A copper-catalyzed aerobic cascade dehydrogenative- dehalogenative reaction

Article abstract of DOI:10.1002/adsc.201300026

A copper-catalyzed cascade dehydrogenative and dehalogenative reaction of halogenated 6-phenyl-4,5-dihydropyridazin-3(2H)-ones to 6-phenylpyridazin-3(2H)- ones has been developed. Moreover, the catalytic system consisting of copper(II) acetate/sodium carbonate/pyridine exhibits high reactivity and selectivity with oxygen as the terminal oxidant. Copyright

Full text of DOI:10.1002/adsc.201300026

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DOI: 10.1002/adsc.201300026
A Copper-Catalyzed Aerobic Cascade Dehydrogenative–
Dehalogenative Reaction
Lei Liang,a Guanyu Yang,a Wei Wang,a Fengrong Xu,a Yan Niu,a Qi Sun,a
and Ping Xua,*
a
State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal Chemistry, School of Pharmaceutical
Sciences, Peking University Health Science Center, Beijing 100191, Peopleꢀs Republic of China
E-mail: pingxu@bjmu.edu.cn
Received: January 12, 2013; Revised: April 9, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300026.
Abstract: A copper-catalyzed cascade dehydrogena-
tive and dehalogenative reaction of halogenated 6-
phenyl-4,5-dihydropyridazin-3(2H)-ones to 6-phe-
nylpyridazin-3(2H)-ones has been developed. More-
over, the catalytic system consisting of copper(II)
acetate/sodium carbonate/pyridine exhibits high re-
activity and selectivity with oxygen as the terminal
oxidant.
efficacy.[1] For example, pyridazinones (Figure 1a), as
a vital sort of pharmacophore with use such as antag-
onist of G-protein-coupled-receptor (GPCR) hista-
mine 3 receptor (H3R), have been developed as clini-
cal candidates and further applied into trials.[2]
There are several routes leading to pyridazin-
3(2H)-ones, among which the dehydrogenation of the
À
C-4 C-5 bond of 4,5-dihydropyridazin-3(2H)-one to
a C=C bond is definitely the key step (Figure 1b). De-
hydrogenative methods with high efficiency and
benign circumstances have attracted tremendous at-
tention in the past decades. However, the develop-
ment of catalytic methodology for dehydrogenation
remains afflicted with several limitations.[3] In previ-
ous reports, excessive amounts of hazardous oxidants
Keywords: copper; dehalogenation; dehydrogena-
tion; oxygen; pyridazinones
The development of synthetic and catalytic methodol- were utilized including MnO2, SeO2, Br2/HOAc and
ogy has undoubtedly made tremendous contributions so on.[4] What is more, neither the efficiency nor the
to the pharmaceutical industry especially for the con- economy meets the demands of large-amount produc-
struction of some significant chemical bonds with high tion or the principles of green chemistry. To solve
Figure 1. (a) Bioactive compounds containing the pyridazinone scaffold. (b) Structures of 6-phenyl-4,5-dihydropyridazin-
3(2H)-one and 6-phenylpyridazin-3(2H)-one.
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A Copper-Catalyzed Aerobic Cascade Dehydrogenative–Dehalogenative Reaction
Table 1. Screening of the optimized condition of the copper-
these problems, molecular oxygen has been widely
used as a benign and economical source of oxidant in-
stead of the toxic and expensive oxidants. Recently,
transition metal-catalyzed oxidation in an aerobic at-
mosphere emerged as a powerful tool for preparation
of pharmaceutical compounds.[5] Among these, palla-
dium complexes were widely used in the dehydrogen-
ation of unsaturated carbonyl compounds.[6] Never-
theless, the substrates accommodated to the palladi-
um catalytic system were limited to alkanes or cyclo-
alkanes. Heterocyclic compounds, as the most impor-
tant skeleton of chemical drugs, have been less
reported as substrates in metal-catalyzed dehydrogen-
ations. In terms of the metal catalyst, copper salts are
generally more economical and available compared to
palladium complexes. However, there is a scarcity of
catalyzed cascade dehydrogenative-dehalogenative reaction
of 2’,3’-dichloro-6-phenyl-4,5-dihydropyridazin-3(2H)-one.[a]
Entry
Catalyst
Cu(OAc)2
Base
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
G
Cs2CO3
K2CO3
Na2CO3
K3PO4
Py
Py
Py
Py
74
70
87
53
trace
55
20
37
81
46
18
trace
10
trace
none
none
none
trace
30[c]
none[d]
15[e]
26[f]
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
R
N
R
N
R
T
T
Et3N
Py
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
–
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Phen
TMEDA
Bpy
Py
Py
Py
Py
Py
Py
Py
Py
Py
–
Py
Py
Py
Py
reports on copper-catalyzed dehydrogenation of satu-
[7]
9
CuCl2
CuBr2
CuCl
CuBr
CuI
À
rated C C bond.
10
11
12
13
14
15
16
17
18
19
20
21
22
On the other hand, the highly efficient and selec-
tive modification of pyridazinone derivatives provides
us with abundant information about the structure-ac-
tivity relationship (SAR) and the choice for design of
drug candidates.[8] Accordingly, dehalogenation on the
6-phenyl ring of pyridazinone is a significant way to
achieve this aim (Figure 1b). The highly efficient and
selective dehalogenative reaction facilitates not only
the chemical modification but also provides improve-
ments of the pharmacokinetic/pharmacodynamic
properties of pyridazinones. However, the high stabili-
ty of the aryl carbon-chlorine bond renders it less re-
active compared to other aryl-halogen bonds in many
organic transformations and reactions.[9] In the past
decades, only a limited number of methods employing
metal catalysts have been reported such as Pd,[10]
Ni,[11] La,[12] Rh,[13] Rh,[14] and others.[15] These systems
can still be improved upon, as most suffer from ex-
pensive precious transition metal systems, unselective
dechlorination, low catalytic activity, low substrate/
catalyst ratio, extreme conditions (high H2 pressure,
long reaction times), and narrow functional group tol-
erance.
Mn
A
Fe
–
A
Cu
Cu
Cu
Cu
Cu
Cu
N
[a]
Reactions were carried out with 2’,3’-dichloro-6-phenyl-
4,5-dihydropyridazin-3(2H)-one (243.0 mg, 1.0 mmol),
catalyst
(10 mol%),
base
(2.0 equiv.),
additive
(2.0 equiv.), in toluene in 1008C for 12 h without other
notes.
Isolated yields.
In the air.
Under N2.
At 258C.
DMF as solvent.
[b]
[c]
[d]
[e]
[f]
In this communication, we present a copper-cata- a trace amount of product was detected with scarce
lyzed cascade dehydrogenative-dehalogenative reac- conversion of substrate (Table 1, entry 5). Pyridine
tion of halogenated 6-phenyl-4,5-dihydropyridazin- (Py) was identified as the most efficient ligand rather
3(2H)-ones with oxygen as the oxidant.
than phenanthroline (Phen), tetramethylethylenedia-
Our investigations commenced with screening con- mine (TMEDA) and bipyridine (bpy). After screen-
ditions using 2’,3’-dichloro-6-phenyl-4,5-dihydropyri- ing a series of copper salts including both Cu(II) and
dazin-3(2H)-one as substrate. The reactions were Cu(I) species and other metal salts, Cu
originally carried out in toluene as solvent and with lected as the catalyst (Table 1, entries 9–13). CuCl2
oxygen as oxidant. Several sets of reactions were car- also gave a considerable yield compared to Cu(OAc)2
ried out including studies on the effects of base, (81%, Table 1, entry 9). We also investigated other
ligand, catalyst and others. We first investigated the metal salts including Mn(OAc)2, Fe(OAc)2. Both of
ACHTUNGRTENUN(NG OAc)2 was se-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
effect of base: inorganic bases such as Cs2CO3, them showed negligible conversion of substrates and
K2CO3, Na2CO3 and K3PO4 were used and Na2CO3 poor yields (Table 1, entries 14 and 15). Control ex-
was found to be the best inorganic base with excellent periments revealed that the reaction could not pro-
yield (Table 1, entries 1–4). Triethylamine was also ceed in the absence of either the copper catalyst or
used as an organic base in this reaction but merely the base (Table 1, entries 16 and 17). Pyridine is also
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an essential component in the catalytic system as the ployed and modest to excellent yields were achieved
reaction hardly proceeded in the absence of pyridine (Table 2, 2aa–2ae). Recently, a structurally similar
(Table 1, entry 18). This is probably due to inactiva- drug candidate based on N-benzylated pyridazinone
tion of copper salt without a proper ligand. The reac- containing fluoride(s) has been developed for the
tion slowed down in the air with lower yield (30%, treatment of allergic inflammatory diseases.[16] Herein,
Table 1, entry 19). However, no product formed when a series of N-benzylated pyridazinone compounds
the reaction was carried out in a nitrogen atmosphere containing fluoride(s) were employed as substrates
(Table 1, entry 20). Lower temperature and other and excellent yields were achieved (Table 2, 2af–2aj).
common organic solvent such as DMF showed nega- Besides, the N(2)-benzothiazole-substituted pyridazi-
tive effects on the reaction (15% and 26%, Table 1, none was prepared with good yield (78%, Table 2,
entries 21 and 22). Above all, the catalytic system was 2ak). Moreover, 2’,3’-dichloro-6-phenyl-4,5-dihydro-
finally confirmed as Cu
oxygen as the oxidant.
ACHTUNGTRENNUNG
In an endeavour to expand the scope of this meth- Cl selectively (Table 2, 2ba–2bj). The catalytic system
odology, the catalytic system was further applied to also exhibited broad substrate scope for NH sub-
a variety of halogenated dihydropyridazinones. To our strates substituted by different groups. As we expect-
delight, most of the substrates exclusively afforded ed, N-arylated 2’,4’-dichloro-6-phenyl-4,5-dihydropyri-
the desired products in good to excellent yields. First dazin-3(2H)-ones afforded the desired products with
of all, monochloro-substituted 6-phenyldihydropyrida- dechlorination of ortho-Cl and retention of para-Cl
zinones were examined with the catalytic system and selectively (Table 2, 2ca and 2cb). Furthermore, we
considerable results were obtained. For example, a va- also observed that when both of the ortho positions
riety of N-alkylated/N-arylated substrates, including are chlorines, only one chlorine has been replace by
methyl, benzyl, n-butyl and phenyl groups, were em- H, which has instructive significance for the reaction
Scheme 1. Mechanistic study: (a) Reaction of 2’,3’-dichloro-6-phenylpyridazin-3(2H)-one and 2’,3’-dichloro-6-phenyl-4,5-di-
hydropyridazin-3(2H)-one with/without extraneous hydrogen donors under the optimized reaction conditions. (b) Reaction
of 2’,6’-dichloro-5-phenyldihydropyridazinone and 2’-chloro-5-phenyldihydropyridazinone under the optimized reaction con-
ditions. (c) Reaction of 6-phenyl-4,5-dihydropyridazin-3(2H)-one under the optimized reaction conditions.
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A Copper-Catalyzed Aerobic Cascade Dehydrogenative–Dehalogenative Reaction
Table 2. Copper-catalyzed cascade dehydrogenative-dehalogenative reaction of various halogenated dihydropyridazinones.[b]
(1) Substrate:
2aa: 86%
2ad: 79%
2ab: 88%
2ae: 89%
2ac: 90%
2af: 82%
2ag: 86%
2ah: 72%
2ak: 78%
2ai: 65%
2aj: 84%
(2) Substrate:
or
2ba: 87%[b]
2bd: 83%
2bb: 90%
2be: 85%
2bc: 92%
2bf: 77%
2bg: 70%
2bh: 53%
2ca: 73%
2bi: 59%
2cb: 89%
2bj: 69%
(3) Substrate:
2da: 90%
2db: 88%
2dc: 91%
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Table 2. (Continued)
2dd: 82%
2de: 88%
(4) Substrate:
2ea: 89%
2eb: 85%
2ee: 86%
2ec: 87%
2ed: 79%
(5) Substrate:
2fa: 90%
2fb: 86%
2fe: 91%
2fc: 94%
2fd: 67%
[a]
Reactions were carried out with substrate (1.0 mmol), CuACHTNUGRTNEUNG(OAc)2 (20.0 mg, 10 mol%), Na2CO3 (312.0 mg, 2.0 mmol), pyri-
dine (159.0 mg, 2.0 mmol), in toluene in 1008C for 12 h, all the results were calculated after column chromatography as
isolated yields.
mechanism (Table 2, 2da–2de, 2ea–2ee). Moreover, not give any dehalogenated products. Deuterated tol-
debromination also proceeded smoothly when the 6- uene and pyridine were also used to testify if the H
phenyl group was substituted by ortho-Br (Table 2, comes from the solvent or ligand. However, there is
2fa–2fe).
no proof revealing that the product contained deuteri-
To explore the mechanism of this reaction, a series um (see Tables S1 and S2 in the Supporting Informa-
of experiments was carried out. First of all, we de- tion). Moreover, if the phenyl group is shifted far
signed a series of control experiments with 2’,3’-di- away from the N-1 as shown in Scheme 1b, only dehy-
chloro-6-phenylpyridazin-3(2H)-one (3) and 2’,3’-di- drogenation occurred without dechlorination. Never-
chloro-6-phenyl-4,5-dihydropyridazin-3(2H)-one (1) theless, yields of the dehydrogenative product were
as the substrates and the results are shown in very low, possibly due to the steric effect. Finally, we
À
Scheme 1a. For compound 3, where the C-4 C-5 found that the ortho-Cl is not essential for the com-
bond has already been dehydrogenated to C=C bond, pletion of the dehydrogenation cycle, which means
no dechlorination products could be observed under the substrates such as 6-phenyl-4,5-dihydropyridazi-
our optimized conditions. Even when hydrosilanes none without chlorines on the 6-phenyl ring could
were added as extra hydrogen sources, only trace also be dehydrogenated by this catalytic system
amounts of dechlorination product could be observed. (Scheme 1c).
Adding other hydride sources (e.g., NaH, LiAlH4) did
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A Copper-Catalyzed Aerobic Cascade Dehydrogenative–Dehalogenative Reaction
Scheme 2. Proposed mechanism for the copper-catalyzed aerobic cascade dehydrogenative and dehalogenative reaction.
On the basis of the results obtained above, a plausi- Experimental Section
ble mechanism is illustrated in Scheme 2. In the first
step, the copper catalyst coordinates to the a-C of di- General Procedure
hydropyridazinone resulting in complex (A) with as-
sistance of the base. And then the b-H elimination is
To a 20-mL Schlenk tube were added halogenated dihydro-
pyridazinone (1.0 mmol), CuACHTNUGTRENUNG(OAc)2 (20.0 mg, 10 mol%),
continued and complex (A) is converted to (B) that
completes the formation of the C=C bond with gener-
ation of a copper(I) species. Consequently, complex
(C) is formed owing to the coordination between
copper species and N-1. Insertion of this copper spe-
Na2CO3 (312.0 mg, 2.0 mmol), pyridine (159.0 mg,
2.0 mmol), followed by addition of toluene (2.0 mL). The
mixture was heated at 1008C under O2 (1 atm) and stirred
12 h. On completion of the reaction, the products were puri-
fied by column chromatography on silica gel using mixtures
of petroleum ether and ethyl acetate (2:1) as the eluent. All
the results were measured as isolated yields.
À
cies into the C Cl bond forms the intermediate (D)
which might explain the selective dehalogenation of
the ortho-Cl of the 6-phenyl ring. Substitution of the
ortho-Cl by an H atom coordinated to copper results
in the product (2). Molecular oxygen plays a role as
the oxidant to trigger the circulation of the catalytic
Acknowledgements
process.[5,17] The detailed mechanism and the assign- This work was supported by the Beijing Natural Science
Foundation (Design, synthesis and optimization of protea-
some inhibitors as novel antitumor agents, 7112088), the Na-
tional Basic Research Program of China (2012CB518000),
and the National Natural Science Foundation of China
(21202003/21172012).
ment of the H replacing the ortho-Cl are now under
investigation in our laboratory.
In conclusion, a cascade dehydrogenative-dehaloge-
native reaction of halogenated 6-phenyl-4,5-dihydro-
pyridazin-3(2H)-ones to 6-phenylpyridazin-3
ACHTUNGTNER(NUNG 2H)-
ones has been developed. Moreover, the Cu(OAc)2/
AHCTUNGTRENNUNG
Na2CO3/pyridine catalytic system exhibits high reac-
tivity and selectivity with oxygen as the oxidant. Fur-
ther work to elucidate the detailed mechanism of this
reaction is underway and will be reported in due
course.
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