Copper-catalyzed aerobic dehydrogenation of C-C to C=C bonds in the synthesis of pyridazinones

Article abstract of DOI:10.1002/ejoc.201300640

A simple and efficient procedure for the synthesis of pyridazin-3(2H)-ones through copper-catalyzed dehydrogenation of a single C-C bond of 4,5-dihydropyridazin-3(2H)-ones to a C=C bond with oxygen as the terminal oxidant is described. Functional groups including hydroxy, carboxylic, bromo, chloro, cyano, nitro and alkoxy were all tolerated under the reaction conditions. Moreover, this methodology was applied to the preparation of a series of structurally similar N-substituted 6-phenylpyridazinone compounds containing fluorine. The dehydrogenation reactions exhibit good yields and selectivity. Copper-catalyzed dehydrogenation of a C-C bond of 4,5-dihydropyridazinones to a C=C bond with oxygen as the terminal oxidant is described. Various functional groups were tolerated under the reaction conditions. The method was also applied to the preparation of a series of N-substituted 6-phenylpyridazinones containing fluoride. The dehydrogenation reactions exhibit good yields and selectivity.

Full text of DOI:10.1002/ejoc.201300640

FULL PAPER
DOI: 10.1002/ejoc.201300640
Copper-Catalyzed Aerobic Dehydrogenation of C–C to C=C Bonds in the
Synthesis of Pyridazinones
Lei Liang,[a] Guanyu Yang,[a] Fengrong Xu,[a] Yan Niu,[a] Qi Sun,[a] and Ping Xu*[a]
Keywords: Medicinal chemistry / Drug discovery / Dehydrogenation / Nitrogen heterocycles / Copper
A simple and efficient procedure for the synthesis of pyr-
idazin-3(2H)-ones through copper-catalyzed dehydrogen-
ation of a single C–C bond of 4,5-dihydropyridazin-3(2H)-
ones to a C=C bond with oxygen as the terminal oxidant is
described. Functional groups including hydroxy, carboxylic,
bromo, chloro, cyano, nitro and alkoxy were all tolerated un-
der the reaction conditions. Moreover, this methodology was
applied to the preparation of a series of structurally similar
N-substituted 6-phenylpyridazinone compounds containing
fluorine. The dehydrogenation reactions exhibit good yields
and selectivity.
pharmacophores with a versatile range of functions (Fig-
ure 1, a).[8] Investigations involving the application of pyrid-
azinones has focused on the cardiovascular system in the
past decades.[9] The 6-phenylpyridazin-3(2H)-one core was
considered essential for the cardiovascular effects, especially
to ensure inhibition of some key targets such as phospho-
diesterase III.[10] However, in recent years, new biologically
active pyridazinones have been developed in which the aryl
group at C(6) was modified or replaced, such as α1-adreno-
receptor antagonists,[11] antiplatelet,[12] anti-inflammatory
agents[13] and inhibitors of HIV-1 reverse transcriptase.[14]
Moreover, the potential application of pyridazinones as G-
protein-coupled receptor (GPCR) antagonists is one of cur-
rent interest that may lead to the treatment of symptoms
associated with the central nervous system.[15] For example,
CEP-26401 (Irdabisant), which consists of a pyridazinone
core, has been developed as a potent and selective clinical
candidate of histamine H3 receptor antagonist.[16]
Traditionally, there have been several synthetic routes
leading to pyridazinones, among which the oxidation of the
C(4)–C(5) bond of dihydropyridazinone to a C=C bond is
a key step (Figure 1, b).[17] Therefore, considerable attention
has been paid to this transformation and several oxidants
have been used including MnO2,[18] SeO2,[19] Br2/HOAc[20]
and others.[21] However, neither the efficiency nor the econ-
omy of these reagents meets the demand of large-scale pro-
duction and the principles of green chemistry. To improve
this reaction and promote its application in drug synthesis,
we wanted to explore an alternative catalytic system with
oxygen as the oxidant. Molecular oxygen, as a benign and
economical oxidant, has been widely used in oxidation reac-
tions instead of toxic and expensive oxidants. Copper, as an
abundant and affordable metal compared to rare metals
such as Ru, Rh, Pd, Pt and Au, has been widely used to
catalyze dehydrogenative functionalization.[22] However, the
Introduction
Conversion of saturated carbon–carbon single bonds to
carbon–carbon double bonds is an important class of C–H
functionalization.[1] Meanwhile, the recognition that metal-
catalyzed reactions involving β-hydride elimination are
often compatible with O2 has prompted the application of
this class of reaction in various fields such as the synthesis
of pharmaceutical compounds.[2] Despite numerous meth-
odologies for the preparation of α,β-unsaturated carbonyl
compounds,[3] highly efficient methods under direct, mild
and green conditions are still required. Since the discovery
of the first catalytic dehydrogenation of cyclooctane to
cyclooctene, tremendous effort has focused on the field of
catalytic dehydrogenation and activation of saturated
carbon–carbon bonds through transition-metal catalysis.[4]
For example, iridium pincer complexes have been used to
advance the scope and efficiency of catalytic dehydrogena-
tion of alkanes.[5] Recently, palladium-catalyzed aerobic de-
hydrogenation has emerged as a powerful tool for the prep-
aration of α,β-unsaturated carbonyl compounds.[6] Stahl
and co-workers developed simple systems utilizing Pd-
(TFA)2 (TFA = trifluoroacetate) for the selective synthesis
of phenols and cyclic enones from cyclic ketones, which rep-
resents a significant advance in terms of chemoselectivity
and practicality.[7]
On the other hand, pyridazinones, as useful scaffolds for
building a broad range of chemicals, have been used as
[a] State Key Laboratory of Natural and Biomimetic Drugs,
Department of Medicinal Chemistry, School of Pharmaceutical
Sciences, Peking University Health Science Center,
Beijing 100191, China
E-mail: pingxu@bjmu.edu.cn
Homepage: http://sps.bjmu.edu.cn/art/2011/6/30/
art_7597_60020.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300640.
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Eur. J. Org. Chem. 2013, 6130–6136

Synthesis of Pyridazinones
Figure 1. (a) Bioactive compounds containing the pyridazinone scaffold. (b) Structure of 6-phenyl-4,5-dihydropyridazin-3(2H)-one and
6-phenyl-pyridazin-3(2H)-one.
application of copper as a catalyst in dehydrogenation of Table 1. Selected representative screening of the reaction.[a]
saturated C–C to C=C bonds with oxygen is still limited.
In this communication, we present a simple and efficient
copper-catalyzed dehydrogenation of a C–C bond of di-
hydropyridazin-3(2H)-ones to a C=C bond, with oxygen as
the terminal oxidant.
Entry Catalyst
Base
Additive Solvent Yield (%)[b]
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
CuBr2
CuCl
CuBr
CuI
Cs2CO3 Py
K2CO3 Py
Na2CO3 Py
toluene 56
toluene 73
toluene 94
toluene 30
toluene trace
toluene 77
K3PO4
Et3N
Py
Py
Result and Discussion
Na2CO3 Bpy
Na2CO3 TMEDA toluene 21
Our investigations commenced with screening conditions
for 6-phenyl-4,5-dihydropyridazin-3(2H)-one as substrate.
Several sets of reaction were carried out that examined the
effect of base, ligand, catalyst and solvent. We first investi-
gated the effect of base; inorganic bases such as Cs2CO3,
K2CO3, Na2CO3 and K3PO4 were used and Na2CO3 was
found to be optimal, giving excellent yield (Table 1, entries
1–4). Organic base such as triethylamine was also employed
in the reaction, however, only a trace amount of product
was detected (Table 1, entry 5). Pyridine (Py) was identified
as the most efficient ligand, being superior to 2,2Ј-bi-
Na2CO3 Phen
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
Na2CO3 Py
–
toluene 52
toluene 86
toluene 37
toluene 11
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
toluene
8
toluene 25
Mn(OAc)2
FeCl3
toluene trace
toluene trace
toluene trace
toluene 23[c]
Co(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
DMF
DCE
54
36
toluene 39[d]
toluene trace
toluene trace
toluene trace
pyridine
(Bpy),
N,N,N,N-tetramethylethylenediamine
(TMEDA) and phenanthroline (Phen) (Table 1, entries 6–
8). After screening a series of metal salts including both
copper(II) and copper(I) salts, manganese(II), iron(III) and
cobalt(II) salts, Cu(OAc)2 was selected as the catalyst
(Table 1, entries 9–16). Lower temperature and the use of
other common organic solvents such as N,N-dimethylform-
amide (DMF) or 1,2-dichloroethane (DCE) had negative
effects on the reaction (Table 1, entries 17–19). This reac-
tion could also proceed under an air atmosphere, albeit
with lower yield (Table 1, entry 20). Control experiments
Cu(OAc)2
Cu(OAc)2
Na2CO3
–
[a] Reaction conditions (unless otherwise noted): substrate
(1.0 mmol), catalyst (10 mol-%), additive (2.0 mmol), base
(2.0 mmol), toluene (2 mL), 100 °C, 12 h. [b] Isolated yield. [c] Re-
action conducted at 25 °C. [d] Reaction conducted in air atmo-
sphere.
With the optimized reaction conditions established, a
were also carried out to confirm the significance of copper series of 6-substituted 4,5-dihydropyridazinones were ap-
catalyst, base and additive for this reaction (Table 1, entries plied in this reaction; the results are listed in Table 2. In
21–23). In the absence of Cu(OAc)2 or Na2CO3, the reac- general, most of the substrates afforded the desired prod-
tion did not proceed at all. Without addition of pyridine, ucts with moderate to excellent yields. We first investigated
only a trace amount of product was detected, indicating the 6-phenyl-substituted substrates. As shown in Table 2, a
that coordination of the copper salt with pyridine as ligand single para-substituent on the 6-phenyl ring had an effect
probably results in high reactivity of the catalytic system.
on the reaction. For example, substrates bearing electron-
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L. Liang, G. Yang, F. Xu, Y. Niu, Q. Sun, P. Xu
FULL PAPER
withdrawing groups such as –Br, –CN and –NO2 afforded Table 3. Copper-catalyzed dehydrogenation of N(2)-substituted di-
hydropyridazinones.[a]
higher yields than those bearing an electron-donating group
such as –OMe or –OH (Table 2, entries 1–5). Substrates
that were meta- or ortho-substituted with chloro or ethoxy
groups were also examined, giving 92 and 76% yields,
respectively (Table 2, entries 6 and 7). Moreover, it was pos-
sible to convert disubstituted substrate into pyridazinone
2ah with good tolerance of both the hydroxy and bromine
groups in considerable yield (67%; Table 2, entry 8).
Furthermore, when the C(6) position of the substrate was
substituted with a nonaromatic group such as –COOH or
–Cl, the dehydrogenative reactions still proceeded with
good yields (85 and 93%, respectively; Table 2, entries 9 and
10).
Table 2. Copper-catalyzed dehydrogenation of 6-substituted di-
hydropyridazinones.[a]
[a] Reaction conditions: substrate (1.0 mmol), Cu(OAc)2 (10 mol-
%), pyridine (2.0 mmol), Na2CO3 (2.0 mmol), toluene (2 mL),
100 °C, 12 h. Isolated yields are reported.
We further investigated N(2)-substituted 6-phenyl di-
hydropyridazinones with the catalytic system. All the sub-
strates converted smoothly into the dehydrogenative prod-
ucts and the results are summarized in Table 3. N(2)-Alkyl-
ated and arylated substrates were employed with modest to
excellent yields being obtained (Table 3, entries 1–10). For
instance, N(2)-substituted pyridazinone with a heterocycle
such as benzothiazole was prepared with respectable yield
[a] Reaction conditions: substrate (1.0 mmol), Cu(OAc)2 (10 mol-
%), pyridine (2.0 mmol), Na2CO3 (2.0 mmol), toluene (2 mL),
100 °C, 12 h. Isolated yields are reported.
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Synthesis of Pyridazinones
3(2H)-one (1.0 mmol) in toluene (2 mL) were added Cu(OAc)2
(20.0 mg, 10 mol-%), Na2CO3 (312.0 mg, 2.0 mmol), and pyridine
(159.0 mg, 2.0 mmol) at room temperature and then the tempera-
ture was raised to 100 °C in pure oxygen atmosphere. On comple-
tion of the reaction (12 h), the products were purified by column
chromatography on silica gel (petroleum ether–ethyl acetate, 2:1).
The results are reported as isolated yields.
(68%; Table 3, entry 5). Recently, a structurally similar
compound based on N(2)-benzylated pyridazinone contain-
ing fluorine has been developed for the treatment of allergic
inflammatory diseases, which exhibits potent, selective and
orally bioavailable antagonists of a chemoattractant recep-
tor homologous molecule expressed on Th2 cells.[23] Herein,
a series of similar substrates were used in the reaction and
excellent yields were obtained, which represents a signifi-
cant advance of this catalytic system in terms of economy
and practicality in pharmaceutical synthesis (Table 3, en-
tries 11–20).
On the basis of the results obtained, we propose that β-
elimination mediated by copper catalyst was involved in this
reaction, converting the C–C single bond of dihydropyrid-
azinone into a C=C double bond.[24] Molecular oxygen
plays a role as the oxidant to trigger the circulation of the
catalytic process by oxidizing the copper(I) species to the
copper(II) complex.[22,25] Finally, when 2,2,6,6-tetramethyl-
piperidine-1-oxyl (TEMPO) was used as a radical scavenger
a considerable amount of product was still obtained, indi-
cating that radicals were not involved in this reaction.
6-Phenylpyridazin-3(2H)-one: (Table 1) White solid; m.p. 122–
1
123 °C. H NMR (400 MHz, [D6]DMSO): δ = 6.99 (d, J = 8 Hz,
1 H), 7.46 (m, 3 H), 7.85 (d, J = 8 Hz, 2 H), 8.02 (d, J = 12 Hz, 1
H), 13.20 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
126.09, 129.35, 129.62, 130.61, 131.90, 135.09, 144.25, 160.69 ppm.
HRMS (ESI): calcd. for C10H8N2O 172.0669; found 173.0771 [M
+ H+].
6-(4-Bromophenyl)pyridazin-3(2H)-one (2aa): (Table 2, entry 1)
White solid; m.p. 189–190 °C. 1H NMR (400 MHz, [D6]DMSO): δ
= 7.00 (d, J = 12 Hz, 1 H), 7.67 (d, J = 12 Hz, 2 H), 7.81 (d, J =
8 Hz, 2 H), 8.03 (d, J = 8 Hz, 1 H), 13.24 (s, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 160.62, 143.28, 134.34, 132.31, 131.68,
130.69, 128.16, 123.15 ppm. HRMS (ESI): calcd. for C10H7BrN2O
249.9776; found 250.9815 [M + H+].
4-(6-Oxo-1,6-dihydropyridazin-3-yl)benzonitrile (2ab): (Table 2, en-
try 2) White solid; m.p. 132–133 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.03 (d, J = 12 Hz, 1 H), 7.95 (d, J = 12 Hz, 2 H),
8.05 (d, J = 8 Hz, 2 H), 8.11 (d, J = 8 Hz, 1 H), 13.39 (s, 1 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 160.65, 146.29, 142.67,
139.35, 133.32, 131.78, 130.70, 126.84, 119.06, 112.00, 109.99 ppm.
HRMS (ESI) calcd. for C11H7N3O 197.06; found 198.0662 [M +
H+].
Conclusions
We have developed a simple, highly efficient and econom-
ical protocol for the copper-catalyzed dehydrogenation of a
C–C bond of dihydropyridazinones to a C=C bond with
oxygen as the oxidant. This method avoids the use of toxic
organic oxidants and stringent inert conditions. Overall, we
believe that this catalytic system could provide an avenue
for copper-catalyzed methods that have rarely been adopted
in the dehydrogenation of saturated C–C to C=C bonds.
6-(4-Nitrophenyl)pyridazin-3(2H)-one (2ac): (Table 2, entry 3) Yel-
1
low solid; m.p. 175–176 °C. H NMR (400 MHz, [D6]DMSO): δ =
7.00 (d, J = 12 Hz, 1 H), 7.68 (d, J = 8 Hz, 2 H), 7.82 (d, J = 8 Hz,
2 H), 8.04 (d, J = 8 Hz, 1 H), 13.27 (s, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 160.63, 143.27, 134.31, 132.31, 131.70,
Further investigations focused on broadening the scope of 130.69, 128.15, 123.16 ppm. HRMS (ESI): calcd. for C10H7N3O3
217.05; found 240.9875 [M + Na+].
this catalytic system to include other dehydrogenative reac-
tions are ongoing in our laboratory.
6-(4-Methoxyphenyl)pyridazin-3(2H)-one (2ad): (Table 2, entry 4)
White solid; m.p. 118–119 °C. 1H NMR (400 MHz, [D6]DMSO): δ
= 3.81 (s, 3 H), 6.95 (d, J = 12 Hz, 1 H), 7.03 (d, J = 8 Hz, 2 H),
Experimental Section
7.80 (d, J = 8 Hz, 2 H), 7.98 (d, J = 12 Hz, 1 H), 13.06 (s, 1 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 160.60, 144.08, 131.75,
130.54, 127.53, 114.77, 55.74 ppm. HRMS (ESI): calcd. for
C11H10N2O2 202.0713; found 203.0813 [M + H+].
General: Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. Col-
umn chromatography was carried out with silica gel (200–
300 mesh). Thin-layer chromatography was carried out using
6-(4-Hydroxyphenyl)pyridazin-3(2H)-one (2ae): (Table 2, entry 5)
White solid; m.p. 98–99 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
6.85 (d, J = 8 Hz, 2 H), 6.93 (d, J = 8 Hz, 1 H), 7.68 (d, J = 8 Hz,
Merck silica gel GF254 plates. H, 13C and 19F NMR spectra were
1
recorded with Bruker AVIII-400 spectrometers with [D6]DMSO or
CDCl3 as solvent. Chemical shifts are reported in ppm using TMS
as internal standard. Synthesis of all halogenated dihydropyridaz-
inone substrates were based on the literature.
2 H), 7.93 (d, J = 8 Hz, 1 H), 9.78 (s, 1 H), 12.99 (s, 1 H) ppm. 13
C
NMR (100 MHz, [D6]DMSO): δ = 160.54, 159.01, 144.39, 131.68,
130.47, 127.58, 126.01, 116.12 ppm. HRMS (ESI): calcd. for
C10H8N2O2 188.0655; found 189.0659 [M + H+].
Procedure for Screening of the Optimized Reaction Conditions: To
6-(3-Chlorophenyl)pyridazin-3(2H)-one (2af): (Table 2, entry 6)
White solid; m.p. 145–146 °C. 1H NMR (400 MHz, [D6]DMSO): δ
= 13.33 (s, 1 H), 8.09 (d, J = 8 Hz, 1 H), 7.91 (s, 1 H), 7.84 (m, 1
H), 7.52 (m, 2 H), 7.04 (d, J = 12 Hz, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 160.19, 142.38, 136.63, 133.77, 131.29,
130.69, 130.13, 128.88, 125.27, 124.20 ppm. HRMS (ESI): calcd.
for C10H7ClN2O 206.0228; found 207.0130 [M + H+].
a
stirred solution of 6-phenyl-4,5-dihydropyridazin-3(2H)-one
(174.2 mg, 1.0 mmol) in toluene (2 mL) were added catalyst (10
mol-%), base (2.0 mmol), and additive (2.0 mmol) at room tem-
perature and then the temperature was raised to 100 °C in pure
oxygen. On completion of the reaction (as monitored by TLC; 12
h), the products were purified by column chromatography on silica
gel (petroleum ether–ethyl acetate, 2:1). The results are reported as
isolated yields.
6-(2-Ethoxyphenyl)pyridazin-3(2H)-one (2ag): (Table 2, entry 7)
White solid; m.p. 117–118 °C. 1H NMR (400 MHz, CDCl3): δ =
11.38 (s, 1 H), 7.82 (d, J = 12 Hz, 1 H), 7.58 (dd, J = 4, 8 Hz, 1
Procedure for the Copper-Catalyzed Dehydrogenative Reaction of
Dihydropyridazinones: To a stirred solution of dihydropyridazin-
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FULL PAPER
H), 7.39 (m, 1 H), 7.03 (m, 1 H), 6.96 (t, J = 8 Hz, 2 H), 4.10 (q,
= 158.70, 157.94, 149.64, 149.08, 146.57, 134.18, 132.26, 131.61,
J = 8 Hz, 2 H), 1.40 (t, J = 8 Hz, 3 H) ppm. 13C NMR (100 MHz, 130.85, 129.56, 127.14, 125.79, 123.03, 122.43 ppm. HRMS (ESI):
CDCl3): δ = 161.15, 156.38, 145.69, 135.90, 131.01, 130.09, 128.31, calcd. for C17H11N3OS 305.0677; found 306.0680 [M + H+].
121.08, 112.31, 64.13, 14.73 ppm. HRMS (ESI): calcd. for
6-(4-Chlorophenyl)-2-phenylpyridazin-3(2H)-one (2bf): (Table 3, en-
C12H12N2O2 216.0901; found 217.0825 [M + H+].
try 6) White solid; m.p. 125–126 °C. 1H NMR (400 MHz, [D6]-
6-(5-Bromo-2-hydroxyphenyl)pyridazin-3(2H)-one (2ah): (Table 2,
entry 8) White solid; m.p. 134–135 °C. H NMR (400 MHz, [D6]-
DMSO): δ = 8.16 (d, J = 8 Hz, 1 H), 7.96 (d, J = 12 Hz, 2 H), 7.66
(d, J = 8 Hz, 2 H), 7.55 (m, 4 H), 7.45 (m, 1 H), 7.21 (d, J = 12 Hz,
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 159.03, 143.56,
142.10, 134.87, 133.56, 131.62, 131.35, 129.44, 129.14, 128.57,
128.31, 126.13 ppm. HRMS (ESI): calcd. for C16H11ClN2O
282.0618; found 283.0623 [M + H+].
1
DMSO): δ = 13.14 (s, 1 H), 10.25 (s, 1 H), 7.91 (t, J = 8 Hz, 1 H),
7.57 (m, 1 H), 7.35 (m, 1 H), 6.93 (m, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 160.41, 155.83, 155.11, 144.93, 143.43,
134.79, 133.37, 131.06, 129.38, 124.23, 121.72, 119.14, 116.96,
110.92 ppm. HRMS (ESI): calcd. for C10H7BrN2O2 265.9763;
found 266.9764 [M + H+].
6-(3-Chlorophenyl)-2-methylpyridazin-3(2H)-one (2bg): (Table 3, en-
1
try 7) White solid; m.p. 133–134 °C. H NMR (CDCl3, 400 MHz):
6-Oxo-1,6-dihydropyridazine-3-carboxylic Acid (2ai): (Table 2, en-
try 9) White solid; m.p. 88–89 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 6.94 (d, J = 12 Hz, 1 H), 7.82 (d, J = 12 Hz, 1 H),
13.50 (s, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.13,
161.15, 137.50, 132.78, 129.70 ppm. HRMS (ESI): calcd. for
C5H4N2O3 140.0275; found 141.0277 [M + H+].
δ = 3.85 (s, 3 H), 6.99 (d, J = 8 Hz, 1 H), 7.37 (m, 2 H), 7.62 (m,
2 H), 7.77 (s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 40.53,
123.79, 125.88, 129.26, 129.72, 129.77, 130.12, 134.98, 136.35,
142.67, 159.86 ppm. HRMS (ESI): calcd. for C11H9ClN2O
220.0433; found 221.0437 [M + H+].
2-Butyl-6-(3-chlorophenyl)pyridazin-3(2H)-one (2bh): (Table 3, en-
1
6-Chloropyridazin-3(2H)-one (2aj): (Table 2, entry 10) White solid;
m.p. 83–84 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 13.17 (s, 1
H), 7.51 (d, J = 8 Hz, 1 H), 6.97 (d, J = 8 Hz, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 160.10, 137.85, 135.20, 133.07 ppm.
HRMS (ESI): calcd. for C4H3ClN2O 129.9909; found 129.0201
[M – H+].
try 8) Colorless oil. H NMR (CDCl3, 400 MHz): δ = 0.97 (t, J =
8 Hz, 3 H), 1.42 (m, 2 H), 1.85 (m. 2 H), 4.23 (m, 2 H), 6.99 (d, J
= 8 Hz, 1 H), 7.36 (m, 2 H), 7.64 (m, 2 H), 7.78 (m, 1 H) ppm. 13
C
NMR (CDCl3, 100 MHz): δ = 13.68, 19.82, 30.44, 51.86, 123.79,
125.85, 129.15, 129.36, 129.95, 130.09, 134.95, 136.55, 142.52,
159.56 ppm. HRMS (ESI): calcd. for C14H15ClN2O 262.0910;
found 263.0881 [M + H+].
2-Methyl-6-phenylpyridazin-3(2H)-one (2ba): (Table 3, entry 1)
White solid; m.p. 129–130 °C. 1H NMR (400 MHz, [D6]DMSO): δ
= 8.03 (d, J = 8 Hz, 1 H), 7.88 (s, 2 H), 7.47 (s, 3 H), 7.04 (d, J =
8 Hz, 1 H), 3.74 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 159.08, 143.30, 134.30, 130.66, 129.26 (d, J = 6 Hz), 128.84,
125.67 ppm. HRMS (ESI): calcd. for C11H10N2O 186.0811; found
187.0726 [M + H+].
2-Benzyl-6-(3-chlorophenyl)pyridazin-3(2H)-one (2bi): (Table 3, en-
1
try 9) White solid; m.p. 167–168 °C. H NMR (CDCl3, 400 MHz):
δ = 5.32 (s, 2 H), 6.86 (d, J = 12 Hz, 1 H), 7.22 (m, 3 H), 7.31 (m,
2 H), 7.43 (m, 3 H), 7.55 (dt, J = 8 Hz, J = 4 Hz, 1 H), 7.71 (s, 1
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 64.88, 124.04, 126.07,
127.01, 127.37, 128.12, 128.46, 128.71, 128.88, 129.49, 130.26,
135.06, 141.39, 143.26, 159.77 ppm. HRMS (ESI): calcd. for
C17H13ClN2O 296.0705; found 297.0454 [M + H+].
2-Butyl-6-phenylpyridazin-3(2H)-one (2bb): (Table 3, entry 2) Col-
orless oil. 1H NMR (400 MHz, [D6]DMSO): δ = 7.93 (d, J = 8 Hz,
1 H), 7.83 (d, J = 4 Hz, 2 H), 7.40 (m, 3 H), 6.99 (d, J = 8 Hz, 1
H), 4.08 (t, J = 4 Hz, 2 H), 1.69 (m, 2 H), 1.26 (m, 2 H), 0.84 (t, J
= 8 Hz, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 159.18,
143.63, 134.87, 130.62, 129.93, 129.52, 129.18, 126.04, 51.11, 30.44,
19.73, 13.89 ppm. HRMS (ESI): calcd. for C14H16N2O 228.1312;
found 229.1224 [M + H+].
6-(3-Chlorophenyl)-2-phenylpyridazin-3(2H)-one (2bj): (Table 3, en-
try 10) White solid; m.p. 169–170 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.19 (d, J = 8 Hz, 1 H), 7.97 (s, 1 H), 7.90 (m, 1 H),
7.67 (d, J = 8 Hz, 2 H), 7.54 (m, 4 H), 7.46 (t, J = 8 Hz, 1 H), 7.21
(d, J = 8 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
159.06, 143.28, 142.05, 136.80, 134.32, 131.58, 131.47, 131.30,
129.82, 129.16, 128.61, 126.15, 125.21 ppm. HRMS (ESI): calcd.
for C16H11ClN2O 282.0611; found 283.0616 [M + H+].
2-Benzyl-6-phenylpyridazin-3(2H)-one (2bc): (Table 3, entry 3)
White solid; m.p. 155–156 °C. 1H NMR (400 MHz, CDCl3): δ =
7.80 (d, J = 8 Hz, 2 H), 7.66 (d, J = 12 Hz, 1 H), 7.50 (m, 5 H),
7.34 (m, 3 H), 7.03 (d, J = 12 Hz, 1 H), 5.44 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.60, 144.39, 136.30, 134.75,
130.33, 130.09, 129.42, 128.90 (d), 128.59, 127.92, 125.90,
55.58 ppm. HRMS (ESI): calcd. for C17H14N2O 262.1116; found
263.0894 [M + H+].
2-(4-Fluorobenzyl)-6-phenylpyridazin-3(2H)-one (2bk): (Table 3, en-
try 11) White solid; m.p. 144–145 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.06 (d, J = 8 Hz, 1 H), 7.88 (d, J = 8 Hz, 2 H), 7.45
(m, 5 H), 7.17 (t, J = 12 Hz, 2 H), 7.09 (d, J = 8 Hz, 1 H), 5.32 (s,
2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.32, 160.90,
159.22, 144.29, 134.69, 133.39 (d), 131.39, 130.74 (d), 130.50,
129.90, 129.39, 126.28, 115.91, 115.70, 54.28 ppm. 19F NMR
(376 MHz, [D6]DMSO): δ = –114.72 ppm. HRMS (ESI): calcd. for
C17H13FN2O 280.1002; found 281.0933 [M + H+].
2,6-Diphenylpyridazin-3(2H)-one (2bd): (Table 3, entry 4) White so-
lid; m.p. 161–162 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.16
(d, J = 12 Hz, 1 H), 7.93 (dd, J = 4, 8 Hz, 2 H), 7.67 (m, 2 H),
7.50 (m, 6 H), 7.20 (d, J = 8 Hz, 1 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 159.09, 144.62, 142.19, 134.70, 131.54, 130.04,
129.42, 129.12, 128.49, 126.51, 126.14 ppm. HRMS (ESI): calcd.
for C16H12N2O 248.0996; found 249.1000 [M + H+].
2-(3-Fluorobenzyl)-6-phenylpyridazin-3(2H)-one (2bl): (Table 3, en-
try 12) White solid; m.p. 138–139 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 8.07 (d, J = 2 Hz, J = 8 Hz, 1 H), 7.88 (dd, J = 8 Hz,
2 H), 7.43 (m, 4 H), 7.15 (m, 4 H), 5.35 (s, 2 H) ppm. 13C NMR
2-(Benzo[d]thiazol-2-yl)-6-phenylpyridazin-3(2H)-one
(2be): (100 MHz, [D6]DMSO): δ = 163.80, 161.38, 159.29, 144.41, 139.96,
(Table 3, entry 5) Yellow solid; m.p. 196–197 °C. 1H NMR
139.89, 134.65, 131.49, 129.92, 129.39, 126.29, 124.42 (d, J = 3 Hz),
(400 MHz, [D6]DMSO): δ = 8.30 (d, J = 12 Hz, 1 H), 8.16 (d, J =
115.32, 115.10, 115.02, 114.81, 54.52 ppm. 19F NMR (376 MHz,
8 Hz, 1 H), 8.08 (m, 3 H), 7.59 (m, 4 H), 7.49 (t, J = 8 Hz, 1 H), [D6]DMSO):
δ = –113.02 ppm. HRMS (ESI): calcd. for
7.42 (d, J = 8 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ C17H13FN2O 280.1002; found 281.0936 [M + H+].
6134
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6130–6136

Synthesis of Pyridazinones
2-(2-Fluorobenzyl)-6-phenylpyridazin-3(2H)-one (2bm): (Table 3, en-
DMSO): δ = 142.37, 136.24, 133.82, 130.87, 130.79, 129.92, 129.20,
try 13) White solid; m.p. 135–136 °C. 1H NMR (400 MHz, [D6]-
125.41, 124.36, 103.93, 48.03 ppm. 19F NMR (376 MHz, [D6]-
DMSO): δ = 8.08 (d, J = 8 Hz, 1 H), 7.85 (dd, J = 4, 8 Hz, 2 H), DMSO): δ = –113.42, –110.12 ppm. HRMS (ESI): calcd. for
7.47 (m, 3 H), 7.34 (m, 2 H), 7.20 (m, 2 H), 7.11 (d, J = 12 Hz, 1
H), 5.39 (s, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
161.96, 159.51, 159.23, 144.26, 134.66, 131.41, 130.70, 130.34,
130.26, 129.91, 129.39, 126.21, 124.98, 124.00, 123.86, 115.96,
115.75, 110.00, 48.77 (d) ppm. 19F NMR (376 MHz, [D6]DMSO):
δ = –117.88 ppm. HRMS (ESI): calcd. for C17H13FN2O 280.1002;
found 281.0941 [M + H+].
C17H11ClF2N2O 332.0501; found 333.0409 [M + H+].
6-(3-Chlorophenyl)-2-[3-(trifluoromethyl)benzyl]pyridazin-3(2H)-one
(2bt): (Table 3, entry 20) White solid; m.p. 148–149 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.14 (d, J = 8 Hz, 1 H), 7.94 (s, 1 H),
7.86 (m, 1 H), 7.77 (s, 1 H), 7.67 (t, J = 8 Hz, 2 H), 7.61 (t, J =
8 Hz, 1 H), 7.53 (m, 2 H), 7.14 (d, J = 12 Hz, 1 H), 5.46 (s, 2
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 158.82, 142.62,
137.87, 136.23, 133.84, 132.11, 130.79, 130.07, 129.73, 129.25,
125.49, 124.87, 124.83, 124.47, 54.13 ppm. 19F NMR (376 MHz,
2-(2,4-Difluorobenzyl)-6-phenylpyridazin-3(2H)-one (2bn): (Table 3,
1
entry 14) White solid; m.p. 122–123 °C. H NMR (400 MHz, [D6]-
[D6]DMSO):
δ
=
–61.13 ppm. HRMS (ESI): calcd. for
DMSO): δ = 8.06 (d, J = 8 Hz, 1 H), 7.84 (d, J = 8 Hz, 2 H), 7.46
(m, 4 H), 7.26 (m, 1 H), 7.08 (m, 2 H), 5.35 (s, 2 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 163.66, 163.54, 161.21, 161.09,
159.73, 159.61, 159.18, 144.26, 132.27, 126.19, 120.23, 111.94,
104.39, 48.31 ppm. 19F NMR (376 MHz, [D6]DMSO): δ = –113.14,
–110.48 ppm. HRMS (ESI): calcd. for C17H12F2N2O 298.0903;
found 299.0847 [M + H+].
C18H12ClF3N2O 364.0609; found 365.0452 [M + H+].
Supporting Information (see footnote on the first page of this arti-
cle): Contains the procedures for screening of reaction conditions
and the copper-catalyzed dehydrogenativereaction of dihydropyrid-
azinones, and 1H, 13C and 19F NMR spectra of isolated com-
pounds.
6-Phenyl-2-[3-(trifluoromethyl)benzyl]pyridazin-3(2H)-one
(2bo):
(Table 3, entry 15) White solid; m.p. 145–146 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.09 (d, J = 12 Hz, 1 H), 7.88 (dd, J
= 2 Hz, J = 8 Hz, 2 H), 7.76 (s, 1 H), 7.66 (d, J = 8 Hz, 2 H), 7.59
(m, 1 H), 7.48 (m, 3 H), 7.12 (d, J = 8 Hz, 1 H), 5.44 (s, 2 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 159.32, 144.51, 138.51,
134.63, 132.55, 131.56, 130.55, 130.20, 129.95, 129.38, 126.28,
54.56 ppm. 19F NMR (376 MHz, [D6]DMSO): δ = –62.53 ppm.
HRMS (ESI): calcd. for C18H13F3N2O 330.1006; found 331.0974
[M + H+].
Acknowledgments
This work was supported by the Beijing Natural Science Founda-
tion (Design, synthesis and optimization of proteasome inhibitors
as novel antitumor agents, 7112088), the National Basic Research
Program of China (2012CB518000), and the National Natural
Science Foundation of China (NSFC) (21202003/21172012).
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6-(3-Chlorophenyl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one
(2bq):
(Table 3, entry 17) White solid; m.p. 144–145 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.13 (d, J = 8 Hz, 1 H), 7.94 (s, 1 H),
7.86 (m, 1 H), 7.53 (m, 2 H), 7.40 (m, 1 H), 7.18 (m, 2 H), 7.12 (d,
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DMSO): δ = 163.30, 160.88, 158.79, 142.55, 133.83, 130.80, 129.21,
124.49, 123.92, 114.85, 114.59, 114.35, 54.12 ppm. 19F NMR
(376 MHz, [D6]DMSO): δ = –113.04 ppm. HRMS (ESI): calcd. for
C17H12ClFN2O 314.0607; found 315.0483 [M + H+].
6-(3-Chlorophenyl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one
(2br):
(Table 3, entry 18) White solid; m.p. 147–148 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.13 (d, J = 8 Hz, 1 H), 7.90 (s, 1 H),
7.83 (m, 1 H), 7.52 (m, 2 H), 7.35 (m, 2 H), 7.21 (m, 2 H), 7.12 (d,
J = 8 Hz, 1 H), 5.40 (s, 2 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 158.71, 142.35, 130.80, 130.28, 129.18, 124.37, 115.47,
115.26, 48.46 ppm. 19F NMR (376 MHz, [D6]DMSO):
δ =
–117.87 ppm. HRMS (ESI): calcd. for C17H12ClFN2O 314.0607;
found 315.0486 [M + H+].
6-(3-Chlorophenyl)-2-(2,4-difluorobenzyl)pyridazin-3(2H)-one (2bs):
(Table 3, entry 19) White solid; m.p. 142–143 °C. 1H NMR
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7.83 (m, 1 H), 7.52 (m, 2 H), 7.44 (q, J = 8 Hz, 1 H), 7.28 (m, 1
H), 7.09 (m, 2 H), 5.37 (s, 2 H) ppm. 13C NMR (100 MHz, [D6]-
Eur. J. Org. Chem. 2013, 6130–6136
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Liang, G. Yang, F. Xu, Y. Niu, Q. Sun, P. Xu
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Received: May 5, 2013
Published Online: July 31,2013
6136
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Eur. J. Org. Chem. 2013, 6130–6136