with EAN/HCl mixture were
unsuccessful under the reaction conditions employed.
Supporting Information Available. Full experimental
details and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX