Lake Como 2|4 October 2011 - CHIMICA Oggi/Chemistry Today

Huisgen cycloaddition to rufi namide: pressure impact on reaction environment and
kinetics
Svetlana Borukhova a , Alvaro C. Varas a , Volker Hessel a , Qi Wang a , Paul Watts b , Charlotte Wiles c
a Eindhoven University of Technology, Department of Chemical Engineering & Chemistry, The Netherlands
b Department of Chemistry, University of Hull, United Kingdom
c Chemtrix BV, Geleen, The Netherlands
Click Chemistry is a multi-step synthetic concept recently introduced by Sharpless (1).
The variant of the Huisgen 1,3-dipolar cycloaddition paves new routes into the discovery and production of drugs.
This work will follow the fi rst fl ow route for Click chemistry, most recently developed (2).
We aim at high-temperature operation to speed up the reaction to industrial productivity and high-pressure operation with
extended (dielectric constant ε, viscosity η, and reaction constant k) material and kinetic parameter space - with hope for a
catalyst-free process while maintaining stereoselectivity.
Then, a commercial drug, Rufi namide, which was reported to be in the top-200 best selling
drugs of recent years (3), would be synthesized under intensifi cation of its fl ow synthesis.
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Using commercial equipment (Labtrix ® S1 system from Chemtrix BV) a safe and effi cient way
of organic azide preparation under continuous fl ow at decreasing the reaction time was
demonstrated, to get acquainted with the fi rst step in Click Chemistry.
3-Phenylpropyl methanesulfonate and 1-bromo-3-phenylpropane were converted to the
respective azides ((3-azidopropyl)benzene) at 100% conversion in 30 s.
Chemical intensifi cation was needed and achieved via a high-T route (195˚C) for 1-chloro-3phenylpropane
2, which is only a fair leaving group; achieving then complete conversion
in 20 min for a 1:1 reactant ratio.
Using high-c conditions in addition (doubling the azide salt) reduced the time for complete
conversion further to 60 s.
In new research, the synthetic plan is to start with 2,6-difl uorobenzylchloride and sodium azide
salt to produce alkyl azide, which will then react according to a procedure proposed (4)
with methyl 3-methoxyacrylate to yield a [3+2] cycloaddition product, that when treated with
ammonia in methanol will result in a precipitated product, Rufi namide.
Massive speed-up of the Rufi namide synthesis is expected to achieve under superheated
conditions, through the exponential dependence of the reaction rate on temperature as
described by Arrhenius equation.
The same can be achieved by pressure only - chemical equilibria and rates as well as the
Gibbs’ enthalpies of reaction and activation volumes are strongly infl uenced by pressure –
caused by the pressure-induced changes of physical properties of matter such as density,
viscosity, dielectric constant, or conductivity.
The model reaction is to be studied under the pressures up to 2000 bars in this research.
Normally, a copper catalyst is used to block one of the addition sites of the alkynes (enes) in
Click Chemistry.
Instead and to simplify the process, we propose to use steric hindrance, normally seen as an
obstacle in reactions, to reach similar stereoselectivity by virtue of the pressure effect, resulting
in a catalyst-free process.
(1) Kolb H.C., Sharpless, K.B. Drug Discov.Today, 2003, 8, 1128.
(2) Smith C.D. , Org. Biomol. Chem., 2007, 5, 1559.
(3) Baumann M., Baxendale I.R., J. Org. Chem.,2011, 7, 442.
(4) Mudd W.H., Stevens E.P., Tetrahedron Letters, 2010, 51, 3229.
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Lake Como
2|4 October 2011