Facile synthesis of novel 7-aminofuro- and 7-aminothieno[2,3-d]pyridazin- 4(5H)-one and 4-aminophthalazin-1(2H)-ones

Article abstract of DOI:10.1016/j.tet.2012.10.010

We hereby report the synthesis of a novel class of compounds, 7-aminofuro- and 7-aminothieno[2,3-d]pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones starting from methyl 2-(2-methoxy-2-oxoethyl)furan- and thiophene-3-carboxylate and methyl 2-(2-methoxy

Full text of DOI:10.1016/j.tet.2012.10.010

Tetrahedron 69 (2013) 395e409
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of novel 7-aminofuro- and 7-aminothieno[2,3-d]
pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones
,
,
c
a
a
d
a,
*
Gani Koza a b, Selbi Keskin a , Merve Sinem Ozer , Betul Cengiz , Ertan S¸ ahin , Metin Balci
€
€
a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
b Department of Chemistry, Ahi Evran University, 40100 Kırs¸ehir, Turkey
c Department of Chemistry, Giresun University, 28100 Giresun, Turkey
d
€
Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2012
Received in revised form 14 September 2012
Accepted 2 October 2012
Available online 16 October 2012
We hereby report the synthesis of a novel class of compounds, 7-aminofuro- and 7-aminothieno[2,3-d]
pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones starting from methyl 2-(2-methoxy-2-
oxoethyl)furan- and thiophene-3-carboxylate and methyl 2-(2-methoxy-2-oxoethyl)benzoate. The es-
ter functionalities connected directly to the aromatic ring were regiospecifically converted to the acid,
whereas methylene groups were oxidized to the corresponding ketoesters. Reaction of the ketoesters
with hydrazine provided the hydrazone derivatives. An intramolecular cyclization in the presence of
thionyl chloride formed a fused pyridazinone skeleton. Hydrolysis of the remaining ester groups and
transformation of the acid functionalities to the acyl azides followed by Curtius rearrangement gave the
isocyanates. Reaction of the isocyanates with methanol and water produced urethane and amino-
pyridazinone derivatives, respectively.
Keywords:
Pyridazinone
Furopyridazinone
Thienopyridazinone
Phthalazinone
Acyl azide
Ó 2012 Elsevier Ltd. All rights reserved.
Curtius rearrangement
1. Introduction
Pyridazinone (1) and phthalazinone (2) derivatives are an im-
portant class of biologically active compounds and they have
attracted the attention of several research groups.1 Pyridazinone (1)
derivatives are well known for their use in the treatment in car-
diovascular and heart diseases.2 4,5-Dihydropyridazin-3(2H)-ones
show a wide range of pharmacological properties.
Fig. 1. Representative pyridazinone and phthalazinone derivatives.
Selected examples are platelet aggregation inhibitors,3 in-
hibitors of cyclooxygenase-2 (COX-2),4 inhibitors of adenosine
30,50-cyclic phosphate phosphodiesterase III (CAMP PDE III),5 p38
mitogen-activated protein (MAP) kinase inhibitors,6 and in com-
pounds with antihypertensive, antithrombotic, antiinflammatory,
and antiulcer activities.7,8
Heteroaromatic fused pyridazinone derivatives are not widely
distributed. 4,5-Fused thienopyridazinone derivatives, such as 5
(Fig. 2), were synthesized as histamine H3 receptor antagonists.14
Yamaguchi et al.15 synthesized some thieno- and furopyr-
idazinone derivatives (6) and showed that thienopyridazinone
derivatives are antiasthmatic agents with dual activities of throm-
boxane A2 synthetase inhibition and bronchodilation. Further-
more, they demonstrated that a thiophene ring is able to replace
the benzene ring of a phthalazinone without loss of biological ac-
tivities.16 Functionalized pyridazinone systems are an important
4-Aminophthalazin-1(2H)-ones (3)9 have shown potential as
anticancer agents10 and in the treatment of autoimmune and
inflammatory diseases (Fig. 1).11 Recently, 2-phenyl-4-amino-
phthalazinone 4 and derivatives have been reported as the core
skeleton for the design of potent and selective human A3 adenosine
receptor antagonists.12 Furthermore, they have been identified as
poly(ADP-ribose) polymerase (PARP) inhibitors.13
class of nitrogen-containing heterocycles possessing
a broad
spectrum of biological activities.17,18 Efforts in our laboratory have
been devoted to developing efficient protocols for the preparation
of diverse fused heterocyclic scaffolds (Fig. 3).
In this paper we report the synthesis of various substituted
aminopyridazinone derivatives fused to thiophene, furan, and
* Corresponding author. E-mail address: mbalci@metu.edu.tr (M. Balci).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.010

396
G. Koza et al. / Tetrahedron 69 (2013) 395e409
Scheme 2. Synthesis of ketoesters 16 and 17.
Fig. 2. Representative fused pyridazinone derivatives.
and 21 by treatment of diacids with concentrated HCl in methanol
in reasonable yields.
Thus, reaction of acids with various substituted hydrazines in
different solvents furnished the hydrazone derivatives 22 and 23,
which were not isolated and used for cyclization reactions (Scheme
3). To increase the reactivity of the acid carbonyl group, the acid
functionalities wereconvertedintoacylchlorides24 and25. Theacids
22 and 23 were treated with SOCl2 in THF and the resulting mixture
was heated at 60e80 ꢀC for 16 h. The in situ formed acyl chlorides
were cyclized to the desired pyridazinone derivatives 26 and 27. The
structures of all compounds were deduced from their NMR spectra.
Conversion of the pyridazinone esters 26 and 27 to the corre-
sponding aminopyridazinone derivatives was achieved through
Curtius rearrangement. First, the esters 26 and 27 were treated
with KOH at 50 ꢀC to give the corresponding acids 28 and 29
(Scheme 4). The most general and versatile synthesis of acyl azides
involves the reaction of acyl chlorides with NaN3 in an aqueous
medium. The acids 28 and 29 were treated with thionyl chloride or
oxalyl chloride in appropriate solvents followed by reaction of the
formed acyl chloride with NaN3 to give the acyl azides 30 and 31.
Finally, heating of the acyl azide 30 and 31 in benzene provided the
expected isocyanates cleanly.
Fig. 3. Representative fused pyridazinone and aminopyridazinone derivatives.
benzene. In the literature, only a single compound 7 having
a thienopyridazinone skeleton is described.19
2. Results and discussion
The synthesis of the starting materials 14 and 15 used in the
synthesis of furo- and thienofused pyridazinones began with the
readily available dimethyl acetonedicarboxylate 12. Treatment of 12
with chloroacetaldehyde in the presence of pyridine yielded the
diester 14 in 80% yield.20 Reaction of 12 with 2,5-dihydroxy-1,4-
dithiane in the presence of lithium bromide in dioxane gave the
diester 15 in 51% yield (Scheme 1).21
Treatment of isocyanates in benzene with MeOH gave the ure-
thane derivatives 32 and 33 in 43e83% yields. The hydrolysis of
isocyanate with 8 M HCl provided the desired aminopyridazinone
derivatives 34 and 35. The 1H and 13C NMR spectra allowed the as-
signment of the structures 32e35. Finally, X-ray diffraction analysis
of a representative sample 32a was carried out. The results of this
study confirmed unambiguously the proposed structure (Fig. 4).
Homophthalic acid 36 was first reacted with thionyl chloride to
give an anhydride that was then treated with methanol to produce
the monoester 37.24 Treatment of 37 with SeO2 in anisole afforded
the ketoester 3825 in 51% yield (Scheme 5). Under conditions sim-
ilar to those as reported in Scheme 4 the ketoesters were reacted
with various substituted hydrazine derivatives to give hydrazone
derivatives, which were directly cyclized with thionyl chloride to
phthalazinone derivatives 39. Conversion of phthalazinone esters
to amino and urethane derivatives 43 and 42 was achieved through
the acyl azides 41. Hydrolysis of 39 with KOH in THF/MeOH afforded
the corresponding acids 40, which were directly used for genera-
tion of acyl azides 41 by treatment with oxalyl chloride followed by
reaction of the formed acyl chlorides with NaN3. Finally, heating of
the acyl azide 41 in benzene provided isocyanate intermediates,
which were converted to urethane and amino derivatives 42 and 43
upon treatment with HCl and MeOH, respectively (Scheme 5).
Scheme 1. The synthesis of furan and thiophene diesters 14 and 15.
The next step was the oxidation of methylene functionality to
a carbonyl group. Selenium dioxide is a useful reagent for allylic
oxidation of alkenes. The allylic alcohols that are initially formed
can be further oxidized to carbonyl groups. Moreover, selenium
dioxide can also oxidize the a-position of carbonyl groups to 1,2-
dicarbonyl compounds.22 Heating of the diesters 14 and 15 in xy-
lene or anisole in the presence of selenium dioxide yielded the
oxidized products 16 and 17 (Scheme 2).
First, the ester functional groups in 16 and 17 were hydrolyzed
to the corresponding carboxylic acids 18 and 19 with KOH at 50 ꢀC
(Scheme 3). Recently, we reported that reactivity of the ester
groups connected to benzene or furan rings is different than the
reactivity of ester groups connected to an alkyl group.23 Similarly,
carboxylic acid functionality adjacent to a methylene group or
a carbonyl group as in 18 and 19 is more reactive than the other.
Therefore, it was possible to convert one of the acid functionalities
in 18 and 19 regiospecifically to the corresponding monoesters 20
3. Conclusion
We have developed a new, facile, and efficient methodology for
the synthesis of aminophthalazinone and thiophene and furan con-
densed pyridazinone derivatives. The strategies and experimental
protocols described here can be applied to the synthesis of benzene
and heteroaromatic ring substitutedphthalazinone and pyridazinone

G. Koza et al. / Tetrahedron 69 (2013) 395e409
397
Scheme 3. Synthesis of furo- and thienocondensed pyridazinone derivatives.
Fig. 4. ORTEP drawing of the molecule 32a. Thermal ellipsoids are shown at 50%
probability level.
Scheme 4. Synthesis of furo- and thieno-condensed aminopyridazinone derivatives.
(i) KOH, CHCl3/THF/MeOH/H2O, 50 ꢀC (57e78%); (ii) a: SOCl2, CHCl3/MeCN reflux or
(COCl)2, DMF, CH2Cl2, b: NaN3, acetone (62e95%); (iii) a: benzene, reflux b: MeOH
(43e83%); (iv) a: benzene, reflux b: 8 M HCl c: 2 M NaOH (42e68%).
for 18 h. The reaction was monitored on TLC and further SeO2 (2.5 g,
22.71 mmol) was added and stirred for 7 h. TLC showed starting
compound and further SeO2 (1.68 g, 15.15 mmol) was added and
stirred for a further 16 h. After the completion of the reaction, the
mixture was cooled, filtered, and washed with ethyl acetate
(100 mL). The filtrate was extracted with ethyl acetate (100 mL) and
water (100 mL) and the water layer re-extracted with ethyl acetate
(100 mL). The combined organic layers were dried over MgSO4 and
the solvent was evaporated. The crude product was purified by
column chromatography (silica gel) eluting with hexane/ethyl ac-
etate (3:1, 2:1) to give oxidized diester 16 as a white solid (1.59 g,
derivatives. Furthermore, amide functionality as well as the amino
group can be further functionalized.
4. Experimental section
4.1. General
50%), mp 49e50 ꢀC. 1H NMR (400 MHz, CDCl3)
1H, H-5), 6.82 (d, J¼1.7 Hz, 1H, H-4), 3.89 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3); 13C NMR (100.6 MHz, CDCl3)
174.9, 162.6, 161.9, 148.6,
d
7.62 (d, J¼1.7 Hz,
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus. IR spectra were recorded on a Perkin Elmer
980spectrometer. NMR spectrawererecorded onaBrukerinstrument
at 400 MHz for 1H and 100.6 MHz for 13C NMR. Apparent splitting is
given in all cases. Elemental analysis was determined on an Leco
CHNS-932 instrument (Ataturk University). Column chromatography
was performed on silica gel (60-mesh, Merck), TLC was carried out on
Merck 0.2 mm silica gel 60 F254analytical aluminum plates.
d
147.5, 126.0, 113.2, 53.1, 52.5; nmax (ATR) 3128, 2956, 1732, 1669,
1574, 1470, 1480, 1438, 1301, 1232, 1206, 1174, 1076, 1050 cmꢁ1
[found: C, 51.03; H, 4.18. C9H8O6 requires C, 50.95; H, 3.80%].
;
4.1.2. Methyl 2-(2-methoxy-2-oxoacetyl)thiophene-3-carboxylate
(17). SeO2 (2.6 g, 23.30 mmol) was added to a stirred solution of
diester 15 (2.0 g, 9.3 mmol) in anisole (50 mL) and heated at 125 ꢀC
for 18 h. The reaction was monitored on TLC. After the completion
of the reaction, the mixture was cooled, filtered, and washed with
4.1.1. Methyl 2-(2-methoxy-2-oxoacetyl)furan-3-carboxylate
(16). SeO2 (3.36 g, 30.30 mmol) was added to a stirred solution of
diester 14 (3.0 g, 15.15 mmol) in xylene (60 mL) and heated at reflux

398
G. Koza et al. / Tetrahedron 69 (2013) 395e409
70%), mp 64e65 ꢀC. 1H NMR (400 MHz, CDCl3)
eCOOH), 7.72 (d, J¼1.7 Hz, 1H, C]CH), 7.14 (d, J¼1.7 Hz, 1H, C]CH),
3.96 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
177.0, 161.6 (2C),
d 12.5 (br s, 1H,
d
148.8, 147.3, 129.3, 116.3, 53.6; nmax (ATR) 3128, 2916, 1744, 1704,
1670, 1578, 1477, 1423, 1385, 1296, 1232, 1217, 1077 cmꢁ1; [found: C,
48.49; H, 3.01. C8H6O6 requires C, 48.50; H, 3.05%].
4.1.6. 2-[Methoxy(oxo)acetyl]-3-thienoic acid (21). The same pro-
cedure was used as described above using diacid 19 (3.1 g,
15.5 mmol) to give monoester 21 as a white solid (2.2 g, 66%), mp
98e100 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.5 (br s, 1H, eCOOH), 7.71
(d, 1H, J¼5.1 Hz, C]CH), 7.64 (d, J¼5.1 Hz, 1H, C]CH), 3.89 (s, 3H,
OCH3); 13C NMR (100.6 MHz, CDCl3)
179.6, 166.6, 162.0, 142.5,
d
136.1, 133.7, 131.2, 53.3; nmax (ATR) 3117, 2960, 1723, 1690, 1664,
1518, 1403, 1312, 1290, 1274, 1172 cmꢁ1; [found: C, 44.44; H, 2.76; S,
14.93. C8H6O5S requires C, 44.86; H, 2.82; S, 14.97%].
4.1.7. Methyl 5-methyl-4-oxo-4,5-dihydrofuro[2,3-d]pyridazine-7-
carboxylate (26a). A solution of methyl hydrazine (0.37 mL,
7.07 mmol) in dry THF (5 mL) was added to a stirred solution of the
monoester 20 (1.4 g, 7.07 mmol) in dry THF (75 mL) and the mixture
was stirred at 50 ꢀC for 2 h. Thionyl chloride (1.03 mL, 14.14 mmol)
was added to the reaction mixture and stirred at 50 ꢀC for 16 h. The
solvent was evaporated and the residue was purified by column
chromatography (silica gel) eluting with ethyl acetate/chloroform/
hexane (3:3:2) to give pyridazine 26a as a white solid (1.25 g, 85%),
Scheme 5. Synthesis of phthalazinone derivatives. (i) a) Hydrazine derivatives, THF or
MeOH, b) SOCl2, THF or benzene, 56e80%; (ii) a) KOH, THF/MeOH/H2O (74e98%); (iii)
(COCl)2, DMF, CH2Cl2, and NaN3, acetone (75e97%); (iv) benzene, reflux, and MeOH
(80e99%); (v) benzene, reflux, 8 M HCl, and 2 M NaOH (80e98%).
ethyl acetate (100 mL). The solvent was evaporated and the crude
product was purified by column chromatography (silica gel) eluting
with hexane/ethyl acetate (2:1) to give oxidized diester 17 as
a brown oil (1.25 g, 61%). 1H NMR (400 MHz, CDCl3) dH 7.61 (d,
J¼5.1 Hz, 1H, H-5), 7.43 (d, J¼5.1 Hz, 1H, H-4), 3.85 (s, 3H, eOCH3),
3.80 (s, 3H, eOCH3); 13C NMR dC (100.6 MHz, CDCl3) 179.6, 162.8,
162.1, 142.0, 136.7, 132.9, 129.9, 53.1, 52.5; nmax (ATR) 3110, 2954,
1758, 1717, 1668, 1262, 1170, 1151 cmꢁ1; [found: C, 46.99; H, 3.54; S,
14.27. C9H8O5S requires C, 47.36; H, 3.53; S, 14.05%].
mp 207e208 ꢀC. 1H NMR (400 MHz, CDCl3)
C]CH), 7.10 (d, J¼2.0 Hz,1H, C]CH), 4.06 (s, 3H, eOCH3), 3.98 (s, 3H,
NeCH3); 13C NMR (100.6 MHz, CDCl3)
161.2, 158.8, 151.3, 147.6,
d
7.80 (d, J¼2.0 Hz, 1H,
d
126.6, 122.9, 107.2, 53.0, 40.4; nmax (ATR) 3126, 3108, 2960, 1739,
1674, 1505, 1428, 1331, 1231, 1155, 1056 cmꢁ1; [found: C, 51.81; H,
3.83; N, 13.37. C9H8N2O4 requires C, 51.93; H, 3.87; N, 13.46%].
4.1.3. 2-(Carboxycarbonyl)-3-furoic acid (18). A solution of KOH
(28.3 mL, 56.6 mmol, 2 M)in methanol wasadded to a stirred solution
of oxidized diester 16 (4.0 g, 18.9 mmol) in THF (60 mL), MeOH
(30 mL), and H2O (4 mL). The mixture was stirred at 50 ꢀC for 4 h and
monitored on TLC. After the completion of the reaction, the mixture
wascooled on anice bathand a solid precipitated. The precipitatewas
filtered, washed with ethyl acetate, and then dissolved in water
(30 mL). The solution was acidified with aq HCl (1 M) to pH¼2 and
then extracted with ethyl acetate (3ꢂ400 mL). The combined organic
layers were dried over MgSO4 and the solvent was evaporated to give
diacid 18 as a white solid (2.96 g, 85%), mp 187e189 ꢀC. 1H NMR
4.1.8. Methyl 5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazine-7-
carboxylate (27a). The same procedure was used as described
above using monoester 21 (1.4 g, 6.5 mmol) to give pyridazine 27a as
a white solid (1.43 g, 91%), mp 200e202 ꢀC.1H NMR (400 MHz, CDCl3)
d
7.69 (d, A-part of AB-system, J¼5.4 Hz, 1H, C]CH), 7.68 (d, B-part of
AB-system, J¼5.4 Hz, 1H, C]CH), 4.00 (s, 3H, eOCH3), 3.92 (s, 3H,
eNCH3); 13C NMR (100.6 MHz, CDCl3)
163.2, 157.6, 138.5, 135.3, 133.9,
d
131.5, 124.3, 53.3, 40.2; nmax (ATR) 3085, 3070, 2964, 1710, 1683, 1451,
1432,1354,1256,1211,1056cmꢁ1;[found:C,48.42;H, 3.59;N,12.49;S,
14.68. C9H8N2O3S requires C, 48.21; H, 3.60; N, 12.49; S, 14.30%].
(400 MHz, DMSO-d6)
d
13.60 (br s, 2H, eCOOH), 8.18 (d, J¼1.7 Hz,1H,
C]CH), 7.00 (d, J¼1.7 Hz, 1H, C]CH);13C NMR (100.6 MHz, DMSO-d6)
4.1.9. Methyl 4-oxo-5-phenyl-4,5-dihydrofuro[2,3-d]pyridazine-7-
carboxylate (26b). A solution of phenyl hydrazine (0.99 mL,
10.1 mmol) in dry THF (5 mL) was added to a stirred solution of the
monoester 20 (2.0 g,10.1 mmol) in dry THF (40 mL) and dry benzene
(40 mL) and the mixture was stirred at 80 ꢀC for 4 h. Thionyl chloride
(1.5 mL, 20.2 mmol) was added to the reaction mixture and stirred at
80 ꢀC for 16 h. The solvents were evaporated and the residue was
purified by column chromatography (silica gel) eluting with ethyl
acetate/hexane (1:1) and then ethyl acetate/dichloromethane (1:1)
to give pyridazine 26b as a white solid (2.46 g, 90%), mp 201e202 ꢀC.
d
177.1, 163.7, 162.9, 148.9, 147.5, 127.5, 113.2; nmax (ATR) 3441, 3154,
2957, 1638, 1478, 1430, 1377, 1269, 1208, 1151, 1076 cmꢁ1; [found: C,
45.54; H, 2.19. C7H4O6 requires C, 45.67; H, 2.19%].
4.1.4. 2-(Carboxycarbonyl)-3-thienoic acid (19). The same pro-
cedure was used as described above using oxidized diester 17 (4.0 g,
17.5 mmol) to give diacid 19 as a white solid (3.1 g, 90%), mp
153e155 ꢀC.1H NMR (400 MHz, DMSO-d6)
d 13.50 (br s, 2H, eCOOH),
8.07 (d, J¼5.0 Hz,1H, C]CH), 7.47 (d, J¼5.0 Hz,1H, C]CH); 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.86 (d, J¼2.0 Hz, 1H, C]CH), 7.61e7.58
d
(100.6 MHz, DMSO-d6) 181.9,163.8,162.8,140.8,138.6,134.2,129.5;
nmax (ATR) 3118, 1719, 1685, 1663, 1526, 1402, 1259, 12,043 cmꢁ1
;
(m, 2H, arom.), 7.53e7.49 (m, 2H, arom.), 7.44 (tt, J¼6.8, 1.2 Hz, 1H),
7.16 (d, J¼2.0 Hz, 1H), 4.05 (s, 3H, eOCH3); 13C NMR (100.6 MHz,
[found: C, 42.04; H, 2.13; S,16.02. C7H4O5S requires C, 42.00; H, 2.01;
S, 16.02%].
CDCl3)
d 161.3, 158.4, 151.0, 147.8, 141.1, 129.0, 128.7, 127.6, 126.1,
123.9,107.9, 53.1; nmax (ATR) 3156, 3099, 2957,1739,1687,1627,1580,
1510,1434,1334,1263,1179,1136,1121,1079 cmꢁ1; [found: C, 62.36;
H, 3.64; N, 10.32. C14H10N2O4 requires C, 62.22; H, 3.73; N, 10.37%].
4.1.5. 2-[Methoxy(oxo)acetyl]-3-furoic acid (20). Concd HCl (20
drops) was added to a stirred solution of diacid 18 (2.0 g,
10.87 mmol) in MeOH (20 mL) and CH2Cl2 (40 mL) and the mixture
was stirred at 40 ꢀC for 15 h. The solvents were evaporated and the
residue was purified and separated by column chromatography
(silica gel) eluting with hexane/ethyl acetate (2:1) and then only
with ethyl acetate to give monoester 20 as a white solid (1.51 g,
4.1.10. Methyl 4-oxo-5-phenyl-4,5-dihydrothieno[2,3-d]pyridazine-
7-carboxylate (27b). The same procedure was used as described
above using monoester 21 (2.0 g, 6.3 mmol) to give pyridazine 27b as
a white solid (2.1 g, 81%), mp 246e248 ꢀC. 1H NMR (400 MHz, CDCl3)

G. Koza et al. / Tetrahedron 69 (2013) 395e409
399
d
7.74 (s, 2H, thiophene), 7.58e7.55 (m, 2H, arom.), 7.46e7.42 (m, 2H,
(m, 1H, arom.), 7.16 (d, J¼2.0 Hz, 1H, C]CH), 7.07e7.00 (m, 2H,
arom.), 4.06 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
163.1
arom.), 7.36 (tt, J¼7.4,1.2 Hz,1H, arom.), 3.98 (s, 3H, eOCH3); 13C NMR
d
(100.6 MHz, CDCl3)
d
163.4, 157.0, 141.1, 138.1, 136.2, 134.2, 132.2, 129.0,
(dd, J¼252.1 and 11.3 Hz), 160.9, 157.9, 157.6 (dd, J¼255.8 and
12.8 Hz), 151.0, 148.1, 129.9 (dd, J¼10.3 and 1.3 Hz), 128.4, 125.2 (dd,
J¼12.9 and 4.0 Hz), 123.6, 112.0 (dd, J¼22.7 and 3.6 Hz), 107.8, 105.1
(dd, J¼26.7 and 23.4 Hz), 53.2; nmax (ATR) 3174, 3072, 2970, 1736,
1702, 1619, 1506, 1435, 1344, 1291, 1229, 1176, 1139, 1105,
1071 cmꢁ1; [found: C, 54.71; H, 2.60; N, 9.08. C14H8F2N2O4 requires
C, 54.91; H, 2.63; N, 9.15%].
128.6,126.0, 125.0, 53.4; nmax (ATR) 3102, 3083,1709,1681,1500,1453,
1356,1192,1155,1045cmꢁ1;[found:C, 58.90;H, 3.67;N, 9.82; S,11.57;
C14H10N2O3S requires C, 58.73; H, 3.52; N, 9.78; S, 11.20%].
4.2. General procedure for the synthesis of furopyridazine
derivatives (26ceg)
The monoester 20 (1.0 g, 5.05 mmol) and phenyl hydrazinium
chloride derivatives (5.3 mmol) were dissolved in dry THF (30 mL) and
MeOH (30 mL) andthe mixturewas stirredat 60ꢀCfor3h.Thesolvents
were evaporated and the residue was dissolved in dry THF (40 mL).
Thionyl chloride (1.3 mL,17.8 mmol) was added to the reaction mixture
and stirred at 60 ꢀC for 16 h. The solvent was evaporated and the
residue was purified by column chromatography eluting with ethyl
acetate/hexane (1:1) and then ethyl acetate/dichloromethane (1:1) to
give furopyridazine derivatives 26ceg as a white solid.
4.3. General procedure for the synthesis of thienopyridazine
derivatives (27ceg)
The monoester 21 (1.0 g, 4.67 mmol) and phenyl hydrazinium
chloride derivatives (5.1 mmol) were dissolved in dry MeOH
(50 mL) and the mixture was stirred at 50 ꢀC for 2 h. The solvent
was evaporated and the residue was dissolved in dry benzene
(50 mL). Thionyl chloride (1.0 mL, 14.0 mmol) was added to the
reaction mixture and stirred at 50 ꢀC for 16 h. The solvent was
evaporated and the residue was purified by column chromatogra-
phy eluting with ethyl acetate/dichloromethane (1:1) to give thie-
nopyridazine derivatives 27ceg as a white solid.
4.2.1. Methyl 5-(4-methylphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
idazine-7-carboxylate (26c). (1.30 g, 91%), mp 205e206 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.78 (d, J¼2.0 Hz,1H, eC]CH), 7.39 (brd, J¼7.6 Hz,
2H, arom.), 7.23 (br d, J¼7.6 Hz, 2H, arom.), 7.08 (d, J¼2.0 Hz, 1H, C]
CH), 3.97 (s, 3H, eOCH3), 2.35 (s, 3H, eCH3); 13C NMR (100.6 MHz,
4.3.1. Methyl
pyridazine-7-carboxylate (27c). (1.33 g, 95%), mp 251e253 ꢀC. 1H
NMR (400 MHz, CDCl3)
5-(4-methylphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
CDCl3)d161.3,158.5,151.0,147.8,138.8,138.6,129.6,127.4,125.9,123.8,
107.8, 53.0, 21.2; nmax (ATR) 3153, 3100, 2960, 1743, 1687, 1509, 1436,
1336, 1260, 1133, 1121, 1076 cmꢁ1; [found: C, 63.06; H, 4.11; N, 9.61.
C15H12N2O4 requires C, 63.38; H, 4.25; N, 9.85%].
d
7.74 (d, A-part of AB-system J¼5.5 Hz, 1H,
C]CH), 7.72 (d, B-part of AB-system, J¼5.5 Hz, 1H, C]CH),
7.45e7.42 (m, A-part of AA0BB0 system, 2H, arom.), 7.25e7.22 (m, B-
part of AA0BB0 system, 2H, arom.), 3.97 (s, 3H, OCH3), 2.35 (s, 3H,
4.2.2. Methyl
5-(4-methoxyphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]
CH3); 13C NMR (100.6 MHz, CDCl3)
d 164.1, 157.7, 139.3, 139.2, 138.7,
pyridazine-7-carboxylate (26d). (1.36 g, 90%), mp 203e204 ꢀC. 1H
136.8, 134.7, 132.7, 130.2, 126.4, 125.6, 53.9, 21.8; nmax (ATR) 3102,
3083, 2959, 1746, 1710, 1679, 1487, 1453, 1442, 1405, 1356, 1270,
1145, 1111, 1086, 1046 cmꢁ1; [found: C, 59.78; H, 4.11; N, 9.43; S,
10.82. C15H12N2O3S requires C, 59.99; H, 4.03; N, 9.33; S, 10.68%].
NMR (400 MHz, CDCl3)
d
7.77 (d, J¼2.0 Hz, 1H, C]CH), 7.46e7.42
(m, A-part of AA0BB0 system, 2H, arom.), 7.08 (d, J¼2.0 Hz, 1H, C]
CH), 6.96e6.92 (m B-part of-AA0BB0 system, 2H, arom.), 3.97 (s, 3H,
eOCH3), 3.79 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 161.3,
159.6, 158.5, 151.0, 147.7, 134.1, 127.3, 127.2, 123.8, 114.2, 107.8, 55.6,
53.0; nmax (ATR) 3142, 3104, 2966, 1741, 1720, 1682, 1506, 1435,
1334, 1253, 1134, 1118, 1076 cmꢁ1; [found: C, 59.64; H, 4.06; N, 9.20.
C15H12N2O5 requires C, 60.00; H, 4.03; N, 9.33%].
4.3.2. Methyl 5-(4-methoxyphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazine-7-carboxy-late (27d). (1.26 g, 85%), mp 189e191 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.73 (d, J¼5.5 Hz, 1H, C]CH), 7.72 (d,
J¼5.5 Hz, 1H, C]CH), 7.50e7.46 (m, A-part of AA0BB0 system, 2H,
arom.), 6.97e6.91 (m, B-part of AA0BB0 system, 2H, arom.), 3.97 (s,
3H, eOCH3), 3.79 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
4.2.3. Methyl 5-(4-chlorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
idazine-7-carboxylate (26e). (1.33 g, 86%), mp 192e193 ꢀC. 1H NMR
d 163.5,159.6,157.1,138.1,136.2,134.1,134.0,132.0,127.2,125.0,114.2,
(400 MHz, CDCl3)
d
7.88 (d, J¼2.0 Hz, 1H, C]CH), 7.61e7.58 (m, A-
55.6, 53.3; nmax (ATR) 3075, 2954, 2839, 1720, 1671, 1511, 1454, 1437,
1358, 1234, 1175, 1147, 1047 cmꢁ1; [found: C, 56.65; H, 3.81; N, 8.81;
S, 9.82. C15H12N2O4S requires C, 56.95; H, 3.82; N, 8.86; S, 10.14%].
part of AA0BB0 system, 2H, arom.), 7.52e7.50 (m, B-part of AA0BB0
system, 2H, arom.), 7.18 (d, J¼2.0 Hz, 1H, C]CH), 4.07 (s, 3H,
eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 161.1, 158.2, 150.9, 148.0,
139.5, 134.5, 129.1, 127.9, 127.4, 123.9, 107.9, 53.2; nmax (ATR) 3148,
3130, 2968, 1744, 1702, 1504, 1488, 1437, 1332, 1258, 1180, 1172,
1136, 1116, 1083, 1074 cmꢁ1; [found: C, 54.85; H, 2.79; N, 8.87.
C14H9ClN2O4 requires C, 55.19; H, 2.98; N, 9.19%].
4.3.3. Methyl
5-(4-chlorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazine-7-carboxylate (27e). (1.47 g, 98%), mp 195e197 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.75 (d, J¼5.3 Hz, 1H, C]CH), 7.73 (d,
J¼5.3 Hz, 1H, C]CH), 7.59e7.52 (m, A-part of AA0BB0 system, 2H,
arom.), 7.44e7.38 (m, B-part of AA0BB0 system, 2H, arom.), 3.98 (s,
4.2.4. Methyl 5-(4-fluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
idazine-7-carboxylate (26f). (1.32 g, 91%), mp 214e215 ꢀC. 1H NMR
3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 163.2, 156.8, 139.5,
138.1, 136.1, 134.5, 134.3, 132.4, 129.1, 127.3, 125.0, 53.4; nmax (ATR)
3103, 3087, 2919, 2849, 1745, 1717, 1686, 1486, 1452, 1405, 1358,
1270, 1143, 1135, 1087, 1011 cmꢁ1; [found: C, 52.39; H, 3.15; N, 8.44;
S, 10.35. C14H9ClN2O3S requires C, 52.42; H, 2.83; N, 8.73; S, 10.00%].
(400 MHz, CDCl3)
d
7.79 (d, J¼2.0 Hz,1H, C]CH), 7.54e7.49 (m, A-part
of AA0BB0 system, 2H, arom.), 7.19e7.10 (m, B-part of AA0BB0 system,
2H, arom.), 7.08 (d, J¼2.0 Hz,1H, C]CH), 3.98(s, 3H, eOCH3);13C NMR
(100.6 MHz, CDCl3)
d
162.8 (d, J¼248.6 Hz), 161.1, 158.3, 150.9, 148.0,
137.0 (d, J¼3.1Hz),128.0(d, J¼8.8Hz),127.7,123.9,115.9(d, J¼23.2Hz),
107.9, 53.1; nmax (ATR) 3174, 3150, 2971, 1740, 1686, 1505, 1435, 1336,
1277, 1215, 1177, 1135, 1112, 1076 cmꢁ1; [found: C, 58.44; H, 3.03; N,
9.67. C14H9FN2O4 requires C, 58.34; H, 3.15; N, 9.72%].
4.3.4. Methyl
5-(4-fluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazine-7-carboxylate (27f). (1.26 g, 89%), mp 201e203 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.75 (d, J¼5.3 Hz, 1H, C]CH), 7.73 (d,
J¼5.3 Hz,1H, C]CH), 7.57 (m, A-partof AA0BB0 system, 2H, arom.), 7.55
(m, B-part of AA0BB0 system, 2H, arom.), 3.98 (s, 3H, eOCH3); 13C NMR
4.2.5. Methyl 5-(2,4-difluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]
pyridazine-7-carboxylate (26g). (1.32 g, 85%), mp 181e182 ꢀC. 1H
(100.6 MHz, CDCl3)
J¼3.4 Hz), 136.2, 134.43, 132.3, 127.9 (d, J¼8.7 Hz), 125.0, 115.9 (d,
J¼23.0 Hz), 53.41; nmax (ATR) 3105, 3084, 2964,1746,1716,1682,1453,
d
163.3, 161.3 (d, J¼248.7 Hz), 157.0, 138.1, 137.1 (d,
NMR (400 MHz, CDCl3)
d
7.89 (d, J¼2.0 Hz, 1H, C]CH), 7.50e7.45

400
G. Koza et al. / Tetrahedron 69 (2013) 395e409
1435,1358,1235,1144,1042 cmꢁ1; [found: C, 55.32; H, 3.04; N, 9.10; S,
11.02. C14H9FN2O3S requires C, 55.26; H, 2.98; N, 9.21; S, 10.54%].
1254, 1229, 1157, 1124 cmꢁ1; [found: C, 58.36; H, 3.43; N, 9.42.
C14H10N2O5 requires C, 58.74; H, 3.52; N, 9.79%].
4.3.5. Methyl 5-(2,4-difluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazine-7-carboxylate (27g). (1.46 g, 97%), mp 224e226 ꢀC. 1H
4.4.5. 5-(4-Chlorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyrida-zine-
7-carboxylic acid (28e). (0.80 g, 84%), mp 226e227 ꢀC. 1H NMR
NMR(400MHz,CDCl3)
1H, C]CH), 7.48e7.38(m,1H, arom.), 7.00e6.92(m,2H,arom.),3.98(s,
3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
and 11.1 Hz), 157.7 (dd, J¼257.0 and 13.0 Hz), 156.5, 138.3, 135.7, 134.7,
133.0,129.9(dd,J¼10.3and1.4Hz),125.3(dd,J¼13.0and 4.2Hz),125.0,
112.0 (dd, J¼22.8 and 3.8 Hz),105.2 (dd, J¼26.5 and 23.5 Hz), 53.5; nmax
(ATR) 3104, 3085, 2963, 1746, 1717, 1687, 1485, 1452, 1435, 1359, 1271,
1143, 1110, 1087 cmꢁ1; [found: C, 52.17; H, 2.50; N, 8.66; S, 10.35.
C14H8F2N2O3S requires C, 52.17; H, 2.50; N, 8.69; S, 9.95%].
d
7.77 (d, J¼5.3Hz,1H,C]CH), 7.73 (d, J¼5.3Hz,
d
(400 MHz, DMSO-d6) 8.37 (d, J¼1.7 Hz, 1H, C]CH), 7.62 (br s,
4H, arom.), 7.29 (d, J¼1.7 Hz, 1H, C]CH); 13C NMR (100.6 MHz,
d
163.1, 163.0 (dd, J¼251.7
DMSO-d6) d 161.5, 157.8, 150.7, 149.3, 140.0, 132.9, 128.7, 128.3,
128.2, 123.1, 107.4; nmax (ATR) 3148, 3112, 2934, 1730, 1640, 1525,
1510, 1491, 1421, 1315, 1230, 1185, 1154, 1120, 1093, 1018 cmꢁ1
;
[found: C, 53.39; H, 2.42; N, 9.44. C13H7ClN2O4 requires C, 53.72;
H, 2.43; N, 9.64%].
4.4.6. 5-(4-Fluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyrida-zine-
7-carboxylic acid (28f). (0.82 g, 86%), mp 244e245 ꢀC. 1H NMR
4.4. General procedure for the hydrolysis of pyridazine de-
rivatives (26aeg and 27aeg)
(400 MHz, DMSO-d6)
d
13.82 (br s, 1H, eCOOH), 8.36 (d, J¼2.0 Hz,
1H), 7.65e7.60 (m, A-part of AA0BB0 system, 2H, arom.), 7.41e7.36
(m, B-part of AA0BB0 system, 2H, arom.), 7.28 (d, J¼2.0 Hz, 1H); 13C
A solution of KOH (4.8e3.1 mL, 2 mol equiv, 2 M) in methanol was
added to a stirred solution of esters 26aeg and 27aeg (1.0 g,
4.8e3.1 mmol) in THF (60 mL), chloroform (80 mL) and H2O (0.5 mL).
The mixturewas stirred at 50 ꢀC for 90minandmonitoredonTLC. After
the completion of thereaction, the mixturewas cooled, hexane (50 mL)
added and a solid precipitated. The precipitate was filtered, washed
with ethyl acetate, and then dissolved in water (40 mL). The solution
was acidified with aq HCl (1 M) to pH¼2 and a white solid precipitated.
The precipitate was filtered on filter paper and allowed to dry at am-
bient temperature to give acids 28aeg and 29aeg as white solids.
NMR (100.6 MHz, DMSO-d6)
d
161.6, 161.5 (d, J¼245.6 Hz), 157.9,
150.8, 149.2, 137.5 (d, J¼2.9 Hz), 128.7 (d, J¼8.9 Hz), 128.1, 123.1,
115.5 (d, J¼22.9 Hz), 107.3; nmax (ATR) 3140, 3114, 2926, 1729, 1651,
1608, 1526, 1423, 1317, 1231, 1185, 1158, 1123, 1022 cmꢁ1; [found:
C, 56.77; H, 2.46; N, 10.07. C13H7FN2O4 requires C, 56.94; H, 2.57;
N, 10.22%].
4.4.7. 5-(2,4-Difluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-]pyrida-
zine-7-carboxylic acid (28g). (0.76 g, 80%), mp 224e225 ꢀC. 1H
NMR (400 MHz, DMSO-d6)
d
8.41 (d, J¼2.0 Hz, 1H, C]CH),
7.74e7.68 (m, 1H, arom.), 7.60e7.54 (m, 1H, arom.), 7.34e7.30 (1H,
4.4.1. 5-Methyl-4-oxo-4,5-dihydrofuro[2,3-d]pyridazine-7-
m), 7.32 (d, J¼2.0 Hz, 1H, C]CH); 13C NMR (100.6 MHz, DMSO-d6)
carboxylic acid (28a). (0.73 g, 78%), mp 258e260 ꢀC. 1H NMR
d
162.3 (dd, J¼248.9 and 11.4 Hz), 161.4, 157.6, 157.0 (dd, J¼252.9
(400 MHz, DMSO-d6)
d
13.3 (br s, 1H, eCOOH), 8.29 (d, J¼2.0 Hz,1H,
and 13.3 Hz), 150.9, 149.6, 130.9 (d, J¼10.4 Hz), 129.1, 125.4 (dd,
J¼12.9 and 3.9 Hz), 122.8, 122.2 (dd, J¼22.7 and 3.4 Hz), 107.3,
104.9 (dd, J¼27.2 and 23.9 Hz); nmax (ATR) 3145, 3120, 2919, 1730,
1656, 1615, 1526, 1506, 1439, 1421, 1369, 1275, 1214, 1145, 1124,
1077 cmꢁ1; [found: C, 53.27; H, 1.97; N, 9.44. C13H6F2N2O4 requires
C, 53.44; H, 2.07; N, 9.59%].
C]CH), 7.20 (d, J¼2.0 Hz, 1H, C]CH), 3.80 (s, 3H, eNCH3); 13C NMR
(100.6 MHz, DMSO-d6) d 161.6, 158.1, 151.0, 148.9, 127.0, 122.1, 106.7,
39.7; nmax (ATR) 3125, 3109, 2875, 1733, 1634, 1572, 1506, 1424,
1370, 1315, 1216, 1165, 1069 cmꢁ1; [found: C, 49.25; H, 3.07; N,
14.37. C8H6N2O4 requires C, 49.49; H, 3.12; N, 14.43%].
4.4.2. 4-Oxo-5-phenyl-4,5-dihydrofuro[2,3-d]pyridazine-7-
carboxylic acid (28b). (0.82 g, 87%), mp 231e233 ꢀC. 1H NMR
4.4.8. 5-Methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazine-7-
carboxylic acid (29a). (0.53 g, 57%), mp 276e278 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
1H, C]CH), 7.56e7.49 (m, 5H, arom.), 7.29 (d, J¼1.6 Hz, 1H, C]CH);
13C NMR (100.6 MHz, DMSO-d6)
161.6, 157.9, 150.8, 149.2, 141.3,
d
13.98 (br s, 1H, eCOOH), 8.37 (d, J¼1.6 Hz,
(400 MHz, DMSO-d6)
d
13.90 (br s, 1H, eCOOH), 8.15 (d, J¼5.3 Hz,
1H, C]CH), 7.66 (d, J¼5.3 Hz, 1H, C]CH), 3.82 (s, 3H, eNCH3); 13
C
d
NMR (100.6 MHz, DMSO-d6) d 163.9, 156.8, 138.1, 135.5, 134.6, 131.7,
128.7, 128.4, 128.1, 126.5, 123.1, 107.3; nmax (ATR) 3140, 3113, 3069,
2913, 1727, 1639, 1526, 1510, 1489, 1421, 1314, 1228, 1184, 1157, 1123,
1082 cmꢁ1; [found: C, 61.19; H, 3.01; N, 10.91. C13H8N2O4 requires C,
60.94; H, 3.15; N, 10.93%].
123.5, 39.6; nmax (ATR) 3073, 2957, 1705, 1619, 1456, 1396, 1189,
1033 cmꢁ1; [found: C, 45.39; H, 2.55; N, 12.97; S, 14.89. C8H6N2O3S
requires C, 45.71; H, 2.88; N, 13.33; S, 15.25%].
4.4.9. 4-Oxo-5-phenyl-4,5-dihydrothieno[2,3-d]pyridazine-7-
4.4.3. 5-(4-Methylphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyridazi-ne-
carboxylic acid (29b). (0.69 g, 73%), mp 245e247 ꢀC 1H NMR
7-carboxylic acid (28c). (0.82 g, 86%), mp 225e227 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
14.20 (br s,1H, eCOOH), 8.22 (d, J¼5.3 Hz,1H,
(400 MHz, DMSO-d6)
d
13.96 (br s, 1H, eCOOH), 8.36 (d, J¼2.0 Hz,
C]CH), 7.73 (d, J¼5.3 Hz, 1H, C]CH), 7.63e7.47 (m, 5H, arom.); 13C
1H, C]CH), 7.44e7.41 (m, A-part of AA0BB0 system, 2H, arom.),
7.36e7.33 (m, B-part of AA0BB0 system, 2H, arom.), 7.27 (d, J¼2.0 Hz,
1H, C]CH), 2.39 (s, 3H, eCH3); 13C NMR (100.6 MHz, DMSO-d6)
NMR (100.6 MHz, DMSO-d6) d 164.6, 157.0, 141.9, 138.5, 136.6, 136.1,
133.1, 129.3, 129.0, 127.1, 124.7; nmax (ATR) 3109, 3076, 2959, 2834,
1714,1536,1456,1401,1393,1153,1126,1036 cmꢁ1; [found: C, 57.07;
H, 3.09; N, 10.63; S, 12.11. C13H8N2O3S requires C, 57.35; H, 2.96; N,
10.29; S, 11.78%].
d
161.6, 157.9, 150.8, 149.1, 138.8, 138.0, 129.1, 127.9, 126.2, 123.0,
107.3, 20.8; nmax (ATR) 3149, 3113, 2919,1732,1641,1526,1510,1420,
1312, 1218, 1155, 1121 cmꢁ1; [found: C, 61.85; H, 3.64; N, 10.12.
C14H10N2O4 requires C, 62.22; H, 3.73; N, 10.37%].
4.4.10. 5-(4-Methylphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyri-da-
zine-7-carboxylic acid (29c). (0.83 g, 87%), mp 233e235 ꢀC. 1H NMR
4.4.4. 5-(4-Methoxyphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyrida-
zine-7-carboxylic acid (28d). (0.81 g, 85%), mp 212e214 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
14.10 (br s,1H, eCOOH), 8.20 (d, J¼5.3 Hz,1H,
C]CH), 7.72 (d, J¼5.3 Hz,1H, C]CH), 7.48 (br d, J¼8.3 Hz, 2H, arom.),
(400 MHz, DMSO-d6)
2H, arom.), 7.25 (br s, 1H, C]CH), 7.06 (br d, J¼6.6 Hz, 2H, arom.),
3.86 (s, 3H, eOCH3); 13C NMR (100.6 MHz, DMSO-d6)
161.6, 158.9,
d
8.34 (br s, 1H, C]CH), 7.46 (br d, J¼6.6 Hz,
7.35 (br d, J¼8.3 Hz, 2H, arom.), 2.40 (s, 3H, eCH3); 13C NMR
(100.6 MHz, DMSO-d6) d 163.9, 156.4, 138.8, 137.9, 137.8, 135.8, 135.5,
d
132.4,129.1,126.2,124.1, 20.7; nmax (ATR) 3102, 2918,1746,1716,1687,
158.0, 150.7, 149.2, 134.1, 127.8, 127.7, 123.0, 113.8, 107.3, 55.6; nmax
(ATR) 3141, 3113, 2910, 2834, 1728, 1642, 1525, 1507, 1423, 1370,
1623,1487,1453,1434,1359,1270,1146, 1039 cmꢁ1; [found: C, 58.41;

G. Koza et al. / Tetrahedron 69 (2013) 395e409
401
H, 3.59; N, 9.53; S, 11.58. C14H10N2O3S requires C, 58.73; H, 3.52; N,
9.78; S, 11.20%].
solid (0.48 g, 84%), mp 134e135 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.76
(d, J¼2.0 Hz, 1H, C]CH), 7.03 (d, J¼2.0 Hz, 1H, C]CH), 3.91 (s, 3H
eNCH3); 13C NMR (100.6 MHz, CDCl3)
167.0, 158.7, 151.0, 147.9,
126.8, 122.9, 107.2, 40.5; nmax (ATR) 3133, 3109, 2164, 1691, 1504,
1421, 1381, 1325, 1248, 1235, 1167, 1087 cmꢁ1
d
4.4.11. 5-(4-Methoxyphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyr-
idazine-7-carboxylic acid (29d). (0.83 g, 87%), mp 230e232 ꢀC. 1H
.
NMR (400 MHz, DMSO-d6)
d 14.05 (br s, 1H, eCOOH), 8.20 (d,
J¼5.3 Hz,1H, C]CH), 7.71 (d, J¼5.3 Hz,1H, C]CH), 7.55e7.49 (m, A-
part of AA0BB0 system, 2H, arom.), 7.11e7.06 (m, B-part of AA0BB0
system, 2H, arom.), 3.83 (s, 3H, eOCH3); 13C NMR (100.6 MHz,
4.6. General procedure for the synthesis of acyl azide de-
rivatives (30beg)
DMSO-d6) d 164.0,158.9, 156.5, 137.8,135.8,135.4, 134.1,132.2,127.7,
124.1, 113.8, 55.5; nmax (ATR) 3111, 3075, 2961, 2834, 1714, 1624,
1609, 1508, 1456, 1330, 1252, 1218, 1155, 1127, 1031 cmꢁ1; [found: C,
55.28; H, 3.38; N, 9.30; S, 10.61. C14H10N2O4S requires C, 55.62; H,
3.33; N, 9.27; S, 10.61%].
Oxalyl chloride (0.35 mL, 4.1 mmol) and then DMF (4 drops) were
addedtoa stirredsuspensionoftheacids 28beg(0.5g,1.7e2.0mmol)
in dichloromethane (60 mL) and the mixture was stirred at rt for
90 min. The solvent and excess oxalyl chloride were evaporated. The
residue was dissolved in acetone (50 mL) and cooled to 2 ꢀC. To this
solution, a solution of NaN3 (0.25 g, 3.85 mmol) in H2O (3 mL) was
added. Precipitation ofinorganicsalts wasimmediatelyobserved. The
resulting mixture was stirred for 1 h and then, H2O (80 mL) was
added. The mixture was extracted with ethyl acetate (2ꢂ150 mL), the
combined organic layers were dried over MgSO4 and the solvent was
evaporated. The crude product was purified by column chromatog-
raphy (silica gel) eluting with ethyl acetate/dichloromethane/hexane
(2:2:1) to give acyl azides 30beg as white solids.
4.4.12. 5-(4-Chlorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyri-da-
zine-7-carboxylic acid (29e). (0.67 g, 70%), mp 244e246 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
14.10 (br s, 1H, eCOOH), 8.22 (d, J¼5.3 Hz, 1H,
C]CH), 7.73 (d, J¼5.3 Hz, 1H, C]CH), 7.70e7.65 (m, A-part of AA0BB0
system, 2H, arom.), 7.65e7.60 (m, B-part of AA0BB0 system, 2H, arom.);
13CNMR(100.6MHz, DMSO-d6)
d163.9,156.3,140.0,137.9,136.1,135.5,
132.8,132.7,128.7,128.2,124.1; nmax (ATR) 3074, 2956,1714,1626,1492,
1394, 1309, 1217, 1155 cmꢁ1; [found: C, 50.71; H, 2.29; N, 8.85; S, 11.18.
C13H7ClN2O3S requires C, 50.91; H, 2.30; N, 9.13; S, 10.45%].
4.6.1. 4-Oxo-5-phenyl-4,5-dihydrofuro[2,3-d]pyridazine-7-car-bonyl
4.4.13. 5-(4-Fluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyri-da-
azide (30b). (0.52 g, 95%), mp 114e116 ꢀC. 1H NMR (400 MHz,
zine-7-carboxylic acid (29f). (0.58 g, 61%), mp 255e257 ꢀC. 1H NMR
CDCl3)
d
7.82 (d, J¼1.6 Hz,1H, C]CH), 7.52e7.38 (m, 5H, arom.), 7.10
(400 MHz, DMSO-d6)
d
14.10 (br s,1H, eCOOH), 8.22 (d, J¼5.3 Hz,1H,
(d, J¼1.6 Hz, 1H, C]CH); 13C NMR (100.6 MHz, CDCl3)
d 167.2, 158.3,
C]CH), 7.73 (d, J¼5.3 Hz, 1H, C]CH), 7.70e7.64 (m, A-part of AA0BB0
150.6, 148.2, 140.9, 129.1, 128.9, 127.7, 125.9, 123.9, 107.9; nmax (ATR)
system 2H, arom.), 7.43e7.36 (m, B-part of AA0BB0 system, 2H, arom.);
3150, 3124, 2150, 1688, 1617, 1593, 1541, 1489, 1385, 1327, 1234,
13C NMR (100.6 MHz, DMSO-d6)
d
163.9, 161.4 (d, J¼245.4 Hz), 156.4,
1168, 1113, 1050 cmꢁ1
.
137.9, 137.5 (d, J¼3.1 Hz),136.0,135.5,132.5,128.7 (d, J¼8.9 Hz),124.1,
115.5 (d, J¼23.1 Hz); nmax (ATR) 3112, 3074, 2960, 1716, 1628, 1604,
1510, 1240, 1218, 1157 cmꢁ1; [found: C, 53.27; H, 2.34; N, 9.61; S,11.38.
C13H7FN2O3S requires C, 53.79; H, 2.43; N, 9.65; S, 11.05%].
4.6.2. 5-(4-Methylphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyrida-zine-
7-carbonyl azide (30c). (0.48 g, 88%), mp 109e110 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.80 (d, J¼2.0 Hz, 1H, C]CH), 7.40e7.37 (m, A-
part of AA0BB0 system, 2H, arom.), 7.26e7.23 (m, B-part of AA0BB0
system, 2H, arom.), 7.08 (d, J¼2.0 Hz,1H, C]CH), 2.35 (s, 3H, eCH3);
4.4.14. 5-(2,4-Difluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyr-
idazine-7-carboxylic acid (29g). (0.65 g, 68%), mp 240e242 ꢀC. 1H
13C NMR (100.6 MHz, CDCl3)
d 167.2, 158.3, 150.6, 148.1, 139.0, 138.4,
NMR (400 MHz, DMSO-d6)
d
14.15 (br s, 1H, eCOOH), 8.27 (d,
129.7, 127.5, 125.7, 123.8, 107.8, 21.2; nmax (ATR) 3136, 3118, 2153,
J¼5.3 Hz, 1H, C]CH), 7.76 (d, J¼5.3 Hz, 1H, C]CH), 7.79e7.73 (m,
1685, 1504, 1385, 1322, 1232, 1162, 1115, 1052 cmꢁ1
.
1H, arom.), 7.58 (ddd, J¼10.4, 9.2, and 2.7 Hz, 1H, arom.), 7.37e7.30
(m, 1H, arom.); 13C NMR (100.6 MHz, DMSO-d6)
d
163.6, 162.3 (dd,
4.6.3. 5-(4-Methoxyphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyri-da-
J¼248.9 and 11.7 Hz), 157.0 (dd, J¼252.9 and 13.3 Hz), 156.0, 138.1,
136.6, 134.9, 133.5, 131.0 (d, J¼10.3 Hz), 125.5 (dd, J¼13.0 and
3.9 Hz), 123.9, 112.2 (dd, J¼22.8 and 3.5 Hz), 104.9 (dd, J¼27.1 and
24.1 Hz); nmax (ATR) 3079, 2930, 1725, 1639, 1534, 1404, 1278, 1163,
1149, 1134 cmꢁ1; [found: C, 50.42; H, 2.03; N, 9.37; S, 10.67.
C13H6F2N2O3S requires C, 50.65; H, 1.96; N, 9.09; S, 10.49%].
zine-7-carbonyl azide (30d). (0.44 g, 81%), mp 109e110 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.80 (d, J¼2.0 Hz, 1H, C]CH), 7.45e7.41 (m, A-
part of AA0BB0 system, 2H, arom.), 7.08 (d, J¼2.0 Hz, 1H, C]CH),
6.97e6.93 (m, B-part of AA0BB0, 2H, arom.), 3.80 (s, 3H, eOCH3); 13C
NMR (100.6 MHz, CDCl3)
127.4, 127.1, 123.8, 114.3, 107.8, 55.6; nmax (ATR) 3147, 3127, 2157,
1697, 1681, 1515, 1504, 1388, 1331, 1241, 1165, 1115 cmꢁ1
d 167.2, 159.8, 158.4, 150.6, 148.1, 133.8,
.
4.5. 5-Methyl-4-oxo-4,5-dihydrofuro[2,3-d]pyridazine-7-
carbonyl azide (30a)
4.6.4. 5-(4-Chlorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyri-dazine-
7-carbonyl azide (30e). (0.47 g, 87%), mp 122e123 ꢀC. 1H NMR
Thionyl chloride (2.5 mL) was added to a stirred suspension of
acid 28a (0.5 g, 2.85 mmol) in chloroform (50 mL) and heated at
reflux for 1 h. Since, a clear solution did not form acetonitrile
(30 mL) and further thionyl chloride (5 mL) were added and heated
at reflux. After 30 min, a clear solution was formed and heating was
continued for additional 20 min. The solvent and excess thionyl
chloride were evaporated. The residue was dissolved in acetone
(50 mL) and cooled to 2 ꢀC. A solution of NaN3 (0.32 g, 4.92 mmol)
in H2O (3 mL) was added and the resulting mixture was stirred for
70 min. Then, H2O (80 mL) was added and extracted with ethyl
acetate (3ꢂ100 mL). The combined organic layers were dried over
MgSO4 and the solvent was evaporated. The crude product was
purified by column chromatography (silica gel) eluting with ethyl
acetate/dichloromethane (1:1) to give acyl azide 30a as a white
(400 MHz, CDCl3)
d
7.82 (d, J¼2.0 Hz, 1H, C]CH), 7.51e7.48 (m, A-
part of AA0BB0 system, 2H, arom.), 7.44e7.41 (m, B-part of AA0BB0
system, 2H, arom.), 7.09 (d, J¼2.0 Hz, 1H, C]CH); 13C NMR
(100.6 MHz, CDCl3)
d 166.9, 158.0, 150.4, 148.3, 139.2, 134.7, 129.1,
127.8, 127.1, 123.8, 107.8. nmax (ATR) 3151, 3127, 2153, 1710, 1693,
1506, 1489, 1407, 1385, 1325, 1239, 1168, 1105, 1088 cmꢁ1
.
4.6.5. 5-(4-Fluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyri-dazine-
7-carbonyl azide (30f). (0.49 g, 90%), mp 159e160 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.82 (d, J¼2.0 Hz, 1H, C]CH), 7.53e7.49 (m, A-
part of AA0BB0 system, 2H, arom.), 7.17e7.10 (m, B-part of AA0BB0
system, 2H, arom.), 7.09 (d, J¼2.0 Hz, 1H, C]CH); 13C NMR
(100.6 MHz, CDCl3)
d
167.0,162.4 (d, J¼249.2 Hz),158.2,150.5,148.4,
136.8 (d, J¼3.2 Hz), 127.9 (d, J¼8.9 Hz), 127.8, 123.9, 116.0 (d,

402
G. Koza et al. / Tetrahedron 69 (2013) 395e409
J¼23.0 Hz), 107.9; nmax (ATR) 3151, 3131, 2155, 1705, 1693, 1510,
1503, 1325, 1238, 1167, 1145, 1111, 1050 cmꢁ1
(400 MHz, CDCl3)
d
7.78 (d, J¼5.3 Hz, 1H, C]CH), 7.74 (d, J¼5.3 Hz,
.
1H, C]CH), 7.59e7.53 (m, A-part of AA0BB0 system, 2H, arom.),
7.18e7.11 (m, B-part of AA0BB0 system, 2H, arom.); 13C NMR
4.6.6. 5-(2,4-Difluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyri-da-
zine-7-carbonyl azide (30g). (0.45 g, 83%), mp 101e102 ꢀC. 1H NMR
(100.6 MHz, CDCl3)
d
169.4, 162.4 (d, J¼248.9 Hz), 156.8, 137.2, 136.9
(d, J¼3.0 Hz), 136.1, 134.8, 132.7, 127.8 (d, J¼8.9 Hz), 125.0, 116.0 (d,
J¼23.1 Hz); nmax (ATR) 3125, 3109, 2155, 1682, 1671, 1506, 1353,
(400 MHz, CDCl3)
d
7.84 (d, J¼2.0 Hz, 1H, C]CH), 7.41e7.35 (m, 1H,
arom.), 7.10 (d, J¼2.0 Hz, 1H, C]CH), 7.01e6.93 (m, 2H, arom.); 13C
1247, 1160, 1151 cmꢁ1
.
NMR (100.6 MHz, CDCl3)
d
166.8,162.3 (dd, J¼152.4 and 11.1 Hz), 157.7,
157.6(dd, J¼256.1 and 12.6 Hz),150.6,148.5,129.8 (d, J¼10.3 Hz), 128.5,
124.9(dd, J¼13.0and4.4Hz),123.7,112.1(dd, J¼23.0 and3.8Hz),107.9,
105.3 (dd, J¼26.7and 23.4 Hz); nmax (ATR)3140, 3113, 3081, 2155,1713,
4.7.7. 5-(2,4-Difluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyr-
idazine-7-carbonyl azide (31g). (0.83 g, 77%), mp 146e148 ꢀC. 1H
NMR (400 MHz, CDCl3)
J¼5.3 Hz, 1H, C]CH), 7.45e7.37 (m, 1H, arom.), 7.02e6.93 (m, 2H,
arom.); 13C NMR (100.6 MHz, CDCl3)
d
7.81 (d, J¼5.3 Hz, 1H, C]CH), 7.74 (d,
1699, 1607, 1502, 1387, 1339, 1261, 1217, 1160, 1107, 1050 cmꢁ1
.
d
169.3, 163.2 (dd, J¼252.4 and
4.7. General procedure for the synthesis of acyl azide de-
rivatives (31aeg)
11.1 Hz), 157.6 (dd, J¼256.1 and 12.6 Hz), 156.4, 137.3, 135.7, 135.1,
133.4, 129.7 (dd, J¼10.3 and 1.0 Hz), 125.1 (d, J¼4.0 Hz), 124.9, 112.1
(dd, J¼22.7 and 3.7 Hz), 105.3 (dd, J¼26.4 and 23.4 Hz); nmax (ATR)
Oxalyl chloride (0.70 mL, 8.2 mmol) and then DMF (7 drops)
were added to a stirred suspension of the acids 29aeg (1.0 g,
3.25e4.76 mmol) in dichloromethane (120 mL) and the mixture
was stirred at rt for 2 h. The reaction mixture was worked up as
described above.
3107, 3083, 2960, 2163, 1698, 1680, 1613, 1510, 1485, 1173 cmꢁ1
.
4.8. General procedure for the synthesis of urethane de-
rivatives (32aeg)
4.7.1. 5-Methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazine-7-
The acyl azide derivatives 30aeg (0.25 g, 0.8e1.1 mmol) were
dissolved in dry benzene (40 mL) and heated at reflux temperature
for 90 min. Dry MeOH (2 mL) was added and stirred at 50 ꢀC for 1 h.
The solvent was evaporated. The crude product was purified by
column chromatography (silica gel) eluting with hexane/ethyl ac-
etate/dichloromethane (2:1:1) to give the urethane derivatives
32aeg as a white solids.
carbonyl azide (31a). (0.69 g, 62%), mp 137e139 ꢀC. 1H NMR
(400 MHz, CDCl3)
1H, C]CH), 3.91 (s, 3H, eNCH3); 13C NMR (100.6 MHz, CDCl3)
169.3, 157.5, 137.6, 135.2, 134.3, 131.9, 124.2, 40.3; nmax (ATR) 3117,
3099, 3073, 2155, 1672, 1659, 1349, 1186 cmꢁ1
d
7.72 (d, J¼5.3 Hz, 1H, C]CH), 7.68 (d, J¼5.3 Hz,
d
.
4.7.2. 4-Oxo-5-phenyl-4,5-dihydrothieno[2,3-d]pyridazine-7-
carbonyl azide (31b). (0.83 g, 75%), mp 152e154 ꢀC. 1H NMR
4.8.1. Methyl 5-methyl-4-oxo-4,5-dihydrofuro[2,3-d]pyridazin-7-
ylcarbamate (32a). (0.21 g, 83%), mp 181e182 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.77 (d, J¼5.3 Hz, 1H, C]CH), 7.75 (d, J¼5.3 Hz,
(400 MHz, CDCl3)
C]CH), 6.90 (br s, 1H, eNH), 3.86 (s, 3H, eOCH3), 3.82 (s, 3H,
eNCH3); 13C NMR (100.6 MHz, CDCl3)
158.4, 153.8, 147.9, 147.0,
d
7.74 (d, J¼2.0 Hz,1H, C]CH), 7.10 (d, J¼2.0 Hz,1H,
1H, C]CH), 7.58e7.54 (m, 2H, arom.), 7.49e7.43 (m, 2H, arom.),
7.39 (tt, J¼7.4 and 1.2 Hz, 1H, arom.); 13C NMR (100.6 MHz, CDCl3)
d
d
169.6, 156.9, 140.9, 137.2, 136.2, 134.6, 132.6, 129.1, 128.8, 125.9,
125.0; nmax (ATR) 3098, 3082, 2155, 1694, 1668, 1347, 1165 cmꢁ1
.
129.8, 124.0, 107.9, 53.2, 39.3; nmax (ATR) 3183, 3135, 3053, 1694,
1664,1588,1556,1506,1400,1251,1211,1055 cmꢁ1; [found: C, 48.63;
H, 3.92; N, 18.90. C9H9N3O4 requires C, 48.43; H, 4.06; N, 18.83%].
4.7.3. 5-(4-Methylphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyr-
idazine-7-carbonyl azide (31c). (0.71 g, 65%), mp 159e161 ꢀC. 1H
4.8.2. Methyl 4-oxo-5-phenyl-4,5-dihydrofuro[2,3-d]pyridazin-7-
NMR (400 MHz, CDCl3)
d
7.76 (d, J¼5.3 Hz, 1H, C]CH), 7.74 (d,
ylcarbamate (32b). (0.20 g, 80%), mp 275e279 ꢀC. 1H NMR
J¼5.3 Hz, 1H, C]CH), 7.45e7.41 (m, A-part of AA0BB0 system, 2H,
(400 MHz, CDCl3)
d
7.80 (d, J¼2.0 Hz, 1H, C]CH), 7.61e7.58 (m, 2H,
arom.), 7.26e7.24 (m, B-part of AA0BB0 system, 2H, arom.), 2.36 (s,
3H, eCH3); 13C NMR (100.6 MHz, CDCl3)
d
169.6, 157.0, 138.9, 138.4,
137.2, 136.1, 134.4, 132.4, 129.7, 125.6, 125.0, 21.2; nmax (ATR) 3098,
3079, 2960, 2919, 2159, 1690, 1669, 1628, 1509, 1346, 1172 cmꢁ1
arom.), 7.51e7.48 (m, 2H, arom.), 7.41 (tt, J¼7.4 and 1.2 Hz,1H, arom.),
7.16 (d, J¼2.0 Hz, 1H, C]CH), 6.98 (br s, 1H, eNH), 3.87 (s, 3H,
eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 157.8, 153.7, 147.5, 147.2,
.
141.1, 130.6, 128.7, 127.9, 125.8, 124.7, 108.3, 53.2; nmax (ATR) 3179,
3161, 3102, 3048,1719,1679,1594,1557,1508,1400,1271,1257,1157,
1037 cmꢁ1; [found: C, 59.23; H, 3.65; N,14.96. C14H11N3O4 requiresC,
58.95; H, 3.89; N, 14.73%].
4.7.4. 5-(4-Methoxyphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyr-
idazine-7-carbonyl azide (31d). (0.66 g, 61%), mp 119e121 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.76 (d, J¼5.3 Hz, 1H, C]CH), 7.74 (d,
J¼5.3 Hz, 1H, C]CH), 7.50e7.45 (m, A-part of AA0BB0 system, 2H,
4.8.3. Methyl 5-(4-methylphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
arom.), 6.98e6.93 (m, B-part of AA0BB0 system, 2H, arom.), 3.80 (s,
idazin-7-ylcarbamate (32c). (0.21 g, 84%), mp 182e183 ꢀC. 1H NMR
3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d
169.5, 159.7, 157.0, 137.1,
136.0, 134.4, 133.8, 132.3, 127.0, 124.9, 114.3, 55.6; nmax (ATR) 3083,
2921, 2835, 2151, 1668, 1507, 1349, 1250, 1166, 1105 cmꢁ1
(400 MHz, CDCl3)
d
7.77 (d, J¼2.0 Hz, 1H, C]CH), 7.46e7.43 (m, A-
part of AA0BB0 system, 2H, arom.), 7.28e7.25 (m, B-part of AA0BB0
system, 2H, arom.), 7.21 (br s, 1H, eNH), 7.15 (d, J¼2.0 Hz, 1H, C]
CH), 3.85 (s, 3H, eOCH3), 2.40 (s, 3H, eCH3); 13C NMR (100.6 MHz,
.
4.7.5. 5-(4-Chlorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyri-da-
CDCl3)
d 158.1, 154.1, 147.8, 147.2, 138.7, 138.0, 130.6, 129.4, 125.7,
zine-7-carbonyl azide (31e). (0.93 g, 86%), mp 128e130 ꢀC. 1H NMR
124.7, 108.4, 53.2, 21.1; nmax (ATR) 3149, 3127, 2925, 1729, 1654,
1592, 1551, 1507, 1431, 1252, 1163, 1042 cmꢁ1; [found: C, 59.95; H,
4.29; N, 13.94. C15H13N3O4 requires C, 60.20; H, 4.38; N, 14.04%].
(400 MHz, CDCl3)
d
7.79 (d, J¼5.3 Hz, 1H, C]CH), 7.74 (d, J¼5.3 Hz,
1H, C]CH), 7.57e7.52 (m, A-part of AA0BB0 system, 2H, arom.),
7.46e7.40 (m, B-part of AA0BB0 system, 2H, arom.); 13C NMR
(100.6 MHz, CDCl3)
132.8, 129.2, 127.1, 125.0; nmax (ATR) 3118, 3101, 2158, 1692, 1671,
1488, 1350, 1260 cmꢁ1
d
169.4, 156.8, 139.3, 137.2, 136.1, 134.9, 134.6,
4.8.4. Methyl
5-(4-methoxyphenyl)-4-oxo-4,5-dihydrofuro[2,3-d]
pyridazin-7-ylcarbamate (32d). (0.21 g, 84%), mp 190e191 ꢀC. 1H
.
NMR (400 MHz, CDCl3)
d
7.78 (d, J¼2.0 Hz,1H, C]CH), 7.51e7.47 (m,
A-part of AA0BB0 system, 2H, arom.), 7.15 (d, J¼2.0 Hz, 1H, C]CH),
4.7.6. 5-(4-Fluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]pyri-da-
7.06 (br s, 1H, eNH), 7.06e6.97 (m, B-part of AA0BB0 system, 2H,
zine-7-carbonyl azide (31f). (0.85 g, 79%), mp 137e239 ꢀC. 1H NMR
arom.), 3.86 (s, 6H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 159.1,

G. Koza et al. / Tetrahedron 69 (2013) 395e409
403
158.09,154.0, 147.7, 147.2,134.2, 130.5, 127.1, 124.7, 114.0,108.4, 55.5,
53.3; nmax (ATR) 3180, 3148, 3128, 3008, 2974,1727,1651,1607,1590,
1553, 1401, 1331, 1248, 1230, 1127, 1042 cmꢁ1; [found: C, 56.90; H,
3.94; N, 13.11. C15H13N3O5 requires C, 57.14; H, 4.16; N, 13.33%].
[found: C, 56.07; H, 3.99; N, 13.88; S, 11.02. C14H11N3O3S requires C,
55.80; H, 3.68; N, 13.95; S, 10.64%].
4.9.3. Methyl
5-(4-methylphenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazin-7-ylcarbamate (33c). (95 mg, 47%), mp 172e174 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.72 (d, J¼5.3 Hz, 1H, C]CH), 7.65 (d,
4.8.5. Methyl 5-(4-chlorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
J¼5.3 Hz, 1H, C]CH), 7.43e7.37 (m, A-part of AA0BB0 system, 2H,
arom.), 7.20e7.18(m, B-partofAA0BB0 system, 2H, arom.), 7.03(brs,1H,
eNH), 3.77 (s, 3H, eOCH3), 2.33 (s, 3H, eCH3); 13C NMR (100.6 MHz,
idazin-7-ylcarbamate (32e). (0.20 g, 79%), mp 187e188 ꢀC. 1H NMR
(400 MHz, CDCl3)
arom.), 7.32 (br d, J¼8.4 Hz, 2H, arom.), 7.19 (br s,1H, C]CH), 7.05 (br
s, 1H, eNH), 3.76 (s, 3H, OCH3); 13C NMR (100.6 MHz, CDCl3)
157.9,
d
7.68 (br s, 1H, C]CH), 7.46 (br d, J¼8.4 Hz, 2H,
CDCl3)
d 156.6, 154.5, 138.6, 138.2, 138.0, 135.9, 135.8, 132.4, 129.4,
d
125.5, 53.2, 21.1; nmax (ATR) 3246, 3107, 3087, 3031, 2959, 1725, 1653,
1552,1481,1240,1135,1044 cmꢁ1;[found:C,56.78;H, 4.27;N,13.05;S,
10.39. C15H13N3O3S requires C, 57.13; H, 4.16; N, 13.33; S, 10.17%].
153.8, 147.6, 147.4, 139.7, 133.6, 131.1, 128.8, 127.1, 124.7, 108.4, 53.3;
nmax (ATR) 3178, 3150, 3128, 3040, 2979,1733,1656,1593,1554,1507,
1493,1405,1331,1251,1233,1162,1126,1081 cmꢁ1; [found: C, 52.96;
H, 3.28; N, 12.78. C14H10ClN3O4 requires C, 52.60; H, 3.15; N, 13.14%].
4.9.4. Methyl 5-(4-methoxyphenyl)-4-oxo-4,5-dihydrothieno-[2,3-d]
pyridazin-7-ylcarbamate (33d). (91 mg, 45%), mp 167e169 ꢀC. 1H
4.8.6. Methyl 5-(4-fluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]pyr-
idazin-7-ylcarbamate (32f). (0.21 g, 83%), mp 181e182 ꢀC. 1H NMR
NMR (400 MHz, CDCl3)
d
7.72 (d, J¼5.3 Hz, 1H, C]CH), 7.66 (d,
J¼5.3 Hz, 1H, C]CH), 7.47e7.42 (m, A-part of AA0BB0 system, 2H,
arom.), 6.99 (br s, 1H, eNH), 6.94e6.89 (m, B-part of AA0BB0 system,
2H, arom.), 3.78 (s, 3H, eOCH3), 3.77 (s, 3H, eOCH3); 13C NMR
(400 MHz, CDCl3)
d
7.70 (d, J¼2.0 Hz, 1H, C]CH), 7.51e7.48 (m, A-
part of AA0BB0 system, 2H, arom.), 7.10e7.05 (m, B-part of AA0BB0
system, 2H, arom.), 7.07(d, J¼2.0 Hz,1H, C]CH), 6.95 (brs,1H, eNH),
(100.6 MHz, CDCl3)
d 156.8, 154.4, 152.2, 135.9, 133.6, 133.5, 131.8,
3.78 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 161.8 (d,
130.2,124.7,123.2,111.7, 53.3, 50.9; nmax (ATR) 3327, 3105, 3089, 2922,
2850, 1735, 1657, 1560, 1512, 1484, 1456, 1098, 1019 cmꢁ1; [found: C,
54.25;H,4.33;N,12.31;S, 9.59. C15H13N3O4SrequiresC,54.37;H, 3.95;
N, 12.68; S, 9.68%].
J¼247.9 Hz), 158.0, 153.9, 147.7, 147.4, 137.2 (d, J¼3.3 Hz), 131.0, 127.7
(d, J¼8.7 Hz),124.7,115.6 (d, J¼22.9 Hz),108.4, 53.3; nmax (ATR) 3181,
3154, 3128, 2980, 1740, 1654, 1589, 1554, 1505, 1404, 1333, 1250,
1238, 1167, 1128, 1082 cmꢁ1; [found: C, 55.47; H, 3.39; N, 13.82.
C14H10FN3O4 requires C, 55.45; H, 3.32; N, 13.86%].
4.9.5. Methyl
5-(4-chlorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazin-7-ylcarbamate (33e). (109 mg, 54%), mp 156e158 ꢀC. 1H
4.8.7. Methyl 5-(2,4-difluorophenyl)-4-oxo-4,5-dihydrofuro[2,3-d]
pyridazin-7-ylcarbamate (32g). (0.20 g, 79%), mp 171e172 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.71 (d, J¼5.3 Hz, 1H, C]CH), 7.67 (d,
J¼5.3 Hz, 1H, C]CH), 7.54e7.49 (m, A-part of AA0BB0 system, 2H,
NMR (400 MHz, CDCl3)
1H, arom.), 7.16 (d, J¼1.9 Hz,1H, C]CH), 7.05e6.98 (m 3H, arom. and
eNH), 3.87 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
162.7 (dd,
d
7.81 (d, J¼1.9 Hz,1H, C]CH), 7.48e7.42 (m,
arom.), 7.37e7.32 (m, B-part of AA0BB0 system, 2H, arom.), 7.14 (br s,
1H, eNH), 3.78 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 156.4,
d
154.3,139.5,138.0,136.3,135.9,133.5,132.8,128.8,126.9,125.5, 53.3;
nmax (ATR) 3208, 3103, 3085, 2955, 2922, 1729, 1682, 1556, 1536,
1486, 1262, 1244, 1126 cmꢁ1; [found: C, 50.36; H, 3.18; N, 12.48; S,
10.16. C14H10ClN3O3S requires C, 50.08; H, 3.00; N, 12.51; S, 9.55%].
J¼251.2 and 11.2 Hz), 157.6, 157.5 (dd, J¼255.8 and 12.6 Hz), 153.7,
147.8,147.4,131.4,129.9 (d, J¼11.7 Hz),125.3 (dd, J¼12.9 and 4.2 Hz),
124.3, 111.8 (dd, J¼22.7 and 3.6 Hz), 108.4, 105.0 (dd, J¼26.4 and
23.5 Hz), 53.3; nmax (ATR) 3182, 3155, 3128, 1974, 1738, 1659, 1653,
1506, 1404,1249,1225,1177,1039 cmꢁ1; [found: C, 52.63; H, 3.10; N,
12.85. C14H9F2N3O4 requires C, 52.34; H, 2.82; N, 13.08%].
4.9.6. Methyl
5-(4-fluorophenyl)-4-oxo-4,5-dihydrothieno[2,3-d]
pyridazin-7-ylcarbamate (33f). (176 mg, 87%), mp 145e147 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
7.71 (d, J¼5.3 Hz, 1H, C]CH), 7.66 (d,
J¼5.3 Hz, 1H, C]CH), 7.55e7.48 (m, A-part of AA0BB0 system, 2H,
4.9. General procedure for the synthesis of urethane de-
rivatives (33aeg)
arom.), 7.16 (br s,1H, eNH), 7.10e7.03 (m, B-partof AA0BB0 system, 2H,
arom.), 3.77 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 161.8 (d,
The acyl azide derivatives 31aeg (0.20 g, 0.60e0.85 mmol) were
reacted with MeOH (6 h and 12 h) as described above. The solvent
and excess MeOH were evaporated. The crude product was washed
with hexane/ethyl acetate/dichloromethane (2:1:1) to give the
urethane derivatives 33aeg as white solids.
J¼248.0 Hz),156.5,154.3,138.0,137.0 (d, J¼3.3 Hz),136.1,136.0,132.7,
127.5 (d, J¼8.6 Hz), 125.5, 115.6 (d, J¼22.9 Hz), 53.2; nmax (ATR) 3280,
3087, 1708, 1660, 1558, 1523, 1495, 1130 cmꢁ1; [found: C, 52.35; H,
3.32; N, 12.87; S, 10.50. C14H10FN3O3S requires C, 52.66; H, 3.16; N,
13.16; S, 10.04%].
4.9.1. Methyl 5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyri-dazin-7-
4.9.7. Methyl 5-(2,4-difluorophenyl)-4-oxo-4,5-dihydrothieno-[2,3-
d]pyridazin-7-ylcarbamate (33g). (129 mg, 64%), mp 199e201 ꢀC.
ylcarbamate (33a). (87 mg, 43%), mp 171e173 ꢀC. 1H NMR
1H NMR (400 MHz, CDCl3)
d
7.72 (d, J¼5.3 Hz, 1H, C]CH), 7.69 (d,
(400 MHz, CDCl3)
1H, C]CH), 7.14 (br s, 1H, eNH), 3.76 (s, 3H, eOCH3), 3.71 (s, 3H,
eNCH3); 13C NMR (100.6 MHz, CDCl3)
157.2, 154.4, 137.3, 136.3,
d
7.65 (d, J¼5.3 Hz, 1H, C]CH), 7.60 (d, J¼5.3 Hz,
J¼5.3 Hz, 1H, C]CH), 7.41e7.34 (m, 1H, arom.), 7.00 (br s, 1H, eNH),
6.97e6.88 (m, 2H, arom.), 3.77 (s, 3H, eOCH3); 13C NMR
d
135.3, 132.2, 124.9, 53.1, 38.9; nmax (ATR) 3236, 3138, 2957, 2922,
2851, 1698, 1640, 1550, 1523, 1462, 1247, 1060 cmꢁ1; [found: C,
45.11; H, 3.91; N, 17.24; S, 13.65. C9H9N3O3S requires C, 45.18; H,
3.79; N, 17.56; S, 13.40%].
(100.6 MHz, CDCl3)
d
162.7 (dd, J¼251.2 and 11.3 Hz), 157.6 (dd,
J¼255.7 and 12.6 Hz), 156.3, 154.3, 137.5, 136.5, 136.4, 132.9, 129.8
(dd, J¼10.2 and 1.8 Hz),125.5, 125.2 (dd, J¼4.3 and 2.6 Hz),111.8 (dd,
J¼22.6 and 3.7 Hz), 105.0 (dd, J¼26.3 and 23.5 Hz), 53.7;nmax (ATR)
3197, 3112, 3069, 2990, 2947, 1727, 1651, 1563, 1508, 1246,
1151 cmꢁ1; [found: C, 50.16; H, 2.74; N, 12.26; S, 9.57. C14H9F2N3O3S
requires C, 49.85; H, 2.69; N, 12.46; S, 9.51%].
4.9.2. Methyl 4-oxo-5-phenyl-4,5-dihydrothieno[2,3-d]pyri-dazin-7-
ylcarbamate (33b). (119 mg, 59%), mp 186e188 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
7.73 (d, J¼5.3 Hz, 1H, C]CH), 7.67 (d, J¼5.3 Hz,
1H, C]CH), 7.57e7.53 (m, 2H, arom.), 7.42 (br t, J¼7.4 Hz, 2H, arom.),
4.10. General procedure for the synthesis of amino-
pyridazinone derivatives (34aeg and 35aeg)
7.32 (tt, J¼7.4, 1.2 Hz, 1H, arom.), 6.97 (br s, 1H, eNH), 3.78 (s, 3H,
eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 156.6, 154.4, 141.1, 138.2,
136.0, 135.9, 132.6, 128.8, 128.0, 125.8, 125.5, 53.2; nmax (ATR) 3244,
Theacyl azide derivatives 30aeg and 31aeg (0.3 g,1.0e1.4 mmol)
were dissolved in dry benzene (40 mL) and heated at reflux for
3107, 2960, 2913, 1724, 1646, 1553, 1488, 1302, 1241, 1046 cmꢁ1
;

404
G. Koza et al. / Tetrahedron 69 (2013) 395e409
90 min. The solution was cooled to 40 ꢀC and HCl (10 mL, 8 M) was
added. The mixture was stirred at 40 ꢀC for 10 min and then the pH
value was adjusted to pH¼10 by addition of 10% NaOH solution at
10 ꢀC. The mixture was extracted with ethyl acetate (3ꢂ100 mL). The
combined organic layers were dried over MgSO4 and the solvent was
evaporated. The crude product was purified by column chroma-
tography (silica gel) eluting with ethyl acetate/dichloromethane
(1:1) to give the amine derivatives 34aeg and 35aeg as white solids.
1415,1336,1216,1152,1050 cmꢁ1; [found: C, 58.70; H, 3.23; N,17.09.
C12H8FN3O2 requires C, 58.78; H, 3.29; N, 17.14%].
4.10.7. 7-Amino-5-(2,4-difluorophenyl)furo[2,3-d]pyridazin-4(5H)-
one (34g). (0.15 g, 60%), mp 232e233 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.66 (d, J¼2.0 Hz, 1H, C]CH), 7.39e7.33 (m, 1H, arom.), 7.05 (d,
J¼2.0 Hz, 1H, C]CH), 6.95e6.88 (m, 2H, arom.), 4.41 (br s, 2H,
eNH2); 13C NMR (100.6 MHz, DMSO-d6)
d
161.5 (dd, J¼247.3 and
11.4 Hz), 157.0 (dd, J¼252.1 and 13.0 Hz), 156.4, 148.2, 146.2, 140.2,
131.0 (dd, J¼10.3 and 1.7 Hz), 126.4 (dd, J¼12.9 and 4.0 Hz), 121.9,
111.7 (dd, J¼22.4 and 3.4 Hz), 107.7, 104.6 (dd, J¼26.9 and 24.4 Hz);
nmax (ATR) 3343, 3195, 3162, 3121,1678,1637,1598,1547,1505,1473,
1415,1347, 1267, 1236, 1134, 1046 cmꢁ1; [found: C, 54.38; H, 2.57; N,
15.70. C12H7F2N3O2 requires C, 54.76; H, 2.68; N, 15.97%].
4.10.1. 7-Amino-5-methylfuro[2,3-d]pyridazin-4(5H)-one
(34a). (0.15 g, 68%), mp 187e188 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.58 (d, J¼1.9 Hz,1H, C]CH), 6.98 (d, J¼1.9 Hz,1H, C]CH), 4.31 (br
s, 2H, eNH2), 3.63 (s, 3H, OCH3); 13C NMR (100.6 MHz, CDCl3)
158.1, 146.5, 146.0, 138.1, 123.3, 108.4, 38.7; nmax (ATR) 3474, 3308,
d
3185, 3116, 3093, 2920, 1625, 1590, 1533, 1475, 1412, 1342, 1225,
1136, 1085 cmꢁ1; [found: C, 51.09; H, 4.31; N, 25.10. C7H7N3O2 re-
quires C, 50.91; H, 4.27; N, 25.44%].
4.10.8. 7-Amino-5-methylthieno[2,3-d]pyridazin-4(5H)-one
(35a). (80 mg, 42%), mp 165e167 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.67 (d, J¼5.2 Hz,1H, C]CH), 7.52 (d, J¼5.2 Hz,1H, C]CH), 4.13 (br
s, 2H, eNH2), 3.65 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
4.10.2. 7-Amino-5-phenylfuro[2,3-d]pyridazin-4(5H)-one
(34b). (0.17 g, 71%), mp 141e142 ꢀC. 1H NMR (400 MHz, CDCl3)
d
156.6, 142.2, 137.2, 133.1, 129.6, 126.1, 38.4; nmax (ATR) 3325, 3158,
3075, 1610, 1531, 1416, 1330, 1249, 1127, 1041 cmꢁ1; [found: C,
46.01; H, 3.87; N, 22.98; S, 18.10. C7H7N3OS requires C, 46.40; H,
3.89; N, 23.19; S, 17.69%].
d
7.72 (d, J¼2.0 Hz, 1H, C]CH), 7.61e7.58 (m, 2H, arom.), 7.50e7.46
(m, 2H, arom.), 7.37 (tt, J¼7.4, 1.2 Hz, 1H, arom.), 7.15 (d, J¼2.0 Hz,
1H, C]CH), 4.17 (br s, 2H, eNH2); 13C NMR (100.6 MHz, CDCl3)
d
157.8, 146.8, 146.1, 142.1, 138.7, 129.0, 127.8, 126.4, 123.9, 108.9;
nmax (ATR) 3328, 3187, 3151, 3119, 1671, 1639, 1592, 1544, 1472, 1414,
1336, 1272, 1231, 1124, 1050 cmꢁ1; [found: C, 63.33; H, 3.83; N,
18.23. C12H9N3O2 requires C, 63.43; H, 3.99; N, 18.49%].
4.10.9. 7-Amino-5-phenylthieno[2,3-d]pyridazin-4(5H)-one
(35b). (94 mg, 46%), mp 187e189 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.75 (d, J¼5.1 Hz, 1H, C]CH), 7.57 (d, J¼5.1 Hz, 1H, C]CH),
7.58e7.55 (m, 2H, arom.), 7.43e7.37 (m, 2H, arom.), 7.29 (tt, J¼7.4 and
1.2 Hz,1H, arom.), 4.21 (br s, 2H, eNH2); 13C NMR (100.6 MHz, CDCl3)
4.10.3. 7-Amino-5-(4-methylphenyl)furo[2,3-d]pyridazin-4(5H)-one
(34c). (0.18 g, 73%), mp 204e205 ꢀC. 1H NMR (400 MHz, CDCl3)
d
156.2,142.6,141.7,137.8,133.4,129.9,128.7,127.6,126.7,125.9; [nmax
7.71 (d, J¼2.0 Hz, 1H, C]CH), 7.48e7.44 (m, A-part of AA0BB0
(ATR) 3336, 3203, 3101, 1632, 1556, 1544, 1403, 1304, 1054 cmꢁ1
;
d
system, 2H, arom.), 7.29e7.26 (m, B-part of AA0BB0 system, 2H,
arom.), 7.14 (d, J¼2.0 Hz, 1H, C]CH), 4.46 (s, 2H, eNH2), 2.41 (s, 3H,
[found: C, 59.12; H, 3.85; N, 17.29; S, 13.61. C12H9N3OS requires C,
59.24; H, 3.73; N, 17.27; S, 13.18%].
eCH3); 13C NMR (100.6 MHz, CDCl3)
d 157.6, 146.4, 145.8, 139.3,
138.3, 137.5, 129.4, 125.9, 123.6, 108.6, 21.1; nmax (ATR) 3371, 3296,
3197, 3157, 2953, 1669, 1625, 1595, 1542, 1508, 1470, 1412, 1337,
1231, 1124, 1049 cmꢁ1; [found: C, 64.72; H, 4.49; N, 17.34.
C13H11N3O2 requires C, 64.72; H, 4.60; N, 17.42%].
4.10.10. 7-Amino-5-(4-methylphenyl)thieno[2,3-d]pyridazin-4(5H)-
one (35c). (91 mg, 44%), mp 245e247 ꢀC.1H NMR (400 MHz, acetone-
d6)
d
7.82 (d, J¼5.2 Hz, 1H, C]CH), 7.54 (d, J¼5.2 Hz, 1H, C]CH),
7.46e7.41 (m, A-part of AA0BB0 system, 2H, arom.), 7.13e7.11 (m, B-part
of AA0BB0 system,2H,arom.),5.44(brs,2H, eNH2), 2.24 (s, 3H, eOCH3);
4.10.4. 7-Amino-5-(4-methoxyphenyl)furo[2,3-d]pyridazin-4(5H)-
13C NMR (100.6 MHz, DMSO-d6)
d155.0,143.8,139.5,136.7,136.1,133.6,
one (34d). (0.19 g, 77%), mp 172e173 ꢀC. 1H NMR (400 MHz, CDCl3)
132.1,128.7,125.8,125.2, 20.6; nmax (ATR) 3351, 3200, 3082,1629,1541,
1401,1324,1259,1088 cmꢁ1; [found:C, 60.31;H, 4.40; N,15.98; S,12.10.
C13H11N3OS requires C, 60.68; H, 4.31; N, 16.33; S, 12.46%].
d
7.69 (br s, 1H, C]CH), 7.48 (br d, 2H, J¼8.4 Hz, arom.), 7.13 (br s,
1H, C]CH), 6.98 (br d, J¼8.4 Hz, 2H, arom.), 4.55 (br s, 2H, eNH2),
3.85 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
158.8, 146.5,
d
145.8, 138.3, 134.8, 132.9, 127.4, 123.6, 114.0, 108.6, 55.5; nmax (ATR)
3342, 3283, 3184, 3143, 3106, 1669, 1624, 1695, 1545, 1507, 1471,
1413, 1337, 1249, 1234, 1171, 1027 cmꢁ1; [found: C, 60.94; H, 4.40; N,
15.97. C13H11N3O3 requires C, 60.70; H, 4.31; N, 16.33%].
4.10.11. 7-Amino-5-(4-methoxyphenyl)thieno[2,3-d]pyridazin-
4(5H)-one (35d). (100 mg, 48%), mp 208e210 ꢀC. 1H NMR
(400 MHz, acetone-d6)
d
7.81 (d, J¼5.1 Hz, 1H, C]CH), 7.54 (d,
J¼5.1 Hz, 1H, C]CH), 7.48e7.43 (m, A-part of AA0BB0 system, 2H,
arom.), 6.89e6.82 (m, B-part of AA0BB0 system, 2H, arom.), 5.43 (s,
2H, eNH2), 3.71 (s, 3H, eOCH3); 13C NMR (100.6 MHz, DMSO-d6)
4.10.5. 7-Amino-5-(4-chlorophenyl)furo[2,3-d]pyridazin-4(5H)-one
(34e). (0.17 g, 68%), mp 198e199 ꢀC. 1H NMR (400 MHz, CDCl3)
d
157.8, 155.0, 143.7, 136.9, 135.0, 133.5, 132.1, 127.2, 125.2, 113.4,
d
7.64 (d, J¼1.6 Hz, 1H, C]CH), 7.51e7.48 (m, A-part of AA0BB0
55.3; nmax (ATR) 3326, 3184, 3078, 1630, 1606, 1506, 1325,
1030 cmꢁ1; [found: C, 56.81; H, 3.99; N,15.29; S,12.24. C13H11N3O2S
requires C, 57.13; H, 4.06; N, 15.37; S, 11.73%].
system, 2H, arom.), 7.36e7.33 (m, B-part of AA0BB0 system, 2H,
arom.), 7.05 (d, J¼1.6 Hz, 1H, C]CH), 4.43 (br s, 2H, eNH2); 13C
NMR (100.6 MHz, CDCl3)
d 157.5, 146.7, 145.8, 140.3, 138.5, 133.0,
128.8, 127.3, 123.6, 108.7; nmax (ATR) 3433, 3342, 3140, 3122, 1683,
1614, 1547, 1491, 1475, 1409, 1330, 1270, 1231, 1135, 1041 cmꢁ1
;
4.10.12. 7-Amino-5-(4-chlorophenyl)thieno[2,3-d]pyridazin-4(5H)-
one (35e). (119 mg, 57%), mp 230e232 ꢀC. 1H NMR (400 MHz, ace-
[found: C, 55.40; H, 2.97; N, 15.92. C12H8ClN3O2 requires C, 55.08;
H, 3.08; N, 16.06%].
tone-d6)
d
7.84 (d, J¼5.2 Hz, 1H, C]CH), 7.68e7.63 (m, A-part of
AA0BB0 system, 2H, arom.), 7.55 (d, J¼5.2 Hz, 1H, C]CH), 7.38e7.30
(m, B-part of AA0BB0 system, 2H, arom.), 5.55 (br s, 2H, eNH2); 13C
4.10.6. 7-Amino-5-(4-fluorophenyl)furo[2,3-d]pyridazin-4(5H)-one
(34f). (0.16 g, 65%), mp 203e204 ꢀC.1H NMR (400 MHz, CDCl3)
d 7.64
NMR (100.6 MHz, DMSO-d6) d 155.0, 144.1, 140.7, 136.7, 133.8, 132.3,
(d, J¼1.9 Hz, 1H, C]CH), 7.52e7.46 (m, A-part of AA0BB0 system, 2H,
arom.), 7.10e7.05 (m, B-part of AA0BB0 system, 2H, arom.), 7.05 (d,
J¼1.9 Hz, 1H, C]CH), 4.43 (br s, 2H, eNH2); 13C NMR (100.6 MHz,
130.9, 128.2, 127.5, 125.2; nmax (ATR) 3355, 3304, 3202, 3077, 1628,
1539,1489,1472,1322,1089 cmꢁ1; [found: C, 52.27; H, 2.86; N,15.13;
S, 11.68. C12H8ClN3OS requires C, 51.90; H, 2.90; N, 15.13; S, 11.55%].
CDCl3)
d
161.6 (d, J¼246.9 Hz), 157.6, 146.6, 145.8, 138.3, 137.8 (d,
4.10.13. 7-Amino-5-(4-fluorophenyl)thieno[2,3-d]pyridazin-4(5H)-
one (35f). (125 mg, 60%), mp 241e243 ꢀC. 1H NMR (400 MHz,
J¼2.8 Hz), 127.9 (d, J¼8.5 Hz), 123.6, 115.5 (d, J¼22.8 Hz), 108.7; nmax
(ATR) 3341, 3198, 3161, 3116, 3085,1674,1636,1596,1545,1502,1473,

G. Koza et al. / Tetrahedron 69 (2013) 395e409
405
CDCl3)
d
7.74 (d, J¼5.2 Hz, 1H, C]CH), 7.59 (d, J¼5.2 Hz, 1H, C]CH),
dissolved in dry benzene (70 mL). Thionyl chloride (4 equiv) was
added dropwise and then the mixture was stirred for 18 h. The re-
action was monitored on TLC. After the completion of the reaction,
the solvent was evaporated and the crude product was purified by
column chromatography (silica gel) eluting with suitable solvent
mixture to give phthalazinone derivatives 39beg as white solids.
7.57e7.50 (m, A-part of AA0BB0 system, 2H, arom.), 7.11e7.04 (m, B-
part of AA0BB0 system, 2H, arom.), 4.21 (br s, 2H, eNH2); 13C NMR
(100.6 MHz, DMSO-d6)
J¼2.8 Hz), 136.4, 133.4, 131.9, 127.7 (d, J¼8.5 Hz), 124.8, 114.7 (d,
J¼22.6 Hz); nmax (ATR) 3339, 3192, 3095, 3083, 1632, 1541, 1501,
1319, 1216, 1057 cmꢁ1; [found: C, 55.01; H, 3.03; N, 15.94; S, 12.84.
C12H8FN3OS requires C, 55.16; H, 3.09; N, 16.08; S, 12.27%].
d
160.1 (d, J¼243.8 Hz), 154.7, 143.7, 137.9 (d,
Compound number Temperature (ꢀC) Time (h) Column solvent Yield (%)
Hexane EtOAc
4.10.14. 7-Amino-5-(2,4-difluorophenyl)thieno[2,3-d]pyridazin-
4(5H)-one (35g). (101 mg, 48%), mp 248e250 ꢀC. 1H NMR
(400 MHz, acetone-d6)
39b
39c
39d
39e
39f
70
50
50
65
65
65
4
4
2.5
4
4
4
4
9
4
3
3
1
1
1
1
1
1
74
74
56
80
73
61
d
7.86 (d, J¼5.2 Hz, 1H, C]CH), 7.54 (d,
J¼5.2 Hz, 1H, C]CH), 7.48 (dt, J¼8.7 and 6.1 Hz, 1H, arom.),
7.10e6.98 (m, 2H, arom), 5.50 (br s, 2H, eNH2); 13C NMR
(100.6 MHz, DMSO-d6)
d
161.5 (dd, J¼247.3 and 11.6 Hz), 157.0 (dd,
39g
4
J¼252.3 and 13.1 Hz), 154.9, 144.3, 136.0, 134.3, 132.5, 130.9 (dd,
J¼10.3 and 1.7 Hz), 126.4 (dd, J¼12.9 and 3.9 Hz), 125.0, 111.7 (dd,
J¼22.5 and 3.4 Hz), 104.6 (dd, J¼26.8 and 24.4 Hz); nmax (ATR) 3337,
3187, 3082, 1639, 1611, 1546, 1504, 1336 cmꢁ1; [found: C, 51.51; H,
2.73; N, 14.74; S, 11.21. C12H7F2N3OS requires C, 51.61; H, 2.53; N,
15.05; S, 11.48%].
4.13.1. Methyl 4-oxo-3-phenyl-3,4-dihydrophthalazine-1-
carboxylate (39b). (1.1 g, 74%), mp 111e112 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
8.67 (ddd, J¼8.2,1.1, and 0.4 Hz,1H), 8.56 (ddd, J¼8.0,1.1, and
0.4 Hz,1H), 7.93 (ddd, J¼8.2, 7.4, and 0.5 Hz,1H), 7.86 (ddd, J¼8.5, 7.3,
and 1.2 Hz, 1H), 7.72e7.68 (m, 2H), 7.56e7.51 (m, 2H), 7.44 (tt, J¼7.4
and 1.2 Hz, 1H), 4.04 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
4.11. 2-[Methoxy(oxo)acetyl]benzoic acid (38)
d
163.8,159.1,141.4,136.1,134.0,132.1,128.9,128.4,128.3,127.7,127.6,
126.4, 125.8, 53.0; nmax (ATR) 3040, 2954, 1719, 1666, 1595, 1427,
1321, 1234, 1175, 1143, 1027 cmꢁ1; [found: C, 68.45; H, 4.40; N, 9.95.
C16H12N2O3 requires C, 68.56; H, 4.32; N, 9.99%].
The monoester 3724 (4.0 g, 20.61 mmol) was dissolved in anisole
(40 mL) and SeO2 (3.43 g, 30.93 mmol) was added. The mixture was
heated at reflux temperature for 6 h. The reaction mixture was
cooled, filtered, and washed with ethyl acetate (100 mL). The filtrate
was evaporated. The crude product was purified by column chro-
matography (silica gel) eluting with hexane/EtOAc (5:1, 2:1) to give
oxidized monoester 38 as a white solid (2.2 g, 51%), mp 72e73 ꢀC (lit.
4.13.2. Methyl 3-(4-methylphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylate (39c). (2.1 g, 74%), mp 152e153 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
8.59 (bdd, J¼7.9 and 0.8 Hz, 1H), 8.47 (dd, J¼7.9
and 1.0 Hz, 1H), 7.83 (ddd, J¼8.3, 7.3, and 1.5 Hz, 1H), 7.76 (ddd,
J¼8.4, 7.4, and 1.2 Hz, 1H), 7.48e7.45 (m, 2H), 7.25e7.22 (m 2H),
3.94 (s, 3H, eOCH3), 2.35 (s, 3H, eCH3); 13C NMR (100.6 MHz,
mp 74e85 ꢀC25). 1H NMR (400 MHz, CDCl3)
d
7.95 (dt, J¼7.6 and
0.8 Hz,1H, arom.), 7.77 (dt, J¼7.5 and 1.1 Hz,1H, arom.), 7.68 (dt, J¼7.5
and 1.0 Hz, 1H, arom.), 7.58 (dt, J¼7.6 and 0.8 Hz, 1H, arom.), 3.82 (s,
CDCl3)
d 163.8, 159.1, 138.9, 138.3, 135.9, 133.9, 132.0, 129.5, 128.4,
3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 168.3,167.9,167.8,144.8,
127.7, 127.5, 126.3, 125.6, 53.0, 21.1; nmax (ATR), 3050, 1720, 1679,
1647, 1515, 1329, 1238, 1142; [found: C, 69.04; H, 4.71; N, 9.40.
C17H14N2O3 requires C, 69.38; H, 4.79; N, 9.52%].
134.9, 131.4, 127.0, 125.8, 122.9, 54.3; nmax (ATR) 3507, 3431, 3046,
2853,1770,1735,1465,1289,1230,1149,1112 cmꢁ1; [found: C, 57.83;
H, 3.99. C10H8O5 requires C, 57.70; H, 3.87%].
4.13.3. Methyl
zine-1-carboxylate (39d). (0.83 g, 56%), mp 181e182 ꢀC. 1H NMR
(400 MHz, CDCl3)
3-(4-methoxyphenyl)-4-oxo-3,4-dihydro-phthala-
4.12. Methyl 3-methyl-4-oxo-3,4-dihydrophthalazine-1-
carboxylate (39a)
d
8.59 (br d, J¼8.7 Hz, 1H), 8.47 (dd, J¼8.0 and
1.2 Hz,1H), 7.83 (ddd, J¼8.7, 7.3, and 1.4 Hz,1H), 7.77 (ddd, J¼8.3, 7.7,
and 1.2 Hz, 1H), 7.53e7.48 (m, A-part of AA0BB0 system, 2H),
6.97e6.93 (m, B-part of AA0BB0 system, 2H), 3.94 (s, 3H, eOCH3), 3.80
Methyl hydrazine (0.35 mL, 6.7 mmol) was added to a stirred
solution of themonoester 38 (1.4 g, 6.7 mmol) in dry THF(25 mL) and
stirred at 50 ꢀC for 3 h. The mixture was cooled to rt, thionyl chloride
(1 mL, 13.5 mmol) was added dropwise and then stirred at 50 ꢀC for
18 h. The reactionwas monitored onTLC. After the completion of the
reaction, the solvent was evaporated and the crude product was
purified by column chromatography (silica gel) eluting with
dichloromethane/ethylacetate/hexane (1:1:1) to give a white solid
(s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 163.8, 159.3, 159.2,
135.8, 134.4, 133.9, 132.0, 128.3, 127.7, 127.5, 127.1, 126.3, 114.1, 55.6,
53.0; nmax (ATR) 3000, 2953, 1722, 1671, 1513, 1435, 1253, 1144,
1046 cmꢁ1; [found: C, 65.45; H, 4.84; N, 8.95. C17H14N2O4 requires C,
65.80; H, 4.55; N, 9.03%].
4.13.4. Methyl 3-(4-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
39a (1.0 g, 68%), mp 125e126 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.57
carboxylate (39e). (0.65 g, 80%), mp 179e181 ꢀC. 1H NMR
(ddd, J¼8.2, 1.2, and 0.6 Hz, 1H, arom.), 8.40 (ddd, J¼8.0, 1.4, and
0.4 Hz, 1H, arom.), 7.79 (ddd, J¼8.4, 7.3, and 1.5 Hz, 1H, arom.), 7.73
(ddd, J¼8.0, 7.7, and 1.3, 7.7 Hz, 1H, arom.), 3.96 (s, 3H, eOCH3), 3.87
(400 MHz, CDCl3)
d
8.67 (br d, J¼8.1 Hz, 1H), 8.55 (dd, J¼7.9 and
0.8 Hz,1H), 7.94 (ddd, J¼8.2, 7.7, and 1.4 Hz,1H), 7.87 (ddd, J¼8.5, 7.6,
and 1.2 Hz, 1H), 7.69e7.66 (m, A-part of AA0BB0 system, 2H),
7.52e7.48 (m, B-part of AA0BB0 system, 2H), 4.04 (s, 3H, eOCH3); 13C
(s, 3H, eNCH3); 13C NMR (100.6 MHz, CDCl3)
d 163.7, 159.7, 135.1,
133.6, 131.8, 128.1, 127.5, 126.9, 126.3, 53.0, 40.1; nmax (ATR) 3046,
2952,1720,1675,1443,1321,1288,1213,1159 cmꢁ1; [found: C, 60.19;
H, 4.78; N, 12.31. C11H10N2O3 requires C, 60.55; H, 4.62; N, 12.31%].
NMR (100.6 MHz, CDCl3)
d 163.6, 159.0, 139.8, 136.4, 134.2, 134.0,
132.3, 129.0, 128.2, 127.6, 127.1 (2C), 126.5, 53.1; nmax (ATR) 3085,
2952,1723,1683,1489,1481,1435,1323,1235,1171,1143,1091,1064,
1046 cmꢁ1; [found: C, 60.79; H, 3.41; N, 8.83. C16H11ClN2O3 requires
C, 61.06; H, 3.53; N, 8.90%].
4.13. General procedure for the synthesis of phthalazinone
derivatives (39beg)
4.13.5. Methyl 3-(4-fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylate (39f). (1.05 g, 73%), mp 125e127 ꢀC. 1H NMR
Phenyl hydrazinium chloride derivatives (1.1 equiv) were added
to a stirred solution of the monoester 38 (1.0 g, 4.8 mmol) in dry
methanol (50 mL). This mixture was stirred at given temperature for
a while (see Table). The solvent was evaporated and the residue was
(400 MHz, CDCl3)
0.9 Hz, 1H), 7.93 (ddd, J¼8.6, 7.4, and 1.4 Hz, 1H), 7.88 (ddd, J¼8.3,
d
8.69 (br d, J¼8.0 Hz, 1H), 8.56 (dd, J¼7.9 and
7.4, and 1.2 Hz, 1H), 7.71e7.66 (m, A-part of AA0BB0 system, 2H),

406
G. Koza et al. / Tetrahedron 69 (2013) 395e409
7.25e7.19 (m, B-part of AA0BB0 system, 2H), 4.05 (s, 3H, eOCH3); 13C
NMR (100.6 MHz, CDCl3)
(d, J¼3.0 Hz), 136.2, 134.1, 132.2, 128.3, 127.8, 127.7, 127.6 (d,
J¼7.3 Hz), 126.5, 115.8 (d, J¼22.8), 53.1; nmax (ATR) 3089, 2953, 1723,
1683, 1505, 1483, 1349, 1233, 1143, 1046 cmꢁ1; [found: C, 64.04; H,
3.70; N, 9.22. C16H11FN2O3 requires C, 64.43; H, 3.72; N, 9.39%].
0.9 Hz,1H), 7.89 (ddd, J¼8.4, 7.2, and 1.2 Hz, 1H), 7.82 (ddd, J¼8.3, 7.2,
and 1.4 Hz,1H), 7.43e7.40 (m, A-part of AA0BB0 system, 2H), 7.28e7.26
(m, B-part of AA0BB0 system, 2H), 2.38 (s, 3H, eCH3); 13C NMR
d
163.6, 162.1 (d, J¼248.1 Hz), 159.1, 137.3
(100.6MHz,CDCl3)d162.0, 159.3, 139.0, 138.1, 134.6, 133.1, 132.8, 129.7,
128.3,127.7,127.4,127.3,125.5, 21.2; nmax (ATR)3003, 2970,1738,1705,
1682, 1510, 1433, 1320, 1250, 1183, 1171 cmꢁ1; HRMS-MALDI [MꢁH]þ
calcd for C16H11N2O3 279.0769; found: 279.0779.
4.13.6. Methyl
zine-1-carboxylate (39g). (0.5 g, 61%), mp 120e121 ꢀC. 1H NMR
(400 MHz, CDCl3)
3-(2,4-difluorophenyl)-4-oxo-3,4-dihydro-phthala-
4.14.4. 3-(4-Methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (40d). (1.01 g, 87%), mp 219e220 ꢀC. 1H NMR
d
8.67 (br d, J¼8.1 Hz, 1H), 8.54 (dd, J¼7.7 and
1.2 Hz, 1H), 7.95 (dt, J¼8.3 and 1.4 Hz, 1H), 7.88 (br dt, J¼7.8 and
(400 MHz, DMSO-d6)
d
8.57 (br d, J¼8.0 Hz, 1H), 8.37 (br dd, J¼7.8
0.8 Hz, 1H), 7.56e7.50 (m, 1H), 7.09e7.01 (m, 2H), 4.04 (s, 3H,
and 0.7 Hz, 1H), 8.02 (ddd, J¼8.4, 7.4, and 1.3 Hz, 1H), 7.94 (dt, J¼8.0
and 1.0 Hz, 1H), 7.56e7.52 (m, A-part of AA0BB0 system, 2H),
7.10e7.06 (m, B-part of AA0BB0 system, 2H), 3.83 (s, 3H, eOCH3); 13C
eOCH3); 13C NMR (100.6 MHz, CDCl3)
d
163.4,163.0 (dd, J¼251.6 and
11.1 Hz), 158.7, 157.7 (dd, J¼255.7 and 12.6 Hz), 137.0, 134.3, 132.4,
129.9 (dd, J¼10.3 and 1.8 Hz), 127.8, 127.8, 127.5, 126.6, 125.5 (dd,
J¼13.0 and 4.1 Hz), 111.9 (dd, J¼22.7 and 3.7 Hz), 105.1 (dd, J¼26.4
and 23.5 Hz), 53.1; nmax (ATR), 3021, 2970, 1742, 1679, 1605, 1533,
1434,1352,1330,1274,1230,1170,1143,1073 cmꢁ1; [found: C, 60.59;
H, 3.32; N, 8.76. C16H10F2N2O3 requires C, 60.76; H, 3.19; N, 8.86%].
NMR (100.6 MHz, DMSO-d6) d 164.5, 158.7, 158.4, 136.7, 134.3, 134.0,
132.2, 127.8, 127.5, 127.2, 126.7, 126.4, 113.8, 55.4; nmax (ATR) 2989,
2839, 2560, 1701, 1609, 1511, 1436, 1313, 1248, 1160 cmꢁ1; [found: C,
64.52; H, 4.00; N, 9.28. C16H12N2O4 requires C, 64.86; H, 4.08; N,
9.46%].
4.14.5. 3-(4-Chlorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
4.14. General procedure for the hydrolysis of phthalazinone
derivatives (39aeg)
carboxylic acid (40e). (1.0 g, 74%), mp 208e209 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
8.58 (br d, J¼7.7 Hz, 1H), 8.39 (dd, J¼8.8 and
0.9 Hz, 1H), 8.04 (dt, J¼7.3 and 1.5 Hz,1H), 7.96 (dt, J¼8.0 and 1.2 Hz,
The esters 39aeg (1.0 g, 3.16e4.59 mmol) were dissolved in THF
(50 mL), methanol (25 mL), and water (1 mL). To the resulting solu-
tion, asolutionof2MKOHinMeOH(3 equiv)wasaddedand stirredat
constant temperature and monitored on TLC. After the completion of
the reaction, the solvent was evaporated and the residue was dis-
solved in water (15 mL) and extracted with ethyl acetate (3ꢂ50 mL).
The water phase was acidified to pH¼2 by addition of 1 M HCl and
extractedwithethyl acetate (3ꢂ75mL). Thecombined organicphases
were dried (MgSO4) and the solvent was evaporated and the acid
derivatives 40aeg were obtained as a white solids.
1H), 7.72e7.69 (m, A-part of AA0BB0 system, 2H) 7.74e7.61 (m, B-
part of AA0BB0 system, 2H); 13C NMR (400 MHz, DMSO-d6)
d 164.3,
158.3, 140.1, 137.1, 134.2, 132.4, 132.3, 128.6, 127.9, 127.7, 127.2, 126.7,
126.5; nmax (ATR) 3003, 2970, 1738, 1683, 1484, 1431, 1372, 1319,
1230, 1154 cmꢁ1; HRMS-MALDI [MþH]þ calcd for C15H10ClN2O3
301.0380, found: 301.0371.
4.14.6. 3-(4-Fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-car-
boxylic acid (40f). (0.96 g, 77%), mp 215e217 ꢀC. 1H NMR (400 MHz,
DMSO-d6)
d
8.58 (br d, J¼8.2 Hz,1H), 8.38 (dd, J¼7.9 and 0.8 Hz,1H),
8.04 (dt, J¼7.4 and 1.4 Hz, 1H), 7.96 (dt, J¼8.2 and 1.1 Hz, 1H),
7.71e7.68 (m, A-part of AA0BB0 system, 2H), 7.41e7.37 (m, B-part of
Compound number
Temperature (ꢀC)
Time (h)
Yield (%)
AA0BB0 system, 2H); 13C NMR (100.6 MHz, DMSO-d6)
d 164.3, 161.2
40a
40b
40c
40d
40e
40f
40
40
40
45
60
60
60
1.5
1.5
1.5
16
4
85
85
90
87
74
77
98
(d, J¼245.1 Hz), 158.3, 137.7 (d, J¼2.8 Hz), 136.7, 134.2, 132.3, 128.4
(d, J¼8.8 Hz), 127.8, 127.2, 126.7, 126.4, 115.5 (d, J¼22.8 Hz); nmax
(ATR) 2980, 2643, 1736, 1672, 1629, 1602, 1507, 1481, 1404, 1346,
1294, 1234, 1216, 1174, 1151, 1130, 1015 cmꢁ1; HRMS-MALDI
[MþH]þ calcd for C15H10FN2O3 285.0675, found: 285.0666.
2
2
40g
4.14.7. 3-(2,4-Difluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (40g). (0.93 g, 98%), mp 225e226 ꢀC. 1H NMR
4.14.1. 3-Methyl-4-oxo-3,4-dihydrophthalazine-1-carboxylic
acid
(40a). (0.8 g, 85%), mp 246e247 ꢀC. 1H NMR (400 MHz, DMSO-d6)
(400 MHz, DMSO-d6)
d
8.57 (dd, J¼8.2 and 0.4 Hz, 1H), 8.37 (dd,
d
8.53 (br d, J¼8.1 Hz, 1H), 8.27 (br d, J¼7.8 Hz, 1H), 7.94 (br t,
J¼7.9 and 0.8 Hz, 1H), 8.07 (dt, J¼7.9 and 1.4 Hz, 1H), 7.98 (dt, J¼8.0
and 1.2 Hz,1H), 7.76 (dt, J¼8.8 and 6.1 Hz,1H), 7.57 (ddd, J¼10.4, 9.2,
and 2.8 Hz, 1H), 7.35e7.30 (m, 1H); 13C NMR (100.6 MHz, DMSO-d6)
J¼7.7 Hz, 1H), 7.86 (br t, J¼7.5 Hz, 1H), 3.77 (s, 3H, eOCH3); 13C NMR
(100.6 MHz, DMSO-d6)
d 164.4, 158.6, 135.4, 133.6, 131.9, 127.4,
126.8, 126.2, 126.0, 40.1; nmax (ATR) 3017, 2875, 1716, 1624, 1575,
1489, 1415, 1346, 1311, 1209, 1186, 1063 cmꢁ1; [found: C, 58.49; H,
4.07; N, 13.43. C10H8N2O3 requires C, 58.82; H, 3.95; N, 13.72%].
d
163.3, 161.3 (dd, J¼248.7 and 11.5 Hz), 157.2, 156.2 (dd, J¼252.7
and 13.2 Hz). 137.0, 133.7, 131.9, 130.1 (d, J¼10.2 Hz), 126.5, 126.4,
125.9, 125.8, 124.8 (dd, J¼13.0 and 4.1 Hz), 111.4 (dd, J¼22.6 and
3.4 Hz), 104.0 (dd, J¼27.1 and 24 Hz); nmax (ATR) 3079, 1730, 1658,
1615, 1604, 1511, 1352, 1274, 1229, 1177, 1159, 1148 cmꢁ1; [found: C,
59.28; H, 2.74; N, 8.92. C15H8F2N2O3 requires C, 59.61; H, 2.67; N,
9.27%].
4.14.2. 4-Oxo-3-phenyl-3,4-dihydrophthalazine-1-carboxylic
acid
(40b). (0.80 g, 85%), mp 217e218 ꢀC. 1H NMR (400 MHz, CDCl3)
d
9.13 (br d, J¼8.2 Hz, 1H), 8.48 (dd, J¼7.8 and 0.8 Hz, 1H), 7.90 (dt,
J¼7.6 and 1.4 Hz, 1H), 7.83 (dt, J¼8.1 and 1.1 Hz, 1H), 7.56e7.54 (m,
2H), 7.51e7.47 (m, 2H), 7.42 (tt, J¼7.2 and 1.1 Hz, 1H); 13C NMR
4.15. General procedure for the synthesis of acyl azide de-
rivatives (41aeg)
(100.6 MHz, CDCl3)
d 161.6, 159.2, 140.1, 134.6, 133.1, 132.9, 129.2,
128.9, 128.4, 127.7, 127.6, 127.3, 125.7; nmax (ATR) 2859, 1735, 1708,
1686, 1596, 1576, 1432, 1317, 1281, 1157, 1125 cmꢁ1; HRMS-ESI
[MþNa]þ calcd for C15H10N2NaO3 267.0764, found: 267.0731.
Oxalyl chloride (2 equiv) was added to a stirred suspension of
acids 40aeg (1.0 g) in dichloromethane at rt and then DMF (3
drops) were added. After 10 min, all acid dissolved and the solution
was stirred at rt for 90 min. The solvent and excess oxalyl chloride
were evaporated. The residue was dissolved in acetone (15 mL) and
cooled in an ice bath. A solution of NaN3 (2 equiv) in water (1 mL)
4.14.3. 3-(4-Methylphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carboxylic acid (40c). (1.05 g, 90%), mp 204e205 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
9.11 (dd, J¼8.3 and 0.6 Hz,1H), 8.47 (dd, J¼7.9 and

G. Koza et al. / Tetrahedron 69 (2013) 395e409
407
was added dropwise and stirred in an ice-cooled bath for 90 min.
The mixture was extracted with ethyl acetate (200 mL) and water
(100 mL). The combined water layers were extracted with EtOAc
(3ꢂ75 mL), dried over MgSO4 and the solvent was evaporated. The
crude product was purified by column chromatography eluting
with ethyl acetate/dichloromethane/hexane (2:2:1) to give acyl
azide derivatives 41aeg as white solids.
0.9 Hz, 1H), 7.87 (dt, J¼7.8 and 1.4 Hz, 1H), 7.80 (dt, J¼8.1 and 1.1 Hz,
1H), 7.45e7.40 (m, 1H), 7.00e6.92 (m, 2H); nmax (ATR) 3092, 2969,
2146, 1692, 1607, 1507, 1481, 1346, 1319, 1276, 1201, 1179, 1129, 1109,
1069 cmꢁ1
.
4.16. General procedure for the synthesis of urethane de-
rivatives (42aeg)
4.15.1. 3-Methyl-4-oxo-3,4-dihydrophthalazine-1-carbonyl
(41a). (0.90 g, 81%), mp 110e111 ꢀC. 1H NMR (400 MHz, CDCl3)
8.75 (br d, J¼7.9 Hz, 1H), 8.39 (dd, J¼7.9 and 1.1 Hz, 1H), 7.82 (ddd,
J¼8.6, 7.3 and 1.5 Hz, 1H), 7.75 (ddd, J¼8.2, 8.1 and 1.2 Hz, 1H), 3.88
(s, 3H, eCH3); 13C NMR (100.6 MHz, CDCl3)
169.3, 159.0, 133.3,
131.8, 131.3, 127.1, 126.5, 126.2, 125.4, 39.5; nmax (ATR) 3123, 2162,
1673, 1603, 1447, 1346, 1322, 1289, 1201, 1044 cmꢁ1
azide
The acyl azide derivatives 41aeg (0.25 g) were dissolved in dry
benzene (40 mL) and heated at reflux for 90 min. To this solution,
dry MeOH (2 mL) was added and stirred at this temperature for
2e16 h. The reaction was monitored with TLC. The solvent and
excess methanol were evaporated. The crude product was purified
by column chromatography (silica gel) with suitable eluent to give
urethane derivatives 42aeg as white solids.
d
d
.
4.15.2. 4-Oxo-3-phenyl-3,4-dihydrophthalazine-1-carbonyl
azide
8.78
(41b). (0.82 g, 75%), mp 87e88 ꢀC. 1H NMR (400 MHz, CDCl3)
d
4.16.1. Methyl (3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)carba-
(br d, J¼8.2 Hz, 1H), 8.47 (dd, J¼7.9 and 0.9 Hz, 1H), 7.87 (dt, J¼7.3
and 1.4 Hz, 1H), 7.79 (dt, J¼8.0 and 1.2 Hz, 1H), 7.62e7.58 (m, 2H),
7.48e7.43 (m, 2H), 7.37 (tt, J¼7.6 and 1.2 Hz, 1H); 13C NMR
mate (42a). (0.24 g, 96%), mp 173e174 ꢀC. 1H NMR (400 MHz,
CDCl3)
3.73 (s, 3H, eOCH3), 3.73 (s, 3H, eNCH3); 13C NMR (100.6 MHz,
CDCl3) 159.4, 155.4, 137.2, 132.9, 132.0, 128.6, 127.6, 127.1, 124.7,
d 8.38e8.35 (m, 1H), 7.73e7.71 (m, 3H), 6.81 (br s, 1H, eNH),
(100.6 MHz, CDCl3)
d
169.3, 159.0, 133.3, 131.8, 131.3, 127.1, 126.5,
d
126.2, 125.4, 39.6; nmax (ATR) 3038, 2924, 2140, 1681, 1595, 1488,
53.1, 39.3; nmax (ATR) 3218, 2950, 1734, 1626, 1578, 1556, 1489, 1452,
1353, 1230, 1060 cmꢁ1; [found: C, 56.45; H, 4.83; N, 17.94.
C11H11N3O3 requires C, 56.65; H, 4.75; N, 18.02%].
1344, 1318, 1227, 1185, 1126, 1075 cmꢁ1
.
4.15.3. 3-(4-Methylphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carbonyl azide (41c). (1.05 g, 97%), mp 111e112 ꢀC. 1H NMR
4.16.2. Methyl (4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)carba-
(400 MHz, CDCl3)
d
8.77 (br d, J¼8.3 Hz, 1H), 8.45 (br d, J¼7.9 Hz,
mate (42b). (0.21 g, 85%), mp 175e176 ꢀC. 1H NMR (400 MHz,
1H), 7.87e7.83 (m, 1H), 7.80e7.75 (m, 1H), 7.47e7.44 (m, A-part of
CDCl3)
7.54e7.50 (m, 2H), 7.41 (tt, J¼7.4 and 7.4 Hz, 1H), 6.77 (br s, 1H,
eNH), 3.85 (s, 3H, eOCH3); 13C NMR (100.6 MHz, CDCl3)
158.9,
d 8.57e8.54 (m, 1H), 7.90e7.86 (m, 3H), 7.70e7.67 (m, 2H),
AA0BB0 system, 2H), 7.26e7.24 (m, B-part of AA0BB0 system, 2H),
2.35 (s, 3H, eCH3); 13C NMR (100.6 MHz, CDCl3)
d
170.3,159.2,138.7,
d
138.6, 134.6, 134.3, 132.2, 129.6, 128.1, 127.7, 127.5, 126.2, 125.4, 21.2;
155.5, 147.1, 141.4, 138.2, 133.3, 132.3, 128.8, 127.8, 127.8, 127.3, 125.7,
125.0, 53.2; nmax (ATR) 3276, 3010, 2969, 2955, 1737, 1706, 1668,
1595, 1556, 1484, 1455, 1313, 1254, 1055 cmꢁ1; [found: C, 65.00; H,
4.27; N, 13.87. C16H13N3O3 requires C, 65.08; H, 4.44; N, 14.23%].
nmax (ATR) 3110, 2917, 2121, 1793, 1752, 1681, 1604, 1510, 1346, 1181,
1127 cmꢁ1
.
4.15.4. 3-(4-Methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-1-
carbonyl azide (41d). (1.01 g, 94%), mp 110e111 ꢀC. 1H NMR
4.16.3. Methyl [3-(4-methylphenyl)-4-oxo-3,4-dihydrophthalazin-1-
(400 MHz, CDCl3)
d
8.78 (dd, J¼8.3 and 0.5 Hz, 1H), 8.46 (dd, J¼7.9
yl]carbamate (42c). (0.21 g, 80%), mp 195e196 ꢀC. 1H NMR
and 0.9 Hz, 1H), 7.86 (dt, J¼7.3 and 1.4 Hz, 1H), 7.78 (dt, J¼8.0 and
1.2 Hz, 1H), 7.52e7.48 (m, A-part of AA0BB0 system, 2H), 6.98e6.94
(m, B-part of AA0BB0 system, 2H), 3.80 (s, 3H, eOCH3); nmax (ATR)
3078, 2954, 2146, 1724, 1694, 1676, 1509, 1323, 1252, 1173,
(400 MHz, CDCl3) d 8.43 (m, 1H), 7.77e7.70 (m, 3H), 7.44e7.40 (m,
A-part of AA0BB0 system, 2H), 7.17 (m, B-part of AA0BB0 system, 2H),
7.00 (br s, 1H, eNH), 3.72 (s, 3H, eOCH3), 2.30 (s, 3H, eCH3); 13C
NMR (100.6 MHz, CDCl3)
d 158.9, 155.6, 138.9, 138.1, 137.8, 133.2,
1031 cmꢁ1
.
132.1, 129.4, 129.3, 127.7, 127.3, 125.4, 125.0, 53.1, 21.1; nmax (ATR)
3206, 3112, 2915, 1709, 1668, 1591, 1512, 1469, 1447, 1354, 1332,
1313, 1180, 1064 cmꢁ1; [found: C, 65.98; H, 4.83; N, 13.23.
C17H15N3O3 requires C, 66.01; H, 4.89; N, 13.58%].
4.15.5. 3-(4-Chlorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carbonyl azide (41e). (1.0 g, 92%), mp 123e124 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
8.77 (dd, J¼8.3 and 0.53 Hz, 1H), 8.46 (dd, J¼7.9,
0.9 Hz, 1H), 7.87 (dt, J¼7.3 and 1.4 Hz, 1H), 7.79 (dt, J¼8.0 and 1.2 Hz,
1H), 7.60e7.56 (m, A-part of AA0BB0 system, 2H), 7.44e7.40 (m, B-
part of AA0BB0 system, 2H); nmax (ATR); 3093, 2969, 2146,1735,1691,
4.16.4. Methyl (3-(4-methoxyphenyl)-4-oxo-3,4-dihydrophthalazin-
1-yl)carbamate (42d). (0.21 g, 83%), mp 153e154 ꢀC. 1H NMR
(400 MHz, CDCl3) d 8.46e8.44 (m,1H), 7.80e7.74 (m, 3H), 7.50e7.46
1608, 1449, 1439, 1347, 1319, 1276, 1201, 1129, 1069 cmꢁ1
.
(m, A-part of AA0BB0 system, 2H), 6.95e6.91 (m, B-part of AA0BB0
system, 2H), 6.67 (br s, 1H, eNH), 3.79 (s, 3H, eOCH3), 3.75 (s, 3H,
4.15.6. 3-(4-Fluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
eOCH3); 13C NMR (100.6 MHz, CDCl3)
d 158.8, 158.7, 155.3, 137.8,
carbonyl azide (41f). (0.96 g, 89%), mp 117e118 ꢀC. 1H NMR
134.2, 133.0, 131.9, 129.0, 127.5, 127.1, 126.6, 124.7, 113.7, 55.3, 52.9;
nmax (ATR) 3264, 3070, 2951, 1731, 1667, 1599, 1505, 1466, 1452,
1305, 1239, 1178, 1131, 1009 cmꢁ1; [found: C, 62.97; H, 4.70; N,
12.88. C17H15N3O4 requires C, 62.76; H, 4.65; N, 12.92%].
(400 MHz, CDCl3)
d
8.78 (dd, J¼8.2 and 0.4 Hz, 1H), 8.46 (ddd, J¼8.0,
0.7, and 0.6 Hz, 1H), 7.90e7.85 (m, 1H), 7.82e7.78 (m, 1H), 7.62e7.56
(m, A-part of AA0BB0 system, 2H), 7.17e7.11 (m, B-part of AA0BB0
system, 2H); 13C NMR (100.6 MHz, CDCl3)
d 170.2, 162.2 (d,
J¼248.7 Hz), 159.1, 137.1 (d, J¼3.0 Hz), 135.0, 134.5, 132.4, 128.3,
128.0, 127.6 (d, J¼15.3 Hz), 127.4, 126.3, 115.9 (d, J¼22.9 Hz); nmax
(ATR), 3131, 2940, 2148, 1698, 1683, 1603, 1507, 1350, 1325, 1237,
4.16.5. Methyl (3-(4-chlorophenyl)-4-oxo-3,4-dihydrophthalazin-1-
yl)carbamate (42e). (0.23 g, 92%), mp 178e179 ꢀC. 1H NMR
(400 MHz, CDCl3) d 8.45e8.43 (m,1H), 7.82e7.74 (m, 3H), 7.60e7.56
1182, 1128, 1076 cmꢁ1
.
(m, A-part of AA0BB0 system, 2H), 7.38e7.35 (m, B-part of AA0BB0
system, 2H), 6.83 (s, 1H, eNH), 3.75 (s, 3H, eOCH3); 13C NMR
4.15.7. 3-(2,4-Difluorophenyl)-4-oxo-3,4-dihydrophthalazine-1-
carbonyl azide (41g). (0.93 g, 86%), mp 104e105 ꢀC. 1H NMR
(100.6 MHz, CDCl3) d 158.8, 155.4, 139.9, 138.4, 133.5, 133.3, 132.4,
129.2, 128.8, 127.9, 127.2, 126.7, 124.9, 53.2; nmax (ATR) 3221, 3053,
(400 MHz, CDCl3)
d
8.75 (br d, J¼8.4 Hz, 1H), 8.44 (dd, J¼7.9 and
2969, 1705, 1668, 1597, 1524, 1485, 1327, 1249, 1173, 1132, 1069,

408
G. Koza et al. / Tetrahedron 69 (2013) 395e409
1041, 1021, 1009 cmꢁ1
C16H13ClN3O3 330.0645, found : 330.0688.
;
HRMS-MALDI [MþH]þ calcd for
3016, 2970, 1738, 1623, 1574, 1553, 1514, 1354, 1229, 1216,
1205 cmꢁ1; [found: C, 71.53; H, 5.09; N, 16.54. C15H13N3O requires
C, 71.70; H, 5.21; N, 16.72%].
4.16.6. Methyl (3-(4-fluorophenyl)-4-oxo-3,4-dihydrophthalazin-1-
yl)carbamate (42f). (0.25 g, 99%), mp 190e192 ꢀC. 1H NMR
4.17.4. 4-Amino-2-(4-methoxyphenyl)phthalazin-1(2H)-one
(400 MHz, CDCl3)
d
8.44e8.42 (m, 1H), 7.79e7.74 (m, 3H), 7.58e7.54
(43d). (0.23 g, 94%), mp 274e275 ꢀC. 1H NMR (400 MHz, CDCl3)
(m, A-part of AA0BB0 system, 2H), 7.10e7.05 (m, B-part of AA0BB0
d
8.50 (dd, J¼8.0 and 0.8 Hz, 1H), 7.79e7.73 (m, 2H), 7.57e7.54 (m,
system, 2H), 6.90 (s, 1H, eNH), 3.74 (s, 3H, eOCH3); 13C NMR
1H), 7.55e7.51 (m, A-part of AA0BB0 system, 2H), 6.90e6.86 (m, B-
(100.6 MHz, CDCl3)
d
161.7 (d, J¼246.1 Hz), 158.9, 155.4, 138.2, 137.4
part of AA0BB0 system, 2H), 3.76 (s, 3H, eOCH3); 13C NMR
(d, J¼3.0 Hz), 133.4, 132.4, 129.2, 127.8, 127.4 (d, J¼8.7 Hz), 127.3,
(100.6 MHz, DMSO-d6) d 160.0, 158.1, 153.7, 138.9, 134.6, 133.3,
125.0, 115.6 (d, J¼22.7 Hz), 53.2; nmax (ATR) 3221, 3072, 2923, 1705,
132.4, 129.4, 128.1, 126.8, 123.5, 114.1, 55.5; nmax (ATR) 3247, 3144,
2839, 1683, 1666, 1650, 1630, 1561, 1508, 1469, 1447, 1323, 1308,
1249, 1170, 1028 cmꢁ1; HRMS-MALDI [MþH]þ calcd for C15H14N3O2
268.1086, found: 268.1112.
1665, 1587, 1556, 1504, 1454, 1324, 1256, 1213, 1140, 1058 cmꢁ1
;
[found: C, 61.08; H, 4.11; N, 13.09. C16H12FN3O3 requires C, 61.34; H,
3.86; N, 13.41%].
4.16.7. Methyl (3-(2,4-difluorophenyl)-4-oxo-3,4-dihydro-phthala-
zin-1-yl)carbamate (42g). (0.24 g, 97%), mp 202e203 ꢀC. 1H NMR
4.17.5. 4-Amino-2-(4-chlorophenyl)phthalazin-1(2H)-one
(43e). (0.24 g, 98%), mp 214e215 ꢀC. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
(m, 1H), 6.97e6.90 (m, 2H), 6.65 (s, 1H, eNH), 3.75 (s, 3H, eOCH3);
13C NMR (100.6 MHz, CDCl3)
162.7 (dd, J¼249.7 and 11.0 Hz),
d
8.45e8.42 (m, 1H), 7.85e7.76 (m, 3H), 7.45e7.40
d 8.48e8.46 (m, 1H), 7.80e7.72 (m, 2H), 7.64e7.61 (m, 1H),
7.62e7.58 (m, A-part of AA0BB0 system, 2H), 7.36e7.32 (m, B-part of
d
AA0BB0 system, 2H), 4.40 (s, 2H, eNH2); 13C NMR (100.6 MHz,
CDCl3) d 158.1, 145.1, 140.5, 133.2, 132.6, 132.0, 129.3, 128.7, 128.3,
126.8, 124.5, 122.4; nmax (ATR) 3453, 3344, 3220, 3035, 1738, 1617,
1589, 1577, 1551, 1490, 1430, 1347, 1088, 683 cmꢁ1; HRMS-MALDI
[MþH]þ calcd for C14H11ClN3O 272.0591, found: 272.0586.
158.7, 156.6 (dd, J¼254.1 and 12.6 Hz), 155.3, 138.8, 133.6, 132.5,
129.8 (dd, J¼10.1 and 1.5 Hz), 128.7, 127.8, 127.5, 125.5 (dd, J¼12.8
and 4.1 Hz), 125.3, 111.8 (dd, J¼22.5 and 3.6 Hz), 105.0 (dd, J¼26.3
and 23.6 Hz), 53.2; nmax (ATR) 3198, 3062, 2970, 2948, 1730, 1650,
1606, 1589, 1509, 1486, 1238, 1216, 1148, 1056, cmꢁ1; [found: C,
58.30; H, 3.44; N, 12.27. C16H11F2N3O3 requires C, 58.01; H, 3.35; N,
12.68%].
4.17.6. 4-Amino-2-(4-fluorophenyl)phthalazin-1(2H)-one
(43f). (0.22 g, 92%), mp 224e225 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.49e8.47 (m,1H), 7.81e7.74 (m, 2H), 7.65e7.62 (m,1H), 7.61e7.58
(m, A-part of AA0BB0 system, 2H), 7.10e7.06 (m, B-part of AA0BB0
system, 2H), 4.36 (s, 2H, eNH2); 13C NMR (100.6 MHz, CDCl3)
161.4
4.17. General procedure for the synthesis of amino-
phthalazinone derivatives (43aeg)
d
(d, J¼246.8 Hz), 158.1, 145.0, 138.0 (d, J¼3.1 Hz), 133.1, 131.9, 129.3,
128.3, 127.4 (d, J¼8.6 Hz), 124.5, 122.4, 115.4 (d, J¼22.8 Hz): nmax
(ATR) 3479, 3358, 3227, 3071, 1617, 1578, 1552, 1431, 1352, 1211,
1153 cmꢁ1; HRMS-MALDI [MþH]þ calcd for C14H11FN3O 256.0886,
found : 256.0888.
The acyl azide derivatives 41aeg (0.3 g, 0.92e1.3 mmol) were
dissolved in dry benzene (30 mL) and heated at reflux for 90 min.
The solution was cooled to 40 ꢀC and HCl (10 mL, 8 M) was added.
The mixture was stirred at rt for 15 mine4 h and then the pH value
was adjusted to pH 10 by the addition of 10% NaOH solution. The
mixture was extracted with ethyl acetate (3ꢂ100 mL). The com-
bined organic layers were dried over MgSO4 and the solvent was
evaporated. The crude product was purified by column chroma-
tography eluting with ethyl acetate/dichloromethane (1:2) to give
amine derivatives 43aeg as white solids.
4.17.7. 4-Amino-2-(2,4-difluorophenyl)phthalazin-1(2H)-one
(43g). (0.23 g, 94%), mp 187e188 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.48e8.46 (m, 1H), 7.83e7.75 (m, 2H), 7.65e7.63 (m, 1H),
7.44e7.39 (m, 1H), 6.97e6.87 (m, 2H), 4.34 (s, 2H, eNH2); 13C NMR
(100.6 MHz, CDCl3)
d
161.4 (dd, J¼245.7 and 11.1 Hz), 157.1, 156.7
(dd, J¼253.8 and 12.6 Hz), 144.4, 132.3, 131.0, 128.9 (dd, J¼10.2 and
2.1 Hz), 127.7, 127.2, 125.2 (dd, J¼12.9 and 4.2 Hz), 123.8, 121.7, 110.7
(dd, J¼22.5 and 3.7 Hz), 103.9 (dd, J¼26.3 and 23.7 Hz); nmax (ATR)
3469, 3343, 3220, 3071, 1738, 1621, 1579, 1553, 1507, 1453, 1429,
1357,1269,1253,1141,1099, 964 cmꢁ1; HRMS-MALDI [MþH]þ calcd
for C14H10F2N3O 274.0792, found: 274.0790.
4.17.1. 4-Amino-2-methylphthalazin-1(2H)-one (43a). (0.18 g, 79%),
mp 151e153 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.44e8.39 (m, 1H),
7.75e7.71 (m, 2H), 7.62e7.58 (m, 1H), 3.65 (s, 3H, eOCH3); 13C NMR
(100.6 MHz, CDCl3) 158.3, 144.6, 132.5, 131.7, 128.8, 127.7, 124.4,
d
122.3, 38.5; nmax (ATR) 3392, 3329, 3203, 1624, 1560, 1497, 1436,
1365, 1133, 1104, cmꢁ1; HRMS-ESI [MþNa]þ calcd for C9H9N3NaO
198.0638, found: 198.0624.
4.18. Crystallography
4.17.2. 4-Amino-2-phenylphthalazin-1(2H)-one (43b). (0.19 g, 80%),
For the crystal structure determination, a single-crystal of
compound 32a was used for data collection on a four-circle Rigaku
R-AXIS RAPID-S diffractometer (equipped with a two-dimensional
mp 176e178 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.50e8.48 (m, 1H),
7.80e7.73 (m, 2H), 7.67e7.63 (m, 1H), 7.62e7.59 (m, 2H), 7.43e7.38
(m, 2H), 7.27 (tt, J¼7.4 and 1.1 Hz, 1H), 4.13 (br s, 2H, eNH2); 13C
area IP detector). Graphite-monochromated Mo-Ka radiation
w¼5ꢀ for one
ꢀ
NMR (100.6 MHz, CDCl3)
d
157.8, 144.8, 141.7, 132.7, 131.6, 129.1,
(l
¼0.71073 A) and oscillation scans technique with
D
128.4, 127.9, 127.1, 125.5, 124.2, 122.2; nmax (ATR) 3421, 3319, 3212,
3064, 1609, 1592, 1578, 1552, 1494, 1455, 1342, 1311 cmꢁ1; HRMS-
MALDI [MþH]þ calcd for C14H12N3O 238.0980, found: 238.0996.
image were used for data collection. The lattice parameters were
determined by the least-squares methods on the basis of all re-
flections with F2>2 (F2). Integration of the intensities, correction
s
for Lorentz and polarization effects and cell refinement was per-
formed using CrystalClear (Rigaku/MSC Inc., 2005) software.26 The
structures were solved by direct methods using SHELXS-9727 and
refined by a full-matrix least-squares procedure using the program
SHELXL-97H atoms were positioned geometrically and refined us-
ing a riding model. The final difference Fourier maps showed no
peaks of chemical significance. Crystal data for 32a: C9H9N3O4,
crystal system, space group: monoclinic, P21/a; (no: 14); unit cell
4.17.3. 4-Amino-2-(4-methylphenyl)phthalazin-1(2H)-one
(43c). (0.22 g, 95%), mp 208e209 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.50e8.48 (m, 1H), 7.80e7.72 (m, 2H), 7.64e7.62 (m, 1H),
7.48e7.45 (m, A-part of AA0BB0 system, 2H), 7.23e7.20 (m, B-part of
AA0BB0 system, 2H), 4.33 (br s, 2H, eNH2), 2.32 (s, 3H, eCH3); 13C
NMR (100.6 MHz, CDCl3)
d 158.1, 144.9, 139.6, 137.2, 132.9, 131.7,
129.4, 129.3, 128.2, 125.5, 124.5, 122.5, 21.1; nmax (ATR) 3295, 3195,

G. Koza et al. / Tetrahedron 69 (2013) 395e409
409
ꢀ
5. Moos, W. H.; Humblet, C. C.; Sircar, I.; Rithner, C.; Weishaar, R. E.; Bristol, J. A.;
McPhailt, A. T. J. Med. Chem. 1987, 30, 1963e1972.
dimensions: a¼8.1317(2), b¼14.0449(2), c¼8.8512(1)A,
a
¼90,
¼90 A; volume: 1007.79(3) A ; Z¼4; calculated den-
sity: 1.471 g/cm3; absorption coefficient: 0.118 mmꢁ1; F(000): 464;
3
ꢀ
ꢀ
b
¼94.48(2),
g
6. Colletti, S. L.; Frie, J. L.; Dixone, E. C.; Singh, S. B.; Choi, B. K.; Scapin, G.; Fitz-
gerald, C. E.; Kumar, S.; Nichols, E. A.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.;
Samuel, K.; Schmatz, D. M.; Schwartz, C. D.; Shoop, W. L.; Thompson, C. M.;
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q
-range for data collection 2.3e26.9ꢀ; refinement method: full
matrix least-square on F2; data/parameters: 2104/148; goodness-
of-fit on F2: 1.009; final R-indices [I>2r(I)]: R1¼0.0833,
ꢀꢁ3
wR2¼0.233; largest diff. peak and hole: 0.518 and ꢁ0.544 e A
;
Crystallographic data that were deposited in CSD under CCDC
registration number 890787 contain the supplementary crystallo-
graphic data for this Letter. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre (CCDC) via
www.ccdc.cam.ac.uk/data_request/cif and are available free of
charge upon request to CCDC, 12 Union Road, Cambridge, UK (fax:
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Acknowledgements
The authors are indebted to the Scientific and Technological
Research Council of Turkey (TUBITAK, Grant No: 110-R001), the
Department of Chemistry at Middle East Technical University and
the Turkish Academy of Sciences (TUBA) for their financial support
of this work.
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Supplementary data
These data include the 1H and 13C NMR spectra of compounds
(228 pages). Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2012.10.010.
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