Synthesis of angular 7,8-pyridazinocoumarins via the transformation of a hydroxy group into a carbonyl group

Article abstract of DOI:10.1055/s-0028-1087805

The synthesis of angular 7,8-pyridazinocoumarins (2H- pyrano[2,3-f] phthalazin-2-ones) is reported via the oxidation of 8- [1-(acylhydrazono)ethyl]- 7-hydroxycoumarin with (diacetoxy-iodo)benzene and subsequent treatment of the derived 7,8-diacyl- coumari

Full text of DOI:10.1055/s-0028-1087805

836
PAPER
Synthesis of Angular 7,8-Pyridazinocoumarins via the Transformation of a
Hydroxy Group into a Carbonyl Group
Synthesisof
Angu
n
lar 7,8-Pyrid
t
azinoco
i
umarin
g
s
oni Kotali,*a Ioannis S. Lafazanis,a Philip A. Harrisb
a
Laboratory of Organic Chemistry, Department of Chemical Engineering, University of Thessaloniki, Thessaloniki 54124, Greece
Fax +30(231)0996253; E-mail: kotali@eng.auth.gr
b
GlaxoSmithKline, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, PA 19426-0989, USA
Received 30 September 2008
has been extracted from the wild mushroom Lactarius
necator (Figure 1).10
Abstract: The synthesis of angular 7,8-pyridazinocoumarins (2H-
pyrano[2,3-f]phthalazin-2-ones) is reported via the oxidation of 8-
[1-(acylhydrazono)ethyl]-7-hydroxycoumarin with (diacetoxy-
iodo)benzene and subsequent treatment of the derived 7,8-diacyl-
coumarins with hydrazine. The procedure involves transformation
of a hydroxy group into an acyl group and formation of a new C–C
bond.
However, to the best of our knowledge no synthetic ana-
logues have been reported in the literature in contrast to
furo- and pyranocoumarins.1,11,12 We now report the syn-
thesis of angular pyradazinocoumarins 5 according to the
synthetic scheme presented in Scheme 1.
Key words: transformation, oxidation, (diacetoxyiodo)benzene,
2H-pyrano[2,3-f]phthalazin-2-ones, angular pyridazinocoumarins,
N-acylhydrazones
The synthesis of pyridazine ring is commonly achieved by
the reaction of 1,2-diacyl compounds13 with hydrazine
N
N
Coumarins (2H-1-benzopyran-2-ones), a well-known
class of compounds, are naturally occurring 1-benzopyran
derivatives possessing diverse pharmacological proper-
ties.1 Among them, they have been recognized to show
anti-inflammatory2 and significant cytotoxic3 activities.
Their pharmacological and biochemical properties de-
pend upon the pattern of substitution.3 Thus it is not diffi-
cult to understand why the design and synthesis of either
simple substituted or fused coumarin derivatives is of
great importance to many researchers. Recently, we
synthesized4 the simple substituted 7,8-diacylcoumarins
in our laboratory via the transformation of a hydroxy
group into an acyl group, by lead tetraacetate oxidation of
8-[1-(acylhydrazono)ethyl]-7-hydroxycoumarins, and we
would like further to synthesize angular 7,8-pyridazino
derivatives. Polyfunctionalized pyridazines have been ex-
tensively used as reactive species for building chemical
diversity.5 Moreover, they exhibit a variety of biological
activity; they have been used as anti-anxiety6 and anti-
inflammatory agents,7 but mainly as kinase inhibitors with
related antileukemic activity.8,9 Thus, the presence of both
the coumarin and pyridazine system in the same molecule
could lead to a new anticancer agent with combined activ-
ity. Necarcotin is a natural 5,6-pyridazinocoumarin that
O
O
OH
Figure 1 Naturally occurring necatorin
Table 1 Substituents in the Synthesis of 7,8-Pyridazinocoumarins
2–5
a
b
c
R
Ph
4-MeC6H4
4-HOC6H4
2-HOC6H4
2-O2NC6H4
2-furyl
2-thienyl
4-pyridyl
Bn
d
e
f
g
h
i
j
Me
PhI(OAc)2, CH2Cl2
0 °C to r.t., 24–48 h
NH2NH2, EtOH
PrOH
r.t. to reflux, 2–24 h
reflux, 24 h
+ RCONHNH2
OH
R
72–93%
91–98%
62–90%
OH
O
O
O
O
O
O
O
O
COR
N
COMe
COMe
Me
N
1
2
Me
NNHCOR
3
4
5
Scheme 1 Synthesis of angular 7,8-pyridazinocoumarins
SYNTHESIS 2009, No. 5, pp 0836–0840
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1087805; Art ID: P11008SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Angular 7,8-Pyridazinocoumarins
837
and in our case, the synthesis of starting 7,8-diacylcou- 4, generally in very good to high yields, 62–90%. 7,8-Di-
marins is crucial. For our purpose, we chose to synthesize acylcoumarins were isolated by column chromatography
a series of functionally diverse 7,8-diacylcoumarins via and the new compounds 4a, 4d, 4f, and 4i as well as the
(diacetoxyiodo)benzene treatment of 8-[1-(acylhydra- new hydrazone derivatives 3d, 3f, and 3i were identified
zono)ethyl]-7-hydroxycoumarins (Scheme 1, Table 1). by their spectral data and by elemental analysis. The
Since (diacetoxyiodo)benzene reactivity14 is known to yields obtained by (diacetoxyiodo)benzene oxidation
bear close analogy to that of lead tetraacetate, but is less were comparable with those obtained by lead tetraacetate
hazardous and toxic than lead(IV) compounds, an alterna- oxidation. There was only one exception in the case of di-
tive approach would be desirable. Commercially available acylcoumarin 4c, which was formed in 18% or 73% yield
aryl, alkyl, or heterocyclic carbohydrazides 2 were react- when (diacetoxyiodo)benzene or lead tetraacetate4 was
ed with 8-acetyl-7-hydroxycoumarin 1, to prepare the hy- used, respectively. The yields for the preparation of 7,8-
drazones 3. Reaction of hydrazones 3a–j with diacylcoumarins with either (diacetoxyiodo)benzene or
(diacetoxyiodo)benzene in dichloromethane at room tem- lead tetraacetate are listed in Table 2.
perature afforded the corresponding 7,8-diacylcoumarins
Table 2 Preparation of the New Synthesized Compounds
Product
Substrates
1 + 2d
1 + 2f
1 + 2i
3a
Reagent
Ratioa
1:1
Solvent
PrOH
PrOH
PrOH
Temp (°C)
reflux
Time (h)
Yield (%)
Mpb (°C)Lit.
262.3–262.9
248–249
3d
3f
24
24
24
95
96
92
1:1
reflux
3i
1:1
reflux
203–205
4a
PhI(OAc)2
Pb(OAc)4
1:1
1:1.2
CH2Cl2
THF
r.t.c
r.t.c
24
2
65
55
134–135
4b
4c
4d
3b
3c
3d
PhI(OAc)2
PhI(OAc)2
1:2.5
1:1.7
CH2Cl2
CH2Cl2
r.t.c
r.t.c
24
48
90
18
169.5–170.74
191.5–193.54
147.7–149.7
PhI(OAc)2
Pb(OAc)4
1:2
1:1.5
CH2Cl2
THF
r.t.c
r.t.c
24
2
62
71
4e
4f
3e
3f
PhI(OAc)2
1:1.5
CH2Cl2
r.t.c
24
70
172.5–174.54
149.3–151.3
PhI(OAc)2
Pb(OAc)4
1:2.5
1:1.5
CH2Cl2
THF
r.t.c
r.t.c
48
2
70
83
4g
4h
4i
3g
3h
3i
PhI(OAc)2
PhI(OAc)2
1:2.5
1:2
CH2Cl2
CH2Cl2
r.t.c
48
48
73
77
153.2–154.24
152.5–154.54
138–140
r.t.c
PhI(OAc)2
Pb(OAc)4
1:2
1:1.7
CH2Cl2
THF
r.t.c
r.t.c
24
24
66
93
4j
3j
PhI(OAc)2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
NH2NH2
1:2
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
r.t.c
reflux
reflux
reflux
r.t.
48
2
62
89
81
87
72
72
78
92
85
82
93
174–175.84
250.3–251.3
287–289
5a
5b
5c
5d
5e
5f
4a
4b
4c
4d
4e
4f
2
2
282.4–284.2
227.4–228.8
187 (dec.)
227.4
2
r.t.
24
24
24
24
24
24
r.t.
5g
5h
5i
4g
4h
4i
r.t.
261.9–263.9
257.5–259
221–223
r.t.
r.t.
5j
4j
r.t.
279.4–280.4
a Substrate/substrate or substrate/reagent.
b Mps are uncorrected. Compounds 4a–k were recrystallized (EtOH).
c The addition of the oxidant took place in an ice bath.
Synthesis 2009, No. 5, 836–840 © Thieme Stuttgart · New York

838
A. Kotali et al.
PAPER
PhI(OAc)2
– AcOH
O
O
OH
– PhI
O
O
OH
Me
NNCOR
O
O
OH
O
O
COR
NCOR
N
Me
I
COMe
OAc
AcO
Ph
Me
NNHCOR
7
3
6
4
Scheme 2 Mechanism for the formation of 7,8-diacylcoumarins
Concerning the mechanism of the transformation, a rea-
sonable pathway could begin with the formation of inter-
mediate 6, followed by reductive elimination of
iodobenzene and addition of the acetate group to the hy-
drazone carbon to produce intermediate 7. Subsequently,
the reaction could follow the same route as that proposed
for the oxidation with lead tetraacetate15 involving forma-
tion of a C–C bond and finally resulting in the transforma-
tion of the phenolic hydroxy group into an acyl group
(Scheme 2).
All solvents for reactions and chromatography were purchased from
Merck whereas, all hydrazides 2 as well as (diacetoxyiodo)benzene
were purchased from Aldrich. Compound 1,12 3a,16 3b,4 3c,4 3e,4
3g,4 3h,4 and 3j4 were prepared according to literature procedures.
TLC plates: Merck plastic plates with silica gel 60 F254 (70–230
mesh). Column chromatography: silica gel 60 F254 (70–230 mesh).
The NMR spectra were recorded on a Bruker Avance 400 spectrom-
eter (1H, 400.15 MHz; 13C, 100.62 MHz) in DMSO using the signal
of the solvent as the internal standard (residual DMSO for 1H: d =
2.50, 13C d = 39.5). Either elemental analysis or HRMS have been
provided for all new compounds 3d, 3f, 3i, 4a, 4d, 4f, 4i, and 5a–j.
With a series of 7,8-diacylcoumarins 4 in hand, we next
performed their reaction with hydrazine to obtain the cor-
responding pyridazinocoumarins 5 in high yields, 72–
93% (Table 2). The reactants were added in a molar ratio
1:1 and dissolved in ethanol. All the reactions were initial-
ly performed at room temperature with stirring and then,
if required, under reflux to obtain the optimum yields. The
reaction conditions, the yields of formation of the new
compounds 5, as well as their melting points are presented
in Table 2. The desired pyridazinocoumarins 5 were iso-
lated by filtration and were identified by their spectral
data and by either exact mass measurement or elemental
analysis. Pyridazinocoumarins 5 show prominent peaks
corresponding to the ions [M + 1] in their mass spectra.
The carbonyl carbon of lactone appeared at d = 158.3 to
159.6 in the 13C NMR spectra, whereas the peaks appear-
ing at d = 151.2 to 158.0 were assigned to methine carbons
in the pyridazine ring and the peaks at d = 24.6 to 25.8 to
the methyl carbon.
8-[1-(Acylhydrazono)ethyl]-7-hydroxy-2H-1-benzopyran-2-
ones 3; General Procedure
8-Acetyl-7-hydroxycoumarin 1 (5 mmol) and the corresponding hy-
drazide 2 (molar ratio 1:1) were refluxed in PrOH (20 mL) for 24 h.
The mixture was allowed to cool and the precipitate was filtered and
subsequently dried to afford the pure hydrazones 3 as white solids
in very good yields (Table 2).
7-Hydroxy-8-{1-[(2-hydroxybenzoyl)hydrazono]ethyl}-2H-1-
benzopyran-2-one (3d)
Isomeric mixture.
1H NMR (400 MHz, DMSO-d6): d = 2.27 (s, 3 H), 2.49 (s, 3 H), 6.27
(d, J = 9.4 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.88–7.07 (m, 5 H),
7.43–7.47 (m, 2 H), 7.59–7.61 (d, J = 8.5 Hz, 1 H), 7.69 (d, J = 8.5
Hz, 1 H), 7.94–8.04 (m, 5 H), 10.68 (s, 1 H), 10.85 (s, 1 H), 11.10
(s, 1 H), 11.58 (s, 1 H), 11.68 (s, 1 H), 11.97 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.5, 24.3, 104.0, 110.0,
111.4, 111.9, 112.4, 113.4, 113.6, 114.0, 114.5, 115.5, 115.65,
117.4, 117.5, 120.2, 124.1, 125.0, 130.4, 130.6, 130.9, 131.1, 145.4,
145.6, 153.0, 153.9, 154.2, 157.1, 158.1, 160.2, 160.4, 160.6, 160.8,
161.0, 161.5, 164.8.
MS (ES+): m/z = 361 (M+ + Na), 339 (M+ + H), 217, 202.
(Diacetoxyiodo)benzene has been shown to be an interest-
ing, alternative oxidative agent to lead tetraacetate in the
transformation of a hydroxy group into an acyl group in
the coumarin substrate. A wide variety of angular 7,8-di-
acylcoumarins can be obtained from inexpensive and eas-
ily prepared starting materials in high yields under mild
conditions. The reagent for the transformation,
(diacetoxyiodo)benzene, is nontoxic, not hazardous, inex-
pensive, and readily available. On the other hand, angular
7,8-pyridazinocoumarins have been synthesized in very
good yields via a convenient and general method. Both
7,8-diacylcoumarins as well as 7,8-pyridazinocoumarins
could be potentially show interesting biological activity
and could also be used for the synthesis of new heterocy-
cles.
Anal. Calcd for C18H14N2O5: C, 63.90; H, 4.17; N, 8.28. Found: C,
63.85; H, 3.90; N, 8.14.
8-{1-[2-Furylcarbonyl)hydrazono]ethyl}-7-hydroxy-2H-1-ben-
zopyran-2-one (3f)
1H NMR (400 MHz, DMSO-d6): d = 2.33 (s, 3 H), 6.30 (d, J = 9.4
Hz, 1 H), 6.66–6.98 (m, 2 H), 7.43–7.99 (m, 3 H), 8.03 (d, J = 9.4
Hz, 1 H), 11.03 (s, 1 H), 12.0 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 23.6, 111.4, 111.8, 112.0,
112.9, 113.6, 129.9, 130.6, 144.6, 145.0, 145.8, 146.2, 152.2, 153.1,
157.4, 159.9.
MS (ES+): m/z = 335 (M+ + Na), 313 (M+ + H), 202.
Anal. Calcd for C16H12N2O5: C, 61.54; H, 3.87; N, 8.97. Found: C,
61.69; H, 3.89; N, 9.00.
In conclusion, we have presented a convenient and gener-
al method for the ready preparation of angular 7,8-diacyl-
coumarins and pyridazinocoumarins in high yields.
7-Hydroxy-8-{1-[(phenylacetyl)hydrazono]ethyl}-2H-1-ben-
zopyran-2-one (3i)
Isomeric mixture.
Synthesis 2009, No. 5, 836–840 © Thieme Stuttgart · New York

PAPER
Synthesis of Angular 7,8-Pyridazinocoumarins
839
1H NMR (400 MHz, DMSO-d6): d = 2.17 (s, 3 H), 2.47 (s, 3 H), 3.69
(s, 2 H), 3.93 (s, 2 H), 6.20 (d, J = 9.6 Hz, 1 H), 6.23 (d, J = 9.6 Hz,
1 H), 6.85–6.89 (m, 2 H), 7.09–7.11 (m, 2 H), 7.20–7.24 (m, 4 H),
7.26–7.32 (m, 4 H), 7.50–7.59 (m, 2 H), 7.91–7.96 (m, 2 H), 9.69
(s, 1 H), 10.64 (s, 1 H), 11.00 (s, 1 H), 12.00 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 24.1, 24.3, 41.15, 41.4, 109.9,
111.9, 112.3, 112.6, 113.5, 113.7, 114.4, 126.9, 127.0, 128.8, 129.0,
129.5, 129.9, 130.2, 130.5, 130.9, 131.0, 136.4, 144.0, 145.2, 145.5,
147.0, 152.5, 153.0, 158.3, 158.4, 160.5, 160.8, 167.0, 172.6.
13C NMR (100 MHz, DMSO-d6): d = 26.6, 46.3, 99.8, 109.7, 116.7,
119.9, 126.7, 128.9, 130.4, 131.0, 136.3, 144.9, 151.8, 159.3, 160.0,
198.8, 200.9.
MS (ES+): m/z = 329 (M+ + Na), 307 (M+ + H).
Anal. Calcd for C19H14O4: C, 74.50; H, 4.61. Found: C, 74.00; H,
4.58.
7-Acyl-10-methyl-2H-pyrano[2,3-f]phthalazin-2-ones 5;
General Procedure
Hydrazine hydrate (1 mmol) was added to the corresponding diacyl-
coumarin 4 (molar ratio 1:1). The reaction temperature and time are
presented in Table 2. The precipitate which was formed was fil-
tered, washed with Et2O (3 mL), and dried in vacuo to afford py-
ridazinocoumarins 5 as pale yellow solids in high yield (Table 2).
MS (ES+): m/z = 337 (M+ + H), 219, 202.
Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C,
67.69; H, 4.80; N, 8.29.
8-Acetyl-7-acyl-2H-1-benzopyran-2-ones 4; General Procedure
with (Diacetoxyiodo)benzene
10-Methyl-7-phenyl-2H-pyrano[2,3-f]phthalazin-2-one (5a)
1H NMR (400 MHz, DMSO-d6): d = 3.27 (s, 3 H), 6.83 (d, J = 9.6
Hz, 1 H), 7.62–7.64 (m, 3 H), 7.68–7.69 (m, 2 H), 7.80 (d, J = 8.6
Hz, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 8.32 (d, J = 9.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 25.0, 116.0, 118.1, 120.1,
121.7, 126.0, 128.6, 129.3, 129.8, 131.9, 135.9, 144.2, 150.5, 154.2,
158.0, 158.8.
PhI(OAc)2 was added to hydrazone 3 (1 mmol) in CH2Cl2 (20 mL)
with stirring in an ice bath; molar ratio [hydrazone 3/PhI(OAc)2]
and the reaction time are presented in Table 2. The mixture was then
stirred at r.t. The oily product obtained after removal of the solvent
was subjected to column chromatography (silica gel 70–230 mesh,
petroleum ether–EtOAc, 1:1) to afford pure 4 as white solids in very
good yields (Table 2).
MS (ES+): m/z = 334 (M+ + 2 Na), 289 (M+).
8-Acetyl-7-benzoyl-2H-1-benzopyran-2-one (4a)
1H NMR (400 MHz, CDCl3): d = 2.75 (s, 3 H), 6.54 (d, J = 9.7 Hz,
1 H), 7.36 (d, J = 7.8 Hz, 1 H), 7.43–7.49 (m, 2 H), 7.58–7.64 (m, 2
H), 7.75–7.81 (m, 3 H).
Anal. Calcd for C18H12N2O2: C, 74.99; H, 4.20; N, 9.72. Found: C,
74.77; H, 4.21; N, 9.76.
10-Methyl-7-(4-tolyl)-2H-pyrano[2,3-f]phthalazin-2-one (5b)
1H NMR (400 MHz, DMSO-d6): d = 2.46 (s, 3 H), 3.27 (s, 3 H), 6.83
(d, J = 9.6 Hz, 1 H), 7.44 (dd, J = 7.8 Hz, 2 H), 7.58 (dd, J = 7.8 Hz,
2 H), 7.82 (d, J = 8.3 Hz, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 8.32 (d,
J = 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 32.4, 118.6, 120.9, 125.1, 128.8,
129.3, 130.1, 133.8, 136.6, 137.9, 141.9, 142.9, 151.3, 159.0, 195.7,
200.0.
MS (ES+): m/z = 293 (M+).
Anal. Calcd for C18H12O4: C, 73.97; H, 4.14. Found: C, 73.77; H,
4.09.
13C NMR (100 MHz, DMSO-d6): d = 20.9, 25.0, 118.0, 120.1,
121.7, 123.0, 129.1, 129.8, 131.8, 134.6, 135.8, 141.0, 142.0, 151.8,
153.0, 154.7, 158.9.
8-Acetyl-7-(2-hydroxybenzoyl)-2H-1-benzopyran-2-one (4d)
1H NMR (400 MHz, CDCl3): d = 2.77 (s, 3 H), 6.54 (d, J = 9.7 Hz,
1 H), 6.80 (d, J = 7.9 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.24–7.31
(m, 2 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.80
(d, J = 9.7 Hz, 1 H), 11.59 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 32.2, 118.4, 118.5, 119.1, 119.3,
120.6, 124.3, 125.2, 128.3, 132.7, 137.8, 141.2, 142.7, 151.5, 158.6,
163.0, 199.0, 200.7.
HRMS (ESI+): m/z [M+] calcd for C19H14N2O2: 303.112804; found:
303.112457.
7-(4-Hydroxyphenyl)-10-methyl-2H-pyrano[2,3-f]phthalazin-
2-one (5c)
1H NMR (400 MHz, DMSO-d6): d = 3.32 (s, 3 H), 6.64 (d, J = 9.4
Hz, 1 H), 6.89–7.03 (m, 2 H), 7.30–7.46 (m, 2 H), 7.64 (d, J = 8.4
Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 9.4 Hz, 1 H), 10.10
(s, 1 H).
MS (ES+): m/z = 331 (M+ + Na), 308 (M+), 291, 215.
13C NMR (100 MHz, DMSO-d6): d = 24.6, 115.8, 115.9, 117.7,
119.0, 119.8, 121.9, 123.0, 127.2, 130.6, 130.7, 131.1, 143.4, 150.5,
154.6, 154.9, 157.3, 158.3.
Anal. Calcd for C18H12O5: C, 70.13; H, 3.92. Found: C, 70.28; H,
3.90.
8-Acetyl-7-(2-furylcarbonyl)-2H-1-benzopyran-2-one (4f)
1H NMR (400 MHz, CDCl3): d = 2.73 (s, 3 H), 6.49 (d, J = 9.5 Hz,
1 H), 6.57 (d, J = 3.5 Hz, 1 H), 7.17 (d, J = 3.7 Hz, 1 H), 7.60–7.63
(m, 3 H), 7.76 (d, J = 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 32.1, 112.9, 118.7, 120.8, 121.3,
124.9, 129.1, 131.3, 140.0, 142.5, 147.7, 151.0, 152.2, 158.6, 181.6,
199.7.
HRMS (ESI+): m/z [M+] calcd for C18H12N2O3: 305.09207; found:
305.09196.
7-(2-Hydroxyphenyl)-10-methyl-2H-pyrano[2,3-f]phthalazin-
2-one (5d)
1H NMR (400 MHz, DMSO-d6): d = 3.17 (s, 3 H), 6.69 (d, J = 9.3
Hz, 1 H), 6.98–7.02 (m, 2 H), 7.30–7.45 (m, 3 H), 8.04 (d, J = 8.2
Hz, 1 H), 8.16 (d, J = 9.4 Hz, 1 H), 9.80 (s, 1 H).
MS (ES+): m/z = 305 (M+ + Na), 265, 215.
13C NMR (100 MHz, DMSO-d6): d = 25.6, 116.1, 116.5, 118.5,
119.4, 120.6, 123.6, 124.1, 127.5, 131.4, 131.7, 131.9, 144.9, 151.1,
154.8, 155.8, 157.8, 159.6.
Anal. Calcd for C16H10O5: C, 68.09; H, 3.57. Found: C, 68.15; H,
3.54.
MS (ES+): m/z = 327 (M+ + Na), 305 (M+).
8-Acetyl-7-(phenylacetyl)-2H-1-benzopyran-2-one (4i)
1H NMR (400 MHz, DMSO-d6): d = 2.44 (s, 3 H), 4.39 (s, 2 H), 6.49
(d, J = 9.5 Hz, 1 H), 7.14–7.17 (m, 1 H), 7.31–7.35 (m, 2 H), 7.66–
7.76 (m, 4 H), 8.08 (d, J = 9.5 Hz, 1 H).
Anal. Calcd for C18H12N2O3: C, 71.05; H, 3.97; N, 9.21; found: C,
70.88; H, 3.90; N, 9.08.
Synthesis 2009, No. 5, 836–840 © Thieme Stuttgart · New York

840
A. Kotali et al.
PAPER
10-Methyl-7-(2-nitrophenyl)-2H-pyrano[2,3-f]phthalazin-2-
one (5e)
7,10-Dimethyl-2H-pyrano[2,3-f]phthalazin-2-one (5j)
1H NMR (400 MHz, DMSO-d6): d = 2.93 (s, 3 H), 3.17 (s, 3 H), 6.80
(d, J = 9.6 Hz, 1 H), 8.10 (d, J = 8.6 Hz, 1 H), 8.26 (d, J = 8.6 Hz, 1
H), 8.32 (d, J = 9.6 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 3.26 (s, 3 H), 6.57 (d, J = 9.5
Hz, 1 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.68–7.94 (m, 4 H), 7.99 (d,
J = 8.7 Hz, 1 H), 8.09 (d, J = 9.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 19.9, 24.9, 117.8, 120.0,
120.7, 132.2, 131.6, 135.7, 145.0, 150.0, 154.3, 155.9, 157.8.
MS (ES+): m/z = 227 (M+).
13C NMR (100 MHz, DMSO-d6): d = 25.6, 116.3, 118.85, 121.1,
121.4, 125.7, 127.0, 131.5, 131.6, 133.0, 133.1, 134.7, 144.7, 139.5,
149.1, 155.7, 156.9, 159.3.
HRMS (ESI+): m/z [M+] calcd for C18H11N3O4: 334.08223; found:
334.08218.
Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C,
68.62; H, 4.45; N, 12.28.
7-(2-Furyl)-10-methyl-2H-pyrano[2,3-f]phthalazin-2-one (5f)
1H NMR (400 MHz, DMSO-d6): d = 3.23 (s, 3 H), 6.81–6.85 (m, 2
H), 7.37–7.38 (m, 1 H), 8.12–8.32 (m, 3 H), 8.45 (d, J = 8.6 Hz, 1
H).
Acknowledgment
The authors thank the Royal Society of Chemistry for financial sup-
port of this work.
13C NMR (100 MHz, DMSO-d6): d = 25.8, 112.7, 114.3, 116.8,
118.8, 120.9, 121.5, 125.1, 132.8, 144.7, 146.4, 148.4, 151.0, 151.2,
154.7, 159.4.
References
(1) Weinmann, I. Coumarins: Biology, Applications and Modes
of Actions; O’Kennedy, R.; Thornes, R. D., Eds.; John
Wiley: Chichester, 1997, 1–22.
(2) (a) Curini, M.; Epifano, F.; Maltese, F.; Marcotullio, M. C.;
Tubato, A.; Altinier, G.; Gonzales, S. P.; Rodriguez, J. C.
Bioorg. Med. Chem. Lett. 2004, 14, 2241.
(b) Kontogiorgos, C. A.; Hadjipavlou-Litina, D. J. J. Med.
Chem. 2005, 48, 6400.
(3) (a) Kostova, I. Curr. Med. Chem.: Anticancer Agents 2006,
5, 29. (b) Raad, I.; Terreux, R.; Richomme, P.; Matera,
E.-L.; Dumontet, C.; Raynaud, J.; Guilet, D. Bioorg. Med.
Chem. 2006, 14, 6979.
MS (ES+): m/z = 301 (M+ + Na), 279 (M+).
Anal. Calcd for C16H10N2O3: C, 69.06; H, 3.62; N, 10.07; found: C,
68.96; H, 3.55; N, 10.03.
10-Methyl-7-(2-thienyl)-2H-pyrano[2,3-f]phthalazin-2-one (5g)
1H NMR (400 MHz, DMSO-d6): d = 3.28 (s, 3 H), 6.88 (d, J = 9.6
Hz, 1 H), 7.39 (q, J = 4.3 Hz, 1 H), 7.84–7.94 (m, 2 H), 8.30–8.40
(m, 3 H).
HRMS (ESI+): m/z [M+] calcd for C16H10N2O2S: 295.05357; found:
295.05323.
(4) Kotali, A.; Lafazanis, I. S.; Harris, P. A. Tetrahedron Lett.
10-Methyl-7-(4-pyridyl)-2H-pyrano[2,3-f]phthalazin-2-one
(5h)
2007, 48, 7181.
(5) Bourguignon, J. J.; Oumouch, S.; Schmitt, M. Curr. Org.
Chem. 2006, 277.
(6) Allen, G. R. Jr.; Hanifin, J. W. Jr.; Moran, D. B.; Albright, J.
D. US 4230705, 1980.
(7) Refaat, H. M.; Khalil, O. M.; Kardy, H. H. Arch. Pharmacal.
Res. 2007, 30, 803.
(8) Babu, R. A.; Narasu, M. L.; Srinivas, K. ARKIVOC 2007,
(ii), 247.
(9) Pogacic, V.; Bullock, A. N.; Filippakopoulos, P.; Gasser, C.;
Biondi, A.; Meyer-Monard, S.; Knapp, S.; Schwaller, J.
Cancer Res. 2007, 67, 6916.
1H NMR (400 MHz, DMSO-d6): d = 3.27 (s, 3 H), 6.85 (d, J = 9.6
Hz, 1 H), 7.72 (dd, J = 5.8 Hz, 2 H), 7.79 (d, J = 8.6 Hz, 1 H), 8.23
(d, J = 8.6 Hz, 1 H), 8.34 (d, J = 9.6 Hz, 1 H), 8.85 (dd, J = 5.8 Hz,
2 H).
13C NMR (100 MHz, DMSO-d6): d = 25.1, 115.95, 118.25, 120.4,
121.2, 124.5, 125.6, 132.3, 143.5, 144.15, 150.0, 150.6, 155.15,
156.2, 158.7.
HRMS (ESI+): m/z [M+] calcd for C17H11N3O2: 290.092403; found:
290.092148.
(10) Suortti, T.; von Wright, A. J. Chromatogr. 1983, 255, 529.
(11) Sardari, S.; Mori, Y.; Horita, K.; Micetich, R. G.; Sansei, N.;
Daneshtalab, M. Bioorg. Med. Chem. 1999, 7, 1933.
(12) Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529.
(13) Kotali, A.; Harris, P. A. Org. Prep. Proced. Int. 2003, 35,
603.
(14) Criege, R. In Oxidation in Organic Chemistry; Wiberg, K.,
Ed.; Academic: New York, 1965, 365.
(15) Katritzky, A. R.; Harris, P. A.; Kotali, A. J. Org. Chem.
7-Benzyl-10-methyl-2H-pyrano[2,3-f]phthalazin-2-one (5i)
1H NMR (400 MHz, DMSO-d6): d = 3.17 (s, 3 H), 4.70 (s, 2 H), 6.76
(d, J = 9.6 Hz, 1 H), 7.18 (d, J = 7.0 Hz, 1 H), 7.24–7.32 (m, 4 H),
8.10 (d, J = 8.6 Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 8.22 (d, J = 9.6
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 24.95, 38.7, 115.9, 117.85,
120.0, 120.7, 126.2, 126.4, 128.5, 131.7, 136.0, 138.5, 144.1, 150.7,
154.15, 157.3, 158.8.
HRMS (ESI+): m/z [M+] calcd for C19H14N2O2: 303.112541; found:
303.112804.
1991, 56, 5049.
(16) Kotali, A.; Lafazanis, I. S.; Papageorgiou, A.; Chrysogelou,
E.; Lialiaris, T.; Sinakos, Z. Molbank 2008, M574; http://
www.mdpi.net/molbank.
Synthesis 2009, No. 5, 836–840 © Thieme Stuttgart · New York