Nov-Dec 2004 A Facile Synthesis of Cytogenin (8-Hydroxy-3-hydroxymethyl-6-methoxyisocoumarin)
977
compound as orange crystals. Mp 117-118°. IR (potassium bro-
mide): 2930, 2849, 1730, 1625, 1575, 1170 cm ; H NMR (deu-
chromatography (Petroleum ether:ethyl acetate 8:2) to afforded 74
mg 1 as light yellow powder (78%). mp152°. (lit. [1] 148.5-
149.5°). IR (film): 3460, 2950, 1685, 1665, 1580, 1480, 1271,
-1
1
teriochloroform): δ 4.29 (s, 2H, CH Cl), 6.51 (s, 1H, H-4), 7.37
2
-1
1
(d, J=7.6, 1H, H-5), 7.51 (t, J=7.6, 1H, H-6), 7.69 (t, J=7.6, 1H,
1162, 741 cm ; H NMR (deuterioacetone): δ 3.95 (s, 3H, MeO-
13
H-7), 8.30 (d, J=8.0, 1H, H-8); C NMR (deuteriochloroform): δ
6), 4.47 (2H,d, J=0.9 CH OH), 6.54 (d, 1H, J=2.76, H-7), 6.67 (d,
2
13
162.5 (C1), 153.7 (C3), 137.7 (C4a), 125.6 (C5), 134.7 (C6),
1H, J=2.64, H-5), 6.70 (1H, s, H-4) ppm; C NMR (deuterioace-
127.6 (C7), 129.4 (C8), 119.9 (C8a), 53.4 (CH Cl); EIMS m/z
(%) =196 [M +2] (43), 194 [M ] (43), 158 (13), 145 (17), 118
(29), 87 (91).
tone): δ 169.3 (C1, CO), 166.9 (C6), 164.7 (C8), 157.9 (C8), 140.2
2
+
+
(C3), 105.3 (C5), 103.2 (C4), 101.9 (C5), 100.1 (C8a), 99.5 (C7),
+
60.31 , 56.5 (MeO-6); EIMS m/z (%): 222 (M , 65), 205 (13), 204
Anal. Calcd. for C H ClO : C, 61.72 H, 3.63 Cl 18.22.
(5), 194 (12), 191 ( 100), 177 (21).
10
7
2
Found: C, 61.28 H, 3.71 Cl 18.38.
Anal. Calcd. For C H O : C 59.46, H 4.54; Found C, 59.21,
11 10 5
H 4.59.
3-Hydroxymethylisocoumarin.
Acknowledgement.
Sodium hydroxide (0.05 % aqueous solution) (8 mL) as added
to a stirred solution of 3-chloromethylisocoumarin (300 mg, 1.54
mmol) in tetrahydrofuran (10 ml). The reaction mixture turned
reddish and was refluxed for 6 h at which time tlc marked the
completion of reaction. The reaction mixture was neutralized and
The author gratefully acknowledges the research grant under
URF, from the department of chemistry, Quaid-I-Azam
University, Islamabad Pakistan.
extracted with ethyl acetate (3x75 mL dried (Na SO ) and con-
2
4
REFERENCES AND NOTES
centrated in vacuo. Thick layer chromatography (petroleum ether:
ethyl acetate=4:6) yielded the 154 mg product (85%) as yellow
amorphous powder. mp 97-98° (lit. [19] 97°). IR (potassium bro-
[1] H. Kumagai, T. Masuda, M. Ohsono, S. Hattori, H.
Naganawa, T. Sawa, M. Hamada, M. Ishizuka and T. Takeuchi, J
Antibiot., 43, 1505 (1990).
-1
mide): 3420, 1705, 1645, 1625, 1575, 1160, 835, 760, 695 cm ;
1
H NMR (deuteriochloroform) δ 4.42 (s, 2H, CH OH), 6.51 (s,
2
[2] M. Ishizuka, H. Kumagai, T. Sawa, H. Naganawa, H.
Iinuma, K. Isshiki, M. Hamada, K. Maeda, and T. Takeuchi, U.S.
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(1994).
1H, H-4), 7.40 (d, J=7.6, 1H, H-5), 7.51 (t, J=7.6, 1H, H-6), 7.69
(t, J=7.6, 1H, H-7), 8.30 (d, J=8.0, 1H, H-8); EIMS m/z (%): 176
[M ] (65), 148 (43), 147 (17), 118 (100), 89 (43).
+
Anal. Calcd. for C H O : C, 68.18; H, 4.58. Found: C, 67.94
10
8 3
H, 4.92.
[4] G. W. McGraw and R. W. Hemmingway, Phytochem. 16,
1315 (1977); G. W. McGraw, R. W. Hemmingway and S. J. Barras, J.
Agric. Food Chem. 25, 717 (1977); W. A. Ayer, L. M. Browne, M. C.
Feng, H. Orszanska, and H. Saeedi-Ghomi, Can. J. Chem., 64, 904
(1986); J. K. Kendall, T. H. Fisher, H. P. Schultz, T. P. Schultz, J.
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Palmblad, Thromb. Haemostasis, 86, 23 (2001).
6,8-Dimethoxy-3-hydroxymethylisocoumarin (4).
Sodium hydroxide (6 mL, 0.05 % aqueous solution) was added
to a stirred solution of 3-chloromethyl-6,8-dimethoxyiso-
coumarin (3) (200 mg, 0.78 mmol) in THF (8 mL). The reaction
mixture turned reddish and was refluxed for 6 h. The reaction
mixture was neutralized and extracted with ethyl acetate (3x75
mL) dried (Na SO ) and concentrated. Thick layer chromatogra-
2
4
phy (petroleum ether:ethyl acetate =3:7) gave 154 mg 4 as yellow
solid (82%) mp 99-102°. IR (potassium bromide) 3450, 2924,
2820, 1730, 1704, 1685, 1602, 1575,1459, 1272, 1074 cm ; H
-1
1
NMR (deuteriochloroform) δ 3.89 (s, 3H, MeO-6) 3.95 (s, 3H,
[6] T. Oikawa, M. Sasaki, M. Inose, M. Shimamura, H.
Kuboki, S. Hirano, H. Kumagai, M. Ishizuka, and T. Takeuchi,
Anticancer Res., 17, 1881 (1997).
MeO-8), 4.41 (br s, or t, 2H, CH OH), 6.54 (s, 1H, H-4), 6.40 (d,
2
13
1H, J=2.3, H-5), 6.51 (d, 1H, J=2.3, H-7); C NMR (deuteri-
[7] H. Kumagai, M. Osono, M. Iijima , M. Sakashita, M.
Ishizuka M and T. Takeuchi , J Antibiot. 48, 317 (1997).
[8] N. Matsumoto, T. Nakashima, K. Isshiki, H. Kuboki, S.
Hirano, H. Kumagai, T. Yoshioka, M. Ishizuka and T. Takeuchi, J
Antibiot., 54, 285 (2001); T. Nakashima, S. Hirano, N. Agata, H.
Kumagai, K. Isshiki, T. Yoshioka, M. Ishizuka, K. Maeda, and T.
Takeuchi, T. J.Antibiot. 52, 426 (1999).
ochloroform) δ 167.5 (C1), 163.5 (C8), 144.3 (C3), 159.5 (C6),
142.6 (4a), 103.1 (C4), 99.6 (C5), 98.3 (C7), 56.4 (MeO-8), 55.7
+
(MeO-6), 60.1 (CH OH); EIMS (70eV): m/z (%) =236 [M ]
2
(63), 220 (43), 206 (17), 205 (100), 177 (52), 149 (38).
Anal. Calcd. for C H O : C, 61.01 H, 5.12. Found: C, 60.98
12 12
5
H, 5.17.
8-Hydroxy-3-hydroxymethyl-6-methoxyisocoumarin (1).
[9] M. Ishizuka, M. Kawatsu, T. Yamashita, M. Ueno and T.
Takeuchi, Int. J. Immunopharmacol., 17, 133 (1997).
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M. Matsufuji, N. Sakata, N. Agata, H. Iguchi and M. Ishizuka, Tissue
React. 17, 175 (1995).
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Ishizuka and T. Takeuchi, J.Antibiot. 47, 440 (1994).
[12] S. Hirano, T. Mase, N. Agata, H. Iguchi, N. Matsumoto, T.
Yoshioka, H. Kumagai, M. Ishizuki and T. Takeuchi U.S. Patent 6, 020,
363 (2000); Chem. Abstr., 137, 169418a (2002).
Aluminum chloride (0.11 g, 0.85 mmol) was added to a solution
of 4 (100 mg, 0.43 mmol) in freshly distilled dry nitrobenzene (6
mL). The reaction mixture was stirred at 50-60° for 6 h, then
poured into ice-water and acidified with dil. hydrochloric acid. The
acidic solution was extracted with ether (3 x 50 mL) and stirred for
10 min. The layers were separated and the aqueous layer extracted
with dichloromethane (2 x 50 mL) and then the combined extracts
with 10% sodium hydroxide (2 x 60 mL). The basic solution was
extracted with ether, acidified and again extracted with ether. The
last extract was evaporated and residue purified by thick layer
[13] H. Yuan, B. Junker, P. Helquist and R. E. Taylor, Curr.
Org. Syn., 1, 1 (2004).