Continuous flow generation and reactions of anhydrous diazomethane using a teflon AF-2400 tube-in-tube reactor

Article abstract of DOI:10.1021/ol4027914

A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and scalable reactions with dry diazomethane to be performed on a laboratory scale.

Full text of DOI:10.1021/ol4027914

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Continuous Flow Generation and
Reactions of Anhydrous Diazomethane
Using a Teflon AF-2400 Tube-in-Tube
Reactor
000–000
Federica Mastronardi, Bernhard Gutmann, and C. Oliver Kappe*
Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
oliver.kappe@uni-graz.at
Received September 26, 2013
ABSTRACT
A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner
tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses
through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and
scalable reactions with dry diazomethane to be performed on a laboratory scale.
Diazomethane (CH N ) is one of the most valuable
2
2
and versatile C building blocks in organic chemistry
1
1
Scheme 1). It is a potent methylation agent for carboxylic
Scheme 1. Versatile Reactivity of Diazomethane
(
acids, phenols, alcohols, and a plethora of other nucleo-
1
philes, such as nitrogen and sulfur heteroatoms. It is also
essential for ArndtꢀEistert homologation chemistry via
R-diazoketones and for ring expansion or homologation
1
,2
of ketones. As a powerful 1,3-dipole, diazomethane
participates in Huisgen [2 þ 3] cycloaddition reactions
with unsaturated compounds to form the corresponding
3
nitrogen-containing heterocycles. Alternatively, in the pre-
sence of suitable catalysts, it forms cyclopropanes, epoxides,
or aziridines from alkenes, ketones, or imines, respectively,
1
by [1 þ 2] additions (Scheme 1). Reactions with diazo-
methane are usually very fast and take place under mild
conditions, often producing nitrogen as the sole byproduct.
Unfortunately, working with diazomethane presents
4
several serious safety hazards. Diazomethane is a highly
(
1) (a) Black, T. H. Aldrichimica Acta 1983, 16, 3–10. (b) Pizey, J. S.
Synthetic Reagents; John Wiley & Sons: New York, 1974; Vol. 2,
pp 65ꢀ142.
(
(
2) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160.
3) Maas, G. In Synthetic Applications of 1,3-Dipolar Cycloaddition
(4) The dangerous nature of CH N is well appreciated: (a) Schoental,
2
2
R. Nature 1960, 188, 420–421. (b) Lewis, C. E. J. Occup. Med. 1964, 6,
91–93. (c) Lewinn, E. B. Am. J. Med. Sci. 1949, 218, 556–562. (d) de Boer,
T. J.; Backer, H. J. Org. Synth. 1963, 4, 250–253.
Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; John Wiley & Sons: New York, 2002; pp 539ꢀ622.
1
0.1021/ol4027914 r XXXX American Chemical Society

poisonous and irritating compound. The severe toxicity
of diazomethane is particularly problematic because of
tube-in-tube reactor. The tube-in-tube device was origin-
ally developed in the Ley laboratory as a gas-addition tool
4
9ꢀ12
its high volatility (bp = ꢀ23 °C). Furthermore, diazo-
for continuous processes.
The inner tube of the device
methane is extremely sensitive to friction, heat, light, and
is made of Teflon AF-2400 (0.8 mm inner diameter, 1 mm
outer diameter, 4 m length). Teflon AF-2400 has a chemi-
cal resistance and mechanical strength comparable to that
4
mechanical shock and tends to decompose explosively.
Thus, any sharp glass edges have to be strictly avoided
when working with diazomethane, and the ends of glass-
ware should be rounded in a flame. Specialized kits for
1
1
of PTFE but has a highly porous, amorphous structure.
Accordingly, the AF-2400 tube serves as a robust, hydro-
the preparation of diazomethane on various scales (up to
3
phobic, permeable membrane which selectively allows
9ꢀ11
1
00 mmol) are commercially available. Due to its instabil-
gases, but not liquids, to cross.
This membrane is
ity and toxicity, the use of diazomethane in the laboratory
is often considered to be problematic or risky, and there-
fore, this extremely powerful reagent today is not often
used in synthetic organic chemistry laboratories.
enclosed within a thick-walled impermeable outer tube
(PTFE; 1.59 mm inner diameter, 3.2 mm outer diameter,
4 m length). Typically, the gas (e.g., CO, CO , H , ethene,
2
2
ethyne, or SO ) is carried between the outer tube and the
2
9
inner tube. It crosses the semipermeable membrane and
Hazardous reagents are preferably produced on demand
by continuous flow processes. Production and consump-
tion of the material can be integrated in multistage pro-
cesses to eliminate the need to handle reactive reagents
and to keep the total amount of stored material as low as
9
dissolves into the liquid carried within. We contemplated
a continuous generation of diazomethane in the inner
chamber of the tube-in-tube device by combining a liquid
stream of a Diazald solution with a stream of a strong base
5
13
possible. In 2002, an industrial process for the continuous
generation of up to 60 t of diazomethane gas per year was
(e.g., KOH). If the highly volatile diazomethane gas is
able to penetrate the hydrophobic AF-2400 membrane,
this strategy should give a steady stream of the dry reagent
into the outer tube, without the need to distill or strip
the reactive reagent from the reaction solution. Handling,
transport paths, and storage time of the highly explosive
diazomethane are thereby reduced to a minimum.
6
described by Proctor and Warr. Diazomethane was pro-
duced from a feed containing N-methyl-N-nitroso-p-
toluenesulfonamide (Diazald) in DMSO and a second feed
of potassium hydroxide in water. The generated diazo-
methane gas was continuously transported by a N stream
2
to a reaction vessel where it was quenched with a solution
6
of benzoic acid in DME. More recently, Kim and co-
Initial optimization experiments with the tube-in-tube
device were performed using benzoic acid (1a) as reagent
in the outer tube as indicated in Figure 1 (for optimization
details, see Table S1 in the Supporting Information).
Reactions of diazomethane with carboxylic acids are
generally quantitative and essentially instantaneous. The
conversion of benzoic acid to the ester therefore charac-
terizes the efficiency of diazomethane formation and the
separation efficiency of diazomethane into the outer tube.
Rapid transportation of the freshly formed diazomethane
into the organic phase is essential to prevent decomposi-
tion in the aqueous phase (the half-life of CH N in
workers presented a dual-channel microreactor for the
continuous generation, separation, and subsequent reac-
7
tion of diazomethane. The microreactor was fabricated
from poly(dimethylsiloxane) (PDMS) and consisted of
two parallel channels separated by a 45 μm thick PDMS
membrane (60 μL residence volume). The PDMS mem-
brane is permeable to gases and small organic molecules.
The diazomethane was produced from Diazald and KOH
in one channel of the microreactor and subsequently
diffused through the membrane where it formed the
2
2
7
6
product in the second channel. Unfortunately, the output
of the PDMS microreactor was quite small (daily output
water at 20 °C and pH 7.2 is ≈12 min). The rate with
which diazomethane is transferred through the membrane
∼
1 mmol). Furthermore, many common nonpolarorganic
solvents, such as THF, CHCl , or Et O, diffuse into the
(
9) For selected references using a variety of gases, see the following.
a) O : O’Brien, M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12,
596–1598. (b)CO : Polyzos, A.;O’Brien, M.; Petersen, T. P.; Baxendale,
3
2
(
1
3
PDMS polymer and cause the material to swell and are
therefore incompatible with the PDMS device. Moreover,
nonpolar solutes can be absorbed in the PDMS material
2
I. R.; Ley, S. V. Angew. Chem., Int. Ed. 2011, 50, 1190–1193. (c) CO:
Koos, P.; Gross, U.; Polyzos, A.; O’Brian, M.; Baxendale, I.; Ley, S. V.
Org. Biomol. Chem. 2011, 9, 6903–6908. (d) H
Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250–1257.
e) Newton, S.; Ley, S. V.; Casas Arc ꢀe , E.; Grainger, D. M. Adv. Synth.
Catal. 2012, 354, 1805–1812. (f) NH : Cranwell, P. B.; O’Brian, M.;
2
: O’Brian, M.; Taylor, N.;
8
and get lost from the reaction stream.
(
Herein, we describe a process in which generation,
separation, and chemical transformations of diazo-
methane are integrated in a robust, commercially available
3
Browne, D. L.; Koos, P.; Polyzos, A.; Pe n~ a-Lop ꢀe z, M.; Ley, S. V. Org.
Biomol. Chem. 2012, 10, 5774–5779.
(
10) For an analysis of mass transfer and scalability of the tube-in-
tube reactor, see: Yang, L.; Jensen, K. F. Org. Process Res. Dev. 2013, 17,
927–933.
(11) The use of the tube-in-tube device employing two liquid feeds
similar to the strategy reported herein has only been reported very
recently. (a) Generation of CO: Brancour, C.; Fukuyama, T.; Mukai, Y.;
Skrydstrup, T.; Ryu, I. Org. Lett. 2013, 15, 2794–2797. (b) Generation of
CH
2
O: Buba, A. E.; Koch, S.; Kunz, H.; L o€ we, H. Eur. J. Org. Chem.
2013, 4509–4513.
(12) The tube-in-tube device (gas addition module) is available from
Uniqsis Ltd. See www.uniqsis.com for more details.
(13) For a continuous flow production of Diazald, see: (a) Struempel,
M.; Ondruschka, B.; Stark, A. Org. Process Res. Dev. 2009, 13, 1014–
1021. (b) See also ref 7b.
(
5) For continuous flow reactions involving diazomethane, see: (a)
Martin, L. J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R. Org. Lett.
011, 13, 320–323. (b) Rossi, E.; Woehl, P.; Maggini, M. Org. Process
2
Res. Dev. 2012, 16, 1146–114. (c) Struempel, M.; Ondruschka, B.; Daute,
R.; Stark, A. Green Chem. 2008, 10, 41–43.
(
6) Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6, 884–
92.
7) (a) Maurya, R. M.; Park, C. P.; Lee, L. H.; Kim, D.-P. Angew.
8
(
Chem., Int. Ed. 2011, 50, 5952–5955. (b) For industrial applications, see:
Poechlauer, P. Chim. Oggi 2012, 30, 51–54.
(
8) Lee, J. N.; Park, C.; Whitesides, G. M. Anal. Chem. 2003, 75,
6
544–6554.
B
Org. Lett., Vol. XX, No. XX, XXXX

depends on several parameters, such as temperature and
residence time, in addition to solvent, concentration of
reagents, and pH in the inner tube. Water greatly reduces
the solubility of diazomethane in the reaction mixture,
thus, increasing separation efficiency and decreasing the
amount of diazomethane lost in the waste stream. How-
ever, since water also reduces the solubility of the Diazald,
a compromise between Diazald solubility and transport
to quantitative yields. As expected, methylation of 5-phenyl-
tetrazole led to a mixture of the 1- and 2-methyltetrazoles
15
(3). The [2 þ 3] cycloaddition of the diazomethane to
N-phenylmaleimide gave the respective 1-pyrazoline (4) in
3
essentially quantitative conversions (Figure 2b). The pure
product was isolated in 76% yield by flash chromatography.
Diazomethane adds to alkenes to form cyclopropanes
via metalꢀcarbene intermediates in the presence of Pd,
1
4
16,17
rate of diazomethane is required.
After considerable experimentation varying solvents,
reagent concentrations, and flow rates for all three feeds
Cu, Rh, and various other transition metal catalysts.
Cyclopropanes are useful synthetic intermediates and fre-
quently employed as building blocks in organic synthe-
1
4
17
ses. Furthermore, the cyclopropyl unit occurs in various
involved (Figure 1), we have found that quantitative
conversions to methyl benzoate (2a) were obtained apply-
ing flow rates of 200 μL/min for the KOH (0.6 M, MeOH/
1
8
natural products and biologically active substances.
Using 4-phenyl-3-buten-2-one in combination with 1 mol %
H O 1:1), the Diazald (0.3 M, MeOH), and the benzoic
2
of Pd(OAc) in the outer tube, the respective cyclopropane
2
acid (1a, 0.15 M, THF) feeds. Solutions of the base and
Diazald (2 equiv relative to benzoic acid 1a) feeds were
combined in a T-mixer, and the combined mixture went
through a short PFA coil (200 μL) before entering the
inner channel of the tube-in-tube reactor (Figure 1). The
aqueous waste stream leaving the inner tube of the reactor
was fed into concentrated acetic acid to decompose any
unconsumed diazomethane. It should be noted that the
temperature of the PFA coil connecting the T-mixer and
the tube-in-tube device did not risenoticeably, eventhough
the reaction of Diazald with KOH to CH N is fast and
(5) was formed in 84% conversion (HPLC-UV at 235 nm)
applying the general reaction conditions without any
further reoptimization. Flash chromatography provided
the pure product in 59% yield (Figure 2c).
2
2
highly exothermic. The product mixture from the outer
tube was collected in a receiver flask with an acetic acid
quench solution, and the mixture was analyzed by HPLC-
UV. Using the flow rates stated above, this corresponds to
a residence time of ∼16 min for the methylation process.
Figure 2. Continuous in situ generation and reactions of diazo-
methane: (a) methylations of various nucleophiles; (b) [2 þ 3]
cycloadditions; (c) cyclopropanation of alkenes (1% mol of
Pd(OAc) ). Isolated yields; for general conditions, see Figure 1
2
and the Supporting Information.
Finally, we attempted the acylation of diazomethane
2
with acid chlorides (ArndtꢀEistert reaction). The result-
ing R-diazocarbonyl compounds are versatile precursors
for a wide variety of chemical transformations under mild
1
,2
conditions. The product stream of the outer tube was fed
directly into 6 M aqueous HCl to convert the generated
diazo compound to the R-chloroketone (Figure 3). When a
Figure 1. Continuous esterification of benzoic acid with diazo-
methane in a tube-in-tube reactor. A graphical image of the
setup is shown in the Supporting Information.
(
15) Koldobskii, G. I.; Kharbash, R. B. Russ. J. Org. Chem. 2003, 39,
453–470. (b) Roh, J.; V ꢀa vrov ꢀa , K.; Hrab ꢀa lek, A. Eur. J. Org. Chem.
012, 6101–6118.
16) For a mechanistic study of the palladium-catalyzed olefin
cyclopropanation, see: Rodriguez-Garcia, C.; Oliva, A.; Ortuno,
R. M.; Branchadell, V. J. Am. Chem. Soc. 2001, 123, 6157–6163.
Apart from 1a, other aromatic carboxylic acids (1bꢀd),
both with electron-donating and -withdrawing groups,
provided full conversion to the corresponding esters
(2bꢀd) under these general reaction conditions (Figure 2a).
The esters were isolated by an extraction procedure in good
2
(
(17) For reviews on the application of cyclopropanes in organic
synthesis, see: (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.
Chem. Rev. 1989, 89, 165–198. (b) Reissig, H.-U.; Zimmer, R. Chem. Rev.
2
003, 103, 1151–1196. (c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev.
(14) Further optimization data are presented in the Supporting
Information.
2009, 38, 3051–3060.
(18) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493–4537.
Org. Lett., Vol. XX, No. XX, XXXX
C

phenylacetyl chloride as starting materials, albeit in the
latter instance, the conditions were slightly modified in
order to obtain 95% conversion (78% isolated yield) of
the corresponding homologated acid chloride (7c) (see the
Supporting Information for details).
In conclusion, we demonstrated the continuous genera-
tion, separation, and reaction of diazomethane in a tube-
in-tube continuous flow reactor. The diazomethane is
generated in the inner tube of the reactor from a feed of
Diazald and a feed of potassium hydroxide. Dry diazo-
methane subsequently diffuses through a hydrophobic
membrane into an outer tube where it dissolves and reacts
in the solution carried within. Diazomethane is an excep-
tionally useful C building block for a variety of reactions.
1
However, the low boiling point, high toxicity, and extreme
explosiveness of diazomethane have in the past severely
limited its widespread use in laboratories and industry. The
on-demand generation and direct separation/consumption
of diazomethane in a commercially available microreactor
environment, as described herein, eliminates human ex-
posure to the reagent and reduces the risk of explosive
decomposition. Therefore, this technique may allow a
plethora of synthetic reactions using this powerful reagent
to be explored and performed in the future and may revive
interest in diazomethane chemistry.
Figure 3. Continuous flow Arndtꢀ-Eistert reaction using the
tube-in-tube reactor. Isolated yields; rt = room temperature.
0
.15 M solution of benzoyl chloride (6a) in anhydrous
THF in the outer tube and 2 equiv of Diazald in the inner
tube was employed, 63% of the acid chloride was con-
verted to the corresponding R-chloroketone (7a). As the
acylation of diazomethane liberates 1 equiv of HCl, part
of the diazomethane is sequestered by the strong acid.
Gratifyingly, when 3.8 equiv of Diazald was employed in
the inner tube, the two-step conversion of the acid chloride
Acknowledgment. F.M. thanks the University of Milano
for a scholarship.
(
(
6a) to the R-chloroketone (7a) was improved to 98%
Figure 3). Importantly, no methyl benzoate could be
detected in the product mixture, confirming that indeed
anhydrous diazomethane penetrates the membrane into
the outer tube, while waterisretainedin the inner tube. The
resulting phenacyl chloride (7a) was isolated by extrac-
tion with Et O/aqueous NaHCO in 91% yield. Similar
Supporting Information Available. Experimental pro-
cedures, optimization of reactions, and characterization
of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
2
3
results were obtained using p-chlorobenzoylchloride and
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX