Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Br?nsted Acid-Base Catalyst with Recycle

Article abstract of DOI:10.1021/acs.oprd.5b00245

A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Br?nsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advanta

Full text of DOI:10.1021/acs.oprd.5b00245

Article
pubs.acs.org/OPRD
Development of an Intermittent-Flow Enantioselective Aza-Henry
Reaction Using an Arylnitromethane and Homogeneous Brønsted
Acid−Base Catalyst with Recycle
Sergey V. Tsukanov,*,†,‡ Martin D. Johnson,† Scott A. May,† Morgan Rosemeyer,† Michael A. Watkins,†
Stanley P. Kolis,† Matthew H. Yates,† and Jeffrey N. Johnston*,‡
†Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States
‡Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United
States
S
* Supporting Information
ABSTRACT: A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a
homogeneous Brønsted acid−base catalyst was translated from batch format to an automated intermittent-flow process. This
work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which
is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR).
A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward
product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst
concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput
of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing
catalyst usage.
has been slower, and only a few applications of organocatalysts
are reported in the literature (predominantly Cinchona
alkaloids, proline, and chiral amine catalysts).8 Analysis of this
situation leads to a conclusion that successful implementation
of organocatalytic procedures on industrial scale would require
finding an appropriate answer to several major challenges.
Generally high catalyst loadings (5−10%) are considered
unattractive, specifically in comparison with metal−mediated
hydrogenation methods where conditions with minute catalyst
amounts are quite effective (S/C ≥ 1000−4000). With high
catalyst loadings, economical constraints play an important role
in the selection process. Slow reaction rates (typically ∼24 h)
followed by the necessity to maintain cryogenic conditions
during the reaction cycle significantly decreases the intensity of
the process and increases the cost of operation, which is further
magnified when specialized equipment is required. Finally, an
organocatalyst needs to be effectively separated from the
organic reaction product without the use of chromatography. In
this first report using Bis(AMidine) [BAM] organocatalysis, an
aza-Henry reaction is scaled by translation of the original batch
reaction into a continuous process. This effort leveraged the
advantages of this format to maintain high selectivity and yield
while intensifying the process.
INTRODUCTION
■
Versatile methods to prepare nitrogen-containing small
molecules remain in high demand in the pharmaceutical
industry, driving the discovery of new reactions and the
refinement of existing methods.1 Although heterocycles devoid
of chiral centers can be effective therapeutics (e.g., tyrosine
kinase inhibitors), the selective disruption of more complex
interactions (e.g., protein−protein interactions) have increased
attention on the expansion and tailoring of molecular space,
leading to drug candidates with complex structures containing
several chiral centers.2 Chiral auxiliaries, kinetic resolution, and
hydrogenation methods are well-established in industrial
settings and continue to be successfully applied to the large
scale preparations of APIs.3−5 However, ever more complex
targets drive the invention and development of approaches
outside of the conventional paradigm, and novel methodologies
must answer emerging challenges as they appear. Contempo-
rary enzymatic approaches have risen to meet this demand in
recent years.6 These tools offer the potential to address the bulk
production of material but still find developmental hurdles
while engineering both high specificity and reactivity.
In the past decade alone, the field of organocatalysis has
achieved major advances, particularly in reactions where metal-
catalyzed methods have traditionally dominated. As a result, an
array of transformative technologies have provided functionally
dense intermediates with high levels of diastereo- and
enantioselectivity.7 These methods also allow straightforward
access to previously unavailable chiral molecules using robust
and easy to handle catalysts, themselves readily prepared
inexpensively and without metal contamination. Adaptation of
these methods, however, to a process chemistry environment
Continuous processing is a powerful alternative to classic
batch chemistry and is often applied to procedures where safety
(high temperatures, pressures, large exotherms and aggressive
reagents) and fast heat or mass transfer (bi- and triphasic
systems, reactions with gases or light) have a major impact.9
Received: August 1, 2015
© XXXX American Chemical Society
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Scheme 1. Initial Parameters for a Batch Aza-Henry Reaction, Targeting a Viable Intermediate to (−)-Nutlin 3
Pharmaceutical companies have embraced continuous tech-
nologies to benefit from fully automatic processes and a
continuous analytical data stream while using dedicated,
inexpensive equipment where scale−up often involves a longer
running time.10 These methodologies are also easily aligned
with the majority of the highest standards of quality and green
chemistry principles recommended by the FDA and EPA.11 By
relying less on process-tailored infrastructure and more on
flexible continuous process equipment, chemists can benefit
from shorter optimization campaigns, improved and simplified
synthetic strategies, timely delivery of the desired quantities of
APIs, and reduced risk and cost associated with the
development and production of APIs.
The use of nitroalkanes has blossomed in recent years due to
an appreciation for, and better understanding of, the chemistry
of the nitro functional group12 and its ability to behave as a
masked amine. To highlight just one case, the aza-Henry
reaction provides a carbon−carbon bond-forming pathway to
the stereoselective construction of vic-diamines in protected
form.13 Furthermore, methods to address the stereocontrol
issues associated with this reaction have proliferated since the
early contributions of Shibasaki and Jørgenson.14 Our interest
has been driven, in part, by the need for stereocontrolled aza-
Henry reactions extending beyond simple aliphatic nitro-
alkanes.15 Among these is the aryl nitromethane addition to
imines, which had limited success16 until 2011.17 These
discoveries have been leveraged to create molecular complexity
in key intermediates that have also been shown to be
competent precursors to heterocyclic pharmacophores. The
focus on protic acid salts of chiral bis(amidine) ligands has
produced a collection of organocatalytic methods capable of
generating highly functionalized and enantioenriched diamine
building blocks, all comparing favorably to traditional metal−
based methods.18
of plugging and clogging due to the formation of solids.
Heterogeneous reactions with solids precipitation can be run in
continuous stirred tank reactors (CSTR) which are more
suitable for handling the solids in flow. For example reactive
crystallization in mixed suspension/mixed product removal
(MSMPR) crystallizers is a legitimate option for handling this
type of process physically. MSMPRs have been used for
antisolvent,19 cooling,20 or reactive21 crystallizations. The intent
is to use a continuous reactive crystallization platform for an
aza-Henry reaction. However, because of the slow reaction
kinetics, the need for full conversion of imine, and the desire for
controlled addition of imine to nitroalkane, a truly continuous
MSMPR is not the best equipment choice for this reaction.
Therefore, an automated intermittent flow stirred tank reactor
was selected instead. Automated intermittent flow is an
equivalent process to continuous flow. Under these operating
conditions, the aza-Henry product continuously crystallizes
from the reaction mixture and is intermittently filtered while
the mother liquor with the solubilized catalyst is returned to the
reactor. Intermittent separation and catalyst recycling should
achieve formally low catalyst loadings and achieve a high
catalyst concentration in the reactor. Thus, a single operating
unit effectively fulfills a triple goal (function): promoting a
faster organocatalytic reaction, crystallizing the product and
also separating the catalyst for the recycle stage.
Unlike nitroarenes, nitroalkanes are relatively underutilized
due to the perception that they are hazardous and unsafe
materials. This proposal to merge organocatalysis and
continuous processing also provided an opportunity to create
a system which utilizes nitroalkanes in a safe and controlled
(reliable) way.
Batch Aza-Henry Chemistry. The initial scale up
conditions for the organocatalytic aza-Henry were first
developed to secure a significant throughput of material
necessary for biological testing (Scheme 1).22 The original
procedure17 was refined23 to provide the desired adduct 4 in
90% yield and with high stereoselectivity. During these studies
we have discovered that to achieve consistent enantioselecti-
vites on a larger scale, it was advantageous to add imine 1
slowly to the mixture of nitroalkane 2 and catalyst 3 in toluene
at −20 °C. This protocol was both effective and reproducible,
generating the β-amino nitroalkane 4 on decagram scale (23.1 g
Our initial goal was to translate the enantioselective aza-
Henry reaction from batch format to continuous conditions in
order to accelerate the large scale production of diamine
building blocks. The formation of a less soluble product is often
the case during heterocycle formation. This provides a unique
opportunity to couple reaction development with separation/
purification. However, a consequence of the insoluble product
is that a typical plug flow reactor (PFR) is not suitable because
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Figure 1. Major drivers for using the intermittent-flow system.
in a single batch). However, after thoughtful analysis we
concluded that, for further development and scale up, several
issues required additional attention:
• Safety: Low molecular weight nitroalkanes can be high-
energy compounds, but the hazards of functionalized
derivatives are largely unstudied.24,25
the PFR inlet, while the aza-Henry chemistry performs best
with controlled addition of the imine to the nitroalkane. It is
possible to mimic controlled addition by injecting the imine at
multiple points along the length of the PFR,28 but this requires
additional feed pumps and flow meters. CSTRs are more suited
to heterogeneous reactions with solids because the agitation
system keeps the solids suspended in the stirred tank. The main
limitations of a simple CSTR for this application are (1) very
long residence times are needed to achieve full conversion of
the imine in a single CSTR, and (2) controlled addition of
imine to nitroalkane is not possible in a CSTR, since both
reagents are added together (coaddition) and the reactor runs
at end-of-reaction conditions. Although the limitations can be
overcome by using a train of CSTRs in series, and feeding the
imine portion-wise into the individual CSTRs, this adds
complexity and still requires a significantly longer overall
residence time compared to batch or PFR to achieve full
conversion. A mathematical comparison of residence times in
batch, PFR, CSTR, and CSTRs in series is provided in the
Supporting Information.
• Preparation of aliphatic nitroalkanes: general methods to
synthesize nitroalkanes on large scale are limited.
• Productivity (moles product/hour): Batch organocatalytic
aza-Henry reactions can require long reaction times (∼24 h).23
Reduced cycle times on the order of 30−40 min would provide
an opportunity for translation of these processes into an
automated intermittent flow format.
• Economy: Highest selectivity is achieved under cryogenic
conditions, leading to lower output of the product and greater
expense. Batch catalyst loadings of 0.5−1% are acceptable, but
additional catalyst economy and recycle are desirable.
Reactor System Design and Major Drivers for a
Translation of Aza-Henry Process to Intermittent-Flow
Format with Recycle. The two main types of continuous
reactors are plug flow reactors (PFRs)26 and continuous stirred
tanks (CSTRs).27 Neither one of these truly continuous reactor
types is ideally suited for the aza-Henry reaction targeted here.
The product precipitates during the course of the reaction and
PFRs generally cannot handle solids in flow due to plugging
and clogging in the tube, pipe, or microchannel. Second PFRs
normally have all-at-once stoichiometric addition of reagents at
The answer to this reactor design challenge was an
intermittent-flow CSTR. It is an automated repeating batch,
with a 40 min total turnover time. The feed pumping, product
slurry pumping to the filter, filtration, and recycle of a desired
fraction of the filtrate back to the reactor are all fully automated
and repeating. The reaction design allows full conversion of the
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Scheme 2. Large-Scale Synthesis of Imine 1
Scheme 3. Nitroalkane Synthesis
imine and the product separated from the product slurry with
the solids forward-processed into the next step.
crystallization from protic solvents (water, alcohols). This
protocol was utilized to prepare the sulfone on 100 g scale;
however, improvements to this are actively investigated.
Elimination was performed in dry THF by refluxing sulfone 8
for 3 h with excess potassium carbonate and sodium sulfate.
The salts were filtered at the end of the reaction, and the
removal of the solvent furnished imine 1 which was utilized in
the next step without further purification. Aldehyde levels were
consistently observed at 1−2% in the crude material. Attempts
to apply more rigorous conditions with extensively dried
solvents and an inert atmosphere did not further lower the
amount of aldehyde. Since we have found that residual
aldehyde does not affect yield or stereoselectivity of the aza-
Henry reaction in a recycling sequence, the initial conditions
were employed for the scale-up of the material for the
automated intermittent flow runs.
We have previously utilized two different methods to
construct the 1-chloro-4-(nitromethyl)benzene. The first
method entailed a radical bromination of para-chlorotoluene
in order to prepare the corresponding benzyl bromide followed
by the subsequent substitution of the bromide with a nitro
group, an approach often referred to as Kornblum’s
procedure.23 Workup with phloroglucinol improved the yield
by converting the nitrite (formed by O-alkylation) to alcohol.
The resulting crude mixture could be purified by column
chromatography to provide nitroalkane in 33% yield over 2
steps containing up to 2% of the corresponding aldehyde. In
another method, aldehyde 6 was easily converted to the oxime
9 in nearly quantitave yield and then oxidized with MCPBA to
generate the desired nitroalkane 2 (Scheme 3). Recently we
have shown that this procedure is highly versatile and could be
applied to a variety of the substrates on a small scale.22
However, upon scale-up of this process the yields plummeted,
extensive chromatographic purification was required, and
excessive amounts of meta-chloroperbenzoic acid raised safety
concerns. An alternative oxidant was considered in order to
produce the nitroalkane on larger scale. Based on literature
precedent,30 we attempted the same reaction using peracetic
acid solution. In comparison with MCPBA oxidation these
conditions have shown a slightly better reaction profile with
decreased reaction times, diminished side product formation
and a simple purification protocol. However, direct crystal-
lization of the product with desired purity from the crude
Compared to a PFR, the intermittent flow reactor is better
suited for solids in flow. Compared to a CSTR, the intermittent
flow reactor achieves the same conversion at much shorter
reaction time for positive order reactions, and thus smaller
reactor volumes. Furthermore, it can accomplish all-at-once
addition, controlled addition of one or more feeds, any order of
addition of multiple feeds, or coaddition, depending on which
gives a higher yield and/or minimizes key impurities.
This type of reaction process is analogous to a truly
continuous process. Continuous processing enables smaller
reactor volumes and also facilitates the integrated recycle. The
higher the recycle ratio, the lower the overall catalyst usage.
The reactor is about 36 times smaller than a batch reactor for
the same kg/week throughput, assuming 1 day start-to-start
cycle time for a typical batch process. The overall logic of the
design, as well as other benefits of automatic intermittent-flow
CSTR, are summarized in Figure 1.
The intermittent flow approach has been taken by other
researchers. In the work of Adams, intermittent flow is termed
semicontinuous operation.29 Adams describes it as a forced
cyclic process, in which there are no steady states. He explains
that it is possible to achieve multiple separation steps and high
reaction conversion using fewer vessels than would be required
in a truly continuous operation.
RESULTS AND DISCUSSION
■
1. Synthesis of Starting Materials and Catalyst. Imine 1
was prepared on decagram scale using previously described
procedures (Scheme 2).23 In a typical experiment chloro-
benzaldehyde 6, tert-butylcarbamate 7, and the sodium salt of
sulfinic acid were stirred in a mixture of methanol and water in
the presence of formic acid at room temperature for 9 days.
Filtration and trituration with diethyl ether to remove residual
aldehyde provided the desired amido-sulfone 8 in 80−82%
yield overall. This method is based on slow formation and
precipitation of the insoluble α-amido sulfone. In this case, the
ease of preparation and straightforward product collection
contrasted the impractical reaction time and use of an ether
solvent. However, purification of these sulfones is generally a
challenge due to low solubility in a majority of nonpolar organic
solvents, and significant decomposition is often observed upon
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Scheme 4. Catalyst Synthesis
reaction mixture was unattainable, and an exothermic profile of
the reaction was a concern. The crude reaction mixture was
initially subjected to chromatographic purification followed by
crystallization from the mixture of heptanes/EtOAc to furnish
nitroalkane 2 as white low-melting needles in 41−44% yield.
This route was amenable to 50 g scale and provided an
appropriate throughput of material for the automated
intermittent flow experiments. This method is suboptimal,
and further development of a safe and reliable protocol
continues.
A preliminary safety evaluation of nitroalkane 2, oxime 9, and
aza-Henry product 4 was conducted. All compounds exhibit
complex decomposition behavior and decomposition energies
>350 J/g. Analysis of differential scanning calorimetry (DSC)
data using Yoshida’s correlation did not indicate that these
compounds were shock-sensitive or explosion-propagating (see
Supporting Information for further details). However, this
analysis has also shown that nitroalkane 2 characteristics are
borderline; therefore, a more detailed evaluation of this
compound would be beneficial and particularly critical upon
further scale-up.
simplified model for a run in automated mode. Although
improving selectivity was not the primary goal of the project,
maintaining the levels of selectivity equal to the batch reaction
was critical. The initial choice of parameters (concentration,
temperature, catalyst loading, mode of imine addition) was
based on prior work.23 The major goal of the optimization at
this level was to achieve intensification of the process.
8
For our optimization we have selected the (MeO)PBAM
catalyst 3 based on two major reasons:
• Access: the catalyst can be easily prepared on a large scale
in three steps.
8
• Process intensification: (MeO)PBAM has exhibited the
highest reaction rate and maintained reasonable stereo-
selectivity, achieving intensification of the process.
Since direct kinetic studies of this aza-Henry system were
complicated by the precipitation of the solid product during the
course of the reaction, a brief screen of different reaction times
and catalyst loadings was conducted. It was found that reaction
time can be shortened from 24 to 4 h, and the catalyst loading
was reduced to 0.5% without loss of yield or selectivity. An
attempt at 0.1% catalyst and 4 h reaction time furnished a very
low yield of the aza-Henry product, and unreacted imine was
observed in the reaction mixture.
Excesses of nitroalkane and concentration of reaction
solution were evaluated. Experiments were usually performed
with a slight excess of nitroalkane (1.2−1.5 equiv at 0.10−0.15
M). High stoichiometric amounts of nitroalkane proved to be
detrimental to selectivity since a larger quantity of the acidic
nitroalkane relative to Brønsted basic catalyst leads to either
catalyst modulation or inactivation as a result of a nitroalkane
solvation phenomenon by hydrogen bond donation. To further
support this data, an attempt to increase concentration further
resulted in lower selectivity.
In order to identify key variables necessary for translation
from batch to intermittent flow with recycle, several iterative
series of batch reactions were conducted. In general,
representative sequences consisted of several (5−8) consec-
utive aza-Henry reactions performed at −20 °C. The product
was removed by filtration and washed with ice-cold toluene,
and the residual filtrate was concentrated and used as a starting
point for the next step. Each step was initiated with dissolution
of residual solid, cooling to the corresponding temperature
followed by a recharge with fresh reactants. The mass of the
filtrate was registered after each iteration, and the composition
of the filtrate was carefully determined by HPLC and NMR
Catalyst 3 was prepared according to the previously reported
procedure.23,31 Several minor modifications were introduced in
order to improve yields and overall throughput of the material
(Scheme 4). In the Combes synthesis of 2,4-dichloro-8-
methoxyquinoline 12, dilution of the reaction mixture
improved the yield of the quinoline 3-fold. Buchwald−Hartwig
amination using potassium carbonate instead of sodium tert-
butoxide resulted in a 10% increase in the yield of ClQuinBAM.
Finally, nucleophilic aromatic substitution with pyrrolidine was
executed under milder microwave conditions. The original
procedure required 180 °C for 30 min and provided the
product in 48% yield. Moreover, extensive chromatographic
purification was needed to isolate the pure material. By
reducing the reaction temperature to 110 °C, the formation of
8
the key byproducts was suppressed, and after 3.5 h (MeO)-
PBAM catalyst 3 was generated as the major product.
Trituration from benzene/hexanes provided the catalyst in
81% yield as a light brown solid.
2. Automated Intermittent-Flow Process with Re-
cycle. Batch Approach to Develop Parameters for the
Process. To find acceptable starting conditions for automated
intermittent flow process, we used series of batch reactions.
After each batch reaction, the solids were filtered off, and the
filtrate was returned to the reaction flask. This created a
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analysis. The final product isolated from each iteration was
washed further with cold hexanes, dried, and similarly analyzed.
Initial batch series were performed using 100% recycle, and
the catalyst was introduced only once in the first iteration.
However, it was shown that in this case good enantioselectivity
could be maintained only during the first 4−5 iterations and
usually dropped (10−15%) after the fifth or sixth iteration and
declined thereafter.32
Batch Experiment with Recycle. Since limited success was
achieved when recycling 100% of the catalyst, introduction of
fresh catalyst at the beginning of each iteration might translate
into a more effective batch sequence without loss of selectivity.
This also aligned well with the overall plan to transform current
batch recycling into a completely automated intermittent flow
process.33 We conducted a sequence with 1.25% of the catalyst
in the flask and an 80% recycling ratio (Scheme 5). The
diastereoselectivity of the process remained high throughout
the entire sequence, and after the eighth iteration the product
was isolated in good yield and close to 90% ee (Figure 2).34 For
this protocol, nitroalkane (1.4 equiv) was introduced at each
step to maintain a proper stoichiometric ratio of the reagent in
the sequence. At the end of the eighth iteration, the overall
catalyst loading was 0.38%. Overall catalyst loading was low
because 1.25% catalyst was added for the first iteration, but only
0.25% fresh catalyst was added in each subsequent iteration.
The recycle kept catalyst loading at 1.25% in the reactor for all
iterations. Significant intensification of the process was achieved
by reduction of the reaction time from 24 to 4 h while
maintaining high concentrations of the catalyst in the flask due
to 80% recycling of the catalyst.
Manual Proof of Concept. With initial success the next goal
of development was to further demonstrate the viability of an
automated process with semibatch filtration of product away
from the solution with catalyst and remaining starting materials.
The batch sequence was designed to closely imitate the planned
sequence. In order to achieve this goal several alterations to the
previously described sequence (vide supra) were introduced:
solvent removal, drying, and redissolution of the recycled
material were omitted between iterations. Thus, upon
completion of each cycle the reaction mixture was filtered
while the collecting vessel for the filtrate was placed in the
cooling bath and kept at temperatures between −15 and −25
°C during the entire process. Upon conclusion of the filtration,
the starting materials were charged directly to the same vessel
and the next iteration was initiated. Additional toluene and
catalyst were added in order to keep concentration of the
reactants and catalyst constant. Under the described conditions
using manual filtration and house vacuum, full transfer of the
recycle was unattainable and on average 10−20% of the recycle
was retained in the filtered solid product. It is also important to
mention that these sequences allowed catalyst examination
(stability and sustainability) under conditions similar to the
actual automated intermittent flow runs which should provide
improved longevity of the catalyst and superior selectivities.35
Our goal was to achieve a reduction of cycle time to 40 min
or less in order to improve the overall intensity of the process.
The sequence was conducted with 1.0% catalyst. At the
beginning of each cycle, 7% of the initial amount (0.5 mg) of
fresh catalyst was introduced (Scheme 6). Initial iterations have
shown lower stereoselectivity. But from one batch to another,
Scheme 5. Sequence with 1.25% Catalyst and 80% Recycle
recycling number 80% indicates that only 80% of the catalyst
was recycled, but 20% of fresh catalyst was introduced at the
beginning of each cycle. The removal of 20% of the reaction
mixture at the end of each cycle was another important
difference of this recycling sequence in comparison with those
using a 100% recycle ratio. The enantioselectivity and
Figure 2. Enantioselectivity trends in the sequence with 80% recycle and 1.25% catalyst loading.
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reduction in the cycle time and intensification of the process.
The technical schematic for the process is shown in Figure 5.
In order to ensure homogeneous solutions for the feeds for
long time durations, a solubility screen was conducted. The
imine exhibited good solubility under the reaction conditions.
While cooling nitroalkane to −20 °C, in concentrations
between 0.5 and 0.7 g per 1 mL, slow crystallization of the
starting material was observed.
Scheme 6. Sequence with 1.0% Catalyst and 80% Recycle
Ratio
After brief optimization of automation and reaction
parameters, a test 10-cycle sequence was conducted with 40
8
min cycle time, 4.0% (MeO)PBAM catalyst loading, and 80%
recycle ratio. The mode of reagent addition was designed to
keep concentration of the imine low relative to nitroalkane,
while simultaneously maintaining excess nitroalkane acid in a
range that does not affect activity of the Brønsted basic catalyst.
Enantioselectivity of the crystallized aza-Henry product after
the first cycle was 85%; it reached 87% in the second cycle and
thereafter remained unchanged for the rest of the first day
campaign (Figure 4). Enantioselectivity in the recycle was
slightly higher: in the first two cycles 91.3% ee was observed,
whereas the next 8 cycles gave lower but very consistent results
in a range between 90.2 and 90.8% ee. The isolated yield of the
filtered product was 15.5 g (80.9% yield, 87% ee, with 96.2%
area by HPLC, and 2.1% area of diastereomer). In this
experiment 80% of the filtrate was recycled back to the reactor,
and 20% flowed to a waste container. Unfortunately, we did not
account for the amount of filtrate sequestered with the solids
on the filter; therefore, the amount of catalyst and excess
nitroalkane in the reactor gradually decreased over the 8
iterations for this automated experiment. Even so, the results
were good for all 10 iterations. Due to the short cycle time and
multiple volume turnovers per day, this setup is significantly
smaller in size compared to a required single batch reactor that
achieves similar throughput. In batch processing without
catalyst recycle, lower catalyst loadings lead to longer reaction
times and require larger reaction vessels.
enantioselectivity progressively increased and plateaued for the
last three runs at 88% (reaching a steady state, Figure 3).36
Diastereoselectivty of the solid decreases from cycle to cycle
but remains high (25:1). This trend is an expected result since
overall diastereoselectivity of the reaction measured for the
product isolated after chromatographic purification is
∼10:1.23,37 After 8 cycles product was isolated in 78% yield
overall. Based on the mass of material collected in the washes
the recycling ratio for this sequence was 80%. This combination
of robust results and significantly improved material throughput
(30 min vs 4 h reaction cycle) provided support for the basic
concept of our design. This series also revealed the stability of
the catalyst under these reaction conditions, including
encouraging levels of selectivity at 1% loading. The potential
advantages of reaching a steady state operation where a higher
enantioselectivity is achieved in comparison with a single batch
reaction were clearly demonstrated.
With successful results from the first automated intermittent
flow campaign, a longer 24-cycle sequence was completed using
a lower catalyst loading (2.64%) and higher recycle ratio. 97%
of the filtrate was recycled to the reactor, while 3% of the filtrate
was pumped to waste. Taking into account loss of solution to
the filter cake, 89% of the liquid that flowed out of the reactor
was recycled back to the reactor each cycle. Therefore, 89% of
the catalyst was returned back to the reactor after each cycle.
Automated Intermittent Flow Development. The auto-
mated intermittent flow unit was designed to conduct an
organocatalytic aza-Henry reaction in a repeating batch fashion
with semibatch filtration of the precipitated product followed
by recycling of the filtrate to the reactor. Recycling catalyst kept
catalyst loading high in the reactor, thereby allowing a
Figure 3. Enantioselectivity and diastereoselectivity trends in 1.0% catalyst loading sequence.
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Figure 4. Enantioselectivity and diastereoselectivity trends in the automated intermittent flow run with 80% recycle ratio.
Figure 5. Technological scheme of the process and mass streams for the 3-day intermittent flow campaign.
The overall structure and timing of the cycle remained
unchanged (23.5 min addition of the imine and 30 min
reaction cycle with 5 min filtration and 5 min precooling of the
recycled filtrate). The average temperature of the process was
sustained at −13 to −15 °C. Initially, three cycles were required
to achieve a steady-state condition, and enantioselectivity of the
solid product steadily increased during these cycles (82.6, 86.0,
88.3% ee, Figure 6). During the following three cycles
selectivity stabilized and remained on the same level (89.4,
89.4, 89.2% ee). This mirrored the situation observed in the
recycle where selectivity decreased during the first three cycles
(91.0, 90.3, 89.5% ee) and again remained essentially
unchanged for the next three (87.9, 88.3, 88.2% ee). After
the sixth cycle, the process was interrupted by stopping for the
night and reinitiated the next morning. During this overnight
period, the arrested reactor with recycle inside was maintained
at the standard temperature. However, after this 24 h period
under consistent operating conditions the reactor slowly
warmed due to circulator problems. During the second day
of the campaign the average temperature increased and was
maintained at −10 to −12 °C. Overall 10 cycles were
conducted during the second day of the campaign. Expectedly,
the first three were necessary to achieve a steady state, and
these cycles delivered slightly lower selectivity (88.0, 87.5,
87.4% ee). Selectivity then restabilized, and during the last five
cycles minimal fluctuations were observed (89.2, 89.1, 89.3,
89.2, 89.2% ee). After a two day campaign, 25.1 g of the
product was isolated (81.3% yield, 88.5% ee and purity of the
product was 98.6% HPLC area). The resulting aza-Henry
H
DOI: 10.1021/acs.oprd.5b00245
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Organic Process Research & Development
Article
Figure 6. Enantioselectivity and diastereoselectivity trends in the continuous run with 97% recycle ratio.
Table 1. Equipment Specifications
description
peristaltic pump
part number
7523-80
supplier
Cole-Palmer
Cole-Palmer
Chemglass
Ace Glass
peristaltic tubing size 35
EW9619-35
250 mL jacketed reactor
CG-1930-22
600 mL pressure filter complete
pressure transmitter, SS, 0−4000 psig
1/4″ actuated valve, 60 series
6384-231
3051S1TG4A2E11A1AQ4
SS-62TS4−31C
Rosemount
Indiana Fluid
product could be further recrystallized from toluene to provide
a single stereoisomer (>200:1 dr, 99% ee).23
the result of prolonged exposure to room temperature, could be
an explanation for the observation.
Careful analysis of the filter cake from the second day of the
campaign led to an interesting observation. The sample from
the top of the cake measured 91.2% ee, while the sample from
the bottom of the cake measured 87.1% ee, and the average
selectivity of the dry product was 88.8% ee. This phenomenon
can be explained by an increased solubility of a single
enantiomer in comparison with the racemate. Thus, after
multiple filtrations, the bottom of the cake is enriched with
racemate, and the top section contains product with the highest
enantioenrichment. In order to eliminate this heterogeneity in
the future, solid product will need to be washed and removed
from the filters more frequently to minimize the influence of
the filtrate solution on the cake. There are many options for
doing this. A centrifugal filter with automated solids peeling or
inverting basket could be used. Dual filters with automated
washing dissolving of solids from the off-line filter are another
option.
CONCLUSIONS
■
This platform both preserves the advantages commonly
ascribed to the continuous systems (reduced waste and
production footprint, atom economy and improved safety)
and incorporates the effectiveness of an organocatalyst to
provide access to a privileged (structurally and stereochemi-
cally) class of diamines. An automated intermittent flow reactor
was used instead of a truly continuous setup due to solids
precipitation, reaction kinetics, and the selectivity advantages of
controlled addition of the imine to the nitroalkane. Automated
intermittent flow is equivalent in this context to a continuous
process. It enabled high throughput for a small reactor size, a
low level of material hazard at any one time, fast cooling by
flowing through heat exchangers leading to the reactor, and
integrated recycle of catalyst and unreacted nitroalkane. The
following improvements of the developed protocol over the
standard batch were accomplished:
After 16 cycles the process was interrupted again. But this
time the cooling system was turned off, and the recycle solution
was warmed to room temperature for a prolonged period of
time. Eight additional cycles were executed during the third day
of the campaign. In comparison with the first reinitiation, the
selectivity of the process dropped more, and ∼85% ee was
observed in the first three cycles. Slow improvement in
selectivity was observed in the subsequent cycles; however, the
maximum selectivity of 87.5% was observed in this sequence
(1.5−1.8% lower than during the second day of campaign).
Surprisingly, the selectivities of the product in the recycle
solution remained mostly unchanged and consistently high
(87−90%). A degree of catalyst deactivation as it is recycled,
• Safety: Operating an automated intermittent flow reactor
affords the safety benefit of only having small amounts of
nitroalkane present at any given time, as opposed to a batch
reaction where the full amount of nitroalkane is subjected to
the reaction from the start.
• Productivity (moles product/hour/reactor volume): Reaction
can be safely run with a higher output and a single cycle
reduced to 40 min from 22 h for the batch process.
• Recycle of nitroalkane and catalyst: higher ratio of the
catalyst and nitroalkane to imine results in process
intensification.
• Reduced production footprint: atom economy, waste
minimization, decreased amount of solvents and catalyst.
I
DOI: 10.1021/acs.oprd.5b00245
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
• Fully automated process: (1) Full control of variables and
high reproducibility (constant enantioselectivity); (2) Flexi-
bility of production volume and scale up with minimum
optimization
• Reduced cost: Reaction performed at a higher temperature,
with a smaller reactor size and diminished single cycle time
provides significant cost benefit. The recycle allows a lower
catalyst loading and reduced solvent amounts.
This process was applied to the multigram synthesis of chiral,
densely functionalized precursors to differentially protected
diamines which are useful building blocks with a broad range of
applications.
EXPERIMENTAL SECTION
■
Materials. Starting materials (nitroalkane, imine, and
catalyst) were prepared according to the description provided
in section “Synthesis of Starting Materials and Catalyst” and
following previously published procedures.22,23 Toluene was
purchased commercially and used without further purification.
Table 1 shows the equipment specifications.
Reagent Solutions. The process is not sensitive to brief
exposure to residual moisture from the air as can be seen from
the recycling sequences described above (Scheme 5 and
Scheme 6) where the product was filtered and manual
iterations were reinitiated under open-air conditions. Despite
the tolerance to adventitious moisture, some precautions are
necessary since imine hydrolysis may eventually be observed.
To avoid potential complications during long-term campaigns,
automated intermittent flow runs were conducted under
nitrogen atmosphere, rigorously dried conditions, and with all
feeding solutions prepared in a glovebox environment at room
temperature in a separate feed bottle using dried degassed
toluene and volumetric flasks.
Imine (18.0 g, 75.2 mmol) was dissolved in toluene to
provide 65.3 mL of the solution. Nitroalkane (13.44 g, 78.4
mmol) and catalyst (122 mg, 0.214 mmol) were dissolved in
toluene to give total 38.2 mL total volume of the desired
solution. The initial charge (38.4 mL total volume) was
prepared by dissolving nitroalkane (287 mg, 1.67 mmol) and
catalyst (62.7 mg, 0.111 mmol). Reagent feed solutions were
transferred to feed vessels.
Figure 7. Reactor with a cooling jacket for the continuous
crystallization process and peristaltic pumps used for the continuous
feeding of solutions.
reaction cycle, 90% of the slurry in the reactor was immediately
pulled out of the reactor from a dip tube and into a transfer
zone (wide diameter tubing) using trapped vacuum. 10% of the
slurry was left behind in the reactor as a heel because the dip
tube did not go completely to the bottom. Slurry moves at high
velocity through 1/4″ o.d. 1/8″ i.d. PFA tubing. The “transfer
zone” for intermittent pumping of slurry at small scale was
introduced earlier.19b The transfer zone was pressurized with
nitrogen, and the slurry was pushed to the filter. The filtration
was performed in a 5 min time period. There was a sample port
located between the first transfer zone and the filter. The slurry
sample (∼1.0 mL) was taken from the port and filtered/washed
manually each cycle (samples were taken using a Whatman
Autovial Syringeless Filter). The composition of solid product
and filtrate, enantioselectivity, diastereoselectivity of the
product, and levels of impurities were determined by HPLC.
The filtrate (38.4 mL total volume, 0.287 g of nitroalkane, 63
mg of catalyst) immediately flowed out of the filter and directly
back to the reactor. Depending on the established recycle ratio,
only the desired amount of filtrate is recycled back to the
reactor, in this case 97% of the filtrate. The ratio between the
recycled and discarded filtrate was adjustable. The recycled
filtrate was passed through a cooling loop before reentering the
reactor. The desired amount of filtrate waste (1.041 g total, 9
mg nitroalkane, 2 mg catalyst) was then pushed into a waste
container. Five minutes was designated for the cool down of
the recycled filtrate before initiation of the next cycle. This
completes one cycle. The automation repeats these cycles for
the number designated by the operator. The overall cycle time
in the reactor was extremely consistent because of the
automated sequence. When the experiment was complete,
DeltaV was stopped and circulator was turned off. Material
from the filtrate waste bottle, filter, and reactor were collected
and measured.
Intermittent Flow Experiment. The following steps were
performed to start the cycle:
1. The circulator was turned on and set to temperature.
2. Utilities were turned on (nitrogen, vacuum, valve to
humidifier was opened).
3. Premeasured material was charged into the reactor.
4. Once the material was at temperature (−15 °C), DeltaV
sequence was initiated.
One Automated Cycle of the Intermittent Flow Reactor Is
As Follows. The catalyst/nitroalkane solution (2.39 mL total
volume, 0.84 g nitroalkane, 7.6 mg catalyst) was pumped into
the stirred tank reactor (250 mL volume, with overhead
stirring, 8) through a cooling heat exchanger over a 53 s period
and entered the reactor at −20 °C temperature (Figure 7).
Once finished the imine solution (4.08 mL total volume, 1.125
g imine) was introduced separately and pumped slowly into the
reactor with a predetermined flow rate during the cycle (over a
period of 23.5 min). The solution mixed in the reactor for 5.5
min after the addition of the imine was complete to ensure full
conversion of imine into the aza-Henry product. The overall
reaction time amounted to 30 min. Upon conclusion of each
After 16 cycles 25.1 g of the product was isolated (81.3%
yield, 88.5% ee, and purity of the product was 98.6% HPLC
J
DOI: 10.1021/acs.oprd.5b00245
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area). Analytical data of the isolated product is in accordance
with the previous report.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00245.
■
S
Additional engineering drawings, calculations, HPLC
analytical data for the continuous campaign, and
preliminary safety evaluation (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: tsukanov_sergey_vladimirovich@lilly.com.
*E-mail: jeffrey.n.johnston@vanderbilt.edu.
■
(7) For reviews, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713−5743. (b) Enders, D.; Niemeier, O.; Henseler, H.
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Notes
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (d) Erkkila,
̈
The authors declare no competing financial interest.
A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416−5470.
(e) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev.
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ACKNOWLEDGMENTS
■
Support from the Lilly Innovation Fellowship Award (LIFA)
for SVT is gratefully acknowledged. The authors also thank
James R. Stout and Megan M. Wong for their extensive help
with the continuous campaign. Catalyst development was
supported by funding from the National Institutes of Health
(GM 084333).
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(33) In automated intermittent flow process necessity to maintain a
constant volume of the solvent in the reactor leads to a recycling
percentage not equal to 100%. A percentage of the liquid phase
remains wetted on the solid product, and wash with solvent would
result in dilution of the recycle stream. Therefore the automated
intermittent flow process would need to pump a small amount of fresh
catalyst into the reactor along with the reagent feeds to maintain
constant catalyst loading over time.
(34) Observed fluctuations in enantioselectivity of the product could
be associated with manual handling, and in case of automated
intermittent flow processes this variability is eliminated.
(35) The catalyst in the previous sequences underwent a series of
manipulations: concentration, drying, and dissolution. While there is
no direct evidence that these iterative operations were detrimental to
the catalyst activity, the new sequence gives an opportunity to
constantly maintain the catalyst in solution under invariable reaction
conditions (∼ −20 °C).
(36) The overall phenomenon of increasing ee upon recycle at the
beginning of the process could be attributed to the difference in
solubility of the product racemate and product single enantiomer. The
racemate is less soluble than a single enantiomer, and the ee eventually
equilibrates upon achieving a steady state. Similar results observed in
intermittent-flow continuous runs (For example in 24 cycle run: after
the first cycle solid product is 82% ee, but selectivity of the product in
the filtrate is 91%. However, moving from cycle to cycle, the solid
product becomes more enantiomerically enriched: after the second
cycle it is 86% for the solid and 90% in filtrate, third cycle is 88% for
solid, and 89% for the filtrate).
(37) The analysis and comparison of diastereoselectivity data in the
solid product and in the filtrate (full numbers for the continuous runs
presented in the Supporting Information) shows that the ratio in the
filtrate is much lower than in the solid product from the beginning of
the process, meaning the overall diastereoselectivity of the reaction is
lower than observed in the solid product during the first several cycle.
Since filtrate gets recycled, diastereomer gets also recycled, and its
concentration in the reactor increases and results in crystallization of
the larger amounts of the diastereomer with the solid product. By
fourth cycle in continuous system this ratio between solid product and
filtrate equilibrates, and relative stabilization of the diastereomeric ratio
is observed. Processes with recycle usually require several turnovers to
reach steady state.
(24) Technical data (product safety assessment) for several
nitroalkanes (e.g. nitromethane, nitroethane) could be found at
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Encyclopedia of Industrial Chemistry: Wiley-VCH Verlag GmbH & Co.
KgaA, 2000.
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DOI: 10.1021/acs.oprd.5b00245
Org. Process Res. Dev. XXXX, XXX, XXX−XXX