A new and efficient synthesis of phthalazin-1(2H)-ones

Article abstract of DOI:10.1055/s-1998-2036

2-Amino-2-(aroylhydrazono)ethyl aryl ethers, readily obtained from a wide range of aryloxyacetonitriles, are converted to phthalazin-1(2H)-ones derivatives in high yields by heating in PrOH in the presence of p-TsOH.

Full text of DOI:10.1055/s-1998-2036

March 1998
SYNTHESIS
317
A New and Efficient Synthesis of Phthalazin-1(2H)-ones
A. M. Bernard,b M. T. Cocco,a* C. Congiu,a V. Onnis,a P. P. Pirasb
a Dipartimento Farmaco Chimico Tecnologico, Università di Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy
Fax +39(70)6758553; E-mail tcocco@vaxcal.unica.it
h Dipartimento di Scienze Chimiche, Università di Cagliari, Via Ospedale 72, I-09124 Cagliari, Italy
Received 28 July 1997
Abstract: 2-Amino-2-(aroylhydrazono)ethyl aryl ethers, readily
obtained from a wide range of aryloxyacetonitriles, are converted
to phthalazin-1(2H)-ones derivatives in high yields by heating in
PrOH in the presence of p-TsOH.
Key words: phthalazin-1(2H)-ones, ethyl aryl ethers, cyclocon-
densation
Phthalazin-1(2H)-ones bearing a substituent at C-4 are
key intermediates in the synthesis of compounds showing
highly interesting pharmacological activities, such as an-
tihypertensive,1 antihistaminic,2 antimicrobic activities.3
In particular, it was found that 4-(hydroxymethyl)phtha-
lazin-1(2H)-one derivatives inhibit blood platelet
aggregation4 and are active in the treatment of diabetic
complications.5
A survey of the available literature reveals that, for the
synthesis of these derivatives, 4-(hydroxymethyl)phtha-
lazin-1(2H)-one is generally utilized as the starting mate-
rial. The preparation of this compound proceed via two
major multistep pathways with unsatisfactory yields. The
first method involves reaction of 2-acetylbenzoic acid
with hydrazine,6 while the second involves reduction of 4-
(ethoxycarbonyl)phthalazin-1(2H)-ones.7 In most cases
both routes can not be applied for derivatives having sub-
a) NaOEt, EtOH; b) p-TsOH, PrOH, reflux; c) AlCl3, toluene, reflux
stituents on the benzene ring, because of the inaccessibil-
ity of the starting compounds.
Scheme
For these reasons it appears to be interesting to study new
and more versatile synthetic methods, that could provide
access to a wider variety of substituted phthalazinones.
contrary, as it is well know that electron-withdrawing sub-
stituents decrease the nucleophilicity of the benzene ring,
the presence of substituents with -M effect on the aroylhy-
drazono ring lower the yields or inhibit the reaction com-
pletely.
Our synthetic approach to the phthalazinone derivatives
involved the preliminary synthesis of 2-amino-2-(aroyl-
hydrazono)ethyl aryl ethers 3 through the reaction of the
corresponding aryloxyacetonitriles 1 and acylhydrazines
2 (Scheme).
The change from propanol to other polar protic solvents,
such as ethanol, decreased reaction rates and yields. The
reaction must be carried out in carefully anhydrous condi-
tions as the presence of traces of water gave rise to a dras-
tic decrease in the yields of phthalazinones due to the
formation of hydrolysis compounds of 3. In fact from the
reaction of 3a carried out in aqueous PrOH a mixture of
phthalazinone 4a and 1-benzoyl-2-(phenoxyacetyl)hydra-
zine 5a was obtained.
The reaction was carried out in ethanol in the presence of
sodium ethoxide and gave high yields of derivatives 3
1
that, as revealed by their H NMR spectra, are only
present as the amide hydrazone tautomers. The above
mentioned 3 were subsequently cyclized to the cor-
responding phthalazinones 4 by refluxing in PrOH for
6 hours in the presence of a catalytic amount of p-TsOH.
The intramolecular cyclization of 2-amino-2-(aroylhydra-
zono)ethyl aryl ethers 3 to phthalazinones 4 is likely to in-
volve an electrophilic attack at the ortho position of the
aroyl ring by the iminic carbon atom. To confirm this hy-
pothesis we reacted 2-amino-2-(aroylhydrazono)ethyl
aryl ethers 3 bearing various substituents on the two aro-
matic rings. Independently from the type and the position
of the substituents on the aryloxy aromatic ring high
yields of phthalazinones 4 were always obtained. On the

318
Papers
SYNTHESIS
To obtain more information regarding the role of the solvent as toluene, in the presence of a catalytic amount of AlCl3
we tested a variety of experimental conditions on 2-amino-2- gave the triazole derivative 6a instead. The same compound
(benzoylhydrazono)ethyl phenyl ether 3a. We found that 6a was also formed by cyclization of 3a with POCl3.
only the phthalazinone 4a was obtained by mild heating of a
mixture of compound 3a in AcOH/H2SO4 in a 5:1 ratio, It is important to note that, on the basis of compelling
whereas, carryingoutthereactioninanapolarsolvent, such spectroscopic evidence, the heterocyclization does not, in
Table 1. 2-Amino-2-(aroylhydrazono)ethyl Aryl Ethers 3 Prepared
Prod-
ucta
R
H
R¢
Yield mp (°C)b IR (Nujol)
(%)
1H-NMR (DMSO-d6/TMS)
d
(solvent) n (cm–1)
3a
H
50
190
3450, 3380, 4.51 (s, 2H, CH2), 6.54 (s, 2H, NH2), 7.01, 7.29, 7.45, 7.80 (m, 10Harom),
(EtOH)
3160, 1650, 9.87 (s, 1H, NH)
1630
3b
3c
3d
2-CH3
3-CH3
4-CH3
H
H
H
65
80
77
170
(EtOH)
3480, 3200, 2.19 (s, 3H, CH3), 4.52 (s, 2H, CH2), 6.51 (s, 2H, NH2), 6.83, 7.00, 7.43,
1670, 1630
7.80 (m, 9Harom), 9.90 (s, 1H, NH)
168
(EtOH)
3450, 3190
2.25 (s, 3H, CH3), 4.48 (s, 2H, CH2), 6.52 (s, 2H, NH2), 6.80, 7.15, 7.44,
1660, 1600, 7.79 (m, 9Haromm), 9.86 (s, 1H, NH)
170
3470, 3140
2.20 (s, 3H, CH3), 4.48 (s, 2H, CH2), 6.59 (s, 2H, NH2), 6.91, 7.07, 7.43,
(EtOH)
1670, 1625, 7.81 (m, 9Harom), 9.90 (s, 1H, NH)
1605, 1575
3e
3f
2-OCH3
3-OCH3
4-OCH3
2-Cl
3-Cl
4-Cl
4-NO2
H
H
55
87
65
73
85
80
92
78
70
76
78
84
58
190
3400, 3210, 3.75 (s, 3H, CH3), 4.50 (s, 2H, CH2), 6.54 (s, 2H, NH2), 6.87, 6.95, 7.08,
(MeOH) 1670, 1630, 7.43, 7.81 (m, 9Harom), 9.90 (s, 1H, NH)
1610, 1590
H
180
(EtOH)
3420, 3220, 3.68 (s, 3H, CH3), 4.49 (s, 2H, CH2), 6.57 (s, 2H, NH2), 6.51, 7.14, 7.41,
1675, 1645, 7.78 (m, 9Harom), 9.92 (s, 1H, NH)
1600
3g
3h
3i
H
190
(EtOH)
3460, 3150, 3.66 (s, 3H, CH3), 4.45 (s, 2H, CH2), 6.52 (s, 2H, NH2), 6.92, 7.43, 7.79
1675, 1640, (m, 9Harom), 9.86 (s, 1H, NH)
1610, 1580
H
187
(EtOH)
3420, 3190, 4.58 (s, 2H, CH2), 6.54 (s, 2H, NH2), 6.94, 7.24, 7.41, 7.78 (m, 9Harom),
1675, 1640, 9.93 (s, 1H, NH)
1620, 1600
H
190
(EtOH)
3430, 3200, 4.52 (s, 2H, CH2), 6.55 (s, 2H, NH2), 6.98, 7.07, 7.29, 7.43, 7.77 (m,
1680, 1650, 9Harom), 9.87 (s, 1H, NH)
1630, 1600
3j
H
197
(EtOH)
3440, 3190, 4.53 (s, 2H, CH2), 6.60 (s, 2H, NH2), 7.04, 7.32, 7.44, 7.80 (m, 9Harom),
1680, 1640, 9.89 (s, 1H, NH)
1625, 1595
3k
3l
H
148
(PrOH)
3440, 3350, 4.70 (s, 2H, CH2), 6.55 (s, 2H, NH2), 7.21, 7.34, 7.87, 8.18 (m, 9Harom +
3170, 1620, NH)
1585
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
185
(PrOH)
3440, 3230, 2.28 (s, 3H, CH3), 4.46 (s, 2H, CH2), 6.40 (s, 2H, NH2), 6.82–7.32 (m,
1690, 1650, 9Harom), 9.81 (s, 1H, NH)
1630, 1600
3m
3n
3o
3p
3q
H
150
(EtOH)
3460, 3210, 2.31 (s, 3H, CH3), 4.49 (s, 2H, CH2), 6.53 (s, 2H, NH2), 6.94, 7.00, 7.27,
1690, 1655, 7.60 (m, 9Harom), 9.83 (s, 1H, NH)
1630
H
190
(PrOH)
3460, 3430, 2.30 (s, 3H, CH3), 4.49 (s, 2H, CH2), 6.54 (s, 2H, NH2), 6.92, 6.99, 7.27,
3220, 1675, 7.70 (m, 9Harom), 9.82 (s, 1H, NH)
1630
H
195
(PrOH)
3420, 3210, 4.47 (s, 2H, CH2), 6.41 (s, 2H, NH2), 6.83–7.48 (m, 9Harom), 9.96 (s, 1H,
1680, 1640, NH)
1615, 1590
H
150
(EtOH)
3430, 3220, 4.51 (s, 2H, CH2), 6.62 (s, 2H, NH2), 6.93, 6.99, 7.26, 7.43, 7.80 (m,
1680, 1640, 9Harom), 10.00 (s, 1H, NH)
1620, 1600
H
180
3440, 3370, 4.50 (s, 2H, CH2), 6.58 (s, 2H, NH2), 6.98, 7.27, 7.47, 7.83 (m, 9Harom),
(PrOH)
3230, 1680
1645, 1620
9.94 (s, 1H, NH)
a Satisfactory microanalyses obtained for all compounds.
b Uncorrected melting points.

March 1998
SYNTHESIS
319
4-(Phenoxymethyl)phthalazin-2(1H)-one (4a); Typical Procedure:
Method A: To a suspension of 2-amino-2-(benzoylhydrazono)ethyl
phenyl ether (3a; 0.5 g, 1.85 mmol) in anhyd PrOH (15 mL) was add-
ed p-TsOH (0.15 g, 0.9 mmol). After heating at reflux for 6 h the sol-
vent was removed in vacuo and the residue treated with H2O (20 mL)
and extracted with CHCl3 (3 ´ 10 mL). The organic layers were dried
(Na2SO4) and the solvent evaporated to give the crude 4a which was
purified by recrystallization (hexane); yield: 0.4 g (86%).
any case, proceed to give benzofuran derivatives which
could also be obtained from compounds 3 in acidic medi-
um.
Melting points were determined on a Kofler hot stage and are uncor-
rected. IR spectra were recorded on Nujol mulls between NaC1 plates
1
on a Perkin–Elmer 398 spectrophometer. H and 13C NMR spectra
13C NMR (CDCl3): d = 59.67 (t, CH2), 114.60 (d, C-2¢, C-6¢), 121.95
(d, C-4¢), 123.21 (s, C-10), 126.83 (d, C-5, C-8), 128.83 (d, C-3¢, C-
5¢), 129.49 (d, C-7), 129.86 (s, C-9), 131.79 (d, C-6, C-7), 157.31 (s,
C-4), 162.09 (s, C-1¢), 166.55 (s, C-1)
were recorded on a Varian Unity 300 spectrometer. MS were record-
ed with a Fisons QMD 1000 spectrometer in EI mode at 70 eV. Ele-
mental analyses were carried out with a Carlo Erba Model 1106
Elemental Analyzer.
MS: m/z (%) = 252 (M+, 45), 159 (87), 105 (100), 77 (41)
2-Amino-2-(aroylhydrazono)ethyl Aryl Ethers 3; General Proce- Method B: To 2-amino-2-(benzoylhydrazono)ethyl phenyl ether (3a;
dure:
0.5 g, 1.85 mmol) in AcOH (5 mL) was added 96% H2SO4 (3 drops)
To a stirred solution of NaOEt (0.005 mol) in anhyd EtOH (5 mL) was and the resulting solution was stirred at r.t. for 0.5 h. The precipitated
added the appropriate aryloxyacetonitrile 1 (0.05 mol). The mixture phthalazinone 4a was filtered off, washed with H2O and purified as
was stirred at r.t. for 1 h and, after cooling to 0 °C, an ethanolic solution described above; yield: 0.46 g (98%).
of aroylhydrazine 2 (0.05 mol) was added dropwise. The resulting so-
lution was stirred at the same temperature for 2 h and then allowed to 1-Benzoyl-2-(phenoxyacetyl)hydrazine (5a):
reach r.t. and stand ovemight. The formed precipitate was collected by To a suspension of 2-amino-2-(benzoylhydrazono)ethyl phenyl ether
filtration and recrystallized from the solvent given in Table 1.
(3a; 0.5 g, 1.85 mmol) in aq PrOH (15 mL) was added p-TsOH
Table 2. 4-(Aryloxymethyl)phthalazin-2(1H)-one Derivatives 4 Prepared
Prod-
ucta
R
R¢
Yield mp (°C)b
(%) (Solvent)
IR (Nujol)
1H-NMR (CDCl3/TMS)
d
n (cm–1)
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
H
86
93
94
98
89
97
98
65
92
98
63
95
(hexane)
3060, 1600
3060, 1600
3040, 1610
3050, 1610,
5.28 (s, 2H, CH2), 6.98, 7.01, 7.48, 8.02 (m, 9H+ NH)
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
4-OCH3
2-Cl
3-Cl
4-Cl
4-NO2
H
87
2.27 (s, 3H, CH3),5.34 (s, 2H, CH2), 6.97, 7.17, 7.54, 8.08 (m,
8Harom + NH)
(cyclohexane)
71
(hexane)
2.28 (s, 3H, CH3), 5.25 (s, 2H, CH2), 6.80, 7.17, 7.43, 8.03 (m,
8Harom + NH)
80
2.30 (s, 3H, CH3), 5.30 (s, 2H, CH2), 6.95, 7.12, 7.50, 8.08 (m,
8Harom + NH)
(cyclohexane) 1585
85
(hexane)
3080, 1600
3060, 1605,
3.80 (s, 3H, CH3), 5.31 (s, 2H, CH2), 6.94, 7.43, 8.01 (m, 8Harom
NH)
+
90
3.80 (s, 3H, CH3), 5.32 (s, 2H, CH2), 6.61, 7.22, 7.53, 8.08 (m,
8Harom + NH)
(cyclohexane) 1595
4g
4h
4i
85
3040, 1610
3.77 (s, 3H, CH3), 5.27 (s, 2H, CH2), 6.86, 6.98, 7.53, 8.08 (m,
8Harom + NH)
(cyclohexane)
125
(cyclohexane)
3060, 1590
3060, 1595,
5.40 (s, 2H, CH2), 6.97, 7.18, 7.41, 7.53, 8.08 (m, 8Harom + NH)
5.32 (s, 2H, CH2), 7.00, 7.22, 7.53, 8.08 (m, 8Harom + NH)
5.47 (s, 2H, CH2), 7.13, 7.34, 7.59, 7.97 (m, 8Harom + NH)
5.37 (s, 2H, CH2), 7.10, 7.46, 8.01, 8.19 (m, 8Harom + NH)
95
(cyclohexane) 1580
4j
124
(ligroine)
3060, 1600
4k
4l
156
(benzene)
3060, 1585
6-CH3 30
7-CH3 97
8-CH3 98
140
(i-PrOH)
3050, 1625,
1600
2.36 (s, 3H, CH3), 5.25 (s, 2H, CH2), 7.00, 7.26, 7.87 (m, 8Harom
NH)
+
4m
4n
4o
4p
4q
H
68
(hexane)
1600, 1550,
1500
1.61 (s, 3H, CH3), 5.33 (s, 2H, CH2), 7.06, 7.35, 7.90 (m, 8Harom + NH)
H
75
(hexane)
3040, 1600,
1585, 1540
2.70 (s, 3H, CH3), 5.35 (s, 2H, CH2), 7.05, 7.31, 7.43, 7.95 (m,
8Harom + NH)
H
6-Cl
7-Cl
8-Cl
43
87
83
70
(hexane)
3050, 1600,
1580
5.26 (s, 2H, CH2), 6.99, 7.26, 7.43, 7.95 (m, 8Harom + NH)
5.26 (s, 2H, CH2), 6.99, 7.38, 7.45, 7.92, 8.00 (m, 8Harom + NH)
5.27 (s, 2H, CH2), 7.06, 7.30–7.57, 8.00 (m, 8Harom + NH)
H
60
(hexane)
3050, 1580
H
75
(hexane)
300, 1590,
1580
a Satisfactory microanalyses obtained for all compounds.
b Uncorrected melting points.

320
Papers
SYNTHESIS
(0.15 g, 0.9 mmol). After heating at reflux for 6 h, the formed preci-
pitate was filtered off and recrystallized from i-PrOH to give 5a;
yield: 0.25 g (50%); mp 185 °C.
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IR (Nujol): n = 3420, 3220, 1700, 1660 cm–1.
1H NMR (DMSO-d6): d = 4.60 (s, 2H, CH2), 6.97, 7.26, 7.46, 7.83
(m, 10Harom), 10.29 (br s, 2H, NH).
From evaporation of the mother solution phthalazinone 4a was isolat-
ed in 20% yield.
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5-(Phenoxymethyl)-3-phenyl-(1H)-1,2,4-triazole (6a):
Method A: A mixture of 2-amino-2-(benzoylhydrazono)ethyl phenyl
ether (3a; 0.5 g, 1.85 mmol) and AlCl3 (0.25 g, 1.85 mmol) in anhyd
toluene (50 mL) was heated at reflux for 10 h. The solvent was evap-
orated to give the triazole 6a (0.36 g, 85%) which was recrystallized
(benzene); mp 157 °C.
IR (Nujol): n = 3130, 3030, 1590, 1580 cm–1.
1H NMR (DMSO-d6): d = 5.16 (s, 2H, CH2), 6.90, 7.23, 7.33, 7.94 (m,
11H, Ar + NH).
Method B: A mixture of 2-amino-2-(benzoylhydrazono)ethyl phenyl
ether (3a; 0.5 g, 1.85 mmol) and POCl3 (5 mL) was heated at reflux
for 3 h. After cooling, H2O was added and the formed precipitate fil-
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in 66% yield.
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