Synthesis of functionalized 3-arylpyridazines via Pd-catalyzed decarboxylative cross-coupling of pyridazine-3-carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2017.01.083

An efficient and general protocol for the decarboxylative cross-coupling of pyridazine-3-carboxylic acids with aryl-bromides has been described. This method provides a new avenue for the synthesis of 3-arylpyridazines via decarboxylative cross-coupling strategy by employing the dual-catalyst system of Pd(PPh₃)₄/Cu₂O in the presence of Li₂CO₃at 160?°C in DMA.

Full text of DOI:10.1016/j.tetlet.2017.01.083

Accepted Manuscript
Synthesis of Functionalized 3-Arylpyridazines via Pd-catalyzed Decarboxyla-
tive Cross-coupling of Pyridazine-3-carboxylic Acids
Shengqiang Wang, Hongtao Lu, Jingya Li, Dapeng Zou, Yusheng Wu, Yangjie
Wu
PII:
S0040-4039(17)30126-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.083
TETL 48586
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2016
23 January 2017
24 January 2017
Please cite this article as: Wang, S., Lu, H., Li, J., Zou, D., Wu, Y., Wu, Y., Synthesis of Functionalized 3-
Arylpyridazines via Pd-catalyzed Decarboxylative Cross-coupling of Pyridazine-3-carboxylic Acids, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.083
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Synthesis of Functionalized 3-Arylpyridazines via
Pd-catalyzed Decarboxylative Cross-coupling of
Pyridazine-3-carboxylic Acids
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Shengqiang Wang, Hongtao Lu, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of Functionalized 3-Arylpyridazines via Pd-catalyzed Decarboxylative Cross-coupling of
Pyridazine-3-carboxylic Acids
∗
∗
∗
Shengqiang Wanga, Hongtao Lua, Jingya Lib,c, Dapeng Zoua,b, , Yusheng Wub,d, , Yangjie Wua,
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou 450052, PR China
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and general protocol for the decarboxylative cross-coupling of pyridazine-3-
carboxylic acids with aryl-bromides has been described. This method provides a new avenue for
the synthesis of 3-arylpyridazines via decarboxylative cross-coupling strategy by employing the
dual-catalyst system of Pd(PPh3)4/Cu2O in the presence of Li2CO3 at 160 °C in DMA.
2016 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Palladium catalysis
Pyridazine-3-carboxylic Acids
3-Arylpyridazines
Decarboxylative cross-coupling
∗Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327(Y.Wu.). E-mail: zdp@zzu.edu.cn, yusheng.wu@tetranovglobal.com,
wyj@zzu.edu.cn.

2
Tetrahedron
Introduction
nitrogen atom that could bind and poison the catalyst. They are
also more π-electron-deficient and less nucleophilic than
pyridine.10 Herein, we report the decarboxylative cross-coupling
reaction of pyridazine-3-carboxylic acids with a variety of aryl
halides for the synthesis of 3-arylpyridazine derivatives.
3-Arylpyridazine is a ubiquitous structural motif frequently
found in pharmaceuticals,1 ligands,2 and functional materials3
(Figure 1). Over the past few years, the synthesis of 3-
arylpyridazine derivatives has attracted a great deal of attention.
Traditional methods such as prefunctionalization of starting
materials before the cyclization have been limited to specific
Results and Discussion
structures.4 Recently,
a
range of 3-arylpyridazines was
Initially, the decarboxylative cross-coupling reaction of
pyridazine-3-carboxylic acid (1a) and bromobenzene (2a) was
selected as the model reaction (Table 1). The reaction was carried
out under 5 mol% PdCl2/Cu2O (0.5 equiv) catalysis in DMA
using K2CO3 as base and BINAP as ligand. But the expected 3-
phenylpyridazine (3a) was formed in a relatively low yield of 25%
(entry 1). Subsequently, other ligands such as PPh3, PCy3, S-phos,
X-phos, Ruphos, Davephos, Xantphos, DPPF were
synthesized from 3-halopyridazines via metal-catalyzed cross-
coupling reactions, such as Pd-catalyzed Suzuki,5 Negishi,6
Kumada7 reactions and Ni-catalyzed electrochemical cross-
coupling reaction.8 However, the instability and the synthetic
difficulty of 3-halopyridazines restrained the applications of these
methodologies. Furthermore, 3-pyridazyl organometallic used as
the nucleophile source in cross-coupling reaction remains largely
unexploited because of the hardly isolation and commonly
decomposition of these organometallic compounds under cross-
coupling reaction conditions. To access more bioactive
molecules, the highly toxic 3-pyridazine stannanes have to be
Table 1. Optimization of reaction conditionsa
[Pd] (5 mol%)
Ligand (10 mol%)
Cu2O (0.5 equiv)
COOH
+
Br
9
Base (3.0 equiv)
DMA, 150 oC, 24 h
employed as nucleophile source in these reactions. In 2006,
N
N
N
N
Fagnou and co-workers reported the palladium-catalyzed direct
arylation of diazine N-oxides with aryl halides to solve the
diazine organometallic cross-coupling problem.10 The
development of new methods for the synthesis of valuable 3-
arylpyridazines from simple and readily available starting
materials by concise steps continues to be a target of intense
interest.
1 eq
1a
2 eq
2a
3a
Yieldb (%)
25
Entry
1
Catalyst
PdCl2
Ligand
Additive
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
BINAP
PPh3
PCy3
S-phos
X-phos
Ruphos
Davephos
Xantphos
DPPF
DPPF
DPPF
DPPF
DPPF
--
2
PdCl2
53
N
O
3
PdCl2
30
N
N
N
4
PdCl2
18
NH
N
N
N
N
N N
5
PdCl2
17
Minaprine (anti-depressant)
Minokine(Alzheimer dementia)
6
PdCl2
21
7
PdCl2
34
O
8
PdCl2
23
O
N
N
N
N
N
9
PdCl2
54
N
N
N
10
11
12
13
14
15
16
17
18
19
20
Pd(OAc)2
Pd(TFA)2
35
Selective CB2 agonist
Helix Mimetics
-
α
57
Fig. 1 Biologically active 3-arylpyridazine derivatives.
Pd2(acac)3
Pd(PPh3)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
45
Since Nilsson first reported the transition-metal mediated
decarboxylative biaryl coupling,11 several groups such as
Myers,12 Gooßen,13 and Liu14 have made pioneering works
toward this reaction. Decarboxylative cross-coupling has proven
to be an efficient modern alternative and complementary process
to traditional cross-coupling methods. This strategy employs low
cost, high stability, and easy availability carboxylic acids rather
than organometallic reagents as the nucleophilic coupling partner
and generates gaseous CO2 instead of toxic metal salts as waste.
Although many Pd-catalyzed decarboxylative arylation of
aromatic and electron-rich heteroaromatic carboxylic acids have
been reported, a very limited number of examples were reported
to use π-deficient heteroaryl carboxylic acids.15 In 2010, the
Gooßen group reported the first successful decarboxylative cross-
coupling of 3-pyridyl carboxylates with naphthyltosylate.16 In
2013, our group reported the first decarboxylative cross-coupling
reaction of 2-picolinic acid with aryl-bromides involving a
bimetallic Cu/Pd catalysis.17 In 2014, Hoarau and co-workers
reported Pd-catalyzed decarboxylative arylations of 2-
carboxyazine N-oxides with copper or silver species as co-
catalysts.18 However, examples of the decarboxylative cross-
coupling of pyridazinecarboxylic acids with aryl halides have not
been reported. Pyridazinecarboxylic acids are more challenging
than simple pyridyl carboxylates, since they possess a free
55
63
--
35
--
CuBr
CuCl
23
--
Trace
Trace
23
--
Cu(OAc)2
Ag2CO3
Ag2O
--
--
26
a
Reaction conditions:1a (0.6 mmol), 2a (1.2 mmol), catalyst (5 mol %),
ligand (10 mol %), additive (0.3 mmol), K2CO3 (1.8 mmol) and 3Å MS (200
mg) in DMA (4.0 mL) at 150 oC under N2 for 24 h.
b Detected by HPLC.
screened and PPh3 was shown to be nearly as efficient as DPPF,
whereas the others were found to be inferior (entries 2-9). Then, a
series of Pd sources were examined and it was identified that the
Pd(PPh3)4 provided the optimal result (entries 10-14). The
additives were also been examined, Cu2O was still the best
additive than other copper source for the current reaction (entries
15-18). Furthermore, replacing Cu2O with Ag2CO3 or Ag2O only
gave worse yields in this reaction system (entries 19-20).

3
Subsequently, various bases were examined. To our delight, a
further jump in yield could be attained by using Li2CO3 as base
(Table 2, entries 1-5). To improve the yield, other reaction
parameters were screened. Increasing the loading of additive
Cu2O could slightly increase the yields (entries 6-7). When the
reaction temperature increased to 160 °C, the desired product was
obtained in 88% yield. We hypothesized that the higher
temperatures might reduce the chelating of metals with the two
adjacent nitrogens (entries 8-9).19 Further optimization of the
solvent revealed that DMA was the best solvent (entries 10-12).
Finally, the ratio of substrates was examined. Because of the
formation of the Ullmann-type dimerization of bromobenzene
under copper-mediated, appropriate excessive of aryl halides was
necessary (entries 13-14).20 Thus, the combination of 5 mol%
Pd(PPh3)4, 2.0 equiv aryl halides, 1.0 equiv Cu2O in DMA in
presence of Li2CO3 at 160 °C was chosen as the optimum
condition.
the reaction. The bromonaphthalene and 3, 4-difluoro- and 3, 5
-dichloro-substituted bromobenzene could also afford the desired
products in good yields (3o, 3r, 3s). In addition, chlorobenzene
and iodobenzene were also checked, unfortunately, only poor
yield of the product was obtained (3a). However, this reaction
was effective for the more active electron-poor 4-
chloronitrobenzene (3p). Notably, when the electron-rich 4-
bromoanisole was employed as substrate, 3-phenylpyridazine
was isolated as
a byproduct up to 30% yield. The
triphenylphosphine should be the source of phenyl group.21 But
under the standard condition absent with aryl bromides, only the
trace of 3-phenylpyridazine was detected. We inferred that aryl
bromide may act as an oxidant in transformation.22
Table 3. Decarboxylative cross-coupling of pyridazine-3-
carboxylic acid 1a with aryl-bromidesa,b
R
R
Pd(PPh3)4, Cu2O
Li2CO3
COOH
X
+
Table 2. Optimization of reaction conditionsa
N
N
DMA, 160 oC, 24 h
N
N
X = Cl, Br, I
2a-s
Pd(PPh3)4 (5 mol%)
Cu2O, Base (3.0 equiv)
3a-s
1a
COOH
+
Br
N
N
N N
Solvent, 24 h
CN
NC
1 eq
1a
2 eq
2a
NC
3a
N
61%
N
N
N
N
N
N
86%
N
3b
3d
3a
3c
15% X = Cl
76% X = Br
45% X = I
95%
Yieldb (%)
63
Entry
1
Base
Solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
NMP
Temp[°C]
150
F
F
CF3
K2CO3
F
N
N
N
2
Cs2CO3
Na2CO3
Li2CO3
K3PO4
150
53
55
75
62
79
72
45
88
68
31
43
76
55
N
N
N
N
N
N
N
3h
3l
trace
3e
3i
3f
3j
3g
3k
55%
76%
65%
35%
3
150
F3C
F3CO
4
150
F3C
O
N
N
N
N
N
N
5
150
78%
86%
6c
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
150
88%
7d
150
O
8c
130
OHC
O2N
N
N
N
N
N
N
N
N
N
9c
160
3n
55%
3m
3o
3p
80%
68%
76% X = Cl
60% X = Br
10c
11c
12c
13e
14f
160
F
Cl
Cl
O
O
DMSO
DMF
160
F
N
N
N
N
N
160
3q
43%
3r
95%
3s 42%
DMA
DMA
160
a Reaction conditions: 1a (0.6 mmol), 2a-s (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.6 mmol), Li2CO3 (1.8 mmol) and 3Å MS (200 mg) in DMA (4.0 mL)
160
a Reaction conditions: 1a (0.6 mmol), 2a (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.3 mmol), Base (1.8 mmol) and 3Å MS (200 mg) in solvent (4.0 mL)
under N2 for 24 h.
b Isolated yields.
under N2 for 24 h.
b Detected by HPLC.
c Cu2O (0.6 mmol).
d Cu2O (0.15 mmol).
e 2a (2.4 mmol).
To further extend the reaction scope, we proceeded to study
the cross coupling reactions of pyridazine-3-carboxylic acid with
heteroaryl bromides under the optimized reaction conditions. The
results are summarized in Table 4. At first, the bromo-pyridines
were examined as cross-coupling partners. 3-Bromopyridine and
4-bromopyridine afforded the corresponding desired product in
good yields respectively (5a, 5b). The substituted bromo-
pyridines could also be successfully converted to the
corresponding products in moderate yields (5c, 5d). The more
electron-deficient 5-bromopyrimidine is also a good coupling
partner (5e). Both the 3-bromothiophene and 5-
bromobenzo[b]thiophene could be efficiently converted into the
corresponding products in 51 and 75 % yields (5f, 5g). 6-
Bromoquinoline gave the desired product in excellent yield (5h).
f 2a (0.9 mmol).
With the optimized conditions in hand, the substrate scope and
limitation of the method were evaluated and the results are
summarized in Table 3. The reaction condition could be
compatible with a wide range of functional groups such as
nitriles, fluoro, ketones, esters, ethers, trifluoromethyl, and nitro
groups. Generally, it was found that both electron-rich and
electron-poor aryl bromides could be successfully converted to
the corresponding products in moderate to good yields. It was
noteworthy that the electron-poor aryl bromides could afford the
corresponding products in better yields than electron-rich aryl
bromides (3d, 3j; 3r vs 3k). Meanwhile, aryl bromides with
groups at ortho-position (3b, 3e, 3h) gave lower yields than those
at meta-position (3c, 3f, 3i) or para-position (3d, 3g, 3j),
indicating that the steric hindrance likely has a negative effect on

4
Tetrahedron
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Table 4. Decarboxylative cross-coupling of pyridazine-3-
carboxylic acid 1a with heterocyclic bromides a,b
Pd(PPh3)4, Cu2O
Li2CO3
COOH
1a
HetAr Br
+
HetAr
NC
DMA, 160 oC, 24 h
N
N
N
N
2. Youinou, M, T.; Rahmouni, N.; Fisclwr, J.; Osborn, J. A. Angew.
5a-h
4a-h
Chem. Int. Ed. Engl. 1992, 31, 733-735.
F
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Baudequin, C.; Plé, N. Dyes. Pigm. 2013, 98, 575-600.
N
N
N
N
N
N
N
N
N
N
N N
5a
5e
5b
5f
5c
5d
60%
63%
80%
58%
N
4. (a) South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.; Dukesherer,
D. R. J. Org. Chem. 1996, 61, 8921-8934. (b) Marriner, G. A.;
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1380-1382.
S
N
S
N
N
N
N
N N
N
N
N
5h
5g
85%
51%
75%
55%
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a Reaction conditions: 1a (0.6 mmol), 4a-h (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.6 mmol), Li2CO3 (1.8 mmol) and 3Å MS (200 mg) in DMA (4.0 mL)
under N2 for 24 h.
b Isolated yields.
Finally, to further examine the versatility of this methodology,
the decarboxylative coupling of substituted pyridazine-3-
carboxylic acids with 4-bromobenzonitrile was also investigated
(Table 5). Both 4-methyl and 5-methylpyridazine-3- carboxylic
acids performed well under these reaction conditions with yields
in 55 and 76% (6b, 6c), which indicating that the ortho-methyl
has slightly steric effect on the cross-coupling reaction.
Furthermore, 5-phenyl and 6-phenylpyridazine-3-carboxylic acid
gave better yields of the desired products (6d, 6e).
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carboxylic acids 1b-e with 4-bromobenzonitrile a,b
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R
Pd(PPh3)4, Cu2O
Li2CO3
R
NC
Ph
COOH
Br
CN
+
DMA, 160 oC, 24 h
N
N
N
N
1b-e
6b e
-
2d
NC
NC
NC
Ph
NC
N
N
N
82%
N
N N
N
N
6c
6d
6e
76%
79%
6b
55%
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a Reaction conditions: 1b-e (0.6 mmol), 2d (1.2 mmol), Pd(PPh3)4 (5 mol %),
Cu2O (0.6 mmol), Li2CO3 (1.8 mmol) and 3Å MS (200 mg) in DMA (4.0 mL)
under N2 for 24 h.
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b Isolated yields.
Conclusion
In conclusion, we have developed an efficient method for the
synthesis of 3-arylpyridazines via the palladium catalyzed
decarboxylative cross-coupling of pyridazine-3-carboxylic acids
with aryl-bromides. The reaction employs an optimized catalytic
system and exhibits good substrate scope. In addition, stable and
commercially available pyridazine-3-carboxylic acids have been
used. The reaction provided a new approach to the synthesis of 3-
arylpyridazines.
Acknowledgments
We are grateful to the Natural Science Foundation of China
(21172200) and Technology Research and Development Funds
of Zhengzhou (141PRCYY516) for financial support.
References and notes
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Highlights
. Palladium catalysized decarboxylative cross-coupling
. One step to make 3-arylpyridazines in modest to excellent yields
. The reaction is compatible with a wide range of functional groups