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Multi-step continuous-flow synthesis

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Cite this: DOI: 10.1039/c6cs00830e

Joshua Britton*† and Colin L. Raston*

Organic chemistry is continually evolving to improve the syntheses of value added and bioactive
compounds. Through this progression, a concomitant advancement in laboratory technology has
occurred. Many researchers now choose to mediate transformations in continuous-flow systems given
the many benefits over round bottom flasks. Furthermore, reaction scale up is often less problematic as
this is addressed at the inception of the science. Although single-step transformations in continuous-flow
systems are common, multi-step transformations are more valuable. In these systems, molecular
complexity is accrued through sequential transformations to a mobile scaffold, much like an in vitro
Received 21st November 2016 version of Nature’s polyketide synthases. Utilizing this methodology, multi-step continuous-flow systems
DOI: 10.1039/c6cs00830e have improved the syntheses of active pharmaceutical ingredients (APIs), natural products, and
commodity chemicals. This Review details these advancements while highlighting the rapid progress,
[Link]/chemsocrev benefits, and diversification of this expanding field.

Key learning points

(1) Continuous-flow synthesis aids multi-step transformations by providing efficient mixing and thermal control.
(2) Continuous-flow chemistry allows reaction and reagent confinement during multi-step transformations.
(3) In-line purification of intermediate compounds is vital to increase reaction yields and efficiencies.
(4) In-line spectroscopy allows detection of intermediate compounds to ensure maximal yields are maintained.
(5) Active Pharmaceutical Ingredients (APIs), natural products and commodity chemicals have benefited from continuous-flow syntheses.

Organic chemistry continually evolves to develop novel rapidly heat and cool reactions,6 micromix solutions,7 and improve
approaches to the construction of active pharmaceutical ingredients reaction homogeneity affords opportunities to explore novel trans-
(APIs), value added compounds, and vital materials. For hundreds formations while being environmentally conscious and creative.8
of years chemists have addressed these challenges by performing In addition, continuous-flow systems incorporate reaction
reactions in round bottom flasks; an approach often suitable for a scale-out at the inception of the science, allowing for effective
plethora of syntheses. However, with a significant advancement in on-demand compound generation in compact, reconfigurable
laboratory technology, chemistry has the opportunity to become devices.9 In this context, ‘scaling-out’, or ‘numbering up’ refers to
more efficient, safer, and automated. Translating reactions into an array of continuous-flow systems operated in parallel to
continuous-flow systems is aiding researchers in pursuit this vision. meet the required output.10 For example, imagine that A and B
Continuous flow chemistry continues to thrive in academic react to give C. In a parallel array, both reagents A and B would
and industrial laboratories fuelled by efficient and innovative be fed into several continuous-flow devices, and the product C
syntheses. As a result, this discipline has diversified and channeled into a central collection. If the required output was
expanded to provide novel, and practical solutions to organic 5 L h1, and each reactor had a capacity of 0.5 L h1, then it
chemistry, biochemistry,1,2 renewable fuels3,4 and materials would require an array of ten reactors to meet the demand.
synthesis.5 Mediating transformations in continuous-flow systems Although several commercially available systems can mediate
offers several advantages compared to the same reaction in a continuous-flow transformations, many laboratories construct
round bottom flask. The ability of continuous-flow systems to their own equipment from affordable and readily available
parts. Furthermore, plans for continuous-flow devices can be
downloaded and printed within hours using a fused-deposition
School of Chemical and Physical Sciences, Flinders University, Bedford Park,
South Australia, 5042, Australia. E-mail: [Link]@[Link]
modeling-type printer,11 expanding opportunities for researchers
† Current address: Department of Chemistry, Massachusetts Institute of Technology, curious about the benefits of continuous flow. However, organic
77 Massachusetts Avenue, Cambridge, MA 02139, USA. E-mail: jbritton@[Link]. solvents are often not compatible with the materials used in the

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fabrication of these devices. Thus, when considering material A multi-step continuous-flow reaction is when more than
choice, care must be taken. For those new to the field, PFA tubing one transformation occurs to a mobile motif in a single sequence.
is a more suitable starting point (vide infra). In this respect, reaction telescoping could also be an adequate
At the core of continuous-flow systems are pumps that drive description. However, unlike reaction telescoping (multiple trans-
fluids through channels, tubes, or packed beds in a continuous formations without purification of intermediates) in round bottom
fashion (Fig. 1). Multi-step continuous-flow platforms are essentially flasks, continuous-flow systems allow the possibility of in-line
several reactors connected into a single flow sequence. To draw a purification and reagent introduction at set points in the
comparison, reactor coils are analogous to round bottom flasks in continuous-flow sequence. Furthermore, plug flow conditions
that they mediate chemical transformation. The injected fluid and reaction compartmentalization can be utilized to drive
flows into reactor coils where the specific transformation is higher reaction efficiencies. Plug flow describes a certain type
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subjected to a range of conditions. For example, the fluid of fluid movement through the reactor. In plug-flow regime, the fluid
entering the reactor coil can be rapidly heated or cooled to moves through the reactor in thin uniform plugs. It is assumed that
mediate an effective transformation. Typically, reactor coils are there is perfect mixing in the vertical direction, but none in the
constructed from PFA or stainless steel, but can be constructed horizontal. To this avail, reactions are compartmentalized to each
from catalytically active metals such as copper (Fig. 1F). Here, plug of fluid moving through the reactor. This means that chemical
the internal diameter and length of the reactor coil dictates the species have limited diffusion from one plug to another.
residence time of the fluid within the system. Mixers and unions This Review focuses on multi-step continuous-flow reactions
connect reactor coils together, and allow the addition of new from 2009 onwards. Prior to 2009, an excellent Review exists,12
reagents to the continuous-flow stream. The solution can be as do several discussion on the benefits of flow chemistry.12,13
flowed through packed bed reactors to ensure efficient mixing, The transformations described herein have been simplified for
or to provide exposure to immobilized reagents for synthetic clarity and consistency. The synthesis of, and towards, 22 APIs
transformations (Fig. 1E). Furthermore, in-line separation of are detailed, as well as numerous other transformations including
immiscible fluids (e.g. toluene and water) is possible through the synthesis of intermediates en route to natural products.
the use of membrane-based liquid–liquid separators (Fig. 1G).
In these separators, the organic component passes through a
membrane into a new continuous-flow stream. In-line liquid–
1. Functional group transformations
liquid separators have been highly utilized, and are discussed This section examines multi-step continuous-flow functional
below. Finally, the continuous-flow system is normally operated group transformations. In each of the examples, the benefits of
under a level of backpressure, controlled by a backpressure mediating the reaction in continuous-flow have been highlighted.
regulator (Fig. 1H). Subjecting the continuous-flow stream to a The purpose of this section is to provide a source of inspiration
backpressure allows solvents to be used above their atmospheric for future transformations while exploring the benefits of
boiling points while ensuring reaction homogeneity as the continuous-flow systems over round bottom flasks.
solution passes between reactor coils at different temperatures.
Such a large toolbox of continuous-flow equipment leads to 1.1 Amides
reaction diversity and flexibility, allowing demanding chemical Amides are fundamentally important molecules due to their
challenges to be met. vast biological occurrence and synthetic versatility. In this

Dr Joshua Britton earned his MSci Prof. Colin Raston AO is SA

at the University of Nottingham, Premier’s Professorial Research
UK and undertook his PhD studies Fellow in Clean Technology. He
at The University of California, completed a PhD with Prof Allan
Irvine and Flinders University, White, and after postdoctoral
South Australia under the studies with Prof. Michael Lappert
guidance of Prof. Gregory A. Weiss at the University of Sussex, was
and Prof. Colin L. Raston. He is appointed a lecturer at The
currently a postdoctoral associate University of Western Australia
with Prof. Timothy F. Jamison at then to chairs at Griffith, Monash,
MIT. His research interests include Leeds (2001) and UWA (2003),
merging the power of biocatalysis before moving to Flinders
Joshua Britton with multi-step organic synthesis in Colin L. Raston University in 2013. Awards from
continuous-flow systems for on the RACI include the Leighton
demand compound generation. His awards include the Kipping Memorial Award and his former Presidency. He is an Officer of the
(2011), GSK (2011), Syngenta (2012) British Petroleum Award (2013), Order of Australia and his research interests include nano- and green
and Taihi Hong Memorial award (2015). chemistry as well as microfluidics.

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Fig. 1 Typical equipment used in continuous-flow chemistry. (A) A T-shaped mixer for micromixing two solutions in a head on fashion, or at 901 (IDEX,
#P-713). (B) A Y-Shaped mixer for micromixing two solutions at 1201 (IDEX, #-P-512). (C) A Quad-mixer for micromixing three solutions (IDEX, #P-722).
(D) A union for joining two components of a continuous-flow system together (IDEX, #-702). (E) A typical packed bed reactor. In this Review, several
examples use metallic tubes packed with polymer-supported (PS) reagents for synthetic applications, or metal chippings/glass beads for improved
mixing. (F) A typical reactor coil created from PFA (perfluoroalkoxy) tubing. (G) An in-line liquid–liquid separator (Zaiput Flow Technologies) that allows
immiscible fluids to be separated into two separate streams; one aqueous, and one organic. (H) A backpressure regulator sets the pressure of the
continuous-flow system. Typically, a backpressure is used for all reactions, but this range varies from low pressures to B300 psi and can be purchased
from Zaiput Flow Technologies. Backpressure allows solvents to be heated at temperatures exceeding their atmospheric boiling points, can limit gas
evolution, while also imposing control on the contents of the continuous-flow system as they pass through several reactors. (I) A typical syringe pump
(Harvard, #70-3005) used to drive fluids into the continuous-flow system. However, these pumps have a finite addition volume. (J) A Syrris continuous-flow
pump (Syrris, #2200292) that allows infinite volume addition into the continuous-flow system. (K) A typical peristaltic pump, noting that these pumps are
limited due to the low level of pressure they can infer on the solution being injected (New era, #NE-9000G). (L) A thermal jacket allows controlled heating of
reactor coils without using an oil bath (Syrris, # 2200527). (M) An oil bath can heat reactor coils to provide a lower cost approach. (N) A typical microfluidic
chip used in continuous-flow synthesis (Dolomite, #3000086). (O) A typical commercially available continuous-flow system. Whole continuous-flow systems
can be purchased in a modular fashion to avoid the need for constructing ‘in-lab’ equipment (Syrris, Asia Premium Systems).

respect, an expedited synthesis of these molecules could have In continuous-flow however, gas release can be managed. The
broad significance in medicinal and biochemical studies. First, deprotected moiety is then subjected to sequential acylation to
the Djuric group recently developed a reaction–deprotection– generate unsymmetrical amides. To note is the high temperature
reaction strategy to afford asymmetric amides (Fig. 2A).14 Here, of the second coil, and the large backpressure required. The
the first reactor coil mediates acylation between a wide variety Phoenix reactor was specifically chosen due to its ability to safety
of amines and acyl chlorides. This solution then exits into a mediate the three-step, eight-minute process under such harsh
second reactor coil where thermal BOC-deprotection affords conditions. Overall, a range of structurally diverse products was
the free amine. The ability to rapidly heat from room temperature synthesized in yields exceeding 99%. This simple continuous-
to 300 1C highlights a major benefit of continuous flow. In flow system has added a useful tool to the medicinal chemistry
batch, it would be extremely difficult to perform rapid thermal toolbox.
changes in short order, with the likelihood of unwanted Next, a microwave assisted continuous-flow reactor generated
byproducts also increasing. Furthermore, as CO2 is produced as a secondary amides from aniline derivatives through in situ azide
byproduct, it would pose a safety concern in large batch reactions. generation (Fig. 2B). In this sequence, a heated reactor coil first

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Fig. 2 Continuous-flow synthesis of amides, and a semi-continuous flow synthesis of a U-shaped compound used in the synthesis of [10]CPP.
(A) A three-step synthesis to asymmetric amides.14 (B) A three-step process converting aniline derivatives to secondary amides via the azide, at 83 mg h1.15
(C) 1,4-Dibromobenzene is fed into the reaction sequence at 3.0 mL min1 along with tBuLi at 1.5 mL min1 in a separate channel. This affords
mono-lithium species over 21 s which then undergoes nucleophilic addition with the introduced ketone over 63 s. MOM-Br is then introduced to protect
the newly formed secondary alcohol with the exiting product stirred in a vial for six hours before isolation.16

mediates azidanation with tert-butyl nitrite. This example high- lithium–halogen exchange at room temperature. In batch reactions,
lights a major benefit of continuous-flow systems; the ability to cryogenic temperatures (78 1C for example) are often required to
handle hazardous species in a safe manner. In batch reactors, the stop byproduct formation. Although this is a great example of a
handling of azides or other unstable species can be problematic due multi-step transformation, the last step was performed in a round
to explosion concerns. In continuous flow, the azide is generated in bottom flask. Presumably, slow reaction rates were unsuitable for
a small volume reactor coil before immediate consumption in a continuous flow approaches. Finally, when performing these
sequential step. This ensures only small concentrations of the azide rapid transformations, the fluid exiting the system should be
are present at all times. However, safety should always be of prime effectively quenched to ensure accurate determination of the
importance when heating nitrogen rich compounds in both continuous flow transformation.
continuous-flow and batch reactors. When using hazardous species,
a full safety review should be carried out and the appropriate 1.3 Heterocycles
measures taken to ensure a controlled reaction. This continuous-
Continuous-flow chemistry has been used to generate libraries
flow system generated the amide shown in Fig. 2B in 86%
of heterocycles such as 5-(thiazol-2-yl)-4,4-dihydropyrimidin-
yield over 18 h.15
2(1H)-one (DHPM) derivatives (Fig. 3A). In this sequence,
two microfluidic chips are used to each mediate a specific
1.2 Materials chemistry compounds transformation. Microfluidic chips are distinctly different to the
Multi-step continuous-flow systems have recently featured in the reactor coils described above as they typical manipulate fluid in
synthesis of compounds for materials chemistry applications. channels ranging 106–1012 L. Their construction, maximum
The synthesis of [10]cycloparaphenylene ([10]CPP) for bottom up flow rates and volumes provide a flexible alternative to continuous-
approaches to carbon nanotube synthesis was translated into flow reactor coils. It is however possible to use a mixture of both
continuous flow for rapid material generation (Fig. 2C).16 This reaction platforms as they often operate the same fittings. In this
example is known as flash-continuous-flow chemistry due to the sequence, the first microfluidic chip generates the b-ketothiazole
incredibly rapid reaction rates. During optimization, nucleophilic motif with concomitant removal of the 1,3-dioxane protecting
addition of the lithium-aryl species required only three seconds. group. The fluid then passes into the second microfluidic chip
Furthermore, other transformations required only tens of seconds. where a rapid Biginelli reaction affords DHPM derivatives in
Performing this transformation in continuous flow allowed medium yields over a 13.75 min residence time.17

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Fig. 3 Continuous-flow synthesis of heterocycles. (A) The synthesis of DHMP derivatives using two serially linked microfluidic chips.17 (B) Continuous-flow
synthesis of 3,3-disubstitutedoxindoles using two-serially linked packed bed reactors. TBAB (tetrabutylammonium bromide) and the packed bed reactors had
180 mL and 90 mL capacities respectively. Yields between 62–95%.18 (C) Two continuous-flow processes harnessing Deoco-Fluor, and activated MnO2,
generate six oxazoles in good yield.19 (D) A three-step process generated nitrogen containing heterocycles in excellent yield.21

Substituted oxindoles comprise a large class of alkaloid amides are converted to oxazolines with inversion of stereo-
natural products that often infer biological activity. The Buchwald chemistry. After intermediate purification using gravity-based
group developed a two-step process that mediates palladium- separation, the resulting solution is flowed through a packed
catalyzed a-arylation of oxindoles with subsequent alkylation to bed reactor housing manganese dioxide to mediate oxidation to
generate 3,3-disubstitutes oxindoles (Fig. 3B). As the reaction was oxazoles in good yield. The ability to expose continuous-flow
run biphasic, solutions were passed through a packed bed reactor streams to solid reagents in a controlled and confined manner
to provide efficient mixing. This provides an example of another avoids problems associated with solid addition and catalyst
benefit of continuous flow; the ability to mediate biphasic removal. However, packed bed reactors have a finite lifetime;
reactions via micromixing apparatus. In round bottom flasks, the supported reagent is consumed or poisoned over time. As
the reaction typically occurs at the interface of the two solutions. described, purification from the complex mixture was achieved
Although this scenario is sometimes beneficial, it often leads to using a gravity-based separator. This type of separator is distinctly
low reactivity rates due to inefficient mixing. This can be over- different to the Zaiput separators as shown in Fig. 1. Membrane
come in continuous flow by using plug flow conditions (the separation allows a true continuous-flow process by passing the
solutions appear as pellets traveling through the reactor) organic phase through a membrane and into a new stream.
where more turbulent mixing occurs. Furthermore, as this Gravity separation is mechanistically similar to a typical organic
example demonstrated, passing the solution through a packed liquid–liquid separation used in batch chemistry. However,
bed reactor containing sand, stainless steel chippings, or glass the incorporation of cameras allows automatic draining of the
beads will provide efficient mixing. This system generated separator to form a semi-continuous purification process.20
14 compounds in good to excellent yields (62–95%) in 58 s to A three-step continuous-flow sequence transformed aromatic
23 min residence time.18 aldehydes into nitrogen containing heterocycles using hetero-
The Ley group synthesized substituted oxazoles via a two- geneous catalysis (Fig. 3D).21 In the first reactor, aldehydes are
step process (Fig. 3C).19 This simple, and robust process was transformed into b-nitrostyrenes via the Henry (Nitro Aldol)
mediated by the Vapourtec R2/R4+ platform, a commercially reaction. Here nitromethane and the aldehyde of choice are
available continuous-flow reactor. In the first reactor, b-hydroxy passed through an amino-functionalized silica gel column to

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mediate Aldol addition and then elimination of water to yield continuous-flow chemistry, but also demonstrates generalizability
nitroalkenes. The amino-functionalized column catalyzes the and efficiency.
reaction and is constructed from commercially available silica The Ley group developed a two-step continuous-flow system
resin (Aldrich, $5.21 USD g1). Once again, care should be taken for preparing natural and unnatural cyclooligomeric depsipeptides
on the longevity of these columns; over time, decreased efficiency (Fig. 5).23 In this system, selective deprotection of O and
will occur through leaching, consumption, or poisoning. There is N-protected amino acids, and subsequent coupling using Ghosez’s
thus some debate on whether the use of immobilized reagents is reagent is achieved in the first reactor coil. In the second reactor
truly continuous-flow; the column will have to be replaced over coil, conversion of the dipeptides through cyclization yields the
time. Finally, the nitroalkene motifs are transformed (via conjugate required peptoides. In this system, low reactor temperatures
addition, for example) to generate a range of compounds. These were required. Although The Polar Bear continuous-flow system
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compounds can further undergo reduction with palladium to access maintained a reactor temperature of 0 1C, it is possible to
the free amine, providing opportunities to synthesize additional place the reactor coil in a well-insulated ice bath, although, this
amides and tryptophan analogues. is a less renewable approach. This process afforded greater
yields than what is previously reported in batch systems,
1.4 Peptide related synthesis adding yet another example of improved yields in continuous
The Kappe group developed a two-step system for the synthesis flow (32–52%, Fig. 5).
of peptoids in high yields with short residence times (Fig. 4).
Peptoids are non-natural amino acid mimics that can have 1.5 Cross-coupling reactions
identical biological activity, but often with increased bioavailability. The power of palladium cross coupling chemistry in continuous
In the first reactor coil, an Ugi coupling generates a scaffold ready flow has been previously described,24 accordingly, this part of
for sequential copper mediated azide–alkyne cycloaddition (CuAAC) the Review details only recent examples.
which is achieved by passing the solution through a copper reactor First, a three-step sequence for transforming aryl bromides
coil to generate the triazole linker.22 This highlights two further to biaryls via Suzuki couplings was developed by Buchwald et al.
benefits of continuous flow. First, passing the solution through a (Fig. 6A). In the first reactor, lithium–halogen exchange occurs
reactor coil constructed from the required catalysts can provide between an aryl bromide and nBuLi to afford the lithium salt in
the necessary conditions for an effective transformation. This a rapid fashion (as quick as two seconds). This salt is then
type of reactivity is both convenient, and in the case of copper, mixed with dilute B(OiPr)3 and passed through a second reactor
relatively inexpensive. Second, azides are highly energetic hazardous coil to afford the borate. This transformation required only one
species. However, they can be safely generated in situ under minute at 60 1C, demonstrating that molecular complexity can
continuous-flow conditions for immediate consumption in a be easily accrued in a rapid fashion in continuous-flow systems.
sequential step. This versatile continuous-flow strategy allowed the In the final reactor coil, the borate is consumed in a Suzuki
changing of the molecules ‘y’ and ‘x’ components to access eight cross-coupling reaction to afford biaryls. In this system, probe
different compounds. This again provides an additional benefit over sonication and dilute concentrations of B(OiPr)3 were required
batch reactions; changing the reagents entering the continuous-flow to quench the lithium–halogen exchange product. This technique
system can generate a large library of compounds through avoided formation of an insoluble salt that would lead to reactor
parallel synthesis. This not only increases the versatility of clogging. This raises a constant consideration in continuous flow;

Fig. 4 Continuous-flow synthesis of peptoides using a two-component multi-step reaction. A general example is detailed here with eight high yielding
(73–91%) examples reported.22

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Fig. 5 Continuous-flow synthesis of natural and unnatural cyclooligomeric depsipeptides using a two-component multi-step reaction. The Polar Bear
Plus reactor is used in the lower temperature coupling (0 1C).23 Reactor A is the commercially available H-cube reactor.

Fig. 6 Continuous-flow synthesis for Suzuki and Sonogashira couplings. (A) A three-step reaction sequence yielded Suzuki products, with the precursor
to diflunisal generated in 89% yield.25 (B) Two serially linked reactors catalyze Sonogashira reactions by harnessing the metal composition of the reactors
for catalysis; the column labeled A in this sequence is a metal scavenging column.26 (C) Mediating a Suzuki reaction, followed by sequential reduction in
the H-cube reactor, afforded the precursor to Boscalid in high yield and purity.27 The H-cube reactor used in this sequence was the X-cube flash reactor
with a QP-TU (quadrapure thiourea) cartridge for scavenging Pd before reduction.

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how can insoluble products be handled in small channels? As 1.6 Specific examples of multi-step transformations
demonstrated in this example, one method is to run the reaction In this section, cyclopropanation, hydroboration/oxidation of
under dilute conditions so that solid formation can be easily olefins, and homologation of esters are discussed. This section
managed. The second approach is for sonication to provide
further highlights the rich diversity of continuous flow chemistry
vibrations to move the solid through the tubing. Furthermore,
with some additional benefits over batch chemistry.
vibrations can also increase solute solubility in avoiding insoluble
Cyclopropane moieties exist in a wide range of biologically
material formation. In conclusion, this system created the core
active molecules due to their ring conformation and constraints.
of API diflunisal, an important compound with analgesic and
In aiding their synthesis, nucleophilic diazo intermediates were
antipyretic effects.25
synthesized, and consumed in a two-step, room temperature
Sonogashira chemistry was mediated by flowing solutions
approach (Fig. 7A).28 First, activated MnO2 converts hydrazine
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through sequential palladium and copper reactors (Fig. 6B).26

derivatives to their corresponding diazo species. The choice of
In the first reactor, oxidative addition between aryl iodides and
solvent and base in this transformation were crucial to afford a
palladium from the walls of the reactor occurs. The resulting
clean stream of product; in this case, the use of EtOAc and
solution then flows into the second (copper) reactor where the
Hünigs base was optimal. After in situ diazo formation, the
alkyne forms the cuprate. The two organometallic species then
highly reactive species is immediately coupled to an olefin
undergo transmetalation, then reductive elimination to form
avoiding stockpiling of hazardous species. This process afforded
the aryl–alkyne motif in high yields in short order. This example
further builds upon the copper reactor used for catalysis as 15 cyclopropane rings in good yield, and once more highlights
described above. the ability of continuous-flow systems to handle hazardous
The Kappe group developed a system for mediating cross- species. Explosion-prone diazo compounds are generated in situ,
coupling reactions followed by sequential reduction in a and then consumed via a sequential reaction. On-demand
commercially available H-cube reactor (Fig. 6C). This elegant generation of hazardous species is appealing, but as described
process afforded the key precursor to the fungicide, Boscalid.27 above, the appropriate safety measures should be taken when
In this multi-step sequence, 1-chloro-2-nitrobenzene is first handling these potentially explosive compounds.
coupled with 4-chlorophenylboronic acid with a 16 min residence Using this same method, a three-step sequence converted
time. The reaction mixture is then flowed through a commercially geraniol to the corresponding cyclopropane amino acid (Fig. 7B). In
available quadrapure cartridge to remove excess palladium from this system, geraniol is oxidized to the aldehyde before sequential,
the reaction stream before final reduction. Reduction in the and safe transformation to the diazo species. The formation of
H-cube reactor afforded 2-amino-40 -chloropheyl in high yield and the diazo species is monitored using in-line IR spectroscopy.
purity (90 and 96% respectively). The H-cube reactor is an attractive Monitoring a peak at 2070 cm1 ensured that the flow rate was
alternative to performing reductions in round bottom flasks. This low enough to provide optimal conversion to the diazo compound
bench top apparatus safely generates hydrogen on demand through as it traveled through the packed bed reactor. The diazo compound
the electrolysis of water. Furthermore, there is no need to filter is then immediately consumed to generate the cyclopropane amino
of the catalyst at the end of the reaction as the system operates acid in 66% yield.
immobilized metal cartridges. Finally, yields are often improved Molecules containing hydroxyl functional groups find broad
in continuous flow compared to the same reaction in batch. application and utility in the synthesis of natural products.

Fig. 7 Continuous-flow synthesis of cyclopropane rings. (A) A two-step process converts hydrazine into cyclopropane rings via the diazo species.28
(B) Extending this to a three-step procedure allows the conversion of alcohols to cyclopropane rings. In both the schematics: Reactor A – column
packed with manganese dioxide, and Reactor B – round bottom flask containing 1.05 eq. N2H4.

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A two-step sequence converted a range of olefins to alcohols The solution then proceeds into the second reactor coil. To
through hydroboration and sequential oxidation (Fig. 8).29 undergo Schiff-base formation, before entering the H-cube reactor
b-Pinene was used as a model substrate with a BH3 complex for subsequent hydrogenation to afford the biaryl motif. In this
in THF. After hydroboration in the first reactor, the intermediate sequence, it was crucial that membrane separation removed
is subjected to a stream of NaOH, H2O2, H2O, and EtOH to water-soluble impurities before reduction.
provide the alcohol in good yield in short residence times. A Our laboratory has developed the synthesis of an a-amino-
continuous reaction–extraction system removed the alcohol from phosphonate through an assembly line inspired approach. This
the organic phase increasing the utility of this process further. thin-film approach uses a vortex fluidic device to generate an
This style of gravity separation has already been described above, a-aminophosphonate in 80% yield in a B7 min residence time
and in this case, allowed decreased human intervention. (Fig. 11).31 In this reaction sequence, all stages are performed
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Next, a Horner–Wadsworth–Emmons homologation of in the most optimal solvent. Although this reaction can be
a,b-unsaturated esters was achieved through a dual reduction- performed as a three-component reaction, creating discrete
olefination sequence (Fig. 9).30 This approach allowed a controlled species at set points in the reactor allowed enhanced reactivity.
partial reduction of esters to reveal aldehydes. In round bottom Processing in thin films allow facile solvent exchange under
flasks, DIBAL-H is often avoided due to over reduction; it is more ambient conditions; imine synthesis is first mediated in methanol,
reliable to reduce the ester through to the alcohol, and then followed by in situ solvent exchange with DMF, then addition of
oxidize it to the aldehyde. Here, this problem was overcome in diethylphosphite.
this continuous-flow system. Furthermore, the E-factor of the Thin film continuous flow reactors are distinctly different to
process was improved by avoiding excess chemistry to achieve microfluidic chips and reactor coils. Thin films are generated
the correct oxidation state. The resulting aldehyde undergoes through rapid rotation of a sample tube. Thin films have
Horner–Wadsworth–Emmons olefination to produce the elongated properties such as rapid heat and mass transfer, enhanced
product in good to excellent yields. solvent evaporation rates, and the ability to confine a particular
In a two-reactor coil sequence, the biaryl unit for the API reaction to a set point in the reactor. The ability to switch
atazanavir was synthesized in 74% yield (Fig. 10).32 This synthesis solvents during reaction sequences allows each step of the
utilized both the power of membrane separation for in-line reaction to be performed in their most ideal solvent.
purification, and the H-cube reactor for reduction. In the The key intermediate for the synthesis of etodolac, a non-
first reaction coil, Suzuki cross coupling is performed at 150 1C. steroidal anti-inflammatory drug was synthesized in 100%
conversion and 75% yield (Fig. 12).33 In this comparative study
between batch and continuous flow, translating the reaction
into a continuous-flow system increased yield, purity and
conversion while decreasing byproducts formation. The ability
to gain higher yields in continuous flow relates to the fundamental
properties of the continuous-flow system. High heat and mass
transfer coupled with micromixing and rapid temperature changes
often provide superior yields compared to the same reaction
Fig. 8 Continuous-flow hydroboration and subsequent oxidation through
in a round bottom flask. Furthermore, the high flow rates
a two-step process.29 In this example, 13 compounds were synthesized in (230 mL min1) used in this system are orders of magnitudes
good to excellent yields. higher than that found in an academic setting.
The combination of continuous flow and batch chemistry
can generate powerful routes to APIs. Vildagliptin, an oral
antidiabetic drug, was synthesized through the generation, and
subsequent reaction of the Vilsmeier reagent created in continuous
flow, with that of an amide produced in batch (Fig. 13).34 Generating
the hazardous Vilsmeier reagent in continuous flow improved the
safety metrics of this reaction. The ability to reduce user interaction
with hazardous intermediates highlights a benefits of this system.
Overall, the reaction sequence generated the key intermediate
for vildagliptin at 5.8 kg h L1. A final substitution outside of the
continuous-flow system afforded the API.

2. Facilitating natural products

Fig. 9 Continuous flow two-carbon extension of a,b-unsaturated esters synthesis
using a Horner–Wadsworth–Emmons in a two-step continuous flow
system.30 In this example, the use of DIBAL-H for a controlled reduction The synthesis of natural products often requires multiple
was achieved by use of a continuous-flow system. complex transformations to generate the required target.

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Fig. 10 Continuous-flow synthesis of the biaryl unit for the API atazanavir. A three-step sequence afforded the bi-aryl motif in 75% yield.32 The reactor
labeled A is the H-cube pro.

Fig. 11 Continuous-flow synthesis of an a-aminophosphonate using dynamic thin films in an assembly line fashion.31 This assembly line inspired approach
synthesized an a-aminophosphonate in 80% yield for a seven min residence time. Reproduced from ref. 31 with permission of Wiley, copyright 2017.

Furthermore, chemists commit large amounts of time to generate Arguably, the most complex continuous-flow synthesis to date
enough material from prior steps, to perform delicate, later steps. was the generation of the key intermediates en route to the
In this respect, continuous flow could streamline natural product natural products spirangien A. Methyl ester and spirodienal A
synthesis through on-demand generation of material for exploring (Fig. 14 and 15).36 A semi-continuous-flow approach accessed
final steps in complex syntheses. Such technology would allow a common homoallylic alcohol that is later transformed to
chemists to concentrate on new reactivity by limiting the time a protected aldehyde or bis-alkyne. Through a series of linked
spent on tedious transformations. Finally, continuous flow could reactor coils, microfluidic platforms, polymer supported reagents,
expedite long syntheses into attractive, cohesive routes. and in situ analysis, a high yielding system requiring only minimal
Although the majority of continuous-flow syntheses focus on downstream processing was achieved.
commodity chemical and API synthesis, there has been a An important feature of this process was the use of in-line
significant advancement in the synthesis of more complex spectroscopy to monitor the concentration of incoming aldehyde for
molecules. The Ley group have pioneered continuous-flow successful crotylation (Fig. 13A). Depending upon the concentration
syntheses of natural products amongst other compounds.35 of the aldehyde in the feed stream, the flow rate of the crotylating

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Fig. 12 Continuous-flow synthesis of intermediate API 7-ethyltryptophol in the synthesis of etodolac. The three-step process produced
7-ethyltryptophol in 75% yield compared to only 45% in the batch process.33

Fig. 13 Continuous-flow synthesis of the intermediate for API vildagliptin. Combining two synthetic steps into a semi-continuous flow system produced
the key intermediate for this API at 4.8 kg h L1.34

reagent was adjusted to ensure optimal reactivity. Such in situ multi-step sequences, the natural product was synthesized in
monitoring techniques allow for a level of control not possible in eleven steps, requiring only two chromatograph separations
many batch type reactors. Using commercially available software, it while avoiding aqueous work up steps (apart from the acetal
is possible to link the in situ analysis back to the syringe pumps in hydrolysis, not shown). Furthermore, translating this sequence
order to control the flow rate of reagents, or solvents into the into continuous flow allowed organometallic reagents to be
continuous-flow system. This level of automation is becoming used at 0 1C, not the usual 78 1C. For example, Peterson
increasingly common in continuous-flow systems. In conclusion, Olefination gave comparable stereoselectivity at 0 1C in continuous
this system mediated 21 out of 25 transformations as a pioneering flow; the high surface/volume ratio of the reagents contained within
advancement in continuous-flow technology. the reactor coils creates an environment for high heat, and mass
There is however a clear difference between many of the transfer. This phenomenon provides new opportunities for avoiding
syntheses above, and the synthesis of these natural product cryogenic temperatures in reactions like those described above.
intermediates. The molecules en route to these natural products
often exit the continuous-flow system into a collection vial
(depicted as a new pump in the scheme). The inherent complexity 3. Active pharmaceutical ingredients
of these species, or technical issues (such as pump capability) could (APIs)
have limited the potential for a true continuous-flow process.
In 2010 the Holmes group reported a semi continuous-flow Active pharmaceutical ingredients often have an inherent complexity
approach to the synthesis of perhydrohistrionicotoxin (Fig. 16).37 associated with their molecular framework. In this respect,
A mixture of reactor coils and microfluidic devices mediated translating their syntheses into continuous-flow reactors
seven transformations in continuous flow. Taking into account often requires advances in purification technology and new

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Fig. 14 Semi multi-step continuous-flow synthesis towards key intermediates for the total synthesis of spirangien A methyl ester and spirodienal A.
(A) A 2,3-butane diacetal protected aldehyde is transformed to the homoallylic alcohol. The lettered boxes detail a specific reactor condition;
A – functionalized triphenylphosphine monolith for the Wittig reaction, B and D – quadrapure benzylamine, C – H2 at 20 bar for the asymmetric
hydrogenation, E – basic alumina, F and G – IRA-743/silica. (B) Transformation of the homoallylic alcohol into the advanced aldehyde. A and D – ozone
generation at 500 mL min1, B – polymer supported hydroxide, C – quadrapure sulfonic acid.36

synthetic routes. Although more challenging than commodity API synthesis in continuous flow often requires using several
chemical synthesis, several exciting advancements have occurred techniques to achieve high yields and purity before subsequent
over the last five years. The synthesis of ibuprofen in 2009 by steps. In-line removal of soluble metal salts was achieved by
McQuade provides a starting point for this section (Fig. 17A).38 passing the continuous-flow stream through a Zaiput membrane
Here, three challenging transformations were incorporated into a separator. After separation, the key intermediate resided in the
single flow system to yield ibuprofen in 68% crude yield, or 51% organic phase, ready for subsequent transformations. These
following recrystallization. Five years later (2015), the Jamison membrane separators have been discussed above, but it is
group improved this synthesis by the removal of triflic acid to noteworthy that these separators are very easy to operate, which
afford a more economical oxidative rearrangment.39 In their is ideal for first time users.
synthesis, ibuprofen required only three minutes residence time Artemisinin is a key API in a range of antimalarial treatments.
and yielded 83% at 8.09 g h1 (498% purity by 1H NMR, Fig. 17B). The synthesis of this molecule was translated into continuous
To note is the short residence times required, and that the reactor flow for reaction scale up and on demand compound generation
coils are constructed from affordable components. This provides (Fig. 17C).40,41 The complexity of this molecule meant that there
an economically attractive alternative to expensive commercially was no commercially viable routes to scale up. Translating this
available continuous-flow reactors. reaction sequence into continuous-flow allowed for an efficient

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Fig. 15 Semi multi-step continuous-flow synthesis towards the di-alkyne intermediate for the total synthesis of spirangien A methyl ester and
spirodienal A. The homoallylic alcohol is transformed into the advanced dialkyne. The lettered boxes detail a specific reactor condition; A – an ozone
generator producing 500 mL min1 of O3 that is fed directly into a three-neck flask via a three-way valve, B – polymer supported hydroxide, C – polymer
supports S2O3 silica, D – dibromo diphenylphosphine monolith for the Wittig reaction and E – IRA-743/silica.36

Fig. 16 Semi continuous-flow synthesis of perhydrohistrionicotoxin. In this example, seven out of the eleven steps were mediated in continuous flow.37

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Fig. 17 Continuous-flow syntheses of ibuprofen and artemisinin. (A) Ibuprofen is synthesized by Friedel–Crafts acylation followed by a 1,2-aryl
migration, and finally ester hydrolysis.38 (B) This improved synthesis of ibuprofen used a membrane separator for in-line work-up while avoiding the need
for triflic acid. This increased the yield to 98% with an overall reactor throughput of 8.09 g h1.39 (C) Photochemical ene reaction using singlet oxygen as
the key step preparing artemisinin at 8.33 g h1.40,41

and safe generation of singlet oxygen. Singlet oxygen is key in the continuous-flow systems (Fig. 18 and 19). First, both enantiomers
transformation of dihydroartemisinic acid to artemisinin via a of rolipram were generated using a system comprised of four
photochemical ene reaction. This efficient transformation was packed columns, each containing a specific heterogeneous
achieved by using 60 high-powered LEDs to create a high photon catalyst. Flowing simple starting materials through the system
flux (420 nm, 72 W). This is another important example of the afforded rolipram in 50% yield and in high enantiomeric excess
beneficial qualities of continuous flow. First, singlet oxygen is (499%) at 42 mg h1 (Fig. 18). Impressively, the opposite
incredibly reactive. Thus, its generation, and immediate consump- enantiomer of rolipram was also accessible by simply switching
tion in continuous flow provides increased safety compared to the the second packed column in the sequence (polymer supported-
round bottom flask. Second, and just as important, the high PYBOX-CaCl2) to a column containing the opposite enantiomer
surface: volume ratio of fluid traveling through the flow system catalyst. This simple system alteration afforded rolipram in
allowed even light penetration to the reagents.40 Performing similar yield and high enantiomeric excess. The ability to switch
photochemistry in round bottom flasks, or even larger batch modules of a continuous-flow system can provide access to a
reactors, is plagued by the inability of light to penetrate past the wide breadth of chemical space in short order compared to the
upper surface of the fluid. Mediating transformation in same reactions in round bottom flasks.
continuous-flow systems (where the thickness of the fluid is Popular renin inhibitor aliskiren hemifumarate was synthesized
minimal) provides greater reaction homogeneity, efficiency, and through a true end-to-end process (Fig. 19A). This continuous-flow
yield. This system generated artemisinin at 8.33 g h1, providing system is one of the highlights from the literature with the
a viable scale up route to this important medicine. synthesis, separation, purification, crystallization, drying and
The synthesis of (R)- and (S)-rolipram,42 aliskiren,43 rufinamide,44 formulation being achieved in a single continuous-flow process.43,45
and (E/Z)-tamoxifen35 have also been effectively translated into Here, acid catalyzed lactone ring opening generated the intermediate

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Fig. 18 Continuous-flow synthesis of rolipram. Both enantiomers of rolipram were synthesized by simply switching the enantiomer of heterogeneous
catalysts used.42

that is next isolated in the organic phase using a membrane efavirenz in 45% yield with a residence time of o2 h. A silica-
separator. Clever in-line pH analysis controlled the flow rate of scavenging column removed byproducts from the continuous-
HCl into the stream to efficiently mediate BOC deprotection. flow stream to provide a method of in-line purification, but as
This truly novel process afforded aliskiren hemifumarate with other columns, there is a finite lifetime. In these situations,
at a maximum and nominal rate of 100 g h1 and 41 g h1 in-line liquid–liquid separation would be attractive, if possible.
respectively. This was the first example of liquid reagents being In acknowledging that the majority of APIs are synthesized
converted to formulated medicines in a continuous fashion. through large-scale batch techniques, the Seeberger laboratory
Ultimately, it provided a new benchmark for continuous flow developed a non-iterative, five-stage assembly line sequence for
API synthesis. the synthesis of numerous APIs (Fig. 21).47 Here, reactors can
The antiseazure medicine rufinamide was synthesized in be interchanged to access a large breadth of chemical space.
eleven minutes using three reactor coils to mediate sequential The first level of complexity affords the core of the API, and by
transformations (Fig. 19B).44 Once again, copper tubing catalyzed changing the starting material entering the system, different
the azide–alkyne cycloaddition to generate the 1,2,3-trizaole ring APIs can be accessed with the same core. Sequentially passing
core of rufinamide. This appears to be the first API synthesis to the core through a series of sequential modules transforms the
utilize the reactor tubing in this manner, with the reaction motif to generate b-amino acids, g-amino acids and g-lactones
sequence affording 217 mg h1 of rufinamide, in 98% yield. in good yields. Furthermore, switching modules determines
Ley et al. translated four sequential transformations into a whether g-amino acids or g-lactones are produced. The ability
continuous-flow system to generate (E/Z)-tamoxifen, an antibreast to generate large libraries of compounds through a modular
cancer drug in 100% conversion and 84% yield (Fig. 19C).35 This continuous-flow platform is beneficial. If automated, this system
sequence utilized seven reactor coils to generate 9.35 g h1 of this could create a large range of structural analogues without being
vital medicine. The diverse temperature gradients of this system halted; the stream would be diverted into the required module to
are noteworthy, with one reactor coil mediating a reaction at perform the required transformation. This sequence afforded
50 1C, and the next reaction at 30 1C. It would be hard to achieve pregabalin, gabapentin, phenibut, baclofen and rolipram in good
such rapid thermal fluctuations in a round bottom flask over the yields (49–75%).
same time. Attempts to perform the same rapid temperature The antiemetic, and antihistamine compounds cyclizine,
changes in batch reactors would likely lead to byproduct formation meclizine, cinnarizine and a buclizine derivative were synthesized
and decreased yields. through transformation of alcohols to their respective chlorides
The combination of novel reactivity and continuous-flow before successive reactions with piperazine (Fig. 22).48 Once again,
synthesis established a three-step route to efavirenz, an essential membrane separators removed aqueous byproducts before
medicine for the treatment of HIV (Fig. 20).46 The previous routes sequential transformations, driving higher reaction efficiencies.
to efavirenz required up to five steps (Merck and Lonza’s routes), This system generated cinnarizine at 2.0 mmol h1 in good yield
demonstrating that continuous flow improved both the efficiency (82% recrystallized) as well as high yields of maclizine, cyclizine
of the synthesis with the possibility of reaction scale-out. In this and buclizine. The authors noted that the development of HCl
continuous-flow system, a novel Ullman cyclization produced gas delivery into continuous-flow systems could revolutionize

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Fig. 19 Continuous-flow synthesis of aliskiren, rufinamide and (E/Z)-tamoxifen. (A) The synthesis of aliskiren combines two synthetic steps to produce
the final API in high yield at a nominal rate of 41 g h1.43 Only the synthesis of the API is described in the figure above. In the earlier publication, many
downstream processes afford the API in a formulated manner.45 (B) A three-step sequence generated rufinamide at 217 mg h1.44 (C) A four-step system
generated (E/Z)-tamoxifen at 9.35 g h1.35

this methodology. However, using HCl gas makes this process It should be noted that gas delivery into continuous-flow
troublesome; many continuous-flow platforms would likely corrode. systems is possible through the use of a mass-flow controller.

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Fig. 20 Continuous-flow synthesis of efavirenz. A three-step sequence produced efavirenz in 45% yield. The final step generated the carbomate ring.
This is the shortest synthesis to efavirenz thus far.46

Fig. 21 Continuous-flow synthesis of phenibut, gabapentin, pregabalin, rolipram and baclofen. A five-step reactor sequence allows for chemical space
to be explored efficiently and rapidly, and changing the order of the reactors allowed access to different molecules.47

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Fig. 22 Continuous-flow synthesis of cinnarizine, maclizine, cyclizine and buclizine. Four transformations convert the respective alcohols into APIs in
good yields.48

This allows the safe and controlled delivery of gases into the Burgess Reagent limited the process. This was overcome using
conventional continuous-flow equipment with ease. If attempted, a controlled release of the Burgess Reagent by in situ IR-detection
safety should be prioritized when operating pressurized toxic and of the concentration of incoming substrate. This once again
explosive gases. amplifies the importance of in situ analysis in continuous-flow
The synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4- systems.
ylidenemethyl)benzamide, a potent and selective d-opioid A high temperature and pressure synthesis of imidazoles
receptor was synthesized in a four-step sequence in 35% yield was developed for aiding in the synthesis of daclatasvir, a NS5A
(Fig. 23).49 This sequence is superior to the previous five-step inhibitor.50 Here a-halo ketones, N-protected L-proline and
sequence that afforded the compound in only 9% yield. When ammonium acetate afforded imidazoles without proceeding through
compiled into a single system, intermediate dehydration using ketoamide intermidiates (Fig. 24). Short residence times of 4–10 min

Fig. 23 Continuous-flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide. The four-step sequence generated the

target API in35% yield.49

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generated the daclatasvir like scaffold in 81% yield. This strategy formation, in situ solvent exchange and final SN2 substitution to
was also general for a range of starting materials, and synthesized afford lidocaine in 15%.
13 other imidazoles in good yields. The use of several immobilized Finally, a collaborative effort at the Novartis-MIT center for
reagents provided an efficient single flow process, and once again, continuous-flow processing produced a reconfigurable continuous-
these reagents are commercially available. flow system for on demand production of diphenhydramine
Our laboratory has achieved a two-step synthesis of lidocaine hydrochloride, lidocaine hydrochloride, diazepam and fluoxetine
in 85% yield using a dynamic thin film continuous-flow reactor hydrochloride, in a rapid and compact system to meet U.S.
(Fig. 25).51 Using an assembly line inspired approach allowed Pharmacopeia standards (Fig. 26).9 This system encompasses
both transformations to occur in a single reactor. One of both upstream and downstream processing, harnesses liquid–
the benefits of using thin films in continuous flow is reactor liquid separators, multiple reaction coils, backpressure regulators,
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compartmentalization. Much like in traditional continuous-flow sonicating reactors, gravity-based separators, heating units,
chemistry where reagents can be injected at specific points, pressure sensors, clamshell reactors, and surface tension driven
dynamic thin films have feed jets that deliver reagents at extraction units. The high temperature and pressure system
set points in the reactor. In a single pass in the vortex fluidic allows the manipulation of reagents in high concentrations, and
device, lidocaine is synthesized via incorporating amide bond sometimes neat. The system generated enough API to afford

Fig. 24 Continuous-flow synthesis of an imidazole fragment en route to the synthesis of Daclatasvir.50

Fig. 25 Continuous-flow synthesis of lidocaine using an assembly line inspired process contained within dynamic thin films using a vortex fluidic
device.50 Reproduced from ref. 50 with permission of Wiley, copyright 2017.

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Fig. 26 Continuous-flow synthesis of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam and fluoxetine hydrochloride.9

4500 doses of diphenhydramine hydrochloride, 3000 doses of and 20 multi-step transformations. These examples provide a
lidocaine hydrochloride, 3000 doses of diazepam and 100–200 doses general overview of this rapidly expanding and diverse area.
of fluoxetine hydrochloride day1. Given the recent growth of the field, more complex multi-step
syntheses are inevitable. In order to achieve this vision there
4. Conclusions must be a concomitant advancement in in-line purification,
isolation, and continuous-flow technology. In this respect,
This Review examines the continuous-flow multi-step syntheses harnessing the power of several approaches seems like an ideal
of 22 APIs, or API related compounds, four natural products, path forward. As we strive to draw inspiration from Nature’s

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multistep procedures, this Review will hopefully act as a starting 22 C. E. M. Salvador, B. Pieber, P. M. Neu, A. Torvisco,
point for those wishing to advance, and learn about the many C. Kleber, Z. Andrade and C. O. Kappe, J. Org. Chem.,
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24 T. Noel and S. L. Buchwald, Chem. Soc. Rev., 2011, 40,
Acknowledgements
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JB and CLR wish to acknowledge the Government of South 25 W. Shu, L. Pellegatti, M. A. Oberli and S. L. Buchwald,
Australia and the Australian Research Council. Angew. Chem., Int. Ed., 2011, 50, 10665–10669.
26 L.-M. Tan, Z.-Y. Sem, W.-Y. Chong, X. Liu, P. Hendra,
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W. L. Kwan and C.-L. K. Lee, Org. Lett., 2013, 15, 65–67.

27 T. N. Glasnov and C. O. Kappe, Adv. Synth. Catal., 2010, 352,
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