A convenient access to thienyl-substituted phthalazines

Article abstract of DOI:10.1002/jhet.5570420701

A synthesis of 1-alkoxy- and 1-amino- substituted 4-(2-thienyl)- phthalazines is described from halo-derivatives of 4-(2-thienyl)-1-(2H)- phthalazinone 3.

Full text of DOI:10.1002/jhet.5570420701

Nov-Dec 2005
A Convenient Access to Thienyl-substituted Phthalazines
1245
M. Manuela M. Raposo,a* Ana M. B. A. Sampaio and G. Kirsch
a
b
a
Centro de Química, Universidade do Minho, Campus de Gualtar
4
710-057 Braga, Portugal
Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique,
UFR SciFA/Université de Metz, 1, Boulevard Arago, Metz Technopôle,
7078 Metz Cedex 3, France
Received November 3, 2004
b
5
A synthesis of 1-alkoxy- and 1-amino- substituted 4-(2-thienyl)-phthalazines is described from halo-
derivatives of 4-(2-thienyl)-1-(2H)-phthalazinone 3.
J. Heterocyclic Chem., 42, 1245 (2005).
Introduction.
Chlorine, bromine and triflate thienyl-substituted phtha-
lazines 4 and 5 were synthesized in order to be used as pre-
cursors on the synthesis of 1-alkoxy- and 1-amino-phtha-
lazines 6-7. These derivatives could also be used in the
future, as coupling components in palladium catalyzed
cross-coupling reactions to obtain more complex mole-
cules with potential applications in NLO [52]. For this
kind of application the substitution of the phenyl ring by
the thiophene ring was already demonstrated to be very
important [53].
The practical interest upon phthalazine derivatives is
based on their widespread applications [1-4]. Phthalazines,
like others members of the isomeric diazine series, have
found wide applications as therapeutic agents [2,5-28].
Phthalazines are also commonly used as ligands in transi-
tion metal catalysis, [29-34] as chemiluminescent materi-
als [35-38] and for optical applications [39].
Despite their significance, there are only a limited num-
ber of routes for the synthesis of phthalazines. The most
commonly employed approach is through o-disubstituted
benzenes. Thus, condensation of 1,2-diacylbenzenes or
their aldehyde counterparts with hydrazine derivatives
gives 1,4-disubstituted- or the parent unsubstituted phtha-
lazines, respectively [1-3,5-7,9-10,12,40-47].
Results and Discussion
The 2-thienyl-subtituted benzoates 2a-b were obtained
in good yields (75-81%), by the standard method of
Friedel-Crafts reaction of thiophene with o-phthalic acid
mono alkyl ester chlorides 1a-b. These compounds were
subsequently cyclized by condensation with hydrazine
hydrate to give phthalazinone 3 in 91% yield from ben-
zoate 2a or in 84% yield from benzoate 2b (Scheme 1,
Table 1). Phthalazinone 3 was already synthesized by Buu-
Hoï et al [50], by condensation of 2-(2'-thienyl)-2-oxo-
benzoic acid with hydrazine hydrate.
Bromine, chlorine and triflate substituted phthalazines
play an important role in diazine chemistry since they offer
the potential for further funcionalization. By nucleophilic
displacement of the halogen or the triflate groups, numer-
ous otherwise inaccessible diazines become available. To
this end we have synthesized and characterized several
halo- and triflate phthalazine derivatives.
From 3, bromo, chloro and triflate derivatives were
prepared by reaction respectively with phosphoryl
halides and triflic anhydride. The chloride 4a, bromide
4b, and triflate 5 were obtained with respectively 87, 94
and 30% yield. 1-Chloro-4-(2'-thienyl)-phthalazine 4a
has been already reported in a patent [51], by condensa-
tion of 1,4-dichlorophthalazine with thienyllithium. No
data about the derivative are given. The triflate derivative
5 was prepared according to a modified version [54], of
the procedure described by Toussaint [55] et al. Reaction
of 3 with a great excess of the brominating agent gave
only the dibromo derivative 4c in 62% yield. Mass spec-
trum of 4c showed the characteristic pattern for a com-
Recently, palladium catalyzed coupling reactions were
also applied in the phthalazine series [48-49]. Guery et al
[
48] obtained several new phthalazine derivatives through
Suzuki coupling.
Due to the nature of the phthalazine nucleus, synthesis
of new derivatives becomes an important issue. There has
been little reported in the literature concerning 2-thienyl-
substituted phthalazines [17-18,50-51].
The synthesis of thienyl- substituted phthalazines 4a, 6
and 7 was achieved through similar reactions used earlier
in the synthesis of phenyl-phthalazines [40-47]. 1-Alkoxy-
and 1-amino-phthalazine derivatives were obtained from
halo-derivatives 4a-b of the phthalazinone 3. Compound 3
was obtained by cyclization of acyl benzoates 2a-b using
hydrazine hydrate. The latter was made through a Friedel-
Crafts reaction between thiophene and phthalic acid mono-
chloride esters 1a-b.
Earlier, several authors [46-47] described the synthesis
and the evaluation of the biological activity of 1-amino-
phthalazines with structure similar to thienyl-phthalazines
7
. These studies showed that the substitution of the phenyl
ring in phenyl-phthalazines (or phenyl-pyridazines) by an
electron rich heterocycle such as furane or thiophene
improve the biological activities for these compounds.
Thus, we decide to synthesize several 1-amino-4-thienyl-
phthalazines to see if the potential biological activities for
these compounds will be improve.

1
246
M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch
Vol. 42
pound with two bromine atoms with molecular ions at
m/z 372 (M , 2x Br, 45), 370 (M , Br Br, 85) and
3-15 h, to yield 1-(alkyl)arylamino-4-(2'-thienyl)-pht-
hazines 7a-e in moderate to good yields (47-84%)
(Scheme 2, Table 2).
+
81
+
79
81
+
79
1
3
68 (M , 2x Br, 45). The H NMR spectrum revealed
two doublets: one at δ 7.23 (3'-H) and the other at δ 7.46
4'-H). On the basis of these data, the 1-bromo-4-(5'-
It has been reported that 3-hydrazino-6-(2-pyrrolyl)-
pyridazine can be obtained from the reaction of
hydrazine hydrate with 3-chloro-6-(2-pyrrolyl)pyri-
dazine in refluxed n-butanol [57]. Using an analogous
route, we hoped to prepare 1-hydrazino-4-(2'-thieny)-
phthalazine but we observed that 1-chloro-4-(2'-thienyl)-
phthalazine 4a failed to react with hydrazine hydrate to
produce the corresponding phthalazine derivative. In our
hands chloro-phthalazine 4a reacted with hydrazine
hydrate in boiling butanol to afford a brown solution
from which an orange solid precipitated. The solution
revealed to be a mixture of two compounds (tlc). "Flash"
chromatography of this mixture on silica with increasing
amounts of diethyl ether in light petroleum gave the
thienyl-phthalazinone 3 in 87% yield. The second com-
pound eluted was an orange solid, mp 233.7-234.9 ºC.
Mass spectrum of this compound showed the molecular
(
bromo-thieno-2-yl)-phthalazine structure 4c was
assigned to this product (Scheme 1).
ion at 452.0880 (C H N S ) and an ion at m/z 226
2
4 16 6 2
(
19%) owing the cleavage into two simple units. The IR
-
1
spectrum showed one absorption band at 3376 cm
(
1
NH). H NMR spectrum revealed a broad singlet (2H)
at 10.65 δ due to the NH protons. On the basis of these
data, the bis-1,2-[4'-(2''-thienyl)phthalazine-1-yl]-
hydrazine structure 8 (8%) was assigned to this product
(Scheme 2, Table 2).
Table 1
Synthesis of Benzoates 2a-b, Phthalazinone 3 and Phthalazine
Derivatives 4a-c and 5
The reaction of 4a with hydrazine hydrate, under these
conditions, gave the oxo derivative 3 in high yield and not
the hydrazino derivative, probably due to the hydrolysis of
chloro phthalazine 4a [2,20,58].
-
1
Compound
Yield (%)
IR υ
[cm ]
max
2
2
3
a
81
75
91
1724 (C=O)
649 (C=O)
1718 (C=O)
650 (C=O)
3301 (NH),
1
b
1
Table 2
1
665 (C=O)
-----
Synthesis of 1-Alkoxy- and 1-Amino-substituted Phthalazine
Derivatives 6a-b, 7a-e and Dimmer 8 from 1-Halophthalazine
Derivatives 4a-b
4
4
4
5
a
b
c
99
87
62
30
-----
-----
-----
-
1
Compound
R
Me
Et
Yield (%)
IR υ
[cm ]
max
-----
6
6
a
b
73
88
84
47
52
62
-----
-----
1
-Halophthalazines reacted to the alkoxy derivatives 6a-
7a
Piperidino
7
7
7
b
c
d
4-Methoxyanilino
2,4-Dimethoxyanilino
4-Cyanoanilino
3418 (NH)
3434 (NH)
3409 (NH),
b when refluxing with the alkoxyde in the corresponding
alcohol. Compounds 6a and 6b, were obtained in good
yields (Scheme 2, Table 2).
2
213 (CN)
Arylamino- and piperidinylphthalazine derivatives show
anti thrombotic properties, anti malarial activity and are
useful for treatment of septic shock, multi-organ failure,
chronic rheumatoid arthritis, multiple sclerosis, SLE,
AIDS, hepatitis, type-II diabetes etc. [2,21,47].
7e
8
4-Nitroanilino
------
71
9
3281 (NH)
3376 (NH)
In summary, we report the synthesis of several deriva-
tives of thienyl-substituted phthalazines in order to obtain
new derivatives which could exhibit biological activity or
in order to be used as precursors on the synthesis of more
complex molecules. The examination of biological activity
of compounds 7a-e and 8 are in course.
In order to synthesize several new 1-(alkyl)arylamino-4-
(
2'-thienyl)-phathazines, 1-chloro-4-(2'-thienyl)-phtha-
lazine 4a was reacted with an excess of piperidine or an
excess of several arylamines, in refluxing acetone [56], for

Nov-Dec 2005
A Convenient Access to Thienyl-substituted Phthalazines
1247
EXPERIMENTAL
H nmr spectra were obtained on a Varian Unity Plus
Acid chloride 1 (17.2 g, 114 mmol) and thiophene (9.59 g, 114
mmol/9.03 mL), in dry dichloromethane (200 mL), were added
dropwise to a stirred solution of stannic chloride (32.7 g/14.7 mL,
125 mmol,) in dry dichloromethane (200 mL), at 0 ºC. After the
addition, the mixture was stirred overnight at rt and then poured
onto ice-water (1000 mL), acidified with con. HCl and stirred at
1
1
3
Spectrometer at 300 MHz and C nmr were determined on a
Varian Unity Plus Spectrometer at 75.4 MHz using the solvent
peak as internal reference. The solvents are indicated in parenthe-
sis before the chemical shift values (δ relative to TMS). Mp's
were determined on a Gallenkamp apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin-Elmer 1600 FTIR
spectrophotometer. EI mass spectra EI (70 eV) and hrms were
run on a Unicam GC-MS 120. Elemental analysis was carried out
on a Leco CHNS-932. Column chromatography was performed
on Merck silica gel 60 (Art 9385). Light petroleum refers to sol-
vent boiling in the range 40-60 °C.
0
ºC during 1 h. This mixture was extracted with dichloro-
methane (3x50 mL) and the combined organic extracts were
washed with a solution of (5 %) NaOH (3x100 mL), water
(
2x100 mL) and dried (MgSO ). Evaporation of the solvent
4
under reduced pressure gave the crude acyl benzoates 2 as oils
that were purified by "flash" chromatography on silica with
increasing amounts of ether in light petroleum as eluent.
Methyl-2-(thiophene-2-carbonyl)benzoate (2a).
General Procedure for the Preparation of Acid chlorides 1a-b.
This compound was obtained in 81% yield as a colorless solid,
1
mp 67-68 ºC; H nmr (deuteriochloroform): δ 3.70 (s, 3H,
The phthalic acid monoalkyl esters (70 mmol) were dissolved
in 50 mL of dry dichloromethane and then thionyl chloride (12.5
g, 105 mmol) was added and the mixture was heated at reflux for
OCH ), 7.08 (m, 1H, 4'-H), 7.28 (dd, 1H, 3'-H, J = 3.5, 1.2 Hz),
3
7
=
1
.50 (dd, 1H, 3 or 6-H, J = 7.8, 1.5 Hz), 7.59 (dt, 1H, 4 or 5-H, J
7.8, 1.5 Hz), 7.65 (dt, 1H, 5 or 4-H, J = 7.8, 1.5 Hz); 7.71 (dd,
H, 5'-H, J = 4.8, 1.2 Hz), 8.05 (dd, 1H, 6 or 3-H, J = 7.8, 1.5 Hz);
ir (nujol) ν 3104, 2952, 1724 (C=O, ester), 1649 (C=O, cetone),
4
-4.5 h. Evaporation of the solvent under reduced pressure gave
the crude acid chlorides 1 which were used without further purifi-
cation in the Friedel-Crafts reactions.
1
596, 1576, 1515, 1485, 1434, 1412, 1355, 1287, 1321, 1085,
Phthalic Monoacid Monomethyl Ester Chloride 1a.
1050, 962, 895, 849, 824, 775, 737, 670, 642 cm-1; ms: m/z (%)
+
=
246 (M , 92), 215 (36), 187 (7), 163 (100), 111 (100), 76 (40),
This compound was obtained in quantitative yield as a colorless
_
69 (20), 57 (58), 50 (75).
oil; H nmr (deuteriochloroform) δ 3.87 (s, 3H, OCH ), 7.60-7.67
3
Anal. Calcd. for C13H10O S: C, 63.42; H, 4.06; S, 13.02.
3
(
m, 2H, 2xAr-H), 7.75-7.80 (m, 1H, Ar-H), 7.82-7.86 (m, 1H, Ar-
Found: C, 63.38; H, 4.17; S, 13.06.
H), ir (nujol) ν 2854, 1791 (C=O, acid chloride), 1710 (C=O,
ester), 1578, 1488, 1457, 1414, 1386, 1375, 1356, 1343, 1285,
Ethyl-2-(thiophene-2-carbonyl)benzoate (2b).
This compound was obtained in 75% yield as a beige solid, mp
-1
1
248, 1181, 1165, 1145, 1128, 1104, 1074, 1037, 995, 826 cm .
1
Phthalic Monoacid Monoethyl Ester Chloride 1b.
65-67 ºC; H nmr (deuteriochloroform): δ 1.14 (t, 3H, OCH CH , J
2
3
=
7
1
6.7 Hz), 4.15 (q, 2H, OCH CH , J = 6.7 Hz), 7.08 (m, 1H, 4'-H),
2 3
This compound was obtained in 95% yield as a colorless oil;
.28 (dd, 1H, 3-H, J = 3.7, 1.2 Hz), 7.49 (dd, 1H, 3 or 6-H, J = 7.5,
.5 Hz); 7.58 (dt, 1H, 4 or 5-H, J = 7.5, 1.5 Hz), 7.65 (dt, 1H, 5 or 4-
H, J = 7.5, 1.5 Hz), 7.71 (dd, 1H, 5'-H, J = 5.0, 1.2 Hz), 8.06 (dd, 1H,
_
H nmr (deuteriochloroform): δ 1.40 (t, 3H, OCH CH , J = 7.2
2
3
Hz), 4.40 (q, 2H, OCH CH , J = 7.2 Hz), 7.60-7.65 (m, 2H,
2
3
2
(
1
xAr-H), 7.72-7.76 (m, 1H, Ar-H), 7.84-7.88 (m, 1H, Ar-H), ir
nujol) ν 2860, 1785 (C=O, acid chloride), 1695 (C=O, ester),
580, 1450, 1465, 1430, 1380, 1360, 1350, 1330, 1230, 1170,
6
(
1
8
or 3-H, J = 7.5, 1.5 Hz); ir (nujol) ν 3098, 1718 (C=O, ester), 1650
C=O, cetone), 1595, 1575, 1514, 1411, 1336, 1288, 1132, 1076,
-1
+
046, 1040, 1017, 841, 777, 734, 718 cm ; ms: m/z (%) = 260 (M ,
-1
1130, 1096, 1050, 980, 820 cm .
2), 215 (86), 217 (10), 187 (27), 171 (14), 149 (68), 115 (33), 111
General Procedure for the Friedel-Crafts Reaction.
(100), 105 (15), 83 (16), 76 (39), 65 (21), 57 (11), 50 (20).

1248
M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch
Vol. 42
Anal. Calcd. for C14H12O S: C, 64.62; H, 4.61; S, 12.32.
Anal. Calcd. for C H BrN S: C, 49.49; H, 2.40; N, 9.62; S,
12 7 2
3
Found: C, 64.60; H, 4.63; S, 12.44.
11.02. Found: C, 49.47; H, 2.62; N, 9.47; S, 10.88.
Synthesis of 4-(2'-Thienyl)-1-(2H)-phthalazinone (3).
Synthesis of 1-Bromo-4-(5'-bromo-thieno-2-yl)-phthalazine (4c).
A mixture of 4-(2'-thienyl)-1-(2H)-phthalazinone 3 (1 g, 4.4
A mixture of benzoate 2a-b (5 g, 20 mmol) and hydrazine
hydrate (1.5 g, 30 mmol, 1.45 mL) was heated at reflux in ethanol
mmol), and POBr (48.4 mmol), was heated for 4 h at 110-120
3
(
35 mL) for l6 h. The mixture was left at -4 ºC overnight. After
ºC. This mixture was cooled till rt and then poured onto ice-
water, basified with a solution of ammonia (2 M) and stirred for
15 min. to give a beige solid which was filtered and washed with
water and light petroleum to give the crude phthalazine 4c as a
beige solid. "Flash" chromatography of this solid with increasing
amounts of ether in light petroleum gave the pure dibromopht-
cooling the obtained crystals were collected by filtration and
washed with ethanol to give the pure phthalazinone 3 [17-18],
[
2
42]. This compound was obtained in 91 % yield from benzoate
a and in 84 % yield from benzoate 2b as colorless needles
1
(ethanol), mp 197-198 ºC, (lit. [42] 195 ºC); H nmr (deuteri-
1
ochloroform) δ 7.25-7.27 (m, 1H, 4'-H), 7.48 (dd, 1H, 3'-H, J =
hazine 5c in 62% yield as a beige solid, mp 164.0-165.5 ºC; H
3
2
1
3
.3, 1.2 Hz), 7.52 (dd, 1H, 5'-H, J = 5.4, 1.2 Hz), 7.80-7.92 (m,
H, 6 and 7-H), 8.15 (dd, 1H, 5 or 8-H, J = 7.5, 2.4 Hz), 8.54 (dd,
H, 8 or 5-H, J = 7.5, 2.4 Hz), 10.6 (br. s., 1H, NH); ir (nujol) ν
301 (NH), 1665 (C=O), 1582, 1431, 1351, 1329, 1229, 1196,
nmr (deuteriochloroform): δ 7.23 (d, 1H, 3' or 4'-H, J = 4 Hz),
7.46 (d, 1H, 4'or 3'-H , J = 4 Hz), 8.01-8.05 (m, 2H, 6 and 7-H),
8.35-8.38 (m, 1H, 5 or 8-H), 8.43-8.46 (m, 1H, 8 or 5-H); ir
(nujol) ν 3851, 3646, 2924, 1562, 1516, 1434, 1364, 1326, 1278,
-
1156, 1083, 1030, 907, 893, 845, 776, 740, 727, 699, 680, 666,
1162, 1118, 980, 971, 842, 805, 770, 698, 689, 664, 614, 506 cm
-1
+
1
+
81
+ 79
81
6
48 cm ; ms: m/z (%) = 228 (M , 100), 227 (44), 199 (17), 171
; ms: m/z (%) = 372 (M , 2x Br, 45), 370 (M , Br Br, 85),
+
79
(
(
52), 149 (26), 145 (5), 139 (6), 127 (22), 111 (10), 97 (25), 83
42), 81 (51); hrms: m/z calc. for C H N OS: 228.0357; found
368 (M , 2x Br, 45), 291 (100), 279 (97), 227 (7), 210 (14), 182
(39), 171 (7), 138 (21), 119 (9), 102 (11), 92 (44), 82 (45); hrms:
1
2 8 2
7
9
2
28.0352.
m/z calc. for C H Br N S: 367.8618; found 367.8620.
12 6 2 2
Anal. Calcd. for C H N OS: C, 63.12, H, 3.51, N, 12.27, S,
Anal. Calcd. for C H Br N S: C, 38.93; H, 1.62; N, 7.57; S,
1
2
8
2
12
6
2 2
1
4.05. Found: C, 63.22, H, 3.67, N, 12.25, S, 14.19.
8.67. Found: C, 39.15; H, 1.92; N, 7.76; S, 8.94.
General Procedure for the Synthesis of 1-Halo-4-(2'-thienyl)-
Synthesis of Trifluoromethanesulfonic Acid [4-(2'-Thienyl)-
phthalazines 4a-b.
phthalazine-1-yl] Ester 5.
A mixture of 4-(2-thienyl)-1-(2H)-phthalazinone 3 (1 g, 4.4
Trifluoromethanesulfonic anhydride (0.372 g/0.22 mL, 1.32
mmol), was added slowly dropwise to a stirred ice cooled sus-
pension of phthalazinone 3 (0.2 g, 0.88 mmol) and triethylamine
(0.134 g/0,18 mL, 1.32 mmol) in dichloromethane (20 mL). After
12 hours, the mixture was poured into water (30 mL and
extracted with dichloromethane (3x50 mL). The combined
organic extracts were washed with water (30 mL), dried with
mmol), and POX (X=Cl or Br) (8.8 mmol), was heated for 4 h at
3
1
10-120 ºC. This mixture was cooled till rt and then poured onto
ice-water, basified with a solution of ammonia (2 M) and stirred
for 15 min. to give a solid which was filtered and washed with
water and light petroleum to give the pure 1-halo-4-(2-thienyl)-
phthalazines 4a-b.
MgSO and the solvent was evaporated under reduced pressure
4
1
-Chloro-4-(2'-thienyl)-phthalazine (4a).
to give the crude trifluoromethanesulfonic acid [4-(2'-thienyl)-
phthalazine-1-yl] ester 5 which was purified by "flash" chro-
matography on silica with increasing amounts of ether in light
petroleum as eluent.
This compound was obtained in 99 % yield as a yellow solid
1
mp 134.5-135.5 ºC (ether), (lit. [51] mp not quoted); H nmr
(
deuteriochloroform): δ 7.27-7.30 (m, 1H, 4'-H), 7.64 (dd, 1H,
5
8
8
1
8
2
'-H, J = 5.3, 1.2 Hz), 7.70 (dd, 1H, 3'-H, J = 3.4, 1.2 Hz), 8.01-
.05 (m, 2H, 6 and 7-H), 8.40 (dd, 1H, 5 or 8-H, J = 8.6, 2.1 Hz),
.52 (dd, 1H, 8 or 5-H, J = 8.6, 2.1 Hz); ir (nujol) ν 1564, 1529,
483, 1434, 1374, 1364, 1288, 1263, 1074, 1018, 987, 853, 854,
This compound was obtained in 30 % yield as a colorless
1
solid, mp 133.2-134.0 ºC. H nmr (deuteriochloroform): δ 7.22-
7.27 (m, 1H, 4'-H), 7.55 (br. d., 1H, 3'-H, J = 3.6 Hz), 7.60 (br. d.,
1H, 5'-H, J = 5.4 Hz), 7.92 (dt, 1H, 6 or 7-H, J = 7.5, 1.2 Hz), 7.98
(dt, 1H, 7 or 6-H, J = 7.5, 1.2 Hz), 8.18 (br. d., 1H, 5-H, J = 8.1
-1
+ 37
46, 777, 701, 689, 666 cm ; ms: m/z (%) = 248 (M , Cl, 37),
+
35
13
46 (M , Cl, 100), 228 (17), 211 (72), 182 (16), 139 (25), 109
Hz), 8.55 (br. d., 1H, 8-H, J = 8.1 Hz); C nmr (deuteriochloro-
3
7
(
10), 91 (6); hrms: m/z calc. for C H ClN S: 247.9989; found
form): δ 30.8, 117.3, 121.6, 127.7, 127.9, 128.6, 129.1, 130.2,
133.2, 134.7, 135.7, 145.2, 158.0; ir (nujol) ν 3851, 3646, 2924,
1714, 1592, 1548, 1428, 1366, 1324, 1281, 1253, 1230, 1197,
1130, 1121, 1086, 1049, 1023, 925, 859, 849, 789, 848, 777, 730,
1
2
7
2
2
47.9989.
Anal. Calcd. for C H ClN S: C, 58.41; H, 2.83; N, 11.35, S,
1
2
7
2
1
3.01. Found: C, 58.60; H, 3.01; N, 11.65; S, 13.35.
-
1
+
6
2
84, 618, 591, 573 cm ; ms: m/z (%) = 360 (M , 41), 199 (100),
28 (17), 171 (45), 127 (12), 85 (6); hrms: m/z calc. for
1
-Bromo-4-(2'-thienyl)-phthalazine (4b).
This compound was obtained in 87% yield as a beige solid, mp
C H F N O S : 359.9850; found 359.9851.
Anal. Calcd. for C H F N O S : C, 43.33; H, 1.94; N, 7.78;
13 7 3 2 3 2
S, 17.78. Found: C, 43.67; H, 2.23; N, 7.53; S, 17.49.
13 7 3 2 3 2
1
1
7
7
77.8-178.2 ºC (ethyl acetate). H nmr (deuteriochloroform): δ
.27-7.30 (m, 1H, 4'-H), 7.64 (dd, 1H, 5'-H, J = 5.0, 1.2 Hz),
.97-8.07 (m, 2H, 6 and 7-H), 8.36 (dd, 1H, 5 or 8-H, J = 8.9, 2.4
General Procedure for the Preparation of 1-Alkoxy-4-(2'-
thienyl)-phthalazines 6a-b.
Hz), 8.48 (dd, 1H, 8 or 5-H, J = 8.9, 2.4 Hz); ir (nujol) ν 3646,
2
7
2
1
923, 1526, 1515, 1432, 1362, 1326, 1278, 1162, 968, 877, 843,
-
1
+ 81
74, 701, 664, 614, 503 cm ; ms: m/z (%) = 292 (M , Br, 68),
Halophthalazine 4a was heated at reflux with NaOR (R=Me or
Et) in methanol or ethanol (45 mL) for 4 h., and then cooled and
the solvent was removed under reduced pressure to give an orange
solid. This solid was poured into water (50 mL), and neutralized
+
79
90 (M , Br, 73), 228 (9), 211 (100), 182 (8), 139 (36), 113 (6),
02 (17), 91 (12); hrms: m/z calc. for C H BrN S: 289.9513;
7
9
12 7 2
found 289.9515.

Nov-Dec 2005
A Convenient Access to Thienyl-substituted Phthalazines
1249
with a solution of HCL (10%). The reaction mixture was then
extracted with dichloromethane (2x40 mL). The organic extract
2xNCH ), 7.20-7.24 (m, 1H, 4'-H), 7.52 (dd, 1H, 5'-H, J = 4.9,
2
1.2 Hz), 7.60 (1H, dd, 3'-H, J = 3.2, 1.2 Hz), 7.78-7.80 (m, 2H, 6
and 7-H), 8.08-8.14 (m, 1H, 5 or 8-H), 8.38-8.44 (m, 1H, 8 or 5-
was dried with MgSO and the solvent was evaporated under
4
1
3
reduced pressure to give the crude 1-alkoxy-4-(2-thienyl)-phta-
lazines 6a-b which were purified by "flash" chromatography on
silica with increasing amounts of ether in light petroleum as eluent.
H); C nmr (deuteriochloroform): δ 24.7, 26.0, 53.4, 121.8,
125.0, 125.9, 126.6, 127.3, 127.7, 128.2, 130.9, 131.5, 139.7,
149.7, 159.9; ir (nujol) ν 1571, 1489, 1438, 1403, 1306, 1288,
1
8
256, 1215, 1150, 1135, 1114, 1041, 1031, 1111, 931, 913, 874,
46, 892, 848, 695 cm ; ms: m/z (%) = 295 ( M , 53), 294 (20),
1-Methoxy-4-(2'-thienyl)-phthalazine (6a).
-1
+
This compound was obtained in 73 % yield as a colorless
266 (38), 252 (7), 239 (21), 227 (8), 213 (40), 196 (10), 171 (16),
129 (6), 110 (16), 103 (15), 84 (100); hrms: m/z calc. for
1
solid, mp 104.5-105.1 ºC; H nmr (deuteriochloroform): δ 4.32
(
s, 3H, OCH ), 7.22-7.27 (m, 1H, 4'-H), 7.55 (dd, 1H, 5'-H, J =
C H N S: 295.1144; found 295.1144.
3
17 17 3
5
2
1
5
1
1
8
1
.5, 1.2 Hz), 7.62 (dd, 1H, J = 3.3, 1.2 Hz, 3'-H), 7.88-7.91 (m,
H, 6 and 7-H), 8.30 (dd, 1H, 5 or 8-H, J = 9.0, 2.2 Hz), 8.40 (dd,
Anal. Calcd. for C H N S: C, 69.14; H, 5.76; N, 14.23; S,
1
7 17 3
1
1
0.87. Found: C, 68.90; H, 5.94; N, 13.94; S, 10.92.
1
3
H, 8 or 5-H, J = 9.0, 2.2 Hz); C nmr (deuteriochloroform): δ
4.9, 120.0, 123.3, 125.3, 127.0, 127.3, 127.9, 128.4, 131.7,
32.4, 139.0, 150.5, 159.7; ir (nujol) ν 2923, 1614, 1578, 1541,
515, 1494, 1433, 1364, 1325, 1278, 1201, 1105, 1051, 969, 852,
-(4-Methoxyanilino)-4-(2'-thienyl)-phthalazine (7b).
This compound was obtained in 47% yield as a yellow solid,
1
mp 140.0-141.0 ºC (ether). H nmr (dimethylsulfoxide-d ): δ
6
-1
+
43, 786, 774, 701, 686, 664, 615 cm ; ms: m/z (%) = 242 (M ,
3.76 (s, 3H, OCH ), 6.86 (d, 2H, 3'' and 5'' or 2'' and 6''-H, J = 9.0
3
00), 213 (40), 199 (6), 171 (33), 127 (11), 110 (16), 103 (15), 85
Hz), 7.23-7.28 (m, 1H, 4'-H), 7.64 (dd, 1H, 3'-H, J = 3.6, 1.0 Hz),
7.72 (dd, 1H, 5'-H, J = 5.4, 1.0 Hz), 7.78 (d, 2H, 2'' and 6'' or 3''
and 5''-H, J = 9.0 Hz), 7.96-8.06 (m, 2H, 6 and 7-H), 8.32-8.37
(m, 1H, 5 or 8-H), 8.60-8.64 (m, 1H, 8 or 5-H), 9.21 (br. s., 1H,
(
5); hrms: m/z calc. for C H N OS 242.0512; found 242.0514.
13 10 2
Anal. Calcd. for C H N OS: C, 64.45; H, 4.13; N, 11.57; S,
1
3 10 2
1
1
3.25. Found: C, 64.49; H, 4.34; N, 11.40; S, 13.21.
1
3
NH); C nmr (dimethylsulfoxide-d ) δ 79.2, 113.6, 118.1,
6
-Ethoxy-4-(2'-thienyl)-phthalazine (6b).
1
22.8, 123.3, 124.9, 125.1, 127.6, 127.8, 127.9, 131.7, 132.5,
This compound was obtained in 88 % yield as a colorless
133.3, 139.6, 146.6, 151.8, 155.0; ir (nujol) ν 3418 (NH), 1616,
1
-1
solid, mp 97.9-99.0 ºC; H nmr (deuteriochloroform): δ 1.58 (t,
1547, 1508, 1382, 1238, 1175, 1032, 838, 768, 708, 646 cm ;
3
H, OCH CH , J = 6.9 Hz), 4.79 (q, 2H, OCH CH , J = 6.9 Hz),
ms: m/z (%) = 333 ( M+, 100), 332 (73), 318 (38), 311 (19), 171
2
3
2
3
7
.22-7.27 (m, 1H, 4'-H), 7.54 (dd, 1H, 5'-H, J = 5.0, 1.0 Hz), 7.61
(3), 166 (5), 122 (4), 102 (5), 92 (4); hrms: m/z calc. for
(
8
1H, dd, 3'-H, J = 3.6, 1.0 Hz), 7.87-7.91 (m, 2H, 6 and 7-H),
.31-8.34 (m,1H, 8-H), 8.38-8.41 (m, 1H, 5-H); C nmr (deu-
C H N OS: 333.0936; found 333.0929.
1
9 15 3
1
3
Anal. Calcd. for C H N OS: C, 68.45; H, 4.50; N, 12.61; S,
19 15 3
teriochloroform): δ 14.6, 63.4, 120.1, 123.4, 125.3, 127.0,
27.3, 127.8, 128.3, 131.6, 132.3, 139.2, 150.2, 159.4; ir (nujol)
ν 2924, 1575, 1536, 1492, 1441, 1413, 1342, 1309, 1166, 1101,
9
1
.63. Found: C, 68.70; H, 4.72; N, 12.83; S, 9.90.
1
-(2,4-Dimethoxyanilino)-4-(2'-thienyl)-phthalazine (7c).
-1
+
1
047, 1024, 927, 877, 774 cm ; ms: m/z (%) = 256 (M , 42), 241
This compound was obtained in 52% yield as a yellow solid,
1
(
71), 228 (100), 211 (12), 199 (17), 171 (58), 139 (5), 127 (19),
mp 228.6-229.7 ºC (dichloromethane); H nmr (dimethylsulfox-
1
2
10 (16), 103 (12), 84 (7); hrms: m/z calc. for C H N OS:
56.0670; found 256.0668.
ide-d ): δ 3.80 (s, 3H, OCH ), 3.85 (s, 3H, OCH ), 6.70 (dd, 1H,
1
4
12
2
6
3
3
5''-H, J = 8.7, 2.4 Hz), 6.80 (d, 1H, 3''-H, J = 2.4 Hz), 7.30-7.36
(m, 1H, 4'-H), 7.39 (d, 1H, 6''-H, J = 8.7 Hz), 7.78 (br. d., 1H, 3'-
H, J = 3.6 Hz), 7.89 (br. d., 1H, 5'-H, J = 4.8 Hz), 8.20-8.30 (m,
Anal. Calcd. for C H N OS: C, 65.62; H, 4.69; N, 10.94; S,
1
4 12 2
1
2.52. Found C, 65.69; H, 4.90; N, 10.50; S, 12.27.
2
H, 6 and 7-H), 8.44-8.91 (m, 1H, 5 or 8-H), 8.89-8.98 (m, 1H, 8
or 5-H), 11.30 (br. s., 1H, NH); ir (nujol) ν 3434 (NH), 1608,
582, 1507, 1461, 1302, 1207, 1161, 1110, 1024, 890, 842, 816,
General Procedure for the Synthesis of 1-(Alkyl)arylamino-4-(2'-
thienyl)-phthalazines 7a-e.
1
-
1
+
Amine (2.43 mmol), water (0.017 mL) and one drop of HCl
784, 759, 662 cm ; ms: m/z (%) = 363 (M , 40), 362 (4), 348
(14), 332 (100), 226 (10), 211 (10), 182 (6); hrms: m/z calc. for
(37%) were added to a stirred solution of 1-chloro-4-(2'-thienyl)-
phthalazine 4a (4.2 g, 0.81 mmol) in acetone (20 mL). This mix-
ture was heated at reflux for 3-15 h then cooled and the amine
chlorohydrate separated by filtration affording a pale brown solu-
tion. This organic solution was evaporated under reduced pres-
sure to give a crude solid that was dissolved in dichloromethane
and the solution obtained was basified with a solution of ammo-
nia (2 M), extracted with chloroform (3x30 mL) and washed with
water (3x30 mL). The combined organic extracts were dried and
the solvent was evaporated under reduced pressure to give the
crude 1-(alkyl)aryl-4-(2'-thienyl)-phthalazines 7a-e which were
purified by recrystallization or by "flash" chromatography on sil-
ica with increasing amounts of ether in light petroleum as eluent.
C H N O S: 363.1041; found 363.1041.
20 17 3 2
Anal. Calcd. for C H N O S: C, 66.10; H, 4.68; N, 11.57; S,
2
0 17 3 2
8.83. Found: C, 66.30; H, 4.90; N, 11.75; S, 9.10.
1
-(4-Cyanoanilino)-4-(2'-thienyl)-phthalazine (7d).
This compound was obtained in a 62% yield as a colorless
1
solid, mp 247.8-249.2 ºC; H nmr (dimethylsulfoxide-d ): δ 7.26-
6
7.32 (m, 1H, 4'-H), 7.74 (br. d., 1H, 3'-H, J = 3.3 Hz), 7.80 (m, 3H,
5', 2'' and 6''-H), 8.06 (m, 2H, 6 and 7-H), 8.18 (d, 2H, 3'' and 5''-
H, J = 9.3 Hz), 8.44 (br. d., 1H, 5 or 8-H, J = 9.0 Hz), 8.66 (br. d.,
1H, 5 or 8-H, J = 9.0 Hz), 9.78 (br. s., 1H, NH); 13C nmr
(dimethylsulfoxide-d ): δ 103.0, 118.8, 119.5, 119.9, 123.0, 125.0,
6
1
1
25.4, 128.0, 128.4, 128.8, 132.2, 132.9, 133.1, 139.0, 145.1,
48.5, 151.2; ir (nujol) ν 3409 (NH), 2213 (CN), 1601, 1510,
1
-Piperidino-4-(2'-thienyl)-phthalazine (7a).
This compound was obtained in a 84% yield as a beige solid,
1442, 1329, 1281, 1245, 1173, 1099, 1045, 925, 837, 781, 737,
625 cm ; ms: m/z (%) = 328 (M , 62), 327 (100), 171 (6), 102 (6);
hrms: m/z calc. for C H N S: 328.0783; found 328.0769.
1
-1
+
mp 125.3-126.3 ºC; H NMR (deuteriochloroform): δ 1.70-1.80
(
m, 2H, CH ), 1.80-2.00 (m, 4H, 2xCH ), 3.40-3.60 (m, 4H,
2
2
19 12 4

1250
M. M. M. Raposo, A. M. B. A. Sampaio and G. Kirsch
Vol. 42
Anal. Calcd. for C H N S: C, 69.50; H, 3.65; N, 17.07; S,
.77. Found: C, 69.75; H, 3.90; N, 17.32; S, 10.01.
A. R. Katritzky, D. Barton and W. D. Ollis, eds, Pergamond Press,
Oxford, 1979; pp 85-143.
1
9 12 4
9
1
[
3] E. Schaumann and C. Zellerfed, eds, Hetarenes IV, Vol. E9a,
Houben-Weyl, Germany, 1997; pp 744.
4] T. L. Gilchrist, Heterocyclic Chemistry, 3 ed, Longmans,
Oxford, 1997.
5] M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G.
Morazzoni, P. Ferlenga and L. Pradella, Bioorg. Med. Chem. Lett., 10,
235, (2000).
6] M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G.
-(4-Nitroanilino)-4-(2'-thienyl)-phthalazine (7e).
rd
[
This compound was obtained in a 71% yield as a pale yellow
1
solid, mp 226.3-228.3 ºC (acetone); H nmr (dimethylsulfoxide-
[
d ): δ 7.31-7.34 (m, 1H, 4'-H), 7.78 (dd, 1H, 3'-H, J = 3.7, 1.2
Hz), 7.84 (dd, 1H, 5'-H, J = 5.6, 1.2 Hz), 8.06-8.16 (m, 2H, 6 and
6
2
7
5
(
-H), 8.20 (d, 2H, 2'' and 6''-H, J = 9.3 Hz), 8.30 (d, 2H, 3'' and
''-H, J = 9.3 Hz), 8.47 (dd, 1H, 5 or 8-H, J = 8.4, 1.5 Hz), 8.73
[
Morazzoni, P. Ferlenga and L. Pradella, Bioorg. Med. Chem. Lett., 11, 33,
(2001).
1
3
dd, 1H, 8 or 5-H, J = 8.4, 1.5 Hz), 10.2 (br. s., 1H, NH); C nmr
(
dimethylsulfoxide-d ): δ 120.5, 121.4, 124.5, 124.9, 126.1,
[7] M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G.
Morazzoni, R. Fattori, P. Ferlenga and L. Pradella, Bioorg. Med. Chem.
Lett., 12, 5, (2002).
[8] M. Van der Mey, H. Boss, A. Hatzelmann, I. J. Van der Laan,
G. J. Sterk, and H. Timmerman, J. Med. Chem., 45, 2520, (2002).
6
1
1
1
3
26.8, 128.3, 130.3, 130.9, 133.8, 134.5, 134.8, 142.4, 145.6,
48.1, 151.6; ir (nujol) ν 3281 (NH), 1608, 1560, 1500, 1379,
-1
324, 1180, 1105, 854, 782, 748, 712, 649 cm ; ms: m/z (%) =
+
48 (M , 84), 347 (100), 301 (31), 211(8), 171 (6); hrms: m/z
[
9] G. Bold, J. Med. Chem., 43, 2310, (2000).
10] P. G. Tsoungas and M. Searcey, Tetrahedron Lett., 42, 6589,
2001).
11] M. Rodríguez-Ciria, A. M. Sanz, M. J. R. Yunta, F. Gomez-
calc. for C H N O S: 348.0681; found 348.0675.
18 12 4 2
[
Anal. Calcd. for C H N O S: C, 62.06; H, 3.45; N, 16.09; S,
1
8 12 4 2
(
9
.21. Found: C, 62.20; H, 3.81; N, 15.30; S, 9.43.
[
Contreras, P. Navarro, I. Fernandez, M. Pardo and C. Cano, Bioorg. Med.
Chem., 11, 2143, (2003).
Synthesis of the Dimmer 1,2-Bis-[4-(thiophene-2-yl)phtha-
lazine-1-yl]-hydrazine (8).
[
12] P. Meresse, E. Bertounesque, T. Imbert and C. Monneret,
A mixture of 1-chlorophthalazine 4a (0.2 g, 0.8 mmol) and
hydrazine hydrate (2.4 mL) in butanol (20 mL) was heated at
reflux for 6 h. The mixture was allowed to stand 1 h at rt. After
this time an orange solid precipitated. The solid formed, the dim-
mer 1,2-bis-[4-(thiophene-2-yl)phthalazine-1-yl]-hydrazine 8
was separated by filtration and washed several times with ether to
afford a pale brown solution. This organic solution was extracted
with ethyl acetate (2x30 mL), and the combined organic extracts
were washed with water (30 mL) and dried with MgSO4.
Evaporation of the solvent under reduced pressure gave an oil
which was purify by "flash" chromatography on silica with
increasing amounts of ether in light petroleum as eluent. The first
compound eluted was the phthalazinone 3 in a yield of 87% as a
pale brown oil. The second component eluted was the dimmer 8.
This compound was obtained in a 9% overall yield as an orange
Tetrahedron, 55, 12805, (1999).
[13] H. Takehara, Z. Tsukamoto, K. Uenishi, Y. Asaumi, K.
Kosegi, Y. Ishizuka and H. Yaginuma, Chem. Abstr., 113, 152451n,
(
1990).
14] K. Uenishi, K. Kosegi, Y. Asaumi, Y. Ishizuka, and H.
Yaginuma, Chem. Abstr., 115, 256195q, (1991).
15] K. Uenishi, Y. Asaumi, K. Kosegi, Y. Ishizuka, and H.
Yaginuma, Chem. Abstr., 115, 256196r, (1991).
16] K. Uenishi, K. Kosegi, Y. Asaumi, , Y. Ishizuka, and H.
[
[
[
Yaginuma, Chem. Abstr., 115, 256197s, (1991).
[17] N. Ohi, T. Kuroki, M. Yamaguchi, M. Akima, T. Koga and K.
Kamei, Chem. Abstr., 115, 256193n, (1991).
[18] M. Yamaguchi, K. Kamei, T. Koga, M. Akima, T. Kuroki and
N. Ohi, J. Med. Chem., 36, 4052, (1993).
[
19] R. Sivakumar, S. K. Gnanasam, S. Ramachandran and J. T.
Leonard, Eur. J. Med. Chem., 37, 793, (2002).
[
[
20] R. D. Haworth and S. Robinson, J. Chem. Soc., 777, (1948).
21] F. Kazushi, M. Shinobu and K. Hajime, Chem. Abstr., 130,
1
solid mp 233.7-234.9 ºC (dichloromethane); H nmr δ (deuteri-
ochloroform): 7.16-7.20 (m, 2H, 2x4''-H), 7.40-7.48 (m, 4H, 2x
9
5558c, (1999).
22] J. S. Kim, H.-J. Lee, M.-E. Suh, H.-Y. P. Choo, S. K. Lee, H.
(
3'' and 5''-H)), 7.58-7.70 (m, 4H, 2x (6' and 7'-H)), 7.94 (dd, 2H,
[
2
7
1
9
4
1
x (5' or 8'-H), J = 7.8, 2.1 Hz), 8.42 (dd, 2H, 2x (8' or 5'-H), J =
.8, 2.1 Hz), 10.65 (br. s., 2H, 2xNH); ir (nujol) ν 3376 (NH),
611, 1570, 1455, 1390, 1349, 1231, 1192, 1141, 1090, 1031,
23, 849, 797, 769, 701, 666 cm ; ms: m/z (%) = 452 (M , 100),
36 (61), 393(7), 226 (19), 211(26), 196 (20), 171 88), 140 (6),
29 (8), 110 (10), 103 (10), 84 (3); hrms: m/z calc. for
J. Park, C. Kim, S. W. Park and C.-O. Lee, Bioorg. Med. Chem., 12, 3683,
(2004).
[23] A. D. Lebsack, J. Gunzner, B. Wang, R. Praccito, H.
Shaffhauser, A. Santini, J. Aiyar, R. Bezverkov, B. Munoz, W. Liu and S.
Venkatraman, Bioorg. Med. Chem. Lett., 14, 2463, (2004).
-1
+
[
24] K. M. Shubin, V. A. Kuznetsov and V. Galishev, Tetrahedron
Lett., 45, 1407, (2004).
25] R. Jiménez, A. M. Sanz, F. Gómez-Contreras, M. C. Cano, M.
J. R. Yunta, M. Pardo and Lucrecia Campayo, Heterocycles, 63, 1299,
2004).
26] Y. Imamura, A. Noda, T. Imamura, Y. Ono, T. Okawara and H.
C H N S : 452.0878; found 452.0880.
24 16 6 2
[
Anal. Calcd. for C H N S : C, 63.70; H, 3.54; N, 18.58; S,
2
4 16 6 2
1
4.18. Found: C, 63.80; H, 3.81; N, 18.30; S, 14.32.
(
[
Acknowledgements.
Noda, Life Sci., 74, 29, (2003).
Thanks are due to Foundation for Science and Technology
Portugal) for financial support through IBQF (UM) and through
FEDER, POCTI (ref. POCTI/QUI/37816/2001).
[27] A. Z. Haikal, E. S. E. Ashry and J. Banoub, Carbohydr. Res.,
338, 2291, (2003).
(
[
28] F. Saczewski, E. Kobierska, J. Petrusewicz, A. Gendzwill and
M. Gdaniec, Heterocycles, 60, 571, (2003).
29] H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless,
Chem. Rev., 94, 2483, (1994).
30] E. Balogh-Hergovich, J. Kaizer and G. Speier, Inorg. Chim.
[
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