Chemistry of 3-hetarylcoumarins 3*. Synthesis and aminomethylation of 7'-hydroxy-3, 4'- bicoumarins

Article abstract of DOI:10.1007/s10593-012-1009-z

An improved procedure for the synthesis of 7?-hydroxy-3, 4?-bicoumarins has been developed. Their 8?-aminomethyl derivatives were obtained by interaction with aminals.

Full text of DOI:10.1007/s10593-012-1009-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
CHEMISTRY OF 3-HETARYLCOUMARINS
3*. SYNTHESIS AND AMINOMETHYLATION
OF 7'-HYDROXY-3,4'- BICOUMARINS
M. S. Frasinyuk1*, S. P. Bondarenko2, and V. P. Khilya3
An improved procedure for the synthesis of 7′-hydroxy-3,4′-bicoumarins has been developed. Their
8′-aminomethyl derivatives were obtained by interaction with aminals.
Keywords: 7'-hydroxy-3,4'-bicoumarin, methyl (7-hydroxycoumarin-4-yl)-acetate, aminomethylation,
Knoevenagel condensation.
Both natural and synthetic coumarins, possessing various forms of biological activity [2, 3], serve as
source models for new synthetic drugs. Flavonoids [4] and coumarins [5] are widely distributed in the plant
world. Two benzopyrone fragments are linked with C–C' or ether C–O–C' bonds in these compounds. As is
known, these compounds are formed biogenetically as a result of free radical oxidative coupling of monomeric
aromatic precursors (coumarins and flavonoids) [6]. Natural bicoumarins are symmetrical compounds in many
cases, such as substituted 3,3'-bicoumarin (from Toddalia asiatica [7] and 4,4'-bicoumarin [8] (from Impatiens
balsamina), and also 8,8'-bicoumarins, the mycotoxins kotanin and desmethylkotanin (from Aspergillus
glaucus) [9]. The isolation of 3,8'-bicoumarins [10, 11] and chromanoylcoumarins [12] from natural sourses is
also known.
The aim of our investigation was the synthesis and a study of the reactivity of 3,4'-bicoumarins, the
regioisomers of the natural 3,3'-bicoumarins or 4,4'-bicoumarins. One should mention that the preparation of
substituted 3,4'-bicoumarins from plant material is unknown, while their synthesis has provoked the interest of
many investigators [13-17].
Various approaches to the creation of the 3,4'-bicoumarin structure are known. The interaction of
4-hydroxycoumarin with substituted Meldrum acids [14], and also the condensation of (coumarin-4-yl)acetic
acids or their esters with substituted salicylic aldehydes [13, 15-17] has been described. For the preparation of
_______
*For Communication 2, see [1].
**To whom correspondence should be addressed, e-mail: mfras@i.kiev.ua.
1Institute of Bioorganic Chemistry and Petroleum Chemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02094, Ukraine.
2National University of Food Technology, 68 Volodymirska St., Kyiv 01601, Ukraine; e-mail:
sp_bondarenko@ukrpost.ua.
3Kyiv Taras Shevchenko National University, 64 Volodymirska St., Kyiv 01601, Ukraine; e-mail:
vkhilya@univ.kiev.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 450-454, March, 2012. Original
article submitted July 9, 2011.
422
0009-3122/12/4803-0422©2012 Springer Science+Business Media, Inc.

hydroxyl derivatives of 3,4'-bicoumarins 1a-d we used the latter method being, in our view, more convenient.
We have improved it to increase the yield of the desired products.
In view of the insignificant reactivity of the methylene group of (7-hydroxycoumarin-4-yl)acetic acid
methyl ester in the condensation reaction with aldehydes it was necessary to select a catalyst capable of
activating the methylene group, and a solvent for carrying out the reaction. Potassium carbonate, potassium
acetate, piperidine, and tertiary amines (triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methyl-
morpholine) were used as base, and ethanol, dioxane, and DMF were used as solvent.
R
O
O
HO
O
O
1'O
OH
R1
4
4'
R
6
3
DBU
CO2Me
O
O
HO
O
6'
1
R1
1a–d
O
CH2(NR2R3)2
R
R2R3N
HO
O
O
R1
2a–n
1a, 2a,d,e,g,i,m R = R1 = H; 1b, 2b,h,j R = Cl, R1 = H; 1c, 2c,n R = Br, R1 = H;
1d, 2f,k,l R = H, R1 = OMe; 2a–c R2 = Me, R3 = Bu; d R2 = R3 = Pr; e,f R2 = R3 = i-Bu;
g,h R2 = R3 = CH2CH2OMe; i,j R2 = Me, R3 = СН2Ph; k NR2R3 = piperidin-1-yl;
l NR2R3 = 3,5-dimethylpiperidin-1-yl; m NR2R3 = 4-methylpiperazin-1-yl;
n NR2R3 = 4-(2-hydroxyethyl)piperazin-1-yl
As a result of the solvent and catalyst variation we concluded that the most suitable solvent for the
synthesis of 3,4'-bicoumarins 1a-c was dioxane in the presence of DBU as catalyst. When introducing
3-methoxysalicylaldehyde into the reaction extended boiling of the reaction mixture was required in order to
finish the reaction, which was accompanied by resinification, but the use of DMF led to shortening of the time
for synthesis of coumarin 1d.
One of the promising routes for the modification of natural phenolic compounds and their analogs is the
synthesis of Mannich bases, because the variation in the broad range of amino components (secondary amine)
makes it possible to obtain promising biologically active compounds [18]. The introduction of an aminomethyl
group into the molecules of a substituted 7'-hydroxy-3,4'-bicoumarins increases their solubility and thereby
broadens the possibility of studying their physiological action.
In view of the structure of synthesized compounds 1a-d, the best approach in our view to obtain
aminomethyl derivatives is the method using aminals of a secondary amines. As it turned out electrophilic
substitution under these conditions proceeds exclusively at position 8'. Thus, as a result of the interaction of
substituted 7'-hydroxy-3,4'-bicoumarins with aminals we have synthesized Mannich bases 2a-n in yields of
48-82%.
Spectral data confirmed the aminomethylation at position 8', indicated by the changes in coupling
1
constants in the H NMR spectra. As opposed to the initial compounds [15], the signal of the H-8' proton was
missing in the aminomethyl derivatives 2a-n and the signals of the H-6' and H-5' protons were observed as a
doublet with coupling constant of 8.7-9.0 Hz.
423

TABLE 1. Physicochemical Characteristics of 3,4'-Bicoumarins 1b and 2a-n
Found, %
——————
Com-
pound
Empirical
formula
Mp, °C
Yield, %
Calculated, %
С
Н
N
Br (Cl)
C18H9ClO5
63.56
63.45
70.93
71.10
65.48
65.53
59.38
59.52
71.66
71.58
72.39
72.46
70.54
70.42
66.35
66.51
62.04
61.80
73.94
73.79
68.56
68.43
69.39
69.27
70.36
70.27
68.75
68.89
57.10
56.94
2.57
2.66
5.68
5.72
4.95
5.04
4.69
4.58
5.99
6.01
6.48
6.53
6.48
6.54
5.55
5.58
5.07
4.98
4.95
4.82
4.16
4.25
5.27
5.35
6.13
5.90
5.09
5.30
4.58
4.40
10.47
10.41
—
278-280
148-150
206-207
200-202
183-185
175-176
188-190
157-158
137-138
188-190
205-206
204-205
146-147
207-208
203-204
58
63
56
48
71
67
59
78
65
63
59
77
62
82
67
1b
2a
2b
2c
2d
2e
2f
—
C24H23NO5
C24H22ClNO5
C24H22BrNO5
C25H25NO5
C27H29NO5
C28H31NO6
C25H25NO7
C25H24ClNO7
C27H21NO5
C27H20ClNO5
C25H23NO6
C27H27NO6
C24H22N2O5
C25H23BrN2O6
3.42
3.45
2.89
3.18
2.66
2.89
3.37
3.34
2.98
3.13
2.89
2.93
3.15
3.10
3.13
2.88
3.27
3.19
3.27
2.96
3.17
3.23
2.95
3.03
6.82
6.69
4.98
5.31
7.89
8.06
16.87
16.50
—
—
—
—
2g
2h
2i
7.33
7.30
—
7.54
7.48
2j
2k
2l
—
—
—
2m
2n
15.40
15.15
It has therefore been shown that the Knoevenagel condensation of substituted salicylaldehydes with the
methyl ester of (7-hydroxycoumarin-4-yl)acetic acid in dioxane in the presence of DBU is a simple and efficient
method of obtaining substituted 7'-hydroxy-3,4'-bicoumarin. It was also established that the aminomethylation
of 7'-hydroxy-3,4'-bicoumarins proceeds under the action of aminals with the formation of 8'-aminomethyl
derivatives.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Varian VXR-300 spectrometer (at 300 MHz), internal standard
was TMS. The spectral data of compounds 2a-n are given in Table 2. The 1H NMR spectral data of compounds
1a,c,d corresponded to literature data [15]. Melting points were measured on a Buchi B-535 instrument. The
progress of reactions and the purity of the obtained compounds were checked by TLC on Silufol UV 254 and
Merck 60 F254 plates, eluent was a CHCl3–MeOH, 9:1 or 19:1 mixture.
7'-Hydroxy-3,4'-bicoumarins 1a-d (General Method). A solution of (7'-hydroxycoumarin-4-yl)acetic
acid methyl ester [15] (23.40 g, 0.1 mol), the corresponding salicylaldehyde (0.1 mol), and DBU (1.52 g,
0.01 mol) in abs. dioxane (100 ml) (or DMF (50 ml) in the case of compound 1d) was stirred at 100-105oC for
4-10 h. The solution was cooled, the solvent evaporated under reduced pressure, and the residue transferred into
acidified water (200 ml). The precipitated crystals were filtered off, washed on the filter with water, dried, and
recrystallized from a DMF–MeOH, 1:3, mixture.
424

425

1
6-Chloro-7'-hydroxy-2H,2'H-3,4'-bichromene-2,2'-dione (1b). H NMR spectrum, δ, ppm (J, Hz):
3
4
4
3
6.35 (1H, s, H-3'); 6.74 (1H, dd, J = 8.6, J = 2.4, H-6'); 6.79 (1H, d, J = 2.4, H-8'); 7.47 (1H, d, J = 8.6,
H-5'); 7.55 (1H, d, 3J = 8.8, H-8); 7.75 (1H, dd, 3J = 8.8, 4J = 2.8, H-7); 7.92 (1H, d, 4J = 2.8, H-5); 8.23 (1H, s,
H-4); 10.65 (1H, br. s, 7'-OH).
8'-Aminomethyl-7'-hydroxy-2H,2'H-3,4'-bichromene-2,2'-diones 2a-n (General Method). The
corresponding aminal (2.2 mmol) was added to a hot solution of bicoumarin 1a-d (2.0 mmol) in dioxane (10 ml)
and the mixture was refluxed for 3-5 h, then cooled. The solvent was evaporated under reduced pressure, and
the residue crystallized from a 2-PrOH–hexane, 1:2 mixture.
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