Synthesis of benzyl bromides with hexabromoacetone: An alternative path to drug intermediates

Article abstract of DOI:10.1016/j.tetlet.2010.10.133

A series of benzyl bromides were efficiently prepared from the corresponding alcohols with Br₃CCOCBr₃/PPh₃ at low temperatures and under neutral conditions. The present protocol was applied to the heterocyclic analogues and to the successful synthesis of the precursor of the antiulcer drug omeprazole, thus furnishing an alternate, mild method for the preparation of these drug intermediates. A significant steric factor was observed throughout both series supporting a S_N2 mechanism.

Full text of DOI:10.1016/j.tetlet.2010.10.133

Tetrahedron Letters 52 (2011) 13–16
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of benzyl bromides with hexabromoacetone: an alternative path
to drug intermediates
⇑
Kara M. Joseph, Isabel Larraza-Sanchez
Department of Chemistry and Physics, Saint Mary’s College, Notre Dame, IN 46556, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of benzyl bromides were efficiently prepared from the corresponding alcohols with Br3CCOCBr3/
PPh3 at low temperatures and under neutral conditions. The present protocol was applied to the hetero-
cyclic analogues and to the successful synthesis of the precursor of the antiulcer drug omeprazole, thus
furnishing an alternate, mild method for the preparation of these drug intermediates. A significant steric
factor was observed throughout both series supporting a SN2 mechanism.
Received 4 September 2010
Revised 22 October 2010
Accepted 26 October 2010
Available online 31 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hexabromoacetone
Benzyl bromides
Benzyl alcohols
Drug intermediates
1. Introduction
gasses. Since benzyl bromides are more reactive than chlorides,12
we considered that the design of an efficient, milder protocol for
Benzyl halides can be considered as versatile intermediates or
final products in organic synthesis.1 Not only are they extensively
used as reactive electrophiles in nucleophilic substitution reac-
tions, but they have also been utilized as starting materials in the
preparation of aldehydes and ketones,2 acids,3 amides,4 labelled
aminoacids,5 oxazoles and triazoles,6 amongst others; in metal-
catalysed couplings to form more complex molecules;7 or as build-
ing blocks of biologically active compounds such as antivirals,8
antifungal agents9 anticonvulsants,10 etc.
the preparation of such bromides would provide a valuable alter-
native to the chemical and pharmaceutical industries.13
OMe
OMe
MeO
N
N
S
N
S
N
N
H
N
H
MeO
F2HCO
O
O
Alkyl halides that have a halogen atom at the ‘benzylic’ position
of diverse heteroaromatic rings have also received wide attention
as precursors in the synthesis of active pharmaceuticals.11 Of par-
ticular importance to our study are those derivatives that possess a
pyridine ring and which are commonly involved in the preparation
of proton pump inhibitors (PPI) ,such as omeprazole 1 (PrilosecÒ),
pantoprazole 2 (ProtonixÒ), etc. These represent some of the most
potent antiulcer drugs available today; omeprazole, in particular, is
a widely prescribed drug internationally. To date many of the
syntheses for these compounds are based on the coupling of the
sodium salt of a 2-mercaptobenzimidazole with a substituted
2-chloromethylpyridine, followed by oxidation of the resulting thi-
oether to the sulfoxide (Scheme 1). The 2-chloromethylpyridines
have traditionally been prepared by the reaction of the correspond-
ing alcohol with harsh, corrosive chlorinating agents like SOCl2, in
dichloromethane at reflux temperature, with the evolution of toxic
1
2
2. Results and Discussion
Even though Gilbert described an accessible preparation of hex-
abromoacetone (HBA) in high yields as early as 1969,14a its appli-
cation as an efficient reagent for the bromination of alcohols and
R
1. SOCl2
N
R
OH
S
N
R'
N
2.
R'
N
H
N
O
SNa
N
H
3. mCPBA
⇑
Corresponding author. Tel.: +1 574 284 4660; fax: +1 574 284 4988.
E-mail address: isanchez@saintmarys.edu (I. Larraza-Sanchez).
Scheme 1. General synthesis of PPIs.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.133

14
K. M. Joseph, I. Larraza-Sanchez / Tetrahedron Letters 52 (2011) 13–16
Table 1
Bromination of benzyl alcohols
CBr3COCBr3 (.5 eq)
PPh3 (1.5 eq)
OH
Br
R
CH3CN, rt or 40º, N2
R
Entry
Alcohol
Temp (°C)
Reaction time
Conversiona (%)
1
2
3
rt
rt
40
200–1 h
Overnight
1 h
81
100
90
OH
OH
OH
4
rt
1 h
100
Me
Me
5
6
rt
40
1 h
70 min
75
100
OH
7
rt
2 h
100
MeO
OMe
OH
8
9
rt
40
Overnight
2 h 45 min
60
100
OMe
MeO
Cl
OH
10
11
rt
40
Overnight
2 h 15 min
80
100
OH
12
13
40
40
1 h
2 h
100
100
Br
OH
OH
O2N
OH
14
15
16
40
40
40
1 h
1 h
1 h
75
100
100
NO2
OH
OH
OH
17
40
2 h
100
18
19
40
40
15 min
50 min
100
95
N
MeO
Me
OH
Me
N
OH
20
21
40
40
50 min
70 min
90
O
S
OH
100
a
Determined by 1H NMR.
acids has been recognized only recently.14b,c In 2008, Chavasiri and
co-workers published a new method for the synthesis of alkyl bro-
mides from alcohols which uses HBA (now commercially available)
and triphenylphosphine (PPh3).14b,d This reaction occurs under
neutral conditions, at 30 °C, and the yields are usually very high
even when only 0.3 equiv of HBA are used. Compared to other
methods that include highly toxic reagents such as Br2 and HBr
gas or coupling reagents like CBr4/PPh3, Br2/PPh3, Br2PPh3 that
require high temperatures and generate the strong acid HBr as a
chemistry that is less energy and materials intensive, but the
chemical compounds involved are also less hazardous to humans
and the environment.
Chavasiri experimented with various primary, secondary and
tertiary alcohols. Although benzyl alcohol was one of his sub-
strates, he did not include alcohols with substituent groups on
the aromatic ring. The objective of the present research was to
examine the bromination of a wider range of benzyl alcohols that
contained electron-withdrawing and electron-releasing groups,
and to develop a reproducible protocol that could be extrapolated
byproduct,15 Chavasiri’s conditions not only comply with
a

K. M. Joseph, I. Larraza-Sanchez / Tetrahedron Letters 52 (2011) 13–16
15
to pyridilcarbinols and other heterocyclic analogues. Our results
are summarized in Table 1.
suggest there is no significant charge developed on the central ben-
zylic carbon in the transition state and thus no dependence upon
the ring substituents’ electronic nature,17 therefore, supporting a
second order mechanism similar to the Appel reaction between
alcohols and PPh3/CCl418 (Scheme 2). The initial step is the reaction
between PPh3 and HBA to form intermediate 3, which subse-
quently reacts with the alcohol yielding an alkoxyphosphonium
salt 4; the latter then transforms to the corresponding bromide
by SN2 displacement.
An opposite steric-related reactivity was observed for the nitro
compounds (entries 14 and 15) where the 2-nitrobenzyl alcohol
converted quantitatively into the bromide in one hour and the 3-
nitro derivative only in 75% under the same conditions. We attrib-
uted this difference in reactivity to an anchimeric assistance of the
nitro group in the ortho position on the oxy-phosphonium moiety
of intermediate 5 (Scheme 3).
In much the same vein, the heterocyclic rings we wanted to
analyse can be classified as electron-rich or electron-poor systems,
so it was foreseen that they would react in a comparable fashion to
the substituted benzenes. Indeed, this method furnished excellent
outcomes in yield and reaction time for the heterocyclic series (en-
tries 18–21). As with the aromatic substrates, we observed the
same steric trend (entries 18 and 19).
It is worth mentioning that the conditions shown in Table 1 dif-
fer from Chavasiri’s. After an optimization study we found that
0.3 equiv of HBA furnished good results, but the method provided
better yields with 0.5 equiv. Likewise, we achieved a higher degree
of reproducibility when we used the greener solvent acetonitrile in
our studies, rather than dichloromethane.16
From Table 1 it is evident that there is a highly influential steric
factor: at room temperature para-derivatives afforded higher con-
version rates and/or lower reaction times than the corresponding
ortho compounds. For example, para-methylbenzyl alcohol con-
verted to the bromide in quantitative yield in 1 h, while the
ortho-derivative rendered only 75% conversion during the same
period of time (entries 4 and 5). This pattern was consistently ob-
served with all other substituents (entries 7–8, 12–13). Fortu-
nately, the steric impediment can be overcome by raising the
temperature to 40 °C (entries 6, 9 and 11) and, in general, shorter
reaction times and good yields were obtained at this temperature.
The present results also indicate that secondary benzylic alcohols
are converted successfully to their bromides (entry 16).
It is interesting to note that both, activating and deactivating
groups furnished surprisingly good conversions. These results
We were able to test the viability of our procedure and apply it
successfully to the synthesis of omeprazole’s precursor 6 in high
yield (Scheme 4).19 Incidentally, the furan (entry 20) and thiophene
(entry 21) derivatives offer a good alternative for the synthesis of
another type of antiulcer agents, specifically histamine H2 blockers
like ranitidine (ZantacÒ) and famotidine (PepcidÒ).
Considering that furan and thiophene act themselves as acti-
vated rings, we were prompted to study the chemoselectivity of
this reaction by isolating20 derivative 7 in almost quantitative yield
and then comparing its spectroscopic features with a sample pre-
pared independently by a different route. We observed no compet-
ing substitution on the ring (Scheme 5).
O
C
O
C
Br2
C
PPh3
RBr
Br2C
CBr3
Br
O
CBr3
Br PPh3
+
+
3
ROH
O
PPh3
+
Br
R
O
Br2HC
C CBr3
PPh3
4
Scheme 2. Proposed mechanism.
We extended our study to other solvents in order to assess their
effect on reaction time and/or need for heating conditions (Table 2).
We carried out comparable experiments using benzyl alcohol, in
which we measured the reaction progress every 20 min by 1H NMR
until no change was observed. From Table 2 it can be seen that, like
acetonitrile, tetrahydrofuran and especially toluene (entries 1 and
3) are effective, green alternatives to the chlorinated solvents
(entries 2 and 7).16 We also observed that the positive effect of
higher temperature relies on heating the reaction mixture from
the beginning (entry 6). Entries 4,5 and 7,8 displayed slight or no
Br
PPh3
O
O
Br
Br
O
+
O
PPh3
N
O
N
O
NO2
5
Scheme 3. Proposed anchimeric effect of the ortho-nitro group.
Table 2
Solvent study
OMe
OMe
1. HBA/PPh3
CH3CN
CBr3COCBr3 (.5 eq)
PPh3 (1.5 eq)
N
OH
Br
2. NaOH
N
S
N
OH
N
N
H
MeO
solvent, rt or 40º, N2
SH
6
Conversiona (%)
N
Entry
Solvent
THF
Temp (°C)
Reaction time
MeO
H
85%
1
2
3
4
5
6
7
8
rt
rt
40 min
1 h
92
89
100
81
84
90
1,2-Dichloroethane
Toluene
Scheme 4. Synthesis of omeprazole’s precursor 6.
rt
rt
20 min
200–1 h
80 min
1 h
Acetonitrileb
Acetonitrilec
rt then 40
40
Acetonitriled
1. HBA/PPh3
Ac2O
Dichloromethane
Dichloromethane
rt
1 h
81
80
rt then 40
2 h
OAc
OH
HO
2. NaOAc
AcOH
Py
O
7
O
O
Reaction progress was measured every 20 min by 1H NMR until no change was
a
observed.
b
only product
Scheme 5. Chemoselectivity study.
Conversion was the same at 20, 40 or 60 min.
Reaction was run at rt for 1 h, then 200 at 40°.
Reaction was run at 40° from the start.
c
d

16
K. M. Joseph, I. Larraza-Sanchez / Tetrahedron Letters 52 (2011) 13–16
improvement when the reaction was started at room temperature
and then heated at 40 °C. Similarly, in an effort to evaluate the ef-
fect of the solvent and the temperature on HBA’s stability, we pre-
pared several solutions in acetonitrile with the same concentration
used in our protocol and monitored them over a period of 3 h at
different temperatures (room temperature to 52 °C). As expected,
we did not observe any decomposition of HBA by 13C NMR or IR
spectroscopy and recovered quantitative amounts of HBA once
the solvent was removed.
In conclusion, we have developed a highly reproducible proto-
col for the preparation of benzyl bromides from alcohols. The pres-
ent process can be applied to a wide range of starting materials,
aromatic and heteroaromatic, with high conversion rates and short
reaction times. Likewise, it can be considered as a mild alternative
to the synthesis of drug intermediates that have a benzyl unit in
their structure.
from the Center for Academic Innovation and the Department of
Chemistry and Physics at Saint Mary’s College, Notre Dame, IN.
References and notes
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3. General procedure for the synthesis of benzyl bromides
A
mixture of alcohol (1.2 mmol) and triphenylphosphine
(1.8 mmol) was stirred in dry acetonitrile (6 mL) for 15 min. Hex-
abromoacetone (0.6 mmol) was added and the stirring continued
at 40° under a nitrogen atmosphere. Conversion of the alcohol into
the bromide was followed by 1H NMR analysis on a sample previ-
ously quenched with cold water.
4. Synthesis of omeprazole’s precursor 6
A solution of 4-methoxy-3,5-dimethyl-2-pyridinemethyl bro-
mide (1.2 mmol) in CH3CN (6 mL) was prepared according the
above procedure and added to a suspension of 2-mercapto-5-meth-
oxybenzimidazole (1.2 mmol) in CH3CN (2 mL). The mixture was
stirred for 30 min at room temperature, under a N2 atmosphere, fol-
lowed by addition of 30% NaOH (0.32 mL, 2.4 mmol) and the stirring
was continued for an additional 30 min. The reaction was quenched
with water, the CH3CN removed under reduced pressure and the
residue was extracted with 1 M HCl (3 ꢀ 30 mL). The latter was then
treated with 1 M NaOH (pH ꢁ11) and extracted with CH2Cl2. The
organic phase was washed with brine and dried over anhydrous
Na2SO4. After evaporation the residue was purified with a plug of
neutral alumina using hexane/EtOAc 1:4 to give omeprazole’s
precursor 6 (85%): IR (film) mmax 3375, 3057, 2951, 1628, 1591,
1568, 1475, 1452, 1435, 1271, 1155, 1078 cmꢂ1.1H NMR (CDCl3)
d (ppm) 2.26 (s, 3H), 2.30 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 4.38
(s, 2H), 6.72 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 2.5 Hz, J = 7.3 Hz, 1H),
7.39 (d, J = 7.5 Hz, 1H), 8.25 (s, 1H), 10.25 (br, 1H).
17. A recent study found that liquid ammonia behaved like a dipolar aprotic
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19. For a related synthesis of omeprazole analogues see: Vidaillac, C.; Guillon, J.;
Arpin, I.; Forfar-Bares, I.; Ba, B. B.; Grellet, J.; Moreau, S.; Caignard, D. H.; Jarry,
C.; Quentin, C. Antimicrob. Agents Chemother. 2007, 831–838.
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Acknowledgements
This project was funded by the Maryjeanne R. Burke and
Daughters SISTAR Grant from Saint Mary’s College and by the
Van Smith family. We are also grateful for the support received