Organic Syntheses Procedure

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Org. Synth. 1976, 55, 45

DOI: 10.15227/orgsyn.055.0045

6,7-DIMETHOXY-3-ISOCHROMANONE

[3H-2-Benzopyran-3-one, 1,4-dihydro-6,7-dimethoxy-]

Submitted by J. Finkelstein¹ and A. Brossi¹^,².

Checked by Yoshinori Hamada and Wataru Nagata.

1. Procedure

A 500-ml., round-bottomed flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, and a reflux condenser is charged with 49.0 g. (0.250 mole) of 3,4-dimethoxyphenylacetic acid (Note 1) and 125 ml. of acetic acid. The solution is stirred and heated at 80° on a steam bath, while 40 ml. of concentrated hydrochloric acid is added rapidly and followed immediately with 40 ml. of formalin (37% formaldehyde, by weight, in water) (Note 2) and (Note 3). The yellow solution is stirred and heated on a steam bath for 1 hour, during which time the reaction temperature reaches 90° (Note 4) and the solution assumes a dark-brown color. After cooling to room temperature the solution is poured, with stirring, into a mixture of 650 g. of chipped ice and 650 ml. of cold water. The mixture is transferred to a 2-l. separatory funnel, and the organic material is extracted with four 300-ml. portions of chloroform (Note 5). The combined chloroform extracts are washed with 250-ml. portions of aqueous 5% sodium hydrogen carbonate until neutral (Note 6), then with two, 250-ml. portions of water, and finally dried over anhydrous magnesium sulfate. The solvent is removed on a rotary evaporator with a water bath up to a temperature of 55° (Note 7), yielding 43.5–44.2 g. (83.7–85.1%) of crude 6,7-dimethoxy-3-isochromanone, m.p. 95–100°, as a yellow solid suitable for general synthetic purposes. A purer product is obtained by recrystallization from 55 ml. of ethanol (Note 8),(Note 9),(Note 10), giving 26–27.6 g. of white crystals which, after drying at 80°, melt at 106–108° (Note 11). Upon concentration of the mother liquor to a smaller volume, an additional 1.7–3.2 g. of the isochromanone, m.p. 103–105°, is obtained. The total yield is 29.2–29.3 g. (56.2–56.4%).

2. Notes

1. The 3,4-dimethoxyphenylacetic acid was purchased from Matheson, Coleman and Bell. The checkers prepared material of m.p. 97–98° according to the procedure described in Org. Synth., Coll. Vol. 2, 333 (1961).

2. "Baker Analyzed" reagent grade formaldehyde solution obtained from J. T. Baker Chemical Company was used. The checkers used material purchased from Wako Pure Chemical Industries, Ltd., Japan.

3. About 30 seconds each is needed for the additions of concentrated hydrochloric acid and formalin.

4. The temperature of the reaction mixture falls to 68° on addition of the reagents but rises again within 10 minutes.

5. Fisher Scientific Company Certified A.C.S. chloroform was used. The checkers used reagent grade chloroform purchased from Wako Pure Chemical Industries, Ltd., Japan.

6. The wash solution should be neutral to litmus. The checkers observed that the pH values of the first and the second wash solutions were 5–5.5 and 7.5, respectively.

7. The viscous, syrupy residue crystallizes on standing at room temperature or by addition of a small amount of methanol.

8. Anhydrous ethanol (Type 2B) was used.

9. Recrystallization can conveniently be performed with the initial syrupy residue.

10. The checkers found that a mixture of dichloromethane and ether was a more suitable solvent for crystallization of the product. The pure sample obtained from this solvent system melts at 108–109°.

11. The product has the following spectral properties; IR (CHCl₃) cm.⁻¹: 3040, 1750, 1616, 1520, 1253, and 1118; ¹H NMR (CDCl₃), δ (multiplicity, number of protons, assignment): 3.63 (s, 2H, CH₂CO₂), 3.88 (s, 6H, 2OCH₃), 5.25 (s, 2H, CH₂OCO), 6.72 (s, 1H, aromatic H), 6.77 (s, 1H, aromatic H).

3. Discussion

The reaction is essentially that described by the submitters.³ The procedure illustrates a convenient method for the synthesis of a type of lactone which could serve as an important intermediate in the synthesis of isoquinolones, tetrahydroisoquinolines, and isoquinoline alkaloids. Several analogous and closely related lactones have been reported.

The parent, unsubstituted isochromanone reacts with a variety of aromatic amines, giving N-substituted 1,4-dihydro-3(2H)-isoquinolones,⁴ and with amines, giving amides.⁵ 6,7-Methylenedioxy-3-isochromanone was used as an intermediate in the synthesis of protopine and its allied alkaloids,⁶ and in the synthesis of the berberine ring system.⁷ The 6-methoxy analog was prepared as a potential intermediate in a camptothecin synthesis⁸ and 8-methoxy-4,5,6,7-tetramethyl-3-isochromanone was used as an intermediate in the synthesis of sclerin.⁹

The compound described herein was the basis of a facile synthesis of (±)-xylopinins,¹⁰ and its reaction with hydrazine has been reported.¹¹ The compound was also used in the synthesis of pseudoberberine,¹² and when reacted with 1-methyltryptamine, 1-methyl-15,16,17,18,19,20-hexahydroyohimban was obtained.¹³ When isochroman-3-ones are treated with tryptamine, the synthesis of the yohimban skeleton is achieved.¹⁴ The preparation of α-methyldopa in a rigid framework is described.¹⁵

The procedure may have considerable scope, as shown by the synthesis of a heterocyclic lactone, an important intermediate in the synthesis of d,l-desoxycamptothecin, which on oxidation gave camptothecin.¹⁶ A new synthesis of benzocyclobutenes by the thermal and electron impact-induced decomposition of 3-isochromanones was described.¹⁷

3-Isochromanone was allowed to react with phenol ethers in polyphosphoric acid, yielding dibenzo [a,d] tropylium salts, but in formic acid homoveratric acids were obtained.¹⁸

The nonaromatic lactones derived from cis-¹⁹ and trans-2-hydroxymethylcyclohexaneacetic acid²⁰ are important intermediates in the synthesis of indole alkaloids.

References and Notes

Chemical Research Department, Hoffmann-LaRoche, Inc., Nutley, New Jersey 07666.
Present address: Section on Medicinal Chemistry, U.S. Public Health Service, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20205.
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G. A. Swan, J. Chem. Soc., 1720 (1949).
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T. Kubota, T. Tokoroyama, T. Nishikawa, and S. Maeda, Tetrahedron Lett., 745 (1967).
W. Meise and F. Zymalkowski, Tetrahedron Lett., 1475 (1969).
G. Rosen and F. D. Popp, Can. J. Chem., 47, 864 (1969).
F. Shinada and T. Kono, Japan. Pat. Kokai 74 96,000 [Chem. Abstr., 82, P57993y (1975)].
W. Meise and H. Pfister, Arch. Pharm., 310, 495 (1977).
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S. N. Rostogi, J. S. Bindra, and N. Anand, Indian J. Chem., 9, 1175 (1971).
R. Volkmann, S. Danishefsky, J. Eggler, and D. M. Solomon, J. Am. Chem. Soc., 93, 5576 (1971); S. Danishefsky, S. J. Etheredge, R. Volkmann, J. Eggler, and J. Quick, J. Am. Chem. Soc., 93, 5575 (1971).
R. J. Spangler, B. G. Beckmann, and J. H. Kim, J. Org. Chem., 42, 2989 (1977).
A. V. Bicherov, G. N. Dorofeenko, and E. V. Kuznetsov, Zh. Org. Khim., 15, 588 (1979).
G. Stork and R. K. Hill, J. Am. Chem. Soc., 76, 949 (1954).
E. E. van Tamelen and M. Shamma, J. Am. Chem. Soc., 76, 950 (1954).

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

d,l-desoxycamptothecin

camptothecin

ethanol (64-17-5)

hydrochloric acid (7647-01-0)

acetic acid (64-19-7)

methanol (67-56-1)

ether (60-29-7)

formaldehyde,
formalin (50-00-0)

chloroform (67-66-3)

sodium hydrogen carbonate (144-55-8)

formic acid (64-18-6)

hydrazine (302-01-2)

dichloromethane (75-09-2)

magnesium sulfate (7487-88-9)

3,4-dimethoxyphenylacetic acid (93-40-3)

6,7-Dimethoxy-3-isochromanone,
3H-2-Benzopyran-3-one, 1,4-dihydro-6,7-dimethoxy- (16135-41-4)

6,7-Methylenedioxy-3-isochromanone

8-methoxy-4,5,6,7-tetramethyl-3-isochromanone

1-methyltryptamine

1-methyl-15,16,17,18,19,20-hexahydroyohimban

tryptamine (61-54-1)

3-Isochromanone (4385-35-7)

trans-2-hydroxymethylcyclohexaneacetic acid

Notes

References/EndNotes

Article Compounds

Authors