Perylenequinonoid-Catalyzed [4 + 1] and [4 + 2] Annulations of Azoalkenes: Photocatalytic Access to 1,2,3-Thiadiazole/1,4,5,6-Tetrahydropyridazine Derivatives

Article abstract of DOI:10.1021/acs.joc.9b00545

Nitrogen-containing heterocycles are especially considered "privileged" structural scaffolds for the development of new drugs. However, traditional methods of organic synthesis are mainly based on thermal cycloaddition reaction; thus, the exploration of n

Full text of DOI:10.1021/acs.joc.9b00545

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Perylenequinonoid-Catalyzed [4 + 1] and [4 + 2] Annulations of
Azoalkenes: Photocatalytic Access to 1,2,3-Thiadiazole/1,4,5,6-
Tetrahydropyridazine Derivatives
Yan Zhang,*,† Yuan Cao,† Liushen Lu,‡ Shiwei Zhang,† Wenhao Bao,‡ Shuping Huang,§
and Yijian Rao*,‡
‡
†School of Pharmaceutical Science and Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education,
School of Biotechnology, Jiangnan University, Wuxi 214122, P. R. China
§College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, P. R. China
S
* Supporting Information
ABSTRACT: Nitrogen-containing heterocycles are especially
considered “privileged” structural scaffolds for the develop-
ment of new drugs. However, traditional methods of organic
synthesis are mainly based on thermal cycloaddition reaction;
thus, the exploration of new strategies for the rapid assembly
of N-heterocycles under mild conditions is highly desirable.
Here, we developed a new method that visible light along with 1 mol % cercosporin, which is one of the perylenequinonoid
pigments with excellent properties of photosensitization and can be easily produced by a new isolated endophytic fungus
Cercospora sp. JNU001 strain with high yield through microbial fermentation, catalyzes the synthesis of 1,2,3-thiadiazoles and
1,4,5,6-tetrahydropyridazines by a photocatalytic process with good regioselectivity and broad functional-group compatibility
under mild conditions. Thus, a bridge between microbial fermentation and organic photocatalysis for the construction of
nitrogen-containing heterocycles was set up in a sustainable, environmentally friendly manner.
research effort has been devoted to development of elegant and
creative strategies to construct these nitrogen heterocycles, of
which most methods are based on thermal cycloaddition
reactions.4 Owing to energy shortage and environmental
pollution, the utilization of solar energy as a sustainable and
renewable energy resource to drive synthetic transformations
has become a hotspot in green chemistry.5 Additionally,
photocatalysis has been recognized as a useful routine6 with
the generation of various reactive species under mild
conditions, frequently without stoichiometric activation
reagents.7 To date, azoalkenes (1,2-diaza-1,3-dienes),8 power-
ful and versatile four-unit intermediates, have seldom been
employed as synthons in photocatalytic annulations by using
metal-based Ru(bpy)3Cl2 as the photocatalyst with high
efficiency for radical cyclization of α-halogeno hydrazine with
β-ketocarbonyls,9 whereas metal-free photocatalyst eosin Y
showed only 7% yield. Compared with transition-metal-based
photocatalysts, metal-free photocatalysts exhibit more environ-
mentally friendly properties.6d,e Therefore, the exploration of
new strategies or new catalysts to develop greener method-
ologies for the rapid assembly of N-heterocycles based on
metal-free photocatalysis is highly desirable.
INTRODUCTION
■
Nitrogen-containing heterocycles are the most abundant and
integral scaffolds that frequently occur in bioactive natural
products, synthetic agrochemicals, and pharmaceuticals.1
Among them, 1,2,3-thiadiazoles2 and 1,4,5,6-tetrahydropyr-
idazines3 are privileged and valuable N−N-bond-containing
heterocyclic scaffolds and serve as versatile intermediates in
organic synthesis (Figure 1). In most cases, they demonstrate
diverse pharmacological activities owing to their substitution
patterns and function groups. Consequently, a great deal of
Naturally occurring perylenequinonoid pigments (PQPs),
such as cercosporin (CP),10 hypocrellin,11 elsinochrome,12 and
phleichrome13 (Figure 2), produced by endophytic fungi, have
Figure 1. Biologically active 1,2,3-thiadiazole and 1,4,5,6-tetrahy-
dropyridazine derivatives.
Received: February 25, 2019
Published: May 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
source and C−S/S−N bond formation in one pot was realized
with cercosporin as a photocatalyst, which was produced by a
new isolated endophytic fungus Cercospora sp. JNU001 strain
with high yield through microbial fermentation (Supporting
Information). Initially, α-bromo-N-benzoyl-hydrazone 1a was
employed as the model substrate to react with potassium
thiocyanate (KSCN) 2 in the presence of CP (1 mol %) and
K2CO3 (1.2 equiv) in 2.0 mL of MeCN with the photo-
irradiation of 5 W blue LED at room temperature under an O2
atmosphere. Gratifyingly, the desired product 3a was given in
50% yield after 16 h of irradiation (Table 1, entry 1). Then,
a
Table 1. Optimization of Reaction Conditions
Figure 2. Representatives of the naturally occurring mold
perylenequinones.
b
entry
photocatalyst
base
solvent
yield (%)
aroused considerable attention owing to their excellent
properties of photosensitization, which function as new
potential compounds in photodynamic therapy and photo-
physical diagnosis.11a,14 These photosensitizers can be
activated to excited state by visible light absorption and then
undergo energy transfer (EnT) and electron transfer
(ET),10e,11c,14a,15 implying that these natural product PQPs
can be used as “metal-free” photocatalysts for organic
synthesis, but have never been investigated.15
Herein, we report an unprecedented photocatalytic [4 + 1]
annulation of azoalkenes with thiocyanate salt as the “S” source
and [4 + 2] cyclodimerization of azoalkenes. It afforded 1,2,3-
thiadiazoles and 1,4,5,6-tetrahydropyridazines with excellent
yields under mild reaction conditions by using one of the
naturally occurring PQPs cercosporin (CP) as a metal-free
photocatalyst. Notable features of our finding include (a) a
natural product cercosporin as an organic photocatalyst for
synthesis of N-heterocycles, (b) mild reaction conditions and
broad substrate scope, and (c) great conversions of substrates
in the gram-scale reactions (Scheme 1).
1
2
3
4
5
6
7
8
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
hypocrellin A
hypocrellin B
cercosporin
cercosporin
K2CO3
KOH
tBuOK
Cs2CO3
DBU
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
CHCl3
DMSO
toluene
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50
62
88
72
59
49
38
65
trace
21
12
25
82
trace
trace
trace
trace
69
9
10
11
12
13
14
15
16
17
18
c
tBuOK
tBuOK
tBuOK
tBuOK
d
cercosporin
cercosporin
cercosporin
e
f
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), photocatalyst (1
mol %), base (0.24 mmol), solvents (2.0 mL), 5 W blue LEDs, 16 h,
at room temperature under an O2 atmosphere. Isolated yield.
NaSCN was used as the S source. Without visible light irradiation.
The reaction was conducted in Ar. Performed with 0.5 mol % of
cercosporin.
b
c
d
Scheme 1. Cercosporin-Catalyzed [4 + 1] and [4 + 2]
Annulations of Azoalkenes
e
f
several experiments were performed to investigate the effect of
base, solvent, and S source on the reaction. The use of tBuOK
gave a superior performance and afforded 3a in 88% yield,
whereas altering the base from tBuOK to Cs2CO3 led to a
slightly lower yield of 3a at 72% (entries 2−5). A brief survey
of reaction media showed that acetonitrile remained the best
solvent for the photocatalytic cyclization. Other solvents such
as ethanol, CHCl3, dimethyl sulfoxide (DMSO), toluene,
methanol, and dichloromethane either gave inferior results or
completely impeded the reaction (entries 6−10). We also
tested other commercially available perylenequinonoid pig-
ments, hypocrellin A and hypocrellin B, but giving extremely
poor catalytic activity (entries 11−12). Although NaSCN as
the S source also delivered 82% yield of 3a (entry 13), KSCN
was believed to be more suitable as the S source in light of the
low cost and similar yields. Control experiments showed that a
base was essential for the reaction because no reaction
occurred without a base (entry 14). No expected product 3a
RESULTS AND DISCUSSION
■
Thiocyanate salts have been proved to be attractive and
versatile reagents in organic transformations16 because of their
easy availability, low cost, and low toxicity. As an ambident
nucleophilic unit, thiocyanate salts can introduce the “SCN”
source to afford thiocyanate products.17 Meanwhile, in recent
years, thiocyanate salts can also be found as a sulfur transfer
reagent18 or a stable “CN” source in organic transformations.19
Thus, carbon−sulfur bond and nitrogen−sulfur bond for-
mations play important roles in the constructions of organo-
sulfur compounds. Here, an unprecedented photocatalytic [4 +
1] annulation of azoalkenes with thiocyanate salt as the S
B
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
was detected as substrate 1a remained in the absence of a
photocatalyst, light irradiation, or O2, thus indicating that the
reaction should proceed via a photocatalytic process (entries
15 and 17). These experiments demonstrated that light, CP,
tBuOK, and O2 were all essential for the reaction. Attempts to
decrease the amount of photocatalyst led to a reduction in
yield (entry 18).
Table 2. Optimization of Cyclodimerization Conditions
With the optimized reaction conditions in hand, the scope of
α-halo-N-acyl-hydrazone 1 was studied as shown in Scheme 2.
b
entry
photocatalyst
base
solvent
yield (%)
1
2
3
4
5
6
7
8
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
cercosporin
K2CO3
KOH
tBuOK
Cs2CO3
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
CHCl3
DMSO
toluene
MeCN/H2O = 20:1
MeCN/H2O = 10:1
MeCN/H2O = 10:1
MeCN/H2O = 10:1
MeCN/H2O = 10:1
MeCN/H2O = 10:1
MeCN/H2O = 10:1
60
51
31
65
22
58
48
12
25
73
80
trace
trace
trace
61
Scheme 2. Cercosporin-Catalyzed [4 + 1] Annulations of
Azoalkenes with KSCN
9
10
11
12
13
14
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
cercosporin
cercosporin
cercosporin
d
e
16
69
a
Reaction conditions: 1a (0.5 mmol), photocatalyst (1 mol %), base
(0.24 mmol), solvents (2.0 mL), 5 W blue LEDs, 16 h, at room
b
c
temperature under a nitrogen atmosphere. Isolated yield. Without
d
visible light irradiation. Performed with 0.5 mol % of cercosporin.
e
Performed with 0.5 equiv of Cs2CO3.
dimerization reaction proceeded well in the presence of
Cs2CO3 (2.0 equiv) and CP (1 mol %) in the mixed solvent
(MeCN/H2O = 10:1) under a nitrogen atmosphere and gave
an 80% yield of 4a. The addition of water has an important
effect on the yield of the reaction, indicating that water may
participate in the [4 + 2] cyclodimerization reaction as a
reactant. Attempts to decrease the amounts of both the
photocatalysis CP and the base resulted in much lower yields
of 4a.
Next, we tested a variety of α-halo-N-acyl-hydrazones 1 to
investigate the generality of this optimized reaction. As
illustrated in Scheme 3, the reaction proceeded effectively
with several substrates and was not found to be much
dependent on the electronic nature of the substituents. They
afforded a wide range of 1,4,5,6-tetrahydropyridazines (4a−
4q) in good to excellent yields. In most cases, 1,4,5,6-
tetrahydropyridazines were isolated in greater than 70% yield.
Importantly, the flexibility of the process allows the strategic
placement of functional groups. For instance, 4c, 4d, 4i, 4k,
and 4n−4o, which contain chlorine and bromine atoms, can
be easily prepared and could be additionally derivatized,
thereby providing a convenient alternative for the generation
of a broad range of analogues. To our delight, not much
electronic effect of R′ on the aromatic ring was observed.
Electron-donating, -withdrawing, and -neutral groups gave
almost similar yields at ∼80% of 1,4,5,6- tetrahydropyridazines,
but alkyl-substituted hydrazones failed to give the desired
products.
As expected, the procedure was applicable for substrates with
both electron-donating and -withdrawing groups in the phenyl
ring, providing 4-aryl-1,2,3-thiadiazoles in moderate to good
yields. The procedure also tolerated the functional groups,
such as trifluoromethyl and cyano (3h, 3i). The Cl and Br
groups were well tolerated in this reaction, providing the
possibility for further functionalization (3c, 3d). The electron-
withdrawing groups such as NO2 (3j) can also afford the
desired sulfone products in excellent yields. The furan
analogue of hydrazone (3k) proceeded smoothly with 65%
yield. However, the pyridine analogue of hydrazone (3l) did
not work under this reaction condition.
Interestingly, 5% yield of 1,4,5,6-tetrahydropyridazine 4a
derived from [4 + 2] cyclodimerization of azoalkene was
detected with liquid chromatography−mass spectrometry
during the optimization process. 1,2-Diaza-1,3-dienes bearing
no substituents at C4 show a tendency of self-condensation. It
gave cyclic dimers in the presence of the base when unsuitable
or inefficient partners for the cycloaddition reaction are
present.20 In view of the important pharmacological activity
of 1,4,5,6-tetrahydropyridazines as valuable N−N-bond-con-
taining heterocyclic scaffolds, this result inspired us to optimize
the photocatalytic reaction conditions and examine the scope
and generality of the present methodology. We started our
investigation by taking 1a as a model substrate to determine
the optimal reaction conditions for the cyclodimerization
reaction to form 4a. Several experiments were performed to
investigate the effect of solvent and base on the reaction (Table
2). As a result, we were pleased to find that the cyclo-
Last, to demonstrate the synthetic utility of the photo-
catalytic [4 + 1] annulation of azoalkenes with thiocyanate salt
and cyclodimerizations, the gram-scale reactions were carried
out (Scheme 4). Comparable yields were obtained, thus
C
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Cercosporin-Catalyzed [4 + 2] Homocyclodimerizations of Azoalkenes
providing a possibility for large-scale synthesis of heterocycles
in a sustainable, environmentally friendly manner.
To further get some insights into the mechanisms, several
control experiments were conducted. The on/off light
experiments of the photoreactions (Supporting Information)
revealed that the reactions were inhibited in the absence of
light. For the [4 + 2] homocyclodimerization of azoalkene,
addition of radical scavenger 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) or 2,6-ditert-butyl-4-methylphenol (BHT) led
to the obvious inhibition of the reaction (Scheme 5a). We also
employed the electron spin resonance (ESR) spin-trap
technique (with 5,5-dimethyl-1-pyrroline N-oxideDMPO)
to probe the nature of the reactive oxygen species generated in
the reaction under visible irradiation, and four characteristic
peaks of DMPO−•OH were obviously observed (Scheme 5b).
These results suggested that a radical pathway should be
involved in the transformation process. However, when 1.5
equiv of TEMPO was introduced to the [4 + 1] annulation
reaction, the desired product was not significantly inhibited.
Furthermore, the effect of DABCO (1,4-diazabicyclo[2.2.2]-
octane, a singlet oxygen scavenger) on the [4 + 1] annulation
reaction was also studied, and the photo-oxidative reaction of
sulfide can be significantly suppressed (Scheme 5c). Therefore,
we propose that the presence of 1O2 is responsible for the [4 +
1] annulation reaction through an energy transfer (EnT)
process.
Scheme 4. Gram-scale Reactions for the Cercosporin-
Catalyzed Annulations
On the basis of our results and previous literature
studies,4b,c,20a,21 a plausible mechanism is proposed in Scheme
6. Treatment of the α-halo hydrazone 1 with a base generates
azoalkene 5 (1,2-diaza-1,3-diene). For the [4 + 1] annulation
D
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 5. Control Experiment and ESR Spin-trap
reaction, azoalkene 5 undergoes aza-Michael addition with the
SCN− to generate a nucleophilic reaction product, which is
isomerized to afford intermediate 6. After that, intramolecular
nucleophilic substitution reaction takes place to afford
compound 7.21 The CN group is hydrolyzed by a base
under the reaction conditions.22 Oxidative aromatization23 of
undergoes protonation to afford the desired 1,4,5,6-tetrahy-
dropyridazine. The catalyst turnover may be accomplished by
the oxidation of water, together with the generation of the OH
radical and the ground state of the photocatalyst CP.
CONCLUSIONS
1
■
intermediate 7 in the presence of O2 generated from CP
through the EnT process10e affords the [4 + 1] annulation
product 3. For the [4 + 2] homocyclodimerization, a radical
pathway should be involved in the transformation process.
Azoalkene 5 undergoes regioselective intermolecular [4 + 2]
cycloaddition to give pyridazine 8. Similar to the effect of
CsF,20a the OH radical,24 which was formed by CP self-
electron transfer,11a may be the only active nucleophilic species
supported by the results of optimization reaction and control
experiments. Regioselective attack of the OH radical at one of
the acyl carbonyls of 8 followed by nitrogen elimination and
breaking of the C−N bond resulted in the intermediate radical
9. Oxidative quenching of the excited state of the photocatalyst
(CP*) by 9 via a single electron transfer process leads to the
formation of an unstable carbanion intermediate, which
In summary, we have developed a new method for the
construction of nitrogen-containing heterocycles by using one
of the perylenequinonoid derivatives, cercosporin, as a metal-
free, cost-effective, and environmentally friendly photocatalyst
under mild conditions. It selectively photocatalyzed [4 + 1]
annulation of azoalkenes with thiocyanate salt as the S source
and [4 + 2] cyclodimerization of azoalkenes to afford 1,2,3-
thiadiazoles and 1,4,5,6- tetrahydropyridazines, respectively.
The use of inexpensive household lights and the ease of
handling make the developed methods particularly attractive
for applications in synthesis. In particular, we set up a
connection between microbial fermentation and organic
photocatalysis for the construction of nitrogen-containing
heterocycles in a sustainable, environmentally friendly manner.
E
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
light intensity was measured to be 6.51 mW/cm2. The emission
spectrum of each light source was measured with a Hitachi F-2700
spectrofluorometer. The intensity of irradiation was measured by an
FZ-A radiometer (Photoelectric Instrument Factory of Beijing
Normal University) equipped with a 400−1000 nm sensor.
Scheme 6. Proposed Mechanism
General Procedure for the Cercosporin-Catalyzed [4 + 1]
Annulations of Azoalkenes with KSCN. In a 10 mL Schlenk tube
with a magnetic stirring bar, the cercosporin (0.01 equiv), α-halo-N-
acyl-hydrazone 1 (0.2 mmol), KSCN 2 (2 equiv), and tBuOK (1.2
equiv) were dissolved in dry CH3CN (2 mL), and the resulting
mixtures were placed under 5 W blue LED for 16 h under an O2
atmosphere. When the reaction was finished, the reaction mixture was
washed with brine. The aqueous phase was re-extracted with ethyl
acetate. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuum, and the resulting residue was purified by
silica gel column chromatography to afford the desired product 3.
4-Phenyl-1,2,3-thiadiazole (3a).4d The representative procedure
was followed using N′-(2-bromo-1-phenylethylidene) benzohydrazide
(1a) (0.2 mmol) and KSCN (0.4 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 10:1) yielded 3a (28 mg, 88%)
as a yellow solid. Mp = 74.2−75.0 °C. 1H NMR (400 MHz, CDCl3):
δ ppm 8.66 (s, 1H), 8.07−8.05 (m, 2H), 7.55−7.44 (m, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ ppm 162.9, 130.8, 129.9, 129.4,
129.2, 127.4. HRMS (ESI-Q-TOF) exact mass calcd for C8H7N2S [M
+ H]+ 162.0330, found 163.0349.
4-(4-Fluorophenyl)-1,2,3-thiadiazole (3b).4d The representative
procedure was followed using N′-(2-chloro-1-(4-fluorophenyl)-
ethylidene)benzohydrazide (1b) (0.2 mmol) and KSCN (0.4
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 3b (25 mg, 72%) as a yellow solid. Mp = 94.5−
1
95.0 °C. H NMR (400 MHz, CDCl3): δ ppm 8.60 (s, 1H), 8.09−
8.02 (m, 2H), 7.23−7.19 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ ppm 164.3, 161.9, 161.3, 133.6, 129.8 (d, JC−F = 9.0 Hz),
127.8 (d, JC−F = 3.0 Hz), 116.3 (d, JC−F = 22.0 Hz). HRMS (ESI-Q-
TOF) exact mass calcd for C8H6FN2S [M + H]+ 181.0236, found
181.0231.
Given the excellent properties of photosensitization, we expect
that this new class of photoredox catalyst can be used for other
chemical reactions, awaiting further investigation.
4-(4-Chlorophenyl)-1,2,3-thiadiazole (3c).4d The representative
procedure was followed using N′-(2-chloro-1-(4-chlorophenyl)-
ethylidene)benzohydrazide (1c) (0.2 mmol) and KSCN (0.4
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 3c (33 mg, 87%) as a yellow solid. Mp =
EXPERIMENTAL SECTION
■
General Methods. Cercosporin was biosynthesized by a new
cercosporin producing strain in our laboratory. Hypocrellin A and
hypocrellin B were commercially available and used without further
purification. α-Halo-N-acyl-hydrazones 1 were synthesized according
to a previously described method (α-Halo-N-acyl-hydrazones 1 were
not stable in the ambient temperature).25 All other commercially
available reagents and solvents were used without further purification.
Thin-layer chromatography was performed using silica gel plates
F254. Visualization was accomplished with short-wavelength UV light
1
131.3−133.0 °C. H NMR (400 MHz, CDCl3): δ ppm 8.65 (s, 1H),
8.00 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ ppm 162.6, 135.5, 132.4, 129.4, 128.9, 128.7. HRMS
(ESI-Q-TOF) exact mass calcd for C8H6ClN2S [M+H]+ 196.9940,
found 196.9940.
4-(4-Bromophenyl)-1,2,3-thiadiazole (3d).4d The representative
procedure was followed using N′-(2-bromo-1-(4-bromophenyl)
ethylidene) benzohydrazide (1d) (0.2 mmol) and KSCN (0.4
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 3d (37 mg, 78%) as a yellow solid. Mp =
(254 nm) and near-UV light (366 nm) sources. H and 13C NMR
1
spectra were recorded on a Bruker AV400 (400 MHz) spectrometer
1
1
in CDCl3 solution with internal solvent signals (for H and 13C) as
145.5−147.0 °C. H NMR (400 MHz, CDCl3): δ ppm 8.66 (s, 1H),
7.94 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ ppm 161.2, 134.3, 132.7, 130.4, 129.6, 123.1. HRMS
(ESI-Q-TOF) exact mass calcd for C8H6BrN2S [M + H]+ 240.9435,
found 240.9429.
the reference (7.26 and 77.2, respectively). Data for 13C NMR are
reported in terms of chemical shift, and no special nomenclature is
used for equivalent carbons. High-resolution mass spectra (HRMS)
were recorded on Waters Xevo G2 Q-TOF instrument. UV−vis and
fluorescence measurements were performed with a Shimadzu UV-
3600 plus spectrophotometer and an F-2700 spectrofluorometer.
Electron spin resonance (ESR) was recorded on EMXplus-10/12.
The lifetime was measured on an Edinburgh FLS920 fluorescence
spectrometer. Cyclic voltammetry was performed using a CHI600E
electrochemical workstation: Au wire (φ = 1.6 mm) sealed in a Teflon
jacket as the working electrode, Pt wire as the counter electrode, Ag/
AgCl (KCl, 3 M) electrode as the reference electrode, and
ferrocenium/ferrocene (Fc+/Fc) as the internal standard. The scan
rate was 50 mV/s (in the range −1 to +2.2 V). Bu4NPF6 (0.1 M in
MeCN) was used as the supporting electrolyte. Photochemical
reaction was carried out in the borosilicate glass bottle under visible
light by a PHILIPS 5 W blue LED at room temperature. The sample
was placed at an approximate distance of 5 cm from the lamp. The
4-(p-Tolyl)-1,2,3-thiadiazole (3e).4d The representative procedure
was followed using N′-(2-bromo-1-(p-tolyl) ethylidene) benzohy-
drazide (1e) (0.2 mmol) and KSCN (0.4 mmol) as the substrate.
Isolation by column chromatography (PE/EtOAc: 10:1) yielded 3e
1
(31 mg, 90%) as a yellow solid. Mp = 65.4−67.2 °C. H NMR (400
MHz, CDCl3): δ ppm 8.59 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.32 (d, J
= 8 Hz, 2H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm
162.4, 139.4, 132.9, 130.2, 128.5, 127.5, 21.4. HRMS (ESI-Q-TOF)
exact mass calcd for C9H9N2S [M + H]+ 177.0486, found 177.0501.
4-(4-Methoxyphenyl)-1,2,3-thiadiazole (3f).4d The representative
procedure was followed using N′-(2-chloro-1-(4-methoxyphenyl)-
ethylidene)benzohydrazide (1f) (0.2 mmol) and KSCN (0.4 mmol)
as the substrate. Isolation by column chromatography (PE/EtOAc:
10:1) yielded 3f (32 mg, 85%) as a yellow solid. Mp = 82.6−84.2 °C.
F
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H NMR (400 MHz, CDCl3): δ ppm 8.52 (s, 1H), 7.99 (d, J = 8 Hz,
2H), 7.04 (d, J = 8 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ ppm 162.3, 160.5, 131.8, 129.0, 123.8, 115.0, 55.7. HRMS
(ESI-Q-TOF) exact mass calcd for C9H9N2OS [M + H]+ 193.0436,
found 193.0429.
2H), 7.60−7.58 (m, 2H), 7.49−7.44 (m, 3H), 7.33−7.30 (m, 5H),
7.26−7.24 (m, 1H), 7.18 (d, J = 8 Hz, 2H), 6.09 (s, 1H), 2.71−2.67
(m, 1H), 2.43−2.16 (m, 3H).
(3,6-Bis(4-fluorophenyl)-5,6-dihydropyridazin-1(4H)-yl) (phenyl)-
methanone (4b). The representative procedure was followed using
N′-(2-chloro-1-(4-fluorophenyl) ethylidene) benzohydrazide (1b)
(0.5 mmol) as the substrate. Isolation by column chromatography
(PE/EtOAc: 10:1) yielded 4b (67 mg, 72%) as a yellow solid. Mp =
189.8−192.5 °C. 1H NMR (400 MHz, CDCl3): δ ppm 7.80−7.78 (m,
2H), 7.57−7.55 (m, 2H), 7.52−7.43 (m, 3H), 7.16−7.12 (m, 2H),
7.03−6.97 (m, 4H), 6.05 (s, 1H), 2.69−2.65 (m, 1H), 2.40−2.25 (m,
2H), 2.22−2.13 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm
4-([1,1′-Biphenyl]-4-yl)-1,2,3-thiadiazole (3g).26 The representa-
tive procedure was followed using N′-(1-([1,1′-biphenyl]-4-yl)-2-
bromoethylidene) benzohydrazide (1g) (0.2 mmol) and KSCN (0.4
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 3g (40 mg, 86%) as a yellow oil. 1H NMR (400
MHz, CDCl3): δ ppm 8.68 (s, 1H), 8.13 (d, J = 8 Hz, 2H), 7.75 (d, J
= 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H), 7.50−7.46 (m, 2H), 7.41−7.37
(m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 162.0, 141.3,
139.8, 133.6, 130.2, 128.3, 128.2, 127.9, 127.2. HRMS (ESI-Q-TOF)
exact mass calcd for C14H11N2S [M + H]+ 239.0643, found 239.0652.
4-(4-(Trifluoromethyl)phenyl)-1,2,3-thiadiazole (3h).4b The rep-
resentative procedure was followed using N′-(2-chloro-1-(4-
(trifluoromethyl)phenyl)ethylidene)benzohydrazide (1h) (0.2
mmol) and KSCN (0.4 mmol) as the substrate. Isolation by column
chromatography (PE/EtOAc: 10:1) yielded 3h (37 mg, 81%) as a
yellow solid. Mp = 105.4−107.2 °C. 1H NMR (400 MHz, CDCl3): δ
ppm 8.77 (s, 1H), 8.19 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ ppm 160.8, 135.8, 135.0, 130.1,
128.3, 127.3 (t, JC−F = 271.0 Hz), 126.6 (t, JC−F = 4.0 Hz), 115.1.
HRMS (ESI-Q-TOF) exact mass calcd for C9H6F3N2S [M + H]+
231.0204, found 231.0226.
1
1
170.2, 163.4 (d, JC−F = 248.1 Hz), 162.0 (d, JC−4F = 244.1 Hz),
4
146.0, 135.5 (d, JC−F = 3.1 Hz), 135.1, 133.2 (d, JC−F = 3.2 Hz),
3
3
130.4, 129.9, 127.5, 127.2 (d, JC−F = 8.2 Hz), 127.1 (d, JC−F = 8.0
2
2
Hz), 115.7 (d, JC−F = 21.5 Hz), 115.4 (d, JC−F = 21.6 Hz), 50.9,
24.0, 18.7. 19F NMR (376 MHz, CDCl3) δ (ppm) −111.7, −115.5.
HRMS (ESI-Q-TOF) exact mass calcd for C23H19F2N2O [M + H]+
377.1465, found 377.1482.
(3,6-Bis(4-chlorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)-
methanone (4c). The representative procedure was followed using
N′-(2-chloro-1-(4-chlorophenyl)ethylidene)benzohydrazide (1c) (0.5
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 4c (71 mg, 70%) as a yellow solid. Mp =
176.9−180.0 °C. 1H NMR (400 MHz, CDCl3): δ ppm 7.78 (d, J = 4
Hz, 2H), 7.50−7.43 (m, 5H), 7.30−7.26 (m, 5H), 7.10 (d, J = 8 Hz,
2H), 6.03 (s, 1H), 2.68−2.63 (m, 1H), 2.39−2.26 (m, 2H), 2.20−
2.11 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.2,
145.8, 138.3, 135.4, 135.3, 134.9, 133.2, 130.5, 129.9, 129.0, 128.6,
127.5, 126.9, 126.6, 51.2, 29.7, 23.8, 18.6. HRMS (ESI-Q-TOF) exact
mass calcd for C23H19Cl2N2O [M + H]+ 409.0874, found 409.0864.
(3,6-Bis(4-bromophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)-
methanone (4d). The representative procedure was followed using
N′-(2-bromo-1-(4-bromophenyl) ethylidene) benzohydrazide (1d)
(0.5 mmol) as the substrate. Isolation by column chromatography
(PE/EtOAc: 10:1) yielded 4d (101 mg, 82%) as a yellow solid. Mp
=176.1−179.2 °C. 1H NMR (400 MHz, CDCl3): δ ppm 7.78 (d, J = 8
Hz, 2H), 7.52−7.40 (m, 9H), 7.04 (d, J = 8 Hz, 2H), 6.01 (s, 1H),
2.67−2.62 (m, 1H), 2.39−2.25 (m, 2H), 2.20−2.11 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.2, 145.9, 138.9, 135.8,
4-(1,2,3-Thiadiazol-4-yl)benzonitrile (3i).4c The representative
procedure was followed using N′-(2-bromo-1-(4-cyanophenyl)-
ethylidene)benzohydrazide (1i) (0.2 mmol) and KSCN (0.4 mmol)
as the substrate. Isolation by column chromatography (PE/EtOAc:
1
10:1) yielded 3i (27 mg, 74%) as a yellow oil. H NMR (400 MHz,
CDCl3): δ ppm 8.80 (s, 1H), 8.19 (d, J = 8 Hz, 2H), 7.82 (d, J = 8
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 160.5, 136.3,
135.3, 133.7, 128.3, 119.0, 1121. HRMS (ESI-Q-TOF) exact mass
calcd for C9H6N3S [M + H]+ 188.0282, found 188.0290.
4-(4-Nitrophenyl)-1,2,3-thiadiazole (3j).27 The representative
procedure was followed using N′-(2-bromo-1-(4-nitrophenyl) ethyl-
idene) benzohydrazide (1j) (0.2 mmol) and KSCN (0.4 mmol) as the
substrate. Isolation by column chromatography (PE/EtOAc: 10:1)
yielded 3j (29 mg, 71%) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ ppm 8.66 (s, 1H), 7.94 (d, J = 12 Hz, 2H), 7.65 (d, J = 8
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 161.2, 134.3,
132.7, 130.4, 129.6, 123.1. HRMS (ESI-Q-TOF) exact mass calcd for
C8H6N3O2S [M + H]+ 208.0181, found 208.0181.
134.8, 132.0, 131.6, 130.5, 129.9, 127.5, 127.2, 126.9, 123.6, 121.2,
51.3, 29.7, 23.8, 18.5. HRMS (ESI-Q-TOF) exact mass calcd for
C23H19Br2N2O [M + H]+ 498.9845, found 498.9799.
(3,6-Di-p-tolyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl)-
methanone (4e). The representative procedure was followed using
N′-(2-bromo-1-(p-tolyl) ethylidene) benzohydrazide (1e) (0.5
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 10:1) yielded 4e (72 mg, 79%) as a yellow solid. Mp =192.6−
4-(Furan-2-yl)-1,2,3-thiadiazole (3k).4b The representative proce-
dure was followed using N′-(2-bromo-1-(furan-2-yl)ethylidene)-
benzohydrazide (1k) (0.2 mmol) and KSCN (0.4 mmol) as the
substrate. Isolation by column chromatography (PE/EtOAc: 10:1)
yielded 3k (19 mg, 65%) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ ppm 8.62 (s, 1H), 7.58 (s, 1H), 7.19−7.18 (m, 1H), 6.62−
6.61 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 154.0,
146.5, 144.7, 132.2, 112.5, 109.9. HRMS (ESI-Q-TOF) exact mass
calcd for C6H5N2OS [M + H]+ 153.0123, found 153.0140.
General Procedure for the Cercosporin-Catalyzed [4+2]
Homocyclodimerizations of Azoalkenes. In a 10 mL Schlenk
tube with a magnetic stirring bar, the cercosporin (0.01 equiv), α-
halo-N-acyl-hydrazone 1 (0.5 mmol), and Cs2CO3 (1.2 equiv) were
dissolved in a mixed solvent (CH3CN/H2O = 10:1, 2 mL), and the
resulting mixtures were placed under 5 W blue LED for 16 h under a
N2 atmosphere. When the reaction was finished, the reaction mixture
was washed with brine. The aqueous phase was re-extracted with ethyl
acetate. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuum, and the resulting residue was purified by
silica gel column chromatography to afford the desired product 4.
(3,6-Diphenyl-5,6-dihydropyridazin-1(4H)-yl)(phenyl)-
methanone (4a).20a The representative procedure was followed
using N′-(2-bromo-1-phenylethylidene) benzohydrazide (1a) (0.5
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 15:1) yielded 4a (68 mg, 80%) as a yellow solid. Mp =
146.2−148.9 °C. 1H NMR (400 MHz, CDCl3): δ ppm 7.84−7.82 (m,
1
194.6 °C. H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, J = 8 Hz,
2H), 7.48−7.40 (m, 5H), 7.12−7.05 (m, 6H), 6.04 (s, 1H), 2.68−
2.63 (m, 1H), 2.61 (s, 3H), 2.41−2.15 (m, 3H), 2.33 (s, 3H), 2.30 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.1, 146.9, 139.2,
137.0, 136.8, 135.5, 134.5, 130.2, 130.1, 129.4, 129.1, 127.3, 125.4,
125.3, 51.5, 24.0, 21.2, 21.0, 18.7. HRMS (ESI-Q-TOF) exact mass
calcd for C25H25N2O [M + H]+ 369.1967, found 369.1965.
(3,6-Di([1,1′-biphenyl]-4-yl)-5,6-dihydropyridazin-1(4H)-yl)-
(phenyl)methanone (4f). The representative procedure was followed
using N′-(1-([1,1′-biphenyl]-4-yl)-2-bromoethylidene) benzohydra-
zide (1g) (0.5 mmol) as the substrate. Isolation by column
chromatography (PE/EtOAc: 10:1) yielded 4f (110 mg, 90%) as a
yellow solid. Mp = 209.6−210.6 °C. 1H NMR (400 MHz, CDCl3): δ
ppm 7.88−7.86 (m, 2H), 7.68 (d, J = 8 Hz, 2H), 7.59−7.53 (m, 8H),
7.48 (d, J = 8 Hz, 2H), 7.45−7.39 (m, 5H), 7.36−7.30 (m, 2H), 7.27
(d, J = 8 Hz, 2H), 6.14 (s, 1H), 2.80−2.72 (m, 1H), 2.49−2.26 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.3, 146.7, 141.9,
140.7, 140.3, 139.0, 136.1, 135.3, 130.3, 130.1, 129.0, 128.8, 127.6,
127.4, 127.3, 127.1, 127.0, 125.9, 125.8, 51.6, 29.7, 24.0, 18.8. HRMS
(ESI-Q-TOF) exact mass calcd for C35H29N2O [M + H]+ 493.2280,
found 493.2260.
G
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3,6-Bis(4-nitrophenyl)-5,6-dihydropyridazin-1(4H)-yl)(phenyl)-
methanone (4g). The representative procedure was followed using
N′-(2-bromo-1-(4-nitrophenyl) ethylidene) benzohydrazide (1j) (0.5
mmol) as the substrate. Isolation by column chromatography (PE/
EtOAc: 5:1) yielded 4g (75 mg, 70%) as a yellow solid. Mp = 71.2−
N′-(2-bromo-1-(4-cyanophenyl)ethylidene)-4-chlorobenzohydrazide
(1q) (0.5 mmol) as the substrate. Isolation by column chromatog-
raphy (PE/EtOAc: 5:1) yielded 4l (79 mg, 75%) as a yellow solid.
Mp = 89.3−91.2 °C. 1H NMR (400 MHz, CDCl3): δ ppm 7.75 (d, J
= 8 Hz, 2H), 7.67−7.63 (m, 6H), 7.46 (d, J = 8 Hz, 2H), 7.26 (d, J =
8 Hz, 2H), 6.07 (s, 1H), 2.76−2.71 (m, 1H), 2.47−2.33 (m, 2H),
2.24−2.12 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm
169.1, 145.4, 144.9, 140.5, 137.3, 132.9, 132.4, 131.5, 128.0, 126.2,
125.8, 118.3, 112.9, 111.8, 52.0, 23.5, 18.6. HRMS (ESI-Q-TOF)
exact mass calcd for C25H18ClN4O [M + H]+ 425.1169, found
425.1201.
(3,6-Bis(4-nitrophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-
chlorophenyl)methanone (4m). The representative procedure was
followed using N′-(2-bromo-1-(4-nitrophenyl)ethylidene)-4-chloro-
benzohydrazide (1r) (0.2 mmol) as the substrate. Isolation by column
chromatography (PE/EtOAc: 5:1) yielded 4m (89 mg, 77%) as a
yellow solid. Mp = 205.9−207.6 °C. 1H NMR (400 MHz, CDCl3): δ
ppm 7.75 (d, J = 8 Hz, 2H), 7.48−7.41 (m, 8H), 7.02 (d, J = 8 Hz,
2H), 5.98 (s, 1H), 2.69−2.64 (m, 1H), 2.39−2.25 (m, 2H), 2.21−
2.12 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 169.0,
146.4, 138.7, 136.7, 135.6, 133.1, 132.0, 131.7, 131.6, 127.8, 127.2,
126.9, 123.9, 121.3, 51.4, 23.7, 18.6. HRMS (ESI-Q-TOF) exact mass
calcd for C23H18ClN4O5 [M + H]+ 465.0865, found 465.0842.
(3,6-Bis(4-chlorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-(tert-
butyl)phenyl)methanone (4n). The representative procedure was
followed using N′-(2-bromo-1-(4-chlorophenyl)ethylidene)-4-(tert-
butyl)benzohydrazide (1s) (0.5 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 5:1) yielded 4n (98 mg, 85%)
as a yellow solid. Mp = 249.6−251.3 °C. 1H NMR (400 MHz,
CDCl3): δ ppm 7.78 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H), 7.47
(d, J = 8 Hz, 2H), 7.30−7.27 (m, 4H), 7.09 (d, J = 8 Hz, 2H), 6.03 (s,
1H), 2.68−2.63 (m, 1H), 2.39−2.26 (m, 2H), 2.21−2.10 (m, 1H),
1.38 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.0, 154.1,
145.7, 138.4, 135.5, 135.2, 133.1, 131.7, 130.1, 129.0, 128.6, 126.9,
126.7, 124.4, 51.3, 34.9, 31.2, 29.7, 23.8, 18.6. HRMS (ESI-Q-TOF)
exact mass calcd for C27H27Cl2N2O [M + H]+ 465.1501, found
465.1480.
1
73.5 °C. H NMR (400 MHz, CDCl3): δ ppm 8.22−8.16 (m, 4H),
7.80 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.57−7.48 (m, 3H),
7.34 (d, J = 8 Hz, 2H), 6.15 (s, 1H), 2.81−2.75 (m, 1H), 2.54−2.38
(m, 2H), 2.24−2.15 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
ppm 170.4, 148.1, 147.5, 147.0, 144.6, 142.4, 134.1, 131.1, 130.0,
127.7, 126.5, 126.1, 124.3, 123.8, 51.8, 29.7, 23.6, 18.7. HRMS (ESI-
Q-TOF) exact mass calcd for C23H19N4O5 [M + H]+ 431.1356, found
431.1327.
(3,6-Bis(4-fluorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-
methoxyphenyl)methanone (4h). The representative procedure was
followed using N′-(2-chloro-1-(4-fluorophenyl)ethylidene)-4-methox-
ybenzohydrazide (1m) (0.5 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 5:1) yielded 4h (73 mg, 72%)
as a yellow solid. Mp = 71.8−72.6 °C. 1H NMR (400 MHz, CDCl3):
δ ppm 7.86 (d, J = 8 Hz, 2H), 7.63−7.59 (m, 2H), 7.14−7.11 (m,
2H), 7.04−6.94 (m, 6H), 6.03 (s, 1H), 3.89 (s, 3H), 2.69−2.64 (m,
1H), 2.39−2.25 (m, 2H), 2.22−2.13 (m, 1H). 13C{1H} NMR (100
1
MHz, CDCl3): δ ppm 169.4, 163.4 (d, JC4−F = 248.1 Hz), 162.0 (d,
1JC−F = 243.9 Hz), 161.5, 145.6, 135.6 (d, JC−F = 3.3 Hz), 133.3 (d,
4JC−F = 3.2 Hz), 132.5, 127.2 (d, 3JC−F = 8.3 Hz), 127.1 (d, 3JC−F = 8.0
2
2
Hz), 115.7 (d, JC−F = 21.5 Hz), 115.4 (d, JC−F = 21.6 Hz), 112.7,
55.4, 51.2, 29.7, 24.0, 18.7. 19F NMR (376 MHz, CDCl3) δ (ppm)
−111.7, −115.5. HRMS (ESI-Q-TOF) exact mass calcd for
C24H21F2N2O2 [M + H]+ 407.1571, found 407.1557.
(3,6-Bis(4-bromophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-
methoxyphenyl)methanone (4i). The representative procedure was
followed using N′-(2-bromo-1-(4-bromophenyl)ethylidene)-4-me-
thoxybenzohydrazide (1n) (0.5 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 5:1) yielded 4i (107 mg, 82%)
as a yellow solid. Mp = 185.2−187.4 °C. 1H NMR (400 MHz,
CDCl3): δ ppm 7.85 (d, J = 8 Hz, 2H), 7.50−7.42 (m, 6H), 7.03 (d, J
= 8 Hz, 2H), 6.96 (d, J = 8 Hz, 2H), 5.99 (s, 1H), 3.89 (s, 3H), 2.68−
2.62 (m, 1H), 2.39−2.24 (m, 2H), 2.22−2.11 (m, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ ppm 182.1, 169.2, 165.0, 162.0, 144.4,
141.8, 135.5, 133.3, 132.5, 132.0, 131.6, 127.1, 126.5, 123.7, 121.5,
114.4, 112.8, 85.9, 55.6, 31.8, 18.0. HRMS (ESI-Q-TOF) exact mass
calcd for C24H21Br2N2O2 [M + H]+ 528.9951, found 528.9954.
(3,6-Bis(4-methoxyphenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-
chlorophenyl)methanone (4j). The representative procedure was
followed using N′-(2-bromo-1-(4-methoxyphenyl) ethylidene)-4-
chlorobenzohydrazide (1o) (0.5 mmol) as the substrate. Isolation
by column chromatography (PE/EtOAc: 5:1) yielded 4j (85 mg,
(3,6-Bis(4-bromophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-(tert-
butyl)phenyl)methanone (4o). The representative procedure was
followed using N′-(2-bromo-1-(4-chlorophenyl)ethylidene)-4-(tert-
butyl)benzohydrazide (1t) (0.5 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 5:1) yielded 4o (113 mg, 82%)
as a white solid. Mp = 192.4−196.5 °C. 1H NMR (400 MHz,
CDCl3): δ ppm 7.78 (d, J = 8 Hz, 2H), 7.48−7.42 (m, 8H), 7.03 (d, J
= 8 Hz, 2H), 6.01 (s, 1H), 2.67−2.62 (m, 1H), 2.39−2.25 (m, 2H),
2.20−2.10 (m, 1H), 1.38 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ ppm 169.9, 154.1, 145.7, 138.9, 136.0, 132.0, 131.7, 131.6, 130.2,
131.7, 131.6, 130.2, 127.2, 126.9, 124.4, 123.6, 121.2, 51.3, 34.9, 31.2,
23.8, 18.6. HRMS (ESI-Q-TOF) exact mass calcd for C27H27Br2N2O
[M + H]+ 555.0472, found 555.0427.
1
75%) as a yellow solid. Mp = 187.5−188.3 °C. H NMR (400 MHz,
CDCl3): δ ppm 7.78 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 2H), 7.42
(d, J = 8 Hz, 2H), 7.08 (d, J = 8 Hz, 2H), 6.87−6.83 (m, 4H), 5.99 (s,
1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.70−2.62 (m, 1H), 2.36−2.15 (m,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 168.8, 160.6, 158.8,
147.3, 136.2, 133.8, 131.8, 131.6, 130.4, 129.7, 127.6, 126.8, 126.6,
114.3, 113.9, 55.4, 51.2, 24.1, 18.7. HRMS (ESI-Q-TOF) exact mass
calcd for C25H24ClN2O3 [M + H]+ 435.1476, found 435.1485.
(3,6-Bis(4-chlorophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-
chlorophenyl)methanone (4k). The representative procedure was
followed using 4-chloro-N′-(2-chloro-1-(4-chlorophenyl)ethylidene)-
benzohydrazide (1p) (0.5 mmol) as the substrate. Isolation by
column chromatography (PE/EtOAc: 5:1) yielded 4k (93 mg, 85%)
as a yellow solid. Mp = 195.8−197.0 °C. 1H NMR (400 MHz,
CDCl3): δ ppm 7.76 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 7.43
(d, J = 8 Hz, 2H), 7.32−7.28 (m, 4H), 7.08 (d, J = 8 Hz, 2H), 6.00 (s,
1H), 2.69−2.64 (m, 1H), 2.39−2.25 (m, 2H), 2.21−2.12 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ ppm 169.0, 146.4, 138.2, 136.7,
(4-(tert-Butyl)phenyl)(3,6-di([1,1′-biphenyl]-4-yl)-5,6-dihydropyr-
idazin-1(4H)-yl) Methanone (4p). The representative procedure was
followed using N′-(1-([1,1′-biphenyl]-4-yl)-2-bromoethylidene)-4-
(tert-butyl)benzohydrazide (1u) (0.2 mmol) as the substrate.
Isolation by column chromatography (PE/EtOAc: 5:1) yielded 4p
1
(121 mg, 89%) as a yellow solid. Mp = 189.2−190.4 °C. H NMR
(400 MHz, CDCl3): δ ppm 7.87 (d, J = 8 Hz, 2H), 7.72 (d, J = 8 Hz,
2H), 7.60−7.58 (m, 3H), 7.56−7.49 (m, 7H), 7.45−7.39 (m, 5H),
7.37−7.27 (m, 4H), 6.14 (s, 1H), 2.80−2.72 (m, 1H), 2.48−2.21 (m,
3H), 1.39 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ ppm 170.0,
153.8, 146.4, 141.9, 140.8, 140.4, 140.2, 139.1, 136.2, 132.1, 130.3,
128.8, 127.6, 127.2, 127.1, 127.0, 126.0, 125.9, 124.4, 51.7, 34.9, 31.3,
24.1, 18.9. HRMS (ESI-Q-TOF) exact mass calcd for C39H37N2O [M
+ H]+ 549.2906, found 549.2922.
(3,6-Bis(4-nitrophenyl)-5,6-dihydropyridazin-1(4H)-yl)(4-(tert-
butyl)phenyl)methanone (4q). The representative procedure was
followed using N′-(2-bromo-1-(4-nitrophenyl)ethylidene)-4-(tert-
butyl)benzohydrazide (1v) (0.2 mmol) as the substrate. Isolation
by column chromatography (PE/EtOAc: 5:1) yielded 4q (85 mg,
135.5, 135.2, 133.3, 131.6, 129.1, 128.8, 127.8, 126.6, 51.3, 23.8, 18.6.
HRMS (ESI-Q-TOF) exact mass calcd for C23H18Cl2N2O [M + H]+
443.0485, found 443.0491.
4,4′-(1-(4-Chlorobenzoyl)-1,4,5,6-tetrahydropyridazine-3,6-diyl)
1
Dibenzonitrile (4l). The representative procedure was followed using
70%) as a yellow solid. Mp = 70.2−72.3 °C. H NMR (400 MHz,
H
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3): δ ppm 8.21−8.17 (m, 4H), 7.81−7.74 (m, 4H), 7.52 (d, J =
8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 6.14 (s, 1H), 2.80−2.75 (m, 1H),
2.52−2.39 (m, 2H), 2.24−2.14 (m, 1H), 1.40 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3): δ ppm 170.1, 154.9, 148.0, 147.5, 147.1, 144.3,
142.5, 130.9, 130.2, 126.5, 126.1, 124.6, 124.3, 123.8, 51.8, 35.0, 31.2,
23.6, 18.7. HRMS (ESI-Q-TOF) exact mass calcd for C27H27N4O5
[M + H]+ 487.1982, found 487.1989.
First-class Discipline Program of Light Industry Technology
and Engineering (LITE2018-14) for the funding support.
REFERENCES
■
(1) (a) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in
Natural Product Synthesis; 1st ed.; Wiley-VCH: Weinheim, Germany,
2011;. (b) Taylor, R. D.; MacCoss, M.; Lawson, A. D. Rings in drugs.
J. Med. Chem. 2014, 57, 5845−5859.
Gram-Scale Reaction for the Cercosporin-Catalyzed [4 + 1]
Annulation. In a 50 mL Schlenk bottle with a magnetic stirring bar,
the cercosporin (0.01 equiv), α-bromo-N-acyl-hydrazone 1a (5
mmol), KSCN 2 (2 equiv), and tBuOK (1.2 equiv) were dissolved
in dry CH3CN (20 mL), and the resulting mixtures were placed under
5 W blue LED for 24 h under an O2 atmosphere. When the reaction
was finished, the reaction mixture was washed with brine. The
aqueous phase was re-extracted with ethyl acetate. The combined
organic extracts were dried over Na2SO4 and concentrated in vacuum,
and the resulting residue was purified by silica gel column
chromatography to afford the desired product 3a (0.67 g, 82%).
Gram-Scale Reaction for the Cercosporin-Catalyzed [4 + 2]
Homodimerization. In a 50 mL Schlenk bottle with a magnetic
stirring bar, the cercosporin (0.01 equiv), α-bromo-N-acyl-hydrazone
1a (10 mmol), and Cs2CO3 (1.2 equiv) were dissolved in a mixed
solvent (CH3CN/H2O = 10:1, 20 mL), and the resulting mixtures
were placed under 5 W blue LED for 24 h under a N2 atmosphere.
When the reaction was finished, the reaction mixture was washed with
brine. The aqueous phase was re-extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4 and concentrated
in vacuum, and the resulting residue was purified by silica gel column
chromatography to afford the desired product 4a (1.29 g, 76%).
(2) (a) Bakulev, V. A.; Dehaen, W. The Chemistry of 1,2,3-
Thiadiazoles; John Wiley & Sons: New York, 2004;. (b) Dong, W. L.;
Liu, Z. X.; Liu, X. H.; Li, Z. M.; Zhao, W. G. Synthesis and antiviral
activity of new acrylamide derivatives containing 1,2,3-thiadiazole as
inhibitors of hepatitis B virus replication. Eur. J. Med. Chem. 2010, 45,
1919−1926.
(3) (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal
Progesterone-Receptor Ligands.1. 3-Aryl-1-Benzoyl-1,4,5,6-Tetrahy-
dropyridazines. J. Med. Chem. 1995, 38, 4878−4879. (b) Combs, D.
W.; Reese, K.; Cornelius, L. A. M.; Gunnet, J. W.; Cryan, E. V.;
Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteroidal
Progesterone-Receptor Ligands. 2. High-Affinity Ligands with
Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem.
1995, 38, 4880−4884.
(4) (a) Xu, S. L.; Chen, R. S.; Qin, Z. F.; Wu, G. P.; He, Z. J.
Divergent Amine-Catalyzed [4+2] Annulation of Morita-Baylis-
Hillman Allylic Acetates with Electron-Deficient Alkenes. Org. Lett.
2012, 14, 996−999. (b) Ishikawa, T.; Kimura, M.; Kumoi, T.; Iida, H.
Coupled Flavin-Iodine Redox Organocatalysts: Aerobic Oxidative
Transformation from N-Tosylhydrazones to 1,2,3-Thiadiazoles. ACS
Catal. 2017, 7, 4986−4989. (c) Chen, J. F.; Jiang, Y.; Yu, J. T.; Cheng,
J. TBAI-Catalyzed Reaction between N-Tosylhydrazones and Sulfur:
A Procedure toward 1,2,3-Thiadiazole. J. Org. Chem. 2016, 81, 271−
275. (d) Liu, B. B.; Bai, H. W.; Liu, H.; Wang, S. Y.; Ji, S. J. Cascade
Trisulfur Radical Anion (S3(*-)) Addition/Electron Detosylation
Process for the Synthesis of 1,2,3-Thiadiazoles and Isothiazoles. J. Org.
Chem. 2018, 83, 10281−10288.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00545.
Biosynthesis, photochemical, and electrochemical char-
acterizations of cercosporin; spectra of the light source;
on/off light experiment; copies of spectral data for
compounds 3 and 4 (PDF)
(5) (a) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Free Radical
Chemistry Enabled by Visible Light-Induced Electron Transfer. Acc.
Chem. Res. 2016, 49, 2295−2306. (b) Corrigan, N.; Shanmugam, S.;
Xu, J. T.; Boyer, C. Photocatalysis in organic and polymer synthesis.
Chem. Soc. Rev. 2016, 45, 6165−6212. (c) Shaw, M. H.; Twilton, J.;
MacMillan, D. W. C. Photoredox Catalysis in Organic Chemistry. J.
Org. Chem. 2016, 81, 6898−6926. (d) Marzo, L.; Pagire, S. K.; Reiser,
O.; Konig, B. Visible-Light Photocatalysis: Does It Make a Difference
in Organic Synthesis? Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
(6) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (b) Reck-
AUTHOR INFORMATION
Corresponding Authors
*E-mail: zhangyan@jiangnan.edu.cn (Y.Z.).
*E-mail: raoyijian@jiangnan.edu.cn (Y.R.).
■
ORCID
Yan Zhang: 0000-0002-4941-8622
Shuping Huang: 0000-0003-4815-1863
Yijian Rao: 0000-0003-2481-0588
̈
enthaler, M.; Griesbeck, A. G. Photoredox Catalysis for Organic
Syntheses. Adv. Synth. Catal. 2013, 355, 2727−2744. (c) Nicewicz, D.
A.; Nguyen, T. M. Recent Applications of Organic Dyes as
Photoredox Catalysts in Organic Synthesis. ACS Catal. 2014, 4,
355−360. (d) Pitre, S. P.; McTiernan, C. D.; Scaiano, J. C.
Understanding the Kinetics and Spectroscopy of Photoredox Catalysis
and Transition-Metal-Free Alternatives. Acc. Chem. Res. 2016, 49,
1320−1330. (e) Romero, N. A.; Nicewicz, D. A. Organic Photoredox
Catalysis. Chem. Rev. 2016, 116, 10075−10166.
Author Contributions
∥Y.Z. and Y.C. contributed equally to this work.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(7) (a) Albini, A.; Fagnoni, M. Photochemically-Generated Inter-
mediates in Synthesis; John Wiley & Sons: Hoboken, NJ, 2013;.
(b) Chen, J. R.; Hu, X. Q.; Lu, L. Q.; Xiao, W. J. Exploration of
Visible-Light Photocatalysis in Heterocycle Synthesis and Function-
alization: Reaction Design and Beyond. Acc. Chem. Res. 2016, 49,
1911−1923.
(8) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Cultivating the Passion
to Build Heterocycles from 1,2-Diaza-1,3-dienes: the Force of
Imagination. Eur. J. Org. Chem. 2009, 2009, 3109−3127. (b) Attanasi,
O. A.; Filippone, P. Working twenty years on conjugated azo-alkenes
(and environs) to find new entries in organic synthesis. Synlett 1997,
1997, 1128−1140. (c) Deng, Y.; Pei, C.; Arman, H.; Dong, K.; Xu, X.;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21703036), Natural Science Foundation of Jiangsu Province
(Grants no BK20160167), the Thousand Talents Plan (Young
Professionals), Jiangsu Specially-Appointed Professor Program
(1016010241160390), the Fundamental Research Funds for
the Central Universities (JUSRP51712B), and the National
I
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Doyle, M. P. Syntheses of Tetrahydropyridazine and Tetrahydro-1,2-
diazepine Scaffolds through Cycloaddition Reactions of Azoalkenes
with Enol Diazoacetates. Org. Lett. 2016, 18, 5884−5887. (d) Guo,
C.; Sahoo, B.; Daniliuc, C. G.; Glorius, F. N-heterocyclic carbene
catalyzed switchable reactions of enals with azoalkenes: formal [4 + 3]
and [4 + 1] annulations for the synthesis of 1,2-diazepines and
pyrazoles. J. Am. Chem. Soc. 2014, 136, 17402−17405. (e) Attanasi,
O. A.; De Crescentini, L.; Favi, G.; Mantellini, F.; Mantenuto, S.;
Nicolini, S. Interceptive [4 + 1] annulation of in situ generated 1,2-
diaza-1,3-dienes with diazo esters: direct access to substituted mono-,
bi-, and tricyclic 4,5-dihydropyrazoles. J. Org. Chem. 2014, 79, 8331−
8338. (f) Li, J.; Huang, R.; Xing, Y. K.; Qiu, G.; Tao, H. Y.; Wang, C.
J. Catalytic Asymmetric Cascade Vinylogous Mukaiyama 1,6-
Michael/Michael Addition of 2-Silyloxyfurans with Azoalkenes:
Direct Approach to Fused Butyrolactones. J. Am. Chem. Soc. 2015,
137, 10124−10127. (g) Huang, R.; Chang, X.; Li, J.; Wang, C. J.
Cu(I)-Catalyzed Asymmetric Multicomponent Cascade Inverse
Electron-Demand Aza-Diels-Alder/Nucleophilic Addition/Ring-
Opening Reaction Involving 2-Methoxyfurans as Efficient Dieno-
philes. J. Am. Chem. Soc. 2016, 138, 3998−4001. (h) Tong, M. C.;
Chen, X.; Li, J.; Huang, R.; Tao, H.; Wang, C. J. Catalytic asymmetric
synthesis of [2,3]-fused indoline heterocycles through inverse-
electron-demand aza-Diels-Alder reaction of indoles with azoalkenes.
Angew. Chem., Int. Ed. 2014, 53, 4680−4684.
(9) Yu, J. M.; Lu, G. P.; Cai, C. Photocatalytic radical cyclization of
alpha-halo hydrazones with beta-ketocarbonyls: facile access to
substituted dihydropyrazoles. Chem. Commun. 2017, 53, 5342−5345.
(10) (a) Kuyama, S.; Tamura, T. Cercosporin. A pigment of
Cercosporina kikuchii Matsumoto et Tomoyasu. I. Cultivation of
fungus, isolation and purification of pigment. J. Am. Chem. Soc. 1957,
79, 5725−5726. (b) Kuyama, S.; Tamura, T. Cercosporin. A pigment
of Cercosporina kikuchii Matsumoto et Tomoyasu. II. Physical and
chemical properties of cercosporin and its derivatives. J. Am. Chem.
Soc. 1957, 79, 5726−5729. (c) Daub, M. E. Resistance of fungi to the
photosensitizing toxin, cercosporin. Phytopathology 1987, 77, 1515−
1520. (d) Jalal, M. A. F.; Hossain, M. B.; Robeson, D. J.; Vanderhelm,
D. Cercospora-Beticola Phytotoxins - Cebetins That Are Photoactive,
Mg2+-Binding, Chlorinated Anthraquinone Xanthone Conjugates. J.
Am. Chem. Soc. 1992, 114, 5967−5971. (e) Daub, M. E.; Ehrenshaft,
M. The photoactivated Cercospora toxin cercosporin: Contributions
to plant disease and fundamental biology. Annu. Rev. Phytopathol.
2000, 38, 461−490.
activities of photoactive perylenequinones. Photochem. Photobiol.
1997, 65, 352−354.
(14) (a) Diwu, Z. J.; Lown, J. W. Photosensitization by Anticancer
Agents.12. Perylene Quinonoid Pigments, a Novel Type of Singlet
Oxygen Sensitizer. J. Photochem. Photobiol., A 1992, 64, 273−287.
(b) Diwu, Z. J.; Zimmermann, J.; Meyer, T.; Lown, J. W. Design,
Synthesis and Investigation of Mechanisms of Action of Novel
Protein-Kinase-C Inhibitors - Perylenequinonoid Pigments. Biochem.
Pharmacol. 1994, 47, 373−385. (c) Guedes, R. C.; Eriksson, L. A.
Photophysics, photochemistry, and reactivity: Molecular aspects of
perylenequinone reactions. Photochem. Photobiol. Sci. 2007, 6, 1089−
1096. (d) Mulrooney, C. A.; O’Brien, E. M.; Morgan, B. J.; Kozlowski,
M. C. Perylenequinones: Isolation, Synthesis, and Biological Activity.
Eur. J. Org. Chem. 2012, 2012, 3887−3904.
(15) (a) Daub, M. E.; Hangarter, R. P. Light-induced production of
singlet oxygen and superoxide by the fungal toxin, cercosporin. Plant
Physiol. 1983, 73, 855−857. (b) Daub, M. E.; Leisman, G. B.; Clark,
R. A.; Bowden, E. F. Reductive Detoxification as a Mechanism of
Fungal Resistance to Singlet Oxygen-Generating Photosensitizers.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9588−9592. (c) Leisman, G. B.;
Daub, M. E. Singlet Oxygen Yields, Optical-Properties, and
Phototoxicity of Reduced Derivatives of the Photosensitizer
Cercosporin. Photochem. Photobiol. 1992, 55, 373−379. (d) Bilski,
P.; Li, M. Y.; Ehrenshaft, M.; Daub, M. E.; Chignell, C. F. Vitamin B6
(pyridoxine) and its derivatives are efficient singlet oxygen quenchers
and potential fungal antioxidants. Photochem. Photobiol. 2000, 71,
129−134. (e) Xing, M. Z.; Zhang, X. Z.; Sun, Z. L.; Zhang, H. Y.
Perylenequinones act as broad-spectrum fungicides by generating
reactive oxygen species both in the dark and in the light. J. Agric. Food
Chem. 2003, 51, 7722−7724. (f) Weng, M.; Zhang, M. H.; Shen, T.
Electron transfer interaction between hypocrellin A and biological
substrates and quantitative analysis of superoxide anion radicals. J.
Chem. Soc., Perkin Trans. 2 1997, 2393−2397. (g) Daub, M. E.; Li,
M.; Bilski, P.; Chignell, C. F. Dihydrocercosporin singlet oxygen
production and subcellular localization: A possible defense against
cercosporin phototoxicity in Cercospora. Photochem. Photobiol. 2000,
71, 135−140.
(16) Castanheiro, T.; Suffert, J.; Donnard, M.; Gulea, M. Recent
advances in the chemistry of organic thiocyanates. Chem. Soc. Rev.
2016, 45, 494−505.
(17) (a) Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Selective
Access to 4-Substituted 2-Aminothiazoles and 4-Substituted 5-
Thiocyano-2-aminothiazoles from Vinyl Azides and Potassium
Thiocyanate Switched by Palladium and Iron Catalysts. Org. Lett.
2015, 17, 4698−4701. (b) Yang, H.; Duan, X. H.; Zhao, J. F.; Guo, L.
N. Transition-metal-free tandem radical thiocyanooxygenation of
olefinic amides: a new route to SCN-containing heterocycles. Org.
Lett. 2015, 17, 1998−2001.
(11) (a) Diwu, Z. J.; Lown, J. W. Photosensitization with Anticancer
Agents.14. Perylenequinonoid Pigments as New Potential Photo-
dynamic Therapeutic Agents - Formation of Tautomeric Semiquinone
Radicals. J. Photochem. Photobiol., A. 1992, 69, 191−199. (b) Hu, Y.
Z.; An, J. Y.; Jiang, L. J.; Chen, D. W. Spectroscopic Study on the
Photoreduction of Hypocrellin-a - Generation of Semiquinone
Radical-Anion and Hydroquinone. J. Photochem. Photobiol., A 1995,
89, 45−51. (c) Hu, Y. -z.; Jiang, L.-j Characteristics of the reaction
between semiquinone radical anion of hypocrellin A and oxygen in
aprotic media. J. Photochem. Photobiol., A 1996, 94, 37−41.
(d) Zhang, M. H.; Weng, M.; Chen, S.; Xia, W. L.; Jiang, L. J.;
Chen, D. W. Study of electron transfer interaction between
hypocrellin and N,N-diethylaniline by UV−visible, fluorescence,
electron spin resonance spectra and time-resolved transient
absorption spectra. J. Photochem. Photobiol., A 1996, 96, 57−63.
(e) He, Y. Y.; An, J. Y.; Jiang, L. J. pH Effect on the spectroscopic
behavior and photoinduced generation of semiquinone anion radical
of hypocrellin B. Dyes Pigm. 1999, 41, 79−87.
(18) (a) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J.
Synthesis of difluoromethyl thioethers from difluoromethyl trime-
thylsilane and organothiocyanates generated in situ. Angew. Chem., Int.
Ed. 2015, 54, 5753−5756. (b) Wang, F.; Chen, C.; Deng, G.; Xi, C.
Concise approach to benzisothiazol-3(2H)-one via copper-catalyzed
tandem reaction of o-bromobenzamide and potassium thiocyanate in
water. J. Org. Chem. 2012, 77, 4148−4151. (c) Ke, F.; Qu, Y.; Jiang,
Z.; Li, Z.; Wu, D.; Zhou, X. An efficient copper-catalyzed carbon-
sulfur bond formation protocol in water. Org. Lett. 2011, 13, 454−
457.
(19) (a) Zhang, G. Y.; Yu, J. T.; Hu, M. L.; Cheng, J. Palladium-
catalyzed cyanation of aryl halides with CuSCN. J. Org. Chem. 2013,
78, 2710−2714. (b) Wagner, A.; Ofial, A. R. Potassium Thiocyanate
as Source of Cyanide for the Oxidative alpha-Cyanation of Tertiary
Amines. J. Org. Chem. 2015, 80, 2848−2854.
(12) Li, C.; He, Y. P.; Ou, L. C.; Tian, M. J.; Yao, Z.; Guo, M. B.
Photophysical and photosensitive properties of Elsinochrome A. Chin.
Sci. Bull. 2006, 51, 1050−1054.
(13) (a) So, K. K.; Jo, I. S.; Chae, M. S.; Kim, J. M.; Chung, H. J.;
Yang, M. S.; Kim, B. T.; Kim, J. K.; Choi, J. K.; Kim, D. H. Improved
production of phleichrome from the phytopathogenic fungus
Cladosporium phlei using synthetic inducers and photodynamic ROS
production by phleichrome. J. Biosci. Bioeng. 2015, 119, 289−296.
(b) Hudson, J. B.; Imperial, V.; Haugland, R. P.; Diwu, Z. Antiviral
(20) (a) Shelke, A. M.; Suryavanshi, G. Fluoride-Assisted Synthesis
of 1,4,5,6-Tetrahydropyridazines via [4+2] Cyclodimerization of in
Situ-Generated Azoalkenes Followed by a C-N Bond Cleavage. Org.
Lett. 2016, 18, 3968−3971. (b) Curtin, D. Y.; Tristram, E. The
Reaction of Phenylhydrazine with α-Haloacetophenones1. J. Am.
Chem. Soc. 1950, 72, 5238−5242. (c) Gilchrist, T. L.; Wasson, R. C.;
J
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
King, F. D.; Wootton, G. Intramolecular cycloaddition of azoalkenes
derived from terminal alkenoic and alkynoic acids. J. Chem. Soc.,
Perkin Trans. 1 1987, 2511−2516. (d) Banert, K.; Hagedorn, M.
Syntheses and Diels-Alder reactions of 2-alkylazo-substituted 1, 3-
butadienes. Tetrahedron Lett. 1992, 33, 7331−7334.
(21) Wang, F.; Chen, C.; Deng, G.; Xi, C. J. Concise Approach to
Benzisothiazol-3(2H)-one via Copper-Catalyzed Tandem Reaction of
o-Bromobenzamide and Potassium Thiocyanate in Water. J. Org.
Chem. 2012, 77, 4148−4151.
(22) Ke, F.; Qu, Y. Y.; Jiang, Z. Q.; Li, Z. K.; Wu, D.; Zhou, X. G. An
Efficient Copper-Catalyzed Carbon-Sulfur Bond Formation Protocol
in Water. Org. Lett. 2011, 13, 454−457.
(23) (a) Chen, Z. K.; Yan, Q. Q.; Liu, Z. X.; Zhang, Y. H. Metal-Free
C-N- and N-N-Bond Formation: Synthesis of 1,2,3-Triazoles from
Ketones, N-Tosylhydrazines, and Amines in One Pot. Chem. - Eur. J.
2014, 20, 17635−17639. (b) Cai, Z. J.; Lu, X. M.; Zi, Y.; Yang, C.;
Shen, L. J.; Li, J.; Wang, S. Y.; Ji, S. J. I-2/TBPB Mediated Oxidative
Reaction of N-Tosylhydrazones with Anilines: Practical Construction
of 1,4-Disubstituted 1,2,3-Triazoles under Metal-Free and Azide-Free
Conditions. Org. Lett. 2014, 16, 5108−5111. (c) Chen, Z. K.; Yan, Q.
Q.; Yi, H.; Liu, Z. X.; Lei, A. W.; Zhang, Y. H. Efficient Synthesis of
1,2,3-Triazoles by Copper-Mediated C-N and N-N Bond Formation
Starting From N-Tosylhydrazones and Amines. Chem. - Eur. J. 2014,
20, 13692−13697.
(24) Nosaka, Y.; Nosaka, A. Y. Generation and Detection of
Reactive Oxygen Species in Photocatalysis. Chem. Rev. 2017, 117,
11302−11336.
(25) (a) Hatcher, J. M.; Coltart, D. M. Copper(I)-catalyzed addition
of Grignard reagents to in situ-derived N-sulfonyl azoalkenes: an
umpolung alkylation procedure applicable to the formation of up to
three contiguous quaternary centers. J. Am. Chem. Soc. 2010, 132,
4546−4547. (b) South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.;
Dukesherer, D. R. Synthesis and Reactions of Haloazodienes. A New
and General Synthesis of Substituted Pyridazines. J. Org. Chem. 1996,
61, 8921−8934. (c) Chen, J. R.; Dong, W. R.; Candy, M.; Pan, F. F.;
Jorres, M.; Bolm, C. Enantioselective synthesis of dihydropyrazoles by
formal [4+1] cycloaddition of in situ-derived azoalkenes and sulfur
ylides. J. Am. Chem. Soc. 2012, 134, 6924−6927.
(26) Saravanan, S.; Mohan, P.; Muthusubramanian, S. Formation of
reagent-selective products from 2-(4,5-dihydrothiazol-2-ylthio)-1-
arylethanone with different nucleophiles. J. Sulfur Chem. 2011, 32,
71−84.
(27) Kumar, A.; Muthyala, M. K.; Choudhary, S.; Tiwari, R. K.;
Parang, K. Ionic Liquid as Soluble Support for Synthesis of 1,2,3-
Thiadiazoles and 1,2,3-Selenadiazoles. J. Org. Chem. 2012, 77, 9391−
9396.
K
DOI: 10.1021/acs.joc.9b00545
J. Org. Chem. XXXX, XXX, XXX−XXX