Novel short-step synthesis of functionalized γ-phenyl-β- hydroxybutenoates and their cyclization to 4-hydroxycoumarins via the N-hydroxybenzotriazole methodology

Article abstract of DOI:10.1055/s-2004-829132

A novel method for the synthesis of functionalized 3-substituted 4-hydroxycoumarins is reported. C-Acylation compounds were derived from the reaction of the N-hydroxybenzotriazole ester of the functionalized acetyl salicylic acids and a variety of active methylene compounds and cyclized to the title compounds. The synthesis is simple and the compounds are produced in yields varying from 39 to 80%. The structure of the newly prepared C-acylation compounds was thoroughly studied through NMR spectroscopy for the first time in the literature.

Full text of DOI:10.1055/s-2004-829132

PAPER
1775
Novel Short-Step Synthesis of Functionalized g-Phenyl-b-hydroxybutenoates
and their Cyclization to 4-Hydroxycoumarins via the N-Hydroxybenzotriazole
Methodology
g
-Phenyl-
b
-hydrox
i
ybuten
o
oates
a
nd the
r
ir Cycliz
g
ation to 4-H
o
ydroxycoum
s
arins Athanasellis,a Georgia Melagraki,a Haralambos Chatzidakis,a Antreas Afantitis,a Anastasia Detsi,a
Olga Igglessi-Markopoulou,*a John Markopoulosb
a
National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry, Zografou Campus, Athens
15773, Greece
b
University of Athens, Department of Chemistry, Laboratory of Inorganic Chemistry, Panepistimiopolis, Zografou, Athens 15771, Greece
Fax +3(210)7723072; E-mail: ojmark@orfeas.chemeng.ntua.gr
Received 27 November 2003; revised 20 April 2004
From what was said above, it is obvious why the synthesis
Abstract: A novel method for the synthesis of functionalized 3-
of coumarin heterocycles is of great importance for many
research groups. The classical von Pechmann synthetic
substituted 4-hydroxycoumarins is reported. C-Acylation com-
pounds were derived from the reaction of the N-hydroxybenzotri-
azole ester of the functionalized acetyl salicylic acids and a variety
route to 4-substituted coumarins consists of the condensa-
of active methylene compounds and cyclized to the title com- tion of phenols with b-keto esters17 in the presence of a va-
riety of reagents18 including several catalysts.19–21 Also,
pounds. The synthesis is simple and the compounds are produced in
yields varying from 39 to 80%. The structure of the newly prepared
coumarins have been synthesized by methods including
C-acylation compounds was thoroughly studied through NMR
Perkin,22 Reformatsky,23 Knoevenagel,24 and Wittig reac-
spectroscopy for the first time in the literature.
tions.25 However, most of the above methods are less con-
Key words: coumarins, N-hydroxybenzotriazole, natural products,
venient, since they require several steps and vigorous
acylations, NMR spectroscopy, heterocycles
conditions.
Over the last years, we have been involved in a one-step
synthesis of tetramic26 and tetronic acids27 employing N-
hydroxybenzotriazole esters of a-amino or a-hydroxy ac-
4-Hydroxy 3-substituted coumarins (Figure 1), a class of
fused ring heterocycles, occur widely among natural prod-
ids as acylating agents of active methylene compounds.
ucts and have importance in medicine.1–3 Several natural
The reaction was used to produce a wide variety of g-ami-
products with the coumarinic moiety exhibit interesting
biological and pharmacological properties. They are anti-
no-28 or g-hydroxybutenoates,29 which can be converted to
five-membered heterocycles of biological interest. With
bacterial, anti-HIV active,4 antiviral, intisecticidal5 and
the previously discussed convenient preparation of a vari-
anticoagulant.6,7 Additionally, coumarin derivatives have
ety of activated systems from a-amino or a-hydroxy acids
in hand, we are in a position now to approach the synthesis
of 3-substituted 4-hydroxycoumarins with several substit-
uents on the aromatic ring, and their C-acylation precur-
sors using as activated building blocks the N-
hydroxybenzotriazole esters of functionalized acetyl sali-
cylic acids.
been used as food additives, perfumes, cosmetics, dyes8,9
fluorescent probes and triplet sensitizers,10 herbicides and
anticancer agents.7 More specifically, we could mention
the preparation of a series of 3-cyano-4-hydroxycou-
marins as inhibitors of passive cutaneous anaphylaxis in
rats.11 In addition, a series of coumarins bearing different
groups on the aromatic ring were synthesized and tested
as caspase activators and apoptosis inducers,12 showing
that these compounds can be used to induce cell death un-
der a variety of conditions in which uncontrolled growth
and spread of abnormal cells occurs. Among the variety of
4-hydroxycoumarins which have been isolated as natural
products, we could mention robustic acid,13 ferulenol and
its analogues14,15and two sesquiterpenecoumarins isolated
from Ferula pallida.16
In this paper, we describe an efficient short-step synthesis
for producing 3-substituted 4-hydroxycoumarins with
several substituents on the aromatic ring via a C-acyla-
tion–cyclization reaction of active methylene compounds
with the N-hydroxybenzotriazole esters of functionalized
acetyl salicylic acids. In addition, the functionalized ‘in-
termediates’, g-phenyl-b-hydroxybutenoates, have been
isolated and their structure was studied by NMR spectros-
copy revealing their existence in different tautomeric
forms. The synthetic route leading to the C-acylation
products and the corresponding functionalized coumarins
is summarized in Scheme 1 and Table 1.
OH
O
Y
Y
O
O
O
O
Our strategy involves the condensation of the N-hydroxy-
benzotriazole esters of the functionalized acetyl salicylic
acids 1a–e with the anions of active methylene com-
pounds 3a–f. The important intermediates 4a–f were con-
verted to the corresponding 3-alkoxycarbonyl-4-
hydroxycoumarins 5a–f via an intramolecular lactoniza-
Figure 1 3-Substituted 4-hydroxycoumarins
SYNTHESIS 2004, No. 11, pp 1775–1782
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829132; Art ID: T12703SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x
.
2
0
0
4

1776
G. Athanasellis et al.
PAPER
Scheme 1 Synthesis of the C-acylation compounds and the corresponding functionalized coumarins by using N-hydroxybenzotriazole
tion, using a methanolic hydrochloric acid solution (10%). marins 7a–f and 3-cyano 4-hydroxycoumarins 9a–e via a
On the other hand, the intermediates 6a–f and 8a–f were cyclization reaction using sodium ethoxide in ethanol.
converted to the corresponding 3-acyl-4-hydroxycou- The N-hydroxybenzotriazole esters of a-amino acids are
Table 1 C-Acylation Compounds and the Corresponding Functionalized Coumarins
Compound R1
R2
H
R
Y
Compound
R1
H
R2
H
Y
4a
4b
4c
4d
4e
4f
H
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
COOMe
COOEt
COOEt
COOEt
COOEt
COOEt
COMe
COPh
COMe
COMe
COMe
COMe
CN
5a (from 4a)
5b (from 4b)
5c (from 4c)
5d (from 4d)
5e (from 4e)
5f (from 4f)
7a (from 6a)
7b (from 6b)
7c (from 6c)
7d (from 6d)
7e (from 6e)
7f (from 6f)
9a (from 8a)
9b (from 8c)
9c (from 8d)
9d (from 8e)
9e (from 8f)
COOMe
COOEt
COOEt
COOEt
COOEt
COOEt
COMe
COPh
COMe
COMe
COMe
COMe
CN
H
H
H
H
Cl
H
H
Cl
H
H
OMe
Me
H
OMe
Me
H
H
H
Me
H
Me
H
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
Cl
H
H
Cl
H
H
OMe
Me
H
OMe
Me
H
H
H
Me
H
Me
H
8a
8b
8c
8d
8e
8f
H
H
H
H
CN
Cl
H
H
CN
Cl
H
H
CN
OMe
Me
H
CN
OMe
Me
H
CN
H
CN
H
CN
Me
CN
Me
CN
Synthesis 2004, No. 11, 1775–1782 © Thieme Stuttgart · New York

PAPER
g-Phenyl-b-hydroxybutenoates and their Cyclization to 4-Hydroxycoumarins
1777
H
well-known activated synthons used in peptide synthe-
sis.30 The requisite N-hydroxybenzotriazole esters of the
functionalized acetyl salicylic acids were synthesized by
condensation of equimolar amounts of functionalized O-
protected salicylic acids 1a–e with N-hydroxybenzotriaz-
ole 2 and dicyclohexylcarbodiimide (DCC) in anhydrous
tetrahydrofuran at 0 °C. After a reaction time of 24 h, the
reaction mixture was filtered off and the filtrate contain-
ing the non-isolated active ester was used as acylating
agent in the next step. In a typical C-acylation reaction,
the active methylene compounds 3a–f (1 equiv) was treat-
ed with sodium hydride (2 equiv) in anhydrous tetrahy-
drofuran at room temperature. After stirring for 2.5 h, the
solvent was removed under reduced pressure, the residue
was diluted with water, washed with diethyl ether and the
aqueous layer was acidified with aq hydrochloric acid
(10%) to give the functionalized intermediates 4a–f, 6a–f
and 8a–f after extraction with dichloromethane. These in-
termediates, the functionalized g-phenyl-b-hydroxy-
butenoates, were purified by flash chromatography and
their structure was assigned on the basis of their 1H NMR
spectral data (see Experimental). Cyclization of the C-
acylation compounds 4a–f to the corresponding function-
alized 3-alkoxycarbonyl-4-hydroxycoumarins 5a–f was
affected by treatment with a methanolic hydrochloric acid
solution (10%) at room temperature for 48 h. On the other
hand, the C-acylation compounds 6a–f and 8a–f were
treated with a solution of sodium ethoxide in absolute eth-
anol at room temperature for 24 h to afford the corre-
sponding functionalized 3-acyl-4-hydroxycoumarins 7a–
f and 3-cyano-4-hydroxy coumarins 9a–e, respectively.
According to the proposed methodology, the active car-
bon of the methylene compound ultimately becomes the
3-carbon of the coumarin ring, and any substituents at-
tached to this carbon will subsequently reside in the cor-
rect position, while the functionalized salicylic acid ring
supplies the remainder of the molecule.
O
O
C
O
O
C
6
6
R1
1
8
R1
1
8
7
OR'
5
4
7
OR'
5
4
COOR
9
COOR
9
2
OCOCH3
2
3
R2
OCOCH3
3
R2
Figure 2 Keto–enol equilibrium of the C-acylation compounds de-
rived from malonates
acquired representative 13C NMR and IR spectra of some
compounds.
Starting the discussion of the NMR spectra with the C-
acylation intermediates 4a–f derived from the use of mal-
onates, we should mention their existence in enol and keto
tautomers in different ratios (Figure 2, see Experimental).
In cases where the substituent on the aromatic ring is the
methoxy or 5-methyl group, the keto form is favorable
whereas the 3-chloro and 3-methyl derivatives show a
preference for the enolic form. In an effort to correlate the
signals of each group to the enol and keto form, we have
also taken into account a relevant paper which presented
1H NMR data for some of these compounds without giv-
ing signals for both forms but only for the dominant one.31
Based on the NMR spectra, the C-acylation compounds
7a–f were found to exist, in CDCl3 solution, in the enolic
form. The H NMR spectra of the intermediates derived
from acetylacetate are not so simple since these com-
pounds participate in the enol–enol equilibrium of tau-
tomers having a hydrogen bond between the enolic proton
at C-7 and the oxygen of acetyl group (tautomers A, B) or
ethoxycarbonyl group (tautomers C, D) (Figure 3).
1
H
H
O
O
O
O
6
6
R1
1
8
R1
1
C
9
8
C
9
7
R'
5
4
7
R'
5
4
An important feature of the proposed methodology has
been the use of N-hydroxybenzotriazole esters as useful
precursors for the synthesis of compounds with interest-
ing biological properties. The activation of acetyl salicylic
acid as its hydroxybenzotriazole ester is an attractive al-
ternative to other activated salicylic acid species6,7 permit-
ting mild reaction conditions. Another advantage is that
there is no need for isolating the intermediate active ester;
this fact reduces the reaction time, in contrast to previous-
ly described methodologies and is beneficial for the over-
all yield of the reaction. Additionally, the absence of
active sites on the N-hydroxybenzotriazole molecule is a
way to control the chemoselectivity of the reaction, a fea-
ture which was studied in one of our previous papers.29 Fi-
nally, the methodology is simple, inexpensive and easily
scaled up.
COOR
OCOCH3
COOR
OCOCH3
2
2
3
R2
3
R2
B
A
H
H
O
O
O
O
6
3
6
C
R1
1
8
C
R1
1
8
7
OR
7
OR
5
5
4
9 COR'
OCOCH3
9COR'
OCOCH3
4
2
2
3
R2
R2
C
All compounds that are presented in this paper have been
studied by means of 1H NMR spectroscopy and their ele-
mental analyses have been acquired. In addition, we have
D
Figure 3 Enol–enol equilibrium of the C-acylation compounds de-
rived from acylacetates
Synthesis 2004, No. 11, 1775–1782 © Thieme Stuttgart · New York

1778
G. Athanasellis et al.
PAPER
H
H
O
O
O
O
O
O
6
1
6
8
6
C
9
8
C
8
C
1
1
7
Ph
5
4
9
7
9
Ph
7
Ph
5
4
5
4
COOEt
OCOCH3
COOEt
OCOCH3
COOEt
OCOCH3
2
2
2
3
3
3
Figure 4 Tautomers of ethyl [(2-acetoxyphenyl)hydroxymethylidene]benzoylacetate
On the other hand, in the case of compound 6b (when ben-
zoyl acetate was used) the keto form is observed in favor
of the enolic tautomer (Figure 4).
Nicolet Magna IR 560. The NMR spectra were recorded on a Varian
Gemini-2000 300 MHz and a Bruker AC 300 300 MHz spectrome-
ter; chemical shifts are quoted in ppm (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad); J values are giv-
en in Hz. Elemental analyses were obtained on a Euro EA3000 Se-
ries Euro Vector CHNS Elemental Analyser.
The NMR and IR spectra of the C-acylation compounds
8a–e bearing a cyano group show some interesting fea-
tures. There is no signal for the methine proton of the keto
tautomer, since these compounds are found only in their
enolic form. This observation is fully in accordance with
the strong electron withdrawing character of the cyano
group and the observation which was made for the C-acyl-
ation compounds of cyano acetates with the N-hydroxy-
benzotriazole esters of a-hydroxy acids.28 In addition, the
hydrogen bond between the alkoxycarbonyl and the hy-
droxy group appears at d = 13.68 in compounds 8a and 8b,
as expected for hydrogen bonds of alkoxycarbonyl
groups.
Petroleum ether refers to the fraction with bp (40–60 ºC). Commer-
cially available THF was dried prior to use by refluxing over Na. All
other solvents (puriss quality) were used without further purifica-
tion. Origin and purity of the other reagents are as follows: salicylic
acid, purum; active methylene compounds, puriss; DCC, puriss;
HOBt, purum.
Functionalized 2-Acetoxybenzoic Acids 1b–e; General
Procedure33
In a typical reaction, the functionalized salicylic acid (20 mmol)
was mixed with acetic anhydride (15 mL) and a few drops of aq
phosphoric acid (85%). The mixture was stirred under reflux for 2
h. Subsequently H2O (3 mL) was added. The reaction was continued
for 5 min and the mixture was poured into cold H2O (30 mL) and
brought to r.t.. The precipitate formed was filtered off, washed with
H2O and dried in vacuo.
1
Total assignments on the H and 13C NMR spectra of 4-
hydroxycoumarins were accomplished by utilizing HET-
COR experiments for compound 5b and the data men-
tioned in a related paper referring to quinolinones.32 So,
correlations were observed between carbons resonating at
d = 14.1 (COOCH2CH3), 62.8 (COOCH2CH3), 116.9 (C-
8), 124.3 (C-6), 125.1 (C-5) and 135.6 (C-7), and protons
Functionalized C-Acylation Compounds 4a–f, 6a–f and 8a–f;
General Procedure
In a typical reaction, the functionalized acetyl salicylic acid 1a–e
(10 mmol) was treated with N-hydroxybenzotriazole (2) (1.35 g, 10
mmol), and DCC (2.05 g, 10 mmol) was added dropwise in anhyd
THF (40 mL) at 0 °C for 1 h. The resulting suspension was refrig-
erated overnight at 3–5 °C. The precipitated solid (DCCU) was fil-
resonating at
(COOCH2CH3), 7.30–7.36 (H-8), 7.30–7.36 (H-6), 8.02
d
=
1.46 (COOCH2CH3), 4.51
(H-5) and 7.68 (H-7), respectively.
In conclusion, we have successfully synthesized a series tered off and the filtrate was added to a solution of sodium hydride
(0.8 g, 20 mmol) and the appropriate active methylene compound
of functionalized 3-substituted 4-hydroxycoumarins and
3a–f (10 mmol) in anhyd THF (80 mL). The resulting mixture was
the C-acylation compounds which are used as precursors
stirred at r.t. for 2.5 h and then concentrated in vacuo. The obtained
gum was diluted with H2O and washed with Et2O. The aq extract
was acidified with aq HCl (10%) in an ice–H2O bath. The precipi-
for their synthesis using a short-step methodology. The
methodology makes use of the N-hydroxybenzotriazole
ester of the functionalized acetyl salicylic acid as acylat-
ing agent and the desired active methylene compounds.
The reaction gives high yields and a short reaction time is
required in contrast to previous methodologies. In addi-
tion, the functionalized intermediate g-hydroxybutenoates
have been isolated in pure form after column chromatog-
tated white solid (N-hydroxybenzotriazole) was filtered off and the
aq filtrate was extracted with CH2Cl2 (3 × 15 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo to
afford the C-acylation compounds 4a–f, 6a–f and 8a–f as oils. The
oily products 4a–f and 6a–f were purified by flash chromatography
(petroleum ether–EtOAc). On the other hand, the cyanoacetates 8a–
f were not purified by flash chromatography since they are unstable
under such conditions, but they were triturated with pentane and
Et2O for purification.
1
raphy and their structure was studied by means of H
NMR spectroscopy, and revealed their existence in differ-
ent tautomeric forms for the first time. Work currently in
progress includes application of the proposed methodolo-
gy on the preparation of other heterocyclic ring systems
with known biological activity. Also, the application of
this methodology in the synthesis of natural products con-
taining the coumarin nucleus is in our future plans.
Functionalized 3-Alkoxycarbonyl-4-hydroxycoumarins; Gen-
eral Procedure
The C-acylation compounds 4a–f (5 mmol) were dissolved in
MeOH (10 mL) and treated with aq HCl (10%; 10 mL) for 48 h at
r.t. to afford the corresponding substituted 3-methoxycarbonyl- 5a
and 3-ethoxycarbonyl-4-hydroxycoumarins 5b–f as white solids.
All solid products were filtered off, washed with petroleum ether
and dried in vacuo.
Mps were determined on a Gallenkamp MFB-595 melting point ap-
paratus and are uncorrected. The FT-IR spectra were recorded on a
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PAPER
g-Phenyl-b-hydroxybutenoates and their Cyclization to 4-Hydroxycoumarins
1779
Functionalized 3-Acyl- and 3-Cyano-4-hydroxycoumarins 7a–f
and 9a–e; General Procedure
Ethyl [(2-Acetoxy-5-chlorophenyl)hydroxymethylidene]eth-
oxycarbonylacetate (4c)
The C-acylation compounds 6a–f and 8a–f (5 mmol) were treated
with a solution of sodium (2.3 g, 10 mmol) in absolute EtOH (10
mL) and stirred at r.t. for 24 h. The mixture was evaporated under
reduced pressure and the residue was diluted with H2O and washed
with Et2O. The aq layer was acidified with aq HCl (10%) to afford
the functionalized 3-acetyl- 7a,c–f and 3-benzoyl-4-hydroxycou-
marins 7b as white solids. All solid products were filtered off,
washed with petroleum ether and dried in vacuo.
Yield: 1.7 g (48%); gummy solid [purified by column chromatogra-
phy (petroleum ether– EtOAc, 7.5:2.5)].
1H NMR (CDCl3): d = 0.97, 1.35 (2 t, J = 6.7, 6.7 Hz, 6 H,
COOCH2CH3 enol), 1.25 (t, J = 7.3 Hz, 2.6 H, COOCH2CH3 keto),
2.25, 2.34 (2 s, 4.3 H, OCOCH3 enol and keto), 4.15, 4.35 (2 q,
J = 6.7, 6.7 Hz, 4 H, COOCH2CH3 enol), 4.22 (q, J = 7.3 Hz, 1.8 H,
COOCH2CH3 keto), 5.12 (s, 0.4 H, methine proton keto), 7.07–
7.12, 7.38–7.58 (2 m, 4.3 H, aromatic protons enol and keto), 13.66
(s, 1 H, OH enol).31
Analytical and Spectroscopic Data of All Compounds
2-Acetoxy-5-chlorobenzoic Acid (1b)
Ethyl [(2-Acetoxy-3-methoxyphenyl)hydroxymethylidene]eth-
oxycarbonylacetate (4d)
Yield: 2.0 g (57%); mp 49–52 °C [purified by column chromatog-
raphy (petroleum ether– EtOAc, 7:3)].
1H NMR (CDCl3): d = 0.93, 1.34 (2 t, J = 7.3, 7.3 Hz, 4 H,
COOCH2CH3 enol), 1.24 (t, J = 7.3 Hz, 6 H, COOCH2CH3 keto),
2.27 (s, 2 H, OCOCH3 enol), 2.35 (s, 3 H, OCOCH3 keto), 3.83,
3.84 (2 s, 4.5 H, OCH3, enol and keto), 3.98, 4.33 (2 q, J = 7.3, 7.3
Hz, 2.4 H, COOCH2CH3 enol), 4.23 (q, J = 7.3 Hz, 4 H,
COOCH2CH3 keto), 5.12 (s, 1 H, methine proton keto), 6.99–7.43
(m, 5 H, aromatic protons enol and keto), 13.54 (s, 0.6 H, OH
enol).31
Yield: 2.8 g, (65%); mp 157–159 °C (lit.34 153–154 °C).
1H NMR (CDCl3): d = 2.34 (s, 3 H, OCOCH3), 7.09 (d, J = 8.5 Hz,
1 H, H-3), 7.58 (dd, J = 2.4, 8.5 Hz, 1 H, H-4), 8.08 (d, J = 2.4 Hz,
1 H, H-6).
2-Acetoxy-3-methoxybenzoic Acid (1c)
Yield: 3.0 g, (71%); mp 140–142 °C.
1H NMR (CDCl3): d = 2.36 (s, 3 H, OCOCH3), 3.86 (s, 3 H, OCH3),
7.19 (dd, J = 1.8, 7.8 Hz, 1 H, H-4), 7.26 (t, J = 7.8 Hz, 1 H, H-5),
7.65 (dd, J = 1.8, 7.8 Hz, 1 H, H-6).
Anal. Calcd for C10H10O5 (210): C, 57.14; H, 4.76. Found: C, 57.29;
H, 4.61.
Ethyl [(2-Acetoxy-3-methylphenyl)hydroxymethylidene]eth-
oxycarbonylacetate (4e)
Yield: 2.1 g (62%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 8:2)].
1H NMR (CDCl3): d = 0.91, 1.33 (2 t, J = 7.3, 7.3 Hz, 6 H,
COOCH2CH3 enol), 1.23 (t, J = 7.3 Hz, 2.4 H, COOCH2CH3 keto),
2.18 (s, 4.2 H, CH3 enol and keto), 2.27 (s, 3 H, OCOCH3 enol),
2.36 (s, 1.2 H, OCOCH3 keto), 3.97, 4.33 (2q, J = 7.3, 7.3 Hz, 4 H,
COOCH2CH3 enol), 4.23 (q, J = 7.3 Hz, 1.6 H, COOCH2CH3 keto),
5.17 (s, 0.4 H, methine proton keto), 7.14–7.30 (m, 4.2 H, aromatic
protons enol and keto), 13.60 (s, 1 H, OH enol).31
2-Acetoxy-3-methylbenzoic Acid (1d)
Yield: 2.4 g, (62%); mp 117–118.5 °C.
1H NMR (CDCl3): d = 2.24 (s, 3 H, CH3), 2.37 (s, 3 H, OCOCH3),
7.24 (t, J = 7.8 Hz, 1 H, H-5), 7.49 (dd, J = 1.8, 7.8 Hz, 1 H, H-4),
7.95 (dd, J = 1.8, 7.8 Hz, 1 H, H-6).
13C NMR (CDCl3): d = 16.0 (CH3), 20.7 (OCOCH3), 122.1, 125.8,
130.2, 132.5, 136.5, 149.9 (aromatic carbons), 169.4, 170.4.
Anal. Calcd for C10H10O4 (194): C, 61.86; H, 5.15. Found: C, 62.00;
H, 5.01.
13C NMR (CDCl3): d = 13.4, 13.8, 14.0 (COOCH2CH3 enol and ke-
to), 16.1, 16.2 (CH3 enol and keto), 20.5 (OCOCH3 enol), 20.7
(OCOCH3 keto), 60.9, 61.8, 62.3 (COOCH2CH3 enol and keto),
63.7 (C-8 keto), 101.7 (C-8 enol), 125.6, 125.8, 125.9, 126.8, 127.7,
128.1, 129.2, 130.0, 131.4, 132.8, 133.2, 135.9, 146.3, 148.2 (aro-
matic carbons enol and keto), 164.5 (COOCH2CH3 enol), 165.1
(COOCH2CH3 keto), 168.5, 168.8 (OCOCH3 enol), 171.1
(OCOCH3 keto), 174.9 (C-7 enol), 188.3 (C-7 keto).
2-Acetoxy-5-methylbenzoic Acid (1e)
Yield: 3.5 g (90%); mp 148–151 °C.
1H NMR (CDCl3): d = 2.33 (s, 3 H, OCOCH3), 2.40 (s, 3 H, CH3),
7.02 (d, J = 8.1 Hz, 1 H, H-3), 7.41 (dd, J = 1.8, 8.1 Hz, 1 H, H-4),
7.91 (d, J = 1.8 Hz, 1 H, H-6).35
Methyl [(2-Acetoxyphenyl)hydroxymethylidene]methoxycar-
bonylacetate (4a)
Yield: 1.6 g (54%); viscous oil [purified by column chromatogra-
phy (petroleum ether–EtOAc, 7:3)].
1H NMR (CDCl3): d = 2.29 (s, 2.5 H, OCOCH3 keto), 2.39 (s, 3 H,
OCOCH3 enol), 3.51, 3.92 (2 s, 6 H, COOCH3 enol), 3.81 (s, 5 H,
COOCH3 keto), 5.27 (s, 0.8 H, methine proton keto), 7.17–7.89 (m,
7 H, aromatic protons enol and keto), 13.67 (s, 1 H, OH enol).
Ethyl [(2-Acetoxy-5-methylphenyl)hydroxymethylidene]eth-
oxycarbonylacetate (4f)
Yield: 1.5 g (45%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 8:2)].
1H NMR (CDCl3): d = 0.93, 1.33 (2 t, J = 7.0, 7.0 Hz, 4.5 H,
COOCH2CH3 enol), 1.23 (t, J = 7.0 Hz, 6 H, COOCH2CH3 keto),
2.23 (s, 2.2 H, OCOCH3 enol), 2.33 (s, 5.3 H, CH3 enol and keto),
2.36 (s, 3 H, OCOCH3 keto), 3.97, 4.33 (2 q, J = 7.0, 7.0 Hz, 3 H,
COOCH2CH3 enol), 4.23 (q, J = 7.0 Hz, 4 H, COOCH2CH3 keto),
5.16 (s, 1 H, methine proton keto), 7.00–7.63 (m, 5.3 H, aromatic
protons enol and keto), 13.63 (s, 0.7 H, OH enol).
Ethyl [(2-Acetoxyphenyl)hydroxymethylidene]ethoxycarbonyl-
acetate (4b)
Yield: 1.7 g (53%); mp 50–52 °C [(purified by column chromatog-
raphy (petroleum ether– EtOAc, 93:7)].
1H NMR (CDCl3): d = 0.82, 1.26 (2 t, J = 7.0, 7.0 Hz, 3.6 H,
COOCH2CH3 enol), 1.15 (t, J = 7.0 Hz, 6 H, COOCH2CH3 keto),
2.18 (s, 1.8 H, OCOCH3 enol), 2.28 (s, 3 H, OCOCH3 keto), 3.89,
4.27 (2 q, J = 7.0, 7.0 Hz, 2.2 H, COOCH2CH3 enol), 4.16 (q,
J = 7.0 Hz, 4 H, COOCH2CH3 keto), 5.14 (s, 1 H, methine proton
keto), 7.07–7.79 (m, 6 H, aromatic protons enol and keto), 13.60 (s,
0.57 H, OH enol).6
4-Hydroxy-3-methoxycarbonylcoumarin (5a)
Yield: 0.76 g (69%); mp 139–140 °C (lit.36 139–140.5 °C).
1H NMR (CDCl3): d = 4.04 (s, 3 H, COOCH3), 7.30–7.36 (pt and
dd, 2 H, H-6, H-8), 7.68 (pt, J = 8.1 Hz, 1 H, H-7), 8.02 (d, J = 8.1
Hz, 1 H, H-5), 14.61 (s, 1 H, OH).
3-Ethoxycarbonyl-4-hydroxycoumarin (5b)
Yield: 0.77 g (66%); mp 100–101 °C (lit.36 98.5–100 °C).
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G. Athanasellis et al.
PAPER
1H NMR (CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H, COOCH2CH3), 4.51
(q, J = 6.9 Hz, 2 H, COOCH2CH3), 7.30–7.36 (pt and dd, 2 H, H-6,
H-8), 7.68 (pt, J = 8.1 Hz, 1 H, H-7), 8.02 (dd, J = 8.1, 1.8 Hz, 1 H,
H-5), 14.76 (s, 1 H, OH).
Ethyl [(2-Acetoxy-5-chloro phenyl)hydroxymethylidene]acetyl-
acetate (6c)
Yield: 1.6 g (49%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 9:1)].
1H NMR (CDCl3): d = 0.84, 0.86 (2 t, J = 7.0, 7.0 Hz, 3 H,
COOCH2CH3), 2.15, 2.18, 2.19, 2.43 (4 s, 6 H, COCH3, OCOCH3),
3.92, 4.01 (2 q, J = 7.0, 7.0 Hz, 2 H, COOCH2CH3), 6.86–7.42 (m,
3 H, aromatic protons), 13.76, 17.35 (2 s, 0.3 + 0.7 H, OH).
13C NMR (CDCl3): d = 13.3 (COOCH2CH3), 20.4, 20.6, 24.6
(OCOCH3, COCH3), 60.8, 61.2 (COOCH2CH3), 106.7, 109.3 (C-8),
118.6, 119.1, 123.7, 124.1, 128.4, 129.7, 119.7, 129.9, 131.2, 131.6,
132.1, 132.7, 134.9, 136.0, 145.4, 146.8 (aromatic carbons), 166.3,
168.5 (COOCH2CH3), 169.1, 171.4 (OCOCH3), 183.6, 188.9 (C-7),
183.6, 195.8 (COCH3).
6-Chloro-3-ethoxycarbonyl-4-hydroxycoumarin (5c)
Yield: 0.73 g (54%); mp 181–184 °C (lit.34 181–183 °C).
1H NMR (CDCl3): d = 1.46 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 4.51
(q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.26 (d, J = 9.1 Hz, 1 H, H-8),
7.61 (dd, J = 2.4, 9.1 Hz, 1 H, H-7), 7.98 (s, 1 H, H-5), 14.77 (s, 1
H, OH).
3-Ethoxycarbonyl-4-hydroxy-8-methoxycoumarin (5d)
Yield: 0.92 g (70%); mp 177–180 °C.
1H NMR (CDCl3): d = 1.45 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 3.95
(s, 3 H, OCH3), 4.49 (q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.16–7.58
(m 3 H, aromatic protons), 14.74 (s, 1 H, OH).
Ethyl [(2-Acetoxy-3-methoxy phenyl)hydroxymethylid-
ene]acetylacetate (6d)
Yield: 1.5 g (47%); mp 90–92 °C [purified by column chromatog-
raphy (petroleum ether– EtOAc, 8:2)].
Anal. Calcd for C13H12O6 (264): C, 59.09; H, 4.55. Found: C, 59.20;
H, 4.51.
1H NMR (CDCl3): d = 0.83, 0.88 (2 t, J = 6.7, 6.7 Hz, 3 H,
COOCH2CH3), 2.16, 2.21, 2.23, 2.43 (4 s, 6 H, COCH3, OCOCH3),
3.81, 3.82 (2 s, 3 H, OCH3), 3.92, 4.05 (2 q, J = 6.7, 6.7 Hz, 2 H,
COOCH2CH3), 6.90–7.07 (m, 3 H, aromatic protons), 13.57, 17.42
(2 s, 0.25 + 0.75 H, OH).
13C NMR (CDCl3): d = 13.3 (COOCH2CH3), 20.2, 20.3, 20.4, 24.8
(OCOCH3, COCH3), 56.2, 56.3 (OCH3), 60.6, 61.0 (COOCH2CH3),
107.5, 109.6 (C-8), 114.3, 115.2, 119.7, 121.3, 126.2, 126.4, 132.3,
134.5, 136.7, 138.1, 151.3, 151.4 (aromatic carbons), 166.7, 168.1
(COOCH2CH3), 168.6, 171.4 (OCOCH3), 181.5, 189.6 (C-7),
181.5, 195.8 (COCH3).
3-Ethoxycarbonyl-4-hydroxy-8-methylcoumarin (5e)
Yield: 0.70 g (56%); mp 104–106 °C.
1H NMR (CDCl3): d = 1.46 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 2.44
(s, 3 H, CH3), 4.50 (q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.21 (t,
J = 7.3 Hz, 1 H, H-6), 7.50 (d, J = 7.3 Hz, 1 H, H-7), 7.85 (d, J = 7.9
Hz, 1 H, H-5), 14.67 (s, 1 H, OH).
Anal. Calcd for C13H12O5 (248): C, 62.90; H, 4.84. Found: C, 63.02;
H, 4.91.
3-Ethoxycarbonyl-4-hydroxy-6-methylcoumarin (5f)
Yield: 0.77 g (62%); mp 124–126 °C.
Anal. Calcd for C16H18O7 (322): C, 60.00; H, 6.00. Found: C, 60.04;
H, 5.90.
1H NMR (CDCl3): d = 1.44 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 2.41
(s, 3 H, CH3), 4.49 (q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.18 (d,
J = 8.5 Hz, 1 H, H-8), 7.45 (dd, J = 8.5, 2.4 Hz, 1 H, H-7), 7.77 (s,
1 H, H-5), 14.71 (s, 1 H, OH).
Ethyl [(2-Acetoxy-3-methylphenyl)hydroxymethylidene]acetyl-
acetate (6e)
Yield: 1.5 g (49%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 8:2)].
1H NMR (CDCl3): d = 0.82, 0.87 (2 t, J = 7.0, 7.0 Hz, 3 H,
COOCH2CH3), 2.18, 2.23, 2.25, 2.45 (4 s, 9 H, COCH3, OCOCH3,
CH3), 3.93, 4.04 (2 q, J = 7.0, 7.0 Hz, 2 H, COOCH2CH3), 7.15–
7.37 (m, 3 H, aromatic protons), 13.60, 17.47 (2 s, 0.25 + 0.75 H,
OH).
Anal. Calcd for C13H12O5 (248): C, 62.90; H, 4.84. Found: C, 63.04;
H, 4.90.
Ethyl [(2-Acetoxyphenyl)hydroxymethylidene]acetylacetate
(6a)
Yield: 1.2 g (41%); mp 54–57 °C [purified by column chromatog-
raphy (petroleum ether– EtOAc, 9:1)].
1H NMR (CDCl3): d = 0.78, 0.83 (2 t, J = 6.7, 6.7 Hz, 3 H,
COOCH2CH3), 2.18, 2.20, 2.43 (3 s, 6 H, OCOCH3, COCH3), 3.89,
4.00 (2 q, J = 6.7, 6.7 Hz, 2 H, COOCH2CH3), 7.00–7.70 (m, 4 H,
aromatic protons), 13.63, 17.46 (2 s, 0.25 + 0.75 H, OH).
Ethyl [(2-Acetoxy-5-methylphenyl)hydroxymethylidene]acetyl-
acetate (6f)
Yield: 1.2 g (39%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 93:7)].
1H NMR (CDCl3): d = 0.80, 0.85 (2 t, J = 7.0, 7.0 Hz, 3 H,
COOCH2CH3), 2.14, 2.16, 2.31, 2.41 (4 s, 9 H, OCOCH3, CH3,
COCH3), 3.90, 4.01 (2 q, J = 7.0, 7.0 Hz, 2 H, COOCH2CH3), 6.86–
7.49 (m, 3 H, aromatic protons), 13.58, 17.48 (2 s, 0.3 + 0.7 H, OH).
Anal. Calcd for C15H16O6 (292): C, 61.64; H, 5.48. Found: C, 61.44;
H, 5.60.
Ethyl [(2-Acetoxyphenyl)hydroxymethylidene]benzoylacetate
(6b)
Yield: 1.4 g (40%); viscous oil [purified by column chromatogra-
phy (petroleum ether– EtOAc, 8:2)].
3-Acetyl-4-hydroxycoumarin (7a)
Yield: 0.72 g, (67%); mp 136–137 °C (lit.37 138.5 °C, lit.38141 °C,
lit.39 138 °C, lit.40 137 °C)
1H NMR (CDCl3): d = 0.82 (t, J = 7.2 Hz, 1.3 H, COOCH2CH3 ke-
to), 1.17, 1.25 (2 t, J = 7.2, 7.2 Hz, 3 H, COOCH2CH3 enol), 2.27,
2.29, 2.31 (3 s, 4.3 H, OCOCH3 enol and keto), 3.89 (q, J = 7.2 Hz,
0.9 H, COOCH2CH3 keto), 4.19–4.34 (2 q, 2 H, COOCH2CH3
enol), 6.11 (s, 0.3 H, methine proton keto), 7.01–7.95 (m, 12.9 H,
aromatic protons enol and keto), 13.46, 13.64, 17.24 (3 s, 0.7 H, OH
enol).
1H NMR (CDCl3): d = 2.79 (s, 3 H, COCH3), 7.29–7.37 (pt and dd,
2 H, H-6, H-8), 7.70 (pt, J = 8.1 Hz, 1 H, H-7), 8.07 (dd, J = 8.1, 1.2
Hz, 1 H, H-5), 17.77 (s, 1 H, OH).
3-Benzoyl-4-hydroxycoumarin (7b)
Yield: 0.81 g, (61%); mp 146–147 °C (lit.41 148–151 °C).
1H NMR (CDCl3): d = 7.32–7.75 (m, 8 H, aromatic protons), 8.12
(dd, J = 7.8, 1.2 Hz, 1 H, H-5), 16.74 (s, 1 H, OH).
Synthesis 2004, No. 11, 1775–1782 © Thieme Stuttgart · New York

PAPER
g-Phenyl-b-hydroxybutenoates and their Cyclization to 4-Hydroxycoumarins
1781
3-Acetyl-6-chloro-4-hydroxycoumarin (7c)
1H NMR (CDCl3): d = 1.41 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 2.30
(s, 3 H, OCOCH3), 4.41 (q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.23 (d,
J = 8.5 Hz, 1 H, H-6), 7.52 (dd, J = 2.4, 8.5 Hz, 1 H, H-4), 7.63 (d,
J = 2.4 Hz, 1 H, H-3).
Yield: 0.74 g (62%); mp 176–178 °C (lit.42 170 °C).
1H NMR (CDCl3): d = 2.78 (s, 3 H, COCH3), 7.25 (d, J = 9.1 Hz, 1
H, H-7), 7.62 (dd, J = 8.6, 2.4 Hz, 1 H, H-8), 8.01 (d, J = 2.4 Hz, 1
H, H-5), 17.81 (s, 1 H, OH).
Ethyl [(2-Acetoxy-3-methoxyphenyl)hydroxymethylidene]cy-
anoacetate (8d)
Yield: 1.5 g (49%); viscous oil.
Anal. Calcd for C11H7ClO4 (238.5): C, 55.35; H, 2.94. Found: C,
55.26; H, 3.08.
1H NMR (CDCl3): d = 1.39 (t, J = 7.3 Hz, 3 H, COOCH2CH3), 2.28,
2.32 (2 s, 3 H, OCOCH3), 3.83 (s, 3 H, OCH3), 4.39 (q, J = 7.3 Hz,
2 H, COOCH2CH3), 7.12–7.24 (m, 3 H, aromatic protons).
3-Acetyl-4-hydroxy-8-methoxycoumarin (7d)
Yield: 0.7 g (60%); mp 170–172 °C.
1H NMR (CDCl3): d = 2.77 (s, 3 H, COCH3), 3.96 (s, 3 H, OCH3),
7.18–7.27 (m, 2 H, H-6, H-7), 7.60 (dd, J = 7.3, 1.8 Hz, 1 H, H-5),
17.71 (s, 1 H, OH).
Ethyl [(2-Acetoxy-3-methylphenyl)hydroxymethylidene]cy-
anoacetate (8e)
Yield: 1.4 g (48%); viscous oil.
Anal. Calcd for C12H10O5 (234): C, 61.54; H, 4.27. Found: C, 61.46;
H, 4.42.
1H NMR (CDCl3): d = 1.37 (t, J = 7.0 Hz, 3 H, COOCH2CH3), 2.20
(s, 3 H, CH3), 2.28 (s, 3 H, OCOCH3), 4.37 (q, J = 7.0 Hz, 2 H,
COOCH2CH3), 7.24 (t, J = 7.3 Hz, 1 H, H-5), 7.41 (d, J = 6.7 Hz, 1
H, H-6), 7.51 (d, J = 7.3 Hz, 1 H, H-4).
3-Acetyl-4-hydroxy-8-methylcoumarin (7e)
Yield: 0.71 g (65%); mp 108–110 °C.
1H NMR (CDCl3): d = 2.46 (s, 3 H, CH3), 2.80 (s, 3 H, COCH3),
7.26 (d, J = 8.1 Hz, 1 H, H-7), 7.55 (d, J = 6.6 Hz, 1 H, H-8), 7.91
(d, J = 8.1 Hz, 1 H, H-5), 17.67 (s, 1 H, OH).
Ethyl [(2-Acetoxy-5-methylphenyl)hydroxymethylidene]cy-
anoacetate (8f)
Yield: 1.4 g (48%); viscous oil.
1H NMR (CDCl3): d = 1.37 (t, J = 7.0 Hz, 3 H, COOCH2CH3), 2.26,
2.36 (2 s, 6 H, OCOCH3, CH3), 4.37 (q, J = 7.0 Hz, 2 H,
COOCH2CH3), 6.83–7.40 (m, 3 H, aromatic protons).
Anal. Calcd for C12H10O4 (218): C, 66.06; H, 4.59. Found: C, 65.96;
H, 4.45.
3-Acetyl-4-hydroxy-6-methylcoumarin (7f)
Yield: 0.90 g (83%); mp 146–149 °C (lit.43 143–145 °C).
3-Cyano-4-hydroxycoumarin (9a)
1H NMR (CDCl3): d = 2.44 (s, 3 H, CH3), 2.79 (s, 3 H, COCH3),
7.20 (d, J = 8.1 Hz, 1 H, H-7), 7.51 (d, J = 6.3 Hz, 1 H, H-8), 7.85
(s, 1 H, H-5), 17.75 (s, 1 H, OH).
Yield: 0.6 g (64%); mp 262–262 °C (lit.11 267–269 °C).
1H NMR (DMSO-d6): d = 7.21 (pt and dd, 2 H, H-6, H-8), 7.51 (pt,
J = 8.1 Hz 1 H, H-7), 7.83 (d, J = 8.1 Hz, 1 H, H-5).
Anal. Calcd for C12H10O4 (218): C, 66.06; H, 4.59. Found: C, 65.99;
H, 4.41.
6-Chloro-3-cyano-4-hydroxycoumarin (9b)
Yield: 0.79 g (71%); mp >300 °C.
1H NMR (DMSO-d6): d = 7.23 (d, J = 8.4 Hz, 1 H, H-8), 7.53 (dd,
J = 2.4, 8.4 Hz, 1 H, H-7), 7.72 (d, J = 2.4 Hz, 1 H, H-5).
Methyl [(2-Acetoxyphenyl)hydroxymethylidene]cyanoacetate
(8a)
Yield: 1.8 g, (69%); viscous oil.
IR (in MeOH): 2229 (CN), 1771, 1663 (C=O), 1614 (C=C) cm–1.
Anal. Calcd for C10H4ClNO3 (221.5): C, 54.18; H, 1.81; N, 6.32.
Found: C, 54.00; H, 1.83; N, 6.53.
1H NMR (CDCl3): d = 2.30 (s, 3 H, OCOCH3), 3.96 (s, 3 H,
COOCH3), 7.26 (d, J = 8.1 Hz, 1 H, H-6), 7.36 (pt, J = 8.1 Hz, 1 H,
H-5), 7.58 (pt, J = 8.1 Hz, 1 H, H-4), 7.70 (dd, J = 8.1, 1.5 Hz, 1 H,
H-3), 13.68 (br s, 1 H, OH).
13C NMR (CDCl3): d = 20.8 (OCOCH3), 53.3 (COOCH3), 82.0 (C-
8), 114.6 (CN), 123.8 (C-1), 124.8 (C-3), 126.1 (C-5), 130.2 (C-6),
133.6 (C-4), 148.3 (C-2), 168.9 (OCOCH3), 171.1 (COOCH3),
182.3 (C-7).
3-Cyano-4-hydroxy-8-methoxycoumarin (9c)
Yield: 0.62 g (57%); mp 254–256 °C.
1H NMR (DMSO-d6): d = 3.85 (s, 3 H, OCH3), 7.10–7.21 (m, 2 H,
H-6, H-7), 7.40 (dd, J = 1.8, 7.9 Hz, 1 H, H-5).
Anal. Calcd for C11H7NO4 (217): C, 60.83; H, 3.23; N, 6.45. Found:
C, 60.80; H, 3.33; N, 6.53.
3-Cyano-4-hydroxy-8-methylcoumarin (9d)
Ethyl [(2-Acetoxyphenyl)hydroxymethylidene]cyanoacetate
(8b)
Yield: 0.59 g (59%); mp 213–215 °C (lit.11 211–214 °C).
1H NMR (DMSO-d6): d = 2.35 (s, 3 H, CH3), 7.16 (t, J = 7.3 Hz, 1
Yield: 2.2 g, (80%); viscous oil.
IR (in MeOH): 2229 (CN), 1771, 1657 (C=O), 1614 (C=C) cm–1.
H, H-6), 7.45 (d, J = 7.3 Hz, 1 H, H-7), 7.73 (d, J = 7.9 Hz, 1 H, H-
5).
1H NMR (CDCl3): d = 1.41 (t, J = 6.9 Hz, 3 H, COOCH2CH3), 2.31
(s, 3 H, OCOCH3), 4.41 (q, J = 6.9 Hz, 2 H, COOCH2CH3), 7.25 (d,
J = 7.8 Hz, 1 H, H-6), 7.36 (pt, J = 7.8 Hz, 1 H, H-5), 7.59 (pt,
J = 7.8 Hz, 1 H, H-4), 7.70 (dd, J = 7.8, 1.8 Hz, 1 H, H-3), 13.69 (br
s, 1 H, OH).
13C NMR (CDCl3): d = 13.9 (COOCH2CH3) 20.8 (OCOCH3), 63.0
(COOCH2CH3), 82.2 (C-8), 114.7 (CN), 123.8 (C-1), 125.0 (C-3),
126.1 (C-5), 130.2 (C-6), 133.6 (C-4), 148.3 (C-2), 168.9
(OCOCH3), 170.8 (COOCH2CH3), 182.3 (C-7).
3-Cyano-4-hydroxy-6-methylcoumarin (9e)
Yield: 0.67 g (67%); mp 235–237 °C (lit.11 238–241 °C).
1H NMR (DMSO-d6): d = 2.32 (s, 3 H, CH3), 7.08 (d, J = 8.4 Hz, 1
H, H-8), 7.33 (dd, J = 2.1, 8.4 Hz, 1 H, H-7), 7.62 (d, J = 1.2 Hz, 1
H, H-5).
Acknowledgment
We wish to thank the Committee of Research of the National Tech-
nical University of Athens for a doctoral assistantship (G. A.).
Ethyl [(2-Acetoxy-5-chlorophenyl)hydroxymethylidene]cy-
anoacetate (8c)
Yield: 1.6 g (52%); viscous oil.
Synthesis 2004, No. 11, 1775–1782 © Thieme Stuttgart · New York

1782
G. Athanasellis et al.
PAPER
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