Safe and Facile Access to Nonstabilized Diazoalkanes Using Continuous Flow Technology

Article abstract of DOI:10.1002/anie.201802092

Despite the high synthetic potential of nonstabilized diazo compounds, their utilization has always been hampered by stability, toxicity, and safety issues. The present method opens up access to the most reactive nonstabilized diazoalkanes. Among diazo compounds, nonstabilized alkyl diazo compounds are the least represented because of their propensity to degrade during preparation. The continuous flow oxidation process of hydrazones on a silver oxide column afforded an output stream of base- and metal-free pure diazo solution in dichloromethane. Starting from innocuous ketones and aldehydes, this methodology allows the production of a broad range of unprecedented diazoalkanes compounds in excellent yields, while highlighting their synthetic potential and the possibility of safe large-scale diazo production.

Full text of DOI:10.1002/anie.201802092

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Accepted Article
Title: Safe and easy access to non-stabilized diazoalkanes using
continuous flow technology
Authors: André Bernard Charette, Pauline Rullière, Guillaume Benoit,
and Emmanuelle M. D. Allouche
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802092
Angew. Chem. 10.1002/ange.201802092
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10.1002/anie.201802092
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COMMUNICATION
Safe and easy access to non-stabilized diazoalkanes using
continuous flow technology
Pauline Rullière, Guillaume Benoit, Emmanuelle M. D. Allouche and André B. Charette*
Abstract: Despite the high synthetic potential of non-stabilized diazo
compounds, their utilization has always been hampered by stability,
toxicity and safety issues. The present method opens up access to
the most reactive non-stabilized diazoalkanes. Among diazo
compounds, non-stabilized alkyl diazo compounds are the least
represented due to their propensity to degrade during preparation.
The continuous flow oxidation process of free hydrazones on a silver
oxide column afforded an output stream of base- and metal-free
pure diazo solution in dichloromethane. Starting from innocuous
ketones and aldehydes, this methodology allows the production of a
broad range of unprecedented diazoalkanes compounds in excellent
yields, while highlighting their synthetic potential and the possibility
of safe large-scale diazo production.
kind.[10] Furthermore, the few previously reported non-stabilized
mono- and bis-alkyl diazoalkanes preparation procedures were
found to be operationally difficult and/or to use toxic heavy
metals[11] In their seminal work, Applequist and Babad reported
the use of silver oxide, affording 2-diazopropane in a low 20-
30% yield due to the in-situ degradation during synthesis and
tedious purification.[12] In addition to limited scope, these
previous methods require the presence of a base, a soluble/toxic
oxidant and either handling of the toxic diazo compound for
purification or in-situ quench of the generated diazoalkane.[13]
We envisioned that continuous flow systems would
overcome the three main drawbacks of non-stabilized
diazoalkanes synthesis: 1) precise control of the production
conditions, limiting degradation; 2) easy purification via the use
of insoluble solid reagents, circumventing the handling of the
diazo solution; and 3) on-demand direct consumption of the
reactive materials at the output of the reactor, avoiding the risks
associated with storage of toxic and unstable reagents (Scheme
1).
Diazo compounds are a powerful and versatile class of
reagents in organic synthesis,[1] as they are precursors of highly
reactive carbenes, carbenoids or carbocations, enabling formal
C–H, C–C and C–X bond insertions as well as various
cycloadditions.[2] However, the sensitivity, explosivity[3] and
toxicity[4] of this species remain huge drawbacks, hence
hindering their common use in laboratories especially on large
scale. By limiting handling, precisely controlling reaction
conditions and avoiding diazo accumulation by its simultaneous
consumption, continuous flow technology provides the ideal
solution to tackle such issues.[5] In recent years, continuous flow
has proven helpful at enabling safe production of a wide range
of stabilized diazo compounds.[6] While tremendous progress
has recently been made with the production of diazomethane[7]
and aryldiazomethanes,[8] syntheses of donor-type diazo
reagents bearing at least one alkyl substituent remain scarce
(Figure 1).[9]
oxidation
H2N-NH2.H2O
N
N
NH2
O
N
Alk
R
Alk
R
Alk
R
-H2O
R = alkyl, H or aryl
unprotected hydrazone
clean diazo
solution
O
R4
R1
R5CO2H
R3
OR2
O
Alk
Alk
R1
R
N
R
O
R5
O
N
nucleophilicity
EWG
substituent
"neutral"
substituent
electron-donating substituent
N2 N2
R4
OR2
Alk
R
R3
[3+2] cycloaddition
esterification
MIRC reaction
N2
N2
N2
R1
R2
R2 = Ar, H
H
Alk
Ar
Alk
H
Alk
Alk
EWG
Scheme 1. Continuous flow strategy towards on-demand generation of non-
R1= EWG, H, Ar
stabilized diazoalkanes.
previous work
this work
stability
Free hydrazones, common precursors to diazo compounds,
are safe, relatively stable and easy to handle.[14] Yet, their
synthesis requires the use of super-stoichiometric amounts of
hydrazine, high temperatures as well as long reaction
times.[11a,15] In addition, dimerization of hydrazones into the
corresponding azine is often observed. Continuous flow
synthesis allowed the use of milder and greener reaction
conditions. Indeed, fast heat transfer and precise stoichiometry
in a pressurized system allowed the full conversion of a broad
range of aliphatic ketones and aldehydes into their
corresponding hydrazones in 10 to 20 min with only 1.5 to 2.4
equivalents of hydrazine monohydrate with minimized formation
of azine by-product (Scheme 2).
Figure 1. Relative stability of diazo compounds[1,10]
Electron-donating substituted diazoalkanes distinguish
themselves by an intrinsic nucleophilicity and basicity, leading to
high reactivity even under mild conditions. Compared to
electron-rich diazoalkanes with aromatic substituents, diazo
compounds bearing alkyl groups are the least stable of their
[*]
Dr. Pauline Rullière, Guillaume Benoit, Emmanuelle M. D. Allouche
and Prof. André B. Charette
Faculty of Arts and Sciences, Department of Chemistry, Université de
Montreal, P.O. Box 6128 Station Downtown, Montreal, Quebec, H3C
3J7 (Canada)
E-mail: andre.charette@umontreal.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802092
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Initial investigations focused on dimethyl hydrazone (1a) as
a model substrate for the generation of 2-diazopropane (2a). To
quantify the generation of the transient diazo species, the output
stream was added to diethyl acetylenedicarboxylate, yielding the
corresponding [3+2]-cycloadduct 3a (Scheme 3).[18] When the
reaction was conducted at room temperature, regardless of the
residence time (from 34 min to 13 s), an output of a colorless
flow mixed with a large volume of gas was observed, and full
conversion of hydrazone (1a) was obtained, indicating 2-
diazopropane (2a) degradation on the column. Lowering the
temperature (–20 °C) and shortening the residence time (36 s)
resulted in a red colored output stream, giving evidence of diazo
formation. As shown by the progressive reduction of the Ag2O
column (Scheme 3b), the stationary oxidant phase was stable,
and stoichiometry could be adjusted to 1.2 equivalent of Ag2O
without any detrimental impact on the yield of the desired
diazo.[16] In order to generate water-free solutions of diazo, 2
equivalents of anhydrous K2CO3 were premixed with the silver
oxide along with oven-dried celite used as filling agent.[16] While
diethyl ether was tolerated as solvent, non-coordinating
dichloromethane, besides offering great advantage in the
context of reaction development and catalyst discovery,
produced a more stable diazo solution. A concentration of 0.1 M
was found to be optimal since, under higher concentration,
dimerization was observed as a degradation process. We then
explored the general application of this process to oxidation of
the previously prepared hydrazone derivatives into diazoalkanes
by adjusting column temperature and residence time to each
substrate (Scheme 3a). Bis-alkyl diazoalkanes (2a-h) were
produced in good yields as bright red solutions. The
diazoalkanes production tolerated alkenes (2d) and sterically
hindered centers (2e-f) as well as cyclic substrates (2g-h).
Cyclic diazo 2h was produced in lower yield due to its especially
high instability. Hydrazones derived from aldehydes were also
oxidized into diazoalkanes under similar conditions, producing
more stable yellow solutions of mono-alkyl diazoalkanes (2i-k).
Moderate yields reflect the instability of aldehydes-derived
hydrazones compared to ketone-derived ones.[16] The reaction
was also compatible with aryl-alkyl hydrazones, affording the
corresponding aryl-alkyl diazoalkanes (2l-s) in good to excellent
yields as purple-red solutions. As electron-neutral aryl-alkyl
diazo compounds are more stable, compounds 2l-p were
obtained at higher temperature without degradation. On the
other hand, electron-rich aryl-alkyl diazo compounds (2q, 2r)
were generated at –15 °C due to their instability. Finally,
diazoalkane 2s immediately reacted in an intramolecular
cycloaddition producing triazole 3s.
Scheme 2. Continuous flow synthesis of hydrazones from aliphatic ketones,
aliphatic aldehydes, and electron-rich aryl ketones. Yields correspond to crude
products after work-up on a 12-mmol scale. THF is used as flow solvent.
Reaction conditions: [a] Neat, 10 min, 100 °C, 1.5 equiv hydrazine
monohydrate. [b] Neat, 10 min, 50 °C, 1.5 equiv hydrazine monohydrate. [c]
EtOH (5 M), 20 min, 100 °C, 2.4 equiv hydrazine monohydrate.
Hydrazones derived from ketones (1a-h) are produced neat in
excellent yields within 10 min of residence time at 100 °C.
Aldehydes (1l-k), on the other hand, require milder reaction
conditions (Treactor = 50 °C). Due to solubility issues, aryl-alkyl
hydrazones (1l-s) were prepared using ethanol (5M).
This safe and easy production of unstabilized diazoalkanes
enabled the exploration of the synthetic potential of these highly
reactive species by directly using them in reactions with suitable
partners, thus providing access to a new chemical space. We
first investigated esterification of various carboxylic acids. 2-
diazopropane 2a reacted quantitatively with various complex
carboxylic acids. Indole (4a), protected amines (4a, 4c-d), free
alcohol (4f), amide (4g) and pyridine substitution (4g) were
tolerated, affording the alkylated products in good to excellent
yields (Scheme 4). The reaction also proceeded efficiently with
furyl-2-diazoethane thus producing (4h). Access to pure
diazoalkane solutions opens the door to using this high-yielding,
mild, chemoselective and by-product-free reaction for
esterification at room temperature.
After a simple work-up, these hydrazones were directly used
in the oxidation step toward diazoalkanes formation. While many
oxidizing reagents have been tested,[16] the combined basicity
and oxidative ability of silver oxide (Ag2O) already proved to be
sufficiently reactive to generate unstable diazoalkanes.[12,17]
However, low yields were obtained due to degradation of the
freshly formed diazo on Ag(I) and reduced Ag(0) as well as
during the long and tedious purification processes. It was
anticipated that a continuous process using a column packed
with Ag2O at controlled low temperature would overcome
degradation of the formed diazo by minimizing contact between
the diazo and Ag2O/Ag(0), which strongly catalyzed its
decomposition.[12]
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Scheme 3. Continuous flow synthesis of diazoalkanes by oxidation of free hydrazones on a silver oxide column. [a] Reactions were run on a 1.4-mmol scale in a
1.7 mL packed column; diazoalkanes were obtained as a ~0.1 M solution in CH2Cl2. Temperatures, residence times and flowrates on the Ag2O column are given.
[b] Yield based on the isolated [3+2]-adduct 3 with dimethyl acetylenedicarboxylate. [c] Yield based on the esterification product 3i with benzoic acid. [d] Yield
based on the electrocyclization adduct triazole 3s.
2a on functionalized targets smoothly inserted the gem-dimethyl
cyclopropane in complex structures (5b-d). Conversely,
diazoalkanes 2p and 2r afforded cyclopropanes 5a and 5e in
moderate yields and as a mixture of diastereomers.
Scheme 4. Esterification with non-stabilized diazoalkanes. Reactions were
performed on a 0.27-mmol diazo scale (2.67 mL at ~0.1 M in CH2Cl2), isolated
yields are reported.
Scheme 5. MIRC reaction with non-stabilized diazoalkanes. Reactions were
performed on a 0.27-mmol diazo scale (2.67 mL at ~0.1 M in CH2Cl2), isolated
yields are reported and dr measured from the crude NMR spectra.
Due to the diazoalkanes’ enhanced nucleophilicity, we
envisaged that they could be good partners in Michael Induced
The practical diazoalkanes production process also allowed
us to screen suitable alkynes and alkenes [3+2]-cycloaddition-
partners to produce a large variety of pyrazolenines and
pyrazolines. The stream of diazoalkane quickly reacted at room
temperature with a variety of unsaturated substrates, providing a
broad range of functionalized pyrazolines in good yields (Table
1). This extremely fast and mild reaction tolerated a-b-
Ring Closure (MIRC) reactions with a-b-unsaturated carbonyls.
This one-step transformation proceeded in good yields in the
presence of various Michael acceptors, producing highly
substituted cyclopropanes (Scheme 5). The gem-dimethyl
cyclopropane motif, for instance, is of particular interest in the
pharmaceutical industry, and versatile methods for preparation
of this building block are lacking.[19] Applying MIRC reaction with
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10.1002/anie.201802092
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COMMUNICATION
unsaturated alkynes as well as aromatic ones (6a-g). Electron-
poor alkenes were also tolerated, providing the corresponding 2-
pyrazoline after isomerization (entries 8, 9 and 11). Notably, it
reacted with vinyl boronate ester, affording the uncommon 2-
pyrazoline boronic acid 6h upon deprotection during purification.
H
N
N
NO2
9
6i
6j
75
O
NO2
O
Remarkably,
2-diazopropane
2a
reacted
with
Ph
difluorocyclopropene to produce a unique difluoro fused bicycle
6l in quantitative yield (entry 12). This last cycloaddition attests
to the high reactivity of diazoalkanes, as this is the first
nucleophilic addition on a difluorocyclopropene ever reported.
N
N
CF3
10
76[d]
CF3
Ph
CO2Me
HN
N
Table 1. [3+2]-Cycloaddition of alkenes and alkynes with non-stabilized
diazoalkanes.
11
12
6k
6l
58[e]
Ph
CO2Me
Ph
N
N
Ph
99
Ph
F
F
F
F
[a] Reactions were run on a 0.16-mmol scale. [b] Isolated yield over two
steps from hydrazone. [c] 38% of regioisomer was observed. [d] Product was
obtained as a mixture of diastereoisomers: dr 45:55. [e] Product was
obtained as a mixture of diastereoisomers: dr 47:53.
6 Yield
Entry
Subtrate[a]
Adduct[b]
[%][b]
N
N
O
O
1
6a
6b
93
N
H
NH-tol
Pyrazolenines are intrinsically interesting motifs, but they are
above all key precursors to cyclopropenes upon release of
nitrogen. Photochemical rearrangement of pyrazolenines into
the corresponding cyclopropene was realized under UVA-
irradiation in continuous flow affording the spiro cyclopropene
derivatives 7a and 7b in only 3 h (Scheme 6a). The suitability of
the method for safe and convenient large scale production of
unstabilized diazoalkanes was demonstrated with the production
of 8.5 mmol of furan diazo compound 2q over 60 min, which was
consumed in line in a [3+2]-cycloaddition (Scheme 6b). Finally, a
telescoped continuous process including the synthesis of
dimethyl hydrazone 1a and its readily oxidation into 2-
diazopropane 2a was developed yielding 50% of the desired
[3+2]-adduct 3a.[18]
O
N
O
N
2
3
84
65
NH-tol
N
H
Ph
S
N
CO2Et
N
6c
6d
CO2Me
Ph
CN
N
N
4
55
CN
Ph
N
N
5
6
6e
6f
63
Ph
Ph
N
CO2Et
N
55[c]
Ph
CO2Et
Ph
Ph
N
N
7
8
6g
6h
34
62
N
N
Ph
HN
N
Bpin2
OH
B
OH
Scheme 6. a) Photochemical conversion of 1-pyrazolenines into
cyclopropenes; b) scale-up synthesis of a furyl-alkyl diazoalkane.
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COMMUNICATION
2013, 15, 5590−5593; d) D. Dallinger, V. D. Pinho, B. Gutmann, C. O.
Kappe, J. Org. Chem. 2016, 81, 5814−5823; e) H. Lehmann, Green
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Lebel, Angew. Chem. Int. Ed. 2017, 56, 6294−6297; Angew. Chem.
2017, 129, 6391−6394.
In conclusion, we described an unprecedented safe and
scalable source of highly reactive alkyl diazoalkanes. Starting
from commercially available ketones or aldehydes, free
hydrazone precursors were efficiently produced in a continuous
flow process, allowing the reduction of hydrazine excess and
reaction time. Oxidation on immobilized non-toxic and relatively
cheap silver oxide circumvent all the stability issues of diazo
compounds on reduced metals. This production method has the
potential to afford a daily production of several grams (~100-200
mmol) of mono- and bis-alkyl diazoalkanes. The output stream
of diazoalkanes in dichloromethane is clean and base-free,
allowing subsequent transformations such as esterification,
Michael Induced Ring Closure (MIRC) cyclopropanation and
[3+2]-cycloaddition. Continuous flow technology applied to diazo
chemistry brought an unprecedented versatility in non-stabilized
diazoalkane production, which, we believe, will unleash their full
synthetic potential.
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After submission of this manuscript, this paper describing a flow
synthesis of unstable diazo compounds and their in-situ coupling
reactions with boronic acids was published: A. Greb, J.-S. Poh, S.
Greed, C. Battilocchio, P. Pasau, D. C. Blakemore, S. V. Ley, Angew.
Chem. Int. Ed. 2017, 56, 16602−16605. However, our work remains the
first methodology allowing the generation of a base-free and clean
stream of non-stabilized diazoalkanes.
Acknowledgements
This work was supported by the Natural Science and
Engineering Research Council of Canada (NSERC) under the
CREATE Training Program in Continuous Flow Science and the
Discovery Grant Program, the Canada Foundation for Innovation,
the Canada Research Chair Program, the FRQNT Centre in
Green Chemistry and Catalysis (CGCC) and Université de
Montréal. G. B. and E. M. D. A. are grateful to Université de
Montréal for postgraduate scholarships. The authors would like
to thank É. Lévesque and C. Audubert for helpful discussions as
well as V. Kairouz for her assistance with the continuous flow
laboratory infrastructure and her constructive comments on the
manuscript.
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Keywords: Continuous flow • Diazoalkane • Hydrazone •
Cycloaddition • Esterification
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COMMUNICATION
Pauline Rullière, Guillaume Benoit
Emmanuelle M. D. Allouche and André
B. Charette*
Page No. – Page No.
Safe and easy access to non-
stabilized diazoalkanes using
continuous flow technology
Red carpet for non-stabilized diazoalkanes: While utility and versatility of diazo
compounds have been demonstrated over the years, toxicity and safety issues still
impede the common use of diazo reagents in academia and industry. Herein we
report the safe and scalable production of the most sensitive and reactive diazo
reagents, non-stabilized alkyl diazoalkanes. The ease of access of these reactive
diazoalkanes allowed various use in esterification, cycloaddition and MIRC reaction.
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