A scalable and safe continuous flow procedure for in-line generation of diazomethane and its precursor MNU

Article abstract of DOI:10.1039/c6gc03066a

Diazomethane is a valuable C₁-building block for organic synthesis. Due to its intrinsic reactivity and instability, handling of this reagent is associated with serious safety hazards. Herein we present a simple and robust continuous flow process, allowing a safe and on-demand generation of diazomethane with a productivity of 95-117 mmol h^-1. The developed two-step process starts from non-hazardous N-methylurea, and generates and consumes N-methyl-N-nitrosourea (MNU) and diazomethane, thus enabling a safe and convenient scale-up to a multi-gram scale in a conventional synthesis laboratory.

Full text of DOI:10.1039/c6gc03066a

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A scalable and safe continuous flow procedure for in-line
generation of diazomethane and its precursor MNU
H. Lehmanna
Received 00th January 20xx,
Accepted 00th January 20xx
Diazomethane is a valuable C1-building block for organic synthesis. Due to its intrinsic reactivity and instability, handling of
this reagent is associated with serious safety hazards. Herein we present a simple and robust continuous flow process,
allowing a safe and on-demand generation of diazomethane with a productivity of 95-117 mmol/h. The developed two-
step process starts from non-hazardous N-methylurea, generates and consumes N-methyl-N-nitrosourea (MNU) and
diazomethane, thus enabling a safe and convenient scale-up to multi-gram scale in a conventional synthesis laboratory.
DOI: 10.1039/x0xx00000x
www.rsc.org/
scale. Thus, in standard medicinal chemistry laboratories, this
powerful reagent was often neglected or replaced by less
hazardous, but sometimes also less suitable, reagents.
Introduction
Over the last 15 years, continuous flow chemistry has made
huge progress as an enabling technology for organic synthesis
with safety issues being one of the major drivers for adaption
of batch reactions to continuous flow mode.1-3 Several reviews
highlight the role of flow methodology in green chemistry and
showcase the advantages of performing hazardous reactions in
continuous flow reactors providing a small reaction volume
and a precise control of reaction parameters.4-6 Unstable,
highly reactive or toxic intermediates can be generated in-situ
in a closed, pressurized system and converted directly into a
more stable, non-hazardous intermediate or product. The
need to handle or to store excessive amounts of highly toxic or
explosive reagents therefore is eliminated.
Results and Discussion
Background
In recent years, the interest in diazo-compounds and especially
diazomethane chemistry, significantly increased both in
academia and in chemical industry as shown by a number of
recent publications.9-12 The chemical industry has rediscovered
the utility of diazomethane and various methods for
continuous production and use have been developed in order
to minimize the associated safety hazards, especially for large
scale processes.13-15 These activities clearly indicate an
increased need for new methodologies that allow a safe
handling of such a highly reactive, but also instable and toxic
reagent, on any scale.
One of those very hazardous but also very useful reagents is
diazomethane. Diazomethane is known to be a very versatile
and useful C1 building block in organic synthesis for a variety of
transformations,7,8 which is usually tolerant to functional
groups and which produces only nitrogen as a byproduct.
Compared to other commonly used methylating agents (e.g.
dimethylsulfate or TMS-diazomethane), diazomethane reacts
selectively under mild conditions with improved atom
efficiency. Unfortunately, the preparation and handling of
diazomethane in a common synthesis lab is associated with
serious safety hazards, which prevent most chemists from
using it. Due to its toxicity, extreme instability and volatility, a
safe generation and handling of diazomethane in batch-mode
is difficult and requires specific safety precautions and
dedicated equipment even for preparation on a very small
Since diazomethane reacts not only with a desired substrate
but also with water, alcohols and solvents containing acidic
OH-functions, commonly used batch-procedures aim for the
preparation of etheral solutions of dry diazomethane (e.g. by
the Aldrich Diazald-Kit), which are relatively stable at
temperatures below -10°C. However due to the above
mentioned safety issues, for a conventional synthesis in batch,
most of these methods are limited to very small scale. A safe
and easy to handle procedure to make diazomethane
accessible on larger scale without the need to go through
extensive safety investigations would therefore be of great
advantage for a synthetic chemist.
To overcome the safety problems of preparing and handling
diazomethane, especially in
a
conventional synthesis
laboratory, a few groups have investigated continuous flow
preparation over the past decade.16-20 An early attempt to
generate diazomethane using
published by the group of Stark in 2008.21 In order to
demonstrate the practicability of such concept, they
a microreactor setup was
a
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investigated the formation of diazomethane from Diazald® nitro-1-nitrosoguanidine (MNNG), N-methyl-N-nitrosourea
over a range of reaction conditions and with the goal of (MNU) and N-methyl-N-nitroso-p-toluene sulfonamide
maximizing the yield, which was determined by methylation of (Diazald®). Despite the fact, that MNU is instable and
benzoic acid. Depending on the chosen conditions, yields carcinogenic, we choose this reagent as a precursor, since we
ranging from 20% up to 75% were reported. Avoiding found that MNU resulted in cleaner and faster reactions
precipitations and the minimization of diazomethane compared to the more commonly used Diazald®. MNU can be
decomposition were two of the major problems the authors easily prepared from cheap and non-hazardous N-
encountered. To achieve an optimum yield of 75%, a complex methylurea,24 which is the most convenient precursor with
mix of solvents containing glycols, alcohols and water had to regard to atom-economy. However, especially isolation and
be used and benzoic acid was directly added to this mixture handling of solid MNU is a safety concern.25 In order to
without separating the in-situ generated diazomethane. The minimize those hazards we decided to develop a continuous
presence of water in such a system implies a strong limitation flow procedure to access this intermediate in situ and directly
since the half-life of diazomethane in water at 20°C is in a couple the generation of MNU with the flow synthesis of
range of half a minute,22 thus limiting the use of their setup to diazomethane. Pivotal for the realization of such a concept
fast reactions and to substrates which are stable under basic was the separation of the generated product streams from
aqueous conditions. A similar approach was reported in 2012 aqueous waste streams. To achieve this, we used commercially
by Maggini who used a modular continuous flow platform and available continuous liquid-liquid separators26 which were
N-methyl-N-nitrosourea (MNU) as
a precursor for the implemented after step 1 and 2 into our flow chemistry
preparation of diazomethane.15 Under optimized reaction system. The resulting setup for the flow synthesis of MNU is
conditions, high yields and high productivity was achieved, illustrated in figure 1, which is the first part of our two-step
allowing a production of diazomethane on mol-scale per day continuous process.
while the maximum amount of this hazardous reagent was
limited to 6.5 mmol at any time. However, both approaches Figure 1: continuous flow synthesis of MNU
have the same major drawback of holding diazomethane,
water and the excess of KOH in the same solution. Any
application of such a mixture to convert acid chlorides or
anhydrides into the corresponding α-diazoketones, which are
important intermediates for the Wolf–rearrangement and
Arndt-Eistert homologation, thus lead to undesired formation
of hydrolyzed by-products, lower yields and eventually result
in a less powerful method. To avoid these problems, other
groups modified the flow setup by introducing devices into
their flow-setup, which allowed a continuous separation of the
generated diazomethane from the basic aqueous stream using
membrane technology.18-20,23 The advantage of providing near
anhydrous solutions of diazomethane in an organic solvent,
which then also could be used for reactions with water
sensitive substrates, on the other hand was accompanied by
the disadvantage of very low productivity in a range of
millimols per day. From a pharma perspective, such low
productivities are sufficient to satisfy the needs in early
research programs, where only milligrams of a compound are
required. However, when larger quantities are needed, for
example when profiling a compound in the profiling phase or
for a tox-study, higher productivities would be mandatory in
order to avoid bottlenecks during the synthesis. Based on
these considerations, our major goal was to develop and
provide a safe and easy to handle method for the generation
and consumption of diazomethane in a conventional synthesis
laboratory on multi-gram scale per day.
BPR = backpressure regulator
The flow-concept shown in figure 1 is based on the idea that
the diazotation of N-methylurea can be performed in a
biphasic system which enables MNU to be extracted from the
aqueous phase into the organic layer as soon as it is formed,
hence preventing it from precipitating. In a first step, a
solution of N-methylurea in water and hydrochloric acid was
mixed in a Y-piece with the organic solvent27 followed by the
addition of aqueous sodium nitrite in a second T-piece. This
biphasic mixture then was reacted in four 10 ml PFA-reactor
coils at 25°C with a residence time of 5 min, which was
sufficient to achieve full conversion of the starting material. In
order to separate the aqueous phase, the reaction mixture
then was pumped through a liquid-liquid-phase separator and
the organic MNU solution was collected. In a test run on 500
ml scale, we isolated 485 ml of MNU, as a 0.395M solution and
with 83% yield. To check the conversion of the reaction and
the purity of MNU, a small quantity (5 ml) of the collected
fraction was carefully evaporated at ambient temperature. The
isolated solid was analyzed by 1H-NMR, showing exclusively
the signals of MNU and a purity of >98%. Since MNU has a
limited solubility in the solvent mixture used (concentrations
above 0.45M tended to precipitate), the flow rate of the
organic solvent was adjusted to produce an approximately
Development of an improved two-step flow concept
Commonly used precursors for the preparation of
diazomethane are N-methyl-N-nitrosoamines, which are
typically treated with an inorganic base in an organic solution.
Commercially available starting materials include 1-methyl-3-
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0.4M solution of MNU, which then was used directly for the
preparation of diazomethane as outlined in figure 2. Under
optimized conditions, the continuous preparation of MNU was
run for hours in a robust, stable and reproducible way,
the preparation of compounds on a multi-gram scale per hour
(scheme 1).
Scheme 1: methylation of carboxylic acids by in-line generated
providing constant yields of 80% and above
.
diazomethane
Figure 2: continuous flow synthesis of diazomethane
Prepared compounds:
To prepare diazomethane in flow, we first mixed the
previously prepared solution of MNU and aqueous potassium
hydroxide in a T-piece and pumped the biphasic reaction
mixture through a 5 ml PFA-reactor at 0°C and with a
residence time of 30 seconds. The separation of the organic
phase containing the diazomethane from the aqueous waste
stream occurred in a liquid-liquid phase separator which was
positioned between reactor 1 and the second mixing point.
The organic solution of diazomethane then was mixed in a
further T-piece with the substrate, for instance a carboxylic
a) prepared amount, b) isolated yield, c) productivity
As the remaining challenge, we designed an instrumental
setup that allowed a telescoping of step 1 and 2 to directly
obtain diazomethane from N-methylurea without any
isolation. Linking of both parts was achieved by feeding the
outlet stream of MNU prepared in step 1 into a 50 ml bottle
forming the reservoir of MNU for pump D, as illustrated in
figure 3. Pump D then fed the MNU into the second part of the
continuous flow system where diazomethane was synthesized
and consumed in further transformations.
acid and fed into
a second reactor-coil at ambient
temperature. For the optimization of reaction parameters and
to characterize the efficiency of formation and separation of
diazomethane with our flow setup, we choose 3-nitrobenzoic
acid as a model substrate. Reactions of carboxylic acids with
diazomethane usually are quantitative and essentially
instantaneous. The residence time therefore can be kept very
short. In fact, we routinely used this reaction to calibrate the
concentration of diazomethane in the separated solution, prior
to apply the in-situ generated diazomethane to a new target
reaction. The ratio of methyl ester to unreacted acid was
detected by HPLC-UV and used to calculate the concentration
of diazomethane after phase separation. This continuously
prepared solution of diazomethane routinely was used for a
variety of transformations, including the methylation of
carboxylic acids, cyclopropanation of alkenes, (2+3)
cycloadditions and the formation of diazo-ketones from acid
chlorides.28 By optimization of a range of reaction parameters,
we found that a reaction temperature of 0°C, a residence time
of 30 seconds and a ratio of KOH to MNU of 2:1 produced an
approximately 0.3M solution of diazomethane with a flow rate
of 6.5 ml/min. This rate translates to a productivity of up to
117 mmol/h or 4.9 g/h of diazomethane and is significantly
higher compared to the current benchmark of 42.6 mmol/h
recently published by the group of Kappe.29 The herein
reported continuous process is based on standard
commercially available flow chemistry equipment and enables
Figure 3: combined setup for in-line preparation of MNU and
diazomethane
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In order to keep the amount of MNU in this reservoir on a low continuous flow reactor setup reaches up to 117 mmol/h and
but constant level, the flow rate of incoming stream of MNU is high enough to prepare compounds on a multi-gram scale
and the flow rate of pump D had to be adjusted to the same per day and to satisfy the needs of medicinal chemists. As a
level. Therefore, we set the flow rate of pump D to 5.9 ml/min consequence, medicinal chemists at Novartis have
and the flow rate of pump E to 3.16 ml/ min, which resulted in rediscovered diazomethane chemistry as a powerful synthetic
a ratio of MNU:KOH of 1:2 and a residence time of 33 seconds tool and the use of this reagent significantly increased with the
in reactor 2. In a proof of concept study, we performed in-house availability of the reported process.
experiments with different amount of 3-nitrobenzoic acid in
order to determine the correct ratio of diazomethane versus
Experimental
acid for obtaining full conversion. The addition of 0.8
equivalents of 3-nitrobenzoic acid resulted in a conversion of
85%, which indicated that the concentration of the
diazomethane was 0.27M. Adjusting the flow rate of pump F
to 3.32 ml/min, which correlates to an addition of 0.7
equivalent of acid, finally led to complete conversion to the
ester. To test the stability and the robustness of the
established flow process, we subsequently run this combined
setup over a period of 30 min and prepared the corresponding
ester on 8.7 gram scale in quantitative yield (scheme 2).
Detailed procedures and experimental data are summarized in
Electronic supplementary information (ESI).
Acknowledgements
The author thanks Alessandra Meli, Thomas Ruppen and Julia
Kleinfelder for their technical support in the laboratory. He
also thanks Cara Brocklehurst for proof-reading of the
manuscript and Guido Koch, Berthold Schenkel and Benjamin
Martin for inspiring discussions.
Scheme 2: methylation of 3-nitrobenzoic acid by in-line
generated MNU and diazomethane
Notes and references
1
B. Gutmann, D. Cantillo, C.O. Kappe, Angew. Chem. Int. Ed.,
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2
3
F. Susanne, L. Malet-Sanz, J. Med. Chem., 2012, 55(9), 4062
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It should be noted, that over this period the volume of the
MNU reservoir was constantly in a range of 20-30 ml. The in-
line generated diazomethane was immediately consumed and
by choosing the exact ratio of carboxylic acid, no unreacted
diazomethane was remaining in the product stream. With
regard to scale-up, a productivity up to 95 mmol/h was
achieved using this setup. Alternatively, for reactions which
required a longer residence time (20 minutes and above), the
outlet stream of diazomethane was fed into a stirred batch
reactor where the diazomethane was reacted in a semi-batch
mode. Connecting the outlet stream to a fraction collector
enabled us to expand the application of this continuous flow
setup and to use it for screening of reactions on small scale.
4
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Conclusions
In conclusion, we have developed an improved two-step
continuous process for the in-line on-demand generation of
MNU and diazomethane starting from cheap and non-
hazardous N-methylurea. This process is atom efficient, gives
high yields and significantly reduces the hazards which are
associated to the preparation and handling of highly toxic
MNU and diazomethane. Both reagents are generated in-line
and consumed directly without any isolation. The closed
reactor system combined with small reaction volumes in
continuous flow, eliminate human exposure and minimize the
risk of an explosive decomposition. The productivity of our
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25 Commercial N-methyl-N-nitrosourea (MNU) is stabilized by
water and acetic acid and sold as wetted powder with ~50%
content. Crystalline MNU can explode spontaneously.
26 Purchased from Zaiput Flow Technologies (US),
http://www.Zaiput.com (accessed October 2016)
27 We used a 1:1 mix of 2-MeTHF and diethyl ether, since the
solubility of MNU in pure 2-MeTHF is very limited
28 Cyclopronanations, (2+3) cycloadditions and formation of
diazoketones were performed with the described setup,
results of these transformations will be topic of a future
publication
29 O. Kappe, D. Dallinger, V. Pinho, B. Gutmann, J. Org. Chem.
2016, 81, 5814
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