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10.1002/chem.201802208
Chemistry - A European Journal
FULL PAPER
Atom- and mass-economical continuous flow production of 3-
chloropropionyl chloride and its subsequent amidation
Marine Movsisyan,[a] Thomas S. A. Heugebaert,[a] Bart I. Roman,[a] Rudolf Dams,[b] Rudy Van
Campenhout,[b] Matthias Conradi,[b] and Christian V. Stevens*[a]
Abstract: 3-Chloropropionyl chloride is a chemically versatile building
block with applications in the field of adhesives, pharmaceuticals,
herbicides and fungicides. Its current production entails problems
concerning safety, prolonged reaction times and the use of excessive
amounts of chlorinating reagents. We developed a continuous flow
procedure for acid chloride formation from acrylic acid and a
consecutive 1,4-addition of hydrogen chloride generating 3-
chloropropionyl chloride, as presented in this paper. Up to 94%
conversion was reached in 25 minutes at mild temperatures and
pressures. This continuous flow method offers a safer alternative and
is highly efficient in terms of consumption of starting product and
shorter residence time. Valorization of this building block is
exemplified by the synthesis of beclamide, a compound with sedative
and anticonvulsant properties. Over 80% conversion towards this
drug was achieved in 1 minute in a continuous flow setup. Further
research is needed to telescope the synthesis of 3-chloropropionyl
chloride and subsequent beclamide formation without intermediate
purification.
Few patents on the batch production of 3-chloropropionyl chloride
[3a],[3b]
have been published over the last 25 years.
Two main
methods have been developed: a direct procedure from acrylic
acid and a two-step approach via the isolation of the intermediate
3-chloropropionic acid. The two-step procedure involved an initial
1,4-addition of HCl across acrylic acid under dry conditions and,
after isolation of the intermediate 3-chloropropionic acid, a
subsequent acid chloride formation with phosphorus trichloride[3a]
or thionyl chloride[3b]. Phosgene, thionyl chloride and phosphoryl
chloride were all found suitable as chlorinating reagents for the
direct chlorination of acrylic acid.[4] From an industrial point of view,
the direct dual chlorination is preferential, thus avoiding the use of
various reagents and purification steps.[3a] For safety reasons, use
of phosgene is, however, not appealing in large-scale
applications.[4d] The prolonged reaction times and significant
4c]
excess of chlorinating reagent (thionyl[4a,
or phosphoryl
chloride[4b]) in the cited processes reveal a considerable need for
improvement. In search of superior selectivity, safety, atom-
efficiency and efficacy while retaining simplicity, we turned
towards continuous flow technology.
Introduction
Chlorination and 1,4-addition reactions have already been
investigated separately in continuous flow systems. The
application of microfluidics for the radical photo-initiated synthesis
of chlorides of cycloalkanes and alkylaromatics with molecular
chlorine were published by respectively Ehrich[5], Matsubara[6]
and Kappe[7]. Heterogeneously catalysed chlorination of
nitrobenzene with trichloroisocyanuric acid has also been
conducted in a flow reactor system.[8] A reagent-bound solid-
phase column was developed by Letcka et al. for the
enantioselective α-chlorination of acid chlorides with 2,2,3,4,5,6-
hexachloro-3,5-cyclohexadien-1-one.[9] In a recent publication by
the group of Hessel, pure hydrogen chloride gas was safely and
continuously used for the conversion of bulk alcohols into the
corresponding chloroalkanes.[10]
Miniaturized systems have emerged as powerful tools to conduct
various types of chemistry, including the use and generation of
hazardous compounds in a safe manner. [1],[2] We have recently
demonstrated the acid chloride formation of saturated,
unsaturated and heterocyclic carboxylic acids.[1] Labile acid
chlorides were safely and continuously generated via an on-
demand and on-site procedure by using a continuous flow
microreactor setup.
Building on this experience, we have investigated alternative
routes and technologies for obtaining 3-chloropropionyl chloride,
a compound with broad use in adhesives, pharmaceuticals,
herbicides and fungicides.[3] The current large-scale synthesis of
3-chloropropionyl chloride poses safety issues given the use of
large amounts of chlorinating reagents for long reaction times. We
report a highly efficient procedure for the preparation of 3-
chloropropionyl chloride from acrylic acid involving the formation
of and 1,4-addition across acryloyl chloride.
The use of microstructured devices for the nucleophilic 1,4-
addition to α,β-unsaturated carbonyl compounds has been
disclosed by different groups. Michael additions are typically
exothermic reactions, making temperature control a crucial
aspect in process design. This can be met by the efficient mixing
and high surface to volume ratio, and thus excellent heat transfer,
in continuous flow reactors.[2, 11] The Michael addition of amines
to α,β-unsaturated carbonyls and nitriles in a continuous flow
setup was reported by Löwe et al..[12] The procedure ensured
excellent heat transfer, resulting in an 650-fold increase in space-
time yield compared to batch. Scale-up of the Michael addition of
[a]
[b]
Marine Movsisyan, Dr. Thomas S. A. Heugebaert, Dr. Bart I.
Roman, Prof. Dr. Christian V. Stevens
Department of Green Chemistry and Technology Ghent University
Coupure Links 653, 9000 Ghent (Belgium).
E-mail: Chris.Stevens@UGent.be.
piperidine to ethyl acrylate in microstructured devices was
Dr. Rudolf Dams, Rudy Van Campenhout, Dr. Matthias Conradi
Materials Resource Division
13]
investigated by Röder and coworkers.[11a,
Transfer to larger
3M Belgium BVBA
Haven 1005, Canadastraat 11, 2070 Zwijndrecht (Belgium)
equipment scale was envisioned by investigating the interaction
of transport and kinetic phenomena in microchannels.
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