Palladium-catalyzed synthesis of phthalazinones: Efficient carbonylative coupling of 2-bromobenzaldehydes and hydrazines

Article abstract of DOI:10.1002/chem.201200267

Phthalazinones made easy! A new, straightforward methodology for the carbonylative synthesis of phthalazinones has been established. Starting from readily available 2-bromobenzaldehydes or 2-bromoacetophenone and hydrazines, a variety of phthalazinones have been produced in good isolated yields (see scheme). Copyright

Full text of DOI:10.1002/chem.201200267

COMMUNICATION
DOI: 10.1002/chem.201200267
Palladium-Catalyzed Synthesis of Phthalazinones: Efficient Carbonylative
Coupling of 2-Bromobenzaldehydes and Hydrazines
Xiao-Feng Wu,*[a, b] Helfried Neumann,[b] Stephan Neumann,[b] and Matthias Beller*[b]
Phthalazinones constitute an interesting family of bioac-
tive N-heterocycles.[1] Due to their diverse pharmacological
activities, selected derivatives are used in the treatment of
asthma, diabetes, hepatitis B, arrhythmia, and vascular hy-
pertension. In addition, certain phthalazinones show antimi-
crobial activity and represent potent inhibitors of poly(-
ADP-ribose)polymerase-1 (PARP-1). Selected examples of
phthalazinone-based drugs and potential drug candidates
are shown in Scheme 1.
original methodologies that avoid strongly basic or acidic re-
action conditions and allow for an efficient assembly of the
phthalazinone core from readily available starting materials.
To fulfil this goal, we became interested in the idea of
a domino sequence consisting of a palladium-catalyzed car-
bonylation of 2-halobenzaldehydes with hydrazines and
a subsequent condensation reaction (Scheme 2). In such an
approach, highly reactive N-(2-formylbenzoyl)hydrazones
would be formed in situ.
Scheme 2. A new approach towards phthalazinones.
Clearly, palladium complexes have been shown to be pow-
[3]
À
erful catalysts for many kinds of C C coupling reaction.
Numerous applications have been reported for the synthesis
of industrially relevant pharmaceuticals, agrochemicals, and
advanced materials. Of the different kinds of palladium-cat-
alyzed coupling reactions, carbonylation reactions allow for
the straightforward synthesis of aromatic and heteroaromat-
ic carboxylic acid derivatives.[4] By applying CO as an inex-
pensive C1 source with the assistance of a suitable palladi-
um catalyst, one or even two molecules of CO can be intro-
duced into the parent substrate. Interestingly, apart from
common alkoxy-, hydroxyl-, and aminocarbonylation reac-
tions, carbonylative coupling processes, such as Suzuki and
Sonogashira carbonylations, are also possible. These meth-
odologies give access to functionalized ketones that are
ready for further synthetic modifications.
Scheme 1. Selected examples of bioactive phthalazinones.
There is a continuing interest in the development of novel
synthetic methodologies for the preparation of phthalazi-
nones. More specifically, in the last decade various routes
based on cyclocondensation reactions, cycloadditions, reduc-
tions, and even biotechnological approaches have been re-
ported.[2] Despite these advances, there is still a need for
Based on our continuing interest in carbonylation reac-
tions[5] and the importance of phthalazinones, we describe
herein the first general and efficient palladium-catalyzed
synthesis of phthalazinones from commercially available 2-
bromobenzaldehydes, CO, and hydrazines.
[a] Dr. X.-F. Wu
The carbonylation of 2-bromobenzaldehyde with methyl-
hydrazine was investigated as a model reaction in the pres-
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou
ence of PdACTHNURGTNEUNG(OAc)2 and di-1-adamantyl-n-butylphosphine
Zhejiang Province, 310018 (P.R. China)
E-mail: xiao-feng.wu@catalysis.de
(BuPAd2, CataCXiumA). This catalyst system has proved to
be generally useful for various carbonylations and related
transformations. Initially, we reacted equimolar amounts of
2-bromobenzaldehyde with N-methylhydrazine in DMF
under CO (5 bar) at 1008C in the presence of different
amines and inorganic bases (Table 1, entries 1–6). The best
result (36% of the desired product) was obtained by apply-
[b] Dr. X.-F. Wu, Dr. H. Neumann, S. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢀt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200267.
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Table 1. Palladium-catalyzed carbonylative synthesis of N-methyl phtha-
tween 74–82% of the N-methyl phthalazinone were ob-
served by using 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (XantPhos), bis(2-diphenylphosphinophenyl)ether
lazinone: Optimization of the model reaction.[a]
(DPEphos),
and
1,1-bis(diphenylphosphino)ferrocene
(DPPF) as the ligand (Table 1, entries 20, 22–23). It should
be noted that apart from the desired product, dehalogena-
tion of 2-bromobenzaldehyde was observed in some cases,
and resulted in the formation of 1-benzylidene-2-methylhy-
drazine.
Based on our experiments and other previously reported
noncarbonylative cyclizations,[6] a possible reaction mecha-
nism is proposed in Scheme 3. The reaction starts with the
Entry
Ligand
Solvent
Base
NEt3
Additive
Yield [%][b]
[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
PPh3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
dioxane
toluene
heptane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
–
–
–
–
–
–
–
–
–
–
–
–
–
0
0
2
36
7
TMEDA[d]
DiPEA[c]
DBU[d]
[c]
K2CO3
K3PO4
[d]
10
21[e]
37[e]
21[e]
18[e]
24[e]
9[e]
52
61
60
46
70
52
0
82
48
74
76
29
69
63
54
66
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
DBU[d]
[d]
MgSO4
Na2SO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
[d]
[c]
[d]
[d]
PCy3
[d]
P
N
[d]
DPPF
[d]
DtBPF
XantPhos
DPEphos
BINAP
Diop
DPPB
DPPP
DPPE
[d]
[d]
[d]
[d]
Scheme 3. Proposed reaction mechanism.
[d]
[d]
[d]
condensation of the hydrazine and the aldehyde group, at
a lower temperature, to give A. Oxidative addition of the in
situ generated active Pd0 complex to A results in the aryl-
palladium complex B. After the coordination and insertion
of carbon monoxide, the acylpalladium complex C is pro-
duced. Next, either nucleophilic substitution and reductive
elimination or direct nucleophilic attack on the carbonyl
group gives the terminal product and the active Pd0 species
for the next catalytic cycle.
With suitable conditions for the model reaction in hand
(Table 1, entry 20), a large variety of substrates was investi-
gated for our protocol. As shown in Table 2, 20 examples of
different phthalazinones were isolated in moderate to good
yields (60–85%). In addition to simple alkylhydrazines (1),
arylhydrazines with electron-donating and -withdrawing sub-
stituents (2–6) were successfully applied in the reaction with
2-bromobenzaldehyde to give 60–80% yields of the corre-
sponding heterocycles (Table 2, entries 1–6).
Moreover, the reaction tolerates 2-bromobenzaldehyde
reagents with different electronic properties, and the corre-
sponding phthalazinone products were isolated in good
yields (Table 2, entries 7–19). Finally, we demonstrated that
in addition to 2-bromobenzaldehydes, 2-bromoacetophe-
none can also be successfully applied in this methodology,
and 2,4-dimethylphthalazinone was synthesized in 71%
yield in a straightforward manner (Table 2, entry 20).
MgSO4
[a] PdACHTUNGTRENNUNG(OAc)2 (2 mol%), ligand (6 mol% in the case of monodentate, and
2 mol% in the case of bidentate ligands), solvent (2 mL), base, 2-bromo-
benzaldehyde (1 mmol), methylhydrazine (1 mmol), CO (10 bar), 1008C,
16 h. TMEDA=N,N,N’,N’-tetramethylethylenediamine, DiPEA=N,N-
diisopropylethylamine, NMP=N-methylpyrrolidinone, Cy=cyclohexyl,
DtBPF=[1,1’-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II),
BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthalene, Diop=2,3-O-
isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, DPPB=
1,4-(diphenylphosphino)butane, DPPP=1,3-bis(diphenylphosphino)pro-
pane, DPPE=1,2-bis(diphenylphosphino)ethane. [b] GC yield, deter-
mined by GC using hexadecane as the internal standard, based on 2-bro-
mobenzaldehyde. [c] 2 mmol of base or additive were added. [d] 1 mmol
of base or additive was added. [e] 1108C.
ing 1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) as the base
(Table 1, entry 4). The investigation of six different solvents
demonstrated that DMSO was optimal for this sequential
carbonylation reaction and gave 52% of the product at
1008C (Table 1, entry 13).
To improve the condensation step in the domino se-
quence, MgSO4 and Na2SO4 were tested as additives, and
slightly improved yields of the corresponding phthalazinones
were obtained (Table 1, entries 14 and 15; 60–61%). Nota-
bly, an excess of MgSO4 decreased the product yield to only
46% (Table 1, entry 16).
Next, we explored the influence of 13 different mono-
and bidentate phosphorus ligands (Table 1, entries 17–28).
In general, electron-rich and bulky ligands resulted in low
yields of the product. On the other hand, good yields be-
In conclusion, a general and straightforward methodology
for the carbonylative synthesis of pharmacologically inter-
esting phthalazinones has been established by using com-
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Palladium-Catalyzed Synthesis of Phthalazinones
COMMUNICATION
Table 2. Palladium-catalyzed carbonylative synthesis of phthalazinones.[a]
Entry Aryl halide
1
Hydrazine Product
Yield [%][b] Entry Aryl halide
Hydrazine Product
Yield [%][b]
80
1
80
67
11
12
1
2
3
2
3
1
1
82
85
65
13
4
5
6
4
5
6
60
71
73
14
15
16
2
2
2
75
79
81
7
8
1
1
69
74
17
18
2
2
82
78
9
1
1
70
75
19
20
2
1
85
71
10
[a] PdACHTUNGTRENNUNG(OAc)2 (2 mol%), DPPF (2 mol%), DMSO (2 mL), DBU (1 mmol), 2-bromobenzaldehydes (1 mmol), hydrazine (1 mmol), CO (10 bar), MgSO4
(1 mmol), 1008C, 16 h. [b] Isolated yield.
mercially available palladium catalysts. Starting from readily
accessible 2-bromobenzaldehydes or 2-bromoacetophenone
and hydrazines, twenty different phthalazinones were syn-
thesized in moderate to good isolated yields (60-85%).
(1 mmol), and DBU (1 mmol) were injected by syringe. The vial (or sev-
eral vials) was (were) placed on an alloy plate and transferred into an au-
toclave (300 mL; 4560 series from Parr Instruments) under an argon at-
mosphere. After flushing the autoclave three times with CO and adjust-
ing the pressure to 10 bar, the reaction was performed for 16 h at 1008C.
After this time, the autoclave was cooled to room temperature and the
pressure was released carefully. The cooled mixture was partitioned be-
tween ethyl acetate and saturated NH4Cl; the organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. After evapora-
tion of the organic solvent, the residue was adsorbed on silica gel and pu-
rified by column chromatography using n-heptane/AcOEt (4:1) as the
eluent.
Experimental Section
General procedure:
A vial (12 mL) was charged with PdACHTNUTGNRUEGN(OAc)2
(2 mol%), DPPF (2 mol%), MgSO4 (1 mmol) and a stirring bar. Then
DMSO (2 mL), 2-bromobenzaldehyde (1 mmol), methyl hydrazine
Chem. Eur. J. 2012, 00, 0 – 0
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Acknowledgements
The authors thank the state of Mecklenburg–Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial support.
We also thank Dr. W. Baumann and Dr. C. Fischer (all LIKAT) for ana-
lytical support.
Keywords: carbonylation
palladium · phthalazinones
· heterocycles · hydrazines ·
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Received: January 25, 2012
Revised: April 29, 2012
Published online: && &&, 0000
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Palladium-Catalyzed Synthesis of Phthalazinones
COMMUNICATION
Carbonylation
X.-F. Wu,* H. Neumann, S. Neumann,
M. Beller* ..................... &&&& — &&&&
Palladium-Catalyzed Synthesis of
Phthalazinones: Efficient Carbonyla-
tive Coupling of 2-Bromobenzalde-
hydes and Hydrazines
Phthalazinones made easy! A new,
straightforward methodology for the
carbonylative synthesis of phthalazi-
nones has been established. Starting
from readily available 2-bromobenzal-
dehydes or 2-bromoacetophenone and
hydrazines, a variety of phthalazinones
have been produced in good isolated
yields (see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!