Synthesis of 1-bromo-3-butyn-2-one and 1,3-dibromo-3-buten-2-one

Article abstract of DOI:10.1080/00397910802654872

Synthetic procedures for the preparation of 1-bromo-3-butyn-2-one and 1,3-dibromo-3-buten-2-one are given. These compounds are prepared from 2-bromomethyl-2-vinyl-1,3-dioxolane, which can readily be prepared from 2-ethyl- 2-methyl-1,3-dioxolane. The synthetic routes are as follows: 2-bromomethyl-2-vinyl-1,3-dioxolane is converted to2-(1,2-dibromoethyl)-2- bromomethyl-1,3-dioxolane. Double dehydrobromination with ^tBuOK affords 2-ethynyl-2-bromomethyl-1,3-dioxolane. Formolysis with formic acid gives 1-bromo-3-butyn-2-one. Deacetalized 2-bromoethyl-2-vinyl-1,3-dioxolane was treated with Br₂ and Li₂CO₃/12-crown-4 in tetrahydrofuran to give 1,3-dibrom-3-buten-2-one in moderate yield.

Full text of DOI:10.1080/00397910802654872

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Synthesis of 1-Bromo-3-
butyn-2-one and 1,3-
Dibromo-3-buten-2-one
Alemayehu Mekonnen a , Andreas Westerlund b ,
Martina Havelkova c , Alexandre Descomps a & Rolf
Carlson a
a Faculty of Science, Department of Chemistry ,
University of Tromsø , Tromsø, Norway
b Cambrex Kalskoga AB , Karlskoga, Sweden
c Faculty of Medicine, Institute of Pharmacy ,
University of Tromsø , Tromsø, Norway
Published online: 16 Jun 2009.
To cite this article: Alemayehu Mekonnen , Andreas Westerlund , Martina Havelkova ,
Alexandre Descomps & Rolf Carlson (2009) Synthesis of 1-Bromo-3-butyn-2-one and
1,3-Dibromo-3-buten-2-one, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:14, 2472-2480, DOI:
10.1080/00397910802654872
To link to this article: http://dx.doi.org/10.1080/00397910802654872
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Synthetic Communications1, 39: 2472–2480, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654872
Synthesis of 1-Bromo-3-butyn-2-one
and 1,3-Dibromo-3-buten-2-one
Alemayehu Mekonnen,1 Andreas Westerlund,2 Martina Havelkova,3
Alexandre Descomps,1 and Rolf Carlson1
1Faculty of Science, Department of Chemistry, University of Tromsø,
Tromsø, Norway
2Cambrex Kalskoga AB, Karlskoga, Sweden
3Faculty of Medicine, Institute of Pharmacy, University of Tromsø,
Tromsø, Norway
Abstract: Synthetic procedures for the preparation of 1-bromo-3-butyn-2-one
and 1,3-dibromo-3-buten-2-one are given. These compounds are prepared from
2-bromomethyl-2-vinyl-1,3-dioxolane, which can readily be prepared from 2-ethyl-
2-methyl-1,3-dioxolane. The synthetic routes are as follows: 2-bromomethyl-2-
vinyl-1,3-dioxolane is converted to 2-(1,2-dibromoethyl)-2-bromomethyl-1,
3-dioxolane. Double dehydrobromination with tBuOK affords 2-ethynyl-2-
bromomethyl-1,3-dioxolane. Formolysis with formic acid gives 1-bromo-3-butyn-
2-one. Deacetalized 2-bromoethyl-2-vinyl-1,3-dioxolane was treated with Br2 and
Li2CO3=12-crown-4 in tetrahydrofuran to give 1,3-dibrom-3-buten-2-one in
moderate yield.
Keywords: Acetal deprotection, bromination, 2-bromomethyl-2-vinyl-1,3-dioxo-
lane, dehydrobromination, formolysis
INTRODUCTION
1-Bromo-3-butyn-2-one, 5, and 1,3-dibromo-3-buten-2-one, 9, contain
four functionalized carbons with three electrophilic sites (Fig. 1). The
electrophilic sites are of different types and can be selectively attacked
Received October 10, 2008.
Address correspondence to Rolf Carlson, Faculty of Science, Department
of Chemistry, University of Tromsø, N-9037, Tromsø, Norway. E-mail: rolf.
carlson@chem.uit.no
2472

1-Bromo-3-butyn-2-one
2473
Figure 1. Target compounds.
by nuclophiles to give regioselective functionalizations. The order of reac-
tivity between the reactive sites can probably also be altered by adjusting
the reactivity of the reagent used. For this reason, they may be highly ver-
satile building blocks, particularly for diversity-oriented synthesis.[4] They
may expand the possibilities for the synthesis of several carbocyclic and
heterocyclic molecules by one-pot procedures.[1,2] However, the synthetic
scope of these compounds remains to be established.
RESULTS AND DISCUSSION
In this article, we present novel procedures under mild and efficient reac-
tion conditions for the syntheses of 1-bromo-3-butyn-2-one and
1,3-dibromo-3-buten-2-one. To the best of our knowledge, a synthetic
procedure for 1-bromo-3-butyn-2-one has not previously been reported.
1,3-Dibromo-3-buten-2-one has previously been synthesized by a rather
ineffective procedure starting from 2-trimethylsilyloxy-1,3-butadiene.[3]
For the syntheses described, the precursor, 2-bromomethyl-2-vinyl-
1,3-dioxolane 2, was prepared from 2-ethyl-2-methyl-1,3-dioxolane 1
(Scheme 1). A procedure for the synthesis of 1-bromo-3-buten-2-one
from 2 has been reported by our laboratory.[1,2]
Synthesis of 1-Bromo-3-butyn-2-one
The synthetic route to 5 is shown in Scheme 2. Addition of bromine to 2
is a smooth process and yielded 3 in quantitative amount. Several organic
Scheme 1. Synthesis of key precursor.

2474
A. Mekonnen et al.
Scheme 2. Synthetic route from key precursor 2 to target 5.
and inorganic bases and different solvents were examined for the
subsequent elimination reaction. The efficiency and rate of dehydrobro-
mination depend strongly on both the nature of the base and the solvent.
It was found that tBuOK in tetrahydrofuran (THF) was the best combina-
tion for this transformation.
The dehydrobromination yields finely divided potassium bromide,
which caused severe clogging upon attempted filtration through celite,
silica, sintered glass filters, or filter paper. This was a known problem,
and a method called Zebrazil filtration has been proposed to overcome
this problem.[1,2] However, this method is unsuitable for large-scale
synthesis. We have developed alternative procedures to remove potas-
sium bromide from the reaction mixture. The most convenient one is
to separate the product by steam distillation after evaporation of the sol-
vent. Other methods that can be used, for example, adding dry silica to
the reaction mixture, removing the solvent by evaporation, and packing
a column with the dry reaction mixture on silica. The product can then be
eluted from the column with diethyl ether. Another method involves
removing THF by evaporation and adding water to dissolve the potas-
sium bromide. The product can then be extracted with diethyl ether.
However, fairly large volumes of water are necessary, and this makes
extraction unsuitable for larger scale synthesis.
Cleavage of the acetal protective group in 4 with Lewis and Brønsted
acids is a rather slow reaction.[1,4,5] For instance, aqueous boric acid
alone did not work at all, but a mixture of aqueous hydrogen bromide
and boric acid afforded hydrolysis. Unfortunately, it also gave some
hydrogen bromide addition to the triple bond as a side reaction.
Attempted transacetalisations[6,7] with a number of carbonyl compounds
did not afford the desired product. It is difficult to displace the equili-
brium to achieve complete conversion in favor of the deprotected pro-
duct. Complete deprotection is essential, because separation of the final
ketone from the acetal is difficult, both by distillation and by chromato-
graphy. We have found that formolysis of the acetal in the presence of
pentane is a useful method for the deprotection of the acetal. The reac-
tion mixture is a two-phase system. The bromoketone is dissolved in
the pentane layer and thereby protected from the aggressive acid layer.
After the reaction is complete, the layers are separated. The bis-formate

1-Bromo-3-butyn-2-one
2475
Scheme 3. Possible routes to the intermediary acetal 4.
esters of diethylene glycol can easily be removed from the pentane layer
by washing with water. This procedure totally avoids polymerization of
the product during the workup procedure.
Attempts to develop a one-pot synthesis of compound 4 from 2 using
different bases and phase-transfer agents such as (n-Bu)4NBr=NaOH,
(n-hexyl)4NBr=NaOH, or (n-Bu)4NHSO4=NaOH were unsuccessful.
For example, when the reaction mixture after the bromination step was
treated with (n-Bu4)2NHSO4=NaOH, both 4 and 6 were formed.
Compound 6 was isolated in pure form only when 1 equivalent of
(n-Bu)4NHSO4=KOH was used. This procedure can therefore be an
alternative to the 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) procedure
described below. Use of excess (n-Bu4)2NHSO4 inevitably gave a
mixtures of 4 and 6 (Scheme 3).
We have also attempted a one-pot procedure for the synthesis of 4
using tetrahydrofuran (THF) as solvent and tBuOK as base (see
Scheme 3). Compared with the two-step procedure, the attempted
one-pot procedure afforded poor yields of the desired product. THF
is obviously an unsuitable solvent for the bromination reaction. In
attempts to use CH2Cl2 instead of THF, only trace amounts of the
expected product were detected. According to our observation, the for-
mation of alkyne compound is favored only when the reaction solvent
does not contain acidic protons. Solvents such as dichloromethane and
t
chloroform could generate carbenes in the presence of BuOK, and the
carbene will immediately attack the target molecule as soon as it is
formed.

2476
A. Mekonnen et al.
Scheme 4. Possible routes to target 9.
Synthesis of 1,3-Dibromo-3-buten-2-one
The attempted routes are summarized in Scheme 4. Compound 6 was
obtained as the only product in quantitative amount when 3 was treated
with DBU. However, all attempts to remove the acetal protection from 6
by acid hydrolysis were unsuccessful, and only trace amounts of 9 were
obtained in attempted formolysis (Scheme 4).
Compound 7 is obtained from 2 by formolysis. When 7 was treated
with Br2 in CH2Cl2 at 0ꢀC, 8 was obtained in good yield. Compound 8
was further treated with base in THF to achieve compound 9. Several
bases were tested. Strong bases (DBU, alkoxides, hydroxide) gave a mix-
ture of several side products due to decomposition and Favorskii rearran-
gement reaction, whereas weak amine bases gave no conversion at all. The
desired product could be obtained when compound 8 was treated with
Li2CO3=12-crown-4=THF and 9 was isolated in moderate yield (31%) after
24 h (Scheme 4). The poor isolated yield was due to polymerization.
EXPERIMENTAL
General
1
All H and 13C NMR spectra were recorded on a Varian 400 Fourier
transform (FT)–NMR system using CDCl3 as a solvent at room tempera-
ture. Chemical shifts are given in parts per million (ppm), and J-values
are given in hertz. Flash chromatography was carried out using matrix

1-Bromo-3-butyn-2-one
2477
silica (Si-60 Aꢀ 35–70 mm). Gas–liquid chromatographic (GLC) analyses
were performed on a Varian 3300 chromatograph equipped with split
injector, flame ionization detector (FID), and a Varian 4400 integrator.
IR spectra were recorded on an FT-IR spectrometer and are reported
as wave numbers. Gas chromatography (GC)–mass spectra (MS) were
registered on a Hewlettz Packard 5890 series II CP Sil 5 CB column
(25 m) followed by VG Quattro mass spectrometer. Finnigan-MAT-
95XL mass spectrometer was used to obtain high-resolution electron
impact mass spectroscopy (HREIMS) data, and the spectra were
obtained at 250ꢀC and 70 eV. All reagents and solvents except com-
pounds 3 were obtained from commercial sources and, with the exception
of THF, used as received without further purification. THF was distilled
from potassium.
Synthesis of 2-(1,2-Dibromoethyl)-2-bromomethyl-1,3-dioxolane (3)
2-Bromomethyl-2-vinyl-1,3-dioxolane (10.0 mmol, 1.93 g) was dissolved
in dichloromethane (5 mL) and placed in a round-bottomed flask
equipped with a dropping funnel and a reflux condenser connected to a
gas trap via a moisture-protecting CaCl2 tube. Bromine (10.6 mmol,
1.70 g) was also dissolved in dichloromethane (5 mL) and placed in the
dropping funnel. At the beginning, a small amount of bromine was added
in one portion (the start of reaction was seen by decolorization of the
reaction mixture), and then the rest of bromine was added dropwise
(60 drops per minute). The temperature of the reaction mixture was
maintained between 5 and 15ꢀC throughout the addition of bromine.
The reaction mixture remained reddish after all the bromine was added
and was stirred at room temperature for 1 h. The solvent was removed
on a rotary evaporator to yield 3.35 g (95%) of a dense reddish-brown
liquid. This product was sufficiently pure for the next reaction. IR (neat,
1
NaCl plates, vmax, cmꢁ1): 2970, 2895; H NMR: d 4.50 (dd, 1H, J ¼ 9.3,
3.5 Hz), 4.08–4.25 (m, 4H), 3.96 (dd, 1H, J ¼ 11.2, 3.5 Hz), 3.85 (d, 1H,
J ¼ 11.4 Hz), 3.59 (d, 1H, J ¼ 11.4 Hz), 3.58 (dd, 1H, J ¼ 11.2, 9.3 Hz);
13C NMR: d 108.5, 67.1, 67.0, 55.5, 34.3, 32.7; HRMS: observed for
C5H7Br2O2: 258.8788; calcd.: 258.8792.
Synthesis of 2-Bromomethyl-2-ethynyl-1,3-dioxolane (4)
A flame-dried, 500-mL, two-necked, round-bottomed flask was equipped
with a reflux condenser and a magnetic stirring bar and was charged with
3 (10.0 mmol, 3.53 g) dissolved in dry THF (20 mL ) at room temperature.
The flask was kept under N2 during the course of the reaction. Potassium

2478
A. Mekonnen et al.
tert-butoxide (23.8 mmol, 2.62 g) was added, in several small portions via
an addition funnel made for addition of solids. After all potassium
tert-butoxide was added, the reaction mixture was stirred at 25ꢀC for
30 min. A sample was taken from the reaction mixture, filtered, and ana-
lyzed by GC and NMR spectroscopy. After completion of the reaction,
the resulting mixture was allowed to cool to room temperature. The sol-
vent was removed by rotary evaporation. Water (300 mL) was then added
to the residual mixture, which was steam distilled. Two layers were
obtained in the receiver, and the layers were separated. The aqueous layer
was extracted with diethyl ether (3 ꢁ 20 mL). The organic extracts were
combined, dried over MgSO4 (25 g), and concentrated by rotary
evaporation to yield 1.74 g (91%) of a dark yellow liquid. IR (neat, NaCl
1
plates, vmax, cmꢂ1): 3275, 2115; H NMR: d 4.05–4.22 (m, 4H), 3.63
(s, 2H), 2.60 (s, 1H); 13C NMR: d 100.1, 79.2, 66.1, 35.8; HRMS:
observed for C5H5O2: 97.0286; calcd.: 97.0290.
Synthesis of 1-Bromo-3-butyn-2-one (5)
A mixture of 4 (10.0 mmol, 1.91g) and formic acid (98%) (87 mmol, 4.0 g) in
pentane (100 mL) were transferred into a one-necked, round-bottomed flask
(500mL) under nitrogen atmosphere and refluxed at 70ꢀC for 6 h. After this
time, GC analysis showed complete conversion of the starting material. The
reaction mixture was allowed to cool to room temperature, and the layers
were separated. The acid phase was extracted with pentane=ether (9:1)
(2ꢁ 15mL). The pentane=ether layers were combined and carefully washed
with water (2 ꢁ 10mL) and saturated aqueous sodium chloride solution
(3ꢁ 15mL), dried over anhydrous MgSO4 for 3 h, and filtered. After filtra-
tion, the solvent was removed under vacuum followed by addition of mag-
nesium oxide (100mg) and hydroquinone (100mg) to suppress
polymerization. The yield was 1.09g (74%) of dark red-brownish liquid.
1
IR (neat, NaCl plates, vmax, cmꢂ1): 3290, 2250, 2100, 1680; H NMR: d
4.05 (s, 2H), 3.41 (s, 1H); 13C NMR: d 177.6, 82.2, 79.1, 35.2; HRMS:
observed for C4H3BrO: 147.9340; calcd.: 147.9347.
Synthesis of 2-Bromomethyl-2-(1-bromovinyl)-1,3-dioxolane (6)
Compound 3 (10.0 mmol, 3.53 g) was dissolved in dry THF under an N2
atmosphere. DBU (17.1 mmol, 2.56 mL) was added dropwise via syringe.
The reaction mixture was stirred at room temperature for 1 h. Then the
reaction mixture was filtered through a plug of silica, which was washed
with Et2O. The solvent was removed in vacuum to give a brownish liquid

1-Bromo-3-butyn-2-one
2479
product. Yield (2.58 g, 95%); IR (neat, NaCl plates, vmax, cmꢂ1): 3100; 1H
NMR: d 6.21 (d, 1H, J ¼ 1.8 Hz), 5.74 (d, 1H, J ¼ 1.8 Hz), 3.94–4.20 (m,
4H), 3.70 (s, 2H); 13C NMR: d 129.1, 120.8, 107.1, 66.2, 34.5; HRMS:
observed for C5H6BrO2: 178.9537; calcd.: 178.9531.
Synthesis of 1,3,4-Tribromobutan-2-one (8)
Compound 5 (1.0 mmol, 149 mg) was dissolved in CH2Cl2 (5 mL) and
transferred into a three-necked, round-bottomed flask equipped with
reflux condenser and magnetic stirrer. Br2 (1.25 mmol, 200 mg) in
CH2C2 (3 mL) was added dropwise until the bromine color persisted at
0ꢀC. After complete addition of bromine, the reaction mixture was stirred
for 5 min, and solvent was removed by rotary evaporation. A colorless oil
was obtained (290 mg, 94%), which was sufficiently pure for the next
reaction; IR (neat, NaCl plates, vmax, cmꢂ1): 2975, 2930, 1725; 1H
NMR d 4.97 (dd, 1H, J ¼ 4.4, 10.6 Hz), 4.28 (d, 1H, J ¼ 12.5 Hz), 4.05
(d, 1H, J ¼ 12.5 Hz), 3.97 (t, 1H, J ¼ 10.4 Hz), 3.67 (dd, 1H, J ¼ 4.4,
10.3 Hz); 13C NMR: d 192.2, 43.3, 31.0, 27.8; CC=MS m=z (relative inten-
sity): 310 (M þ 3), 308, 231 (13), 229 (27), 227, 217 (4), 215 (8), 213, 189
(7), 187 (14), 185, 135 (27), 133, 123 (100), 121, 108 (14), 107, 106, 105, 95
(40), 93, 81 (20), 79, 55 (45).
Synthesis of 1,3-Dibromo-3-buten-2-one (9)
Compound 8 (1.0 mmol, 309 mg), Li2CO3 (5 mol%, 3.4 mg), and a cataly-
tic amount of 12-crown-4 (5 mol%, 8.81 mg) were placed in a two-necked,
round-bottomed flask and dissolved in dry THF (5 mL) under N2. The
reaction mixture was stirred at 23ꢀC for 24 h. The resulting mixture
was filtered through a short plug of silica, washed with Et2O, and concen-
trated using rotary evaporation to get the target compound in moderate
1
yield (70.68 mg, 31%). H NMR d 6.92 (d, 1H, J ¼ 2.7 Hz), 6.45 (d, 1H,
J ¼ 2.7 Hz), 4.33 (s, 2H); 13C NMR: d 186.1, 131.0, 127.1, 30.1; GC=MS
m=z (relative intensity) 230 (15), 228 (28), 226, 135 (100), 133, 107 (41),
105, 95 (19), 93, 81 (12), 79.
ACKNOWLEDGMENT
We thank the Research Council of Norway for generous financial
support.

2480
A. Mekonnen et al.
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