N-Heterocyclic Carbene-Catalyzed Oxidative Annulations of α,β-Unsaturated Aldehydes with Hydrazones: Selective Synthesis of Optically Active 4,5-Dihydropyridazin-3-ones and Pyridazin-3-ones

Article abstract of DOI:10.1021/acs.joc.5b00784

A novel and efficient method for the highly enantioselective synthesis of chiral 4,5-dihydropyridazin-3-one derivatives has been developed based on the chiral N-heterocyclic carbene-catalyzed oxidative annulation between α,β-unsaturated aldehydes and hydrazones. Meanwhile, the selective synthesis of either 4,5-dihydropyridazin-3-ones or pyridazin-3-one derivatives from the same reactants has been achieved by simply varying catalytic and reaction conditions.

Full text of DOI:10.1021/acs.joc.5b00784

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Article
N-Heterocyclic Carbene-Catalyzed Oxidative Annulations of alpha,
beta-Unsaturated Aldehydes with Hydrazones: Selective Synthesis
of Optically Active 4,5-Dihydropyridazin-3-ones and Pyridazin-3-ones
Jian-Hui Mao, Zi-Tian Wang, Zhan-Yong Wang, and Ying Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00784 • Publication Date (Web): 27 May 2015
Downloaded from http://pubs.acs.org on June 3, 2015
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N-Heterocyclic Carbene-Catalyzed Oxidative Annulations
of α,β-Unsaturated Aldehydes with Hydrazones: Selective
Synthesis of Optically Active 4,5-Dihydropyridazin-3-ones
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and Pyridazin-3-ones
Jian-Hui Mao, Zi-Tian Wang, Zhan-Yong Wang and Ying Cheng*
College of Chemistry, Beijing Normal University, Beijing 100875, China
E-mail: ycheng2@bnu.edu.cn
O
O
R1
R2
catalyst 3g (10 mol%)
oxidant 4 (2.3 equiv.)
O
2
catalyst 3f (10 mol%) R
oxidant 4 (1.3 equiv.)
1
N
N
N
N
+
H
N
R3
R1
(2.5 equiv.) R2
R1
CsCO
DCM,
3
N
DIPEA (20 mol%)
DCM,
24h-48h/rt
R3
2
O
O
R3
O
6h/rt, 12h-30h/reflux
3
R = OEt, Alk, Ph
5: 16 examples
up to 87% yield
up to 99% ee
6
: 12 examples
up to 89% yield
O
t-Bu
Bu-t
N
N
N
N
N
N
O
O
Ph
Mes
3g BF4
t-Bu
4
Bu-t
3f Cl
Abstract:
A novel and efficient method for highly enantioselective synthesis of chiral
,5-dihydropyridazin-3-one derivatives has been developed based on the chiral
4
N-heterocyclic carbene-catalyzed oxidative annulation between α,β-unsaturated
aldehydes and hydrazones. Meanwhile, the selective synthesis of either
4
,5-dihydropyridazin-3-ones or pyridazin-3-one derivatives from the same reactants has
been achieved by simply varying catalytic and reaction conditions.
Introduction
Members of 4,5-dihydropyridazin-3(2H)-one and pyridazin-3(2H)-one families have
1
been demonstrated to possess a wide range of biological activities. Some of them have
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been used in commercial pharmaceuticals and agrochemicals. For example, both
2
3
Levosimendan and Pimobendan are calcium sensitizers and inhibitors of
phosphodiesterase with positive inotropic effects, which have been used in the treatment
of heart failures. A larger number of 4,5-dihydropyridazin-3-one derivatives, such as
0
1
2
3
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9
0
1
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9
0
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9
0
1
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3
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5
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8
9
0
4
5
6-8
CI-930,
inhibit phosphodiesterases,
anti-inflammatory activities (Figure 1). In addition, 4,5-dihydropyridazin-3-one
MCI-154
and compounds A-C,
have been reported to
and have positive inotropic/vasodilator effects
or
9
10
11
compounds also have anticancer, anticonvulsant, and hypotensive activities, etc.
Pyridazin-3-one derivatives, on the other hand, also are known to possess wide spread
12
13
and powerful pharmacologic properties, varying from antiulcer, antihistamine,
1
4
15
antitumor, anti-inflammatory activities to inhibitory activity to HIV-1 reverse
1
6
17
18
transcriptase, phosphodiesterases, platelet aggregation, etc. Various substituted
19
19
pyridazin-3-ones were reported to have insecticides, acaricides, and herbicides
20
activities.
O
O
O
O
O
O
R4
R5
R6
O
HN
N
HN
N
HN
N
N
N
HN
N
HN
N
HN
N
Z
Z
Y
F C
3
X
NH
N
N
NH
HN
N
R2
N
R1
NH
OMe
X, Y = C, N
Y = O, S, N
p-MeOPh
N
N
O
(
CH )
NC CN
R3
2 x
N
Levosimendan Pimobendan CI-930
MCI-154
A
B
C
Figure 1. Some pharmacologically active 4,5-dihydropyridazin-3-one derivatives.
Due to their broad and powerful pharmacologic activities, the syntheses of
,5-dihydropyridazin-3-one and pyridazin-3-one compounds have attracted continuous
4
interests from both organic and medicinal chemists. The most frequently used strategy for
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the construction of a 4,5-dihydropyridazin-3-one or a pyridazin-3-one ring is based on the
condensation of a hydrazine or substituted hydrazines with γ-carbonyl acids or their
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, 8, 11, 21-25
derivatives.
Another method for the formation of dihydropyridazin-3-ones or
pyridazin-3-ones is to utilize a hydrazone of 1,2-dicarbonyl compound as a substrate to
2
6
27
react with ethyl cyanoacetate,
2-benzylidenecyanoacetate or 2-benzylidenemalononitrile, followed by intramolecular
cyclization. In recent years, several new methods, including the AgNO -catalyzed
multicomponent radical reaction of aryldiazonium salts with pent-4-enoate and sodium
phosphonium ylides of carboxylates,
2
8
3
2
9
triflinate, the copper-catalyzed multicomponent reaction of aldehydes with hydrazines
3
0
and alkynylesters, the KSF-catalyzed multicomponent cyclocondensation of γ-keto
3
1
acids with thiosemicarbazide and phenacyl bromide, the Brønsted acid assisted Lewis
base-catalyzed asymmetric reaction between hydrazones and α,β-unsaturated
32
aldehydes,
and the reaction between aryldiazonium salts and potassium
3
3
2
-furantrifluoroborate,
have been developed for the construction of
4,5-dihydropyridazin-3-ones or pyridazin-3-ones. Although it has been shown that the
(
+)- and (-)-enantiomers of the 4,5-dihydropyridazin-3-one derivatives have different
34
bioactivities on the physiologic system, the studies on asymmetric synthesis of chiral
4,5-dihydropyridazin-3-ones
are
very
limited.
Enantiomerically
pure
4
,5-dihydropyridazin-3-one compounds are obtained mainly from the transformations of
23e, 35a
24b
chiral reactants,
the chiral substrate induced asymmetric reaction, the lipase-
3
5b
catalyzed resolution of racemates of 4,5-dihydropyridazin-3-one derivatives, or the
3
5c
32
resolution of racemic reactants by a chiral reagent. Recently, Rueping and co-workers
reported the chiral Brønsted acid assisted amine-catalyzed asymmetric reaction between
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N-aryltrifluoromethylhydrazones and α,β-unsaturated aldehydes, which produced good
yields of 1,4-dihydropyridazine derivatives with excellent enantioselectivity via the
dehydration of two diastereomeric 2,3,4,5-tetrahydropyridazin-3-ol intermediates. The
oxidation of the 2,3,4,5-tetrahydropyridazin-3-ol intermediate by PCC could provide
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9
0
4
,5-dihydropyridazin-3-one in excellent yield, however, no ee value was reported. Ye and
co-workers reported the highly efficient and enantioselective cinchona alkaloid-catalyzed
asymmetric annulation of α,β-unsaturated acid chlorides with azodicarboxylates and the
chiral NHC-catalyzed annulation of γ-(methoxycarbonyloxy)-α,β-unsaturated aldehydes
with azodicarboxylates. Both of them generated chiral 1,2-dihydropyridazin-3-ones rather
36, 37
than 4,5-dihydropyridazin-3-ones.
To the best of our knowledge, the direct
construction of enantiopure 4,5-dihydropyridazin-3-ones by chiral catalysis has not been
reported yet. Therefore, the development of highly efficient and enantioselective
reactions for the preparation of enantiomercally pure 4,5-dihydropyridazin-3-one
compounds is of great importance.
Oxidative N-heterocyclic carbene (NHC) catalysis has attracted increasing attentions in
38
recent years. Oxidative NHC-catalyzed reactions of α,β-unsaturated aldehydes, which
initially form α,β-unsaturated acylazolium intermediates, undergo annulation reactions
with various nucleophilic substrates to produce diverse cyclic compounds. For instance,
in the presence of a quinone oxidant, NHC-catalyzed reaction of α,β-unsaturated
aldehydes or 3-bromoenals with 1,3-diones produces 3,4-dihydropyran-2-one or
3
9
pyran-2-one derivatives. On the other hand, under the oxidative NHC catalysis
conditions, the annulation of α,β-unsaturated aldehydes with imines or enamines
4
0
produces dihydropyridin-2-ones. In addition, the γ-activation of α,β-unsaturated
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aldehydes has also been achieved by means of oxidative NHC catalysis, allowing the
γ-addition of 3-alkylenals to the carbonyls of trifluoromethyl ketones or isatins to form
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4
1
dihydropyran-2-one derivatives. In 2010, Scheidt and co-workers reported the
cooperative chiral NHC/Lewis acid-catalyzed reaction of α,β-unsaturated aldehydes with
N-acylhydrazones to produce N-benzamido substituted γ-lactams with high
4
2
stereoselectivity via a formal [3+2] annulation.
In Scheidt’s reaction, the
α,β-unsaturated aldehydes act as nucleophiles via the Breslow intermediates to add to the
electrophilic imine groups of hydrazones that are activated by a Lewis acid (Scheme 1,
Eq. 1). We envisioned that, under the cooperative NHC/oxidant catalysis,
α,β-unsaturated aldehydes would behave as electrophiles via α,β-unsaturated
acylazolium intermediates to undergo a formal [3+3] annulation with the nucleophilic
hydrazones to yield 4,5-dihydropyridazin-3-one compounds (Scheme 1, Eq. 2). Herein
we report
dihydropyridazin-3-ones
,5-dihydropyridazin-3-ones or pyridazin-3-ones from oxidative NHC catalysis of the
a
novel method for the enantioselective synthesis of chiral
and the selective synthesis of either
4
reaction between α,β-unsaturated aldehydes and hydrazones by varying catalytic and
reaction conditions.
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1
1
1
1
1
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1
1
2
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2
2
2
2
2
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2
2
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5
5
6
Eq.1. Scheidt's work (ref. 42):
O
OH
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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9
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9
0
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8
9
0
O
N
N
O
N
N
Ar
Mes
nucleophile
Ar
O
N
Ar1
N
N
NH
Et
BF4
Mes
+
+
[
3+2] annulation
L
Ar
base
O
O
L
Mg
CO
2
O
O
O
N
Ar1
1electrophile
EtO
N
N
MgL2
O
H
EtO
N
Ar
H
Eq. 2. This work:
O
N
N
Ar1
N
O
O
N
Mes
N
(
Alk) Ar
O
electrophile
N
Cl
Ar (Alk)
OEt (R)
(Alk) Ar
N N
+
base
+
Mes
N
O
oxidant
[3+3] annulation
nucleophile
O
O
Ar1
Ar1
N
(
R) EtO
N
(R) EtO
N
H
H
Scheme 1. The comparison between the reactions of α,β-unsaturated aldehydes with hydrazones
under Scheidt’s and our catalytic conditions.
Results and Discussion
The first experiment on the feasibility of [3+3] annulation reaction between enals and
hydrazones
was
carried
out
with
cinnamaldehyde
1a
and
ethyl
2
-(N-phenylhydrazono)acetate 2a as substrates. We initiated our study by examining the
reaction of 1a with 2a employing a variety of chiral triazolium salts 3a-3f bearing a
different fused-ring or a varied N-substituent as NHC precursors. The NHC catalysts
3
a’-3f’ were generated in situ from the deprotonization of triazolium salts 3a-3f with
DBU in dichloromethane at ambient temperature. In the presence of DBU (20 mol%) and
quinone oxidant 4 (1.3 equiv.), a bicyclic triazolium salt 3a (10 mol%) was found almost
inactive to catalyze the reaction of enal 1a with hydrazone 2a (1a:2a = 1.3:1). However,
the pyrrolidine- (3b) and morpholine-fused triazolium salt 3c were able to promote the
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reaction to produce (+)-1,4-diphenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5a in good
yields (73%-84%) with low enantioselectivity (33%-49% ee) (Table 1, entries 2 and 3).
When tetracyclic triazolium salts 3d-3f were utilized as precatalysts, the reactions
catalyzed by N-phenyl- (3d) and N-mesityl (2,4,6-trimethylphenyl) substituted triazolium
salt 3f provided 68%-72% yields of (-)-5a with 59%-74% ee (Table 1, entries 4 and 6).
However, only a trace amount of product was isolated from the reaction catalyzed by
N-perfluorophenyl substituted triazolium salt 3e. Since the best enantioselectivity was
observed from the reaction using N-mesityltriazolium salt 3f as a precatalyst, the reaction
conditions were further optimized by varying bases, solvents and reaction temperature in
the presence of triazolium salt 3f. It was found that the replacement of DBU by a strong
base t-BuOK or KOH diminished the chemical yield or both the yield and ee value of 5a
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(
2 3
Table 1, entries 7, 8). Pleasingly, the employment of Cs CO or diisopropylethylamine
(DIPEA) as a base led to the improvement of chemical yield of 5a to 81% or 87%,
respectively, with excellent enantioselectivity (92%-96% ee) being also obtained (Table 1,
entries 9, 10). In the presence of N-mesityltriazolium salt 3f, DIPEA and quinone 4, the
use of THF, toluene or acetonitrile as reaction media caused the decrease of both
chemical yield and enantioselectivity (Table 1, entries 11-13). In dichloromethane, either
o
decease reaction temperature to 0 C or increase to the boiling point of solvent was not
beneficial to the yield of product (Table 1, entries 14-15).
Table 1. Optimization of reaction conditions for the chiral NHC-catalyzed oxidative annulation of
cinnamaldehyde 1a with 2-(N-phenylhydrazono)acetate 2a.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
H
NHC precursor 3
Ph
(10 mol%)
base (20 mol%)
N
OEt
Ph
O
+
Ph
N
N
N
*
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
a
Ph
2a
oxidant 4 (1.3 equiv)
1
a:2a = 1.3:1
solvent
O
O
OEt
N
O
N
N
(R)-5a or (S)-5a
N
N
N
N
Ph
Ph
N
N
O
Ph
BF4
BF4
Ph
BF
4
Ph 3a
3b
Ph
3c
N
N
t-Bu
Bu-t
N
X
Ar
O
O
3
d: Ar = Ph, X = BF4
e: Ar = C F , X = BF
4
3
6
5
t-Bu
Bu-t
4
3f: Ar = 2,4,6-Me C H , X = Cl
3 6 2
b
Entry
NHC
base
solvent
temp.
time (h) yield of 5a
ee (%)
-
a
precursor 3
(%)
1
2
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
DBU
DBU
DBU
DBU
DBU
DBU
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
24
24
48
48
24
48
trace
84
73
72
9
c
49
c
3
33
d
4
59
5
-
d
6
68
50
43
81
87
8
74
d
7
t-BuOK
94
d
8
KOH
12
d
9
Cs
2
CO
3
92
d
10
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
96
11
-
d
12
toluene
28
88
55
70
59
d
13
CH
3
CN
70
o
d
14
DCM
DCM
0 C
96
d
15
3f
reflux
24
92
a
b
c
d
Isolated yields. Determined by HPLC analysis on a OD-H column. (+)-enantiomer. (-)-enantiomer.
The optimized reaction conditions were adopted for further studies of the reaction
scope (Table 2). With respect to the α,β-unsaturated aldehyde substrates,
cinnamaldehyde 1a and its analogues 1b and 1c bearing an electron-donating group
(
4-Me and 4-MeO) reacted with 2-(N-phenylhydrazono)acetate 2a to produce
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6
7
8
9
4
,5-dihydropyridazin-6-one-3-carboxylates 5a-5c in 71%-87% yields with excellent
enantioselectivity (96%-99% ee) (Table 2, entries 1-3). However, the cinnamaldehydes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1d and 1e substituted by an electron-withdrawing group (4-Br and 4-Ac) gave products
5
d and 5e in 51-72% yields with lower enantioselectivity (64%-67% ee) (Table 2, entries
and 5). The lower chemical yield of product 5e derived from the strong
4
electron-withdrawing acetyl substituted cinnamaldehyde 1e is probably due to the lower
stability of 1e than other cinnamaldehydes 1a-1d. It was found that the substitution
pattern of cinnamaldehydes also influenced the outcome of the reaction, as
3
-methylcinnamaldehyde 1f produced a higher yield (87%) of product than that of
2-methylcinnamaldehyde 1g (67%). The enantioselectivity was however not affected
96%-98% ee) (Table 2, entries 6 and 7). In comparison to the aromatic enals, the
(
reactions of aliphatic enals 1h and 1i produced lower yields of products 5h and 5i
(47%-49%) with 93%-96% ee, probably because the aliphatic enals were less stable
under the reaction conditions (Table 2, entries 8 and 9). We next examined the chiral
NHC-catalyzed oxidative annulation of cinnamaldehyde 1a with different hydrazones. It
was found that the substituents attached to hydrazones 2 influenced both the chemical
yields and enantioselectivity. For example, while N-(4-methoxyphenyl)- (2b),
N-(4-methylphenyl)- (2c) and N-(4-bromophenyl)hydrazonoacetate (2d) reacted with
enal 1a to give products 5j-5l in 69%-79% yields with 90%-95% ee, the reaction of
N-(4-trifluoromethylphenyl)hydrazonoacetate 2e with 1a formed product 5m in moderate
yield (51%) and enantioselectivity (74% ee) (Table 2, entries 10-13). The
N-(4-trifluoromethylphenyl)hydrazonoacetate 2e produced a lower yield of product than
other N-arylhydrazonoacetates 2a-2d, probably because the strong electron-withdrawing
9
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
trifluoromethyl group decreased the nucleophilicity of hydrazone 2e. When
2
-(N-arylhydrazono)acetates were replaced by 2-(arylhydrazono)ketones 2f-2h, the
reactions of 1a with 2-(arylhydrazono)ketones 2f-2h proceeded smoothly to produce
-carbonyl-4,5-dihydropyridazin-3-ones 5n-5p in 60%-83% yields with excellent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
enantioselectivity (94%-97% ee) (Table 2, entries 14-16). The acetyl substituted
hydrazone 2f gave a better yield of product than the bulky isobutyryl- and benzoyl
substituted hydrazones 2g and 2h, probably due the larger steric hindrances of 2g and 2h.
The reaction between cinnamaldehyde 1a and N-benzoylhydrazone 2i, which were the
substrates of Scheidt’s reaction (see Eq. 1 in Scheme 1), was also examined under our
oxidative NHC catalysis conditions. However, no reaction of 1a with 2i occurred. This
was probably attributable to much weaker nucleophilicity of N-acylhydrazones in
comparison to N-arylhydrazones (Table 2, entry 17). The results summarized in Table 2
indicated that the products 5d, 5e and 5m containing an electron-withdrawing group have
lower enantiomeric excess values (64%-74% ee). That is probably because the
electron-withdrawing substituents enhance the acidity of the proton in stereogenic center
of 5 and therefore causes the partial racemization of products 5d, 5e and 5m under the
basic reaction conditions.
Table 2. Enantioselective synthesis of chiral 4,5-dihydropyridazinone derivatives 5.
O
H
N
catalyst 3f (10 mol%)
R2
R3 oxidant 4 (1.3 equiv.)
R1
R2
N
N
N
O
+
1
DIPEA (20 mol%)
DCM, rt, 24h-48h
2
O
R1
O
t-Bu
Bu-t
O
R3
5
N
N
N
O
O
Mes
Cl
3f
t-Bu
4
Bu-t
1
0
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8
9
1
2
3
b
entry
1
R
2
R
R
time
h)
yield of 5 ee (%)
a
(
(%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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29
30
31
32
33
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36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
24
48
24
24
24
24
24
48
48
24
24
24
24
24
24
24
24
5a: 87
5b: 71
5c: 72
5d: 72
5e: 51
5f: 87
5g: 67
5h: 49
5i: 47
5j: 79
5k: 78
5l: 69
5m: 51
5n: 83
5o: 69
5p: 60
NR
96
99
98
67
64
96
98
93
96
93
95
90
74
94
97
95
6 4
4-MeOC H
4-MeC
6
H
4
Ph
4-BrC
6
H
4
Ph
4-AcC
6
H
4
Ph
3-MeC
6
H
H
4
4
Ph
1g
1h
1i
2-MeC
6
Ph
n-Pr
i-Pr
Ph
Ph
Ph
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1a
6 4
4-MeOC H
Ph
4-MeC
6 4
H
Ph
4-BrC H
6
4
Ph
3 6 4
4-CF C H
Ph
Ph
Ph
Ph
Ph
2g
2h
2i
i-Pr
Ph
Ph
Ph
PhCO
OEt
a
b
Isolated yields. Determined by HPLC analysis on a OD-H column (The details of HPLC separation
conditions for each product 5 have been listed in Supporting Information).
During the preparation of racemic 4,5-dihydropyridazin-3-ones 5 using an achiral NHC
catalyst, we detected a trace amount of pyridazin-3-ones 6 in some cases. It was also
observed that 4,5-dihydropyridazin-3-ones 5 could be oxidized into pyridazin-3-ones 6
upon the treatment with the oxidant 4 and a base. We expected that the selective synthesis
of pyridazin-3-ones 6 from the NHC-catalyzed oxidative annulation between enals 1 and
hydrazones 2 might be achieved by varying the catalytic conditions. Thus, we scrutinized
11
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the reaction conditions for the selective synthesis of pyridazin-3-ones 6 using the model
reaction of p-bromocinnamaldehyde 1d with 2-(N-phenylhydrazono)acetate 2a. The
achiral triazolium salts were employed as catalysts in this reaction, as pyridazin-3-ones 6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were achiral compounds. Since pyridazin-3-ones
,5-dihydropyridazin-3-ones 5, we first optimized the reaction conditions by screening
carbene catalysts and bases in order to obtain a high yield of racemic
,5-dihydropyridazin-3-one 5d. As indicated by the results in Table 3, in the presence of
6
were derived from
4
4
DIPEA (20 mol%) and quinone oxidant 4 (1.3 equiv.) at ambient temperature,
dihydropyrrolo[2,1-c]triazolium salt 3g appeared as the most efficient catalyst for the
formation of racemic 5d among the examined achiral triazolium salts 3g-3i (Table 3,
2 3
entries 1-3). On the other hand, in the reactions catalyzed by triazolium salt 3g, Cs CO
was most beneficial to the reaction comparing to DIPEA and DBU (Table 3, entries 4-6).
Having had the optimized catalysts in hand, we then increased the loading of oxidant and
base to promote the transformation of 4,5-dihydropyridazin-3-one 5d to pyridazin-3-one
6
d. At ambient temperature, the increasing of oxidant 4 to 2.3 equiv. alone did not
promote the reaction at all. Increasing the loadings of both oxidant and Cs CO to 2.3
equiv. and 1.2 equiv., respectively, led to the formation of 5d in 74% yield along with the
formation of 6d in only 12% yield. Further increase of the loading of Cs CO to 2.5 equiv.
2
3
2
3
improved the yield of 6d to 26%, with the isolation of 61% yield of 5d (Table 3, entry 8).
Since the oxidation of 5d to 6d was inefficient at ambient temperature, the reaction
temperature was then elevated to the boiling point of solvent to accelerate this
transformation. To avoid the oxidation of cinnamaldehyde to cinnamic acid at high
temperature, the reaction was carried out initially in dichloromethane at ambient
1
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temperature for 6h to form dihydropyridazinone 5d, followed by heating the reaction
mixture in refluxing solvent for 24h to promote the oxidation of 5d into pyridazin-3-one
6d. Delightfully, 83% yield of pyridazin-3-one 6d was isolated from the reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
catalyzed by triazolium salt 3g (10 mol%), Cs
2 3
CO (2.5 equiv.) and oxidant 4 (2.3 equiv.)
in refluxing dichloromethane (Table 3, entry 9).
Table 3. Optimization of reaction conditions for selective synthesis of pyridazin-3-one 6d using
achiral NHC catalysts.
O
O
O
Ph
+
Ph
N
N
N
N
catalyst 3 (10 mol%)
oxidant 4
Br
1
d
+
H
base
DCM
N
OEt
O
OEt
Br
O
OEt
Bn
Br
t-Bu
Ph
N
5d
6d
1
d:2a = 1.3:1
O
2
a
Ph
Bu-t
N
N
N
N
N
Bn
N
N
N
O
O
N
Ph
Ph
Ph
Br
3i
BF
4
Cl
h
t-Bu
Bu-t
3
g
3
4
Entry
catalyst
base
(equiv.)
oxidant 4
reaction conditions
yield of
yield of
3
(equiv.)
5d (%)
6d (%)
T (h)/rt
10
T (h)/reflux
1
2
3
4
5
6
7
8
9
3g
3h
3i
DIPEA (0.2)
DIPEA (0.2)
DIPEA (0.2)
DBU (0.2)
1.3
1.3
1.3
1.3
1.3
2.3
2.3
2.3
2.3
-
-
71
54
-
-
10
10
-
51
-
3g
3g
3g
3g
3g
3g
10
-
58
-
Cs
Cs
2
2
CO
3
3
(0.2)
(0.2)
10
-
96
-
CO
24
-
87
-
Cs CO (1.2)
24
-
74
12
26
83
2
3
Cs
2
CO
3
(2.5)
24
-
61
Cs CO (2.5)
2
3
6
24
trace
The generality for the selective synthesis of pyridazin-3-ones 6 from α,β-unsaturated
aldehydes 1 and hydrazones 2 was then investigated by using dihydropyrrolotriazolium
1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
salt 3g (10 mol%), Cs
2
CO
3
(2.5 equiv.) and oxidant 4 (2.3 equiv.) as a catalytic system in
dichloromethane. The reactions catalyzed by the achiral carbene 3g’ are more reactive
than the reactions catalyzed by the bulky chiral carbene 3f’. Thus, the reactions were first
carried out at ambient temperature for 6h to form dihydropyridazinone 5, and then in
refluxing dichloromethane for another period of time to finish the oxidation of 5 into
pyridazin-3-ones 6. It was found that this reaction tolerated both electron-rich and
electron-deficient enals, as cinnamaldehyde 1a and cinnamaldehydes 1b-1e substituted
by methyl, methoxy, bromo and acetyl groups reacted effectively with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-(N-phenylhydrazono)acetate 2a to produce pyridazin-3-ones 6a-6e in good yields
(71%-89%) (Table 4, entries 1-5). With respect to the hydrazone substrates, the variation
of the substituents of 2-(N-arylhydrazono)acetates 2 only marginally affected the reaction,
as substrates 2b-2e attached by either an electron-donating or an electron-withdrawn
group reacted equally well with enal 1a to afford 67%-84% yields of products 6j-6m
(
Table 4, entries 6-9). The reactions of 2-(arylhydrazono)ketones 2f-2h with 1a
proceeded analogously albeit the corresponding products 6n-p were obtained in slightly
lower yields (Table 4, entries 10-12).
Table 4. The selective synthesis of pyridazin-3-ones 6.
catalyst 3g (10 mol%)
oxidant 4 (2.3 equiv.) R2
O
H
R3
R1
N
O +
R2
N
N
N
1
Cs CO (2.5 equiv.)
2
3
2
O
R1
DCM, rt, 6h,
then reflux 12h-30h
O
R3
t-Bu
Bu-t
N
6
N
N
Ph
O
O
BF4
3
g
t-Bu
4
Bu-t
reaction conditions yield of 6 (%)
1
2
3
a
entry
1
R
2
R
R
1
4
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5
6
7
8
9
1
2
3
4
5
6
1a
1b
1c
1d
1e
1a
Ph
2a
2a
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
6h/rt, 15h/reflux
6h/rt, 24h/reflux
6h/rt, 17h/reflux
6h/rt, 24h/reflux
6h/rt, 17h/reflux
6h/rt, 12h/reflux
6a: 89
6b: 71
6c: 78
6d: 83
6e: 75
6j: 82
6 4
4-MeOC H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-MeC H
6
4
6 4
4-BrC H
4-AcC
6 4
H
Ph
6 4
2b 4-MeOC H
7
8
9
1a
1a
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Ph
Ph
2c
2d
2e
2f
4-MeC
4-BrC
4-CF
6
H
4
OEt
OEt
OEt
Me
i-Pr
Ph
6h/rt, 36h/reflux
6h/rt, 12h/reflux
6h/rt, 33h/reflux
6h/rt, 17h/reflux
6h/rt, 30h/reflux
6h/rt, 18h/reflux
6k: 84
6l: 67
6
H
4
3
C
6
H
4
6m: 74
6n: 58
6o: 41
6p: 52
1
0
1
2
Ph
Ph
Ph
1
2g
2h
1
a
A trace amount of racemic 5 was detected without isolation in some reactions.
To account for the formations of 4,5-dihydropyridazin-3-ones 5 and pyridazin-3-ones 6
from α,β-unsaturated aldehydes and hydrazones, a cascade reaction pathway was
proposed in Scheme 2. Interaction between the NHC catalyst and cinnamaldehydes 1
forms homoenolate intermediates 7, which are oxidized into α,β-unsaturated acylazolium
salts 8 by oxidant 4. The hydrazones 2 act as C-nucleophiles, probably via the resonance
structures 9 (see the resonance structures 2 and 9 in ref. 43a), to undergo Michael
addition toward α,β-unsaturated acylazolium salts 8, formating diazene intermediates 10.
A proton transformation of 10 yields the diazene compounds 11. To avoid the steric
hindrance of the indane ring, the nucleophiles 9 attack preferentially to the Re-face of
α,β-unsaturated acylazolium salts 8 to form a S-configured stereogenic carbon center (In
the case of 2-hexenal 1h, this chiral center is R-configured.). The absolute configuration
of product (S)-5l, which contains an N-bromophenyl group, was established by X-ray
1
5
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6
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
diffraction analysis (See Supporting Information). Theoretically, the hydrazones 2 could
either act as a C-nucleophile or a N-nucleophile toward Michael acceptors. In this work,
however, no regioisomer of 4,5-dihydropyridazin-3-ones 5 was detected. In fact, the
regioselective Carba-Michael rather than Aza-Michael addition of different hydrazones to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
43
enals and enones catalyzed by amine catalysts have been documented in literature. In
the presence of a base catalyst, diazene compounds 11 probably undergo a base-catalyzed
1
,3-H migration to form the amino substituted imines 12 (A similar [1,3]-hydride shift of
diazenes to imine has been reported in ref. 43a). The intramolecular cyclization of 12
leads to the formation of 4,5-dihydropyridazin-3-ones 5. Finally, a base-catalyzed
oxidation of 4,5-dihydropyridazin-3-ones 5 by quinone 4 affords pyridazin-3-ones 6.
O
O
HO
O
O
O
N
base
N
oxidant 4
N
N N
3f
Ar
Cl
Ar
Ar
H +
Re-face N N
N N
Mes
Mes
EWG
8
Mes
7
1
EWG
N
Ar1
Ar1
N
N
N
H
H
9
2
O
O
Ar1
base-catalyzed
1,3-H shift
Ar1
O proton
O
O
N
N
O
O
O
N
N
oxidant
base
shift
N
N
N
Ar
Ar
N
N
N
EWG
Ar
EWG
Ar
EWG
Mes
Mes
N
Ar
Mes
N
EWG
H
H
N
N
Ar1
Ar1
N
N
Ar1
EWG
6
5
12
11
1
0
Scheme 2. Proposed mechanism for the formations of 4,5-dihydropyridazin-3-ones 5 and
pyridazin-3-ones 6 from NHC-catalyzed oxidative annulation between α,β-unsaturated aldehydes and
hydrazones.
It is worth mentioning that Chi and co-workers reported in 2013 that the chiral NHC
3
f’-catalyzed annulation of α,β-unsaturated esters with N-Ts imines, which produced
1
6
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3
,4-dihydropyridin-2-ones in moderate to good yields with excellent enantioselectivity.
In their reaction, the key intermediates, α,β-unsaturated acylazolium salts 8, were derived
from the addition of chiral carbene 3f’ to 4-nitrophenyl α,β-unsaturated esters. We
envisioned that the chiral NHC-catalyzed reaction between 4-nitrophenyl α,β-unsaturated
esters and hydrazones would also provide an alternative route to enantiomerically pure
10
11
12
13
14
15
16
17
18
19
20
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
,5-dihydropyridazin-3-ones 5. Thus, we examined the reactions of 4-nitrophenyl
cinnamate 13a and 4-nitrophenyl p-bromocinnamate 13d with
2-(N-phenylhydrazono)acetate 2a catalyzed by chiral NHC catalyst 3f in the absence of
oxidant 4. Disappointingly, under our reaction conditions (10 mmol% of 3f, 20 mmol%
DIPEA, DCM, rt, 24h) or the Chi’s conditions (20 mmol% of 3f, 100 mmol% DBU, THF,
rt, 14h), all reactions gave 4,5-dihydropyridazin-3-one products in very low yields
(4%-14% yields) (Scheme 3). Meanwhile, although the reaction in dichloromethane
displayed excellent enantioselectivity (92% ee), the products 5a and 5d were racemized
in the reactions conducted in THF solvent. Since most of the hydrazone 2a was
unconsumed in these reactions, we considered that the acidic 4-nitrophenol released from
4
-nitrophenyl cinnamate probably inhibits the nucleophilicity of hydrazone 2a. To
neutralize the p-nitrophenol, we then used an excess amount of DIPEA in the reactions of
13a and 13d with 2a in DCM. However, the chemical yields of products 5a and 5d were
not significantly improved in these reactions (Scheme 3). The outcomes of these
reactions showed clearly that the chiral NHC-catalyzed reaction of p-nitrophenyl
α,β-unsaturated esters 13 with hydrazones 2 is not an efficient method for the synthesis
of 4,5-dihydropyridazin-3-ones 5.
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2
2
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2
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2
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4
4
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5
5
5
5
5
5
6
O
NO2
O
O
N
N
N
Ph
Ar
O
N
N
O
O
Mes
1
1
3a: Ar = Ph
3d: Ar = p-BrPh
2a
0
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0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cl
N
Ar
CO Et
3
f
Ar
+
N
2
N
EtO C
N
Ph
2
N
base, solvent, rt
Mes
5a or 5d
H
2
a
8
Reaction conditions:
Yield (ee value):
5a: 14% (92% ee); 5d: trace
5a: 12% (6% ee); 5d: 4% (0% ee)
5a: 11% (0% ee); 5d: 8% (4% ee)
5a: 14% (92% ee); 5d: 10% (91% ee)
5a: 11% (90% ee); 5d: 19% (89% ee)
(
(
(
a) 10 mol% of 3f, 20 mol% DIPEA, DCM, rt, 24 h
b) 20 mol% of 3f, 100 mol% DBU, THF, rt, 14 h
c) 20 mol% of 3f, 100 mol% DBU, THF, rt, 24 h
(d) 20 mol% of 3f, 100 mol% DIPEA, DCM, rt, 24 h
e) 20 mol% of 3f, 120 mol% DIPEA, DCM, rt, 24 h
(
Scheme 3. The chiral NHC-catalyzed reaction of p-nitrophenyl α,β-unsaturated esters 13 with
hydrazones 2.
Conclusion
In summary, we have developed an efficient method for enantioselective synthesis of
chiral 4,5-dihydropyridazin-3-one derivatives with high enantioselectivity from chiral
NHC-catalyzed oxidative annulation reaction of α,β-unsaturated aldehydes with
hydrazones. Meanwhile, the selective syntheses of 4,5-dihydropyridazin-3-ones and
pyridazin-3-ones have been achieved by varying catalytic and reaction conditions. This
work provided not only a new strategy for the constructions of enantiopure
4
,5-dihydropyridazin-3-ones and pyridazin-3-one compounds, but also new chemical
entities of potential biological properties and valuable intermediates subject to further
elaborations owing to their functional structures.
Experimental Section
General
4,5-dihydropyridazin-3-one derivatives 5.
Under nitrogen atmosphere and at room temperature, α,β-unsaturated aldehydes 1 (1.3
procedure
for
enantioselective
synthesis
of
chiral
43a,
45
mmol),
hydrazones
2
(1
mmol),
chiral
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N-mesityl-indeno[2,1-b]triazolo[4,3-d][1,4]oxazinium salt 3f
(37mg, 0.1 mmol),
4
7
oxidant 4 (530mg, 1.3 mmol) were mixed in dry dichloromethane (15 mL), and then
10
11
12
13
14
15
16
17
18
19
20
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23
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DIPEA (26mg, 0.2 mmol) was added using a microsyringe. The reaction mixture was
o
stirred at room temperature (20-30 C) for 24-48 h until the enals 1 and hydrazones 2
were almost completely consumed. After removal of the solvent, the residue was
chromatographyed on a silica gel column eluting with a mixture of petroleum ether, ethyl
3
acetate and triethylamine (PE:EA:Et N = 10:1.5:0.1－10:3:0.1) to give products 5 in
47%-87% yields.
(S)-Ethyl 1,4-diphenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5a: white crystals,
20
o
o
-1
280 mg, 87%, ee 96%, [α]
D
= -52.0 (c = 0.5, acetone), mp 108-109 C; IR v (cm )
1
1
716, 1696; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.50 (dd, J = 8.8, 1.6 Hz, 2H), 7.43 (t,
J = 7.2 Hz, 2H), 7.29-7.36 (m, 4H), 7.23-7.27 (m, 2H), 4.59 (dd, J = 8.4, 2.0 Hz, 1H),
.25-4.36 (m, 2H),3.13 (dd, J = 16.8, 8.4 Hz, 1H), 2.99 (dd, J = 16.8, 2.0 Hz, 1H), 1.31 (t,
4
1
3
3
J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 164.2, 163.0, 144,7, 140.3, 137.4,
129.4, 128.8, 128.0, 127.4, 126.9, 125.1, 62.2, 38.5, 35.4, 14.1; HRMS (ESI-TOF): [M +
+
H] calcd for C19
19
H N
O
2 3
: 323.1396; found: 323.1404.
(
S)-Ethyl 4-(4-methoxyphenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate
2
0
o
o
5b: white crystals, 250 mg, 71%, ee 99%, [α] = -2.8 (c = 1.0, acetone), mp 98-99 C;
D
-
1
1
IR v (cm ) 1713, 1696; H NMR (400 MHz, CDCl
.36 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4
Hz, 2H), 4.46 (dd, J = 8.4, 1.6 Hz, 1H), 4.19-4.29 (m, 2H), 3.71 (s, 3H), 3.03 (dd, J =
3
) δ (ppm) 7.43 (d, J = 8.0 Hz, 2H),
7
1
3
1
7.2, 8.4 Hz, 1H), 2.89 (dd, J = 16.8, 1.6 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3) δ (ppm) 164.4, 163.0, 159.3, 145.0, 140.3, 129.4, 128.8, 128.0, 127.4,
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2
2
2
2
2
2
2
2
2
3
3
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5
5
5
5
5
5
5
5
6
+
1
25.1, 114.7, 62.2, 55.3, 37.7, 35.5, 14.1; HRMS (ESI-TOF): [M + H] calcd for
C
20
H
21
N
2
O
4
: 353.1501; found: 353.1501.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
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2
3
4
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8
9
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3
4
5
6
7
8
9
0
(S)-Ethyl 4-(4-methylphenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5c:
2
0
o
o
white crystals, 242 mg, 72%, ee 98%, [α]
D
= -29.8 (c = 0.51, acetone), mp 68-70 C;
-1
1
IR v (cm ) 1708; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.49 (d, J = 7.7 Hz 2H), 7.43 (t, J
= 7.5 Hz, 2H), 7.32 (t, J = 7.1 Hz, 1H), 7.14 (d, J = 9.8 Hz 2H), 7.12 (d, J = 8.2 Hz 2H),
4
.55 (dd, J = 8.1, 1.2 Hz, 1H), 4.27-4.34 (m, 2H), 3.11 (dd, J = 16.8, 8.4 Hz, 1H), 2.96
13
(
dd, J = 16.8, 1.6 Hz, 1H), 2.32 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 164.4, 163.0, 144.9, 140.3, 137.8, 134.3, 130.0, 128.8, 127.4, 126.7,
+
1
25.1, 62.3, 38.1, 35.5, 21.1, 14.1; HRMS (ESI-TOF): [M + H] calcd for C20
H
21
N
2
O
3
:
3
37.1552; found: 337.1561.
S)-Ethyl 4-(4-bromophenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5d:
(
2
0
o
-1
white crystals, 288 mg, 72%, ee 67%, [α]
D
= -9.3 (c = 1.0, acetone), oil; IR v (cm )
1
1732, 1697; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.47-7.50 (m, 4H), 7.44 (t, J = 8.4 Hz,
2
H), 7.34 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 4.56 (dd, J = 8.4, 1.6 Hz, 1H),
4.26-4.38 (m, 2H), 3.13 (dd, J = 16.8, 8.4 Hz, 1H), 2.96 (dd, J = 16.8, 2.0 Hz, 1H), 1.33 (t,
13
J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 163.9, 162.9, 144.0, 140.2, 136.4,
1
32.5, 128.8, 128.6, 127.5, 125.0, 122.1, 62.4, 37.9, 35.1, 14.1; HRMS (ESI-TOF): [M +
+
H] calcd for C19
H18BrN
2
O
3
: 401.0501; found: 401.0511.
(
S)-Ethyl 4-(4-acetylphenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5e:
2
0
o
o
white crystals, 186 mg, 51%, ee 64%, [α]
D
= +3.8 (c = 0.5, acetone), mp 125-126 C;
) δ (ppm) 7.94 (d, J = 8.4 Hz,
H), 7.49 (dd, J = 8.2, 1.6 Hz, 2H), 7.44 (t, J = 8.2 Hz, 2H), 7.32-7.36 (m, 3H), 4.65 (dd,
-1
1
IR v (cm ) 1738, 1703, 1681; H NMR (400 MHz, CDCl
3
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J = 8.4, 2.0 Hz, 1H), 4.27-3.38 (m, 2H), 3.17 (dd, J = 16.8, 8.4 Hz, 1H), 2.99 (dd, J =
1
3
1
3
6.8, 2.0 Hz, 1H), 2.59 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ppm) 197.3, 163.9, 162.9, 143.8, 142.5, 140.1, 136.8, 129.4, 128.9, 127.6, 127.2, 125.0,
+
6
2.5, 38.4, 35.1, 26.6, 14.1; HRMS (ESI-TOF): [M + H] calcd for C21
21 2 4
H N O :
365.1501; found: 365.1495.
(
S)-Ethyl 4-(3-methylphenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5f:
2
0
o
o
white crystals, 294 mg, 87%, ee 96%, [α]
D
= -70.4 (c = 0.51, acetone), mp 70-71 C;
IR v (cm ) 1705; H NMR (400 MHz, CDCl ) δ (ppm) 7.50 (dd, J = 8.2, 1.4 Hz, 2H),
7.44 (t, J = 8.2 Hz, 2H), 7.32 (tt, J = 7.3, 1.3 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.10 (d, J
7.6 Hz, 1H), 7.04 (s, 1H), 7.2 (d, J = 8.0 Hz, 1H), 4.55 (dd, J = 8.4, 2.0 Hz, 1H),
.24-4.35 (m, 2H), 3.11 (dd, J = 16.8, 8.4 Hz, 1H), 2.97 (dd, J = 17.2, 2.0 Hz, 1H), 2.32
-1
1
3
=
4
1
3
(
3
s, 3H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 164.3, 163.0,
144.8, 140.4, 139.1, 137.3, 129.2, 128.81, 128.79, 127.6, 127.4, 125.1, 123.8, 62.2, 38.4,
+
3
5.5, 21.5, 14.1; HRMS (ESI-TOF): [M + H] calcd for C20
21 2 3
H N O : 337.1552; found:
337.1544.
(S)-Ethyl 4-(2-methylphenyl)-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5g:
20
o
o
white crystals, 225 mg, 67%, ee 98%, [α] = -0.6 (c = 1.0, Acetone), mp 85-86 C; IR
D
-
1
1
v (cm ) 1737, 1710; H NMR (400 MHz, CDCl
7.45 (dt, J = 8.0, 2.0 Hz, 2H), 7.33 (tt, J = 7.6, 1.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.17
dt, J = 7.2, 1.2 Hz, 1H), 7.15-7.11 (dt, J = 7.2, 1.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H),
.76 (dd, J = 8.8, 2.0 Hz, 1H), 4.22-4.29 (m, 2H), 3.12 (dd, J = 16.8, 8.8 Hz, 1H), 2.82
3
) δ (ppm) 7.55 (td, J = 8.4, 1.2 Hz, 2H),
(
4
1
3
(dd, J = 16.9, 2.4 Hz, 1H), 2.45(s, 3H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl3) δ (ppm) 163.8, 162.9, 145.2, 140.4, 135.4, 131.6, 128.8, 128.1, 127.4, 127.0,
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
25.4, 125.0, 62.2, 35.6, 34.9, 19.4, 14.0; HRMS (ESI-TOF): [M + H] calcd for
C
20
H
21
N
2
O
3
: 337.1552; found: 337.1544.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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8
9
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4
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6
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8
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0
(R)-Ethyl 1-phenyl-4-propyl-4,5-dihydropyridaz-6-one-3-carboxylate 5h: oil, 141
2
0
o
-1
1
mg, 49%, ee 93%, [α]
D
= -280.4 (c = 0.5, acetone); IR v (cm ) 1703; H NMR (400
MHz, CDCl
3
) δ (ppm) 7.46 (td, J = 8.8, 1.4 Hz, 2H), 7.40 (dt, J = 7.4, 2.3 Hz, 2H), 7.29
(tt, J = 7.2, 1.2 Hz, 1H), 4.31-4.40 (m, 2H), 3.30-3.35 (m, 1H), 2.71-2.81 (m, 2H),
1
3
1
.46-1.69 (m, 5H), 1.36 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 165.1, 163.2, 147.3, 140.4, 128.7, 127.3, 125.1, 62.1, 32.6, 32.4, 19.5,
+
14.2, 13.8; HRMS (ESI-TOF): [M + H] calcd for C16
H
21
N
2
O
3
: 289.1552; found:
289.1557.
(
S)-Ethyl 4-isopropyl-1-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5i: oil, 134
2
0
o
-1
mg, 47%, ee 96%, [α]
D
= -251.2 (c = 0.68, acetone); IR v (cm ) 2964, 2878, 1704,
1
1157, 693; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.45 (td, J = 8.4, 2.0 Hz, 2H), 7.41 (dt, J
=
7.6, 2.0 Hz, 2H), 7.29 (tt, J = 7.2, 1.6 Hz,1H), 4.35 (q, J = 6.8 Hz, 2H), 3.17-3.21 (m,
1
H), 2.83 (dd, J = 17.2, 1.6 Hz, 1H), 2.73 (dd, J =17.2, 8.0 Hz, 1H), 2.04-2.14 (m, 1H),
1
3
1.37 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 7.2 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl
3
) δ (ppm) 165.3, 163.6, 146.5, 140.4, 128.7, 127.2, 125.0, 62.1, 38.7, 30.2,
+
29.9, 20.2, 18.8, 14.4; HRMS (MALDI-TOF): [M + H] calcd for C16
H
21
N
2
O
3
:289.1547;
found: 289.1545.
(
S)-Ethyl 1-(4-methoxyphenyl)-4-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate
2
0
o
o
5
j: white crystals, 278 mg, 79%, ee 93%, [α]
D
= -71.4 (c = 0.51, acetone), mp 98-99 C;
) δ (ppm) 7.38 (td, J = 8.8, 2.0 Hz,
H), 7.28-7.34 (m, 3H), 7.23-7.25 (m, 2H), 6.95 (td, J = 9.2, 2.0 Hz, 2H), 4.58 (dd, J =
-1
1
IR v (cm ) 1707, 1690; H NMR (400 MHz, CDCl
3
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.0, 2.0 Hz, 1H), 4.25-4.34 (m, 2H), 3.83 (s, 3H), 3.12 (dd, J = 16.8, 8.4 Hz, 1H), 2.98
1
3
(
3
dd, J = 16.8, 2.0 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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36
37
38
39
40
41
42
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47
48
49
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164.4, 163.0, 158.8, 144.4, 137.4, 133.4, 129.4, 128.0, 126.9, 126.6, 114.1, 62.2, 55.5,
+
3
8.4, 35.3, 14.1; HRMS (ESI-TOF): [M + H] calcd for C20
21 2 4
H N O : 353.1501; found:
353.1494.
(
S)-Ethyl 1-(4-methylphenyl)-4-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5k:
2
0
o
o
white crystals, 262 mg, 78%, ee 95%, [α]
D
= -59.6 (c = 0.57, acetone), mp 119-120 C;
IR v (cm ) 1715, 1696; H NMR (400 MHz, CDCl ) δ (ppm) 7.32-7.37 (m, 4H),
7.28-7.30 (m, 1H), 7.22-7.25 (m, 4H), 4.57 (dd, J = 8.4, 2.0 Hz, 1H), 4.26-4.32 (m, 2H),
-1
1
3
3
7
1
.12 (dd, J = 16.8, 8.0 Hz, 1H), 2.97 (dd, J = 16.8, 2.0 Hz, 1H), 2.37 (s, 3H), 1.30 (t, J =
13
.2 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 164.3, 163.0, 144.5, 137.9, 137.5,
37.4, 129.42, 129.37, 128.0, 126.9, 125.0, 62.2, 38.5, 35.4, 21.1 14.1; HRMS (ESI-TOF):
+
[M + H] calcd for C H N O :337.1547; found: 337.1551.
2
0
21
2
3
(
S)-Ethyl 1-(4-bromophenyl)-4-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5l:
2
0
o
white crystals, 275 mg, 69%, ee 90%, [α]
D
= -53.5 (c = 0.54, acetone), mp 108-109
) δ (ppm) 7.55 (td, J = 8.8, 2.0 Hz,
H), 7.42 (td, J = 8.8, 2.0 Hz, 2H), 7.29-7.36 (m, 3H), 7.20-7.22 (m, 2H), 4.59 (dd, J =
.4, 2.0 Hz, 1H), 4.26-4.35 (m, 2H), 3.11 (dd, J =16.8, 8.0 Hz, 1H), 2.98 (dd, J =16.8, 2.0
o
-1
1
C; IR v (cm ) 1720, 1691; H NMR (400 MHz, CDCl
3
2
8
1
3
Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 164.2, 162.8,
145.2, 139.3, 137.2, 131.8, 129.4, 128.1, 126.8, 126.4, 120.8, 62.3, 38.5, 35.4, 14.1;
+
2 3
HRMS (ESI-TOF): [M + H] calcd for C19H18BrN O : 401.0501; found: 401.0492.
(S)-Ethyl
1
-(4-(trifluoromethyl)phenyl)-4-phenyl-4,5-dihydropyridaz-6-one-3-carboxylate 5m:
2
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20
o
white crystals, 197 mg, 51%, ee 74%, [α]
D
= -28.2 (c = 0.55, acetone), mp 102-103
C; IR v (cm ) 1746, 1703; H NMR (400 MHz, CDCl ) δ (ppm) 7.71 (d, J = 9.3 Hz, 2H),
7.69 (d, J = 9.3 Hz, 2H), 7.30-7.36 (m, 3H), 7.20-7.22 (m, 2H), 4.62 (dd, J = 8.0, 2.0 Hz,
o
-1
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H), 4.28-4.35 (m, 2H), 3.15 (dd, J = 17.2, 8.4 Hz, 1H), 3.02 (dd, J = 16.8, 2.0 Hz, 1H),
1
3
1
3
.32 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ (ppm) 164.3, 162.7, 145.6, 143.0,
137.0, 129.5, 129.0 (q, JCF = 32 Hz), 128.2, 126.8, 125.9 (q, JCF = 4 Hz), 124.7, 123.9 (q,
+
J
CF = 271 Hz), 62.5, 38.5, 35.5, 14.1; HRMS (ESI-TOF): [M + H] calcd for
C
20
H
18
F
3
2
N O
3
: 391.1270; found: 391.1273.
(S)-6-Acetyl-2,5-diphenyl-4,5-dihydropyridazin-3-one 5n:
2
0
o
o
white crystals, 243 mg, 83%, ee 94%, [α]
D
= -95.9 (c = 0.49, acetone), mp 97-98 C;
IR v (cm ) 1707, 1688; H NMR (400 MHz, CDCl ) δ (ppm) 7.46 (td, J = 8.0, 1.6 Hz,
2H), 7.46 (dt, J = 7.2, 2.0 Hz, 2H), 7.35 (tt, J = 7.2, 1.2 Hz, 1H), 7.30 (dt, J = 7.2, 1.2 Hz,
-1
1
3
2
H), 7.24-7.28 (m, 1H), 7.20 (td, J = 8.4, 1.6 Hz, 2H), 4.68 (dd, J = 6.4, 3.6 Hz, 1H), 3.05
13
(
dd, J = 17.2, 3.2 Hz, 1H), 3.00 (d, J = 14.0 Hz, 1H), 2.48 (s, 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 196.0, 164.8, 150.4, 140.3, 137.5, 129.3, 128.8, 127.9, 127.4, 126.9,
+
124.8, 35.4, 35.0, 24.8; HRMS (ESI-TOF): [M + H] calcd for C18
17 2 2
H N O : 293.1290;
found: 293.1293.
(
S)-6-Isobutyryl-2,5-diphenyl-4,5-dihydropyridazin-3-one 5o：
20
o
white crystals, 220 mg, 69%, ee 97%, [α]
D
= -110.7 (c = 0.53, acetone), mp 79-80
) δ (ppm) 7.46 (td, J = 8.4, 2.0 Hz,
2H), 7.46 (dt, J =7.2, 2.0 Hz, 2H), 7.23-7.36 (m, 4H), 7.18 (td, J = 7.2, 1.6 Hz, 2H), 4.69
o
-1
1
C; IR v (cm ) 1703, 1687; H NMR (400 MHz, CDCl
3
(
dd, J = 6.4, 3.2 Hz, 1H), 3.69-3.79 (m, 1H), 3.06 (dd, J = 17.0, 3.9 Hz, 1H), 3.01 (d, J =
13
1
3.9 Hz, 1H), 1.06 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 7.2 Hz, 3H); C NMR (100 MHz,
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CDCl
3
) δ (ppm) 202.0, 164.8, 149.2, 140.5, 137.6, 129.3, 128.8, 127.8, 127.3, 126.8,
+
124.7, 35.7, 35.0, 33.9, 18.8, 18.6; HRMS (ESI-TOF): [M + H] calcd for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
33
34
35
36
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38
39
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45
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47
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50
51
52
53
54
55
56
57
58
59
60
C
20
H
21
N
2
O
2
:321.1603; found: 321.1597.
(
S)-6-Benzoyl-2,5-diphenyl-4,5-dihydropyridazin-3-one 5p：
2
0
o
white crystals, 213 mg, 60%, ee 95%, [α] = -113.7 (c = 0.51, acetone), mp 69-70
D
o
-1
1
C; IR v (cm ) 1698, 1645; H NMR (400 MHz, CDCl
.54 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2 Hz, 4H), 7.28-7.35 (m,
5H), 4.90 (dd, J = 7.6, 2.0 Hz, 1H), 3.18 (dd, J = 17.2, 8.0 Hz, 1H), 3.10 (dd, J = 17.2,
3
) δ (ppm) 8.00 (d, J = 7.2 Hz, 2H),
7
1
3
2
1
3
.4 Hz, 1H); C NMR (100 MHz, CDCl ) δ (ppm) 189.7, 164.5, 150.7, 140.4, 137.5,
35.9, 133.0, 130.7, 129.4, 128.8, 128.1, 128.0, 127.2, 126.8, 124.6, 37.0, 35.2; HRMS
+
(
ESI-TOF): [M + H] calcd for C23
H
19
N
2
O
2
: 355.1447; found: 355.1446.
General procedure for selective synthesis of pyridazin-3-one derivatives 6.
Under nitrogen atmosphere and at room temperature, α,β-unsaturated aldehydes 1
0.65 mmol), hydrazones 2 (0.5 mmol), dihydropyrrolo[2,1-c]triazolium salt 3g (14 mg,
(
0.05 mmol), oxidant 4 (469 mg, 1.15 mmol) were mixed in dry dichloromethane (15 mL),
and then Cs
2
CO
3
(407 mg, 1.25 mmol) was added. The reaction mixture was stirred at
o
room temperature (20-30 C) for 6 h, and then refluxed with stirring for another 12-36 h
until dihydropyridazin-3-one intermediates 5 were almost completely converted into
pyridazin-3-ones 6. After removal of the solvent, the residue was chromatographyed on a
silica gel column eluting with a mixture of petroleum ether, ethyl acetate and
dichloromethane (PE:EA:DCM = 10:1.5:1－10:3:2) to give products 6 in 41%-89%
yields.
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Ethyl 1,4-diphenylpyridaz-6-one-3-carboxylate 6a: white crystals, 143 mg, 89%, mp
o
-1
1
1
18-119 C; IR v (cm ) 1739, 1669; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.68 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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0
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0
1
2
3
4
5
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7
8
9
0
7.6 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.45-7.49 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H),
13
7
.36-7.38 (m, 2H), 7.02 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz , 3H); C
NMR (100 MHz, CDCl
3
) δ (ppm) 163.3, 159.3, 144.8, 140.8, 139.3, 134.8, 129.6, 129.5,
+
1
28.9, 128.8, 128.7, 127.4, 125.4, 62.2, 13.7; HRMS (MALDI-TOF): [M + H] calcd for
C
19
H
17
N
2
O
3
: 321.1234; found: 321.1233.
Ethyl 4-(4-methoxyphenyl)-1-phenylpyridaz-6-one-3-carboxylate 6b: white crystals,
o
-1
1
1
3
24 mg, 71%, mp 146-147 C; IR v (cm ) 1726, 1672; H NMR (400 MHz, CDCl ) δ
(ppm) 7.66 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.31 (d,
J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.99 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.87 (s,
1
3
3
3
H), 1.16 (t, J = 6.8 Hz , 3H); C NMR (100 MHz, CDCl ) δ (ppm) 163.7, 160.9, 159.5,
144.3, 140.8, 139.5, 128.9, 128.7, 128.6, 126.8, 125.4, 114.3, 62.3, 55.4, 13.8; HRMS
+
(
MALDI-TOF): [M + H] calcd for C20
H
19
N
O
2 4
:351.1339; found: 351.1342.
Ethyl 4-(4-methylphenyl)-1-phenylpyridaz-6-one-3-carboxylate 6c: white crystals,
o
-1
1
1
3
30 mg, 78%, mp 121-122 C; IR v (cm ) 1737, 1671; H NMR (400 MHz, CDCl ) δ
(ppm) 7.66 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.26 (s,
13
4
H), 6.99 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.13 (t, J = 7.2 Hz , 3H); C
NMR (100 MHz, CDCl
3
) δ (ppm) 163.5, 159.4, 144.7, 140.8, 139.8, 139.4, 131.8, 129.5,
+
129.1, 128.8, 128.6, 127.3, 125.4, 62.2, 21.3, 13.7; HRMS (MALDI-TOF): [M + H]
calcd for C20 :335.1390; found: 335.1391.
Ethyl 4-(4-bromophenyl)-1-phenylpyridaz-6-one-3-carboxylate 6d: white crystals,
19 2 3
H N O
o
-1
1
3
165 mg, 83%, mp 140-141 C; IR v (cm ) 1731, 1678; H NMR (400 MHz, CDCl ) δ
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(
ppm) 7.59 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.36 (t,
J = 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.09 (t, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
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33
34
35
36
37
38
39
40
41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
= 7.2 Hz , 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 163.0, 159.1, 143.8, 140.7, 138.5,
1
33.8, 132.0, 129.6, 129.0, 128.9, 128.8, 125.3, 124.1, 62.4, 13.8; HRMS (MALDI-TOF):
+
[
M + H] calcd for C19
2 3
H16BrN O :399.0339; found: 399.0340.
Ethyl 4-(4-acetylphenyl)-1-phenylpyridaz-6-one-3-carboxylate 6e: white crystals,
o
-1
1
1
3
35 mg, 75%, mp 189-190 C; IR v (cm ) 1736, 1680; H NMR (400 MHz, CDCl ) δ
(
ppm) 8.06 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 2H), 7.47 (d,
J = 8.4 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.66 (s,
1
3
3H), 1.14 (t, J = 7.2 Hz , 3H); C NMR (100 MHz, CDCl
3
) δ (ppm) 197.1, 162.9, 159.0,
1
1
44.0, 140.6, 139.4, 138.2, 137.6, 129.9, 128.93, 128.85, 128.6, 127.7, 125.3, 62.4, 26.7,
+
19 2 4
3.8; HRMS (MALDI-TOF): [M + H] calcd for C21H N O : 363.1339; found:
363.1340.
Ethyl 1-(4-methoxyphenyl)-4-phenylpyridaz-6-one-3-carboxylate 6j: white crystals,
o
-1
1
1
43 mg, 82%, mp 121-122 C; IR v (cm ) 1721, 1674; H NMR (400 MHz, CDCl
3
) δ
(
ppm) 7.59 (td, J = 9.0, 2.0 Hz, 2H), 7.46-7.47 (m, 3H), 7.35-7.37 (m, 2H), 6.99-7.01 (m,
1
3
3H), 4.18 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.08 (t, J = 7.2 Hz , 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 162.4, 158.6, 158.5, 143.7, 138.0, 133.9, 132.8, 128.5, 128.3, 127.7,
+
1
26.3, 125.6, 113.1, 61.2, 54.6, 12.6; HRMS (MALDI-TOF): [M + H] calcd for
C
20
H
19
N
2
O
4
: 351.1339; found: 351.1340.
Ethyl 1-(4-methylphenyl)-4-phenylpyridaz-6-one-3-carboxylate 6k: white crystals,
o
-1
1
1
40 mg, 84%, mp 108-109 C; IR v (cm ) 1736, 1672; H NMR (400 MHz, CDCl
3
) δ
(ppm) 7.54 (d, J = 8.4 Hz, 2H), 7.45-7.48 (m, 3H), 7.35-7.38 (m, 2H), 7.30 (d, J = 8.2 Hz,
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13
2
H), 7.01 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.08 (t, J = 7.1 Hz , 3H); C
NMR (100 MHz, CDCl
3
) δ (ppm) 163.4, 159.4, 144.7, 139.1, 138.8, 138.3, 134.9, 129.54,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
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2
3
4
5
6
7
8
9
0
+
129.49, 129.3, 128.8, 127.4, 125.2, 62.2, 21.2, 13.7; HRMS (ESI-TOF): [M + H] calcd
for C20
H
19
N
2
O
3
: 335.1396; found: 335.1395.
Ethyl 1-(4-bromophenyl)-4-phenylpyridaz-6-one-3-carboxylate 6l: white crystals,
o
-1
1
1
3
33 mg, 67%, mp 112-113 C; IR v (cm ) 1729, 1678; H NMR (400 MHz, CDCl ) δ
(
ppm) 7.63 (d, J = 9.2 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.45-7.48 (m, 3H), 7.35-7.37 (m,
13
2
H), 7.00 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.09 (t, J = 7.2 Hz , 3H); C NMR (100 MHz,
CDCl
3
) δ (ppm) 163.2, 159.1, 144.9, 139.7, 139.6, 134.6, 132.0, 129.7, 129.5, 128.8,
+
127.3, 126.9, 122.5, 62.3, 13.6; HRMS (MALDI-TOF): [M + H] calcd for
C
19
H
16BrN
2
O
3
: 399.0339; found: 399.0338.
Ethyl 1-(4-(trifluoromethyl)phenyl)-4-phenylpyridaz-6-one-3-carboxylate 6m:
o
-1
1
white crystals, 143 mg, 74%, mp 144-145 C; IR v (cm ) 1744, 1668; H NMR (400
MHz, CDCl ) δ (ppm) 7.88 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.47-7.49 (m,
H), 7.36-7.39 (m, 2H), 7.03 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.1 Hz , 3H);
3
3
1
3
3
C NMR (100 MHz, CDCl ) δ (ppm) 163.1, 159.1, 145.1, 143.4, 139.9, 134.5, 130.5 (q,
J
CF = 33 Hz), 129.8, 129.6, 128.9, 127.3, 126.1 (q, JCF = 3 Hz), 125.7, 123.7 (q, JCF = 270
+
Hz), 62.4, 13.7; HRMS (MALDI-TOF): [M + Na] calcd for C20
15 3 2 3
H F N O Na: 411.0927;
found: 411.0929.
6-Acetyl-2,5-diphenylpyridazin-3-one 6n: white crystals, 84 mg, 58%, mp 162-163
o
-1
1
C; IR v (cm ) 1705, 1670; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.72 (d, J = 8.8 Hz, 2H),
7
.54 (t, J = 8.0 Hz, 2H), 7.43-7.48 (m, 4H), 7.26-7.29 (m, 2H), 6.94 (s, 1H), 2.58 (s, 3H);
1
3
C NMR (100 MHz, CDCl
3
) δ (ppm) 195.4, 159.4, 145.3, 142.5, 140.9, 135.3, 130.3,
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29.1, 128.9, 128.7, 128.4, 127.6, 125.1, 27.3; HRMS (MALDI-TOF): [M + H] calcd for
: 291.1128; found: 291.1129.
6-Isobutyryl-2,5-diphenylpyridazin-3-one 6o：white crystals, 65 mg, 41%, mp
18 15 2 2
C H N O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
-1
1
1
39-140 C; IR v (cm ) 1705, 1678; H NMR (400 MHz, CDCl
3
) δ (ppm) 7.71 (td, J
=
7.2, 1.4Hz, 2H), 7.53 (dt, J =7.2, 1.8 Hz, 2H), 7.42-7.47 (m, 4H), 7.25-7.27 (m, 2H),
1
3
6.95(s, 1H), 3.73-3.62 (m, 1H), 1.17 (d, J = 7.0 Hz, 6H); C NMR (100 MHz, CDCl
3
) δ
(
ppm) 201.5, 159.4, 145.7, 142.4, 140.9, 135.3, 130.3, 129.2, 128.9, 128.7,128.5, 127.3,
+
1
19 2 2
25.2, 36.3, 18.2; HRMS (MALDI-TOF): [M + H] calcd for C20H N O :319.1441;
found: 319.1439.
-Benzoyl-2,5-diphenylpyridazin-3-one 6p ：white crystals, 92 mg, 52%, mp
6
o
48
o
180-181 C. [lit. : mp 180-181 C].
ASSOCIATED CONTENT
Supporting Information Available. General procedure for the synthesis of racemic
1
4
,5-dihydropyridazin-3-ones 5, the copies of HPLC chromatographs for products 5, H
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NMR and C NMR spectra of enantiopure 4,5-dihydropyridazin-3-ones 5 and
pyridazin-3-one products 6 excluding the known compound 6p, single crystal data of
enantiopure 5l (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author：
E-mail: ycheng2@bnu.edu.cn
Notes：
The authors declare no competing financial interest.
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ACS Paragon Plus Environment