Download The integration of flow reactors into synthetic organic chemistry

Review
Received: 2 May 2012
Revised: 30 November 2012
Accepted article published: 13 December 2012
Published online in Wiley Online Library: 25 February 2013
(wileyonlinelibrary.com) DOI 10.1002/jctb.4012
The integration of flow reactors into synthetic
organic chemistry
Ian R. Baxendale∗
Abstract
The material presented in this review is based upon discussions and interactions with members of the Department of Chemistry
and Biochemistry within the University of Windsor, Ontario, Canada. This article explores the changing face of chemical
synthesis with regard to the impact of flow based chemical processing technologies. Highlighted works from the Innovative
Technology Centre (ITC), Cambridge, UK, are used to illustrate the alternative synthetic practices available to modern research
chemists. The dominant theme of the review is the synergistic effects encountered by combining the advantages of continuous
processing regimes with the power of immobilized reagents and scavenger systems for multi-step organic chemistry.
c 2012 Society of Chemical Industry
Keywords: review; flow chemistry; organic synthesis; heterocycles; automation; technology
OUR CURRENT SYNTHESIS CAPABILITY
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It is probably not unreasonable to conclude that with the current
level of knowledge and synthetic tools almost any molecule that
we may wish to prepare could be synthesized in a reasonable
timeframe.
∗
Correspondence to: I.R. Baxendale, The Department of Chemistry, Durham University. South Road, Durham, DH1 3LE, UK. Email: [email protected]
The Department of Chemistry, Durham University, South Road, Durham, DH1
3LE, UK
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c 2012 Society of Chemical Industry
519
In recent years great advances have been made in our ability to
design assemble and test the products derived from chemical
synthesis. From the development of drugs in the ongoing fight
against disease to the more aesthetic aspects of society with the
preparation of perfumes and cosmetics, synthetic chemistry is the
pivotal science. Furthermore, the quality and quantity of our food
supply relies heavily upon synthesized products, as do almost all
other aspects of our modern society ranging from paints, pigments
and dyestuffs to plastics, polymers and other man-made materials.
As chemists our scientific and creative capacity to assemble
complex functional molecules from small chemical building
blocks has reached an impressive level of sophistication.
Much of this has been permitted as a consequence of our
greater understanding of chemical mechanics and molecular
interactions (e.g. Quantum mechanics, Frontier orbital theory,
in silico design). However, the standardization of synthetic route
planning using theoretical methodologies such as retro-synthetic
analysis or reaction selection and optimization through the use
of statistical analysis and factorial design have aided greatly
(i.e. Chemometrics, Principle Component Analysis, Design of
Experiment methodology).1 – 5
Another aspect of the synthesis process that has seen
tremendous change and progress is the analytical and
characterization tools that are now available. It would be
unthinkable to most modern molecule markers to embark on
a chemical route without having access to high resolution
NMR facilities, X-ray crystallography or some form of automated
analysis such as LC- or GC-mass spectroscopy. These and related
technologies have significantly enriched the information we as
chemists can derive from crude chemical reactions helping in
reaction profiling or aiding in elucidating the structural specifics
of the synthesized compounds. Indeed, characterization and
confirmation of a compounds identity that only a decade ago
would have been a week’s hard intense manual work can now
be processed and validated against literature sources in less than
a day. Such resources have as a consequence greatly enhanced
the quality and quantity of new chemical structures that can be
synthesized.
Furthermore, having easier on-line access and the ability to
call upon published or in-house archived chemical information
at the touch of a button has certainly affected the way in which
we approach and conduct chemical synthesis. The large number
of chemical search tools and literature- based databases that are
routinely available means that a greater degree of precedence can
be brought to bear on a chemical problem. This can enable the
odds to be stacked in the favour of the chemist by predetermining
the most appropriate sequence of reactions or offering alternative
strategic bond forming reactions that can provide lower costs,
alternative starting points or simply higher yielding processes. To
facilitate the searching and recording of new chemical data many
institutions and companies are adopting electronic laboratory
notebook (ELN)6 systems that will further enhance the level of
data retention and information that can be called upon for future
chemical syntheses.
The combination of many of these features has allowed for
the discovery of many new chemical transformations leading to
unique chemical architectures and the discovery of several novel
reagents with highly specific chemical reactivities. This in turn has
propagated and accelerated the rapid expansion of several areas of
synthesis such as organometallic chemistry, asymmetric synthesis
and catalyst promoted processes including organocatalysis.7 – 11
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Evaporate
Pure
product
Reaction
(heat/cool)
Quench/Work-up
Purify
Evaporate
Purify (distill/recryst)
Sequence involving a chemical transformation (involving heating or cooling in a round bottom flask), quenching
(neutralisation or decomposition of reactive intermediates), extraction (phase separation), drying, evaporation
of the solvent (isolation of the crude material), chromatographic purification (or alternatively distillation,
crystallisation or similar additional processing) and finally a further solvent evaporation (isolation of the required
pure fractions).
Figure 1. General processing sequence of a chemical reaction.
520
However, despite all the obvious successes resulting from our
synthesis programmes the fundamental way in which we physically
conduct chemical synthesis has remained relatively unchanged for
over two centuries.12 – 14 Remarkably, apparatus such as standard
glass round bottom flasks, condensers, measuring cylinders, test
tubes and Bunsen burners are all still commonly in use today
despite them being invented over 160 years ago. Consequently
laboratory practices have also become standardized to make the
best use of these tools and associated pieces of equipment. A
standard sequence for a reaction today and over a century ago
would still be easily recognizable to both bench chemists (Figure 1).
From a simple analysis of the individual processing steps it
is evident that for a single chemical transformation, which may
involve only one bond-forming or bond-breaking event, a series of
up to six additional manipulations (work-up and purification) can
be required. Interestingly, these supplementary operations, which
are essential but costly (in time and resources), add very little
intrinsic value to the compounds; they are necessary only because
of inefficiencies in our current synthetic practice (removal of spent
reagents and by-products).15 Many of these deficiencies result from
poor reactivity, low selectivity, incomplete reaction or extensive
by-product formation which is often a result of poor mixing
and temperature control in conjunction with the use of highly
reactive reagents. Our current chemical inclination is often to select
reagents for a particular transformation based on their enhanced
(high) reactivity thereby leading to quick chemical transformations
(short reactions times). However, the flip side of such a selection is
that the highly reactive reagents are less stable, being more prone
to decomposition and offering a higher potential for side reactions
(resulting in more waste). Consequently, a greater emphasis is
ultimately placed on purification, often translating into the need
to resort to column chromatography to facilitate the removal
of numerous small impurities. Interestingly, this is often still
the preferred option of many chemists even balanced against
a reaction with a longer processing time (no manual intervention)
yet then enabling a simple crystallization or distillation as the
only required work-up and purification. This philosophy of
quick and dirty chemistry coupled with substantial investment
in purification technology such as HPLC has largely been driven
by a time pressured discovery industry (both pharmaceutical and
agrochemical lead discovery) feeding a high throughput screening
monster.16 – 20 Unfortunately, such an approach, although fulfilling
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a role, does not ideally align itself with performing highly efficient
and well optimized chemical synthesis.
In addition the physical structure of the apparatus and types
of manipulation used in the reactions also impart limitations in
terms of the scale at which most synthesis can be conducted.
The ease of manual handling and the dimensions of the reaction
flasks used in standard laboratories define the practical lower
limit range to millilitres and hundreds of milligrams of substances
(without utilizing additional specialized equipment). Indeed, even
small-scale syntheses are often calibrated not due to a need
for such quantities of material but as a consequence of human
handling and convenience.21 This can mean that over long
synthetic sequences large quantities of starting materials are
required in order to elaborate the structures (loss of material
through incomplete reaction, by-product formation or manual
intervention). Furthermore, testing and optimizing the required
synthetic steps involves a significant investment of time and
manpower as well as precious substrates/reagents. This is
compounded by the complexity of evaluating and tuning the
many interlinked variables and parameters (for example, reaction
times, temperature, solvents, concentration, catalysts/additives
and stoichiometry) that can affect each chemical reactions
outcome (i.e. regiochemistry, stereochemistry, purity and yield).
Considering all these negative/impinging factors we need to
recognize the limitations of current working practice and acknowledge the need for improvement. This is especially true if we wish
to move to more sustainable chemical practices, as we must, if we
are to protect our rapidly dwindling natural resources. Therefore
in order to safely respond to the requirements of improving
productivity and efficiency we must embrace new opportunities
and explore alternative approaches to compound synthesis. The
current costs, scale-up issues, lack of reproducibility, manpower
wastage through repetitive and or routine tasks are unacceptable;
therefore change is inevitable and should be embraced.
AN ALTERNATIVE SYNTHESIS STRATEGY
During the last decade there has been a steady growth in
interest within the chemical community for flow based approaches
to synthetic targets due to the inherent benefits such as
automated and telescoped reaction sequences, quick reaction
optimizations and in-line work-up and purification.22 – 48 The
holistic nature of flow chemistry targets many aspects of both
c 2012 Society of Chemical Industry
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Integration of flow reactors into synthetic organic chemistry
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Figure 2. Cross-discipline synergistic interaction of flow chemical processing.
synthesis methodology and process engineering deriving both
environmental and economic drivers. Indeed, flow synthesis cuts
across several traditional boundaries within the sequential scaling
routes of syntheses (research scale, re-synthesis, kilo labs and
full scale manufacturing/formulation), combining aspects of both
chemical optimization and process intensification (Figure 2). As
a result it is a prerequisite to develop a working knowledge of
both the science of synthesis and an understanding of chemical
engineering principles. Consequently conducting flow chemistry
requires significant changes in synthesis planning and execution
and so we should be confident that the benefits derived are worth
the change in working practice. After all chemists have had over
230 years to perfect current synthesis techniques so why should
we suddenly attempt to change all this, what real benefits can
be derived? This is a sensible question to pose and one that may
take academia and industry several years to fully evaluate and
determine where the best returns can be made. In the meantime,
it is hope that throughout this article a number of areas can
be discussed which can already be adopted by synthesis groups
providing definable and tangible benefits.
FLOW CHEMISTRY: BACKGROUND
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521
Examples of flow-based chemical syntheses have existed for
several decades49 and are in fact a well-established practice
at manufacturing scales especially for the production of large
quantities of a given material. However, the innovative uses of
flow in the early stages of synthesis development – laboratory
based synthesis – are far less common. Unfortunately, although the
concepts of increased mixing efficiency, controlled scaling factors,
enhanced safety ratings and continuous processing capabilities
have all been well recognized, these benefits have not been
generically leveraged into conventional synthetic laboratories
(Figure 3).50,51 Over the last 10–12 years there has been a popular
resurgent interest in the use of flow based synthesis techniques
mainly driven by the availability of several commercial laboratory
flow synthesis platforms.52 – 61 During this period most academic
literature within the field has focused primarily upon aspects of
flow equipment development or its application to esoteric single
step reactions using the expanded processing window capabilities
that are available (Figure 4). Significantly less effort has been
directed at the more challenging issue of devising general and
versatile platforms capable of performing multi-step syntheses and
leading to pure final products that can be used directly in biological
evaluations or for the determination of some other fundamental
physical property.62 – 64 This is particularly important as it has
become increasingly apparent that the task of chemical synthesis
must become more closely linked with the immediate testing of
the newly prepared product. Working the two aspects in isolation
inherently leads to wasted synthesis time and the generation of
unwanted materials. Therefore more integrated and continuous
relay of information regarding the ongoing synthesis and its
products in terms of basic characterization, physical property
and biological/physical functions needs to be addressed. This act
of immediately gathering and analysing such data will ultimately
enable more educated and responsive choices to be made, varying
from mundane factors such as reaction optimization to higher level
decisions about which molecules should be synthesized next.
Although such a change will have a broad impact across all areas
of chemical production it will undoubtedly have a more drastic
and immediate effect on the production of therapeutic entities.
Although flow based chemical processing does provide many
advantages it should also be noted it does create certain inherent
difficulties when considering multi-step synthesis, such as: (i)
compensating for the kinetics of the different reaction steps
(integrating reactions in sequence with different reaction times); (ii)
compatibility of the solvent with all reaction steps; hence creating
the potential need for solvent switching protocols; (iii) the need
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Figure 3. Continuous flow synthesis benefits.
•
•
•
•
•
•
•
•
•
•
Shorter reaction times due to improved mixing and heating.
Higher yields and purities.
Easy Access to increased reaction window enabling access to pressures of 300 bar and
superheating of solvents up to 300°C.
Enabled cold reaction zones −120°C.
Multi-stage temperature zones for increased sensitivity processing windows.
Real-time analysis and optimization, incorporated DoE (less waste and more automation).
Scalability (simply increase the quantity made by running for longer).
Improved safety due to containment. Toxic or explosive chemistries can be performed which
would be problematic using traditional glassware/apparatus.
Small footprint reactors (more available laboratory space, less expensive glassware).
Direct in-line purificationcan be conducted (less costly purification requirements).
Figure 4. Some advantages of flow processing.
522
for intermediate purification by scavenging or in-line preparative
purification (preventing by-product build-up); (iv) dilution effects
of adding additional downstream flow streams; and (v) monitoring
and control of each concurrent operation. As such, although there
are many advantages to be gained from adoption of flow synthesis
approaches, a strong synthetic experience and good engineering
understanding are essential to fully reap the benefits.
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Flow chemistry for multi-step chemical processing
Conceptually, if a sequence of stepwise reactions can be performed
all in the same solvent (or a simple mechanism for solvent
exchange is available), and each reaction is highly optimized
then the reactions could be easily processed in tandem. In this
way the reaction mixture for one step becomes the reactant/s for
the next chemical transformation creating a telescoped sequence
c 2012 Society of Chemical Industry
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Integration of flow reactors into synthetic organic chemistry
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A
B
Figure 5. Processing modes of tandem chemical reactions.
(Figure 5(a)). In addition moving from a batch based working
regime to a continuous flow mode would significantly simplify the
processing requirements in terms of scheduling and manipulation
of the solutions (Figure 5(b)). Such an idealized scenario is in reality,
not feasible, due to the inevitable lower conversions and the need
to quench reactions, work-up intermediates and consequently
purify the reaction streams between chemical transformations. It
is however, possible to combine another enabling technology,
namely, solid-supported reagents and scavengers to facilitate this
process and maintain a continuous flowing sequence.
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Solid-supported reagents and scavengers in flow chemistry
Solid supported reagents have been used extensively in multistep organic syntheses in batch.65 – 83 Ideally, the use of such
reagents should provide clean products without chromatography,
crystallization, distillation or any traditional work-up procedures.
Supported reagents are reactive species that are associated
with a heterogeneous support material.84 They transform a
solution resident substrate (or substrates) into a new chemical
product (or products), with the excess or spent reagent remaining
tethered to the solid matrix making separation a simple processes.
In a similar fashion, impurities can be removed from a flow
stream using a scavenger species immobilized on a support. This
scavenger creates either an electrostatic or covalent interact with
the impurity, sequestering it from solution and binding it to the
solid matrix thereby effecting purification of the reaction stream.
By utilizing these supported components packed into simple
columns or reactor cartridges it is immediately possible to perform
multi-step organic sequences employing an orchestrated suite of
supported reagents to effect all the chemical transformations and
purifications.
As an illustration we have investigated the formation of 4,5disubstituted oxazoles in flow facilitated by solid-supported
reagents.85 An isocyanide and an acid chloride were mixed using
a glass microfluidic chip (274 µL or 1 mL in volume), typically
heated to 60◦ C, forming a reactive adduct (the imidoyl chloride);
the stream was then passed through a column containing
an immobilized P1 base, PS-BEMP, which facilitated cyclization
forming the oxazole (Scheme 1). In the sequence a slight excess
of the acid chloride starting material was used (1.1–1.2 equiv.) to
ensure complete consumption of the corresponding isocyanide
coupling partner. The residual acid chloride was later removed
by scavenging using a column of QP-BZA (a macroporous benzyl
amine resin). Using this approach a small library of 23 compounds
was generated, with yields in the range 83–98% and all members
being isolated in high purities (>95% as determined by LCMS and NMR); no further purification or work-up was required.
Sulfonates (from the corresponding tosyl substituent) could also
be prepared (nine examples, 81–94%) as well as phosphonates
(three examples, 84–85%) by using a similar synthetic strategy.
Of particular note was that the immobilized BEMP column
could be quickly regenerated for repeated use by washing
with a solution of BEMP in hexane or either NaOMe or t BuOK
in MeOH.
Interestingly, when these same oxazoles forming reactions were
conducted in batch the yields were generally poor, typically ≤50%.
The improvement in flow was ascribed to the different mixing
regime used to form the initial imidoyl chloride intermediate
under neutral conditions then rapidly processing this species
using an in-line base. In addition, the scaled synthesis of these
compounds could be achieved by simply using larger columns
of supported reagents and allowing the system to run for longer
periods of time (∼12 h, generating 10–25 g), clearly illustrating
the versatility of the instrumentation and the potential scalability
of this technology.
In these oxazole forming reactions the reactant concentration
was typically of the magnitude of 0.75 mol L –1 concentration. This
was selected as a standard value at which to prepare stock solutions
as several of the starting materials and resulting products were
highly crystalline and at higher concentrations proved insoluble.
The insolubility of materials in flow chemistry is a potential major
limitation (due to blockage of the reactors) and obviously needs
careful consideration in the planning stages. This aspect can
also be compounded by the in-line scavenging process which
increases the purity of the reaction stream making crystallization
or precipitation a more likely occurrence. Consequently for library
preparation using a variety of starting materials with differing
solubility remove or when employing a new/unknown reaction
it is often advisable to initially run the reaction under increased
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R
O
EtO
Cl
N
O
4-Br; 88%
4-I; 88%
3-Br; 85%
2-Cl; 98%
4-NO2; 83%
3-NO2; 91%
4-F; 94%
2-CF3; 98%
4-CF3; 95%
4-CN; 83%
2,5-F; 94%
3,4-OMe; 83%
N N
O
Pr
O
R
Cl
Cl
N
94% OEt
88%
O
O
O
O
O
N
O
O S O
Me
R = 3-NO2; 84%
R = 4-F; 84%
R = 4-Br; 84%
Me
N O
N O
O
EtO
O
N
O
N
S
92% O
O
81%
Me
O
EtO
O
Me
O
N
EtO
O
92%
Me
N
t
N
Me
EtO
99% O
92%
N
N
O
EtO
S
Me
t
O
N
S
O
Me
N N Me
EtO
N
O
EtO
Cl
O
N
O
86% O
O
R
EtO
Cl
O
O
N
F
O
Me
O
N
83% OEt
N
P
O
F
O
Me
O
N
OEt
83%
EtO
N
O
N
OEt
S
O
O
EtO
3-NO2; 85%
4-CF3; 84%
4-Br; 85%
90%
O
Cl
Me
Cl
O
O
N
S
Cl
O
O
89% O
O
N
94%
Bu
85% O
N
O
89%
N
O
N
N
Me
N
O
O
N
O
86% O
O
Me
87%
EtO
N
Me
O
Cl
O
O
N
N
N N Me
Bu
N
S
N
O
92%
EtO
N
93% O
Scheme 1. Synthesis of 4,5-disubstituted oxazoles using a flow reactor.
524
dilution. Running the reaction for longer periods of time can still
generate significant quantities of material using this approach or
the stock solutions can be made more concentrated for subsequent
runs or systematically increased during the same run period. An
advantage of flow processing is that stock solutions do not need
to be prepared in bulk, consequently with knowledge of the flow
rates being used it is possible to prepare additional volumes of
stock solution and by judicious modification of the flow rates
substitute the new reactant solutions at opportune timings. In
this way a staged concentration increase can be applied to the
reactor to maximize the throughput for a given reaction. This
is particularly beneficial when scaling a chemical transformation
and is significantly enhanced when employing in-line monitoring
techniques that allow for the rapid re-optimization of the reactor
conditions (temperature/flow rate) following a change in reagent
concentration thereby establishing a new steady state operation.
The accessible chemical structures were further expanded using
isothiocyanates and carbon disulfide as electrophiles, providing a
bifurcated route for the preparation of thiazoles and imidazoles.86
When aryl isothiocyanates inputs were used, often initially a
low yield of the desired thiazole was obtained from the reactor
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(Scheme 2). However, by eluting the PS-BEMP column with an
additional flow stream containing an electrophile (an α-bromo
ketone in the example shown), the regioisomeric imidazole
adduct could be isolated, providing combined yields of 76–100%
(Scheme 3). Investigation of the initially formed intermediate
suggested an open chain species was becoming trapped on the
resin, and that only after ring closure, instigated by alkylation,
was the secondary imidazole product being formed and released.
In a similar fashion the reaction between ethyl isocyanide and
carbon disulfide furnished a collection of the corresponding Salkylated thiazoles, again in good yields (72–97%) and excellent
purities.
We have also adopted similar strategies for the synthesis
of peptides in flow, generating rapidly optimized, highly
reproducibly, automated sequences that yield the desired product
in high purity; and isolated yields of 50–200 mg from a single
injection.87 In a standard procedure an N-protected amino acid
is pre-treated with PyBrOP, prior to flowing through a column of
PS-HOBt. The activated amino acid reacts with the immobilized
HOBt thereby becoming sequestered onto the solid phase as
the corresponding active ester (Scheme 4, Step 1). During the
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Integration of flow reactors into synthetic organic chemistry
Scheme 2. Synthesis of thiazoles in flow.
Scheme 3. Bifurcated synthesis of imidazole using solid-supported
reagents.
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repetition of the above procedure. For example, the tripeptide
Cbz-Phe-Ala-Gly-OEt was obtained in 59% overall yield in 6.5 h
starting from glycine.
Using a flow-based processing regime provides chemists with
an expanded range of capabilities and opportunities, providing
improved safety considerations, enhanced dispensing and mixing
coefficients, and when utilsing in-line real-time diagnostics with
the ability to make instant changes creating a new dynamic
chemical environment. Throughout these processes, the packed
cartridges or reactor coils can also be interacted upon by
various physical means such as heating/cooling, oscillation,
ultrasound, microwaves, irradiation or electrochemistry giving
a full range of chemical activations. Microwave heating of flow
reactors has proven particularly beneficial for several chemical
transformations.88 – 90 We and others have shown that it is possible
to simply modify standard laboratory microwave reactors to
function in continuous flow through mode.91 – 96 For example,
a glass insert reactor can be placed into the microwave cavity
allowing solutions to flow through the focused microwave field. By
applying a flow restriction by way of a back pressure regulator (BPR)
to the output of the reactor superheated reaction conditions can be
accessed. Illustrative of this process is the high temperature nonmetal catalysed intramolecular [2+2+2] alkyne cyclotrimerization
reaction shown in Scheme 5.97 A solution of the substrate in DMF,
a strongly absorbing microwave solvent, was easily maintained at
200◦ C for the duration of the reaction.
An alternative set-up which consists of a simple coil of
fluorinated polymer tubing (11.5 m of 0.4 mm i.d. tubing) wound
around a central Teflon core provides a flow microwave insert
with an internal volume of 1.45 mL (Figure 6).98 The Teflon spigots
can be easily spooled to replace a blocked or damaged unit
or to allow access to new configurations; for example, wrapping
different lengths of tubing to provide reactors with varying internal
volumes or multiple tubing lengths to accommodate different
reactions or flow rates within the same microwave device. The unit
is then easily accommodated within the cavity of a commercially
available microwave reactor such as the Emrys Optimiser with
the input and exit tubes on the underside of the microwave unit
(Figure 6(c)). One or more HPLC pumps are then used to deliver the
fluidic flows to the system, which is kept under positive pressure
through the use of a back-pressure regulator at the exit.
This reactor configuration has been successfully used to
synthesize a collection of 5-amino-4-cyanopyrazoles as building
blocks and starting materials for subsequent transformation
into more structurally diverse 4-aminopyrazolopyrimidines by
dimerization or the 1H-pyrazolo[3,4-d]pyrimidin-4-amine by
condensation with a nitrile (Scheme 6 and 7). To prepare the
pyrazole precusors various hydrazines and ethoxymethylene
malononitrile were heated together in the flow microwave reactor
(flow rates of 0.36–1.75 mL min−1 equating to residence times of
0.8–4.0 min) and then progressed through a scavenging sequence
to remove excess ethoxymethylene malononitrile followed by
a carbon based decolourising stage. The set-up could be
continuously run for periods up to 36 h at temperatures of
100–120◦ C in order to prepare 120–350 g batches of the bulk
intermediates in high yields and excellent purities.
The design and evaluation of novel microwave reactor inserts is
a valuable method of utilizing existing batch based processing
capabilities as offered by commercial microwave units and
adapting them to enable a more facile scale up. Conventionally
the direct scale up of a microwave reactions has been problematic.
Typical operating frequency of most commercial microwave
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525
loading sequence any unreacted starting material or by-products
can be washed through the column and directed to waste. The
HOBt-supported ester column is then automatically connected
in-line to a series of other reagents: PS-DMAP, and PS-SO3 H (a
polymer-supported sulfonic acid) (Scheme 4, Step 2). A solution of
a second, O-protected, amino acid as its hydrochloride salt is then
eluted through the column series. The PS-DMAP acts to furnish the
free-based in situ, which then progresses through the supported
active ester, forming the peptide bond. The flow stream then enters
the PS-SO3 H column, scavenging any unreacted amine. Finally, the
solvent is evaporated to give the product; several Boc, Fmoc and
Cbz N-protected dipeptides were generated in isolated yields of
61–81% without the need for purification by chromatography.
This same process can also be extended to the synthesis of
polypeptides. By simply incorporating a flow based N-deprotection
of a Cbz-protected dipeptide (Cbz-Ala-Gly-OEt) using the H-Cube
system, the free amine is produced which can be used in a
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Step 1: Loading
Step 2: Reaction
Scheme 4. Automated peptide synthesis in flow.
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Scheme 5. Flow microwave aromatization reactions using a glass insert reactor.
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Integration of flow reactors into synthetic organic chemistry
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B
C
Figure 6. (A) Teflon core; (B) spiral coil cavity insert reactor; (C) microwave insert twin tube.
Scheme 6. Continuous flow synthesis of pyrazoles under microwave
irradiation.
Scheme 7. Dimerization of pyrazoles and reaction with nitriles under
microwave irradiation.
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reactors (2.45 GHz) means they have a restricted penetration
depth of only a few centimetres into the reaction media.
Consequently the heating effect will decrease exponentially from
the surface to the inner region of a large reactor leading to nonhomogeneous heating. This intrinsic complication has tended to
prevent the direct scaling of microwave reactors past a couple of
litres inhibiting their use for the production of larger quantities
of material. Alternatively exploring the use of continuous
flow microwave processing avoids such considerations. Our
investigations have led us to construct a number of different
reactor designs which make use of existing microwave reactors to
establish flow through microwave experiments. As an illistration
two basic channel designs are shown in Figure 7.99 These consist
of a simple recessed baffled core (with an alternating stepwise
inclination) and a classical helical coil unit (easily prepared from
Teflon rods using standard machine cutting techniques). These
components were then placed into a simple straight glass cylinder
capped with Teflon end pieces which allowed connects to be
established to the flow stream whilst also securing the device in
the microwave camber.
By adopting these reactor configurations a series of different
chemistries have been successfully processed with regard to
scaling the reactions over time and in quantity of material
generated. For example, the Hantzsch reaction between
3-nitrobenzaldehyde and ethyl 3-oxobutanoate in the presence of
ammonium acetate and catalyzed by phenyl boronic acid (5 mol%)
was preformed. The reactor was operated continuously for 48 h
processing a total of 576 mL of reaction solution with a residence
time of 12.5 min equating to 349 g of isolated product (following
crystallization) (Scheme 8). This gives a good indication of the level
of enhanced processing that could be achieved using such simple
set-ups.
A simple glass column or coil containing an immobilized reagent
can also be utilized to conduct heterogeneous flow catalysis under
microwave irradiation. Reactions with metal-tethered catalysts,
e.g. polyurea microencapsulated palladium species (PdEnCat) are a
good example, whereby microwave heating activates the encased
palladium species (Figure 8).100
The microencapsulated catalyst can be packed into a simple
design U-tube reactor for easy alignment in the microwave
cavity. Often with microwave heating accurate and consistent
temperature measurement is difficult to achieve therefore to assist
in calibrating the system a modified reactor was commissioned
that allowed the insertion of a fibre optic probe into the flow
stream permitting more detailed thermal readings to be taken
(Figure 9). However, it should be noted that this reference point
still only supplies a bulk solution value which can be significantly
different to the actual localized temperature of a heterogeneous
species or catalytic site.101 – 112
Using this U-tube design in combination with a fixed bed of
the PdEnCat catalyst we were able to generate a flow system
for the rapid assembly of biaryl units via the Suzuki reaction
(Figure 10).113,114 A basic set-up delivered ethanolic solutions of
the aryl bromide, boronic acid and tetra-butylammonium acetate
as the base to mix prior to passage through the catalyst bed. A final
scavenging step with a polymer-supported sulfonic acid facilitated
the clean-up of the reaction stream upon exiting the reactor.
This approach gave products which were generally of a
higher purity than those generated through the analogous
batch reactions. This was ascribed to the fast reaction times;
the substrates were only heated for approximately one minute,
although during that period the effective catalyst concentration
was extremely high. Thus the desired cross-coupling was able to
take place, but the short time frame involved avoids decomposition
and prevents many side reactions from occurring.
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Figure 7. Microwave reactor Teflon flow tube inserts and dye flow injections highlights.
strategies to ensure that no hazardous starting materials or byproducts are carried through into the later multi-step processes,
thereby causing final product contamination. Some examples of
these processes from our laboratory which involve this concept of
direct in-line clean-up are illustrated below.
Scheme 8. An example of scaled microwave reaction.
Another advantage of this mode of operation was that the
same catalyst bed could be used to generate multiple products
in a serial fashion. Aliquots of the paired starting materials were
introduced in succession to the reactor interspersed by a washing
stage to ensure complete elution of the product before the next
pair of substrates was coupled (Figure 11). The yields of the
products obtained were consistent with those isolated from batch
processing and following solvent evaporation gave the desired
material directly in high purity. It was also shown that more efficient
use of the catalysts could be achieved when larger quantities of
the substrates were processed through the catalyst bed. In batch
most reactions required between 3–5 mol% of catalyst to ensure
complete conversion of the starting materials. Alternatively, in
flow, the reactor could be maintained under steady state operation
resulting in greater catalyst utilization pertaining to an effective
catalyst concentration of only 0.2 mol% (Figure 12). This concept
of increased efficiency with continued use is a significant benefit
of applying immobilized catalysts under flow conditions.
528
Reactive intermediates in multi-step chemical
transformations
The generation and in situ telescoping of reactive or unstable
intermediates directly into a secondary transformation is one of
the major processing advantages of flow chemistry. The capacity
to constantly produce a manageable quantity of a hazardous
chemical entity which remains contained within the reactor for
the duration of it existence offers may safety and handling benefits.
Several groups have demonstrated specific advantages in terms of
superior overall isolated yields, enhanced purities, increased safety
windows and shortened overall reaction times by integrating an
initial generation step with a subsequent reaction.115 – 118 We
believe it is also of critical importance to include in-line purification
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Curtius rearrangement
The Curtius rearrangement transforms carboxylic acids or acid
chlorides to the corresponding isocyanate functionality. The
reaction proceeds via an intermediate acyl azide which undergoes
rearrangement to give a reactive isocyanate which can in turn be
intercepted by a nucleophile to give a modifed product. We have
employed a Merrifield type azide ion-exchange monolith119 – 125 to
facilitate this transformation generating reactive acyl azides from
various acid chlorides which then undergo Curtius rearrangements
to give a variety of aryl isocyanates in a subsequent heated coil
reactor (Scheme 9).126
Alternatively for larger-scale applications the reactive acyl azide
could be generated using diphenylphosporyl azide (DPPA) directly
from carboxylic acids.127 In this protocol a solution of the carboxylic
acid with triethylamine plus a suitable nucleophile was loaded as
one reaction stream which was then combined with a second
stream containing diphenylphosphoryl azide (DPPA) (Scheme 10).
In practice an excess of the carboxylic acid was used to ensure
complete consumption of the DPPA reagent. On mixing of the
streams, an acyl azide was generated which on heating in a
convection flow coil (CFC) produced the isocyanate which was
quenched immediately with the in situ resident nucleophile
to give the desired products. A mixed acid/base scavenger
work-up was then used to remove the base, excess carboxylic
acid and by-products. For nitrogen-containing heterocyclic
carboxylic acid starting materials it was found necessary to
use a catch-and-release protocol128,129 to afford the purified
products.
Fluorination reactions
Fluorine is often added to drug molecules to improve binding or
provide greater metabolic stability. However, its introduction can
be difficult due to the hazards associated with the fluorinating
reagents. Using a flow microreactor system with immobilized
in-line purification means many of these hazards are eliminated
owing to the contained environment and the robustness of the
scavenging protocols.130
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Figure 8. PdEnCat, an immobilized palladium catalyst.
(a)
(b)
(c)
Figure 9. (a) Microencapsulated PdEnCat with the lower image being a TEM recording showing the palladium nano-clusters. (b) Simple U-tube PdEncat
packed reactor. (c) Side arm inlet reactor with Fibre optic probe insert for more accurate temperature measurement.
529
Figure 10. Flow microwave Suzuki reactions.
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IR Baxendale
Figure 12. Scaled-up processing of Suzuki reactions in flow using PdEnCat
catalyst.
Figure 11. Sequential processing of Suzuki coupling partners using a single
catalyst cartridge in flow.
530
Trifluoromethylation of aldehydes has been demonstrated using
TMS-CF3 (Ruppert’s reagent) as a source of nucleophilic ‘CF3 ’.131 In
particular, a fluoride monolith provided a versatile source of fluoride anions (Scheme 11). The reaction stream was purified using a
solid supported aldehyde to trap any unreacted Ruppert’s reagent,
while an acid resin acid deprotects the initially formed intermediate silylated product. Finally, an immobilized hydrazine sequesters
any unreacted aldehyde delivering a purified reaction stream.
Other flow methods for the introduction of fluorine involve
the use of commercially available fluorinating agents such as
1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetra
fluoroborate (Selectfluor) and diethylamino sulfurtrifluoride
(DAST). The safe work-up of these reactions is particularly
important but can again be achieved by the application of
immobilized reagents. The α-fluorination of an activated ketone
can be conducted using Selectfluor while similarly a fluoro-Ritter
reaction with olefinic substrates can be realized in the same reactor
set-up.132
In the first reaction, a stream of the activated carbonyl
was combined with a corresponding stream of Selectfluor and
heated (100–120◦ C) (Scheme 12). The product stream then
was purified using a combination of an’ immobilized sulfonic
acid and dimethylamine resins to scavenge excess reagents and
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by-products. This process afforded the desired products in high
yield and excellent purity.
The same reactor arrangement was also used for several fluoroRitter reactions whereby an alkene starting material in the presence
of wet acetic acid (<5% mol water) reacts with acetonitrile to
furnish a monofluorinated product (Scheme 13).
DAST (diethylaminosulfur trifluoride) is another useful reagent
for substituting fluorine for an alcohol or a carbonyl functionality
(aldehyde or activated ketone) yielding the corresponding mono
or di-fluorinated products (Scheme 14).130,132 In the process excess
DAST along with liberated HF were scavenged using a calcium
carbonate quench immediately followed by a silica gel plug to
trap inorganic salts. Although this scavenging procedure produces
quantities of carbon dioxide this is easily managed using the
continuous flow system thus avoiding pressure build-up. While
yields were affected by the electronics of the carbonyl moiety, the
reaction was found to be tolerant of a wide range of functional
groups, e.g. epoxides, alkenes, acetals, amines, esters, amides and
various heterocycles creating a very useful protocol.
DAST has also found application in the cyclodehydration
of β-hydroxy amines which are efficiently converted to the
corresponding oxazolines in excellent yields (Scheme 15).130,132
This has also allowed for the construction of a number of chiral
PyBOX ligands in flow.133,134
Flow synthesis of novel chemical building blocks
Access to a wide array of chemical building blocks is an
essential perquisite for many medicinal chemistry synthesis
programmes. These compounds can be simple core templates
enabling rapid chemical decoration in initial hit finding screens or
more specially tailored structures designed to enhance a certain
physical characteristic or present a particular functional pattern
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Scheme 9. Synthesis of acyl azides using a monolith reactor.
in later stage compound development. Their availability and cost
ultimately determines the scope of their usage, consequently
more automated ways of preparing these materials on demand
is particularly important. The next sections highlight some of the
flow chemistry methods that can be employed to generate specific
classes of useful building blocks.
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Diagnostics integrated with flow processes
Owing to the dynamic environment of a flow process it is
possible to effect rapid changes in reaction parameters leading
to immediate downstream changes in the reaction conditions.
Therefore utilizing real-time analysis of the flow stream it is
possible to harvest large amounts of data regarding multiple
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531
Ynones and pyrazoles as primary building blocks
The flow synthesis of ynones facilitated by in-line purification
furnishes reactive building blocks for further transformation to
numerous heterocyclic scaffolds.135 The attractive feature of this
process is the ability to split the product stream and divert these
towards different product outcomes by varying the subsequent
coupling agents. Using palladium catalysis an acid chloride and
acetylene can undergo a Sonogashira coupling to yield various
ynones (Scheme 16). The acid chloride and acetylene are combined
in flow with a stream containing a catalytic amount of Pd(OAc)2
and Hünig’s base. The reaction was then heated at 100◦ C for 30
min and the reactor output purified by passage through a series of
four solid reagents and scavengers. First, a polyol resin is used to
remove excess acid chloride, then a column of CaCO3 to trap HCl
formed during the reaction and to deprotonate any ammonium
salts. The resultant tertiary amine base (iPr2 NEt, Hünig’s base)
was next trapped on a sulfonic acid resin and finally a column
of immobilized thiourea removes palladium contamination. The
ynone products were thus obtained in high yield (41–95%) and
purity following removal of the solvent.
The ynones can be further elaborated by combination with
an additional input stream containing a nucleophile such as a
hydrazine or guanidine derivative. By uniting the flow streams and
heating the resultant mixture the corresponding heterocycles can
be prepared as a single linked flow sequence (Scheme 17). In this
way, a collection of pyrimidines, pyrazoles, oximes, guanidines and
flavones have been obtained.
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IR Baxendale
Scheme 10. Curtius rearrangements using DPPA.
reaction parameters that can be usefully employed to rapidly
optimize the transformation.136 – 138
Qualitative spectral data can be easily acquired using adjustable
wavelength photodiode detectors (or similar spectrometers)
placed as in-line analysis cells. Other diagnostic devices can be used
to report on reaction progress, e.g. impedance measurements,
Raman spectroscopy, near or React IR, fluorescence measurements
and various bioassays. Alternatively, or in addition, automated
sampling techniques can be used to divert aliquots of reaction
media into auxiliary monitoring equipment allowing LCMS or
GCMS to be assimilated into the system.
Butane-2,3-diacetal protected diols synthesis
React IR flow cells can be easily integrated to analyse flow streams
in real time including monitoring for the presence of important
transient or reactive intermediates (Scheme 18).139,140 We have
used such a system to help evolve a flow route to various
butane-2,3-diacetals (BDAs) which are key building block in many
natural product syntheses. The flow approach allowed the BDA
units to be prepared generally in higher yields and with higher
reproducibility than the corresponding batch processes.141 – 145
532
For example, the BDA protected tartrate was obtained from a
mixed stream of dimethyl-L-tartrate and trimethyl orthoformate
and a stream containing butane-2,3-dione together with catalytic
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quantities of camphorsulfonic acid (CSA). Mixing the dimethyl-Ltartrate and trimethylorthoformate resulted in the formation of an
intermediate orthoester which was observed using the ReactIR
flow cell and was identified as an important reactive species in
the diol protection. The processed product stream was finally
purified using an immobilized benzylamine scavenger to remove
any remaining butanedione and CSA catalyst which could again
be confirmed using the React IR flow cell. A periodate resin was
then employed to perform a rapid glycol cleavage of the residual
tartrate ester to generate a volatile by-products that could be easily
removed. This enabled the generation of multi-gram quantities
of the BDA protected adduct in a very reproducible fashion. Only
evaporation of volatiles was required in order to isolate the product
in a crystalline form.
This BDA-protected tartrate was further used as a starting
material in a two-step transformation first to furnish the
unsaturated system by treatment with a strong base in the
presence of iodine (Scheme 19). To clean up the reaction stream it
was quenched with simultaneous removal of the diisopropylamine
(HNiPr2 ) by elution through a sulfonic acid resin whilst the excess
iodine was scavenged using a thiosulfate resin. Finally, a short
plug of silica gel was used to remove the inorganic salts. Next
the selective hydrogenation of the alkene was achieved at scale
using the H-cube Midi system (from ThalesNano) yielding the
c 2012 Society of Chemical Industry
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Scheme 11. Synthesis of trifluoromethylated alcohols using a fluoride monolith.
Scheme 12. Electrophilic fluorine reactions with Selectfluor.
NHAc
OH
NHAc
NHAc
F
F
F
F
F
97%
86%
86%
F
NHAc
F
NHAc
83%
NHAc
NHAc
F
Cl
91%
96%
F
O
O
91%
89%
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Scheme 13. Ritter reactions performed using Selectfluor as an activator.
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N
Cl
Alcohols
OMe O
Cl
F
OH
R
N
97%
N
NO2
F
F
TrtO
83%
OH
O
Br
F
N
Aldehydes/Ketones
50%
N
F
F
N
O
F
F
94%
F
F
N
H
O
F
F
O
O
O
CN
50%
Cl
O
F
F
H/R
F
OMe
50%
O
R
Br
O
OMe
0.3 mL/min,
60 °C
NO2
O
96%
87%
DAST, DCM,
OMe
65%
Ph
F
F
92%
80%
Br
O
83% F
88% F
F
F
O
73%
I
IR Baxendale
F
71%
F
N
N
N
F
N
Cl
O2N
N
86%
87%
F
F
89%
F
O
F
O
F
N
75%
96%
N
Cl
O
F
F
F
83%
75%
Scheme 14. Synthesis of mono or di-fluorinated products using DAST.
Cl
O
R
HO
NH
N
R
O
O
Dehydration
Cl
Br
N
N
R
O
O
MeO
R = Ph 95%
R = i Pr 92%
R = t Bu 90%
N
N
O
MeO
O
87%
N
O
O
O
MeO
F
91%
F
N
N
O
90%
Scheme 15. Synthesis of oxazolines using DAST.
534
corresponding meso reduced form in quantitative conversion
using a Rh on alumina catalyst.
A more challenging sequence was also investigated involving
the generation of a BDA protected glyceraldehyde from the
corresponding mannitol starting material (Scheme 20). When a
small excess of butadione was used with gentle heating of the
reaction stream (40◦ C) an optimum yield of the desired product
was obtained. Applying the ReactIR system the procedure was
quickly optimized to reduced the propensity for the formation of
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the tris-protected by-product. A column of benzylamine resin was
used in-line at the end of the reactor to scavenge excess reagents
generating a clean flow stream.
From this protected material the half-aldehyde fragment was
readily obtained by oxidative cleavage of the diol unit using a resin
bound periodate oxidant (Scheme 21). Similarly, the analogous
methyl ester could also be formed (via additional oxidation of
the intermediate aldehyde) using an immobilized pyridinium
perbromide resin.
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Scheme 16. Synthesis of ynones.
Scheme 17. Synthesis of pyrazoles and pyrimidines.
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improved ratio of 24:1, exo:endo, compared with variable ratios of
between 15:1 and 5:1 in batch. The final double bond cleavage
employed a combination of Osmium EnCat and sodium perioidate
with N-methyl morpholine as a solution-phase reoxidant to give
the corresponding lactone. Clean-up of the reaction stream was
affected by passage through a sulfonic acid resin to scavenge
the morpholine then an immobilized thiourea to scavenge any
leached osmium. Isolation of the pure lactone product involved
only solvent evaporation.
3-Nitropyrrolidine building blocks
A functionalized heterocycle that is becoming increasingly
common in medicinal chemistry projects is the 3-nitropyrrolidine.
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535
In a final sequence a BDA protected glycolate, another
useful building block, was synthesized using related procedures
(Scheme 22).141,142 Applying similar conditions to those used
for the tartrate protection reaction above, enantiomericly pure
chloropropanediol was converted to the bis-acetal in 95% yield
without racemization. Indeed, this conversion proceeded so
efficiently that it was not necessary to incorporate the previously
used periodate cleavage protocol to remove unreacted diol (cf .
Scheme 18). The resulting chloride substituted product was then
treated with a strong base to effect elimination furnishing the exoalkene, the product stream being in this case collected into water
and extracted in a typical batch fashion. Interestingly, the new
flow procedure consistently produced high quality product, in an
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IR Baxendale
MeO
MeO
MeO
MeO
OH
MeO2C
CO2Me
OH
OMe
MeO2C
MeO2C
OO
OMe
CH(OMe)3
O
O
Scheme 18. Mettler Toledo ReactIR Flow Cell and flow synthesis of BDA protected tartrate.
Scheme 19. Flow synthesis of a BDA-protected tartate derivative.
This versatile motif can be readily prepared using TFA
(trifluoroacetic acid) or a fluoride source to generate a dipolar
structure from N-(methoxymethyl)-N-(trimethylsilyl)benzylamine
which will undergo cycloaddition with an alkene.143 – 145 Under
flow conditions a stream of the nitroalkene with TFA can
be combined with a second stream containing the coupling
partner (Scheme 23).146,147 The united flow stream is then heated
to facilitate the reaction and purified by scavenging with a
benzylamine resin and a short plug of silica gel thereby removing
any unreacted nitroalkene and releasing the product from its
initially formed TFA salt. Optimization studies revealed that
nitropyrrolidines could also be obtained under milder conditions
when a fluoride monolith was used to generate the dipole
component. Here the starting materials flowed through a heated
fluoride monolith prior to scavenging with a benzylamine resin to
afford pure products in high yields.
Using the H-Cube flow hydrogenator (ThalesNano) selective
reduction of the nitro group to the amine while retaining the
benzyl group could be performed using a Raney nickel catalyst.
This selective reduction ultimately enabled libraries of derivatives
to be rapidly assembled for biological testing (Figure 13).148
Alternatively both the nitro reduction and benzyl deprotection
could be achieved simultaneously when a Pd/C catalyst system
was employed.
536
Scheme 20. Flow synthesis of BDA protected glyceraldehyde.
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Scheme 21. BDA protected glyceraldehyde aldehyde or ester.
Scheme 22. Synthesis of BDA protected glycolate.
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Scheme 23. Synthesis of 3-nitropyrrolidines from the nitroalkene.
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IR Baxendale
Figure 13. A small sample set of pyrrolidine templates prepared in flow.
Triazoles
1,4-disubstituted triazole formation by copper(I) mediated [3+2]
Huisgen cycloadditions of an organic azide with a terminal
acetylene is of much current interest, with applications in many
different areas from cell biology to materials science. Our group
has used a series of immobilized reagent to prepare the triazoles
products in flow (Scheme 24).149 The cycloaddition was catalysed
using Amberlyst 21 (a benzylic dimethyl amine functionalized
resin) preloaded with copper(I) iodide with the flow stream being
directed through a cartridge of QP-TU (a thiourea metal scavenger)
to remove any leached copper residues. Finally, an immobilized
triphenylphosphine equivalent, PS-PPh2 , was used to scavenge
excess organic azide. This system afforded the desired compounds
in high purity without the need for chromatography and with no
Glaser homo-coupled acetylene products being observed.
Although this type of ‘Click chemistry’ is synthetically very
valuable it is restricted by the commercial availability of the
starting materials. In addition the azide and acetylene coupling
components have associated safety considerations regarding their
synthesis and use especially at scale. Consequently it would be
preferable to generate such species in situ and immediate use
them without isolation. We therefore devised a set of protocols
that allow the preparation of the individual units that can be
readily telescoped into our previously described cycloadditions
flow sequence as as shown in scheme 24.
538
Azide formation
We modified a set of batch conditions developed by Moses and
coworkers150 as a convenient starting point for the development
of a flow process for aryl azides (Scheme 25). However, in
this transformation the resulting azide products are potentially
contaminated with unreacted trimethylsilyl azide and aniline
starting materials both of which are toxic. The trimethylsilyl
azide can also be readily hydrolysed to toxic, volatile and highly
explosive hydrazoic acid. Thus, contamination with unreacted
starting material is not only a concern in terms of product purity,
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but presents an unacceptable risk in terms of process safety,
particularly for large scale synthesis. Therefore, a scavenging
protocol was developed to purify in-line the azide product stream
using readily available and inexpensive scavenger resins. As shown
in Scheme 25, following azide synthesis, the reaction stream
passes through a scavenging column containing PS-sulfonic acid,
followed by PS-dimethylamine. The PS-sulfonic acid traps any
unreacted aniline (red band) while at the same time converting
any remaining trimethylsilyl azide to hydrazoic acid, which is in
turn trapped onto the QP-DMA (orange colouration).
Having established a reliable sequence to these azide intermediates they can be telescoped into a number of additional
transformations for example a Staudinger aza-Wittig reaction
employing a monolithic triphenylphosphine reagent or cycloadditions reactions to form 5-amino-4-cyano-1,2,3-triazoles.151,152
Acetylene formation
The Seyferth–Gilbert homologation of an aldehyde using
the Bestmann–Ohira reagent has been successfully run in
a flow microreactor leading to the formation of acetylenes
(Scheme 26).153 The aldehyde starting material along with the
Bestmann–Ohira reagent were combined with a secondary stream
of potassium tert-butoxide and introduced to a heated flow
coil. The reaction stream was first scavenged with immobilized
benzylamine to remove excess aldehyde, then a sulfonic acid
resin to both remove excess base and protonate any phosphoric
residues. Finally, a dimethylamine resin was employed to remove
acidic impurities. The acetylene could then be collected in high
yield. A small modification to the sequence was necessary for
nitrogen-containing starting materials where the sulfonic acid
resin was substituted for an alumina packed cartridge to avoid
capture of the newly formed product.
Demonstrating the full utility of working in a multi-step regime
the Bestmann–Ohira reagent was further used in the direct
transformation of an alcohol through to the corresponding
triazoles in a single continuous sequence (Scheme 27). The
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Scheme 24. Copper catalysed [3+2] Huisgen cycloadditions.
Scheme 25. Formation of aryl azides in flow.
benzyl alcohol starting material was first selectively oxidized
upon passage through a column of immobilized TEMPO, with the
resulting aldehyde reacting with the Bestmann–Ohira reagent
under subsequently established basic conditions. The freshly
generated acetylene was immediately coupled with the in situ
azide (Cu catalysed) and progressed through the previously
described train of scavenger and reaction cartridges to finally
afford the triazole in high purity and 55% isolated yield after
crystallization.
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Preparation of casein kinase inhibitors
As an illustration a four-step flow assisted synthesis of a series of
casein inhibitors has been described.154 The route was developed
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539
Target orientated synthesis
As has been aptly demonstrated flow chemistry is ideally suited
to the rapid production of small building blocks enhancing the
diversity of available structures by making use of the improved
safety profile and extended processing windows inherent with
the contained reactor design. The inclusion of high levels of
automation and an improved safety profile also allow the option
of preforming several traditionally ‘forbidden chemistries’ further
expanding the chemical repertoire available to the operator.
However, this is only a small component part of the wider
task of a synthesis chemist who must also assemble these
molecular fragments into more elaborate constructs. Here again,
flow chemistry can be used to assist in the multi-step assembly
process. Indeed, it is often more apparent what the true processing
potential of flow chemistry provides when viewed in the context
of a target driven synthesis.
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H
H
H
IR Baxendale
H
H
OMe
H
Cl
81%
NO2
NO2
>90%
H
MeO2C
N
77%
84%
H
H
H
N
Cl
Br
65%
73%
Cl
78%
O
O
N
Me
N
71%
H
H F3 C
Ph
79%
82%
64%
88%
Scheme 26. Synthesis of acetylenes using the Bestmann–Ohira reagent in flow.
Scheme 27. Synthesis of a triazole direct from an alcohol starting material in a multi-step sequence.
540
to allow variations of the substituents at positions 2, 3 and 6 of the
imidazopyridazine core, in total a collection of 20 analogues were
rapidly assembled. The sequence necessitated the development
of a continuous flow method to safely scale up an organometallic
reaction conducted at low temperature (Scheme 28). To provision
the reactor a dual loop filling system was devized that enabled
a constant supply of a butyllithium solution (or LiHMDS) to the
reaction stream. By using a simple valve selection system one
sample loop could be filled while the second fed the reactor. A
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rapid exchange between the two loops permitted an essentially
seamless feed of the organometallic solution.
In the second step an immobilized perbromide was used
to enable mono-bromination through controlled contact time
of the solution passing through the polymeric packed bed
reactor (Scheme 29). The resulting mono-bromo intermediate
was immediately subjected to a high temperature condensation
reaction with 6-chloro-3-pyridazinamine to furnish the bicyclic
imidazopyridazine core. Finally, a liquid handler was used to
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Scheme 28. Organolithium deprotonation in flow.
J Chem Technol Biotechnol 2013; 88: 519–552
reactor at low temperatures for several days with a consistent and
stable temperature, there is no need to supply coolant or dose
the device with liquid nitrogen or dry ice and so maintenance
and user involvement is minimal. Consequently we were able to
generate libraries of boronic acid components and also conduct
scaled experiments by simply running the reactor for a longer
period of time.
Target orientated synthesis of a 5HT1B antagonist
A seven-step batch synthesis of the potent 5HT1B antagonist
developed by AstraZeneca160 was previously described in an
overall yield of 7%. This synthesis consequently became a
benchmark for the evaluation of the potential benefits of using
flow chemistry for target development (Figure 16).
Our flow synthesis of this pharmaceutical was instigated by
combining streams of 3-fluoro-4-nitroanisole and piperizine at
135◦ C to promote the SN Ar. The exiting reaction was scavenged
with a benzylamine resin to remove the liberated hydrofluoric acid
prior to its transmission to a continuous flow hydrogenation.161 The
outflow containing the aniline intermediate was scavenged with
a thiourea resin to ensure complete removal of any potentially
leached palladium species (Scheme 31). Following a solvent
switch, from ethanol to toluene, the flow stream containing
the newly formed aniline was combined with a solution of
dimethyl acetylenedicarboxylate and heated. An in-line scavenge
for residual dicarboxylate and the use of anhydrous potassium
carbonate to remove traces of water allowed the stream to be
telescoped into a high temperature cyclo-condensation reaction.
An in-line BPR operating at 250 psi was fitted to the system to
maintain the system pressure under these superheated conditions.
The output stream from the stainless steel reactor coil was rapidly
cooled to ambient temperature and mixed with a third input
flow of THF/H2 O. The combined flow stream was then progressed
through a column containing an ion exchange hydroxide resin
which promoted ester hydrolysis and simultaneous capture of the
resulting carboxylic acid on the basic resin. The final step involved
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541
automate sequential compound generation through an SN Ar
reaction to give amine diversified imidazopyridazine derivatives
(Figure 14).
The ability to access low temperature domains for chemical
processing is a vital prerequisite for many selective chemical
transformations. As well as impacting upon selectivity it can
also influence the stability of many chemical reagents such as
organometallic reagents and facilitates control of reaction rates
reducing the propensity for uncontrolled run away reactions.
This therefore becomes particularly important when considering
process development routes and scaled manufacture where
cryogenic temperatures also become expensive and challenging
engineering problems. It has therefore been of significant general
interest to the chemical community that as a consequence of
their high surface to volume ratios many microreactor systems
display excellent heat transfer charactoristics.155 – 158 This often
means a greater stability in reaction temperature especially when
mixing reactive reagents. As a consequence many reactions can
be effectively conducted at higher temperatures than would
be possible under the corresponding classical batch set-ups (a
lower temperature is often used in batch to compensate for the
formation of hot-spots, mixing fluctuations and inherent reactor
gradients – cooling from the outside of the reactor towards the
centre). Because of the high surface to volume ratio encountered
in many flow systems (coil and chip reactors) cooling is very
efficient. We have evaluated the potential of scaling processes
under reduced temperatures for example the formation of the
versatile coupling components aryl boronic acids (Scheme 30).159
Two independent flow streams were pre-cooled in a short length
of tubing prior to being combined and reacted at −60◦ C. The
halogenated aromatic underwent lithium halogen exchange and
then rapidly quenched upon the pinicol boranate ester in situ. The
newly formed ate species was decomposed under acid conditions
using an in-line sulfonic acid quench. To conveniently establish
the cryogenic conditions we made use of a polar bear flow reactor
(Figure 15). The device allowed the continual running of the
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IR Baxendale
Scheme 29. Construction of a series of imidazopyridazine compounds in flow.
Figure 14. Compound collection of casein kinase inhibitors.
542
an amide coupling reaction and a catch-and-release purification.
This was conducted by flowing a solution of O-(benzotriazol1-yl)-N,N,N ,N -tetramethyluronium tetrafluoroborate (TBTU) and
HOBt (hydroxybenzotriazole) through the column containing the
immobilized carboxylate intermediate. This resulted in activation
of the carboxylate by formation of the active ester thereby releasing
it from the resin. The flow stream containing the HOBt-activated
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ester was directed to merge with an additional stream of
4-morpholinoaniline leading to amide coupling. Purification of the
reaction stream was achieved using a ‘catch-and-release’ strategy
with a sulfonic acid containing column. This resulted in trapping
of the product which was washed and subsequently released
by eluting with methanolic ammonia. The final solution was
concentrated and the crude inhibitor isolated by recrystallization
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Scheme 30. Synthesis of aryl boronic acids at reduced temperatures.
Figure 15. The polar bear cold flow reactor from Cambridge Reactor Design.
Figure 16. AstraZeneca’s 5HT1B antagonist.
to obtain an 18% overall yield of the product effectively trebling
that of the original batch process.
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Imatinib (Gleevec)
The synthesis of the tyrosine kinase inhibitor Gleevec, a treatment
for chronic myeloid leukaemia and gastrointestinal stromal
tumours, proved an interesting test of the capabilities of flow
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543
δ-opioid receptor agonist
The use of a React IR flow cell to evaluate reaction progression
greatly aided in the construction of the multi-step synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide, a potent δ-opioid receptor agonist originally developed by AstraZeneca (Scheme 32).162 A twofold excess of the
Grignard reagent, diisopropylmagnesium bromide, was used as
a base to catalyse amide formation between diethylamine and
the methyl ester and then to further deprotonate the bridging methylene group which was subsequently added into a
Boc-protected piperidinone. The resulting tertiary alcohol was
quenched and scavenged by passage through a sulfonic acid containing cartridge, with any residual piperidinone being removed
via a hydrazine functional resin. The React IR cell was positioned
in the flow path at the end of this series to determine the dispersion and effective concentration of the passing alcohol product
stream. This enabled the controlled and automatically regulated
introduction of a solution of Burgess’ reagent to meet the alcohol
inducing the dehydration at an elevated temperature. The final
stage of the process involved a ‘catch-and-release’ purification on
a additional column of sulfonic acid resin which at 60◦ C also promoted the cleavage of the Boc-protecting group. The release step
was conducted with a solution of ammonia in methanol allowing
the isolation of the target molecule in an impressive 35% overall
yield and in high purity.
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Scheme 31. Flow synthesis of 5HT1B antagonist.
544
chemistry since all the previous batch syntheses involved the
generation of very insoluble intermediates.163,164 This is an issue
which is often raised as a significant hurdle for the wider adoption
of flow processing. Nevertheless, a flow synthesis was realized
through a reverse coupling strategy to that employed in the batch
route.165,166
Following Scheme 33, solutions of the appropriate acid chloride
and aniline coupling partner were united prior to entering a flow
coil generating the corresponding amide. The product stream was
collected using an automated fraction collector (triggered by a
UV detector) after its passage through an in-line acid and base
scavenger sequence. The product aliquot was collected into an
incubated vial which already contained a known concentration of
N-methylpiperazine in DMF. A nitrogen gas purge was then used
to evaporate the volatile DCM solvent producing a homogeneous
DMF mixture of known relative stoichiometry ready for the next
transformation. Both the collection and reintroduction of the
reaction solution into the system was automated via the use
of an autosampler. Passage of the reaction mixture through a
heated column containing calcium carbonate, as a basic media,
promoted the substitution of the benzylic chloride. An immobilized
isocyanate species placed in-line ensured complete removal of any
excess N-methylpiperazine allowing the product to be efficiently
caught onto a column of silica-supported sulfonic acid. After
washing, the product was released from the silica support by
elution with a solution of DBU (the base for the next step). The
solution was then subjected to a Buchwald-Hartwig coupling with
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an advanced amine fragment prepared as described in Scheme 17.
Following an extensive screening study the most effective catalyst
system was found to be the ligand stabilized BrettPhos Pd precatalyst. It was further discovered that the introduction of an
additional water stream input just prior to the reactor exit aided
dissolution of precipitate salts ensuring easy separation at the end
of the sequence. The organic output was concentrated in vacuo
and directly loaded onto a silica samplet cartridge for automated
flash chromatography to give imatinib in 32% yield and greater
than 95% purity.
Using the same sequence but modifying the various inputs also
allowed the generation of several derivatives (Figure 17). Running
the reactor set-up in a fully automated mode allowed a new
compound to be generated on average every 8 hours.
Grossamide
As an example of using directed feedback routines to optimize
and facilitate the synthesis of new materials the assembly of
the natural product grossamide is a key defining synthesis
(Scheme 34).167 A number of important techniques and procedures
were brought together in this work that have been significant in
influencing many recent multi-step syntheses: (a) both the input of
starting materials and the product elution were controlled using
liquid handlers; (b) throughout the optimization process, the
reactions were monitored using in-line LC-MS analysis enabling
flow rates and stoicheiometries of reagents to be changed in
order to deliver the product in maximum yield and purity; and
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Scheme 32. Preparation of a δ-opioid receptor agonist.
545
Scheme 33. Flow synthesis of the tyrosine kinase inhibitor Gleevec.
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IR Baxendale
Figure 17. Gleevec derivatives formed using the automated flow reactor.
(c) the system employed a number of automated exchangeable
reagent columns, and an in-line UV detector was used to monitor
the flow stream’s progress. This enabled many valve switching
operations to be performed automatically under computer
control.
For the initial amide bond forming reaction we built upon
our previous work constructing peptides in flow (Scheme 4).87
In this case (Scheme 34) the desired amide was synthesized
by coupling tyramine and ferulic acid using the immobilized
HOBt protocol previously described. Following elution from
the sulfonic acid scavenging column the product stream was
diluted (3:1) with a second input solution containing a hydrogen
peroxide–urea complex and sodium dihydrogen phosphate buffer
(pH 4.5). The entire mixture was then passed through a prepacked column containing the enzyme horseradish peroxidase
(type II) supported on silica to perform the oxidative dimerization
and intramolecular cyclization to yield grossamide. This compact
synthesis demonstrates many advantages of drawing together
enabling technologies such as automation, immobilized reagents,
enzymatic reagents and flow chemistry to generate complex
chemical structures.
One major advantage of flow chemistry and the level of
automation that is involved is that once a synthetic sequence
has been worked out and implemented, it is relatively trivial to
perform the same reaction again. Indeed, many of the operational
parameters can be simply reloaded into the software from
the original run providing duplicate reaction conditions. We
have used this approach to repeatedly prepare quantities of
various coumarin-8-carbaldehydes as selective IRE1-binders for
investigations of mRNA splicing (Scheme 35).168 Having access
to freshly prepared material has been benifical for the biological
work as the aldehyde substrates tend to undergo auto oxidation
upon storage. One particular route to these molecules is depicted
in the scheme as shown below. The synthesis provides clean,
easily isolated material (via filteration) which requires only drying
prior to use. Furthermore, the operation of the reactor can be
performed by numberous people and actually requires very little
chemical experience in order to conduct the repeat synthesis. This
significantly increases access times to these compounds when
scheduling time allocation in a busy synthesis laboratory.169,170
546
Oxmaritadine
A further convincing showcase for this mode of working is the
total synthesis of the biologically interesting natural product
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oxomaritidine which utilizes a combination of scavengers and
five different immobilized reagents to conduct each of the eight
contiguous steps of the sequence (Scheme 36).171
The initial step of the synthesis involved the transformation
of 4-(2-bromoethyl)phenol to its corresponding azide which
was achieved by the action of a packed bed azide exchange
resin. The output stream containing the organic azide was
then directed into a second column containing an immobilized
phosphine species; this resulted in the formation of a solidphase aza-Wittig intermediate. In a convergent sequence the
aldehyde, 3,4-dimethoxybenzaldehyde, was prepared. For this
reaction a column of polymer-supported tetra-N-ethylammonium
perruthenate (PSP) was used to oxidize the prerequisite alcohol,
and the aldehyde product stream was passed directly into the
column containing the aza-Wittig intermediate, reacting to yield
the imine adduct. This imine-containing solution flowed on and
was next subjected to continuous flow hydrogenation using an
H-Cube system, to yield the resultant secondary amine. A solvent
exchange was affected using a V-10 solvent evaporator and the
crude material re-dissolved in DCM for continued processing.
The amine solution was next passed into a microfluidic reaction
chip to combine with an additional stream of trifluoroacetic
anhydride (TFAA) resulting in trifluoroacetylation of the amine.
The reaction stream was directed through a column of polymersupported (ditrifluoroacetoxyiodo)benzene (PS-PIFA) which acted
to perform the phenolic oxidative coupling, generating the
seven-membered spirodieneone. Finally, removal of the amide
protecting group was conducted with a column of hydroxide
ion-exchange resin, acting to facilitate deprotection of the
secondary amine which spontaneously undergoes cyclization to
give oxomaritidine in 40% overall yield and 90% purity. The
entire route took only approximately 6 h of flow processing time
which compares favourably with the batch run time of about
4 days.
CONCLUSION
Although flow chemistry has already proven itself as a valuable tool
in manufacturing settings its adoption for small-scale laboratory
applications or within research environments has until recently
only been via a small number of enthusiastic pioneers and
innovators. However, there is a rapidly expanding body of scientific
evidence which continues to demonstrate the tremendous
benefits and enhanced processing capabilities inherent to the
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Scheme 34. Flow synthesis of Grossamide using in-line LC-MS monitoring.
547
Scheme 35. Synthetic flow route to coumarin-8-carbaldehyde.
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Scheme 36. The multi-step flow synthesis of oxomaritidine using solid-supported reagents.
548
bench chemist by embracing flow processing. Consequently, even
many of the original sceptics are now exhorting the merits of
flow synthesis. However, despite the growing acceptance and
adoption of this technology it is certainly true there are still a
number of limitations that need to be overcome in order for it
to be truly accepted as a mainstream chemistry technique. For
example, one important pre-requisite in flow chemistry is the
choice of an effective solvent that avoids precipitation that can
lead to blockages in the flow pathway. Although this is often
over-emphasized as a critical issue (as it can be easily avoided)
it does still require careful consideration as part of the synthesis
planning stage and so imparts certain restrictions. Furthermore,
in many synthetic routes it is also essential to be able to modify
concentrations or fully exchange solvents between steps, therefore
to harness the full benefits of continuous flow synthesis this
should ideally be accomplished as part of an in-line telescoped
sequence in a fully automated fashion. Without this facility to
make adjustments to the reaction solution the complex multi-step
synthetic transformations which are currently regularly performed
in batch will always remain difficult to translate to flow. Therefore
a greater degree of development is urgently needed with regard
to procedures and equipment for direct solvent exchange and inline evaporation. In fact the whole area of downstream chemical
work-up and purification is becoming an increasingly important
aspect of flow processing. Currently very few practical solutions
to continuous reaction quenching and aqueous extractions are
available within research environments despite these already
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existing for use at large scale (i.e. counter current extraction
methodologies). This is obviously limiting the scope and wider
adoption of flow technologies.
Heavily linked to synthesis in the future will be a direct increase
in the real time monitoring and analysis of each stage of the
chemical process. Advances in the integration of diagnostic tools
will enable greater use of smart automated monitoring routines
capable of first harvesting comprehensive reaction data and then
interpreting the results to make informed decisions regarding the
minor calibration and tailoring or full optimization of an operation.
This work is currently a major research area which will rapidly
expand the capabilities of many flow operations.
In the long term, the future of flow chemistry hinges, more,
upon its ability to adapt rapidly to the demands of changing
scale, allowing the reproducible production of varying quantities
of final product for multiple applications in short time frames. New
flow platforms will be required to generate both large numbers
of structural diversity products albeit in small quantities for highthroughput screens yet also simplify the operational up-scaling of
the routes to furnish hundreds of grams to kilograms for early stage
physiochemical profiling and toxicology testing. Of additional
interest will be the concept of ‘make and screen’ which attempts
to remove a traditional bottleneck in the discovery process by linking the synthesis component to rapid in-line biological evaluation
or property determination. Indeed, the processing requirements
to only prepare and then evaluation a microgram or less of a
final material would considerably reduce cycle times, streamline
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Integration of flow reactors into synthetic organic chemistry
compound logistics and ultimately lead to reduced synthesis cost.
In addition it becomes entirely possible to address several biological or physical assays at once. For example, a single experiment
could provide kinetics in terms of on- and off-rates directly yielding
a comparable measure of affinity and activity. Simultaneously in
another part of the system measurements of other physical characteristics such as pKa, log P or solubility could be taken by simply
diverting part of the synthesis product flow stream.
Many of the fundamental requirements in terms of information
retrieval and flexibility of synthetic implementation seem ideally
suited to a flow based approach to chemical synthesis. However,
for this concept to be successfully realized the delivery of
clean material for testing is essential, and immobilization
techniques – both in terms of synthetic reagents, and particularly
heterogeneous purification agents – will have a central role to play.
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Storer RI, Takemoto T, Jackson PS, Brown DS, Baxendale IR and Ley SV,
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Baxendale IR and Ley SV, Synthesis of the alkaloid natural products
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and scavengers. Ind Eng Chem Res 44:8588–8592 (2005).
Baxendale IR and Ley SV, Synthesis of alkaloid natural products
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Hodge P, Synthesis of organic compounds using polymer-supported
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Salimi H, Rahimi A and Pourjavadi A, Applications of polymeric reagents in organic synthesis. Monatshefte für Chemie
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Baxendale IR, Ley SV and Sneddon HF, A clean conversion of
aldehydes to nitriles using a solid-supported hydrazine. Synlett
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Baxendale IR, Ernst M, Krahnert WR and Ley SV, Application
of polymer-supported enzymes and reagents in the synthesis of gamma-aminobutyric acid (GABA) analogues. Synlett
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Kann N, Recent applications of polymer supported organometallic
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Lu J and Toy PH, Organic polymer supports for synthesis and for
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Ley SV, Baxendale IR, Bream RN, Jackson PS, Leach AG, Longbottom
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using solid-supported reagents and scavengers: a new paradigm in
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Baumann M, Baxendale IR, Ley SV, Smith CD and Tranmer GK,
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Baxendale IR, Ley SV, Tamborini L and Voica F, A bifurcated pathway
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Baxendale IR, Ley SV, Smith CD and Tranmer GK, A flow reactor process
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Lidström P, Tierney JP, Wathey B and Westman J, Microwave assisted
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Wilson NS, Sarko CR and Roth GP, Development and applications of
a practical continuous flow microwave cell. Org Process Res Dev
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Baxendale IR and Pitts MR, Microwave flow chemistry: the next
evolutionary step in synthetic chemistry? Chem Today 24:241–245
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Baxendale IR, Hayward JJ and Ley SV, Microwave reactions under
continuous flow conditions. Comb Chem High Throughput Screen
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Glasnov TN and Kappe CO, Microwave-assisted synthesis
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Glasnov TN and Kappe CO, The microwave-to-flow paradigm:
translating high-temperature batch microwave chemistry to
scalable continuous-flow processes. Chem Eur J 17:11956–11968
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Saaby S, Baxendale IR and Ley SV, Non-metal-catalysed
intramolecular alkyne cyclotrimerization reactions promoted by
focussed microwave heating in batch and flow modes. Org Biomol
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Smith CJ, Iglesias-Sigüenza J, Baxendale IR and Ley SV, Flow and batch
mode focused microwave synthesis of 5-amino-4-cyanopyrazoles
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Pears DA and Smith SC, Polyurea-encapsulated palladium
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Integration of flow reactors into synthetic organic chemistry
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131 Baxendale IR, Ley SV, Lumeras W and Nesi M, Synthesis of
trifluoromethyl ketones using polymer-supported reagents. Comb
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132 Baumann M, Baxendale IR and Ley SV, The use of diethylaminosulfur
trifluoride (DAST) for fluorination in a continuous-flow
microreactor. Synlett 14:2111–2114 (2010).
133 Baumann M, Baxendale IR, Brasholz M, Hayward JJ, Ley SV and Nikbin
N, An integrated flow and batch-based approach for the synthesis
of O-methyl siphonazole. Synlett 10:1375–1380 (2010).
134 Battilocchio C, Baumann M, Baxendale IR, Biava Kitching MO, Ley
SV, Martin RE, Ohnmacht SA and Tappin NDC, Scale-up of flowassisted synthesis of C 2-symmetric chiral PyBox ligands. Synthesis
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135 Baxendale IR, Schou SC, Sedelmeier J and Ley SV, Multi-step synthesis
by using modular flow reactors: the preparation of yne--ones and
their use in heterocycle synthesis. Chem Eur J 16:89–94 (2010).
136 Parrott AJ, Bourne RA, Akien GR, Irvine DJ and Poliakoff M, Selfoptimizing continuous reactions in supercritical carbon dioxide.
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137 Bourne RA, Skilton RA, Parrott AJ, Irvine DJ and Poliakoff M, Adaptive
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supercritical carbon dioxide. Org Process Res Dev 15:932–938
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138 Stevens JG, Bourne RA, Twigg MV and Poliakoff M, Angew Chem Int
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139 Carter CF, Lange H, Ley SV, Baxendale IR, Wittkamp B, Goode JG and
Gaunt NL, ReactIR flow cell: a new analytical tool for continuous
flow chemical processing. Org Process Res Dev 14:393–404 (2010).
140 Carter CF, Lange H, Sakai D, Baxendale IR and Ley SV,
Diastereoselective chain-elongation reactions using microreactors
for applications in complex molecule assembly. Chem Eur J
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141 Carter CF, Baxendale IR, O’Brien M, Pavey JBJ and Ley SV, Synthesis of
acetal protected building blocks using flow chemistry with flow I.R.
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142 Carter CF , Baxendale IR, Pavey JBJ and Ley SV, The continuous flow
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143 Bigotti S, Malpezzi L, Molteni M, Mele A, Panzeri W and
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144 Wright SW, Ammirati MJ, Andrews KM, Brodeur AM, Danley
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145 Bucsh RA, Domagla JM, Laborde E and Sesnie JC, Synthesis
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146 Baumann M, Baxendale IR and Ley SV, Synthesis of 3-nitropyrrolidines
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147 Baumann M, Baxendale IR, Wegner J, Kirschning A and Ley SV,
Synthesis of highly substituted nitropyrrolidines, nitropyrrolizines
and nitropyrroles via multicomponent-multi-step sequences
within a flow reactor. Heterocycles 82:1297–1316 (2011).
148 Baumann M, Baxendale IR, Kuratli C, Ley SV, Martin RE and Schneider
J, Synthesis of a drug-like focused library of trisubstituted
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149 Smith CD, Baxendale IR, Lanners S, Hayward JJ, Smith SC and Ley
SV, [3 + 2] Cycloaddition of acetylenes with azides to give 1,4disubstituted 1,2,3-triazoles in a modular flow reactor. Org Biomol
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150 Barral K, Moorhouse AD and Moses JE, Efficient conversion of aromatic
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151 Smith CJ, Nikbin N, Smith CD, Ley SV and Baxendale IR, Flow synthesis
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108 Blackwell HE, Out of the oil bath and into the oven – microwaveassisted combinatorial chemistry heats up. Org Biomol Chem
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109 Baxendale IR and Ley SV, A flow reactor process for the synthesis
of peptides utilizing immobilized reagents, scavengers and catch
and release protocols. J Comb Chem 7:483–489 (2005).
110 Baxendale IR, Martinelli M and Ley SV, The rapid preparation of
2-aminosulfonamide-1,3,4-oxadiazoles using polymer-supported
reagents and microwave heating. Tetrahedron 61:5323–5349
(2005).
111 Herrero MA, Kremsner JM and Kappe CO, Nonthermal microwave
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112 Obermayer D, Gutmann B and Kappe CO, Microwave chemistry in
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effects. Angew Chem Int Ed 48:8321–8324 (2009).
113 Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S and
Tranmer GK, Microwave-assisted Suzuki coupling reactions with
an encapsulated palladium catalyst for batch and continuous-flow
transformations. Eur J Chem 12:4407–4416 (2006).
114 Sedelmeier J, Ley SV, Lange H and Baxendale IR, Pd-EnCat (TM)
TPP30 as a catalyst for the generation of highly functionalized
aryl- and alkenyl-substituted acetylenes via microwave-assisted
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115 Illg T, Löb P and Hessel V, Flow chemistry using milli- and
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116 Webb D and Jamison TF, Continuous flow multi-step organic
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117 Yoshida J-I, Flash chemistry: flow microreactor synthesis based on
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118 Ley SV and Baxendale IR, The changing face of organic synthesis.
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119 Roper KA, Lange H, Polyzos A, Berry MB, Baxendale IR and Ley SV,
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120 Lange H, Capener MJ, Jones AX, Smith CJ, Nikbin N, Baxendale IR and
Ley SV, Oxidation reactions in segmented and continuous flow
chemical processing using an N -(tert -Butyl)phenylsulfinimidoyl
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124 Urban J, Svec F and Frechet JMJ, Hypercrosslinking: new approach to
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125 Pirkle WH and Pochapsky TC, Considerations of chiral recognition
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126 Baumann M, Baxendale IR, Ley SV, Nikbin N and Smith CD,
Azide monoliths as convenient flow reactors for efficient Curtius
rearrangement reactions. Org Biomol Chem 6:1587–1593 (2008).
127 Baumann M, Baxendale IR, Ley SV, Nikbin N, Smith CD and Tierney JP,
A modular flow reactor for performing Curtius rearrangements as
a continuous flow process. Org Biomol Chem 6:1577–1586 (2008).
128 Solinas A and Taddei M, Solid-supported reagents and catch-andrelease techniques in organic synthesis. ChemInform 38:45 (2007).
129 Palmieri A, Ley SV, Polyzos A, Ladlow M and Baxendale IR, Continuous
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130 Baumann M, Baxendale IR, Martin LJ and Ley SV, Development
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Smith CJ, Nikbin N, Ley SV, Lange H and Baxendale IR, A fully
automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3triazoles. Org Biomol Chem 9:1938–1947 (2011).
Baxendale IR, Ley SV, Mansfield AC and Smith CD, Multistep
synthesis using modular flow reactors: Bestmann-ohira reagent
for the formation of alkynes and triazoles. Angew Chem Int Ed
48:4017–4021 (2009).
Venturoni F, Nikbin N, Ley SV and Baxendale IR, The application of
flow microreactors to the preparation of a family of casein kinase I
inhibitors. Org Biomol Chem 8:1798–1806 (2010).
Cukalovic A, Monbaliu J-CMR and Stevens CV, Microreactor
technology as an efficient tool for multicomponent reactions.
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Nagaki A, Takizawa E and Yoshida J, Generations and reactions of
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Ducry L and Roberge DM, Controlled autocatalytic nitration of phenol
in a microreactor. Angew Chem Int Ed 44:7972–7975 (2005).
Browne DL, Baumann M, Harji BH, Baxendale IR and Ley SV, A new
enabling technology for convenient laboratory scale continuous
flow processing at low temperatures. Org Lett 13:3312–3315
(2011).
Horchler CL, McCauley Jr. JP, Hall JE, Snyder DH, Moore WC, Hudzik TJ
and Chapdelaine MJ, Synthesis of novel quinolone and quinoline2-carboxylic acid (4-morpholin-4-yl-phenyl)amides: a late-stage
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Qian Z, Baxendale IR and Ley SV, A flow process using microreactors
for the preparation of a quinolone derivative as a potent 5HT(1B)
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Qian Z, Baxendale IR and Ley SV, A continuous flow process
using a sequence of microreactors with in-line IR analysis
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for the preparation of N,N-diethyl-4-(3-fluorophenylpiperidin4-ylidenemethyl)benzamide as a potent and highly selective
δ-opioid receptor agonist. Chem Eur J 16:12342–12348 (2010).
Hopkin MD, Deadman B, Baxendale IR and Ley SV, The synthesis of BcrAbl inhibiting anticancer pharmaceutical agents Imatinib, Nilotinib
and Dasatinib. Org Biomol Chem DOI 10.1039/C2OB27003J: (2012).
Latest info required
Hopkin MD, Baxendale IR and Ley SV, A flow-based synthesis
of imatinib: the API of Gleevec. Chem Commun 46:2450–2452
(2010).
Hopkin MD, Baxendale IR, Deadman B and Ley SV, An expeditious
synthesis of Imatinib and analogues utilising flow chemistry
methods. Org Biomol Chem DOI: 10.1039/C2OB27002A (2012).
Latest info required
Ingham RJ, Riva E, Nikbin N, Baxendale IR and Ley SV, A
‘‘catch–react–release’’ method for the flow synthesis of 2Aminopyrimidines and preparation of the Imatinib base. Org Lett
14:3920–3923 (2012).
Baxendale IR, Griffiths-Jones CM, Ley SV and Tranmer GK, Preparation
of the neolignan natural product grossamide by a continuous-flow
process. Synlett 427–430 (2006).
Cross BCS, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM,
Silverman RH, Neubert TA, Baxendale IR, Ron D and Harding HP, The
molecular basis for selective inhibition of unconventional mRNA
splicing by an IRE1-binding small molecule. PNAS 15:E869–E878
(2012).
Zak J, Ron D, Riva E, Harding HP, Cross BCS and Baxendale
IR, Establishing a flow process to Coumarin-8-carbaldehydes
as important synthetic scaffolds. Chem Euro J 32:9901–9910
(2012).
Battilocchio C, Baxendale IR, Biava M, Kitching MO and Ley SV, A
flow-based synthesis of 2-Aminoadamantane-2-carboxylic acid.
Org Process Res Dev 16:798–810 (2012).
Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby
S and Tranmer GK, A flow process for the multi-step
synthesis of the alkaloid natural product oxomaritidine: a new
paradigm for molecular assembly. Chem Commun 2566–2568
(2006).
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J Chem Technol Biotechnol 2013; 88: 519–552