Photoredox Catalysis Enables Decarboxylative Cyclization with Hypervalent Iodine(III) Reagents: Access to 2,5-Disubstituted 1,3,4-Oxadiazoles

Article abstract of DOI:10.1021/acs.orglett.0c03663

A novel approach to 2,5-disubstituted 1,3,4-oxadiazoles derivatives via a decarboxylative cyclization reaction by photoredox catalysis between commercially available α-oxocarboxylic acids and hypervalent iodine(III) reagent is described. This powerful transformation involves the coupling reaction between two different kinds of radical species and the formation of C-N and C-O bonds.

Full text of DOI:10.1021/acs.orglett.0c03663

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Letter
Photoredox Catalysis Enables Decarboxylative Cyclization with
Hypervalent Iodine(III) Reagents: Access to 2,5-Disubstituted 1,3,4-
Oxadiazoles
Jian Li,* Xue-Chen Lu, Yue Xu, Jin-Xia Wen, Guo-Quan Hou, and Li Liu*
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ABSTRACT: A novel approach to 2,5-disubstituted 1,3,4-oxadiazoles
derivatives via a decarboxylative cyclization reaction by photoredox
catalysis between commercially available α-oxocarboxylic acids and
hypervalent iodine(III) reagent is described. This powerful trans-
formation involves the coupling reaction between two different kinds
of radical species and the formation of C−N and C−O bonds.
Scheme 1. Synthetic Strategies of 1,3,4-Oxadiazoles
1,3,4-Oxadiazoles are important nitrogen-containing hetero-
cycles and building blocks that exhibit versatile biological
properties in medicinal chemistry.1 Among 1,3,4-oxadiazole,
the 2,5-disubstituted 1,3,4-oxadiazole derivatives are a
particularly important core in pharmaceutical chemistry
because of their role as a bioisosteric replacement of ester,
amide, and acid functionalities.2 Consequently, the develop-
ment of methodologies for the synthesis of the 2,5-
disubstituted 1,3,4-oxadiazole scaffold is of importance for
drug discovery and represents a worthwhile goal of organic
chemistry. Many elegant synthetic approaches have been
developed.3 Generally, methods for preparing 1,3,4-oxadiazole
rely on the oxidative cyclization of N-acylhydrazones4 or
dehydrative cyclization of 1,2-diacylhydrazines.5 For example,
to promote the oxidative cyclization of N-acylhydrazones
(Scheme 1), a number of cyclodehydration systems have been
used including Fe(III)/TEMPO,6 I2/K2CO3,7 Cu(OTf)2,8 and
isobutylaldehyde/O2/PhI.9 Recently, several elegant ap-
proaches for their synthesis have been disclosed. In 2015,
Das reported a copper(II) oxide nanoparticle catalyzed
coupling reaction between 1,3,4-oxadiazoles with alkenyl or
aryl halides for the synthesis of 2-alkenyl- and 2-aryl-1,3,4-
oxadiazoles.10 Subsequently, He et al. demonstrated a metal-
and base-free one-pot reaction to assemble 2,5-diaryl 1,3,4-
oxadiazoles through N-acylation of aryl tetrazoles with aryl
aldehydes/thermal rearrangement.11
generally available in nature, have offered unconventional
access to various organic transformations.13 α-Oxocarboxylic
acids (glyoxylic acids) are a special class of versatile synthetic
intermediates, and they were extensively utilized as environ-
Received: November 4, 2020
The decarboxylative-cross-coupling reactions have been
employed as an effective approach in organic synthesis to
forge biologically potent molecules.12 The radicals generated
from decarboxylation of carboxylic acid derivatives, which are
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Letter
mentally benign acyl surrogates.14 A variety of elegant cross-
coupling reactions involving radicals process have been
developed by employing glyoxylic acids. To achieve acyl
radicals from the acids, silver catalysts have been commonly
utilized to trigger the decarboxylation.15 Despite great
progress, these protocols are limited by the requirement of
expensive and nonsustainable catalysts for practical use in
organic synthesis.16 Therefore, developing alternative methods
to achieve acyl radicals via metal-free catalyst mediated
decarboxylation of α-oxocarboxylic acid is highly desirable.
Recently, direct decarboxylation of α-ketoacids to generate acyl
radicals via photoredox catalysis has been extensively
investigated for the cross-coupling reactions.17 However, the
photoredox cyclization of α-oxocarboxylic acid to prepare
heterocyclic compound has rarely been reported. In this work,
we demonstrate a photoredox catalyzed strategy for the
synthesis of 2,5-disubstituted 1,3,4-oxadiazole by direct
benzoyl radical addition to hypervalent iodine(III) reagent
benziodoxolone 1, which is decorated with a hypervalent
iodine moiety [I(III)(Ar)(OTf)] and a diazo functionality (
N2).18
In 2018, the Suero group described the first catalytic
generation of diazomethyl radicals by means of photoredox
catalysis.19 We questioned whether the radicals might be
captured by other radical species. Considering the generation
of acyl radicals from the decarboxylation of α-ketoacids by
photoredox catalysis, we anticipated that the radical coupling
would happen catalyzed by photoredox catalysis and enable a
novel route to diazo compounds. In order to address the
challenges for the synthesis of diazo compounds, we started
our preliminary research. We chose hypervalent iodine reagent
1 and benzoyl formic acid 2a as model substrates (Table 1).
Initially, Ru(bpy)3(PF6)2 was utilized as the catalyst and
dichloromethane (DCM) as the solvent, and the reaction
mixture was irradiated with blue light at room temperature.
Unexpectedly, we did not observe the diazo product we
expected, but cyclized product ethyl 5-phenyl-1,3,4-oxadiazole-
2-carboxylate 3a was found in 36% yield (Table 1, entry 1).
Subsequently, our study focused on the cross-coupling of
hypervalent iodine reagent and α-ketoacids for the synthesis of
1,3,4-oxadiazole. We screened some metal photocatalysts
(Table 1, entries 2, 3); however, no superior results were
achieved when Ru(bpy)3(PF6)2 was replaced by Ru(bpy)3Cl2
(14%) and Ir(ppy)3 (8%). Other organic photocatalysts were
examined for this transformation, such as rhodamine B, eosin
Y, 4CzPN, 4CzIPN, 4CzTPN, and DCA (entries 4−9).
Among these catalysts, relatively higher yield was acquired
when 4CzPN was utilized, instead of Ru(bpy)3(PF6)2,
delivering the product in 33% yield (entry 6). The result was
quite motivating for further optimization of the reaction
conditions to obtain high yields of the desired 1,3,4-oxadiazole.
Next, several other solvents were tested (entries 10−15), such
as CH3CN, 1,4-dioxane, THF, CH3OH, DMSO, and DCE.
However, no better result was obtained than DCM. The light
source was also investigated, the reaction proceeded under 15
W white LED irradiation, which increased the yield of the
target product 3a to 45% (Table 1, entry 16). To increase the
efficency of the reaction, we explored the varying amounts of
hypervalent iodine(III) reagent benziodoxolone 1 from 1.2 to
2.0 equiv (Table 1, entries 18−20). It was observed that 1.5
equiv was identified as an optimum loading, which afford the
desired product 3a in 68% yield (Table 1, entry 19).
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
LED
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
solvent
DCM
yield (%)
1
2
3
4
5
6
7
8
Ru(bpy)3(PF6)2
Ru(bpy)3Cl2
Ir(ppy)3
Rhodamine B
Eosin Y
4CzPN
4CzIPN
4CzTPN
DCA
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
4CzPN
36
14
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CH3CN
1,4-dioxane
THF
CH3OH
DMSO
DCE
DCM
DCM
DCM
DCM
DCM
7
33
11
13
8
9
10
11
12
13
14
15
16
17
23
10
45
32
52
68
61
White
sunlight
white
white
white
c
18
d
19
e
20
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), catalyst (0.01
mmol), rt, light, 5 h. Isolated yield. 1 (0.6 mmol), 2a (0.5 mmol).
1 (0.75 mmol), 2a (0.5 mmol). 1 (1.0 mmol), 2a (0.5 mmol).
4CzIPN: 2,4,5,6-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene,
4CzTPN: 1,2,4,5-tetrakis(car-bazol-9-yl)-3,6-dicyanobenzene,
4CzPN: 1,2,3,4-tetrakis(carbazol-9-yl)-5,6-dicyanobenzene.
b
c
d
e
With the above optimized conditions in hand, we started to
explore the versatility and limitations of the method. Through
the observation of the reaction of various benzoyl formic acids,
the corresponding monosubstituted oxadiazole compounds
were collected in moderate to good yields, and the result is
summarized in Scheme 2. Generally, α-oxocarboxylic acids
containing substituents of varying electronic character (such as
donating or withdrawing) and steric demand (such as para-,
meta-, and ortho-) were smoothly transformed to afford the
desired oxadiazole derivatives 3a−3z and 3aa in 40−97%
yields. It was observed that the functional groups such as
halogen (F, Cl, and Br) were satisfactorily compatible with the
reaction conditions, furnishing products 3b−3d in 86−91%
yields. In addition, a range of aromatic α-ketoacids bearing
either various electron-donating (e.g., Me, Et, n-Pr, n-Bu,
MeO) or electron-withdrawing (e.g., CF3, CN) groups at the
para-position of the phenyl ring proceeded smoothly,
providing the corresponding products 3e−3l with yields in
the range of 81−97%. The structure of compound 3l was
confirmed by the X-ray diffraction analysis. Moreover, as
shown in the reactions of 3p−3r, the substrates, featuring the
functionalized special ether groups such as long-chain alkane
(2p), acrylic (2q), and propyne (2r), also participated in the
process, affording the target compounds in 88−93% yields.
Furthermore, the meta-substituted (3s−3v) and ortho-sub-
stituted substrates (3w−3z, 3aa) were also amenable to this
transformation, providing the oxadiazole products in decent
B
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a,b
phenyl rings also proceeded smoothly to produce 3ab−3ai
with satisfactory yields. Notably, this approach could be
successfully expanded to the naphthyl substrate, and 2-
(naphthalen-2-yl)-2-oxoacetic acid participated in the reaction
smoothly, leading to ethyl 5-(naphthalen-2-yl)-1,3,4-oxadia-
zole-2-carboxylate 3ai in 68% yield.
Scheme 2. α-Oxocarboxylic Acid Scope
To demonstrate the feasibility of this protocol, we carried
out the reaction with ethyl 5-phenyl-1,3,4-oxadiazole-2-
carboxylate 3a and phenylmethanamine 4a in EtOH at reflux
for the preparation of N-benzyl-5-phenyl-1,3,4-oxadiazole-2-
carboxamide 5a in 97% yield (Scheme 4). The same strategy
Scheme 4. Product Application
could be achieved with piperidine, and (5-phenyl-1,3,4-
oxadiazol-2-yl)(piperidin-1-yl)methanone 5b was obtained in
45% yield. Thus, this method provided a convenient approach
to these 2,5-disubstituted 1,3,4-oxadiazole skeleton drugs and
candidates, such as AZD1979, which is a melanin-concentrat-
ing hormone receptor 1 (MCHr1) antagonist with favorable
physicochemical properties.20
The decarboxylation of α-ketoacids by photoredox catalysis
usually complete through the free-radical course. In order to
gain an understanding of the reaction mechanism, we
performed the following controlled experiments (Scheme 5).
a
Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), 4CzPN (0.01
b
mmol), rt, white LED, 5 h. Isolated yield.
yields. However, the steric effect could not be forgotten; when
the ortho-position of the substrates was substituted, the
reaction showed decreased reactivity (3w 58%, 3x 43%, 3y
62%, 3z 49%, and 3aa 40%). Unfortunately, no reactions were
observed when the heterocyclic or aliphatic α-oxocarboxylic
acids were used (3A−3C).
Next, we continued to evaluate the generality of this
decarboxylative cyclization by using disubstituted benzoyl
formic acids. As shown in Scheme 3, the reactions of the α-
oxocarboxylic acids with either 2,4-, 3,4-, or 2,5-disubstituted
Scheme 5. Control Experiment
a,b
Scheme 3. Other Substrates for the Cyclization
Initially, TEMPO (2,2,6,6-tetramethylpiperidinyloxyl; 1 equiv)
was added to the reaction system between 2a and 1 under
standard conditions, but no corresponding 1,3,4-oxadiazole
product 3a was detected. Subsequently, several alternative
radical quenchers, such as ethene-1,1-diyldibenzene, were
investigated under our optimum reaction conditions, and the
oxadiazole product 3a was not obtained. It suggests that a
radical pathway should be involved. Ethyl 2-diazoacetate was
not involved in this reaction by the experiment between 2a and
a
Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), 4CzPN (0.01
b
mmol), rt, white LED, 5 h. Isolated yield.
C
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ethyl 2-diazoacetate. The light on/off experiment of the model
reaction further verified this statement (Scheme 6).
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
Scheme 6. Time Profile Experiment
CCDC 2021425 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, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Jian Li − Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, School of Pharmacy, Changzhou
University, Changzhou 213164, China; orcid.org/0000-
0001-6713-1302; Email: lijianchem@cczu.edu.cn
Li Liu − Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, School of Pharmacy, Changzhou
University, Changzhou 213164, China; Email: liliu@
cczu.edu.cn
On the basis of the mechanistic investigations described
above and related literature,19,21 a plausible reaction mecha-
nism is depicted for the formation of compounds 3 in Figure 1.
Authors
Xue-Chen Lu − Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, School of Pharmacy, Changzhou
University, Changzhou 213164, China
Yue Xu − Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, School of Pharmacy, Changzhou
University, Changzhou 213164, China
Figure 1. Possible mechanistic pathways.
Jin-Xia Wen − Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, School of Pharmacy, Changzhou
University, Changzhou 213164, China
Guo-Quan Hou − Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology, School of Pharmacy,
Changzhou University, Changzhou 213164, China
Initially, 4CzPN can be excited by white light-emitting diode
irradiation to afford *4-CzPN. The excited *4-CzPN is
reductively quenched by benzoyl formic acid, leading to a
benzoyl cation radical A and the reductive species 4CzPN•−.
Then, the benzoyl radical B would be formed by CO2
extrusion from A. On the other hand, species 4CzPN•−
would be oxidized by hypervalent iodine(III) reagent 1 to
generate the radical N2C(•)−CO2Et (intermediate C),
which has been proposed to form D by resonance. Both acyl
radical and diazo radical would likely coexist within our
reaction conditions. Consequently, a direct radical coupling
between benzoyl radical B and diazo radical D would provide
intermediate E, which could be transformed into the target
compound 3a.
In conclusion, a concise and efficient strategy has been
developed for the construction of a 2,5-disubstituted 1,3,4-
oxadiazoles by a direct cyclization reaction between hyper-
valent iodine(III) reagent and α-ketoacids by photoredox
catalysis. This powerful transformation involves the coupling of
two different kinds of radical reaction. Furthermore, this
cascade cyclization strategy allows the formation of C−N bond
and C−O bond. Applying this methodology, an easy synthesis
of 2,5-disubstituted 1,3,4-oxadiazoles has been accomplished
without a multiple-step process in good to excellent yields
under simple reaction conditions. Further investigation of
synthetic applications and a mechanism for the reaction is
currently underway in our laboratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03663
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21402013), Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology (BM2012110), and
Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center in Changzhou University.
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