Synthesis of analogues of natural coumarins and coumarinolignans

Article abstract of DOI:10.1007/s11171-005-0040-6

3-Aryl-4H-coumarins with the 1,3-benzodioxol, 1,4-benzodioxane, and 1,5-benzodioxepane moieties were synthesized by modified methods.

Full text of DOI:10.1007/s11171-005-0040-6

Russian Journal of Bioorganic Chemistry, Vol. 31, No. 3, 2005, pp. 292–296. Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 3, 2005, pp. 326–330.
Original Russian Text Copyright © 2005 by Ismailova.
Synthesis of Analogues of Natural Coumarins
and Coumarinolignans
1
G. O. Ismailova
Complex Institute of Natural Sciences, Karakalpak Branch, Uzbek Academy of Sciences,
pr. Berdakh 41, Nukus, 742000 Uzbekiston
Received April 14, 2004; in final form, December 13, 2004
Abstract—3-Aryl-4H-coumarins with the 1,3-benzodioxol, 1,4-benzodioxane, and 1,5-benzodioxepane moi-
eties were synthesized by modified methods.
Key words: 3-aryl-4H-coumarin, benzodioxol, benzodioxane, benzodioxepane, Knoevenagel reaction
1
INTRODUCTION
analogues of 3-aryl-4H-coumarins in order to study
chemical and biological properties of these com-
pounds, as well as the dependence of these properties
on the nature and size of heterocycle at the ring B.
The search for compounds that can play role of flu-
orescent probes while studying the structure and con-
formational transitions in proteins and membranes is
currently in progress. Analogues of natural biologically
active substances that have an intrinsic fluorescence
sensitive to various environmental conditions are of
great interest. Coumarins, which have a wide spectrum
of biological activities, belong to this type of com-
pounds.
Three methods (A, B, and C) were used for the
synthesis of 3-aryl-4H-coumarins with 1,3-benzo-
dioxol, 1,4-benzodioxane, and 1,5-benzodioxepane
moieties.
The method A utilized salicylaldehyde (I) and the
corresponding heteroarylacetonitrile (III, n = 1, 2, or
3) or heteroarylacetic acid (II, n = 1 or 2) for conden-
sation under the conditions of the Perkin reaction [16]
(see the scheme). According to the method B, the
starting aldehydes and the corresponding substituted
acetic acids or nitriles were subjected to the Knoeve-
nagel condensation [17] in the presence of alcohol and
piperidine. The method C consisted in the reflux of the
starting components in ethanol in the presence of tri-
ethylamine.
Coumarins with benzodioxol and benzodioxane
structural fragments are often isolated from plants [1–
14]. The natural bioregulators of coumarin series are
convenient subjects for chemical modifications.
3-Aryl-4H-coumarins with the 1,3-benzodioxol and
1,5-benzodioxepane moieties had previously been syn-
thesized by the classical Perkin method from α-(1,3-
benzodioxol-5-yl)- and α-(1,4-benzodioxan-6-yl)ace-
tic acids by the condensation with an appropriate sali-
cylaldehyde in the presence of potassium acetate and
acetic anhydride. Some substances with antiathero-
sclerotic activity were found among the compounds
synthesized [15].
A comparison of the results of synthesis of cou-
marins (III)–(XX) (Table 1) shows that, under the con-
ditions of Knoevenagel reaction by the method B, the
reaction proceeded mildly and in higher yields (19–
82%) than by the methods A and C and practically
resulted in negligible resinification.
RESULTS AND DISCUSSION
Valuable properties of natural and synthetic cou-
marins prompted us to undertake a search for more con-
venient and effective methods of their preparation. We
developed the methods of synthesis of 1,3-benzo-
dioxol, 1,4-benzodioxane, and 1,5-benzodioxepane
Note that the use of heteroarylacetonitriles by the
method A led to the formation, along with the target
products, also side products (XVI)–(XIX) that con-
tained no aryl substituents in position 3. At the same
time, such side products were not observed while the
reaction was carried out with substituted acetic
acids.
1
Corresponding author; phone (99861) 223-6647; e-mail:
bakhytn@mail.ru
1068-1620/05/3103-0292 © 2005 Pleiades Publishing, Inc.

SYNTHESIS OF ANALOGUES OF NATURAL COUMARINS
293
(AcO)2O, AcOK(Ä)
R
OH
XH2C
O
O
R
O
O
EtOH, pip (B)
+
(CH2)n
O
O
O
R1
R1
(CH2)n
R2
H
R2
EtOH, (C2H5)3 N(C)
(I)
(II) X = COOH; n = 1, 2
X = CN; n = 1, 2, 3
(III)–(XX) n = 1, 2, 3
R = R1 = R2 = H
R = R2 = H, R1 = Cl
R = R2 = H, R1 = Br
R = H, R1 = R2 = –CH=CH–CH=CH–
R = R2 = H, R1 = NO2
R1 = R2 = H, R = AcO
A comparison of the results of synthesis of cou-
marins (III)–(XX) indicates various availabilities of
4H-coumarins modified with the 1,3-benzodioxol, 1,4-
benzodioxane, and 1,5-benzodioxepane nuclei [18–
20].
O
O
O
O
R
Thus, the cyclization of salicylaldehydes and het-
eroarylacetonitriles in the presence of piperidine in eth-
anol proceeds under milder conditions and in higher
yields of target products than those by the methods A
and C.
(XVI) R = Cl
(XVII) R = Br
(XIX) R = NO2
(XVIII)
The product mixtures were separated by fractional
crystallization.
The boiling of reaction mixture for 4–5 h by the
method B results in the formation of coumarins (XI),
(XIII), and (XIX) (X = CN, n = 2 or 3) in higher yields
(56–82%). These substances are easily detected at TLC
by their fluorescence under UV light (Table 1).
EXPERIMENTAL
The course of reactions and the purity of products
were monitored by TLC on Silufol UV-254 developed
1
with 9 : 1 benzene–ethanol mixture. H NMR spectra
were recorded on a WP-100 SY (Bruker, working fre-
The resulting 3-aryl-4H-coumarins (III)–(XX) are quency 100 MHz) and Tesla-100 NMR spectrometers
colorless crystalline substances, which are readily sol- in deuterochloroform or deuterodimethyl sulfoxide rel-
uble in the majority of organic solvents and are insolu- ative tetramethylsilane as an internal standard. The
ble in water. They are easily detected by blue or violet results of elemental analyses of all the compounds syn-
fluorescence in UV light (Table 1).
thesized corresponded to the calculated values.
The structures of newly obtained coumarins were
proved by the elemental analysis and 1H NMR spectra
measured in CDCl3 (Tables 1, 2). The signals of meth-
yne protons of pyrone ring (H4) are the most character-
istic in their spectra. They are exhibited as singlets in a
low field, at 7.62–8.1 ppm. In the case of 5-unsubsti-
tuted coumarins (R2 = H), the protons in position 5
manifest doublets with spin–spin coupling constants, J,
of 2 Hz in the area of 7.4–7.8 ppm. The 1H NMR spec-
tra of 7-acetoxycoumarins (VIII), (XIV), and (XX)
exhibit a three-proton signal of acetyl group at 2.3 ppm
3-Heteroaryl-4H-coumarins. Method A, com-
pounds (III)–(XX). A mixture of heteroarylacetoni-
triles (10 mmol) or heteroarylacetic acid (II), corre-
sponding aldehyde (I), potassium acetate (2.95 g,
30.1 mmol) and acetic anhydride (10.3 ml) was
refluxed for 5–7 h. In the case of heteroarylacetonitrile,
the reaction product was hydrolyzed with 50% acetic
acid (5 ml) for 2 h. After cooling, the precipitated prod-
uct was filtered and recrystallized from ethyl acetate
(Table 1).
Method B, compounds (III)–(XX). A mixture of
instead of the signal of hydroxyl group. The protons of (II) X = COOH, n = 1 or 2 or X = CN, n = 1, 2, or 3)
methylenedioxy and ethylenedioxy groups display sin- (10 mmol), corresponding aldehyde (I) (10 mmol), pip-
glets at 6.00–6.06 and 4.27–4.30 ppm; propylenedioxy eridine (0.12 ml), and 95% ethanol (10 ml) was
group is observed as a triplet and quintet at 4.20 and refluxed for 4–6 h. In the case of heteroarylacetonitrile,
2.16 ppm, respectively.
the reaction product was hydrolyzed with 2 N HCl
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 3 2005

294
ISMAILOVA
Table 1. Physicochemical characteristics of 3-heteroaryl-4H-coumarins
Yield, %**
Empirical
Elemental analysis
Compound
Mp, °C*
formula
method A
method B
method C
element
found, %
calc., %
(III)
C16H10O4
174–175 11.3
19
–
39
–
35
C
72.2
3.7
72.2
3.6
H
Cl
Br
C
(IV)
(V)
C16H19ClO4
C16H9BrO4
C20H12O4
237–239 58
234–235 63.5
204–206 33
–
–
58
–
–
–
52
–
–
–
–
11.9
23.3
75.9
3.8
11.8
23.3
76.0
3.8
–
(VI)
34
44
–
H
N
O
C
(VII)
(VIII)
(IX)
C16H9NO6
C18H12O6
C17H12O4
264–265 30
193–195 20
190–191 13
–
–
–
30
–
–
–
4.5
4.5
30.8
66.8
3.5
30.7
66.7
3.7
18
–
29
H
C
21.4 18
25
15
20
73.0
4.2
73.0
4.3
H
Cl
Br
C
(X)
C17H11ClO4
C17H11BrO4
C21H14O4
199–201 76.3 35.5
–
–
–
–
–
–
–
11.3
22.4
76.7
4.1
11.3
22.2
76.4
4.2
(XI)
(XII)
206–207 31
212–214 34
48
23
33.5 56
40.33
–
35
H
N
O
C
(XIII)
(XIV)
(XV)
C17H11NO6
C19H14O6
C18H14O4
245–247 72
73.1 76
82
–
–
–
–
4.3
4.2
29.5
68.0
4.2
30.0
67.5
4.1
171–172 25.5 23
–
–
31
–
H
C
177–178
–
21
28.3
22
73.5
4.7
72
H
Cl
Br
C
4.7
(XVI)
C18H13ClO4
C18H13BrO4
167–168
213–215
173–175
–
–
–
25
–
–
–
–
–
–
–
–
10.8
21.4
76.7
4.6
10.7
21.3
75
(XVII)
31.3
25
37
33.5
–
(XVIII) C22H16O4
32.5
H
N
O
C
4.6
(XIX)
(XX)
C18H13NO6
C20H16O6
184–186
165–166
–
–
60
15
–
–
65.3
19
–
–
55
–
4.6
4.5
20.8
75
21.0
75
H
5
4.7
* Crystallization from ethyl acetate.
** The yields obtained in the reaction with heteroarylacetic acids and heteroarylacetonitriles are given for each method in the first and in
the second column, respectively.
(5 ml) for 2 h. After cooling, the precipitated product (10 ml) was refluxed for 8–10 h. In the case of het-
was filtered, washed with 1% NaHCO3, and recrystal-
lized from ethyl acetate (Table 1).
eroarylacetonitrile, the reaction product was hydro-
lyzed with 2 N HCl (5 ml) for 1 h. After cooling, the
precipitated product was filtered, washed with 1%
NaHCO3, and recrystallized from ethyl acetate (Table 1).
Method C, compounds (III)–(XX). A mixture of
(II), (I), triethylamine (0.35 ml), and 95% ethanol
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 3 2005

SYNTHESIS OF ANALOGUES OF NATURAL COUMARINS
295
n 2
O ) –
– O ( C H
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 31 No. 3 2005

296
ISMAILOVA
10. Lin, L.J. and Cordell, G.A., J. Chem. Soc., Chem. Com-
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