Continuous Platform to Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

Article abstract of DOI:10.1021/acs.oprd.8b00113

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction is reported. A uniquely designed pipes-in-series plug-flow tube reactor addresses a range of process challenges, including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane, which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors with high selectivity, thus completely avoiding isolation of the potentially unsafe low-molecular-weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.

Full text of DOI:10.1021/acs.oprd.8b00113

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Continuous Platform To Generate Nitroalkanes On-Demand (in Situ)
Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series
Reactor
Sergey V. Tsukanov,*,†,‡ Martin D. Johnson,† Scott A. May,† Stanley P. Kolis,† Matthew H. Yates,†
and Jeffrey N. Johnston*,‡
†Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
‡Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United
States
S
* Supporting Information
ABSTRACT: The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with
the use of peracid to prepare nitroalkane substrates and the nitroalkanes themselves. In response, a continuous and scalable
chemistry platform to prepare aliphatic nitroalkanes on-demand using the oxidation of oximes with peracetic acid and direct
reaction of the nitroalkane intermediate in an aza-Henry reaction is reported. A uniquely designed pipes-in-series plug-flow tube
reactor addresses a range of process challenges, including stability and safe handling of peroxides and nitroalkanes. The
subsequent continuous extraction generates a solution of purified nitroalkane, which can be directly used in the following
enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors with high selectivity, thus completely
avoiding isolation of the potentially unsafe low-molecular-weight nitroalkane intermediate. A continuous campaign (16 h)
established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.
KEYWORDS: nitroalkane, peroxide, pipes-in-series reactor, sustainable or green chemistry, continuous processing, flow chemistry
continuous recycle have been published,9 but no examples exist
that detail the synthesis and immediate reaction of nitro-
alkanes. A general safety assessment and the development of an
innovative strategy to provide comprehensive solutions to
these challenges are therefore highly valuable. This report
describes the development of a flexible platform for the safe
and reliable preparation, purification, and downstream trans-
formation of nitroalkane intermediates. The nature of the
INTRODUCTION
■
Aliphatic nitroalkanes are highly useful synthetic intermediates
that can be utilized in a variety of organic transformations and
serve as valuable precursors to chiral amines.1 Amines,2
diamines,3 α-amino acids,4 and α-amino phosphonates5
derived from a nitro group are also key intermediates in
therapeutic development.6 Despite their established utility,
nitroalkanes remain generally underutilized in industrial
process provides on-demand nitroalkane access without
settings because of the safety risks associated with the nitro
isolation by a safe and straightforward continuous format,
group. There are several research examples that address the
one that can be further grown in scale.
issue of the nitro functional group in chemical transformations
by application of flow chemistry.7 Flow technologies offer a
We recently reported a scale-up procedure to conduct an
enantioselective aza-Henry reaction using semicontinuous
safer and improved alternative to batch reactions by reducing
conditions,10 an investigation that required large quantities of
the quantity of nitroalkane in the reactor, where it may be
aliphatic nitroalkanes. A literature search of nitroalkane
under forcing conditions. Additional advantages of a
preparations led to the conclusion that efficient and high-
continuous format include improved heat transfer and
temperature control for exothermic transformations and
yielding methods to generate nitroalkanes on a large scale are
rather limited.11 The most commonly utilized method is direct
minimization of solvent, resulting in an overall greener, more
cost-effective, and often more reliable process.8 While
substitution of the corresponding alkyl halide with sodium
nitrite as a nucleophile.12 This mild procedure uses a simple
numerous publications have detailed the use of nitroalkanes
and convenient nitrite source and inexpensive halides, and it
in flow reactors, very little attention has been paid to the safety
risks associated with batch handling, storage, and processing of
has certain advantages for small-scale preparations. However,
because of the ambident nature of nitrite, the procedure results
large volumes of low-molecular-weight nitroalkanes used as
in larger quantities of the corresponding nitrite O-alkylation
starting materials, intermediates, or products. For example,
product during scale-up, requiring tedious chromatographic
there are potential risks associated with the use of large feeding
purifications.13 Most recently developed alternatives, while
and collecting vessels on a kilogram scale. When applied to a
potentially hazardous nitroalkane, the concentration and
being valuable additions, remain impractical from safety and
isolation steps become no less important than the safety of
the chemical reaction itself, even on a relatively small scale.
Approaches that minimize nitroalkane quantities through a
Received: April 18, 2018
© XXXX American Chemical Society
A
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Organic Process Research & Development
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economic standpoints (Scheme 1).14,15 Despite the fact that
scaling large amounts of m-chloroperoxybenzoic acid
catalysis.17 These conditions also require distillation of the
product in order to reach the desired concentration. An
alternative and simpler protocol via an ion-exchange resin
(Amberlite IR-120)-catalyzed process was also reported in the
literature.19 Using 10−20 mass % of the resin at 50 °C, we
could generate a 15 mass % solution in a 3 h period, with a
maximum concentration of 16.5 mass % (∼60−63% yield)
reached after 24 h. With these encouraging results, we pursued
this transformation under continuous conditions in a packed-
bed reactor. A 20 in. (508 mm) tall perfluoroalkoxy (PFA)
copolymer resin tube-in-tube reactor with a 15 in. (381 mm)
heated zone was packed with ∼18 g of the resin, and using a
flow rate of 1 mL/min (∼6 min residence time) in 2 h we were
able reach a steady state and produce peracetic acid solution
with a concentration of 16.5 mass %. The packed-bed reactor
was used intermittently over a 5 month period of time with an
overall run time of over 80 h and consistently generated
peracetic acid with maximal equilibrium concentration and
without any sign of activity deterioration.
Scheme 1. Methods for Nitroalkane Synthesis
With this reliable source of peracid reagent, a preliminary
evaluation of the oxime oxidation reaction was made by means
of a traditional approach in batch. The corresponding oxime
(20.0 mmol scale) was dissolved in acetic acid, and the
solution was heated to 90 °C and then treated with peracetic
acid in dropwise fashion (over 20−30 min). Not unexpectedly,
the reaction was dependent on the electronic nature of the
substrate. Reactions of aromatic substrates with electron-
donating groups (Table 1, entries 9−12) proceeded in a rapid
fashion, and the temperature of the reaction strongly depended
on the rate of the peroxide addition. Furthermore, because of
the exothermic nature of the process, proper temperature
control was identified as a potential challenge for scale-up. For
aromatic oximes with electron-withdrawing substituents
(Table 1, entries 2−5), the kinetics of the reaction were
slower, and conditions with an additional 2 equiv of peracetic
acid were therefore utilized. A wide variety of nitroalkanes with
both electron-rich and electron-deficient phenyl rings were
successfully prepared. Aliphatic (Table 1, entries 6−8) and
secondary nitroalkanes (Table 1, entries 15 and 16) could be
generated in reasonable yields. The oxidation of ketoximes is
notable, as these are known to be recalcitrant substrates.
Further optimization of the reaction conditions for each
substrate could be beneficial to achieve optimal yield,
especially with volatile low-molecular-weight nitroalkanes. In
situ-generated peracetic acid showed results similar to the
commercial peracetic acid.20 Since the commercial oxidant is
more concentrated the reaction resulted in higher yields for
electron-poor substrates, but in contrast, more diluted acid
generated by ion-exchange catalysis provided better outcomes
with electron-rich substrates.
In order to understand the potential thermal risks presented
by the oxidation of oximes to nitroalkanes in a batch reactor,
calorimetry studies were executed to assess (a) the thermal
stability of the reactants (oxime and peracetic acid) and
product (nitroalkane) as well as (b) the energy liberated
during the oxidation reaction (see the Supporting Information
for the detailed results). Peracetic acid decomposition was also
studied in detail by Wang.21 Differential scanning calorimetry
(DSC) of peracetic acid solutions showed two low-onset
exotherms (at 38−41 and 83−102 °C) and enthalpies of
decomposition in a wide range from 556 to 1503 J/g. These
data clearly demonstrate the energetic nature of this material.
Both oxime and nitroalkane also have low onsets (223 and 142
(MCPBA) was not a suitable strategy, the general approach
of oxime oxidation was attractive because of its simplicity and
cost efficiency.10 Oximes are readily available starting materials
that can be prepared in one step using hydroxylamine and a
wide variety of aldehydes. Further investigation of oxime
oxidations using peroxide reagents showed that it is a well-
known transformation with multiple literature precedents.16
Among alternative oxidants considered, a solution of peracetic
acid offers the benefits of low molecular weight, low cost, and
ease of removal from the product stream (base wash) in
addition to a favorable safety profile among peracids.17 After
careful analysis, we came to the conclusion that reaction using
peracetic acid solution could serve as the most practical option
for the scale-up and further development.
RESULTS AND DISCUSSION
■
We initiated our study with a detailed look at the oxidant for
the process. Peracetic acid is a commercially available and
relatively inexpensive peracid. However, a solution of this
reagent represents an equilibrium mixture of peroxy acid,
hydrogen peroxide, water, and acetic acid. Furthermore, the
peracid is relatively unstable and degrades at room temperature
(via reversible reaction to give hydrogen peroxide and acetic
acid) at a rate of ∼1−2% over 24 h.18 The recommended
storage temperature for peracetic acid is 2−8 °C, which
significantly reduces the degradation pathway (to ∼0.3% a
day) but does not eliminate it. Finally, peracetic acid is a highly
reactive and hazardous material with a variety of risks related
to its usage (HMIS: Health, 3; Flammability, 2; Reactivity, 4).
The poor safety and stability of this reagent not only create
additional challenges for storage and handling but also affect
the quality and reliability of the oxidation process. To avoid
these problems, we envisioned the use of in situ continuous
generation of peracetic acid.
The most common way to generate this reagent is the
reaction of acetic acid and hydrogen peroxide under acid
B
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a
Table 1. Substrate Evaluation for Oxime Oxidation with Peracetic Acid (Traditional Batch Preparation)
a
Conditions: All of the reactions employed 20 mmol of nitroalkane in 7 mL of AcOH (2.86 M) warmed to 92 °C, 15−16% wt AcOOH was added
dropwise, while the temperature was maintained in the 90−97 °C range. Conditions A: 4.0 equiv of AcOOH over 30 min with an overall reaction
time of 50 min. Conditions B: 2.0 equiv of AcOOH over 20 min with a reaction time of 30 min. Conditions C: 4.0 equiv of AcOOH over 30 min
with a reaction time of 40 min. Conditions D: 1.2 equiv of AcOOH over 10 min with a reaction time of 15 min. Conditions E: 1.05 equiv of
AcOOH over 9 min with a reaction time of 10 min.
°C, respectively) and high decomposition energetics (>300 J/
g), which prompted further studies to determine the explosive
behavior.
perspective. The calculated maximum temperature of the
synthesis reaction (MTSR), 189 °C, would likely not be
reached, as boiling of the acetic acid solvent (boiling point =
118−119 °C) would prevent the reaction from reaching this
temperature. However, two exothermic onsets for peracetic
acid that occur below the process temperature and one that
occurs just above the maximum temperature for technical
reasons (MTT) cause this reaction to be dangerous in the
batch or semibatch mode of operation. From the perspective of
batch chemistry on scale, this oxidation clearly represents a
high risk. Therefore, the development of an alternative
continuous synthetic procedure that incorporates engineering
controls was pursued.
The energetics of the semibatch oxidation reaction was
studied using a Thermal Hazard Technology power
compensation microcalorimeter, and the reaction safety was
evaluated using the method of Stoessel22 for reaction criticality
class determination (Figure 1). The heat of the reaction was
determined to be −112.8 J/g for the reaction mass, and the
adiabatic temperature rise was calculated to be +99 °C. On
their own, these results would be enough to classify this
reaction as “medium risk” from the Stoessel criticality
After evaluating the substrates, we turned our attention to
the development of a continuous oxidation. We started the
process utilizing two separate feeds: a 2.2 M solution of
peracetic acid and a 1.35 M solution of 4-tert-butylbenzalde-
hyde oxime in acetic acid. The solutions were mixed together
and pumped through a 2.5 mL stainless steel plug-flow reactor
(PFR) at 90−95 °C (heated in a GC oven). The pressure
control was achieved by a standard membrane back-pressure
regulator. However, despite multiple attempts with residence
times of 3 to 30 min, very little nitroalkane was formed under
these conditions (Table 2).
Figure 1. Stoessel diagram for oxime oxidation by peracetic acid.
C
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Table 2. Oxime Oxidation Using Different Platforms
a
a
a
b
entry
reactor type
conditions
nitroalkane starting material benzoic acid isolated yield
1
2
3
4
batch: open flask (0.5 M)
stainless steel
PFR (2.5 mL)
PFA
90−96 °C, 20 min
90 °C, 20 min
80 °C, 3 min
83%
11%
8%
2%
−
37%
15%
63%
55%
47%
52%
95 °C, 20 min
34%
15%
PFR (2.5 mL)
port connector24
PFA
5
6
7
8
9
95 °C, 15 min
90 °C, 35 min
95 °C, 40 min
95 °C, 35 min
95 °C, 40 min
87−89 °C, 33 min
25%
69%
69%
75%
81%
81%
82−84.5%
−
63%
24%
28%
19%
16%
12%
12−13%
7%
3%
6%
2%
7%
3−5%
52%
pipes-in-series (12 mL)
PFA pipes-in-series (2 × AcOOH split, 12 mL)
PFA pipes-in-series (4 × AcOOH split, 12 mL)
PFA pipes-in-series (4 × AcOOH split, 42 mL)
54%
62%
10
11
PFA pipes-in-series (1 × 60%, 3 × 13.3 AcOOH split, 42 mL) 87−89 °C, 33 min
a
Ratios of nitroalkane, oxime, and benzoic acid (as the percent of the sum) were determined by NMR analysis of the crude reaction mixtures.
b
Yields of material isolated after batch extraction and flash column chromatography (silica gel, 0−4% heptane/EtOAc).
Scheme 2. Technological Scheme of the Continuous Process
The major products isolated from the reaction were the
corresponding benzoic acid and aldehyde with varying
amounts of oxime starting material and nitrile. Gas pockets
were observed at the outlet of the reactor, highlighting the
incompatibility of the peroxide reagent with the metal surface
of the reactor. Substituting the metal PFR with a PFA PFR
resulted in a slightly improved result, with nitroalkane and
benzoic acid representing the major products of the process. A
second difference between a PFR reaction and an open-flask
reaction is the headspace. It was noted that in the PFA reactor
fitted with a back-pressure regulator, large amounts of gas
generated in a process would be trapped inside the reaction
mixture, whereas this gas could easily escape in a batch
scenario with headspace. The literature also confirmed that
peracetic acid can spontaneously decompose, generating
oxygen23 that might overoxidize the reaction intermediates,
leading to increased amounts of benzoic acid. A test reaction
conducted in a closed vessel (port connector)24 with a limited
amount of headspace supported this hypothesis, as evidenced
by an improved nitroalkane yield relative to the regular metal
PFR.
To address these issues of material incompatibility and
generation of gaseous products, we designed a novel PFA
pipes-in-series reactor. The principal idea of a pipes-in-series
reactor constructed from metal was described previously and
successfully applied for chemical processes where gas transport
is a critical factor25 and where the reaction requires gas−liquid
contact and long reaction times.26 In the same manner, the
PFA version consists of pipes (d = 0.8 cm, V = 3.2−3.3 mL per
pipe) connected by jumper tubes (d = 1.6 mm, V = 0.05−0.5
mL per connecting tube). The reaction mixture spends the
majority of its residence time inside the pipes (∼85% liquid
filled), while a neutral gas carrier (nitrogen) enables mixing
inside the pipes and carries small liquid slugs through the
jumpers into the next pipe while providing effective gas/liquid
mixing. The major role of the carrier gas in this application is
to remove oxygen and other gaseous products from the
reaction mixture. Alternative solutions to entrapment of the
D
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Scheme 3. Aza-Henry Reaction of the Continuously Generated Nitroalkane
Figure 2. Major drivers for continuous platform development.
gases during reaction by switching to a continuous stirred tank
reactor or using a unique annular flow regime in a PFR have
been successfully utilized.27
extraction of the water layer with fresh toluene in order to
prevent loss of the material to the water waste. The first and
second stages operated in countercurrent fashion to minimize
waste loss to the aqueous phase. The toluene played a dual role
in the high-yield nitroalkane recovery. In this solvent,
deprotonation of the nitroalkane by the base was relatively
slow, leading to selective carboxylic acid extraction. The use of
heptane instead gave complete loss of the nitroalkane to the
base layer.
Furthermore, the toluene solution of the nitroalkane could
be directly used in the subsequent aza-Henry chemistry28
(Scheme 3) without further manipulation or addition of an
isolation procedure, thereby producing the desired product
with 89−91% ee after 3 h. The reactivity of the crude solution
under monoamidine (MAM) catalysis was indistinguishable
from that of the purified material.
Several major challenges were considered while developing
an oxime oxidation process (Figure 2). The exothermic
reaction at elevated temperatures (90−100 °C) proceeds
with a significant heat release and requires several equivalents
of peroxide as a reagent to produce the nitroalkane product.
The newly developed continuous platform not only delivered
appropriate solutions to all of these questions (Figure 2) but
also provided extensive opportunities related to the application
of flow chemistry with labile and unstable reagents and the
chemistry of peroxides and nitroalkanes.
We tested a four-pipe reactor (12 mL) at 95 °C with a
(mean) residence time of 30 min. Immediate improvement
was noted with a ∼69% yield of the nitroalkane as the major
product, coinciding with a reduced yield of benzoic acid
(∼28%). Taking into account the instability of the starting
material, the peracetic acid feed was initially divided into two
equal streams and then into four equal streams introduced
between the pipes. The yield of nitroalkane improved to 80%,
and only a 10−12% yield of benzoic acid was registered. A
larger reactor (42 mL, 16 pipes) was next designed (Scheme
2), and in this reactor the jumpers containing addition T’s
were removed from the heating bath to ensure minimal heat
exposure and decomposition of the unstable oxidant before it
entered the pipes. Kinetic studies were also performed in order
to determine the best splitting of the peracetic acid feed. It was
found that feeding 60% up front and 13.3% after the fourth,
eighth, and 12th pipes was the most successful distribution of
the reagent, giving maximum product (82−85%) and minimal
amounts of starting material (3−5%) and benzoic acid (12−
13%).
The resulting nitroalkane mixture was subjected to a
continuous extraction with toluene as an organic phase that
included three mixer−settler stages. The second stage (vessel
II) in the mixer−settler process was a water wash to remove
acetic acid, and the third stage (vessel III) was a sodium
hydroxide wash to remove the rest of acetic acid and also the
benzoic acid byproduct. The first stage (vessel I) was a back-
CONCLUSIONS
We have developed a new platform to prepare a major class of
nitroalkanes that offers an effective and general strategy for the
■
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quaternary centres in aza-Henry reactions. Org. Biomol. Chem. 2005,
3, 1362. (d) Shen, B.; Johnston, J. N. A Formal Enantioselective
Acetate Mannich Reaction: The Nitro Functional Group as a
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safe and controlled preparation/utilization of nitroalkane
compounds on an industrially relevant scale. This approach
benefits from a synthesis of nitroalkanes from simple and
inexpensive starting materials and an option to utilize them in
situ without isolation or additional purification of potentially
hazardous intermediates. A simple PFA packed-bed reactor
and a PFA pipes-in-series reactor provide distinctive qualities
to the system that enable the use of labile reagents at high
temperatures. An opportunity to combine this platform with
flow aza-Henry chemistry gives a direct alternative for the short
enantioselective synthesis of widespread and impactful chiral
diamines and their valued derivatives.
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enantioselective synthesis of α-substituted anti-α,β-diaminophos-
phonic acid derivatives. Chem. Commun. 2008, 35, 4177. (b) Blaszc-
zyk, R.; Gajda, A.; Zawadzki, S.; Czubacka, E.; Gajda, T. N-Carbamate
α-aminoalkyl-p-tolylsulfonesconvenient substrates in the nitro-
Mannich synthesis of secondary N-carbamate protected syn-2-
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at Decagram Scale. J. Org. Chem. 2013, 78, 10605. (b) Dobish, M. C.;
Villalta, F.; Waterman, M. R.; Lepesheva, G. I.; Johnston, J. N.
Organocatalytic, Enantioselective Synthesis of VNI: A Robust
Therapeutic Development Platform for Chagas, a Neglected Tropical
Disease. Org. Lett. 2012, 14, 6322. (c) Davis, T.; Danneman, M.;
Johnston, J. N. Chiral proton catalysis of secondary nitroalkane
additions to azomethine: synthesis of a potent GlyT1 inhibitor. Chem.
Commun. 2012, 48, 5578. (d) Hynes, P. S.; Stupple, P. A.; Dixon, D. J.
Organocatalytic Asymmetric Total Synthesis of (R)-Rolipram and
Formal Synthesis of (3S,4R)-Paroxetine. Org. Lett. 2008, 10, 1389.
(e) Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.;
Lu, G. L. A Practical and Azide-Free Synthetic Approach to
Oseltamivir from Diethyl d-Tartrate. J. Org. Chem. 2010, 75, 3125.
(f) Xie, H.; Zhang, Y.; Zhang, S.; Chen, X.; Wang, W. Bifunctional
Cinchona Alkaloid Thiourea Catalyzed Highly Efficient, Enantiose-
lective Aza-Henry Reaction of Cyclic Trifluoromethyl Ketimines:
Synthesis of Anti-HIV Drug DPC 083. Angew. Chem., Int. Ed. 2011,
50, 11773. (g) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki,
M. Heterobimetallic Transition Metal/Rare Earth Metal Bifunctional
Catalysis: A Cu/Sm/Schiff Base Complex for Syn-Selective Catalytic
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00113.
■
S
Experimental procedures for oxime preparation, nitro-
alkane synthesis, and aza-Henry reaction; NMR spectra
of key compounds; continuous flow equipment, setup,
and procedure; and microcalorimetry and ARC data for
1-(tert-butyl)-4-(nitromethyl)benzene (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: tsukanov_sergey_vladimirovich@lilly.com.
*E-mail: jeffrey.n.johnston@vanderbilt.edu.
■
ORCID
Sergey V. Tsukanov: 0000-0003-4287-7268
Scott A. May: 0000-0001-5168-0913
Jeffrey N. Johnston: 0000-0002-0885-636X
Notes
(7) (a) Tsubogo, T.; Oyamada, H.; Kobayashi, S. Multistep
continuous-flow synthesis of (R)- and (S)-rolipram using heteroge-
neous catalysts. Nature 2015, 520, 329. (b) Ghislieri, D.; Gilmore, K.;
Seeberger, P. H. Chemical Assembly Systems: Layered Control for
Divergent, Continuous, Multistep Syntheses of Active Pharmaceutical
Ingredients. Angew. Chem., Int. Ed. 2015, 54, 678. (c) Rossi, S.;
Benaglia, M.; Puglisi, A.; De Filippo, C. C.; Maggini, M. Continuous-
Flow Stereoselective Synthesis in Microreactors: Nucleophilic
Additions to Nitrostyrenes Organocatalyzed by a Chiral Bifunctional
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the Lilly Innovation
Fellowship Award (LIFA) for S.V.T. The authors also thank
Richard Miller for his extensive help with the continuous
campaigns. Catalyst development was supported by funding
from the National Institutes of Health (GM 084333).
̈
Catalyst. J. Flow Chem. 2015, 5, 17. (d) Braune, S.; Pochlauer, P.;
Reintjens, R.; Steinhofer, S.; Winter, M.; Lobet, O.; Guidat, R.;
Woehl, P.; Guermeur, C. Selective nitration in a microreactor for
pharmaceutical production under cGMP conditions. Chim. Oggi 2009,
27, 26. (e) Knapkiewicz, P.; Skowerski, K.; Jaskolska, D. E.;
Barbasiewicz, M.; Olszewski, T. K. Nitration Under Continuous
Flow Conditions: Convenient Synthesis of 2-Isopropoxy-5-nitro-
benzaldehyde, an Important Building Block in the Preparation of
Nitro-Substituted Hoveyda−Grubbs Metathesis Catalyst. Org. Process
Res. Dev. 2012, 16, 1430. (f) Cantillo, D.; Damm, M.; Dallinger, D.;
Bauser, M.; Berger, M.; Kappe, C. O. Sequential Nitration/
Hydrogenation Protocol for the Synthesis of Triaminophloroglucinol:
Safe Generation and Use of an Explosive Intermediate under
Continuous-Flow Conditions. Org. Process Res. Dev. 2014, 18, 1360.
(8) For reviews, see: (a) Malet-Sanz, L.; Susanne, F. Continuous
Flow Synthesis. A Pharma Perspective. J. Med. Chem. 2012, 55, 4062.
(b) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Deciding Whether
To Go with the Flow: Evaluating the Merits of Flow Reactors for
Synthesis. Angew. Chem., Int. Ed. 2011, 50, 7502. (c) Tsubogo, T.;
Ishiwata, T.; Kobayashi, S. Asymmetric Carbon−Carbon Bond
Formation under Continuous-Flow Conditions with Chiral Hetero-
geneous Catalysts. Angew. Chem., Int. Ed. 2013, 52, 6590. (d) Mak, X.
Y.; Laurino, P.; Seeberger, P. H. Asymmetric reactions in continuous
flow. Beilstein J. Org. Chem. 2009, 5, 19. (e) Wegner, J.; Ceylan, S.;
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