Xanthones in heterocyclic synthesis. An efficient and general route for the synthesis of regioselectively substituted phthalazines

Article abstract of DOI:10.3987/COM-11-12168

Xanthone undergoes regioselective substitution and nucleophically - triggered ring opening to the corresponding ketone. Hydrazone of the latter oxidatively rearranges to ortho-diacylarenes, which, then, with hydrazine gives regioselectively substituted phthalazines. Molecular modeling analysis and 1HNMR spectra indicate an intramolecular H-bonding engaging phenol OH and phthalazine N-3 atom.

Full text of DOI:10.3987/COM-11-12168

HETEROCYCLES, Vol. 83, No. 6, 2011
1291
HETEROCYCLES, Vol. 83, No. 6, 2011, pp. 1291 - 1302. © The Japan Institute of Heterocyclic Chemistry
Received, 8th February, 2011, Accepted, 30th March, 2011, Published online, 1st April, 2011
DOI: 10.3987/COM-11-12168
XANTHONES IN HETEROCYCLIC SYNTHESIS. AN EFFICIENT AND
GENERAL ROUTE FOR THE SYNTHESIS OF REGIOSELECTIVELY
SUBSTITUTED PHTHALAZINES
Yiannis Gardikis,a Petros G. Tsoungas,b* Constantinos Potamitis,c George
Pairas,a Maria Zervou,c and Paul Cordopatisa*
a Department of Pharmacy, University of Patras, Rio-Patra 26504, Greece
b Ministry of Education/Research & Technology, Athens 14631, Greece
c Institute of Organic & Pharmaceutical Chemistry, National Hellenic Research
Foundation, Athens 11635, Greece
Fax: +30-210-7713810; +30-2610-997714
E-mail: pgt@gsrt.gr; pacord@upatras.gr
Abstract - Xanthone undergoes regioselective substitution and nucleophically -
triggered ring opening to the corresponding ketone. Hydrazone of the latter
oxidatively rearranges to ortho-diacylarenes, which, then, with hydrazine gives
1
regioselectively substituted phthalazines. Molecular modeling analysis and H
NMR spectra indicate an intramolecular H-bonding engaging phenol OH and
phthalazine N-3 atom.
INTRODUCTION
Phthalazines, like the other members of the isomeric benzodiazine series, have found wide application as
therapeutic agents.1 Despite their significance, there are a rather limited number of efficient routes for
their synthesis, especially when diverse substitution on both rings is required. Phthalazines bearing no
substitution on the pyridazine ring can be prepared from o-phthalaldehydes through suitable precursors,2
reductive3 or oxidative4 cleavage of heterocycles or lithiation followed by formylation.5 1- or
1,4-substituted congeners are usually accessible from their corresponding 1,2-diacyl arenes,6
acid-catalyzed cyclodehydration of hydrazones,7 acid-catalyzed rearrangement of Reissert compounds,8
acid-catalyzed cyclization of azines,9 thermally-induced cyclization of phthalanol,10 reductive opening of
γ-lactones11 or Suzuki coupling of chloro-substituted phthalazines.12 Drawbacks common to most of these

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HETEROCYCLES, Vol. 83, No. 6, 2011
methods are multi-step schemes, rather forcing conditions and, most important, no diversity in
substitution.
A phthalazine scaffold, incorporating a phenol ring directly attached to the heterocycle, has been essential
to our needs for a recently developed project on selective binding at nicotinic acetylcholine receptor
orthosteric sites. To that end, we report, herein, an efficient and general route for the synthesis of
phthalazines, substituted or derivatized regioselectively, on either of the rings. The resulting structure can,
thus, be a scaffold for a diverse array of analogues bearing at least one(het)aryl group. The diversity of
phenols, their simple conversion to bromides13 or triflates14 and the value of these derivatives in coupling
reactions, in addition to their well-known medical applications,15 are a useful asset to the synthetic
potential of the proposed route.
RESULTS AND DISCUSSION
R1
O
O
R2
R1
OR3
(i) or (ii) or (iii)
(iv)
R2
Y
O
O
1
2
OH
a. R1 = H; R2 = H
(a) R3 = H, (b) R3 = Me
(c) R3 = Et, (d) R3 = iPr
b. R1 = 2-NO2; R2 = H
c. R1 = 2-Br; R2 = H
d. R1 = 2-Br; R2 = 7-Br
e. R1 = 4-Me; R2 = H
f. R1 = 4-Me; R2 = 5-Me
g. R1 = 4-I; R2 = 5-I
h. R1 = 2-Ph; R2 = H
i. R1 = 2-Ph; R2 = 7-Ph
3 Y = O
(v)
4 Y = H2NNHCOX
(vi)
R1
R1
R1
R1
X
OR3
OR3
R2
X
R2
R2
O
R2
O
O
+
(vii)
+
O
N
N
N
N
OR3
23 - 28
OR3
X
X
6
5
7 - 22
o
Scheme 1. (i) c. HNO3/c. H2SO4/rt.16 or (ii) a) Br2/AlCl3/Δ or b) Br2 (10-fold excess)/AcOH/100 C. or
t
o
(iii) a) SOCl2/DMF/Δ, b) NaOMe/MeOH-THF, c) BuLi/THP/-13 – (-10) C/H+/H2O.16,17 (iv) 12N
KOH/Δ/H+ or NaOR (R = Me, Et, Pr)/Δ sealed tube/H+.18 (v) H2NNHCOX/iPrOH/py/Δ/12 h. (vi)
Pb(OAc)419 or PhI(OAc)2 /Et2O or THF/0 oC to rt. (vii) H2NNH2/EtOH (or iPrOH)/ rt/45 min.
i
19

HETEROCYCLES, Vol. 83, No. 6, 2011
1293
The proclivity of 117,20 to substitution with a synthetically useful degree of regioselectivity allows its
diverse functionalisation. Conventional electrophilic substitution, using nitration and bromination, has
been detailed in a preceding report.16 The NO2 group is introduced at C-2 (or C-7). The bromine, on the
other hand, enters C-2, predominantly but C-7 is also attacked to a lesser extend to give the dibromo
derivative. Clearly, entries at C-2 and C-7 are facilitated by and directed from the pyran O lone pair.
These entries serve as sites of further functionalisation. For example a phenyl group can be incorporated
into 2c or 2d (Scheme 1), under Suzuki conditions, to give 2h or 2i, respectively. Complementary to the
above functionalisation of 1 is a lithiation-electrophilic quench protocol17 to C-1, C-4 and C-5 as the
active sites for mono- or disubstitution (Scheme 1). Having 2 regioselectively substituted, it undergoes a
nucleophilically-triggered ring opening to the ketone (3). The cleaving nucleophile, through an SNAr
process, ends up ortho- to the ketone carbonyl moiety. The cleavage is efficiently performed with alkali
(yields up to 80%) whereas moderate yields of ca.50% are obtained when an alkoxide is used.16 In the
latter case one of the OH groups is protected as an alkyl ether (Scheme 1, 3b-d).
Generation of hydrazone 4, straightforward as would be expected, presented difficulties at first,
presumably due to the interfering intramolecularly H-bonded OH groups. Protection by O-benzylation
was initially carried out as the obvious means to remove the H-bonding effect. Having prepared the
benzyl ether of 3, the release of the OH groups was then attempted by either Mg/MeOH21 or MgBr2,22 in
both cases unsuccessfully. Deprotection was then accomplished by ammonium formate over Pd/C.23
Removing the protection-deprotection steps adds to the elegance and performance of the scheme.24 Thus,
4 was finally obtained very efficiently by simply heating unprotected 3 with the hydrazide in the presence
of pyridine.
Treatment of 4 with either lead(IV) acetate (LTA)19 or phenyliododiacetate (PIDA)19 induces an oxidative
rearrangement leading to 5 (and 6). This reaction encompasses25 a ligand coupling followed by a series of
rearrangements. The overall process is a C-O to C-C bond conversion. The last step of the scheme is a
simple condensation of 5 (or 6) with hydrazine hydrate (stirring for 45 min in isopropanol at room
temperature) to 7-28 (Table 1).
From the scheme and the tabulated results certain features emerge: (a) the cleavage of 2 introduces the
desired phenol, regioselectively substituted or not, ultimately at C-1 (or C-4) of the phthalazine structure.
(b) when unsubstituted, 3 leads to a single phthalazine isomer (Table 1, entries 7-9 and 17, 19, 20 and 22).
Similarly the alkyl ether of 3 also leads to a single isomer (Table 1, entries 10-12), (c) the type of
hydrazide used to form 4 determines the o-diacyl arene substitution pattern and ultimately that of
phthalazine isomer(s) formed, (d) 5 and 6 need not be separated but can be reacted as a mixture to yield
7-28, (e) 13-16 and 21 as well as their regioisomers 23-26 and 28 are generated from the alternative
modes of oxidative rearrangement of 4 whereas 17, 19, 20 and 22, being symmetrically substituted, yield
only one isomer.

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Table 1. Regioselectively Substituted Phthalazines 7-22 and 23-28
R1
R1
X
OR3
R2
R2
N
N
N
N
OR3
X
23 - 28
7 - 22
Yield
%
Yield
%
Entry
R1
H
R2
H
R3
X
(mp oC) Entry
(168)
R1
R2 R3
X
(mp oC)
7
8
H
Me
Ph
88
H
H
H
90
(222)
9
H
H
H
H
H
H
H
H
Me
Et
2΄-py
Me
90
84
88
81
52
(172)
(oil)
(64)
(61)
10
11
12
13
H
Ph
H
i Pr 2´-py
5´-NO2
H
H
Me
Ph
(164)
(178)
23
24
6- NO2
6- NO2
H
H
H
H
Me
Ph
22
(136)
14
5´-NO2
H
58
26 a)
15
16
17
18
19
20
21
22
5´-Br
5´-Br
5´-Br
3´-Me
3´-Me
3´-I
H
H
H
H
H
H
H
H
H
H
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
42
44
89
43
88
90
45
85
(116)
(127)
(153)
(76)
25
26
6-Br
6-Br
H
H
H
H
Me
Ph
44 a)
47a)
6 -Br
H
27
28
8-Me
6-Ph
H
H
H
H
Ph
Ph
38a)
8-Me
8-I
(94)
(228)
(231)
(246)
5´-Ph
5´-Ph
H
42a)
6-Ph
a) Not isolated. Identified by 1H NMR spectra.
A molecular modeling analysis26 was performed on 9 to depict inherent conformational features (Figure
1). Indeed, lowest energy conformers A-D exhibit the potential of an intramolecular H-bonding
1
interaction between the phenolic OH and the nearest ring N atom. This is in concert with a H NMR
signal at δ = 9.05 ppm and an IR absorption at 3360 cm-1 attributed to the OH bonded proton. A very
modest elongation of 0.001Å, observed in A-D conformers lends support to a weak such interaction. The
bond length shows a more notable increase of 0.003Å when compared to that of parent phenol.27

HETEROCYCLES, Vol. 83, No. 6, 2011
1295
A
E = 164,252 kJ/mol
B
E = 164,252 kJ/mol
C
E = 164,437 kJ/mol
E= 164,252 kJ/mol
OH
N
N
N
9
6c
D
E = 164,437 kJ/mol
E
E = 165,701kJ/mol
Figure 1. Conformers A-D of 9 forming intramolecular hydrogen bond (green dashed lines). The
potential energy of each conformer is depicted under each one of them.
Interestingly, the H-bonded sites, particularly in conformers B and D, as well as those in conformers B
and C, having the pyridine and phthalazine N atoms in-phase, are in effect bidentate sites, available for
metal chelation or intermolecular H-bonding. Sites of this type are important for interaction with a
protein’s “hinge” region.28
In conclusion, an efficient protocol for the synthesis of regioselectively substituted phthalazines has been
developed. Key features, integrated in the scheme, signifying its scope and potential are (a) the
regioselectivity of substitution pattern of xanthone (1) that secures and extends regioselectivity for all
ensuing structures and eventually the target phthalazines (not accessible by other methods) (b) the
nucleophilically–triggered cleavage of xanthone 2, (c) C-arylation of phenols29 and thence molecular
harpoons30 (d) the oxidative rearrangement of hydrazones 4 to phthalazines 7-28 and (d) the effect of the
nature and pattern of substitution on the isolation of a single or both possible phthalazine isomers.
Credence to the value of this protocol are the simplicity and efficiency of its individual transformations.
It is clear at the outset that the derivatization potential of 1, as exemplified by this protocol, sets the scene
for various transformations on 7-28, hence inviting for a diverse array of heterocyclic structures with a
phthalazine scaffold. Work on this line will be reported in due course.

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HETEROCYCLES, Vol. 83, No. 6, 2011
EXPERIMENTAL
Melting points were measured on an Electrothermal IA9000 Series apparatus and are uncorrected.
Infrared spectra were recorded or an FT/IR-5300 spectrometer as KBr discs. Elemental analyses were
performed on a Carlo Erba 1106 analyser. NMR spectra were measured on a Bruker Avance 400MHz and
a Varian 600 MHz spectrometers, in CDCl3 or DMSO-d6 solutions. Mass spectra were recorded by
Micromass - Platform LC or JEOL JMS-AX505W low or high resolution instruments. Analytical TLC
was run on Fluka Silica Gel F254. Preparative Flash Chromatography was run on MERCK 9385 Silica
Gel. Reagents were used as commercially purchased while solvents such as CH2Cl2, EtOAc, hexane and
MeOH were purified and dried according to standard procedures.
Xanthones (2): prepared and identified as described in recent reports.16,17
2,2Dihydroxybenzophenones (3): prepared and identified as described in recent reports.19
Hydrazones (4). Typical procedure: To a solution of 3 in isopropanol the hydrazide (3-fold excess)
andpyridine (5-fold excess) were added and the mixture was heated for 12 h. Cooling to room
temperature, addition of xylene and concentration in vacuo was followed by column chromatography
(ethylacetate/petroleum ether 3:1) to give 4 as a pale yellow solid (yields 65-72%).
All compounds were identified by their IR or 1H NMR spectra and were compared with literature data.19
4b: Rf = 0.43. Mp 137 oC. IR (KBr) 3317, 3280, 1649 cm-1. 1H NMR (400MHz, CDCl3):  10.97 (br, 6H,
aromatic), 7.20 (dd, 1H, J = 7.6 Hz, aromatic), 7.10 (d, 1H, J = 8.0 Hz, aromatic), 7.05-6.95 (m, 3H,
13
aromatic), 6.84 (dd, 1H, J = 7.67 Hz, aromatic), 6.81-6.72 (m, 1H, aromatic). C NMR (400 MHz,
CDCl3):  163.4, 161.5, 161.0, 155.7, 133.0, 132.5, 130.7, 130.0, 129.3, 128.9, 127.8, 127.6, 121.5, 120.0,
118.0, 117.9, 117.5. ESMS (M+H): m/z 333.
4c: Rf = 0.23. Mp 165 oC. IR (KBr): 3320, 3270, 1647 cm.-1 1H NMR (400 MHz, CDCl3):  13.06 (s, 1H,
OH), 8.75-8.02 (m, 2H, aromatic), 7.55-7.47 (m, 2H, aromatic), 7.41 (dd, 1H, J = 7.72 Hz, aromatic),
7.29 (dd, 1H, J = 7.72 Hz, aromatic), 7.19 (d, 1H, J = 6.53 Hz, aromatic), 7.08 (d, 1H, J = 8.24 Hz,
13
aromatic), 7.03-6.6.96 (m, 2H, aromatic), 6.85-6.74 (m, 3H, aromatic). C NMR (100MHz, CDCl3): 
161.3, 161.1, 157.6, 155.6, 151.3, 147.6, 137.5, 133.0, 132.4, 131.0, 126.7, 124.5, 122.1, 121.4, 121.1,
118.4, 117.9, 117.6. ESMS (M+H): m/z 334.
Ortho-Diacylbenzenes (5) (and (6)). Typical procedure: To a solution of 4 in THF, Pb(OAc)4 (or
o
PhI(OAC)2) (in 25% excess) was added portiorwise, under stirring, over 15 min. at ca.0-5 C. The
mixture was, then, allowed to reach room temperature and was stirred for 3-4 h. Filtration, concentration
of filtrate and column chromatography (ethylacetate/petroleum ether 5:1) gave 5 and 6 as off- white solids
(yields 74-86%). All compounds were identified by their IR or 1H NMR spectra and were compared with
literature data.19

HETEROCYCLES, Vol. 83, No. 6, 2011
1297
Where isomers are formed they may not be isolated and can be reacted as a mixture to generate
phthalazine isomers (7) and (8).
1
5c: Rf = 0.53. Mp 142 oC. IR (KBr) 3241, 1687, 1685 cm-1. H NMR (400 MHz, CDCl3):  11.64 (s, 1H,
OH), 8.07 (d, 1H, J = 7.91 Hz), 7.73-7.65 (m, 2H, aromatic), 7.61 (d, 1H, J = 7.17 Hz), 7.43-7.40 (m, 3H,
aromatic), 7.22 (s, 1H, aromatic), 7.51-7.44 (m, 2H, aromatic), 7.00 (d, 1H, J = 8.55 Hz, aromatic), 6.82
(dd, 1H, J = 7.61 Hz, aromatic). 13C NMR (100 MHz, CDCl3):  196.4, 189.3, 162.2, 155.1, 151.6, 148.2,
143.8, 137.5, 133.9, 133.2, 133.0, 132.3, 127.7, 126.3, 124.1, 123.9, 120.5, 117.5. ESMS (M+H): m/z
304.
5d: Rf = 0.72. Viscous oil. IR (KBr) 1680, 1675 cm-1. 1H NMR (400 MHz, CDCl3):  1 7.64-7.40 (m, 4H,
13
aromatic), 7.40-7.30 (m, 5H, aromatic), 6.90-6.70 (m, 4H, aromatic), 3.80 (s, 3H, OMe), C NMR (100
MHz, CDCl3):  195.8, 189.6, 161.1, 151.2, 138.7, 137.4, 135.6, 134.4, 133.6, 133.1, 132.3, 128.4, 127.1,
126.2, 124.1, 123.1, 121.6, 121.2, 119.0, 116.4, 57.6. ESMS (M+H): m/z 317.
1-Methyl-4-[2-hydroxyphenyl]phthalazine (7): off-white microcrystals, Mp 168 oC. IR (KBr) max cm-1.
3350 (OH), 3045, 1605. 1H NMR (CDCl3) : 2.71, (s, 3H), 6.88-6.55 (m, 2H), 7.25-7.15 (m, 2H), 7.41 (d,
13
2H, J = 7.6 Hz), 7.65-7.60 (m, 2H), 7.75 (s, 1H, OH). C NMR (CDCl3) : 155.1, 152.1, 133.5, 133.2,
130.1, 129.5, 129.1,128.8, 127.6, 126.5, 126.4,121.4, 120.6, 115.7, 44.2. ESMS (M+H): m/z 237. Anal.
Calcd for C15H12N2O: C, 76.27; H, 5.08; N, 11.86. Found: C, 76.03; H, 4.89; N, 11.70%.
o
1-Phenyl-4-[2-hydroxyphenyl]phthalazine (8): off-white powder, Mp 222 C. IR (KBr): 3360 (OH),
1
3030, 1602 cm-1. H NMR (CDCl3): 7.40 (s, 2H, J = 7.8 Hz) 7.66-7.55 (m, 3H), 7.82-7.44 (m, 3H),
13
8.40-7.90 (m, 2H), 10.21(brs, 1H, OH). C NMR (CDCl3) : 155.3, 152.2, 152.1, 133.4, 133.2, 133.1,
131.5, 130.1, 129.5, 129.2, 128.8, 127.6, 127.4, 126.6, 126.4,121.9, 121.4, 120.6, 117.9. ESMS (M+H):
m/z 299. Anal. Calcd for C20H14N2O: C, 80.53; H, 4.69; N, 9.38. Found: C, 80.25; H, 4.50; N, 9.10%.
o
1
1-[2-Pyridyl]-4-[2-hydroxyphenyl]phthalazine (9): Mp 172 C. IR: 3360 (OH), 3082, 1602 cm-1. H
NMR (CDCl3). : 7.06-7.11 (m, 1H), 7.41-7.44 (m, 1H), 7.46-7.49 (m, 1H), 7.55-7.61 (m, 1H), 7.74 (dd,
1H, J = 7.81 Hz, J = 1.59 Hz), 7.93-8.01 (m, 2H). 13C NMR (CDCl3) : 155.6, 155.3, 152.3,149.3, 137.5,
133.5, 133.3, 131.2, 126.9, 126.8, 126.6, 124.8, 124.6,124.2,123.8, 123.4, 121.8, 120.7, 117.8. ESMS
(M+H): m/z 300. Anal. Calcd for C15H13N3O: C, 76.25; H, 4.34; N, 14.04. Found: C, 76.02; H, 4.18; N,
13.86%.
1
1-Methyl-4-[2-methoxyphenyl]phthalazine (10): viscous oil. IR (KBr): 3050, 1605 cm-1. H NMR
(CDCl3) : 3.70 (t, 3H), 4.30 (q, 2H), 7.45 (d, 2H, J = 7.8 Hz), 7.70-7.60 (m, 3H), 7.85-7.75 (m, 3H),
13
8.50-7.90 (m, 2H). C NMR (CDCl3) : 159.8, 152.4, 133.2, 133.1, 131.4, 130.1, 129.4, 128.8, 127.6,
127.4, 126.4,126.2, 121.9, 120.5, 114.0, 82.0, 54.50, 44.0. ESMS (M+H): m/z 265. Anal. Calcd for
C17H16N2O: C, 77.27; H, 6.06; N, 10.60. Found: C, 77.01; H, 5.88; N, 10.36%.

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HETEROCYCLES, Vol. 83, No. 6, 2011
1-Phenyl-4-[2-ethoxyphenyl]phthalazine (11): off-white powder, Mp 64 oC. IR (KBr): 3050, 1605cm-1.
1H NMR (CDCl3) : 1.30 (t , 3H), 4.3 (m, 1H), 7.50 (d, 2H, J = 7.9 Hz), 7.65-7.60 (m, 3H), 7.80-7.75 (m,
13
3H), 8.40-7.80 (m, 2H). C NMR (CDCl3) : 155.3, 152.3, 133.4, 133.2, 133.1, 129.9, 129.6, 128.8,
127.6, 126.7, 126.4,126.2, 126.0, 121.8, 121.5, 121.2 ,120.0, 117.4, 115.5, 78.0, 43.0. ESMS (M+H): m/z
341. Anal. Calcd for C23H20N2O: C, 81.17; H, 5.88; N, 8.23. Found: C, 80.89; H, 5.68; N, 8.01%
o
1-[2Pyridyl]-4-[2-isopropoxyphenyl]phthalazine (12): off-white powder, Mp 61 C. IR (KBr): 3030,
1
1605 cm-1. H NMR (CDCl3) : 3.20 (dd, 6H), 4.2 (m, 1H), 7.10-7.06 (m, 1H), 7.45-7.40 (m, 1H),
7.60-7.50 (m, 1H), 7.65-7.60 (m, 1H), 7.757.50 (dd, 1H, J = 7.9 Hz, J = 1.60 Hz), 8.0-7.90 (m, 2H),
8.13-8.06 (m, 1H), 8.20-8.15 (m, 1H), 8.50 (dd, 1H, J = 6.8 Hz, J = 2.4 Hz), 8.80 (dd, 1H, J = 4.8 Hz, J =
1.5Hz). 13C NMR (CDCl3) : 155.6, 155.3, 152.3, 149.3, 137.5, 133.5, 133.3, 131.2, 126.9, 126.7, 126.4,
124.8, 124.6,124.2, 123.8, 123.4,121.8 ,120.7, 117.8, 76.4, 44.5. ESMS (M+H): m/z 341. Anal. Calcd. for
C22H19N2O: C, 77.19; H, 5.55; N, 12.28. Found: C, 77.01; H, 5.39; N, 11.99%
o
1-Methyl-4-[2-hydroxy-5-nitrophenyl]phthalazine (13): pale yellow flakes, Mp 164 C. IR (KBr):
1
3360 (OH), 1610, 152 5 (NO2), 1340 (NO2) cm-1. H NMR (DMSO-d6) : 2.80 (s, 3H), 8.23 (m, 2H),
13
8.73 (s, 1H), 6.90-6.60 (m, 2H), 7.25-7.20 (m, 2H), 7.75 (brs, 1H,OH). C NMR (DMSO-d6) : 155.2,
152.2, 148.3, 134.3, 133.5, 130.1, 129.4, 129.2, 128.6, 126.4, 124.2, 121.4, 120.5, 115.4, 44.5. ESMS
(M+H): m/z 282. Anal. Calcd for C15H11N3O3: C, 64.05; H, 3.91; N, 14.94. Found: C, 63.88; H, 3.69;
N,14.77%.
o
1-Methyl-4-[2-hydroxyphenyl]-6-nitrophthalazine (23): pale yellow flakes, Mp 136 C. IR (KBr):
1
3400 (OH), 3040, 1530 (NO2), 1340 (NO2) cm-1. H NMR (DMSO-d6) : 2.80 (s, 3H), 6.96 (d, 2H, J =
13
8.1 Hz), 8.14 (d, 2H, J = 8.4 Hz), 7.65-7.60 (m, 2H), 7.45-7.40 (m, 2H), 11.10 (s, 1H, OH). C NMR
(DMSO-d6) : 155.2, 148.3, 134.7, 133.2, 131.1, 130.1, 129.4, 129.2, 126.6, 126.4, 123.4, 121.5, 120.1,
115.4, 44.8. ESMS (M+H): m/z 282. Anal. Calcd for C15H14N3O3: C, 64.05; H, 3.91; N, 14.94. Found: C,
63.90; H, 3.71; N, 14.74%
o
1-Phenyl-4-[2-hydroxy-5-nitrophenyl]phthalazine (14): Mp 178 C. IR (KBr): 3423, 3078, 1620,
1510, 1340 cm-1. 1H NMR (DMSO-d6):  3.06 (s, 3H), 7.07 (t, 1H, J = 7.4 Hz), 7.11 (d, 2H, J = 8.2 Hz),
7.42 (dd, 1H, J = 7.4 Hz, J = 1.5 Hz), 7.46-7.49 (m, 1H), 8.44 (d, 1H, J = 2.2 Hz), 8.54 (d, 1H, J = 9.0
13
Hz), 8.68 (dd, 1H, J = 9.0 Hz, J = 2.2 Hz), 9.99 (s, 1H). C NMR (DMSO-d6) : 155.3, 149.4, 133.5,
133.3, 131.5, 131.2, 130.1, 129.5, 129.2, 128.8, 128.1, 127.2, 126.8, 126.5, 126.4, 126.1, 124.8, 124.2,
120.6, 117.9. ESMS (M+H): m/z 282. Anal. Calcd for C15H11N3O3: C, 64.06; H, 3.91; N, 14.94%. Found:
C, 63.88; H, 3.74; N, 14.65%
o
1-Methyl-4-[2-hydroxy-5-bromophenyl]phthalazine (15): off-white needles, Mp 116 C. IR (KBr):
1
3360, 3040, 1610cm-1. H NMR (CDCl3) : 2.70 (s, 3H), 6.90-6.60 (m, 2H), 7.25-7.20 (m, 2H),

HETEROCYCLES, Vol. 83, No. 6, 2011
1299
13
7.50-7.40 (m, 2H), 7.55(s, 1H),7.75(s, 1H, OH). C NMR (CDCl3) : 155.2, 152.3, 133.6, 133.2, 131.5,
130.0, 129.5, 128.6, 127.0, 126.6, 126.4, 122.6, 121.0, 115.6, 45.6. ESMS (M+H): m/z 316. Anal. Calcd
for C15H11 BrN2O: C, 57.14; H, 3.49; N, 8.88. Found: C, 56.90; H, 3.28; N, 8.70%
1-Phenyl-4-[2-hydroxy-5-bromophenyl]phthalazine (16): white powder, Mp 127 oC. IR (KBr): 3365,
1
3040, 1605 cm-1. H NMR (CDCl3) : 7.90(d, 1H, J = 8.10 Hz), 7.40-7.30 (m, 2H), 7.25-7.15 (m, 2H),
7.20 (d, 2H, J = 8.0 Hz), 7.80 (s, 1H, OH). 13C NMR (CDCl3) : 155.2, 152.3, 133.4, 133.2, 131.4, 130.0,
129.6, 129.4, 128.8, 127.4, 126.4, 126.2, 123.4, 123.1, 122.6, 121.0, 120.0, 117.4, 115.5. ESMS (M+H):
m/z 378. Anal. Calcd for C20H13 BrN2O: C, 63.66; H, 3.44; N, 7.42. Found: C, 63.50; H, 3.28; N, 7.30%.
o
1-Phenyll-4-[2-hydroxy-5-bromophenyl]-6-bromophthalazine (17): white needles, Mp 153 C. IR
(KBr): 3360, 3040, 1605 cm-1. 1H NMR (CDCl3) : 7.85 (d, 1H, J = 7.90 Hz), 7.45-7.30 (m, 3H), 7.20 (d,
2H, J = 7.85 Hz), 7.95 (s, 1H, OH). 13C NMR (CDCl3) : 155.2, 152.1, 133.4, 133.2, 133.1, 131.5, 130.0,
129.4, 128.6, 127.4, 127.0, 126.4, 126.2, 123.4, 123.1, 122.6, 121.0, 120.1, 117.4, 115.4. ESMS (M+H):
m/z 457. Anal. Calcd for C20H12 Br2N2O: C, 52.63; H, 2.63; N, 6.14. Found: C, 52.50; H, 2.48; N, 5.98%.
o
1-Phenyll-4-[2-hydroxy-3-methylphenyl]phthalazine (18): white microcrystals, Mp 76 C. IR (KBr):
1
3360, 3035, 1600 cm-1. H NMR (CDCl3) : 2.60(s, 3H), 6.68-6.80 (m, 3H), 7.80-7.75(m, 2H), 8.40-8.0
(m, 2H), 7.25-7.20 (m, 5H). 13C NMR (CDCl3) : 155.2, 152.3, 137.8, 133.4, 133.2, 133.0, 129.2, 128.6,
128.4, 127.4, 126.6, 126.2, 126.0, 125.5, 123.0, 122.4, 121.2, 117.4, 115.5, 55.2. ESMS (M+H) : m/z 313.
Anal. Calcd for C21H16 N2O: C, 80.76; H, 5.12; N, 8.97. Found: C, 80.60; H, 4.98; N, 8.81%.
o
1-Methyl-4-[2-hydroxy-3-methylphenyl]-6-methyphthalazine (19): off-white powder, Mp 94 C. IR
1
(KBr): 3280, 3040, 1600 cm-1. H NMR (CDCl3) : 2.55 (s, 3H), 2.65 (m, 3H), 6.90-6.80 (m, 3H),
13
7.60-7.50 (m, 3H), 7.25-7.20 (m, 5H), 7.80 (brs, 1H, OH). C NMR (CDCl3) : 155.3, 152.2, 137.6,
133.4, 133,1, 131.0, 130.1, 129.4, 128.8, 128.4, 127.2, 126.6, 126.2, 125,4, 123.4, 122.6, 121.0, 117.5,
115.6, 55.0. ESMS (M+H): m/z 327. Anal. Calcd for C22H18 N2O: C, 80.98; H, 5.52; N, 8.58. Found: C,
80.75; H, 5.40; N, 8.38%.
1-Phenyll-4-[2-hydroxy-3-iodophenyl]-8-iodophthalazine (20): off-white amorphous solid, Mp 228
1
oC. IR (KBr): 3380, 3040, 1600 cm-1. H NMR (CDCl3) : 7.80 (d, 1H, J = 8.0 Hz), 7.40-7.30 (m, 3H),
7.20 (d, 2H, J = 7.9 Hz), 7.25-7.20 (m, 5H), 7.85 (brs, 1H, OH). 13C NMR (CDCl3) : 155.3, 152.1, 137.2,
133.6, 133.2, 131.4, 130.1, 129.6, 129.2, 128.8, 127.0, 126.6, 126.4, 123.4, 122.6, 121.4, 120.4, 115.5,
94.5, 87.0. ESMS (M+H): m/z 551. Anal. Calcd for C20H12 I2N2O: C, 43.63; H, 2.18; N, 5.09. Found: C,
43.40; H, 2.02; N,4.95%.
o
1-Phenyll-4-[2-hydroxy-5-phenylphenyl]phthalazine (21): off-white microcrystals, Mp 231 C. IR
1
(KBr):3360, 3030, 1610 cm-1. H NMR (CDCl3) : 7.30-7.25 (m, 5H), 7.25-7.20 (m, 5H), 7.25-7.15 (m,

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HETEROCYCLES, Vol. 83, No. 6, 2011
13
3H), 7.15-6.80 (m, 4H), 7.70 (brs, 1H, OH). C NMR (CDCl3) : 155.3, 152.3, 152.2, 133.6, 133.4,
133.1, 131.4, 130.2,130.0, 129.6, 129.4, 129.0, 128.6, 128.4, 127.2, 126.6, 126.4, 126.2, 126.0, 123.4,
122.6, 121.0, 120.4, 117.5, 115.5. ESMS (M+H): m/z 375. Anal. Calcd for C26H18 N2O: C, 83.42; H, 4.81;
N, 7.48. Found: C, 83.20; H, 4.68; N, 7.28%.
1-Phenyl-4-[2-hydroxy-5-phenylphenyl]-6-phenylphthalazine (22): off-white amorphous solid, Mp
o
1
246 C. IR (KBr):3360, 3030, 1610 cm-1. H NMR (CDCl3) : 7.25-7.20 (m, 5H), 7.30-7.25 (m, 5H),
13
7.20-7.15 (m, 5H), 7.15-7.0 (m, 3H), 7.10-6.90 (m, 3H), 7.70 (s,1H,OH). C NMR (CDCl3) : 155.1,
138.4, 133.8, 133.4, 133.2, 133.1, 131.4, 131.1, 130.6, 130.2, 130.0, 129.8, 129.6, 129.2, 128.8, 128.4,
127.6, 127.2, 127.0, 126.4, 126.0, 123.4, 122.4, 121.6,121.4, 121.1, 120.8, 117.4, 117.2, 115.5. 115.0.
ESMS (M+H): m/z 451. Anal. Calcd for C32H22 N2O: C, 85.33; H, 4.88; N, 6.22. Found: C, 85.15; H,
4.72; N, 6.01%.
ACKNOWLEDGEMENT
The authors thank Professor G. Varvounis (Department of Chemistry, University of Ioannina, Greece) for
constructive comments during the work.
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