Synthesis of structural fragments of natural 3-phenoxycoumarins

Article abstract of DOI:10.1134/S1068162012030065

The synthesis of substituted and unsubstituted 3-phenoxycoumarins is described. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1068162012030065

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 4, pp. 435–437. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © G.O. Ismailova, S.M. Mavlyanov, F.G. Kamaev, 2012, published in Bioorganicheskaya Khimiya, 2012, Vol. 38, No. 4, pp. 496–498.
Synthesis of Structural Fragments of Natural 3ꢀPhenoxycoumarins
G. O. Ismailova1, S. M. Mavlyanov, and F. G. Kamaev
Institute of Bioorganic Chemistry, Uzbekistan Academy of Sciences, ul. M. Ulugbeka 83, Tashkent, 100125 Uzbekistan
Received June 27, 2011; in final form, October 11, 2011
Abstract—The synthesis of substituted and unsubstituted 3ꢀphenoxycoumarins is described.
Keywords: 3ꢀphenoxycoumarins, synthesis
DOI: 10.1134/S1068162012030065
Natural coumarin and phenoxycoumarin bioreguꢀ herbicidal, fungicidal, and insecticidal activity, as well
lators have a broad range of physiological activity and as activity against dermatophytes [5], were identified
are a fertile field for chemical modifications [1].
during the study of biological activity.
Traditionally, substituted and unsubstituted 3ꢀpheꢀ
noxycoumarins are synthesized using the Perkin reacꢀ
tion [2], the Edgeworin synthesis procedure [3], the
Kostanetsky–Robinson reaction, or modified versions
of them [4].
RESULTS AND DISCUSSION
The known biological activity of natural and synꢀ
thetic 3ꢀphenoxycoumarins prompted us to develop
The most common method used to synthesize pheꢀ convenient and efficient methods for synthesizing
noxycoumarins containing ꢀaryl substituents in the these compounds. We used three methods, A, B, and
O
3 position is the interaction of the appropriate aldeꢀ C (Scheme) for the synthesis of substituted and unsubꢀ
hydes with phenoxyacetic acids and their functional stituted 3ꢀphenoxycoumarins, which are analogues of
derivatives. Compounds possessing antimicrobial [2], natural compounds.
(AcO)2O, AcOK (A)
OCH2COOH
R
R
O
O
OH
A
5
2
7
4
5
CCl3COOH, AcO (B)
3
+
6
6
DMF
H
R1
R1
O
R2
R2
(I)–(IV)
O
B
SOCl2, CHCl3 (C)
AcOK
(V)
(VI)–(IX)
(I), (VI) R=R1=R2=H
(II), (VII) R=OAc, R1=R2=H
(III), (VIII) R=R2=H, R1=Br
(IV), (IX) R=H, R1=R2=–CH=CH–CH=CH–
Scheme.
According to method A, the appropriate salicylalꢀ refluxed in dry chloroform in the presence of thionyl
chloride and potassium acetate.
dehyde (I)–(IV) phenoxyacetic acid (V) was conꢀ
densed in the Perkin reaction [1]. In method B, startꢀ
ing compounds were condensed in dimethylformaꢀ
mide in the presence of trichloroacetic acid and acetic
anhydride according to the Edgeworin synthesis proꢀ
cedure [3]. In method C, the starting materials were
Comparison of results for the three methods of
3ꢀphenoxycoumarin (VI)–(IX) synthesis shows that in
the conditions used in Edgeworin synthesis (B), the
reaction occurs in milder conditions and gives higher
yields (20–80%) than in methods A and C and is
hardly accompanied at all by resinification or the forꢀ
mation of byꢀproducts.
1
Corresponding author: phone: (99890) 356ꢀ11ꢀ47; eꢀmail:
ismailova.gulzira@mail.ru.
435

436
ISMAILOVA et al.
It should be noted that the synthesis in method A
results in the formation of byꢀproducts VIIа)–(IXа
along with the desired products, while the synthesis in
method C leads to resinification. Those byꢀproducts
Elemental analysis was performed on the instruꢀ
ment for microdetection of carbon, hydrogen, and
halogen (Russia). Aldehydes )–(IV by Reakhim
(Russia) were used. Phenoxyacetic acid ( ) prepared
according to procedure [6]. Other chemical agents
were produced by Reahim (Russia) and Khimreakꢀ
tivkomplekt (Uzbekistan).
(
)
(I
)
V
do not contain
Оꢀaryl substituents in position 3.
10
9
R
O
O
R
O
O
7
Synthesis of compounds VI–IX. Method A. A mixꢀ
3
8
3
ture of an appropriate aldehyde
(I)–(IV) (10 mmol),
4
6
R1
4
5
R2
7
5
acid (10 mmol), acetate (2.95 g, 30.1 mmol), and
(V)
6
acetic anhydride (10.3 mL) was refluxed for 18–19 h.
After the reaction mixture was cooled, the precipitate
that formed was filtered off and recrystallized from
ethanol.
(VIIa) R=OAc, R1=R2=H (IXa) R=H
(VIIIa) R1=Br, R=R2=H
Product mixtures formed in the reaction were sepaꢀ
rated by fractional crystallization.
When applying method B, refluxing the reaction mixꢀ
ture for 30–32 h leads to the formation of 3ꢀphenoxycouꢀ
marins (VI)–(IX) with high yields (20–80%). These
products are easily detectable on a TLC plate under
UV light.
3ꢀPhenoxyꢀ2
(17.2%), Rf = 0.44, mp 108–110
[3]). Found, %: C 75.5, H 4.2. С15
H
ꢀchromenꢀ2ꢀon (VI). Yield 0.41 g
(lit. mp 110
10О3 (M 238). Calꢀ
culated, %: C 75.6, H 4.2. H NMR: 7.63 (1 H, dd,
8.2; 2.4, H8), 7.55 (1 H, td, 8.2; 2.4, H6), 7.43
(1 H, s, H4), 7.40–7.47 (2 H, m, H2', H6'), 7.38 (H,
dd, 8.2; 2.4, H5), 7.34 (1 H, dd, 8.3; 2.4, H7),
7.15–7.25 (3 H, m, H3', H4', H5').
°
H
С
°С
1
J
J
J
J
The resulting 3ꢀphenoxycoumarins (VI)–(IX) are
colorless crystalline compounds soluble in various
organic solvents and insoluble in water. Due to blue or
violet fluorescence under UV light, these compounds
are easily detectable.
7ꢀAcetoxyꢀ3ꢀphenoxyꢀ2 ꢀchromenꢀ2ꢀon (VII).
H
Yield 0.21 g (7.2%), Rf = 0.53, mp 140–143
°С.
Found, %: C 69.0, H .0. С17Н12О5 (296). Calculated, %:
1
68.9, 4.0. H NMR: 7.69 (1 H, s, H4), 7.50 (1H, d,
J
8.4, H5), 7.40–7.45 (2 H, m, H2', H6'), 7.18–7.25
(3 H, m, H3', H4', H5'), 7.12 (H, d, 2.2, H8), 7.01
(H, dd, 8.3; 2.2, H6), 2.31 (H, s, H7).
The structure of the new 3ꢀsubstituted phenoxyꢀ
coumarins was confirmed by H NMR spectroscopy,
using acetoneꢀd6 as a solvent.
1
J
J
Signals of methine protons of the pyrone cycle
(H4) are the most characteristic signals in the spectra.
They appear as singlets in a low field at 7.43 ppm. In
the case of 5ꢀunsubstituted phenoxycoumarins
6ꢀBromoꢀ3ꢀphenoxyꢀ2 ꢀchromenꢀ2ꢀon (VIII).
H
0.57 g (18%), Rf = 0.62, mp 153–155 . Found, %:
°
С
C 56.6, H 2.4, Br 49.0. С15Н9BrО3 (M 317). Calcuꢀ
lated, %: C 56.8, H2.8, Br 48.8. 1H NMR: 7.95 (H, d,
(
R2 = H), protons at position 5 give doublets at 7.3–
J
2.2 2.2, H5), 7.92 (1 H, s, H4), 7.62 (1 H, dd,
8.2; 2.4, H7), 7.41–7.46 (2 H, m, H2', H6'), 7.32 (1 H,
d, 2.3 2.3, H8), 7.15–7.25 (3 H, m, H3', H4', H5').
J 8.2
7.9 ppm with spin–ꢀspin coupling constants (SSCC)
1
of 2 Hz. In H NMR spectra of 7ꢀacetoxycoumarins
J
(
VII), a threeꢀproton peak of the acetyl group appears
3ꢀPhenoxyꢀ2Hꢀbenzo[f]chromenꢀ2ꢀon (IX). Yield
0.32 g (11.5%), Rf = 0.31, mp 113–115 . Found, %:
at 2.31 ppm instead of the hydroxyl group signal. Proꢀ
tons H2' and H6' of ring B give a multiplet signal at
7.40–7.47 ppm, while the characteristic signals of H3',
H4' and H5' protons are at 7.15–7.28 ppm.
So, comparison of the results of 3ꢀphenoxycouꢀ
marin synthesis by different methods shows that the
second method (B) provides the formation of the
desired compounds with the highest yields and withꢀ
out the formation of byꢀproducts.
°
С
C 79.2, H 4.0. С19Н12О3 (M 288). Calculated, %:
C 79.2, H 4.2. 1H NMR: 8.50 (1 H, s, H4), 8.28 (1 H,
dd,
7.83 (1 H, dd,
7.50 (1 H, td, H6), 7.45 (1 H, d,
J
8.3 8.3; 2.4, H5), 7.85 (1 H, d,
8.3 8.3; 2.4, H8, 7.61 (1 H, td, H7),
8.3 8.3, H10), 7.40ꢀ
J 8.3 8.3, H9),
J
J
7.46 (2 H, m, H2', H6'), 7.15ꢀ7.28 (3 H, m, H3', H4',
H5').
Method B. A mixture of an appropriate aldehyde
(I)–
(
IV (10 mmol), phenoxyacetic acid (10 mmol),
)
(V)
dimethylformamide (5 mL), trichloroacetic acid
(10 g), and acetic anhydride (10.3 mL) was refluxed
for 30–32 h. After that, the reaction mixture was
diluted with cold water, and the precipitated solid was
filtered off and recrystallized from ethanol.
MATERIALS AND METHODS
Monitoring of the progress of the reactions and the
identification of synthesized compounds was perꢀ
formed by TLC on Silufol UVꢀ254 plates (eluent, benꢀ
zene : ethanol, 9 : 1). 1H NMR spectra were recorded
on a Unityꢀ400+ device (Varian, United States,
Yields: 1.90 g (80%) for compound
VII ; 1.12 g (35.5%) for (VIII); 1.44 g
(52.2%) for (IX).
(VI), 0.59 g
400 MHz) in acetoneꢀd6
(δ, ppm;
J
, Hz). Tetramethꢀ (20%) for
(
)
ylsilane was used as an internal standard.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012

SYNTHESIS OF STRUCTURAL FRAGMENTS OF NATURAL 3ꢀPHENOXYCOUMARINS
437
Method C. Thionyl chloride (0.72 mL, 10 mmol)
was added to phenoxyacetic acid (10 mmol) at
Then, an appropriate aldehyde )–(IV
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(V)
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0°
С.
(I
)
no. 3, pp. 292–297.
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off and recrystallized from ethanol.
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Yields: 1.24 g (52%) for compound
(25.6%) for VII ; 0.60 g (19%) for VIII
(50%) for IX
(VI
)
; 0.75 g
(
)
(
); 1.38 g
(
).
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ACKNOWLEDGMENTS
Chem. Papers, 1986, vol. 40, no. 1, pp. 121–126.
The work was supported by the Basic Research
Foundation (grant no. 144ꢀ06) and grant FAꢀA12ꢀ
T160.
6. Gitis, S.S., Glaz, A.I., and Ivanov, A.V., Praktikum po
organicheskoi khimii (A Practical Course in Organic
Chemistry), Moscow, 1991.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 4
2012