Dual oxidation/bromination of alkylbenzenes

Article abstract of DOI:10.1016/j.tetlet.2016.01.062

In the presence of sodium bromide and Oxone, a range of alkylbenzene derivatives are brominated and/or oxidized with up to four C-H bonds being functionalized.

Full text of DOI:10.1016/j.tetlet.2016.01.062

Accepted Manuscript
Dual oxidation/bromination of alkylbenzenes
Marwa M. Aborways, Wesley J. Moran
PII:
S0040-4039(16)30061-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.062
TETL 47226
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 November 2015
13 January 2016
18 January 2016
Please cite this article as: Aborways, M.M., Moran, W.J., Dual oxidation/bromination of alkylbenzenes, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.062
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COMMUNICATION
Dual oxidation/bromination of alkylbenzenes
a
a*
Marwa M. Aborways and Wesley J. Moran
Received 00th January 20xx,
Accepted 00th January 20xx
Abstract:
In the presence of sodium bromide and Oxone, a range of alkylbenzene derivatives are brominated and/
or oxidized with up to four C-H bonds being functionalized.
DOI: 10.1039/x0xx00000x
www.rsc.org/
o
In the presence of sodium bromide and Oxone, a range of
alkylbenzene derivatives are brominated and/or oxidized with up in the light conversion increased significantly and ketone
3
(entry 3). However, when the reaction was repeated at 50 C
was
3
to four C-H bonds being functionalized.
isolated in 65% yield (entry 4). At this point, the requirement
for the acid was evaluated and it was found that its removal
led to no detriment in yield (entry 5). Small amounts of the
ortho- and meta-bromination products were evident in the
crude reaction mixtures but these could be removed by
recrystallization. Lowering the number of equivalents of
sodium bromide and oxidant led to lower yield.
The development of new methods for the functionalization of
simple inexpensive aromatic compounds is an important area
of investigation. In particular, developing conditions that do
not require the use of expensive, toxic or difficult to handle
compounds is a worthwhile endeavor. For example, the
halogenation of arenes is
a
ubiquitous chemical
transformation for which there are many published
procedures, however the use of elemental halogen or reagents
1,2
such as N-halosuccinimide are often required.
These
reactants have disadvantages such as toxicity, corrosiveness,
ease-of-use, relative high cost, low atom efficiency or supply
issues.
We previously reported the use of sodium halides, in the
presence of an oxidant, as electrophilic halogenating agents
for the conversion of propargyl alcohols to -iodoenones, ,-
3
dibromoketones and
,-dichloroketones. We wished to
extend this concept to the functionalization of simple
alkylbenzenes. We envisaged that halogenation of the
aromatic ring would occur with concomitant oxidation of the
benzylic methylene to a ketone (Fig. 1).
Fig. 1 Previous study of oxidative halogenation and this work
We started our study with ethylbenzene
1 using our
previously published conditions of sodium bromide with Table 1 Investigation of reaction conditions
Oxone in the presence of trichloroacetic acid dissolved in a
3a
mixture of acetonitrile and water (Table 1). Performing the
reaction at room temperature in the dark led to very low
conversion to
-bromoketone 3 (entry 1). Repeating the
reaction in the light also led to low conversion of the starting
o
material (entry 2). Heating the reaction mixture at 50 C in the
dark led to higher conversion and a mixture of products
2 and
a.
Department of Chemistry, University of Huddersfield, Huddersfield HD1 3DH, UK.
E-mail: w.j.moran@hud.ac.uk
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
a
b
Yield of isolated compound. No Cl
3
CCO
2
H added.
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a
With these reaction conditions in hand, we evaluated a Table 2 Scope of alkylbenzene oxidative bromination
range of substrates to explore this interesting reactivity profile.
Benzylic oxidation and arene bromination are both known
processes, with reports of these transformations using related
4,5
conditions to ours, but performing both transformations
simultaneously has not been reported. Subjecting n-
propylbenzene
4 to the reaction conditions led to oxidation of
the benzylic position and bromination of the ring, however
bromination adjacent to the ketone did not occur (entry 2). In
a similar fashion, n-butylbenzene
6
was converted into ketone
7
with efficient conversion evident at room temperature.
Cumene
8 has only one benzylic proton and cannot be
converted to the ketone. Under the reaction conditions it was
doubly brominated to provide compound at room
9
temperature (entry 4). Upon heating, elimination of HBr was
observed. Isobutylbenzene 10 was converted to ketone 11 as
expected (entry 5). With these results in hand, we turned our
attention to substrates with aryl substituents to determine
their effect on reactivity. Surprisingly, 4-chloro(ethylbenzene)
1
2
was oxidized to ketone 13 with bromination adjacent to the
ketone not occurring unlike with ethylbenzene (entry 6). The
1
presence of a phenol shuts down the benzylic oxidation and
double bromination of the ring occurs (entry 7). A nitro
substituent shuts down all reactivity (entry 8) as does a ketone
group (entry 9). Surprisingly, 2-ethylnaphthalene 18 is
dibrominated without any benzylic oxidation (entry 10).
In order to probe the mechanism of this process, we
subjected acetophenone 20 to the reaction conditions.
Approximately 12%
-bromination was observed but no ring
bromination was evident (Scheme 1). This suggests that
bromination of the aromatic ring must occur before the
benzylic site oxidation. We can also propose that
-ketone
bromination is possible under these conditions, but that it is
slow. Therefore, an alternative mechanistic pathway must be
in operation here. In a second reaction, we subjected 1’-
bromoethylbenzene 22 to the reaction conditions and
observed complete conversion with approximately a 2:1 ratio
6
of acetophenone 20 and bromide 21
.
a
o
Reaction conditions: NaBr (6 equiv), Oxone (5 equiv), 1:1 MeCN/H
2
O, 50 C (or
b
c
room temperature where indicated), in the light. Yield of isolated compound.
Reaction performed at room temperature.
The mechanism of this process is proposed to initiate by
7
the oxidation of bromide. This is a complicated process but
Scheme 1 Reactions to probe mechanistic features.
bromine radical and elemental bromine will be generated with
light (Scheme 2). Bromination of the arene by bromine takes
place first, if possible, followed by benzylic hydrogen atom
abstraction. This can combine with bromine (or another
bromine radical) to generate the benzyl bromide. A second
hydrogen abstraction then occurs followed by coupling with
2
| J. Name., 2012, 00, 1-3
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5
Examples of arene bromination: (a) S. Song, X. Sun, X. Li, Y.
bromine (or another bromine radical). Finally, dibromide 23 is
converted to the ketone 24 by displacement with water.
Yuan and N. Jiao, Org. Lett., 2015, 17, 2886; (b) Q. Zhang, S.
Gong, L. Liu and H. Yin, Proc. Safety Environ. Prot., 2013, 91
,
8
6; (c) A. Podgorsek, S. Stavber, M. Zupan and J. Iskra
Tetrahedron, 2009, 65, 4429; (d) S. M. Bennett, Y. Tand, D.
McMaster, F. V. Bright and M. R. Detty, J. Org. Chem. 2008,
7
3, 6849; (e) K.-J. Lee, H. K. Cho and C.-E. Song, Bull. Korean
Chem. Soc., 2002, 23, 773.
6
7
K. N. Parida, S. Jhulki, S. Mandal and J. N. Moorthy,
Tetrahedron, 2012, 68, 9763.
(a) J. Yousefi-Seyf, K. Tajeian, E. Kolvari, N. Koukabi, A.
Khazaei and M. A. Zolfigol, Bull. Korean Chem. Soc., 2012, 33
,
2
619; (b) N. Tada, K. Ban, T. Ishigami, T. Nobuta, T. Miura
and A. Itoh, Tetrahedron Lett., 2011, 52, 3821; (c) R. Mestres
and J. Palenzuela, Green Chem., 2002, , 314; (d) A. Citterio,
R. Santi and A. Pagani, J. Org. Chem., 1987, 52, 4925.
4
Scheme 2 Postulated reaction mechanism
Conclusions
In summary, we have shown that in the presence of the
inexpensive oxidant Oxone, NaBr can be used to functionalize
a range of simple alkylbenzenes with up to four C-H bonds
being replaced. These conditions provide a greener access into
functionalized aromatic compounds. The reactions are easy to
carry out, use reagents with relatively low toxicity and
generally lead to the installation of more than one functional
group in one operation. This simple and environmentally
friendly procedure to rapidly functionalize simple aromatics
should find applicability in synthesis.
Acknowledgements
We thank the State of Libya for a graduate studentship (MMA).
Notes and references
1
Examples with halogens: (a) B. I. Roman, N. De Kimpe and C.
V. Stevens, Chem. Rev., 2010, 110, 5914; (b) N. Iranpoor, H.
Firouzabadi, A. Jamalian and F. Kazemi, Tetrahedron, 2005,
61, 5699.
2
Examples with NXS: (a) A. Kumar, P. Lohan and O. Prakash,
Synth. Commun., 2012, 42, 2739; (b) G. K. S. Prakash, T.
Mathew, D. Hoole, P. M. Esteves, Q. Wang, G. Rasul and G.
A. Olah, J. Am. Chem. Soc., 2004, 126, 15570; (c) J. Prakash
and S. Roy, J. Org. Chem., 2002, 67, 7861.
3
4
(a) M. M. Aborways and W. J. Moran, Tetrahedron Lett.,
2
014, 55, 2127; (b) W. J. Moran and A. Rodríguez, Org.
Biomol. Chem., 2012, 10, 8590.
Examples of benzylic oxidation: (a) K. Moriyama, M.
Takemura and H. Togo, Org. Lett. 2012, 14, 2414; (b) A. T.
Khan, T. Parvin, L. H. Choudhury and S. Ghosh, Tetrahedron
Lett., 2007, 48, 2271.
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Graphical abstract
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