DOI: 10.1002/chem.201602373
Communication
&
Continuous-Flow Synthesis
Harnessing Thin-Film Continuous-Flow Assembly Lines
Joshua Britton,[a, b] Jared W. Castle,[b] Gregory A. Weiss,*[a] and Colin L. Raston*[b]
This synthetic tactic can improve product yields and reaction
safety by avoiding the buildup of reactive intermediates.[5]
Recently, our efforts have focused on applying thin films for
continuous flow syntheses.[6] The vortex fluidic device (VFD)
mediates organic transformations in thin films that are about
250 mm thick. Rapid rotation of an angled sample tube con-
fines liquid reagents into a dynamic thin film without reactor
clogging. Here, vortexing, micromixing, and vibrations can
have dramatic effects on covalent and non-covalent bond for-
mation.[6b,7] These conditions have benefited both single-step
synthetic transformations and a thin-film assembly line synthe-
sis of lidocaine.[6a] This low-yielding proof-of-concept with lido-
caine has now matured into a high yielding and well-under-
stood system.
Abstract: Inspired by nature’s ability to construct complex
molecules through sequential synthetic transformations,
an assembly line synthesis of a-aminophosphonates has
been developed. In this approach, simple starting materi-
als are continuously fed through a thin-film reactor where
the intermediates accrue molecular complexity as they
progress through the flow system. Flow chemistry allows
rapid multistep transformations to occur via reaction com-
partmentalization, an approach not amenable to using
conventional flasks. Thin film processing can also access
facile in situ solvent exchange to drive reaction efficiency,
and through this method, a-aminophosphonate synthesis
requires only 443 s residence time to produce 3.22 ghÀ1
.
a-Aminophosphonates are bioisosteres of amino acids.
These well-studied pharmacophores appear in a large number
of pharmaceuticals including antibiotic,[8] antiviral,[9] and antitu-
mor compounds.[10] Our laboratories recently became interest-
ed in these molecules for single molecule enzymatic and bio-
synthesis experiments. As we required large quantities of such
compounds, a rapid continuous flow approach was developed.
This continuous flow setup simplified reaction scale-up, as the
process reported here can be run for long times without inter-
vention to yield large quantities of material using a relatively
small footprint VFD.
Assembly-line synthesis allows unprecedented reaction
flexibility and processing efficiency.
Plants and microbes synthesize a highly diverse range of poly-
ketide natural products through multistep enzymatic process-
es. Polyketide intermediates pass from one active site to an-
other, building up molecular complexity in an assembly line
fashion.[1] Through iterative modifications to a transferable
skeleton, this process of substrate channeling avoids inter-
mediate stockpiling. Such enzymatic pathways prevent reactive
species from diffusing back into bulk solution to avoid side re-
actions and also increase reaction efficiency.[2] As an analogous
laboratory process, multistep continuous flow has opened new
horizons in organic synthesis.[3]
Two common synthetic routes provide access to a-amino-
phosphonates. The first method applies a two-step process,
namely imine synthesis and then addition of a functionalized
phosphite. The imine is isolated before the second reaction,
termed the Pudovik reaction.[11] The Kabachnik–Fields reaction
avoids imine isolation through a three-component coupling re-
action with an amine, aldehyde/ketone, and a functionalized
phosphite (Figure 1A).[12] The versatility of a three-component
reaction makes it ideal for translation into a continuous-flow
assembly line process. Here, we also avoid imine isolation, har-
nessing optimal conditions for each individual step to improve
overall reaction efficiency.
Reaction telescoping applies multiple transformations to
a single scaffold without intermediate isolation and purifica-
tion. Although examples of reaction telescoping have been re-
ported in round-bottom flasks, continuous flow can improve
the efficiency of multistep transformations.[3a,4] Round-bottom
flasks cannot easily isolate reagents, reactions, and intermedi-
ates. In contrast, continuous flow can compartmentalize reac-
tions for specific amounts of time as governed by flow rates.
Continuous-flow synthesis in a VFD offers several advantag-
es. First, vigorous vortexing in thin films can drive evaporation
of H2O,[7a] a by-product during imine formation, thus accelerat-
ing the reaction. Second, translating a three-component reac-
tion into a continuous-flow system could facilitate reaction tel-
escoping through solvent-specific reaction confinement for the
individual steps.
[a] J. Britton, Prof. G. A. Weiss
Departments of Chemistry, Molecular Biology and Biochemistry
University of California, Irvine
California, 92697-2025 (USA)
[b] J. Britton, J. W. Castle, Prof. C. L. Raston
School of Chemical and Physical Sciences
First, conditions for each reaction step were optimized to
limit reaction residence times whilst maintaining high product
yields (Figure 1A; Supporting Information, Figures S1–S8). After
optimization, the total reaction time for imine formation and
the Pudovik reaction was only 5.5 min, which is far shorter
Flinders University, Bedford Park, Adelaide, 5001 (South Australia)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 1 – 5
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ