Synthesis and properties of 4-chloromethyl-6-hydroxy-coumarins and 4-(2-benzofuryl)-6-hydroxycoumarins

Article abstract of DOI:10.1007/s10593-009-0275-x

New 4-chloromethyl-6-hydroxycoumarins have been obtained by the condensation of hydroquinone derivatives with 4-chloroacetoacetic ester, and have been used for the synthesis of 4-(2-benzofuryl)-6-hydroxycoumarins. Alkylation and acylation of the phenolic

Full text of DOI:10.1007/s10593-009-0275-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
SYNTHESIS AND PROPERTIES
OF 4-CHLOROMETHYL-6-HYDROXY-
COUMARINS AND 4-(2-BENZOFURYL)-
6-HYDROXYCOUMARINS
M. S. Frasinyuk1*, S. P. Bondarenko2, and V. P. Khilya2
New 4-chloromethyl-6-hydroxycoumarins have been obtained by the condensation of hydroquinone
derivatives with 4-chloroacetoacetic ester, and have been used for the synthesis of 4-(2-benzofuryl)-
6-hydroxycoumarins. Alkylation and acylation of the phenolic hydroxyl of the synthesized 4-(2-benzo-
furyl)coumarins have been investigated.
Keywords: 4-(2-benzofuryl)coumarins, 4-chloromethylcoumarins, alkylation, acylation, hetero-
cyclization.
4-Halomethylcoumarins, which may be obtained under the conditions of the Pechmann reaction [1-3] by
the chlorination of derivatives of coumarin-4-acetic acid in AcOH [4] and by the interaction of 4-hydroxy-
methylcoumarins with PCl5 in benzene [5], are convenient reactants for the synthesis of various heterocyclic
compounds. Substituted chloromethylcoumarins are converted into derivatives of 3-benzofurylacetic acid by the
action of alkalis [6]. The alkylation of amines and phenols by substituted 4-halomethylcoumarins is known
[7-11].
Various methods have been described for the synthesis of 4-(2-benzofuryl)coumarins including
alkylation with 4-halomethylcoumarins of salicylaldehyde derivatives [12-15], of 2-hydroxyacetophenone [16],
or methyl salicylate [16] with subsequent intramolecular cyclization of the methylene and carbonyl groups,
interaction of 2-(2-hydroxybenzoyl)benzofuran with ethyl (triphenylphosphorylidene)acetate [13], or Pechmann
condensation of resorcinol with 2-benzofuroylacetic ester [13]. At the present moment only the last method
permits derivatives of 2-benzofurylcoumarin containing a free hydroxyl group to be obtained.
In this connection it was of interest to study the possibility of using 4-(2-benzofuryl)hydroxycoumarins
without previous protection of the phenolic hydroxyl group for the synthesis of 4-chloromethylcoumarins. To
achieve this aim we synthesized the new 4-chloromethyl-6-hydroxycoumarins 1a-c, and also used the previously
described 4-chloromethyl-7-hydroxycoumarins 1d,e [6].
_______
* To whom correspondence should be addressed, mfras@i.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kiev 02094,
Ukraine.
2 Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: vkhilya@univ.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 361-369, March, 2009. Original
article submitted November 27, 2007.
290
0009-3122/09/4503-0290©2009 Springer Science+Business Media, Inc.

As it turned out, the interaction of substituted 4-chloromethyl-6-hydroxycoumarins 1a-c with
salicylaldehydes 2a-d was effected in DMF in the presence of potassium carbonate. This alkylation reaction
proceeds selectively with the formation of 4-(2-benzofuryl)-6-hydroxycoumarins 3a-g. Alkylation of the
hydroxyl group of substituted 4-chloromethyl-6-hydroxycoumarins was not observed. To all appearances this is
caused by the lower reactivity of the phenolic hydroxyl in position 6 of the coumarin compared with the
hydroxyl group of salicylaldehyde.
O
O
O
R2
R2
R
O
O
H
+
O
HO
HO
R1
R1
Cl
1a–c
2a–d
R
OH
3a–g
1a, 3a,c,g R = H, 1b, 3b,d,f R = Me, 1c, 3e R = Ph; 2a, 3a,b R1 = R2 = H;
2b, 3c–e R1 = OMe, R2 = H; 2c, 3f R1 = OEt, R2 = H; 2d, 3g R1 = H, R2 = Br
At the same time the interaction of 4-chloromethyl-7-hydroxycoumarins [6] with salicylaldehydes under
analogous conditions led to the formation of a mixture of difficultly separable products.
O
O
R
R2
HO
O
O
2a–d
+
O
R1
R
Cl
1d,e
HO
1 d R = H, e R = Me
In view of the special features of the structure of the synthesized compounds 3a-e,g, we studied their
reaction at the phenolic hydroxyl. As it turned out, the alkylation of these compounds proceeds under the action
of various reactants in the presence of potassium carbonate in DMF with the formation of 6-O-alkyl derivatives
4a-l in high yield.
R
R
O
O
O
O
R4
O
R5
O
O
R3
O
R3
4a–l
5a–e
3a,e–g
R
R
O
O
O
O
R6
O
R7
S
N
R8
O
O
O
R3
R3
7a,b
6a,b
4a,d,e,g,j–l, 5b, 6b R = H, 4 b, c, f, h, 5a, e, 6a, 7a R = Me, 4 i, 5c, d, 7 b R = Ph, 4a–c, 5a, 7a R3 = benzofuryl-2,
4d–j, 5b–e, 6a,b, 7b R3 = 7-methoxybenzofuryl-2, 4 k, l R3 = 5-bromobenzofuryl-2, 4 a,d,k R4 = Me, b, e, f R4 = Et;
c, g–i, l R4 = CH2CO2Et; j R4 = CH2CH=CMe2; 5 a, c R5 = furyl-2, b R5 = thienyl-2; d R5 = Ph; e R5 = 3,4-OCH2OC6H3;
6 a R6 = Me, b R6 = 4-MeOC6H4, 7 a R7 = R8 = Me, b R7R8 = CH2CH2OCH2CH2
291

Acylation of compounds 3b-e was effected on extended exposure of the initial 4-(2-benzofuryl)-
6-hydroxycoumarins to the acid chlorides of carboxylic and sulfonic acids, and also to dialkylcarbamoyl-
chlorides with the formation of the corresponding derivatives 5a-e, 6a,b, and 7a,b.
TABLE 1. Characteristics of 2-(4-Benzofuryl)coumarins 3-7
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
Н
Br (S) [N]
3a
3b
3c
3d
3e
3f
C17H10O4
C18H12O4
C18H12O5
C19H14O5
C24H16O5
C20H16O5
C17H9BrO4
C18H12O4
C20H16O4
C22H18O6
C19H14O5
C20H16O5
C21H18O5
C22H18O7
C23H20O7
C28H22O7
C23H20O5
C18H11BrO4
C21H15BrO6
C23H14O6
C23H14O6S
C29H18O7
C31H20O6
C27H18O8
C20H16O7S
C25H18O8S
C21H17NO5
C29H23NO7
73.56
73.38
73.82
73.97
70.25
70.13
70.68
70.80
75.21
74.99
71.25
71.42
57.28
57.17
73.67
73.97
74.74
74.99
69.67
69.84
71.03
70.80
71.35
71.42
72.14
71.99
66.84
67.00
67.52
67.64
71.32
71.48
73.26
73.39
58.33
58.25
56.68
56.91
71.24
71.50
65.81
66.02
72.65
72.80
76.01
76.22
69.16
68.94
59.73
59.99
62.68
62.76
69.27
69.41
69.83
70.01
3.48
3.62
4.26
4.14
3.86
3.92
4.26
4.38
4.04
4.20
4.96
4.80
2.81
2.54
4.25
4.14
5.13
5.03
4.95
4.80
4.24
4.38
4.68
4.80
4.98
5.18
4.67
4.60
5.06
4.94
4.62
4.71
5.06
5.36
3.18
2.99
3.41
3.41
3.67
3.65
3.45
3.37
3.87
3.79
4.25
4.13
3.92
3.86
3.82
4.03
3.92
3.79
4.93
4.72
4.71
4.66
262-263
265-267
271-273
310-312
288-290
249-251
290-292
165-167
206-208
148-150
223-224
156-167
190-191
159-161
219-220
198-200
155-156
233-234
143-144
204-205
235-237
272-274
233-234
237-239
215-216
161-162
190-191
198-199
56
47
65
57
56
43
39
78
82
68
86
74
67
80
77
73
77
83
75
67
65
53
78
83
76
81
87
68
3g
4a
4b
4c
4d
4e
4f
22.09
22.37
4g
4h
4i
4j
4k
4l
21.25
21.53
18.18
18.03
5a
5b
5c
5d
5e
6a
6b
7a
7b
(7.38)
(7.66)
(8.33)
(8.01)
(6.95)
(6.70)
[4.01]
[3.85]
[2.66]
[2.82]
292

293

294

We have therefore shown that the selective alkylation of the phenolic hydroxyl of salicylic aldehydes by
the action of 4-chloromethyl-6-hydroxycoumarins with subsequent intramolecular cyclization makes possible
the synthesis of derivatives of 4-(2-benzofuryl)-6-hydroxycoumarin, without previous protection of the hydroxyl
group of the alkylating agent. The alkylation and acylation of the synthesized benzofuryl-substituted
6-hydroxycoumarins have been investigated.
EXPERIMENTAL
A check on the progress of reactions and an assessment of the purity of the obtained compounds was
effected by TLC on Silufol UV-254 and Merck 60 F254 plates. Chloroform–methanol mixtures, 9:1, 95:5, and
also hexane–ethyl acetate, 1:2, were used as eluent. The 1H NMR spectra were measured on a Varian VXR 300
(300 MHz) instrument in DMSO-d6, internal standard was TMS.
Synthesis of 4-Chloromethylcoumarins 1a-c [6]. A mixture of 4-chloroacetoacetic ester (100 mmol)
and the appropriate (un)substituted hydroquinone (100 mmol) was poured into 73% sulfuric acid (50 ml) and the
mixture stirred at room temperature for 18-24 h. The reaction mixture was poured onto ice, the precipitated solid
filtered off, and crystallized from dioxane.
1
4-Chloromethyl-6-hydroxycoumarin (1a). Yield 47%; mp 220-222°C. H NMR spectrum, δ, ppm (J,
Hz): 4.97 (2H, s, 4-CH2); 6.33 (1H, s, H-3); 7.09 (1H, dd, J = 8.6, J = 2.2, H-7); 7.15 (1H, d, J = 2.2, H-8); 7.30
(1H, d, J = 8.6, H-5); 9.86 (1H, s, 6-OH). Found, %: Cl 16.56. C10H7ClO3. Calculated, %: Cl 16.83.
1
4-Chloromethyl-6-hydroxy-7-methylcoumarin (1b). Yield 56%; mp 223-225oC. H NMR spectrum,
δ, ppm (J, Hz): 2.21 (3H, s, 7-CH3); 4.91 (2H, s, 4-CH2); 6.58 (1H, s, H-3); 7.11 (1H, s, H-8); 7.21 (1H, s, H-5);
9.82 (1H, s, 6-OH). Found, %: Cl 16.03. C11H9ClO3. Calculated, %: Cl 15.78.
4-Chloromethyl-6-hydroxy-7-phenylcoumarin (1c). Yield 53%; mp 234-235oC. 1H NMR spectrum, δ,
ppm (J, Hz): 4.97 (2H, s, 4-CH2); 6.68 (1H, s, H-3); 7.31 (1H, s, H-8); 7.37 (1H, s, H-5); 7.39-7.47 (5H, m,
7-C6H5); 10.06 (1H, s, 6-OH). Found, %: Cl 12.54. C16H11ClO3. Calculated, %: Cl 12.37.
Preparation of 4-(2-Benzofuryl)-6-hydroxycoumarins 3a-g (General Method). Potassium carbonate
(40 mmol) was added to a solution of the appropriate salicylaldehyde 2a-d (10 mml) in DMF (20 ml). The
mixture was stirred and heated to 60-80°C and the appropriate 4-chloromethyl-6-hydroxycoumarin 1a-c
(10 mmol) was added. The reaction mixture was maintained for 8 h at 100oC (the end of the reaction was
determined by TLC). After cooling, the reaction mixture was poured into cold water (100 ml), the mixture was
acidified to pH 4 with dilute H2SO4, the solid was filtered off, and crystallized from DMF.
Preparation of 6-Alkoxy-4-(2-benzofuryl)coumarins 4a-l (General Method). Freshly calcined potassium
carbonate (4.1 g, 30 mmol) was introduced into a hot solution of the appropriate 6-hydroxycoumarin 3a-e (10 mmol)
in DMF (30 ml), and then the appropriate alkyl halide or dialkyl sulfate (12 mmol) was added with stirring and
heating to 60-80°C. The reaction mixture was maintained for 1-4 h (the end of the reaction was determined by TLC)
and then poured into acidified ice-water (100 ml). The precipitated solid was filtered off and crystallized from
ethanol.
Preparation of 6-Acyloxy-4-(2-benzofuryl)coumarins 5a-e, 6a,b, and 7a,b (General Method). The
acid chloride (12 mmol) was added to a solution of the appropriate 6-hydroxycoumarin 3b-e (10 mmol) in the
minimum quantity of absolute pyridine. The reaction mixture was maintained at room temperature for 1 day (the
end of the reaction was determined by TLC), then poured into ice-water. The precipitated solid was filtered off
and crystallized from a suitable solvent.
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