Synthesis of 1,4-dihydropyridazines from propargylic alcohols and hydrazones via a Cs2CO3-mediated process

Article abstract of DOI:10.1246/cl.160397

An efficient catalyst-free annulation process between propargylic alcohols and hydrazones has been reported. Under the optimized conditions, a wide variety of propargylic alcohols bearing an aromatic group or an aromatic heterocyclic group and hydrazones

Full text of DOI:10.1246/cl.160397

Received: April 20, 2016 | Accepted: May 5, 2016 | Web Released: May 14, 2016
CL-160397
Synthesis of 1,4-Dihydropyridazines from Propargylic Alcohols and Hydrazones
via a Cs CO -mediated Process
2
3
Zong-Cang Ding, Ying Yang, Shu-Ning Cai, Jia-Jie Wen, and Zhuang-Ping Zhan*
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry
and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China
(
E-mail: zpzhan@xmu.edu.cn)
An efficient catalyst-free annulation process between prop-
argylic alcohols and hydrazones has been reported. Under the
optimized conditions, a wide variety of propargylic alcohols
bearing an aromatic group or an aromatic heterocyclic group and
hydrazones were well tolerated to afford the corresponding 1,4-
dihydropyridazines in moderate to good yields via a Cs2CO3-
mediated process.
highly arylated 1,4-dihydropyridazines from propargylic alco-
hols and hydrazones via a Cs2CO3-mediated process.
Initially, substrates 1a and 2a were treated with Cs CO
2
3
(1.5 equiv) in dichloromethane (DCM) under room temperature
(r.t.), which, however, gave no product at all (Table 1, Entry 1).
The solvent 1,2-dichloroethane (DCE) or 1,4-dioxane led to the
recovery of the starting materials (Table 1, Entries 2 and 3). To
our delight, the reaction performed in CH3CN can result in 42%
yield of the aimed product (Table 1, Entry 4). The test of the
other solvents such as CH NO , THF, and PhCl was unsuccess-
Keywords: Pyridazine
| Drug | Propargylic alcohol
3
2
Pyridazines and its derivatives have been proven to be the
ful (Table 1, Entries 5­7). In contrast, the use of dimethyl
sulfoxide (DMSO) and dimethylformamide (DMF) as solvents
could increase the reaction yield to 65% and 54%, respectively
(Table 1, Entries 8 and 9). Bases screening indicated that bases
including K2CO3, CsF, NaH, t-BuOK, and NaOH either did not
lead to any detectable product formation or decreased the yield
(Table 1, Entries 10­14). Furthermore, the amounts of Cs CO
were also tested, and the results reveal that reducing the amounts
of Cs2CO3 to 1 equiv led to the decreasing yield of the aimed
product (Table 1, Entry 15), and raising the amounts gave a
more excellent reaction yield (Table 1, Entry 16). Hence, the
optimal reaction conditions for this reaction were determined
core units of many commercial drugs and related candidates
1
(
Figure 1), which deserve chemists’ attention. For instance,
2
3
chloridazon and pyridate are extensively employed for weed
4
control. Minaprine is recognized as selective GABA-A receptor
antagonists, which is an antidepressant. Moreover, the calcium-
sensitizing inotropic agent levosimendan and cardiotonic vaso-
dilator pimobendan are present in the market.
2
3
Among pyridazine derivatives, 1,4-dihydropyridazines are a
class of compounds that is receiving much attention for their
5
versatile pharmacological activities such as anti-inflammatory
6
and antihypertensive. For these reasons, a variety of strategies
have been developed for the synthesis of 1,4-dihydropyridazines
and the reports of the synthetic methods of 1,4-dihydropyrida-
zine rings could be classified in four methods: 1) from the
reaction of 1,2-diaza-1,3-butadienes with activated methine
Table 1. Optimization of reaction conditionsa
Br
OH
Ph
N
6 4
p-BrC H
condition
12 h
N
+
7
compounds, 2) from the reactions of tetrazines with unsaturated
Br
N
6 4
p-BrC H
NH
Ph
8
compounds, 3) from the acid-catalyzed reaction of α,β-unsat-
1
a
2a
3a
9
urated ketones and hydrazones, and 4) from the reaction based
on cyclopropenecarboxylic acids10 or 1,2-diazepin-4-ones. Our
group has been making great efforts to synthesize heterocycles
by using propargylic alcohols as the substrates.12 As part of our
continuing work in this area, we herein report the synthesis of
11
b
Entry
Base (equiv)
Solvent
Yield /%
n.r.c
n.r.
n.r.
42
n.r.
n.r.
n.r.
65
54
n.r.
15
38
47
1
2
3
4
5
6
7
8
9
Cs CO (1.5 equiv)
DCM
DCE
1,4-dioxane
CH3CN
CH3NO2
THF
2
3
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.5 equiv)
Cs CO (1.5 equiv)
O
N
2
3
HN
O
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.5 equiv)
K2CO3 (1.5 equiv)
CsF (1.5 equiv)
PhCl
DMSO
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cl
N
N
N
N
O
O
N
N
H
2
N
S
Cl
1
1
1
1
1
0
1
chloridazon
pyridate
minaprine
(herbicide)
(herbicide)
(antidepressant)
2
3
4
15
16
NaH (1.5 equiv)
t-BuOK (1.5 equiv)
NaOH (1.5 equiv)
Cs2CO3 (1.0 equiv)
Cs2CO3 (2.0 equiv)
O
36
52
85
O
NH
N
NH
N
N
NC
N
MeO
N
H
N
H
CN
Levosimendan
a
Pimobendan
Reaction conditions: 2a (0.3 mmol), 1a (0.36 mmol), solvent
b
(
5 mL), room temperature (r.t.), in schlenk tube. Isolated
c
Figure 1. Several herbicides and drugs.
yield. n.r.: no reaction.
Chem. Lett. 2016, 45, 925–927 | doi:10.1246/cl.160397
© 2016 The Chemical Society of Japan | 925

Table 2. The synthesis of 1,4-dihydropyridazinea,b
Cl
R4
N
N
OH
R2
Cl
R3
N
Cs CO3 (2 equiv)
2
N
R2
+
Br
Br
N
OH
Cl
3p
R4 NH
DMSO, rt
R3
R1
2 3
Cs CO (2 equiv)
+
H2O
R1
N
NH
DMSO
r.t., 12 h
Cl
Cl
1
2
3
1l
2a
N
N
Ph
N
Ph
Cl HO
Ph
p-BrC
6
H
4
p-BrC
6
H
4
N
N
p-BrC
6
H
4
N
N
Br
N
4
p-BrC
6
H
4
p-BrC
6
H
4
41% yield
6 4
p-BrC H
Ph
a, 85%
6 4
p-OMeC H
3
3b, 0%
3
c, 78%
Scheme 1. The reaction of substrate 1l and 2a.
Ph
Ph
N
Ph
Ph
N
N
p-BrC H4
Ph
N
N
6
N
p-BrC
6
H
4
p-BrC H4
Ph
6
p-NO
2
C
6
H4
2-thienyl
Ph
3
d, 0%
3e, 72%
Ph
3
f, 82%
Ph
Ph
p-MeC
6
H
4
N
p-OMeC
6
H
4
N
N
1-naphthyl
N
N
N
p-BrC
6
H
4
p-BrC
6
H
4
6 4
p-BrC H
Ph
g, 83%
Ph
3h, 84%
Ph
3
3
i, 75%
Ph
Ph
Ph
2-furyl
N
N
N
p-BrC H4
N
N
6
N
p-BrC
6
H
4
p-BrC
6
H
4
6 4
p-OMeC H
Ph
Ph
Ph
3
j, 73%
3k, 0%
Ph
3
l, 88%
H
6 4
Ph
N
p-OMeC
p-BrC
6
H
4
p-BrC H4
N
N
p-BrC H4
N
6
6
Figure 2. X-ray crystal structure of product 4.
N
N
1-naphthyl
6 4
p-BrC H
Ph
Ph
Ph
pyridazines 3i was obtained in good reaction yield as well.
Moreover, 2-furyl-substituted substrate could also react smooth-
ly to give product 3j in 73% yield. However, the disappointing
thing was that the ethyl substituent was not tolerated in this
reaction (Table 2, product 3k, 0% yield).
3
m, 79%
3n, 42%
3
o, 91%
a
Reaction conditions: 2 (0.3 mmol), 1 (0.36 mmol), solvent
5 mL), room temperature (r.t.), in schlenk tube. Isolated
b
(
Finally, we investigated the influence of R and R4 on
3
yield.
3
hydrazones 2. When R were p-OMeC H and 1-naphthyl,
6
4
to be performing the reaction in DMSO at room temperature
with Cs2CO3 (2.0 equiv) as the base for about 12 h (Table 1,
Entry 16).
corresponding 1,4-dihydropyridazines were formed in 88% and
79% yields, respectively. Of note is that hydrazone derived from
propanal as a substituent was also tolerated and the related
substrate was transformed into the aimed product 3n in 42%
We next evaluated the scope of the reaction under the
1
2
3
4
optimal conditions by placing different substituents (R , R , R ,
yield. Additionally, replacing the R phenyl group with p-
4
R ) on various positions of propargylic alcohols 1 and
OMeC6H4 also gave the aimed product 3o in 91% yield.
Note that when propargylic alcohols 1l and hydrazone 2a
were tested as the substrates to synthesize product 3p under the
optimal conditions (Scheme 1), 6-hydroxyl-1,4,5-trihydropyri-
dazine 4 was isolated in 41% yield and the definite structure of
4 was confirmed by single-crystal X-ray diffraction analysis
(Figure 2). We conjectured that 4 came from the hydrolysis of
3p when the crude product was purified by silica gel column
chromatography, and the transformation of 3p to 4 was
reversible.
hydrazones 2 (Table 2). First of all, we tested the influence of
1
1
R on propargylic alcohols 1. A terminal alkyne (R = H) was
not tolerated in this reaction, which could not lead to the aimed
product (Table 2, product 3b, 0% yield). The alkynyl position
1
R was found to the tolerate phenyl group substituted with an
electron-donating group (OMe) (Table 2, product 3c, 78%
yield), but the phenyl group substituted with an electron-
withdrawing group (NO2) seemed to completely abolish the 1,4-
dihydropyridazine formation, which gave 0% yield of product
3
d. The investigation of the R1 group also revealed that
As a note, under the optimal conditions, propargylic alcohol
1a could smoothly convert to α,β-unsaturated ketone 5a, and we
could obtain the final product 3a from the reaction between 5a
and 2a in 60% yield (Scheme 2).
heteroaryl-substituted substrate 1e could react smoothly to give
the aimed product 3e in 72% yield.
2
Next, the R group at the propargylic position was
examined. The substrate bearing a phenyl group could react
smoothly to give the aimed product 3f in 82% yield.
Similarly, substrates bearing p-MeC6H4 and p-OMeC6H4
groups at the propargylic position also gave product 3g and 3h
in 83% and 84% yields, respectively. In addition, 1,4-dihydro-
Based on the experimental results presented above and our
previous reports, a proposed reaction mechanism is depicted in
Scheme 3. Firstly, under the base condition, propargylic alcohol
1 was transformed to α,β-unsaturated ketone 5 and hydrazone
2 converted to intermediate 6. There are two possible reaction
1
3
926 | Chem. Lett. 2016, 45, 925–927 | doi:10.1246/cl.160397
© 2016 The Chemical Society of Japan

OH
O
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Scheme 3. Proposed mechanism.
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1
2
the case of R = H and R = ethyl, the α,β-enone formation step
may be inhibited, resulting in no aimed product of 3b and 3k.
In conclusion, we have reported a highly efficient method
for the synthesis of 1,4-dihydropyridazines from propargylic
alcohols and hydrazones via a Cs CO -mediated process. This
2
3
protocol provided an alternative way to synthetize 1,4-dihydro-
pyridazines.
We are grateful to the National Natural Science Foundation
of China (No. 21272190), NFFTBS (No. J1310024), and
PCSIRT in University.
Supporting Information is available on http://dx.doi.org/
1
0.1246/cl.160397.
Chem. Lett. 2016, 45, 925–927 | doi:10.1246/cl.160397
© 2016 The Chemical Society of Japan | 927