Transformation of a hydroxyl into an acyl group on α-pyrone ring: A novel route to 3,4-diacylcoumarins

Article abstract of DOI:10.1016/j.tet.2011.10.086

The transformation of a hydroxyl into an acyl group, a transformation which has been extensively investigated on the benzene nucleus of several substrates, is now applied successfully for the first time to a heterocyclic ring and specifically to the pyron

Full text of DOI:10.1016/j.tet.2011.10.086

Tetrahedron 68 (2012) 761e766
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transformation of a hydroxyl into an acyl group on
to 3,4-diacylcoumarins
a-pyrone ring: a novel route
,
a
b
c
c
Antigoni Kotali a , Despina A. Nasiopoulou , Philip A. Harris , Madeleine Helliwell , John A. Joule
*
a Laboratory of Organic Chemistry, Department of Chemical Engineering, University of Thessaloniki, 54124, Greece
b GlaxoSmithKline, 1250 South Collegeville Road, P.O. Box 5089, Collegeville, PA 19426-0989, USA
c The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2011
Received in revised form 7 October 2011
Accepted 24 October 2011
Available online 4 November 2011
The transformation of a hydroxyl into an acyl group, a transformation which has been extensively in-
vestigated on the benzene nucleus of several substrates, is now applied successfully for the first time to
a heterocyclic ring and specifically to the pyrone ring of coumarin to yield novel 3,4-diacylcoumarins in
good yields. The reaction involves formation of a new CeC bond.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Diacylcoumarins
Acylhydrazones
4-Hydroxycoumarin
Lead tetraacetate
Diacetoxyiodoso benzene
CeC bond formation
1. Introduction
anticoagulant drug is metabolized from coumarin in sweet clover
by mold.10 It has been also found that antimutagenicity of couma-
Coumarins, a class of fused ring heterocycles, also known as
chromen-2-ones or benzopyran-2-ones, occur widely in nature and
show interesting biological activity.1 Coumarins are found in sev-
eral plants, including grasses, orchids, citrus fruits, and legumes
and are involved in the actions of plant growth hormones and
growth regulators, the control of respiration, photosynthesis as
well as defense against infection.1,2 In addition, these compounds
exhibit a variety of pharmacological properties.2e4 Coumarins vary
in structure due to the various types of substituents on their basic
structure, which can influence their biological activity.5
Among the substituted coumarins, 3,4-disubstituted coumarins
constitute an interesting class of derivatives with important phar-
maceutical properties. Coumestans, which occur naturally in alfalfa
and ladino clover are typical examples among the natural 3,4-
substituted coumarin derivatives with estrogenic activity.6 Novo-
biocin and clorobiocin are coumarin antibiotics of natural origin,
which are inhibitors of DNA gyrase, and have a broad spectrum of
activity toward Gram-positive bacteria, including methicilin-
resistant strains of Staphylococci species.7e9 Dicoumarol, a natural
rins is linked to the presence of polar functions at the 3-, 4-, and 7-
positions.11,12 Thus, it is understandable why development of new
synthetic methods for coumarins and study of their biological
properties are topics of growing interest for a great number of re-
search groups. For example several coumarins bearing various
groups on the pyrone ring at the 3- and 4-positions were synthe-
sized and tested and many new syntheses of 3,4-disubstituted
coumarins appeared recently in the literature.13e19 Gilvocarcins
(Fig. 1) are interesting natural 3,4-disubstituted coumarin de-
rivatives with antibiotic activity synthesized recently by Snieckus
et al.20 The synthetic compound warfarin (Fig. 1) has been widely
used as an oral anticoagulant.15,19,21,22 Phenprocoumon has been
found to possess antiviral activity and it significantly inhibits the
HIV-1 protease.6
MeO OH
OH Ph O
OH Et
MeO
Me
O
O
O
O
R
O
O
gilvocarcins
warfarin
phenprocoumon
* Corresponding author. Tel.: þ30 230996253; fax: þ30 2310996253; e-mail
address: kotali@eng.auth.gr (A. Kotali).
Fig. 1. 3,4-Disubstituted coumarins with biological activity.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.086

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A. Kotali et al. / Tetrahedron 68 (2012) 761e766
Recently, we synthesized23e25 6,7- and 7,8-diacylcoumarins in
our laboratory and here we extend that work and describe the
synthesis of novel 3,4-diacylcoumarins 4 (Scheme 1).
3-Acetyl-4-hydroxycoumarin N-acylhydrazones 4 were syn-
thesized via treatment of 3-acetyl-4-hydroxycoumarin 2 with the
appropriate hydrazide 3 in propanol, as depicted in Scheme 1. The
molar ratio of the reactants was 1/1 and the reaction was per-
formed under reflux either for 24 h to yield hydrazones 4aei in very
good yields (70e98%) or for 2 h to lead to the formation of hydra-
zones 4aei in slightly lower yield (60e81%). Hydrazones 4 were
subsequently treated with lead tetraacetate (LTA) in THF at rt to
give the desired products 5 in good yields, 49e70%. Alternatively,
3,4-diacylcoumarins 5 were obtained via (diacetoxyiodo)benzene
(DIB) treatment of 3-acetyl-4-hydroxycoumarin N-acylhydrazones
4 (Scheme 1). DIB is known to exhibit reactivity analogous to that of
LTA and is less hazardous and toxic than lead(IV) compounds.30
Reaction of hydrazones 4aei with DIB in dichloromethane at rt
afforded the corresponding 3,4-diacylcoumarins 5 in yields of
62e90%, which are slightly lower than those of comparable prod-
ucts obtained using LTA oxidation. The reaction conditions, the
yields of formation of the new compounds 4 and 5 as well as their
melting points are presented in Table 1.
OH
OH Me
O
O
O
O
O
1
2
RCONHNH2 (3)
PrOH
Me
OH
87-98%
NNHCOR
O
O
R
4
a
b
c
d
e
f
CH3
Ph
Pb(OAc)4
THF
4-H3CC6H4
4-O2NC6H4
4-ClC6H4
2-HOC6H4
2-O2NC6H4
2-furyl
O
R
Me
Hydrazones 4aei were purified via recrystallization from
propanol, whereas the desired 3,4-diacylcoumarins 5 were isolated
by column chromatography. Products 4bei and 5aei are new
compounds and their structures were identified by their 1H, 13C
NMR and mass spectra as well as by either their elemental analysis
or high resolution exact mass measurement.
49-80%
or
O
g
h
i
O
O
PhI(OAc)2
CH2Cl2
2-thienyl
5
40-65%
In their 1H NMR spectra, hydrazones 4 showed a characteristic
singlet at about 2.65e2.77 ppm, which is assigned to the methyl
protons attached at the 3-C]N carbon. The proton at C-5 of the
coumarin appeared mainly as doublet of doublets at about
7.95e8.02 ppm, whereas the signals for the protons at C-6 and C-7
were ddds at about 7.32e7.34 and 7.66e7.69 ppm, respectively, and
the proton at C-8 appeared at about 7.31 ppm. Finally, the amide
protons give a singlet at 11.30e12.18 ppm, and the hydroxy protons
appeared as broad peaks at 15.50e15.95 ppm. All the above data
are in accordance with the literature data for other 3-substituted-4-
hydroxycoumarin derivatives.31e33 It should be noted that the ddd
peaks for the protons at C-6 and C-7 have also been referred to as
‘pseudotriplet’ (pst) in the literature.32
Scheme 1. Synthesis of 3,4-diacylcoumarins 5.
2. Results and discussion
We have reviewed the synthesis of aromatic 1,2-diacyl com-
pounds by the transformation of the phenolic hydroxy group of an
ortho-hydroxyaryl ketone into an acyl group.26 This transformation
has been applied26 to a variety of aromatic substrates and it has
proved valuable for the synthesis of interesting heterocycles.27,28 In
the present context, we chose to synthesize a series of functionally
diverse 3-acetyl-4-acyl coumarins. Following our earlier work, 3-
acetyl-4-hydroxycoumarin N-acylhydrazones were the desired
precursors, which would then be treated with lead tetraacetate
(LTA) in order to apply the transformation of hydroxy into an acyl
group, this time on the pyrone ring of coumarin (Scheme 1). The
starting ketone 2 was prepared according to the literature29 by
direct acetylation of 4-hydroxycoumarin 1 with acetic anhydride.
In the 13C NMR spectra of compounds 4, characteristic peaks
appeared at 17.3e18.1 ppm, assigned to methyl carbon attached at
the 3-C]N carbon. The signals at the highest
d values at
178.7e179.7 were assigned to C-4, whereas those at 169.2 to 170.5
and 161.4e167.0 ppm were assigned to the amide carbon ]NHCOe
Table 1
4-Hydroxy-3-acetyl N-acylhydrazones 4aei and 3,4-diacylcoumarins 5aei produced via Scheme 1
Compound
R
Reagents method A (method B)
Ratio of reactants
1/1
React. time (h)
24 (2)
Solvent
PrOH
React. temp
Yield %
Mp (ꢀC)
248e249
4a
CH3
2þ3a
Reflux
87 (81)
lit. 8635
95 (91)
87 (79)
98 (93)
98 (91)
97 (95)
91 (89)
89 (86)
94 (94)
49 (45)
60 (45)
53 (65)
60 (40)
66 (45)
63 (48)
60 (49)
68 (63)
60 (45)
250e251a, 35
225e226
250e251
264e265
248e248.5
271e272
219
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
2þ3b
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1.5 (1/1.5)
1/1.5 (1/1.5)
1/1.5 (1/1.5)
1/1.5 (1/1.5)
1/1.6 (1/1.5)
1/1.1 (1/1.5)
1/1.5 (1/2)
1/1.5 (1/1.5)
1/2 (1/1.5)
24 (2)
24 (2)
24 (2)
24 (2)
24 (2)
24 (2)
24 (2)
24 (2)
2 (2)
2 (1.5)
24 (2)
2 (2)
24 (2)
24 (2)
24 (2)
24 (2)
0.5 (1)
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
THF (CH2Cl2)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
rt
rt
rt
rt
4-H3CC6H4
4-O2NC6H4
4-ClC6H4
2-HOC6H4
2-O2NC6H4
2-Furyl
2-Thienyl
CH3
Ph
4-H3CC6H4
4-O2NC6H4
4-ClC6H4
2-HOC6H4
2-O2NC6H4
2-Furyl
2þ3c
2þ3d
2þ3e
2þ3f
2þ3g
2þ3h
254.5e255
228e228.5
137e138
182e183
199e200
234e236
239e240
177e179
206e208
200e201
158e159
2þ3i
4aþLTA (4aþDIP)
4bþLTA (4bþDIP)
4cþLTA (4cþDIP)
4dþLTA (4dþDIP)
4eþLTA (4eþDIP)
4fþLTA (4fþDIP)
4gþLTA (4gþDIP)
4hþLTA (4hþDIP)
4iþLTA (4iþDIP)
rt
rt
rt
rt
2-Thienyl
a
Recrystallized from MeOCH2CH2OH/H2O.

A. Kotali et al. / Tetrahedron 68 (2012) 761e766
763
and the hydrazono 3-C]N carbon, respectively. Furthermore,
hydrazones 4 showed prominent ions corresponding to [MþNa] in
their mass spectra.
Based on the above data, we concluded that compounds 4 exist
in the hydroxy tautomeric form A (Fig. 2), stabilized by hydrogen
bonding, as shown, and this is also in accordance with relevant
literature data.30 Interestingly, X-ray analysis of 4i has shown that
the pyran ring adopts a 2,4-dione tautomeric form in the solid state
(Fig. 2, structure B).
S
O
H
4
O
NNHCOR
Me
H
N
5
O
O
N
H
6
7
3
Me
O
O
2
8
O
A
B
Fig. 2. Tautomeric forms of 3-acetyl-4-hydroxycoumarin hydrazones 4.
The benzopyran ring system is almost coplanar with the thio-
phene ring [dihedral angle 0.9 (2)ꢀ]. The exocyclic C]C double
bond has an E geometry.
The molecular conformation is stabilized by an intramolecular
NeH/O hydrogen bond.34
3,4-Diacylcoumarins 5 display in their 1H NMR spectra a singlet
at about 2.52e2.61 ppm for the methyl protons attached at the 3-
C]O carbon; the proton at C-5 of the coumarin appeared as
a doublet of doublets at about 7.51e7.62 ppm. The protons at C-6
and C-7 both gave characteristic ddd peaks at about 7.30e7.44 and
7.67 to 7.62 ppm, respectively; the proton at C-8 appeared at
7.16e7.59 ppm. The resonances of the methyl protons in diac-
ylcoumarins 5 were at higher field values than the relevant methyl
protons in hydrazones 4 due to the relative anisotropy of carbonyl
C]O and hydrazonic C]N bonds, respectively.
In 13C NMR characteristic resonances appeared at
30.4e31.0 ppm and can be assigned to methyl carbon attached at
the 3-C]N carbon, whereas the signals that were obtained at the
lowest field values at 179.3e201.2 ppm are assigned to the carbonyl
carbons. Finally, 3,4-diacylcoumarins 5 showed prominent ions
corresponding to [Mþ1] in their mass spectra.
Fig. 3. Chem3D representations of compound 5f.
pyrone ring in coumarin derivatives, giving the ability for the
synthesis of 3,4-diacyl substituted coumarin derivatives. The
presence of two acyl groups at neighboring positions is often de-
sirable in alicyclic or heterocyclic derivatives. It is significant that
there are no other general methods for the preparation of such
derivatives.20 The above transformation which has been already
proved to be the most appropriate way for the synthesis of ortho-
diacyl substituted aromatic derivatives has now been extended to
the synthesis of ortho-diacyl substituted heterocycles. The sim-
plicity of the method as well as the low cost of the reagents and the
good yields add to the synthetic value of the transformation. 3,4-
Diacylcoumarins 5 could serve as very useful intermediates to
new coumarin derivatives with possible pharmaceutical properties.
An X-ray diffraction analysis was carried out on diketone 5f. As
well as confirmingthe overall connectivity, and thus the operation of
the rearrangement process, the three-dimensional structure
showed the planarity of the coumarin moiety and that its 3-acetyl
substituent is fully conjugated with it, there being only a dihedral
angle of 10ꢀ between the coumarin C3eC4 bond and the acetyl C]O
bond. In the 2-hydroxybenzoyl subunit, the phenolic hydroxyl hy-
drogen is hydrogen bonded to the aromatic carbonyl oxygen making
this a second essentially planar moiety. However this second acyl
unit (the 2-hydroxybenzoyl unit) is totally out of conjugation with
the coumarin unit, as one can see from the dihedral angle between
the C3eC4 and the benzoyl C]O bonds, being 89ꢀ. Chem3D repre-
sentations of compound 5f taken from the atomic coordinates de-
termined by X-ray crystallography are shown in Fig. 3.
Concerning the mechanism of the transformations of hydroxy
into an acyl group as well as of the formation of a new CeC bond,
we assume it to be completely analogous to the mechanism that
has been proposed and discussed in detail for the transformation of
o-hydroxyacetophenone N-benzoylhydrazone into 1-acetyl-2-
benzoylbenzene.36,37
4. Experimental section
4.1. General
All solvents were purchased from Merck or Panreac, whereas all
reagents were purchased from Aldrich. Compound 2 was prepared
according to the literature procedure.29 TLC plates were Merck
plastic plates with silica gel 60 F254 (70e230 mesh). Column
chromatography was performed on silica gel 60 F254
(70e230 mesh). Melting points were recorded by a Fischer Scien-
tific melting point measurement apparatus. 1H (400 MHz) and 13C
3. Conclusion
In conclusion, the transformation of a hydroxy into an acyl
group (2/4/5 in Scheme 1) was successfully applied in the

764
A. Kotali et al. / Tetrahedron 68 (2012) 761e766
(100 MHz) NMR spectra were recorded on a Bruker Avance 400
400 MHz):
d
2.77 (s, 3H), 7.30e7.36 (m, 2H), 7.68 (ddd, J¼7.5 Hz,
instrument and the chemical shifts are reported in
d
(ppm) values
1H), 8.01 (d, J¼7.6 Hz, 1H), 8.19 (d, J¼8.5 Hz, 2H), 8.41 (d, J¼8.3 Hz,
relative to DMSO-d6
(d
¼2.50 and 39.5 ppm for 1H and 13C NMR,
2H), 12.1 (br, 1H), 15.75 (s, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz):
respectively, for DMSO-d6). Coupling constants are reported in
hertz (Hz). MS were measured on a Platform II spectrometer. Either
elemental analysis or high resolution mass measurement was ac-
quired for all new compounds 4bei and 5aei as well as for 4a,
which has been mentioned in the literature but for which there is
no spectral data.34
d 18.1, 95.9, 116.8, 120.1, 124.2, 124.4, 126.2, 130.0, 134.9, 137.7, 150.2,
153.6, 161.9, 163.9, 172.6, 179.7 ppm; MS (ESIþ): m/z 368 (Mþ1).
Anal. Calcd for C18H13N3 O6: C, 58.86; H, 3.57; N, 11.44. Found: C,
58.59; H, 3.39; N, 11.40.
4.2.6. 3-{1-[(2-Hydroxybenzoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4f, Scheme 1). White solid; 1H NMR (DMSO-d6,
4.2. Procedure for the synthesis of 3-[1-(acyl-hydrazono)-
ethyl]-4-hydroxy-2H-1-benzopyran-2-ones (4)
400 MHz)
d
2.74 (s, 3H, 3-CCH3), 6.99 (ddd, J¼7.8, 7.0, 1.0 Hz, 1H, 50-
H), 7.02 (dd, J¼8.0, 1.0 Hz, 1H, 30-H), 7.32 (dd, J¼8.6, 1.0 Hz, 1H, 8-H),
7.35 (ddd, J¼7.8, 7.2, 1.0 Hz, 1H, 6-H), 7.47 (ddd, J¼8.0, 7.0, 1.5 Hz,
1H), 7.68 (ddd, J¼8.5, 7.2, 1.5 Hz, 1H), 7.87 (dd, J¼7.8, 1.5 Hz, 1H),
8.01 (dd, J¼7.8, 1.5 Hz, 1H), 11.55 (br s, 1H), 15.93 (br, 1H); 13C NMR
The appropriate hydrazide (3, 1 mmol) was added to a solution
of 3-acetyl-4-hydroxy-coumarin
2
(1 mmol) in n-propanol
(15e20 mL). The mixture was refluxed for 24 h and cooled to rt. The
resulting precipitate was collected by filtration, dried in vacuum,
and recrystallized from n-propanol to give the 3-[1-(acyl-hydra-
zono)ethyl]-4-hydroxy-coumarins (4aei) as solids in very good
yields. The yields of formation of the new compounds 4 as well as
their melting points are presented in Table 1.
(DMSO-d6, 100 MHz) d 17.5, 95.3, 116.2, 116.3, 117.0, 119.44, 119.51,
123.9, 125.6, 130.0, 134.1, 134.3, 153.1, 157.3, 161.4, 164.2, 170.5,
178.8 ppm. HRMS (ESIþ) calcd for C18H14N2O5 m/z 361.07949
(MþNaþ), 699.16976 (2MþNaþ). Found 361.07939 (MþNaþ),
699.17016 (2MþNaþ).
4.2.7. 3-{1-[(2-Nitrobenzoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
4.2.1. 3-[1-(Acetylhydrazono)ethyl]-4-hydroxy-2H-1-benzopyran-2-
benzopyran-2-one (4g). Yellow solid; 1H NMR (DMSO-d6, 400 MHz)
one (4a). Light yellow solid; 1H NMR (DMSO-d6, 400 MHz)
d
2.07 (s,
d
2.73 (s, 3H), 7.32 (dd, J¼8.6,1.0 Hz,1H), 7.36 (ddd, J¼7.9, 7.4,1.0 Hz,
3H), 2.66 (s, 3H), 7.29 (dd, J¼8.3, 1.0 Hz, 1H), 7.32 (ddd, J¼7.9, 7.3,
1.0 Hz, 1H), 7.66 (ddd, J¼8.3, 7.3, 1.8 Hz), 7.97 (dd, J¼7.9, 1.8 Hz),
11.42 (s, 1H), 15.90 (br s, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz)
1H), 7.69 (ddd, J¼8.6, 7.4, 1.5 Hz, 1H), 7.84 (ddd, J¼8.1, 6.9, 2.1 Hz,
1H), 7.91 (dd, J¼8.0, 2.1 Hz, 1H), 7.94 (ddd, J¼8.0, 6.9, 1.0 Hz, 1H),
8.02 (dd, J¼7.8, 1.5 Hz, 1H), 8.22 (dd, J¼8.1, 1.0 Hz, 1H), 12.18 (br, 1H),
d
17.3, 20.4, 94.9, 116.3, 119.5, 123.8, 125.5, 134.2, 153.0, 161.8, 167.0,
15.95 (br, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz)
d 17.3, 95.5,
169.2, 178.7 ppm. HRMS (ESIþ): m/z [MþH]þ calcd for C13H12N2O4:
116.4, 119.4, 123.9, 124.5, 125.6, 129.2, 129.9, 132.0, 134.2, 134.4,
146.7, 153.1, 161.3, 163.3, 171.4, 178.9 ppm. HRMS (ESIþ) calcd for
C18H13N3O6 m/z 390.06966 (MþNaþ), 757.15009 (2MþNaþ). Found
390.06973 (MþNaþ), 757.15048 (2MþNaþ).
261.08698. Found 261.08688.
4.2.2. 3-[1-(Benzoylhydrazono)ethyl]-4-hydroxy-2H-1-benzopyran-
2-one (4b). White solid; 1H NMR (DMSO-d6, 400 MHz)
d 2.77 (s,
3H), 7.31 (dd, J¼8.6, 1.0 Hz, 1H), 7.35 (ddd, J¼7.8, 7.2, 1.0 Hz, 1H),
7.57e7.61 (m, 2H), 7.66e7.71 (m, 2H), 7.95e7.97 (m, 2H, 20,60-H),
8.01 (dd, J¼7.8, 1.5 Hz, 1H, 5-H), 11.82 (s, 1H, NNH), 15.80 (br s, 1H);
4.2.8. 3-{1-[(2-Furoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4h). Yellow solid; 1H NMR (DMSO-d6, 400 MHz)
d
2.71 (s, 3H), 6.76 (dd, J¼3.5, 1.8 Hz, 1H), 7.31 (dd, J¼8.3, 1.0 Hz, 1H),
13C NMR (DMSO-d6, 100 MHz)
d
17.7, 95.3, 116.4, 119.7, 123.9, 125.7,
7.34 (ddd, J¼7.8, 7.2, 1.0 Hz, 1H), 7.40 (dd, J¼3.5, 1.0 Hz, 1H), 7.68
(ddd, J¼8.3, 7.4, 1.6 Hz, 1H), 8.00 (ddd, J¼7.9, 7.4, 1.6 Hz, 1H), 8.03
(dd, J¼1.8, 1.0 Hz, 1H), 11.80 (br, 1H), 15.50 (br, 1H) ppm. 13C NMR
127.9, 128.7, 131.2, 132.7, 134.4, 153.1, 161.5, 164.9, 172.2 (NHCO),
179.3 (C-4). HRMS (ESIþ) calcd for C18H14N2O2 m/z 345.08458
(MþNaþ), 667.17993 (2MþNaþ). Found 345.08471 (MþNaþ),
667.18067 (2MþNaþ).
(DMSO-d6, 100 MHz)
d 17.7, 95.6, 112.4, 116.4, 116.6, 119.6, 123.9,
125.8, 134.5, 145.0, 146.8, 153.2, 156.0, 161.4, 173.5, 179.4 ppm.
HRMS (ESIþ) calcd for C16H12N2O5 m/z 335.06384 (MþNaþ),
647.13846 (2MþNaþ). Found 335.06379 (MþNaþ), 647.13832
(2MþNaþ).
4.2.3. 3-{1-[(4-Methylbenzoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4c). White solid; 1H NMR (DMSO-d6, 400 MHz)
d
2.41 (s, 3H), 2.76 (s, 3H), 7.31 (dd, J¼8.3, 1.0 Hz, 1H), 7.34 (ddd,
J¼7.8, 7.2, 1.0 Hz, 1H), 7.39 (d, J¼8.1 Hz, 2H), 7.68 (ddd, J¼8.3, 7.2,
1.6 Hz, 1H), 7.87 (d, J¼8.1 Hz, 2H), 8.01 (dd, J¼7.8, 1.6 Hz, 1H), 11.73
4.2.9. 3-{1-[(2-Thienylcarbonyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4i, Scheme 1). Light yellow solid; 1H NMR
(s, 1H), 15.70 (br s, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz)
d
17.6,
(DMSO-d6, 400 MHz)
d
2.73 (s, 3H), 7.28 (dd, J¼5.1, 3.8 Hz, 1H),
21.1, 95.3, 116.3, 119.7, 123.8, 125.7, 127.9, 128.3, 129.2, 134.3, 142.9,
153.1, 161.4, 164.7, 172.1, 179.2 ppm. HRMS (ESIþ) calcd for
C19H16N2O4 m/z 359.10023 (MþNaþ), 695.21124 (2MþNaþ). Found
359.10015 (MþNaþ), 695.21124 (2MþNaþ).
7.31 (dd, J¼8.6, 1.0 Hz, 1H), 7.34 (ddd, J¼7.8, 7.2, 1.0 Hz, 1H), 7.68
(ddd, J¼8.3, 7.4, 1.6 Hz, 1H), 7.95 (dd, J¼3.8, 1.0 Hz, 1H), 7.98 (dd,
J¼5.1, 1.0 Hz, 1H), 8.00 (dd, J¼7.9, 1.6 Hz, 1H), 11.80 (br, 1H), 15.60
(br s, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz)
d 18.1, 96.0, 116.8,
120.1, 124.3, 126.2, 128.8, 131.1, 133.5, 134.9, 135.7, 153.6, 160.2,
161.9, 173.5, 179.7 ppm. HRMS (ESIþ) calcd for C16H12N2O4S m/z:
329.05905 (MþHþ). Found 329.05893 (MþHþ).
4.2.4. 3-{1-[(4-Chlorobenzoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4d). White solid; 1H NMR (DMSO-d6, 400 MHz)
d
2.76 (s, 3H), 7.31 (dd, J¼8.6, 1.0 Hz, 1H), 7.34 (ddd, J¼8.1, 7.0, 1.0 Hz,
1H), 7.66 (d, J¼8.6 Hz, 2H), 7.68 (ddd, J¼8.6, 7.0, 1.5 Hz, 1H), 7.98 (d,
J¼8.6 Hz, 2H), 7.99 (dd, J¼8.1, 1.5 Hz, 1H), 11.89 (br, 1H), 15.72 (br,
4.3. Reaction of N-acylhydrazones 4 with lead tetraacetate
1H) ppm; 13C NMR (DMSO-d6, 100 MHz)
d
17.6, 95.4, 116.3, 119.6,
Lead tetraacetate (LTA) was added to a stirred solution of
hydrazone 4 (1 mmol) in THF (20 mL), in an ice bath. The molar
ratio of hydrazone/LTA and the reaction time are presented in Table
1. The mixture was then stirred at rt. The oily product obtained after
filtration of lead diacetate and evaporation of solvent from the fil-
trate was subjected to column chromatography (silica gel
70e230 mesh) and products were eluted with a mixture of petro-
leum ether/ethyl acetate 1/1 to afford the pure products 5 as solids.
123.9, 125.7, 128.8, 129.8, 130.0, 134.5, 137.5, 153.1, 161.4, 163.9,
172.3, 179.2 ppm; MS (ESIþ) m/z 356 (Mþ). Anal. Calcd for
C18H13ClN2O4: C, 60.60; H, 3.67; N, 7.85; Cl, 9.94. Found C, 60.36; H,
3.52; N, 7.92; Cl, 9.91.
4.2.5. 3-{1-[(4-Nitrobenzoyl)hydrazono]ethyl}-4-hydroxy-2H-1-
benzopyran-2-one (4e). Yellow solid; 1H NMR (DMSO-d6,

A. Kotali et al. / Tetrahedron 68 (2012) 761e766
765
The yields of formation of the new compounds 5 as well as their
melting points are presented in Table 1.
4.3.7. 3-Acetyl-4-(2-nitrobenzoyl)-2H-1-benzopyran-2-one
(5g). White solid; 1H NMR (DMSO-d6, 400 MHz):
2.57 (s, 3H), 7.34
d
(dd, J¼7.8, 1.5 Hz, 1H), 7.40 (ddd, J¼8.1, 7.1, 1.0 Hz, 1H), 7.60 (d,
J¼7.8 Hz, 1H), 7.67 (ddd, J¼8.2, 7.1, 1.2 Hz, 1H), 7.80 (ddd, J¼8.3, 7.5,
1.5 Hz, 1H), 7.90 (ddd, J¼8.1, 7.6, 1.2 Hz, 1H), 8.00 (dd, J¼8.1, 1.0 Hz,
4.3.1. 3,4-Diacetyl-2H-1-benzopyran-2-one (5a). Pale yellow solid;
1H NMR (DMSO-d6, 400 MHz):
d 2.48 (s, 3H), 2.61 (s, 3H), 7.44
(ddd, J¼8.1, 7.1, 1.2 Hz, 1H), 7.50 (dd, J¼7.9, 1.6 Hz, 1H), 7.55 (d,
2H) ppm; 13C NMR (DMSO-d6, 100 MHz):
d 30.9, 116.8, 117.6, 123.5,
J¼7.8 Hz, 1H), 7.82 (ddd, J¼8.3, 7.1, 1.8 Hz, 1H) ppm; 13C NMR
124.3, 126.0, 126.8, 127.5, 132.5, 133.1, 135.5, 136.0, 148.8, 152.9,
154.8, 158.6, 190.8, 196.9 ppm. HRMS (ESIþ): m/z [MþH]þ calcd for
C18H11NO6: 338.06650. Found: 338.06670.
(DMSO-d6, 100 MHz):
d 30.9, 31.1, 115.6, 117.4, 119.6, 125.9, 128.0,
135.5, 154.9, 157.6, 158.9, 197.0, 201.2 ppm; MS (ESIþ): m/z 231
(Mþ1). Anal. Calcd for C13H10O4: C, 67.82; H, 4.38. Found: C, 67.88;
H, 4.27.
4.3.8. 3-Acetyl-4-(2-furylcarbonyl)-2H-1-benzopyran-2-one
(5h). White solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.53 (s, 3H),
4.3.2. 3-Acetyl-4-benzoyl-2H-1-benzopyran-2-one (5b). White solid;
6.74 (ddd, J¼3.6, 1.8 Hz, 1H), 7.33e7.39 (m, 2H), 7.54 (d, J¼3.6 Hz,
1H NMR (DMSO-d6, 400 MHz):
d
2.54 (s, 3H), 7.18 (dd, J¼8.0, 1.4 Hz,
1H), 7.57 (d, J¼8.3 Hz, 1H), 7.78 (ddd, J¼8.3, 6.6, 2.3 Hz, 1H), 8.11 (d,
1H), 7.32 (ddd, J¼8.2, 7.1, 1.2 Hz, 1H), 7.51e7.59 (m, 3H), 7.69 (t,
J¼7.5 Hz, 1H), 7.77 (ddd, J¼8.6, 7.1, 1.5 Hz, 1H), 7.95 (d, J¼7.9 Hz, 2H)
J¼1.0 Hz, 1H) ppm; 13C NMR (DMSO-d6, 100 MHz):
d 30.5, 113.1,
116.4, 116.9, 121.6, 123.3, 125.3, 127.4, 134.7, 149.5, 150.8, 151.9, 154.1,
158.3, 179.3, 196.7 ppm. HRMS (ESIþ): m/z [MþH]þ calcd for
C16H15O5: 283.06010. Found: 283.05996.
ppm; 13C NMR (DMSO-d6, 100 MHz):
d 30.5, 116.7, 117.0, 122.1, 125.3,
127.7, 128.6, 129.1, 134.3, 134.8, 135.1, 154.3, 154.9, 158.3, 193.2,
196.2 ppm. HRMS (ESIþ): m/z [MþNa]þ calcd for C18H12O4:
315.06278. Found: 315.06309.
4.3.9. 3-Acetyl-4(2-thienylcarbonyl)-2H-1-benzopyran-2-one
(5i). Yellow solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.53 (s, 3H),
4.3.3. 3-Acetyl-4-(4-methylbenzoyl)-2H-1-benzopyran-2-one
6.93e6.97 (m, 2H), 7.28 (dd, J¼8.1, 1.5 Hz, 1H), 7.34 (ddd, J¼8.1, 7.5,
1.0 Hz, 1H), 7.51e7.58 (m, 2H), 7.77 (ddd, J¼8.3, 7.3, 1.8 Hz, 1H), 7.83
(dd, J¼8.4, 1.8 Hz, 1H) 10.85 (s, 1H) ppm; 13C NMR (DMSO-d6,
(5c). Pale yellow solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.38 (s,
3H), 2.52 (s, 3H), 7.16 (dd, J¼8.1, 1.5 Hz, 1H), 7.29e7.34 (m, 3H), 7.57
(d, J¼7.6 Hz, 1H), 7.77 (ddd, J¼8.3, 7.4, 1.5 Hz, 1H), 7.84 (d, J¼8.1 Hz,
100 MHz): d 30.4, 116.6, 116.9, 117.6, 119.6, 120.3, 121.4, 125.3, 127.3,
2H) ppm; 13C NMR (DMSO-d6, 100 MHz):
d
21.7, 31.0, 117.2, 117.4,
130.4,134.6,136.6,154.1,156.5,158.6,159.5,193.8,196.1 ppm. HRMS
(ESIþ): m/z [MþH]þ calcd for C16H15O4S: 299.03726. Found:
299.03707.
122.6, 125.7, 128.1, 129.2, 130.1, 133.3, 135.2, 145.6, 154.7, 155.3,
158.9, 193.2, 196.7 ppm. HRMS (ESIþ): m/z [MþNa]þ calcd for
C19H14O4: 329.07843. Found: 329.07873.
4.4. Oxidation of hydrazones 4 with (diacetoxyiodo)benzene
(DIB)
4.3.4. 3-Acetyl-4-(4-chlorobenzoyl)-2H-1-benzopyran-2-one
(5d). White solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.55 (s, 3H), 7.18
(dd, J¼7.8,1.5 Hz,1H), 7.32 (ddd, J¼8.1, 7.3,1.0 Hz,1H), 7.57e7.62 (m,
(Diacetoxyiodo)benzene (DIB) was added to hydrazones 4
(1 mmol) in dichloromethane (20 mL), under stirring, in an ice
bath. The molar ratio of hydrazone/DIB and the reaction time are
presented in Table 1. The mixture was then stirred at rt. The oily
product obtained after evaporation of the solvent was subjected to
column chromatography (silica gel 70e230 mesh) and was eluted
with a mixture of petroleum ether/ethyl acetate 1/1 to afford the
pure coumarins 5 as white solids in good yields (Table 1).
3H), 7.78 (ddd, J¼8.6, 7.1, 1.5 Hz, 1H), 7.98 (d, J¼8.6, 2H) ppm; 13C
NMR (DMSO-d6, 100 MHz):
d 31.0, 117.0, 117.5, 122.6, 125.8, 128.1,
129.8,130.8,134.4,135.4,139.8,154.8,155.0,158.8,192.7,196.7 ppm.
HRMS (ESIþ): m/z [MþH]þ calcd for C18H11ClO4: 327.04240. Found:
327.04260.
4.3.5. 3-Acetyl-4-(4-nitrobenzoyl)-2H-1-benzopyran-2-one
(5e). White solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.57 (s, 3H), 7.19
(d, J¼7.8, 1H), 7.32 (ddd, J¼8.1, 7.3, 1.0 Hz, 1H), 7.61 (d, J¼8.4 Hz, 1H),
Acknowledgements
7.80 (ddd, J¼8.3, 7.3, 1.2 Hz, 1H), 8.22 (d, J¼8.6 Hz, 2H), 8.33 (dd,
J¼8.6, Hz, 2H) ppm; 13C NMR (DMSO-d6, 100 MHz):
d 31.0, 116.9,
The authors are grateful to Royal Society of Chemistry for fi-
nancial support of this work.
117.6, 122.5, 124.7, 125.9, 128.1,130.2, 135.7, 139.9, 151.0, 154.9, 155.0,
158.7, 192.6, 196.77 ppm. HRMS (ESIþ): m/z [MþH]þ calcd for
C18H11NO6: 338.06650. Found: 338.06670.
References and notes
4.3.6. 3-Acetyl-4(2-hydroxybenzoyl)-2H-1-benzopyran-2-one
1. Weinmamm, I. In Coumarins: Biology, Applications and Modes of Actions;
O’Kennedy, R., Thornes, R. D., Eds.; John Wiley: England, 1997; pp 1e2.
2. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005,
12, 887e916.
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10. Bellis, D. M.; Spring, M. S.; Stoker, J. R. Biochem. J. 1967, 103, 202e206.
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13. Al-Mawsawi, L. Q.; Fikkert, V.; Dayaam, R.; Witvrouw, M.; Burke, T. R.; Borchers,
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(5f). White solid; 1H NMR (DMSO-d6, 400 MHz):
d 2.53 (s, 3H),
6.93e6.97 (m, 2H), 7.28 (dd, J¼8.1, 1.5 Hz, 1H), 7.34 (ddd, J¼8.1, 7.5,
1.0 Hz, 1H), 7.51e7.58 (m, 2H), 7.77 (ddd, J¼8.3, 7.3, 1.8 Hz, 1H), 7.83
(dd, J¼8.4, 1.8 Hz, 1H) 10.85 (s, 1H) ppm; 13C NMR (DMSO-d6,
100 MHz): d 30.4, 116.6, 116.9, 117.6, 119.6, 120.3, 121.4, 125.3, 127.3,
130.4,134.6,136.6,154.1,156.5,158.6,159.5,193.8,196.1 ppm. HRMS
(ESIþ): m/z [MþH]þ calcd for C18H12O5: 309.07575. Found:
309.07559.
4.3.6.1. Crystal structure determination. Data were collected on
ꢀ
a Bruker Smart Apex CCD diffractometer. Wavelength: 0.71073 A;
temperature: 100(2) K; reflections collected/unique: 7820/2885
[R(int)¼0.0863]; completeness to theta¼26.43:99.8%; space group:
ꢀ
ꢀ
ꢀ
monoclinic, P21/c; a¼9.099(3) A; b¼11.584(4) A; c¼13.341(4) A;
3
ꢀ
V¼1404.9(8) A ; Z¼4; R indices [I>2
s
(I)]: R1¼0.0567, wR2¼0.1101;
R indices (all data): R1¼0.0963, wR2¼0.1227. The structure was
solved with SIR2004 and refined with SHELXL97.

766
A. Kotali et al. / Tetrahedron 68 (2012) 761e766
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N. J. Heterocycl. Chem. 2010, 47, 513e516.
€
€
ꢁ
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ꢃ
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