Improved synthesis of 1-bromo-3-buten-2-one

Article abstract of DOI:10.1080/00397911.2010.515369

A convenient procedure for the synthesis of 1-bromo-3-buten-2-one, 4, from commercially available 2-ethyl-2-methyl-1,3-dioxolane, 1, is described. The procedure involves three reaction steps: (1) The acetal 1 is converted to 2-(1-bromoethyl)- 2-bromomethyl-1,3-dioxolane, 2, by reacting 1 with elemental bromine in dichloromethane to yield 98% of 2. (2) Dehydrobromination of 2 with potassium tert-butoxide in tetrahydrofuran gives 2-bromomethyl-2-vinyl-1,3- dioxolane, 3, in 84-93% yield. (3) Removal of the acetal protection from 3 by formolysis for 6-10 h afforded 1-bromo-3-buten-2-one, 4, in 85-94% yield. A more rapid method is acid hydrolysis of 3 under microwave activation (100°C, 8-10 min), by which 4 was obtained in 75% yield. Full experimental details are given. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515369

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Improved Synthesis of 1-Bromo-3-
buten-2-one
a
a
a
Rolf Carlson , Alexandre Descomps , Alemayehu Mekonnen
,
b
c
Andreas Westerlund & Martina Havelkova
a
Department of Chemistry , University of Tromsoe , Tromsoe ,
Norway
b
Cambrex Karlskoga AB , Karlskoga , Sweden
c
Institute of Pharmacy, University of Tromsoe , Tromsoe , Norway
Published online: 29 Jun 2011.
To cite this article: Rolf Carlson , Alexandre Descomps , Alemayehu Mekonnen , Andreas
Westerlund & Martina Havelkova (2011) Improved Synthesis of 1-Bromo-3-buten-2-one, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:19, 2939-2945, DOI: 10.1080/00397911.2010.515369
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515369
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1
Synthetic Communications , 41: 2939–2945, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515369
IMPROVED SYNTHESIS OF 1-BROMO-3-BUTEN-2-ONE
1
Rolf Carlson, Alexandre Descomps, Alemayehu Mekonnen,
1
1
2
Andreas Westerlund, and Martina Havelkova
3
1
Department of Chemistry, University of Tromsoe, Tromsoe, Norway
Cambrex Karlskoga AB, Karlskoga, Sweden
Institute of Pharmacy, University of Tromsoe, Tromsoe, Norway
2
3
GRAPHICAL ABSTRACT
Abstract A convenient procedure for the synthesis of 1-bromo-3-buten-2-one, 4, from
commercially available 2-ethyl-2-methyl-1,3-dioxolane, 1, is described. The procedure
involves three reaction steps: (1) The acetal 1 is converted to 2-(1-bromoethyl)-
2
-bromomethyl-1,3-dioxolane, 2, by reacting 1 with elemental bromine in dichloromethane
to yield 98% of 2. (2) Dehydrobromination of 2 with potassium tert-butoxide in tetrahydro-
furan gives 2-bromomethyl-2-vinyl-1,3-dioxolane, 3, in 84–93% yield. (3) Removal of the
acetal protection from 3 by formolysis for 6–10 h afforded 1-bromo-3-buten-2-one, 4, in
8
(
5–94% yield. A more rapid method is acid hydrolysis of 3 under microwave activation
ꢀ
100 C, 8–10 min), by which 4 was obtained in 75% yield. Full experimental details are
given.
Keywords Acetal deprotection; bromination; 2-bromomethyl-2-vinyl-1,3-dioxolane;
dehydrobromination; formolysis; microwave activation
INTRODUCTION
In this article, we present an improved procedure for the synthesis of
-bromo-3-buten-2-one. The compound contains three electrophilic sites at which
1
nucleophilic agents can attack. This makes the compound interesting as a C-4 build-
ing block for synthesis. A laboratory-scale procedure for the synthesis of 1-bromo-3-
[
buten-2-one has previously been presented in this journal. This laboratory-scale
1]
Received August 10, 2010.
Address correspondence to Rolf Carlson, Department of Chemistry, University of Tromsoe,
NO-9037, Tromsoe, Norway. E-mail: rolf.carlson@chem.uit.no
2
939

2940
R. CARLSON ET AL.
Scheme 1. Synthetic route to 1-bromo-3-butene-2-one.
procedure contained two chromatographic steps, which made it unsuitable for
large-scale synthesis. We have now been able to eliminate these chromatographic
steps, and the reaction can be run on a larger scale. The procedure is summarized
in Scheme 1.
DISCUSSION OF THE REACTION STEPS AND RESULTS
Bromination of the Acetal (1)
Experimental conditions for maximum yield were determined by an
experimental design using orthogonal experiments. A full account of this is given
in Ref. 2. Preparative-scale synthesis runs on 1 mol of acetal and gives 98% isolated
yield of pure (>99%) dibromoacetal, 2. It could be directly used in the dehydrobro-
mination reaction.
Dehydrobromination of the Dibromoacetal (2)
This is a difficult step: we tested a large number of different bases in a large
number of solvents. It is essential that the dibromoacetal is completely converted
to 2 bromomethyl-2-vinyl-1,3-dioxololane, 3, because these compounds are very diff-
cult to separate by either distillation or chromatography. The only combination of
base and solvent we have found to be suitable is potassium tert-butoxide in tetrahy-
drofuran (THF). The use of sodium tert-butoxide was less efficient. Two procedures
have been found to be useful, and both have been run on a preparative scale: Either
(
1) an excess of potassium tert-butoxide is added in portions to the dibromoacetal
1
dissolved in THF. The reactions are run to completion and monitored by H
NMR. The reaction mixure in this procedure is usually slightly yellowish; or (2)
the dibromoacetal is added dropwise to an excess of potassium tert-butoxide in
THF. The reaction mixture in this procedure is almost colorless. The problem is
that both procedures produce finely divided potassium bromide, which is almost

1
-BROMO-3-BUTEN-2-ONE
2941
[
1]
impossible to remove by filtration. In the first published procedure, this was over-
come by a chromatographic technique called the Zebrasil filtation. For large-scale
preparation, this filtration is, unsuitable. Instead, we have developed two alternative
methods for removing the potassium bromide: (1) steam distillation and (2)
extraction.
The reaction mixture after the dehydrobromination is evaporated to dryness to
yield a sticky residue of 2-bromomethyl-2-vinyl-1,3-dioxolane and potassium
bromide.
Steam distillation. Water is added to the residule in the evaporation flask
ca. 1 L per mol of substrate), the flask is arranged for distillation, and ca. 600 mL
(
is distilled. The product, 3, separates in the distillate as a colorless oil and can easily
be separated in 80–85% yield. This procedure is suiable for larger scale preparation.
Extraction. A sufficient amount of water is added to the residue in the evap-
oration flask to dissolve the potassium bromide. The product, 3, separates as a color-
less oil. The aqueous layer is extracted with diethyl ether. The etheral layers are
combined with the crude product and dried over magnesium sulfate. The product
is obtained in 80–85% yield after filtration and removal of the ether. This procedure
is suitable for moderate preparative-scale (50–100 g) runs.
Either of these procedures yields a product of very high purity (>98%), and
it can be used directly for the next step. The product crystallized in the
ꢀ
freezer, mp < 0 C.
Deprotection of the Monobromoacetal (3)
The acetal protection is very difficult to remove. It is essential to have a com-
plete conversion because 3 and 4 are very difficult to separate by chromatographic
means. Compound 4 polymerizes easily, and it is not possible to isolate it by distil-
lation. Standard hydrolytic cleavage is inefficient. We have tested a large number of
such methods.
Transacetalizations with other corbonyl componds are slow and inefficient.
[
1]
The method that was used in the first published procedure was to heat the acetal
with 42% phosphoric acid, followed by ether extraction. Later, it was found that stir-
ring the acetal at room temperature with 98% formic acid for 24 h followed by
[
3]
extraction with diethyl ether also was efficient. Both procedures afforded complete
conversion of the acetal. However, the ketone obtained by these procedures has to be
purified by chromatography on silica, and the product was obtained in diethyl ether
solution. Attempts to remove the ether inevitably led to polymerization. Some
synthetic transformations of 1-bromo-3-buten-2-one carried out in diethyl ether
[3]
solution have been published.
Formolysis in a two-phase system. To obtain a method that can be used
on a larger scale, any chromatographic isolation of 4 must be eliminated. This can
be accomplished by carrying out the formolytic cleavage in the presence of a hydro-
carbon solvent (pentane or hexane). The reason for this is that the acetal is soluble in
formic acid but the ketone is less soluble. The ketone is transferred to the hydro-
carbon layer and thereby protected from the aggressive acid. The use of diethyl ether

2942
R. CARLSON ET AL.
or dichloromethane instead of pentane gave very poor conversions. Minor amounts
of formic esters of glycol are sometimes formed, but these impurities can easily be
removed by washing the hydrocarbon layer with water. After the addition of small
amouts of magnesium oxide (acid scavenger) and hydroquinone (radical scavenger),
the solvent-free ketone can be obtained by evaporation. However time consuming,
this procedure is suitable for larger scale synthesis.
Microwave-assisted hydrolysis. Under microwave radiation the acetal can
be rapidly cleaved by acid hydrolysis with aqueous 50% formic acid or aqueous
phosporic acid (20%). The reaction is complete within 10 min and compares favor-
ably with the formolysis in the two-phase system, which takes 6–10 h for completion.
The drawback is that only smaller amounts (ca. 5 g) can be reacted in the laboratory
microwave reactor. This technique is well suited for the liberation of 4 used in further
laboratory-scale transformations.
EXPERIMENTAL
1 13
All H and C NMR spectra were recorded on a Varian 400 Fourier transform
(FT) NMR system using CDCl as a solvent at room temperature. Chemical shifts
3
are given in parts per million (ppm), and J values are given in hertz. Gas chromato-
graphic (GC) analyses were performed on a Varian 3300 chromatograph equipped
with split injection. The microwave experiments were carried out using a Biotage
Initiator reaction system. The starting acetal, 1, all reagents, and solvents were
obtained from commercial sources and used as received without further purification,
with the exception of THF, which was distilled from potassium.
Synthesis of 2-(1-Bromoethyl)-2-bromomethyl-1,3-dioxolane (2)
The reactor was a four-necked, 2-L, mantled cylindrical flask. The reaction
temperature was controlled by circulating ethanol through the cooling mantle using
a Julabo F70 thermostat. The flask was mounted with an anchor-shaped Teflon stir-
rer for which the stirring rate was adjusted using a Peaktech 2780 tachometer, a
reflux condenser connected to a HBr trap, a 500-mL pressure-equalized dropping
funnel with a nitrogen inlet, and a temperature probe (Pt 100 sensor) dipped into
the reaction mixture.
The flask was charged with 2-ethyl-2-methyl-1,3-dioxolane, 1 (116.2 g, 1.00 mol),
and 1 L of dichloromethane. The stirring rate was adjusted to 300 rpm, and the tem-
ꢀ
perature was adjusted to 30 C. When the temperature was stabilized, bromine
(100 mL, 2 mol) dissolved in 250 ml of dichloromethane was added over 20 min,
and the mixture was stirred at 30 C for 4 h.
ꢀ
Workup. Water (300 mL) was added, and the mixture was stirred. Powdered
sodium bisulfite was added carefully until the yellowish color of unreacted bromine
had disappeared. The organic layer was separated and washed a second time with
3
00 mL of water and finally with 300 mL of saturated aqueous sodium bicarbonate
to remove any remaining trace of HBr. The organic layer was dried over anhydrous
magnesium sulfate overnight. Filtration and evaporation of the solvent gave 267.9 g

1
-BROMO-3-BUTEN-2-ONE
2943
(98%) of 2. The product was >97% pure. An analytical sample was obtained by
distillation (bp 82 C=13 mbar).
ꢀ
Elemental analysis. Calcd. C, 26.02%; H, 3.68%; Br, 58.04%. Found: C,
1
2
3
5.71%; H, 3.77%; Br, 57.89%. Spectral properties: H NMR d ¼ 1.69 (d, J ¼ 7.0 Hz,
H), 3.57 (d, J ¼ 11.1 Hz, 1 H), 3.79 (d, J ¼ 11.1 Hz, 3H), 4.13–4.18 (m, 4 H), 4.45 (q,
1
3
J ¼ 7.0 Hz, 1H); C NMR n ¼ 20.8, 35.0, 50.6, 67.7, 109.2; IR (neat, NaCl plates,
ꢁ
1
=cm ) 2990, 2900, 1470, 1420, 1370, 1320, 1260, 1220, 1200, 1160, 1120,
n
1
2
1
max
070, 1050, 1040, 990, 675; MS (EI 70 ev) m=z (relative abundance = %) [assignment]
þ
75 (0) [M ], 181 (63), 179 (63) [M ꢁ CH Br], 167 (100), 165 (98) [M ꢁ CH CHBr],
2
3
þ
þ
23, 121, 109 (13), 107 (12) [CH CHBr ], 100, 95 (7), 93 (6) [CH Br ].
3
2
2-Bromomethyl-2-vinyl-1,3-dioxolane (3)
Procedures for the dehydrobromination. (1) Adding potassium tert-
butoxide to 2 and workup by steam distillation: A flame-dried, 500-mL, two-necked,
round-bottomed flask was equipped with a reflux condenser. A magnetic stirring bar
was placed in the flask. The flask was charged with 2 (23.29 g, 0.085 mol) dissolved in
dry THF (80 mL). The flask was placed in an oil bath at room temperature and kept
under nitrogen during the course of the reaction. Potassium tert-butoxide (17.15 g,
0
funnel. When the addition was completed, the reaction mixture was stirred at
.153 mol) was added in several small portions over 30 min via a solid-addition
ꢀ
5
0 C for 1 h. The reaction can be monitored by analyzing samples from the reaction
1
mixture by GC or H NMR to ensure a complete conversion. When the conversion
was complete, the reaction mixture was cooled to room temperature and transferred
ꢀ
to a 500-mL, round-bottomed flask. The solvent was removed by evaporation (25 C,
2
00 mbar). Water (300 mL) was then added to the semisolid residue, and the flask
was arranged for steam distillation. The flask was heated by means of an elctric heat-
ing mantle, and ca. 200 mL of distillate was collected. The distillated formed two
layers, which were separated. The upper aqueous layer was extracted with diethyl
ether (3 ꢂ 20 mL). The organic layers were combined, washed with water
(
3 ꢂ 20 mL), dried over magnesium sulfate (25 g), and concentrated by rotary evap-
ꢀ
oration (25 C, 190 mbar) to yield 13.94 g (85%) of 3. The purity was 97%.
An analytical sample (purity > 99%) can be obtained by fractionation over a
ꢀ
2
0-cm Vigreux column, bp 71–73 C, 12 mbar.
This procedure has been scaledup using 2 (274.0 g, 1.00 mol) in 750 mL of THF
and potassium tert-butoxide (229.0 g, 2.04 mol). After the steam distillation, 181.0 g
1
(
94%) of 3 was obtained. The purity was >98% (GC, H NMR).
2) Adding 2 to potassium tert-butoxide and workup by extraction: A 500-mL,
two-necked flask was equipped with a moisture-protected reflux condeser and a
00-mL pressure-equalized dropping funnel. A magnetic stirring bar was placed in
(
2
the flask, which was then flame dried and purged with nitrogen. The flask was
charged with potassium tert-butoxide (75.5 g, 0.70 mol) and 200 mL of dry THF.
The flask was placed in an oil bath at room temperature. The mixture was vigorously
stirred, and 2 (137.0 g, 0.50 mol) dissolved in 100 mL of dry THF was added drop-
ꢀ
wise over 20 min. Then, the temperature of the oil bath was raised to 50 C, and
the reaction mixture was stirred at this temperature for 45 min.

2944
R. CARLSON ET AL.
After cooling, the reaction mixture was transferred to an evaporation flask,
ꢀ
and THF was evaporated (25 C, 200 mbar). Water (300 mL) was added to the
slightly brownish residue to dissolve the potassium bromide, followed by extraction
with diethyl ether (3 ꢂ 100 mL). The etheral layers were combined and dried over
magnesium sulfate (25 g). After filtration, the ether was removed by evaporation
ꢀ
(25 C, 200 mbar) to yield 77.0 g (80%) of 3 as a slightly yellowish oil. The purity
was >97%. Fractionation over a 20-cm Vigreux column afforded 69.0 g (51%) of
ꢀ
pure (>99%) 3, bp 71–73 C, 12 mbar.
Properties of 3. Elemental analysis: Calcd. (C 37.33%, H 4.71%, Br 41.39%,
1
and O 16.58%); Found (C 37.63%, H 4.84%, Br 38.84%). Spectral properties: H
NMR d ¼ 3.46 (s, 2H), 4.01 (m, 4H), 5.28 (dd, 1H, J ¼ 1.5 Hz, 10.3 Hz), 5.51 (dd,
1
3
1
6
1
H, J ¼ 1.5 Hz, 17.1 Hz), 6.55 (dd, 1H, J ¼ 10.3 H, 17.1 Hz); C NMR d ¼ 36.9,
ꢁ
max
1
6.3, 106.7, 118.5, 135.5; IR n =cm
(neat, NaCl plates) 3100, 3020, 1475,
410, 1405, 1050, 945; MS (EI 70 eV) m=z (relative abundance) [Assignment] 193
þ
þ
(
0) [M ], 167 (17), 165 (17) [M ꢁ vinyl], 123 (17), 99 (100), 95 (7), 93 (7) [CH Br ].
2
1-Bromo-3-buten-2-one (4)
Caution! 1-Bromo-3-buten-2-one is a powerful lachrymator. It is a bis-
funtionalised alkylating agent and it can be suspected to be mutagenic.
Procedures. (1) Removal of the acetal protection in 3 by formolysis: A
2
50-mL, one-necked flask was purged with nitrogen, and an egg-shaped magnetic
stirring bar was introduced. The flask was charged with 3 (13.51 g, 0.070 mol),
8% formic acid (28.01 g, 0.699 mol), and pentane (10 mL). The flask was placed
9
in an oil bath, and a reflux condenser was mounted on the flask. The mixture was
vigorously stirred and heated to reflux. After 6 h, GC analysis showed complete con-
version of 3. The reaction mixture was cooled and transferred to a 250-mL separa-
tory funnel. The top pentane layer was separated. The bottom layer was extracted
with pentane (3 ꢂ 15 mL). The combined pentane layers were washed with water
(
(
3 ꢂ 20 mL) and saturated NaCl solution (2 ꢂ 20 mL), dried over magnesium sulfate
30 g) for 3 h, and then filtered. After the filtration, magnesium oxide (20 mg) and
hydroquinone (20 mg) were added to the pentane solution of 4. The solvent was
ꢀ
removed on a rotary evaporator (15 C, 280 mbar) to yield 8.96 g (86%) of 4 as a
slightly yellowish liquid. It is of utmost importance to add magnesium oxide and
hydroquinone before evaporation. Without this precaution, any attempt to remove
the solvent leads to a rapid polymerization of 4. The purity was >97%. Sometimes 4
is contaminated with trace amounts of the mono- and diformate esters of ethylene
1
glycol. The presence of these impurites can be detected by their H NMR signals,
singlets at d 4.41, 8.09, and 8.75. These impurities can easily be removed from by
repeated shaking with icewater. The product is rather unstable, prone to polymeriza-
tion, and should be used immediatly. It can, however, be stored under nitrogen in the
freezer for a couple of days.
This procedure has been scaledup using 3 (50 g, 0.26 mol), 98% formic acid
50 g, 1.08 mol), and pentane (200 mL). It was necessary to heat it to reflux for 9 h
(
for complete conversion. The yield of 4 was 34.1 g (89%).

1
-BROMO-3-BUTEN-2-ONE
2945
(2) Removal of the acetal protection by microwave-assisted hydrolysis: The
reaction vessel was a 30-mL vial. The vial was charged with 3 (5.00 g, 25.9 mmol),
diethyl ether–pentane (50:50) (5 mL), and formic acid–water (50:50) (5 mL). The vial
ꢀ
was sealed and placed in the instrument. The temperature was set to 100 C for
8
–10 min. After cooling, the vial was opened carefully (4 is a powerful lachrymator),
and the contents were transferred to a 100-mL separatory funnel. Diethyl ether
25 mL) and water (25 mL) were added, and the funnel was shaken to obtain two dis-
(
tinct phases. The lower aqueous layer was removed, and the upper organic layer was
washed with 100 mL of water. Saturated sodium bicarbonate (30 mL) was then
added cautiously (gas evolution). When the evolution of carbon dioxide had ceased,
the funnel was shaken vigorously. The organic layer was separated and dried over
magnesium sulfate (20 g), for 3 h and filtered. After the addition of magnesium oxide
ꢀ
(
2
>
20 mg) and hydroquinone (20 mg), the solvent was removed by evaporation (15 C,
80 mbar) to yield 2.80 g (75%) of 4. The purity was >97%. An analytical sample
ꢀ
99% purity can be obtained by Kugelrohr distillation. b.p. 100–105 C, 8 mbar.
Properties of 4: The product is unstable and it was not possible to send a sam-
1
ple for elemental analysis. Spectral properties: H NMR d ¼ 4.03 (s, 2H), 5.95 (dd,
1
H, J ¼ 10. 6 Hz, 0.9 Hz), 6.38 (dd. 1H, J ¼ 17.5 Hz, 0.9 Hz), 6.55 (dd, 1H,
1
3
J ¼ 17.5 Hz, 10.6 Hz); C NMR d ¼ 32.6, 131.1, 133.2, 191.5; IR (neat between NaCl
ꢁ
1
plates) n =cm 1690 (C=O), 1620 (C=C–C=O); MS (EI 70 eV) m=z (relative
max
þ
abundance) [Assignment] 150 (78) 148 (77) [M ], 123 (35), 121 (32) [M ꢁ vinyl], 95
þ
(
100), 93 (99) [CH Br ], 79, 69 (60) [M ꢁ Br], 55 (92) [M ꢁ CH Br].
2
2
ACKNOWLEDGMENTS
We thank the American Chemical Society for the kind permission to reproduce
the experimental proceddure for the synthesis of the dibromoactal, 2 published in
Ref. [2]. We also thank the Research Council of Norway for financial support via
the KOSK-II program.
REFERENCES
1
2
3
. Westerlund, A.; Carlson, R. Synthesis of 1-bromo-3-buten-2-one. Synthetic Communica-
tions 1999, 29, 4035–4042.
. Carlson, R.; Simonsen, G.; Descomps, A., Orthogonal experiments in the development of
organic synthetic procedures. Organic Process Research & Development 2009, 13, 798–803.
. Westerlund, A.; Gras, J.-L. Carlson, R. Investigation of 1-bromo-3-buten-2-one as building
blocks in organic synthesis. Tetrahedron 2001, 57, 5879–5883.