Synthesis and characterization of some coumarins with two hydroxy or methoxy substituents

Article abstract of DOI:10.1002/jhet.5570380534

The first synthesis of the 6-hydroxy-4-methoxycoumarin (5) was carried out in 25% overall yield from 6-methoxy-4-hydroxycoumarin (1) by hydrolysis of the methoxy group and subsequent selective methylation of the hydroxyl group at position 4. The ¹H and ¹³C NMR data of compounds 1-6 are reported.

Full text of DOI:10.1002/jhet.5570380534

Sep-Oct 2001
Synthesis and Characterization of Some Coumarins with Two Hydroxy
or Methoxy Substituents
1231
Yagamare Fall [a], Lourdes Santana [b],* and Eugenio Uriarte [b]
[a] Department of Organic Chemistry, University of Vigo, Spain
[b] Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Spain
The first synthesis of the 6-hydroxy-4-methoxycoumarin (5) was carried out in 25 % overall yield from 6-
methoxy-4-hydroxycoumarin (1) by hydrolysis of the methoxy group and subsequent selective methylation
1
13
of the hydroxyl group at position 4. The H and C NMR data of compounds 1-6 are reported.
J. Heterocyclic Chem., 38, 1231 (2001).
Though long known, coumarins have in recent years
(compounds 2, 4 and 6) [8-12], only the 4-hydroxy-7-
methoxy derivative 4 has been totally characterized [12],
while the 4-methoxy-6-hydroxy compound 5 appears not to
have been synthesized and its precursors in Scheme 1 (1 and
3) have been only very incompletely characterized [8,9].
Here we describe the first synthesis of compound 5, and pre-
sent H and C NMR data for this compound and for the
other disubstituted coumarins shown in Scheme 1.
Compound 3 was obtained from 1 [9] in 45% yield by
hydrolysis of the methoxy group with HI in acetic acid
[10], and selective methylation of the 4-OH group by a
mixture of hydrochloric acid and methanol [11] then
attracted growing interest, some having been found to pos-
sess properties of considerable pharmacological or industrial
significance [1-5]. In the course of our previous work in this
field [5-7] we realized that several very simple coumarins of
apparent interest have not yet been synthesized, and that oth-
ers have been characterized only incompletely. In particular,
this is true of coumarins with hydroxy or methoxy groups in
positions 4, 6 and/or 7 (the usual substitution positions in
both natural and synthetic coumarins), which have great syn-
thetic potential. For example, in spite of abundant references
in the literature to 4,7-disubstituted coumarins of this type
1
13
Table 1
1
H NMR Spectra of Coumarins 1-6 in DMSO-d : Chemical Shifts and Coupling Constants
6
Compoumd
H3
H5
H6
H7
H8
OH-4
OH-6 OH-7
CH3
1
5.59, s
7.22
d, J = 2.40
7.71
d, 7.87
7.10
7.19
dd, J= 8.33, 2.40
7.30
d, J = 8.33
6.90
d, 2.43
7.20
12.56, s
3.79, s
2
3
4
5.43
6.93
12.45, s
3.83
dd, J = 7.87, 2.43
5.53, s
5.37, s
7.04
12.35, s 9.72, s
12.23, s
d, J = 2.87
7.62
dd, J = 8.87, 2.80
d, J = 8.87
6.65
6.75
10.51, s
d, J = 8.65
dd, J = 8.65, 2.24
d. J = 2.24
5
6
5.85, s
5.65, s
7.09
d, J = 2.86
7.61
7.09
7.24
d, J = 8.73
6.68
9.80, s
3.80, s
dd, J = 8.73, 2.86
6.76
10.60, s 3.95, s
d, J = 8.78
dd, J = 8.78, 2.23
d, J = 2.23

1232
Y. Fall, L. Santana, and E. Uriarte
Vol. 38
Table 2
13
C NMR Spectra of Coumarins 1-6 in DMSO-d
6
Compound
C2
C3
C4
C4a
C5
C6
C7
C8
C8a
CH
3
1
2
3
4
5
6
162.42
162.82
162.50
162.40
162.29
162.53
91.54
87.46
91.60
87.75
90.62
87.20
165.78
167.05
165.83
166.00
165.99
166.79
120.71
108.03
123.12
107.50
115.94
107.40
105.29
124.75
110.40
124.45
107.08
124.47
155.61
114.53
154.72
112.48
153.99
113.18
116.58
163.14
121.03
161.50
117.87
162.02
117.92
100.79
119.89
101.93
121.31
102.37
148.19
155.79
145.73
156.03
146.311
154.96
55.97
56.18
57.30
57.33
CH Cl /MeOH, yielding the desired compound 5 (0.6 g 55%),
afforded compound 5 in 55% yield. Compound 6 was pre-
pared analogously from 2 via 4 [9], with an overall yield
of 48%. H and C NMR data for compounds 1-6 are
2
2
and 0.16 g (15%) of the starting coumarin 3; mp 283-285 °C
(EtOH); RF: 0.43 (9:1 CH Cl /MeOH); ir: υ 3186, 1664, 1571,
1
13
2
2
-1
+
1468, 1398, 1243, 1092 cm ; MS m/z (%): 192 (M , 100), 164
(M - CO, 41), 149 (M - CO , 46), 134 (27), 121 (14), 78 (25).
listed in Tables 1 and 2, respectively.
+
+
2
Anal. Calcd. for C H O : C, 60.68; H, 3.39. Found: C, 60.51;
H, 3.55.
10
8 4
EXPERIMENTAL
Acknowledgment.
Melting points were determined in a Reichert Kofler ther-
mopan, and are uncorrected. IR spectra were recorded in a
We thank the Xunta de Galicia (PGIDTOOPXI20317PR) for
financial support.
-1
1
13
Perkin-Elmer 1640FT spectrometer (υ in cm ). H and
C
NMR spectra were recorded in a Bruker AMX spectrometer at
300 and 75.47 MHz, respectively, using TMS as internal standard
(chemical shifts in δ values, J in Hz). Mass spectrometry was car-
ried out in a Hewlett Packard 5988A spectrometer. Elemental
analyses were performed on a Perkin-Elmer 240B microanalyser.
Flash chromatography (FC) was performed on silica gel (Merck
60, 230-400 mesh).
REFERENCES AND NOTES
[1] R. D. H. Murray, The Natural Coumarins: Occurrence,
Chemistry and Biochemistry. Wiley-Interscience, NY 1982.
[2] S. Wang, G. Milne, W. A. Yan and I. J. Posey, J. Med.
Chem., 39, 2047 (1996).
[3] B. Rendenbach-Müller, R. Schleker, M. Traut and H.
Weifenbach, Bioorg. Med. Chem. Lett., 42, 2662 (1999).
[4] L Xie, Y. Takeuchi, L. M Cosentino, and K-H. Lee, J. Med.
Chem., 42, 2662 (1999).
[5] L. Santana, C. Teran, E. Uriarte, Y. Fall, L. Unellius and
B-R. Tolf, Bioorg. Med. Chem. Lett., 8, 3567 (1998).
[6] Y. Fall, C. Teran, M. Teijeira, L. Santana, and E. Uriarte,
Synthesis, 5, 643 (2000).
[7] E. Estrada, J. C. González, L. Santana and E. Uriarte,
Struc. Chem., 11, 249 (2000).
[8] J. F. Garden, N. F. Hayes and R. H. Thomson, J. Chem.
Soc., 3315 (1956).
[9] D. R. Buckle, B. C. C. Cantello, H. Smith and B. A. Spicer,
J. Med. Chem., 18, 391 (1975).
[10] T. Mizuno, I. Nishiguchi, T. Hirashima, A. Ogawa, N.
Kambe and N. Sonoda, Synthesis, 3, 257 (1988).
[11] V. K. Ahluwalia and D. Kumar, Indian J. Chem., 15B, 945
(1977).
4,6-Dihydroxycoumarin (3).
Compound 1 (1 g, 5.2 mmol) was added to a mixture of hydri-
odic acid (25 ml), acetic anhydride (10 ml) and acetic acid (10
ml), and the mixture was heated at 80 °C for 1 hour. After cooling
to room temperature, 100 ml of water was added. The resulting
precipitate was isolated by filtration and purified by flash chro-
matography (FC) using 4:1 CH Cl /MeOH as eluent. Yield 0.4 g.
(45%), mp 286-288 °C (MeOH); RF: 0.22 (4:1 CH Cl /MeOH);
2
2
2
2
-1
ir: υ 3100-2800, 1663, 1567, 1462, 1325, 1153, 1097, 1002 cm ;
+
+
+
MS m/z (%): 178 (M , 96), 150 (M - CO, 30), 136 (M - CO ,
2
100), 108 (47), 78 (64).
Anal. Calcd. for C H O : C, 62.5; H, 4.20. Found: C, 62.38;
9
6 4
H, 4.43.
6-Hydroxy-4-methoxycoumarin (5).
A mixture of 3 (1 g, 5.6 mmol), MeOH (40 ml) and concen-
trated HCl (5 ml) was refluxed for 1.5 hours. The solvent was
removed in vacuo and the residue was purified by FC using 9:1
[12] V. F. Traven, V. V. Negrebetsky, L. I. Vorobjeva and A. C.
Carberry, Can. J. Chem., 75, 377 (1977).