Copper-Catalyzed Oxidation of Hydrazones to Diazo Compounds Using Oxygen as the Terminal Oxidant

Article abstract of DOI:10.1021/acscatal.1c00264

A mild method for accessing diazo compounds via aerobic oxidation of hydrazones is described. This catalytic transformation employs a Cu(OAc)2/pyridine catalyst and molecular oxygen from ambient air as the terminal oxidant, generating water as the sole byproduct and affording the desired diazo compounds within minutes at room temperature. A broad array of electronically diverse aryldiazo esters, ketones, and amides can be accessed. Pyridine dramatically enhances the rate of the reaction by solubilizing the copper catalyst and serving as the Br?nsted base in the turnover-limiting proton-coupled oxidation of hydrazone by copper(II). Insights gained from mechanistic studies led to expansion of the scope of this method to include diaryl hydrazones, delivering diaryl diazomethane derivatives, which cannot be accessed via established diazo transfer methods. The products of this method may be employed in rhodium carbene catalysis without isolation of the diazo intermediate to afford cyclopropane products in good yield with high enantioselectivity.

Full text of DOI:10.1021/acscatal.1c00264

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Research Article
Copper-Catalyzed Oxidation of Hydrazones to Diazo Compounds
Using Oxygen as the Terminal Oxidant
Wenbin Liu, Jack Twilton, Bo Wei, Maizie Lee, Melissa N. Hopkins, John Bacsa, Shannon S. Stahl,*
and Huw M. L. Davies*
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ABSTRACT: A mild method for accessing diazo compounds via
aerobic oxidation of hydrazones is described. This catalytic
transformation employs a Cu(OAc)2/pyridine catalyst and
molecular oxygen from ambient air as the terminal oxidant,
generating water as the sole byproduct and affording the desired
diazo compounds within minutes at room temperature. A broad
array of electronically diverse aryldiazo esters, ketones, and amides
can be accessed. Pyridine dramatically enhances the rate of the
reaction by solubilizing the copper catalyst and serving as the Brønsted base in the turnover-limiting proton-coupled oxidation of
hydrazone by copper(II). Insights gained from mechanistic studies led to expansion of the scope of this method to include diaryl
hydrazones, delivering diaryl diazomethane derivatives, which cannot be accessed via established diazo transfer methods. The
products of this method may be employed in rhodium carbene catalysis without isolation of the diazo intermediate to afford
cyclopropane products in good yield with high enantioselectivity.
KEYWORDS: copper, aerobic oxidation, dehydrogenation, hydrazones, diazo compounds, mechanism
Simple hydrazones are appealing precursors to diazo
compounds because they are readily accessible and stable.
Their oxidation to diazo compounds, however, typically
employs stoichiometric metal-based oxidants, such as HgO,11
Ag2O,12 MnO2,13 Ni2O3,14 and Pb(OAc)4 (Scheme 1b).15
This challenge has been addressed, in part, by the development
of alternative oxidation methods. Examples include the use of
chlorodimethylsulfonium chloride (generated from dimethyl
sulfoxide (DMSO) and oxalyl chloride),16 iodine-based
oxidants, such as o-Iodoxybenzoic Acid (IBX)17 and N-iodo-
p-toluenesulfonamide (TsNIK),18 and a catalytic system using
TEMPO and NaOCl as the terminal oxidant.19 Molecular
oxygen (O2) would be an ideal oxidant; however, catalytic
methods demonstrating the feasibility of aerobic oxidation of
hydrazone exhibit very limited scope.20
Herein, we describe a copper-catalyzed method for the
oxidation of hydrazones with O2, in which water is the only
byproduct. It operates efficiently under mild conditions,
reaching completion within minutes at room temperature
with ambient air as the oxidant, and shows excellent scope in
reactions with hydrazones bearing adjacent donor and acceptor
INTRODUCTION
■
α-Diazo carbonyl compounds and diaryl diazomethane
derivatives are versatile reagents with broad synthetic utility.
Release of dinitrogen from diazo compounds is thermodynami-
cally very favorable, enabling facile generation of carbene or
metal carbene species via thermolysis,1 photolysis,2 or
activation by metal complexes.3 Carbene intermediates are
very reactive and engage in diverse synthetically useful
transformations, including insertion into C−H and X−H
bonds (X = N, S, O, Si),4 cycloadditions,5 and other coupling
reactions.6 One of the challenges with the use of diazo
compounds on scale is the intrinsic high energy of these
compounds,1d,7 and there is considerable interest in preparing
diazo compounds in situ to avoid safety hazards associated with
their generation and isolation in large quantities.8 Traditional
approaches for the synthesis of diazo compounds use reactive
starting materials, such as azides (i.e., diazo transfer) or
stoichiometric oxidants, which generate undesirable by-
products (Scheme 1a-i).9 Base-induced fragmentation of
sulfonylhydrazones (Bamford−Stevens reaction) represents
another method (Scheme 1a-ii).10 The stoichiometric sulfinate
byproduct is an undesirable feature, especially for large-scale
applications, and the common need for strong bases or
elevated temperatures can lead to decomposition or undesired
reactivity of the diazo product. The development of more
practical methods for the synthesis of diazo compounds could
bypass these limitations and expand the utility of synthetic
methods employing diazo reagents.
Received: January 19, 2021
Revised: January 26, 2021
Published: February 12, 2021
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© 2021 American Chemical Society
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a
Scheme 1. Previous and Current Work on α-Diazo carbonyl
Table 1. Optimization of Hydrazone Oxidation
Synthesis
a
Reaction conditions: a solution of (Z)-1 (0.5 mmol) in 1 mL of
CH2Cl2 was added in 1-pot to a vial with [Cu] and additive in 4 mL
of CH2Cl2 under 1 atm O2 (balloon) at 23 °C. The mixture was
b
c
o
stirred vigorously for 1 h. Reaction run in Et2O at 0 C. Oxidation
substituents (electron-donating and -withdrawing groups,
respectively) (Scheme 1c). The resulting diazo compounds
are precursors to synthetically versatile donor/acceptor
carbenes employed in diverse stereoselective and synthetically
useful transformations.2−6 Pyridine derivatives play a crucial
role in the catalytic reactions, and kinetic and mechanistic
studies show that electron-rich pyridines significantly increase
the catalytic rate and support expansion of the substrate scope
to diaryl hydrazones, accessing diaryl diazomethane derivatives.
The utility of these advances is highlighted in tandem
processes that feature in situ generation and use of the diazo
compounds in catalytic enantioselective cyclopropanation of
alkenes.
1
byproducts were observed in the H NMR spectrum of the crude
reaction mixture. Ambient air used instead of a pure O2 balloon.
d
triflate salts of copper(I) resulted in hydrazone decomposition
but no desired diazo compound was observed (entry 6). The
known activity of copper(I) triflate salt, activation of diazo
compounds,21 accounts for the observed byproducts derived
from carbene intermediates, such as O−H insertion with H2O,
N−H insertion with the hydrazone (Z)-1, and dimerization.
Copper(II) acetate showed the greatest promise and was found
to facilitate both formation and retention of the diazo
compound 2, affording a 20% yield of 2 with 40% unreacted
hydrazone (Z)-1 (entry 7). The use of the less expensive
hydrated copper acetate, Cu(OAc)2·H2O, was similarly
effective (entry 9). However, addition of approximately 10%
water by volume to the reaction mixture inhibited the reaction
and resulted in complete recovery of (Z)-1 (entry 8). Both
molecular sieves and silica were found to be slightly beneficial,
affording the desired product in comparable yield, likely due to
the removal of deleterious water. The use of silica resulted in
significantly reduced formation of undesirable byproducts
(entry 10 and 12). MgSO4 was also tested as a desiccant, but it
inhibited the reactivity (entry 11).
Addition of a base, such as NEt3 or pyridine, led to
dramatically improved conversion of hydrazone (Z)-1 to the
desired diazo compound 2 (80 and 92% yield in entries 13 and
14, respectively). Excellent yield was maintained with reduced
loading of Cu(OAc)2·H2O and pyridine (10 mol % and 0.6
equiv, respectively; entry 15). In addition, ambient air proved
to be competent as the source of O2, affording 2 in a yield
nearly identical to that obtained with pure O2 (entry 16). The
beneficial effect of NEt3 and pyridine is especially clear from
React-infrared (IR) studies of the reaction progress, using the
IR absorbance of diazo functionality at ∼2100 cm−1 (Figure
1A). The reactions conducted with NEt3 and pyridine reached
completion in less than 10 min. The reactions with no base
RESULTS AND DISCUSSION
■
Catalyst Optimization. Prior work by Ibata and Singh
demonstrated that Cu(acac)2 (acac = acetylacetonate)
catalyzes aerobic oxidation of the narrow set of benzil-derived
diaryl hydrazones; however, the products are susceptible to
further oxidation to benzophenone azines if the reaction time
and temperature are not strictly controlled.20b In spite of these
limitations, this precedent prompted us to consider simple Cu
salts as catalysts for aerobic oxidation of hydrazones bearing
donor/acceptor substituents. Initial efforts focused on
oxidation of hydrazone (Z)-1 to 2,2,2-trichloroethyl 2-(4-
bromophenyl)-2-diazoacetate 2 (Table 1). This substrate was
used because the resulting diazo compound has found broad
application in catalyst-controlled C−H functionalization
reactions.4c A double oxygen balloon and vigorous stirring
(800 rpm) with a large magnetic stir bar were used to support
efficient oxygen mixing between the headspace and reaction
solution. Ibata and Singh used Cu(acac)2 as the catalyst,20b but
the hydrazone starting material 1 was completely unreactive
under the previously reported conditions. Similar behavior was
observed under modified conditions with several different Cu
sources, including Cu(acac)2, copper(I) iodide, copper(I)
oxide, and copper(II) triflate (Table 1, entries 2−5). The
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passing the crude reaction mixture through a plug of silica gel.
The Z isomer is the dominant isomer obtained from the
synthesis of hydrazone 1 and was used in the optimization
studies in Table 1. The E isomer proved to be equally effective,
generating 2 in 96% isolated yield. Hence, the other hydrazone
substrates were evaluated as mixtures of E/Z isomers without
extensive separation. Efficient hydrazone oxidation was
observed with different ester substituents, generating 3−5 in
high yields (89−97%). The oxidation was similarly effective for
the synthesis of a variety of aryldiazoacetates, as illustrated for
6−13. The reaction was especially effective when the aryl
substituents were electron withdrawing or slightly electron
donating, with products isolated in ≥93% yield. The reaction
yield was diminished for substrates with the electron-donating
methoxy group (88% yield of 8 and 69% yield of 13). This
result is consistent with previous observations, showing that
aryldiazoacetates with strongly donating groups decompose
more rapidly.1d,22 In the reaction affording 13, byproducts
observed from further reaction of the carbene with oxygen and
water were detected. The reaction was also effective in the
formation of pyridyldiazoacetate 14 and even an alkyldiazoa-
cetate 15 in high yields (94 and 82%, respectively).
Diazoketone 16 was obtained in good yield, necessitating
minor modification of the reaction conditions due to the
instability of the product. Specifically, the reaction was
conducted in the dark using an O2 balloon with higher loading
of the pyridine additive to minimize the decomposition of the
diazoketone product via Wolff rearrangement.23 Furthermore,
the isatin-derived hydrazones were converted to the corre-
sponding diazoamides 17 and 18 in near-quantitative yields.
Mechanistic Studies. Additional studies provided valuable
insights into these reactions. The addition of 1 equiv of
pyridine to a solution of Cu(OAc)2 in dichloromethane
formed the previously reported pyridine-capped Cu(OAc)2
dimer, Cu2(OAc)4(py)2.24 This complex was found to be a
Figure 1. React-IR analysis of the formation of diazo product 2 from
hydrazone 1 (A), together with reaction outcomes observed at longer
reaction times with the different base additives (B).
and with the bulky base, 2,6-t-Bu2py, showed very little
conversion during the same time period, albeit with moderate
product formation over longer time periods (Figure 1B).
Assessment of Substrate Scope. The optimized
conditions identified for oxidation of hydrazone (Z)-1
provided a starting point for evaluation of a broader range of
substrates, using ambient air as the source of the oxidant and
pyridine as an additive (Table 2). In most of these cases, the
diazo products could be obtained in good purity simply by
a
Table 2. Substrate Scope of Diazo Compounds from Cu(OAc)2-Catalyzed Oxidation of Hydrazones Under Ambient Air
a
Reaction condition: a solution of (Z)-hydrazone (0.5 mmol) in 1 mL of CH2Cl2 (0.5% pyridine) was added to a vial with Cu(OAc)2·H2O (10
mol %) and SiO2 (100 mg) in 4 mL of CH2Cl2 (0.5% pyridine) under ambient air (without cap) at 23 °C. The mixture was stirred vigorously for 1
h before silica plug. 1:1 (Z/E)-hydrazone was used. (E)-hydrazone was used. Reaction was conducted using 2.4 equiv of pyridine with O2
balloon in dark (aluminum foil). 2:1 (Z/E)-hydrazone was used. 17:1 (Z/E)-hydrazone was used.
b
c
d
e
f
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competent catalyst for the aerobic oxidation hydrazone 1,
without the inclusion of additional pyridine, affording diazo
compound 2 in nearly quantitative yield (Figure 2).
Figure 2. Oxidation of hydrazone (Z)-1 catalyzed by Cu(OAc)2·2py,
which was characterized by X-ray crystallography.
To probe the mechanism of this Cu-catalyzed hydrazone
oxidation, the rate of the catalytic reaction was then monitored
under standard conditions with a series of 4-substituted
pyridine derivatives (Figure 3). The reaction of hydrazone 19
Figure 4. Proposed catalytic mechanism and rate law.
reversible substitution of a pyridine ligand on Cu2(OAc)4(py)2
by the hydrazone substrate, followed by turnover-limiting
deprotonation of the coordinated hydrazone by pyridine. The
latter step is expected to be coupled to reduction of the CuII
centers, resulting in formation of the diazo compound and 2
equiv of CuIOAc. The catalyst can then be reoxidized by O2,
supported by protons derived from the substrate oxidation
step. A rate law derived for this mechanism (Figure 4, eq 2)
rationalizes the zero-order kinetic dependence on [py], even
while pyridine is crucial to enable the reaction to proceed (cf.
Figure 1). The influence of the electronic properties of
pyridine (cf. Figure 3)27 may be rationalized by electronic
contributions to the fundamental rate constants incorporated
in the kobs term (Figure 4, eq 3: k1, k−1, and k2). The positive
slope in Figure 3 suggests that the influence of pyridine basicity
on turnover-limiting proton transfer (k2) is the most significant
electronic contribution.
Expansion of Reactivity to Diaryl Hydrazones. Diaryl
hydrazones are precursors to diaryl diazomethane derivatives.
The latter compounds are noteworthy because they behave as
donor−acceptor carbenes in rhodium-catalyzed cyclopropana-
tions, affording the desired products with high stereo-
selectivity.28 Catalytic methods for aerobic dehydrogenation
of diaryl hydrazones to prepare diazo compounds have not
been reported, and the catalytic conditions shown in Table 2
are unreactive with these substrates (cf. Table S2 in the
Supporting Information).29 Nonetheless, we wonder whether
the more reactive catalyst systems featuring electron-rich
pyridines might be effective with these substrates.
A range of copper carboxylate salts and basic pyridine
derivatives were evaluated for the oxidation of benzophenone
hydrazone (Table 3). The diphenyl diazomethane product
(24) is relatively unstable, and to facilitate product
quantitation, AcOH was added to the reaction mixture at the
end of the reaction to convert the diazo compound 24 to the
corresponding acetate 25. Moderate reactivity was observed
with Cu(OAc)2 in combination with DMAP or another
electron-rich pyridine derivative (20−23, entries 3−6). 9-
Figure 3. Analysis of pyridine electronic effects on the rate of
hydrazone oxidation to afford diazo compound 11. See the
Supporting Information for experimental details.
was analyzed by following O2 consumption via gas-uptake
methods, and well-behaved time-course data were amenable to
initial-rate analysis (see the Supporting Information (SI) for
details). A Brønsted plot correlating the logarithm of the
relative rates with the pyridinium pKa values25 exhibits a linear
fit with a positive slope,26 showing that more basic pyridine
derivatives lead to faster rates. Use of 4-(N,N-dimethyamino)-
pyridine (DMAP) as the base led to complete conversion of 19
into diazo compound 11 within 2 min at room temperature.
These data were complemented by additional kinetic
analysis to determine a catalytic rate law. The catalytic rate
for oxidation of 19 exhibited a first-order dependence on
[Cu(OAc)2] and [19] but little-to-no dependence on [py] or
pO2 (3−28 psi) (see Figure S6 in the Supporting Information).
These results provide the basis for the proposed catalytic
mechanism shown in Figure 4. The reaction is initiated by
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a
a
Table 3. Optimization of Diaryl Hydrazone Oxidation
Table 4. Diaryl Hydrazone Oxidation
a
Reaction conditions: Hydrazone (0.20 mmol) was added to a vial
with 5 mol % Cu(TFA)2·H2O and 20 mol % 9-azajulolidine (21) in 2
mL of DCE under air at 0 °C. The mixture was stirred vigorously for
12 h. Yields shown reflect 1H NMR analysis of the crude reaction with
1,3,5-trimethoxybenzene as the internal standard; yields shown in
a
Reaction conditions: a solution of hydrazone (0.01 mmol) in 0.05
mL of solvent was added in 1 to a vial with [Cu] and additive in 0.05
mL of DCE under air at 23 °C. The mixture was stirred vigorously for
2 h then cooled to 0 °C and quenched with AcOH (20 uL in 200 uL
MeCN). Product 24 was converted to acetate to facilitate ultra
performance liquid chromatography (UPLC) analysis. A stock
solution of IS 1,3,5-triemthoxybenzene was added and assay yield
was determined by calibrated UPLC analysis. DCE = 1,2-dichloro-
ethane.
b
c
parenthesis are isolated.31 Reaction run for 6 h. Product isolated as
an inseparable 4:1 mixture with a ketone byproduct.
Tandem Catalytic Diazo Synthesis and Carbene
Transfer. The present method provides a means to prepare
diazo compounds in situ and use, without isolation, in tandem
one-pot reactions with Rh-catalyzed carbene transfer. This
concept was tested using a hydrazone precursor to both classes
of diazo compounds (Scheme 2). Hydrazone 1 was converted
to the corresponding diazo compound 2 using a Cu(OAc)2/
DMAP catalyst system. The crude reaction mixture containing
2 and residual copper catalyst were then used directly in the
cyclopropanation of styrene with a chiral rhodium carboxylate
catalyst, Rh2(R-p-PhTPCP)4.32 The cyclopropane product was
obtained in good yield and excellent stereoselectivity (31, 67%
yield, >20:1 dr, 99% ee). This tandem reactivity has even
greater implications for diaryldiazomethanes, owing to their
instability and challenges in their isolation (cf. Table 4).28 The
crude diaryl diazomethane derivative 27, obtained from
aerobic dehydrogenation of the corresponding hydrazone
using a Cu(TFA)2/23 catalyst system, was used directly in
the cyclopropanation of styrene with Rh2(S-PTAD)4 as the
catalyst. The cyclopropane product 32 was obtained in
moderate yield and good stereoselectivity (56% yield, 2:1 dr,
and 94% ee). These results highlight the potential applicability
of sequential Cu-catalyzed aerobic oxidation and Rh-catalyzed
carbene transfer without purification of the reactive diazo
intermediate.
Azajulolidine (23) showed the best reactivity (59%, entry 6),
probably reflecting the coplanarity of the amino group and the
pyridine π-system, which enhances the basicity of 23 relative to
DMAP and other 4-aminopyridine derivatives.30 Further
improvement was observed when Cu(OAc)2 was replaced
with Cu(O2CCF3)2·H2O. The combination of 5 mol %
Cu(O2CCF3)2·H2O and 20 mol % 23 delivered 87% assay
yield of acetate derivative 25 (entry 7; see Table S2 for
additional screening data).31
These optimized conditions were then employed with a
series of additional di(hetero)aryl hydrazone derivatives (Table
4). The innate reactivity of the diaryl diazomethane derivatives
can lead to relatively large differences between the NMR and
isolated yields. For example, benzophenone hydrazone affords
the corresponding diazo compound (24) in excellent in situ
yield (98% by NMR), but only 58% isolated yield (see the SI
for experimental detail). A similar outcome is observed upon
substitution of one of the aromatic rings with an electron-
donating p-OMe group (26: 89% NMR, 62% isolated yield).
Substrates bearing electron-withdrawing substituents are
particularly effective under these conditions, furnishing the
diazo compounds in excellent yield (27 and 28, 90 and 86%
isolated yield, respectively). This outcome likely reflects a
combination of factors, including the more acidic nature of the
N−H bonds of the hydrazone starting materials, which leads to
enhanced reactivity and increased stability of the diazo
products under the reaction conditions and during isolation.
Finally, benzoylpyridine-derived hydrazones were subjected to
the optimized reaction conditions and proceeded to the
corresponding diazo compounds in moderate to good yield
(29 and 30, 44 and 79% isolated yield, respectively),
demonstrating that Lewis basic heterocycles can be tolerated
in the substrates.
CONCLUSIONS
■
A new Cu-catalyzed method has been developed for aerobic
dehydrogenation of hydrazones to the corresponding diazo
compounds. The catalyst is entirely composed of low-cost,
commercially available materials, and the reaction proceeds
very efficiently at room temperature or below with ambient air
as the source of the oxidant. React-IR and gas-uptake kinetic
studies provide valuable insights into the accelerating effect of
the pyridine in the reaction, which is proposed to arise from its
role as a base for the turnover-limiting proton-coupled
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a
Scheme 2. Tandem Oxidation Cyclopropanation
AUTHOR INFORMATION
Corresponding Authors
■
Shannon S. Stahl − Department of Chemistry, University of
Wisconsin-Madison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-9000-7665; Email: stahl@
chem.wisc.edu
Huw M. L. Davies − Department of Chemistry, Emory
University, Atlanta 30322, Georgia; orcid.org/0000-
0001-6254-9398; Email: hmdavie@emory.edu
Authors
Wenbin Liu − Department of Chemistry, Emory University,
Atlanta 30322, Georgia; orcid.org/0000-0001-8854-
8174
Jack Twilton − Department of Chemistry, University of
Wisconsin-Madison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0003-3500-4901
Bo Wei − Department of Chemistry, Emory University,
Atlanta 30322, Georgia
Maizie Lee − Department of Chemistry, Emory University,
Atlanta 30322, Georgia
Melissa N. Hopkins − Department of Chemistry, University of
Wisconsin-Madison, Madison, Wisconsin 53706, United
States
John Bacsa − Department of Chemistry, Emory University,
Atlanta 30322, Georgia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c00264
Author Contributions
W.L. and J.T. contributed equally. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
See the SI for experimental details. Yields of cyclopropanes shown
are isolated.
■
We thank members of the CCHF for helpful discussions,
especially Dr. Christopher W. Jones and Taylor A. Hatridge,
who are considering extending this system to flow, and Drs.
Cora MacBeth and Simon B. Blakey, who have been examining
a similar oxidation using cobalt catalysis. We thank Chase
Salazar (University of Wisconsin−Madison) for assistance with
gas-uptake measurements. Financial support for HMLD and
his group was provided by NSF under the CCI Center for
Selective C−H Functionalization (CHE-1700982), and
funding for SSS and his group was provided by the
Department of Energy (DE-FG02-05ER15690).
oxidation of the CuII-coordinated hydrazone substrate.
Inspired by these mechanistic studies, we extended the scope
of this method to the oxidation of diaryl hydrazones to access
diazo compounds, which cannot be prepared by diazo transfer,
utilizing a more basic pyridine co-catalyst. This method shows
exceptionally broad substrate scope and in contrast to many
traditional approaches enables access to multiple classes of
structurally diverse diazo compounds. The utility of this new
technology was further demonstrated by conducting hydrazone
oxidation in tandem with Rh-catalyzed cyclopropanation
without isolation of the diazo compound from the crude
reaction mixture. These results have important implications for
the practical utility of catalytic processes using diazo
compounds as synthetic intermediates. Further studies to
streamline this method for organic synthesis and extend its
utility in flow chemistry are on-going.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c00264.
Complete experimental procedures and compound
characterization (PDF)
́
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