Annulation Reaction of in Situ Generated Azoalkenes with Azlactones: Access to 4,5-Dihydropyridazin-3(2 H)-Ones

Article abstract of DOI:10.1021/acs.joc.0c01592

An unprecedented [4 + 2] annulation reaction between in situ formed azoalkenes and azlactones has been developed. This reaction provides a facile access to an array of 4,5-dihydropyridazin-3(2H)-one derivatives, which are very promising in medicinal applications as potential biologically active candidates. Notably, these dihydropyridazinones could also be synthesized via a one-pot reaction protocol by using the in situ formed azlactones from N-Acyl amino acids and in situ generated azoalkenes from α-halogeno hydrazones. The potential applications of the methodology were also demonstrated by gram-scale experiments and the versatile conversions of the products into other nitrogen-containing compounds.

Full text of DOI:10.1021/acs.joc.0c01592

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Article
[4+2] Annulation Reaction of in situ Generated Azoalkenes
with Azlactones: Access to 4,5-Dihydropyridazin-3(2H)-ones
Wei-Cheng Yuan, Bao-Xue Quan, Jian-Qiang Zhao, Yong You, Zhen-Hua Wang, and Ming-Qiang Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01592 • Publication Date (Web): 28 Aug 2020
Downloaded from pubs.acs.org on August 30, 2020
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[
4+2] Annulation Reaction of in situ Generated Azoalkenes with
Azlactones: Access to 4,5-Dihydropyridazin-3(2H)-ones
Wei-Cheng Yuan,†,‡,* Bao-Xue Quan, Jian-Qiang Zhao, * Yong You, Zhen-Hua Wang,
‡
†,
†
†
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Ming-Qiang Zhou‡
†Institute for Advanced Study, Chengdu University, Chengdu 610106, China
‡National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China
Table of Contents
Abstract
An unprecedented [4+2] annulation reaction between in situ formed azoalkenes and
azlactones has been developed. This reaction provides a facile access to an array of
4
,5-dihydropyridazin-3(2H)-one derivatives, which are very promising in medicinal application as
potential biologically active candidates. Notably, these dihydropyridazinones also could be
synthesized via a one-pot reaction protocol by using the in situ formed azlactones from N-acyl
amino acids and in situ generated azoalkenes from α-halogeno hydrazones. The potential
applications of the methodology were also demonstrated by the gram scale experiments and the
versatile conversions of the products into other nitrogen-containing compounds.
INTRODUCTION
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Pyridazinones have becoming the privileged scaffolds for drug discovery. Due to the easy
functionalization to result in structurally novel compounds with rich biological activities,
extensive effort has been devoted to the development of various methods for the synthesis of
pyridazinone derivatives.2 In particular, 4,5-dihydropyridazin-3(2H)-ones, as one type of
pyridazinone derivatives, are ubiquitous core structure unit found in many pharmaceuticals and
biologically active molecules (Figure 1). For examples, clinical trials showed that Indolidan and
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Bemoradan have effective antihypertensive activity, and Levosimendan and Pimobendan exhibit
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certain anti-congestive heart failure activities. Although several elegant synthetic strategies to
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obtain diverse 4,5-dihydropyridazin-3(2H)-one compounds have been reported, given their great
potential value in organic and medicinal chemistry for drug research and development, exploiting
creative methods to construct diversified 4,5-dihydropyridazin-3(2H)-one derivatives is an
important goal in the area of organic synthesis.
Figure 1. Pharmaceutical molecules containing 4,5-dihydropyridazin-3(2H)-one unit.
Azoalkenes (1,2-diaza-1,3-dienes), which are in situ generated from α-halogeno hydrazones
with a base, have been widely employed as powerful four-atom building units in the [4+1],6
[
4+2],7 or [4+3]8 annulation to access various valuable nitrogen-containing heterocyclic
compounds. Actually, the involvement of azoalkenes in [4+2] annulation belongs to one of the
direct and convenient strategies for the construction of nitrogen-containing six-membered
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heterocycles. However, the most [4+2] annulation reactions developed to date are based on the
reaction of α-halogeno hydrazones with various reactants containing carbon-carbon double bonds
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to access diversified tetrahydropyridazine compounds (Scheme 1a). Surprisingly, there exists
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only one report by Yao and co-workers, who realized the formal [4+2] cycloaddition of azoalkenes
with arylacetic acids under the catalysis of isothiourea to access 4,5-dihydropyridazin-3(2H)-ones
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(Scheme 1b). On the other hand, azlactones have been proved to be a robust and versatile
two-carbon synthetic building block and found wide application in the construction of lactam
compounds.10-11 By this token, azlactone serving as two-carbon synthon can firstly react with a
wide variety of electrophiles from its α-position. Subsequently, ring opening the azlactone via a
possible intramolecular aminolysis will assemble cyclic lactam system. In this context, we
envisioned that the in situ formed azoalkenes could react with azlactones via [4+2] annulation
reaction (Scheme 1), giving structurally important 4,5-dihydropyridazin-3(2H)-one compounds
containing an α-quaternary α-acylamino moiety, which may have promising application as potential
biologically active candidates in the research and development of drug discovery.
Scheme 1. Outline of This Work
As a continuation of our research program on the development of new methodology for the
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construction of heterocyclic compounds,12 herein, we wish to report our success in the [4+2]
annulation reaction of α-halogeno hydrazones and azlactones for the synthesis of
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,5-dihydropyridazin-3(2H)-one compounds with catalyst-free under basic conditions. Moreover,
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in order to avoid the elaborate preparation of azlactones, we also demonstrate that these
dihydropyridazinones could also be synthesized via a one-pot reaction process by using in situ
formed azlactones from N-acyl amino acids and in situ generated azoalkenes from α-halogeno
hydrazones (Scheme 1).
RESULTS AND DISCUSSION
Our initial investigation began with the reaction of α-bromo-N-Ts hydrazone 1a and
2
3 2 2
,4-diphenyloxazol-5(4H)-one 2a by using KHCO as the base in CH Cl under nitrogen
atmosphere. To our delight, the expected [4+2] annulation reaction occurred well and furnished
2 3 2 3
adduct 3a in 68% yield (Table 1, entry 1). Afterwards, various bases including Na CO , K CO ,
2 3 3
Cs CO , Et N and N,N-diisopropylethylamine (DIPEA) were examined with the model reaction,
2 3
and it was found that Na CO was the best choice in light of yield of product 3a (Table 1, entry 2
vs entries 3-6). Having identified Na
Table 1, entries 7-11), and it was observed that different solvents had significant effect on the
reactions. For instances, in the application of chlorinated solvents such as CH Cl and
2 3
CO as the best base, a series of solvents were screened
(
2
2
1
,2-dichloroethane (DCE), the reaction gave 3a in good yield (Table 1, entries 7 and 8). When the
reaction was carried out in ethyl acetate (EtOAc) or THF, 3a was obtained in 52% and 61% yield,
respectively (Table 1, entries 9 and 10). Excitingly, running the reaction in toluene led to an
obviously increased yield to give 3a in 96% yield (Table 1, entry 11). Ultimately, reducing the
loading of Na
2
CO
3
from 2.0 equivalents to 1.0 equivalent, the reaction also afforded 3a in 98%
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yield (Table 1, entry 12).
Table 1. Optimization of Reaction Conditionsa
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Entry
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
KHCO
3
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
68
69
54
35
48
50
71
61
52
61
96
98
Na
2
CO
CO
CO
3
K
2
3
Cs
2
3
Et
3
N
DIPEA
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
CHCl
DCE
3
EtOAc
THF
1
0
11
toluene
toluene
2c
1
aUnless specified, the reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol) and base
(0.2 mmol, 2.0 equiv) in 2.0 mL of solvent under nitrogen atmosphere at room temperature for 24
b
c
2 3
h. isolated yield. 1.0 equivalent of Na CO was used.
With the optimal reaction conditions in hand, we next explored the reaction scope and
generality. Various α-halo hydrazone substrates were firstly examined by reacting with α-phenyl
azlactone 2a, and the results are summarized in Table 2. Diverse sulfonyl substitutents of the
N-protecting group of α-halo hydrazones, such as Ts-, Ms-, and Bs- were found to be suitable for
the current reaction system, affording corresponding products 3a-c in high yields (Table 2, entries
1
-4). However, as for N-acyl protected α-halo hydrazones such as N-Boc, N-Cbz and N-Bz
substituents, the reactions did not proceed, probably due to the lower reactivity (not shown in
Table 2). In addition, different electron-donating substituents at different positions on the phenyl
ring of α-halo hydrazones were also tolerated well, giving the desired
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4,5-dihydropyridazin-3(2H)-one derivatives 3d-f in 85-94% yields (Table 2, entries 5-7).
3 2
Meanwhile, the substrates 1h-k, with an electron-withdrawing group (F-, Cl-, F C-, and NO -) at
the para- or meta-position on the phenyl ring, also showed good reactivities and provided
products 3g-j in yields ranging from 85% to 99% (Table 2, entries 8-11). The reaction with
substrate 1l bearing sterically hindered 2-naphthyl group also proceeded well and afforded product
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3k in 91% yield (Table 2, entry 12). Disappointingly, when R is alkyl group, such as Me-, the
reaction became messy monitored by TLC and no main product could be obtained (not shown in
Table 2).
Table 2. Substrate Scope of α-Halo Hydrazones 1a
entry
1
3
X = Br 1a 3a
X = Cl 1b 3a
X = Cl 1c 3b
X = Br 1d 3c
1e 3d
yield (%)b
1
1
2
3
4
5
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7
8
9
R = Ts
98
78
84
81
88
85
94
85
93
99
99
91
1
R = Ts
2
R = Ph
1
R = Ms
1
R = Bs
2
6 4
R = 4-MeC H
2
R = 4-MeOC
6
H
4
4
1f 3e
2
R = 3-MeOC
6
H
1g 3f
2
R = 4-FC
6
H
4
1h 3g
X = Br
1
R = Ts
2
R = 4-ClC
6
H
4
1i 3h
2
1
1
1
0
1
2
R = 4-CF
3
C
6
H
4
1j 3i
1k 3j
1l 3k
2
R = 3-NO
2
C
6
H
4
2
R = 2-naphthyl
aUnless specified, the reactions were carried out with 1 (0.2 mmol), 2a (0.3 mmol) and Na
CO
2 3
b
(0.2 mmol) in toluene (4.0 mL) under N
2
at room temperature for 24 h. isolated yield. Ts =
Toluenesulfonyl; Ms = Methanesulfonyl; Bs = Benzenesulfonyl.
Next, a variety of azlactones were examined by reacting with α-bromo-N-Ts hydrazone 1a to
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further explore the generality of the reaction (Table 3). We first investigated the effects of the
3
substituent (R ) at the C2-position of azlactones, and found that ortho-substitution on the phenyl
ring led to a significantly reduced chemical yield, presumably due to the steric hindrance effect
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(Table 3, entry 1). Substrates bearing different electron-withdrawing groups, such as Cl- and F- at
the meta- or para-position were compatible well with the conditions, providing the products 3m-o
in 83-98% yields (Table 3, entries 2-4). As for electron-donating group on the phenyl ring such as
substrate 2f, the reaction gave product 3p only in 38% yield (Table 3, entry 5), which is probably
due to the instable and decomposed easily property of azlactone 2f in the basic mixture. However,
with alkyl substituent at the C2-position of azlactone (such as 4-benzyl-2-phenyloxazol-5(4H)-one
and 4-methyl-2-phenyloxazol-5(4H)-one), the desired [4+2] annulation reaction did not take place
4
under the standard conditions (not shown in Table 3). Furthermore, as for R group, we found the
substituent on the aromatic ring did not influence the reactivity, regardless of electric nature or
steric hindrance of the substituent, the reactions gave the products 3q-t in yields ranging from 80%
to 96% (Table 3, entries 6-9). Ultimately, the heteroaromatic ring substituted substrates also prove
to be amenable to this [4+2] annulation protocol, providing the corresponding products 3u and 3v
in 52% and 79% yields, respectively (Table 3, entries 10-11).
Table 3. Substrate Scope of Azlactones 2a
entry
2
3
yield (%)b
3
1
2
3
4
5
R = 2-ClC
6
6
6
H
H
H
4
4
4
2b 3l
2c 3m
2d 3n
2e 3o
2f 3p
25
83
84
98
38
3
R = 3-ClC
3
4
R = 4-ClC
R = Ph
3
R = 4-FC
6
H
4
3
R = 4-MeC
6
H
4
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R = 4-MeC
6
H
4
2g 3q
2h 3r
2i 3s
2j 3t
2k 3u
2l 3v
88
80
87
96
52
79
6 4
3-MeC H
3-BrC
6
H
4
3
R = Ph
1-naphthyl
2-thiophenyl
3-thiophenyl
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aUnless specified, the reactions were carried out with 1a (0.2 mmol), 2 (0.3 mmol) and Na
CO
3
2
b
(
0.2 mmol) in toluene (4.0 mL) under N
2
at room temperature for 24 h. isolated yield.
In fact, the separation and purification of azlactone substrates is a relatively tedious operation
1
3
during the preparation of them. In order to avoid this tedious operation and conveniently use this
kind of compounds in organic synthesis, we attempted to develop a one-pot protocol to synthesize
the 4,5-dihydropyridazin-3(2H)-ones by using the in situ formed azlactones and the in situ
generated azoalkenes. As shown in Scheme 2, when we added 1.5 equivalents of
dicyclohexylcarbodiimide (DCC) into the reaction mixture to promote the cyclodehydration of
2
-benzamido-2-phenylacetic acid 4a for the formation of azlactone, to our delight, the desired 3a
was able to be obtained in almost quantitative yield in the reaction of 1a and 4a in the presence of
14
2 3
DCC and Na CO in toluene under nitrogen atmosphere after 24 h. Nevertheless, under the same
conditions, the reaction of α-chloro-N-Ts hydrazone 1b and 4a also proceeded smoothly and
afforded 3a in 93% yield. And then, we further investigated the scope of the reactions of 4a and
different α-halo-hydrazones with the developed one-pot protocol. It was found that the expected
4
,5-dihydropyridazin-3(2H)-one products 3b-j could be obtained in good to excellent chemical
yields, regardless of the pattern of sulfonyl substituents in the N-protecting group and the
substituent’s electronic nature and position on the phenyl ring for the α-halo-hydrazone substrates.
The bulker naphthyl group also tolerated well in the one-pot protocol, and the corresponding
cycloadduct 3k was obtained in 99% yield. On the other hand, diverse substituted amino acids 4,
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possessing electron-withdrawing or electron-donating groups at ortho-, meta- or para-position of
3
the phenyl ring (R ), reacted well with α-bromo-N-Ts hydrazone 1a, delivering their
corresponding products 3l-p in moderate to high yields. Meanwhile, different aryl substituents of
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4
the N-protecting group (R ) of the amino acids, regardless of electronic property and steric
hindrance of the substituents, as well as the heteroaromatic ring as substituent group, were
tolerated in this one-pot reaction to give the products 3q-w in yields ranging from 33% to 96%.
It's worth noting that the substrates bearing aliphatic substituent as the N-protecting group of the
amino acids were able to participate in the [4+2] annulation transformation, affording the
corresponding products 3x and 3y in 29% and 37% yields, respectively.
Scheme 2. One-pot [4+2] Annulation Reaction of in situ Generation of Two Substrates for
the Synthesis of 4,5-Dihydropyridazin-3(2H)-onesa
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aReaction conditions: The reactions were carried out with 1 (0.2 mmol), 4 (0.24 mmol), DCC (0.3
mmol) and Na
2
CO
3
2
(0.24 mmol) in toluene (4.0 mL) under N at room temperature for 24 h. The
b
reported yields of 3 refer to the isolated yield. Replacing α-bromo-N-Ts hydrazone 1a with
α-chloro-N-Ts hydrazone 1b for the reaction.
In order to demonstrate the potential utility of the [4+2] annulation reaction, we performed
the reactions 1a with 2a and 1a with 4a on a gram scale, respectively. As shown in Scheme 3,
under the standard conditions, both reactions proceeded well and afforded 3a in good yield.
Notably, when the gram scale reactions were complete, product 3a could be obtained conveniently
by filtration and no silica gel column chromatography isolation required, which is generally
deemed to be a more reliable and industrially convenient operation for large-scale production.
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Certainly, the gram-scale experiments suggest that the developed protocol has good scalability and
the potential value in organic synthesis.
Scheme 3 Gram-scale Experiments
1
1
1
1
1
1
1
1
1
1
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To further illustrate the synthetic potential value and versatility of this methodology, we
explored several transformations of the product 3a into other nitrogen-containing compounds
(
Scheme 4). Treating 3a with potassium hydroxide in MeOH at room temperature for 30 mins,
ring-opening alcoholysis product 5 was obtained in 97% yield. The C=N double bond in 3a could
be reduced by using NaBH in THF to give tetrahydropyridazinone 6 in 78% yield with 10:9
4
diastereoselectivity. In addition, treating 3a with p-toluenesulfonic acid in CHCl
for 24 h, pyridazinone derivative 7 could be obtained in 95% yield.
Scheme 4. Different Transformations of Compound 3a
3
under refluxing
The structure of product 3a was unambiguously determined via X-ray crystallographic study
of single crystal (see Supporting Information).15 All the dihydropyridazinone compounds in this
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work were characterized by nuclear magnetic resonance spectroscopy and high resolution mass
spectrometry.
A plausible reaction mechanism was proposed for this [4+2] annulation reaction (Scheme 5).
0
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In the presence of Na
2
3
CO , α-halogeno hydrazones 1 in situ produce reactive azoalkenes. At the
1
same time, azlactones 2 can give the reactive azlactone enolate M under the basic conditions.
1
And then, the enolates M attack the electrophilic azoalkenes for the C-C bond formation to give
2
intermediate M . Subsequently, opening the azlactone ring via an intramolecular aminolysis
results in the 4,5-dihydropyridazin-3(2H)-one products 3. On the other hand, the readily available
N-acyl amino acids 4 are able to be in situ converted into azlactones 2 with DCC. Thus under the
basic conditions, the in situ formed azlactones 2 can react with the in situ generated azoalkenes via
one-pot [4+2] annulation reaction to afford 4,5-dihydropyridazin-3(2H)-one products 3.
Scheme 5. Reaction Mechanism Proposal
CONCLUSION
In summary, we have developed an unprecedented [4+2] annulation reaction between in situ
formed azoalkenes and azlactones. With the developed protocol, a wide range of structurally
important dihydropyridazinone compounds, which are very promising in medicinal application as
potential biologically active candidates, could be smoothly obtained in up to 99% yield under mild
conditions. Notably, these dihydropyridazinones also could be synthesized via a one-pot reaction
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protocol by using the in situ formed azlactones from N-acyl amino acids and in situ generated
azoalkenes from α-halogeno hydrazones. The potential applications of the methodology were also
demonstrated by the gram scale experiments and the versatile conversions of the products into
other nitrogen-containing compounds.
1
1
1
1
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Experimental Section
General Methods
Chemicals were purchased from commercial suppliers and used without further purification
unless otherwise stated. Solvents were dried and purified according to the standard procedures
before use. Reactions were monitored by TLC. Flash column hromatography was performed on
1
13
1
silica gels (200-300 mesh). H NMR and C{ H} NMR (300 and 75 MHz, respectively) spectra
were recorded on a Bruker 300 MHz NMR spectrometer in CDCl
. 1H NMR chemical shifts are
reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as
the internal standard (CDCl , δ 7.26 ppm, DMSO-d δ 2.50 ppm). Data are reported as follows:
3
3
6
chemical shift, multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, td = triplet of
doublets, q = quartet, m = multiplet), coupling constants (Hz) and integration. 13C{ H} chemical
shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal
1
standard (CDCl
3 6
, δ 77.00 ppm, DMSO-d at 39.51 ppm). HRMS data were obtained on a Bruker
Daltonics. Inc mass instrument (ESI). Melting points were recorded on a Buchi Melting Point
B-545. The α-halo hydrazone substrates 16,7,8, azlactones 2 and N-acyl amino acids used in this
13
13
work, are known compounds and prepared according to the reported literature procedures.
Representative procedure for preparing 3 via the reaction of azlactones and α-halo
hydrazones. To a flame dried reaction tube were added α-halo hydrazone 1 (0.2 mmol), azlactone
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2 3
2 (0.3 mmol) and anhydrous Na CO (21.2 mg, 0.2 mmol), followed by adding anhydrous toluene
2
(4 mL). The atmosphere in tube was replaced by N , and the reaction was carried out at room
2
temperature under N for 24 h. After completion, water (10 mL) was added to the reaction system,
0
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2 2
and the mixture was extract with CH Cl (10 mL × 3). The organic layers were combined, dried
2 4
over by Na SO , and concentrated in vacuo. The residue was purified by column chromatography
(petroleum ether : ethyl acetate = 5:1~4:1 as eluent) to give 3 as white solid.
Representative procedure for preparing 3 via one-pot process of in situ azlactones
formation from the corresponding N-acyl amino acids with α-halo hydrazones. To a flame
dried reaction tube were added α-halo hydrazone 1 (0.2 mmol), N-acyl amino acid 4 (0.24 mmol),
2 3
dicyclohexylcarbodiimide (DCC, 61.8 mg, 0.3 mmol) and anhydrous Na CO (25.4 mg, 0.24
2
mmol), followed by adding anhydrous toluene (4 mL). The atmosphere in tube was replaced by N ,
2
and reaction was carried out at room temperature under N for 24 h. After completion, water (10
2 2
mL) was added to the reaction system, and the mixture was extract with CH Cl (10 mL × 3). The
2 4
organic phases were combined, dried over by Na SO , and concentrated in vacuo. The residue was
purified by column chromatography (petroleum ether : ethyl acetate = 5:1~4:1 as eluent) to give 3
as white solid.
N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide (3a). Purified by
silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent); White solid;
o
1
1
02.4 mg, 98% yield; m.p.: 225.1-226.0 C. H NMR (300 MHz, CDCl
3
) δ 7.91-7.88 (m, 2H),
7.83 (d, J = 8.4 Hz, 2H), 7.75-7.73 (m, 3H), 7.52-7.38 (m, 6H), 7.27-7.18 (m, 3H), 7.14-7.07 (m,
13
1
4
3
H), 4.97 (d, J = 17.6 Hz, 1H), 3.42 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). C{ H} (75 MHz, CDCl )
δ 166.1, 165.9, 152.6, 145.5, 134.6, 134.3, 134.0, 133.6, 132.1, 131.0, 129.5 (2C), 129.0, 128.9
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(2C), 128.8 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C), 126.6 (2C), 126.1 (2C), 58.7, 32.2, 21.7.
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C30
H
25
N
3
NaO
4
S: 546.1458; found: 546.1454.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
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3
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N-(2-(methylsulfonyl)-3-oxo-4,6-diphenyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide (3b).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 75.0 mg, 84% yield; m.p.: 189.0-191.5 C. H NMR (300 MHz, CDCl
3
) δ 7.88-7.85
(
(
m, 2H), 7.80-7.77 (m, 2H), 7.56-7.42 (m, 9H), 7.34-7.32 (m, 3H), 4.70 (d, J = 17.4 Hz, 1H), 3.79
13
1
3
d, J = 17.5 Hz, 1H), 3.39 (s, 3H). C{ H} (75 MHz, CDCl ) δ 166.6, 166.5, 153.1, 134.9, 134.2,
133.5, 132.2, 131.1, 129.6, 129.4 (2C), 128.9 (2C), 128.7 (2C), 127.0 (2C), 126.5 (2C), 126.2 (2C),
+
5
9.2, 41.3, 32.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C24
H N
21 3
NaO
4
S: 470.1145; found:
470.1131.
N-(3-oxo-4,6-diphenyl-2-(phenylsulfonyl)-2,3,4,5-tetrahydropyridazin-4-yl)benzamide (3c).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 82.2 mg, 81% yield; m.p.: 221.8-222.0 C. H NMR (300 MHz, CDCl
3
) δ 7.95 (d, J =
.9 Hz, 2H), 7.88 (d, J = 6.5 Hz, 2H), 7.75-7.71 (m, 3H), 7.64 (t, J = 7.9 Hz, 1H), 7.53-7.38 (m,
H), 7.22-7.18 (m, 1H), 7.11-7.09 (m, 4H), 4.94 (d, J = 17.5 Hz, 1H), 3.47 (d, J = 17.4 Hz, 1H).
7
8
13
1
3
C{ H} (75 MHz, CDCl ) δ 166.1, 166.0, 152.8, 136.9, 134.5, 134.2 (2C), 133.5, 132.1, 131.1,
129.1, 128.9 (2C), 128.87 (2C), 128.65 (2C), 128.64 (2C), 127.0 (2C), 126.6 (2C), 126.0 (2C),
+
5
5
8.8, 32.2. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C29
23 3 4
H N NaO S: 532.1301; found:
32.1319.
N-(3-oxo-4-phenyl-6-(p-tolyl)-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3d).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
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5
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5
5
5
5
5
6
o
1
White solid; 95.0 mg, 88% yield; m.p.: 159.4-161.1 C. H NMR (300 MHz, CDCl
3
) δ 7.83-7.73
(
m, 7H), 7.50 (t, J = 7.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.28-7.17 (m, 5H), 7.14-7.06 (m, 4H), 4.97 (t,
13
1
J = 17.6 Hz, 1H), 3.36 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H), 2.42 (s, 3H). C{ H} (75 MHz, CDCl
3
)
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δ 166.1, 166.0, 152.6, 145.4, 141.5, 134.7, 134.0, 133.6, 132.0, 131.5, 129.6 (2C), 129.4 (2C),
1
28.9, 128.8 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C), 126.6 (2C), 126.1 (2C), 58.7, 32.1, 21.7,
+
21.4. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C31
H
27
N
3
NaO
4
S: 560.1614; found: 560.1611.
N-(6-(4-methoxyphenyl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
(3e). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 4:1 as
o
1
eluent); White solid; 94.0 mg, 85% yield; m.p.: 208.0-209.5 C. H NMR (300 MHz, CDCl
3
) δ
7.88-7.80 (m, 5H), 7.74 (t, J = 7.3 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.43-7.38 (m, 2H), 7.26-7.18
(
(
m, 3H), 7.14-7.06 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 4.97 (d, J = 17.4 Hz, 1H), 3.87 (s, 3H), 3.33
13
1
3
d, J = 17.5 Hz, 1H), 2.43 (s, 3H). C{ H} (75 MHz, CDCl ) δ 166.1, 166.0, 161.9, 152.3, 145.4,
134.7, 134.1, 133.6, 132.2, 129.4 (2C), 128.9, 128.8 (2C), 128.7 (2C), 128.6 (2C), 128.3 (2C),
1
27.0 (2C), 126.7, 126.1 (2C), 114.2 (2C), 58.7, 55.4, 31.9, 21.7. HRMS (ESI-TOF) m/z: [M +
+
Na] Calcd. for C31
H
27
N
3
NaO
5
S: 576.1564; found: 576.1560.
N-(6-(3-methoxyphenyl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
(3f). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 4:1 as eluent);
o
1
White solid; 104.0 mg, 94% yield; m.p.: 179.1-180.3 C. H NMR (300 MHz, CDCl
8.3 Hz, 2H), 7.75-7.72 (m, 3H), 7.52-7.34 (m, 6H), 7.26-7.17 (m, 3H), 7.15-7.08 (m, 4H), 7.02
dd, J = 8.1, 1.7 Hz, 1H), 4.89 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H), 3.44 (d, J = 17.6 Hz, 1H), 2.43 (s,
3
) δ 7.81 (d, J
=
(
1
3
H). 13C{ H} (75 MHz, CDCl
3
) δ 166.1, 165.9, 159.9, 152.3, 145.4, 135.6, 134.6, 133.9, 133.5,
132.0, 129.8, 129.4 (2C), 129.0, 128.8 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C), 126.1 (2C), 119.1,
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+
116.8, 111.7, 58.7, 55.4, 32.3, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C31
27 3 5
H N NaO S:
5
76.1564; found: 576.1569.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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6
0
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N-(6-(4-fluorophenyl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
3g). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
(
o
1
eluent); White solid; 92.0 mg, 85% yield; m.p.: 212.1-213.0 C. H NMR (300 MHz, CDCl
3
) δ
7
9
.91-7.81 (m, 4H), 7.74-7.72 (m, 3H), 7.50 (t, J = 7.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.27-7.09 (m,
13
1
3
H), 4.91 (d, J = 17.5 Hz, 1H), 3.42 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). C{ H} (75 MHz, CDCl )
δ 166.1, 164.3 (d, J = 224.3 Hz, 1C), 151.6, 145.5, 134.6, 133.9, 133.5, 132.1, 130.5 (d, J = 3.0 Hz,
2
C), 129.5 (2C), 129.0, 128.8 (2C), 128.73 (2C), 128.71 (2C), 128.6 (2C), 127.0 (2C), 126.0 (2C),
+
116.0 (d, J = 21.8 Hz, 2C), 58.7, 32.2, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for
30 3 4
C H24FN NaO S: 564.1364; found: 564.1370.
N-(6-(4-chlorophenyl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
3h). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
(
o
1
eluent); White solid; 104.0 mg, 93% yield; m.p.: 228.3-229.4 C. H NMR (300 MHz, CDCl
3
) δ
7
3
.84-7.80 (m, 4H), 7.74-7.71 (m, 3H), 7.50 (t, J = 7.3 Hz, 1H), 7.44-7.38 (m, 4H), 7.27-7.19 (m,
13
1
H), 7.13-7.07 (m, 4H), 4.90 (t, J = 17.6 Hz, 1H), 3.42 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). C{ H}
) δ 166.2, 165.7, 151.4, 145.6, 137.2, 134.5, 133.9, 133.5, 132.7, 132.1, 129.5
2C), 129.1 (2C), 129.0, 128.9 (2C), 128.7 (2C), 128.6 (2C), 127.9 (2C), 127.0 (2C), 126.0 (2C),
(75 MHz, CDCl
3
(
+
5
3 4
8.7, 32.1, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C30H24ClN NaO S: 580.1068;
found: 580.1054.
N-(3-oxo-4-phenyl-2-tosyl-6-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydropyridazin-4-yl)be
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nzamide (3i). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1
o
1
as eluent); White solid; 117.0 mg, 99% yield; m.p.: 180.0-181.0 C. H NMR (300 MHz, CDCl
3
) δ
.99 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.75-7.68 (m, 5H), 7.50 (t, J = 7.5 Hz, 1H),
.43-7.38 (m, 2H), 7.28-7.21 (m, 3H), 7.14-7.07 (m, 4H), 4.91 (d, J = 17.6 Hz, 1H), 3.52 (d, J =
7
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0
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8
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0
13
1
3
7.6 Hz, 1H), 2.45 (s, 3H). C{ H} (75 MHz, CDCl ) δ 166.3, 165.6, 151.0, 145.7, 137.6, 134.5,
133.9, 133.5, 132.6 (q, J = 33.0 Hz, 1C), 132.1, 129.6 (2C), 129.2, 129.0 (2C), 128.8 (2C), 128.7
(2C), 127.0 (2C), 126.9 (2C), 126.0 (2C), 125.9 (q, J = 3.8 Hz, 2C), 123.8 (q, J = 270.0 Hz, 1C),
+
5
8.8, 32.3, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C31
H
24
F
3
N
3
NaO
4
S: 614.1332;
found: 614.1333.
N-(6-(3-nitrophenyl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
(3j). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
3
White solid; 112.4 mg, 99% yield; m.p.: 198.8-199.8 C. H NMR (300 MHz, CDCl ) δ 8.59 (s,
1H), 8.33 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.3
Hz, 2H), 7.69-7.63 (m, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.44-7.39 (m, 2H), 7.32-7.23 (m, 3H),
13
1
7.17-7.09 (m, 4H), 4.84 (d, J = 17.6 Hz, 1H), 3.65 (d, J = 17.6 Hz, 1H), 2.47 (s, 3H). C{ H} (75
MHz, CDCl ) δ 166.3, 165.4, 150.1, 148.6, 145.9, 136.1, 134.4, 133.6, 133.3, 132.2 (2C), 130.0,
29.6 (2C), 129.3, 129.0 (2C), 128.8 (2C), 128.6 (2C), 127.0 (2C), 125.9 (2C), 125.3, 121.2, 58.8,
3
1
+
32.4, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C30
24 4 6
H N NaO S: 591.1309; found:
5
91.1315.
N-(6-(naphthalen-2-yl)-3-oxo-4-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
3k). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
(
o
1
3
eluent); White solid; 104.0 mg, 91% yield; m.p.: 175.9-176.8 C. H NMR (300 MHz, CDCl ) δ
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8.34 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.97-7.94 (m, 1H), 7.90-7.84 (m, 5H), 7.77 (d, J = 7.1 Hz,
2
H), 7.61-7.49 (m, 3H), 7.45-7.40 (m, 2H), 7.28-7.25 (m, 2H), 7.22-7.16 (m, 3H), 7.11-7.06 (m,
13
1
2
3
H), 5.21 (d, J = 17.6 Hz, 1H), 3.46 (d, J = 17.5 Hz, 1H), 2.44 (s, 3H). C{ H} (75 MHz, CDCl )
1
1
1
1
1
1
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8
9
0
δ 166.2, 166.0, 152.1, 145.5, 134.5, 134.5, 134.0, 133.6, 132.9, 132.1, 131.6, 129.5 (2C), 129.0,
1
28.9, 128.8 (2C), 128.7 (2C), 128.6 (2C), 127.8 (2C), 127.7, 127.1, 127.0 (2C), 126.9, 126.1 (2C),
+
123.2, 58.7, 31.9, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C34
27 3 4
H N NaO S: 596.1614;
found: 596.1616.
N-(4-(2-chlorophenyl)-3-oxo-6-phenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3l). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 28.0 mg, 25% yield; m.p.: 214.4-216.5 C. H NMR (300 MHz, CDCl
3
) δ 8.01 (d, J =
8
8
.3 Hz, 2H), 7.80-7.75 (m, 4H), 7.53-7.33 (m, 10H), 7.20 (td, J = 8.3, 1.3 Hz, 1H), 6.93 (td, J =
.0, 1.1 Hz, 1H), 6.80 (dd, J = 7.9, 1.1 Hz, 1H), 4.76 (d, J = 17.5 Hz, 1H), 3.84 (d, J = 17.5 Hz,
1H), 2.46 (s, 3H). 13C{ H} (75 MHz, CDCl
1
) δ 166.4, 165.8, 153.3, 145.5, 134.3, 134.2, 133.5,
3
1
32.6, 132.4, 132.1, 132.0, 130.9, 130.6, 129.6 (2C), 129.2, 129.0 (2C), 128.8 (2C), 128.6 (2C),
+
127.1 (2C), 126.9, 126.6 (2C), 60.1, 33.3, 21.8. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for
30 3 4
C H24ClN NaO S: 580.1068; found: 580.1064.
N-(4-(3-chlorophenyl)-3-oxo-6-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
3m). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
(
o
1
3
eluent); White solid; 92.0 mg, 83% yield; m.p.: 192.0-193.2 C. H NMR (300 MHz, CDCl )
7
7
.93-7.90 (m, 2H), 7.83-7.80 (m, 3H),7.75-7.72 (m, 2H), 7.54-7.40 (m, 6H), 7.29-7.26 (m, 2H),
.18-7.02 (m, 3H), 6.93 (t, J = 1.7 Hz, 1H), 5.03 (d, J = 17.6 Hz, 1H), 3.32 (d, J = 17.7 Hz, 1H),
13
1
3
2.44 (s, 3H). C{ H} (75 MHz, CDCl ) δ 166.1, 165.4, 152.7, 145.9, 136.3, 134.8, 134.0, 133.5,
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133.3, 132.2, 131.2, 129.8, 129.6 (2C),129.2, 129.0 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C),
+
1
26.6 (2C), 126.4, 124.6, 58.2, 31.8, 21.8. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for
+
C
30
H24ClN
3
NaO
4
S [M+Na] : 580.1068; found: 580.1072.
0
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0
N-(4-(4-chlorophenyl)-3-oxo-6-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
(3n). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
o
1
eluent); White solid; 94.0 mg, 84% yield; m.p.: 215.0-216.0 C. H NMR (300 MHz, CDCl
3
)
7
.92-7.89 (m, 2H), 7.85 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.75-7.72 (m, 2H), 7.54-7.39 (m, 6H),
7.27-7.24 (m, 2H), 7.03-7,04 (m, 4H), 5.00 (d, J = 17.7 Hz, 1H), 3.31 (d, J = 17.7 Hz, 1H), 2.46 (s,
1
3
H). 13C{ H} (75 MHz, CDCl
3
) δ 166.0, 165.5, 152.2, 145.7, 135.0, 134.0, 133.6, 133.3, 132.9,
132.2, 131.2, 129.5 (2C), 129.0 (2C), 128.9 (2C), 128.7 (2C), 128.6 (2C), 127.6 (2C), 126.9 (2C),
+
1
26.6 (2C), 58.0, 31.9, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C30
3 4
H24ClN NaO S:
5
80.1068; found: 580.1075.
N-(4-(4-fluorophenyl)-3-oxo-6-phenyl-2-tosyl-2,3,4,5-tetrahydro-pyridazin-4-yl)benzamide
3o). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
(
o
1
eluent); White solid; 106.0 mg, 98% yield; m.p.: 216.5-217.2 C. H NMR (300 MHz, CDCl
.92-7.89 (m, 2H), 7.84-7.81 (m, 3H), 7.75-7.69 (m, 2H), 7.54-7.39 (m, 6H), 7.28-7.26 (m, 2H),
7.13-7.08 (m, 2H), 6.79-6.74 (m, 2H), 5.01 (d, J = 17.6 Hz, 1H), 3.32 (d, J = 17.7 Hz, 1H), 2.45 (s,
3
) δ
7
13
1
3
H). C{ H} (75 MHz, CDCl
3
) δ 166.1, 165.8, 162.7 (d, J = 248.3 Hz, 1C), 152.4, 145.7, 134.1,
1
33.8, 133.4, 132.2, 131.2, 130.3 (d, J = 3.8 Hz, 1C), 129.5 (2C), 129.0 (2C), 128.70 (2C), 128.68
(2C), 128.2 (d, J = 8.3 Hz, 2C), 127.0 (2C), 126.6 (2C), 115.7 (d, J = 21.8 Hz, 2C), 58.0, 32.1,
+
2
1.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C30
H24FN
3
NaO
4
S: 564.1364; found: 564.1363.
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N-(3-oxo-6-phenyl-4-(p-tolyl)-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3p).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 41.0 mg, 38% yield; m.p.: 221.8-222.7 C. H NMR (300 MHz, CDCl
3
) δ 7.91-7.88
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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0
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0
(
(
m, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.75-7.72 (m, 3H), 7.52-7.38 (m, 6H), 7.27-7.24 (m, 2H), 7.01
d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 4.92 (d, J = 17.6 Hz, 1H), 3.41 (d, J = 17.6 Hz, 1H),
2.45 (s, 3H), 2.23 (s, 3H). 13C{ H} (75 MHz, CDCl
1
) δ 166.1, 166.0, 152.5, 145.4, 138.9, 134.3,
3
1
1
34.0, 133.6, 132.0, 131.6, 131.0, 129.5 (2C), 129.4 (2C), 128.8 (2C), 128.7 (2C), 128.6 (2C),
27.0 (2C), 126.6 (2C), 126.0 (2C), 58.5, 32.2, 21.7, 21.0. HRMS (ESI-TOF) m/z: [M + Na]+
27 3 4
Calcd. for C31H N NaO S: 560.1614; found: 560.1633.
4-Methyl-N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3q).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 4:1 as eluent);
o
1
White solid; 95.0 mg, 88% yield; m.p.: 224.3-225.4 C. H NMR (300 MHz, CDCl
3
) δ 7.90-7.88
(m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51-7.43 (m, 3H),
7
.26-7.19 (m, 5H), 7.13-7.06 (m, 4H), 4.96 (d, J = 17.6 Hz, 1H), 3.41 (d, J = 17.6 Hz, 1H), 2.44 (s,
3H), 2.37 (s, 3H). 13C{ H} (75 MHz, CDCl
1
) δ 166.0, 165.9, 152.6, 145.4, 142.6, 134.7, 134.2,
3
1
33.9, 131.0, 130.7, 129.5 (2C), 129.3 (2C), 128.9,128.8 (2C), 128.7 (2C), 128.6 (2C), 127.0 (2C),
+
1
26.6 (2C), 126.1 (2C), 58.6, 32.2, 21.7, 21.4. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for
31 27 3 4
C H N NaO S: 560.1614; found: 560.1607.
3
-Methyl-N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3r).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 4:1 as eluent);
o
1
3
White solid; 86.0 mg, 80% yield; m.p.: 224.8-226.0 C. H NMR (300 MHz, CDCl ) δ 7.91-7.88
(m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.75 (s, 1H), 7.55-7.46 (m, 5H), 7.30-7.18 (m, 5H), 7.11-7.06
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1
(m, 4H), 4.97 (d, J = 17.6 Hz, 1H), 3.41 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 3H). C{ H}
75 MHz, CDCl ) δ 166.3, 166.0, 152.6, 145.5, 138.5, 134.6, 134.2, 134.0, 133.5, 132.8, 131.0,
29.5 (2C), 128.9, 128.8 (2C), 128.7 (2C), 128.6 (2C), 128.5, 127.6, 126.6 (2C), 126.1 (2C), 124.0,
(
3
1
5
0
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0
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0
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9
0
1
2
3
4
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6
7
8
9
0
+
27 3 4
8.7, 32.2, 21.7, 21.3. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C31H N NaO S: 560.1614;
found: 560.1615.
3
-Bromo-N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)benzamide
(3s).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 105.0 mg, 87% yield; m.p.: 225.0-226.1 C. H NMR (300 MHz, CDCl
3
) δ 7.89-7.81
(
m, 5H), 7.70 (s, 1H), 7.66-7.60 (m, 2H), 7.52-7.43 (m, 3H), 7.31-7.19 (m, 4H), 7.10-7.09 (m, 4H),
4.91 (d, J = 17.5 Hz, 1H), 3.41 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). 13C{ H} (75 MHz, CDCl
1
) δ
3
1
1
65.7, 164.6, 152.5, 145.5, 135.5, 135.0, 134.2, 134.1, 133.9, 131.1, 130.2, 130.1, 129.5 (2C),
29.1, 128.90 (2C), 128.80 (2C), 128.7 (2C), 126.6 (2C), 126.1 (2C), 125.5, 122.8, 58.8, 32.0,
+
21.7. HRMS (ESI) m/z: [M + Na] Calcd for C30
H24BrN
3
NaO
4
S 624.0563; found: 624.0573.
N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)-1-naphthamide (3t). Purified
by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent); White solid;
o
1
1
3
10.0 mg, 96% yield; m.p.: 206.8-207.6 C. H NMR (300 MHz, CDCl ) δ 8.15-8.12 (m, 1H),
7.93-7.82 (m, 6H), 7.59 (d, J = 7.1 Hz, 1H), 7.53-7.40 (m, 6H), 7.34 (s, 1H), 7.27-7.13 (m, 7H),
1
4
1
1
1
.91 (d, J = 17.4 Hz, 1H), 3.74 (d, J = 17.5 Hz, 1H), 2.43 (s, 3H). 13C{ H} (75 MHz, CDCl
3
) δ
68.8, 165.5, 152.5, 145.4, 134.7, 134.3, 134.1, 133.6, 133.2, 131.2,131.0, 130.0, 129.5 (2C),
29.2, 129.0 (2C), 128.9 (2C), 128.7 (2C), 128.3, 127.3, 126.6 (2C), 126.5, 126.1 (2C), 125.2,
+
25.1, 124.5, 59.4, 32.4, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C34
H
27
N
3
NaO
4
S:
596.1614; found: 596.1619.
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N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)thiophene-2-carboxamide
(
3u). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
o
1
eluent); White solid; 55.0 mg, 52% yield; m.p.: 226.6-227.7 C. H NMR (300 MHz, CDCl
3
) δ
1
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7
.89-7.87 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.50-7.43 (m, 5H), 7.27-7.16 (m, 3H),
13
1
.10-7.04 (m, 5H), 4.97 (d, J = 17.6 Hz, 1H), 3.36 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). C{ H} (75
) δ 165.8, 160.8, 152.5, 145.5, 138.3, 134.4, 134.2, 133.9, 131.1, 130.9, 129.5 (2C),
29.0, 128.9 (2C), 128.8 (2C), 128.7 (2C), 128.68, 127.8, 126.6 (2C), 126.1 (2C), 58.7, 32.2, 21.7.
MHz, CDCl
3
1
+
23 3 4 2
HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C28H N NaO S : 552.1022; found: 552.1043.
N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)thiophene-3-carboxamide
(3v). Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as
o
1
eluent); White solid; 84.0 mg, 79% yield; m.p.: 224.5-225.1 C. H NMR (300 MHz, CDCl
3
) δ
7
.89-7.80 (m, 5H), 7.55 (s, 1H), 7.52-7.42 (m, 3H), 7.35-7.16 (m, 5H), 7.10-7.08 (m, 4H), 4.95 (d,
J = 17.6 Hz, 1H), 3.38 (d, J = 17.6 Hz, 1H), 2.44 (s, 3H). 13C{ H} (75 MHz, CDCl
1
) δ 165.9,
3
1
61.7, 152.5, 145.5, 136.7, 134.5, 134.2, 133.9, 131.0, 129.5 (2C), 129.1, 129.0, 128.9 (2C), 128.8
(2C), 128.7 (2C), 126.8, 126.6 (2C), 126.1 (2C), 125.9, 58.6, 32.2, 21.7. HRMS (ESI-TOF) m/z:
+
[
M + Na] Calcd. for C28
H N
23 3
NaO
4
S
2
: 552.1022; found: 552.1021.
N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)picolinamide (3w). Purified
by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent); White solid;
o
1
1
01.0 mg, 96% yield; m.p.: 186.5-187.8 C. H NMR (300 MHz, CDCl
m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.89-7.85 (m, 4H), 7.80 (td, J = 7.7, 1.6 Hz, 1H), 7.49-7.39 (m,
H), 7.27-7.19 (m, 3H), 7.14-7.07 (m, 4H), 4.76 (d, J = 17.4 Hz, 1H), 3.61 (d, J = 17.4 Hz, 1H),
3
) δ 9.39 (s, 1H), 8.54-8.53
(
4
13
1
3
2.44 (s, 3H). C{ H} (75 MHz, CDCl ) δ 165.5, 163.7, 152.4, 149.2, 148.2, 145.3, 137.3, 134.8,
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134.4, 134.1, 130.9, 129.4 (2C), 129.0, 128.9 (2C), 128.8 (2C), 128.7 (2C), 126.6 (2C), 126.1 (2C),
+
1
21.9, 58.7, 32.2, 21.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd. for C29
H
24
N
4
NaO
4
S: 547.1410;
found: 547.1429.
0
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N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)propionamide (3x). Purified
by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent); White solid;
o
1
2
7
3
8.0 mg, 29% yield; m.p.: 200.7-201.3 C. H NMR (300 MHz, CDCl ) δ 7.84-7.80 (m, 4H),
.49-7.41 (m, 3H), 7.26-7.17 (m, 3H), 7.11-7.01 (m, 4H), 6.87 (s, 1H), 4.74 (d, J = 17.5 Hz, 1H),
3.37 (d, J = 17.5 Hz, 1H), 2.44 (s, 3H), 2.23-2.14 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H). 13C{ H} (75
1
3
MHz, CDCl ) δ 173.0, 165.9, 152.6, 145.4, 134.9, 134.3, 134.1, 130.9, 129.4 (2C), 128.9, 128.84
(2C), 128.74 (2C), 128.7 (2C), 126.6 (2C), 126.0 (2C), 58.5, 32.3, 29.8, 21.7, 9.2. HRMS
+
(
ESI-TOF) m/z: [M + Na] Calcd. for C26
H
25
N
3
NaO
4
S: 498.1458; found: 498.1468.
2-Methoxy-N-(3-oxo-4,6-diphenyl-2-tosyl-2,3,4,5-tetrahydropyridazin-4-yl)acetamide (3y).
Purified by silica gel column chromatography (petroleum ether : ethyl acetate = 5:1 as eluent);
o
1
White solid; 36.0 mg, 37% yield; m.p.: 138.7-139.4 C. H NMR (300 MHz, CDCl
3
) δ 7.85-7.81
(
m, 5H), 7.45-7.43 (m, 3H), 7.27-7.19 (m, 3H), 7.12-7.02 (m, 4H), 4.63 (d, J = 17.3 Hz, 1H),
13
1
3
3
.87-3.73 (m, 2H), 3.50 (d, J = 17.3 Hz, 1H), 3.38 (s, 3H), 2.44 (s, 3H). C{ H} (75 MHz, CDCl )
δ 169.0, 165.4, 152.4, 145.4, 134.6, 134.3, 134.1, 130.9, 129.4 (2C), 128.9 (2C), 128.8 (2C), 128.7
2C), 126.5 (2C), 126.0 (2C), 71.9, 59.2, 58.4, 32.2, 21.7. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd. for C26 NaO S: 514.1407; found: 514.1418.
(
H
25
N
3
5
Scale-up experiments
(a) The reaction of α-bromo-N-Ts hydrazone 1a and azlactone 2a. α-bromo-N-Ts hydrazone
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2 3
1a (1.0 g, 2.73 mmol), azlactone 2a (0.97 g, 4.10 mmol) and anhydrous Na CO (289 mg, 2.73
mmol) was added into a dry tube, followed by adding anhydrous toluene (27.3 mL). The
atmosphere in tube was replaced by N , and reaction was carried out at room temperature under
2
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0
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0
2 2 2
N for 24 h. After completion, the solvent was removed. The residue was suspended in CH Cl (50
mL), and kept stirring for 30 mins, then filtered. The filtrate was dried in vacuo by rotary
evaporator, the residue was suspended in MeOH (10 mL), and kept stirring at room temperature
for 30 mins, then filtered to collect the white solid that was dried in vacuo to give product 3a (1.22
g, 86% yield) as white solid.
(
b) One-pot process of in situ azlactone formation from N-benzoyl phenylglycine with
α-bromo-N-Ts hydrazone 1a. α-bromo-N-Ts hydrazone 1a (1.0 g, 2.73 mmol), N-benzoyl
phenylglycine 4a (0.84 g, 3.28 mmol), DCC (0.84 g, 4.10 mmol) and anhydrous Na CO (348 mg,
.28 mmol) was added into a dry tube, followed by adding anhydrous toluene (27.3 mL). The
2
3
3
2
atmosphere in tube was replaced by N , and reaction was carried out at room temperature under
2 2 2
N for 24 h. After completion, the solvent was removed. The residue was suspended in CH Cl (50
mL), and kept stirring for 30 mins, then filtered. The filtrate was dried in vacuo by rotary
evaporator, the residue was suspended in MeOH (10 mL), and kept stirring at room temperature
for 30 mins, then filtered to collect the white solid that was dried in vacuo to give product 3a (1.10
g, 77% yield) as white solid.
Synthesis of compound 5. To a solution of 3a (52.3 mg, 0.1 mmol) in anhydrous MeOH (2
mL) was added dry KOH (22.4 mg, 0.4 mmol), and the reaction mixture was stirred at room
temperature for 30 mins. When reaction completed, the mixture was poured into aq. citric acid and
2 4
extracted with EtOAc. The combined organic layers were dried over by Na SO and concentrated
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6
in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate =
2
0:1 ~ 3:1) to give 5.
Methyl 2-benzamido-2,4-diphenyl-4-(2-tosylhydrazono)butanoate (5). White solid; 54.0 mg,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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2
3
4
5
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7
8
9
0
o
1
9
7
7% yield; m.p.: 88.1-89.3 C. H NMR (300 MHz, CDCl
3
) δ 9.16 (s, 1H), 7.66-7.54 (m, 4H),
.46 (d, J = 7.2 Hz, 2H), 7.41-7.29 (m, 10H), 7.20 (d, J = 6.8 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H),
13
1
4.40 (d, J = 14.7 Hz, 1H), 4.22 (d, J = 14.7 Hz, 1H), 3.43 (s, 3H), 2.25 (s, 3H). C{ H} (75 MHz,
CDCl ) δ 171.9, 167.9, 154.6, 143.0, 138.9, 137.3, 135.0, 133.2, 132.1, 129.7, 128.9 (2C), 128.8
2C), 128.6 (2C), 128.5, 128.2 (2C), 128.0 (2C), 127.4 (2C), 126.9 (2C), 125.2 (2C), 63.3, 53.7,
3
(
+
3
5.2, 21.5. HRMS (ESI-TOF) m/z: [M + H] Calcd for C31
Synthesis of compound 6. To a solution of 3a (52.3 mg, 0.1 mmol) in anhydrous THF (2 mL)
was added NaBH (7.6 mg, 0.2 mmol), and the reaction mixture was stirred at room temperature
30 3 5
H N O S: 556.1901; Found: 556.1895.
4
for 10 h. When reaction completed, the reaction mixture was concentrated in vacuo. The residue
was purified by column chromatography (petroleum ether/ethyl acetate = 10:1 ~ 2:1) to give 6.
N-(3-oxo-4,6-diphenyl-2-tosylhexahydropyridazin-4-yl)benzamide (6). White solid; 41.0 mg,
o
1
7
8% yield; m.p.: 165.1-166.7 C. 1:0.9 dr. H NMR (300 MHz, DMSO-d
δ 8.53 (s, 1H, major), 7.91-7.86 (m, 3.8H, major + minor), 7.76-7.70 (m, 5.70H, major + minor),
.55-7.53 (m, 1.9H, major + minor), 7.48-7.35 (m, 17.1H, major + minor), 7.28-7.25 (m, 8.5H,
major + minor), 7.14-7.12 (m, 1H, major), 6.71 (d, J = 6.7 Hz, 1H, major), 6.43 (d, J = 6.6 Hz,
6
) 8.71 (s, 0.9H, minor),
7
0
1
.9H, minor), 4.10 (d, J = 18.4 Hz, 0.9H, minor), 3.88 (d, J = 17.7 Hz, 1H, major), 3.10-3.03 (m,
.9H, major + minor), 2.33 (s, 2.7H, minor), 2.30 (s, 3H, major). 13C{ H} (75 MHz, DMSO-d
1
) δ
6
(major + minor) 166.4, 165.6, 147.5, 147.0, 143.6, 143.4, 142.4, 141.9, 136.7, 135.7, 135.6, 135.0,
1
34.6, 131.4, 131.0, 129.7, 129.2, 129.1, 128.7, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.6,
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127.4, 127.3, 127.0, 126.9, 125.4, 125.3, 76.7, 75.5, 57.8, 57.7, 29.8, 28.5, 21.0. HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C30
H
27
N
3
NaO
4
S: 548.1614; Found: 548.1617.
3
Synthesis of compound 7. To a solution of 3a (52.3 mg, 0.1 mmol) in CHCl (2 mL) was
1
1
1
1
1
1
1
1
1
1
2
2
2
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0
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0
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2
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5
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9
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3
4
5
6
7
8
9
0
2
added TsOH∙H O (114 mg, 0.6 mmol), and the reaction mixture was kept stirring at reflux in oil
bath for 24 h. When reaction completed, the reaction mixture was concentrated in vacuo. The
residue was purified by column chromatography (petroleum ether : ethyl acetate = 8:1 as eluent)
to give 7.
o
4
,6-diphenylpyridazin-3(2H)-one (7). White solid; 24.0 mg, 95% yield; m.p.: 183.6-184.1 C.
1H NMR (300 MHz, CDCl
) δ 12.09 (s, 1H), 7.92-7.83 (m, 5H), 7.54-7.42 (m, 6H). 13C{ H} (75
1
3
MHz, CDCl
3
) δ 161.1, 146.3, 140.3, 134.9, 133.6, 129.9, 129.5, 129.0 (2C), 128.7 (2C), 128.5
+
(2C), 127.9, 126.0 (2C). HRMS (ESI-TOF) m/z: [M + H] Calcd for C16
H
13
N
2
O: 249.1022; Found:
2
49.1025.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
http://pubs.acs.org.
1
13
Copies of H, C NMR spectra data for all compounds; single crystal X-ray crystallography data
for 3a (PDF).
AUTHOR INFORMATION
Corresponding Author
*
e-mail: yuanwc@cioc.ac.cn
zhaojianqiang@cdu.edu.cn
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We are grateful for financial support from the National Key R&D Program of China
(2018YFC0807301-3), the National NSFC (No. 21871252, 21801024, 21801026 and 21901024),
and the Start-up Fund of Chengdu University (2081919035)
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Org. Chem. 2004, 8, 1463. (b) Wermuth, C. G. Are pyridazines privileged structures? Med.
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8
9
0
2
008, 16, 5547. (e) Cao, P.; Qu, J.; Burton, G.; Rivero, R. A. Facile Synthesis of 6-Aryl
5-N-Substituted Pyridazinones: Microwave-Assisted Suzuki-Miyaura Cross Coupling of
-Chloropyridazinones. J. Org. Chem. 2008, 73, 7204. (f) Pattison, G.; Sandford, G.; Yufit, D.
6
S.; Howard, J. A. K.; Christopher, J. A.; Miller, D. D. Polysubstituted Pyridazinones from
Sequential Nucleophilic Substitution Reactions of Tetrafluoropyridazine. J. Org. Chem. 2009,
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4, 5533.
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