CHEMICAL SYNTHESIS


New synthesis methods: unsaturated ketones plus preparation of vinyl azides


This article describes two new chemical procedures with potential industrial applications, with a report on a a continuous- flow hydration–condensation protocol to access a series of valuable differently substituted chalcones starting from commercially available alkynes and aldehydes; the second new process is the first telescope protocol for preparing vinyl azides starting from the corresponding alkenes.


R


esearchers at the Institute of Organic Chemistry of RWTH Aachen University have developed a simple, practical and efficient continuous-flow hydration-condensation protocol for the synthesis of α,β-unsaturated ketones starting from alkynes and aldehydes by employing a heterogeneous catalyst in a flow microwave. The procedure gives straightforward and convenient access to valuable differently substituted chalcones and can be applied at multi-gram scale. The work is reported in Beilstein J. Org. Chem. 2011, 7, 1680–1687. In recent years, the development of continuous flow technology has expanded considerably and has had a significant impact on modern organic synthetic chemistry. Continuous flow processes offer advantages, such as operational simplicity, energy savings, reduced reagent consumption, and improved mixing quality, as well as precise control of reaction parameters, including pressure, temperature, residence time and heat transfer. In addition, the improved operational safety over classical batch reactions reduces the problems of working with hazardous chemicals. Furthermore, continuous-flow technologies allow chemical processes to be easily and rapidly scaled up, either by changing the volume of the single reactor, by performing the reaction for an extended reaction time, or by running the reaction in multiple reactors in parallel. Moreover, the products may be collected continuously and formation of byproducts may be reduced by the immediate separation of the products from the reaction mixtures. More recently, it has been shown that even asymmetric reactions can be conducted in a continuous- flow manner. Recently, the combination of flow processes and microwave technology has


22 sp2 Inter-Active March/April 2012


become of interesting in both academia and in industry. The combination of continuous- flow technology and microwave heating offers advantages such as a cleaner reaction profile, reduction of reaction times, higher yields and better selectivity.


Unsaturated ketones: key intermediates


α,β-Unsaturated ketones are a common motif found in the principal core of a large number of important biologically active compounds. They show pharmacological properties such as anti-malarial, anti- tumour, anti-viral and anti-inflammatory activities. They are also key intermediates in the synthesis of flavones, flavonoids, isoflavonoids and other heterocyclic compounds. Consequently, the development of an efficient synthesis to obtain these valuable compounds attracted the researchers interest.


“The development of continuous flow technology has


significant impact in modern organic


synthetic chemistry ”


They decided to develop an efficient continuous-flow synthesis of α,β-unsaturated ketones starting from alkynes and aldehydes by employing a heterogeneous solid acid catalyst. In the continuous-flow apparatus for the experiment, a 10ml reaction vessel was charged with the heterogeneous solid acid catalyst (10g) and inserted into the reactor. By means of a peristaltic pump the reagents were continuously pumped through the reaction vessel under microwave irradiation


expanded considerably and has had a


(50 W). The product solution was collected from the outlet tube, which was connected to a 250 psi backpressure regulator of the commercial flow microwave system. Initial reaction development was focused on finding the optimal conditions for the continuous-flow reaction of phenylacetylene with benzaldehyde applying the ion-exchange resin amberlyst-15 as a heterogeneous solid acid catalyst. Performing the reaction at 80°C afforded the α,β-unsaturated ketone in 70% yield. Running the reaction at higher temperature (90°C) showed a noticeable impact on the conversion and the product was isolated in 84%. However, a further temperature increase did not result in improved yield.


Next, the researchers examined the influence of the flow rate on the chemical yield. Performing the reaction at 90°C and 0.5 ml/min gave the product in 84% yield. A significant drop in chemical yield was observed when the


flow rate increased from 0.5 ml/min to 1.0 ml/min, indicating that the flow rate should be 0.5 ml/min. Further reaction optimisation was accomplished by varying the substrate concentration. While the chemical yields remained constant during an increase from 0.2M to 0.3M, performing the reaction at lower concentration (0.1M) afforded the product in lower yield. A slightly better conversion was obtained when the reaction was performed in dry solvent. However, the


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