A scalable procedure for light-induced benzylic brominations in continuous flow

Article abstract of DOI:10.1021/jo402409k

A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl₄. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h^-1), which is not easily possible in batch photochemical reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h ^-1 for the desired bromide was achieved.

Full text of DOI:10.1021/jo402409k

Article
pubs.acs.org/joc
A Scalable Procedure for Light-Induced Benzylic Brominations
in Continuous Flow
David Cantillo,† Oscar de Frutos,‡ Juan A. Rincon,‡ Carlos Mateos,*,‡ and C. Oliver Kappe*,†
†Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
‡Centro de Investigacion
́
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-Madrid, Spain
S
* Supporting Information
ABSTRACT: A continuous-flow protocol for the bromination of benzylic
compounds with N-bromosuccinimide (NBS) is presented. The radical reactions
were activated with a readily available household compact fluorescent lamp (CFL)
using a simple flow reactor design based on transparent fluorinated ethylene
polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as
the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each
substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic
starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a
diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases.
The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods
(throughput 30 mmol h−1), which is not easily possible in batch photochemical reactors. The bromination protocol can also be
performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as
a model, a productivity of 180 mmol h−1 for the desired bromide was achieved.
general is a powerful and versatile synthetic technique that can
be used to generate complex structures otherwise difficult to
obtain.18 Despite the large potential of organic photochemistry, it
has generally been underutilized both in academic laboratories
and the pharmaceutical industry. The main difficulties reside in
the problems associated with large-scale synthesis using UV or
visible light. Photochemical transformations are difficult to scale
because of the low penetration of light into the reaction mixture,
which, according to the Beer−Lambert law, decreases exponen-
tially with the path length.19 In addition, the heat typically
generated by the light source is difficult to control on a large scale,
and efficient cooling methods are required. Moreover, in a batch
reaction the time during which the substances are irradiated
cannot be sufficiently controlled. Thus, the ensuing products are
irradiated together with the remaining substrates for long periods,
often producing side reactions and undesired materials.
INTRODUCTION
■
Benzylic brominations represent a rather important class of trans-
formations in organic chemistry, as the resulting brominated
derivatives are useful and versatile intermediates in synthesis.1 The
classical Wohl−Ziegler bromination2 using N-bromosuccinimide
(NBS) in refluxing CCl4 in the presence of a radical initiator
such as benzoyl peroxide or 2,2′-azobis(isobutyronitrile) has
traditionally been used for the bromination of benzylic groups3
and nowadays is still often the method of choice for substitu-
tions of this type.4 Although NBS is a relatively safe and user-
friendly brominating agent compared with liquid bromine (Br2),
the classical Wohl−Ziegler bromination protocol suffers from
the use of the toxic and ozone-depleting solvent CCl4.5 Because
of these properties, this solvent has been internationally banned
by the so-called Montreal Protocol, and its use is therefore
prohibited on an industrial scale.6
Recently it has been demonstrated that microreactor/
continuous-flow technology can overcome the problems associated
with larger-scale photochemical transformations.20−22 In
addition to the benefits derived from the microfluidics approach
such as enhanced heat and mass transfer,23 the relatively low
reactor volume and especially the high surface area to volume
ratio of capillary flow reactors have proven to be key advantages
for light-initiated reactions, as intense and uniform irradiation
of the reaction mixture can be assured. Because of the short
path length of the light in a capillary microreactor, higher
substrate concentrations can be used, and therefore, the reaction
throughput can be significantly increased. In a photochemistry
In the past few years, important efforts have been made to
develop greener bromination procedures, mainly focusing on
the substitution of hazardous CCl4 by more benign solvents.
Thus, several bromination protocols using nonchlorinated
solvents such as methyl acetate,7 ethyl acetate and pivalate,8
trifluoromethylbenzene,9 acetonitrile,10 water,11 or ionic liquids12
or even solvent-free conditions12,13 have been described.
Alternative brominating agents such as the bromide/hydrogen
peroxide8,11b,14 and the bromide/bromate15 systems have also
been studied, as well as different activation methods, in particular
UV- or visible-light-induced brominations,7a,8,11a,b,13b,16 to avoid
the use of hazardous and potentially explosive radical initiators
such as benzoyl peroxide.17 It can be argued that light-induced
protocols are among the cleanest, safest, and most economical
methods of activation in organic chemistry. Photochemistry in
Received: October 29, 2013
© XXXX American Chemical Society
A
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flow setup, the light exposure can be very precisely controlled
by the pump flow rate, which minimizes overirradiation of the
mixture, avoiding undesired side products. Importantly, the
optimized reaction conditions can be readily scaled to multigram
quantities by a simple scale-out or numbering-up of the
reactor.24 Not surprisingly, therefore, in the past few years an
increasing amount of scientific work has appeared describing
photochemical transformations enhanced by a continuous-flow
device.21 In this context, examples describing photocycloaddi-
tions,24,25 photorearrangements,26 singlet oxygen reactions,27
and photoredox catalysis28 have been reported.
As a result of the above-mentioned importance of benzylic
bromination in organic synthesis and the unique advantages
that microreactor/continuous-flow technology offers to photo-
chemical transformations, we envisaged that the development
of a general continuous-flow protocol for the light-induced
bromination of benzylic positions would be highly desirable.
Only very few examples of general bromination reactions per-
formed in continuous flow exist in the literature. Electrophilic
bromination of aromatic rings with NBS29 and brominations
of alkenes30 or acetophenone31 using Br2 in flow have been
described. One very recent published example discusses the
benzylic bromination of a 5-methylpyrimidine precursor to
Figure 1. Schematic diagram of the flow setup employed for the
continuous-flow photochemical benzylic brominations.
30 W cool-white lamp (A), a 15 W plant-growing lamp (B), and a
25 W black-light lamp (C).
Model Reaction Optimization. We initiated our inves-
tigation by studying the bromination of 4-tert-butyltoluene (1a)
(Scheme 1) as a model reaction. This substituted toluene has
Scheme 1. Bromination of 4-tert-Butyltoluene, Selected as a
Model Substrate
̌
rosuvastatin in continuous flow. In that paper, Casar and co-
workers32 utilized a 150 W UV lamp and NBS to obtain the
desired benzyl bromide intermediate in good purity, signifi-
cantly improving on the corresponding batch procedure.
Herein we present a general protocol for the continuous-flow
visible-light-induced bromination of benzylic compounds with
NBS. The radical reaction is activated with a simple household
compact fluorescent lamp (CFL) under mild conditions using
acetonitrile as the solvent. With this straightforward procedure,
several substituted toluenes as well as other substrates
containing benzylic groups have been transformed into the
corresponding bromides with excellent selectivities and very
good yields. The process is readily scalable and, to the best of
our knowledge, constitutes the first general protocol for the
bromination of benzylic compounds in a continuous-flow regime.
frequently been used as a model in previous studies of benzylic
brominations.11,13 Variable amounts of the dibrominated product
(3a) are typically observed during the benzylic bromination of
toluene derivatives. Tetrahydrofuran (THF) and acetonitrile
were initially selected as solvents, as both NBS and the ensuing
succinimide are relatively well soluble in these solvents;33 this
avoided workup issues related to handling of polar high-boiling-
point solvents (e.g., DMF, DMSO). The set of optimization
reactions was performed on a 2 mmol scale. Thus, 2.1 mmol
(1.05 equiv) of NBS, 2 mmol of 4-tert-butyltoluene, and
acetonitrile (0.5 M 1a) were placed into a vial and stirred for a
few seconds until the mixture was completely homogeneous.
The solution was then pumped through the reactor, and the
crude reaction mixture collected from the output was analyzed
by GC−MS.
When THF was used as the solvent, poor conversions of the
substrate were obtained (Table 1, entries 1−3), even when the
reaction was carried out at 40 °C and a residence time of
50 min was used (entry 3). Notably, much better performance
was observed in MeCN, and the conversion dramatically
increased when this solvent was used. The temperature was also
an important parameter and had an influence on the efficiency
of the bromination. Thus, when the temperature was increased
from 20 to 60 °C (entries 4−6), the conversion improved from
69% to 96% using the 30 W white lamp. Excellent selectivity
(99%) for the monobrominated product was observed at 20
and 40 °C, but the selectivity significantly decreased (to 93%)
when the reaction was performed at 60 °C (entry 6). Apart
from the solvent and temperature employed, the type of CFL
utilized to irradiate the reactor had an important influence
on the bromination. The efficiency of the light source for the
reaction was C > B > A (see Table 1), and therefore, the 25 W
CFL black-light lamp was the preferred choice and the light
RESULTS AND DISCUSSION
■
Flow Reactor Setup. Our flow reactor was designed so that
different types of household CFLs could be used as the light
source and easily exchanged, thus providing the reactor with
high flexibility. The materials used are readily available in any
organic chemistry lab, and all of the domestic lamps were
purchased from standard commercial vendors (details about the
lamps used are contained in the Supporting Information). The
reactor design (Figure 1 and Figure S1 in the Supporting
Information) followed the general concept described by Booker-
Milburn24a and consisted of fluorinated ethylene propylene
(FEP) tubing (ø 1/8″) coiled around a standard 300 mL Pyrex
beaker. The inner volume of the tubing exposed to the light
source was 13 mL, and the reaction mixture was pumped through
the reactor with an HLPC pump (flow rate 0.1−10.0 mL min−1).
The outer surface of the reactor was wrapped with aluminum foil
to enhance the light irradiation, and the reactor was immersed in
an external thermostatted bath. Thus, the reaction temperature
could be controlled by setting the bath to the desired value.
Furthermore, an air cooling device was installed inside the reactor
to ensure that the heat generated by the lamp would not influence
the reaction. During our initial set of experiments, three different
household CFLs were evaluated for the benzylic bromination: a
B
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Table 1. Optimization of the Reaction Conditions for the
Table 2. Optimization of the Reaction Conditions for the
Photochemical Bromination of 4-Nitrotoluene (1b) with
NBS under Flow Conditions
Photochemical Bromination of 4-tert-Butyltoluene with NBS
a
a
under Continuous-Flow Conditions (Scheme 1)
light
source
t
T
conv.
c
selectivity
cd
b
,
entry solvent
[min] [°C]
[%]
[%]
1
2
THF
A
A
A
A
A
A
B
B
B
C
C
C
C
25
50
50
25
25
25
25
13
25
25
13
25
13
45
45
45
20
20
40
20
40
60
20
20
40
20
20
20
20
20
50
70
<10
<10
<10
69
91
96
98
68
98
98
98
99
99
−
99
99
99
99
99
93
96
99
96
97
97
94
94
−
THF
3
THF
b
bc
,
4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
entry light source t [min] T [°C] conv. [%]
selectivity [%]
5
1
2
3
4
5
6
C
C
C
C
C
C
13
25
25
50
25
25
20
40
60
60
60
60
−
13
67
90
71
87
−
99
99
99
99
98
6
7
8
9
d
e
10
11
12
13
14
15
16
a
Conditions: 2 mmol of substrate, MeCN (0.5 M), NBS (1.05 equiv),
e
e
b
c
25 W black-light irradiation. Measured by GC−MS. Selectivity for
the monobrominated product 2b. 1.2 equiv of NBS. 1.5 equiv of NBS.
d
e
f
none
none
none
f
−
−
−
−
Table 3. Optimization of the Reaction Conditions for the
Photochemical Bromination of 4-Chlorotoluene (1c) with
NBS under Flow Conditions
f
a
b
a
Conditions: 2 mmol of 1a, MeCN (0.5 M), NBS (1.05 equiv). A =
30 W cool-white lamp; B = 15 W plant lamp; C = 25 W black-light
c
d
lamp. Measured by GC−MS. Selectivity for the monobrominated
e
f
product. 1.1 equiv of NBS was used. The reaction mixture was placed
in a sealed vial covered with aluminum foil and kept at room temperature
or heated in an oven.
b
c
cd
,
source employed for all of the substrates. In this case, only
13 min (1 mL min−1 flow rate) was necessary to obtain
excellent conversion and selectivity without the need to apply
heat to the reaction (entry 11). When the amount of NBS was
increased to 1.1 equiv (entries 12 and 13), full conversion was
obtained but the selectivity was lower, with higher amounts of
the dibrominated product 3a being detected. In the absence of
light the reaction does not proceed, as demonstrated by runs in
which a sample of the reaction mixture was kept in a sealed vial
covered with aluminum foil for 45 min at room temperature,
50 °C, or 70 °C (entries 14−16, respectively). In each case, no
significant conversion of the substrate was observed.
entry light source
t [min] T [°C] conv. [%]
selectivity [%]
1
2
3
4
5
6
C
13
13
25
13
25
50
20
0
96
60
99
97
97
−
92
99
96
94
94
−-
C
C
0
A
20
0
A
e
none
20
a
Conditions: 2 mmol of substrate, MeCN (0.5 M), NBS (1.05 equiv).
A = 30 W white lamp; C = 25 W black-light lamp. Measured by
GC−MS. Selectivity for the monobrominated product 2c. The
reaction mixture was placed in a sealed vial covered with aluminum foil
and kept at room temperature.
b
c
d
e
We next turned our attention to the benzylic bromination of
two further substrates, 4-nitrotoluene (1b) and 4-chlorotoluene
(1c), to test the versatility of our flow reactor. The bromination
of 4-nitrotoluene was expected to proceed very slowly relative
to that for 4-tert-butyltoluene, while the reaction with
4-chlorotoluene is prone to yield large amounts of the double-
brominated side product. Gratifyingly, both reactions could be
successfully carried out with good conversion and selectivity by
tuning the reactor temperature and residence time (see Tables 2
and 3). Thus, 90% conversion and excellent selectivity (99%)
could be achieved for the bromination of 4-nitrotoluene using
the standard procedure (1.05 equiv of NBS, 0.5 M in
acetonitrile) by exposing the reaction mixture to light for
50 min (flow rate 0.25 mL min−1) at 60 °C (Table 2, entry 4).
In the case of the chlorinated substrate, employing the optimal
conditions for 4-tert-butyltoluene (13 min, 20 °C) provided a
relatively low selectivity (92%), and unreacted starting material
was detected in the crude reaction mixture (Table 3, entry 1).
However, very good control of the selectivity for this reaction
could be obtained by irradiating the sample at low temperature
(0 °C; Table 3, entries 2 and 3).
procedure by tuning of the reactor temperature and residence
time. Thus, unreactive substrates could be transformed to the
corresponding bromides by increasing the temperature of the
reactor to 40 or 60 °C. In the case of more reactive substrates,
where considerable amounts of the dibromide product are
expected, the selectivity could be controlled by operating the
reactor at low temperature (0 °C).
Reaction Scope. To demonstrate the scope and general
applicability of our continuous-flow bromination procedure, a
series of substituted toluenes and other benzylic substrates were
transformed into the corresponding bromides (Table 4). All
of the reactions were carried out on a 5 mmol scale (see the
Experimental Section for details), and the method showed
very good conversions and selectivities for a wide range of
substrates containing alkyl chains or halogen, ketone, ester,
nitro, or cyano functionalities. In some cases, small amounts of
the dibrominated product were detected by GC−MS analysis,
but gratifyingly, selectivities above 90% were obtained for all of
the substrates. Full details on the conversions and selectivities
(GC−MS analysis) observed for all transformations are collected
in Table S1 in the Supporting Information.
Therefore, it appeared that the bromination of a wide range
of substrates could be efficiently performed using this
C
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a
Table 4. Photochemical Bromination of Benzylic Positions under Continuous-Flow Conditions
a
b
c
Conditions: 5 mmol of substrate 1, MeCN (0.5 M), NBS (1.05 equiv). Isolated yields after silica gel column chromatography. Purified by
d
extraction in water/diethyl ether. Isolated with small impurities (5−10%) of the dibrominated product.
The brominated products were purified by silica gel flash
chromatography using hexane/ethyl acetate as the eluent to
remove small amounts of unreacted starting material and
dibrominated side products. In all cases, good to excellent
yields were obtained after purification (Table 4). When full
conversion and complete selectivity were obtained, alternative
workup procedures were also evaluated. Thus, (1-bromoethyl)-
benzene (entry 3) was additionally isolated by extraction with
diethyl ether/water or by precipitation of the succinimide with
a petroleum ether/Et2O mixture, providing the pure bromide in
yields of 97% and 95%, respectively.
Notably, very good selectivity was obtained in the case of
halogenated toluenes (entries 5−9). It should be noted that
iodine−bromine exchange had been reported during radical
brominations of iodine-substituted toluenes.7a With our flow
protocol, no traces of halogen-exchanged products were
observed (GC−MS), even when the reaction temperature
was raised to 60 °C to shorten the reaction time (entry 9). As
expected, a higher temperature was required for ortho-
compared with para-substituted substrates (entries 5 and 6),
and the reactivity toward benzylic bromination decreased in the
order Cl > Br > I.
selectivities in the range of 90−95% (Table S1 in the Supporting
Information). However, the corresponding products could be
readily separated by chromatography and isolated in good yields.
1-Indanone was brominated at the benzylic position at 20 °C
(entry 17), but the corresponding bromide partially decom-
posed on the column, leading to significant amounts of the
elimination product, 1-indenone. This compound was therefore
purified by extraction with ether/water. A pyridine derivative
was also successfully brominated in excellent yield at 60 °C and
a residence time of 25 min (entry 19).
It must be pointed out that the continuous-flow protocol was
typically not successful when applied to the benzylic bromina-
tion of electron-rich toluene derivatives (e.g., 4-methoxytoluene).
Following the general flow reaction conditions, full conversion
of the starting materials could readily be obtained. However, in
these cases the bromination exclusively occurred on the aromatic
ring instead of the benzylic position, as confirmed by GC−MS
1
and H NMR analyses. This clearly is the main limitation of
light-induced NBS bromination procedures, as previously
reported.11a,12,13b
Reaction Scale-Out and Scale-Up. One of the main
advantages of continuous-flow processing is the ease with which
a reaction can be scaled to larger product quantities simply by
operating the reactor for longer periods of time (scale-out), in
contrast with batch chemistry, where a larger scale normally
For the carbonyl-substituted toluenes (entries 11−13) and for
methyl 4-methyltoluenesulfonate (entry 16), higher amounts
of the dibrominated product were detected by GC−MS, with
D
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radical initiators or hazardous CCl4 as the solvent. By careful
tuning of the reactor temperature and residence time, several
benzylic compounds were successfully transformed into the
corresponding benzylic bromides in good to excellent yields.
Multigram quantities of the desired bromides can easily be
obtained simply by operating the reactor for longer periods of
time, which is difficult to achieve in a batch photochemical
procedure. Moreover, we successfully scaled up our continuous-
flow protocol by building a larger photochemical reactor. Thus,
higher flow rates of up to 6 mL min−1 could be employed to
carry out the bromination of phenylacetone, providing a
productivity of 180 mmol h−1.
Scheme 2. Bromination Reaction Selected as an Example for
the Scale-Out and Scale-Up of the Continuous-Flow
Protocol
requires a new reactor design. To test the robustness of our
method, we selected as a representative example the bromina-
tion of phenylacetone (Scheme 2 and Table 4, entry 18) for
a larger-scale experiment. Thus, a 50 mmol solution of the
substrate and NBS (1.05 equiv) in acetonitrile (0.5 M, 100 mL)
was pumped through the reactor (preheated to 40 °C) at a flow
rate of 1.0 mL min−1. The total operation time was therefore
100 min. Subsequently, the crude reaction mixture collected
from the reactor output was evaporated under reduced pressure,
and the residue was dissolved in diethyl ether and washed with
distilled water. Evaporation of the organic phase after drying
over magnesium sulfate provided 9.9 g (93% yield) of pure
1-bromo-1-phenylacetone. It is worth pointing out that larger
quantities of the desired bromide can be obtained by operating
the reactor for longer periods. This is not easily achieved in a
batch photochemical reactor, where the effective reactor volume
is limited by the penetration of light into the reaction mixture.
We next decided to scale up our bromination procedure by
building a photochemical reactor with a larger internal volume
and incorporating a more powerful light source. The principle
of the new reactor design was the same as of the small-scale
reactor (cf. Figure 1), but in the larger-volume reactor the FEP
tubing was coiled around a glass cylinder, which allowed
more efficient cooling of the lamp (see Figures S2 and S3 in
the Supporting Information). This was important because the
CFLs used for this reactor (100 W) generated a considerable
amount of heat. The volume of the FEP tubing exposed to the
light for this reactor was 28 mL, which is approximately 2-fold
the volume of the reactor employed for the smaller-scale reactions.
Gratifyingly, our large-scale reactor showed a very high
efficiency toward light-induced benzylic brominations. Thus,
the model substrate 4-tert-butyltoluene (Scheme 1) could be
fully converted into the corresponding bromide at a flow rate of
6 mL min−1 at room temperature using the standard conditions
(0.5 M in acetonitrile, 1.05 equiv of NBS) with a 100 W cool-
white CFL. This flow rate corresponds to a residence time of
less than 5 min. In addition, phenylacetone (Scheme 2) was
brominated at room temperature at a flow rate of 4 mL min−1.
In a 50 mmol scale run at this flow rate, full conversion and
complete selectivity were obtained for the desired brominated
product, which could be isolated in pure form by extraction in
96% yield. This corresponds to a productivity of 25 g h−1.
When a black-light CFL of comparable power (105 W) was used
instead of the cool-white lamp, the flow rate could be increased
to 6 mL min−1 without loss of selectivity, thus increasing the
throughput of the desired 1-bromo-1-phenylacetone to 38 g h−1.
EXPERIMENTAL SECTION
■
General Remarks. 1H NMR spectra were recorded on a 300 MHz
instrument. 13C NMR spectra were recorded on the same instrument
at 75 MHz. Chemical shifts (δ) are expressed in parts per million
downfield from TMS as an internal standard. The letters s, d, t, q,
and m are used to indicate singlet, doublet, triplet, quadruplet, and
multiplet, respectively. GC−MS monitoring was based on electron
impact ionization (70 eV) using an HP/5MS column (30 m × 0.250
mm × 0.025 μm). After 1 min at 50 °C, the temperature was increased
in 25 °C min−1 steps up to 300 °C and kept at 300 °C for 1 min. The
carrier gas was helium, and the flow rate was 1.0 mL min−1 in constant-
flow mode. HPLC-grade solvents were used in all experiments. Flash
chromatography purifications were carried out on an automated flash
chromatography system using cartridges packed with KP-SIL, 60 Å
(32−63 μm particle size). N-Bromosuccinimide of 99% purity was
purchased from Acros Organics (code 107451000, lot A0330482).
Chemicals were obtained from standard commercial vendors and
used without any further purification. In all of the flow experiments,
the lamp was turned on at least 15 min prior use to ensure maximum
and constant irradiation.
All of the compounds synthesized herein are known in the literature.
1
Proof of purity and identity was obtained by H NMR spectroscopy
and mass spectrometry.
General Procedure for the Continuous-Flow Benzylic
Bromination (Table 4). N-Bromosuccinimide (934 mg, 5.25 mmol,
1.05 equiv), HPLC-grade acetonitrile, and the corresponding substrate
(5 mmol) were placed into a vial and stirred until the mixture was
completely homogeneous. The solution was then pumped through the
reactor at the desired flow rate. The reaction mixture collected from
the reactor output was evaporated under reduced pressure, and the
crude mixture was purified by flash column chromatography using
petroleum ether/ethyl acetate as the eluent.
Alternative workup A: The reaction mixture collected from the
reactor output was evaporated under reduced pressure, and the residue
was treated with 30 mL of diethyl ether. The white precipitate was
filtered off, and the solvent was extracted with distilled water (3 × 10 mL).
Then the organic phase was dried over magnesium sulfate and evaporated
under reduced pressure, providing the corresponding benzyl bromide.
Alternative workup B: The reaction mixture collected from the
reactor output was evaporated under reduced pressure, and the residue
was treated with 10 mL of 1:1 petroleum ether/diethyl ether and then
stirred at room temperature. The white precipitate was filtered off, and
the solvent was evaporated. The process was repeated until no new
precipitate was observed.
4-tert-Butylbenzyl Bromide (Table 4, entry 1). Yield: 1032 mg
1
(91%). H NMR (300 MHz, CDCl3): δ 7.42−7.35 (m, 4H), 4.53 (s,
2H), 1.35 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 151.57, 134.76,
128.77, 125.78, 34.66, 33.66, 31.27. MS-EI: m/z 147 (100%), 132
(40%), 117 (35%).
CONCLUSIONS
■
We have developed a general protocol for the visible-light-
induced bromination of benzylic compounds in continuous flow.
The photochemical reactor was set up using readily available
materials, and the light source is an inexpensive household CFL.
With acetonitrile as the solvent, the reaction proceeds to comple-
tion within minutes under mild conditions, avoiding the use of
Benzyl Bromide (Table 4, entry 2). Yield: 787 mg (92%). 1H NMR
(300 MHz, CDCl3): δ 7.44−7.32 (m, 4H), 4.53 (s, 2H). 13C NMR
(75 MHz, CDCl3): δ 137.8, 129.1, 128.8, 128.4, 33.6. MS-EI: m/z 91
(100%), 65 (22%).
(1-Bromoethyl)benzene (Table 4, entry 3). Yield: 786 mg (85%).
1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 12.0 Hz, 2H), 7.41−7.28
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(m, 3H), 5.25 (q, J = 8.0 Hz, 20.0 Hz, 1H), 2.09 (d, J = 12.0 Hz). 13
NMR (75 MHz, CDCl3): δ 143.3, 128.7, 128.4, 126.8, 49.6, 26.9, 26.8.
MS-EI: m/z 105 (100%), 79 (25%), 77 (25%).
C
3-Bromoindan-1-one (Table 4, entry 17). Yield: 990 mg (94%). 1H
NMR (300 MHz, CDCl3): δ 7.77−7.71 (m, 3H), 7.54−7.46 (m, 1H),
5.61 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 3.37 (dd, J = 8.0 Hz, 28.0 Hz, 1H),
3.06 (dd, J = 4.0 Hz, 28.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
201.5, 154.3, 136.0, 135.6, 129.7, 127.5, 123.4, 48.1, 40.7, 40.7. MS-EI:
m/z 131 (100%), 103 (60%), 77 (40%).
2-Methylbenzyl Bromide (Table 4, entry 4). Yield: 647 mg (70%).
1H NMR (300 MHz, CDCl3): δ 7.30−7.18 (m, 4H), 4.55 (s, 2H),
2.45 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 137.3, 135.7, 130.8,
130.0, 129.0, 126.4, 32.4, 18.8. MS-EI: m/z 105 (100%), 103 (20%),
79 (22%), 77 (22%).
4-Chlorobenzyl Bromide (Table 4, entry 5). Yield: 894 mg (87%).
1H NMR (300 MHz, CDCl3): δ 7.34 (s, 4H), 4.48 (s, 2H). 13C NMR
(75 MHz, CDCl3): δ 136.3, 134.3, 130.4, 129.0, 32.5. MS-EI: m/z 127
(30%), 125 (100%), 89 (45%).
2-Chlorobenzyl Bromide (Table 4, entry 6). Yield: 905 mg (88%).
1H NMR (300 MHz, CDCl3): δ 7.48−7.40 (m, 2H), 7.31−7.26 (m,
2H), 4.62 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 135.4, 134.3, 131.3,
130.1, 130.0, 127.3, 30.6. MS-EI: m/z 127 (30%), 125 (100%), 89
(40%).
1-Bromo-1-phenylacetone (Table 4, entry 18). Yield: 992 mg
1
(93%). H NMR (300 MHz, CDCl3): δ 7.48−7.36 (m, 5H), 5.46 (s,
1H), 2.32 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 199.2, 135.1, 129.2,
129.1, 128.7, 56.4, 26.3. MS-EI: m/z 171 (30%), 169 (35%), 133
(90%), 118 (25%), 105 (35%), 90 (95%), 89 (100%).
2-(1′-Bromoethyl)pyridine (Table 4, entry 19). Yield: 860 mg
(92%). 1H NMR (300 MHz, CDCl3): δ 8.58 (d, J = 4.0 Hz, 1H), 7.70
(t, J = 12.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.0 Hz,
12.0 Hz, 1H), 5.24 (q, J = 8.0 Hz, 1H), 2.08 (d, J = 12.0 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 161.0, 149.3, 137.0, 123.0, 121.6, 49.4,
25.0, 25.0. MS-EI: m/z 105 (100%), 103 (20%), 79 (25%), 77 (25%).
4-Bromobenzyl Bromide (Table 4, entry 7). Yield: 975 mg (78%).
1H NMR (300 MHz, CDCl3): δ 7.49 (d, J = 12.0 Hz, 2H), 7.28 (d, J =
12.0 Hz, 2H), 4.46 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 136.81,
131.99, 130.71, 122.49, 32.46. MS-EI: m/z 171 (80%), 169 (90%), 90
(100%), 89 (75%).
ASSOCIATED CONTENT
■
S
* Supporting Information
Supporting tables and figures and copies of 1H NMR spectra of
all prepared compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
3-Bromobenzyl Bromide (Table 4, entry 8). Yield: 1025 mg (82%).
1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H),
7.34 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 4.45 (s, 2H). 13C
NMR (75 MHz, CDCl3): δ 139.9, 132.1, 131.5, 130.3, 127.7, 122.6,
32.1. MS-EI: m/z 171 (80%), 169 (90%), 90 (100%), 89 (75%).
4-Iodobenzyl Bromide (Table 4, entry 9). Yield: 1175 mg (79%).
1H NMR (300 MHz, CDCl3): δ 7.70 (d, J = 12.0 Hz, 2H), 7.15 (d, J =
12.0 Hz, 2H), 4.44 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 138.0,
137.4, 130.9, 94.2, 32.5. MS-EI: m/z 217 (99%), 90 (100%), 89 (75%).
4-Nitrobenzyl Bromide (Table 4, entry 10). Yield: 927 mg (86%).
1H NMR (300 MHz, CDCl3): δ 8.22 (d, J = 12.0 Hz, 2H), 7.58 (d, J =
12.0 Hz, 2H). 5.54 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 147.7,
144.8, 129.9, 124.1, 31.0. MS-EI: m/z 136 (100%), 106 (20%), 90
(45%), 89 (60%), 78 (60%).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mateos_gutierrez_carlos@lilly.com.
*E-mail: oliver.kappe@uni-graz.at.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Eli Lilly and Company through the
Lilly Research Award Program (LRAP). We thank Dr. Scott A.
May for his contributions to this work.
4-(Bromomethyl)benzophenone (Table 4, entry 11). Yield: 1047
1
mg (76%). H NMR (300 MHz, CDCl3): δ 7.83−7.79 (m, 4H), 7.62
REFERENCES
■
(t, J = 8.0 Hz, 2H), 7.59−7.48 (m, 4H), 4.56 (s, 2H). 13C NMR (75
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128.4, 32.3. MS-EI: m/z 195 (90%), 167 (100%), 118 (20%), 105
(35%).
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1
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