Access to phthalazinones via palladium-catalyzed three-component cycloamino-carbonylation of 2-formylaryl tosylates, hydrazines and CO

Article abstract of DOI:10.1016/j.tet.2016.10.065

The palladium-catalyzed three-component cycloaminocarbonylation of 2-formylaryl tosylates with hydrazines and carbon monoxide has been established, which provides an efficient method for synthesis of substituted phthalazinones. In addition, by applying this protocol as the key step, Hydralazine can easily be synthesized in 65% yield.

Full text of DOI:10.1016/j.tet.2016.10.065

Accepted Manuscript
Access to phthalazinones via palladium-catalyzed three-component cycloamino-
carbonylation of 2-formylaryl tosylates, hydrazines and CO
Bin Liu, Chunlei Zhang, Xigeng Zhou
PII:
S0040-4020(16)31124-3
10.1016/j.tet.2016.10.065
TET 28206
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 August 2016
Revised Date: 22 October 2016
Accepted Date: 25 October 2016
Please cite this article as: Liu B, Zhang C, Zhou X, Access to phthalazinones via palladium-catalyzed
three-component cycloamino-carbonylation of 2-formylaryl tosylates, hydrazines and CO, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.10.065.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Access to Phthalazinones via Palladium-
Catalyzed Three-Component Cycloamino-
carbonylation of 2-Formylaryl Tosylates,
Hydrazines and CO
Leave this area blank for abstract info.
Bin Liu,a,b Chunlei Zhang,b * and Xigeng Zhoua *
aDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan
University, Shanghai 200433, People’s Republic of China
bTechnology Research Insititute of Shanghai Huayi (Group) Company, Shanghai 200241, People’s Republic of
China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Access to Phthalazinones via Palladium-Catalyzed Three-Component
Cycloaminocarbonylation of 2-Formylaryl TosylatesꢀHydrazines and CO
Bin Liu,a,b Chunlei Zhang,b, and Xigeng Zhoua,
aDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, People’s Republic
of China
bTechnology Research Insititute of Shanghai Huayi (Group) Company, Shanghai 200241, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The palladium-catalyzed three-component cycloaminocarbonylation of 2-formylaryl tosylates
with hydrazines and carbon monoxide has been established, which provides an efficient method
for synthesis of substituted phthalazinones. In addition, by applying this protocol as the key step,
Hydralazine can easily be synthesized in 65% yield.
Available online
Keywords:
Palladium
2009 Elsevier Ltd. All rights reserved
.
Cycloaminocarbonylation
C-O bond activation
2-Formylaryl tosylates
Phthalazinones
Introduction
Phthalazinones are important structural units of a vast array
of naturally occurring and active molecules such as Azelastine,1
PARP-1 inhibitor,2 and PDE-4 inhibitor.3 Many phthalazinone-
based polymers4 exhibit interesting properties for extensive
applications. Furthermore, such type of heterocycles are also
valuable intermediates in organic synthesis.5 Therefore,
development of new methods for synthesis of phthalazinones and
new phthalazinone derivatives is of broad interest.
Since the first work by Heck and co-workers in 1974,6
palladium-catalyzed aminocarbonylation has become a powerful
tool for the construction of the amide moiety in organic
synthesis.7 In 2012, Beller and co-workers reported the synthesis
of
phthalazinone
derivatives
via
Pd-catalyzed
Scheme 1. Comparison of metal-catalyzed cycloamino-
carbonylations for synthesis of phthalazinones.
cycloaminocarbonylation of o-halobenzaldehydes and hydrazines
using CO as a carbonyl source.8a More recently, the synthetic
routes to phthalazinones using Mo(CO)68b, and Co2(CO)8 as the
8c
2-Formylaryl tosylates are lower toxic and cheaper than the
corresponding o-halobenzaldehydes, replacement of aryl halides
with aryl tosylates would make chemical processes more
environmental tolerance by reducing the production of halide-
containing wastes.10 Inspired by our previous work on the
palladium-catalyzed cycloaminocarbonylation of 2-aminomethyl
and 2-alkylcarbamoylaryl tosylates with CO,11 we become
interested in the synthesis of functionalized phthalazinones from
2-formylaryl tosylates that are readily prepared from
carbonyl source were also described (Scheme 1, eq. (1)). In
2015, Deng and co-workers developed the palladium-catalyzed
carbonylative coupling reaction of 2-halomethyl benzoates and
aryl hydrazines using paraformaldehyde as the carbon source via
methyl 2-formylbenzoate intermediates (Scheme l, eq. (2)).9
———
Corresponding author. Tel.: (+86)-21-6564-3769; (+86)-21-6564-3769; e-mail: xgzhou@fudan.edu.cn (X. Zhou).

2
Tetrahedron
salicylaldehydes. Herein, we report our results on the
18
Pd(TFA) (5)
trace
29
ACCEPTED MANUSCRIPT
2
DBU (1.2)
DBU (1.2)
DBU (1.2)
development of a practical process for the multicomponent
carbonylative synthesis of phthalazinones from 2-formylaryl
tosylates, hydrazines and CO as well as its application in
synthesis of Hydralazine.
19e
Pd(TFA)2 (5)
Pd(TFA)2 (5)
dppp (10)
dppp (10)
20f
41
a
Conditions: 2-formylaryl tosylate (2 mmol), PhNHNH2 (2 mmol),
anhydrous MgSO4 (2 mmol), CO (1.0 MPa), catalyst, ligand, base, CH3CN,
Results and discussion
c
e
140 oC, 21 h. b Isolated yield. DMSO as solvent. d Toluene as solvent.
f
Without the use of anhydrous MgSO4. Anhydrous MgSO4 was replaced by
4 Å molecular sieves (240 mg).
We initiated our research on the model reaction of 2-
formylaryl tosylate (1a), phenylhydrazine (2a) and CO under
different reaction conditions (Table 1). We firstly elected to
employ Pd(OAc)2 as the catalyst. Screening several different
phosphine ligands such as 1,3-bis(diphenylphosphino)propane
With the optimum reaction conditions in hand, we
subsequently explored the scope of the reaction to various 2-
formylaryl tosylates and hydrazines. As shown in Table 2,
hydrazines bearing various electron-rich or -deficient aryl
substituents at the nitrogen atom were appropriate substrates for
this methodology, and the corresponding substituted
phthalazinones were obtained in satisfactory yields (Table 2,
entries 1-13). The position of substituents on the benzene ring
arylhydrazines slightly influenced the cyclization. p-
Fluorophenylhydrazine gave a higher yield than its o- and m-
analogues (Table 2, entries 2-4). It is well-known that C-Cl
bonds are generally more reactive than C-O bonds in metal-
mediated transformations of carbon-heteroatom bonds via
oxidative/reductive mechanism.12 Significantly, phthalazinones
bearing chlorine substituent in aryl ring were also obtained in
62 % and 60 % yields (Table 2, entries 5-6).
(dppp),
(Xantphos), 1,3-bis(diphenylphosphino)ferrocene (dppf), 1,3-
bis(diphenylphosphino)ethane (dppe) and 1,3-
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
bis(diphenylphosphino)butane (dppb) (Table 1, entries 1-5), it
was found that dppp gave the best result with 43 % yield (Table 1,
entry 1). Then, other Pd catalysts were examined (Table 1,
entries 7-8). Pd(TFA)2 showed a higher catalytic activity
compared to Pd(OAc)2. Among the bases tested, DBU gave the
most promising results (Table 1, entries 9-11). Other solvents,
such as DMSO and toluene, were less effective (Table 1, entries
12-13). No significant improvement on the yield appeared when
the larger amount of Pd(TFA)2 loading was used (Table 1, entry
14). Using smaller amount of dppp, Pd(TFA)2 or anhydrous
MgSO4 led to a decrease of yields (Table 1, entries 15-19).
Replacing anhydrous MgSO4 with 4 Å molecular sieves resulted
in a significant drop of yield (Table 1, entry 20).
The effect of the substituents on the arene ring of 2-formylaryl
tosylates is also examined. In general, the presence of substituent
such as 4-methyl, 5-NEt2, 5-MeO, 4-MeO, or 4-F on the benzene
ring of 2-formylaryl tosylates has a slightly negative impact on
the catalytic reaction, leading to the formation of the desirable
products in relatively lower yields (Table 2, entries 14-23).
Surprisingly, replacement of hydrazines with hydroxylamine
hydrochloride gave no desired carbonylative product; instead, 2-
hydroxybenzonitrile was obtained in 50% yield (Table 2, entry
24). Significantly, NH2NHBoc reacted with 2-formylphenyl
tosylate and CO, giving the deprotected phthalazin-1(2H)-one
(3y) in 68% yield (Table 2, entry 25).
Table 1. Catalyst, Ligand, Base, and Solvent Effectsa
CHO
[Pd], Ligand, CO
Base, Solvent
N
N
+
PhNHNH2
Ph
OTs
O
2a
1a
3a
Catalyst (amount,
mol%)
Ligand (amount,
mol%)
Base
Yield
(%)b
Entry
(amount, eq)
1
2
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
Pd(PhCN)2Cl2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (10)
Pd(TFA)2 (5)
Pd(TFA)2 (3)
dppp (10)
Xantphos (10)
dppf (10)
dppe (10)
dppb (10)
dppp (15)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (5)
K2CO3 (1.2)
43
trace
15
Table 2. Cycloaminocarbonylation of 2-aminomethylaryl
tosylates, hydrazines and CO a
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
Cs2CO3 (1.2)
Na2CO3 (1.2)
DBU (1.2)
3
4
8
5
trace
46
Yield
6
Entry
1
Substrate
Product
(%)b
7
65
8
46
70
9
trace
58
10
11
12c
13d
14
15
16
17
2
3
4
75 c
60 c
65 c
70
DBU (1.2)
54
trace
71
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
60
dppp (5)
48
dppp (10)
trace

3
N
N
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5
6
7
62 c
21
38 c
3e
O
Cl
MeO
60 c
N
N
22
45
3v
O
50 c
23
25 c
8
9
40 c
24
50 d,e
72 c
68 d,f
25
10
67 c
a Conditions: 2-formylaryl tosylate (2 mmol), hydrazine derivative (2 mmol),
Pd(TFA)2 (5 mol%), dppp (10 mol%), DBU (1.2 eq), anhydrous MgSO4 (2
b
c
mmol), CH3CN (30 ml), CO (1.0 MPa), 140 oC, 21 h. Isolated yield.
Hydrazine hydrochloride derivative (2 mmol), 150 oC, base (2.2 eq). d K2CO3
(2.2 eq). e H2NOH HCl (1 eq). f H2NNHBoc (1 eq).
11
60 c
Hydralazine (4) is an important antihypertensive agent.13a
Recently, many new pharmacological properties of hydralazine
derivatives, such as inhibiting malaria parasite and plasmodium
12
13
14
15
16
17
68 c
50
falciparum13b
,
recovering
ischemic
hepatitis13c
and
antituberculous13d are also discovered. Currently, hydralazine and
their derivatives are primarily prepared from phthalazin-1(2H)-
one (3y).13,14 Several methods to synthesize phthalazin-1(2H)-one
using 2-formylbenzoic acid15, isobenzofuran-1(3H)-one14,
phthalazine16 or 2-(2-bromoethyl)isoindoline-1,3-dione17 as the
raw materials have been reported in the literatures. Having
successfully developed a new route to phthalazin-1(2H)-one, we
finally turned our attention to the application of this method to
synthesis of Hydralazine, which is easily functionalized.
Treatment of 3y with POCl3 followed by reacting with hydrazine
hydrate at refluxing temperature and sequential quenching with
15% hydrochloric acid allowed the isolation of hydralazine in
65% yield (Scheme 2).
50
47 c
49 c
41
Scheme 2. Synthesis of Hydralazine (antihypertensive agent).
Based on our results and other previously reported work on
carbonylative cyclizations of 2-bromobenzaldehyde or aryl
sulfonate,8a,12b,18 a possible mechanism for synthesis of 3 is
proposed in Scheme 3. The condensation of aldehyde with
hydrazine gives the imine intermediate A. Then, oxidative
addition of the in situ generated Pd0 species with A leads to the
formation of the key aryl palladium complex B, which undergoes
the CO insertion into a Pd-C bond to afford the aroyl complex C.
The intramolecular substitution of OTs ligand by hydrazinate
would give intermediate D. Finally, the reductive elimination
forms the cycloaminocarbonylation product and regenerates the
active Pd0 species for the next catalytic cycle. Consistent with
this suggestion, a 13CO(g) labeling reaction gave the desirable
[13C]-2-Phenylphthalazin-1(2H)-one (3a*) in complete selectivity.
18
44 c
19
20
42 c
42

4
Tetrahedron
ACCEPTED MANUSCRIPT
o
1
Yellow solid; mp 159.9 C; H NMR (CDCl3, 400 MHz): δ
8.48 (d, J = 8.3 Hz, 1H), 8.28 (s, 1H), 7.80-7.90 (m, 2H), 7.76 (d,
J = 7.6 Hz, 1H), 7.46-7.52 (m, 1H), 6.97-7.04 (m, 2H). 13C NMR
(CDCl3, 100 MHz): δ 162.5 (dd, JCF = 250, 10.7 Hz), 158.9,
157.5 (dd, JCF = 253, 12.5 Hz), 139.1, 133.8, 132.2, 129.7 (d, JCF
=10.0 Hz), 129.5, 127.8, 127.0, 126.3, 125.8 (d, JCF = 3.6 Hz),
114.7 (dd, JCF = 22.2, 3.5 Hz) 104.8 (dd, JCF = 26.2, 23.7 Hz).
HRMS (ESI) Calcd for C14H9F2N2O [M+H]+: 259.0683; Found:
259.0679.
6-Methyl-2-phenylphthalazin-1(2H)-one (3n)
Brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.39 (d, J = 8.1 Hz,
1H), 8.23 (s, 1H), 7.40-7.66 (m, 6H), 7.36-7.42 (m, 1H), 2.57 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 159.3, 144.5, 141.8, 138.5,
133.5, 129.6, 128.7, 127.7, 127.1, 126.1, 125.8, 125.7, 21.9.
HRMS (ESI) Calcd for C15H13N2O [M+H]+: 237.1028; Found:
237.1033.
Scheme 3. Proposed mechanism for the formation of substituted
phthalazinones
.
2-(4-Methoxyphenyl)-6-methylphthalazin-1(2H)-one (3o)
Brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.37 (d, J = 8.2 Hz,
1H), 8.20 (s, 1H), 7.61 (dd, J = 8.2, 1.1Hz, 1H), 7.51-7.56 (m,
2H), 7.51 (s, 1H), 6.97-7.00 (m, 2H), 3.84 (s, 3H), 2.56 (s, 3H).
13C NMR (CDCl3, 100 MHz): δ 159.4, 158.8, 144.3, 138.3, 135.0,
133.4, 129.7, 127.1, 126.9, 126.2, 125.8, 113.9, 55.5, 21.8.
HRMS (ESI) Calcd for C16H15N2O2 [M+H]+: 267.1134; Found:
267.1146.
In summary, we have developed an efficient and versatile
method for preparation of phthalazinone derivatives via the Pd-
catalyzed cycloaminocarbonylation of 2-formylaryl tosylates,
hydrazines and CO. The easy synthesis of 2-formylaryl tosylates
from cheap salicylaldehyde and their low toxicity makes them an
attractive and practical alternative to commonly used o-
halobenzaldehyde as counterparts in aminocarbonylation
protocols. Further investigations on the synthetic applications of
this method are underway in our lab.
2-(4-Fluorophenyl)-6-methylphthalazin-1(2H)-one (3p)
o
1
White solid; mp 177.0 C; H NMR (CDCl3, 400 MHz): δ
8.38 (d, J = 8.2 Hz, 1H), 8.21 (s, 1H), 7.62-7.66 (m, 3H), 7.53 (s,
1H), 7.14-7.20 (m, 2H), 2.57 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 161.6 (d, JCF = 245 Hz), 159.2, 144.6, 138.5, 137.9,
133.5, 129.6, 127.5 (d, JCF =8.5 Hz), 127.2, 126.2, 125.9, 115.5
(d, JCF = 23 Hz), 21.9. HRMS (ESI) Calcd for C15H12FN2O
[M+H]+: 255.0934; Found: 255.0947.
Experimental Section
General
procedure
for
the
Pd-catalyzed
cycloaminocarbonylation of 2-formylaryl tosylate, hydrazine
and CO.
2-Formylaryl tosylate (2 mmol), hydrazine (2 mmol),
Pd(TFA)2 (5 mol%), dppp (10 mol%), DBU (2.4 mmol),
anhydrous MgSO4 (2 mmol) and CH3CN (30 ml) were charged in
a 200 ml-autoclave. The autoclave was flushed using CO three
times. The mixture was pressurized with CO to 1.0 MPa, and
7-(Diethylamino)-2-phenylphthalazin-1(2H)-one (3q)
o
1
Brown solid; mp 148.7 C; H NMR (CDCl3, 400 MHz): δ
8.09 (s, 1H), 7.64 – 7.68 (m, 2H), 7.55-7.57 (m, 2H), 7.44-7.48
(m, 2H), 7.33-7.38 (m, 1H), 7.12 (dd, J = 8.9, 2.7 Hz, 1H), 3.51
(q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3,
100 MHz): δ 159.6, 150.4, 142.5, 138.5, 130.3, 128.6, 128.0,
127.3, 125.9, 118.6, 117.6, 105.6, 44.7, 12.4. HRMS (ESI) Calcd
for C18H20N3O [M+H]+: 294.1606; Found: 294.1628.
o
stirred at 140 C for 21 h. Then, the mixture was cooled to room
temperature and the excess CO was vented. Solvent was removed
under reduced pressure and the crude residue was purified by
column chromatography on silica gel with petroleum ether-ethyl
acetate as the eluent to afford the desired product.
7-(Diethylamino)-2-(4-methoxyphenyl)phthalazin-1(2H)-one
(3r)
[13C]-2-Phenylphthalazin-1(2H)-one (3a*)
o
1
1
Brown solid; mp 100.8 C; H NMR (CDCl3, 400 MHz): δ
8.48-8.55 (m, 1H), 8.30 (s, 1H), 7.78-7.89 (m, 2H), 7.75 (d, J =
7.7 Hz, 1H), 7.64-7.67 (m, 2H), 7.47-7.52 (m, 2H), 7.37-7.41 (m,
1H). 13C NMR (CDCl3, 100 MHz): δ 159.2 (13C-enriched), 141.8,
138.5 (d, J = 6.1 Hz), 133.5, 131.9 (d, J = 3.4 Hz), 129.5, 128.8,
128.2, 127.8, 127.2, 126.1 (d, J = 2.4 Hz), 125.7. HRMS (ESI)
Calcd for C1313CH11N2O [M+H]+: 224.0905; Found: 224.0898.
Brown oil; H NMR (CDCl3, 400 MHz): δ 8.07 (s, 1H), 7.56
(d, J = 8.9 Hz, 4H), 7.11 (dd, J = 8.8, 2.6 Hz, 1H), 6.96-7.00 (m,
2H), 3.85 (s, 3H), 3.51 (q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz,
6H). 13C NMR (CDCl3, 100 MHz): δ 159.7, 158.5, 150.2, 138.4,
135.6, 130.2, 128.0, 127.0, 118.6, 117.5, 113.8, 105.4, 55.5, 44.7,
12.3. HRMS (ESI) Calcd for C19H22N3O2 [M+H]+: 324.1712;
Found: 324.1724.
7-(Diethylamino)-2-(4-fluorophenyl)phthalazin-1(2H)-one (3s)
2-(3-Fluorophenyl)phthalazin-1(2H)-one (3c)
Brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.06 (s, 1H), 7.62-
7.66 (m, 2H), 7.53-7.56 (m, 2H), 7.10-7.16 (m, 3H), 3.50 (q, J =
7.1 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3, 100
MHz): δ 161.4 (d, JCF = 245 Hz), 159.6, 150.4, 138.6, 138.4 (d,
JCF = 2.8 Hz), 130.1, 128.0, 127.6 (d, JCF = 8.5 Hz), 118.4, 117.6,
115.3 (d, JCF = 23 Hz), 105.4, 44.6, 12.2. HRMS (ESI) Calcd for
C18H19FN3O [M+H]+: 312.1512; Found: 312.1519.
o
1
White solid; mp 104.1 C; H NMR (CDCl3, 400 MHz): δ
8.49 (d, J = 7.6 Hz, 1H), 8.28 (s, 1H), 7.76-7.93 (m, 2H), 7.74 (d,
J = 8.1 Hz, 1H), 7.41-7.53 (m, 3H), 7.08 (td, J = 8.3, 2.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz): δ 162.4 (d, JCF = 244 Hz), 159.0,
143.0 (d, JCF = 9.9 Hz), 138.7, 133.6, 132.1, 129.7 (d, JCF = 8.8
Hz), 129.3, 128.3, 127.2, 126.2, 121.1 (d, JCF = 2.9 Hz), 114.5 (d,
JCF = 20.0 Hz), 113.2 (d, JCF = 24.7 Hz). HRMS (ESI) Calcd for
C14H10FN2O [M+H]+: 241.0777; Found: 241.0775.
2-(4-Fluorophenyl)-7-methoxyphthalazin-1(2H)-one (3u)
o
1
Yellow solid; mp 167.9 C; H NMR (CDCl3, 400 MHz): δ
8.21 (s, 1H), 7.86 (s, 1H), 7.62-7.69 (m, 3H), 7.40 (dd, J = 8.2,
2-(2,4-Difluorophenyl)phthalazin-1(2H)-one (3g)

5
2.0 Hz, 1H), 7.15-7.24 (m, 2H), 3.98 (s, 3H). 13C NMR (CDCl3,
8.
(a) Wu, X. -F.; Neumann, H.; Neumann, S.; Beller, M. Chem.
ACCEPTED MANUSCRIPT
Eur. J. 2012, 18, 8596-8599; (b) Rao, K. P.; Basak, A. K.; Deb, P.
K.; Sharma, S.; Reddy, L. K. Tetrahedron Lett. 2013, 54, 3694-
3696; (c) Suresh, A. S.; Baburajan, P.; Ahmed, M. Tetrahedron
Lett. 2014, 55, 3482-3485.
Wang, H.; Cai, J.; Huang, H.; Deng, G. -J. Org. Lett. 2014, 16,
5324-5327.
100 MHz): δ 162.7, 161.6 (d, JCF = 245 Hz), 159.1, 138.2, 130.4,
128.1, 127.5 (d, JCF =8.7 Hz), 123.7, 123.5, 122.9, 115.5 (d, JCF
=
22.7 Hz), 107.2, 56.0. HRMS (ESI) Calcd for C15H12FN2O2
[M+H]+: 271.0883; Found: 271.0895.
9.
6-Fluoro-2-(4-methoxyphenyl)phthalazin-1(2H)-one (3w)
10. (a) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754–2755; (b) Li, B.-J.; Yu, D.-G.; Sun, C.-L.;
Shi, Z.-J. Chem. Eur. J. 2011, 17, 1728-1759; (c) Reeves, D. C.;
Rodriguez, S.; Lee, H.; Haddad, N.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2011, 13, 2495–2497; (d) Ueda, T.;
Konishi, H.; Manabe, K. Tetrahedron Lett. 2012, 53, 5171-5175;
(e) Chung, S.; Sach, N.; Choi, C.; Yang, X.; Drozda, S. E.; Singer,
R. A.; Wright, S. W. Org. Lett. 2015, 17, 2848-2851; (f) Fu, W.
C.; So, C. M.; Yuen, O. Y.; Lee, I. T. C.; Kwong, F. Y. Org. Lett.
2016, 18, 1872-1875.
Gray solid; mp 189.1 oC; 1H NMR (CDCl3, 400 MHz): δ 8.50-
8.54 (m, 1H), 8.22 (s, 1H), 7.47-7.55 (m, 3H), 7.38 (dd, J = 8.1,
2.4 Hz, 1H), 6.96-7.02 (m, 2H), 3.86 (s, 3H). 13C NMR (CDCl3,
100 MHz): δ 165.5 (d, JCF = 254 Hz), 159.0, 158.6, 137.2, 134.6,
134.4, 131.6 (d, JCF = 9.4 Hz), 130.7 (d, JCF = 9.6 Hz), 126.9,
120.5 (d, JCF = 23.3 Hz), 114.0, 111.2 (d, JCF = 21.9 Hz), 55.5.
HRMS (ESI) Calcd for C15H12FN2O2 [M+H]+: 271.0883; Found:
271.0887.
11.
Liu, B.; Wang, Y.; Liao, B.; Zhang, C.; Zhou, X. Tetrahedron
Lett. 2015, 56, 5776-5780.
Hydralazine hydrochloride (4)
12. (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818-11819; (b) Kozhushkov, S. I.; Potukuchi, H. K.;
Ackermann, L. Catal. Sci. Technol. 2013, 3, 562-571; (c) Zhang,
Y.; Lavigne, G.; Cesar, V. J. Org. Chem. 2015, 80, 7666-7673.
13. (a) Nelson, D. J. U.S. Patent 20050137397, 2005; Chem. Abstr.
2005, 143, 78195; (b) Gowtham, S.; C. P. Babu R.; Chakrabhavi,
D. M.; Ameya, S.; Trang T. T. C.; Sebastian, A.; Huang, X.; Julian,
E. F.; Andreas, B.; Kanchugarakoppal, S. R.; Rajesh, C.; Basappa,
Bioorg. Med. Chem. Lett. 2016, 26, 3300–3306; (c) Ahmed MD,
A.; Luis MD, Q.; Noella MD, B. Am. J. Ther. 2016, 23, 1094-
1095; (d) Veau, D.; Krykun, S.; Mori, G.; Orena, B. S.; Pasca, M.
R.; Frongia, C.; Lobjois, V.; Chassaing, S.; Lherbet, C.; Baltas, M.
Chemmedchem 2016, 11, 1078-1089.
14. Zhao, B. -H.; Lin, J. -M. Chin. J. Org. Chem. 2011, 31, 1914-1916.
15. (a) Outerbridge, V. M.; Landge, S. M.; Tamaki, H.; Torok, B.
Synthesis 2009, 11, 1801-1806; (b) Shi, L.; Hu, L.; Wang, J.; Cao,
X.; Gu, H. Org. Lett. 2012, 14, 1876-1879; (c) Wang, Y.; Yang, Z.
-Y.; Wang, Q.; Cai, Q. -K.; Yu, K. -B. J. Organomet. Chem. 2005,
690, 4557-4563.
Pale yellow solid; mp 277.0 oC (Lit.[14] 272-274 oC); 1H NMR
(D2O, 400 MHz): δ 8.61 (s, 1H), 8.01-8.09 (m, 2H), 7.94-8.01 (m,
2H). 13C NMR (D2O, 100 MHz): 152.4, 144.9, 136.6, 134.7,
128.9, 127.6, 123.5, 118.6. HRMS (ESI) Calcd for C8H9N4 [M-
Cl]+: 161.0827; Found: 161.0822.
Acknowledgements
We thank the National Natural Science Foundation of China,
973 program (2015CB856600) and the Research Fund for the
Doctoral Program of Higher Education of China
(2013007113009) for financial support.
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