Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection

Article abstract of DOI:10.1039/c9ob00044e

BrCCl₃ represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.27 kg L^?1 h^?1

Full text of DOI:10.1039/c9ob00044e

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10.1039/C9OB00044E.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Photochemical Benzylic Bromination in Continuous Flow using
BrCCl3 and its Application to Telescoped p-Methoxybenzyl
Received 00th January 20xx,
Accepted 00th January 20xx
Protection
DOI: 10.1039/x0xx00000x
Yuma Otake,a,† Jason D. Williams,a,b Juan A. Rincón,c Oscar de Frutos,c Carlos Mateos,c and C.
Oliver Kappe*a,b
www.rsc.org/
BrCCl3 represents a rarely used benzylic brominating reagent with be fruitful in many areas, particularly in scaling up, due to
complementary reactivity to other reagents. Its reactivity has been improved and evenly distributed light penetration throughout
revisited in continuous flow, revealing compatibility with electron- the reaction medium.13-18 Indeed, many examples of Wohl-
rich aromatic substrates. This has brought about the development Ziegler reactions under continuous flow conditions have been
of a p-methoxybenzyl bromide generator for PMB protection, reported.19-22 Furthermore, the advent of continuous flow
which was successfully demonstrated on a pharmaceutically photochemistry has encouraged re-evaluation of many
relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br previously examined reaction methodologies which, upon their
space-time-yield of 1.27 kg L–1 h–1.
initial discovery, were often limited in their application. A
greater potential for these procedures may now be realized,
owing to significant advances in synthesis technology over the
past two decades.
Photochemical benzylic bromination (the Wohl-Ziegler
reaction) represents one of the most well used methods within
synthetic organic photochemistry.1,2 This simple procedure is
initiated by the photolysis of the Br-Br bond in Br2, present in
low levels in the synthetic reagent N-bromosuccinimide (NBS).3-
Br
+ sole by-product is CHCl3
BrCCl3
+ compatible with electron-rich aromatics
R
R
+ no solubility issues with liquid reagent
h
6
However, despite the simplicity and wide implementation of
Scheme 1. Proposed photochemical bromination in continuous flow using BrCCl3.
this methodology, it suffers from a number of drawbacks; most
notably incompatibility with electron-rich aromatic substrates,
due to competing electrophilic (ring) bromination.7 Although
multiple alternative bromine sources for benzylic bromination
have been described, these are almost exclusively comprised of
other N-Br compounds,8 which can also function as electrophilic
Br sources, or in situ Br2 generation methods.9-12
In recent years continuous flow and photochemistry, which
previously lay in the realm of specialist users, have been
increasingly applied to challenges faced by synthetic organic
chemists. The combination of these two methods has proved to
Photochemical benzylic bromination using BrCCl3 as a
source of bromine was initially reported in 196023,24 and
expanded upon in 1976,25 where a small number of substrates
were examined using simple irradiation by a “sun lamp”, in
traditional batch apparatus. Outside of these three short
reports, no further use of this approach has been disseminated
in the following four decades.26 As a reagent, BrCCl3 is readily
available,27 does not have any significant identified health
concerns28 and is not listed as an ozone depleting substance.29
It has seen numerous applications in atom-transfer radical
addition (ATRA) reactions, both photochemically30,31 or by
classical radical methods32-35 and also as an oxidizing agent;
used directly,36-38 or within a photoredox catalytic cycle.39-42 It
was anticipated that by utilizing advancements in light source
and reactor technology, an improved methodology could be
developed. Accordingly, the advantages of simple separation of
a single by-product (CHCl3), highly concentrated reactions
without precipitation of solid reagents and the possibility of
accessing electron-rich benzyl bromides may be realized
(Scheme 1).
a. Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010
Graz, Austria.
b. Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
c. Centro de Investigación Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas-
Madrid, Spain.
E-mail: oliver.kappe@uni-graz.at; http://goflow.at
†Current address: Laboratory for Chemistry and Life Science, Institute of Innovative
Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama
226-8503, Japan.
Electronic Supplementary Information (ESI) available: Equipment, procedures,
product characterization and NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Initial screening of the benzylic bromination of toluene (1a) Hg lamp (light source B entry 6), due to the mulVtiiepwleArtdicilsecOrnelitnee
in continuous flow using different light sources demonstrated emission bands of this light source whichDeOxIc:i1t0e.1b0o39th/CB9OrCBC0l030a4n4dE
only a minor extent of reaction, aside from under irradiation by benzophenone, which lead to a high transient radical
a 254 nm lamp (light source A, Table 1 entry 1) or medium concentration and reduced selectivity. This effect was
pressure Hg lamp (light source B, entry 2).43 This can be simply exacerbated upon increasing the reaction temperature to 70 °C
explained, since BrCCl3 shows significant absorption at (entry 7), which prompted far higher selectivity towards
wavelengths shorter than 300 nm.44 Accordingly, only short dibrominated product (3a). Although the dibrominated product
wavelength light-
is undesired in this case, it should be noted that its derivitization
to yield the corresponding aldehyde is facile, so in many cases
it may be the preferred reaction product.46 Surprisingly, it was
found that an array of high power LEDs at a narrow emission of
365 nm gave a far lesser extent of reaction than the 365 nm 8
W fluorescent lamp (see ESI Table S1). This is likely due to the
shorter wavelengths reached by the broad emission of the 365
nm fluorescent lamp (light source C).43
Table 1. Optimization of reaction conditions in the benzylic bromination of toluene 1a.
BrCCl3 (4 equiv)
Br
Br
h
Br
neat (1.89 M)
1a
2a
3a
Entry
Light
PhCOPh 4
loading [mol%]
Remaining
1a [%]a
2a
[%]a
3a
[%]a
Use of a sensitizer bestows additional reaction control and
allows the use of lower energy wavelengths which, in turn,
lowers the likelihood of observing reactor fouling by
degradation and polymerization pathways.47,48 For these
reasons, optimization using the 365 nm lamp (light source C)
was pursued further. Both higher and lower benzophenone
loadings were examined, whereby it was observed that a lower
loading (1 mol%) provided lower conversion (entry 8 vs entry 4),
yet a higher loading (5 mol%) began to significantly reduce
selectivity (entry 9 vs entry 4). Several alternative triplet
sensitizers or photoredox catalysts were examined (see ESI,
Table S2), but none were observed to provide a combination of
product formation and selectivity comparable to that of
benzophenone. Diluting the reaction mixture with a range of
different solvents was observed to have a detrimental effect on
the progress of this reaction. DCM (entry 10) performed far
better than other solvents, yet still decreased reaction rate
substantially, hence neat reaction conditions were retained.43
Subsequently, the impact of brominating agent loading was
evaluated, finding that a decrease from 4 equiv (1.89 M toluene
solution) to 2 equiv (3.31 M toluene solution) resulted in a
slightly lower rate of reaction (entry 4 vs entry 11). However,
increasing this loading to 6 equiv (1.44 M toluene solution) was
observed to reduce reaction selectivity (entry 4 vs entry 12).
Accordingly, we opted to remain with 4 equiv (1.89 M toluene
solution) and examine longer residence times in attempt to
achieve complete reaction. A 15 min residence time (entry 13)
gave an improvement in yield of monobrominated product (2a)
to 52%, yet further increasing this to 30 min (entry 14) actually
resulted in a drop in yield of the desired product, due to
preferential formation of the dibrominated product (3a).
Unfortunately, as described in previous reports, there is a low
energy barrier to H-atom abstraction from both starting
material (1a) and monobrominated product (2a), implying that
differentiation between the two can be difficult to achieve in
many cases.20 Finally, a control reaction run at high temperature
without light demonstrated that this process does not proceed
to any appreciable extent when performed thermally (entry 15).
Although conversion to the desired product (2a) was relatively
low, reaction selectivity was maintained, throughput is high due
to neat conditions and CHCl3 is the only reaction by-product, so
its removal is straightforward.
source
1
2
A
B
C
C
A
B
B
C
C
C
C
C
C
C
-
-
75
71
96
58
75
17
1
23
26
4
2
3
-
3
-
0
4
2
2
2
2
1
5
2
2
2
2
2
2
38
24
40
26
35
44
22
34
49
52
50
1
4
5
1
6
43
73
2
7b
8
63
46
78
63
37
29
17
99
9
10
0
10c
11d
12e
13f
14g
15h
3
14
19
33
0
Light sources are as follows: A = 254 nm UV-C lamp (8 W), 7.7 min residence time;
B = medium pressure Hg lamp (150 W), 10 min residence time; C = 365 nm UV-A
lamp (8 W), 7.7 min residence time. See ESI for full details of each setup. aProduct
ratios were determined by NMR. bReaction was run at 70 °C using a 5 bar
backpressure regulator. cReaction was run at 0.5 M in DCM. dReaction was run
using 2 equiv BrCCl3. eReaction was run using 6 equiv BrCCl3. Reaction was run
using 15 min residence time. gReaction was run using 30 min residence time.
hReaction was run at 80 °C, with no light source.
f
sources are capable of initiating this reaction to any significant
extent, by directly homolyzing the C-Br bond. The
computationally examined triplet energy of BrCCl3 reveals that
a very low energy (46.4 kcal/mol) is required to form the
diradical species.45 Capitalizing on this observation, addition of
benzophenone (4) as a triplet sensitizer resulted in an increased
extent of reaction when using the 365 nm lamp (light source C,
entry 3 vs entry 4). However, no improvement was observed
using the 254 nm lamp (light source A entry 5). Furthermore, an
unselective reaction was observed using the medium pressure
2 | J. Name., 2012, 00, 1-3
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In order to assess the generality of this procedure, reactions
COMMUNICATION
Of these substrates, the successful reaction of p-
View Article Online
DOI: 10.1039/C9OB00044E
were carried out with various substrates (Fig. 1). For ease of methoxytoluene (1k) is of particular interest, since p-
isolation (separation of mono and dibrominated products),49 methoxybenzyl (PMB) is a commonly used protecting group in
and to avoid handling the hazardous benzyl bromide itself, the organic synthesis.50 This protection is generally performed by
continuous flow reactor output was collected and reacted alkylation, but since p-methoxybenzyl bromide (2k) is unstable
directly with morpholine (2 equiv). The toluene-derived product under long-term storage conditions,51 the corresponding
(5a) was isolated in a 47% yield, corroborating well with NMR chloride (which also suffers from stability issues)52 is often used
yields from previous optimization experiments (Table 1 entry in its place. This less reactive benzyl halide can require more
13). Ethylbenzene proved to be less susceptible to forcing conditions such as strong bases,53 or addition of an
dibromination, furnishing its tertiary amine (5b) in 81% yield, (undesirable) iodide salt for reaction to proceed via the benzyl
when processed using a longer residence time of 30 min. To iodide.54 For these reasons, an in situ method of generating the
varying degrees, para-substitution was also tolerated (products alkylating agent in a mild manner would be of clear advantage.
5c to 5g), but a more significantly electron-deficient aromatic The concept of generating and consuming hazardous or
(product 5e) required higher sensitizer loading and residence unstable reagents such as these in situ has received significant
time to achieve a synthetically useful level of conversion.
attention in recent years, for the resulting improvement in
Methylbenzenes bearing ortho-substitutents were safety and reaction reproducibility.55 The electron-rich nature
reasonably well tolerated (products 5h to 5i), and a good level of p-methoxytoluene means that its benzylic bromination by
of selectivity was observed when an o-methyl group was NBS under photochemical conditions is challenging due to
present (product 5h). As previously observed,24 p- competing electrophilic bromination processes.7 Consequently,
methoxytoluene undergoes reaction quickly using this reagent, the procedure reported herein is particularly fitting for the
and the corresponding amine (5k) was isolated in 84% yield. The novel application of this brominating agent.56
influence of methoxy substituents was probed further, and was
K2CO3, MeCN,
60 °C, 1 h
O
found to follow the expected reactivity trend, where a meta-
methoxylated substrate (more electron-deficient) required
more forcing conditions to achieve 41% yield of its product (5l),
similarly to trimethoxy product (5m), where the negative
reactivity contribution from two m-methoxy groups appears to
outweigh the positive contribution from a single p-methoxy
group. When the p-methoxy group is counteracted by only one
m-methoxy group, reactivity returns to a good level (product
5n).
O
Cl
Cl
O
O
N
PMB
Br
N
H
7
6
11 g (91% yield)
MeO
2k
1.3 equiv
F
2 mL
tres = 15 min
Cl
HN
N
Cl
1k
H
MeO
O
BrCCl3 (4 equiv),
benzophenone
(2 mol%), neat
N
H
0.133 mL/min
Flow
Batch
8 W
365 nm
45 °C
Cipargamin (KAE609)
BrCCl3 (4 equiv),
anti-malarial
PhCOPh 4 (2 mol%),
NH
(= HNR2)
(2 equiv)
Fig. 2. Continuous flow photochemical generation of p-methoxybenzyl bromide 2k, fed
into a batch protection of API precursor 6 on a multigram scale.
h
(365 nm)

N
O
Br
O
16 h, room temp.
neat (1.89 M),
45 °C, 15 min
5
1
2
We sought to apply the developed p-methoxybenzyl
bromide (2k) generation to an intermediate in API (active
pharmaceutical ingredient) synthesis. Cipargamin is a potent
anti-malarial candidate currently in phase II clinical trials and, as
a spiroindole, represents the first new family of antimalarial
drugs in two decades.57 An asymmetric route to this compound
begins with PMB protection of 5-chloroisatin (6); a more
challenging protection which requires addition of potassium
iodide, due to the poor nucleophilicity of the aromatic amide
nitrogen.52 To achieve this transformation using in situ
generated alkylating agent, p-methoxytoluene (1k) was
continuously flowed through a tubing-based photoreactor,
under the developed bromination conditions, before entering a
NR2
NR2
NR2
NR2
R
R
5b, 81%a
5c, R = Br, 43%
5d, R = Cl, 40%
5h, R = Me, 67%
5i, R = Cl, 55%a
5a, 47%
5e, R = CO2Et, 38%a,b 5j, R = OMe, 71%a
5f, R = tBu, 63%
5g, R = Me, 67%
MeO
NR2
NR2
NR2
NR2
MeO
MeO
MeO
OMe
OMe
OMe
5l, 41%a,b
5m, 28%a,b
5n, 47%
(84% crude)c
5k, 84%
Fig. 1. Substrate scope of benzylic bromination in continuous flow. Yields shown are
those of isolated morpholine adducts. aContinuous flow reaction was carried out with a batch vessel containing substrate (6) and potassium carbonate
30 min residence time. bAn increased quantity (5 mol%) of benzophenone 4 was used.
in acetonitrile (Fig. 2). An elevated temperature was used to
ensure the rapid consumption of benzyl bromine (2k) as it
entered the reaction flask. Under these conditions, the PMB-
cCrude yield by NMR is displayed, since product isolated in poor yield, despite effective
bromination.
protecting isatin derivative (7) was isolated in 91% yield on a 0.6
mmol scale then scaled up, with no decrease in yield, to isolate
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10 P. Galloni, M. Mancini, B. Floris and V. Conte, Dalt. Trans.,
11 grams following 4 hours of continual p-methoxybenzyl
bromide (2k) dosing.
View Article Online
2013, 42, 11963–11970.
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Conclusions
Within this study a previously reported, but seldom used,
photochemical bromination method has been examined in
detail under continuous flow photochemical conditions. BrCCl3
represents an underutilized bromine source for benzylic
halogenation, since it is readily available and possesses no
significant safety or environmental issues. Optimization was
performed by considering multiple distinct light sources, which
also highlighted the benefits of introducing a photosensitizer to
the reaction mixture. The optimized conditions were examined
against a number of substrates with reasonable yields attained
across different substitution patterns. Most significantly, p-
methoxytoluene, an electron-rich substrate which is
challenging for NBS-based benzylic bromination procedures,
reacted smoothly. This appeared suitable in the application of a
p-methoxybenzyl (PMB) protection, where the alkylating agent
is generated from cheap and safe starting materials in situ, with
high space-time-yield of 1.27 kg L–1 h–1, then consumed in the
reaction. The protection method was exemplified on an 11 g
scale, achieving facile reaction and an excellent 91% yield,
which demonstrates the compatibility of the bromination
reaction mixture with these general PMB protection conditions.
Acknowledgements
28 H. Shinokubo, K. Oshima, Z. Gu and A. Zakarian,
Bromotrichloromethane, in e-EROS Encyclopedia of Reagents
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The CC Flow Project (Austrian Research Promotion Agency FFG
No. 862766) is funded through the Austrian COMET Program by
the Austrian Federal Ministry of Transport, Innovation and
Technology (BMVIT), the Austrian Federal Ministry of Science,
Research and Economy (BMWFW), and by the State of Styria
(Styrian Funding Agency SFG).
29 Not listed as an depleting substance: United States
Environmental
Protection
Agency,
https://www.epa.gov/ozone-layer-protection/ozone-
depleting-substances (accessed December 2018).
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There are no conflicts to declare.
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43 See ESI Section 1.2 for experimental setup and lamp emission
spectra.
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DOI: 10.1039/C9OB00044E
44 See ESI Fig. S8 for an absorption spectrum of BrCCl3.
45 See ESI Section 4 for details of computational experiments.
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49 The dibrominated product was observed to be unreactive
towards morpholine, by NMR comparison before and after its
addition. Indeed, in the case of 5k, the aldehyde derivative
was also isolated, assumedly having reacted during column
chromatography. See ESI for characterization of aldehyde
product 5k’.
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