Copper-catalyzed aerobic 6-endo-trig cyclization of β,γ-Unsaturated Hydrazones for the Divergent Synthesis of Dihydropyridazines and Pyridazines

Article abstract of DOI:10.1021/acs.joc.9b00228

A divergent synthetic strategy to 1,6-dihydropyridazines and pyridazines through Cu(II)-catalyzed controllable aerobic 6-endo-trig cyclization was developed. The selectivity can be rationally tuned via the judicious choice of reaction solvent. It was found that the 1,6-dihydropyridazines were obtained in moderate to high yields with CH₃CN as the reaction solvent, whereas employment of AcOH directly afforded pyridazines in up to 92% yields, probably arising from the oxidation of the in situ generated 1,6-dihydropyridazines.

Full text of DOI:10.1021/acs.joc.9b00228

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Article
Copper-Catalyzed Aerobic 6-endo-trig Cyclization
of #,#-Unsaturated Hydrazones for the Divergent
Synthesis of Dihydropyridazines and Pyridazines
Zhenwei Fan, Zhangjin Pan, Liangsen Huang, and Jiajia Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00228 • Publication Date (Web): 18 Mar 2019
Downloaded from http://pubs.acs.org on March 18, 2019
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Copper-Catalyzed Aerobic 6-endo-trig Cyclization of β,γ-
Unsaturated Hydrazones for the Divergent Synthesis of
Dihydropyridazines and Pyridazines
Zhenwei Fan,# Zhangjin Pan,# and Liangsen Huang, Jiajia Cheng*
State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry,
Fuzhou University, 2 Xueyuan Road, Fuzhou 350116, P. R. China
R4
N
R4
NH R3
R3
R2
Cu(OAc)2 (cat.)
O2 (balloon)
Cu(OAc)2 (cat.)
O2 (balloon)
AcOH, 100 oC
N
R3
R2
N
N
N
R1
R1
CH3CN, reflux
R1
R2
Controllable and selective diversity-oriented synthesis
6-Endo-trig cyclization
O2 as the oxidant
Wide functional group tolerance
ABSTRACT: A divergent synthetic strategy to 1,6-dihydropyridazines and
pyridazines through Cu(II)-catalyzed controllable aerobic 6-endo-trig cyclization was
developed. The selectivity can be rationally tuned via the judicious choice of reaction
solvent. It was found that the 1,6-dihydropyridazines were obtained in moderate to high
yields with CH3CN as the reaction solvent, whereas employment of AcOH directly
afforded pyridazines in up to 92% yields, probably arising from the oxidation of the in-
situ generated 1,6-dihydropyridazines.
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Introduction
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Pyridazine and dihydropyridazine derivatives, which contain unique and valuable N-
N bonds, are abundant structural components of bioactive molecules and functional
materials (Figure 1).1 Synthetic efforts for preparing these two scaffolds have been
continuously devoted in the past few years. Reactions of the 1,4-dicarbonyl compound
with hydrazine2 or [4+2] cycloadditions of 1,2,4,5-tetrazine with alkynes3 were the
typical methods for the pyridazine synthesis. For dihydropyridazine, while the most
progress focused on the construction of 1,4-dihydropyridazines, rare protocols has been
developed for the synthesis of 1,6-dihydropyridazines. For example, Lewis acid-
mediated ring expansion of methylenecyclopropyl hydrazones and cycloaddition of
diazonium salts with dienes has recently been reported for the straightforward synthesis
of 1,6-dihydropyridazines.4 Despite these fascinating achievements, an efficient,
controllable strategy for the construction of both pyridazines and 1,6-
dihydropyridazines from commercially available starting materials would be highly
desirable.
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Figure 1. Examples of useful compounds containing pyridazine and 1,6-
dihydropyridazine cores.
COOH
Cl
O
Ph
H2N
N
Cl
N
O
N
H
Cl
N
N
N
F3C
HN
C
A
B
Br
O
NH2
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In recent years, olefin-substituted hydrazones have emerged as an important and
versatile reagent for the assembly of diverse substituted aza-heterocycles (Scheme 1).5
Nevertheless, most developed strategies were restricted to 5-exo-trig cyclization,6 6-
endo-trig cyclization reaction still face challenge in terms of efficiency and
environmental friendliness even if some interesting results have been described. Xiao
et al. recently reported a visible-light photocatalyzed 6-endo-trig mode reaction of -1-
styrene-substituted hydrazones for the synthesis of 1,6-dihydropyridazines with
TEMPO as the oxidant.7 Quite recently, Guan et al. reported a strategy to prepare 1,6-
dihydropyridazines via a stoichiometric amount of copper salt promoted cyclization of
-unsaturated hydrazones.8 Therefore, it is necessary to establish a controllable and
atom-economical route that allows divergent synthesis of pyridazines and 1,6-
dihydropyridazines through 6-endo-trig cyclization of -unsaturated hydrazones.
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Scheme 1. Controllable 6-endo-trig cyclization for dihydropyridazines and
pyridazines.
a) Previous work:
R2
R2
N
R2
[M]
5-exo-trig
[M]
N
N
NH
6-endo-trig
N
[M]
N
R1
many examples
[M]
R3
limited studies
R3
R1
R3
R1
b) This work:
R4
R4
NH R3
Cu(OAc)2 (cat.)
O2 (balloon)
R3
R2
Cu(OAc)2 (cat.)
O2 (balloon)
N
R3
N
N
N
N
AcOH, 100 o
C
R1
R2
R1
CH3CN, reflux
R1
R2
2
3
1
6-Endo-trig cyclization
Controllable and selective diversity-oriented synthesis
O2 as the oxidant
Wide functional group tolerance
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As an environmentally benign alternative to traditional oxidants, molecular oxygen
does not give rise to any waste byproducts. Inspired by the biological metalloenzymatic
oxidizing systems based on copper and oxygen,9 Cu-catalyzed aerobic oxidative
reactions have gradually became one of the most valuable methods for the C-C bond
formation.10 As part of our continuous efforts to develop regiodivergent catalytic
processes of hydrazones,11 herein we report copper-catalyzed aerobic 6-endo-trig
cyclization for pyridazines and 1,6-dihydropyridazines synthesis based on β,γ-
unsaturated hydrazones.12 This Cu-catalyzed aerobic oxidative transformation features
synthetic simplicity, broad substrate scope, and good functional group tolerance under
mild conditions. The using of O2 as terminal oxidant made this strategy even more
synthetically advantageous, practical and green.
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Results and Discussion
We launched our study by subjecting -unsaturated hydrazones 1a to various
reaction conditions (Table 1). The feasibility of the transformation was first tested by
exposing the substrates to catalytic Cu(OAc)2 under balloon pressure of O2 atmosphere.
Gratifyingly, the desired 6-endo-trig cyclization product 1,6-pyridazine 2a was
obtained in 8% isolated yield when the reaction was performed at 70 oC for 8 h (entry
1). No over-oxidation product pyridazine 3a was observed during the process. Although
no product was obtained with dioxane as the solvent, we are pleased to find that reaction
conducted in CH3CN delivered 2a in 61% yield (entries 2-3). Furthermore, compared
with the other Cu catalysts such as CuI, Cu(OTf)2, Cu(acac)2 and CuCl2•2H2O,
Cu(OAc)2 still proved to be the best reaction catalyst choice (entries 4-7). We then
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found that 81% yield of 2a was generated as the sole product by elevating the reaction
temperature (entry 8). Attempt to perform the reaction in air or reduce the amount of
copper catalyst failed (entries 9-11). Reactions were then conducted with the
expectation to deliver pyridazine 3a with high yield and selectivity. To assist the release
of the Ac group, CF3CO2H was added to the reaction mixtures. CH3CN was chosen as
solvent in the beginning which afforded no generation of 3a (entry 12). Delightedly, 74%
yield of 3a was observed as the sole product by switching the reaction solvent to toluene
(entry 13). However, replacement of CF3CO2H with AcOH gave inferior result (entry
14). Finally, pyridazine 3a was isolated in 85% yield and excellent selectivity in AcOH
with 20 mol% of Cu(OAc)2 as the catalyst under 1 atm O2 atmosphere (entry 15).
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Table 1. Screening of the optimal reaction conditionsa
Ac
N
Ac
N
cat. (20 mol%)
O2 (balloon)
NH
N
N
N
or
CH3
CH3
CH3
solvent, T, 8 h
1a
3a
2a
yield(%)b
2a 3a
nd
entry
cat.
solvent
T (oC)
1
2
3
4
5
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7
8
9c
10d
11e
12f
13f
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
Cu(OTf)2
Cu(acac)2
CuCl2•2H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Toluene
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
70
70
70
70
70
8
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
74
nd
61
nd
nd
nd
nd
81
21
46
38
nd
-
70
70
reflux
reflux
reflux
reflux
reflux
100
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14g
15h
Cu(OAc)2
Cu(OAc)2
toluene
AcOH
100
100
-
-
40
85
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aReaction conditions: 1a (0.1 mmol), catalysis (20 mol%), O2 (balloon) in solvent (2.0
mL) for 8 h. bIsolated yield. cair. d10 mol% Cu(OAc)2 was added. e5 mol% Cu(OAc)2
was added for 24 h. f5 equiv. of CF3COOH was added for 9 h. g5 equiv. of AcOH was
added. h9 h.
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The results shown in Table 2 demonstrate that this approach has a great potential in
the divergent synthesis of functionalized dihydropyridazines and pyridazines. As
shown in the left section of Table 2, various substituted hydrazone derivatives worked
well to provide the desired dihydropyridazines 2 in good to excellent yields with
Cu(OAc)2 as the catalyst. It was observed that the reaction was slightly affected by the
substitution patterns and electronic property of the substitute on the aromatic ring.
Numerous β,γ-unsaturated hydrazones bearing electron-donating (e.g., CH3, OCH3)
and electron-withdrawing groups (e.g., F, Cl, Br) at the 4-position of the phenyl ring
were well tolerated to afford the expected dihydropyridazines 2b-2f with good to high
yields (68%-92%). When the 3,4-dimethoxy-substituted β,γ-unsaturated hydrazone
was subjected to the reaction conditions, 63% yield of dihydropyridazine 2g was
isolated. Moreover, we found that substrates derived from naphthalenyl and thiophenyl
ketones served as suitable substrates to give the corresponding products efficiently (2h
and 2i). Then, we examined the possible structural scope of the olefin moiety.
Fortunately, different hydrazones with monosubstituted terminal olefin moiety led to
the effective formation of pyridazines (2j-2o) in high yields. A larger-scale preparation
of 2k with slightly decreased efficiency further demonstrate the practicability of the
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method. Substrates bearing aryl substituent also proceeded cleanly to provide 2p in 79%
yield. Furthermore, substituent on N atom of 1 was also investigated. N-Boc and N-2-
thienyl-substituted hydrazones 1q and 1r also proved to be applicable substrates,
leading to 2q and 2r in 45% and 78% yields, respectively.
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Table 2. Substrate scope of the chemoselective cyclizationa,b
R4
R4
R3
R2
Cu(OAc)2 (20 mol%)
O2 (balloon)
N
R3
R2
Cu(OAc)2 (20 mol%)
O2 (balloon)
NH R3
N
N
N
N
AcOH, 100 o
C
R1
R1
CH3CN, reflux
R1
R2
2
3
Conditions B
1
Conditions A
Ac
N
Ac
N
Ac
N
N
N
N
N
N
N
N
N
N
CH3
CH3
CH3
CH3
CH3
CH3
2a
, 8 h
2b
2c
, 12 h
, 11 h
F
3c
, 9 h
F
3b
79% yield
Cl
, 9 h
81% yield
3a
, 10 h
Cl
73% yield
92% yield
Ac
85% yield
85% yield
Ac
Ac
N
N
N
N
N
N
N
N
N
N
N
N
CH3
CH3
CH3
CH3
CH3
CH
2d
, 10 h
2f
, 11 h
2e
, 12 h
H3CO
Br
H3C
98% yield
68% yield
77% yield
H3C
Br
3e
H3CO
, 9 h
3d
3f
, 9 h
50% yield
, 9 h
Ac
70% yield
Ac
N
86% yield
Ac
N
N
N
N
N
N
N
N
N
N
N
H3CO
H3CO
S
CH3
CH3
CH3
H3CO
H3CO
S
CH3
CH3
2i
CH3
, 9 h
2h
58% yield
, 21 h
2g
63% yield
, 8 h
68% yield
3i
3g
, 9 h
, 9 h
3h
, 9 h
Ac
Ac
N
68% yield
66% yield
Ac
62% yield
N
N
N
N
N
N
N
N
N
N
N
H3CO2C
H3C
2j
2l, 9 h
58% yield
, 8 h
2k
, 9 h, 76% yield;
H3CO2C
O2N
82% yield
9 h, 0.72 g, 67% yield (5 mmol)
3j
, 9 h
92% yield
3l
, 9 h
3m
53% yield
, 10 h
Ac
Ac
Ac
64% yield
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O2N
NC
2m
63% yield
, 10 h
2o
, 9 h
71% yield
2n
67% yield
, 8 h
NC
S
3o
, 9 h
55% yield
3s
, 10 h
67% yield
3n
55% yield
, 9 h
S
Boc
O
N
Ac
N
N
N
N
N
N
N
3t
, 9 h
H3C
2r
, 9 h
2p
, 10 h
79% yield
2q
45% yield
, 9 h
73% yield
H3C
78% yield
aConditions A: 1a (0.1 mmol), Cu(OAc)2 (20 mol%), O2 (balloon) in CH3CN (2.0
mL) at reflux for 8 h; conditions B: 1a (0.1 mmol), Cu(OAc)2 (20 mol%), O2
(balloon) in AcOH (2 mL) at 100 oC for 9 h. bYields of the isolated products.
The substrate scope of the pyridazine is shown in the right section of Table 2.
Generally, -unsaturated hydrazones containing either electron-rich or electron-
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deficient substituents on the phenyl moiety were well tolerated, generating the desired
products as a single isomer (3a-3g). Naphthalene and heteroarenes were also suitable
substrates for this methodology (3h and 3i). Additionally, replacement of the methyl
group on the olefin moiety with other substituent furnished the amination products in
good yield (3j-3t).
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In order to gain preliminary insight into this transformation, we conducted additional
experiments to elucidate the reaction mechanism (Scheme 2). The reaction proceeded
smoothly to afford the dihydropyridazine 2a when an excess amount of radical
scavenger, butylated hydroxytoluene (BHT) or 1,1-diphenylethylene was added under
the reaction conditions A. The results of the inhibition experiments indicate that the
transformation may not involve a radical mechanism.13 However, when 3 equiv. of
TEMPO (2,2,6,6-tetramethylpiper-idine-1-oxyl) was added, a five-membered TEMPO
trapping product 4 was isolated in 9% yield along with 2a in 60% yield. No product
was observed when Cu catalyst was removed from the above reaction mixture. In an
attempt to trap the radical intermediate, the experiment with 1,4-cyclohexadiene as
hydrogen atom donor was conducted. While the isolation of the hydrogen atom transfer
product 5 failed, the determination of the crude reaction mixture by HRMS clearly
confirmed the existence of the HAE product (Please see the SI for details). Furthermore,
-deprotonation of hydrazone, electrophilic addition of the Cu catalyst to the terminal
carbon and reductive elimination from the 7-membered intermediate may also led to
the formation of the product. However, when 2,2-dimethyl-substituted hydrazone 1u
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was used as substrate, the isolation of 6-endo-trig cyclization product 6 as a sole regio-
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isomer strongly disfavored this possible reaction pathway.
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Scheme 2. Mechanism studies.
Ac
Ac
NH
N
N
N
Conditions A
, 8 h
CH3
radical scavenger (3 equiv.)
CH3
1a
2a
79%
radical scavenger:
BHT
1,1-diphenylethylene 71%
Ac
Ac
Ac
N
NH
N
N
N
N
N
Conditions A
, 2 h
+
O
CH3
CH3
CH3
TEMPO (3 equiv.)
1a
4
, 9% yield
2a
, 60% yield
Ac
Ac
N
Ac
N
NH
N
N
N
N
TEMPO (3 equiv.)
CH3CN, O2, 2 h
+
O
CH3
CH3
CH3
1a
4
, 0% yield
2a
, 0% yield
Ac
Ac
Ac
N
NH
N
N
N
Conditions A
, 6 h
N
CH3
CH3
+
1,4-cyclohexadiene (3 equiv.)
CH3
CH3
, 68% yield
1a
2a
5
, < 5% yield,
determined by HRMS
Ac
Ac
N
NH
N
N
Conditions A
, 15 h
H3C CH3
H3C CH3
, 41% yield (82% brsm)
1u
6
On the basis of these results as well as the literature reports,7,8,10 a postulated reaction
pathway was summarized in Scheme 3, although a detailed mechanism remains unclear.
The interaction of substrate 1a and copper catalyst first lead to the formation of a copper
complex I. Carbometalation with the intramolecular alkene subsequently affords the
cyclization intermediate II. After that, -H elimination of intermediate II offered
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delivery of 1,6-dihydropyridazine 2a and Cu(0),14 which could be reoxidized to Cu(II)
by O2 to finish the catalytic cycle (path A). Alternatively, 5-exo-trig cyclization of
intermediate I may lead to the formation of intermediate III, which could undergo
homocleavage to form the radical intermediate IV (path B).15 The observation of the
radical trapping product 4 suggested the possible reaction pathway. However, the
absence of 5-exo-trig cyclization side-product under the standard conditions implied
that the addition step could be reversible and the equilibration favored the formation of
ring opening intermediate I. While the homolysis of C-Cu(II) bond of intermediate II
to afford the C-centered radical intermediate V may lead to the formation of the product
(path C), a different reaction pathway of Cu(III)/Cu(II)/Cu(I) catalytic cycle could also
be involved in the reaction (path D). Furthermore, we cannot exclude another scenario
where the homocleavage of C-Cu(III) bond of intermediate VII to afford the N-centered
radical intermediate IX, which then undergoes endo alkene addition to deliver the final
product (path E).
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Scheme 3. Proposed reaction mechanism
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Ac
4
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6
7
8
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[CuII]
NH
[CuII]
N
Ph
CH3
1a
Ac
N
Ac
N
Ac
Ac
N
[CuII]
CH3
[CuI]
CH3
[CuII]
path B
N
[CuII]
CH3
N
N
N
N
Ph
Ph
Ph
Ph
I
CH3
IV
III
I
[O]
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path D
TEMPO
Ac
N
Ac
path A
Ac
[CuII]
CH3
N
N
N
N
[CuIII
CH3
]
N
N
O
CH3
Ac
Ph
Ph
Ph
VII
N
N
IX
4
CH3
[CuII]
path E
Ph
Ac
N
Ac
N
II
path
Ac
Ac
N
N
N
[CuII]
CH3
N
C
CH3
N
Ac
N
[O]
CH3
[CuI]
- H
CH3
Ph
Ph
2a
[CuIII
]
VIII
N
X
Ph
N
Ph
V
VI
[O]
[O]
[Cu0]
[CuII]
[CuI]
[CuII]
Ph
CH3
2a
The possible transformation of dihydropyridazine 2 to pyridazine 3 was also
investigated (Scheme 4). The smooth production of 3f when 2f was subjected to the
conditions B (65% yield, the yield based on the recovered starting material (brsm) was
as high as 99%) indicated that 3f was probably formed through the oxidation of 2f.
Removing Cu(OAc)2 from the reaction mixture slowed down the reaction, because only
less than 5% of 3f was afforded when the reaction was continued for 9 h. Extension of
the reaction time to 24 h delivered 86% yield of 3f. Moreover, no reaction took place if
Cu(OAc)2 and O2 were both absent from the reaction mixture. Therefore, we speculated
that the single electron oxidation of 2f by Cu(II) or O2 may led to the formation of N-
centered radical ion intermediate I (Scheme 5b). The subsequent oxidation and loss of
a hydrogen atom would generate the carbocation II, which probably undergoes H2O-
assisted acetyl group cleavage to deliver product 3f.
Scheme 4. Study about the transformation of 1,6-dihydropyridazines to
pyridazines
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a) Control reaction study:
Ac
N
6
7
8
9
N
N
N
conditions
CH3
CH3
3f
2f
H3CO
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H3CO
Conditions B
65% (99% brsm)
< 5%
, 9 h
O2 (balloon),
AcOH, 100 oC, 9 h
O2 (balloon),
AcOH, 100 oC, 24 h
86%
0%
AcOH, 100 oC, 24 h
b) Proposed reaction pathway:
H3C
N
O
H3C
N
O
H3C
O
H2O
[CuII]/O2
- H
N
[CuII]/O2
- e
N
N
N
N
N
Ar
CH3
Ar
CH3
3f
Ar
CH3
Ar
CH3
2f
II
I
1,4-Dihydropyridazine and heteroaromatic N-oxides existed in a number of
biologically active compounds and were widely employed in transition-metal-catalyzed
C-H functionalization reactions.16 The cyclization product obtained in our studies could
be readily transformed by using simple protocols (Scheme 5). For example, treatment
of 1,6-dihydropyridazine 2f with NaOH resulted in the facile formation of C=C bond
migration 1,4-dihydropyridazine 7 in 63% yield. Moreover, the oxidation of 3t gave
the pyridazine N-oxide derivative 8 in 81% yield that are not easily obtained by other
methods.
Scheme 5. Application of the synthetic methodology.
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a)
Ac
N
Ac
N
N
N
NaOH (2 equiv.)
7
8
9
CH3
MeOH, reflux, 10 h
H3CO
CH3
2f
H3CO
b)
7
, 63% yield
O
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N
N
N
N
m-CPBA (2 equiv.)
CHCl3, 0 oC to rt, 12 h
3t
8
, 81% yield
CONCLUSION
In conclusion, a mild 6-endo-trig cyclization of -unsaturated hydrazones via
copper-catalyzed aerobic system have been developed. The approach allowed
controllable and selective access to a diverse range of both pyridazines and 1,6-
dihydropyridazines from low-cost and readily available starting materials. The switch
in selectivity is attributed to the judicious choice of different reaction solvent. The value
of the protocol has been demonstrated by the broad functional group tolerance and the
application in the synthesis of bioactive compounds. The mild reaction conditions,
synthetic simplicity and the use of O2 as terminal oxidant make this methodology a
sustainable and promising tool in the diversity-oriented complex molecule synthesis.
Further investigations to uncover the detailed mechanism are currently underway in our
laboratory.
EXPERIMENTAL SECTION
General Methods and Materials. Commercially available materials purchased
from Alfa Aesar or Aldrich was used as received. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded on a Bruker AV400 (400 MHz) spectrometer.
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Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane
(δ 0.00). 1H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t),
quartet (q), dd (doublet of doublets); m (multiplets), and etc. All first-order splitting
patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns
that could not be easily interpreted are designated as multiplet (m) or broad (br). Carbon
nuclear magnetic resonance (13C{1H} NMR) spectra were recorded on a Bruker AV400
(100 MHz) spectrometer. High resolution mass spectral analysis (HRMS) was
performed on Waters Q-TOF Premier mass spectrometer. Analytical thin-layer
chromatography (TLC) was carried out on Merck 60 F254 pre-coated silica gel plate
(0.2 mm thickness). Visualization was performed using a UV lamp.
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General Procedure for Preparation of β,γ-Unsaturated Hydrazones 1. To a
solution of the β,γ-unsaturated ketone (5 mmol) in methanol was added acetyl hydrazine
(1.5 equiv) and acetic acid (0.2 equiv). The mixture was stirred at 60 oC overnight. After
the completion of the reaction as monitored by TLC, the solvent was then concentrated
in vacuo. The reaction mixture was extracted with ethyl acetate and the combined
extracts were washed with water. The solvent was then removed in vacuo and the
resulting crude residue was purified via column chromatography on silica gel (4:1
hexanes/EtOAc) to afford the desired hydrazones in 67-97% yield.8h
(E)-N'-(3-Methyl-1-phenylbut-3-en-1-ylidene)acetohydrazide (1a). White solid,
m. p. 141.7-143.3 oC, Yield: 1.0 g (93%); 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H),
7.82-7.64 (m, 2H), 7.42-7.35 (m, 3H), 4.93 (s, 1H), 4.73 (s, 1H), 3.36 (s, 2H), 2.39 (s,
3H), 1.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 148.1, 137.9, 137.7, 129.3,
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128.5, 126.1, 113.3, 35.6, 23.0, 20.5; HRMS (ESI) calcd for C13H17N2O (M+H+):
217.1335, found: 217.1331.
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(Z)-N'-(1-(4-Fluorophenyl)-3-methylbut-3-en-1-ylidene)acetohydrazide (1b).
White solid, m. p. 153.2-154.1 oC, Yield: 1.1 g (95%); 1H NMR (400 MHz, CDCl3) δ
8.82 (s, 1H), 7.78-7.68 (m, 2H), 7.14-7.04 (m, 2H), 4.92 (s, 1H), 7.71 (s, 1H), 3.34 (s,
2H), 2.38 (s, 3H), 1.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 163.4 (d, J
= 249.9 Hz), 147.2, 137.8, 133.8, 128.0 (d, J = 8.3 Hz), 115.4 (d, J = 21.7 Hz), 113.2,
35.5, 22.9, 20.5; 19F NMR (376 MHz, CDCl3) δ -111.8; HRMS (ESI) calcd for
C13H16FN2O (M+H+): 235.1241, found: 235.1242.
(Z)-N'-(1-(4-Chlorophenyl)-3-methylbut-3-en-1-ylidene)acetohydrazide (1c).
White solid, m. p. 154.1-156.2 oC, Yield: 1.2 g (92%); 1H NMR (400 MHz, CDCl3) δ
8.76 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.92 (s, 1H), 4.69 (s,
1H), 3.33 (s, 2H), 2.38 (s, 3H), 1.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6,
147.0, 137.7, 136.1, 135.3, 128.7, 127.4, 113.3, 35.4, 23.0, 20.5; HRMS (ESI) calcd for
C13H16ClN2O (M+H+): 251.0946, found: 251.0949.
(Z)-N'-(1-(4-Bromophenyl)-3-methylbut-3-en-1-ylidene)acetohydrazide (1d).
White solid, m. p. 154.2-155.7 oC, Yield: 1.3 g (87%); 1H NMR (400 MHz, CDCl3) δ
8.79 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.92 (s, 1H), 4.68 (s,
1H), 3.32 (s, 2H), 2.38 (s, 3H), 1.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6,
147.0, 137.7, 136.5, 131.6, 127.7, 123.6, 113.3, 35.3, 23.0, 20.5; HRMS (ESI) calcd for
C13H1679BrN2O(M+H+): 295.0441, found: 295.0444.
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(Z)-N'-(3-Methyl-1-(p-tolyl)but-3-en-1-ylidene)acetohydrazide (1e). White solid,
m. p. 167.2-167.8 oC, Yield: 0.98 g (85%); 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H),
7.62 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.91 (s, 1H), 4.72 (s, 1H), 3.34 (s,
2H), 2.38 (s, 3H), 2.37 (s, 3H), 1.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6,
148.2, 139.5, 138.0, 134.9, 129.2, 126.0, 113.2, 35.5, 22.9, 21.2, 20.5; HRMS (ESI)
calcd for C14H19N2O (M+H+): 231.1492, found: 231.1488.
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(Z)-N'-(1-(4-Methoxyphenyl)-3-methylbut-3-en-1-ylidene)acetohydrazide (1f).
White solid, m. p. 139.1-140.2 oC, Yield: 1.0 g (82%); 1H NMR (400 MHz, CDCl3) δ
8.73 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.91 (s, 1H), 4.72 (s,
13
1H), 3.83 (s, 3H), 3.33 (s, 2H), 2.38 (s, 3H), 1.84 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 173.5, 160.6, 147.9, 138.1, 130.2, 127.5, 113.8, 113.2, 55.3, 35.4, 22.9, 20.4;
HRMS (ESI) calcd for C14H19N2O2 (M+H+): 247.1441, found: 247.1449.
(Z)-N'-(1-(3,4-Dimethoxyphenyl)-3-methylbut-3-en-1-ylidene)acetohydrazide
(1g). White solid, m. p. 142.0-142.9 oC, Yield: 1.0 g (74%); 1H NMR (400 MHz, CDCl3)
δ 8.69 (s, 1H), 7.44 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 4.93 (s,
1H), 4.74 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.35 (s, 2H), 2.39 (s, 3H), 1.85 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 150.4, 149.0, 147.9, 130.5, 119.5, 113.3,
110.5, 108.7, 55.9, 55.8, 35.4, 22.9, 20.4; HRMS (ESI) calcd for C15H21N2O3 (M+H+):
277.1547, found: 277.1544.
(E)-N'-(3-Methyl-1-(naphthalen-2-yl)but-3-en-1-ylidene)acetohydrazide (1h).
White solid, m. p. 153.5-154. 6 oC, Yield: 0.99 g (74%); 1H NMR (400 MHz, CDCl3)
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δ 8.88 (s, 1H), 8.08-7.98 (m, 2H), 7.88-7.80 (m, 3H), 7.55-7.44 (m, 2H), 4.94 (s, 1H),
4.77 (s, 1H), 3.47 (s, 2H), 2.44 (s, 3H), 1.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 173.7, 148.0, 138.1, 135.0, 133.7, 133.1, 128.5, 128.1, 127.6, 126.8, 126.4, 126.0,
123.4, 113.3, 35.4, 23.0, 20.6; HRMS (ESI) calcd for C17H19N2O (M+H+): 267.1492,
found: 267.1495.
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(E)-N'-(3-Methyl-1-(thiophen-2-yl)but-3-en-1-ylidene)acetohydrazide
(1i).
Yellow solid, m. p. 148.5-149.1 oC, Yield: 0.74 g (67%); 1H NMR (400 MHz, CDCl3)
δ 8.79 (s, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.01 (t, J = 4.4 Hz,
1H), 4.94 (s, 1H), 4.81 (s, 1H), 3.39 (s, 2H), 2.35 (s, 3H), 1.83 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 173.4, 144.1, 143.3, 137.9, 127.8, 127.3, 126.5, 113.6, 36.1, 22.7,
20.3; HRMS (ESI) calcd for C11H15N2OS (M+H+): 223.0900, found: 223.0894.
(Z)-N'-(1-Phenylbut-3-en-1-ylidene)acetohydrazide (1j). White solid, m. p.
110.2-110.9 oC, Yield: 0.98 g (97%); 1H NMR (400 MHz, CDCl3) δ 8.85-8.65 (m, 1H),
7.78-7.72 (m, 2H), 7.42-7.36 (m, 3H), 5.98-5.76 (m, 1H), 5.25-5.10 (m, 2H), 3.52-3.42
(m, 2H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 147.6, 137.4, 129.7,
129.4, 128.5, 126.1, 118.4, 31.2, 20.5; HRMS (ESI) calcd for C12H15N2O (M+H+):
203.1179, found: 203.1184.
Methyl (E)-4-(1-(2-acetylhydrazono)but-3-en-1-yl)benzoate (1l).8 Yield: 1.87 g
(72%); 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.81 (d, J
= 8.2 Hz, 2H), 5.89 (ddt, J = 15.7, 10.2, 5.1 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 5.14 (d,
J = 17.3 Hz, 1H), 3.94 (s, 3H), 3.48 (d, J = 4.4 Hz, 2H), 2.41 (s, 3H).
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(E)-N'-(1-(4-Nitrophenyl)but-3-en-1-ylidene)acetohydrazide (1m). Yellow solid,
m. p. 146.8-148.3 oC, Yield: 1.73 g (70%); 1H NMR (400 MHz, CDCl3) δ 9.02 (br, 1H),
8.25 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 5.90 (ddt, J = 15.5, 9.7, 4.7 Hz, 1H),
5.26 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 16.0 Hz, 1H), 3.50 (s, 2H), 2.42 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 173.7, 148.1, 145.2, 143.3, 129.1, 126.9, 123.8, 118.7, 30.9,
20.6; HRMS (ESI) calcd for C12H14N3O3 (M+H+): 248.1030, found: 248.1028.
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(E)-N'-(1-(4-Cyanophenyl)but-3-en-1-ylidene)acetohydrazide (1n). White solid,
m. p. 168.6-170.2 oC, Yield: 0.95 g (42%); 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H),
7.84 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 5.87 (dq, J = 15.2, 4.5 Hz, 1H), 5.24
(d, J = 10.2 Hz, 1H), 5.12 (d, J = 20.0 Hz, 1H), 3.45 (d, J = 2.7 Hz, 2H), 2.40 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 145.4, 141.5, 132.3, 129.1, 126.6, 118.7,
118.6, 112.7, 30.8, 20.6; HRMS (ESI) calcd for C13H14N3O (M+H+): 228.1131, found:
228.1128.
(E)-N'-(1-(Furan-2-yl)but-3-en-1-ylidene)acetohydrazide (1o).8 Yield: 0.98 g
(51%); 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.49 (s, 1H), 6.75 (s, 1H), 6.48 (s,
1H), 5.82 (ddt, J = 16.2, 10.5, 5.5 Hz, 1H), 5.34-5.10 (m, 2H), 3.39 (d, J = 4.4 Hz, 2H),
2.36 (s, 3H).
N'-((1E,3E)-1,4-Diphenylbut-3-en-1-ylidene)acetohydrazide (1p).8 Yield: 1.35 g
(97%); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.82-7.77 (m, 2H), 7.44-7.38 (m,
4H), 7.33-7.28 (m, 4H), 6.46 (d, J = 16.0 Hz, 1H), 6.23 (dt, J = 16.2, 5.4 Hz, 1H), 3.59
(d, J = 5.2 Hz, 2H), 2.42 (s, 3H).
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tert-Butyl (E)-2-(1-(p-tolyl)but-3-en-1-ylidene)hydrazine-1-carboxylate (1q).8
Yield: 1.5 g (55%); 1HNMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.68 (d, J = 7.5 Hz, 2H),
7.16 (d, J = 7.6 Hz, 2H), 5.91 (ddd, J = 16.2, 10.8, 5.9 Hz, 1H), 5.20 (dd, J = 22.3, 13.9
Hz, 2H), 3.45-3.35 (m, 2H), 2.35 (s, 3H), 1.54 (s, 9H).
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(E)-N'-(1-(p-Tolyl)but-3-en-1-ylidene)thiophene-2-carbohydrazide (1r).8 Yield:
1.84 g (65%); 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.21 (s, 1H), 7.77 (d, J = 7.7
Hz, 2H), 7.66 (s, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.18-7.12 (m, 1H), 6.02-5.87 (m, 1H),
5.28-5.05 (m, 2H), 3.68-3.49 (m, 2H), 2.39 (s, 3H); HRMS (ESI) calcd for C16H16N2OS
(M+H+): 285.1056, found:285.1054.
3-(Benzo[b]thiophen-2-yl)pyridazine (1s). White solid, m.p. 163.2-165.0 oC, Yield:
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1.63 g (63%); H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H),
7.73 (d, J = 7.0 Hz, 1H), 7.46 (s, 1H), 7.38-7.30 (m, 2H), 5.88 (ddt, J = 15.8, 10.2, 5.3
Hz, 1H), 5.30-5.18 (m, 2H), 3.52 (d, J = 3.9 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 173.5, 143.8, 143.1, 140.4, 139.7, 129.4, 125.8, 124.5, 124.1, 123.5,
122.3, 118.8, 31.2, 20.4; HRMS (ESI) calcd for C14H15N2OS (M+H+): 259.0900, found:
259.0900.
(E)-N'-(1,3-Diphenylbut-3-en-1-ylidene)acetohydrazide (1t). White solid, m. p.
157.3-158.5 oC, Yield: 1.3 g (93%); 1H NMR (400 MHz, CDCl3) δ 8.86-8.74 (m, 1H),
7.80-7.70 (m, 2H), 7.54-7.46 (m, 2H), 7.44-7.34 (m, 6H), 5.50 (s, 1H), 4.97 (s, 1H),
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3.81 (s, 2H), 2.38 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 173.7, 148.0, 139.6,
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139.5, 137.6, 129.4, 128.6, 128.5, 128.3, 126.2, 125.7, 113.9, 32.9, 20.5; HRMS (ESI)
calcd for C18H19N2O (M+H+): 279.1492, found: 279.1490.
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Typical Procedure for the Synthesis of Dihydropyridazine Derivatives 2. To a
dry Schlenk tube equipped with a magnetic stir bar, was added β,γ- unsaturated
hydrazone 1a (0.1 mmol), Cu(OAc)2 (20 mol%) and CH3CN (2 mL). The tube was
closed with a rubber stopper and filled with O2 (balloon). The reaction mixture was then
stirred at reflux till 1a was completely consumed (monitored by TLC). The mixture was
then concentrated under reduced pressure and the resulting crude residue was purified
via column chromatography on silica gel (4:1 hexanes/EtOAc) to afford the desired
product 2a (17.4 mg, 81%).
1-(5-Methyl-3-phenylpyridazin-1(6H)-yl)ethan-1-one (2a). Yellow solid, m. p.
89.1-89.8 oC, Yield: 17.4 mg (81%); 1H NMR (400 MHz, CDCl3) δ 7.82-7.67 (m, 2H),
7.45-7.30 (m, 3H), 6.28 (s, 1H), 4.35 (s, 2H), 2.42 (s, 3H), 1.94 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.9, 145.2, 141.0, 135.7, 129.4, 128.5, 125.6, 112.0, 44.0, 21.2,
21.1; HRMS (ESI) calcd for C13H15N2O (M+H+): 215.1179, found: 215.1184.
1-(3-(4-Fluorophenyl)-5-methylpyridazin-1(6H)-yl)ethan-1-one (2b). Yellow
solid, m. p. 92.8-93.3 oC, Yield: 17.0 mg (73%); 1H NMR (400 MHz, CDCl3) δ 7.77-
7.70 (m, 2H), 7.09 (t, J = 8.4 Hz, 2H), 6.24 (s, 1H), 4.34 (s, 2H), 2.40 (s, 3H), 1.95 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.8, 163.49 (d, J = 249.3 Hz), 144.3, 141.3,
131.9, 127.5 (d, J = 8.3 Hz), 115.5 (d, J = 21.7 Hz), 111.8, 44.0, 21.2, 21.1; 19F NMR
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(376 MHz, CDCl3) δ -111.7; HRMS (ESI) calcd for C13H14FN2O (M+H+): 233.1085,
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1-(3-(4-Chlorophenyl)-5-methylpyridazin-1(6H)-yl)ethan-1-one (2c). Yellow
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solid, m. p. 93.2-94.1 C, Yield: 22.8 mg (92%); H NMR (400 MHz, CDCl3) δ 7.69
(d, J = 7.2 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2H), 6.23 (s, 1H), 4.34 (s, 2H), 2.40 (s, 3H),
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1.95 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 172.9, 144.1, 141.3, 135.3, 134.2,
128.7, 126.9, 111.6, 44.0, 21.2, 21.1; HRMS (ESI) calcd for C13H14ClN2O (M+H+):
249.0789, found: 249.0796.
1-(3-(4-Bromophenyl)-5-methylpyridazin-1(6H)-yl)ethan-1-one (2d). Yellow
solid, m. p. 104.1-104.8 oC, Yield: 28.7 mg (98%); 1H NMR (400 MHz, CDCl3) δ 7.62
(d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 4.34 (s, 2H), 2.40 (s, 3H),
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1.94 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 172.9, 144.1, 141.4, 134.7, 131.7,
127.1, 123.6, 111.5, 44.1, 21.3, 21.1; HRMS (ESI) calcd for C13H14BrN2O (M+H+):
293.0284, found: 293.0279.
1-(5-Methyl-3-(p-tolyl)pyridazin-1(6H)-yl)ethan-1-one (2e). Yellow solid, m. p.
96.2-97.1 oC, Yield: 17.6 mg (77%); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz,
2H), 7.21 (d, J = 8.0 Hz, 2H), 6.31-6.27 (m, 1H), 4.33 (s, 2H), 2.41 (s, 3H), 2.38 (s,
3H), 1.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 145.3, 140.9, 139.5, 132.9,
129.2, 125.5, 112.1, 44.0, 21.3, 21.2, 21.1; HRMS (ESI) calcd for C14H17N2O (M+H+):
229.1335, found: 229.1339.
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1-(3-(4-Methoxyphenyl)-5-methylpyridazin-1(6H)-yl)ethan-1-one (2f). Yellow
solid, m. p. 125.5-126.1 oC, Yield: 16.6 mg (68%); 1H NMR (400 MHz, CDCl3) δ 7.71
(d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.26 (s, 1H), 4.32 (s, 2H), 3.84 (s, 3H),
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2.40 (s, 3H), 1.94 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 172.7, 160.6, 145.0,
140.9, 128.3, 127.0, 113.9, 112.0, 55.3, 43.9, 21.2, 21.1; HRMS (ESI) calcd for
C14H17N2O2 (M+H+): 245.1285, found: 245.1282.
1-(3-(3,4-Dimethoxyphenyl)-5-methylpyridazin-1(6H)-yl)ethan-1-one
(2g).
Yellow solid, m. p. 127.3-127.9 oC, Yield: 17.2 mg (63%); 1H NMR (400 MHz, CDCl3)
δ 7.40 (s, 1H), 7.27 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 4.34 (s, 2H), 3.94 (s,
3H), 3.92 (s, 3H), 2.42 (s, 3H), 1.95 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6,
150.4, 149.1, 145.1, 140.9, 128.6, 118.7, 112.0, 110.6, 108.4, 55.9, 55.8, 43.9, 21.2,
21.1; HRMS (ESI) calcd for C15H19N2O3 (M+H+): 275.1390, found: 275.1396.
1-(5-Methyl-3-(naphthalen-2-yl)pyridazin-1(6H)-yl)ethan-1-one (2h). Yellow
solid, m. p. 142.3-143.2 oC, Yield: 15.3 mg (58%); 1H NMR (400 MHz, CDCl3) δ 8.09
(s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.90-7.80 (m, 3H), 7.58-7.47 (m, 2H), 6.45 (s, 1H),
4.38 (s, 2H), 2.47 (s, 3H), 1.98 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 172.9,
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145.0, 141.0, 135.7, 133.8, 133.1, 128.4, 128.3, 127.7, 126.7, 126.5, 125.2, 123.1, 111.9,
44.2, 21.3, 21.2; HRMS (ESI) calcd for C17H17N2O (M+H+): 265.1335, found:
265.1338.
1-(5-Methyl-3-(thiophen-2-yl)pyridazin-1(6H)-yl)ethan-1-one (2i). Yellow solid,
m. p. 135.1-136.2 oC, Yield: 15.0 mg (68%); 1H NMR (400 MHz, CDCl3) δ 7.34-7.30
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(m, 2H), 7.26 (s, 1H), 6.22 (s, 1H), 4.33 (s, 2H), 2.38 (s, 3H), 1.94 (s, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 172.6, 141.5, 141.03, 140.96, 127.4, 125.4, 111.6, 44.2,
21.1, 20.9; HRMS (ESI) calcd for C11H13N2OS (M+H+): 221.0743, found: 221.0736.
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1-(3-Phenylpyridazin-1(6H)-yl)ethan-1-one (2j). Yellow Liquid, Yield: 16.4 mg
(82%); 1H NMR (400 MHz, CDCl3) δ 7.76-7.70 (m, 2H), 7.45-7.37(m, 3H), 6.48 (d, J
= 10.0 Hz, 1H), 6.41-6.27 (m, 1H), 4.49 (s, 2H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.0, 144.5, 135.4, 130.1, 129.5, 128.6, 125.5, 116.6, 39.9, 21.0; HRMS
(ESI) calcd for C12H13N2O (M+H+): 201.1022, found: 201.1026.
1-(3-(p-Tolyl)pyridazin-1(6H)-yl)ethan-1-one (2k).8 Yield: 16.2 mg (76%);
0.72 g (67% yield, 5 mmol of substrate 1k was used); 1H NMR (400 MHz, CDCl3) δ
7.64 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.47 (d, J = 10.1 Hz, 1H), 6.40-6.29
(m, 1H), 4.49 (s, 2H), 2.40 (s, 3H), 2.39 (s, 3H).
Methyl 4-(1-acetyl-1,6-dihydropyridazin-3-yl)benzoate (2l).8 Yield: 14.9 mg
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(58%); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz,
2H), 6.49 (d, J = 10.5 Hz, 1H), 6.42-6.34 (m, 1H), 4.51 (d, J = 3.9 Hz, 2H), 3.94 (s,
3H), 2.42 (s, 3H).
1-(3-(4-Nitrophenyl)pyridazin-1(6H)-yl)ethan-1-one (2m). Yellow solid, m. p.
169.5-170.9 oC, Yield: 15.4 mg (63%); 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.6
Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 10.3 Hz, 1H), 6.45-6.38 (m, 1H), 4.54
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(d, J = 3.2 Hz, 2H), 2.43 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 173.1, 148.2,
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142.1, 141.3, 130.6, 126.1, 123.9, 115.8, 40.3, 21.1; HRMS (ESI) calcd for C12H12N3O3
(M+H+): 246.0873, found: 246.0874.
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4-(1-Acetyl-1,6-dihydropyridazin-3-yl)benzonitrile (2n). Yellow solid, m. p.
144.8-146.1 oC, Yield: 15.1 mg (67%); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2
Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 6.46 (d, J = 11.3 Hz, 1H), 6.40-6.25 (m, 1H), 4.52
(s, 2H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.1, 142.4, 139.5, 132.4,
130.6, 125.9, 118.6, 115.7, 112.7, 40.2, 21.0; HRMS (ESI) calcd for C13H12N3O
(M+H+): 226.0975, found: 226.0974.
1-(3-(Furan-2-yl)pyridazin-1(6H)-yl)ethan-1-one (2o).8 Yield: 13.5 mg (71%); 1H
NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.76 (s, 1H), 6.53-6.46 (m, 1H), 6.39 (d, J =
10.7 Hz, 1H), 6.36-6.27 (m, 1H), 4.48 (d, 2H), 2.37 (s, 3H).
1-(3,6-Diphenylpyridazin-1(6H)-yl)ethan-1-one (2p).8 Yellow Liquid, Yield: 21.8
mg (79%); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 4.0 Hz, 2H), 7.46-7,42 (m, 3H),
7.39-7.27 (m, 5H), 6.66 (d, J = 9.9 Hz, 1H), 6.47 (dd, J = 9.8, 6.0 Hz, 1H), 6.32 (d, J =
5.8 Hz, 1H), 2.44 (s, 3H).
tert-Butyl 3-(p-tolyl)pyridazine-1(6H)-carboxylate (2q).8 Yield: 12.2 mg (45%);
1HNMR (400MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.44
(d, J = 10.0 Hz, 1H), 6.30-6.20 (m, 1H), 4.37 (d, J = 3.4 Hz, 2H), 2.36 (s, 3H), 1.57 (s,
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Thiophen-2-yl(3-(p-tolyl)pyridazin-1(6H)-yl)methanone (2r). Yellow solid,
m.p.106.4-108.2 oC, Yield: 21.9 mg (78%); 1HNMR (400MHz, CDCl3) δ 8.16 (s, 1H),
7.77 (d, J = 7.4 Hz, 2H), 7.60 (s, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.11 (s, 1H), 6.54 (d, J
= 10.2 Hz, 1H), 6.49-6.39 (m, 1H), 4.71-4.60 (m, 2H), 2.41 (s, 3H);13C{1H} NMR (100
MHz, CDCl3) δ 162.5, 145.8, 140.0, 135.5, 134.2, 132.8, 132.5, 130.4, 129.4, 126.5,
126.2, 117.1, 40.8, 21.4; HRMS (ESI) calcd for C16H15N2OS (M+H+): 283.0900,
found:283.0899.
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Typical Procedure for the Synthesis of Pyridazine Derivatives 3. To a dry
Schlenk tube equipped with a magnetic stir bar, was added β-γ unsaturated hydrazone
1a (0.1 mmol), Cu(OAc)2 (20 mol%) and AcOH (2 mL). The tube was closed with a
rubber stopper and filled with O2 (balloon). The reaction mixture was then stirred at
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100 C till 1a was completely consumed (monitored by TLC). The reaction mixture
was cooled to room temperature and was diluted with H2O (2 mL), neutralized with a
saturated aqueous solution of NaHCO3, and extracted with CH2Cl2 (5 mL × 3). The
organic extract was washed with brine (2 mL) and dried with Na2SO4. After filtration
the solvent was evaporated under reduced pressure and the crude product was purified
by flash column chromatography on silica gel (2:1 hexanes/EtOAc) to afford the
desired product 3a (14.4 mg, 85%).
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5-Methyl-3-phenylpyridazine (3a). Brown solid, m. p. 91.3-92.1 C, Yield: 14.4
mg (85%); 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.67
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(s, 1H), 7.56-7.44 (m, 3H), 2.44 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 158.9,
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151.6, 137.9, 136.4, 129.9, 128.9, 127.1, 124.3, 18.6; HRMS (ESI) calcd for C11H11N2
(M+H+): 171.0917, found: 171.0921.
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3-(4-Fluorophenyl)-5-methylpyridazine (3b). Brown solid, m. p. 128.5-129.2 oC,
Yield: 14.9 mg (79%); 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.06 (t, J = 8.4 Hz,
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2H), 7.64 (s, 1H), 7.21 (t, J = 8.4 Hz, 2H), 2.44 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 164.1 (d, J = 250.0 Hz), 157.9, 151.6, 138.0, 132.5, 129.0 (d, J = 8.6 Hz),
124.0, 116.0 (d, J = 21.7 Hz), 18.6; 19F NMR (376 MHz, CDCl3) δ -111.3; HRMS (ESI)
calcd for C11H10FN2 (M+H+): 189.0823, found: 189.0828.
3-(4-Chlorophenyl)-5-methylpyridazine (3c). Brown solid, m. p. 146.4-147.6 oC,
Yield: 17.3 mg (85%); 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.02 (d, J = 7.2 Hz,
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2H), 7.65 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H), 2.44 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 157.7, 151.8, 138.0, 136.2, 134.8, 129.2, 128.4, 124.0, 18.6; HRMS (ESI)
calcd for C11H10ClN2 (M+H+): 205.0527, found: 205.0529.
3-(4-Bromophenyl)-5-methylpyridazine (3d). Brown black solid, m. p. 173.1-
173.8 oC, Yield: 21.3 mg (86%); 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.95 (d, J
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= 7.2 Hz, 2H), 7.70-7.62 (m, 3H), 2.44 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
157.8, 151.2, 138.1, 135.3, 132.1, 128.6, 124.6, 124.0, 18.6; HRMS (ESI) calcd for
C11H10BrN2 (M+H+): 249.0022, found: 249.0015.
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5-Methyl-3-(p-tolyl)pyridazine (3e). Brown solid, m. p. 121.5-122.2 C, Yield:
13.0 mg (70%); 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H),
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7.64 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.43 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 158.8, 151.4, 140.1, 137.8, 133.5, 129.7, 127.0, 124.0, 21.3, 18.5; HRMS (ESI) calcd
for C12H13N2 (M+H+): 185.1073, found: 185.1070.
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3-(4-Methoxyphenyl)-5-methylpyridazine (3f). Brown solid, m. p. 145.3-146.2 oC,
Yield: 10.1 mg (50%); 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.03 (d, J = 8.4 Hz,
2H), 7.62 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.2, 158.4, 151.1, 137.8, 128.8, 128.5, 123.7, 114.3, 55.4, 18.6;
HRMS (ESI) calcd for C12H13N2O (M+H+): 201.1022, found: 201.1016.
3-(3,4-Dimethoxyphenyl)-5-methylpyridazine (3g). Brown solid, m. p. 149.1-
150.6 oC, Yield: 15.2 mg (66%); 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.84 (s,
1H), 7.63 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.95
(s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.2, 151.2, 150.8, 149.5,
137.7, 129.1, 123.6, 119.6, 111.1, 110.1, 56.1, 56.0, 18.5; HRMS (ESI) calcd for
C13H15N2O2 (M+H+): 231.1128, found: 231.1123.
5-Methyl-3-(naphthalen-2-yl)pyridazine (3h). Brown solid, m. p. 178.3-179.2 oC,
Yield: 13.6 mg (62%); 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.54 (s, 1H), 8.21
(d, J = 8.8 Hz, 1H), 8.01-7.95 (m, 2H), 7.93-7.89 (m, 1H), 7.83 (s, 1H), 7.58-7.50 (m,
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2H), 2.47 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 151.4, 134.1, 133.5, 133.3,
128.80, 128.78, 127.7, 127.1, 127.0, 126.6, 124.8, 124.3, 100.0, 18.6; HRMS (ESI)
calcd for C15H13N2 (M+H+): 221.1073, found: 221.1069.
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5-Methyl-3-(thiophen-2-yl)pyridazine (3i). Brown solid, m. p. 162.4-163.2 C,
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Yield: 12.0 mg (68%); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.71-7.68 (m, 1H),
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MHz, CDCl3) δ 154.5, 151.5, 140.7, 137.8, 129.1, 128.0, 126.1, 122.4, 18.5; HRMS
(ESI) calcd for C9H9N2S (M+H+): 177.0481, found: 177.0478.
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3-Phenylpyridazine (3j). Brown solid, m. p. 92.3-92.8 C, Yield: 14.5 mg (92%);
1H NMR (400 MHz, CDCl3) δ 9.22-9.16 (m, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.86 (d, J =
13
8.4 Hz, 1H), 7.57-7.49 (m, 4H); C{1H} NMR (100 MHz, CDCl3) δ 150.0, 146.2,
130.1, 129.0, 127.1, 126.8, 123.9; HRMS (ESI) calcd for C10H9N2 (M+H+): 157.0760,
found: 157.0758.
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Methyl 4-(pyridazin-3-yl)benzoate (3l).8 Yield: 13.7 mg (64%); H NMR (400
MHz, CDCl3) δ 9.21 (d, J = 4.9 Hz, 1H), 8.25-8.10 (m, 4H), 7.92 (d, J = 8.5 Hz, 1H),
7.59 (dd, J = 8.9, 5.0 Hz, 1H), 3.97 (s, 3H).
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3-(4-Nitrophenyl)pyridazine (3m). White solid, m. p. 160.3-161.8 C, Yield:10.7
mg (53%); 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 7.5 Hz,
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2H), 8.29 (d, J = 7.4 Hz, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.69-7.61 (m, 1H); C{1H}
NMR (100 MHz, CDCl3) δ 157.4, 150.8, 149.0, 142.2, 128.0, 127.1, 124.3, 124.2;
HRMS (ESI) calcd for C10H8N3O2 (M+H+): 202.0611, found: 202.0607.
4-(Pyridazin-3-yl)benzonitrile (3n). White solid, m. p. 130.5-131.8 oC, Yield: 10.0
mg (55%); 1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 4.6 Hz, 1H), 8.23 (d, J = 7.2 Hz,
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2H), 7.92 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 7.1 Hz, 2H), 7.66-7.60 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 157.7, 150.7, 140.5, 132.8, 127.7, 127.0, 124.1, 118.4, 113.8;
HRMS (ESI) calcd for C11H8N3 (M+H+): 182.0713, found: 182.0709.
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3-(Furan-2-yl)pyridazine (3o).8 Yield: 8.0 mg (55%); 1H NMR (400 MHz, CDCl3)
δ 9.07 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.50 (dd, J = 8.3, 5.0
Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 6.61 (s, 1H).
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3-(Benzo[b]thiophen-2-yl)pyridazine (3s). White solide, m. p. 158.2-159.8 C,
Yield: 14.2 mg (67%); 1H NMR (400 MHz, CDCl3) δ 9.11 (br, 1H), 7.95-7.87 (m, 3H),
7.86-7.80 (m, 1H), 7.52 (br, 1H), 7.43-7.35 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 141.2, 140.7, 139.9, 125.8, 124.8, 124.4, 123.2, 122.8, 122.7; HRMS (ESI) calcd for
C12H9N2S (M+H+): 213.0481, found: 213.0477.
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3,5-Diphenylpyridazine (3t). Yellow solid, m. p. 175.4-176.1 C, Yield: 17.0 mg
(73%); 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.14 (d, J = 6.8 Hz, 2H), 8.00 (s,
1H), 7.73 (d, J = 6.8 Hz, 2H), 7.60-7.52 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
148.4, 139.1, 136.5, 134.9, 130.10, 130.07, 129.5, 129.0, 127.3, 127.2, 121.1; HRMS
(ESI) calcd for C16H13N2 (M+H+): 233.1073, found: 233.1077.
Radical inhibition study. To a dry Schlenk tube equipped with a magnetic stir
bar, was added β-γ unsaturated hydrazone 1a (0.05 mmol), Cu(OAc)2 (20 mol%),
radical scavenger (BHT or 1,1-diphenylethylene, 3.0 equiv) and CH3CN (1 mL). The
tube was closed with a rubber stopper and filled with O2 (balloon). The reaction mixture
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