Title of Invention	"MICROWAVE ASSISTED RAPID AND ECONOMICAL PROCESS FOR THE PREPARATION OF SUBSTITUTED PHENYLALDEHYDES FROM TRANS AND CISPHENYPROPENES: A COMMERCIAL UTILISATION OF TOXIC CIS-ISOMER"
Abstract	The present invention provides microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes from trans and cis-phenyipropene, a commercial utilization of toxic cis-isomer of the general formula (I) using meta-periodate and osmium tetraoxide (catalytic amount) as an efficient oxidizing agent in the presence of catalyst namely amberlite IRA-410 and quaternary ammonium salt.

Title of Invention

"MICROWAVE ASSISTED RAPID AND ECONOMICAL PROCESS FOR THE PREPARATION OF SUBSTITUTED PHENYLALDEHYDES FROM TRANS AND CISPHENYPROPENES: A COMMERCIAL UTILISATION OF TOXIC CIS-ISOMER"

Abstract

The present invention provides microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes from trans and cis-phenyipropene, a commercial utilization of toxic cis-isomer of the general formula (I) using meta-periodate and osmium tetraoxide (catalytic amount) as an efficient oxidizing agent in the presence of catalyst namely amberlite IRA-410 and quaternary ammonium salt.

Full Text	MICROWAVE ASSISTED RAPED AND ECONOMICAL PROCESS FOR THE PREPARATION OF SUBSTITUTEFD PHENYLALDEHYDES FROM TRANS AND CIS-PHENYLPROPENES: A COMMERCIAL UTILISATION OF TOXIC CIS-ISOMER Field of the invention The present invention relates to "microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes from trans and toxic cisphenylpropenes: a commercial utilization of toxic cis-isomer" in which industrially important phenylaldehydes (e.g. asaronaldehyde where RI is CHO, R2 = R4 = RS is - OMe and R3=R6 is H; p-anisaldehyde where, Rt is -CHO, R2 = R3 = RS = Re is H and R4 is -OMe and vetralaldehyde where Rf is -CHO, R2 = RS = R« is H; R3 = R4 is - OMe or the like) of the formula I are obtained via oxidation of easily available isomeric forms (trans and cis-isomer) of (R2-R3-R4-Rs-R6)phenylpropene bearing essential oils (i.e. p-asarone, anethole, and methyl isoeugenol or the like) wherein R2 to R& equal or different, being hydrogen or hydroxy or acyl or alkyl or methylenedioxy or alkoxy groups or the like, under microwave irradiation using meta-periodate/osmium tetraoxide (catalytic amount) for a reaction time less than 20 minutes in biphasic system comprising a solvent and aqueous phase containing a catalyst (such as quaternary ammonium salt and amberlite IRA-410 etc) with high yield varying from 71-82% depending upon the reagent, reaction time, condition and the phenylpropene used. In addition crude Acorns calamus oil (rich in P-asarone present in 70-94%) used directly for microwave assisted oxidation is an added benefit as remaining constituents of calamus oil do not interfere for the preparation of asaronaldehyde (yield just less by 5-10% depending upon asarone percentage in calamus oil) which makes the above process further cost effective since tetraploid and hexaploid varieties of Acorus calamus has been internationally banned for their use in human consumption. Moreover, we have observed that the preparation of asaronaldehyde (a versatile drugs precursor) requires lesser time (2-20 minutes) under microwave irradiation while oxidation takes 2-6 hours when conducted at room temperature (conventional method). Background of the invention Naturally occurring substituted phenylaldehydes (Harbome, J.B. and Baxter, H., In: Phytochemical Dictionary, A Handbook of Bioactive Compounds from Plants, Taylor & Francis Ltd., London WC1N 2ET, 472-488 (1993)) e.g. vanillin, panisaldehyde, p-hydroxybenzaldehyde, asaronaldehyde, heliotropin and vetralaldehyde etc possess in common an aromatic ring bearing one or more hydroxy or dioxymethylene or alkoxy groups or the like, attached to a aldehyde group (CHO) contribute significantly to the taste and flavour of many foods, drinks, perfumery and serve as a pharmaceutical aid. In addition, phenylaldehyde derivatives serve as a raw material for the preparation of a large number of aromatic compounds useful in the perfume industry e.g. treatment of phenylaldehyde with alkali alcoholate results in the formation of phenyl benzoate and condensation of phenylaldehyde derivative with acetaldehyde gives cinnamic aldehyde which are useful in both the perfume and pharmaceutical industries. In addition, large quantities of phenylaldehydes are used in the manufacture of dyes, medicines (Patel, P.J.; Messer Jr., W.S. and Hudson, R.A., J. Med. Chem., 36, 1893-1901 (1993)), photographic films, cosmetics, dyes, agrochemicals etc. The widespread aromatic aldehydes such as vanillin is obtained from the pods of Vanilla planifolia (family: Orchidaceae), the bulbs of Dahlia spp. (Compositae), the sprouts of Asparagus spp. (Liliaceae), the beats of Beta spp. (Chenopodiaceae) and also from the essential oils of Syzygium aromaticum (Myrtaceae), Ruta spp. (Rutaceae), Spiraea spp. (Rosaceae) and Gymnadenia spp. (Orchidaceae), while 3,4- methylenedioxybenzaldehyde ( heliotropin) is obtained from the essential oils of the flowers and leaves of Robinia pseudocode (Legumminosae), Doryphora sassafras, Eryngium potericum (Umbelliferae), Heliotropium spp. (Boraginaceae), Vanilla spp. (Orchidaceae) and from extracts of Viola spp. (Violaceae) and Baccharis rosmarinifolia (Compositae). Other phenylaldehydes are restricted to a few families such as p-anisaldehyde occurs in the fruits of Pelea madagascariensis (Rutaceae), Agastache ntgosa (Labiatae), leaves of Magnolia salicifolia (Magnoiiaceae) and also in the essential oils of Vanilla spp. (Orchidaceae), Acacia spp. (Leguminosae), Cassia spp. (Leguminosae), Finns spp. (Pinaceae), Pimpinella anisum (Umbelliferae), Illicium venim (Illiciaceae), whereas p-hydroxybenzaldehyde occurs in traces in Plocama pendula (Rubiaceae), Pterocarpus marsupium (Leguminosae), and asaronaldehyde in the essential oils of Acorns spp. (Motley, T.J., Economic Botany, 48: 397-412, (1994) and Piper spp. (Koul, S.K., Taneja, S.C., Malhotra, S. and Dhar, K.L., Phytochemistry, 32(2): 478-480, (1993)). However, the limited percentage of these substituted phenylaldehydes present in the plant kingdom is not sufficient to fulfill the world demand and as a result, the major amounts of phenylaldehydes are made synthetically. A number of processes have been proposed to prepare substituted phenylaldehydes such as p-anisaldehyde, dimethoxybenzaldehyde, vanillin, heliotropin, asaronaldehyde etc. For the most part, these methods involves reacting the substituted benzene, such as p-methoxybenzene, 1,2,4-trimethoxybenzene with freshly distilled phosphorus oxychloride (POC13) in the presence of anhydrous N, Ndimethylformamide (DMF). However, while this Vilsmeier-Haack method has been proven to be useful, they suffer from one or more process deficiencies. For example, some processes of this type necessarily involve resort to sub ambient temperatures, which, of course, involves some considerable process control. In addition, large excesses of DMF and POCb must necessarily be employed to carry out the synthesis to obtain appreciable yields and moreover, POCh give rise to a violent exothermic reaction leading to obvious problems. Lastly, in some cases, the reaction is effected by the formation of some side reaction products (Toril, S., Uneyama, K. and Ueda, K., J. Org. Chem., 49, 1830-1832 (1984). Typical prior art refrences include U.S. Pat. Nos. 2,794,813; 5,358,861; 3,799,940; European Patent No. EP-A 405,197; Japanese Pat. Nos. 10,754,442A2; 55,87, 739; British Pat. Nos. 417,072; 774,608; 1,092,615; U.S.S.R. Pat. No. 490,793 and German Pat. Nos. 57,808; 207,702. It therefore becomes an object of the invention to provide rapid and economical process for the preparation of substituted phenylaldehydes from trans and cis-phenylpropenes which further provide commercial utilization of toxic cis-isomer as well as eliminate the above discussed disadvantages and others. Objectives of the invention The main object of the present invention is to develop a rapid and economical process for the preparation of useful phenylaldehydes (such as pmethoxybenzaldehyde, vetralaldehyde, asaronaldehyde etc) in one step. Another object of the invention is to develop a simple process for the preparation of phenylaldehyde in high purity. Another object of the invention is to develop a simple process for the preparation of phenylaldehyde with minimum or no side product formation such as corresponding acid. Yet another object of the invention is to develop an easy work-up of the reaction product. Yet another object of the invention is to develop a simple process for high degree of conversion. Yet another object of the invention is to develop a process, which does not require anhydrous reaction medium, a condition preferred by industries. Yet another object of the invention is to develop a simple process which does not require explosive and expensive reagents, hence, capable of undergoing commercial scale production. Yet another object of the invention is to develop a simple and quick process for the preparation of substituted phenylaldehydes in a short time ranging from 2 to 20 minutes under microwave irradiation. Yet another object of the invention is to develop a process for the preparation of value added products from toxic compound (such as p-asarone). Yet another object of the present invention is to explore the possibilities of preparing important aldehydes utilizing otherwise toxic essential oil e.g. crude calamus oil of tetraploid or hexaploid varieties or the other essential oil rich in anethole, isosafrole, methyl isoeugenol (atleast above 75% in crude oil) or the like, thereby, enhancing the profitable use thereof. Yet another object of the present invention is to explore a simple and cheaper starting material in which what ever percentage of cis (toxic) and trans-isomer (nontoxic) exists in crude essential oil or formed during alkaline isomerisation of yphenylpropenes (such as methylchavicol, safrole, methyl eugenol etc) are capable of Undergoing oxidation into high valued phenyldehydes otherwise the percentage of cis-isomer higher than a limited amount is not allowed with trans-isomer for commercial use in perfumery, flavour and pharmaceutics. Summary of the invention In brief, the present invention provides microwave assisted rapid (reaction time less than 20 minutes) and economical process for the preparation of substituted phenylaldehydes from trans and cis-phenylpropene derivatives using meta-periodate and osmium tetraoxide (catalytic amount) as an efficient oxidizing agent in the presence of catalyst namely amberlitelRA-410 and quantenary ammonium salt. It is worthwhile to mention that the conversion of toxic p-asarone (cis-isomer) from Acorus calamus or p-asarone (70-94%) rich crude calamus oil directly into asaronaldehyde (a versatile drugs precursor) is an economical gain of the above invention since it provides a proper utilization of internationally banned tetraploid and hexaploid varieties derived essential oil of Acorus calamus. Detailed description of the invention Accordingly, the present invention provides a microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes of the general formula (I) as given below (Formula Removed) wherein R1 is -CHO, R2, R3, R4, R5, R6 are independently selected from I. a hydrogen atom; II. an alkoxy group at least two of R2, R3, R4, R5, R6 being hydrogen atom; or an alkoxy group buy one of R2, R3, R4, R5, R6 being methylenedioxy group in combination with either hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group and a hydrogen atom or an alkoxy group but one of R2, R3, R4, R5, R6 being hydroxyl group in combinationwitheither methylenedioxy group, a hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group (-C6H5) or a hydrogen atom; III. a methylenedioxy group at least three of R2, R3, R4, R5, R6being in combination with either an alkoxy group, a hydroxyl group, an alkyl group having atleast one carbon atom, an aryl group or a hydrogen atom; IV. a hydroxyl group at least one of R2, R3, R4, R5, R6 being a hydrogen atom in combination with either an alkoxy group, a hydroxyl group, a methylenedioxy group, an alkyl group having atleast one carbon atom, an aryl group or a hydrogen atom; V. a protected hydroxyl group such as acetyl , benzyl, etc at least one of R2, R3, R4, R5, R6 being a hydrogen atom in combination with either an alkoxy, a hydroxyl group. A methylenedioxy group, an alkyl group having one or more carbon atoms, an aryl group or a hydrogen atom; said substituted phenylaldehydes being from corresponding (R2, R3, R4, R5, R6 ) phenylpropene derivatives said process comprising steps of: a) oxidizing said substituted phenylpropene in the presence of oxidizing agent and optionally with a co-catalyst in a solvent at a mole ratio of 1:1 to 1:12 for a period ranges from 20 seconds to 20 minutes under microwave irradiation b) filtering the reaction mixture of step (a) and washing the residue with an organic solvent c) washing the organic solution of step(b) with aquous sodium bisulfite or sodium thiosulphate followed by brine and water, d) drying the organic layer of step (c) over anhydrous sodium sulphate filtering and evaporating to dryness to remove completely the solvent to obtain a residue and e) purifying the residue of step (d) by recrystallization or column chromatography to obtain require substituted phenyl aldehyde of general formula (1). In an embodiment the solvent used is selected from the group consisting of ether solvent such as tetrahydrofuran, dimentyoxyethane, dioxane; ketonic solvents selected from acetone, ethylmethyl ketone; alcohol selected from methanol, ethanol and in presence of water. In another embodiment of the invention, the oxidizing agent used is selected from potassium permanganate/base, manganese dioxide/sulphanilic acid, meta-periodate/osmium tetraoxide. In still another embodiment of the invention, the co catalyst used is selected from amberlite such as amberlite-410, quaternary ammonium salt such as benzyltriethyl ammonium chloride, base such as triethyamine, pyridine. In yet another embodiment of the invention, the mole ratio of phenylpropene derivatives to oxidizing agent is ranging from 1:1 to 1:6. In yet another embodiment of the invention, the radiation frequency of microwave used is ranging from 2000 to 2800 MHz. In yet another embodiment of the invention, the starting material phenylpropene is widely available natural phenylpropanoid. In yet another embodiment, both isomeric forms (E & Z) of phenylpropene are utilized for phenylaldehyde formation. In yet another embodiment of the invention, toxic cis-isomer is converted into value added natural aldehyde. In yet another embodiment, an internationally banned (3-asarone from Acorus calamus is utilized by its conversion into a useful asaronaldehyde. In yet another embodiment, the above process is capable of preparing phenylaldehyde derivatives on commercial scale. In yet another embodiment of the invention, the above process oxidizes crude calamus oil of tetraploid or hexaploid varieties or the other essential oil rich in anethole, isosafrole, dimethoxy isoeugenol (at least above 75% in crude oil). In yet another embodiment of the invention provides a process wherein, the phenylaldehyde derivatives in highest purity without any contamination of corresponding acid and alcohol. In yet another embodiment, the above process provides phenylaldehyde derivatives in a very short time period ranging from 2-20 minutes. In yet another embodiment of the invention, the above process allows conducting reaction in aqueous medium, a condition preferred by industries and provides easy work-up of the reaction product. In yet another embodiment provides a simple process and cheaper starting material, in which what ever percentage of cis (toxic) and trans-isomer (preferred) exists in crude essential oil or formed during alkaline isomerisation of y-phenylpropenes (such as methylchavicol, safrole, methyl eugenol etc) are oxidized into high valued phenylaldehydes, otherwise higher than the allowed percentage of cis-isomer formed along with the trans-isomer is not allowed for commercial use in perfumery, flavour and pharmaceutics. In yet another embodiment of the invention provides a process wherein, in the above process for the preparation of some new phenylaldehydes, which are useful as a simple starting material for synthesis of corresponding acids, esters, amides, alcohol, and p-unsaturated aldehyde and are also useful for the dyes, alkaloids, agrochemical etc. Broadly speaking the invention relates to cis and trans-isomeric forms of (R2-R3-Rr R5-R6)phenylpropene bearing essential oils such as p-asarone, anethole and methyl isoeugenol or the like wherein Ra to Re equal or different, being hydrogen or hydroxy or acyl or alkyl or methylenedioxy or alkoxy groups or the like, are oxidized under microwave irradiation using meta-periodate/osmium tetraoxide for a reaction time less than 20 minutes in biphasic system comprising a solvent and aqueous phase containing a catalyst and thus high valued industrially important substituted phenylaldehydes such as asaronaldehyde, p-anisaldehyde, vetralaldehyde or the like derivatives are obtained in a single step in high yield varies from 71-82% depending upon the reagent, reaction time, condition and the phenylpropene used, the conversion of toxic p-asarone (cis-isomer) from Acorns calamus or p-asarone (70-94%) rich crude calamus oil directly into asaronaldehyde (a versatile drugs precursor) is an economical gain of the above invention since well explored Acorus calamus (tetraploid and hexaploid varieties) has recently been banned internationally for their use in human consumption. Accordingly, the present invention provides microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes from trans and toxic cisphenylpropenes of Formula I, a commercial utilization of toxic cis-isomer wherein RI is fixed as a -CHO, however, R2, Rs, R4, Rs, R* are independently; i) a hydrogen atom; ii) a alkoxy group but atleast two of them from R2, RS, R4, RS, R6 are hydrogen atom or a alkoxy group but one methylenedioxy group with combination of either hydroxyl group, alkoxy group, alkyl group having atleast one carbon atoms, aryl group (-CeHs) and hydrogen atom or a alkoxy group but one hydroxyl group with combination of either methylenedioxy group, hydroxyl group, alkoxy group, alkyl group having atleast one carbon atom, aryl group and hydrogen atom; iii) a methylenedioxy with atleast three of them from R2, RS, Rt, RS, Re are combination of either alkoxy, hydroxy group, alkyl group having atleast one carbon atoms, aryi group and hydrogen atom; vi) a hydroxyl group but atleast one of them from R2, R3, R4, RS, Re is hydrogen atom with combination of either alkoxy, hydroxyl group, methylenedioxy group, alkyl group having atleast one carbon atoms, aryl group and hydrogen atom; vii) a protected hydroxyl group such as acetyl, benzyl, etc but atleast one of them from R2, R3, R4, RS, Re is hydrogen atom with combination of either alkoxy, hydroxyl group, methylenedioxy group, alkyl group having one or more carbon atoms, aryl group and hydrogen atom or the like, obtained from corresponding (R2-R3-R4-R5- R6)phenylpropene derivatives (e.g. anethole where R2= R3=R5= R6=H; R4=OMe; methyl isoeugenol where R2= RS= R6=H; R3= R4=OMe and (3-asarone where R2=R4=R5-=OMe; R3=R6=H etc) and the above process comprising the steps of (a) providing phenylpropene such as but not limited to 2,4,5-trimethoxyphenylpropene (p-asarone) in the following solvents namely ether such as but not limited to tetrahydrofuran, dimethoxyethane, dioxane, and the like; ketone such as but not limited to acetone, ethylmethyl ketone; alcohol such as but not limited to methanol, ethanol and the like and water; (b) oxidation of phenylpropene derivatives in above solution by adsorbing on oxidizing reagents such as but not limited to metaperiodate/ osmium tetraoxide (catalytic amount) and the like to be used in the ratio of 1-12 times moles, preferably 1-6 moles in a short period ranging from 2-20 minutes under microwave irradiation; (c) oxidation step proceeds more smoothly along with higher yield in presence of co-catalyst amberlite such as but not limited to amberlite- 410, quaternary ammonium salt such as but not limited to benzyltriethylammonium chloride or base such as but not limited triethylamine, pyridine; (d) filtering the mixture and removing the solvent under reduced pressure, where the product is to be isolated by a conventional manner, i.e. extraction, recrystallization and chromatography and the yield of the product (e.g. 2,4,5-trimethoxybenzaldehyde where Rj= -CHO, R2=R4=R5-=OMe; R3=R6=H; 4-methoxybenzaldehyde where R\= - CHO, R2= R3=R5=R6=H; R4-=OMe and 3,4-dimethoxybenzaldehyde where RI= - CHO, R2=R5=R6=H; R3=R4-=OMe etc in the above formula I) varies from 68-81% preferably more in case of meta-periodate/osmium tetraoxide as a oxidizing reagent. In one more embodiment of the present invention, a simple and cheaper starting material phenylpropene is utilized for high valued phenylaldehyde derivatives, and one step process is described for substituted phenylaldehyde in high purity and yield without contamination of corresponding acid and alcohol. In another embodiment of the present invention, a simple and quick process for the preparation of substituted phenylaldehydes in a short time ranging from a few seconds to a few minutes under microwave irradiation. In another embodiment of the present invention, a process for the preparation of value added products from toxic compound (such as (3-asarone). In another embodiment of the present invention, a simple and cheaper starting material in which what ever percentage of cis (toxic) and trans-isomer (non-toxic) exists in crude essential oil or formed during alkaline isomerisation of yphenylpropenes (such as methylchavicol, safrole, methyl eugenol etc) are capable of undergoing oxidation into high valued phenylaldehydes otherwise the percentage of cis-isomer higher than a limited amount is not allowed with trans-isomer for commercial use in perfumery, flavour and pharmaceutics. Plant cells are highly sophisticated chemical factories where a large variety of chemical compounds are synthesized with great precision and ease from simple raw materials at normal pressure and temperature. Beside foods, plant materials/chemicals are used for many purposes for example, for treating medical ailments, dyeing clothes, colouring food items and for perfumery, cosmetics, flavour etc. Flavours represent a growing demand within the food industry. Several methods including chemical synthesis, biotechnology and natural extraction are under progress for the smooth production of aroma chemicals. Some of aromatic phenylaldehydes, mainly produced in plants in response to pathogen attack, possess strong antimicrobial activity due to hydroxy and an aldehyde group attached to the aromaic ring of phenylaldehyde. Therefore, as per applications concern, these phenylaldehydes are not only widely used in fragrances, flavours, cosmetics, liquors, Pharmaceuticals but they are also utilized as antibacterials, antifungais, and as biologically active compounds. Moreover, phenylpropenes, produced by plants in high concentration (sometimes unto 95-96% ) are also widely used by perfumery, flavour and pharmaceutical industries, e.g. anethole (4-methoxyphenylpropene) is well exploited essential oil which exists in cis- and trans-form (Miraldi, E.; Flavour & Fragrance Journal, 14(6) 379-382 (1999)), but its corresponding phenylaldehydes have more demand, as only trans-anethol is allowed since cis-anethol is possibly considered toxic and hazardous to human beings. On the other side, vanillin (a phenylaldehyde) is one of the most commonly consumed flavour chemicals (5,550 t/a worldwide) (Somogyi, L.P., Chem. Ind. L., 5, 170, (1996). However, the limited percentage and high price of these natural phenylaldehyde led to the necessity of using large amount of synthetic materials. At present, 97% of the world vanilla flavour market is synthetic vanillin and remaining 3% (weight basis) is a natural vanilla extract (Taylor, A.J. and Mottram, D.S., In: Flavour Science, Recent Developments, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK, 111-137, (1996). Various processes are known for the preparation of phenylaldehydes (Schiraldi, D.A. and Kenvin, J.C., U.S. Pat. No. 5910613; and Soma, Y., JP Pat. No. 11049734A2; Kashima, M., Yoshimoto, H., Noda, Y. and Jibiki, H. JP Pat. No. 7330655A2; Kajisori, S., JP Pat. No. 2268130A2; Tanaka, M., Sakakura, T., Wada, H. and Sasaki, Y. JP Pat No. 3264546A2; Kawamoto, K., Yoshioka, T., Yamagata, H., JP Pat. No. 5087739A2 and Ito, N. and Hasebe, A. JP Pat. No. 11279104A2) using phenylpropenes as a starting material. Considering the cost of starting material and reagents, phenylpropenes are found best suitable and cost effective starting material for the synthesis of substituted phenylaldehydes such as vanillin from isoeugenol, p-methoxybenzaldehyde from anethole and heliotropin from isosafarole (U.S. Pat. Nos, 1,643,804; 2,794,813). However, there is so far no such industrial method available for the preparation of a versatile drug intermediate "2,4,5- trimethoxybenzaldehyde" (a phenylaldehyde) from P-asarone (a toxic phenylpropene). It is worthwhile to mention that the selection of P-asarone for the preparation of asaronaldehyde has several fold benefits such as a simple and cheaper starting material and a proper utilization of internationally banned toxic calamus oil. Since Pasarone has recently been proved to be toxic and carcinogenic (Taylor, J. M., Jones, W. I., Hogan, E. C., Gross, M. A., David, D. A. and Cook, E. L., Toxicol. Appl. Phannacol., 10: 405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta Medica, 1: 6-9 (1985) and Kim, S.C., Liem, A., Stewart, B.C. and Miller, J.A., Carcinogensis, 20(7), 1303-1307 (1999)) and the most affected plant is Acorns calamus (familyrAraceae) in which percentage of toxic P-asarone depends upon the varieties of A. calamus (Riaz, M., Shadab, Q., Chaudhary, F. M., Hamdard Medicus 38(2): 50-62 (1995) and McGuffin, M., Hobbs, C., Upton, R. and Goldberg, A., In: American Herbal Products Association's Botanical Safety Handbook, CRC Press, Inc.; Boca Raton, Florida; USA, 231, (1997)). The content of P-asarone in the tripioid variety is 8-19 %, while P-asarone reaches upto 96% in the tetraploid and hexaploid varieties (extensively found in Asian countries). In contrast, p-asarone is not found in the diploid variety. As a result, the calamus oil obtained from North American diploid strain (zero, P-asarone) and East European tripioid strain (unto 12 % Pasarone) are allowed for clinical effectiveness and safety while the calamus oil produced in Asian belt (such as India, Pakistan, Bangladesh, Nepal, Japan and China) has diminished the market potential of calamus oil due to high percentage of Pasarone ranging from 70 to 94% (Mazza, G., J. of Chromatography 328:179-206 (1985); Nigam, M. C., Ateeque, A., Misra, L. N. and Ahmad, A., Indian Perfumer 34: 282-285 (1990) and Bonaccorsi, L, Cortroneo, A., Chowdhury, J. U. and Yusuf, M., Essenze Derv. Agrum, 67(4): 392-402 (1997)). Therefore, our objective to utilize toxic p-asarone for value added phenylaldehyde does not provide only economical gain for calamus oil of tetraploid or hexaploid strain but also as a simple and cheaper starting material for the preparation of a natural 2,4,5-trimethoxyphenylbenzaldehyde (asarylaldehyde), a versatile drug intermediate for synthesis of several biologically active compounds (Ahmad, S., Wagner, H. and Razaq, S., Tetrahedron, 34 (10): 1593- 1594, (1978)) including Makaluvamine-D and Discorhabdin-C marine alkaloids (Sadanandan, E.V., Pillai, S.K., Lakshmikantham, M.V., Billimoria, A.D., Culpepper, J.S. and Cava, M.P. J. Org. Chem., 66: 1800-1805, (1995)). Phenylpropenes are relatively electron rich (pi bonds) which can be oxidized to corresponding aldehyde with a number of oxidizing agents such as chromic acid (Ger. Pat. No. 576 and U.S. Pat. No. 2,794, 813), manganese dioxide (Br. Pat. No. 774,608), potassium permanganate (Erlenmeyer, Chem. Ber. 9, 273 (1876)), chromyl chloride (U.S. Pat. No. 365,918), air (Ger. Pat. No. 224,071), oxygen (Ger. Pat. No. 150,981), ozonolysis (Ger. Pat. No. 321,567 and C.A., 54,:5538 (I960)), electrolysis (Ger. Pat. No. 92,007), peroxide (Ger. Pat. No. 93,938), nitrobenzene (Brit. Pat. No. 271,819 and U.S. Pat No. 1,643,804), nitrobenzene (Brit. Pat. No. 285,156) and by several others process. All the above methods have various limitations, for example, low yield, expensive reagents and formation of unwanted side products. Our initial efforts to oxidize Pasarone by using known oxidizing reagents such as potassium permanganate or manganese dioxide/suiphanilic acid (Br. Pat. No. 774,608)) coupled in microwave to obtain asaronaldehyde is remained unsuccessful due to poor yield with various side product formation (such as asaronic acid). Fortunately, the combination of osmium tetroxide (OsO4) and periodate reagent (Cainelli, G., Contento, M., Manescalchi, F. and Plessi, L, Synthesis, 47-48, (1989)) in microwave is found an effective and high yielding method for preparing asaronaldehyde from toxic p-asarone (Example la). In addition, microwave assisted oxidation of phenylpropenes or the like with osmium tetroxide conducting in fuming hood is easy and safe otherwise handling of osmium tetraoxide requires special precaution due to its poisonous nature. After success of asarone, oxidation of a-asarone into asaronaldehyde is also found as effective as Pasarone. These experiments gave us idea that geometry (i.e. cis/trans-isomer) of phenylpropene does not effect the yield of final oxidized product. In continuation of this oxidation, calamus oil (rich in phenylpropene i.e. 85-90% o/p-asarone) is also capable of undergoing oxidation without any problem in purification or loss in yield since other constituents of calamus oil does effect interfere in asaronaldehyde formation (Example Ic). Although, OsO4/NaIO4 is well known system for converting alkene into aldehyde, however, microwave assisted oxidation of phenylpropene has not been reported so far for the preparation of substituted phenylaldehydes especially from toxic isomer of phenylpropene i.e. P-asarone (cisisomer) or phenylpropene rich crude oil (i.e. crude calamus oil). Having successfully achieved an efficient process for asaronaldehyde, we decided to extend the process to convert various phenylpropenes into phenylaldehyde via OsO4/NaIC>4 such as anethole into 3,4-dimethoxyisoeugenol into 3,4-dimethoxybenzaldehyde (Example II), 4- methoxybenzaldehyde (Example III) or the like. It is further worthwhile to mention that what ever percentage of cis/trans anethole from methyl chavicol, cis/trans isosafrole from safrole, cis/trans isoeugenol from eugenol or the like obtained during alkaline isomerisation of y-phenylpropene (allylbenzene) or crude essential oil rich cis/trans phenylpropene (above 70% for industrial scale) can be easily utilized for the formation of corresponding phenylaldehydes. Our present invention is also beneficial to those industries which are engaged in alkaline isomerisation of allylbenzene into trans-phenylpropene for wide scope in flavour, perfumery and pharmaceutical industries, however, formation of cis-phenylpropene along with trans-phenylpropene diminished their applications, since separation of isomers is tedious and expensive on industrial point of view whereas, both isomeric forms can be used for the preparation of high valued phenylaldehydes. PhenylaUebyde Brief description of the accompanying drawings Figure 1 is H NMR (300 MHz) spectra of asaronaldehyde. (2,4,5- trimethoxybenzaldehyde) (in CDCb) of the reaction product of Example I containing the compound having the structure: ##STR1##. Figure 2 is 13C NMR (75.4 MHz) spectra of asaronaldehyde (2,4,5- trimethoxybenzaldehyde) (in CDCU) of the reaction product of Example I containing the compound having the structure: ##STR1##. Figure 3 is the electro spray (ES) mass spectrum of asaronaldehyde (2,4,5- trimethoxybenzaldehyde) (MW 196) of the reaction product of Example I containing the compound having the structure: ##STR1##. EXAMPLES The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of the present invention. Example I Reaction: ##STR1## (a) Preparation of asaronaldehyde (2,4,5-trimethoxybenzaldehyde) from \|Jasarone (by microwave irradiation method): A mixture of (3-asarone (3.1 g, 0.015 mmol), catalytic amount of OsO4 (0.04 to 0.002 g), NaIO4 (11.75 g, 0.055 mmol), benzyltriethyl ammonium chloride (catalytic amount) and THF-H2O (8-10 mL, 4:1) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside a microwave oven operating at medium power level and irradiated for 2-12 minutes in parts. After completion of the reaction (monitored by TLC), the contents of the flask were poured into chloroform and passed through a bed of Celite and further washed with chloroform. The filtrate and washings were combined and the chloroform layer were washed with sodium thiosulphate to destroy the excess periodate. The chloroform layers were then combined and washed with saturated sodium chloride (3 x 15 m), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude solid product which was recrytallised with water to afford 2.39 g (82%) of asaronaidehyde as a feathery white needles, Rf (0.34 in 28% ethylacetate in hexane); mp 114 °C (lit mpl 14 °C); IR (film) vmax 1662 (carbonyl group), 1620, 1518, 1481, 1419, 1361, 1300, 1278, 1222, 1199, 1138, 1025, 865 cm'1; 1H NMR 8 10.32 (1H, s, CHO), 7.33 (1H, s, 6H), 6.50 (1H, s, 3H), 3.98 (3H, s, 2- OCH3), 3.93 ((3H, s, 4-OCH3), 3.88 (3H, s, 5-OCH3); 13 C NMR 5 187.96 (CHO), 158.60 (C-2), 155.76 (C-4), 143.56 (C-5), 117.35 (C-l), 109.03 (C-6), 56.19 (2- OCH3, 4-OCH3 and 5-OCH3); EIMS m/z 196 [M]+ (100), 181 (49), 150 (32), 125 (33), 110 (23), 69 (37). (b) Asaronaldehyde from a-asarone (by conventional method): A solution of OsCU (0.065 g, 0.25 mmol) in water (2 mL) was added dropwise to ice cold solution of a-asarone (0.624 g, 0.003 mole) (procured from Sigma) in THF-H2O (25 mL, 4:1) over a period of 5 min with constant stirring. After 20 min at 0-5 °C, finely powdered Nal(>4 (2.35 g, 0.011 mole) was added in parts and reaction mixture was stirred for 4- 6 hr at room temperature. After completion of reaction (monitored by TLC), the precipitated sodium iodate was filtered and the filtrate was washed with CH2C12. The combined organic layers were washed with 10% solution of sodium bisulphite (to destroy the excess of sodium meta-periodate), saturated brine and dried (Na2SC>4). Evaporation of the solvent furnished a crude mixture, which was loaded on silica gel column, and the column was eluted with an increasing amount of hexane/ethy 1 acetate (95:5 to 70:30). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 0.49 g (84%) as a white solid; mp 114 °C. The physical and spectral data was found similar as above (Example I). (c) Preparation of asaronaldebyde from crude calamus oil: The rhizomes of 'Acorus calamus Linn was collected in March-April 1999 from Palampur (H.P.) and was confirmed by comparison with the specimen (IHBT no. 1066) kept in the herbarium of our Institute. The hydrodistillation of rhizomes of Acorus calamus gave pungent smelling oil in 1.7 % yield (w/w) with a presence of (3-asarone (85 %) and a-asarone (3-4%) (by GC) and used directly for oxidation step. A mixture of pale yellow crude calamus oil (9.00 g), catalytic amount of OsO4 ((0.08 to 0.002 g), NaIO4 (50 to 55 g) and dioxane-H2O (50-60 mL or more, 4:1) were taken in a 500 ml beaker fitted with a loose watch glass at the top. The beaker was placed inside a microwave oven operating at medium power level and irradiated for 3-16 minutes in parts. After completion of the reaction (monitored by TLC), the contents of the beaker were filtered and washed with ethyl acetate. The ethylacetate layers were washed with water, aqueous sodium bisulphite (to destroy the excess periodate) and brine, dried over (anhydrous sodium sulphate) and filtered. The solvent was removed under reduced pressure and crude solid was recrystallised with hexane and chloroform to obtain 5.66 g (76%, based on % of a and (3-asarone in crude calamus oil) of pure asaronaldehyde as a white solid; mp 114 °C. The physical and spectral data was found similar as above (Example I). Example II Preparation of 3,4-dimethoxybenzaldehyde from methyl isoeugenol (by microwave method): The starting material methyl isoeugenol (3,4-dimethoxy phenylpropene) can be easily prepared by fast 0-methylation of cheaper and easily available isoeugenol (3-methoxy-4-hydroxy-phenylpropene) for which a mixture of isoeugenol (2.46 g, 0.015 mole), dry dimethyl sulphate (1.8 g, 0.14 mole), anhydrous potassium carbonate (6g, 0.062 mole) and dry acetone (15-20 mL) was irradiated in a microwave oven for 8-10 minutes in parts. After completion of reaction (monitored by TLC) the contents of the flask were poured into ice water. The product was taken in ether (50-60 mL) and the ether layer was washed with dilute hydrochloric acid, saturated sodium bicarbonate and brine respectively and dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford a desired product methyl isoeugenol (2.32 g, 87% yield) which was used directly for next step. A solution of OsO4 (0.006-0.008 g), methyl isoeugenol (0.53 g, 0.003 mole), finely powdered NaIO4 (2.35 g, 0.011 mole), amberlite IRA-410 (O.lg) in THF-H2O (25 mL, 4:1) was irradiated in a microwave oven for 3-11 minutes. After completion of reaction (monitored by TLC), the precipitated sodium iodate was filtered and the filtrate was washed with CH2Cl2. The combined organic layers were washed with sodium thiosulphate (to destroy the excess of sodium meta-periodate), saturated brine and dried over Na2SO4. Evaporation of the solvent furnished a crude mixture, which was loaded on silica gel column, and the column was eluted with an increasing amount of hexane/ethyl acetate (95:5 to 70:30). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 3,4-dimethoxybenzaldehyde in 79% yield as a solid; !H NMR 8 9.86 (1H, s, CHO), 7.45 (1H, s, 6H), 7.41 (1H, s, 2H), 6.98 (1H, s, 5H), 3.97 (3H, s, 4-OCH3), 3.95 (3H, s, 3-OCH3). The remaining physical and spectral data was found similar as reported. Example in Preparation of 4-methoxybenzaldehyde from anethole (by microwave method): A solution of OsO4 (0.004-0.007 g), anethole (2.22 g, 0.015 mole), finely powdered NaIO4 (9.0 g, 0.044 mole) in THF-H2O (20-25mL) was irradiated in a microwave oven for 2-8 minutes in parts. The precipitated sodium iodate was filtered and the filtrate was washed with CHjCh. The combined organic layers were washed with sodium thiosulphate, brine and dried over NajSC^. Evaporation of the solvent furnished a crude mixture, which was loaded on silica gel column, and the column was eluted with increasing amount of hexane/ethyl acetate (98:2 to 80:20). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 4-methoxybenzaldehyde in 71% yield as a sweet smell liquid; !H NMR 8 9.95 (1H, s, CHO), 7.82 (1H, s, 6H), 7.79 (1H, s, 2H), 6.99 (1H, s, 5H), 6.96 (1H, s, 5H), 3.84 (3H, s, 4-OCH3). The remaining physical and spectral data was found similar as reported and yield was found less may be due to evaporation of anethole during microwave irradiation. The main advantages of the present invention are 1. A simple and economical industrial process to convert phenylpropene derivatives into corresponding phenylaldehyde in one step. 2. A simple process to convert phenylpropene derivatives into corresponding phenylaldehyde in high yields. 3. A process to convert an internationally banned toxic compound p-asarone of calamus oil or cis anethol or the like into useful products. 4. Preparation of phenylaldehyde as an inexpensive and simple starting material for corresponding acid, ester, and alcohol or the like and are also useful for a,(3-unsaturated aldehyde and the dyes, alkaloids, agrochemicals etc. 5. The present chemical process can increase the price of calamus oil by its conversion into asaronaldehyde, otherwise, calamus oil of tetraploid or hexaploid varieties (distributed extensively in Asian origin) has very low price in comparison to the oil of diploid and triploid (distributed in American or European origin) varieties. 6. A simple process by which any kind of phenylpropene can be converted into corresponding aldehyde in a shorter time ranging from 2-20 seconds. 7. A simple process for preparation of phenylaldehyde which does not require anhydrous reaction medium , a condition preferred by industries. 8. A simple process for the preparation of value added products from toxic compounds such as p-asarone few seconds to minutes under microwave irradiation. 9. A simple process for preparation of phenylaldehyde in which what ever percentage of cis (toxic) and trans-isomer (preferred) exists in crude essential oil or formed during alkaline isomerisation of y-phenylpropenes (such as methylchavicol, safrole, methyl eugenol etc) are capable of undergoing oxidation into high valued phenylaldehydes otherwise the percentage of cisisomer higher than a limited amount is not allowed with trans-isomer for commercial use in perfumery, flavour and pharmaceutics. We Claim. 1. Microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes of the general formula (I) as given below: (Formula Removed) wherein R1 is-CHO, R2, R3, R4, R5, R6 are independently selected from I. a hydrogen atom; II. an alkoxy group wherein two of R2, R3, R4, R5, Re being hydrogen atom; or an alkoxy group wherein one of R2, R3, R4, R5, R6 being methylenedioxy group in combination with either hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group and a hydrogen atom or an alkoxy group when of R2, R3, R4, R5, R6 being hydroxyl group in combinationwitheither methylenedioxy group, a hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group (-C6H5) or a hydrogen atom; III. a methylenedioxy group IV. a hydroxyl group v. a protected hydroxyl group such as acetyl, benzyl, said substituted phenylaidehydes being from corresponding (R2, R3, R4, R5, R6 ) phenylpropene derivatives said process comprising steps of: a) oxidizing said substituted phenylpropene in the presence of oxidizing agent and optionally with a co-catalyst in a solvent at a mole ratio of 1:1 to 1:12 for a period ranges from 20 seconds to 20 minutes under microwave irradiation b) filtering the reaction mixture of step (a) and washing the residue with an organic solvent c) washing the organic solution of step(b) with aquous sodium bisulfite or sodium thiosulphate followed by brine and water, d) drying the organic layer of step (c) over anhydrous sodium sulphate filtering and evaporating to dryness to remove completely the solvent to obtain a residue and e) purifying the residue of step (d) by recrystallization or column chromatography to obtain require substituted phenyl aldehyde of general formula (1). 2 A process as claimed in claim 1 wherein, the solvent used is selected from the group consisting tetrahydrofuran, dimethyyoxyethane, dioxane; acetone ethylmethyl ketone; methanol diluted with water ethanol. 3 A process as claimed in claim 1 wherein, the oxidizing agent used is selected from potassium manganese dioxide/sulphanilic acid, meta-periodate/osmium tetraoxide- 4 A process as claimed in claim 1 wherein, the co catalyst used is selected from amberlite resine benzyltriethyl ammonium chloride, triethylamine or pyridine. 5. A process as claimed in claim 1 wherein, the mole ratio of phenylpropene derivatives to oxidizing agent is ranging from 1:1 to 1:6. 6. A process as claimed in claim 1 wherein the microwave radiation frequency used is ranging from 2000 to 2800 MHz. 7. A process as claimed in claim 1 wherein the starting material phenylpropene is phenylpropanoid. 8. a process as claimed in claim 1 wherein, both isomeric form of phenylpropene are utilized for phenylaldehyde formation. 9. A process as claimed in claim 1 wherein toxic cis-isomer is converted into substituted phenylaldehyde of general formula (1) which is a natural aldehyde. 10. A process as claimed in claim 11 wherein step (a) is conducted in an aqueous medium and provides easy work-up. 11. A process as claimed in claim 1 wherein the time period in step (a) is 2-20 minutes. 12. A process as claimed in claim 1 wherein a mixture of the trans- and cis-isomers are converted to the substituted phenyldehyde regardless of the proportions of said isomers in said mixture. 13. A process as claimed in claim 1, wherein the substituted phenylaldehyde is selected from the group consisting of asaronaldehyde, asarylaldehyde, 4-methoxybenzaldehyde and 3,4-diinethoxybenzaldehyde.

Full Text

MICROWAVE ASSISTED RAPED AND ECONOMICAL PROCESS FOR THE
PREPARATION OF SUBSTITUTEFD PHENYLALDEHYDES FROM TRANS
AND CIS-PHENYLPROPENES: A COMMERCIAL UTILISATION OF
TOXIC CIS-ISOMER
Field of the invention
The present invention relates to "microwave assisted rapid and economical
process for the preparation of substituted phenylaldehydes from trans and toxic cisphenylpropenes:
a commercial utilization of toxic cis-isomer" in which industrially
important phenylaldehydes (e.g. asaronaldehyde where RI is CHO, R2 = R4 = RS is -
OMe and R3=R6 is H; p-anisaldehyde where, Rt is -CHO, R2 = R3 = RS = Re is H and
R4 is -OMe and vetralaldehyde where Rf is -CHO, R2 = RS = R« is H; R3 = R4 is -
OMe or the like) of the formula I
are obtained via oxidation of easily available isomeric forms (trans and cis-isomer) of
(R2-R3-R4-Rs-R6)phenylpropene bearing essential oils (i.e. p-asarone, anethole, and
methyl isoeugenol or the like) wherein R2 to R& equal or different, being hydrogen or
hydroxy or acyl or alkyl or methylenedioxy or alkoxy groups or the like, under
microwave irradiation using meta-periodate/osmium tetraoxide (catalytic amount) for
a reaction time less than 20 minutes in biphasic system comprising a solvent and
aqueous phase containing a catalyst (such as quaternary ammonium salt and amberlite
IRA-410 etc) with high yield varying from 71-82% depending upon the reagent,
reaction time, condition and the phenylpropene used. In addition crude Acorns
calamus oil (rich in P-asarone present in 70-94%) used directly for microwave
assisted oxidation is an added benefit as remaining constituents of calamus oil do not
interfere for the preparation of asaronaldehyde (yield just less by 5-10% depending
upon asarone percentage in calamus oil) which makes the above process further cost
effective since tetraploid and hexaploid varieties of Acorus calamus has been
internationally banned for their use in human consumption. Moreover, we have
observed that the preparation of asaronaldehyde (a versatile drugs precursor) requires
lesser time (2-20 minutes) under microwave irradiation while oxidation takes 2-6
hours when conducted at room temperature (conventional method).
Background of the invention
Naturally occurring substituted phenylaldehydes (Harbome, J.B. and Baxter,
H., In: Phytochemical Dictionary, A Handbook of Bioactive Compounds from Plants,
Taylor & Francis Ltd., London WC1N 2ET, 472-488 (1993)) e.g. vanillin, panisaldehyde,
p-hydroxybenzaldehyde, asaronaldehyde, heliotropin and vetralaldehyde
etc possess in common an aromatic ring bearing one or more hydroxy or
dioxymethylene or alkoxy groups or the like, attached to a aldehyde group (CHO)
contribute significantly to the taste and flavour of many foods, drinks, perfumery and
serve as a pharmaceutical aid. In addition, phenylaldehyde derivatives serve as a raw
material for the preparation of a large number of aromatic compounds useful in the
perfume industry e.g. treatment of phenylaldehyde with alkali alcoholate results in the
formation of phenyl benzoate and condensation of phenylaldehyde derivative with
acetaldehyde gives cinnamic aldehyde which are useful in both the perfume and
pharmaceutical industries. In addition, large quantities of phenylaldehydes are used in
the manufacture of dyes, medicines (Patel, P.J.; Messer Jr., W.S. and Hudson, R.A., J.
Med. Chem., 36, 1893-1901 (1993)), photographic films, cosmetics, dyes,
agrochemicals etc.
The widespread aromatic aldehydes such as vanillin is obtained from the pods
of Vanilla planifolia (family: Orchidaceae), the bulbs of Dahlia spp. (Compositae),
the sprouts of Asparagus spp. (Liliaceae), the beats of Beta spp. (Chenopodiaceae)
and also from the essential oils of Syzygium aromaticum (Myrtaceae), Ruta spp.
(Rutaceae), Spiraea spp. (Rosaceae) and Gymnadenia spp. (Orchidaceae), while 3,4-
methylenedioxybenzaldehyde ( heliotropin) is obtained from the essential oils of the
flowers and leaves of Robinia pseudocode (Legumminosae), Doryphora sassafras,
Eryngium potericum (Umbelliferae), Heliotropium spp. (Boraginaceae), Vanilla spp.
(Orchidaceae) and from extracts of Viola spp. (Violaceae) and Baccharis
rosmarinifolia (Compositae). Other phenylaldehydes are restricted to a few families
such as p-anisaldehyde occurs in the fruits of Pelea madagascariensis (Rutaceae),
Agastache ntgosa (Labiatae), leaves of Magnolia salicifolia (Magnoiiaceae) and also
in the essential oils of Vanilla spp. (Orchidaceae), Acacia spp. (Leguminosae), Cassia
spp. (Leguminosae), Finns spp. (Pinaceae), Pimpinella anisum (Umbelliferae),
Illicium venim (Illiciaceae), whereas p-hydroxybenzaldehyde occurs in traces in
Plocama pendula (Rubiaceae), Pterocarpus marsupium (Leguminosae), and
asaronaldehyde in the essential oils of Acorns spp. (Motley, T.J., Economic Botany,
48: 397-412, (1994) and Piper spp. (Koul, S.K., Taneja, S.C., Malhotra, S. and Dhar,
K.L., Phytochemistry, 32(2): 478-480, (1993)). However, the limited percentage of
these substituted phenylaldehydes present in the plant kingdom is not sufficient to
fulfill the world demand and as a result, the major amounts of phenylaldehydes are
made synthetically.
A number of processes have been proposed to prepare substituted
phenylaldehydes such as p-anisaldehyde, dimethoxybenzaldehyde, vanillin,
heliotropin, asaronaldehyde etc. For the most part, these methods involves reacting
the substituted benzene, such as p-methoxybenzene, 1,2,4-trimethoxybenzene with
freshly distilled phosphorus oxychloride (POC13) in the presence of anhydrous N, Ndimethylformamide
(DMF). However, while this Vilsmeier-Haack method has been
proven to be useful, they suffer from one or more process deficiencies. For example,
some processes of this type necessarily involve resort to sub ambient temperatures,
which, of course, involves some considerable process control. In addition, large
excesses of DMF and POCb must necessarily be employed to carry out the synthesis
to obtain appreciable yields and moreover, POCh give rise to a violent exothermic
reaction leading to obvious problems. Lastly, in some cases, the reaction is effected
by the formation of some side reaction products (Toril, S., Uneyama, K. and Ueda, K.,
J. Org. Chem., 49, 1830-1832 (1984).
Typical prior art refrences include U.S. Pat. Nos. 2,794,813; 5,358,861;
3,799,940; European Patent No. EP-A 405,197; Japanese Pat. Nos. 10,754,442A2;
55,87, 739; British Pat. Nos. 417,072; 774,608; 1,092,615; U.S.S.R. Pat. No. 490,793
and German Pat. Nos. 57,808; 207,702.
It therefore becomes an object of the invention to provide rapid and
economical process for the preparation of substituted phenylaldehydes from trans and
cis-phenylpropenes which further provide commercial utilization of toxic cis-isomer
as well as eliminate the above discussed disadvantages and others.
Objectives of the invention
The main object of the present invention is to develop a rapid and economical
process for the preparation of useful phenylaldehydes (such as pmethoxybenzaldehyde,
vetralaldehyde, asaronaldehyde etc) in one step.
Another object of the invention is to develop a simple process for the
preparation of phenylaldehyde in high purity.
Another object of the invention is to develop a simple process for the
preparation of phenylaldehyde with minimum or no side product formation such as
corresponding acid.
Yet another object of the invention is to develop an easy work-up of the
reaction product.
Yet another object of the invention is to develop a simple process for high
degree of conversion.
Yet another object of the invention is to develop a process, which does not
require anhydrous reaction medium, a condition preferred by industries.
Yet another object of the invention is to develop a simple process which does
not require explosive and expensive reagents, hence, capable of undergoing
commercial scale production.
Yet another object of the invention is to develop a simple and quick process
for the preparation of substituted phenylaldehydes in a short time ranging from 2 to
20 minutes under microwave irradiation.
Yet another object of the invention is to develop a process for the preparation
of value added products from toxic compound (such as p-asarone).
Yet another object of the present invention is to explore the possibilities of
preparing important aldehydes utilizing otherwise toxic essential oil e.g. crude
calamus oil of tetraploid or hexaploid varieties or the other essential oil rich in
anethole, isosafrole, methyl isoeugenol (atleast above 75% in crude oil) or the like,
thereby, enhancing the profitable use thereof.
Yet another object of the present invention is to explore a simple and cheaper
starting material in which what ever percentage of cis (toxic) and trans-isomer (nontoxic)
exists in crude essential oil or formed during alkaline isomerisation of yphenylpropenes
(such as methylchavicol, safrole, methyl eugenol etc) are capable of
Undergoing oxidation into high valued phenyldehydes otherwise the percentage of cis-isomer higher than a limited amount is not allowed with trans-isomer for commercial use in perfumery, flavour and pharmaceutics. Summary of the invention
In brief, the present invention provides microwave assisted rapid (reaction time less than 20 minutes) and economical process for the preparation of substituted phenylaldehydes from trans and cis-phenylpropene derivatives using meta-periodate and osmium tetraoxide (catalytic amount) as an efficient oxidizing agent in the presence of catalyst namely amberlitelRA-410 and quantenary ammonium salt. It is worthwhile to mention that the conversion of toxic p-asarone (cis-isomer) from Acorus calamus or p-asarone (70-94%) rich crude calamus oil directly into asaronaldehyde (a versatile drugs precursor) is an economical gain of the above invention since it provides a proper utilization of internationally banned tetraploid and hexaploid varieties derived essential oil of Acorus calamus.
Detailed description of the invention
Accordingly, the present invention provides a microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes of the general formula (I) as given below
(Formula Removed)
wherein R1 is -CHO,
R2, R3, R4, R5, R6 are independently selected from

I. a hydrogen atom;
II. an alkoxy group at least two of R2, R3, R4, R5, R6 being hydrogen atom; or an alkoxy group buy one of R2, R3, R4, R5, R6 being methylenedioxy group in combination with either hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group and a hydrogen atom or an alkoxy group but one of R2, R3, R4, R5, R6 being hydroxyl group in combinationwitheither methylenedioxy group, a hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group (-C6H5) or a hydrogen atom;
III. a methylenedioxy group at least three of R2, R3, R4, R5, R6being in combination with either an alkoxy group, a hydroxyl group, an alkyl group having atleast one carbon atom, an aryl group or a hydrogen atom;
IV. a hydroxyl group at least one of R2, R3, R4, R5, R6 being a hydrogen atom in combination with either an alkoxy group, a hydroxyl group, a methylenedioxy group, an alkyl group having atleast one carbon atom, an aryl group or a hydrogen atom;
V. a protected hydroxyl group such as acetyl , benzyl, etc at least one of R2, R3, R4, R5, R6 being a hydrogen atom in combination with either an alkoxy, a hydroxyl group. A methylenedioxy group, an alkyl group having one or more carbon atoms, an aryl group or a hydrogen atom;
said substituted phenylaldehydes being from corresponding (R2, R3, R4, R5, R6 ) phenylpropene derivatives said process comprising steps of:
a) oxidizing said substituted phenylpropene in the presence of oxidizing agent and optionally with a co-catalyst in a solvent at a mole ratio of 1:1 to 1:12 for a period ranges from 20 seconds to 20 minutes under microwave irradiation
b) filtering the reaction mixture of step (a) and washing the residue with an organic solvent

c) washing the organic solution of step(b) with aquous sodium bisulfite or sodium thiosulphate followed by brine and water,
d) drying the organic layer of step (c) over anhydrous sodium sulphate filtering and evaporating to dryness to remove completely the solvent to obtain a residue and
e) purifying the residue of step (d) by recrystallization or column chromatography to obtain require substituted phenyl aldehyde of general formula (1).
In an embodiment the solvent used is selected from the group consisting of ether solvent such as tetrahydrofuran, dimentyoxyethane, dioxane; ketonic solvents selected from acetone, ethylmethyl ketone; alcohol selected from methanol, ethanol and in presence of water.
In another embodiment of the invention, the oxidizing agent used is selected from potassium permanganate/base, manganese dioxide/sulphanilic acid, meta-periodate/osmium tetraoxide. In still another embodiment of the invention, the co catalyst used is selected from amberlite such as amberlite-410, quaternary ammonium salt such as benzyltriethyl ammonium chloride, base such as triethyamine, pyridine.

In yet another embodiment of the invention, the mole ratio of phenylpropene
derivatives to oxidizing agent is ranging from 1:1 to 1:6.
In yet another embodiment of the invention, the radiation frequency of microwave
used is ranging from 2000 to 2800 MHz.
In yet another embodiment of the invention, the starting material phenylpropene is
widely available natural phenylpropanoid.
In yet another embodiment, both isomeric forms (E & Z) of phenylpropene are
utilized for phenylaldehyde formation.
In yet another embodiment of the invention, toxic cis-isomer is converted into value
added natural aldehyde.
In yet another embodiment, an internationally banned (3-asarone from Acorus calamus
is utilized by its conversion into a useful asaronaldehyde.
In yet another embodiment, the above process is capable of preparing phenylaldehyde
derivatives on commercial scale.
In yet another embodiment of the invention, the above process oxidizes crude calamus
oil of tetraploid or hexaploid varieties or the other essential oil rich in anethole,
isosafrole, dimethoxy isoeugenol (at least above 75% in crude oil).
In yet another embodiment of the invention provides a process wherein, the
phenylaldehyde derivatives in highest purity without any contamination of
corresponding acid and alcohol.
In yet another embodiment, the above process provides phenylaldehyde derivatives in
a very short time period ranging from 2-20 minutes.
In yet another embodiment of the invention, the above process allows conducting
reaction in aqueous medium, a condition preferred by industries and provides easy
work-up of the reaction product.
In yet another embodiment provides a simple process and cheaper starting material, in
which what ever percentage of cis (toxic) and trans-isomer (preferred) exists in crude
essential oil or formed during alkaline isomerisation of y-phenylpropenes (such as
methylchavicol, safrole, methyl eugenol etc) are oxidized into high valued
phenylaldehydes, otherwise higher than the allowed percentage of cis-isomer formed
along with the trans-isomer is not allowed for commercial use in perfumery, flavour
and pharmaceutics.
In yet another embodiment of the invention provides a process wherein, in the above
process for the preparation of some new phenylaldehydes, which are useful as a
simple starting material for synthesis of corresponding acids, esters, amides, alcohol,
and p-unsaturated aldehyde and are also useful for the dyes, alkaloids, agrochemical
etc.
Broadly speaking the invention relates to cis and trans-isomeric forms of (R2-R3-Rr
R5-R6)phenylpropene bearing essential oils such as p-asarone, anethole and methyl
isoeugenol or the like wherein Ra to Re equal or different, being hydrogen or hydroxy
or acyl or alkyl or methylenedioxy or alkoxy groups or the like, are oxidized under
microwave irradiation using meta-periodate/osmium tetraoxide for a reaction time
less than 20 minutes in biphasic system comprising a solvent and aqueous phase
containing a catalyst and thus high valued industrially important substituted
phenylaldehydes such as asaronaldehyde, p-anisaldehyde, vetralaldehyde or the like
derivatives are obtained in a single step in high yield varies from 71-82% depending
upon the reagent, reaction time, condition and the phenylpropene used, the conversion
of toxic p-asarone (cis-isomer) from Acorns calamus or p-asarone (70-94%) rich
crude calamus oil directly into asaronaldehyde (a versatile drugs precursor) is an
economical gain of the above invention since well explored Acorus calamus
(tetraploid and hexaploid varieties) has recently been banned internationally for their
use in human consumption.
Accordingly, the present invention provides microwave assisted rapid and economical
process for the preparation of substituted phenylaldehydes from trans and toxic cisphenylpropenes
of Formula I, a commercial utilization of toxic cis-isomer wherein RI
is fixed as a -CHO, however, R2, Rs, R4, Rs, R* are independently; i) a hydrogen atom;
ii) a alkoxy group but atleast two of them from R2, RS, R4, RS, R6 are hydrogen atom
or a alkoxy group but one methylenedioxy group with combination of either hydroxyl
group, alkoxy group, alkyl group having atleast one carbon atoms, aryl group (-CeHs)
and hydrogen atom or a alkoxy group but one hydroxyl group with combination of
either methylenedioxy group, hydroxyl group, alkoxy group, alkyl group having
atleast one carbon atom, aryl group and hydrogen atom; iii) a methylenedioxy with
atleast three of them from R2, RS, Rt, RS, Re are combination of either alkoxy,
hydroxy group, alkyl group having atleast one carbon atoms, aryi group and hydrogen
atom; vi) a hydroxyl group but atleast one of them from R2, R3, R4, RS, Re is hydrogen
atom with combination of either alkoxy, hydroxyl group, methylenedioxy group, alkyl
group having atleast one carbon atoms, aryl group and hydrogen atom; vii) a
protected hydroxyl group such as acetyl, benzyl, etc but atleast one of them from R2,
R3, R4, RS, Re is hydrogen atom with combination of either alkoxy, hydroxyl group,
methylenedioxy group, alkyl group having one or more carbon atoms, aryl group and
hydrogen atom or the like, obtained from corresponding (R2-R3-R4-R5-
R6)phenylpropene derivatives (e.g. anethole where R2= R3=R5= R6=H; R4=OMe;
methyl isoeugenol where R2= RS= R6=H; R3= R4=OMe and (3-asarone where
R2=R4=R5-=OMe; R3=R6=H etc) and the above process comprising the steps of (a)
providing phenylpropene such as but not limited to 2,4,5-trimethoxyphenylpropene
(p-asarone) in the following solvents namely ether such as but not limited to
tetrahydrofuran, dimethoxyethane, dioxane, and the like; ketone such as but not
limited to acetone, ethylmethyl ketone; alcohol such as but not limited to methanol,
ethanol and the like and water; (b) oxidation of phenylpropene derivatives in above
solution by adsorbing on oxidizing reagents such as but not limited to metaperiodate/
osmium tetraoxide (catalytic amount) and the like to be used in the ratio of
1-12 times moles, preferably 1-6 moles in a short period ranging from 2-20 minutes
under microwave irradiation; (c) oxidation step proceeds more smoothly along with
higher yield in presence of co-catalyst amberlite such as but not limited to amberlite-
410, quaternary ammonium salt such as but not limited to benzyltriethylammonium
chloride or base such as but not limited triethylamine, pyridine; (d) filtering the
mixture and removing the solvent under reduced pressure, where the product is to be
isolated by a conventional manner, i.e. extraction, recrystallization and
chromatography and the yield of the product (e.g. 2,4,5-trimethoxybenzaldehyde
where Rj= -CHO, R2=R4=R5-=OMe; R3=R6=H; 4-methoxybenzaldehyde where R\= -
CHO, R2= R3=R5=R6=H; R4-=OMe and 3,4-dimethoxybenzaldehyde where RI= -
CHO, R2=R5=R6=H; R3=R4-=OMe etc in the above formula I) varies from 68-81%
preferably more in case of meta-periodate/osmium tetraoxide as a oxidizing reagent.
In one more embodiment of the present invention, a simple and cheaper
starting material phenylpropene is utilized for high valued phenylaldehyde derivatives,
and one step process is described for substituted phenylaldehyde in high purity and
yield without contamination of corresponding acid and alcohol.
In another embodiment of the present invention, a simple and quick process
for the preparation of substituted phenylaldehydes in a short time ranging from a few
seconds to a few minutes under microwave irradiation.
In another embodiment of the present invention, a process for the preparation
of value added products from toxic compound (such as (3-asarone).
In another embodiment of the present invention, a simple and cheaper starting
material in which what ever percentage of cis (toxic) and trans-isomer (non-toxic)
exists in crude essential oil or formed during alkaline isomerisation of yphenylpropenes
(such as methylchavicol, safrole, methyl eugenol etc) are capable of
undergoing oxidation into high valued phenylaldehydes otherwise the percentage of
cis-isomer higher than a limited amount is not allowed with trans-isomer for
commercial use in perfumery, flavour and pharmaceutics.
Plant cells are highly sophisticated chemical factories where a large variety of
chemical compounds are synthesized with great precision and ease from simple raw
materials at normal pressure and temperature. Beside foods, plant materials/chemicals
are used for many purposes for example, for treating medical ailments, dyeing clothes,
colouring food items and for perfumery, cosmetics, flavour etc. Flavours represent a
growing demand within the food industry. Several methods including chemical
synthesis, biotechnology and natural extraction are under progress for the smooth
production of aroma chemicals. Some of aromatic phenylaldehydes, mainly produced
in plants in response to pathogen attack, possess strong antimicrobial activity due to
hydroxy and an aldehyde group attached to the aromaic ring of phenylaldehyde.
Therefore, as per applications concern, these phenylaldehydes are not only widely
used in fragrances, flavours, cosmetics, liquors, Pharmaceuticals but they are also
utilized as antibacterials, antifungais, and as biologically active compounds.
Moreover, phenylpropenes, produced by plants in high concentration (sometimes unto
95-96% ) are also widely used by perfumery, flavour and pharmaceutical industries,
e.g. anethole (4-methoxyphenylpropene) is well exploited essential oil which exists in
cis- and trans-form (Miraldi, E.; Flavour & Fragrance Journal, 14(6) 379-382 (1999)),
but its corresponding phenylaldehydes have more demand, as only trans-anethol is
allowed since cis-anethol is possibly considered toxic and hazardous to human
beings. On the other side, vanillin (a phenylaldehyde) is one of the most commonly
consumed flavour chemicals (5,550 t/a worldwide) (Somogyi, L.P., Chem. Ind. L., 5,
170, (1996). However, the limited percentage and high price of these natural
phenylaldehyde led to the necessity of using large amount of synthetic materials. At
present, 97% of the world vanilla flavour market is synthetic vanillin and remaining
3% (weight basis) is a natural vanilla extract (Taylor, A.J. and Mottram, D.S., In:
Flavour Science, Recent Developments, The Royal Society of Chemistry, Thomas
Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK, 111-137,
(1996). Various processes are known for the preparation of phenylaldehydes
(Schiraldi, D.A. and Kenvin, J.C., U.S. Pat. No. 5910613; and Soma, Y., JP Pat. No.
11049734A2; Kashima, M., Yoshimoto, H., Noda, Y. and Jibiki, H. JP Pat. No.
7330655A2; Kajisori, S., JP Pat. No. 2268130A2; Tanaka, M., Sakakura, T., Wada,
H. and Sasaki, Y. JP Pat No. 3264546A2; Kawamoto, K., Yoshioka, T., Yamagata,
H., JP Pat. No. 5087739A2 and Ito, N. and Hasebe, A. JP Pat. No. 11279104A2)
using phenylpropenes as a starting material. Considering the cost of starting
material and reagents, phenylpropenes are found best suitable and cost effective
starting material for the synthesis of substituted phenylaldehydes such as vanillin from
isoeugenol, p-methoxybenzaldehyde from anethole and heliotropin from isosafarole
(U.S. Pat. Nos, 1,643,804; 2,794,813). However, there is so far no such industrial
method available for the preparation of a versatile drug intermediate "2,4,5-
trimethoxybenzaldehyde" (a phenylaldehyde) from P-asarone (a toxic phenylpropene).
It is worthwhile to mention that the selection of P-asarone for the preparation of
asaronaldehyde has several fold benefits such as a simple and cheaper starting
material and a proper utilization of internationally banned toxic calamus oil. Since Pasarone
has recently been proved to be toxic and carcinogenic (Taylor, J. M., Jones,
W. I., Hogan, E. C., Gross, M. A., David, D. A. and Cook, E. L., Toxicol. Appl.
Phannacol., 10: 405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta
Medica, 1: 6-9 (1985) and Kim, S.C., Liem, A., Stewart, B.C. and Miller, J.A.,
Carcinogensis, 20(7), 1303-1307 (1999)) and the most affected plant is Acorns
calamus (familyrAraceae) in which percentage of toxic P-asarone depends upon the
varieties of A. calamus (Riaz, M., Shadab, Q., Chaudhary, F. M., Hamdard Medicus
38(2): 50-62 (1995) and McGuffin, M., Hobbs, C., Upton, R. and Goldberg, A., In:
American Herbal Products Association's Botanical Safety Handbook, CRC Press, Inc.;
Boca Raton, Florida; USA, 231, (1997)). The content of P-asarone in the tripioid
variety is 8-19 %, while P-asarone reaches upto 96% in the tetraploid and hexaploid
varieties (extensively found in Asian countries). In contrast, p-asarone is not found
in the diploid variety. As a result, the calamus oil obtained from North American
diploid strain (zero, P-asarone) and East European tripioid strain (unto 12 % Pasarone)
are allowed for clinical effectiveness and safety while the calamus oil
produced in Asian belt (such as India, Pakistan, Bangladesh, Nepal, Japan and China)
has diminished the market potential of calamus oil due to high percentage of Pasarone
ranging from 70 to 94% (Mazza, G., J. of Chromatography 328:179-206
(1985); Nigam, M. C., Ateeque, A., Misra, L. N. and Ahmad, A., Indian Perfumer 34:
282-285 (1990) and Bonaccorsi, L, Cortroneo, A., Chowdhury, J. U. and Yusuf, M.,
Essenze Derv. Agrum, 67(4): 392-402 (1997)). Therefore, our objective to utilize
toxic p-asarone for value added phenylaldehyde does not provide only economical
gain for calamus oil of tetraploid or hexaploid strain but also as a simple and cheaper
starting material for the preparation of a natural 2,4,5-trimethoxyphenylbenzaldehyde
(asarylaldehyde), a versatile drug intermediate for synthesis of several biologically
active compounds (Ahmad, S., Wagner, H. and Razaq, S., Tetrahedron, 34 (10): 1593-
1594, (1978)) including Makaluvamine-D and Discorhabdin-C marine alkaloids
(Sadanandan, E.V., Pillai, S.K., Lakshmikantham, M.V., Billimoria, A.D., Culpepper,
J.S. and Cava, M.P. J. Org. Chem., 66: 1800-1805, (1995)).
Phenylpropenes are relatively electron rich (pi bonds) which can be oxidized
to corresponding aldehyde with a number of oxidizing agents such as chromic acid
(Ger. Pat. No. 576 and U.S. Pat. No. 2,794, 813), manganese dioxide (Br. Pat. No.
774,608), potassium permanganate (Erlenmeyer, Chem. Ber. 9, 273 (1876)), chromyl
chloride (U.S. Pat. No. 365,918), air (Ger. Pat. No. 224,071), oxygen (Ger. Pat. No.
150,981), ozonolysis (Ger. Pat. No. 321,567 and C.A., 54,:5538 (I960)), electrolysis
(Ger. Pat. No. 92,007), peroxide (Ger. Pat. No. 93,938), nitrobenzene (Brit. Pat. No.
271,819 and U.S. Pat No. 1,643,804), nitrobenzene (Brit. Pat. No. 285,156) and by
several others process.
All the above methods have various limitations, for example, low yield, expensive
reagents and formation of unwanted side products. Our initial efforts to oxidize Pasarone
by using known oxidizing reagents such as potassium permanganate or
manganese dioxide/suiphanilic acid (Br. Pat. No. 774,608)) coupled in microwave to
obtain asaronaldehyde is remained unsuccessful due to poor yield with various side
product formation (such as asaronic acid). Fortunately, the combination of osmium
tetroxide (OsO4) and periodate reagent (Cainelli, G., Contento, M., Manescalchi, F.
and Plessi, L, Synthesis, 47-48, (1989)) in microwave is found an effective and high
yielding method for preparing asaronaldehyde from toxic p-asarone (Example la). In
addition, microwave assisted oxidation of phenylpropenes or the like with osmium
tetroxide conducting in fuming hood is easy and safe otherwise handling of osmium
tetraoxide requires special precaution due to its poisonous nature. After success of
asarone, oxidation of a-asarone into asaronaldehyde is also found as effective as Pasarone.
These experiments gave us idea that geometry (i.e. cis/trans-isomer) of
phenylpropene does not effect the yield of final oxidized product. In continuation of
this oxidation, calamus oil (rich in phenylpropene i.e. 85-90% o/p-asarone) is also
capable of undergoing oxidation without any problem in purification or loss in yield
since other constituents of calamus oil does effect interfere in asaronaldehyde
formation (Example Ic). Although, OsO4/NaIO4 is well known system for
converting alkene into aldehyde, however, microwave assisted oxidation of
phenylpropene has not been reported so far for the preparation of substituted
phenylaldehydes especially from toxic isomer of phenylpropene i.e. P-asarone (cisisomer)
or phenylpropene rich crude oil (i.e. crude calamus oil). Having successfully
achieved an efficient process for asaronaldehyde, we decided to extend the process to
convert various phenylpropenes into phenylaldehyde via OsO4/NaIC>4 such as anethole
into 3,4-dimethoxyisoeugenol into 3,4-dimethoxybenzaldehyde (Example II), 4-
methoxybenzaldehyde (Example III) or the like. It is further worthwhile to mention
that what ever percentage of cis/trans anethole from methyl chavicol, cis/trans
isosafrole from safrole, cis/trans isoeugenol from eugenol or the like obtained during
alkaline isomerisation of y-phenylpropene (allylbenzene) or crude essential oil rich
cis/trans phenylpropene (above 70% for industrial scale) can be easily utilized for the
formation of corresponding phenylaldehydes. Our present invention is also beneficial
to those industries which are engaged in alkaline isomerisation of allylbenzene into
trans-phenylpropene for wide scope in flavour, perfumery and pharmaceutical
industries, however, formation of cis-phenylpropene along with trans-phenylpropene
diminished their applications, since separation of isomers is tedious and expensive on
industrial point of view whereas, both isomeric forms can be used for the preparation
of high valued phenylaldehydes.
PhenylaUebyde
Brief description of the accompanying drawings
Figure 1 is H NMR (300 MHz) spectra of asaronaldehyde. (2,4,5-
trimethoxybenzaldehyde) (in CDCb) of the reaction product of Example I containing
the compound having the structure: ##STR1##.
Figure 2 is 13C NMR (75.4 MHz) spectra of asaronaldehyde (2,4,5-
trimethoxybenzaldehyde) (in CDCU) of the reaction product of Example I containing
the compound having the structure: ##STR1##.
Figure 3 is the electro spray (ES) mass spectrum of asaronaldehyde (2,4,5-
trimethoxybenzaldehyde) (MW 196) of the reaction product of Example I containing
the compound having the structure: ##STR1##.
EXAMPLES
The following examples are given by way of illustration of the present invention and
should not be construed to limit the scope of the present invention.
Example I
Reaction: ##STR1##
(a) Preparation of asaronaldehyde (2,4,5-trimethoxybenzaldehyde) from |Jasarone
(by microwave irradiation method): A mixture of (3-asarone (3.1 g, 0.015
mmol), catalytic amount of OsO4 (0.04 to 0.002 g), NaIO4 (11.75 g, 0.055 mmol),
benzyltriethyl ammonium chloride (catalytic amount) and THF-H2O (8-10 mL, 4:1)
were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The
flask was shaken well and placed inside a microwave oven operating at medium
power level and irradiated for 2-12 minutes in parts. After completion of the reaction
(monitored by TLC), the contents of the flask were poured into chloroform and passed
through a bed of Celite and further washed with chloroform. The filtrate and
washings were combined and the chloroform layer were washed with sodium
thiosulphate to destroy the excess periodate. The chloroform layers were then
combined and washed with saturated sodium chloride (3 x 15 m), dried over
anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude
solid product which was recrytallised with water to afford 2.39 g (82%) of
asaronaidehyde as a feathery white needles, Rf (0.34 in 28% ethylacetate in hexane);
mp 114 °C (lit mpl 14 °C); IR (film) vmax 1662 (carbonyl group), 1620, 1518, 1481,
1419, 1361, 1300, 1278, 1222, 1199, 1138, 1025, 865 cm'1; 1H
NMR 8 10.32 (1H, s, CHO), 7.33 (1H, s, 6H), 6.50 (1H, s, 3H), 3.98 (3H, s, 2-
OCH3), 3.93 ((3H, s, 4-OCH3), 3.88 (3H, s, 5-OCH3); 13 C NMR 5 187.96 (CHO),
158.60 (C-2), 155.76 (C-4), 143.56 (C-5), 117.35 (C-l), 109.03 (C-6), 56.19 (2-
OCH3, 4-OCH3 and 5-OCH3); EIMS m/z 196 [M]+ (100), 181 (49), 150 (32), 125 (33),
110 (23), 69 (37).
(b) Asaronaldehyde from a-asarone (by conventional method): A solution of
OsCU (0.065 g, 0.25 mmol) in water (2 mL) was added dropwise to ice cold solution
of a-asarone (0.624 g, 0.003 mole) (procured from Sigma) in THF-H2O (25 mL, 4:1)
over a period of 5 min with constant stirring. After 20 min at 0-5 °C, finely powdered
Nal(>4 (2.35 g, 0.011 mole) was added in parts and reaction mixture was stirred for 4-
6 hr at room temperature. After completion of reaction (monitored by TLC), the
precipitated sodium iodate was filtered and the filtrate was washed with CH2C12. The
combined organic layers were washed with 10% solution of sodium bisulphite (to
destroy the excess of sodium meta-periodate), saturated brine and dried (Na2SC>4).
Evaporation of the solvent furnished a crude mixture, which was loaded on silica gel
column, and the column was eluted with an increasing amount of hexane/ethy 1 acetate
(95:5 to 70:30). The fractions were monitored on TLC plate and the desired fractions
were combined and solvent was removed under vacuum to afford 0.49 g (84%) as a
white solid; mp 114 °C. The physical and spectral data was found similar as above
(Example I).
(c) Preparation of asaronaldebyde from crude calamus oil: The rhizomes of
'Acorus calamus Linn was collected in March-April 1999 from Palampur (H.P.) and
was confirmed by comparison with the specimen (IHBT no. 1066) kept in the
herbarium of our Institute. The hydrodistillation of rhizomes of Acorus calamus gave
pungent smelling oil in 1.7 % yield (w/w) with a presence of (3-asarone (85 %) and
a-asarone (3-4%) (by GC) and used directly for oxidation step. A mixture of pale
yellow crude calamus oil (9.00 g), catalytic amount of OsO4 ((0.08 to 0.002 g), NaIO4
(50 to 55 g) and dioxane-H2O (50-60 mL or more, 4:1) were taken in a 500 ml beaker
fitted with a loose watch glass at the top. The beaker was placed inside a microwave
oven operating at medium power level and irradiated for 3-16 minutes in parts. After
completion of the reaction (monitored by TLC), the contents of the beaker were
filtered and washed with ethyl acetate. The ethylacetate layers were washed with
water, aqueous sodium bisulphite (to destroy the excess periodate) and brine, dried
over (anhydrous sodium sulphate) and filtered. The solvent was removed under
reduced pressure and crude solid was recrystallised with hexane and chloroform to
obtain 5.66 g (76%, based on % of a and (3-asarone in crude calamus oil) of pure
asaronaldehyde as a white solid; mp 114 °C. The physical and spectral data was found
similar as above (Example I).
Example II
Preparation of 3,4-dimethoxybenzaldehyde from methyl isoeugenol (by
microwave method): The starting material methyl isoeugenol (3,4-dimethoxy
phenylpropene) can be easily prepared by fast 0-methylation of cheaper and easily
available isoeugenol (3-methoxy-4-hydroxy-phenylpropene) for which a mixture of
isoeugenol (2.46 g, 0.015 mole), dry dimethyl sulphate (1.8 g, 0.14 mole), anhydrous
potassium carbonate (6g, 0.062 mole) and dry acetone (15-20 mL) was irradiated in a
microwave oven for 8-10 minutes in parts. After completion of reaction (monitored
by TLC) the contents of the flask were poured into ice water. The product was taken
in ether (50-60 mL) and the ether layer was washed with dilute hydrochloric acid,
saturated sodium bicarbonate and brine respectively and dried over anhydrous sodium
sulphate and filtered. The solvent was removed under reduced pressure to
afford a desired product methyl isoeugenol (2.32 g, 87% yield) which was used
directly for next step.
A solution of OsO4 (0.006-0.008 g), methyl isoeugenol (0.53 g, 0.003 mole),
finely powdered NaIO4 (2.35 g, 0.011 mole), amberlite IRA-410 (O.lg) in THF-H2O
(25 mL, 4:1) was irradiated in a microwave oven for 3-11 minutes. After completion
of reaction (monitored by TLC), the precipitated sodium iodate was filtered and the
filtrate was washed with CH2Cl2. The combined organic layers were washed with
sodium thiosulphate (to destroy the excess of sodium meta-periodate), saturated brine
and dried over Na2SO4. Evaporation of the solvent furnished a crude mixture, which
was loaded on silica gel column, and the column was eluted with an increasing
amount of hexane/ethyl acetate (95:5 to 70:30). The fractions were monitored on TLC
plate and the desired fractions were combined and solvent was removed under
vacuum to afford 3,4-dimethoxybenzaldehyde in 79% yield as a solid; !H NMR 8
9.86 (1H, s, CHO), 7.45 (1H, s, 6H), 7.41 (1H, s, 2H), 6.98 (1H, s, 5H), 3.97 (3H, s,
4-OCH3), 3.95 (3H, s, 3-OCH3). The remaining physical and spectral data was found
similar as reported.
Example in
Preparation of 4-methoxybenzaldehyde from anethole (by microwave method):
A solution of OsO4 (0.004-0.007 g), anethole (2.22 g, 0.015 mole), finely
powdered NaIO4 (9.0 g, 0.044 mole) in THF-H2O (20-25mL) was irradiated in a
microwave oven for 2-8 minutes in parts. The precipitated sodium iodate was filtered
and the filtrate was washed with CHjCh. The combined organic layers were washed
with sodium thiosulphate, brine and dried over NajSC^. Evaporation of the solvent
furnished a crude mixture, which was loaded on silica gel column, and the column
was eluted with increasing amount of hexane/ethyl acetate (98:2 to 80:20). The
fractions were monitored on TLC plate and the desired fractions were combined and
solvent was removed under vacuum to afford 4-methoxybenzaldehyde in 71% yield as
a sweet smell liquid; !H NMR 8 9.95 (1H, s, CHO), 7.82 (1H, s, 6H), 7.79 (1H, s,
2H), 6.99 (1H, s, 5H), 6.96 (1H, s, 5H), 3.84 (3H, s, 4-OCH3). The remaining
physical and spectral data was found similar as reported and yield was found less may
be due to evaporation of anethole during microwave irradiation.
The main advantages of the present invention are
1. A simple and economical industrial process to convert phenylpropene
derivatives into corresponding phenylaldehyde in one step.
2. A simple process to convert phenylpropene derivatives into corresponding
phenylaldehyde in high yields.
3. A process to convert an internationally banned toxic compound p-asarone of
calamus oil or cis anethol or the like into useful products.
4. Preparation of phenylaldehyde as an inexpensive and simple starting material
for corresponding acid, ester, and alcohol or the like and are also useful for
a,(3-unsaturated aldehyde and the dyes, alkaloids, agrochemicals etc.
5. The present chemical process can increase the price of calamus oil by its
conversion into asaronaldehyde, otherwise, calamus oil of tetraploid or
hexaploid varieties (distributed extensively in Asian origin) has very low price
in comparison to the oil of diploid and triploid (distributed in American or
European origin) varieties.
6. A simple process by which any kind of phenylpropene can be converted into
corresponding aldehyde in a shorter time ranging from 2-20 seconds.
7. A simple process for preparation of phenylaldehyde which does not require
anhydrous reaction medium , a condition preferred by industries.
8. A simple process for the preparation of value added products from toxic
compounds such as p-asarone few seconds to minutes under microwave
irradiation.
9. A simple process for preparation of phenylaldehyde in which what ever
percentage of cis (toxic) and trans-isomer (preferred) exists in crude essential
oil or formed during alkaline isomerisation of y-phenylpropenes (such as
methylchavicol, safrole, methyl eugenol etc) are capable of undergoing
oxidation into high valued phenylaldehydes otherwise the percentage of cisisomer
higher than a limited amount is not allowed with trans-isomer for
commercial use in perfumery, flavour and pharmaceutics.

We Claim.
1. Microwave assisted rapid and economical process for the preparation of substituted phenylaldehydes of the general formula (I) as given below:
(Formula Removed)
wherein R1 is-CHO, R2, R3, R4, R5, R6 are independently selected from
I. a hydrogen atom;
II. an alkoxy group wherein two of R2, R3, R4, R5, Re being hydrogen atom; or an alkoxy group
wherein one of R2, R3, R4, R5, R6 being methylenedioxy group in combination with either hydroxyl
group, an alkoxy group, an alkyl group having atleast one carbon atom, an aryl group and a hydrogen
atom or an alkoxy group when of R2, R3, R4, R5, R6 being hydroxyl group in combinationwitheither
methylenedioxy group, a hydroxyl group, an alkoxy group, an alkyl group having atleast one carbon
atom, an aryl group (-C6H5) or a hydrogen atom;
III. a methylenedioxy group
IV. a hydroxyl group
v. a protected hydroxyl group such as acetyl, benzyl,
said substituted phenylaidehydes being from corresponding (R2, R3, R4, R5, R6 ) phenylpropene derivatives said process comprising steps of:
a) oxidizing said substituted phenylpropene in the presence of oxidizing agent and optionally
with a co-catalyst in a solvent at a mole ratio of 1:1 to 1:12 for a period ranges from 20 seconds to
20 minutes under microwave irradiation
b) filtering the reaction mixture of step (a) and washing the residue with an organic solvent
c) washing the organic solution of step(b) with aquous sodium bisulfite or sodium thiosulphate
followed by brine and water,
d) drying the organic layer of step (c) over anhydrous sodium sulphate filtering and evaporating
to dryness to remove completely the solvent to obtain a residue and

e) purifying the residue of step (d) by recrystallization or column chromatography to obtain
require substituted phenyl aldehyde of general formula (1).
2 A process as claimed in claim 1 wherein, the solvent used is selected from the group consisting
tetrahydrofuran, dimethyyoxyethane, dioxane; acetone ethylmethyl ketone; methanol diluted with water ethanol.
3 A process as claimed in claim 1 wherein, the oxidizing agent used is selected from potassium manganese dioxide/sulphanilic acid, meta-periodate/osmium tetraoxide-
4 A process as claimed in claim 1 wherein, the co catalyst used is selected from amberlite resine benzyltriethyl ammonium chloride, triethylamine or pyridine.
5. A process as claimed in claim 1 wherein, the mole ratio of phenylpropene derivatives to
oxidizing agent is ranging from 1:1 to 1:6.
6. A process as claimed in claim 1 wherein the microwave radiation frequency used is ranging from 2000 to 2800 MHz.
7. A process as claimed in claim 1 wherein the starting material phenylpropene is phenylpropanoid.
8. a process as claimed in claim 1 wherein, both isomeric form of phenylpropene are utilized for phenylaldehyde formation.
9. A process as claimed in claim 1 wherein toxic cis-isomer is converted into substituted phenylaldehyde of general formula (1) which is a natural aldehyde.
10. A process as claimed in claim 11 wherein step (a) is conducted in an aqueous medium and provides easy work-up.
11. A process as claimed in claim 1 wherein the time period in step (a) is 2-20 minutes.
12. A process as claimed in claim 1 wherein a mixture of the trans- and cis-isomers are converted to the substituted phenyldehyde regardless of the proportions of said isomers in said mixture.
13. A process as claimed in claim 1, wherein the substituted phenylaldehyde is selected from the group consisting of asaronaldehyde, asarylaldehyde, 4-methoxybenzaldehyde and 3,4-diinethoxybenzaldehyde.

Documents:

01502-delnp-2003-abstract.pdf

01502-delnp-2003-claims.pdf

01502-delnp-2003-complete specification (granted).pdf

01502-delnp-2003-correspondence-others.pdf

01502-delnp-2003-description (complete)-(30-03-2009).pdf

01502-delnp-2003-description (complete).pdf

01502-delnp-2003-form-1.pdf

01502-delnp-2003-form-18.pdf

01502-delnp-2003-form-2.pdf

01502-delnp-2003-form-3.pdf

1502-DELNP-2003-Claims-(10-10-2008).pdf

1502-DELNP-2003-Claims-(30-03-2009).pdf

1502-DELNP-2003-Claims-(31-03-2009).pdf

1502-DELNP-2003-Correspondence-Others-(10-10-2008).pdf

1502-DELNP-2003-Description (Complete)-(10-10-2008).pdf

1502-DELNP-2003-Petition-137-(10-10-2008).pdf

abstract.jpg

« Previous Patent

Next Patent »

Patent Number

233596

Indian Patent Application Number

01502/DELNP/2003

PG Journal Number

14/2009

Publication Date

27-Mar-2009

Grant Date

31-Mar-2009

Date of Filing

19-Sep-2003

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	ARUN KUMAR SINHA	INSTITUTE OF HIMALAYAN BIORESOURCES, TECHNOLOGY, PALAMPUR, HIMACHAL PRADESH,INDIA
2	BHUPENDRA PRASAD JOSH	INSTITUTE OF HIMALAYAN BIORESOURCES, TECHNOLOGY, PALAMPUR, HIMACHAL PRADESH,INDIA
3	RUCHI DOGRA	INSTITUTE OF HIMALAYAN BIORESOURCES, TECHNOLOGY, PALAMPUR, HIMACHAL PRADESH,INDIA

PCT International Classification Number

C07C 45/30

PCT International Application Number

PCT/IN01/00060

PCT International Filing date

2001-03-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA