Revisiting the bromination of c-h bonds with molecular bromine by using a photo-microflow system

Article abstract of DOI:10.1002/chem.201402303

The photobromination of C-H bonds by using molecular bromine was reinvestigated under microfluidic conditions. The continuous-flow method suppressed the production of dibrominated compounds and effectively produced the desired monobrominated products with high selectivity. Rapid bromination of benzylic substrates containing a photoaffinity azide group was achieved without any decomposition. Go with the (micro)flow: Photobromination of C-H bonds by using molecular bromine under microfluidic conditions has been investigated (see scheme). The continuous-flow method suppressed the production of dibrominated compounds and effectively produced the desired monobrominated compounds with high selectivity. Rapid bromination of benzylic substrates containing a photoaffinity azide group was achieved without any decomposition.

Full text of DOI:10.1002/chem.201402303

DOI: 10.1002/chem.201402303
Communication
&
Selective Bromination
Revisiting the Bromination of CÀH Bonds with Molecular Bromine
by Using a Photo-Microflow System
Yoshiyuki Manabe,[a] Yuriko Kitawaki,[a] Masahiro Nagasaki,[a] Koichi Fukase,*[a]
Hiroshi Matsubara,[b] Yoshiko Hino,[b] Takahide Fukuyama,[b] and Ilhyong Ryu*[b]
Recently, photoreactions have been investigated by using
Abstract: The photobromination of CÀH bonds by using
molecular bromine was reinvestigated under microfluidic
conditions. The continuous-flow method suppressed the
production of dibrominated compounds and effectively
produced the desired monobrominated products with
high selectivity. Rapid bromination of benzylic substrates
containing a photoaffinity azide group was achieved with-
out any decomposition.
microreactors,[6,7] which enable efficient photoirradiation and
realize a reproducible and energy-saving system. In general,
microreactors suppress undesired over-reactions because the
flow-reaction system allows the products to be rapidly trans-
ferred from the reactor. Consequently, various microfluidic pro-
cesses for photoreactions, such as photoadditions, photorear-
rangements, photooxygenation, and specific examples of pho-
tohalogenation, have been examined.[8] This study aims to
modernize the photoinduced CÀH/CÀBr conversion by molecu-
lar bromine by using microfluidic processes. Recent research
has demonstrated that effective a-bromination of alkylben-
zenes is possible based on microflow photobromination using
bromine-related reagents, such as HBrÀH2O2 and N-bromosuc-
cinimide (NBS).[9]
Organobromine compounds are among the most versatile in-
termediates in organic synthesis. They serve as precursors to
carbanions, carbon radicals, carbocations, and organo–transi-
tion-metal species.[1] Among the various methodologies to pre-
pare bromoalkanes, the most straightforward is the direct con-
version of CÀH bonds into CÀBr bonds by using molecular bro-
mine; this method originated a century ago.[2] Kharasch and
coworkers established the reactivity of this method towards
different CÀH bonds and radical-chain mechanisms.[3] A bro-
mine radical, arising from homolysis of molecular bromine by
photoirradiation, abstracts a hydrogen atom from a CÀH bond
to form a carbon radical, liberating HBr. The resulting carbon
radical then abstracts a bromine atom from molecular bromine
to give a CÀBr bond, liberating a bromine radical, which partic-
ipates in the next radical chain.
We examined the flow bromination of cyclohexane with mo-
lecular bromine under visible-light irradiation (15 W black light,
peak wavelength 352 nm) by using microflow devices
(Scheme 1, Table 1). When a cyclohexane solution of Br2 (Br2/
The disadvantage of this synthetic procedure is that the side
products include a significant amount of 1,2-dibromoalkanes.
A recent study using a batch flask reported that photobromi-
nation of cyclohexane (1a) with a stoichiometric amount of
molecular bromine in water gives a 3:2 mixture of desired bro-
mocyclohexane (2a) and undesired trans-1,2-dibromocyclohex-
ane (3a).[4,5]
Scheme 1. Microflow devices for photobromination of cyclohexane (1a).
1a=1:5) was mixed with water by using a micromixer (diame-
ter 500 mm), and the mixture subsequently introduced into
a glass-made flow device with a residence photoirradiation
time of 19 min, bromocyclohexane (2a) was formed in 42%
yield, together with a 13% yield of 1,2-dibromocyclohexane
(3a) (entry 1). A higher selectivity of 2a/3a was attained when
a larger excess of cyclohexane was used (entries 2–4). For ex-
ample, an 80-fold excess of 1a increased the selectivity of 2a/
3a to 96:4 (entry 5). The residence time could be reduced to
5.7 min (entry 7), whereas the reaction using a batch reactor
(Pyrex, 3 cm internal diameter test tube) gave only 11% con-
version. The use of two black-light bulbs (30 W) further in-
creased the reaction rate with a residence time of 2.9 min
(entry 8).
[a] Dr. Y. Manabe, Y. Kitawaki, M. Nagasaki, Prof. K. Fukase
Department of chemistry, Graduate School of Science
Osaka University
Toyonaka, Osaka 560-0043 (Japan)
Fax: (+81)6-6850-5391
E-mail: koichi@chem.sci.osaka-u.ac.jp
[b] Prof. H. Matsubara, Y. Hino, Prof. T. Fukuyama, Prof. I. Ryu
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Sakai, Osaka 599-8531 (Japan)
After successfully converting CÀH bonds into CÀBr bonds,
microflow photobromination was then applied to various alk-
anes (Table 2). Continuous-flow bromination of cyclopentane
E-mail: ryu@c.s.osakafu-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402303.
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Communication
ceeded even under ambient light. Thus, a FC-72 (perfluorohex-
anes) solution of bromine with these alkanes was mixed by
using an additional micromixer, and the resulting mixture was
quickly mixed with water. These reactions occurred selectively
at the tertiary CÀH bond, giving corresponding tertiary alkyl
bromides 2e, 2 f, and 2g in good yields (entries 5–7).
The ability of Br2 to convert CÀH bonds into CÀBr bonds is
much less than that of Cl2 or F2 for CÀH/CÀCl or CÀH/CÀF con-
version, respectively.[10] However, Br2 provides site selectivity.
The site selectivity of the photoinduced CÀH/CÀBr conversion
is tertiary alkyl>secondary alkyl>primary alkyl. This trend can
be rationalized by the low-barrier transition states for H-atom
abstraction by the bromine radical, predicted by DFT calcula-
tions (Scheme 2).[11] It is interesting to compare H-atom ab-
Table 1. Photoinduced continuous-flow bromination of cyclohexane (1a).
Entry[a]
Residence
time [min]
Ratio of
1a/Br2
Yield [%][b]
Selectivity
for 2a [%]
2a
3a
1
2
3
4
5
6
7
8[c]
19
19
19
19
19
9.5
5.7
2.9
5:1
10:1
40:1
60:1
80:1
40:1
40:1
40:1
42
78
84
87
96
80
78
77
13
13
8
5
4
10
9
7
76
86
91
95
96
89
90
92
[a] Reaction conditions: Br2 (0.5 mmol), Mikroglas Dwel Device (channel
size: 500 mm deep, 1000 mm wide, and 1.9 m long, Foturanꢁ glass), Micro-
mixer (500 mm) and 15 W black light (352 nm), room temperature. [b] De-
termined by GC analysis with chlorobenzene as an internal standard.
[c] Two bulbs of black light (total 30 W) were used.
Table 2. Photoinduced flow bromination of various alkanes.
Entry[a]
Substrate
Product
Yield [%][b]
Selectivity
for 2 [%]
1
2
1a
2a
84
92
91
93
3
99
99
4
93
58
94
84
Scheme 2. Transition states for H-atom abstraction from CÀH bonds by the
bromine radical (energies (in kJmolÀ1) calculated at the BHandHLYP/6-
311+ +G(d,p)+LanL2DZdp(Br) level).
5[c]
6[c,d]
76
58
87
99
straction, by the bromine radical, of trimethylmethane and tol-
uene. Although both have almost identical activation energies,
the energy barrier of the backward reaction with the tertiary
butyl radical is more facile than that with the benzyl radical,
predicting that benzylic bromination is more likely. Therefore,
we then focused on flow photobromination of alkylarenes by
using Br2.
7[c,e]
[a] Reaction conditions: Br2 (0.5 mmol),
1 (40 equiv), Mikroglas Dwel
Device (channel size: 500 mm deep, 1000 mm wide, 1.9 m long) Micromix-
er (500 mm) and 15 W black light (Toshiba, 352 nm), room temperature,
residence time=19 min. [b] Determined by GC analysis. [c] Alkanes were
mixed with a FC-72 (perfluorohexanes) solution of molecular bromine by
using a micromixer. The resulting solution was mixed with water by using
a-Brominated alkylbenzenes have diverse applications in or-
ganic synthesis, especially as benzylation reagents. Conse-
quently, numerous methods have been developed for bromi-
nation of the benzylic position, including using molecular bro-
mine,[12] NBS,[13] H2O2/HBr,[14] or NaBrO3/NaHSO3.[15] Herein, we
focused on flow photobromination using molecular bromine,
which is a simple and cost-effective bromine source. Using 4-
phenyltoluene (4a) as a model substrate, we examined flow
photobromination (Table 3). A mixture of 4a and 1.2 equiva-
lents of Br2 in CCl4 was introduced into the microreactor
a
second micromixer (for details, see the Supporting Information).
[d] Two stereoisomers of 2 f (product ratio=4:1) were detected by GC
1
analysis and H NMR spectroscopy. [e] Residence time=1.9 min.
(1b), cycloheptane (1c), and cyclooctane (1d) gave the corre-
sponding bromocycloalkanes (2b, 2c, and 2d) in good yields
with high selectivity (entries 2, 3, and 4). Bromination of sub-
strates with a tertiary CÀH bond, such as 1e, 1 f, and 1g, pro-
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give corresponding benzylic bromide 5b in good yield
(entry 2). In contrast, methyl p-methyl benzoate (4c) required
a prolonged residence time (7.5 min) to give corresponding
monobrominated compound 5c (entry 3). Interestingly, the
flow bromination of ethylbenzene (4d) gave monobrominated
compound 5d with complete selectivity (entry 4).
Table 3. Photoinduced flow bromination of 4a under microfluidic condi-
tions.
Next, to determine which functionalities were compatible
with the rapid flow reaction, we examined the bromination of
substrates with a photosensitive functionality. Thus, the benzyl-
ic positions of p-azidotoluene (4e) and p-benzoyltoluene (4 f),
which are sensitive to photoirradiation and widely used as
photoaffinity groups,[17] were investigated. Compound 4e was
brominated, without decomposition of the parent structure, to
give 5e in 80% yield (entry 5). Although bromination of 4 f re-
quired a longer residence time (2.5 min), desired product 5 f
was obtained in 61% yield. To the best of our knowledge, this
is the first example of photobromination of substrates contain-
ing a photoaffinity group, such as an azide or benzoyl group,
in its structure. These results demonstrate that judiciously con-
trolled photoirradiation, coupled with a microflow reactor, ena-
bles a highly selective benzylic bromination reaction by using
Br2.
Entry[a]
Solvent
Light
source
Residence
time
Yield
[%][b]
5a
Selectivity
for 5a [%]
6a
1
2
3
CCl4
CCl4
BTF
black light[c]
LED lamp[d]
LED lamp[d]
43 s
43 s
3.6 min
72
75
74
11
8
9
86
90
89
[a] Reaction conditions: 4a (0.1m), Br2 (1.2 equiv), microreactor (300 mm
deep, 1000 mm wide, 2.35 m long), room temperature. [b] Determined by
NMR spectroscopy. [c] 15 W black light (Toshiba, 352 nm). [d] LED lamp
(YMC Co., Ltd., YMC-P-0049, 1.95 W 360 nm).
(MiChS L-1, 300 mm deep, 1000 mm wide, 2.35 m long, quartz)
by means of a syringe pump, at a flow rate of 1.0 mLminÀ1
,
under black-light (15 W) irradiation (entry 1). The resultant so-
lution was quenched by aqueous saturated Na2S2O3 and ana-
lyzed by NMR spectroscopy. The reaction gave desired mono-
brominated product 5a in 72%, along with 11% of dibromi-
nated byproduct 6a. An experiment using an LED lamp
(1.95 W, peak wavelength 360 nm) gave a slightly improved
result (entry 2). CCl4 could be substituted by benzotrifluoride
(BTF)[16] as a solvent. In this case, the residence time was pro-
longed from 43 s to 3.6 min (entry 3).
We previously reported that the 4-azido-3-chloro-benzyl
group functions as a promising hydroxy protecting group,
which can be selectively cleaved by a Staudinger reduction,
followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
oxidation.[18] 4-Azido-3-chloro-benzylation of the hydroxy
group was performed with 4-azido-3-chlorobenzyl bromide
(5g) as a benzylating reagent. Originally 5g was synthesized
by a batch bromination of 4-azido-3-chlorotoluene (4g) by
using NBS and 2,2’-azobis(isobutyronitrile) (AIBN) under reflux;
however, this batch reaction produced a considerable amount
of dibrominated product 6g and a tedious chromatographic
purification was necessary to
Table 4 lists several examples of benzylic bromination under
the microfluidic conditions. Bromination of p-fluorotoluene
(4b) proceeded very smoothly with a residence time of 11 s to
remove the resultant succini-
mide. We then applied our flow
Table 4. Photoinduced flow benzylic bromination.
conditions using Br2 to obtain
Entry[a]
Substrate
Product
Residence
time
Yield [%][b]
Selectivity
for 5 [%]
5g with high product selectivity,
without decomposition of the
photosensitive arylazide struc-
ture. Thus, 4-azido-3-chloroto-
luene (4g) was reacted with
1.2 equivalents of molecular bro-
mine under photomicrofluidic
1
2
3
4
5
43 s
75
73
69
75
80
90
91
11 s
conditions at
a flow rate of
7.5 min
8.5 s
22 s
87
0.05 mLminÀ1, realizing a highly
selective monobromination (5g/
100
91
6g=90:10,
determined
by
1H NMR spectroscopy) without
affecting the aryl azide structure
(Scheme 3). The resultant HBr
could be removed easily by an
aqueous treatment, and product
5g was easily isolated by recrys-
tallization from methanol in 61%
yield.
6[c]
2.5 min
61
87
[a] Reaction conditions: 4a–4 f (0.1m), Br2 (1.2 equiv), microreactor (300 mm deep, 1000 mm wide, 2.35 m long),
LED lamp (YMC Co., Ltd., YMC-P-0049, 1.95 W 360 nm), room temperature. [b] Determined by H NMR spectros-
copy. [c] 1.5 equiv of Br2 was used.
1
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Keywords: bromination
·
bromine
·
microreactors
·
photoreactions
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Received: February 21, 2014
Published online on August 29, 2014
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