Regioselective Synthesis of Substituted 4-Alkylamino and 4-Arylaminophthalazin-1(2 H)-ones

Article abstract of DOI:10.1021/acs.joc.5b02652

(Chemical Equation Presented). An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1(1H)-ones 5 is described. This new method features the formation of substituted phthalazin-1(1H)-ones 3 by the reaction of 2-formylbenzoic acids 1 or 3-hydroxyisobenzofuran-1(3H)-ones 2 with hydrazine to generate phthalazin-1(2H)-ones 3. Subsequent regioselective bromination of phthalazin-1(2H)-ones 3 with benzyltrimethylammonium tribromide (BTMA-Br₃) followed by mixed copper-copper oxide-catalyzed amination of 4-bromophthalazin-1(2H)-ones 4 with primary amines generates aminophthalazin-1(2H)-ones in good overall yields.

Full text of DOI:10.1021/acs.joc.5b02652

Article
pubs.acs.org/joc
Regioselective Synthesis of Substituted 4‑Alkylamino and
4‑Arylaminophthalazin-1(2H)‑ones
Subramaniam Krishnananthan,*,† Daniel Smith,† Dauh-Rurng Wu,† Shiuhang Yip,† Prashantha Gunaga,‡
Arvind Mathur,† and Jianqing Li*,†
†Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, PO Box 4000, Princeton, New Jersey
08543-4000, United States
‡Biocon Bristol-Myers Squibb R&D Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India
S
* Supporting Information
ABSTRACT: An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1(1H)-ones 5 is
described. This new method features the formation of substituted phthalazin-1(1H)-ones 3 by the reaction of 2-formylbenzoic
acids 1 or 3-hydroxyisobenzofuran-1(3H)-ones 2 with hydrazine to generate phthalazin-1(2H)-ones 3. Subsequent regioselective
bromination of phthalazin-1(2H)-ones 3 with benzyltrimethylammonium tribromide (BTMA-Br3) followed by mixed copper−
copper oxide-catalyzed amination of 4-bromophthalazin-1(2H)-ones 4 with primary amines generates aminophthalazin-1(2H)-
ones in good overall yields.
thalazine derivatives. To overcome these limitations, Orru and
co-workers recently reported the multicomponent synthesis of
4-aminophthalazin-1(2H)-ones via palladium-catalyzed isocya-
nide insertion, which allowed regioselective introduction of
substituents; however, only tertiary-substituted isocyanides
were used.8
INTRODUCTION
■
Phthalazine derivatives are a class of attractive heterocycles
found to be potentially useful to treat many diseases, for
instance, Carbazeran for congestive heart failure,1 Vatanalib as a
tyrosine kinase inhibitor of angiogenesis,2 Zopolrestat as a
potent aldose reductase inhibitor for chronic diabetes,3 p38
MAP kinase inhibitor for inflammatory disease,4 and Aurora-A
kinase inhibitors as antitumor agents5 (Figure 1).
Despite interest in the pharmaceutical industry, the reported
synthetic methods for the substituted and functionalized
phthalazines are quite limited and not easily accessible due to
lengthy synthesis with lack of regio control and chemo-
selectivity, particularly for 4-aminophthalazin-1(2H)-ones. The
most straightforward previously published synthesis involves
condensation of phthalic anhydride with substituted hydrazines,
dehydroxyhalogenation, and Buchwald−Hartwig amination or
condensation of phthalic anhydride with hydrazine, bis-
dehydroxyhalogenation, monodehalogenhydrolysis, N-alkyla-
tion, and Buchwald−Hartwig amination5 or monoamination
of 1,4-dichlorophthalazine followed by hydrolysis.6,7 These
methods have two limitations: (1) limited commercial
availability of substituted hydrazines and phthalic anhydride
and (2) lack of regiochemistry control in condensation of
substituted phthalic anhydrides with substituted hydrazines,
monodehalogenhydrolysis, and monoamination of dichloroph-
We envisioned that phthalazin-1(2H)-ones 3, which can be
readily prepared by condensation of 2-formylbenzoic acids 1 or
3-hydroxyisobenzofuran-1(3H)-ones 2 with hydrazine,9 would
be selectively brominated at the 4-position to give 4-
bromophthalazin-1(2H)-ones 4. Subsequent metal-catalyzed
C−N coupling of 4 with amines would give the desired 4-
alkylamino and 4-arylaminophthalazin-1(2H)-ones 5 (R2
=
alkyl or aryl) (Scheme 1).
RESULTS AND DISCUSSION
■
2-Formylbenzoic acids 1a−c are commercially available and can
be easily converted to phthalazin-1(2H)-ones 3a−c by heating
with hydrazine in EtOH (Scheme 2). To demonstrate the
convenient access to 3, we prepared 3-hydroxy-4-bromoiso-
benzofuran-1(3H)-one 2 through lithiation of 3-bromobenzoic
acid formylation and cyclization based on a literature
Received: November 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02652
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Figure 1. Some bioactive phthalazine derivatives.
Scheme 1. Regioselective Synthesis of Aminophthalazin-1(2H)-ones 5
procedure.10 Following the same procedure as for 2-
formylbenzoic acids 1, 2 was readily condensed with hydrazine
to give 3e in good yield. 3e was converted to 3f via Suzuki
reaction in 82% yield. Besides the above synthesis, the other
attractive approach to 4-unsubstituted phthalazin-1(2H)-ones 3
was reported by Knochel and Crestey11 via condensation of
isoindolinone with hydrazine in glacial acetic acid.
(Table 1). No reaction occurred by heating 4e with 6 at 130 °C
for 48 h (entry 1). However, when DMSO was used as the
solvent and the reaction mixture was heated in a sealed tube at
130 °C for 16 h, desired product 5k was observed in 30% yield
by LCMS (entry 2). Prolonged heating did not improve the
conversion. Under Buchwald conditions12 using Pd2(dba)3 (5
mol %) as the catalyst and JohnPhos (10 mol %) as the ligand
in the presence of t-BuONa (1.4 equiv), no product 5k was
observed (entry 3). The conditions using copper powder as the
catalyst, without solvent (entry 4) or with DMSO as the solvent
(entry 5), failed to give any product after heating at 100 °C for
1 h. When ethylene glycol, a superior solvent for copper-
catalyzed amination,13 was used (entry 6), desired product 5k
was observed in 23% conversion. In the presence of K3PO4 as a
base, we were pleased to see 5k as the major product, which
was isolated in 44% yield (entry 7). The condition was further
optimized by using the combination of Cu powder and Cu2O
as the catalysts, which were first reported by Wolf and co-
workers14 (entry 8). Thus, a mixture of 4e, 6 (3 equiv), Cu
powder (0.1 equiv), Cu2O (0.05 equiv), and K3PO4 (2.2 equiv)
in glycol was heated to 90 °C for 4 h to give 5k in 72% isolated
yield.
We began our investigation on the selective 4-bromination of
phthalazin-1(2H)-ones 3 using 5-phenylphthalazin-1(2H)-one
3f as the substrate, NBS (4 equiv) as the brominating agent,
and potassium carbonate (5 equiv) as the base in various
solvents such methanol, THF, acetonitrile, NMP, and DMF at
room temperature for 16 h. Only when DMF was used as the
solvent was the desired product 4-bromo-5-phenylphthalazin-
1(2H)-one 4e observed in the reaction mixture by LCMS;
however, bromination occurred at multiple positions, and the
reaction did not go to completion. Nevertheless, encouraged by
the result, we examined the reaction utilizing benzyltrimethy-
lammonium tribromide (BTMA-Br3) as the brominating agent.
To our delight, BTMA-Br3 had a cleaner reaction profile, and
bromination at other positions was not detected by LCMS.
After further optimization, the reaction of 3f with BTMA-Br3 (2
equiv) in the presence of K2CO3 (2 equiv) at 40 °C for 5 h
gave 4e in 80% isolated yield. Similarly, intermediates 3a−d
were converted to the corresponding 4-bromophthalazin-
1(2H)-ones 4a−d in satisfactory yields (Scheme 2).
It must be noted that, under the same conditions, Cu2O
(0.15 equiv) alone promoted the reaction; however, a lower
yield (40%) was obtained. The role of Cu/Cu2O in the
amination reaction was not clear. The use of K3PO4 was critical
as K2CO3 and Cs2CO3 failed to faciliate the reaction under the
same conditions. Although Kormendy and Ruff reported that
With 4e in hand, we explored the amination reaction under
thermal coupling, palladium-, and copper-catalyzed conditions
B
DOI: 10.1021/acs.joc.5b02652
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ab c
, ,
Scheme 2. Regioselective Synthesis of 4-Bromophthalazin-1(2H)-ones 4
a
b
A mixture of 1 or 2 and NH2NH2 (5 equiv) in EtOH was heated to 70−80 °C for 2 h. A mixture of 3, K2CO3 (2 equiv), and BTMA-Br3 (2 equiv)
c
d
in DMF was heated to 40 °C for 5 h. Isolated yields (%) are in parentheses and were not optimized. A mixture of 3e, phenylboronic acid (1.2
equiv), sodium carbonate monohydrate (3 equiv), and PdCl2(dppf) (5 mol %) in a mixture of dioxane and water (4:1) heated at 90 °C for 1.5 h.
Table 1. Amination Reaction Screening
a
entry equiv of 6
catalyst
base
solvent
temp (°C) time (h) yield of 5k (%)
b
1
2
3
4
5
6
7
8
10
10
none
none
none
none
neat
130
130
100
100
100
75
48
16
24
1
0
30
0
b
DMSO
1.2
Pd2(dba)3 (5 mol %) JohnPhos (10 mol %)
Cu powder (1 equiv)
t-BuONa (1.4 equiv)
none
toluene/EtOH (2:1)
neat
10
10
2
0
Cu powder (1 equiv)
none
DMSO
1
0
Cu powder (0.5 equiv)
none
glycol
2.5
23
c
3
Cu powder (1 equiv)
K3PO4 (2.2 equiv)
K3PO4 (2.2 equiv)
glycol
90
4
4
44
c
3
Cu powder (0.1 equiv)/Cu2O (0.05 equiv)
glycol
90
72
a
b
c
Based on LCMS unless otherwise noted. The reaction was ran in a sealed tube. Isolated yield.
glycol can have a catalytic effect to promote amination of
chlorophthalazin-1(2H)-one with aniline to give 4-
(phenylamino)phthalazin-1(2H)-one (5h) at high temperature,
range of amines. As shown in Scheme 3, aliphatic primary
amines 5a−d, 5g, and 5i−l generally had better conversions
than the aromatic primary amines 5e−f and 5h. With the cyclic
secondary amine, such as piperidine, the reaction only showed a
trace amount of product 5m based on LCMS. No product 5n
was observed in the case of 4-methoxy-N-methylaniline as the
secondary amine. This could be due to the steric hindrance of
secondary amines as the nucleophiles in the copper-catalyzed
C−N coupling with aryl halides as also observed by Jiao and co-
15
in our hands, the reaction of the bromo analogue 4d and
aniline (5 equiv) in glycol did not occur below 190 °C, and
only <30% conversion was observed by LCMS after heating at
190 °C for 20 h.
Having found optimized conditions for the amination of 4e
with amine 6, we examined the reaction scope of 4a−e with a
C
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a
Scheme 3. C−N Coupling of 4-Bromophthalazin-1(2W)-ones 4 with Amines
a
A mixture of 4-bromo-phthalazin-1(2H)-one 4, amine (3−10 equiv), potassium phosphate tribasic (3 equiv), copper powder (0.1 equiv), copper(I)
oxide (0.05 equiv), and ethylene glycol was stirred at 90 °C under nitrogen for 4−20 h. Isolated yields (%) are in parentheses except for 5m−n and
b
c
were not optimized. Detected by LCMS. Not found by LCMS.
workers,16 especially for 4-bromophthalazin-1(2H)-one deriv-
atives 4a−4e as studied by Kormendy and Ruff on the steric
effect of the reaction of chlorophalazin-1(2H)-one with
secondary amines at high temperature.15 The secondary- and
tertiary-substituted primary amines also worked well as
illustrated with examples 5b and 5j.
In summary, we have developed a convenient regioselective
synthesis of substituted 4-alkylamino and 4-arylaminophthala-
zin-1(2H)-ones 5 via the condensation of 2-formylbenzoic
acids 1 or 3-hydroxyisobenzofuran-1(3H)-ones 2 with
hydrazine followed by regioselective bromination of the
phthalazin-1(2H)-ones 3 with benzyltrimethylammonium
tribromide (BTMA-Br3) and subsequent copper- and copper(I)
oxide-catalyzed amination of 4-bromophthalazin-1-ols 4 with
primary amines. Compounds 4 and 5 could be further
functionalized to bioactive molecules as illustrated in Figure 1.
measured with electrospray ionization (ESI) and a Fourier transform
mass spectrometer.
5-Bromophthalazin-1(2H)-one (3e). According to the literature
procedure,10 to a stirred solution of n-butyllithium (109 mL, 274
mmol) (2.5 M in hexanes) was added dropwise at −20 °C 2,2,6,6-
tetramethylpiperidine (46.5 mL, 274 mmol) in anhydrous THF (250
mL) under N2. After cooling to −50 °C, 3-bromobenzoic acid (25 g,
124 mmol) in THF (150 mL) was added dropwise, and then the
reaction mixture was stirred for 1 h at −50 °C. N,N-Dimethylforma-
mide (38.4 mL, 497 mmol) was added dropwise. The resulting
reaction mixture was allowed to warm to rt. Water (200 mL) was
added slowly at rt, and the aqueous layer was washed with ether (500
mL) and acidified with 1 N HCl. The acidic mixture was extracted
with ether (1 L), and the organic layer was separated, dried with
Na2SO4, filtered, and concentrated in vacuo to give the crude product
4-bromo-3-hydroxyisobenzofuran-1(3H)-one (2) (16.7 g, 72.9 mmol,
58.6% yield), which was used in the next step without further
purification.
To a 1 L, three-necked round-bottom flask was added 4-bromo-3-
hydroxyisobenzofuran-1(3H)-one (2) (16.7 g, 72.9 mmol) and
ethanol (250 mL). To the resulting solution was added hydrazine
(19.7 mL, 406 mmol) over 4 min. The reaction mixture was heated
with stirring at 80 °C for 2 h. The reaction mixture was cooled to rt
and then vacuum filtered. The filter cake was rinsed with 100 mL of
ethanol and then dried by vacuum suction to give product 5-
bromophthalazin-1(2H)-one (3e) (7.3 g, 44% yield) as white needles.
1H NMR (400 MHz, DMSO-d6): δ 12.94 (br s, 1H), 8.42 (s, 1H),
8.26−8.19 (m, 2H), 7.76 (t, J = 7.9 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 159.0, 138.0, 136.5, 133.4, 130.0, 129.0, 126.0, 120.5.
EXPERIMENTAL SECTION
■
All reagents were obtained commercially and used without further
purification unless otherwise stated. All reactions were performed
under a nitrogen atmosphere. All glassware was dried and purged with
nitrogen before use. All reactions were monitored by LCMS using the
following conditions: C18 column 1.7 μm 2.1 × 50 mm. Solvent: A =
100% water with 0.05% TFA; B = 100% acetonitrile with 0.05% TFA.
Gradient: 2−98% B over 1.5 min. Flow: 0.8 mL/min, Wavelength: 220
nm. All 1H NMR and 13C NMR spectra were recorded on a 400 MHz
spectrometer using DMSO-d6 or CDCl3 as the solvent. HRMS were
D
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HRMS (ESI-FTMS): m/z calcd for C8H6BrN2O [M + H]+, 224.9658;
found, 224.9655.
HRMS(ESI-FTMS): m/z calcd for C8H5ClBrN2O [M + H]+,
258.9268; found, 258.9265.
4-Bromo-7,8-dimethoxyphthalazin-1(2H)-one (4b). 7,8-Dime-
thoxyphthalazin-1(2H)-one (3b, 1.5 g) gave 1.52 g of product 4b as an
off white solid in 73% yield after purification by trituration with a
mixture MeOH and heptane (1:10). Mp: 250−253 °C. 1H NMR (400
MHz, DMSO-d6): δ 12.46 (s, 1H), 7.79−7.69 (m, 2H), 3.97 (s, 3H),
3.80 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 157.8, 156.3, 148.3,
129.2, 125.2, 124.2, 122.5, 119.6, 61.8, 56.9. Anal. Calcd for
C10H9BrN2O3: C, 42.13; H, 3.18; N, 9.83. Found: C, 42.16; H,
2.95; N, 9.69.
5-Phenylphthalazin-1(2H)-one (3f). To a N2 flushed round-
bottom flask were added 5-bromophthalazin-1(2H)-one (3e) (8.3 g,
36.9 mmol), phenylboronic acid (5.40 g, 44.3 mmol), sodium
carbonate monohydrate (13.72 g, 111 mmol), dioxane (400 mL),
and water (100 mL). The suspension was bubbled with N2 for 5 min.
PdCl2(dppf) (1.35 g, 1.84 mmol) was added. It was then heated at 90
°C under nitrogen for 1.5 h. After it was cooled to rt, the dark reaction
mixture was concentrated to yield a gray semisolid. This semisolid was
partitioned between water (500 mL) and DCM (500 mL). The
organic layer was separated, and the aqueous layer was extracted with
DCM (250 mL). The combined DCM layers were washed with brine
(500 mL), dried with Na2SO4, and concentrated to give the crude
product, which was purified by column chromatography using EtOAc
and hexane as the eluents to give pure 5-phenylphthalazin-1(2H)-one
4-Bromo-7-methoxyphthalazin-1(2H)-one (4c). 7-Methoxyph-
thalazin-1(2H)-one (3c, 0.50 g) gave 0.403 g of product 4c as a light
yellow solid in 56% yield after purification by column chromatography
1
using 0−100% EtOAc/hexanes as the eluent. H NMR (400 MHz,
DMSO-d6): δ 12.85 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 2.7
Hz, 1H), 7.58 (dd, J = 8.9, 2.8 Hz, 1H), 3.97 (s, 3H). 13C NMR (100
MHz, DMSO-d6): δ 163.1, 159.4, 130.6, 130.3, 129.5, 124.0, 123.9,
107.9, 56.6. Anal. Calcd for C9H7BrN2O2: C, 42.38; H, 2.77; N, 10.98.
Found: C, 42.53; H, 2.80; N, 11.02.
1
(3f) (6.72 g, 82% yield) as a white solid. Mp: 203−205 °C. H NMR
(400 MHz, DMSO-d6): δ 12.77 (s, 1H), 8.29 (dq, J = 7.8, 0.7 Hz, 1H),
8.08−8.05 (m, 1H), 7.94−7.82 (m, 2H), 7.59−7.48 (m, 5H). 13C
NMR (100 MHz, DMSO-d6): δ 159.9, 140.1, 137.8, 136.1, 134.9,
131.9, 130.3, 129.2, 128.9, 128.7, 127.6, 125.4. HRMS (ESI-FTMS):
m/z calcd for C14H11N2O [M + H]+, 223.0866; found, 223.0862.
General Procedure for the Synthesis of 3. To a three necked
round-bottom flask was added 2-formylbenzoic acid 2 (1 equiv) and
ethanol (15 mL/g). To the resulting solution was added hydrazine (5
equiv) over several mins. The reaction mixture was heated with stirring
at 70−80 °C for 2 h. The reaction mixture was cooled to rt and then
vacuum filtered. The filter cake was rinsed with ethanol and then dried
by vacuum suction to give the product phthalazin-1(2H)-one 3.
7-Chlorophthalazin-1(2H)-one (3a). 5-Chloro-2-formylbenzoic
acid (1a, 2.5g) gave 2.09 g of product 3a as a white solid in 90% yield.
4-Bromophthalazin-1(2H)-one (4d).5 Phthalazin-1(2H)-one
(3d, 5.0 g) gave 6.05 g of the product as an off white solid in 79%
yield after purification by trituration with a mixture of DCM and
1
heptane (1:1). Mp: 277−279 °C. H NMR (400 MHz, DMSO-d6): δ
12.93 (br s., 1H), 8.29−8.22 (m, 1H), 8.08−7.99 (m, 1H), 7.97−7.91
(m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 159.5, 135.1, 133.7,
130.3, 129.8, 128.7, 128.0, 126.9. HRMS (ESI-FTMS): m/z calcd for
C8H6BrN2O [M + H]+, 224.9658; found, 224.9659.
4-Bromo-5-phenylphthalazin-1(2H)-one (4e). Phthalazin-
1(2H)-one (3e, 6.5 g) gave 7.0 g of product 4e as a white solid in
80% yield after purification by trituration with a mixture ethyl acetate
1
1
and heptane (2:5). Mp: 229−231 °C. H NMR (400 MHz, DMSO-
Mp: 246−247 °C. H NMR (400 MHz, DMSO-d6): δ 12.81 (br s,
d6): δ 13.02 (br s, 1H), 8.38 (dd, J = 7.9, 1.4 Hz, 1H), 7.97−7.90 (m,
1H), 7.81 (dd, J = 7.5, 1.5 Hz, 1H), 7.49−7.42 (m, 3H), 7.39−7.31
(m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 159.3, 141.1, 140.0,
138.0, 132.1, 130.5, 129.9, 128.5, 128.3, 127.4, 126.7, 126.3. Anal.
Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C, 55.77;
H, 2.92; N, 9.27.
1H), 8.40 (d, J = 0.4 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 1.0 Hz, 2H).
13C NMR (100 MHz, DMSO-d6): δ 159.0, 138.1, 137.0, 134.4, 129.7,
129.5, 129.0, 125.1. HRMS (ESI): m/z calcd for C8H6ClN2O [M +
H]+, 181.0163; found, 181.0160.
7,8-Dimethoxyphthalazin-1(2H)-one (3b). 6-Formyl-2,3-dime-
thoxybenzoic acid (1b, 4.7 g) gave 4.4 g of product 3b as a white solid
General Procedure for the Synthesis of 5. A mixture of 4-
bromo-phthalazin-1(2H)-one derivative 4 (1 equiv, 300 mg, 0.996
mmol), an appropriate amine (3−10 equiv), ethylene glycol (10 mL/
g), potassium phosphate tribasic (2.2 equiv), copper powder (0.1
equiv), and copper(I) oxide (0.05 equiv) was stirred at 90 °C for 4−20
h. EtOAc or DCM (10-fold volume of ethylene glycol) was added.
The mixture was stirred at rt for 5 min and filtered through a Celite
pad. The resulting filtrate was washed with water three times and brine
once, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography using 0−20% of MeOH in DCM as
the eluent to give product 5.
in 95% yield. Mp: 165−167 °C (lit.17 mp 162−164 °C). H NMR
1
(400 MHz, DMSO-d6): δ 12.17 (s, 1H), 8.15 (s, 1H), 7.70−7.65 (m,
2H), 3.93 (s, 3H), 3.78 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
158.4, 155.3, 147.6, 138.2, 125.3, 124.1, 122.2, 119.5, 61.7, 56.8.
HRMS (ESI-FTMS): m/z calcd for C10H11N2O3 [M + H]+, 207.0764;
found, 207.0761.
7-Methoxyphthalazin-1(2H)-one (3c). 2-Formyl-5-methoxyben-
zoic acid (1c, 1.0 g) gave 1.24 g of product 3c as an off white solid in
1
85% yield. H NMR (400 MHz, DMSO-d6): δ 12.57 (br s, 1H), 8.29
(s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.51 (dd, J
= 8.7, 2.7 Hz, 1H), 3.94 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
162.2, 160.0, 138.3, 130.0, 129.4, 124.5, 123.4, 106.5, 56.3. HRMS
(ESI-FTMS): m/z calcd for C9H9N2O2 [M + H]+, 177.0659; found,
177.0658.
General Procedure for the Synthesis of 4. To a solution of
phthalazin-1(2H)-one 3 (1 equiv) in DMF (10 mL/g) was added
potassium carbonate (2 equiv). After the mixture was stirred for 5 min,
benzyl trimethylammonium tribromide (BTMA-Br3) (2 equiv) was
added. The reaction mixture was stirred at 40 °C for 5 h. After cooling
to rt, the mixture was vacuum filtered through a Celite pad. To the
filtrate were added water and DCM. The organic layer was washed
with water three times and brine once, dried over Na2SO4, and
concentrated. The residue was purified by trituration with an
appropriate solvent or column chromatography.
7-Chloro-4-((3-hydroxypropyl)amino)phthalazin-1(2H)-one
1
(5a). White solid, 193 mg, 95% yield. Mp: >198 °C (dec). H NMR
(400 MHz, DMSO-d6): δ 11.72 (s, 1H), 8.23−8.11 (m, 2H), 7.97 (dd,
J = 8.7, 2.3 Hz, 1H), 6.64 (t, J = 5.1 Hz, 1H), 4.47 (t, J = 5.1 Hz, 1H),
3.55−3.48 (m, 2H), 3.30−3.23 (m, 2H), 1.78 (q, J = 6.7 Hz, 2H). 13C
NMR (100 MHz, DMSO-d6): δ 157.1, 145.0, 136.5, 133.4, 130.2,
126.2, 126.0, 124.2, 59.4, 39.1, 32.1. HRMS (ESI-FTMS): m/z calcd
for C11H13ClN3O2 [M + H]+, 254.0691; found, 254.0688.
(R)-7-Chloro-4-((1-hydroxypropan-2-yl)amino)phthalazin-
1(2H)-one (5b). Off white solid, 165 mg, 56% yield. Mp: 244−246
°C. 1H NMR (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 8.25 (d, J = 8.8
Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.7, 2.4 Hz, 1H), 6.25
(d, J = 7.3 Hz, 1H), 4.66 (t, J = 5.7 Hz, 1H), 3.89 (dq, J = 12.7, 6.5 Hz,
1H), 3.55 (dt, J = 10.6, 5.3 Hz, 1H), 3.39 (dt, J = 10.5, 6.1 Hz, 1H),
1.19 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 157.0,
144.4, 136.5, 133.3, 130.3, 126.4, 125.9, 124.3, 64.5, 48.7, 17.6. HRMS
(ESI-FTMS): m/z calcd for C11H13ClN3O2 [M + H]+, 254.0691;
found, 254.0686.
4-Bromo-7-chlorophthalazin-1(2H)-one (4a). 7-Chlorophthala-
zin-1(2H)-one (3a, 0.63 g) gave 0.498 g of product 4a as an off white
solid in 55% yield after purification by column chromatography using
1
0−50% EtOAc in hexane as the eluent. Mp: 221−223 °C. H NMR
(400 MHz, DMSO-d6): δ 13.08 (s, 1H), 8.23−8.19 (m, 1H), 8.08 (dd,
J = 8.7, 2.2 Hz, 1H), 7.97−7.93 (m, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 158.5, 138.3, 135.2, 130.5, 130.0, 129.1, 129.1, 126.1.
3-(6-Chloro-4-hydroxyphthalazin-1-yl)amino)propane-1,2-
1
diol (5c). White solid, 228 mg, 73% yield. Mp: >231 °C (dec). H
NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 8.22 (d, J = 8.7 Hz,
E
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The Journal of Organic Chemistry
Article
1H), 8.15 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.7, 2.3 Hz, 1H), 6.62 (t, J
= 5.3 Hz, 1H), 4.79 (d, J = 4.3 Hz, 1H), 4.57 (t, J = 5.6 Hz, 1H), 3.80
(d, J = 2.9 Hz, 1H), 3.46−3.35 (m, 3H), 3.20−3.10 (m, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 157.1, 145.1, 136.6, 133.4, 130.2,
126.3, 126.0, 124.2, 70.0, 64.7, 45.4. HRMS (ESI-FTMS): m/z calcd
for C11H13ClN3O3 [M + H]+, 270.0640; found, 270.0637.
MHz, CDCl3): δ 159.0, 156.9, 148.6, 145.4, 140.1, 139.0, 136.6, 136.2,
130.1, 129.5, 129.4, 128.8, 128.3, 127.2, 122.8, 121.7, 121.4, 47.3. Anal.
Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C, 72.85;
H, 4.88; N, 17.13.
4-((2-Hydroxyethyl)amino)-5-phenylphthalazin-1(2H)-one
(5l). Yellow-white solid, 95 mg, 34% yield. 1H NMR (400 MHz,
DMSO-d6): δ 11.73 (s, 1H), 8.35 (dd, J = 7.9, 1.4 Hz, 1H), 7.89−7.77
(m, 1H), 7.70−7.60 (m, 1H), 7.55−7.48 (m, 3H), 7.46−7.38 (m, 2H),
4.30 (t, J = 5.0 Hz, 1H), 4.12 (t, J = 5.0 Hz, 1H), 3.17 (q, J = 5.5 Hz,
2H), 2.99 (q, J = 5.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ
158.2, 144.8, 140.2, 139.0, 136.5, 130.8, 129.9, 129.5, 129.1, 129.0,
126.8, 122.7, 59.2, 44.6. HRMS (ESI-FTMS): m/z calcd for
C16H16N3O2 [M + H]+, 282.1237; found, 282.1239.
4-(Butylamino)-7,8-dimethoxyphthalazin-1(2H)-one (5d).
1
White solid, 152 mg, 52% yield. Mp: 195−197 °C. H NMR (400
MHz, DMSO-d6): δ 11.13 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.60 (d, J
= 9.0 Hz, 1H), 6.45−6.14 (m, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.25−
3.07 (m, 2H), 1.67−1.52 (m, 2H), 1.47−1.26 (m, 2H), 0.92 (t, J = 7.4
Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 156.8, 155.0, 148.4,
144.9, 122.8, 120.2, 120.1, 118.2, 61.5, 56.7, 41.6, 31.1, 20.5, 14.4.
HRMS (ESI-FTMS): m/z calcd for C14H20N3O3 [M + H]+, 278.1499;
found, 278.1496.
ASSOCIATED CONTENT
* Supporting Information
■
4-((4-Chlorophenyl)amino)-7-methoxyphthalazin-1(2H)-one
(5e). Off white solid, 86 mg, 24% yield. 1H NMR (400 MHz, DMSO-
d6): δ 11.89 (s, 1H), 8.67 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.68 (d, J =
2.8 Hz, 1H), 7.66−7.60 (m, 2H), 7.55 (dd, J = 9.0, 2.8 Hz, 1H), 7.35−
7.29 (m, 2H), 3.95 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 162.1,
158.5, 142.2, 141.2, 131.0, 128.7, 126.3, 124.6, 122.3, 120.8, 119.5,
107.9, 56.3. HRMS (ESI-FTMS): m/z calcd for C15H13ClN3O2 [M +
H]+, 302.0691; found, 302.0692.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02652.
1H and 13C NMR spectra of compounds 3−5 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
7-Methoxy-4-((4-methoxyphenyl)amino)phthalazin-1(2H)-
1
one (5f). Off white solid, 31 mg, 9% yield. H NMR (400 MHz,
*Phone: 609-252-5150. Fax: 609-252-7410. E-mail:
Krishnananthan.Subramaniam@bms.com.
*Phone: 609-252-3409. Fax: 609-252-7410. E-mail:
Jianqing·Li@bms.com.
DMSO-d6): δ 11.70 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H),
7.67 (d, J = 2.8 Hz, 1H), 7.53−7.47 (m, 3H), 6.90−6.86 (m, 2H), 3.95
(s, 3H), 3.73 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 161.9,
158.4, 154.6, 143.1, 135.0, 131.0, 126.2, 122.2, 122.1, 119.4, 114.2,
107.9, 56.2, 55.7. HRMS (ESI-FTMS): m/z calcd for C16H16N3O3 [M
+ H]+, 298.1186; found, 298.1185.
4-(Isopentylamino)phthalazin-1(2H)-one (5g). Yellow solid,
162 mg, 53% yield. 1H NMR (400 MHz, CDCl3): δ 10.18 (br s, 1H),
8.57−8.43 (m, 1H), 7.86−7.74 (m, 2H), 7.70−7.62 (m, 1H), 4.41 (br
s, 1H), 3.48−3.30 (m, 2H), 1.83−1.71 (m, 1H), 1.67−1.53 (m, 2H),
1.00 (d, J = 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 159.2,
145.4, 133.0, 131.1, 128.5, 127.6, 125.3, 121.2, 40.4, 38.3, 26.2, 22.6.
HRMS (ESI-FTMS): m/z calcd for C13H18N3O [M + H]+, 232.1444;
found, 232.1444.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors thank Dr. Jennifer Qiao for helpful suggestions and
Ms. Bei Wang for assistance in preparation of the Experimental
Section and Supporting Information.
REFERENCES
■
4-(Phenylamino)phthalazin-1(2H)-one (5h). Off white solid,
143 mg, 45% yield. Mp: 246−251 °C (lit.15 mp 257−258 °C). H
1
(1) Follath, F.; Kersting, F.; Lewis, G. R. J.; Walden, R. J.;
Woolhouse, N. M.; Dollery, C. T. Clin. Pharmacol. Ther. 1976, 20, 24.
(2) Jost, L. M.; Gschwind, H.-P.; Jalava, T.; Wang, Y.; Guenther, C.;
Souppart, C.; Rottmann, A.; Denner, K.; Waldmeier, F.; Gross, G.;
Masson, E.; Laurent, D. Drug Metab. Dispos. 2006, 34, 1817.
(3) Mylari, B. L.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.;
Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Singleton, D. H. J. Med.
Chem. 1991, 34, 108.
NMR (400 MHz, DMSO-d6): δ 11.88 (s, 1H), 8.58 (s, 1H), 8.35 (d, J
= 8.1 Hz, 1H), 8.29 (dd, J = 7.9, 1.0 Hz, 1H), 7.99 (td, J = 7.6, 1.5 Hz,
1H), 7.92−7.87 (m, 1H), 7.63−7.58 (m, 2H), 7.32−7.26 (m, 2H),
6.97−6.90 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ 158.6, 142.5,
142.1, 133.5, 132.0, 129.3, 129.098, 128.9, 126.8, 126.0, 124.1, 121.5,
119.7, 119.6. HRMS (ESI-FTMS): m/z calcd for C14H12N3O [M +
H]+, 238.0975; found, 238.0971.
(4) Herberich, B.; Cao, G.-Q.; Chakrabarti, P. P.; Falsey, J. R.; Pettus,
L.; Rzasa, R. M.; Reed, A. B.; Reichelt, A.; Sham, K.; Thaman, M.;
Wurz, R. P.; Xu, S.; Zhang, D.; Hsieh, F.; Lee, M. R.; Syed, R.; Li, V.;
Grosfeld, D.; Plant, M. H.; Henkle, B.; Sherman, L.; Middleton, S.;
Wong, L. M.; Tasker, A. S. J. Med. Chem. 2008, 51, 6271.
(5) Prime, M. E.; Courtney, S. M.; Brookfield, F. A.; Marston, R. W.;
Walker, V.; Warne, J.; Boyd, A. E.; Kairies, N. A.; von der Saal, W.;
Limberg, A.; Georges, G.; Engh, R. A.; Goller, B.; Rueger, P.; Rueth,
M. J. Med. Chem. 2011, 54, 312.
(6) Elagawany, M.; Ibrahim, M. A.; Ahmed, H. E. A.; El-Etrawy, A. S.;
Ghiaty, A.; Abdel-Samii, Z. K.; El-Feky, S. A.; Bajorath, J. Bioorg. Med.
Chem. Lett. 2013, 23, 2007.
(7) Papaioannou, N.; Marathias, V.; Wan, Z.-K.; Kaila, N.; Ali, Z.;
Saiah, E. Tetrahedron Lett. 2011, 52, 6317.
4-((3-(Dimethylamino)propyl)amino)phthalazin-1(2H)-one
(5i). Colorless liquid, 242 mg, 74% yield. 1H NMR (400 MHz,
CDCl3): δ 9.32 (br s, 1H), 8.49−8.43 (m, 1H), 7.82−7.75 (m, 2H),
7.61−7.57 (m, 1H), 7.17 (br s, 1H), 3.48−3.43 (m, 2H), 2.59−2.54
(m, 2H), 2.37 (s, 6H), 1.89 (dt, J = 11.8, 6.0 Hz, 2H). 13C NMR (100
MHz, DMSO-d6): δ 158.6, 145.8, 133.7, 131.9, 129.1, 127.2, 126.0,
123.8, 63.7, 58.3, 46.1, 27.1. HRMS (ESI-FTMS): m/z calcd for
C13H19N4O [M + H]+, 247.1553; found, 247.1551.
3-((4-Hydroxyphthalazin-1-yl)amino)-3-methylbutanoic
1
Acid (5j). Off white solid, 140 mg, 40% yield. H NMR (400 MHz,
DMSO-d6): δ 11.60 (s, 1H), 8.21 (dd, J = 7.8, 1.2 Hz, 1H), 8.11 (d, J =
7.8 Hz, 1H), 7.90−7.84 (m, 1H), 7.83−7.76 (m, 1H), 5.90 (br s, 1H),
2.86 (s, 2H), 1.51 (s, 6H). 13C NMR (100 MHz, DMSO-d6): δ 173.3,
158.0, 144.2, 133.2, 131.5, 128.8, 126.6, 126.2, 123.8, 52.6, 43.5, 27.5.
HRMS (ESI-FTMS): m/z calcd for C13H16N3O3 [M + H]+, 262.1186;
found, 262.1184.
(8) Vlaar, T.; Mampuys, P.; Helliwell, M.; Maes, B. U. W.; Orru, R. V.
A.; Ruijter, E. J. Org. Chem. 2013, 78, 6735.
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Laplanche, L.; Dinges, J.; Jakob, C.; Black, L. US2013/0116233 A1,
2013.
5-Phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1(2H)-
1
one (5k). Off white solid, 352 mg, 72% yield. Mp: 204−206 °C. H
NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 8.66−8.53 (m, 1H), 8.27
(dt, J = 4.1, 0.7 Hz, 1H), 7.80−7.73 (m, 1H), 7.61 (dd, J = 7.5, 1.5 Hz,
1H), 7.56 (td, J = 7.6, 1.7 Hz, 1H), 7.50−7.42 (m, 5H), 7.13−7.03 (m,
2H), 5.36 (t, J = 4.1 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H). 13C NMR (100
(11) Crestey, F.; Knochel, P. Synthesis 2010, 7, 1097.
F
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Chem. 2006, 71, 3270.
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155.
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Y.; Chen, Z.-G. J. Org. Chem. 2011, 76, 1180.
(17) Outerbridge, V. W.; Landge, S. M.; Tamaki, H.; Torok, B.
Synthesis 2009, 11, 1801.
G
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