Scalable On-Demand Production of Purified Diazomethane Suitable for Sensitive Catalytic Reactions

Article abstract of DOI:10.1021/acs.oprd.0c00485

We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ～80% yield. Diazomethane (CH2N2) made with this reactor is extracted into nitrogen gas from the liquid reaction mixture, effectively removing it from reagents and byproducts that may interfere in subsequent reactions. Vertically oriented tubular reactors were used to produce and consume diazomethane in situ. Key features of this reactor include high productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min) and a commercially available gas/liquid separator equipped with a selectively permeating hydrophilic membrane. The design of the reactor keeps the inventory below 53 mg of CH2N2 during normal operation. The reactor was demonstrated by generating CH2N2 that was used in a connected continuous reactor. We evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor and achieved high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.

Full text of DOI:10.1021/acs.oprd.0c00485

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Article
Scalable On-Demand Production of Purified Diazomethane Suitable
for Sensitive Catalytic Reactions
Jillian W. Sheeran, Kiersten Campbell, Christopher P. Breen, Gerald Hummel, Changfeng Huang,
Anamika Datta, Serge H. Boyer, Scott J. Hecker, Matthew M. Bio, Yuan-Qing Fang, David D. Ford,*
and M. Grace Russell*
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ABSTRACT: We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-
N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this reactor is extracted into nitrogen
gas from the liquid reaction mixture, effectively removing it from reagents and byproducts that may interfere in subsequent reactions.
Vertically oriented tubular reactors were used to produce and consume diazomethane in situ. Key features of this reactor include
high productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min) and a commercially available
gas/liquid separator equipped with a selectively permeating hydrophilic membrane. The design of the reactor keeps the inventory
below 53 mg of CH2N2 during normal operation. The reactor was demonstrated by generating CH2N2 that was used in a connected
continuous reactor. We evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor
and achieved high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.
KEYWORDS: Diazomethane, cyclopropanation, plug flow reactor, continuous manufacturing
Liquid−liquid extraction is another simple method to
prepare organic solutions of CH2N2, and it has been applied
to continuous processes including at the kilogram scale.8 A
drawback of liquid−liquid extraction is that undesirable
impurities (e.g., base, unreacted N-methyl-N-nitroso-p-tolue-
nesulfonamide) could contaminate the organic phase and
poison downstream catalytic reactions. In the palladium-
catalyzed cyclopropanation reaction of interest, we found that
diazomethane prepared by liquid−liquid extraction did not
lead to appreciable levels of conversion, whereas diazomethane
purified by codistillation with diethyl ether gave nearly
complete conversion. For that reason, we sought to develop
a diazomethane synthesis strategy based on gas extraction and
gas/liquid-phase separation that would be convenient for
process development and kilo-lab deliverables.
In addition to the distillation process described above, there
are two other known strategies to purify diazomethane by
taking advantage of the high vapor pressure and low molecular
weight of CH2N2. Gas-permeable tubing has successfully been
demonstrated to allow diazomethane to diffuse into another
solution while leaving behind undesired byproducts.9 This
approach has been used to generate CH2N2 suitable for
palladium-catalyzed cyclopropanation reactions.10 Although
INTRODUCTION
■
Diazomethane (CH2N2) is a powerful synthetic reagent, but it
is rarely used beyond the laboratory scale because it is toxic,
explosive, and a gas under ambient conditions (bp = −23 °C).1
Continuous flow technology can be used to simultaneously
produce and consume hazardous reagents, mitigating the risks
associated with larger quantities of these materials that would
be necessary in a batch process. This opportunity has drawn
several academic and industrial groups to develop continuous
processes for preparing diazomethane.2 In order to prepare a
complex intermediate needed to prepare an investigational
drug, we were interested in developing an approach to prepare
diazomethane suitable for a palladium-catalyzed cyclopropa-
nation reaction.3 After a range of cyclopropanation conditions
were tested for this compound, the palladium-catalyzed
conditions using diazomethane proved the most promising.
This approach to cyclopropanation has been noted in the
literature to provide a good complement to the more
commonly used Simmons−Smith conditions.4
One significant challenge is purification of diazomethane to
meet the requirements of downstream chemistry. The harsh
conditions of diazomethane synthesis (basic and oxidizing)
mean that a workup or purification is typically needed before
using the CH2N2 reagent.5 The traditional lab-scale method for
purification of diazomethane is codistillation with diethyl
ether.6 This approach has been practiced by hazardous
chemistry specialists to prepare multikilogram quantities of
diazomethane, but the operations were performed under
remote control behind explosion-proof barriers, capabilities
that are not widely available in the pharmaceutical industry.7
Special Issue: Celebrating Women in Process Chem-
istry
Received: October 30, 2020
Published: December 31, 2020
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© 2020 American Chemical Society
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Figure 1. Design of previously reported CSTR-type reactors for CH2N2 synthesis and extraction into nitrogen gas (left) compared with the plug
flow reactor (PFR)-type design that is the subject of this article (right). In the PFR design, the tubing diameter is large enough to allow the gas to
bypass the liquid, allowing it to experience a shorter residence time in the reactor.
this approach is appealing, the tubing needed is not widely
available. To the best of our knowledge, this concept has not
been extended beyond a laboratory demonstration.
we opted to use MNTS for our process. Anhydrous MNTS
suffers from thermal instability and can only be shipped in
small quantities due to its low self-accelerating decomposition
temperature, but it has been determined that bulk quantities
up to 50 kg can be safely handled and stored by preparing
MNTS wetted with 10−15% w/w water.11
Two examples of diazomethane synthesis that are reported
on a kilogram scale and beyond use an approach similar to
codistillation, but instead of using solvent vapor to carry the
diazomethane away from the preparation reaction mixture, the
diazomethane is extracted using a nitrogen sweep or
sparge.11,12 This approach can be performed using nonflam-
mable solvents such as DMSO, and the nitrogen flow rate can
be selected to keep the diazomethane headspace concentration
below the lower explosive limit (LEL). In both cases, the
reagents needed to prepare CH2N2 are mixed in an
overflowing vessel analogous to a continuous stirred tank
reactor (CSTR) enclosed within a larger vessel that is purged
with nitrogen (Figure 1). In one case, the large volume of the
reactor required the authors to perform a test to ensure that a
detonation within the reactor would not cause it to rupture.
Whereas the approach of gas−liquid extraction is attractive
because it allows access to high-quality diazomethane while
also avoiding the use of flammable solvents, the previously
reported reactor designs had a large headspace volume.
Minimizing headspace is a guiding principle for designing
systems with hazardous gaseous reagents, as a smaller
headspace will reduce the consequences in the event of a
violent decomposition of diazomethane. Herein, we present a
scalable reactor design to continuously produce and consume
diazomethane suitable for metal-catalyzed cyclopropanation
reactions. This reactor is based on a tubular reactor design that
provides safety advantages over the CSTR designs previously
reported (Figure 1), chiefly by operating with a much smaller
headspace volume.
A high-boiling solvent is required to avoid solvent
evaporation during the process of extracting diazomethane
into the gas phase from the aqueous/organic solvent system.
Though we drew inspiration from the DMSO solvent system
reported by Proctor and Warr,11 we elected to use sulfolane in
place of DMSO to avoid thermal instability issues that have
been recently reported in the literature.14 Various composi-
tions of sulfolane/H2O were examined, aiming for high
solubility and stability of MNTS in solution. The 95:5 (w/
w) mixture of sulfolane and H2O, a liquid at room
temperature, is a suitable solvent for MNTS at concentrations
up to 20% w/w and is stable up to 4 days when stored as a
solution at 2−8 °C without appreciable decomposition of the
reagent by high-performance liquid chromatography (HPLC)
1
or H NMR spectroscopy. Compared to the process reported
by Proctor and Warr, we also increased the concentration of
the KOH solution to reduce the amount of water in the
reaction mixture. This change made the process less prone to
crystallization in the reactor, a major challenge in earlier work
with diazomethane synthesis performed in our laboratories.
Reactor Design. Our reactor design is based on a coil of
relatively large diameter (1/4 in. i.d.; 3/8 in. o.d.) PFA tubing
oriented so that the axis of the coil is parallel to the ground,
like a wheel (Figure 2). This configuration allows for a gas to
advance through the reactor more quickly than the liquid by
bubbling through liquid-phase slugs at the bottom of the coil.
In one reported example, the liquid residence time was 3 times
longer than the corresponding gas phase (4 h for the liquid
phase versus 1.3 h for gas phase).15 We reasoned that this
effect would be beneficial for diazomethane synthesis because a
longer liquid residence time would allow more time for MNTS
to react, whereas a short gas residence time would allow the
unstable CH2N2 product to be removed from the reactor
quickly, minimizing decomposition. In our process, nitrogen
was used to extract the gaseous diazomethane from the liquid
medium. We took advantage of the same vertical tubing coil
reactor design for the downstream chemistry, which requires
the CH2N2 to be extracted from the gas phase into the liquid
phase. Photographs of the two reactors are shown in the
Supporting Information.
RESULTS AND DISCUSSION
■
Choice of Reagents and Solvent. Diazomethane can be
synthesized from several precursors, but N-methyl-N-nitroso-p-
toluenesulfonamide (MNTS) is attractive for gas-phase
extraction of CH2N2 due to its low vapor pressure (eq 1).1b
MNTS is also significantly less toxic than alternative precursors
derived from urea and guanidine.13 Given the concerns of
handling these materials and introducing trace quantities of
toxic N-nitroso compounds into the product of the reaction,
The reactor mixes the liquid reaction mixture with a
nitrogen carrier gas that serves three purposes. First, the carrier
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Figure 2. Process flow diagram of diazomethane synthesis reactor and downstream carboxylic acid methylation. R1 = 240 mL, R2 = 120 mL. Feed
rates: KOH in H2O (13.7% w/w), 4.11 g/min; MNTS in 95:5 sulfolane/H2O (12.3% w/w), 14.6 g/min; N2, 1.02 slpm per feed (2.04 slpm total);
carboxylic acid in THF (0.5 mmol/g solution), 8.34 g/min.
Table 1. Summarized Results from Diazomethane Generation System Using Zaiput SEP-200 with 1.52 equiv of KOH and 1.5
equiv of Benzoic Acid (0.5 M)
flow rates in diazomethane generator
entry
MNTS throughput (mmol/min)
solvent
liquid (g/min)
N2 (slpm)
yield (%) of CH2N2
a
1
2
3
4
5
4.9
4.9
9.6
13.7
19.6
DMSO/DGME /H2O
sulfolane/H2O
7.4
0.685
1.07
2.13
2.99
4.27
75−80
76−82
77−79
64
12.0
24.0
33.7
47.7
sulfolane/H2O
sulfolane/H2O
sulfolane/H2O
incomplete gas−liquid separation
a
DGME = diethylene glycol monoethyl ether.
gas extracts CH2N2 from the reaction mixture and acts as a
solvent to carry it into downstream processes. Second, the
carrier gas prevents the gas-phase concentration of CH2N2
from reaching levels that could lead to an explosion. Finally,
the nitrogen carrier gas is also used to prevent liquid reagent
feeds from migrating back up the other reagent’s dosing line,
which causes precipitation. The nitrogen feed is split so that
half was introduced with the KOH feed, while the other half
was introduced with the MNTS feed to protect both feed lines
from blockage (Figure 2).
The flow rate of nitrogen gas was selected to prevent the gas-
phase concentration of CH2N2 from exceeding the LEL, which
has been established to be ∼15% v/v in nitrogen gas.11 To
provide a margin of safety, we designed our total nitrogen flow
rate to keep the CH2N2 concentration below 50% of the LEL.
For conditions with 9.6 mmol/min MNTS throughput, we
used a total nitrogen flow rate of 3.0 slpm (standard liters per
minute), which would result in a CH2N2 concentration of less
than 48% of the LEL, the exact concentration depending on
the yield of CH2N2 in the generator.
To separate the CH2N2-containing gas phase from the liquid
phase, we evaluated two approaches for a gas−liquid separator.
The first was a small glass pressure-rated vessel. We allowed
liquid to accumulate in the vessel and then drained it
periodically. While this was effective to establish a proof of
concept, the headspace in that vessel posed a risk of explosion;
the mechanical valves used can trap unstable reaction mixture
in the valve body when closed, and the periodic draining
introduces additional operational complexity. We opted to
replace that system with a commercially available gas−liquid
separator based on selective wetting of a membrane (Zaiput
SEP-200, Figure 2). By comparison, this piece of equipment
has no moving parts and a much smaller overall volume (35
mL). The separator was fitted with a hydrophilic PTFE
membrane, which causes the liquid phase to permeate the
membrane while the gas phase is retained. The overall reactor
volume including the downstream reactor for cyclopropanation
is 515 mL; therefore, during normal operation, the total
inventory of CH2N2 is expected to be less than 29 mLN
(volume at 1 bar pressure and 273 K) or 1.3 mmol (53 mg).
Demonstration of the Diazomethane Synthesis
Reactor System. Having established our reactor design, a
downstream reaction was introduced to the system to evaluate
the yield and productivity of CH2N2. To establish the limiting
throughput of the reactor system, we performed a series of
experiments increasing the MNTS feed rate given in Table 1.
The gas stream containing CH2N2 was mixed with a solution
containing an excess of benzoic acid. These reactions were run
at incomplete conversion of benzoic acid to ensure high
conversion of diazomethane. The yield of methyl benzoate was
used to establish the productivity of the diazomethane
synthesis reaction. Overall, the platform was able to consume
9.6 mmol/min of MNTS while maintaining a diazomethane
yield of 75−80% (Table 1, entry 3). At higher throughput, we
observed some liquid in the retentate stream of the separator.
Larger gas−liquid separators based on the same design are
commercially available, and they would allow access to faster
flow rates and therefore greater throughput.
To establish the utility of the reactor system, we performed a
second set of experiments under preparative conditions with an
excess of MNTS (and therefore CH2N2) compared to the
carboxylic acid substrate. Results were analyzed with a
calibrated HPLC method. From the results in Table 2, it is
apparent that the reactor uses the diazomethane very
efficiently, requiring only a slight excess of diazomethane to
reach high yields of the ester product.
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Table 2. Diazomethane Stoichiometry Studies for the
Methylation of Benzoic Acid (Performed at MNTS
throughput of 6.6 mmol/min)
a
entry
equiv of MNTS
equiv of CH2N2
yield (%)
1
2
3
1.00
1.25
1.50
0.75−0.80
0.94−1.00
1.13−1.20
82
100
99
a
Based on 75−80% yield from MNTS.
Table 3. Summary of Results from the Cyclopropanation
Using Styrene with a MNTS throughput of 9.7 mmol/min
with 2 mol % of Pd(OAc)2 with Regard to Styrene
styrene throughput
(mmol/min)
MNTS equiv relative
to styrene
molar
a
Figure 3. System stability of benzoic acid esterification with
diazomethane over 5.5 h. Conversion was monitored by HPLC at
each 0.5 h data point.
entry
conversion (%)
1
2
2.38
3.56
4.1
2.7
99
84
a
Defined as [product]/([starting material] + [product]).
equiv of MNTS, 99% molar conversion was achieved,
indicating that the purification strategy was sufficient for this
metal-catalyzed reaction. The results are reported in molar
conversion, which was calculated with a calibrated HPLC
method. While we observed high conversion in these reactions,
the cyclopropanation reactor gradually became fouled with
black solids near the catalyst addition point (presumed to be
palladium black) and white solids elsewhere in the cyclo-
propanation reactor (presumed to be hydrocarbon polymer
formed from diazomethane). Whereas this fouling appears
downstream of the sensitive gas−liquid separator, managing
reactor fouling will be an important consideration for extended
operation of this process.
Having established that these methylation reactions can be
performed at very low excess of diazomethane, we extended
the conditions to three additional carboxylic acids (Scheme 1)
Scheme 1. Methylation of Carboxylic Acids
CONCLUSION
■
We have developed a small-footprint, on-demand CH2N2
generation system that is robust and able to support
development lab activities and early material deliveries with a
diazomethane generation rate of 0.44 mol/h. The key reactor
technology used is scalable, with a straightforward path to 10×
scale (∼4−5 mol/h) with commercially available equipment
that does not rely on specialized materials such as gas-
permeable tubing. At that scale, CH2N2 inventory would
remain below 1 g, and the throughput could support small-
volume manufacturing. This approach highlights the advan-
tages of using continuous manufacturing to prepare hazardous
reagents. By removing the constraints of only working with
materials that are safe to use in large batch reactors, it may be
possible to identify more direct synthetic routes to compounds
of interest.
using 1.5 equiv of MNTS. Compound 1 is an important
intermediate in the synthesis of clopidogrel, an antiplatelet
medication on the World Health’s Organization List of
Essential Medicines. All reactions reached full conversion
from the respective carboxylic acids, and 1 and 2 and were
isolated in greater than 99% yield. Compound 3 had a lower
isolated yield possibly due to evaporation during isolation.16
The stability of this methylation process using benzoic acid
was tested over 5.5 h of continuous operation. The conversion
of benzoic acid to methyl benzoate was periodically monitored
by HPLC during the run shown in Figure 3. Throughout the
duration of the reaction, all feed flows were steadily delivered
and no rise in pressure was observed.
EXPERIMENTAL SECTION
■
WARNING! Diazomethane is extremely toxic and explosive.
Any operations involving diazomethane should undergo a
detailed process hazard assessment. Care should also be taken
when handling MNTS, as N-methyl-N-nitroso compounds are
known to be toxic, as well. MNTS-contaminated waste should
be separated from other waste streams to prevent formation of
diazomethane in waste containers.
Once the efficiency and stability of the diazomethane
generation reaction were established, we investigated the
reaction of interest, palladium-catalyzed cyclopropanation
(Figure 4).
1
General Materials and Methods. H NMR spectra were
recorded on a Varian 300 MHz instrument. 1,3,5-Trimethox-
ybenzene (Sigma-Aldrich, QNMR grade provided with trace-
able potency documentation) internal standard was used for
quantification. Analytical HPLC analysis was carried out
We repeated the diazomethane synthesis at the highest flow
rate (9.6 mmol/min) and designed the reaction to have 2.7 or
4.1 equiv of MNTS with respect to styrene (Table 3). With 4.1
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Figure 4. Process flow diagram of the cyclopropanation reactor. R1 = 240 mL, R2 = 120 mL, R3 = 0.5 mL, R4 = 120 mL. Flow rates: MNTS (10%
w/w in 95:5 sulfolane/water), 20.7 g/min; KOH (25% w/w in water), 1.26 g/min; styrene (1.24% w/w in THF), 20−30 g/min; Pd(OAc)2 (0.91%
w/w in THF), 1.2−1.8 g/min.
separator was fitted with an IL-2000 hydrophilic PTFE
membrane (pore size 1 μm).
Table 4. Reactor Specifications Used in Methylation or
Cyclopropanation
The tubing reactors were constructed of 3/8 in. o.d., 1/4 in.
i.d. PFA tubing, except for the catalyst precooling coil, which
was 1/16 in. o.d. and 1/32 in. i.d. The reactors and their
dimensions are found in Table 4. The catalyst precooling coil
and cyclopropanation reactor were not used in the methylation
reactions; the reaction was completed in the dissolution coil.
Palladium-Catalyzed Cyclopropanation. MNTS (237
g; 80.7% w/w potency) was dissolved in 80:20 w/w sulfolane/
H2O (1.67 kg) to give a 10% w/w yellow solution. Sonication
was required to fully dissolve the MNTS. KOH (255 g) was
dissolved in 764 g of water. Styrene (108 g) was dissolved in
8.61 kg of THF to give a 1.24% w/w solution. Pd(OAc)2 (0.65
g) was dissolved in 71 g of THF and then filtered through a
disposable filter under nitrogen to give a light red/orange-
colored 0.91% w/w solution.
volume
reactor
ID
(mL)
tubing type
CH2N2 generation reactor
R1
240
PFA 3/8 in. o.d.;
1/4 in. i.d.
PFA 3/8 in. o.d.;
1/4 in. i.d.
PFA 1/16 in. o.d.;
1/32 in. i.d.
dissolution of diazomethane
R2
R3
120
0.5
precooling coil for Pd(OAc)2
catalyst (only used for
cyclopropanation reaction)
cyclopropanation or methylation
reactor
R4
120
PFA 3/8 in. o.d.;
0.25 in. i.d.
according to a method provided in the Supporting
Information.
All chemicals were purchased from commercial suppliers
and used as received unless otherwise noted: KOH (BDH
Chemicals), benzoic acid (Sigma-Aldrich), tetrahydrofuran
stabilized with BHT (Oakwood Chemicals), methyl benzoate
(Sigma-Aldrich), 2-chloromandelic acid (Sigma-Aldrich, 94.5%
w/w), 2-chlorobenzoic acid (Sigma-Aldrich), cyclohexanecar-
boxylic acid (Sigma-Aldrich), styrene (Sigma-Aldrich), Pd-
(OAc)2 (Oakwood Chemicals), sulfolane (Oakwood Chem-
icals). MNTS was synthesized following a published
procedure.17
Reactor Configuration. Solutions of KOH, benzoic acid,
Pd(OAc)2, styrene, and 95:5 w/w sulfolane/H2O were
delivered to the reactor through dual diaphragm pumps, and
the flow rates were controlled by feedback control with
Coriolis mass flow meters. MNTS solution in 95:5 w/w
sulfolane/H2O was delivered from a pressurized vessel using a
metering valve that was controlled by feedback with a Coriolis
mass flow meter. Nitrogen dosing was controlled by thermal
gas mass flow meters. The Zaiput SEP-200 gas−liquid
The metering system was designed to facilitate two
stoichiometries of MNTS (Table 5).
We started the process using the conditions for 4.1 equiv of
MNTS. The reactor effluent was diverted to a quench vessel
charged with acetic acid for 6 min followed by product
collection. The crude product stream was collected for 2 min
and analyzed on a calibrated HPLC method to give molar
conversion of the reaction (99% molar conversion). The
metering system was reconfigured to deliver the conditions for
2.7 equiv of MNTS by increasing the flow rates for the styrene
and Pd(OAc)2 solutions. After the flow rates stabilized, the
reactor effluent was diverted to a quench vessel charged with
acetic acid for 6 min followed by product collection. The crude
product stream was collected for 2 min and analyzed on a
calibrated HPLC method to give molar conversion of the
reaction (84% molar conversion).
Table 5. Operating Conditions for the Cyclopropanation Process
4.1 equiv of MNTS
2.7 equiv of MNTS
feed stream
flow rate
throughput (mmol/min)
flow rate
throughput (mmol/min)
10.0% w/w MNTS
25.0% w/w KOH(aq)
nitrogen gas
1.24% w/w styrene in THF
0.91% w/w Pd(OAc)2 in THF
20.7 g/min
1.26 g/min
3120 sccm
19.87 g/min
1.18 g/min
9.7
1.52
29
2.38
0.05
20.7 g/min
1.26 g/min
3120 sccm
29.67 g/min
1.76 g/min
9.7
1.52
29
3.56
0.07
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ASSOCIATED CONTENT
DEDICATION
■
■
sı
Dedicated to Eric N. Jacobsen on the occasion of his 60th
birthday.
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00485.
ABBREVIATIONS
■
Procedure for carboxylic acid methylation, HPLC
method (PDF)
CSTR, continuous stirred tank reactor; in., inch; LEL, lower
explosive limit; MNTS, N-methyl-N-nitroso-p-toluenesulfona-
mide; PFA, perfluoroalkoxy alkane; PFR, plug flow reactor;
PT, pressure transmitter; PTFE, polytetrafluoroethylene; slpm,
standard liters per minute (gas flow); TE, temperature element
AUTHOR INFORMATION
■
Corresponding Authors
David D. Ford − Snapdragon Chemistry, Waltham,
Massachusetts 02451, United States; orcid.org/0000-
0002-3947-3978; Email: david.ford@
REFERENCES
■
(1) (a) Black, T. H. The Preparation and Reactions of Diazo-
methane. Aldrichimica Acta 1983, 16, 3−10. (b) Dallinger, D.; Kappe,
C. O. Recent Enabling Technologies for Diazomethane Generation
and Reactions. Aldrichimica Acta 2016, 49, 57−66.
(2) Yang, H.; Martin, B.; Schenkel, B. On-Demand Generation and
Consumption of Diazomethane in Multistep Continuous Flow
Systems. Org. Process Res. Dev. 2018, 22, 446−456.
snapdragonchemistry.com
M. Grace Russell − Snapdragon Chemistry, Waltham,
Massachusetts 02451, United States; orcid.org/0000-
0001-7426-0209; Email: grace.russell@
snapdragonchemistry.com
(3) Review articles on the topic: (a) Lebel, H.; Marcoux, J.-F.;
Molinaro, C.; Charette, A. B. Stereoselective Cyclopropanation
Reactions. Chem. Rev. 2003, 103, 977−1050. (b) Lautens, M.;
Klute, W.; Tam, W. Transition Metal-Mediated Cycloaddition
Reactions. Chem. Rev. 1996, 96, 49−92.
(4) Carlson, E.; Boutin, R.; Tam, W. Type 3 ring opening reaction of
cyclopropanated oxabenzonorbornadienes with alcohol nucleophiles.
Tetrahedron 2018, 74, 5510−5518.
Authors
Jillian W. Sheeran − Snapdragon Chemistry, Waltham,
Massachusetts 02451, United States
Kiersten Campbell − Snapdragon Chemistry, Waltham,
Massachusetts 02451, United States
Christopher P. Breen − Snapdragon Chemistry, Waltham,
Massachusetts 02451, United States
(5) In some cases, cyclopropanation reactions of relatively simple
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00485
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Zaiput Flow Technologies for
assisting us by selecting the optimal membrane for the gas−
liquid separator in the process and in troubleshooting issues
that arose in process development with unoptimized
conditions. This project was funded in part with Federal
funds from the Department of Health and Human Services;
Office of the Assistant Secretary for Preparedness and
Response; Biomedical Advanced Research and Development
A u t h o r i t y ( B A R D A ) , u n d e r O T A n u m b e r
HHSO100201600026C.
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