Base Promoted Three-Component Annulation of 4-Diazoisochroman-3-imines with Dimethylsulfonium Ylides: Synthesis of Highly Functionalized Isochromeno[4,3- c]pyridazines

Article abstract of DOI:10.1021/acs.joc.0c02204

A novel method has been developed to synthesize a unique class of highly functionalized isochromeno[4,3-c]pyridazines. This reaction features an intermolecular functionalization of terminal nitrogen atom of diazo group of 4-diazoisochoman-3-imine with two dimethylsulfonium ylide components, followed by a base promoted 6-exo-trig cyclization step. Readily available starting materials, a broad substrate scope, and operationally simple, mild, and catalyst-free reaction conditions are the prominent features of this method.

Full text of DOI:10.1021/acs.joc.0c02204

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Article
Base Promoted Three-Component Annulation of
4‑Diazoisochroman-3-imines with Dimethylsulfonium Ylides:
Synthesis of Highly Functionalized Isochromeno[4,3‑c]pyridazines
Muhammad Suleman, Jianwei Xie, Zaibin Wang, Ping Lu,* and Yanguang Wang*
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ABSTRACT: A novel method has been developed to synthesize a unique class of highly functionalized isochromeno[4,3-
c]pyridazines. This reaction features an intermolecular functionalization of terminal nitrogen atom of diazo group of 4-
diazoisochoman-3-imine with two dimethylsulfonium ylide components, followed by a base promoted 6-exo-trig cyclization step.
Readily available starting materials, a broad substrate scope, and operationally simple, mild, and catalyst-free reaction conditions are
the prominent features of this method.
Considerable acquisition of Lewis basicity and electron density
of terminal nitrogen atom of diazo compounds require highly
reactive nucleophiles for their functionalization.15 Dimethylsul-
fonium ylides have been highly ranked as strong nucleophilic
reagents on Mayr’s nucleophilicity scale.16 In 2017−18, Doyle
and co-workers demonstrated the nucleophilic addition of
dimethylsulfonium ylides to electrophilic metal carbenes
generated in situ from diazo-acetates/imides.17 Recently, Xu’s
group reported a direct functionalization of the terminal
nitrogen atom of α-diazo-β-ketoesters/ketones by utilizing
dimethylsulfonium ylides as nucleophiles under catalyst-free
conditions (Scheme 1A).18 This functionalization proceeds via
the formation of zwitterionic intermediates, which are quite
stable as compared to their azo-counterparts.19
We have been working on the chemistry of three different
classes of stable cyclic diazo compounds, e.g., 3-diazoindolin-2-
imines,20a,b 4-diazoisochroman-3-imines,20c and 4-diazoisoqui-
nolin-3-ones,20d developed in our group. Previously, we utilized
dimethylsulfoxonium ylides as active nucleophiles, which were
added to electrophilic copper carbenes generated in situ from 3-
diazoindolin-2-imines (Scheme 1B).21 As a continuation of our
INTRODUCTION
■
Molecules containing pyridazine heterocycles have been in the
limelight for the past two decades. They have numerous
applications as chemo-luminescent materials,1 photovoltaic
materials,2 ligands for heterogeneous catalysis,3 nonlinear
optical materials,4 and in supramolecular chemistry.5 Moreover,
the pyridazine ring system has been considered as one of the best
for drug design by GlaxoSmithKline, as incorporation of
pyridazine ring into medically active drugs leads to the formation
of new diazines having promising pharmacological activities.6
Some examples of medicinally important pyridazine derivatives
with various biological activities like anticancer, anti-inflamma-
tory, anticonvulsant, antimicrobial, cytotoxic, and antifungal are
shown in Figure 1.7
General methods for pyridazine ring construction includes
annulation reactions between hydrazines and 1,4-dicarbonilic
precursors,8,9 functionalization of pyridazines via ortho metal-
ation,8,10 nucleophilic substitution,8,11 or cross-coupling reac-
tions (e.g., Sonogoshira, Stille, Suzuki reactions)8,12 as well as a
combination of cross-coupling and cyclization reactions.8
Despite all of these methods, the immense importance of the
pyridazine ring system demands the development of operation-
ally simple and efficient approaches for their synthesis.
Received: September 12, 2020
Diazo compounds are ambiphilic reagents intrinsically, as
they possess an electrophilic terminal nitrogen atom and a
nucleophilic carbon atom bonded to the diazo group.13 In the
past, research mainly focused on exploring the nucleophilic
character of diazo compounds,13 while the electrophilicity of
their terminal nitrogen atom has been rarely explored.13b,14
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Figure 1. Biologically ative pyridazine derivatives.
Scheme 1. Previous Work and Our Current Design
works on diazo chemistry and inspired by the recent success of
Xu and co-workers,18 we envisioned that the functionalization of
the terminal nitrogen atom of 4-diazoisochroman-3-imines with
dimethylsulfonium ylides in the presence of a base would lead to
the formation of hydrazones having a highly acidic proton
(Scheme 1C). If an excess of base is present, removal of the
acidic proton of hydrazone would generate a strong nucleophilic
center, which would be added to the electrophilic carbon atom
of 4-diazoisochroman-3-imines. Formation of a six-membered
pyridazine ring and the presence of a good leaving group like
tosyl at the electrophilic carbon atom of 4-diazoisochroman-3-
imines should favor the cascade annulation step (Scheme 1C).
The results of our successful effort in the catalyst-free
environment are disclosed here.
RESULTS AND DISCUSSION
■
To verify our hypothesis, 4-diazoisochroman-3-imines 1a and 2-
oxo-2-phenylethyl sulfonium bromide 2a (dimethylsulfonium
B
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a
Table 1. Optimization of Reaction Conditions
b
entry
base (equiv)
solvent
temp (°C)
yield (%)
c
1
K2CO3 (3.0)
K2CO3 (3.0)
Na2CO3 (3.0)
K3PO4 (3.0)
Et3N (3.0)
DIPEA (3.0)
t-BuOK (3.0)
none
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (2.5)
K2CO3 (3.5)
K2CO3 (4.0)
K2CO3 (4.5)
K2CO3 (5.0)
K2CO3 (4.0)
K2CO3 (4.0)
Cs2CO3 (4.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
46
66
ND
43
ND
ND
13
ND
8
5
10
10
51
71
82
82
71
84
46
trace
2
3
4
5
6
7
d
8
9
10
11
12
13
14
15
16
17
toluene
THF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
e
18
19
20
f
e
a
b
c
d
Reaction conditions: 1a (0.1 mmol), 2a (0.24 mmol), 2 mL of solvent, N2 atmosphere, 24 h reaction time. Isolated yields. Air atmosphere. No
e
f
base was used. Dry acetonitrile was used. Sulfonium bromide was replaced with corresponding sulfonium ylide, ND = not detected, rt = room
temperature.
Scheme 2. Substrate Scope of Diazo Compounds 1
ylide precursor) were selected as model substrates. As our first
trial, 1a and 2a were allowed to react in the presence of 3 equiv of
potassium carbonate (K2CO3) base in acetonitrile solvent at
room temperature under an air atmosphere (Table 1, entry 1).
The color of the reaction mixture was instantly changed from
yellow to purple, but a complex mixture formation was indicated
C
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Scheme 3. Substrate Scope of Sulfonium Salts 2
by TLC analysis. As the reaction time was prolonged, the color
of the reaction mixture was changed to deep red, and fortunately
after 24 h, product 3a was isolated in 46% yield. It is noteworthy
that a hydrazone intermediate was not obtained or detected even
by TLC after 24 h. The structure of 3a was identified through
HRMS, IR, and 1H and 13C NMR spectroscopic analysis and was
later confirmed with X-ray single crystal analysis.22 Delighted by
this result, we focused on optimization of reaction conditions.
While the reaction was performed under a nitrogen atmosphere,
3a was isolated in an improved yield of 66% (Table 1, entry 2).
When K2CO3 was replaced with other inorganic bases like
Na2CO3 and K3PO4 under a N2 atmosphere, the desired product
3a was not observed with the former, while a lower yield was
obtained with the latter (Table 1, entries 3 and 4). Tertiary
amines Et3N and DIPEA were also employed as base, but only a
trace amount of a visible yellow spot was detected by TLC while
desired product 3a was not detected (Table 1, entries 5 and 6).
Potassium tert-butoxide gave a poor yield of 3a with a complex
mixture of inseparable side products, while there was no reaction
when no base was used (Table 1, entries 7 and 8). K2CO3 turned
out to be necessary and an ideal base for this reaction. Several
other solvents like dichloroethane (DCE), toluene, tetrahydo-
furan (THF), and dimethyl sulfoxide (DMSO) were also
screened, but a poor yield of 3a was isolated in these cases
(Table 1, entries 9−12). Once the base loading was decreased to
2.5 equiv, the yield decreased to 51% (Table 1, entry 13).
Increasing the base loading from 3.5 equiv to 4.0 equiv improved
the reaction, and 3a was isolated in 71% and 82% yields,
respectively (Table 1, entries 14 and 15). Further increasing the
base loading to 4.5 equiv did not affect the reaction, while a
further increment of base to 5.0 equiv dropped the yield of 3a to
71% (Table 1, entries 16 and 17). When dried acetonitrile was
used along with 4.0 equiv of base, a slight improvement in
reaction was observed (Table 1, entry 18). While 2a was
replaced with its corresponding dimethylsulfonium ylide, the
yield of 3a was drastically decreased to 46% (Table 1, entry 19).
This drop in yield suggested that a controlled and sequential
supply of reactive sulfonium ylide is a key point in this
transformation, as the yield was better using ylide precursor 2a.
When 4.0 equiv of Cs2CO3 were used to replace K2CO3, only a
trace of the desired product was observed (Table 1, entry 20).
Finally, optimal reaction conditions were established to be 4
D
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Scheme 4. Gram Scale Reaction and Controlled Experiments
equiv of K2CO3 base, dry acetonitrile solvent, 24 h of reaction
time, a N2 atmosphere, and room temperature (Table 1, entry
18).
the ortho position of 2, the corresponding products 3k and 3l
were isolated in 66% and 62% yields, respectively. Even a lower
yield of product 3m (50%) was obtained when an electron-
withdrawing group (Cl) was present at the ortho position of 2.
The reaction was improved when both electron-donating and
-withdrawing groups CH3, OCH3, and Cl were present at the
meta position of 2. Thus, the corresponding products 3n−3p
were isolated in 78%, 80%, and 63% yields, respectively. The
presence of a substituent at the para position of 2 favored the
formation of 3. When electron-donating groups OCH3 and CH3
were present at the para position of 2, the corresponding
products 3q and 3r were obtained in excellent yields of 97% and
88%, respectively. The presence of halogens at the para position
of 2 gave the desired products 3s−3u in reasonable yields (72−
77%). When a strong electron-withdrawing group like cyano was
present at the para position of 2, 3v was obtained in a relatively
lower yield of 41%. 2-Oxo-2-naphthalenylethyl sulfonium
bromide 2n and 2-oxo-2-thiophenylethyl sulfonium bromide
2o were also feasible for these transformations to give
corresponding products 3w and 3x in 75% and 84% yields,
respectively. The reaction exhibited great potential when 6,7-
dioxolo-4-diazoisochroman-3-imine 1j was treated with 4-
methoxy sulfonium bromide 2h and 2-oxo-2-naphthalenylethyl
sulfonium bromide 2n. The corresponding products 3y and 3z
were isolated in 63% and 75% yields, respectively. Aliphatic
sulfonium salts like (2-methoxy-2-oxoethyl)- and (2-ethoxy-2-
oxoethyl)-dimethylsulfonium bromides were also tried, but a
very complex inseparable mixture formation was indicated by
TLC even after 24 h.
After establishing the optimal reaction conditions, we focused
on the substrate scope of 4-diazoisochroman-3-imines 1
(Scheme 2). The presence of electron-withdrawing groups like
CF3, F, and Cl at the 7 position of diazo compounds 1 slightly
retarded the reaction, and the corresponding products 3b−3d
were isolated in 74−76% yields. The presence of an electron-
donating group like OCH3 at the 7 position gave the
corresponding product 3e in an excellent yield of 92%. A
somewhat similar trend was observed for the substituents
present at the 6 position of diazo compounds 1, and
corresponding products 3f−3h were obtained in 73−81%
yields. Substituent R at one position of diazo compound 3 could
be a methyl or phenyl group, giving the corresponding products
3i and 3IA in 79% and 70% yields, respectively. When 6,7-
dioxolo-4-diazoisochroman-3-imine 1j was used for this trans-
formation, the desired product 3j was obtained in 67% yield.
Diazo compounds 1 with various sulfonyl groups attached like 4-
chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 2-
naphthalenesulfonyl, benzenesulfonyl,4-methoxybenzene-
sulfonyl, and methylsulfonyl were also useful for these
transformations. The highest yield of 3a (87%) was obtained
when diazo component 1k, with a 4-chlorobenzenesulfonyl
group attached, was used.
Subsequently the substrate scope of sulfonium ylides 2 was
explored (Scheme 3). The presence of substituents at the ortho
position of 2 had a significant effect on this reaction. When
electron-donating groups like OCH3 and CH3 were present at
E
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Scheme 5. Plausible Mechanism
A gram scale reaction of diazo compound 1a and sulfonium
bromide 2a was performed to demonstrate the practicality of
this method. Reaction of 4 mmol of 1a with 9.6 mmol of 2a
under standard conditions gave 1.296 g of product 3a (83%),
while 0.597 g of tosyl amine (87%) was also obtained as side
product (Scheme 4a). In order to verify the sequential addition
of two molecules of sulfonium bromides 2 to diazo compounds
1, a crossover experiment of 1a with 2k and 2o was performed.
Luckily, we isolated both the cross products 3za and 3zb in a 1:1
ratio along with usual products 3t and 3x (Scheme 4b).
Furthermore, to confirm our hypothesis of in situ formation of a
hydrazone intermediate, a controlled experiment was performed
to isolate it. When we decreased the base loading to 2 equiv in
the model reaction between 1a and 2a, hydrazone 4 was isolated
in 23% yield as the E isomer (Scheme 4c).23 It was surprising to
observe that the product 3a was not even detected by TLC by
using 2 equiv of base for 24 h and only a trace amount of 3a was
detected when the reaction time was prolonged to 48 h (Scheme
4c).
4 (Scheme 5). First, dimethylsulfonium ylide A is generated
from 2a in the presence of a base. Then the nucleophilic addition
of ylidic carbon to the electrophilic terminal nitrogen atom of 1a
leads to the formation of zwitter ionic intermediate B. Removal
of dimethyl sulfide from B leads to the formation of C, which
possesses a less sterically hindered aldimine moiety. The
nucleophilic carbon of second molecule of ylide A adds to this
aldimine carbon atom of C to form intermediate D with
resonance structure D′. In the presence of an excess of base
(Scheme 5, path A), D′ undergoes an elimination to form E with
the release of dimethyl sulfide. Subsequently, E undergoes a 6-
exo-trig cyclization to form intermediate F, which gives the final
product 3a by elimination of tosylamine. Alternatively (Scheme
5, path B), enamine 4 is generated from D through elimination
of dimethyl sulfide and can be isolated if only 2 equiv of base are
used. Excess base can promote the transformation of 4 to 3a via
intermediate E or its resonance structure E′.
In conclusion we have developed an efficient method to
synthesize a novel class of highly functionalized isochromeno-
[4,3-c]pyridazines through direct functionalization and cascade
annulation of 4-diazoisochroman-3-imines with sulfonium salts.
This reaction comprises a nucleophilic dimerization of in situ
generated dimethylsulfonium ylides with diazo compounds,
followed by a base promoted 6-exo-trig cyclization/aromatiza-
tion cascade process. Ease of preparation of starting materials, a
broad substrate scope, and operationally simple and mild
Moreover, when 4 was treated with 2 equiv of K2CO3 for 8 to
10 h in acetonitrile at room temperature, 3a was isolated in 98%
yield (Scheme 4d). This conversion suggests that hydrazone 4
should be the reaction intermediate generated in situ during the
formation of 3.
Based on our controlled experiments and literature report,18
the following mechanism is proposed for the formation of 3a and
F
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diazoisochroman-3-imine 1a (0.20 mmol), dimethyl(2-oxo-2-
phenylethyl)sulfonium bromide 2a (0.48 mmol), and K2CO3 (0.40
mmol). The Schlenk tube was evacuated and backfilled with nitrogen
three times. Freshly distilled acetonitrile (3.0 mL) was added to the
Schlenk tube in the continuous flow of nitrogen. The resulting mixture
was stirred vigorously at room temperature for 24 h. The solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (PE/EA = 3:1, v/v) to give pure
products 4 as a yellow solid.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3a). White solid; Rf = 0.20 (PE/EA = 5:1); Yield: 33 mg,
84%; Mp 202−205 °C; 1H NMR (600 MHz, CDCl3) δ 8.62 (d, J = 7.2
Hz,1H), 8.15 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.62−7.59
(m, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.47−7.47 (m, 4H), 7.14 (d, J = 7.2
Hz, 1H), 5.33 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.7,
191.0, 155.9, 151.1, 146.7, 136.4, 135.4, 134.0, 133.7, 132.2, 131.7,
131.4, 129.5, 129.0, 128.8, 128.3, 127.0, 126.0, 124.5, 68.8; IR (film,
cm−1):3062, 2929, 2865, 1681, 1667, 1597, 1522, 1449, 1408, 1363,
1297, 1266, 1181, 1079, 951, 863, 761; HRMS (ESI) m/z: [M + Na]+
Calcd for C25H16N2NaO3 415.1053; Found 415.1050.
reaction conditions in a catalyst-free environment are the merits
of this reaction. As the isochroman and pyridazine ring system is
an extensive part of biologically active compounds, these newly
synthesized isochromeno[4,3-c]pyridazines may find their
applications in medicinal chemistry in future.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise mentioned, all reactions
were carried out under a nitrogen atmosphere. Solvents and reagents
were purchased from commercial sources and used as received.
Acetonitrile was distilled over sodium. Melting points were measured
with a micro melting point apparatus. NMR spectra were obtained at
400 or 600 MHz for 1H NMR and 100 or 150 MHz for 13C NMR. 1H
NMR chemical shifts were quoted in parts per million (ppm)
referenced to 0.0 ppm for tetramethylsilane. 13C{1H} NMR spectra
were obtained by using the same NMR spectrometers, and chemical
shifts were reported in ppm referenced to the center line of a triplet at
77.00 ppm of CDCl3. The following abbreviations are used to describe
peak patterns as appropriate: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, dd = doublet of doblets, td = triplet of doublets,
ddd = doublet of doublet of doublets, dt = doublet of triplets. Coupling
constants J were reported in hertz (Hz). All high-resolution mass
spectra (HRMS) data were recorded by using an ESI ionization on
Quadrupole Time-of-Flight (Q-TOF) mass spectrometer. Flash
column chromatography was performed employing 300−400 mesh
silica gel. Thin layer chromatography (TLC) was performed on silica
gel HSGF254.
(8-(Trifluoromethyl)-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)-
bis(phenylmethanone) (3b). White solid; Rf = 0.33 (PE/EA = 6:1);
Yield: 34.1 mg, 74%; Mp 193−195 °C; 1H NMR (400 MHz, CDCl3) δ
8.75 (d, J = 8.4 Hz, 1H), 8.14 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.87−7.82
(m, 3H), 7.65−7.61 (m, 2H), 7.51−7.49 (m, 4H), 7.43 (s, 1H), 5.39 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.2, 190.7, 156.5, 151.4,
145.5, 136.2, 135.2, 134.2, 133.9, 133.8, 133.7 (q, CF3, 2JC−F = 32.9 Hz),
3
132.1, 131.3, 128.99, 128.91, 128.3, 126.4 (q, CF3, JC−F = 3.6 Hz),
125.0, 123.4 (q, CF3, 1JC−F = 270.1 Hz), 121.7 (q, CF3, 3JC−F = 3.7 Hz),
68.4; 19F NMR (376 MHz, CDCl3) δ − 63.14 (s, 3F); IR (film, cm−1):
3063, 2942, 2873, 1675, 1669, 1597, 1520, 1450, 1401, 1331, 1293,
1171, 1128, 1083, 955, 864, 779, 694; HRMS (ESI) m/z: [M + H]+
Calcd for C26H16F3N2O3 461.1108; Found 461.1107.
Diazo compounds 1 were synthesized according to our published
procedure.20c Sulfonium salts 2 were prepared according to the known
procedure.24
General Procedure for the Preparation of Compounds 3. To
an oven-dried Schlenk tube equipped with a magnetic stirrer bar were
added 4-diazoisochroman-3-imine 1 (0.10 mmol), dimethyl (2-oxo-2-
phenylethyl)sulfonium bromide 2 (0.24 mmol), and K2CO3 (0.40
mmol). The Schlenk tube was evacuated and backfilled with nitrogen
three times. Freshly distilled acetonitrile (2.0 mL) was added to the
Schlenk tube in the continuous flow of nitrogen. The resulting mixture
was stirred vigorously at room temperature for 24 h. Diazo compound 1
was consumed completely, and a sole major product was indicated by
TLC. The solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography on silica gel
(petroleum ether (PE)/ethyl acetate (EA) = 6:1−3:1, v/v) to give pure
products 3 as whitish solids.
Preparation of Compound 3a at 4 mmol Scale (Gram Scale).
To an oven-dried 100 mL Schlenk tube equipped with a magnetic
stirrer bar were added 4-diazoisochroman-3-imine 1a (1.308 g, 4
mmol), dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 2a (2.507 g,
9.6 mmol), and K2CO3 (2.211 g, 16 mmol). The Schlenk tube was
evacuated and backfilled with nitrogen three times. Freshly distilled
acetonitrile (60 mL) was added to the Schlenk tube in the continuous
flow of nitrogen. The resulting mixture was stirred vigorously at room
temperature for 24 h. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography on silica
gel (PE/EA = 3:1, v/v) to give pure products 3a. Tosyl amine was also
isolated as a side product.
Procedure of the Cross over Controlled Experiment. To an
oven-dried Schlenk tube equipped with a magnetic stirrer bar were
added 4-diazoisochroman-3-imines 1a (0.20 mmol) and 1.2 equiv each
of sulfonium bromide 2k (0.24 mmol) and 2o (0.24 mmol). A 4 equiv
amount of K2CO3 (0.80 mmol) was added, and the Schlenk tube was
evacuated and backfilled with nitrogen three times. Freshly distilled
acetonitrile (3.0 mL) was added to the Schlenk tube in the continuous
flow of nitrogen. The resulting mixture was stirred vigorously at room
temperature for 24 h. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography on silica
gel (PE/EA = 15:1−10:1, v/v) to give two cross products 3za and 3zb
in a 1:1 ratio along with usual products 3t and 3x.
(8-Fluoro-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3c). White solid; Rf = 0.24 (PE/EA = 6:1); Yield: 31.2
mg, 76%; Mp 202−205 °C; 1H NMR (400 MHz, CDCl3) δ 8.65−8.61
(m, 1H), 8.14 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.87 (dd, J = 8.4 Hz, 1.2 Hz,
2H), 7.61 (td, J = 7.2 Hz, 1.6 Hz, 2H), 7.51−7.46 (m, 4H), 7.27−7.25
(m, 1H), 6.88 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 5.30 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 191.5, 190.8, 165.1 (d, C−F, 1JC−F = 253.0 Hz),
155.9, 150.5, 146.0, 136.3, 135.3, 134.2 (d, C−F, 3JC−F = 8.2 Hz), 134.0,
133.7, 131.4, 128.9, 128.8, 128.3, 127.2, 127.1, 127.0, 122.3 (d, C−F,
4JC−F = 3.1 Hz), 117.0 (d, C−F, 2JC−F = 22.0 Hz), 111.7 (d, C−F, 2JC−F
=
23.3 Hz), 68.3 (d, C−F, 4JC−F = 2.2 Hz); 19F NMR (376 MHz, CDCl3)
δ −105.81 to −105.87 (m); IR (film, cm−1): 3067, 2933, 1675, 1659,
1595, 1449, 1368, 1268, 1208, 1109, 985, 924, 863, 719; HRMS (ESI)
m/z: [M + H]+ Calcd for C25H16FN2O3 411.1139; Found 411.1141.
(8-Chloro-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3d). White solid; Rf = 0.31 (PE/EA = 6:1); Yield: 32 mg,
75%; Mp 213−215 °C; 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.4
Hz, 1H), 8.13 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.86 (dd, J = 8.4 Hz, 1.2 Hz,
2H), 7.62 (td, J = 7.6 Hz, 1.6 Hz, 2H), 7.53 (dd, J = 8.4 Hz, 2.0 Hz, 1H),
7.51−7.46 (m, 4H), 7.16 (d, J = 2.0 Hz, 1H), 5.29 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 191.5, 190.8, 156.0, 150.8, 146.0, 138.5,
136.3, 135.3, 134.1, 133.8, 133.2, 131.3, 129.9, 128.9, 128.8, 128.3,
127.1, 125.9, 124.7, 124.6, 68.2; IR (film, cm−1): 3067, 2920, 2843,
1678, 1662, 1597, 1448, 1364, 1292, 1198, 1091, 978, 863, 778; HRMS
(ESI) m/z: [M + H]+ Calcd for C25H16ClN2O3 427.0844; Found
427.0845.
(8-Methoxy-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis-
(phenylmethanone) (3e). White solid; Rf = 0.28 (PE/EA = 3:1); Yield:
39 mg, 92%; Mp 213−216 °C; 1H NMR (600 MHz, CDCl3) δ 8.55 (d, J
= 9.0 Hz, 1H), 8.15 (dd, J = 8.4 Hz, 1.8 Hz, 2H), 7.86 (dd, J = 8.4 Hz,
1.2 Hz, 2H), 7.61−7.58 (m, 2H), 7.48−7.45 (m, 4H), 7.06 (dd, J = 9.0
Hz, 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 5.27 (s, 2H), 3.87 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3) δ 191.8, 190.9, 162.9, 155.2, 150.1,
146.7, 136.5, 135.5, 133.8, 133.7, 133.5, 131.4, 128.9, 128.8, 128.2,
126.60, 126.56, 118.6, 115.3, 109.6, 68.7, 55.6; IR (film, cm−1): 3058,
2938, 2843, 1679, 1659, 1611, 1515, 1449, 1398, 1367, 1212, 1157,
Procedure for the Preparation of Hydrazone 4. To an oven-
dried Schlenk tube equipped with a magnetic stirrer bar were added 4-
G
https://dx.doi.org/10.1021/acs.joc.0c02204
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1029, 958, 864, 721, 694; HRMS (ESI) m/z: [M + H]+ Calcd for
C26H19N2O4 423.1339; Found 423.1342.
101.9, 68.8; IR (film, cm−1):3058, 2903, 2854, 1674, 1668, 1596, 1457,
1357, 1268, 1174, 1037, 937, 875, 735; HRMS (ESI) m/z: [M + H]+
Calcd for C26H17N2O5 437.1132; Found 437.1132.
(9-Fluoro-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3f). White solid; Rf = 0.23 (PE/EA = 6:1); Yield: 30 mg,
73%; Mp 208−210 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 9.0
Hz, 2.4 Hz, 1H), 8.13 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.86 (dd, J = 8.4 Hz,
1.2 Hz, 2H), 7.64−7.60 (m, 2H), 7.45 (t, J = 7.6 Hz, 4H), 7.23 (dd, J =
8.4 Hz, 2.8 Hz, 1H), 7.16−7.13 (m, 1H), 5.31 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 191.5, 190.8, 163.3 (d, C−F, 1JC−F = 247.0 Hz),
145.9 (d, C−F, 4JC−F = 2.9 Hz), 136.3, 135.2, 134.1, 133.8, 131.3, 128.9,
128.8, 128.3, 128.2, 128.1, 127.3 (d, C−F, 4JC−F = 3.3 Hz), 127.2, 126.5
(d, C−F, 3JC−F = 8.1 Hz), 119.3 (d, C−F, 2JC−F = 22.6 Hz), 111.3 (d,
C−F, 2JC−F = 24.0 Hz), 68.5; 19F NMR (376 MHz, CDCl3) δ − 110.40
to −110.46 (m); IR (film, cm−1): 3062, 2916, 2843, 1685, 1669, 1595,
1449, 1356, 1266, 1175, 1087, 988, 876, 772, 716, 690; HRMS (ESI)
m/z: [M + H]+ Calcd for C25H16FN2O3 411.1139; Found 411.1138.
(9-Chloro-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3g). White solid; Rf = 0.27 (PE/EA = 6:1); Yield: 32 mg,
75%; Mp 256−258 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.0
Hz, 1H), 8.14 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.86 (dd, J = 8.4 Hz, 1.2 Hz,
2H), 7.62 (td, J = 6.8 Hz, 1.2 Hz, 2H), 7.52−7.47 (m, 5H), 7.10 (d, J =
8.4 Hz, 1H) 5.30 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.4,
190.8, 156.2, 151.1, 145.8, 136.3, 135.8, 135.2, 134.1, 133.8, 132.1,
131.4, 129.8, 128.9, 128.8, 128.3, 127.6, 127.2, 125.9, 124.4, 68.4; IR
(film, cm−1): 3054, 2920, 2856, 1685, 1669, 1597, 1522, 1457, 1408,
1350, 1286, 1159, 1090, 962, 876, 739, 691; HRMS (ESI) m/z: [M +
H]+ Calcd for C25H16ClN2O3 427.0844; Found 427.0842.
(9-Methoxy-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis-
(phenylmethanone) (3h). White solid; Rf = 0.20 (PE/EA = 3:1); Yield:
34.2 mg, 81%; Mp 222−224 °C; 1H NMR (400 MHz, CDCl3) δ 8.17−
8.13 (m, 3H), 7.87 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 7.61 (td, J = 7.6 Hz, 1.2
Hz, 2H), 7.51−7.46 (m 4H), 7.11−7.04 (m, 2H), 5.29 (s, 2H), 3.93 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.8, 190.9, 160.5, 155.9,
151.2, 146.6, 136.4, 135.3, 133.9, 133.7, 131.4, 128.9, 128.8, 128.3,
127.1, 127.0, 125.6, 123.9, 120.0, 107.4, 68.7, 55.7; IR (film, cm−1):
3066, 2951, 2843, 1686, 1666, 1596, 1457, 1354, 1206, 1175, 1053, 963,
894, 741; HRMS (ESI) m/z: [M + H]+ Calcd for C26H19N2O4
423.1339; Found 423.1341.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((2-methoxy-
phenyl)methanone) (3k). White solid; Rf = 0.30 (PE/EA = 3:1); Yield:
1
30 mg, 66%; Mp 209−211 °C; H NMR (400 MHz, CDCl3) δ 8.56
(dd, J = 6.4 Hz, 2.8 Hz, 1H), 8.06 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.55−
7.45 (m, 5H), 7.14−7.12 (m, 1H), 7.09−7.06 (m, 1H), 7.03−6.91 (m,
3H), 5.30 (s, 2H), 3.72 (s, 3H), 3.56 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 193.4, 189.5, 159.8, 158.9, 154.9, 149.9, 146.3, 135.3,
133.5, 131.8, 131.6, 131.1, 130.8, 129.6, 129.2, 127.2, 126.7, 125.8,
124.4, 124.1, 120.9, 120.4, 112.2, 111.8, 68.6, 55.8, 55.7; IR (film,
cm−1): 3071, 2943, 2843, 1673, 1661. 1597, 1465, 1366, 1305, 1253,
1162, 1020, 953, 868, 754; HRMS (ESI) m/z: [M + H]+ Calcd for
C27H21N2O5 453.1445; Found 453.1445.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(o-tolyl-
methanone) (3l). White solid; Rf = 0.26 (PE/EA = 6:1); Yield: 26.2 mg,
62%; Mp 158−160 °C; 1H NMR (400 MHz, CDCl3) δ 8.58−8.55 (m,
1H), 7.58−7.51 (m, 3H), 7.48−7.38 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H),
7.26−7.18 (m, 3H), 7.15−7.13 (m, 1H), 5.34 (s, 2H), 2.74 (s, 3H),
2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 193.1, 156.2,
150.7, 146.8, 140.7, 138.7, 136.3, 135.3, 132.8, 132.3, 132.1, 131.7,
131.6, 131.5, 131.2, 131.1, 129.4, 127.6, 126.1, 125.7, 125.3, 124.5,
124.4, 68.8, 21.7, 20.7; IR (film, cm−1): 3067, 3015, 2927, 2869, 1682,
1669, 1600, 1570, 1458, 1362, 1293, 1256, 1073, 951, 866, 736; HRMS
(ESI) m/z: [M + H]+ Calcd for C27H21N2O3 421.1547; Found
421.1545.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((2-chlorophenyl)-
methanone)(3m). White solid; Rf = 0.19 (PE/EA = 6:1); Yield: 23 mg,
50%; Mp 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 8.57−8.55 (m,
1H), 7.95 (dd, J = 7.6 Hz,1.6 Hz, 1H), 7.56 (dd, J = 7.6 Hz,1.6 Hz, 1H),
7.54−7.51 (m, 2H), 7.49−7.35 (m, 6H), 7.16−7.14 (m, 1H), 5.39 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.1, 189.6, 154.0, 150.9,
147.1, 136.8, 134.7, 133.8, 133.7, 132.6, 132.3, 132.2, 131.7, 131.4,
130.6, 130.1, 129.5, 127.6, 127.0, 126.6, 126.0, 124.6, 124.4, 68.9; IR
(film, cm−1): 3049, 2920, 2852, 1691, 1683, 1588, 1435, 1411, 1364,
1301, 1202, 1055, 952, 862, 746; HRMS (ESI) m/z: [M + H]+ Calcd
for C25H15Cl2N2O3 461.0454; Found 461.0457.
(6-Methyl-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone)(3i). White solid; Rf = 0.20 (PE/EA = 6:1); Yield: 32.2 mg,
79%; Mp 165−167 °C; 1H NMR (600 MHz, CDCl3) δ 8.65−8.63 (m,
1H), 8.16 (dd, J = 7.2 Hz, 1.2 Hz, 2H), 7.87 (dd, J = 8.4 Hz, 1.2 Hz, 2H),
7.62−7.59 (m, 2H), 7.55−7.53 (m, 2H), 7.49−7.46 (m, 4H), 7.15−
7.13 (m, 1H), 5.50 (q, J = 7.2 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 191.8, 191.1, 155.9, 149.9, 146.5,
136.7, 136.5, 135.5, 133.9, 133.6, 132.1, 131.4, 129.2, 128.9, 128.7,
128.2, 127.5, 125.0, 124.5, 124.4, 75.8, 22.9; IR (film, cm−1): 3064,
2979, 1667, 1597, 1449, 1404, 1354, 1291, 1256, 1180, 1079, 960, 906,
856, 733; HRMS (ESI) m/z: [M + H]+ Calcd for C26H19N2O3
407.1390; Found 407.1389.
(6-Phenyl-6H-isochromeno[4,3-c]pyridazine-3,4-diyl)bis(phenyl-
methanone) (3IA). Light green solid, Rf = 0.27 (PE/EA = 6:1); Yield:
33 mg, 70%; Mp 115−117 °C 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J
= 7.6 Hz, 1H), 8.12 (dd, J = 7.2 Hz, 1.2 Hz, 2H), 7.64−7.50 (m, 6H),
7.48−7.44 (m, 2H), 7.31- 7.28 (m, 3H), 7.23−7.19 (m, 2H), 7.08 (d, J
= 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 2H), 6.41 (bs, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 191.8, 190.9, 155.9, 149.7, 146.8, 138.1, 136.2,
135.4, 133.7, 133.6, 133.5, 132.1, 131.1, 129.6, 129.1, 128.8, 128.7,
128.6, 128.2, 127.9, 127.7, 126.4, 126.0, 124.5, 80.3; IR (film, cm−1):
3063, 2978, 1666, 1597, 1519, 1449, 1399, 1292, 1074, 943, 862, 732,
693; HRMS (ESI) m/z: [M + H]+ Calcd for C31H21N2O3 469.1547;
Found 469.1547.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(m-tolyl-
methanone)(3n). White solid; Rf = 0.30 (PE/EA = 6:1); Yield: 33 mg,
1
78%; Mp 82−84 °C; H NMR (400 MHz, CDCl3) δ 8.62−8.60 (m,
1H), 7.96 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 7.91 (t, J = 1.6 Hz, 1H), 7.71 (bs,
1H), 7.62 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 7.57−7.50 (m, 2H), 7.43−7.41
(m, 2H), 7.39−7.33 (m, 2H), 7.16−7.13 (m, 1H), 5.32 (s, 2H), 2.40 (s,
3H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.8, 191.2,
156.0, 151.1, 146.6, 138.7, 137.9, 136.3, 135.4, 134.9, 134.5, 132.1,
131.7, 131.6, 129.4, 129.2, 128.7, 128.6, 128.1, 127.0, 126.4, 126.0,
124.4, 124.3, 68.8, 21.3, 21.2; IR (film, cm−1): 3067, 2921, 2860, 1682,
1668, 1602, 1460, 1407, 1363, 1302, 1171, 967, 796, 734; HRMS (ESI)
m/z: [M + H]+ Calcd for C27H21N2O3 421.1547; Found 421.1547.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((3-methoxy-
phenyl)methanone)(3o). White solid; Rf = 0.23 (PE/EA = 5:1); Yield:
36.2 mg, 80%; Mp 98−100 °C; 1H NMR (600 MHz, CDCl3) δ 8.61
(dd, J = 7.2 Hz, 1.8 Hz, 1H), 7.78 (dt, J = 7.2 Hz, 1.2 Hz, 1H), 7.61 (q, J
= 1.2 Hz, 1H), 7.54−7.52 (m, 2H), 7.49 (t, J = 1.8 Hz, 1H), 7.39−7.32
(m, 3H), 7.17−7.13 (m, 3H), 5.33 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 191.4, 190.7, 160.0, 159.5, 155.8,
151.1, 146.7, 137.7, 136.6, 132.1, 131.7, 129.8, 129.4, 129.2, 126.9,
126.0, 124.7, 124.4, 122.2, 120.75, 120.73, 114.7, 112.5, 68.8, 55.5,
55.4; IR (film, cm−1): 3072, 2940, 2836, 1683, 1667, 1596, 1486, 1463,
1364, 1274, 1195, 1039, 970, 862, 765; HRMS (ESI) m/z: [M + H]+
Calcd for C27H21N2O5 453.1445; Found 453.1446.
(6H-[1,3]Dioxolo[4′,5′:6,7]isochromeno[4,3-c]pyridazine-3,4-
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((3-chlorophenyl)-
methanone)(3p). White solid; Rf = 0.26 (PE/EA = 6:1); Yield: 29 mg,
63%; Mp 186−189 °C; 1H NMR (600 MHz, CDCl3) δ 8.62−8.61 (m,
1H), 8.14 (t, J = 1.8 Hz, 1H), 8.09−8.07 (m, 1H), 7.85−7.84 (m, 1H),
7.71−7.69 (m, 1H), 7.59−7.54 (m, 4H), 7.45−7.42 (m, 2H), 7.16−
7.15 (m, 1H), 5.35 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 190.4,
189.6, 155.3, 151.1, 147.0, 137.9, 136.8, 135.3, 134.6, 133.9, 133.7,
132.4, 131.7, 131.2, 130.2, 129.6, 128.7, 127.1, 126.5, 125.7, 124.6,
diyl)bis(phenylmethanone) (3j). White solid; Rf = 0.22 (PE/EA =
1
4:1); Yield: 29.4 mg, 67%; Mp 205−207 °C; H NMR (400 MHz,
CDCl3) δ 8.14 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 8.03 (s, 1H), 7.87 (dd, J =
8.0 Hz, 1.2 Hz, 2H), 7.63−7.58 (m, 2H), 7.50−7.46 (m, 4H), 6.57 (s,
1H), 6.09 (s, 2H), 5.23 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
191.8, 190.9, 155.4, 151.3, 150.4, 149.0, 146.6, 136.4, 135.4, 133.9,
133.6, 131.4, 128.9, 128.8, 128.2, 127.1, 126.5, 120.3, 104.6, 104.4,
H
https://dx.doi.org/10.1021/acs.joc.0c02204
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
124.5, 68.9; IR (film, cm−1): 3067, 2929, 1684, 1668, 1569, 1521, 1461,
1408, 1364, 1300, 1256, 1202, 1079, 963, 879, 767, 726; HRMS (ESI)
m/z: [M + H]+ Calcd for C25H15Cl2N2O3 461.0454; Found 461.0457.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((4-methoxy-
phenyl)methanone)(3q). White solid; Rf = 0.25 (PE/EA = 3:1); Yield:
44 mg, 97%; Mp 114−116 °C; 1H NMR (400 MHz, CDCl3) δ 8.61−8.
59 (m, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.57−
7.49 (m, 2H), 7.15−7.13 (m, 1H), 6.96−6.93 (m, 4H), 5.31 (s, 2H),
3.88 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2,
189.2, 164.21, 164.16, 156.5, 151.0, 146.5, 133.9, 131.9, 131.7, 131.4,
129.7, 129.6, 129.4, 128.3, 127.0, 126.4, 126.2, 124.4, 124.3, 114.1,
113.6, 68.8, 55.53, 55.51; IR (film, cm−1): 3080, 2936, 2840, 1674,
1660, 1597, 1510, 1460, 1408, 1364, 1260, 1172, 1079, 974, 868, 772;
HRMS (ESI) m/z: [M + H]+ Calcd for C27H21N2O5 453.1445; Found
453.1441.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(p-tolyl-
methanone)(3r). White solid; Rf = 0.27 (PE/E.A = 6:1); Yield: 37 mg,
88%; Mp 236−238 °C; 1H NMR (400 MHz, CDCl3) δ 8.62−8.60 (m,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.77−7.75 (m, 2H), 7.57−7.50 (m, 2H),
7.26−7.26 (m, 4H), 7.15−7.13 (m, 1H), 5.32 (s, 2H), 2.424 (s, 3H),
2.415 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.3, 190.4,
156.2, 151.0, 146.6, 145.0, 144.7, 134.1, 132.9, 132.0, 131.7, 131.6,
129.5, 129.4, 129.1, 129.0, 127.1, 126.1, 124.44, 124.37, 68.7, 21.83,
21.81; IR (film, cm−1): 3032, 2921, 2841, 1678, 1661, 1605, 1460,
1411, 1363, 1298, 1180, 1078, 974, 867, 738; HRMS (ESI) m/z: [M +
H]+ Calcd for C27H21N2O3 421.1547; Found 421.1547.
773; HRMS (ESI) m/z: [M + H]+ Calcd for C27H15N4O3 443.1139;
Found 443.1141.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(naphthalen-2-
ylmethanone)(3w). White solid; Rf = 0.24 (PE/EA = 6:1); Yield: 37
1
mg, 75%; Mp 140−142 °C; H NMR (400 MHz, CDCl3) δ 8.83 (s,
1H), 8.66 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.14
(dd, J = 8.8 Hz, 1.6 Hz, 1H), 8.04 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.95 (t, J
= 8.4 Hz, 2H), 7.89−7.84 (m, 4H), 7.62−7.48 (m, 6H), 7.13 (d, J = 6.8
Hz, 1H), 5.32 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.7,
190.7, 156.3, 151.3, 146.8, 136.1, 135.8, 134.7, 133.9, 132.5, 132.2,
132.1, 131.8, 131.6, 130.1, 129.8, 129.5, 128.9, 128.8, 128.1, 127.8,
127.9, 127.7, 126.8, 126.6, 126.1, 125.8, 124.5, 124.4, 123.8, 68.8; IR
(film, cm−1): 3058, 2925, 2852, 1681, 1661, 1625, 1595, 1467, 1409,
1364, 1300, 1197, 1076, 973, 889, 734; HRMS (ESI) m/z: [M + H]+
Calcd for C33H21N2O3 493.1547; Found 493.1550.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis(thiophen-2-ylme-
thanone) (3x). White solid; Rf = 0.22 (PE/EA = 4:1); Yield: 34 mg,
84%; Mp 132−134 °C; 1H NMR (400 MHz, CDCl3) δ 8.66−8.63 (m,
1H), 8.38 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 7.82 (dd, J = 4.8 Hz, 1.2 Hz, 1H),
7.74 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.59−7.54 (m, 2H), 7.45 (dd, J = 4.0
Hz, 1.2 Hz, 1H), 7.21−7.16 (m, 2H), 7.11 (dd, J = 4.8 Hz, 4.0 Hz, 1H),
5.28 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.1, 180.9, 153.7,
151.3, 147.4, 143.6, 139.3, 137.7, 137.6, 134.8, 133.7, 132.3, 131.8,
129.5, 128.4, 127.9, 125.9, 124.53, 124.52, 68.9; IR (film, cm−1): 3071,
2919, 2852, 1653, 1633, 1524, 1411, 1366, 1266, 1199, 1050, 913, 848,
761; HRMS (ESI) m/z: [M + H]+ Calcd for C21H13N2O3S2 405.0362;
Found 405.0366.
(6H-[1,3]Dioxolo[4′,5′:6,7]isochromeno[4,3-c]pyridazine-3,4-
diyl)bis((4-methoxyphenyl)methanone) (3y). White solid; Rf = 0.21
(PE/EA = 5:1); Yield: 31.3 mg, 63%; Mp 244−246 °C; 1H NMR (400
MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 8.03 (s, 1H), 7.83 (d, J = 8.8
Hz, 2H), 6.94 (2d, J = 8.8 Hz, 4H), 6.58 (s, 1H), 6.09 (s, 2H), 5.22 (s,
2H), 3.88 and 3.87 (2s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
190.3, 189.2, 164.2, 164.1, 156.0, 151.1, 150.2, 148.9, 146.4, 133.9,
131.4, 129.8, 129.7, 128.4, 127.0, 126.6, 126.4, 120.5, 114.1, 113.6,
104.6, 104.4, 101.9, 68.7, 55.54, 55.52; IR (film, cm−1): 3071, 2961,
2843, 1669, 1660, 1597, 1457, 1356, 1261, 1167, 1034, 935, 878, 767;
HRMS (ESI) m/z: [M + H]+ Calcd for C28H21N2O7 497.1343; Found
497.1341.
(6H-[1,3]Dioxolo[4′,5′:6,7]isochromeno[4,3-c]pyridazine-3,4-
diyl)bis(naphthalen-2-ylmethanone) (3z). White solid; Rf = 0.26
(PE/EA = 6:1); Yield: 40.2 mg, 75%; Mp 174−176 °C; 1H NMR (400
MHz, CDCl3) δ 8.82 (s, 1H), 8.32 (s, 1H), 8.12 (dd, J = 8.8 Hz, 1.6 Hz,
1H), 8.09 (s, 1H), 8.03 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.96 and 7.94 (2d, J
= 8.8 Hz, 2H), 7.89−7.85 (m,4H), 7.61 and 7.59 (2d, J = 7.2 Hz, 2H),
7.53 and 7.50 (2d, J = 7.2 Hz, 2H), 6.56 (s, 1H), 6.09 (s, 2H), 5.22 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.8, 190.7, 155.8, 151.3,
150.5, 149.0, 146.7, 136.1, 135.8, 134.6, 133.9, 132.7, 132.5, 132.2,
131.5, 130.1, 129.8, 128.9, 128.8, 128.1, 127.9, 127.7, 127.1, 126.8,
126.7, 126.6, 125.8, 123.9, 120.4, 104.7, 104.4, 102.0, 68.8; IR (film,
cm−1): 3057, 2908, 2267, 1677, 1661, 1595, 1457, 1358, 1247, 1173,
1037, 928, 816, 735; HRMS (ESI) m/z: [M + H]+ Calcd for
C34H21N2O5 537.1445; Found 537.1449.
(4-(4-Chlorobenzoyl)-6H-isochromeno[4,3-c]pyridazin-3-yl)-
(thiophen-2-yl)methanone (3za). White solid; Rf = 0.21 (PE/EA =
6:1); Yield: 7 mg, 8%; Mp 212−214 °C; 1H NMR (600 MHz, CDCl3) δ
8.65 (dd, J = 6.6 Hz, 1.8 Hz, 1H), 8.41 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.82
(dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.58−7.53
(m,2H), 7.47−7.44 (m, 2H), 7.21−7.19 (m, 1H), 7.15 (d, J = 6.6 Hz,
1H), 5.34 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 190.2, 181.1,
154.2, 151.3, 147.2, 140.3, 139.1, 137.8, 137.7, 134.8, 132.4, 131.7,
130.0, 129.6, 129.3, 127.9, 126.3, 125.9, 124.6, 124.5, 68.9; IR (film,
cm−1): 3068, 2934, 2854, 1678, 1635, 1587, 1463, 1368, 1264, 1171,
1091, 971, 843, 770; HRMS (ESI) m/z: [M + H]+ Calcd for
C23H14ClN2O3S 433.0408; Found 433.0407.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((4-fluorophenyl)-
methanone)(3s). White solid; Rf = 0.29 (PE/EA = 6:1); Yield: 31 mg,
72%; Mp 152−154 °C; 1H NMR (600 MHz, CDCl3) δ 8.62−8.60 (m,
1H), 8.24 (dd, J = 9.0 Hz, 5.4 Hz, 2H), 7.88 (dd, J = 8.4 Hz, 4.8 Hz, 2H),
7.58−7.53 (m, 2H), 7.17−7.14 (m, 5H), 5.34 (s, 2H); 13C{1H} NMR
(150 MHz, CDCl3) δ 190.1, 189.2, 166.3 (d, C−F, 1JC−F = 255.1 Hz),
3
155.8, 151.1, 146.8, 134.3 (d, C−F, JC−F = 9.4 Hz), 132.9 (d, C−F,
4JC−F = 1.8 Hz), 132.3, 131.7, 131.68, 131.65, 129.6, 126.8, 125.9, 124.5,
116.1 (d, C−F, 2JC−F = 22.2 Hz), 115.5 (d, C−F, 2JC−F = 21.7 Hz), 68.9;
IR (film, cm−1): 3075, 2916, 2869, 1671, 1662, 1595, 1506, 1412, 1362,
1297, 1243, 1153, 1070, 972, 851, 772; 19F NMR (376 MHz, CDCl3) δ
−103.08 to −103.16 (m), −103.24 to −103.32 (m); HRMS (ESI) m/z:
[M + H]+ Calcd for C25H15F2N2O3 429.1045; Found 429.1046.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((4-chlorophenyl)-
methanone) (3t). White solid; Rf = 0.31 (PE/EA = 6:1); Yield: 33.2
mg, 72%; Mp 253−255 °C; 1H NMR (400 MHz, CDCl3) δ 8.62−8.60
(m, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.59−7.54
(m, 2H), 7.47−7.45 (m, 4H), 7.17−7.15 (m, 1H), 5.34 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 189.6, 155.5, 151.1, 146.9,
140.6, 140.5, 134.7, 133.5, 132.9, 132.4, 131.7, 130.3, 129.6, 129.3,
128.7, 126.6, 125.8, 124.5, 68.9; IR (film, cm−1): 3062, 2925, 2860,
1684, 1662, 1586, 1457, 1409, 1362, 1266, 1177, 1091, 974, 864, 763;
HRMS (ESI) m/z: [M + H]+ Calcd for C25H15Cl2N2O3 461.0454;
Found 461.0454.
(6H-Isochromeno[4,3-c]pyridazine-3,4-diyl)bis((4-bromophenyl)-
methanone) (3u). White solid; Rf = 0.28 (PE/EA = 6:1); Yield: 42.2
mg, 77%; Mp 250−252 °C; 1H NMR (600 MHz, CDCl3) δ 8.60 (d, J =
6.6 Hz, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.64−
7.55 (m, 6H), 7.15 (d, J = 6.6 Hz, 1H), 5.34 (s, 2H); 13C{1H} NMR
(150 MHz, CDCl3) δ 190.7, 189.7, 155.5, 151.1, 146.9, 135.2, 133.9,
132.9, 132.4, 132.2, 131.7, 130.3, 129.6, 129.41, 129.39, 126.6, 125.8,
124.5, 124.4, 68.9; IR (film, cm−1): 3071, 2946, 2841, 1678, 1668, 1583,
1457, 1363, 1264, 1173, 1068, 973, 862, 767; HRMS (ESI) m/z: [M +
H]+ Calcd for C25H15Br2N2O3 548.9444; Found 548.9442.
4,4′-(6H-Isochromeno[4,3-c]pyridazine-3,4-dicarbonyl)dibenzo-
nitrile (3v). White solid; Rf = 0.22 (PE/EA = 5:1); Yield: 18.2 mg, 41%;
Mp 292−294 °C; 1H NMR (400 MHz, CDCl3) δ 8.63−8. 61 (m, 1H),
8.28 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.83−7.79 (m, 4H),
7.60−7.58 (m, 2H), 7.19−7.17 (m, 1H), 5.37 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 190.3, 189.6, 154.7, 151.2, 147.2, 139.0, 138.3,
132.85, 132.81, 132.1, 131.8, 131.6, 129.8, 129.1, 126.3, 125.4, 124.7,
124.6, 117.9, 117.7, 117.2, 116.9, 69.1; IR (film, cm−1): 3101, 2933,
2843, 2228, 1691, 1683, 1597, 1412, 1364, 1261, 1199, 1079, 975, 866,
(3-(4-Chlorobenzoyl)-6H-isochromeno[4,3-c]pyridazin-4-yl)-
(thiophen-2-yl)methanone (3zb). White solid; Rf = 0.19 (PE/EA =
5:1); Yield: 7 mg, 8%; Mp 208−210 °C; 1H NMR (600 MHz, CDCl3) δ
8.61−8.59 (m, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 5.4 Hz, 1.2
Hz, 1H), 7.57−7.55 (m, 2H), 7.52 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.46 (d,
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J = 8.4 Hz, 2H), 7.18−7.16 (m,1H), 7.46 (t, J = 4.2 Hz, 1H), 5.39 (s,
2H); 13C{1H} NMR (150 MHz, CDCl3) δ189.6, 183.0, 155.1, 151.1,
147.1, 143.5, 140.4, 135.2, 134.2, 133.8, 132.7, 132.3, 131.7, 130.0,
129.6, 129.2, 128.7, 128.5, 126.3, 125.9, 124.5, 68.9; IR (film, cm−1):
3062, 2916, 2860, 1665. 1652, 1586, 1411, 1364, 1265, 1175, 1077, 970,
865, 769, 727; HRMS (ESI) m/z: [M + H]+ Calcd for C23H14ClN2O3S
433.0408; Found 433.0410.
N-((3E,4Z)-4-(2-((Z)-1,4-Dioxo-1,4-diphenylbut-2-en-2-yl)-
hydrazono)isochroman-3-ylidene)-4-methylbenzenesulfonamide
(4). Yellow solid; Rf = 0.27 (PE/EA = 3:1); Yield: 26 mg, 23%; Mp
208−210 °C; 1H NMR (400 MHz, CDCl3) δ 14.74 (s, 1H), 8.13 (d, J =
8.0 Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 7.2 Hz, 2H), 7.63−
7.60 (m, 1H), 7.55−7.48 (m, 3H), 8.13 (t, J = 7.6 Hz, 2H), 7.35 (d, J =
8.0 Hz, 2H), 7.28−7.24 (m, 1H), 7.12−7.05 (m,2H), 6.87 (d, J = 7.6
Hz, 1H), 6.25 (s, 1H), 5.41 (s, 2H), 2.44 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 191.5, 189.4, 155.9, 154.4, 143.7, 138.1, 138.0, 135.5,
134.1, 132.4, 129.6, 129.3, 129.25, 129.21, 129.0, 128.9, 128.5, 128.4,
127.9, 125.9, 123.6, 123.5, 96.8, 70.8, 21.7; IR (film, cm−1); 3326, 3054,
2988, 2912, 1679, 1667, 1611, 1584, 1467, 1397, 1266, 1066, 963, 878,
750; HRMS (ESI) m/z: [M + Na]+ Calcd for C32H25N3O5SNa
586.1407; Found 586.1406.
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AUTHOR INFORMATION
■
Corresponding Authors
Ping Lu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P. R. China; orcid.org/0000-0002-
3221-3647; Email: pinglu@zju.edu.cn
Yanguang Wang − Department of Chemistry, Zhejiang
University, Hangzhou 310027, P. R. China; orcid.org/
0000-0002-5096-7450; Email: orgwyg@zju.edu.cn
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Authors
Muhammad Suleman − Department of Chemistry, Zhejiang
University, Hangzhou 310027, P. R. China
Jianwei Xie − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P. R. China
Zaibin Wang − Department of Chemistry, Zhejiang University,
Hangzhou 310027, P. R. China
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Notes
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ACKNOWLEDGMENTS
■
The authors thank the financial support from the National
Natural Science Foundation of China (Grant Nos. 21772169
and 21632003).
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