Relay catalysis by a multifunctional Cu catalyst in a tandem dehydro-/dehalogenation sequence along with N-arylation

Article abstract of DOI:10.1021/ol401105x

A Cu-catalyzed tandem dehydrogenation/dehalogenation sequential reaction along with N-arylation has been developed for the synthesis of pyridazinone derivatives in an aerobic and aqueous environment. To achieve the transformation of three chemical bonds in a one-pot reaction, a multifunctional copper catalyst was used which afforded excellent activity, high selectivity, and recyclability. The catalytic system consists of a water-soluble Cusalen complex and Na₂CO₃ in neat water and an air atmosphere.

Full text of DOI:10.1021/ol401105x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Relay Catalysis by a Multifunctional
Cu Catalyst in a Tandem
Dehydro-/Dehalogenation Sequence
along with N‑Arylation
Lei Liang, Wei Wang, Fengrong Xu, Yan Niu, Qi Sun, and Ping Xu*
State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal
Chemistry, School of Pharmaceutical Sciences, Peking University Health Science
Center, Beijing 100191 China
pingxu@bjmu.edu.cn
Received April 21, 2013
ABSTRACT
A Cu-catalyzed tandem dehydrogenation/dehalogenation sequential reaction along with N-arylation has been developed for the synthesis of
pyridazinone derivatives in an aerobic and aqueous environment. To achieve the transformation of three chemical bonds in a one-pot reaction, a
multifunctional copper catalyst was used which afforded excellent activity, high selectivity, and recyclability. The catalytic system consists of a
water-soluble Cusalen complex and Na2CO3 in neat water and an air atmosphere.
Presently, an increasing interest in developing ‘green’
processes has emerged, as the green initiative and sustain-
ability have become major trends in the pharmaceutical
industry.1 According to the 12 principles of Green Chem-
istry, water is the premier solvent recommended since it is
abundant, nontoxic, noncorrosive, and nonflammable,
and the use of water as the sole reaction medium is one
of the latest challenges for modern chemists.2 Recently,
tremendous effort has been focused toward using water as
the solvent, and several reactions have been proven suc-
cessful such as Cu-catalyzed Ullmann reactions, Cu-
catalyzed alkyneꢀazide cycloadditions.3
have been developed as G-Protein-Coupled Receptor
(GPCR) histamine 3 receptor (H3R) antagonists asso-
ciated with central nervous system (CNS) diseases.4 How-
ever, neither the synthetic route nor the individual steps for
the synthesis of pyridazinone derivatives have been fully
developed [Figure 1b].5 For instance, although numerous
attempts have been made to facilitate the aqueous Cu-
catalyzed reaction, it has not been applied in the N-
arylation of pyridazinones since most of the substrates
are insoluble in water, resulting in poor reactivity.6
Besides the N-arylation, two key steps in the syn-
thetic route of pyridazinones have been less developed
On the other hand, pyridazinone, as a useful heterocyclic
scaffold, was used as a pharmacophore with versatile
functions [Figure 1a]. Recently, N-arylated pyridazinones
(4) (a) Tao, M.; Aimone, L. D.; Huang, Z.; Mathiasen, J.; Raddatz,
R.; Lyons, J.; Hudkins, R. J. Med. Chem. 2012, 55, 414. (b) Hudkins, R.;
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10.1021/ol401105x
XXXX American Chemical Society

[Figure 1b]. The dehydrogenation of a C(4);C(5) single
bond to a CdC double bond is one of them. In previous
reports, several oxidants were used such as MnO2, SeO2,
Br2/HOAc, etc.7 However, neither the efficiency nor the
economy meets the green chemistry standards. Recently,
transition-metal catalyzed oxidation in aerobic condition
emerged as a powerful tool for dehydrogenation of C;C
single bond to CdC double bond.8 However, most of the
reactions were carried out in organic solvents and the
catalysts are expensive and unrecyclable. Another essential
is the dehalogenation which represents critical sig-
nificance in improvement of the medicinal properties of
pyridazinones.9 However, the high stability of the aryl
C;Cl bond renders it less reactive. Furthermore, only a few
methods using transition-metal catalysts are reported.10
The traditional catalytic systems can still be improved, as
most suffer from expensive transition-metal systems, poor
selectivity, extreme conditions, ornarrow functional group
tolerance. So far, few Cu-catalyzed dehydrogenations of
C;C bond to CdC bond and Cu-catalyzed dechlorina-
tion in an aerobic and aqueous environment have been
reported.11
In order to combine the three essentials including (i)
functionalization of the NH group, (ii) dehydrogenation of
the C;C bond to a CdC bond, and (iii) dehalogenation,
herein we report a highly selective and environmentally
benign reaction of starting material 1 to 2 using a compre-
hensive strategy. Thisisalsothe first aqueous Cu-catalyzed
one-pot reaction for the synthesis of pyridazinone deriva-
tives with three chemical bonds transformed.
Initially, we chose 20,30-dichloro-6-phenyl-4,5-dihydro-
pyridazin-3(2H)-one and bromobenzene as the substrates,
and the results of the screening of the reaction conditions
are summarized in Table 1. First, Na2CO3 was used as the
base, and a series of copper salts were used to study the
efficiency of the catalyst (Table 1, entries 1ꢀ4). Although
the use of Cu(OAc)2 gave a detectable yield (21%, Table 1,
entry 1), other copper salts barely gavethe desiredproduct.
We attribute the poor reactivity to the reaction of the
copper ion with the inorganic base in water. To solve this
problem, we synthesized several water-soluble copperꢀsalen
complexes and introduced them to this reaction. To our
delight, the results improved dramatically (for detailed
information of the copper salen complexes, see Support-
ing Information (SI) Table S1). After catalyst screening,
inorganic and organic bases including Cs2CO3, K2CO3,
K3PO4, NaOH, KOH, and triethylamine were investi-
gated and Na2CO3 was found to be the best choice
(Table 1, entries 6ꢀ11). Moreover, the catalytic system
showed low reactivity in organic solvents such as DMF
(26%, Table 1, entry 12). A low temperature decelerated
the reaction rate and resulted in a lower yield with a
prolonged reaction time (48 h, 62%, Table 1, entry 13). A
decreased yield was also observed when 1% catalyst was
loaded, while 10% loading of the catalyst gave a negli-
gible increase in yield (Table 1, entries 14 and 15). In
addition, a series of experiments were carried out to
identify the relationship of this reaction. In an oxygen
atmosphere, dechlorinated pyridazinone was obtained
without N-arylation occurring (Table 1, entry 16). How-
ever, the desired product was not observed in a nitrogen
atmosphere (Table 1, entry 17). Therefore, we hypothe-
size that N-arylation is independent of the dehydrogena-
tion/dechlorination sequence; the detailed mechanism of
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Figure 1. (a) Bioactive compounds containing a pyridazinone
scaffold. (b) Improved procedure of 6-phenyl-4,5-dihydropyrida-
zin-3(2H)-one reaction to N(2) substituted 6-phenyl-pyridazin-
3(2H)-one.
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Org. Lett., Vol. XX, No. XX, XXXX

this reaction is now under our investigation. In the
absence of Cu4 or Na2CO3, the reaction could not
proceed (Table 1, entries 18 and 19). As a result, Cu4
was chosen and Na2CO3 was confirmed as the base for
our following study.
70%, 68%). Disubstituted aryl bromides such as 3,5-
bis(trifluoromethyl)bromobenzene, 3,5-dichlorobromobenzene,
and 3,5-dimethylbromobenzene also gave good yields
(86%, 85%, 80%). In addition, other aryl halides such as
2-bromonaphthalene, 6-bromo-1,4-benzodioxane, 3-
bromoquinoline, 4-bromoisoquinoline, 2-iodothiophene,
1-bromopentafluorobenzene, and 5-bromo-30-propoxy-
1,10-biphenyl-3-carbonitrile gave good to modest yields.
Alkyl bromides including cyclopentyl bromide and cyclo-
hexyl bromide were also examined, and considerable yields
were obtained (69%, 78%).
Table 1. Selected Screening of the Cu-Catalyzed Reactiona
Table 2. Reaction of Various Organic Halides with 20,30-Di-
chloro-6-phenyl-4,5-dihydropyridazin-3(2H)-one under the
Optimized Conditionsa
a Reactions were carried out with dihydropyridazinone (1.0 mmol),
bromobenzene (1.1 mmol), catalyst (5 mol %), and base (2.0 mmol), in
H2O (2 mL) at 100 °C for 12 h in the air. b Isolated yields. c DMF as
solvent. d 80 °C. e 1% catalyst loading. f 10% catalyst loading.
g O2 atmosphere. h N2 atmosphere.
With the optimized conditions obtained, we further
investigated the generality of the reactions between aryl/
alkyl halides and 20,30-dichloro-6-phenyl-4,5-dihydropyr-
idazin-3(2H)-one, and the results are listed in Table 2. For
example, 4-bromonitrobenzene, 4-bromobenzotrifluoride,
4-bromobenzonitrile, 1-bromo-4-chlorobenzene, and 1-bromo-
4-fluorobenzene afforded excellent yields. The para-
substituted aryl bromides bearing an electron-donating
group such as methoxy, tert-butyl, and methyl showed lower
yields (78%, 82%, 84%). The meta-substituted aryl
bromides bearing an electron-withdrawing group also
showed higher reactivity than those bearing electron-
donating groups. 3-Bromonitrobenzene, 3-bromobenzonitrile,
1-bromo-3-chlorobenzene, and 1-bromo-3-fluorobenzene
afforded high yields respectively (87%, 92%, 85%, 84%).
3-Bromoanisole and 3-bromotoluene afforded modest
yields (76%, 82%). The ortho-substituted aryl bromides
showed remarkably lower yields probably due to the steric
effect. For instance, 2-bromonitrobenzene, 1-bromo-2-
chlorobenzene, 1-bromo-2-fluorobenzene, and 2-bromo-
toluene afforded modest yields respectively (70%, 79%,
a Reactions were carried out with dihydropyridazinone (1.0 mmol),
halide (1.1 mmol), Cu4 (5 mol %), and Na2CO3 (2.0 mmol), in H2O
(2 mL) at 100 °C for 12 h in the air; yields were calculated as isolated results.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 2 shows the crystal structure of 2ca. The dihydropyr-
idazinone converted to the aromatic pyridazinone scaffold, and
the 20-Cl of the 6-phenyl group has been removed. A different
view reveals that the N(2) and C(6) substituted phenyl rings
show certain dihedral angles with the pyridazinone ring.
Table 3. Reaction of Halogenated Dihydropyridazinone with
Bromobenzene or 1,4-Dibromobenzenea
Figure 2. X-ray structure of compound 2ca.
In order to expand the substrate scope, we applied this
catalytic system to a variety of dihydropyridazinones. To
our delight, most of the substrates afforded the desired
products with good yields. As shown in Table 3, a mono-
chloride substrate, 20-chloro-6-phenyl-4,5-dihydropyrida-
zin-3(2H)-one, converted to arylated pyridazin-3(2H)-one
in high yields (Table 3, entries 1 and 5). Highly selective
dehalogenations of dichloride substrates were also ob-
served. For example, both 20,30-dichloro and 20,40-dichloro
substrates converted to the products with dechlorination
of the ortho-Cl and retention of the meta-Cl or para-Cl
(Table 3, entries 2, 3, 6, 7). Moreover, the dehalogenation
also proceeded smoothly with 20-bromo-6-phenyl-4,5-di-
hydropyridazin-3(2H)-one(90% and 83%, Table3, entries
4 and 8). Furthermore, a nonhalogenated substrate was also
investigated. In the absence of ortho-Cl on the 6-phenyl
group, a dehydrogenated product along with N-arylation
was obtained in high yield (86%, Table 3, entry 9).
We further investigated the reusability of this catalytic system.
After the first cycle, the product could be separated from the
reaction mixture by filtration. Subsequently the second por-
tion of substrates and Na2CO3 were added to the remaining
aqueous solution for the next round. Three parallel sets of
experiments were carried out, and Cu4 could be reused at least
5 times in relatively high yields above 80% (see SI Figure S1).
In conclusion, a simple and efficient one-pot reaction
has been developed for the synthesis of N-functionalized
pyridazinone derivatives with transformation of multiple
chemical bonds. The multifunctional copper catalyst af-
fords excellent activity, high selectivity, and recyclability.
The catalytic system consists of a water-soluble Cusalen
complex and Na2CO3 in neat water and an air atmosphere.
Further work to explore the detailed mechanism and the
application of thisapproach toothersubstrates iscurrently
underway in our laboratory.
a Reactions were carried out with dihydropyridazinone (1.0 mmol),
bromobenzene or 1,4-dibromobenzene (1.1 mmol), Cu4 (5 mol %), and
Na2CO3 (2.0 mmol), in H2O at 100 °C for 12 h in the air. b Isolated
yields.
Acknowledgment. This work was supported by the
Beijing Natural Science Foundation (Design, synthesis
and optimization of proteasome inhibitors as novel
antitumor agents, 7112088), the National Basic Re-
search Program of China (2012CB518000), and the
National Natural Science Foundation of China
(21202003/21172012).
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX