A facile process for the preparation of 2-bromoethyl methyl ether

Article abstract of DOI:10.1021/op060229k

A convenient and large-scale synthesis of 2-bromoethyl methyl ether is described.

Full text of DOI:10.1021/op060229k

Organic Process Research & Development 2007, 11, 468−469
A Facile Process for the Preparation of 2-Bromoethyl Methyl Ether
Varaprasad Dasari,† Rao V. Srinivas,† Sunil R. Rao,† Kalyan Chakravarthy Akula,† Ravi Dhamjewar,*,† and
Yogesh S. Sanghvi‡
Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, California 92024-6615, U.S.A., and Sai Life Sciences,
11-15-12/4 Siris Complex, L.B Nagar, Hyderabad 500 074, India
Abstract:
of pyridine.6 Because of the toxic and hazardous nature of
A convenient and large-scale synthesis of 2-bromoethyl methyl
ether is described.
phosphorus tribromide, we decided not to utilize this protocol
for scale up. The second procedure utilized a high-temper-
ature (140 °C) and high-pressure (50 kg/cm2) reaction of
ethylene, oxygen, and methanol with cupric bromide.9 In
order to scale up the later protocol, we will need specialized
equipment and stringent safety measures. The lack of a
scaleable protocol for the synthesis of 2-bromoethyl methyl
ether triggered the current investigation.
Introduction
Alkyl bromides are useful electrophilic reagents for the
alkylation of organic compounds. The alkyl bromides are
synthesized on large-scale by a variety of brominating
reagents,1 of which hydrobromic acid2 is by far the most
popular. For ongoing antisense development projects,3 an
alkyl bromide, 2-bromoethyl methyl ether was required on
a large scale. The 2-bromoethyl methyl ether has been
utilized as an alkylating agent for the synthesis of 2′-modified
nucleosides3c as building blocks for therapeutic oligonucle-
otides, serotonin receptor agonists,4 antitumor agents,5 in-
secticides,6 photoinitiators,7 and for compounds containing
organic metal complexes that are used in nuclear magnetic
resonance studies.8
Results and Discussion
We elected to use 2-methoxyethanol (1) as the starting
material due to its commercial availability and low-cost. The
bromination 1 was carried out under a variety of reaction
conditions. The results are summarized in Table 1. The
efficiency of the reaction was judged by the formation of
2-bromoethyl methyl ether (2) detected by gas chromatog-
raphy (GC). Our initial bromination attempts were based on
the use of conventional reagents. The use of hydrobromic
acid under acidic conditions (entries 1 and 2) furnished the
desired product 2 (<10% by GC) contaminated with several
byproducts. An improvement in the product formation was
observed (18% or 14% by GC) with a combination of sodium
bromide, sulphuric acid, and tetrabutylammonium bromide
(TBAB) (entry 3), thionyl chloride and TBAB under reflux
(entry 4), chlorotrimethylsilane, sodium bromide or lithium
bromide in refluxing acetonitrile (entry 5). The combination
of lithium bromide with thionyl chloride in DMF or
acetonitrile furnished a complex mixture of products (entries
6 and 7). Next, refluxing 1 in toluene with TBAB in the
presence of phosphorous pentoxide exhibited significant
improvement in product formation (74% by GC; entry 8).
However, separation of 2 from toluene via distillation proved
to be very difficult due to the closeness of their boiling points.
Therefore, the latter reaction was repeated with dichlo-
romethane as a low-boiling solvent, assuming that the
separation will be easier. Unfortunately, the use of dichlo-
romethane as a solvent led to the formation of multiple
products (entry 9). Interestingly, the reaction of the more
reactive 2-methoxyethyl tosylate with TBAB in refluxing
toluene for 3-4 h showed a complete conversion of the
starting material to the desired product by GC (entry 10).
Our attempts to isolate the product from the reaction mixture
by distillation resulted in an inseparable mixture of toluene
and 2-bromoethyl methyl ether. We also tried reacting
2-methoxyethyl mesylate with TBAB in acetone under reflux
without much success (entry 11).
The synthesis of 2-bromoethyl methyl ether is reported
in two patents. The first protocol describes the bromination
of 2-methoxyethanol with phosphorus tribromide in presence
* To whom correspondence should be addressed. E-mail: svpdasari@
yahoo.co.in.
† Sai Life Sciences.
‡ Rasayan Inc.
(1) (a) Lin, C.-H.; Aristoff, P. A.; Johnson, P. D.; McGrath, J. P.; Timko, J.
M.; Robert, A. J. Org. Chem. 1987, 52, 5594-5601. (b) Babler, J. H. J.
Org. Chem. 1976, 41, 1262-1264. (c) Wijnberg, J. B. P.; Wiering, P. G.;
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Haoyun, A.; Murthy, V. S.; Reddy, K. S.; Barr, J. R.; Hecht, S. M. J. Am.
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Kohn, H. Tetetrahedron Lett. 1995, 36, 7011-7014. (i) Olah, G. A.; Gupta,
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(3) (a) Von Pierre, M. HelVetica Chim. Acta 1995, 78, 486-504. (b) Xie, C.;
Staszak, M. A.; Quatroche, J. T.; Sturgill, C. D.; Khau, V. V.; Martinelli,
M. J. Org. Process Res. DeV. 2006, 9, 730-737. (c) Taj, S. A. S.;
Gurumurthy, R. S.; Narayanan, S.; Suman, M. S.; Sanghvi, Y. S.
Nucleosides Nucleotides Nucleic Acids 2003, 22, 1327-1330.
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468
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Published on Web 03/16/2007

Table 1. Experimental conditions for various brominations
loss of product during vacuum distillation. It is important to
note that the overall product purity could be further improved
at the cost of lower yield by pooling only high-purity
fractions after distillation.
In summary, we have developed a convenient, one-pot
procedure for the large-scale synthesis of 2-bromoethyl
methyl ether from 2-methoxyethanol. Multikilogram quanti-
ties of 2-bromoethyl methyl ether have been synthesized and
used as an alkylating agent for the preparation of 2′-modified
nucleosides required for the assembly of antisense oligo-
nucleotides.
R in
1
reaction
conditions
2 in crude mixture
entry
(% by GC)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
Ts
Ms
H
HBr/H2SO4
HBr/AcOH (37%)
NaBr/H2SO4/TBAB/ACN
SOCl2/TBAB/Reflux
TMS-Cl/NaBr/ACN
SOCl2/LiBr/DMF/reflux
SOCl2/LiBr/CH3CN/reflux
P2O5/toluene/TBAB/reflux
P2O5/DCM/TBAB/reflux
Toluene/TBAB/reflux
acetone/TBAB/reflux
SOCl2/pyridine/HBr (g)
complex mixture of products
complex mixture of products
18
14
14
complex mixture of products
complex mixture of products
74
complex mixture of products
99
no reaction
80
10
11
12
Experimental Section
Scheme 1
A 20-L, three-necked, round-bottomed flask equipped
with a condenser, thermometer, and addition funnel was
charged with thionyl chloride (5.1 kg, 42.86 mol) under
nitrogen atmosphere. To the stirred solution was gradually
added 2-methoxyethanol (1, 3.1 kg, 40.78 mol) over a period
of 1 h while maintaining the internal temperature at 35-
40 °C. After complete addition, the stirring was continued
for 0.5 h at the same temperature until there was no visible
(gas bubbler) elimination of HCl gas from the reaction
mixture. The HCl gas was passed through a sodium hydrox-
ide scrubber to prevent its discharge in the air. The reaction
mixture was cooled to 10 °C after evolution of HCl gas had
ceased. Anhydrous gaseous HBr (3.47 kg, 42.9 mol) was
bubbled into the reaction mixture over a period of 2-3 h,
while maintaining the internal reaction temperature at 0-
5 °C. After completion of the bubbling of HBr (gas),
anhydrous pyridine (310 g, 3.9 mol) was added dropwise
while maintaining the same temperature over 0.5-1.0 h. The
resulting reaction mixture was stirred and gradually heated
to 70 °C and held at this temperature until completion.
Progress of the reaction was monitored by quenching an
aliquot of the reaction mixture with sodium bicarbonate
solution followed by washing with water and analyzing the
organic layer by GC. The reaction was found to be complete
in 5-6 h by GC analysis (80% area of the desired product).
The reaction mass was diluted with dichloromethane and
washed with saturated sodium bicarbonate, water, and brine
solution until the washings were of neutral pH. The dichlo-
romethane layer was dried over sodium sulfate and carefully
concentrated by atmospheric distillation at 45-50 °C. The
crude product (contains ∼10-15% dichloromethane) was
distilled under vacuum (50-60 mm) using a tall Vigreux
column (3 feet), and six fractions were collected. The
fractions collected at the vapor temperature of 107-109 °C
were found to be 94% pure by GC. These fractions were
pooled to furnish 2.4 kg of 2-bromoethyl methyl ether (2)
as a pale-yellow liquid. The integrity of the final product
was further confirmed by GC/MS analysis.
The reactivity of 2-methoxyethyl tosylate prompted us
to consider a route in which alcohol 1 is transformed into a
reactive intermediate, which is then brominated in situ to
furnish the desired product 2. A literature search revealed
that the treatment of alcohols with thionyl chloride, followed
by halogen exchange (Cl f Br) with gaseous HBr, resulted
in the formation of bromosulfite, which upon heating in the
presence of a base furnished the brominated products.10 We
implemented this protocol for the synthesis of compound 2.
Thus, the reaction of alcohol 1 with 1.05 equiv of thionyl
chloride furnished the chlorosulfite, which underwent halo-
gen exchange with HBr (1.05 equiv) to provide bromosulfite
as the reactive intermediate. Heating of the bromosulfite in
the presence of triethylamine furnished the expected product
in low yield (10% isolated). Switching over to pyridine as
the base for the final reaction with bromosulfite gave the
product 2 in a significantly improved yield (Scheme 1; 80%
crude by GC; entry 12). The reaction mixture was diluted
with dichloromethane and the organic layer washed with
saturated sodium bicarbonate and brine. The organic layer
was dried over sodium sulfate, and the solution was
concentrated by distillation to remove excess of dichlo-
romethane at 45-50 °C. The residual oil was then subjected
to fractional distillation under vacuum (50-60 mm) using a
3-foot-tall Vigreux column. The GC analysis of all fractions
and pooling of appropriate fractions (>93 area % by GC)
furnished 40% isolated yield of the 2-bromoethyl methyl
ether. The forgoing protocol was repeated on small scale (3
× 100 grams) to check the reproducibility of the reaction.
The optimized bromination protocol (see Experimental
Section) had been transferred successfully to the pilot plant
on kilogram scale. The isolated yield of 40% (distilled
product) was maintained on kilogram scale with the final
product purity between 93 and 95% by GC. One possible
reason for the lower isolated yield could be attributed to the
Received for review November 6, 2006.
OP060229K
(10) Mas, J. M.; Metivier. P. Synth. Commun. 1992, 22, 2187-2191.
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