Laboratory-Scale Membrane Reactor for the Generation of Anhydrous Diazomethane

Article abstract of DOI:10.1021/acs.joc.6b01190

A configurationally simple and robust semibatch apparatus for the in situ on-demand generation of anhydrous solutions of diazomethane (CH₂N₂) avoiding distillation methods is presented. Diazomethane is produced by base-mediated decomposition of commercially available Diazald within a semipermeable Teflon AF-2400 tubing and subsequently selectively separated from the tubing into a solvent- and substrate-filled flask (tube-in-flask reactor). Reactions with CH₂N₂ can therefore be performed directly in the flask without dangerous and labor-intensive purification operations or exposure of the operator to CH₂N₂. The reactor has been employed for the methylation of carboxylic acids, the synthesis of α-chloro ketones and pyrazoles, and palladium-catalyzed cyclopropanation reactions on laboratory scale. The implementation of in-line FTIR technology allowed monitoring of the CH₂N₂ generation and its consumption. In addition, larger scales (1.8 g diazomethane per hour) could be obtained via parallelization (numbering up) by simply wrapping several membrane tubings into the flask.

Full text of DOI:10.1021/acs.joc.6b01190

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Featured Article
A Lab-Scale Membrane Reactor for the
Generation of Anhydrous Diazomethane
Doris Dallinger, Vagner D Pinho, Bernhard Gutmann, and C. Oliver Kappe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01190 • Publication Date (Web): 30 Jun 2016
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A LabꢀScale Membrane Reactor for the Generation of
Anhydrous Diazomethane
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Doris Dallinger,† Vagner D. Pinho,† Bernhard Gutmann,*,‡ and C. Oliver Kappe*,†
† Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Aꢀ8010 Graz, Austria
‡ Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
* Bernhard Gutmann. Eꢀmail: bernhard.gutmann@uniꢀgraz.at
* C. Oliver Kappe. Eꢀmail: oliver.kappe@uniꢀgraz.at.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
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Abstract: A configurationally simple and robust semiꢀbatch apparatus for the in-situ onꢀdemand
generation of anhydrous solutions of diazomethane (CH2N2) avoiding distillation methods is presented.
Diazomethane is produced by baseꢀmediated decomposition of commercially available Diazald within
a semiꢀpermeable Teflon AFꢀ2400 tubing and subsequently selectively separated from the tubing into a
solventꢀ and substrateꢀfilled flask (tubeꢀinꢀflask reactor). Reactions with CH2N2 can therefore be
performed directly in the flask without dangerous and labor intensive purification operations or
exposure of the operator to CH2N2. The reactor has been employed for the methylation of carboxylic
acids, the synthesis of αꢀchloro ketones and pyrazoles, and palladiumꢀcatalyzed cyclopropanation
reactions on laboratory scale. The implementation of in-line FTIR technology allowed monitoring the
CH2N2 generation and its consumption. In addition, larger scales (1.8 g diazomethane per h) could be
obtained via parallelization (numbering up) by simply wrapping several membrane tubings into the
flask.
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Introduction
The most timeꢀ and atomꢀefficient routes in organic synthesis frequently demand the use of
highly reactive, often lowꢀmolecular weight reagents. One such reagent is diazomethane (CH2N2)
which is an exceptionally powerful building block to introduce a methyl or a methylene group into
organic structures.1 However, as many strong alkylation agents, CH2N2 is a potent carcinogen and
extremely poisonous.2 The severe acute and chronic toxicity of CH2N2 is especially problematic
because of its high volatility (bp = ꢀ23 °C). In addition, the extreme sensitivity to explosive
decomposition makes the handling of CH2N2 challenging. Yet, despite the hazards associated with its
generation and utilization, CH2N2 is among the most versatile and useful reagents in organic synthesis.1
The reactions often proceed fast at room temperature and nitrogen is obtained as the sole byꢀproduct.
Generally, CH2N2 is produced by baseꢀmediated decomposition of NꢀmethylꢀNꢀnitroso amines in the
presence of diethyl ether. Various specialized kits for the laboratory scale generation (up to 300 mmol)
and purification of ethereal solutions of CH2N2 have been developed and commercialized.1a Coꢀ
distillation into a receiver flask cooled to ꢀ78 °C yields an ethereal solution of anhydrous CH2N2. It
should be noted though, that most CH2N2 explosions occur during its distillation.3 As CH2N2 has a
unique importance in contemporary organic synthesis, new methods and techniques for its safe and
convenient preparation and handling are continuously developed.
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We and others have recently demonstrated the in-situ generation of anhydrous CH2N2 in continuous
flow systems.4ꢀ8 Key to those strategies was the use of semiꢀpermeable, microꢀporous membranes
which selectively allow hydrophobic, lowꢀmolecular weight compounds to cross.4ꢀ6 Specifically, our
group used a commercially available tubeꢀinꢀtube reactor to accomplish generation and separation of
CH2N2.4,9 The inner tube of the device was made of a gasꢀpermeable Teflon AFꢀ2400 membrane which
was enclosed within a thickꢀwalled impermeable outer tubing.4,10,11 Diazomethane was generated from
commercially available NꢀmethylꢀNꢀnitrosoꢀpꢀtoluenesulfonamide (Diazald) and aqueous KOH within
the inner tubing. Anhydrous CH2N2 concurrently diffused through the AFꢀ2400 membrane, and was
finally consumed in the substrateꢀcarrying chamber formed between the outer and inner tubing.4
However, since production of CH2N2 is coupled with its separation and consumption in this tubeꢀinꢀ
tube configuration, the residence time of the substrate in the outer chamber and the contact time of the
substrate solution with the diazomethane carrying solution cannot be independently varied.
Consequently, the flow rate of the solution in the outer chamber determines not only the reaction time
but, further, the concentration or stoichiometry of CH2N2 attained in the outer solution.4 In addition,
any formation of solids in the outer chamber of the tubeꢀinꢀtube reactor may lead to clogging and may
thus prevent specific chemistry to be conducted in this type of flow device.12
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In order to enable operational simplicity and flexibility, in particular with respect to solid handling,
concentration and scale, a tubeꢀinꢀflask reactor design for the generation of anhydrous CH2N2 was
developed.13 Herein, we present a semiꢀbatch CH2N2 generator capable of safely producing up to 1.8 g
of anhydrous CH2N2 per hour, and its application to diverse chemistries including methylation of
carboxylic acids and the synthesis of αꢀchloro ketones and pyrazoles. A particular focus is placed on
palladiumꢀcatalyzed cyclopropanation reactions.
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Results and Discussion
Tube-in-Flask Reactor. The proofꢀofꢀconcept reactor used in the present work consists of a
commercially available AFꢀ2400 tubing of 5 m length (0.8 mm inner diameter, 1.0 mm outer diameter,
2.5 mL residence volume) wrapped inside a 50 mL Erlenmeyer flask (Figure S1a in the Supporting
Information).14 Similar reactor designs have been previously developed for reactions with ozone15 and
oxygen gas.16 In those approaches, the reaction mixture was carried in the membrane tubing inside the
flask, while the flask was filled with the respective gas. We have chosen a design where CH2N2 is
generated within the tubing.4 The AFꢀ2400 tubing was connected to standard 1/16 inch gasꢀtight PFA
(perfluoroalkoxy alkane) tubings on both sides. The two PFA tubings penetrated the rubber septum
sealing the Erlenmeyer flask. One of these PFA tubings connected the reactor to two syringe pumps.
For the actual experiments, a Diazald solution and 2 equiv of a KOH solution in MeOH/H2O were
pumped into a Yꢀmixer (M) at equal flow rates. The combined mixture then passed through the PFA
inletꢀtubing (230 µL residence volume) and then further through the AFꢀ2400 membrane immersed in
the Erlenmeyer flask (Figure 1). Stirring in the Erlenmeyer flask was performed with a Teflonꢀcoated
stir bar. The solution left the apparatus through the PFA outlet tubing and was directed into a quench
solution of acetic acid. In order to prevent a pressure increase or blockage of the Yꢀmixer due to
precipitation of potassium pꢀtoluenesulfonate, the mixer was immersed into an ultrasonic bath held at
25 °C. The flask itself was cooled in an iceꢀbath to 0°C.
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Figure 1. Continuous flow setꢀup: feed A: KOH in MeOH/H2O; feed B: Diazald in DMF or MeOH;
M: Yꢀmixer in an ultrasonic (US) bath; AFꢀ2400: 5 m AFꢀ2400 tubing in a 50 mL Erlenmeyer flask.
For more details, see Figure S1 in the Supporting Information.
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CAUTION: Diazomethane should be treated with extreme caution. It can be explosive in its pure
and undiluted form. In addition, it is highly toxic by inhalation or contact with skin or eyes, therefore
contact in any form should be avoided. Excess CH2N2 should be destroyed by addition of acetic acid.
All reactions should be carried out in an efficient fumehood with the sash closed and laboratory
personnel working with CH2N2 MUST familiarize themselves with the potential hazards and prevention
measures.17
Our initial conditions for the reactor performance studies were based on those we have applied using
the tubeꢀinꢀtube reactor.4 To determine the yield of CH2N2 in the flask as a function of the residence
time in the AFꢀ2400 membrane, 10 mL of a 0.6 M Diazald solution (6 mmol) in MeOH and a 1.2 M
KOH solution in MeOH/H2O (1:1) were pumped through the reactor at varying flow rates. The
Erlenmeyer flask was filled with 35 mL of anhydrous diethyl ether (Et2O), and after the consumption
of the Diazald solution an aliquot of 5 mL was taken from the flask and quenched with a stoichiometric
amount of benzoic acid. The conversion of benzoic acid to the methyl ester was used to evaluate the
CH2N2 concentration of the ethereal solution and CH2N2 yield (analyzed by HPLCꢀUV/Vis). The yield
of CH2N2 initially increased up to 68% at a flow rate of 250 µL/min (Figure 2a, red graph), but then
decreased with increasing flow rates for the Diazald and KOH feed (decreasing residence time in the
reactor). It should be noted, that a 0.6 M Diazald solution in MeOH was the maximum possible
concentration to obtain a homogeneous Diazald solution and that the ultrasonic bath had to be set to 30
°C in order to suppress precipitation and thus blockage. To achieve more concentrated Diazald
solutions, the solvent was changed to DMF: a concentration of 1 M was attainable and, in combination
with a 2 M KOH solution in MeOH/H2O (1:2), the precipitation problems were minimized. However,
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to prevent precipitation at higher flow rates, the Yꢀmixer was immersed in an ultrasonic bath set to 25
°C also for all subsequent experiments. The same trend was observed with respect to increasing flow
rates, although higher CH2N2 yields were obtained in particular at lower flow rates (Figure 2a, blue
graph). Since the difference in yield for the flow rates of 250 µL/min and 500 µL/min was only 5 %
(73 vs. 68%), but the time for complete Diazald consumption was halved (80 vs. 40 min), we opted for
500 µL/min as total flow rate – which results in a nominal residence time of 5 min –18 for all
subsequent experiments. With this flow rate, approximately 0.10 M ethereal solutions of CH2N2
(Figure 2b, red graph) were generated from 10 mL Diazald in MeOH (0.6 M), corresponding to a
CH2N2 generation of ca. 89 µmol/min. On the other hand, for a solution of 10 mL Diazald in DMF (1
M) these values were doubled: a concentration of 0.19 M of CH2N2 could be reached (ca. 165 µmol
CH2N2 /min). When the amount of Diazald pumped through the reactor was increased, the CH2N2
concentration in the flask increased essentially linearly (Figure 2b). As the concentration gradient
between the solution in the tubing and the flask then diminishes, an equilibrium concentration of ca.
0.38 M is approached for Diazald in MeOH and the CH2N2 yield decreases (Figure 2b, red graph). The
equilibrium concentration is expected to depend on the partition coefficient of CH2N2 between Et2O
and MeOH/H2O. Accordingly, the final concentration of CH2N2 in the Et2O solution was higher than
the highest possible CH2N2 concentration in the AFꢀ2400 membrane tubing (0.38 M vs. 0.30 M),
indicating the comparatively low solubility of CH2N2 in the aqueous solution. After pumping 40 mmol
of Diazald in DMF a rather high CH2N2 concentration of 0.62 M was reached (Figure 2b, blue graph),
however, owing to safety concerns, larger amounts of Diazald were not processed and thus the
equilibrium concentration was not determined. It appears entirely feasible to reach CH2N2
concentrations of ca. 1 M.
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Figure 2. Generation of CH2N2 with (a) 10 mL of a 0.6 M MeOH solution of Diazald (red) and 10 mL
of an 1 M DMF solution of Diazald (blue) at different flow rates (equal flow rates for Diazald and
KOH feed) 18 and (b) varying amounts of Diazald in MeOH (red) and DMF (blue) at a total flow rate of
500 µL/min.
The CH2N2 concentrations obtained in this way compare well with those achieved with traditional
distillation methods (ca. 0.25ꢀ0.68 M ethereal solutions).3,19 Employing Diazald in DMF proved to be
superior to MeOH as solvent. Not only are the CH2N2 yields and thus concentrations higher, but
importantly, the processing times are significantly shorter: for example, to obtain a ca. 0.2 M ethereal
CH2N2 solution, 10 mL of a 1 M Diazald solution in DMF need to be pumped at 500 µL/min total flow
rate for 40 min, whereas 20 mL of a 0.6 M Diazald solution in MeOH are necessary and thus twice the
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processing time (Figure 2b). For all subsequent chemistry examples, therefore, the 1 M Diazald in
DMF and 2 M KOH in MeOH/H2O (1:2) system, and a 500 µL/min total flow rate was used,
generating a 0.19 M ethereal CH2N2 solution.
It should be stressed that a concentration gradient will be maintained when CH2N2 would be allowed
to react directly with a substrate contained in the flask. Moreover, under such conditions the buildup of
hazardous concentrations of CH2N2 could be avoided and the risk of uncontrollable decomposition
eliminated (see below). A key advantage of the present membraneꢀbased reactor system is that
anhydrous CH2N2 solutions can be easily prepared in solvents other than diethyl ether. Indeed, similar
CH2N2 concentrations were obtained in a variety of organic solvents, including higher boiling solvents
such as toluene (Figure 3).
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Figure 3. Generation of CH2N2 using 35 mL of different solvents in the flask at 0 °C (dioxane at rt):
12 mmol Diazald (0.6 M in MeOH, red) and 10 mmol Diazald (1 M in DMF, blue) at a total flow rate
of 500 µL/min.
Methylation of Carboxylic Acids. To evaluate the principle of performing reactions directly in the
flask, the conversion of carboxylic acids into their corresponding methyl esters (Table 1) was initially
chosen. The advantages of this reaction are rapid reaction times, only volatile byꢀproducts (N2) and
high selectivity.1 With 10 mmol of benzoic acid dissolved in 35 mL of anhydrous Et2O in the flask, 1.5
equiv (15 mmol) of Diazald, which corresponds to ca. 10 mmol CH2N2 (see Figure 2), were prepared.
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Notably, complete conversion to the methyl ester 1a was already obtained after pumping 1.35 equiv
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of Diazald through the system (74% yield of CH2N2; determined by kinetic analysis via HPLC),
indicating a highly efficient transport of CH2N2 from the membrane tubing into the flask when a
concentration gradient is maintained. In order to develop a general protocol taking into account the
varying reactivities of the acid substrates, a total of 1.5 equiv (15 mmol) of Diazald were employed.
Any excess of CH2N2 in the flask after the reaction was quenched with AcOH (10ꢀ15 drops). The
reaction mixture was then extracted with sat NaHCO3, and 1a was obtained after evaporation of the
solvent in 90% yield (1.2 g) and >99% purity (HPLC at 215 nm). Other aromatic carboxylic acids (1b-
d), both with electronꢀdonating and ꢀwithdrawing groups, also provided full conversion to the
corresponding esters (Table 1). Although 4ꢀNO2ꢀ and 4ꢀMeOꢀbenzoic acids were not completely
soluble in Et2O at the starting concentration (5 mmol), the corresponding methyl esters were, and full
conversion was obtained nonetheless. Other functional groups were well tolerated, only 1% of the
bismethylated 2ꢀhydroxy benzoic acid was generated, and cinnamic acid was exclusively converted to
the ester 1e.
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TABLE 1. Methylation of Carboxylic Acidsa
compound
R
H
n
0
0
0
0
1
yield [%]
90
90
89
99
95
1a
1b
1c
1d
1e
4ꢀNO2
4ꢀMeO
2ꢀOH
H
a Conditions: 1M Diazald in DMF, 2 M KOH in MeOH/H2O (1:2), 500 µL/min total flow rate, 35 mL
Et2O at 0 °C. For detailed reaction conditions, see the Experimental Section.
Synthesis of α-Chloroketones. In order to determine that the CH2N2 separated from the tubing into the
flask is indeed anhydrous, the reaction of acyl chlorides with CH2N2 was conducted (Table 2). The
generation of αꢀdiazoketones via a modified ArndtꢀEistert reaction only proceeds satisfactorily under
strictly anhydrous conditions. This reaction type is of particular interest because of its use in the
synthesis of modern HIV protease inhibitors and was recently reported by our group using continuous
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flow protocols.4,13 Using 5 mmol of benzoyl chloride (2a) in anhydrous Et2O and 3 equiv of Diazald,
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a 7:1 mixture of αꢀdiazoketone 3a and αꢀchloroketone 4a was obtained. It is known, that the in-situ
generated HCl either reacts with the diazoketone to form the chloroketone via the Nierenstein reaction,
or contributes to the decomposition of CH2N2 to CH3Cl and N2.20 With excess CH2N2 at lower
temperatures preferentially the diazoketones are generated, as the HCl is consumed in the reaction with
CH2N2. Since the chloroketone could not be removed by a simple extraction/evaporation workꢀup, we
decided to convert the diazoketone to the chloroketone in-situ by adding 1.5 mL conc. HCl. Stirring for
20 min and extraction with H2O and sat NaHCO3 provided pure αꢀchloroketone 4a in 88% yield (Table
2). Importantly, no methyl ester could be detected, confirming that anhydrous CH2N2 was generated. A
similar result as for benzoyl chloride was obtained for 4ꢀbromobenzoyl chloride 2c. With the electron
withdrawing NO2 functionality a 4:1 mixture of αꢀdiazoketone 3b and αꢀchloroketone 4b was obtained
after complete Diazald consumption. The subsequent HCl quench and extraction furnished 4b in 90%
yield. On the other hand, when an electron donating group is present, the reaction proceeds much
slower. For 4ꢀmethoxybenzoyl chloride, incomplete conversion to diazoketone 3d or chloroketone 4d
after consumption of 3 equiv of Diazald was observed. After 2 h stirring 13% of acyl chloride 2d was
still present. Therefore, the amount of Diazald was increased to 4 equiv and optimum results were
achieved after 1.5 h of stirring after complete Diazald uptake (3% 2d, 90% 3d, 7% 4d). After addition
of HCl, and stirring for 20 min, αꢀchloroketone 4d could be isolated in 90%. Notably, also for αꢀ
chloroketones 4bꢀ4d only traces of ≤ 1% of the corresponding esters could be detected in the NMR,
indicating the clean formation of anhydrous CH2N2 using the membraneꢀbased separation technique.
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TABLE 2. Synthesis of α-Chloroketonesa
compound
R
H
equiv Diazald
yield [%]
3
3
3
4
88
90
88
90
4a
4b
4c
4d
NO2
Br
MeO
a Conditions: 1M Diazald in DMF, 2 M KOH in MeOH/H2O (1:2), 500 µL/min total flow rate, 35 mL
Et2O at 0 °C. For detailed reaction conditions, see the Experimental Section.
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Palladium-catalyzed Cyclopropanations. Cyclopropanation of olefins with CH2N2 is of major
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synthetic importance since the cyclopropane subunit is found as a basic structural element in a wide
range of naturally occurring compounds and in several bioactive unnatural analogues.21,22 In addition,
the cyclopropane ring is a versatile synthetic building block which can be converted into a range of
functionalities.8b Generally, Pd is the catalyst of choice, but also other transition metal catalysts,
including Cu, Ni and Rh, have been reported to efficiently catalyze the reaction under mild
conditions.21 The reaction commonly proceeds with excellent stereoꢀ and chemoselectivity and is
compatible with a wide range of functional groups.21,23 Biphasic cyclopropanations have been
developed, whereby CH2N2 is generated in-situ in the strongly basic aqueous phase and is then
transferred into an organic phase where the cyclopropanation takes place.23 Even though this protocol
does not require any purification of CH2N2, the biphasic reaction necessitates a water soluble Diazald
derivative, is limited to water insoluble substrates and to reagents which tolerate the strongly basic
aqueous conditions.23a Cyclopropanations in flow were conducted by employing the more stable αꢀ
diazocarbonyl24 or unstabilized nucleophilic diazo intermediates.25
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For our initial optimization reactions, a variety of catalysts and catalyst loadings were screened in
parallel using 5 mL glass vials. For these transformations, 0.2 mmol of the substrate and the respective
catalyst in THF as solvent were added into the glass vials equipped with a magnetic stir bar. A sample
of 2.2 mL (2 equiv) of CH2N2 in THF was then slowly pipetted from the flask into each of the glass
vials under stirring at 0 °C. With styrene as the model substrate, various palladium species proved to be
very active catalysts for the cyclopropanation while, in contrast, Cu(II) species did not exhibit any
catalytic activity. With 2 mol% of Pd(OAc)2 as catalyst, nitrogen evolved vigorously upon addition of
CH2N2 and the yellow color of CH2N2 quickly vanished. Similar results were obtained with PdCl2 and
zeroꢀvalent palladium precatalysts such as Pd2(dba)3. In all of these experiments a precipitate of Pd
black formed in the early stages of the reaction (see Figure 4), and the reaction generally stopped well
before full conversion was attained. Furthermore, independent experiments without substrate
demonstrated that Pd(OAc)2 effectively catalyzes the decomposition of CH2N2 (monitored by UVꢀVis
spectroscopy at 410 nm). The initial rate of CH2N2 decomposition is roughly proportional to the
catalyst concentration, but again Pd black then quickly forms and the decomposition rate dropped. The
main products of the Pdꢀcatalyzed decomposition of CH2N2 in deuterated chloroform were tentatively
1
assigned to cyclopropane, methanol, ethene and acetaldehyde by HꢀNMR analysis (Figures S4ꢀS6 in
the Supporting Information). Importantly, considerably higher conversions for the cyclopropanation
were obtained when the catalyst loading was decreased (Figure 4). With a catalyst loading of only 0.25
mol% of Pd(OAc)2 a conversion of 73% was obtained using styrene as substrate. Appreciable Pd black
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precipitation was not observed at this catalyst loading. Noteworthy, full conversion was achieved
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within seconds at 0 °C when the CH2N2 solution was added rapidly to the reaction mixture containing
the substrate and the catalyst (Figure S7 in the Supporting Information). However, catalyst loadings
below <0.1 mol% reduced the reaction rate noticeably. For electronꢀrich olefins such as pꢀMeOꢀstyrene
with a weak coordinating ability for Pd(0), the speed of CH2N2 addition is by far more critical. When
the CH2N2 was added slowly to a solution containing pꢀMeOꢀstyrene and Pd(OAc)2, Pd(0) precipitates
and the reaction stops at 60 % conversion. An increase to 89% was observed by fast addition of the
CH2N2 solution, and even 96% was possible when the catalyst was added slowly to the
substrate/CH2N2 solution (Figure S8 in the Supporting Information).
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Figure 4. Pd(OAc)2ꢀcatalyzed cyclopropanation of styrene at different catalyst loadings (0.2 mmol of
styrene, 2 equiv of CH2N2 in THF as solvent).
The occurrence of Pd(0) precipitates during the reaction has previously been reported,26 and the
reaction inhibiting effect of larger amounts of Pd(OAc)2 was already observed by the Hacksell group
during cyclopropanation of enoyl sultams.27 The mechanism of transition metalꢀcatalyzed
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cyclopropanation is still rather controversial and not very well understood.28 Nefedov29 and others26a
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proposed that the palladiumꢀcatalyzed cyclopropanation proceeds through a Pd(0)/Pd(II) cycle. The
results described above suggest that the intermediate Pd(0) species can either insert into the CꢀN bond
of CH2N2 and reꢀenter the catalytic cycle or, alternatively, aggregate to generate Pd clusters, which
ultimately irreversibly precipitate in the form of Pd black. By lowering the catalyst concentration, the
autoꢀcatalyzed aggregation becomes slow and is eventually outperformed by reꢀoxidation of Pd(0) to
Pd(II) by addition of CH2N2. The same effect was described for ligandꢀfree Heck reactions which
efficiently proceed in the presence of homeopathic quantities of Pd(OAc)2 as catalyst.30 Similarly,
depletion of CH2N2 upon slow addition prevents reꢀoxidation of Pd(0) and favors its agglomeration and
precipitation.
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For preparative reactions in the tubeꢀinꢀflask reactor, solutions containing 3 mmol of the styrene and
the respective amount of Pd(OAc)2 in Et2O were directly loaded into the Erlenmeyer flask (Table 3).
Since byꢀproducts derived from THF were observed in the final product, the solvent was changed to
Et2O. A solution of 3 equiv Diazald (ca. 2 equiv CH2N2) was pumped through the AFꢀ2400. The
reaction with styrene 5a proceeded to completion with a catalyst loading of 0.05 mol% and 1.5 equiv of
CH2N2. On the other hand, with 0.25 mol% Pd(OAc)2, the reaction stopped at a conversion of only
49%. Due to the volatility of 6a only 79% was isolated after an AcOH quench and extraction with sat
NaHCO3. The reaction with electronꢀpoor 3ꢀNO2ꢀstyrene 5b gave a conversion >99% without
significant Pd precipitation, as long as the Pd concentration did not exceed 0.15 mol%. As expected,
the addition of CH2N2 to the internal olefins 5c and 5d occurred stereospecifically to afford the transꢀ
cyclopropanes 6c and 6d as the sole products. In accordance with the experiments described above –
since the diffusion of CH2N2 through the tubing into the solution equates to a slow addition of CH2N2 –
the use of this approach for a reaction with the electronꢀrich pꢀMeOꢀstyrene as the substrate resulted in
immediate Pd precipitation and the conversion stopped at 6 and 56% with 0.05 and 0.25 mol%
Pd(OAc)2, respectively.31
Cyclopropanations are clearly not a trivial affair when full conversions and high isolated yields are
envisaged, thus a general protocol for diverse alkene substrates is hardly feasible. Depending on the
coordination abilities of the alkenes for Pd(0), the precipitation of Pd black – and therefore termination
of the reaction – occurs at different catalyst concentrations. Also the reagent addition is crucial:
whereas for neutral and electronꢀpoor alkenes the Pd catalyst can be charged into the flask, for
electronꢀrich alkenes, the catalyst needs to be added slowly to the substrate/CH2N2 solution.
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TABLE 3. Palladium-catalyzed Cyclopropanationsa
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compound
R1
H
R2
H
equiv Diazald Pd(OAc)2 [mol%] yield [%]
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2.25
0.05
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94
6a
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NO2
H
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CO2Me
H
Ph
a Conditions: 1M Diazald in DMF, 2 M KOH in MeOH/H2O (1:2), 500 µL/min total flow rate, 35 mL
Et2O at 0 °C. For detailed reaction conditions, see Experimental Section.
Synthesis of Pyrazoles. The pyrazole motif is an attractive building block for the pharmaceutical as
well as for the agrochemical industry, since those derivatives display a broad spectrum of biological
activities.32 Of particular importance are pyrazole carboxylates,33 e.g., ethyl 5ꢀpropylꢀ1Hꢀpyrazoleꢀ3ꢀ
carboxylate is a key intermediate for the synthesis of sildenafil (Viagra).34 Pyrazoles are usually
prepared either by condensation of a hydrazine derivative and a 1,3ꢀdicarbonyl compound or by 1,3ꢀ
dipolar cycloaddition of diazo compounds and alkynes, which provides a direct access to substituted
pyrazoles.35 We have performed the reaction of ethyl propiolate and CH2N2 under standard conditions
using 1.5 equiv of Diazald and Et2O as solvent (Scheme 1). The reaction did go to completion (>99%,
GCꢀMS analysis), however, after purification via simple extraction/evaporation only 71ꢀ80% could be
isolated. The reason for the low yield was product precipitation during the reaction. The low solubility,
also in excess Et2O, made it difficult to remove the solid product entirely out of the flask. Therefore,
Et2O was substituted by CHCl3 as solvent for the reaction (Scheme 1), which facilitated workꢀup, since
the product was perfectly soluble in excess CHCl3. Generally, this reaction is regioselective, and only
the 3ꢀsubstituted pyrazole isomer 7 is obtained.36 However, when Et2O was employed, 5% of the 4ꢀ
substituted pyrazole 8 and 3ꢀ8% of N1ꢀmethylated pyrazole 9 was attained. The product distribution
changed in favour of 7 using CHCl3 as solvent, providing 8 and 9 only in 1.5% and 0.7%, respectively
(Scheme 1). As expected, the deactivated propargyl alcohol was completely unreactive.
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SCHEME 1. Synthesis of Pyrazoles via 1,3-Dipolar Cycloaddition.
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Scale-up Concepts. It should be noted that with the tubeꢀinꢀtube reactor, although it has the advantage
to be fully continuous, the scale is quite limited (up to 70 mg CH2N2/h).4 Larger scales – e.g., by
increasing the size between the inner and outer compartment – are not so easy to achieve, since several
aspects need to be taken into account: diffusion of CH2N2,37 the flow rates for the CH2N2, KOH and
substrate feed, concentration of the feeds, etc.. With the above shown setꢀup ca. 420 mg (10 mmol)
CH2N2/h can be generated, which would theoretically lead to ca. 2 g/h productivity assuming a product
molecular weight of ca. 200. Larger scales in a reasonable time frame would be problematic to achieve,
therefore the reactor design needed further development. Our initial attempt was to employ an AFꢀ2400
membrane with a larger inner diameter (1.55 vs. 0.8 mm). To be comparable with the “smaller” tubing,
a length of 1.5 m was chosen, so that approximately the same residence volume (2.8 vs. 2.5 mL) was
reached. The tubing was wrapped into a 250 mL Duran flask which was filled with 100 mL of Et2O
(Figure S2 in the Supporting Information). To achieve a similar concentration of 0.19 M in the flask,
28.6 mL of a 1 M solution of Diazald in DMF and a 2 M KOH solution in MeOH/H2O (1:2) were
pumped with a total flow rate of 500 µL/min. A CH2N2 yield of 34% was obtained, which is exactly
half the amount generated with the original membrane tubing, indicating that the conversion is
inversely proportional to the inner diameter and thus the surface area of the membrane.37 For the same
throughput twice the residence volume would be necessary. The next logical step was a parallelization
approach (numbering up).16 Therefore, four standard AFꢀ2400 membrane tubings, each 4 m in length
(2 mL residence volume), were connected to the inlet and outlet tubing via a 5ꢀport manifold and
wrapped into a 250 mL Duran flask (Figure 5). With this setꢀup four times the scale should be
accomplished within the same time frame (40 min) as for the single membrane reactor.
For the scaleꢀup experiments, reaction monitoring with in-situ FTIR spectroscopy (Mettler Toledo
ReactIR with a silicon probe) was applied. The IR probe was inserted into the solution in the flask via a
screwꢀcap adapter (Figure 5a and S3 in the Supporting Information). The CH2N2 generation and
consumption could thus be precisely examined, due to the strong characteristic C=N2 stretch around
2100 cmꢀ1. Proctor and Warr have reported the continuous monitoring of the gasꢀphase concentration of
CH2N2 at 2102 cmꢀ1 employing a photoacoustic FTIR instrument in a pilot scale reactor.7a The Ley
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group, on the other hand, used the ReactIR flow cell to monitor e.g., the generation of diazo
intermediates25 or the concentration of CO in the liquid stream in a tubeꢀinꢀtube reactor,10b respectively.
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Figure 5. a) Largeꢀscale CH2N2 generator with the AgX fiber probe attached for in-line FTIR analysis.
SC: screwꢀcap for reaction sampling and reagent addition. b) Parallelization using two Teflon 5ꢀport
manifolds. c) 4 x 4 m AFꢀ2400 tubing wrapped inside a 250 mL Duran flask.
To evaluate the performance of the reactor, the CH2N2 yield in the flask was first determined. All the
amounts were quadrupled: 40 mL of a 1 M solution of Diazald in DMF were pumped at a total flow
rate of 2 mL/min and 140 mL of anhydrous Et2O were filled into the flask. It has to be noted, that at
this high flow rate, precipitation in the Yꢀmixer occurred at 25 °C in the ultrasonic bath. This problem
could be solved though, by setting the temperature to 30 °C. For a reaction calibration, samples were
taken every 10 min and analyzed by HPLC and were then correlated to the peak area of the absorption
measured with the IR probe for the C=N2 stretch at 2091 cmꢀ1 (Figures 6a and 6d). As can be seen, the
CH2N2 concentration increases linearly with a maximum concentration of 0.209 M reached after ca. 43
min. The CH2N2 concentration then keeps constant in the flask, until a quench with acetic acid was
performed after ca. 60 min, upon which the CH2N2 concentration drops instantly to zero (Figure 6b).
From 40 mmol Diazald (1 M), pumped with a flow rate of 1 mL/min, and a determined CH2N2 yield of
71% after 40 min, theoretically 0.71mmol (29.8 mg) CH2N2 should be generated per min. The
experimental value of 0.7085 (see Figure 6c) perfectly fits this calculation and a maximum of 29 mmol
CH2N2 was obtained, after complete consumption of Diazald. The data obtained also match those of the
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small scale experiment remarkably well: 0.19 M of CH2N2 could be reached correlating to the
generation of ca. 0.66 mmol CH2N2/min.
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Figure 6. a) Correlation between CH2N2 concentration (HPLC analysis) and peak area of the C=N2
stretch at 2091 cmꢀ1 (IR analysis). b) Correlation of CH2N2 concentration with time. c) Correlation of
mmol CH2N2 generation with time. d) 3ꢀD surface image for the C=N2 stretch at 2091 cmꢀ1.
Next, we wanted to apply our largerꢀscale CH2N2 generator to chemistry examples. The synthesis of αꢀ
chloroketone 4d (Table 2) was now performed on fourfold scale. A sample of 20 mmol of 4ꢀMeOꢀ
benzoyl chloride (2d) was dissolved in 140 mL Et2O in the flask and 80 mmol Diazald (4 equiv) in 80
mL DMF were employed. The reaction again was monitored via FTIR (Figure 7). Benzoyl chloride 2d,
which was traced by its C=O stretch at 1773 cmꢀ1, decreased during the course of the reaction, whereas
diazoketone 3d with the C=N2 stretch at 2091 cmꢀ1 increased. Unfortunately, the C=N2 stretch for
CH2N2 and diazoketone overlayed, but supported by the data we have observed so far (also see Figure
8), we assume that the concentration increase can be assigned to diazoketone product formation. As
already described above, the reaction does not go to completion after full consumption of Diazald: after
86 min, 20% of 2d was still present (HPLC conversion). This correlates very well to the value obtained
from the decrease in peak area in Figure 7. Full conversion to diazoketone 3d was achieved after
stirring for additional 90 min. Subsequently, 6 mL of conc HCl were added, the diazoketone
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concentration drops immediately, and after stirring for 1 h, extractive workꢀup and evaporation,
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Figure 7. Reaction monitoring of the conversion of benzoyl chloride 2d to the corresponding
diazoketone 3d using in-line FTIR spectroscopy.
The methylation of benzoic acid was then used as a model reaction to demonstrate the productivity of
the reactor over an 8 h working day. For this proofꢀofꢀconcept study 0.32 mol (39 g) benzoic acid were
dissolved in 200 mL Et2O in the flask and 0.48 mol Diazald (1.5 equiv) in 480 mL DMF were pumped
through the reactor with a flow rate of 1 mL/min. According to the FTIR analysis, no CH2N2 was
present in the solution in the flask until the reaction was completed after ca. 7 h (Figure 8). When all
substrate was consumed (C=O stretch at 1696 cmꢀ1), the C=N2 stretch for CH2N2 at 2091 cmꢀ1appeared,
and the experiment theoretically could be stopped. This nicely corroborates our findings on small scale
(see above): only 1.34 equiv Diazald are necessary for full conversion to the methyl ester 1a. After
addition of 2 mL AcOH and extraction, 42.22 g (97%) of ester 1a was obtained, equating to 6 g
product/h.
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Figure 8. Reaction monitoring for the methylation of benzoic acid using in-line FTIR spectroscopy (3ꢀ
D surface image).
Conclusion
A simple and easy to construct reactor setꢀup for the in-situ onꢀdemand generation of solutions of
anhydrous CH2N2 is described. Diazomethane is generated from Diazald in DMF and aqueous KOH
within a hydrophobic, gasꢀpermeable tubing. Anhydrous CH2N2 subsequently diffuses through the
tubing into the surrounding flask. This approach allows the convenient preparation of solutions of
CH2N2 in any desired solvent, which can be further used for optimization or screening studies. The
concentration of the CH2N2 solution or stoichiometry can be adjusted simply by varying the amount of
Diazald pumped through the reactor. With a tubing of only 2.5 mL residence volume, the reactor
provides ca. 165 µmol (3.9 mg) of anhydrous CH2N2 per minute. A larger scale can easily be achieved
via parallelization (numbering up) by wrapping more membrane tubings into the flask. With 4
membranes in parallel – 2 mL residence volume each – ca. 42.6 mmol (1.8 g) CH2N2/h can be
generated, ideally leading to approximately 70 g of product/day (based on an 8 h working day and a
molecular weight of 200). Compared to the previously reported tubeꢀinꢀtube method, the tubeꢀinꢀflask
protocol is not sensitive to solubility issues with respect to starting material, products, or any byꢀ
products which may be formed. CH2N2 is intensively used in contemporary organic synthesis but it is
notoriously dangerous to handle, since it is volatile, toxic, carcinogenic and highly explosive. The labꢀ
scale CH2N2 generator proposed herein eliminates cumbersome and potentially dangerous isolation and
purification procedures and, thus, offers the promise of a safer and simpler synthetic protocol, since the
generated CH2N2 can be utilized directly in the flask without any exposure to CH2N2. We could also
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show that in-line FTIR spectroscopy is ideally suited for safe and reliable reaction monitoring, which
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is of specific relevance when toxic or hazardous intermediates or products are generated. Further
investigations toward new reactor designs with respect to scaleꢀup are currently evaluated in our group.
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Experimental Section
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General Methods. HꢀNMR spectra were recorded on a 300 MHz instrument. CꢀNMR spectra
were recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield
from TMS as internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet,
quadruplet, and multiplet. GCꢀMS spectra were recorded using a Focus GC coupled with a DSQ II (EI,
70 eV). A HP5ꢀMS column (30 m × 0.250 mm × 0.25 ꢁm) was used with Helium as carrier gas (1 mL
minꢀ1 constant flow). The injector temperature was set to 280 °C. After 1 min at 50 °C the temperature
was increased in 25 °C minꢀ1 steps up to 300 °C and kept at 300 °C for 4 min. Analytical HPLC
analysis was carried out on a C18 reversedꢀphase (RP) analytical column (150 × 4.6 mm, particle size 5
ꢁm) at 37 °C using a mobile phase A (water/MeCN 90:10 (v/v) + 0.1% TFA) and B (MeCN + 0.1%
TFA) at a flow rate of 1.5 mL minꢀ1. The following gradient was applied: linear increase from solution
30% B to 100% B within 10 min. Melting points were obtained on a standard melting point apparatus
in open capillary tubes. In-line FTIR analysis (software package iC IR 4.3.35) was performed using a
AgX Fiber Conduit with an integrated attenuated total reflectance (ATR) gold sealed silicon sensor and
a mercury cadmium telluride (MCT) detector. All solvents and chemicals were obtained from standard
commercial vendors and were used without any further purification. Diazald was synthesized following
a literature procedure.38 Products were characterized by H NMR and identified by comparison of the
1
spectra with those reported in the literature. All compounds synthesized herein are known in the
literature. Proof of purity was obtained by 1H NMR and HPLCꢀUV spectroscopy.
General Method for Methylation of Carboxylic Acids. 30 mmol of KOH were dissolved in 15 mL
MeOH/H2O 1:2 (feed A) and 7.5 mmol of Diazald were dissolved in 7.5 mL DMF (feed B). The
Erlenmeyer flask – fitted with a stir bar – was filled with 5 mmol of the respective benzoic acid in 35
mL of anhydrous diethyl ether and was cooled in an iceꢀbath to 0 °C. Feed A and feed B were pumped
by two syringe pumps (Asia, Syrris, see Figure S1b) into a Yꢀmixer, which was immersed into an
ultrasonic bath set to 25 °C, at flow rates of 250 µL minꢀ1 each (2 equiv of KOH with respect to
Diazald). The combined mixture then passed through the PFA inletꢀtubing (1/16 inch o.d.; 0.8 mm i.d.;
230 µL residence volume) and then further through the AFꢀ2400 membrane within the Erlenmeyer
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flask (Figure S1a). The solution left the reactor through the PFA outlet tubing and was directed into
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a quench solution of aqueous acetic acid. Towards the end of the experiment, the reaction solution in
the Erlenmeyer flask became yellow, indicating the full consumption of the carboxylic acids. After the
Diazald solution was consumed, the reaction mixture in the Erlenmeyer flask was quenched with acetic
acid. The now decolorized ethereal solution was subsequently extracted with sat NaHCO3. Drying of
the organic phase with MgSO4 and evaporation of the solvent provided the products 1aꢀ1e in >99%
purity.
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Methyl Benzoate (1a). 60 mmol of KOH in 30 mL MeOH/H2O (1:2), 15 mmol of Diazald in 15 mL
DMF and 10 mmol benzoic acid were employed. 1.23 g (90%); light yellow oil;39 1H NMR (300 MHz,
CDCl3) δ 8.09 – 8.05 (m, 2H), 7.61 – 7.55 (m, 1H), 7.49 – 7.43 (m, 2H), 3.94 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 167.1, 132.9, 130.1, 129.6, 128.4, 52.1.
Methyl 4-Nitrobenzoate (1b). 18 mmol of KOH in 9 mL MeOH/H2O (1:2), 4.5 mmol of Diazald in
4.5 mL DMF and 3 mmol 4ꢀnitrobenzoic acid were employed. 491 mg (90%); light yellow solid, mp.
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99ꢀ100 °C, lit40mp 95ꢀ96 °C; H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 9.1
Hz, 2H), 4.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 165.2, 150.6, 135.5, 130.7, 123.6, 52.8.
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Methyl 4-Methoxybenzoate (1c). 743 mg (89%); white solid, mp 48ꢀ50 °C, lit41 mp 48ꢀ50 °C; H
NMR (300 MHz, CDCl3) δ 8.01 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 166.9, 163.3, 131.6, 122.6, 113.6, 55.4, 51.8.
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Methyl 3-Hydroxybenzoate (1d). 753 mg (99%); white solid; mp 70ꢀ71 °C, lit42 mp 69ꢀ71 °C; H
NMR (300 MHz, CDCl3) δ 7.63 – 7.60 (m, 2H), 7.33 (t, J = 4.6 Hz, 1H), 7.12 – 7.08 (m, 2H), 3.94 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 156.0, 131.2, 129.8, 121.8, 120.4, 116.4, 52.5.
Methyl Cinnamate (1e). 770 mg (95%); light yellow solid, mp 36ꢀ37 °C, lit43 mp 36ꢀ37 °C; 1H NMR
(300 MHz, CDCl3) δ 7.72 (d, J = 16.0 Hz, 1H), 7.56 – 7.53 (m, 2H), 7.42 – 7.40 (m, 3H), 6.47 (d, J =
13
16.0 Hz, 1H), 3.83 (s, 3H). C NMR (75 MHz, CDCl3) δ 167.5, 144.9, 134.4, 130.3, 128.9, 128.1,
117.8, 51.7.
Synthesis of Methyl Benzoate (1a) on 0.32 mol Scale. 1.92 mol of KOH were dissolved in 960 mL
MeOH/H2O (1:2) (feed A) and 0.48 mol of Diazald were dissolved in 480 mL DMF (feed B). The 250
mL Duran flask (Ø: 95 mm, h: 105 mm) – fitted with a stir bar – was filled with 0.32 mol benzoic acid
in 200 mL anhydrous diethyl ether and was cooled in an iceꢀbath to 0 °C. Feed A and feed B were
pumped by two syringe pumps (Asia, Syrris, see Figure S3 in the SI) into a Yꢀmixer, which was
immersed into an ultrasonic bath set to 30 °C, at flow rates of 1 mL minꢀ1 each (2 equiv of KOH with
respect to Diazald). The combined mixture then passed through the PFA inletꢀtubing (1/16 inch o.d.;
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0.8 mm i.d.; 300 µL residence volume) and then further through the 4 AFꢀ2400 membranes within
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the Duran flask (Figure 5). The solution left the reactor through the PFA outlet tubing and was directed
into a quench solution of aqueous acetic acid. After the Diazald solution was consumed, the reaction
mixture in the flask was quenched with acetic acid. The now decolorized ethereal solution was
subsequently extracted with sat NaHCO3. Drying of the organic phase with MgSO4 and evaporation of
the solvent provided 42.22 g of the product in >99% purity. For characterization data, see above.
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Synthesis of α-Chloroketones. Diazomethane was generated as described above with feed solutions of
60 mmol of KOH in 30 mL MeOH/H2O 1:2 (feed A), and 15 mmol of Diazald in 15 mL DMF (feed
B). For 4ꢀmethoxy benzoyl chloride 80 mmol of KOH in 40 mL MeOH/H2O 1:2 and 20 mmol of
Diazald in 20 mL DMF were employed. The Erlenmeyer flask – fitted with a stir bar – was filled with
5 mmol of the respective benzoyl chloride in 35 mL anhydrous diethyl ether and was cooled in an iceꢀ
bath to 0 °C. After the Diazald solution was consumed, the reaction mixture in the Erlenmeyer flask
was quenched with 1.5 mL of conc. HCl and the reaction mixture was stirred for 20 min. The ethereal
solution was subsequently extracted with H2O and sat NaHCO3. Drying of the organic phase with
MgSO4 and evaporation of the solvent provided the products 4aꢀ4d in >96% purity.
Phenacyl Chloride (4a). 679 mg (88%), yellow solid, mp 55ꢀ56 °C, lit.44 mp 53ꢀ55 °C; 1H NMR (300
MHz, CDCl3) δ 8.01 – 7.97 (m, 2H), 7.67 – 7.62 (m, 1H), 7.56 – 7.50 (m, 2H), 4.74 (s, 2H). 13C NMR
(75 MHz, CDCl3) δ 191.1, 134.2, 134.0, 128.9, 128.5, 46.1.
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4-Nitrophenacyl Chloride (4b). 899 mg (90%), yellow solid, mp 89ꢀ90 °C, lit.45 mp 87ꢀ91 °C; H
NMR (300 MHz, CDCl3) δ 8.38 (d, J = 8.9 Hz, 2H), 8.16 (d, J = 9.0 Hz, 2H), 4.73 (s, 2H). 13C NMR
(75 MHz, CDCl3) δ 189.9, 150.7, 138.6, 129.8, 124.1, 45.6.
1
4-Bromophenacyl Chloride (4c). 1.04 g (88%), white solid, mp 119ꢀ120 °C, lit.44 mp 116 °C; H
NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 4.68 (s, 2H). 13C NMR
(75 MHz, CDCl3) δ 190.3, 132.9, 132.3, 130.0, 129.4, 45.6.
4-Methoxyphenacyl Chloride (4d). 832 mg (90%), light yellow solid, mp 97ꢀ98 °C, lit.44 mp 98 °C;
1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.67 (s, 2H), 3.90 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 189.7, 164.2, 130.9, 127.2, 114.1, 55.6, 45.7.
Synthesis of 4-Methoxyphenacyl chloride (4d) on 20 mmol Scale. 0.24 mol of KOH were dissolved
in 120 mL MeOH/H2O 1:2 (feed A) and 80 mmol of Diazald were dissolved in 80 mL DMF (feed B).
The 250 mL Duran flask (Ø: 95 mm, h: 105 mm) – fitted with a stir bar – was filled with 20 mmol of 4ꢀ
MeOꢀbenzoyl chloride in 140 mL anhydrous diethyl ether and was cooled in an iceꢀbath to 0 °C. Feed
A and feed B were pumped by two syringe pumps (Asia, Syrris, see Figure S3 in the SI) into a Yꢀ
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equiv of KOH with respect to Diazald). The combined mixture then passed through the PFA inletꢀ
tubing (1/16 inch o.d.; 0.8 mm i.d.; 300 µL residence volume) and then further through the 4 AFꢀ2400
membranes within the Duran flask (Figure 5). The solution left the reactor through the PFA outlet
tubing and was directed into a quench solution of aqueous acetic acid. After the Diazald solution was
consumed, the reaction mixture was stirred for further 90 min, 6 mL of conc. HCl were added and the
reaction mixture was stirred for 1 h. The now decolorized ethereal solution was subsequently extracted
with H2O and sat NaHCO3. Drying of the organic phase with MgSO4 and evaporation of the solvent
provided the product 4d 99% yield (3.65 g) and >99% purity. For characterization data, see above.
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Cyclopropanations. Diazomethane was generated as described above with feed solutions 36 mmol of
KOH in 18 mL MeOH/H2O 1:2 (feed A), and 9 mmol of Diazald in 9 mL DMF (feed B). For styrene
27 mmol of KOH in 13.5 mL MeOH/H2O 1:2 and 6.75 mmol of Diazald in 6.75 mL DMF were
employed. The Erlenmeyer flask – fitted with a stir bar – was filled with 3 mmol of the alkene and the
respective amount of Pd(OAc)2 (from a stock solution in THF, see Table 3) in 35 mL anhydrous diethyl
ether and was cooled in an iceꢀbath to 0 °C. After the Diazald solution was consumed, the reaction
mixture was stirred for further 15ꢀ30 min. The ethereal solution was subsequently quenched with acetic
acid and extracted with sat NaHCO3. Drying of the organic phase with MgSO4 and evaporation of the
solvent provided the products 6a-d in >98% purity.
Cyclopropylbenzene (6a). 281 mg (79%), colorless oil;46 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.29
(m, 2H), 7.23 – 7.11 (m, 3H), 2.00 – 1.91 (m, 1H), 1.05 – 0.99 (m, 2H), 0.79 – 0.73 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 144.0, 128.3, 125. 7, 125.4, 15.4, 9.2.
1-Cyclopropyl-3-nitrobenzene (6b). 488 mg (99%), orange oil;23a 1H NMR (300 MHz, CDCl3) δ 8.03
– 7.97 (m, 1H), 7.92 – 7.91 (m, 1H), 7.45 – 7.38 (m, 2H), 2.06 – 1.97 (m, 1H), 1.13 – 1.07 (m, 2H),
0.80 (dt, J = 6.7, 4.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 148.4, 146.4, 132.1, 129.0, 120.4, 15.3,
9.9.
Methyl 2-Phenylcyclopropane-1-carboxylate (6c). 503 mg (95%), yellow oil;47 1H NMR (300 MHz,
CDCl3) δ 7.33 – 7.20 (m, 3H), 7.14 – 7.11 (m, 2H), 3.74 (s, 3H), 2.59 – 2.52 (m, 1H), 1.96 – 1.91 (m,
13
1H), 1.66 – 1.60 (m, 1H), 1.38 – 1.32 (m, 1H). C NMR (75 MHz, CDCl3) δ 173.9, 140.0, 128.5,
126.5, 126.2, 51.9, 26.3, 24.0, 17.0.
1,2-Diphenylcyclopropane (6d). 545 mg (94%), yellow oil;46 1H NMR (300 MHz, CDCl3) δ 7.39 –
13
7.33 (m, 4H), 7.27 – 7.18 (m, 6H), 2.26 – 2.21 (m, 2H), 1.54 – 1.49 (m, 2H). C NMR (75 MHz,
CDCl3) δ 142.6, 128.4, 125.8, 28.1, 18.3.
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Synthesis of Ethyl 1H-pyrazole-3-carboxylate (7). Diazomethane was generated as described
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above with feed solutions 18 mmol of KOH in 9 mL MeOH/H2O (1:2) (feed A), and 4.5 mmol of
Diazald in 4.5 mL DMF (feed B). The Erlenmeyer flask – fitted with a stir bar – was filled with 3
mmol (304 µL) of ethyl propiolate in 35 mL CHCl3 (prior passed through basic Al2O3) and was cooled
in an iceꢀbath to 0 °C. After the Diazald solution was consumed, the reaction mixture was stirred for
further 15 min. The solution was subsequently quenched with acetic acid and extracted with sat
NaHCO3. Drying of the organic phase with MgSO4 and evaporation of the solvent provided the product
as colourless solid in 88% yield (370 mg) and >99% purity. Mp 162ꢀ163 °C, lit.48 mp 160 ꢀ162 °C; 1H
NMR (300 MHz, CDCl3) δ 13.55 (brs, 1H), 7.84 (d, J = 2.3 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 4.45 (q,
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J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ 162.1, 141.9, 132.2, 107.7,
61.0, 14.4.
Acknowledgement. We thank Dr. Peter Pöchlauer (DPx Fine Chemicals Austria GmbH & Co KG)
for constructive discussions and the workshop of the Institute of Chemistry at University of Graz for
constructing parts of the reactor. Funding from NAWI Graz and Research Center Pharmaceutical
Engineering (RCPE) for the ReactIR system is gratefully acknowledged.
Supporting Information Available. Pictures of the reactor, optimization of reactions and 1H and 13C
NMR spectra of all compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
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(5) Maurya, R. M.; Park, C. P.; Lee, L. H.; Kim, D.ꢀP. Angew. Chem., Int. Ed. 2011, 50, 5952.
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