Microwave-promoted synthesis of some novel 4-(4-methyl-phenyl)-substituted phthalazin-1-one derivatives

Article abstract of DOI:10.1080/00397911.2011.622847

In this study, a series of 4-(4-methyl-phenyl)-substituted phthalazin-1-one derivatives have been synthesized with the combination of rapid microwave synthesis and phasetransfer catalyst methodology, which is characterized by very short reaction times and easy workup procedures and which can be exploited to generate some novel phthalazinone heterocycles. Substituted phthalazin-1-one derivatives have been synthesized from phthalyl derivatives as starting material. The structures of these compounds were confirmed by NMR and mass spectral studies.

Full text of DOI:10.1080/00397911.2011.622847

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Microwave-Promoted Synthesis of Some
Novel 4-(4-Methyl-phenyl)-Substituted
Phthalazin-1-one Derivatives
Freddy H. Havaldar a , Bhushan V. Dabholkar a & Ganesh B. Mule a
a Department of Chemistry, Nadkarni-Sacasa Research Laboratory,
St. Xavier's College, Mumbai, India
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Freddy H. Havaldar , Bhushan V. Dabholkar & Ganesh B. Mule (2013): Microwave-
Promoted Synthesis of Some Novel 4-(4-Methyl-phenyl)-Substituted Phthalazin-1-one Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:8, 1127-1137
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Synthetic Communications1, 43: 1127–1137, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.622847
MICROWAVE-PROMOTED SYNTHESIS OF SOME
NOVEL 4-(4-METHYL-PHENYL)-SUBSTITUTED
PHTHALAZIN-1-ONE DERIVATIVES
Freddy H. Havaldar, Bhushan V. Dabholkar, and
Ganesh B. Mule
Department of Chemistry, Nadkarni-Sacasa Research Laboratory,
St. Xavier’s College, Mumbai, India
GRAPHICAL ABSTRACT
Abstract In this study, a series of 4-(4-methyl-phenyl)-substituted phthalazin-1-one deriva-
tives have been synthesized with the combination of rapid microwave synthesis and phase-
transfer catalyst methodology, which is characterized by very short reaction times and easy
workup procedures and which can be exploited to generate some novel phthalazinone
heterocycles. Substituted phthalazin-1-one derivatives have been synthesized from phthalyl
derivatives as starting material. The structures of these compounds were confirmed by
NMR and mass spectral studies.
Keywords Alkylation; bicyclic compounds; cyclization; heterocycles; phase-transfer
catalyst
INTRODUCTION
The diverse biological activities of various functional derivatives of 4-sub-
stituted alkyl-1-(2H)-phthalazinones are well known. Some of the phthalazinone
derivatives have found application in clinical medicine because of their pronounced
antipyretic, analgesic, and tuberculostatic activity while others have shown interest-
ing vasodilator[1] and antihypertensive properties. Phthalazine-1-(2H)-ones bearing
a substitutent at the C-4 position represent key intermediates in the syntheses of vari-
ous compounds with highly interesting pharmacological properties, such as the blood
platelet aggregation inhibitor MV-5445 [1-(3-chloroanilino)-4-phenylphthalazine],[2]
Received April 25, 2011.
Address correspondence to Bhushan V. Dabholkar, Department of Chemistry, Nadkarni-Sacasa
Research Laboratory, St. Xavier’s College, Mumbai, India. E-mail: bhushan_dabholkar@hotmail.com
1127

1128
F. H. HAVALDAR, B. V. DABHOLKAR, AND G. B. MULE
which has been found to be a selective phosphodiesterase VA inhibitor, and the
thromboxane A2 syntheses inhibitor and bronchodilator 2-[2-(1-imidazolyl)ethyl]-4-
[3-pyridyl]-phthalazine-1[2H]-one.[3] The phthalazinone nucleus has been proved to
be a versatile system in medicinal chemistry.
A literature survey revealed that phthalazinone-based compounds have wide-
spread applications in the field of pharmaceuticals. The heteroderivatives of phthala-
zinones were claimed to have antiviral, antibacterial, and antitumor activity as well as
sedative and tranquilizing properties. Moreover, a number of established drug
Table 1. Some of the commercially important phthalaziones
Structure
Generic name
Hydralazine
Brand name
Apresoline
Activity
Antihypertensive
Budralazine
Buterazine
Antihypertensive
Azelastine
Astelin
Histamine antagonist
Talastine
Ahanon
Antihistamine
Ponalrestat
Zopolrestat
Statil
Aldose reductase inhibitor
Alond
Aldose reductase inhibitor

MICROWAVE-PROMOTED SYNTHESIS
1129
molecules such as hydralazine, budralazine,[4] azelastine,[5] ponalrestat,[6] and
zopolrestat[7] are accessible starting from the corresponding phthalazinones. Some
of the commercially important phthalaziones are described in Table 1.
The development of new and efficient methodologies for the synthesis of such
potentially bioactive phthalazine derivatives was important. Despite the useful nature
of phthalazinone, there are very few synthetic approaches in the literature for the
formation of 4-phenyl and 4-substituted alkyl-1-(2H)-phthalazinones and their
derivatives.[8–11] Therefore, functionalization of the nucleus continues to be of syn-
thetic interest. In general, most of the structural modifications of the parent system
that have been carried out to optimize the biological activity of phthalazine-derived
drugs can be seen as a variation of the substitution pattern at positions 1, 2, and 4,
that is, the substitution pattern of the 1,2-diazine part of the bicyclic system.
Most of the methods available for the construction of the phthalazinone nucleus
suffer from one or more drawbacks, such as long reaction time or the use of expensive
and hazardous reagents and solvents. Recent advances in technology have now made
microwave energy a more efficient means of heating.[12] Chemical transformations
that took hours or even days for completion can now be accomplished in minutes
or seconds. Microwave energy offers numerous benefits for performing synthesis
including enhancements in reaction rate, yield, and clean chemistry. These advantages
are of the special importance in traditional organic synthesis, high-speed combina-
torial and medicinal chemistry, as well as industrial-scale production.[13,14] We
report synthesis of some novel phthalazinones and their derivatives with use of
a highly sophisticated instrument, CEM Discover.
RESULTS AND DISCUSSION
In this article, we report the synthesis of novel phthalazines through microwave-
assisted synthesis.
In our first approach, phthalic anhydride 1 was condensed with 4-chloro
phenyl acetic acid 2 to obtain condensed product 3. This was converted to phthala-
zine derivative 4 by treatment with hydrazine hydrate, which was further reacted
with halogenated aliphatic molecules to obtain selective compounds 5a and 5b
(Scheme 1). The reactions were carried out under microwave irradiation using micro-
wave synthesizer CEM Discover.
The compounds 5a and 5b were synthesized using a novel green chemistry
approach by condensing compound 4 with different pharmacologically active haloge-
nated aza heterocyles. The aliphatic compound was coupled with compound 4
in biphasic condition in the presence of a phase-transfer catalyst to get product in
greater yield with less reaction time.
To optimize the reaction conditions, we selected the various phase-transfer
catalysts, such as tetraethyl ammonium iodide (TEAI), tetramethyl ammonium
bromide (TMAB), tetrabutyl ammonium bromide (TBAB), tetraethyl ammonium
bromide (TEAB), and cetrimide. It is shown that the use of a phase-transfer catalyst
can significantly improve the yield in all of the cases studied, but different phase-
transfer catalysts can give different results. Cetramide was the most suitable catalyst
for the reaction studied. These phase-transfer catalysts under microwave irradiation
afford better yields than the conventional method.

1130
F. H. HAVALDAR, B. V. DABHOLKAR, AND G. B. MULE
Scheme 1. Synthesis of compounds 6(a–d).
We therefore decided to investigate the reaction upon microwave irradiation
with simultaneous cooling. As advocated in the literature,[15] this should allow for
greater levels of microwave energy to be introduced into the reaction mixture, while
maintaining the bulk of the material at a relatively low temperature by cooling the
vial with a stream of compressed air or a microwave transparent cooling liquid.
Using the same reagent ratios and solvent as those for the reactions run at room
temperature, the reaction condition was optimized using different phase transfer
condition as described in Table 2.
As illustrated in Table 2 use of cetrimide as phase-transfer catalyst in micro-
waves shows remarkable efficiency for the reaction.
Table 2. Comparison of microwave and conventional syntheses of
compounds 5a and 5b
Microwave methoda
Conventional methodb
Phase-transfer
catalysts
5a yield (%) 5b time (h) 5a yield (%) 5b time (h)
TEAI
88
78
90
60
92
0.3
0.3
0.3
0.3
0.3
37
39
48
56
61
14
14
14
14
14
TMAB
TBAB
TEAB
Cetrimide
aMicrowave condition at 100 W for 30 min.
bConventional heating at 50 ꢀC for 14 h.

MICROWAVE-PROMOTED SYNTHESIS
1131
Scheme 2. Synthesis of compound 6e.
The compounds 5a and 5b were condensed with various pharmacologically
active halogenated aza heterocyles under microwave conditions to give products
6(a–d) (Scheme 1). The reactions were carried out under microwave irradiation using
microwave synthesizer CEM Discover.
In a second approach, compound 6e was synthesized by condensing 1-(2-
bromoethoxy)-2-methoxybenzene with compound 4 using phase-transfer catalyst
cetrimide under microwave irradiation as per Scheme 2. The reaction condition
was optimized based on reaction data described in Table 1.
In summary, we have developed a direct and efficient method for the synthesis
of substituted phthalazine derivatives synthesized from phthalyl derivatives as start-
ing material, with a combination of rapid microwave synthesis and phase-transfer
catalyst methodology.
EXPERIMENTAL
Microwave reactions were conducted using a CEM Discover Synthesis unit
(CEM Corp. Matthews, NC).[12] The machine consists of a continuous focused micro-
wave power delivery system with operator-selectable power output from 0 to 300 W.
Reactions were performed in glass vessels. The temperature of the contents of the ves-
sel was monitored using a calibrated infrared (IR) temperature control mounted under
the reaction vessel. All experiments were performed using a stirring option whereby the
contents of the vessel are stirred by means of a rotating magnetic plate located below
the floor of the microwave cavity and a Teflon-coated magnetic stir bar in the vessel.
Chromatographic purification was performed using instrument Combiflash
Teledyne model companion with Ultraviolet–visible detector [flow rate, 25.0 ml
minꢁ1; detector dual wavelength, 254 and 272 nm; chromatographic columns
Redisep Silica Gel (24 gm)]. Mass spectrometer Agilent 6300 series with electrospray
ionization (ESI) probe was operated in the positive ion mode.
1H NMR spectra were recorded in CDCl3 on a 400 MHz spectrometer. Chemi-
cal shifts are reported in parts per million (ppm) relative to the appropriate
1
standards: tetramethylsilane (TMS) as an internal standard for H NMR. All melt-
ing points were determined in open capillary tubes and are uncorrected. Thin-layer
chromatogrphic (TLC) analysis was performed with aluminum-backed plates pre-
coated with silica gel and examined under ultraviolet (UV) fluorescence (254 nm).
Synthesis of 3-(4-Chlorobenzylidene)-2-benzofuran-1(3H)-one (3)
Phthalic anhydride 1 (14.8 g, 0.1 mol), 4-chlorophenyl acetic acid 2 (17.05 g,
0.1 mol), sodium acetate (4.2 g, 0.05 mol), and acetonitrile (10 ml) was added in

1132
F. H. HAVALDAR, B. V. DABHOLKAR, AND G. B. MULE
a round-bottom glass flask equipped with a magnetic stirring bar and reflux con-
denser. The flask was placed in a CEM Discover focused microwave synthesis sys-
tem. The reaction mixture was stirred for 1 min at room temperature. The
reaction mass was exposed to microwave irradiation at 85 ꢀC at initial power
120 W for 20 min in a self-tuning single-mode CEM Discover synthesizer. The pro-
gress of reaction was monitored (using TLC) after 5-min intervals. The resulting
mixture was allowed to cool to room temperature and the reaction was poured into
ice water. The resulting precipitated solid was collected by vacuum filtration, washed
with chilled water and dried. The crude product on recrystallization from methanol
yielded 3-(4-chlorobenzylidene)-2-benzofuran-1(3H)-one (3).
Yield 65%, mp 138 ꢀC (lit.[16] 268–272 ꢀC) MS (ESI): m=z [M þ H] calcd. for
C15H9ClO2:256.6; found: 257.4.
Synthesis of 4-(4-Chlorobenzyl)phthalazin-1(2H)-one (4)
Compound 3 (26.0 g, 0.101 mol) was charged into a solution of 10% NaOH
(10 ml) in a round-bottom glass flask equipped with a magnetic stirring bar and reflux
condenser. The flask was placed in a CEM Discover focused microwave synthesis sys-
tem. The reaction mixture was stirred for 1 min at room temperature. Hydrazine
hydrate (1 ml) was added dropwise under stirring. The reaction mixture was exposed
to microwave irradiation at initial power 80 W at 90 ꢀC for 30 min in a self-tuning
single-mode CEM Discover synthesizer. The progress of the reaction was monitored
(using TLC) after 15-min intervals. The resulting mixture was allowed to cool
at room temperature and the reaction was poured into ice water. The resulting preci-
pitated solid was collected by vacuum filtration and washed with chilled water.
The crude product was recrystallized in ethanol and yielded 4-(4-chlorobenzyl)
phthalazin-1(2H)-one (4).
Yield 70%, mp 270 ꢀC (lit.[17] 268–272 ꢀC). MS (EI): m=z [M þ H] calcd. for
C15H11ClN2O: 270.71; found: 271.2.
4-(4-Chlorophenyl)-2-(3-chloropropyl) phthalazine-1-(2H)-one (5a)
A compound 4 (2.70 g, 0.01 mol) was suspended in toluene (10 ml) and a solution
of 10% NaOH (10 ml) was added to the reaction mass. 1-Bromo-3-chloropropane
(4.8 g, 0.03 mol) was added, and the reaction mixture was stirred at room temperature
(around 26 ꢀC) for 5 min. Cetrimide (1.9 g) was added to the reaction mass. The reac-
tion mixture was exposed to microwave irradiation at initial power of 100 W and
simultaneous cooling to maintain reaction temperature below 50 ꢀC for 30 min using
a self-tuning single-mode CEM Discover synthesizer. The progress of the reaction
was monitored (using TLC) after 15-min intervals. After completion of the reaction,
the resulting mixture was allowed to cool to room temperature. The organic layer
was separated and washed with water (3 ꢂ 25 ml). The solvent was evaporated on
a rotavapor under vacuum, maintaining temperature below 60 ꢀC. The obtained
solid was recrystallized by ethanol, yielding 4-(4-chlorophenyl)-2-(3-chloropropyl)
phthalazine-1-(2H)-one (5a).
Yield 80%, mp 205 ꢀC. 1H NMR (CDCl3): d ¼ 2.11–2.20 (m, 2H, -CH2),
3.51–3.53 (t, 2H, -CH2), 4.29–4.36 (m, 4H, 2 -CH2), 7.21–7.31 (m, 4H, Ar-H),

MICROWAVE-PROMOTED SYNTHESIS
1133
7.70–7.76 (m, 3H, Ar-H), 8.49–8.51 (m, 1H, Ar-H). MS (EI): m=z [M þ H] calcd.
for C18H16Cl2N2O: 347.23; found: 347.2. Anal. calcd. for C18H16Cl2N2O: C,
62.26%; H, 4.64; Cl, 20.42; N, 8.07. Found: C, 62.19%; H, 4.67; Cl, 20.30; N, 8.11.
4-(4-Chlorophenyl)-2-(4-chlorobutyl) phthalazin-1-(2H)-one (5b)
Compound 4 (2.70 g, 0.01 mol) was suspended in toluene (10 ml) and solution of
10% NaOH (10 ml) was added to reaction mass. 1-Bromo-3-chlorobutane (5.1 g,
0.03 mol) was added, and the reaction mixture was stirred at room temperature
(around 26 ꢀC) for 5 min. Cetrimide (1 g) was added to the reaction mass. The reaction
mixture was exposed to microwave irradiation at initial power of 100 W and simul-
taneous cooling to maintain reaction temperature below 50 ꢀC for 30 min in a
self-tuning single-mode CEM Discover synthesizer. The progress of the reaction
was monitored (using TLC) after 15-min intervals. After completion of the reaction,
the resulting mixture was allowed to cool to room temperature. The organic layer was
separated and washed with water (3 ꢂ 25 ml). The solvent was evaporated on a
rotavapor under vacuum, maintaining temperature below 60 ꢀC. The solid was recrys-
tallized by ethanol, yielding 4-(4-chlorophenyl)-2-(4-chlorobutyl) phthalazin-1-(2H)-
one (5b).
1
Yield 60%, mp 290 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 1.84–1.92 (m, 2H, -
CH2), 2.02–2.10 (m, 2H, -CH2), 3.60–3.63 (t, 2H, -CH2), 4.27–4.33 (m, 4H,
2-CH2), 7.19–7.29 (m, 4H, Ar-H), 7.68–7.73 (m, 3H, Ar-H), 8.45–8.48 (m, 1H,
Ar-H). MS (EI): m=z [M þ H] calcd. for C19H18Cl2N2O: 361.26; found: 361.0. Anal.
calcd. for C18H16Cl2N2O: C, 62.26%; H, 4.64; Cl, 20.42; N, 8.07. Found: C, 62.19%;
H, 4.67; Cl, 20.30; N, 8.11.
4-(4-Chlorobenzyl)-2-(3-(4-methylpiperazin-1-yl)propyl)phthalazin-1
(2H)-one (6a)
A mixture of compound 5a (3.8 g, 0.01 mol), N-methyl piperazine (2.0 g,
0.02 mol), and acetonitrile (5 ml) was stirred at room temperature (around 26 ꢀC) for
5 min. The reaction mixture was exposed to microwave irradiation at initial power
of 120 W at 75 ꢀC for 20 min in a self-tuning single-mode CEM Discover synthesizer.
The progress of reaction was monitored (using TLC) after 5-min intervals. The reac-
tion mixture was allowed to cool to room temperature and poured into ice water.
The precipitated solid was collected by vacuum filtration and washed with chilled
water. The product was purified by flash chromatography under normal phase
condition on a silica-gel column using hexane–ethyl acetate as eluent, yielding the 4-
(4-chlorobenzyl)-2-(3-(4-methylpiperazin-1-yl)propyl) phthalazin-1(2H)-one (6a).
1
Yield 70%, mp 228 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 2.30–2.50 (m, 15H, -
CH2 & -CH3), 4.26–4.32 (m, 4H, -CH2), 7.19–7.66 (m, 4H, Ar-H), 7.67–7.72 (m,
3H, Ar-H), 8.44–8.47 (d, 1H, Ar-H). 13C NMR (400 MHz, CDCl3): d ¼ 25.9 (CH2),
38.3 (CH3), 46.1 (CH2), 49.4 (CH3), 53.2 (CH2), 55.2 (CH2), 55.8 (-CH2), 124.8
(ArC), 127.4 (2-ArC), 128.3 (ArC), 128.8 (ArC), 129.0 (-ArC), 129.8 (ArC), 131.2
=
(ArC), 132.6 (ArC), 132.8 (ArC), 136.3 (ArC), 144.5 (C N), 159.2 (CO). MS (EI):
m=z [M þ H] calcd. for C23H27ClN4O: 410.93; found: 411.42. Anal. calcd. for

1134
F. H. HAVALDAR, B. V. DABHOLKAR, AND G. B. MULE
C23H27ClN4O: C, 67.22; H, 6.62; Cl, 8.63; N, 13.63. Found: C, 67.27; H, 6.66; Cl,
8.59%; N, 13.63.
4-(4-Chlorobenzyl)-2-(3-(piperidin-1-yl)propyl)phthalazin-1
(2H)-one (6b)
A mixture of compound 5a (3.4 g, 0.01 mol), piperidine (1.7 g, 0.02 mol), and
acetonitrile (5 ml) was stirred at room temperature (around 26 ꢀC) for 5 min. The
reaction mixture was exposed to microwave irradiation at initial power of 120 W
at 75 ꢀC for 20 min in a self-tuning single-mode CEM Discover synthesizer. The pro-
gress of the reaction was monitored (using TLC) after 5-min intervals. The reaction
mixture was allowed to cool to room temperature and poured into ice water. The
precipitated solid was collected by vacuum filtration, washed with chilled water,
and dried. The product was purified by flash chromatography under normal-phase
condition on a silica-gel column using hexane–ethyl acetate as a eluent, yielding
4-(4-chlorobenzyl)-2-(3-(piperidin-1-yl)propyl)phthalazin-1(2H)-one (6b).
1
Yield 60%, mp 110 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 1.25–1.63 (m, 4H, -
CH2), 1.84–1.91 (m, 3H, -CH2), 2.33–2.36 (m, 7H, -CH2), 4.25–4.29 (m, 4H, -CH2),
7.19–7.26 (m, 4H, Ar-H), 7.64–7.69 (m, 3H, Ar-H), 8.43–8.46 (d, 1H, Ar-H). 13C
NMR (400 MHz, CDCl3): d ¼ 24.0 (CH2), 24.4 (CH2), 25.9 (CH2), 26.6 (CH3), 38.2
(CH2), 50.8 (CH2), 54.5 (CH2), 124.7 (ArC), 127.2 (2-ArC), 128.2 (ArC), 128.8
=
(ArC), 131.1 (2-ArC), 132.4 (ArC), 132.7 (ArC), 136.3 (ArC), 144.3 (C N), 159.1
(CO). MS (EI): m=z [M þ H] calcd. for C23H26ClN3O: 395.92; found: 396.5. Anal.
calcd. for C23H26ClN3O: C, 69.77; H, 6.62; Cl, 8.95; N, 10.61. Found: C, 69.71; H,
6.59; Cl, 8.89; N, 10.64%.
4-(4-Chlorobenzyl)-2-(3-(4-methylpiperazin-1-yl)butyl)phthalazin-1
(2H)-one (6c)
A mixture of compound 5a (3.8 g, 0.01 mol), N-methylpiperazine (0.02 mol),
and acetonitrile (5 ml) was stirred at room temperature (around 26 ꢀC) for 5 min.
The reaction mixture was exposed to microwave irradiation at initial power of
120 W at 75 ꢀC for 20 min in a self-tuning single-mode CEM Discover synthesizer.
The progress of reaction was monitored (using TLC) after 5-min intervals. The reac-
tion mixture was allowed to cool at room temperature. The reaction mixture was
poured into ice water, and the precipitated solid was collected by vacuum filtration.
The solid was washed with chilled water and dried. The product was purified by flash
chromatography under normal phase condition on a silica-gel column using hexane–
ethyl acetate as a eluent, yielding 4-(4-chlorobenzyl)-2-(3-(4-methylpiperazin-1-yl)
butyl) phthalazin-1(2H)-one (6c).
1
Yield 60%, mp 110 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 1.18–2.38 (m, 17H, -
CH2-& CH3), 4.17–4.22 (m, 4H, -CH2), 7.11–7.57 (m, 4H, Ar-H), 7.58–7.62 (m, 3H,
Ar-H), 8.35–8.38 (t, 1H, Ar-H). 13C NMR (400 MHz, CDCl3): d ¼ 24.0 (CH2), 26.5
(CH2), 29.9 (CH2), 38.2 (CH2), 46.1 (CH2), 50.8 (CH3), 53.2 (CH2), 55.1 (2-CH2),
58.2 (CH2), 124.8 (ArC), 127.3 (ArC), 128.2 (ArC), 128.8 (ArC), 128.9 (ArC), 129.7
=
(ArC), 131.1 (ArC), 132.5 (ArC), 132.7 (ArC), 136.3 (ArC), 144.4 (C N), 159.1
(CO). MS (EI): m=z [M þ H] calcd. for C24H29ClN4O: 424.96; found: 425.4. Anal.

MICROWAVE-PROMOTED SYNTHESIS
1135
calcd. for C24H29ClN4O: C, 67.83; H, 6.88; Cl, 8.34; N, 13.18. Found: C, 67.89; H,
6.84; Cl, 8.29; N, 13.14%.
4-(4-Chlorobenzyl)-2-(4-(piperidin-1-yl)butyl)phthalazin-1
(2H)-one (6d)
A mixture of compound 6d (3.6 g, 0.01 mol), piperidine (1.7 g, 0.02 mol), and
acetonitrile (5 ml) was stirred at room temperature (around 26 ꢀC) for 5 min. The
reaction mixture was exposed to microwave irradiation at initial power of 120 W at
75 ꢀC for 20 min in a self-tuning single-mode CEM Discover synthesizer. The progress
of reaction was monitored (using TLC) after 5-min intervals. The reaction mixture
was allowed to cool at room temperature and poured into ice water. Precipitated solid
was collected by vacuum filtration, washed with chilled water, and dried. The product
was purified by flash chromatography under normal phase condition on a silica-gel
column using hexane–ethyl acetate as a eluent, yielding 4-(4-chlorobenzyl)-2-(4-
(piperidin-1-yl)butyl)phthalazin-1(2H)-one (6d).
Yield 60%, mp 220 ꢀC. 1H NMR (400 MHz, CDCl3): d ¼ 1.4–1.6 (m, 8H, -CH2),
1.83–1.9 (m, H, -CH2), 2.32–2.36 (m, 3H, -CH2), 4.24–4.28 (m, 4H, -CH2), 7.18–7.25
(m, 6H, Ar-H), 7.64–7.69 (m, 2H, Ar-H), 8.42–8.45 (d, 1H, Ar-H). 13C NMR
(400 MHz, CDCl3): d ¼ 24.2 (CH2), 24.5 CH2), 26.0 (CH2), 26.7 (CH2), 38.3 (CH2),
50.9 (CH2), 54.6 (CH2), 59.2 (CH2), 124.8 (ArC), 127.3 (ArC), 128.3 (ArC), 128.9
(ArC), 129.7 (ArC), 131.2 (ArC), 132.5 (ArC), 132.8 (ArC), 136.4 (ArC), 144.4
=
(C N), 159.1 (CO). MS (EI): m=z [M þ H] calcd. for C24H28ClN3O: 409.95; found:
410.4. Anal. calcd. for C24H28ClN3O: C, 70.31; H, 6.88; Cl, 8.65; N, 10.25. Found:
C, 70.34; H, 6.90; Cl, 8.61; N,10.28%.
4-(4-Chlorobenzyl)-2-(2-(3-methoxyphenoxy)ethyl)phthalazin-1
(2H)-one (6e)
A mixture of compound 4 (2.7 g, 0.01 mol), 1-(2-bromoethoxy)-2-methoxyben-
zene (2.31 g, 0.01 mol), and toluene was stirred at room temperature (around 26 ꢀC)
for 5 min. Cetrimide (1 g) was added to the reaction mass. The reaction mixture
was exposed to microwave irradiation at initial power of 100 W and simultaneous
cooling maintained reaction temperature below 50 ꢀC for 30 min in a self-tuning
single-mode CEM Discover synthesizer. The progress of reaction was monitored
(using TLC) after 15-min intervals. The reaction resulting mixture was allowed to cool
to room temperature. The organic layer was separated and washed with water
(3 ꢂ 25 ml). The solvent was evaporated on a rotavapor under vacuum, maintaining
temperature below 60 ꢀC. The product was purified by flash chromatography under
normal phase condition on a silica-gel column using hexane–ethyl acetate as a eluent,
yielding 4-(4-chlorobenzyl)-2-(2-(3-methoxyphenoxy)ethyl)phthalazin-1(2H)-one (6e).
1
Yield 75%, mp 130 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 1.28–1.32 (s, 3H,
-OCH3), 3.9–4.27 (m, 6H, -CH2), 6.88–7.27 (m, 8H, Ar-H), 7.68–7.74 (m, 3H,
Ar-H), 8.47–8.5 (m, 1H, Ar-H). 13C NMR (400 MHz, CDCl3): d ¼ 38.3 (CH2),
50.2 (CH2), 55.9 (CH2), 64.5 (CH2), 66.5 (CH3), 114.5 (ArC), 115.0 (ArC), 121.1
(ArC), 121.8 (ArC), 124.9 (ArC), 127.4 (ArC), 128.3 (ArC), 128.8 (ArC), 129.1
(ArC), 129.8 (ArC), 131.3 (ArC), 132.5 (ArC), 133.0 (ArC), 136.2 (ArC), 144.7

1136
F. H. HAVALDAR, B. V. DABHOLKAR, AND G. B. MULE
=
(ArC), 148.5 (ArC), 149.1 (C N), 159.9 (CO). MS (EI): m=z [M þ H] calcd. for
C24H21ClN2O3: 420.88; found: 421.1. Anal. calcd. for C24H21ClN2O3: C, 68.49; H,
5.03; Cl, 8.42; N, 6.66. Found: C, 68.46; H, 5.07; Cl, 8.39; N, 6.70%.
CONCLUSION
A synergistic combination of phase-transfer catalyts and microwave techniques
can be used to carry out a number of organic reactions under mild conditions. The
substitution reactions under conventional heating take many hours and poor yields
of desired products were obtained. Our present study demonstrated that microwave
irradiation can greatly facilitate the synthesis of phthalazine moiety. Microwave
irradiation is a promising method for the synthesis organic compounds. In summary,
we have developed a simple procedure for the rapid synthesis of some biologically
active phthalazinone analogs.
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