Continuous Flow Synthesis and Purification of Aryldiazomethanes through Hydrazone Fragmentation

Article abstract of DOI:10.1002/anie.201608444

Electron-rich diazo compounds, such as aryldiazomethanes, are powerful reagents for the synthesis of complex structures, but the risks associated with their toxicity and instability often limit their use. Flow chemistry techniques make these issues avoidable, as the hazardous intermediate can be used as it is produced, avoiding accumulation and handling. Unfortunately, the produced stream is often contaminated with other reagents and by-products, making it incompatible with many applications, especially in catalysis. Herein is reported a metal-free continuous flow method for the production of aryldiazomethane solutions in a non-coordinating solvent from easily prepared, bench-stable sulfonylhydrazones. All by-products are removed by an in-line aqueous wash, leaving a clean, base-free diazo stream. Three successful sensitive metal-catalyzed transformations demonstrated the value of the method.

Full text of DOI:10.1002/anie.201608444

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608444
German Edition: DOI: 10.1002/ange.201608444
Continuous Flow Synthesis
Continuous Flow Synthesis and Purification of Aryldiazomethanes
through Hydrazone Fragmentation
ꢀric Lꢁvesque, Simon T. Laporte, and Andrꢁ B. Charette*
Abstract: Electron-rich diazo compounds, such as aryldiazo-
methanes, are powerful reagents for the synthesis of complex
structures, but the risks associated with their toxicity and
instability often limit their use. Flow chemistry techniques
make these issues avoidable, as the hazardous intermediate can
be used as it is produced, avoiding accumulation and handling.
Unfortunately, the produced stream is often contaminated with
other reagents and by-products, making it incompatible with
many applications, especially in catalysis. Herein is reported
a metal-free continuous flow method for the production of
aryldiazomethane solutions in a non-coordinating solvent
from easily prepared, bench-stable sulfonylhydrazones. All
by-products are removed by an in-line aqueous wash, leaving
a clean, base-free diazo stream. Three successful sensitive
metal-catalyzed transformations demonstrated the value of the
method.
amine through a column packed with an excess of solid
manganese dioxide. Unfortunately, the resulting diazo solu-
tions still contain a superstoichiometric amount of base, which
is incompatible with catalytic systems involving base-sensitive
transition metals. Furthermore, the solid oxidizer needs to be
conditioned before use and gets reduced and contaminated as
the reaction proceeds, requiring interruption of production
for column repacking or regeneration. The free hydrazones
used as starting materials are also problematic due to their
tendency to self-condense into azines,[11] especially when
derived from aldehydes.
The base-mediated fragmentation of sulfonylhydrazones
is an alternative, metal-free approach to aryldiazomethane
synthesis. These innocuous,[12] solid and bench-stable[13] com-
pounds readily form via condensation of a sulfonylhydrazide
with the corresponding aldehyde and are purified by simple
precipitation. Under heat, their conjugate base undergoes
sulfinate anion elimination, generating the diazo functional
group (Scheme 1).[14]
D
iazo compounds are versatile intermediates in organic
synthesis. Driven by the release of dinitrogen, this unique
structure gives access to highly reactive carbenes,[1] carbe-
noids[2] or carbocations.[3] However, the toxicity and insta-
bility inherent to these compounds usually discourage the
exploitation of their chemical potential, especially on large
scale applications.[4] Continuous flow chemistry can circum-
vent these risks.[5] Flow systems allow reagent mixing and
product isolation with minimal operator intervention, reduc-
ing the risk of exposure. Furthermore, simultaneous reagent
production and consumption enables scale-up without
increasing the maximum reagent accumulation. Larger quan-
tities can be accessed by increasing the tubingꢀs internal
diameter or by running reactors in parallel.[6] The develop-
ment of continuous-flow methods for the safe handling of
hazardous intermediates is relevant to the pharmaceutical
industry, as safety is the main driver for implementation of
continuous flow processing.[7]
Scheme 1. Alternate approaches for the continuous synthesis of aryl-
diazomethanes: hydrazone oxidation by metal oxides[10] and sulfonyl-
hydrazone fragmentation (this work).
To be compatible with the most stringent catalytic
applications, aryldiazomethanes must be base- and contam-
inant-free and dissolved in a non-coordinating solvent.[15]
Continuous flow production of such solutions requires
removal of the base and the sulfinate byproduct from the
stream. Several methods have previously been employed to
purify specific classes of diazo reagents in flow systems, such
as SiO2-filled scavenger columns (R1C(N2)CO2R2),[16] AF-
2400 tube-in-tube reactors (CH2N2 and CF3CHN2)[17] and
membrane-based phase separation (CH2N2 and HC-
(N2)CO2Et).[18] An aqueous wash followed by a phase sepa-
ration was deemed the most suitable approach for the
preparation of aryldiazomethanes, as it is compatible with
most substrates and allows unlimited continuous flow.
Electron-rich diazo compounds, such as alkyl- or aryldi-
azomethanes, are of particular interest because of their
inherent nucleophilicity and basicity, allowing alkylations[3]
and homologations[8] under mild conditions. However, these
same properties increase their Lewis or Brønsted acid
sensitivity, complicating their synthesis, storage and use.[9]
A straightforward approach for the continuous flow
generation of aryldiazomethanes was recently reported by
Ley and co-workers.[10] The reagents are obtained by running
a CH2Cl2 solution of free hydrazone and diisopropylethyl-
[*] ꢀ. Lꢁvesque, S. T. Laporte, Prof. A. B. Charette
Department of Chemistry, Universitꢁ de Montrꢁal
P.O. Box 6128 Stn Downtown, Montreal, Quebec, H3C 3J7 (Canada)
E-mail: andre.charette@umontreal.ca
The system design for such a reaction–purification
sequence includes base and sulfonylhydrazone feeds meeting
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before entering a heated reactor. The reactorꢀs output is then
cooled before addition of an aqueous stream. After sufficient
biphasic extraction, the mixture runs through a Zaiputꢁ phase
separator, leaving all the reaction byproducts behind in the
aqueous phase. The cleaned reactive organic phase is then
added to the reaction mixture intended to consume the diazo
reagent (Figure 1). In order for such a system to operate
unsatisfactory, but tetramethylguanidine (TMG)[20] turned
out to have the perfect combination of a high pKb and
a hydrophilic conjugate acid (entry 5).
At this point, the only remaining issue was the insolubility
of the neutral sulfonylhydrazone precursor in CH2Cl2 before
addition of base. Fortunately, it was discovered that one to
five equivalents of water-soluble formamide ensured the
complete dissolution of most sulfonylhydrazones in CH2Cl2
without negatively impairing the product yield or purity
(entry 6).
[21]
The reaction conditions were then suitable to be tested in
the flow reactor (Figure 2). While conditions imitating the
Figure 1. Flow setup concept and expected solution compositions.
properly, chemicals must be chosen or designed to satisfy its
associated constraints. Namely, all reagents and byproducts
must be soluble at all times to avoid clogging, and everything
but the desired aryldiazomethane must be transferred into the
aqueous layer upon extraction. Since the most common
reagents for aryldiazomethane preparation do not satisfy
Figure 2. Final flow setup to generate and purify aryldiazomethanes.
those constraints,
a
de novo
approach had to be designed.
Table 1: Optimization of the sulfonylhydrazone fragmentation into phenyldiazomethane and subse-
At first, the optimal sulfonyl
substituent was selected. The 4-
tolylsulfonylhydrazones commonly
used for batch synthesis[14] fragment
very slowly at temperatures com-
patible with the sensitive aryldiazo-
methanes (Table 1, entry 1). Steri-
cally congested sulfonylhydrazones
have been reported to undergo
elimination more readily,[19] a pro-
cess probably accelerated by steric
decompression. The mesityl (Mes)
group (entry 2) was optimal, as the
equally efficient triisopropylphenyl
(Trip) yielded a water-insoluble sul-
finate (TripSO2Li, entry 3).
The typically used alkoxide/
alcohol base and solvent system
proved problematic. Alcohols can
react with diazo reagents (entry 2),
and alkali salts tend to be poorly
soluble in organic media (entry 4).
Dichloromethane was chosen as
quent purification.
Entry
Exp.
type
Solvent(s)
R
Base
Wash
Yield
Major by-
product(s)
2a[a]
1[b]
2[b]
3[b]
4[d]
5[d]
6[d]
7[g]
8[h]
9[h]
10[h]
11[k]
batch
batch
batch
batch
batch
batch
flow
flow
flow
flow
batch
MeOH/toluene
MeOH/toluene
MeOH/toluene
CH2Cl2
4-Tolyl
Mes
Trip
LiOMe
LiOMe
LiOMe
LiOiPr
TMG
TMG
TMG
TMG
TMG
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
7%
1
47%
48%
35%
55%
60%
63%
79%
78%
79%
75%
BnOMe[c]
Trip, SO2Li
1
Mes
Mes
Mes
Mes
Mes
Mes
Mes
Mes
CH2Cl2
1 + TMG[e]
1 + TMG[e]
1 + TMG[e]
TMG[e]
[f]
[f]
[f]
[f]
[f]
[f]
HCONH2/CH2Cl2
HCONH2/CH2Cl2
HCONH2/CH2Cl2
HCONH2/CH2Cl2
HCONH2/CH2Cl2
HCONH2/CH2Cl2
[i]
NH4Cl/H2O
NH5CO3/H2O
NH5CO3/H2O
NH3
TMG
TMG
none[j]
none[j]
[a] Titrated with BzOH or AcOH and corresponding ester quantified by 1H-NMR using 1,3,5-
trimethoxybenzene or triphenylmethane as internal standard. [b] 558C, 30 min, 1.0 equiv base. [c] From
benzylation of MeOH by phenyldiazomethane. [d] 408C, 30 min, 1.0 equiv base. [e] Up to 15% TMG.
[f] 1.0 equiv of formamide. [g] Unoptimized flow conditions (508C, 20 min, 1.0 equiv base). [h] Opti-
mized flow conditions (658C, 6 min, 2.0 equiv base). [i] Ammonium benzoate observed after titration
[j] No impurity >3%, no TMG. [k] Sealed tube heated to 658C for 12 min, 2 equiv base, 2 aqueous
a
non
Common organic bases, such as
triethylamine and DBU, were washes.
Lewis-basic
solvent.
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batch reaction gave a similar result (entry 7), the higher
with a 1:1 mixture of dried Celiteꢁ and 4 ꢂ molecular sieves
temperature and short reaction time made possible in the
pressurized flow reactor increased the yield to a satisfactory
79% (entry 8). The only major impurity still present in the
diazo stream was the excess base. Several mild aqueous
proton sources were then tested (entries 9 and 10), and
ammonium bicarbonate yielded a clean, uncontaminated
aryldiazomethane stream (entry 10). The batch procedure
using these optimal parameters resulted in a similar diazo
yield, but heating time had to be doubled to achieve complete
conversion.
Diazo-consuming reactions often use slow addition rates
that are usually achieved via syringe pump.[1,2] To accommo-
date this constraint, the system was tested at different
concentrations and flow rates, adjusting the reactor volume
to keep the reaction time constant. Aryldiazomethanes can be
produced at rates between 1.0 to 10.0 mmolhÀ1[22] and at
concentrations between 0.50m and 0.25m[23] without signifi-
cant variations in the yield or purity.
with no loss of yield.[25]
To investigate the produced aryldiazomethanesꢀ applic-
ability to metal-catalyzed reactions, three reagent systems
known for their sensitivity to Lewis-basic contaminants were
selected. In all cases, the output stream from the flow
apparatus was added directly to a stirred reaction mixture.
First, the scandium-catalyzed cyclic ketone ring expansion
developed by Kingsbury and co-workers was reported to fail
when the diazo nucleophile solution is not of high purity.[26]
This semipinacol rearrangement was successfully performed
with 4 different continuously produced diazo compounds in
good yields (Scheme 3).
Second, the copper-catalyzed epoxidation of aldehydes
reported by Aggarwal and co-workers[1a] involves a typically
The methodology was shown to be quite general
(Scheme 2), giving excellent yields of electron-poor aryldi-
azomethanes (2b–2i and 2s–2t) and acceptable yields of their
highly reactive electron-rich counterparts (2j–2n).[24] Diaryl-
diazomethanes (2u–2w) could also be accessed, as well as
heterocyclic diazo compounds (2o–2p), showcasing the
excellent chemoselectivity of the method. For 2a and 2l,
reagents were pumped continuously for 1 h, producing,
respectively 7.1 mmol (71%) and 6.5 mmol (65%)
No precautions were taken to exclude water and oxygen
from the solvents and reagents, as these did not increase the
yield and purity of the streams. However, if the diazoꢀs
intended use involves an air- and water-sensitive reagent
system, the stream can be passed through a column packed
Scheme 3. Sc(OTf)3-catalyzed ring expansion of cycloheptanone.
0.23 mmol scale, 0.35m diazo, 333 mLminÀ1. [a] Reaction run at
À788C.
Scheme 2. Flow synthesis of aryldiazomethanes: Scope study using various aldehydes and ketones. Yields are calculated from the isolated ester
after titration with benzoic acid. [a] 1 to 5 equiv formamide added in sulfonylhydrazone (1) solution. [b] Sulfonylhydrazone (1) premixed with TMG
before injection. [c] Reactor temperature=658C. [d] Reactor temperature=758C. [e] Target concentration: 0.50m, 0.24 mmol scale [f] Target
concentration: 0.25m, 0.12 mmol scale. [g] Target concentration : 0.25m, 0.25 mmol scale. [h] Target concentration : 0.50m, 10.0 mmol scale.
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problems usually requiring extensively purified reagents. We
are hopeful that this technology will allow a more widespread
exploitation of diazo reagentsꢀ chemical potential.
Experimental Section
Typical procedure for the synthesis of mesitylsulfonylhydrazones
from aldehydes: Mesitylsulfonylhydrazide (1.00 equiv) was sus-
pended in EtOH in a 20-mL vial open to air and aldehyde
(1.01 equiv) was added at once, followed by AcOH (0.005 equiv).
Heterogeneous mixture was kept under strong agitation for 90 min.
Excess hexanes were added and the resulting off-white solid was
recovered by filtration (washing with hexanes).
Typical procedure for the continuous flow synthesis and purifi-
cation of aryldiazomethanes: Stream 1 (1.0m 1a, 1.0m formamide in
CH2Cl2, 1.0 equiv, 166 mLminÀ1) and stream 2 (2.0m tetramethylgua-
nidine in CH2Cl2, 2.0 equiv, 166 mLminÀ1) meet in a “T” connector,
run through a 2.0 mL coiled tube reactor heated at 658C and
a 0.25 mL room temperature cooling loop. Stream 3 (1.0m NH4HCO3/
H2O, 1.00 mLminÀ1) is added via a second “T” connector. Biphasic
stream runs in a 0.25 mL loop to a Zaiputꢁ phase separator (PTFE
membrane with 1.0 mm pores). Zaiputꢁ back pressure regulators are
set at 3 atm. Organic stream (333 mLminÀ1, approx. 0.4m phenyl-
diazomethane in DCM) is added directly to the target reaction
mixture.
Caution! Diazo compounds are presumed to be highly toxic and
potentially explosive. Acetic acid should be used to neutralize any
spilled or unwanted material. No diazo accumulation was observed in
any part of the system after prolonged use. Acetic acid was added
upon quenching the catalytic reactions as a precaution, but in all
reported examples the diazo was already consumed.
Scheme 4. Cu(acac)2-catalyzed epoxidation of 4-NO2-benzaldehyde.
0.28 mmol scale, 0.18m diazo, 66 mLminÀ1
.
water-sensitive copper carbene and a sulphur ylide as
intermediates and requires a very slow addition of the diazo
reagent. Nonetheless, the selected aromatic aldehyde under-
went smooth epoxidation with 4 different diazo partners
(Scheme 4).
Finally, the catalytic Simmons–Smith cyclopropanation
previously developed in our group[2a] requires the formation
of a notoriously Lewis-base sensitive zinc carbenoid.[27] The
protected allylic alcohol substrate still underwent cyclopro-
panation in moderate to excellent yields (Scheme 5).
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,
the Canada Foundation for Innovation, the Canada Research
Chair Program, the FRQNT Centre in Green Chemistry and
Catalysis and Universitꢃ de Montrꢃal. E.L. is grateful to
NSERC and Universitꢃ de Montrꢃal for postgraduate schol-
arships.
Conflict of interest
The authors declare no conflict of interest.
Keywords: continuous flow · cyclopropanation ·
diazo compounds · hydrazones · ring expansion
Scheme 5. ZnI2-catalyzed cyclopropanation of MOM-protected cinn-
amyl alcohol. 0.14 mmol scale, 0.35m diazo, 166 mLminÀ1
.
In summary, a safe and efficient method for the on-
demand production of clean, uncontaminated reactive aryl-
diazomethane solutions was developed. The sulfonylhydra-
zone precursors are safe, bench-stable solids easily prepared
from the corresponding aldehydes or ketones. The diazo
streamꢀs concentration and flow rate can be modulated to suit
the subsequent reaction. Three typically sensitive reactions
were performed on multiple aryldiazomethanes to demon-
strate the applicability of this method on real synthetic
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Manuscript received: August 29, 2016
Revised: November 16, 2016
Final Article published: && &&, &&&&
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Communications
Continuous Flow Synthesis
ꢁ. Lꢂvesque, S. T. Laporte,
A. B. Charette*
&&&& — &&&&
Continuous Flow Synthesis and
Purification of Aryldiazomethanes
through Hydrazone Fragmentation
Minimizing risks: A continuous flow
method for the production of clean
aryldiazomethane solutions was devel-
oped. The reagents are generated by the
fragmentation of easily prepared, bench-
stable mesitylsulfonylhydrazones and
purified by an in-line aqueous wash. A
wide array of electron-rich and electron-
poor aryldiazomethanes was prepared.
The quality of the produced streams is
demonstrated by their use in three metal-
catalyzed reactions.
6
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