Synthesis of Heliotropin ~O-(J 5

Synthesis of Heliotropin

By Libor Cerveny, Josef Kozel and Antonfn Marhoul, Department of Organic Technology, Institute of Chemical Technology, Prague, Czechoslovakia

eliotropin (piperonal) is a trivial name of lated from camphor oil and Chinese sassafras H 3,4-methy lenedioxybenzaldehyde, which oils, is the natural source of raw materials for its is used mostly in the industry of odoriferous and production.s Alkali hydroxides shift the double flavour compounds.' It possesses a very sweet, bond in the side chain in safrol to conjugation warm, slightly spicy cherry flower fragrance and with the benzene ring, thus giving rise to isosa- a sweet, spicy, very slightly bitter taste. Helio- frole." Destructive oxidation of the latter, which

tropin is used to add an exotic touch to perfumery can be caused by e.g. HN03, KMn04>H202V20s, composites and in flavour composites such as O2 gamma-rays, Cr03H3P04> Na2CrZ07Mn4+, 03 strawberry, cola, rum, nuts and tutti-frutti. It also etc., gives heliotropin 3.1'>-7 is applied in mixtures with vanillin and ethylva- Purely synthetic procedures usually are based nillin. on pyrocatechol. Heliotropin can be obtained In nature heliotropin occurs as an unessential from it by employing several routes (see struc- component of ethereal oils in many tropical and ture). subtropical plants." Safrole, which can be iso- Methylenation of pyrocatechol with dihalo-

HO-O:-' 7 HO- ~ .-?H-COOH •• OH

1 4 CH~O-(J _CH5 /' 0-0 2_ 0- ~ -CHO 2 -- 0- ~ -COCOOH

genmethane (step 1) has been described in many the formation of a subsequent by-product.P-" papers.B-3SAlkali hydroxides, alkoxides, carbon- According to unpublished results obtained by ates or fluorides are used as the ionizing bases. In Haarman-Heime r;" the oxidative decarboxyla- most usual solvents, the yields do not exceed tion of 3,4-methylenedioxymandelic acid to he- 40%. Significant progress could be observed in liotropin (step 3) proceeds very readily by acting the '60s when the use of dimethvlsulfoxide+v-" with dilute nitric acid. and dimethylformamidev'" as a solvent consider- Step 6 involves various other procedures to in- ably raised the yield of 1,2-methylenedioxyben- troduce the aldehyde group into the molecule of zene (over 90%). Only in the '70s were high 1,2-methylenedioxybenzene. These procedures yields obtained also with water,12,18.20.2bec8 ause usually are multistage and are regarded at pres- of the application of phase transfer catalysts. Di- ent as less suitable than those involving glyoxylic benzo-(b,g)-1,4,6,9-tetraoxadecadiene, arising by acid. an intermolecular condensation of two molecules The procedure described by the sequence of of pyrocatechol and two molecules of dichlor- steps 7-10 differs from that expressed by steps methane, is the by-product in this reaction.v-" 1-3, basically in that the aldehyde group is intro- The reaction between 1,2-methylenedioxy- duced into the pyrocatechol molecule by means benzene and glyoxylic acid (step 2) must be car- of glyoxylic acid first, while the methylenation of ried out in an acid medium. In the presence of hydro xylic groups is the last step of the reaction. weaker acids elevated temperatures (60-80°C) In view of the presence of free hydroxylic groups must be used, at which a considerable amount of up to the last reaction step, the whole process of consecutively arising disubstituted derivative, synthesis is completely different from that previ- bis (3,4-methylenedioxyphenyl) acetic acid is ously described. formed. With a strong acid (sulfuric, hydro- The condensation of pyrocatechol with chloric, etc.) the reaction temperature can be re- glyoxylic acid (step 7) proceeds in an alkaline duced to 5-200C, thus significantly suppressing medium.P similarly to the oxidation to ketoacid with Cu(II) oxide (step 8). Its decarboxylation to 3,4-dihydroxybenzaldehyde (step 9) takes places in an acid medium." The methylenation of 3,4- dihydroxybenzaldehyde is performed similarly World classfragrances ... to that of pyrocatechol. 12.18.28.39.40.The41 total yield of heliotropin (related to pyrocatechol) is some- what lower than in the case of the sequence of steps 1-3. The aim of this study has been optimization of ;;~;';, "--~,~ ~', the reaction conditions of steps 1-3 with respect ';;,":~"',~",

.<:)" -v ,-,·:'':t,!·'v" to the yield of heliotropin .

Experimental section The chemicals used were: pyrocatechol (cryst. from water, m.p. 245°C, Lachema Brno), dichlormethane (distil., b.p. 38,5°C/101 kl'a), dimethylsulfoxide (distil., b.p. 700C/1.33 kPa), glyoxylic acid 49,2% (Farmakon Olomouc), toluene, sodium hydroxide and nitric acid reagent grade, sulfuric acid chemically pure (all Lachema Brno). Appcratus and procedure: Methylenation reaction of pyrocatechol with dichlormethane was conducted in a 250 ml three-necked flask, provided with a stirrer, thermometer, reflux and septum for sampling. The flask was placed in a thermo stated bath. To a mixture of 44 g of dimethylsulfoxide and 9.3 g of dichloromethane heated to 100-llO°C, 7.5 g of pyrocatechol in 16.5 g of dimethylsulfoxide and a solution of 5.5 g of sodium hydroxide in lO g water were dosed in parallel by means of a peristaltic pump through the reflux, with stirring for three hours.

14/Perfumer & Flavorist Vol. 14, March/April 1989 I Synthesis of Heliotropin

On completion of the dosage, the reaction mixture was stirred at the same temperature for another hour. The precipitated sodium chloride 100~------~------~--~ was removed by filtration, and a mixture of dichloromethane and of the azeotropic mixture of x(%) water with 1,2-methylenedioxybenzene was removed by distillation (b.p. 98-100°C). The dis- 75 tillate was divided by layer separation, water re- turned to distillation, and the organic layer was divided by distillation into dichlormethane (b.p. 40°C) and 1,2-methylenedioxybenzene (b.p. 50 173-175°C). The yield of 1,2-methylenedioxybenzene was 94% theor. 1,2-Methylenedioxybenzene was transformed into 3,4-methylenedioxymandelic acid in a flat- 25 bottom test tube, 50 ml in volume, with a ground joint for the stirrer in the upper part. The stirrer was of a rectangular cross-section, moved closely 0'------1------'----1 to the walls of the test tube, reaching to about one o 1 -1 2 half of its height from the bottom. Construction of c(moll) the stirrer is important for collection of 3,4-methylenedioxymandelic acid formed from the walls Figure 1. Effect of the concentration of sodium of the reactor. 7.3 g of 96% sulfuric acid, 1 g of pyrocatecholate on the yield of water and 6.1 g of 49% glyoxylic acid were intro- 1,2-methylenedioxybenzene duced into the test tube and cooled with water x = yield of 1,2-methylenedioxybenzene (%) c = concentration of sodium pyrocatecholate in with ice to O°C. 4.9 g of 1,2-methylenedioxyben- reaction mixture (mol/1) zene was added, and the mixture was thermo- stated again to O°C. The reaction began to proceed at a perceptible rate only after stirring had been started. On com- 144, dimethylsulfoxide 164, n-propylbenzene pletion of the reaction, the reaction mixture was 184, 1,2-methylenedioxybenzene 216, pyrocate- diluted with 20 g of water and stirred, the product cho1300, heliotropin 456. was filtered by suction, washed with water and In the first reaction step, the concentrations of dried freely in the air. The yield of 3,4-inethyl- pyrocatechol and 1,2-methylenedioxybenzene, enedioxymandelic acid was 92%. Reactions of in the second step the concentration of methyl- 3,4-methylenedioxymandelic acid to heliotropin enedioxybenzene were determined. The third were carried out in a test tube with a ground joint degree was evaluated on the basis of the amount and provided with a reflux. 0.5 g of 3,4-methyl- of heliotropin obtained; its purity was checked enedioxymandelic acid and 5.25 g 3.1% nitric chromatographically. acid were introduced into the test tube and the mixture was heated on a boiling water bath. The Results and discussion reaction was completed virtually within a few 1. Methylenation of pyrocatechol to 1,2-meth- minutes. ylenedioxybenzene: Various dosage procedures Heliotropin was separated at the bottom as a of the reactants were tested, leading to the fol- dark oil. Therefore it could be removed and sub- lowing conclusions. During the reaction a low jected to purification by distillation. The yield of concentration of sodium pyrocatecholate must be crude heliotropin was 83% (chromatographically maintained (see Figure 1), which suppresses the without impurities). intermolecular condensation of two molecules of this compounds with two molecules of dichloro- Analytical methods methane to dibenzo (b,g)-1,4,6,9-tetraoxadeca- The analyses were conducted in a CHROM 4 diene. A separately prepared solution of sodium apparatus with flame ionization detection at pyrocatecholate in water is not too stable, so that 210°C. The column (2.5 m x 2.5 mm), was packed sodium pyrocatecholate is prepared advantage- with 15%SE 31 on Chromaton NAW-DMCS,with ously by controlled parallel dosage of pyrocate- dimethylsulfoxide or propylbenzene as the in- chol and sodium hydroxide into the reactor at the ternal standard. Retention times of the com- molar ratio 1:2. It is advantageous to use pyroca- pounds (see) were: dichlormethane 112, toluene techol in a dimethylsulfoxide solution and sodium

16/Perfumer & Flavorist Vol. 14, March/April 1989 I Synthesis of Heliotropin

cause of the precipitation of the solid phase). To remove this; it is sufficient to add 1.55 mole water 1,0,----...... ,....----,....---,...--, to the reaction mixture. The temperature range 0-5°e is quite adequate. If the condensation takes place in the range of 8-12° or 18-22°, the yield of 3,4-methylenedioxymandelic acid is x(%) much lower (83%or 69%, respectively). 3. The transformation of 3,4-methylenedioxymandelic acid into heliotropin: The reaction 0,5 between 3,4-methylenedioxymandelic acid and ) nitric acid is very fast, and its course is difficult to be followed by analytical methods. We have found that the best molar ratio of both reactants is 1:1. Table I gives the yields of heliotropin reached at various concentrations of nitric acid and various temperatures. It was found that the optimal concentration of nitric acid is about 3%; o~----~------~----~~ at lower concentrations the reaction does not o 10 20 30 proceed at all, at higher ones the yield of helio- t (minl tropin decreases.

Figure 2. Time dependence of the formation of Conclusion 1,2-methylenedioxybenzene x = amount of 1,2-methyleneclloxybenzene in the The reaction conditions of three-stage synthe- reaction mixture (% by weight) sis of heliotropin from pyrocatechol were opti- t = time (min) mized. Yields obtained in the individual degrees concentration of sodium pyrocatecholate in reaction mixture 0, 1 mol/1

hydroxide in the form of a concentrated aqueous solution. The amount of water should not exceed approximately 10% by mass of the whole reaction mixture. If it is higher, the system becomes a two-phase one, and the reaction proceeds with The much lower yields. Figure 2 shows that the reaction between sodium pyrocatecholate and dichlormethane is very fast under the conditions Aroma used. 2. The transformation of 1,2-methylene- Therapy dioxybenzene into 3,4-methylenedioxymandelic acid: 1,2-Methylenedioxybenzene and glyoxylic acid were used in a stoichiometric ra- Vehicles? tio, and the effect of quantity of sulfuric acid on the course of the reaction and on the yield of 3,4-methylenedioxymandelic acid was investi- gated. The results are shown in Figure 3. The temperature was maintained in the range 0-5°e for some time by intensive cooling, and after that it was left to reach the room temperature. Yield of 3,4-methylenedioxymandelic acid was found to be affected favourably by a high concentration of sulfuric acid. We came to a conclusion that 1.8 mole sulfuric acid is needed for 1 mole, 1,2- methylenedioxybenzene and 1 mole glyoxylic acid (in the form of a 49% aqueous solution).

Under such conditions, however, stirring of the 183 Madison Ave., New York, NY 10016 212683·3089 reaction mixture gives rise to some problems (be-

Vol. 14, March/April 1989 Perfumer & Flavorist/17 I Synthesis of Heliotropin

100~------~------~ Table I. Results of the oxidation of 3,4-methylenedioxymandelic acid with nitric acid

concentration yield of x(%l of nitric acid temperature heliotropin (%) by weight eC) (%)

65,0 40 25 36,2 60 51 50 13,4 60 68 " . 12,5 60 76 ...... 8,0 80 78 6,5 80 75 4,8 100 78 3,1 100 83 2,3 100 o 1,6 100 o O~------~~K-~~~"~. o 5 10 t (hr) 8. W Bonthrone and J W Cornforth, J Chem Soc cs, 1202 (1969) Figure 3. Time dependence of the concentration of 9. N V Choppij, Neth pat 6614265 (1967) 1,2-methylenedioxybenzene in the reaction with 10. M Tomita and Y Aoyagi: Chem Pharm Bull 16, 523 (1968) glyoxylic acid 11. H Fujita and M Yamashita: Jap pat 7619772 (1976) x = amount of 1,2-methylenedioxybenzene in the 12. A P Bashall and J F Collins: Tetrahedron Let! 40, 3489 reaction mixtur.e (% by weight) (1975) t = time (hrs) 13. J H Clark, H L Holland and J M Miller, Tetrahedron Lett 38, 0-5°C 3361 (1976) ------•••• 18·22°C 14. W H Perkin, Jr and V M Trikojus, J Chem Soc 2925 (1926) 15. P P Shorigin, et ai, Zh Obshch Chim 8, 975 (1938) yield of 3,4-methylenedioxymandelic acid (%) ~ 16. E D Laskin, et ai, Zh Prikl Chim 34, 2214 (1961) o 7,3 9 96% H2S04 + 1 9 H20 92 17. JapAppl SH04734274 (1972) • 4,4 9 96% H2S04 •••••••••••••••••••• 89 18. Jap pat SHO 5946949 (1984) • 2,8 9 96% H2S04 •••••••••••••••••••• 54 19. J A Kirby, US pat 4082772 (1978) 6.1 9 of 49% glyoxylic acid and 4.9 9 of 20. Z Yiuguing, J Hongbin, L Xingfu, L Ningfang and S Yushang, 1,2·methylenedioxybenzene was used Jilin Daxue Ziran Kexue Xuebao 2,92 (1983) 21. K N Campbell, P F Hopper and K B Campbell, J Org Chem 16,1736 (1951) were the following: methylenation of pyrocate- 22. F Schmit!, Manuf Chem 12, 519 (1953) 23. R Raft and B Silverman, Ind Eng Chem 43,1423 (1951) chol with dichlormethane in dimethylsulfoxide 24. R A Bachrak, Maslo-Zh Delo 4, 42 (1938) 94%, transformation of 1,2-methylenedioxyben- 25. W Gensler and C Samur, J Org Chem 18,9 (1953) zene into 3,4-methylenedioxymandelic acid 92%, 26. B N Ghosh, J Chem Soc 107, 1597 (1915) transformation of 3,4-methylenedioxymandelic 27. C Moureu, Bull Soc Chim France 15, 655 (1986) acid into heliotropin 83%, so that the total yield 28. Ger Appl2703640 (1977) 29. A Sonnand F Benirschke, Ber 54,1753 (1921) of the synthesis is 71%, related to pyrocatechol. 30. X Barger, J Chem Soc 93, 563 (1908) 31. E Spath and R Posega, Ber 62, 1032 (1929) References 32. W Barker, J Chem Soc 1765 (1931) 33. W H Perkin, Jr, R Robinson and F Thomas, J Chem Soc 95, Address correspondence to Dr. Libor Cerveny, Department of 1979 (1909) Organic Technology, Prague Institute of Chemical Technology, 34. J D Laskina, Zh Prikl Chim 32, 878 (1959) Suchbatarova 5, 16628 Praha 6, Czechoslovakia. 35. J D Laskina, Zh Prikl Chim 34, 2338 (1961) 36. Ger Offen 2754490 (1979) 1. S Arctander, Perfume and Flavour Chemicals, Arctander, 37. K Bauer and R. Molleken, US pat 4190583 (1980) New York, 1969 38. Fragrance and Flavour Substances, Proceedings of the 2. E Gildemeister, Die atherische Ole, Akademie-Verlag Berlin, Second Intern Haarman and Reimer Symposium 1979, D 1961 and PS Verlag, W Germany, 1980 3. F Schmitt, Parf Kosmet 34, 445 (1953) 39. S Umemura, N Takamitsu, T Enomiga, T Nakamura and 4. X X Hirao, J Soc Chem Ind Japan 30, 2413 (1927) H Shirashi, DOS 2804063 (1978) 5. J D Laskina, T A Devitskaya, P F Shilina, TV Suchorukova 40. J Takeuchi, T Enomiya and T Nakamura, Jap pat 76100077 and S N Bychkova, UdSSR pat 142302 (1961) (1976) 6. V N Yeliseyeva and T A Devitskaya; Angew Chem 29, 1894 41. J Takeuchi, T Enomiya and Z Nakamura, Jap pat 76100078 (1958) (1976) J:) 7. Z Bidlo and F Vonasek: Prurn Potravin 9, 589 (1958) 42. N V Maatschappij, Neth pat 6614265 'f

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