Electrochemical desulfurative cyclization accessing oxazol-2-amine derivatives via intermolecular C?N/C?O bond formation

Article abstract of DOI:10.1021/acs.orglett.0c04218

A practical protocol has been established to access diverse oxazol-2-amine derivatives in one step via the electrochemical desulfurative cyclization of isothiocyanates and α-amino ketones. On the basis of the cycle of in situ generation of iodine/ desulfurative cyclization/iodide anion regeneration, the reaction is performed under metal-free and external-oxidant-free electrolytic conditions to achieve the formation of intermolecular C?O and C?N bonds, providing oxazol-2-amines in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.0c04218

pubs.acs.org/OrgLett
Letter
Electrochemical Desulfurative Cyclization Accessing Oxazol-2-amine
Derivatives via Intermolecular C−N/C−O Bond Formation
Jinhui Hu,* Huanliang Hong, Yongwei Qin, Yunfei Hu, Suyun Pu, Gen Liang, and Yubing Huang
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ABSTRACT: A practical protocol has been established to access
diverse oxazol-2-amine derivatives in one step via the electro-
chemical desulfurative cyclization of isothiocyanates and α-amino
ketones. On the basis of the cycle of in situ generation of iodine/
desulfurative cyclization/iodide anion regeneration, the reaction is
performed under metal-free and external-oxidant-free electrolytic
conditions to achieve the formation of intermolecular C−O and
C−N bonds, providing oxazol-2-amines in moderate to excellent yields.
Scheme 1. Synthesis of Oxazol-2-amine Derivatives via
Electrochemical Desulfurative Cyclization
xazoles contain O and N heteroatoms that have attracted
long-term attention due to their widespread presence in
O
natural products, pharmaceuticals,1 catalysts, and functional
materials. Among them, many molecules with an oxazol-2-amine
motif have shown pharmaceutical and therapeutic activities,
such as antituberculosis, antiviral, and analgesic activities.2,3
Although many efforts have been made for oxazole synthesis,4−8
the synthesis of valuable oxazol-2-amine derivatives is still rare.
Among transition-metal-catalyzed methods, the Buchwald−
Hartwig reaction5 is considered effective for oxazol-2-amine
preparation, which is achieved by the Pd-catalyzed arylation of
amines under a strong base. Additionally, the Au-catalyzed
heterocyclization of alkynes and nitriles has also been developed
for preparing oxazol-2-amines.6 Despite the high efficiency, the
use of noble-metal catalysts still has problems such as high cost
and residues in drug production. In recent years, the metal-free
synthesis of oxazol-2-amines has received great attention, and
some strategies have been implemented, including the multistep
conversion of isocyanide dichlorides7 and PPh3-mediated
cyclization reactions.3 Among them, the PPh3-mediated
cyclization between β-ketoazides and isothiocyanates often
occurs during the synthesis of oxazol-2-amine active molecules.
Recently, a two-step synthesis method of 2-amino-substituted
oxazoles with stoichiometric I2 as an oxidant was described
(Scheme 1a).8 To reduce the use of stoichiometric oxidants, it is
necessary to develop a facile and sustainable catalytic system to
achieve the efficient synthesis of oxazol-2-amines.
which will be regenerated at the anode after undergoing the
reaction cycle. Therefore, a smaller amount of iodide salt is
required in the electrochemical system. For example, Tang et al.
have synthesized various thiadiazoles using a catalytic amount of
iodine salts under electrolysis conditions.11 For the development
of environmentally friendly methods for oxazol-2-amines
synthesis, we propose a metal-free and external-oxidant-free
electrochemical strategy for the one-pot synthesis of oxazol-2-
amine derivatives from isothiocyanates and α-amino ketones via
desulfurative cyclization using nBu4NI as an electrolyte (Scheme
1b).
In a preliminary study, we selected phenyl isothiocyanate (1a)
and 2-aminoacetophenone hydrochloride (2a) as model
substrates to optimize the conditions (Table 1). To prevent
the intermediate from being hydrolyzed, electrolysis was
Carbon−heteroatom bonds, including C−O and C−N
bonds, are important moieties that exist in a variety of functional
heterocycles.9 With the development of electrochemical syn-
thesis, tremendous progress has been made in the formation of
carbon−heteroatom bonds.10 Electrochemical technology can
be used for heterocyclic synthesis by replacing the use of
stoichiometric oxidants with anodic oxidation. For iodine-
requiring heterocyclic synthesis reactions, the anodic oxidation
can convert the iodide ion to an iodine radical or cation in situ,
Received: December 21, 2020
Published: January 21, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04218
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1016−1020
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Letter
a b
,
basis of the above results, the optimized reaction conditions
were 0.5 equiv of nBu4NI and 2 equiv of Et3N in MeCN/MeOH
(1:1) under a constant current of 15 mA at 0 °C.
Table 1. Optimization of the Reaction Conditions
Under the optimized electrolysis conditions, we subsequently
investigated the substrate scope of thiocyanates for this
electrochemical desulfurative cyclization (Scheme 2). Gratify-
entry
variation from standard conditions
yield (%)
a
Scheme 2. Substrate Scope of Thiocyanates
1
none
86
2
3
4
5
6
7
8
9
10
11
12
13
14
15
MeCN or MeOH as solvent
35, 32
68, 77, 36
trace
trace
21
MeCN/MeOH (5:1, 2:1, or 1:2) as solvent
K2CO3 (2 equiv) instead of Et3N
KOtBu (2 equiv) instead of Et3N
DABCO (1 equiv) instead of Et3N
DBU (2 equiv) instead of Et3N
with E3N (1 or 0 equiv)
with nBu4NI (0.2 or 0 equiv)
with nBu4NI (0.2 equiv) and nBu4NPF6 (0.3 equiv)
nBu4NBr or nBu4NPF6 instead of nBu4NI
NH4I or KI instead of nBu4NI
graphite rod as anode
8
76, 0
39, 0
32
trace, 0
55, 38
13
10 mA, 3 h or 20 mA, 1.5 h
no electricity
69, 84
0
a
Reaction conditions: undivided cell, 1a (0.2 mmol), 2a (0.24 mmol),
Pt plates (1 cm × 1 cm) as anode and cathode, constant current = 15
mA, nBu4NI (0.5 equiv), Et3N (2 equiv), MeCN/MeOH (1/1 v/v, 2
b
mL), air, 0 °C, 2 h, Q = 5.6 F mol−1. Yield is determined by H
NMR analysis with CH2Br2 as the internal standard.
1
performed in an ice bath at 0 °C. Initially, the reaction was
electrolyzed in an undivided cell equipped with Pt plates as the
anode and cathode using nBu4NI as an electrolyte and Et3N as a
base in the solvent mixture MeCN/MeOH (1:1) under a
constant current of 15 mA. Satisfyingly, the desired product
(3aa) was detected in 86% yield after the reaction was
performed for 2 h (entry 1). In the process of condition
optimization, we found that using MeCN or MeOH as a solvent
could dramatically lower the yield of 3aa (entry 2). Because
slightly changing the ratio of MeCN and MeOH to 5:1, 2:1, or
1:2 led to a slight decrease in yield (entry 3), the use of the
solvent mixture MeCN/MeOH (1:1) was considered the best
chose. Subsequently, several bases were examined. Some
inorganic salts, including K2CO3 and KOtBu, were not suitable
for this electrochemical reaction due to their lower solubility
under low-temperature conditions (entries 4 and 5). Replacing
Et3N with a stronger organic base such as DABCO or DBU also
reduced the reaction efficiency (entries 6 and 7). Reducing the
amount of Et3N resulted in a slight decrease in yield, and no 3aa
was produced without the addition of Et3N (entry 8). A lower
yield was given when the amount of nBu4NI was decreased to 0.2
equiv, and no desired product was detected without the addition
a
Reaction conditions: undivided cell, 1 (0.5 mmol), 2a (0.6 mmol),
Pt plates (1 cm × 1 cm) as anode and cathode, constant current = 15
n
mA, Bu4NI (0.5 equiv), Et3N (2 equiv), MeCN/MeOH (1/1 v/v, 5
b
mL), air, 0 °C, 5 h, Q = 5.6 F mol−1. Isolated yields. Yield
determined by GC analysis with n-dodecane as the internal standard.
ingly, substrates with electron-rich substituents (methyl-, tbutyl-,
methoxy-, and trifluoromethoxy-) were well compatible with the
system, and the target products (3ba−3ea) were given in
moderate to excellent yields. Among them, the reaction of
thiocyanate containing a trifluoromethoxy proceeded smoothly
to give the oxazol-2-amine products (3ea) in a higher yield of
93%. Furthermore, thiocyanates with valuable substituents
(cyano-, trifluoromethyl-, and nitro-) or halogens (F, Cl, and
Br) underwent the reaction smoothly, and the corresponding
products (3fa−3ka) were delivered in good to excellent yields.
The reaction of benzyloxy-containing thiocyanate with 2-
aminoacetophenone hydrochloride gave 3la in a moderate
yield, probably due to the low solubility of the intermediate in
the system. The use of meta- or ortho-brominated phenyl
isothiocyanate produced the corresponding products (3ma and
3oa) in 85 and 87% yield, respectively, indicating that the steric
position of substituents had no significant effect on this
conversion. 2-Fluorophenyl isothiocyanate was also suitable
for electrolysis, and the desired product (3na) was obtained in
77% yield. Notably, disubstituted phenyl isothiocyanates were
n
of Bu4NI, which was probably affected by the electrolyte
concentration (entry 9). The addition of nBu4NPF6 (0.3 equiv)
as a supporting electrolyte did not increase the yield (entry 10),
n
n
and other electrolytes such as Bu4NBr and Bu4NPF6 were
proved to be ineffective (entry 11). These results indicated that
the concentration of iodide ions would affect the yield. Other
iodide salts could also be used for electrolysis to obtain the
desired product in moderate yields (entry 12). Electrode
examination showed that using a graphite rod as an anode could
seriously reduce the cyclization efficiency (entry 13). Neither
reducing nor increasing the current could increase the reaction
yield (entry 14). No product (3aa) was detected when the
reaction was performed without electricity (entry 15). On the
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all suitable substrates for this electrolysis (3pa−3ra). Among
them, the reaction provided oxazol-2-amine product (3pa) in a
yield of up to 95% when 3,5-ditrifluoromethyl phenyl
isothiocyanate was used as the substrate. Furthermore,
naphthalene ring and pyridine groups were also compatible
with the electrolysis conditions, and the corresponding products
(3sa and 3ta) were delivered in 87 and 76% yields, respectively.
However, only a trace of oxazol-2-amine product (3ua) was
detected when alkyl isothiocyanate was used as the substrate,
probably due to the poor stability of the corresponding
intermediate.
desulfurative cyclization (Scheme 4). When the reaction was
performed on a 5 mmol scale, the desired products 3aa was
Scheme 4. Scale-up Experiment
obtained in an isolated yield of 73%. Although the yield
decreased slightly in the scale-up experiment, the experimental
result still exhibited the application value of electrochemical
strategies in the synthesis of heterocycles.
Next, we turned our attention to investigate the substrate
scope of substituted 2-aminoacetophenone hydrochloride
(Scheme 3). Different substituents, including methyl-, me-
To investigate the mechanism involved in the electrochemical
intermolecular C−O and C−N formation in the synthesis of
oxazol-2-amines, several control experiments were then
conducted (Scheme 5). First, because of the observation of
Scheme 3. Substrate Scope of Substituted 2-
Aminoacetophenone Hydrochloride
a
Scheme 5. Control Experiments
the released elemental sulfur, we speculated that the reaction
required a desulfurization process. Subsequently, phenyl
isothiocyanate was replaced with 4-tolyl isocyanate as the
substrate for electrolysis under optimal conditions, and no
desired product 3ba was detected, except for a large amount of
methyl 4-methylbenzoate (eq a). Subsequently, 1a and 2a were
mixed in the presence of Et3N to form the thiourea intermediate
4aa, and the desired product 3aa was delivered in a 74% yield
after electrolysis, where the thiourea intermediate 4aa ([M +
H]+ = 271.0905) was confirmed by HRMS analysis (eq b).
These results proved that desulfurization cyclization was the key
step during the electrolysis process. We next added 1.5 equiv of
free-radical scavenger (BHT or TEMPO) to the optimal
electrolytic system, and the reaction gave 3aa in a yield of 68
or 73%, respectively (eqs c and d). When the amount of
TEMPO was increased to 4 equiv, the yield of 3aa decreased
slightly, probably because the TEMPO anion could form adduct
5 with 1a through nucleophilic addition and desulfurization
processes, wherein adduct 5 ([M + H]+ = 277.1910) was further
confirmed by the high-resolution mass spectrometry (HRMS)
analysis (eq d). Therefore, our electrochemical desulfurization
cyclization may not undergo a free-radical process.
a
Reaction conditions: undivided cell, 1a (0.5 mmol), 2 (0.6 mmol),
Pt plates (1 cm × 1 cm) as anode and cathode, constant current = 15
mA, nBu4NI (0.5 equiv), Et3N (2 equiv), MeCN/MeOH (1/1 v/v, 5
b
mL), air, 0 °C, 5 h, Q = 5.6 F mol−1. Isolated yields. Yield
determined by GC analysis with n-dodecane as the internal standard.
thoxy-, phenyl-, trifluoromethyl- and halo-, could be tolerated in
the electrochemical desulfurative cyclization. The reaction of the
para-methoxy-containing substrate exhibited a good yield of
83% (3ac), whereas the reaction of the para-methyl-containing
substrate gave 3ab in a moderate yield. The substrate with a large
conjugated group (Ph) was converted in moderate yield (3ad)
due to the low solubility of the intermediate. With the substrate
containing a trifluoromethyl substituent at the para position, the
reaction produced 3ae in up to 91% yield. When a halogen atom
was contained at the para position of the benzene ring, the target
products were isolated in moderate to good yields (3af−3ah).
Substrates containing a fluorine atom in the para or meta
position (3ah and 3ai) seemed to react better than those
containing a fluorine atom in the ortho position (3aj). The
naphthalene substrate (2k) could also be applied for electro-
chemical desulfurative cyclization and was converted to 3ak in
65% yield. In addition, when 2-amino-1-(4-fluorophenyl)-
propan-1-one was employed to react with phenyl isothiocyanate,
the desired product (3la) was detected in 12% yield.
To further investigate the reaction mechanism, cyclic
voltammetry (CV) experiments were also implemented, and
the results are recorded in Figure 1. Within the scanning window
n
(0−2 V), the CV of Bu4NI (curve b) showed two oxidation
The scale-up experiment was subsequently conducted to
demonstrate the practical utility of the electrochemical
signals at 0.78 and 1.17 V vs Ag/AgCl, responding to the
oxidation process of iodide ions in electrolysis. After the addition
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Letter
In conclusion, a novel synthesis of oxazol-2-amine derivatives
through the electrochemical desulfurative cyclization of
isothiocyanates and α-amino ketones has been established. A
series of substituted oxazol-2-amines are provided in moderate
to excellent yields under metal-free and external-oxidant-free
electrolytic conditions. The reaction is achieved through the
formation of intermolecular C−O and C−N bonds at low
temperatures based on the cycle of in situ generation of iodine/
desulfurative cyclization/iodide anion regeneration. Further-
more, the protocol is practical and environmentally friendly and
is characterized by simple electrolytic conditions and readily
available substrates. Further efforts are currently underway to
further expand the synthetic applications of oxazol-2-amine
derivatives.
Figure 1. Cyclic voltammograms of reactants and their mixtures in 0.05
n
M Bu4NPF6 solution in MeCN/MeOH (1:1): (a) background, (b)
ASSOCIATED CONTENT
* Supporting Information
■
nBu4NI (0.05 M), (c) nBu4NI (0.05 M) + Et3N (0.2 M), (d) 1a (0.1 M)
+ 2a (0.1 M), and (e) 1a (0.1 M) + 2a (0.1 M) + nBu4NI (0.05 M). The
voltammogram was obtained at a scan rate of 0.2 V/s with the Pt
electrode as a counter electrode, Ag/AgCl (saturated KCl) as a
reference electrode, and glassy carbon electrode as a working electrode.
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04218.
Details of complete experimental procedures, character-
ization data, and NMR spectra (PDF)
of Et3N, an oxidation peak appeared at 1.51 V vs Ag/AgCl in
curve c. The mixture of isothiocyanate (1a) and 2-amino-
acetophenone hydrochloride (2a) displayed no significant
oxidative peak (curve d). Different from curve d, the oxidation
peak was observed at 1.29 V vs Ag/AgCl in curve e due to the
AUTHOR INFORMATION
Corresponding Author
■
Jinhui Hu − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529090, P. R. China; orcid.org/
0000-0001-7924-1656; Email: wyuchemhjh@126.com
n
addition of Bu4NI. On the basis of the cyclic voltammetry
curves, we speculated that nBu4NI could promote the
desulfurative cyclization through the in situ formation of iodine
through anodization.
Authors
On the basis of the above experimental results, a plausible
mechanism is proposed in Scheme 6. Initially, thiourea
Huanliang Hong − School of Biotechnology and Health
Sciences, Wuyi University, Jiangmen 529090, P. R. China
Yongwei Qin − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529090, P. R. China
Yunfei Hu − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529090, P. R. China
Scheme 6. Proposed Mechanism
Suyun Pu − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529090, P. R. China
Gen Liang − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529090, P. R. China
Yubing Huang − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529090, P. R. China;
orcid.org/0000-0002-3025-8366
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04218
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Foundation of Guangdong Basic and Applied
Basic Research (2019A1515110516 and 2019A1515110266),
the Foundation for Young Talents (2019KQNCX159 and
2019KQNCX160), the Science Foundation for Young Teachers
of Wuyi University (pdjh2020a0595), and the National College
Students Innovation and Entrepreneurship Training Program
(201911349031, 202011349022, and 3344100114) for financial
support.
intermediate (A) is generated through the nucleophilic addition
of α-amino ketone (2) to isothiocyanate (1) at 0 °C in the
presence of a base. Meanwhile, an iodine molecule is formed on
a platinum electrode through the anodic oxidation of iodide
anions. Subsequently, the thiourea intermediate (A) undergoes
desulfurization under the promotion of an iodine molecule and a
base to form a carbodiimide intermediate (B)12 and release two
protons while regenerating the iodine anion. The isomerization
of carbodiimide intermediate (B) forms the enol intermediate
(C) followed by intramolecular cyclization to form the oxazol-2-
amine product (3). In addition, the released protons are reduced
to hydrogen on the platinum cathode.
REFERENCES
■
(1) (a) Harris, P. A.; Cheung, M.; Hunter, R. N., III; Brown, M. L.;
Veal, J. M.; Nolte, R. T.; Wang, L.; Liu, W.; Crosby, R. M.; Johnson, J.
1019
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Letter
H.; Epperly, A. H.; Kumar, R.; Luttrell, D. K.; Stafford, J. A. Discovery
and Evaluation of 2-Anilino-5-aryloxazoles as a Novel Class of VEGFR2
Kinase Inhibitors. J. Med. Chem. 2005, 48, 1610−1619. (b) Sriram, D.;
Yogeeswari, P.; Thirumurugan, R.; Pavana, R. K. Discovery of New
Antitubercular Oxazolyl Thiosemicarbazones. J. Med. Chem. 2006, 49,
3448−3450. (c) Chai, X.-X.; Cai, Z.-P.; Yang, M.-T.; Zhou, Y.; Fu, Y.-J.;
Xiong, Y.-Z. 2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives
as Potent Inhibitors of Chronic Myeloid Leukemia K562 Cells. Arch.
Pharm. 2016, 349, 523−531.
(2) (a) Bilodeau, M. T.; Rodman, L. D.; McGaughey, G. B.; Coll, K.
E.; Koester, T. J.; Hoffman, W. F.; Hungate, R. W.; Kendall, R. L.;
McFall, R. C.; Rickert, K. W.; Rutledge, R. Z.; Thomas, K. A. The
Discovery of N-(1,3-Thiazol-2-yl)pyridin-2-amines as Potent Inhib-
itors of KDR Kinase. Bioorg. Med. Chem. Lett. 2004, 14, 2941−2945.
(b) Ryu, H.; Choi, H.-K.; Kim, H. J.; Kim, A.-Y.; Song, J.-Y.; Hwang, S.-
G.; Kim, J.-S.; Kim, D.-U.; Kim, E.-H.; Kim, J.; Ahn, J. Antitumor
Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to
Abrogation of the DNA Damage Repair in Non-Small Cell Lung
Cancer Cells. Int. J. Mol. Sci. 2019, 20, 4728.
(3) (a) Dhar, T. G. M.; Guo, J.; Shen, Z.; Pitts, W. J.; Gu, H. H.; Chen,
B.-C.; Zhao, R.; Bednarz, M. S.; Iwanowicz, E. J. A Modified Approach
to 2-(N-Aryl)-1,3-oxazoles: Application to the Synthesis of the IMPDH
Inhibitor BMS-337197 and Analogues. Org. Lett. 2002, 4, 2091−2093.
(b) Perner, R. J.; Koenig, J. R.; DiDomenico, S.; Gomtsyan, A.;
Schmidt, R. G.; Lee, C.-H.; Hsu, M. C.; McDonald, H. A.; Gauvin, D.
M.; Joshi, S.; Turner, T. M.; Reilly, R. M.; Kym, P. R.; Kort, M. E.
Synthesis and Biological Evaluation of 5-Substituted and 4,5-
Disubstituted-2-arylamino Oxazole TRPV1 Antagonists. Bioorg. Med.
Chem. 2010, 18, 4821−4829.
(4) (a) Querard, P.; Girard, S. A.; Uhlig, N.; Li, C.-J. Gold-catalyzed
Tandem Reactions of Amide-Aldehyde-Alkyne Coupling and Cycliza-
tionsynthesis of 2,4,5-Trisubstituted Oxazoles. Chem. Sci. 2015, 6,
7332−7335. (b) Wu, X.; Geng, X.; Zhao, P.; Zhang, J.; Wu, Y.-d.; Wu,
A.-X. I2-Promoted Formal [3 + 2] Cycloaddition of α-Methylenyl
Isocyanides with Methyl Ketones: A Route to 2,5-Disubstituted
Oxazoles. Chem. Commun. 2017, 53, 3438−3441. (c) Han, X.-L.;
Zhou, C.-J.; Liu, X.-G.; Zhang, S.-S.; Wang, H.; Li, Q. Regioselective
Synthesis of 5-Aminooxazoles via Cp*Co(III)-Catalyzed Formal [3 +
2] Cycloaddition of N-(Pivaloyloxy)amides with Ynamides. Org. Lett.
2017, 19, 6108−6111. (d) Liao, L.; Zhang, H.; Zhao, X. Selenium-π-
Acid Catalyzed Oxidative Functionalization of Alkynes: Facile Access
to Ynones and Multisubstituted Oxazoles. ACS Catal. 2018, 8, 6745−
6750.
12045−12090. (c) Huang, H.; Cai, J.; Ji, X.; Xiao, F.; Chen, Y.; Deng,
G.-J. Internal Oxidant-Triggered Aerobic Oxygenation and Cyclization
of Indoles under Copper Catalysis. Angew. Chem., Int. Ed. 2016, 55,
307−311. (d) Bhunia, S.; Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D.
Selected Copper-Based Reactions for C−N, C−O, C−S, and C−C
Bond Formation. Angew. Chem., Int. Ed. 2017, 56, 16136−16179.
(e) Zhang, Z.; Chen, P.; Liu, G. Copper-mediated Intramolecular
Aminofluorination of 1,3-Dienes by Using Nucleophilic Fluorine
Reagents. Chem. Commun. 2018, 54, 8709−8712. (f) Huang, H.; Xu,
Z.; Ji, X.; Li, B.; Deng, G.-J. Thiophene-Fused Heteroaromatic Systems
Enabled by Internal Oxidant-Induced Cascade Bis-Heteroannulation.
Org. Lett. 2018, 20, 4917−4920. (g) Wang, Z.; Li, C.; Huang, H.; Deng,
G.-J. Elemental Sulfur-Promoted Aerobic Dehydrogenative Aromatiza-
tion of Cyclohexanones with Amines. J. Org. Chem. 2020, 85, 9415−
9423. (h) Zhou, S.; Zhang, G.; Fu, L.; Chen, P.; Li, Y.; Liu, G. Copper-
Catalyzed Asymmetric Cyanation of Alkenes via Carbonyl-Assisted
Coupling of Alkyl-Substituted Carbon-Centered Radicals. Org. Lett.
2020, 22, 6299−6303.
(10) (a) Yuan, Y.; Yu, Y.; Qiao, J.; Liu, P.; Yu, B.; Zhang, W.; Liu, H.;
He, M.; Huang, Z.; Lei, A. Exogenous-oxidant-free Electrochemical
Oxidative C−H Sulfonylation of Arenes/Heteroarenes with Hydrogen
Evolution. Chem. Commun. 2018, 54, 11471−11474. (b) Ye, Z.; Ding,
M.; Wu, Y.; Li, Y.; Hua, W.; Zhang, F. Electrochemical Synthesis of
1,2,4-Triazole-fused Heterocycles. Green Chem. 2018, 20, 1732−1737.
(c) Yang, Q.-L.; Xing, Y.-K.; Wang, X.-Y.; Ma, H.-X.; Weng, X.-J.; Yang,
X.; Guo, H.-M.; Mei, T.-S. Electrochemistry-Enabled Ir-Catalyzed
Vinylic C-H Functionalization. J. Am. Chem. Soc. 2019, 141, 18970−
18976. (d) Ruan, Z.; Huang, Z.; Xu, Z.; Mo, G.; Tian, X.; Yu, X.-Y.;
Ackermann, L. Catalyst-Free, Direct Electrochemical Tri- and
Difluoroalkylation/Cyclization: Access to Functionalized Oxindoles
and Quinolinones. Org. Lett. 2019, 21, 1237−1240. (e) Duan, Z.;
Zhang, L.; Zhang, W.; Lu, L.; Zeng, L.; Shi, R.; Lei, A. Palladium-
catalyzed Electro-oxidative C-H Amination toward the Synthesis of
Pyrido[1,2-a]benzimidazoles with Hydrogen Evolution. ACS Catal.
2020, 10, 3828−3831. (f) Wang, X.-Y.; Zhong, Y.-F.; Mo, Z.-Y.; Wu, S.-
H.; Xu, Y.-L.; Tang, H.-T.; Pan, Y.-M. Synthesis of Seleno Oxindoles via
Electrochemical Cyclization of N-Arylacrylamides with Diorganyl
Diselenides. Adv. Synth. Catal. 2021, 363, 208−214.
(11) (a) Mo, S.-K.; Teng, Q.-H.; Pan, Y.-M.; Tang, H.-T. Metal- and
Oxidant-free Electrosynthesis of 1,2,3-Thiadiazoles from Element
Sulfur and N-Tosyl Hydrazones. Adv. Synth. Catal. 2019, 361, 1756−
1760. (b) Zhang, Y.-A.; Ding, Z.; Liu, P.; Guo, W.-S.; Wen, L.-R.; Li, M.
Access to SCN-containing Thiazolines via Electrochemical Regiose-
lective Thiocyanothiocyclization of N-allylthioamides. Org. Chem.
Front. 2020, 7, 1321−1326. (c) Zhong, P.-F.; Lin, H.-M.; Wang, L.-
W.; Mo, Z.-Y.; Meng, X.-J.; Tang, H.-T.; Pan, Y.-M. Electrochemically
Enabled Synthesis of Sulfide Imidazopyridines via a Radical Cyclization
Cascade. Green Chem. 2020, 22, 6334−6339. (d) Li, J.-S.; Xie, X.-Y.;
Yang, P.-P.; Jiang, S.; Tao, L.; Li, Z.-W.; Lu, C.-H.; Liu, W.-D.
Electrochemical Synthesis of 1,2,4-Thiadiazoles through Intermolecu-
lar Dehydrogenative S−N Coupling. Adv. Synth. Catal. 2020, 362,
771−775.
(12) (a) Ali, A. R.; Ghosh, H.; Patel, B. K. A Greener Synthetic
Protocol for the Preparation of Carbodiimide. Tetrahedron Lett. 2010,
51, 1019−1021. (b) Duangkamol, C.; Pattarawarapan, M.; Phakhodee,
W. Ultrasonic-assisted Synthesis of Carbodiimides from N,N′-
Disubstituted Thioureas and Ureas. Monatsh. Chem. 2016, 147,
1945−1949.
(5) (a) Olsen, E. P. K.; Arrechea, P. L.; Buchwald, S. L. Mechanistic
Insight Leads to a Ligand Which Facilitates the PalladiumCatalyzed
Formation of 2-(Hetero)Arylaminooxazoles and 4-(Hetero)-
Arylaminothiazoles. Angew. Chem., Int. Ed. 2017, 56, 10569−10572.
(b) Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L. Breaking the
Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use
of a Common Soluble Base in C−N Coupling. J. Am. Chem. Soc. 2018,
140, 4721−4725. (c) Azzali, E.; Girardini, M.; Annunziato, G.; Pavone,
M.; Vacondio, F.; Mori, G.; Pasca, M. R.; Costantino, G.; Pieroni, M. 2-
Aminooxazole as a Novel Privileged Scaffold in Antitubercular
Medicinal Chemistry. ACS Med. Chem. Lett. 2020, 11, 1435−1441.
(6) Rassadin, V. A.; Boyarskiy, V. P.; Kukushkin, V. Y. Facile Gold-
Catalyzed Heterocyclization of Terminal Alkynes and Cyanamides
Leading to Substituted 2-Amino-1,3-Oxazoles. Org. Lett. 2015, 17,
3502−3505.
(7) Soeta, T.; Matsumoto, A.; Sakata, Y.; Ukaji, Y. Development of a
One-Pot Synthetic Method for Multifunctional Oxazole Derivatives
Using Isocyanide Dichloride. J. Org. Chem. 2017, 82, 4930−4935.
(8) Zhang, S.; Zhao, Q.; Zhao, Y.; Yu, W.; Chang, J. Synthesis of 2-
Amino Substituted Oxazoles from α-Amino Ketones and Isothiocya-
nates via Sequential Addition and I2-Mediated Desulfurative Cycliza-
tion. Adv. Synth. Catal. 2020, 362, 1993−1997.
(9) (a) Wu, W.; Jiang, H. Haloalkynes: A Powerful and Versatile
Building Block in Organic Synthesis. Acc. Chem. Res. 2014, 47, 2483−
2504. (b) Ouyang, K.; Hao, W.; Zhang, W.-X.; Xi, Z. Transition-Metal-
Catalyzed Cleavage of C−N Single Bonds. Chem. Rev. 2015, 115,
1020
https://dx.doi.org/10.1021/acs.orglett.0c04218
Org. Lett. 2021, 23, 1016−1020