Synthesis of methylenebis(4-hydroxy-2-pyrone) or methylenebis(4- hydroxycoumarin) derivatives by organic solid state reaction

Article abstract of DOI:10.3987/COM-99-8817

Methylenebis(4-hydroxy-2-pyrone) or methylenebis(4-hydroxycoumarin) derivatives (5) have been synthesized from 4-hydroxy-2-pyrones or 4- hydroxycoumarin (3) with aldehydes (4) by organic solid state reaction.

Full text of DOI:10.3987/COM-99-8817

HETEROCYCLES, Vol. 53, No. 3, 2000, pp. 549 - 552, Received, 26th November, 1999
SYNTHESIS OF METHYLENEBIS(4-HYDROXY-2-PYRONE)
OR METHYLENEBIS(4-HYDROXYCOUMARIN)
DERIVATIVES BY ORGANIC SOLID STATE REACTION1
Hisahiro Hagiwara,*a Norikazu Fujimoto,b Toshio Suzuki,a
and Masayoshi Andob
Graduate School of Science and Technology,a and Faculty of Engineering,b
Niigata University, 8050, 2 no-cho, Ikarashi, Niigata 950-2181, Japan
Abstract–Methylenebis(4-hydroxy-2-pyrone) or methylenebis(4-hydroxy-
coumarin) derivatives (5) have been synthesized from 4-hydroxy-2-pyrones or 4-
hydroxycoumarin (3) with aldehydes (4) by organic solid state reaction.
The methylene bridged biscoumarins namely dicoumarol (1) and coumetarol (2) find application as oral
anticoagulants in the treatment of thromboemblic disorders,2,3 besides retaining their role as reagents for
biochemical use. Some literature precedents do offer methods to synthesize these compounds, for
example, methylenebis(4-hydroxy-2-coumarin) derivatives (5) was prepared by condensation of 4-
hydroxycoumarin (3) with aqueous formaldehyde under basic condition.3 Similarly, the electrochemical
oxidation4 and the treatment of 6 under Knoevenagel reaction conditions5 are the other alternative
procedure described for the preparation of these bis compounds. However, the first method lacks
generality as it involves aqueous reaction media and the second procedure is useful to obtain only the
methylene bridged bispyrone derivatives (11a).
OH
OH
R
1 R=H
Dicoumarol
2 R=CH OMe Coumetarol
2
O
O
O
O
In connection with the synthetic studies directed towards some natural products together with our
continued interest in the organic solid state reaction,6 we delineate herein a general and alternative
procedure to combine two units of 4-hydroxy-2-pyrone derivatives (3) with aldehydes (4) to provide
methylenebis(4-hydroxy-2-pyrone) derivatives (5) simply by grinding the substrates in a mortar
(Scheme 1).
Recently, we reported Et2AlCl promoted coupling of 4-hydroxy-2-pyrone or 4-hydroxycoumarin
derivatives (3) leading to methylenebis(4-hydroxy-2-pyrone) or methylenebis(4-hydroxycoumarin)
derivatives (5)7 in good yield.

Scheme 1. Coupling of 4-hydroxy-2(2H)-pyrone derivatives
OH
O
OH
O
OH
O
OH
O
R
O
Solid state reaction
base
+
or
H
R
O
O
O O
4a: (CH O)
2
n
or
R
3
b: R=C H
9
19
OH
O
OH
O
c: R=(CH ) OTHP
2 4
d: R=(CH ) OTBDMS
2 4
e: R=C H -p-OMe
6 4
O O
f:
5
Though our previous procedure cited above offered some advance in preparing compounds (5), one of
the difficulties in carrying out the reaction is the low solubility of starting pyrones or coumarin
derivatives (3) in the solvents. Another drawback was the low yields of coupling products (5) derived
from aldehydes (4c) and (4d) having acid sensitive THP or TBDMS protecting group, electron rich
aldehydes such as p-anisaldehyde (4e), or acid sensitive substrates like citronellal (4f). In order to
overcome these limitations, we turned our attention to basic solid state reaction whose utility is well
recognized8 though application to synthetic organic chemistry has been limited.
The proper reaction condition was investigated by using 6-methyl-4-hydroxypyrone (6) or 4-
hydroxycoumarin (9) with paraformaldehyde. Among the bases used for the reaction, coupling reaction
proceeded to give constant yields of products with DBU. Potassium carbonate gave comparable yields
though the reaction was sluggish. On the other hand, organic solid base such as dimethylaminopyridine
gave poor yields. Without base, the reaction resulted in complete recovery of starting materials. The
reaction was carried out by simple grinding of a mixture of pyrone (3), aldehyde (4) and DBU in a
mortar with a pestle in open air at ambient temperature. Products (5) were directly purified by silica gel
column chromatography.
Some representative results are listed in Table 1. Not only 4-hydroxypyrones (6) and (7), or 4-
hydroxycoumarins (9) and (10), but also 5,6-dihydro-4-hydroxy-(2H)-pyrane (8) afforded dimeric
products (11 ~ 15) in fair to good yield. It is noteworthy that p-anisaldehyde (4e) provided coupling
product in high yield.7 In Entry 4, low purity of aldehyde (4d) resulted in low yield of the product. In
Entry 19, substantial amount of aldehyde (4e) (39%) was recovered back due to interruption of the
reaction at earlier stage. Self condensation of aldehydes (4) was not a problem under the present basic
reaction conditions.
In order to demonstrate the utility of this method, the present procedure was applied to the synthesis of
bisnorhelipyrone (20) isolated from the roots of Helichrysum arenarium9 (Scheme 2). β,δ-Diketo ester
(18) was prepared by condensation of methyl propionylacetate dianion with acetaldehyde followed by
Jones oxidation. Base assisted cyclization10 of 18 gave pyrone derivative (19) whose solid state reaction
with paraformaldehyde in the presence of DBU furnished bisnorhelipyrone (20) in high yield.

Table 1. Solid state reactions of 4-hydroxypyrones, 5,6-dihydro-4-hydroxypyrone, and
4-hydroxycoumarin with aldehydes
DBU/ Condition
(eq/ h)
Starting Material
Pyrone R-CHO
Entry
Products
R
Yield (%)a
OH
O
OH
O
1
2
3
4
5
OH
11a: 62
b: 80
c: 81
4a:
b:
c:
0.2/ 2
0.1/ 5
0.1/ 24
0.2/ 26
0.2/ 9
d: 47
e: 99
d:
e:
Me
C9H19
Me
Me
O O
Me
C9H19
Me
O
O
O
O
6
11
OH
OH
O
OH
O
R
4a:
e:
12a: 73
e: 64
7
8
0.4/ 2
0.4/ 4
O
C9H19
O O
7
12
OH
O
OH
O
OH
R
13a: 87
b: 61
e: 78
4a:
b:
e:
9
10
11
0.4/ 1.2
0.4/
3
0.4/ 1.5
Me
O
O O
13
8
4a:
b:
c:
e:
f:
12
13
14
15
16
0.4/ 24
0.1/ 16
0.1/ 4.3
0.2/ 16
14a: 65
b: 88
c: 81
e: 99
f: 78
OH
O
OH
O
OH
R
O O
O
O
0.2/
9
14
9
OH
OH
O
OH
O
R
17
18
19
0.4/ 2.5
0.8/13.5
15a: 95
4a:
b:
e:
Me
Me
Me
Me
Me
Me
b: 90
e: 56
0.4/
5
O
O
O O
10
15
4a: (CH2O)n, b: R=C9H19, c: R=(CH2)4OTHP, d: R=(CH2)4OTBDMS, e: R=C6H4-p-OMe,
f:
a: Yield is based on pyrone or coumarin derivatives.

Scheme 2. Synthesis of bisnorhelipyrone
O
O
O
OH O
O
O
O
i
ii
OMe
OMe
OMe
16
17
18
OH
OH
OH
Me
Me
Me
Me
Me
Me
iii
iv
O
O
O
O O
O
19
20
Reagents and conditions: i, NaH, n-BuLi, acetaldehyde, 51%; ii, Jones reagent, 68%; iii, DBU,
benzene, 54%; iv, DBU (0.4 eq), (CH O) , rt, 15 h, 99%.
2
n
In conclusion, we have clearly established that substituted methylenebis(4-hydroxy-2-pyrone) or
methylenebis(4-hydroxycoumarin) derivatives (5) can be conveniently prepared from their respective
parent compounds through DBU assisted solid state reaction with corresponding aldehydes (4) in
satisfactory yields. The reaction is more general and complementary to the previously reported Et2AlCl
assisted condensation,7 and would be helpful towards acid sensitive or less reactive electron rich
aldehydes.
ACKNOWLEDGMENTS
H. H. thanks the Uchida Energy Science Promotion Foundation and the Sasaki Environmental
Technology Foundation for partial financial support.
REFERENCES
1. A part of this work was presented in 74 annual meeting of Chemical Society of Japan, April
1998, Kyoto (Abstract II, p 838).
2. J. Staunton, in Comprehensive Organic Chemistry, ed. by P. G. Sammes, Vol. 4, pp. 629-658,
Pergamon Press, 1979.
3. R. C. Hayward, J. Chem. Educ., 1984, 61, 87.
4. M. Iguchi, A. Nishiyama, H. Eto, and S. Yamamura, Chem. Lett., 1980, 1323.
5. P. de March, M. Moreno-Manas, R. Pi, and A. Trius, J. Heterocycl. Chem., 1982, 19, 335.
6. Our current efforts in this area: H. Hagiwara, K. Morohashi, T. Suzuki, M. Ando, I. Yamamoto,
and M. Kato, Syn. Comm., 1998, 28, 2001; H. Hagiwara, S. Ohtsubo, and M. Kato, Tetrahedron,
1997, 53, 2415.
7. H. Hagiwara, S. Miya, T. Suzuki, M. Ando, I. Yamamoto, and M. Kato, Heterocycles, 1999, 51,
497.
8. F. Toda, J. Synth. Org. Chem. Jpn., 1994, 52, 923.
9. J. Vakoc, L. Dolejs, and M. Budesinsky, Phytochem., 1975, 14, 1383.
10. Y. Ishibashi, S. Ohba, S. Nishiyama, and S. Yamamura, Tetrahedron Lett., 1996, 37, 2997.