FEATURE ARTICLE

Safe and efficient synthesis of 3-bromo-3-butene-2-one from methyl vinyl ketone

Published: October 16, 2017

Sahadeva R Damireddi and J Robert Durrwachter from Cambrex share a case study of improving synthesis pathways. By conducting the bromination of methyl vinyl ketone (MVK) in water, the risk of reaction runaway can be avoided, and safety of the dehydrobromination reaction step can be improved by increasing the reaction temperature.

The α,β-unsaturated carbonyl compound, 3-bromo-3-butene-2-one (Br-MVK) is a versatile synthon for a wide range of synthetic transformations (Figure 1a). Synthesizing Br-MVK is of particular interest to medicinal and drug development chemists, as the heterocycles derived from Br-MVK are known to possess various biological properties. In particular, it is useful for the generation of heterocyclic compounds such as furans, thiophenes, aziridines, benzodiazepines, isoxazoles, imidazoles, spirocycles and fused heterocycles.


Figure 1 – 3-Bromo-3-butene-2-one (Br-MVK) is a versatile synthon for a number heterocycles

A major drawback is that Br-MVK is unstable at ambient temperature and is typically prepared in situ from its reasonably stable precursor, 3,4-dibromo-2-butanone (dibromo-MVK). Dibromo-MVK is prepared from brominating commercially available methyl vinyl ketone (MVK, Figure 2). Bromination of MVK has been reported in the literature under various reaction conditions, such as using low-boiling solvents (e.g. chloroform, pentane or ether), using a mixture of basic ionic liquids and water, acetic acid, or by reacting MVK with bromine neat (solvent-free) at -20°C. In nearly every case, there is some disadvantage, such as expensive reagents or selectivity, side reactions and polymerization resulting in poor yields.


Figure 2 – Synthesis of Br-MVK starting from MVK

Although the neat bromination of MVK works rather well, it is highly exothermic and hazardous to run. Based on reaction calorimetry (RC1) data, the adiabatic temperature rise (∆T) is 500 degrees. During the bromination, any loss of cooling, agitation or inadvertent bromine addition can lead to a runaway reaction and possibly a safety incident. Even during a laboratory scale bromination of MVK under these conditions, a cloud of fumes forms when each drop of bromine comes in contact with the MVK in the reaction flask, and the temperature jumps up. Bromine will also freeze inside the drip tube of the addition funnel during this process (bromine freezing point: -7.2°C). The major issue with this approach is the lack of solvent to absorb the heat of reaction (i.e. 82.8 kJ.mol-1); this should be amenable to attenuation with a solvent. To circumvent the thermal hazard, MVK bromination can be conducted in water.

Bromination of MVK in water

Water was chosen as the solvent as it has a very high heat capacity, MVK is readily soluble in it and it should be unreactive. To test this hypothesis, MVK was dissolved in 10 volumes of water and bromine was added at 0°C. The reaction exotherm was mild and bromine was added within a reasonable timeframe without any safety issue.

As soon as the addition of bromine was complete, two layerswere observed; a top light yellow aqueous phase, and a lower red-orange organic layer (3,4-dibromo-2-butanone). After phase separation, the dibromo compound wasobtained at 70% yield and in > 95% purity. The calculated adiabatic temperature rise of the MVK bromination reaction in 10 volumes of water was 24.3o.

There are several advantages in conducting the bromination of MVK in water. It eliminates the reaction runaway possibility, and bromine can be added at a much faster rate than under neat bromination conditions. Additionally, there is no freezing issue with bromine in the addition funnel drip tube as the reaction was conducted above the freezing point of bromine. Water not only controlled the reaction exotherm, it also removed some of the water-soluble impurities present in the starting MVK. Upon completion of the reaction, the dibromo compound was easily isolated by simple phase separation as it is significantly denser than water.

After the reaction, some residual bromine was detected in the aqueous waste by a qualitative Fuchsin Test. In order to quench the residual bromine prior to disposal, a hypo solution (60:1 mixture of Na2S2O3 and sodium carbonate in water) was added; however this led to elemental sulfur precipitation. To overcome this, the aqueous waste pH was adjusted to about 7 with 50% sodium hydroxide followed by 15% aqueous sodium sulfite.

Dehydrobromination of 3,4-dibromo-2-butanone

The dehydrobromination of dibromo-MVK to produce Br-MVK (Figure 3) has been reported in the literature using triethylamine in tetrahydrofuran at -15°C.


Figure 3 – Dehydrobromination of dibromo-MVK 

The reaction is moderately exothermic with an adiabatic temperature rise of 93 degrees.When the reaction was conducted at temperatures lower than -10°C, the RC1 data indicated that the energy equivalent of 35 degrees is generated during triethylamine addition, and energy equivalent to a 58o is released upon ramping the reaction temperature to 0°C. Conducting the reaction under these conditions and ramping to 0°C prior to workup may, therefore, cause a sudden exotherm and a runaway reaction on scale-up. To avoid this possibility, the reaction was successfully conducted close to 0°C without any quality issue. Under inert atmosphere, Br-MVK is reasonably stable at 0°C.

In conclusion

By conducting the bromination of methyl vinyl ketone (MVK) in water, the risk of reaction runaway was avoided. In addition, the safety of the dehydrobromination reaction step was greatly improved by increasing the reaction temperature to 0°C.

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