Visible-Light-Mediated Hydroacylation of Azobenzenes with α-Keto Acids

Article abstract of DOI:10.1021/acs.orglett.0c03039

A visible-light-mediated protocol for the hydroacylation of azobenzenes with α-keto acids has been developed. In the absence of any catalyst or additive, decarboxylative hydroacylation proceeded smoothly under visible-light irradiation at room temperature. A wide range of azobenzenes and α-keto acids were well-tolerated and afforded hydroacylation products in high to excellent yields. Preliminary investigations indicated that photoactive azobenzenes absorb visible light to enable the transformation.

Full text of DOI:10.1021/acs.orglett.0c03039

pubs.acs.org/OrgLett
Letter
Visible-Light-Mediated Hydroacylation of Azobenzenes with α‑Keto
Acids
Jingya Yang,* Menghui Song, Hongyan Zhou, Ganggang Wang, Ben Ma, Yuanyuan Qi,
and Congde Huo*
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ABSTRACT: A visible-light-mediated protocol for the hydro-
acylation of azobenzenes with α-keto acids has been developed. In
the absence of any catalyst or additive, decarboxylative hydro-
acylation proceeded smoothly under visible-light irradiation at
room temperature. A wide range of azobenzenes and α-keto acids
were well-tolerated and afforded hydroacylation products in high to
excellent yields. Preliminary investigations indicated that photo-
active azobenzenes absorb visible light to enable the transformation.
Scheme 1. NN Bond Functionalization of Azobenzenes
and the Reactions with α-Keto Acids
zobenzene and its derivatives have been used in many
fields as organic dyes, food additives, photosensitive
A
materials, and biomolecules.1 Meanwhile, azobenzenes are
important synthetic intermediates used in modern organic
synthesis. In the past decades, using an azo moiety as a
directing group, azobenzenes were commonly employed to
realize ortho-C−H functionalization2 and the further synthesis
of some heterocyclic compounds, such as indazoles,3
phenazines4 and cinnolines.5 In addition, azobenzenes could
be converted to others valuable compounds via NN bond
cleavage.6 However, to the best of our knowledge, only a few
examples on the functionalization of the NN bond of
azobenzenes have been reported.7 In this context, Wang and
co-workers demonstrated the hydrophosphination of azoben-
zenes with diarylphosphine oxides (Scheme 1a).7a Subse-
quently, the Wang and Li group realized the N-methylation
and N-sulfonylation of azobenzenes with DMSO by using
inexpensive Fenton’s reagent (Fe2+/H2O2) (Scheme 1b).7b
Recently, upon exposure to visible light, the diboration of
azobenzenes with highly Lewis-acidic tetraaryldiborane (o-
tol)2BB-(o-tol)2 was achieved by Yamashita’s group.7c
Hydroacylation is an important transformation used to
synthesize carbonyl compounds.8 Therein, the hydroacylation
of CC,9 CO,10 and CN11 double bonds has been
extensively studied. As for azo compounds, the hydroacylation
of alkyl azodicarboxylates with aldehydes has been widely
investigated.12 In addition, the hydroalkylation of alkyl
azodicarboxylates with indoline-2-carboxylic acids has been
described.13 However, hydroacylation of stable azobenzenes is
rarely reported. In 2005, Murata and co-workers observed a
small amount of hydroacylated azobenzene as a byproduct of
the process of converting benzaldehyde to the corresponding
thiol ester, using azobenzene as an oxidant and thiazolium salt
as a catalyst.14
α-Keto acids have been widely reported as common reagents
to provide protic hydrogen and acyl radicals.15 For the reaction
of azobenzenes with α-keto acids, ortho-acylation has been
achieved by palladium catalysis or merging visible-light
Received: September 11, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03039
© XXXX American Chemical Society
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A

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a
Scheme 2. Scope of Symmetrical Azobenzenes
Figure 1. UV-vis absorption spectra in CH2Cl2 (1 mM).
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
light source
yield (%)
1
2
3
4
5
6
7
8
CH3OH
CH3CN
DMF
blue LED (15 W)
blue LED (15 W)
blue LED (15 W)
blue LED (15 W)
blue LED (15 W)
blue LED (15 W)
green LED (15 W)
white LED (15 W)
blue LED (7 W)
blue LED (3 W)
blue LED (20 W)
blue LED (30 W)
sunlight
21
87
trace
29
97
36
92
95
93
95
95
96
87
36
0
THF
CH2Cl2
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
c
9
d
10
e
11
f
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), CH2Cl2 (3 mL),
12
15 W blue LED, rt. Isolated yields are shown.
13
14
15
ambient light
−
−
we report the implementation of this visible-light-mediated
hydroacylation of azobenzenes with α-keto acids under
catalyst-free and mild conditions (Scheme 1d).
g
16
h
0
95
17
blue LED (15 W)
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), solvent (3 mL),
To assess the feasibility of the transformation, we used
azobenzene (1a) and benzoylformic acid (2a) as the model
substrates to investigate the reaction conditions (Table 1).
First, a variety of solvents was screened under 15 W blue LED
irradiation at room temperature (Table 1, entries 1−6). To our
delight, when the reaction was performed in dichloromethane
(DCM), the desired hydroacylation product 3aa was obtained
in the highest yield of 97% (Table 1, entry 5). Subsequently,
with DCM as the solvent, the light sources were examined
(Table 1, entries 7−14). Changing the light source to a 15 W
green or white LED, the reaction also proceeded well and
afforded 3aa in comparative yields (Table 1, entries 7 and 8).
By decreasing (or increasing) the power of light, a longer (or
shorter) time was required to complete the reaction (Table 1,
entries 9−12). Although the reaction could proceed under
sunlight or ambient light, 3aa was obtained in a lower yield
(Table 1, entries 13 and 14). In contrast, no reaction occurred
at all in darkness, even at elevated temperature, indicating that
light is crucial to this reaction (Table 1, entries 15 and 16). In
addition, performing the reaction under a nitrogen atmosphere
still afforded 3aa in a 95% yield, suggesting that oxygen is not
involved in this reaction (Table 1, entry 17).
b
c
d
e
f
g
h
rt, 24 h. Isolated yields. 28 h. 30 h. 22 h. 18 h. 80 °C. Under
N2.
photocatalysis and palladium catalysis, where the azo moiety
acts as a directing group (Scheme 1c).2f,15b,c However, the
hydroacylation of azobenzenes with α-keto acids has not yet
been disclosed.
Over the past few decades, visible-light-promoted reactions
have attracted widespread attention and have been rapidly
developed for organic synthesis.16 As we know, azobenzenes
exhibited important photochemical and electrochemical
behaviors under light irradiation to enable the corresponding
reactions through electron transfer.17 Therein, azobenzene
radical cations or radical anions were generated via an electron
transfer process between azobenzenes and the electron
acceptors or electron donors. We examined the ultraviolet−
visible (UV-vis) absorption spectra of azobenzene (1a),
benzoylformic acid (2a), and their mixture, and we found
that the absorption spectrum of azobenzene extended to the
visible region (Figure 1). Therefore, based on our previous
research foundation of visible-light-promoted reactions,18 we
assume that azobenzenes can directly react with α-keto acids
under visible-light irradiation to achieve hydroacylation. Here,
With the optimal reaction conditions in hand, we then
investigated the substrate scope. First, a series of symmetrical
B
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a
a
Scheme 3. Scope of Unsymmetrical Azobenzenes
Scheme 4. Scope of α-Keto Acids
a
Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), CH2Cl2 (4.5
mL), 15 W blue LED, rt, 30 h. Isolated yields are shown.
Figure 2. X-ray crystal structure of 3ta (CCDC 2027365).
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), CH2Cl2 (3 mL),
azobenzenes were subjected to the reaction with benzoylformic
acid (2a) (Scheme 2). Generally, azobenzenes with either an
electron-donating or electron-withdrawing group on the
benzene ring at the para-, meta-, or ortho-position delivered
the corresponding products 3aa−3na in high yields. Notably, a
slightly longer reaction time was required for para-trifluor-
omethyl (3ha) and meta-electron-withdrawing group sub-
stitution to occur on the azobenzenes (3ka−3ma) to complete
the reaction. Moreover, disubstituted azobenzene was also a
potent substrate, delivering the target product 3oa in a 91%
yield.
Next, various unsymmetrical azobenzenes were also
examined by the reaction with 2a (see Scheme 3). When 4-
methyl- and 4-tert-butyl-substituted azobenzenes (1p and 1q)
were used, an inseparable mixture of the hydroacylation
products was obtained in high total yields (94% and 92%).
Other unsymmetrical azobenzenes (1r−1w) bearing methoxyl,
halogen, ester, cyano, or nitro groups on the phenyl ring at the
para-position facilely reacted and afforded isolated re-
gioisomers with varied regioselectivities. In addition, the
structure of product 3ta was further confirmed by single-
crystal X-ray crystallographic analysis (Figure 2).
15 W blue LED, rt. Isolated yields are shown.
Scheme 5. Gram-Scale Synthesis
Moreover, the scope of α-keto acids was investigated, as
illustrated in Scheme 4. The substituted benzoyl formic acids
2b−2o were efficiently converted to the corresponding
products 3ab−3ao in high yields (79%−96%) under the
standard conditions. Moreover, 2-naphthyl and 2-thienyl α-
keto acids (3ap and 3aq) also underwent the reaction
smoothly. In addition, aliphatic α-keto acids were viable to
the established method, leading to the products 3ar−3at in
30%−90% yields.
To demonstrate the practicability of the established method,
a gram-scale reaction of 1a and 2a was conducted (Scheme 5).
The reaction proceeded smoothly under the standard
C
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irradiation. Excited 1a* interacts with benzoylformic acid 2a
through single electron transfer, leading to the oxidative
decarboxylation of 2a, to give radical anion A17b,19 and acyl
radical B. Radical anion A then combines with acyl radical B to
form the anion intermediate C. Finally, the protonation of
anion C affords the desired product 3aa. However, the
possibility of protonation first and then radical coupling cannot
be ruled out.
Scheme 6. Control Experiments
In conclusion, we have developed a visible-light-mediated
protocol for the hydroacylation of azobenzenes with α-keto
acids. The hydroacylation reaction was facilely completed
under direct visible-light irradiation at room temperature. A
variety of azobenzenes and α-keto acids were well-tolerated
and delivered the corresponding products in yields up to 97%.
No external catalyst or additive was employed, and CO2 is the
only byproduct. Light is crucial to excite the photoactive
azobenzene, which is the key to enabling the reaction. Other
visible-light-promoted reactions of azobenzenes for NN
bond functionalization are under investigation in our
laboratory.
Scheme 7. Plausible Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03039.
Experimental procedures, characterization data, and
copy of NMR spectra (PDF)
Accession Codes
CCDC 2027365 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: + 44 1223 336033.
conditions to afford the desired product 3aa in a 91% isolated
yield (1.31 g) after 36 h.
To gain insight into this visible-light-mediated trans-
formation, several control experiments were conducted
(Scheme 6). First, when the radical scavenger 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) was added, the
reaction was significantly inhibited, only a trace amount of
3aa was observed, and a TEMPO-trapped acyl radical was
detected by high-resolution mass spectroscopy (HRMS)
(Scheme 6, eq 1). These findings suggest that the reaction
might proceed by involving a radical process. Subsequently,
using sodium 2-oxo-2-phenylpropanoate to replace benzoyl-
formic acid 2a, no reaction occurred at all (Scheme 6, eq 2).
Nevertheless, when trifluoroacetic acid (TFA) was added into
the reaction system of sodium 2-oxo-2-phenylpropanoate and
azobenzene, the target product 3aa was obtained in a yield of
78% (Scheme 6, eq 3). These results indicate that the proton
in the target product 3 comes from α-keto acid 2. In addition,
the excited-state potential of 1a [E(1a*/1a• −) = 1.19 V vs
SCE in CH2Cl2] and the oxidation peak potentials of 2a (1.08
V vs SCE in CH2Cl2) were obtained based on electrochemical
and spectroscopic data (see the Supporting Information). This
demonstrates that excited 1a* can readily oxidize 2a.
Meanwhile, an on−off experiment was conducted, and the
result ruled out a chain-propagation-type mechanism (see the
Supporting Information).
AUTHOR INFORMATION
Corresponding Authors
■
Jingya Yang − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China;
orcid.org/0000-0002-7419-5133; Email: yangjy@
nwnu.edu.cn
Congde Huo − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China;
orcid.org/0000-0002-3374-7931;
Email: huocongde1978@hotmail.com
Authors
Menghui Song − College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou 730070,
China
Hongyan Zhou − College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou 730070,
China; College of Science, Gansu Agricultural University,
Lanzhou 730070, China
Ganggang Wang − College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou 730070,
China
Based on the experimental results and literature prece-
dents,17,19 we propose a plausible reaction mechanism, as
depicted in Scheme 7. First, photoactive azobenzene 1a is
excited to its excitation state 1a*,7b,17 under visible-light
Ben Ma − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China
Yuanyuan Qi − College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China
D
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03039
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21961035, 22061001, and 21901213), the Program for
Improving Scientific Research Ability of Young Teachers of
Northwest Normal University (Nos. NWNU-LKQN-17-3 and
NWNU-LKQN-18-22), and the Gansu International Scientific
and Technological Cooperation Base of Water-Retention
Chemical Functional Materials for financial support.
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