43. on the Synthesis of Hinokitiol

No. 7.] (7) 43

43. On the Synthesis o f Hinokitiol (m.Isopropyltropo1one).l~

By Tetsuo NOzoE, Shuichi SETO, Katsuo KIKUCHI, Tosio MUKAI, Satoshi MATSUMOTO, and Masao MURASE. Chemical Institute, Faculty of Science, Tohoku University. (Comm. by R. MAJIMA,M.J.A., July 12, 1950.)

From the studies of hinokitiol by Nozoe 2) and of ,@-thujaplicin by Erdtman3~, it was found that they have the same structure, namely m-isopropyltropolone (I)4~ by the analytical method, and moreover, their identity was established by Erdtman by the method of mixed melting point. But the synthesis of the hinokitiol has not yet been reported. As synthesis of tropolone5~ was recently succeeded in our laboratory, an attempt was made to synthesize the hinokitiol and its isomers, starting from 3 and 4-isopropylcycloheptanones (III and VII). The synthesis was represented in the following scheme, and except (VI) all intermediate compounds are new substances.

1) Presented at the 3rd Annual Meeting of the Chemical Society of Japan, in Kyoto, April 2, 1950. 2) Nozoe : Science of Drugs, (Review in Japanese), 3, 174 (1949). 3) Erdtman : Nature, 161, 718 (1948), Acta Chim. Scand., 2, 644 (1948). 4) In regard to numbering of position of substituents in tropoloids, refer to Nozoe : Science of Drugs, 3, 184 (1949). 5) Nozoe et al.: This number of the Proceedings, p. 38. (7) 44 T. NozoE and Others. [VoL26,

Both isopropylcycloheptanediones, obtained from (III) or (VII), on dibromination with N.B.S. and subsequent dehydrobromination, gave crystals, m. p. 51.5°. This compound showed no depression of melting point by admixutre with the natural hinokitiol. Its dibromo derivative, m. p. 133°, was also identified with a-dibroro- hinokitiol, m.p. 134°, by the method of mixed melting point. On the other hand, the dibromination of the diones obtained from (III) with bromine in glacial acetic acid and subsequent dehydrobromination, gave hinokitiol and monobromohinokitiol. In spite of the possibility of the formation of 3-isopropylcy- cloheptanedione-(1, 2) (IV) besides (V) in the oxidation of (III), we could not find practically o-isopropyltropolone (a-thujaplicin) arising from (IV) on " tropolization " using either N. B. S. or bromine.5~ While, diones from (VII), after the same treatment with bromine in acetic acid, gave monobromo derivative, m.p. 59.5°, in addition to hinokitiol. This monobromo derivative and the dibromo derivative, m.p. 143.5°, obtained from it were different from the monobromohinokitiol, m.p. 54°, a- and /3-dibromohinoki- tiol (m.p. 134° and 96°). It appears that this monobromo derivative would be hitherto unknown monobromo-y-thujaplicin. In this detail, it will be reported later. From above mentioned synthesis there can be no doubt that hinokitiol is identical with m-isopropyltropolone (I).

Experimental

$•Isopropylsuberic acid (11)6) The acid chloride, obtained from a-isopropyladipic acid (13 g.) and thionyl chloride, was dissolved in absolute ether (80 c.c.). The resulting solution was dropped in 800 c.c. of absolute ethereal solution containing 16.8 g. of diazomethane, under cooling with ice, and was left overnight. After removing the ether, 1-isopropyl-1,4-bisdiazoacetylbutane (15 g.) was obtained as a reddish-brown oil. The methanol solution of this oil was refiuxed with ammonia- cal silver nitrate solution. After the removal of the solvent, pale yellow or brown material (15g.), m.p. 130-140°, was obtained. This crude diamide of $-isopropylsuberic acid, on recrystallization from dilute alcohol, separated in colourless crystals, m.p. 154-156°. (Found : N, 12.60, Ci1H2202N2requires N, 13.O8/o). The crude diamide (32 g.) was hydrolyzed with potassium

6) James Walker : J.C.S. 1940, 1304. No. 7. on the Synthesis of Hinokitiol. (7) 45 hydroxide solution, when ,Q-isopropylsuberic acid (II) (28 g.) was separated as an oily matter which, on standing, partially crysta- lized. 3' isopropylcycloheptanone (xlI)7~. A mixture of crude isopropylsuberic acid (II) (33 g.), iron filings (33 g.) and crystallized baryta (1.8 g.) was slowly heated to 350° during 6 to 7 hours. Distillate was diluted with ether and washed with potassium hydroxide solution in order to remove the acidic parts. On distillation, 3-isopropylcycloheptanone (III) (10.4 g.), b.p. 140-150°/95 mm. (mainly 145-148°), passed over. nr, 1.4627. Semicarbazone : ~T_p. 190.5°. 2.4-Dinitrophenylhydrazone ; m.p. 129.5°. 4•Isopropylcycloheptanone (VII)8. Nitrosomethylurethane 42 g.) was added drop by drop with constant stirring, to the solution of 4-isopropylcyclohexanone (VI) (38 g.) in methanol (50 c.c.) containing dry potassium carbonate (3.5 g.) at 24-26°. After being left for 2 days, the potassium carbonate was removed by filtration and then distilled, when 4-isopropylcycloheptanone (VII) (22.5 g.), b.p. 153-157°/100 mm., was obtained, which after purification through sodium bisulphite compound, gave colourless oil, b.p. 152- 155°/100 mm., nD5 14694. Semicarbazone; m.p. 155.5°. Oxidation of 3• and 4•isopropylcycloheptanones (III and VI1)9~. A mixture of 3-isopropylcycloheptanone (III) (10.4 g.), absolute alcohol (25 c. c.) and selenium dioxide (8.4 g.) was refluxed for 12 hours. The selenium which separated was removed by filtration and the product was then distilled, when isopropylcycloheptanediones (6.3 g.) were obtained as a yellow viscous oil, b.p. 90-110°/4 mm., n 1.4822-1.4848. In the same manner, 4-isopropylcycloheptanone (VII) (21.5 g.) yielded isopropylcycloheptanediones (10 g.) as a yellow viscous oil, b.p. 110-120°/6.5 mm., n~, 1.4828-1.4852. m•Isopropyltropolone (Hinokitiol). (A). N.B.S. (10.7 g.) was added to the solution of isopropylcycloheptanediones (5 g.), obtained from (VII), in chloroform (100 c.c.) and the whole was refluxed on the water bath for about 6 hours. After removing the suc- cinimide and solvent, the residual oil was distilled in steam. The distillate was neutralized with sodium hydroxide solution and con- centrated. The sodium salt thus obtained was recrystallized from water, and then liberated with acid. The crystals (0,36 g.), melting at 43-47, was separated, which after recrystallization from petroleum ether, melted at 51.5°.

7) Israel Vogel : ibid. 1928, 2032; 1929, 721; 1931, 902. 8) E. P. Kohler : J. A. C. S. 61, 1059 (1939). 9) Godchot : C.r. 2C2, 326 (1936). (7,; 46 T. NozoE and Others. [Vol. 26,

In the same manner, isopropylcycloheptanediones, obtained from (III) gave the crystals, melting at 51.5°. This compound showed no depression of melting point by admixture with the natural hinokitiol. Moreover this compound gave dibromo derivative melting at 133° , which was identified by the mixed melting point as a-dibromohmokitiol, m.p. 134°. (B). The solution of bromine (3g.) in glacial acetic acid (9c.c.) was added to the solution of isopropylcycloheptanediones (1.5 g.), obtaimed from (III), in glacial acetic acid (4.5 c. c.) with stirring at 12-14°. After being left overnight, the mixture was heated on the water bath for 3.5 hours and then solvent was distilled off under reduced pressure. Residual oil was distilled in steam and the distillate was treated in the same manner as (A). We obtained two different crystals, melting at 46-49° (0.17 g.) and 42-46° (0.3 g.). After recrystallization from petroleum ether, the former melted at 54° and identified as monobromohinokitiol, and the latter, m. p. 50.5°, as hinokitiol. On the other hand, isopropylcycloheptanediones (1.8 g.) from (VII), on the same treatment as above, gave monobromo substituted product (0.15 g.), m.p. 59.5°, in addition to hinokitiol. This compound, on monobromination gave the crystals melting at 143.5°. These two compounds, on admixture with any bromoderivatives of hinokitiol, showed the depression of melting points. It appears that the crystals, m.p. 59.5°, would be the monobromo derivative of 'p-isopropyltropolone (7-thujaplicin). For the expense and materials of this research the authors are indebted to the Scientific Research Grant of the Department of Education, Takasago Chemical Industry Co., and Kao Soap Co.