Regioselective, Efficient and Sustainable Bromination Process for the Synthesis of the Antimicrobial Agent Bromiphen Bromide

Full text of DOI:10.1080/00304948.2021.1956849

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Regioselective, Efficient and Sustainable
Bromination Process for the Synthesis of the
Antimicrobial Agent Bromiphen Bromide
Angelica Artasensi, Alessandro Pedretti, Giulio Vistoli & Laura Fumagalli
To cite this article: Angelica Artasensi, Alessandro Pedretti, Giulio Vistoli & Laura Fumagalli
(2021): Regioselective, Efficient and Sustainable Bromination Process for the Synthesis of the
Antimicrobial Agent Bromiphen Bromide, Organic Preparations and Procedures International, DOI:
10.1080/00304948.2021.1956849
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2021.1956849
OPPI BRIEF
Regioselective, Efficient and Sustainable Bromination
Process for the Synthesis of the Antimicrobial Agent
Bromiphen Bromide
Angelica Artasensi, Alessandro Pedretti, Giulio Vistoli, and Laura Fumagalli
ꢀ
Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Milano, Milan, Italy
ARTICLE HISTORY Received 4 September 2020; Accepted 14 May 2021
In the drug discovery process, the role of halogen atom substitution has greatly influ-
enced outcomes in the hit-to-lead-to-candidate optimization.1–3 Useful reasons for halo-
gen insertion have included increasing steric hindrance or improving lipophilicity,
among many others; and a recent review4 reports that fully one-quarter of the total
number of papers and patents in medicinal chemistry involves halogen atom
substitution.
As an example, during our recent studies5,6 on the degradation of domiphen brom-
ide, we found that the p-bromo analogue (Scheme 1, 1, bromiphen bromide), which
had initially been seen as an undesirable impurity deriving from harsh conditions,
showed improved antimicrobial activity.
As a result, compound 1 was patented7 as a new antimicrobial agent with good activ-
ity against both Gram negative and Gram positive bacteria and against fungi. The
patented synthesis (Scheme 2) applied traditional organic procedures and gave an over-
all yield of about 57%.
A key intermediate for the synthesis of bromiphen bromide is p-bromophenol, which
is prepared via the bromination of phenol. Conventional preparations of bromophenol
typically use strong oxidizing agents, a variety of metal catalysts and halogenated sol-
vents.8 These reagents are corrosive and toxic therefore their use is less desirable.
Moreover, the lack of regioselectivity is a drawback since the phenol contains an ortho/
para director which affords a mixture of isomers and requires a subsequent separation.
Considering only regioselective procedures, to the best of our knowledge none is atom-
economical or sustainable.
With a view to preparing larger quantities of bromiphen bromide for further bio-
logical and toxicological investigations, and based on our own past experience,9 we
sought a more regioselective, eco-friendly and sustainable synthetic method. We consid-
ered protocols focused on ecologically more acceptable bromination10–13 and we now
report the resulting regioselective procedure for bromiphen bromide, capitalizing on
our observation that it could be formed from domiphen bromide. A source of bromide
and an oxidizing agent were necessary to enhance the formation of Br2 in situ. The
ꢀ
Dipartimento di Scienze Farmaceutiche, Universita degli
CONTACT Laura Fumagalli
laura.fumagalli@unimi.it
Studi di Milano, via Mangiagalli 25, I-20133, Milan, Italy
Supplemental data for this article can be accessed online at https://doi.org/10.1080/00304948.2021.1956849.
ß 2021 Taylor & Francis Group, LLC

2
A. ARTASENSI ET AL.
Scheme 1. Formation of bromiphen bromide (1) under harsh conditions.
Scheme 2. Patented synthesis of bromiphen bromide. a) Methylethylketone, Cs2CO3, KI, 2-chloro-N,N-
dimethylethylamine hydrochloride. b) bromododecane, acetone.
Scheme 3. Net reaction of peroxide with bromide in water.
oxidant needed to be atom-economical and not increase difficulties in purification, rul-
ing out the use of Oxone, tert-butylhydroperoxide and dimethylsulfoxide. We chose
KBr as the bromide source because of its enhanced solubility over NaBr, and we chose
hydrogen peroxide as the best oxidant because its by-product is water (Scheme 3).
Surmising that both domiphen bromide and bromiphen bromide should behave as sur-
factants, due to their charged head groups and long alkyl chains, we felt that water
should be the choice of solvent. Aside from its ability to act as a heat reservoir, water
reacts with Br2 to produce HOBr, and the reaction of peroxide with KBr generates an
intermediate of the form KOBr.14
An acidic environment is necessary for the oxidative reaction, so we examined HCl
and HBr. Table 1 reports our optimization of reaction conditions, represented in
Scheme 4.
The removal of inorganic salts from the crude bromiphen bromide is achieved by
flash chromatography, so we evaluated different columns in order to find the best load
capacity. We were able to use 12 g of C-18 silica to directly purify the crude bromiphen
bromide coming from 500 mg of domiphen bromide, with 70 mL of mobile phase com-
prised of water and acetonitrile, with pH 3.75.
We would like to compare the environmental impact of our bromination method to
one recently reported in the literature15 which is highly regioselective. We focus our
attention on the reaction to obtain p-bromophenol since it represents the main differ-
ence between the conventional synthesis of bromiphen bromide and the new method,
described here, which starts from domiphen bromide. We have calculated the environ-
mental factor (E-factor) commonly used to evaluate the greenness of a reaction
(Figure 1).16
Comparison of the environmental impact of the two methods by means of the E-fac-
tors indicates that the method which includes bromination of domiphen bromide “on

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 1. Optimization studies.
Domiphen
bromide (mg)
KBr
(eq.)
H2O2
30%
10%
HBr (eq.)
10% HCl
(eq.)
Time
(min)
Water
(mL)
Full
conversion
Temperature ꢀC
200
200
200
200
200
200
200
200
200
500
2
2
2
1
1.5
1.5
1.5
1.0
1.2
1.2
2
2
2
1
1.5
1.5
1.5
1.0
1.2
1.2
2
2
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
No product
30
30
30
30
30
40
Y
Y
N
Y
Y
Y
N
N
Y
2
2
2
1
0.1
0.1
0.1
0.1
40
40
Synthesis of bromiphen bromide by bromination on water. Complete conversion of domiphen bromide was evaluated
by HPLC analysis (see Supplementary Materials). Y: complete conversion. N: reaction does not give complete conver-
sion even though bromiphen bromide is detectable.
Scheme 4. Improved preparation of bromiphen bromide.
Figure 1. E-factor values calculated on regioselective method reported in reference 15 and on our
method. (The colors that do not show up indicate extremely small values.)
water” is more sustainable with respect to the regioselective halogenation of the start-
ing phenol.
In conclusion, we have developed a suitable and sustainable bromination “on water”
to synthetize a new promising antimicrobial agent, bromiphen bromide. The new
method is highly efficient and regioselective.

4
A. ARTASENSI ET AL.
Experimental section
HPLC, LC/MS grade acetonitrile, LC/MS grade ammonium formate, formic acid, 30%
hydrogen peroxide solution, 37% HCl, methyl ethyl ketone, acetone, dichloromethane
1
and methanol were purchased from Merck KGaA, Darmstadt, Germany. H-NMR spec-
tra were recorded at 300 MHz and 13C-NMR at 75.43 MHz, using a Varian Oxford 300
instrument. Chemical shifts are reported in ppm relative to residual solvent (CHCl3 or
DMSO) as internal standard. Purifications were performed by flash chromatography
using C-18 silica gel (particle size 30 lm) on IsoleraTM (Biotage, Uppsala, Sweden)
apparatus. A Milli-Q water purification system (Millipore, Bedford, Massachusetts,
USA) was used to further purify demineralized water. HPLC analyses were performed
on an Elite LaChrom HPLC (VWR/HITACHI, Milan, Italy/Tokyo, Japan) apparatus
equipped with a L-2130 high pressure quaternary gradient delivery system, a L-2455
diode array detector (DAD), a L-2300 column oven and an L-2200 autosampler. The
separation was achieved on an XBridgeTM column (4.6mm X 150 mm, 5 lm) (Waters).
LC-MS experiments were performed on a Surveyor LC system, connected to a TSQ
Quantum Ultra mass spectrometer through a Finnigan IonMax electrospray ionization
(ESI) source assembled with a stainless steel emitter (Thermo Fisher Scientific, Rodano,
MI, Italy). Complete details of the HPLC monitoring of the sustainable synthesis were
submitted for review and are available in the Supplementary Material in the online ver-
sion or from the corresponding author upon request.
Sustainable synthesis of dodecyldimethyl-2-(p-bromophenoxyethyl)ammonium
bromide (bromiphen bromide, 1)
To a stirring solution of dodecyldimethyl-2-(phenoxyethyl)ammonium bromide (domi-
phen bromide) (500 mg, 1.2 mmol) in water (2.5 mL) were added 30% H2O2 (1.2 eq),
KBr (1.2 eq), and 10% HCl (0.1 eq). The reaction was monitored by HPLC (see gradient
elution conditions and data reported in the Supplementary Material). Once full conver-
sion was obtained, the reaction mixture was directly loaded onto C-18 silica gel (12 g;
mobile phase acetonitrile/ammonium formate, pH ¼ 3.75) to obtain the title compound
as a white solid (98% yield), mp 136.0 ꢀC, lit5 mp 136.6 ꢀC. The residue of potassium
(441 ppm) was determined via an inductively coupled plasma method. The title com-
pound has been previously characterized,5 but for the sake of completeness we provide
the NMR data below, with original copies in the Supplementary Material, also available
1
upon request from the corresponding author. H NMR (CD3OD, 300 MHz) 0.82-0.98
(m, 3H), 1.22-1.42 (m, 18H), 1.80-1.91 (m, 2H), 3.21 (s, 6H), 3.41-3.50 (m, 2H), 3.80-
3.87 (m, 2H), 4.41-4.48 (m, 2H), 6.95 (d, J ¼ 9.0 Hz, 2H), 7.43 (d, J ¼ 9.0 Hz, 2H). 13C
NMR (CD3OD, 75.43 MHz) d 13.06, 22.29, 22.32, 25.97, 28.84, 29.06, 29.13, 29.22,
29.35, 31.67, 50.87, 61.80, 62.50, 65.39, 113.57, 116.30, 132.18, 156.70.
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