252 Vol. 72

70. Shigehiko Sugasawa, Sumito Toda and Hiroshi Tomisawa: A Simplified Isoquinoline Synthesis. I.*

(Pharmaceutical Institute, Medical Faculty, University of Tokyo**)

The most important method for the synthesis of isoquinolines is that o f Bischler - Napieralskil) modified by Perkin. In this method an appropriately substituted acyl ƒÀ-

phenethylamide, which is prepared and dried beforehand, is treated with an excess of phosphoryl chloride preferably in boiling benzene hydrocarbons. The reaction proceeds presumably according to the following equation (1):

(1)

Many of the useful isoquinoline type of drugs are now being synthesized in this way. It is well known that phosphoryl chloride, the cyclizing agent here used, is also a chlorination agent, by which means metallic salt of organic acid forms the corresponding acid chloride according to the following equation (2):

2 R•ECOONa+POCl3=2 RCOCl+NaPO3+NaCl...... (2)

In case a salt of orgnic base (RCOOH¥B:B stands for organic base) is substituted for RCOONa in the above equation, a similar reaction may take place; i.e.

2 R•ECOOH•EB+POCl3=2 RCOCl+B•EHPO3+B•EHCl...... (3)

At a higher temperature the acid chloride here formed will enter into reaction with B•EHPO3 and probably further with B. HCl, producing acid amide, which then undergoes cyclization by an excess of phosphoryl chloride, in case the amide is appropriately constructed. Thus it appeared that preparation of acid amide is not prerequisite in the isoquinoline synthesis. And this was found to be really the case by the following experiment. Each one mole of ƒ¿-methyl-ƒÀ-methoxy-ƒÀ-3, 4-methylenedioxyphenethy famine (1)2) (designate hereafter as M. S. A.) and benzoic acid (II) were mixed in toluene" and from the mixture some of the solvent was distilled off to ensure anhydrous condition. Phosphoryl chloride was now added and the whole was boiled gently under reflex. The reaction product was worked up as usual and 1-phenyl-3-methyl-6, 7-methylenedioxyiso-

quinoline (III) was obtained in different yields according to the reaction conditions. The base (III) was identified by a direct comparison with an authentic specimen. The reaction proceeded presumably as follows:

I II III In one experiment, where phosphorus pentoxide was used in place of phosphoryl chloride, hardly any isoquinoline base was traced in the reaction mixture, showing,

* This paper was read at the Medicinal Section, XI. International Congress of Pure and Applied Chemistry, New York, Sept. 1951. ** Bunkyo-ku, Tokyo. (菅沢 重 彦,戸 田 佳 人,富 沢 宏) 1) Bischler and Napieralski: Ber. 26, 1903 (1893). 2) This amine was chosen for the readiness of preparations. 3) Toluene gave better result than either benzene or xylene. No. 2 253

that direct dehydration is not how the isoquinoline is formed in the present method of synthesis. According to the above equation a mixture of each one mole of acid and amine requires 1.5 moles of phosphoryl chloride, but for the best result at least eight times the theoretical amount of phosphoryl chloride was necessary, as can be seen by the following experimental data:-

When two moles of the amine were used the yield as high as 60% of (III) was obtained. Since, however, the amine is usually the most expensive of all the materials in the isoquinoline synthesis, each one mole of acid and amine were used throughout this work. In the present synthesis the acid amide seems to be the intermediate. An attempt was, therefore, made to arrest the reaction at this intermediate stage. For that purpose a mixture of each one mole of ƒÀ-phenethylamine and benzoic acid were mixed under toluene and was treated with phosphoryl chloride as above. From the reaction mixture benzoyl ƒÀ-phenethylamide, C6H5CH2CH2NH•ECOC6H5, was isolated as a main product. In our view the acid amide owes its formation to the interaction of acid chloride first formed According to the equation (2) with B•EHPO3 and probably further with B•EHCl. And this view was supported by the following independent experiments. Each one mole of benzoyl chloride and M. S. A. HPO3 were mixed under toluene and treated with phosphoryl chloride as above. By working up the reaction product properly the base (III) was isolated in about 40% yield. In the second experiment M. S. A. HCl was substituted for the phosphate and the base (III) was obtained in about 20% yield. Thus it was proved that the phosphate enters into reaction with acid chloride in

preference. Therefore, it can be regarded that the present method is a simplified Bischler- Napieralski-Perkin type synthesis of isoquinoline. But there is still something left to be desired about the yield of the final product, and our effort is being focused upon its amelioration5). The authors are grateful to the Ministry of Education for the Science Research Grant for the year of 1951, which enabled them to carry out this work. They are also thankful to Messrs. Hung and Wu for microanalyses.

Experimental

General Procedure-M. S. A. (2g. 1 mole) and benzoic acid (1.17g. 1 mole) were mired in pure toluene (20cc.) and about 5cc. were distilled off. Phosphoryl chloride .(10cc. or 17.5g.) was now added and the mixture was refluxed gently for 2hrs. (oil bath temp. 120•`130•‹). On cooling the solvent and excess of phosphoryl chloride were removed in vac., leaving dark reddish oily residue. This was dissolved in ice-cold hydrochloric acid (ca. 5% strength), clarified by shaking with ether. The aqueous solution was now basified with ammoniak, separating oily base, which was extracted with benzene, washed, dried and evaporated, leaving yellowish gum, which solidified on standing.

4) Results of each one experiment. 5) The reaction in the presence of potassium hydrogen phosphate seems to give better yield of isoquinoline. The detail will be published in the next paper. 254 Vol. 72

This was purified from 80% methanol, forming colorless needles of m. p. 142•`143•K, which was not depressed when admixed with an authentic specimen, prepared by Sugasawa and Sakurai.6) Yield, 1.2 g. or 48%. Phosphorus pentoxide in place of phosphoryl chloride gave hardly any isoquinoline base. Some other examples are tabulated below:-

*New compound:Benzene solution of 1-ƒÁ-pyridyl-3-methyl-6, 7-methylenedioxyisoquinoline was purified through alumina column. Recrystallized from alcohol, forming colorless needles of m. p. 175•` 176.5•‹. Anal. Calcd. for C16H12O2N2.: C, 72. 72; H, 4.54; N, 10.6. Found C, 72.82; H, 4.61; N, 10.52. As can be seen from the above table aliphatic acids generally gave better yield of isoquinoline. Isolation of benzoyl ƒÀ-phenethylamine-In order to prove the intermediate formation of acid amide in the above synthesis, the intermediate stage was arrested in the following model experiment. ƒÀ -Phenethylamine (2g .) and benzoic acid (2g.) were mixed under toluene and the mixture was boiled with phosphoryl chloride (20g. , 8 times of the theoretical amount) for 1.5hrs., during which time the evolution of hydrogen chloride was observed. From the clear reddish brown solution obtained the solvent and excess of phosphoryl chloride were removed in vac., and the gummy residue was treated with an ice-cold mixture of 10% hydrochloric acid and benzene. The benzene layer was washed free from acid, dried and evaporated, leaving reddish brown neutral gum (2.2g.) which solidified on cooling. Purified from alcohol, forming white grains of m. p. 108•`110, which was identified as benzoyl ƒÀ-phenethyl amide by direct comparison with an authentic specimen. By basifying the acid solution obtaind above some basic substance (0.4g.) was isolated, which was probably 1-phenyl-3, 4-dihydroisoquinoline, but was not yet identified. Formation of (III) i) from, M. S. A. metaphosphate and benzoyl chloride: Phosphorus pen toxide (0.7g. 12mole) and M. S. A. (2g. 1mole) were mix , ed under toluene (15cc.) and to this was added water (0.09g., 1/2mole) so as to form M. S. A. metaphosphate. The whole was shaken for sometime, separating white solid. Benzoyl chloride (1.4g., 1 mole) and phosphoryl chloride

(9g.) were now added and the mixture was boiled gently for 1.5hrs., forming greenish yellow brown solution with some gummy substance separating in the bottom. The reaction mixture was worked up as usual and the benzene solution of the base obtained was purified chromatographically, yielding yellow viscous oil (1g. or 40%), which solidified on standing. Purified from aqueous alcohol, forming colorless needles of m.p. 137•`138, which was not depressed when admixed with an authentic specimen (III) of m. p. 142•`143•K. ii) From M. S. A. hydrochloride and benzoyl chloride: Dry M. S. A. hydrochloride, prepared from 2g. (1 mole) of the amine, was mixed with benzoyl chloride (1.4g. or 1 mole), phosphoryl chloride (9g.) and toluene (15cc.), and the whole was boiled and worked up as above. 0.5g. (or 20%) of the isoquinoline (Iil) was obtained.

Summary A simplified isoquinoline synthesis is described. In this method one mole each of appropriately substituted ,C3-phenethylamine and acid were mixed under toluene and the mixture was boiled with an excess of phosphoryl chloride, giving isoquinoline in a fair yield. The isolation of the intermediate acid amide in the usual Bischler-Napieralski Perkin method was thus made unnecessary. (Received October 22, 1951)

6) This Journal, 56, 568 (1936). 7) Results of each one experiment