Phenyl based compounds substituted with aldehyde moieties and their use in perfumery

Abstract

A compound represented by the formula 1 ##STR00001##
wherein R.sub.1 is H, or when R.sub.2 and R.sub.3 is H, then R.sub.1 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; R.sub.2 is H, or when R.sub.1 and R.sub.3 is H, then R.sub.2 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; R.sub.3 is H, or when R.sub.1 and R.sub.2 is H, then R.sub.3 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; and R.sub.4 is methyl or a branched or linear, saturated or unsaturated, unsubstituted or substituted (optionally with cyclopropyl groups), C.sub.2-C.sub.7 alkyl or alkenyl residue, preferentially isobutyl, isoamyl.
Said compounds are useful as perfume ingredients in personal care and household care products.

Claims

1. .[.A compound according to formula 1 ##STR00023## wherein R.sub.1 is H; R.sub.2 is H, or when R.sub.1 and R.sub.3 is H, then R.sub.2 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; R.sub.3 is H, or when R.sub.1 and R.sub.2 is H, then R.sub.3 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; and R.sub.4 is a branched or linear, saturated or unsaturated, unsubstituted or substituted residue, or a C.sub.2-C.sub.7 alkyl or alkenyl residue.]..Iadd.The compound, 3-(2-isobutyl-4-methylphenyl)propanal.Iaddend..

2. .[.The compound according to claim 1 which is a perfume ingredient.]. .Iadd.A pro-perfume which releases the compound, 3-(2-isobutyl-4-methylphenyl)propanal.Iaddend..

.[.3. The compound of claim 2, which exhibits green odour characteristics..].

.[.4. A pro-perfume, which releases the compound represented by the formula 1 ##STR00024## wherein R.sub.1 is H; R.sub.2 is H, or when R.sub.1 and R.sub.3 is H, then R.sub.2 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; R.sub.3 is H, or when R.sub.1 and R.sub.2 is H, then R.sub.3 is CHR.sub.5CHR.sub.6CHO, CR.sub.5═CR.sub.6CHO or C(CH.sub.3)CHO, wherein R.sub.5, R.sub.6 each independently may represent H or methyl; and R.sub.4 is a branched or linear, saturated or unsaturated, unsubstituted or substituted residue, C.sub.2-C.sub.7 alkyl or alkenyl residue..].

.[.5. The pro-perfume of claim 4, which is an imine, aminal, hemi-aminal or enamine of the compound according to formula I..].

.[.6. The pro-perfume of claim 4 which is a perfume ingredient..].

.[.7. The pro-perfume of claim 6 which exhibits green odor characteristics..].

.[.8. A perfume composition comprising the pro-perfume of claim 4..].

.[.9. A personal care or household care composition comprising at least a pro-perfume as defined in claim 4..].

.[.10. A method of imparting muguet odour characteristics to a fine fragrance or consumer product comprising the step of adding thereto a pro-perfume as defined in claim 4 and, selectively excluding from said fine fragrance or consumer product any aryl-substituted alkanal compounds, which are unsubstituted on the ring at the position ortho to the substituent containing aldehyde functionality, said selective addition or exclusion being based on the susceptibility of said compounds to enzymatically-mediated degradation to their benzoic acid derivatives when incubated with hepatocytes isolated from rats, said compounds being suitable for addition on the basis that they do not degrade to their benzoic acid derivatives, whereas said compounds being excluded on the basis that they do degrade to their benzoic acid derivatives..].

.[.11. A perfume composition comprising a compound according to claim 1..].

.[.12. A perfume composition according to claim 11 that is substantially free of any aryl-substituted propanal odourants, that are unsubstituted on the aryl ring at a position ortho to the substituent bearing the aldehyde functionality..].

.[.13. A perfume composition according to claim 11 comprising one or more additional fragrance ingredients..].

.[.14. A perfume composition according to claim 13 which comprises 3-(4-isobutyl-2-methylphenyl)propanal..].

.[.15. A personal care or household care composition comprising at least a perfume composition according to claim 11..].

.[.16. A perfume composition according to claim 11 that is substantially free of LILIAL..].

.[.17. A personal care or household care composition comprising at least a compound as defined in claim 1..].

.[.18. A personal care or household care composition according to claim 17, further comprising enzymes..].

.[.19. A personal or household care composition according to claim 17, which is a textile treatment product..].

.[.20. A personal or household care composition according to claim 17 which is a detergent composition..].

21. A method of imparting muguet odour characteristics to a fine fragrance or consumer product comprising the step of adding thereto .[.a compound as defined in.]. .Iadd.the compound of .Iaddend.claim 1 and, selectively excluding from said fine fragrance or consumer product any aryl-substituted alkanal compounds, which are unsubstituted on the ring at the position ortho to the substituent containing aldehyde functionality, said selective addition or exclusion being based on the susceptibility of said compounds to enzymatically-mediated degradation to their benzoic acid derivatives when incubated with hepatocytes isolated from rats, said compounds being suitable for addition on the basis that they do not degrade to their benzoic acid derivatives, whereas said compounds being excluded on the basis that they do degrade to their benzoic acid derivatives.

.Iadd.22. The compound of claim 1, which exhibits green odour characteristics. .Iaddend.

.Iadd.23. A perfume composition comprising the compound of claim 1. .Iaddend.

.Iadd.24. The perfume composition of claim 23 which is substantially free of any aryl-substituted propanal odourants, that are unsubstituted on the aryl ring at a position ortho to the substituent bearing the aldehyde functionality. .Iaddend.

.Iadd.25. A perfume composition according to claim 23 comprising one or more additional fragrance ingredients. .Iaddend.

.Iadd.26. A personal care or household care composition comprising the compound of claim 1. .Iaddend.

.Iadd.27. A personal care or household care composition comprising a perfume composition of claim 23. .Iaddend.

.Iadd.28. A personal care or household care composition of claim 26, further comprising an enzyme. .Iaddend.

.Iadd.29. A personal care or household care composition of claim 26, which is a textile treatment product. .Iaddend.

.Iadd.30. A personal care or household care composition of claim 26, which is a detergent composition. .Iaddend.

.Iadd.31. The perfume composition of claim 25 which comprises 3-(4-isobutyl-2-methylphenyl)propanal. .Iaddend.

.Iadd.32. The pro-perfume of claim 2, which is an imine, aminal, hemi-aminal or enamine of 3-(2-isobutyl-4-methylphenyl)propanal. .Iaddend.

.Iadd.33. The pro-perfume of claim 32 which releases a compound which exhibits green odor characteristics. .Iaddend.

.Iadd.34. A perfume composition comprising the pro-perfume of claim 2. .Iaddend.

.Iadd.35. A personal care or household care composition comprising the pro-perfume of claim 2. .Iaddend.

.Iadd.36. A method of imparting muguet odour characteristics to a fine fragrance or consumer product comprising the step of adding thereto the pro-perfume of claim 2 and, selectively excluding from said fine fragrance or consumer product any aryl-substituted alkanal compounds, which are unsubstituted on the ring at the position ortho to the substituent containing aldehyde functionality, said selective addition or exclusion being based on the susceptibility of said compounds to enzymatically-mediated degradation to their benzoic acid derivatives when incubated with hepatocytes isolated from rats, said compounds being suitable for addition on the basis that they do not degrade to their benzoic acid derivatives, whereas said compounds being excluded on the basis that they do degrade to their benzoic acid derivatives. .Iaddend.

.Iadd.37. A perfume composition according to claim 23 that is substantially free of 3-(4-tert-butylphenyl)-2-methylpropanal. .Iaddend.

Description

EXAMPLE 1

Synthesis of 3-(3-Isobutyl-5-methylphenyl)propanal (1)

(1) Compound 1 of the present invention was prepared according to Scheme 1.

(2) ##STR00013##

(3) A) Isobutylmagnesiumchloride (2M in THF, 12.0 mL) was added to a suspension of ZnCl.sub.2 (2.34 g, 17.2 mmol) in THF (8.5 mL) at 0° C. After the grey-white thick suspension was stirred at 25° C. for 1 h, it was added to a suspension of [PdCl.sub.2(dppf)].CH.sub.2Cl.sub.2 (93 mg, 0.11 mmol), CuI (44 mg, 0.23 mmol) and 2-(3-bromo-5-methylphenyl)-1,3-dioxolane (2, 2.78 g, 11.4 mmol) in THF (11.5 mL). The mixture was stirred at 25° C. for 2 h and again for 1 h after addition of 2M aq. HCl (11.5 mL). H.sub.2O was added and the aq. layer was extracted with MTBE (2×). The org. phases were washed with brine, dried (MgSO.sub.4), filtered and the filtrate was concentrated. The residue was purified by distillation in the “Kugelrohr” oven (120° C., 0.09 mbar) to yield 1.93 g (96%) of 3-isobutyl-5-methylbenzaldehyde (3) as a colorless oil.

(4) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=9.97 (s, 1H), 7.52 (br. s, 1H), 7.47 (br. s, 1H), 7.25-7.23 (m, 1H), 2.52 (d, J=7.3 Hz, 2H), 2.41 (d, J=0.5 Hz, 3H), 1.90 (nonet, J=6.9 Hz, 1H), 0.92 (d, J=6.6 Hz, 6H) ppm.

(5) B) Ethyl 2-(diethoxyphosphoryl)acetate (3.1 mL, 15.4 mmol) was added to a suspension of NaH (50% dispersion in mineral oil, 0.74 g, 15.4 mmol) in THF (8 mL) at 0° C. After the suspension was stirred at 25° C. for 30 min and re-cooled to 0° C., 3-isobutyl-5-methylbenzaldehyde (3, 2.46 g, 14.0 mmol) in THF (7 mL) was added and the mixture was stirred at 25° C. for 5 h. After addition of H.sub.2O at 25° C., the aq. layer was extracted with MTBE (2×). The org. phases were washed with H.sub.2O and brine, dried (MgSO.sub.4), filtered and the filtrate was concentrated. The residue was purified by distillation in the “Kugelrohr” oven (130° C., 0.09 mbar) to yield 2.38 g (69%) of (E)-ethyl 3-(3-isobutyl-5-methylphenyl)acrylate (4) as a light yellow oil.

(6) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=7.66 (d, J=16.1 Hz, 1H), 7.18 (br. s, 1H), 7.12 (br. s, 1H), 7.00 (br. s, 1H), 6.43 (d, J=16.1 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.46 (d, J=7.3 Hz, 2H), 2.35 (s, 3H), 1.87 (nonet, J=6.9 Hz, 1H), 1.35 (t, J=7.1 Hz, 3H), 0.92 (d, J=6.6 Hz, 6H) ppm.

(7) C) Pd/C (5% wt, 0.21 g) was added to a solution of (E)-ethyl 3-(3-isobutyl-5-methylphenyl)acrylate (4, 2.11 g, 8.57 mmol) in EtOH (17 mL). The suspension was stirred under H.sub.2 (1 atm) at 25° C. for 3 h, filtered through a pad of Celite and washed with hexane. The filtrate was concentrated and the residue was purified by distillation in the “Kugelrohr” oven (130° C., 0.08 mbar) to yield 1.91 g (90%) of ethyl 3-(3-isobutyl-5-methylphenyl)propanoate (5) as a colorless oil having a sweet, fruity, candy odour.

(8) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=6.85 (br. s, 1H), 6.82 (br. s, 1H), 6.79 (br. s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.92-2.88 (m, 2H), 2.63-2.59 (m, 2H), 2.41 (d, J=7.1 Hz, 2H), 2.31 (d, J=0.5 Hz, 3H), 1.84 (nonet, J=6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.90 (d, J=6.6 Hz, 6H) ppm.

(9) D) DIBAL-H (1M in CH.sub.2Cl.sub.2, 4.0 mL) was added to a solution of ethyl 3-(3-isobutyl-5-methylphenyl)propanoate (5, 1.01 g, 4.03 mmol) in CH.sub.2Cl.sub.2 (16 mL) at −78° C. and the mixture was stirred at −78° C. for 3 h. After warming to 0° C., MTBE was added and the reaction was quenched with H.sub.2O (0.2 mL), 3 M aq NaOH (0.2 mL) and H.sub.2O (0.4 mL), and stirred vigorously for 10 min. MgSO.sub.4 was added, the mixture was stirred for an additional 10 min and the white solid was removed by filtration. The filtrate was concentrated and the residue was purified by distillation in the “Kugelrohr” oven (120° C., 0.07 mbar) to yield 0.77 g (94%) of 3-(3-isobutyl-5-methylphenyl)propanal (1) as a colorless oil.

(10) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=9.83 (t, J=1.6 Hz, 1H), 6.85 (br. s, 1H), 6.84 (br. s, 1H), 6.79-6.77 (m, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.79-2.75 (m, 2H), 2.42 (d, J=7.1 Hz, 2H), 2.31 (d, J=0.7 Hz, 3H), 1.85 (nonet, J=6.9 Hz, 1H), 0.91 (d, J=6.6 Hz, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 100 MHz): δ=201.8 (d), 142.0 (s), 139.9 (s), 137.8 (s), 127.9 (d), 126.4 (d), 126.2 (d), 45.4 (t), 45.3 (t), 30.2 (d), 28.1 (t), 22.4 (2q), 21.3 (q) ppm. MS (EI): m/z (%)=204 (M.sup.+.circle-solid., 23), 176 (9), 161 (12), 148 (18), 133 (53), 119 (100), 105 (44), 91 (33), 77 (12), 43 (14), 41 (19), 29 (9).

(11) Odour description: green aldehydic, citrus juicy orange

EXAMPLE 2

Synthesis of (E)-3-(2-isobutyl-4-methylphenyl) Acrylaldehyde (6) and 3-(2-isobutyl-4-methylphenyl)propanal (7)

(12) Compounds 6 and 7 were prepared in four or five steps, respectively, according to Scheme 2.

(13) ##STR00014##

(14) A) A mixture of ZnCl.sub.2 (53.9 g, 395 mmol), 1-isobutyl-3-methylbenzene (8, 293 g, 1.98 mol), paraformaldehyde (66.3 g, 2.21 mol) and AcOH (230 mL) under Ar was warmed gently to 40° C. Hydrogen chloride gas was bubbled into the reaction solution during 2 h at 40° C. until consumption of 1-isobutyl-3-methylbenzene completed. The reaction mixture was cooled to 25° C. H.sub.2O was added, and the reaction mixture was extracted with MTBE (3×). The comb. org. layers were washed with H.sub.2O (5×), sat. aq. NaHCO.sub.3 solution and brine. The org. layer was dried (MgSO.sub.4), filtered and concentrated. The crude product was distilled under vacuum to give a colorless liquid (275 g, 70% yield) which was a mixture of 1-(chloromethyl)-2-isobutyl-4-methylbenzene (9) and 1-(chloromethyl)-4-isobutyl-2-methylbenzene in a ratio of 22:78.

(15) 1-(Chloromethyl)-2-isobutyl-4-methylbenzene: .sup.1NMR (CDCl.sub.3, 300 MHz): δ=7.20 (d, J=7.4 Hz, 1H), 7.02 (d, J=7.4 Hz, 1H), 6.98 (s, 1H), 4.60 (s, 2H), 2.57 (d, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.96-1.81 (m, 1H), 0.95 (d, J=6.6 Hz, 6H) ppm.

(16) 1-(Chloromethyl)-4-isobutyl-2-methylbenzene: .sup.1H NMR (CDCl.sub.3, 300 MHz): δ=7.20 (d, J=7.4 Hz, 1H), 7.02 (d, J=7.4 Hz, 1H), 6.98 (s, 1H), 4.60 (s, 2H), 2.43 (d, J=7.4 Hz, 2H), 2.40 (s, 3H), 1.89-1.79 (m, 1H), 0.90 (d, J=6.6 Hz, 6H) ppm.

(17) B) A mixture of 1-(chloromethyl)-2-isobutyl-4-methylbenzene (9) and 1-(chloromethyl)-4-isobutyl-2-methylbenzene (273 g, 1.39 mol, in ratio of 22:78), hexamethylenetetramine (Urotropine, 292 g, 2.08 mmol), and AcOH (120 g, 2.00 mol) in EtOH (300 mL) and H.sub.2O (200 mL) under Ar was refluxed for 10 h. The reaction was cooled to 25° C., and the org. phase was separated. The aq. phase was extracted with MTBE (3×). The comb. org. layers were washed with H.sub.2O (3×), sat. aq. NaHCO.sub.3 solution and brine. The org. layer was dried (MgSO.sub.4), filtered and concentrated. The crude product was distilled under vacuum to give a colorless liquid (180 g) which was a mixture of 2-isobutyl-4-methylbenzaldehyde and 4-isobutyl-2-methylbenzaldehyde in ratio of 22:78. The product was further fractional distilled to give pure 2-isobutyl-4-methylbenzaldehyde (10, 15.0 g, 6% yield) and 4-isobutyl-2-methylbenzaldehyde (95.0 g, 39% yield).

(18) 2-Isobutyl-4-methylbenzaldehyde: Boiling point: 98-101° C./0.15 mbar; .sup.1H NMR (CDCl.sub.3, 300 MHz): δ=10.22 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 2.85 (d, J=7.1 Hz, 2H), 2.38 (s, 3H), 1.92-1.77 (m, 1H), 0.93 (d, J=6.6 Hz, 6H) ppm.

(19) Odour description: green leathery, spicy saffron

(20) 4-Isobutyl-2-methylbenzaldehyde: Boiling point: 102-108° C./0.15 mbar; .sup.1H NMR (CDCl.sub.3, 300 MHz): δ=10.20 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.03 (s, 1H), 2.64 (s, 3H), 2.49 (d, J=7.2 Hz, 2H), 1.99-1.81 (m, 1H), 0.91 (d, J=6.6 Hz, 6H) ppm.

(21) Odour description: weak, green aromatic, thyme origanum, resinous, slightly isobutyl benzoate;

(22) C) To a mixture of 2-isobutyl-4-methylbenzaldehyde (10, 11.0 g, 62.4 mmol) and boron trifluoride etherate (0.044 g, 0.31 mmol) under Ar, trimethoxymethane (7.95 g, 74.9 mmol) was added dropwise over 33 min at 25° C. After completion of the addition, the reaction was stirred for 20 min at 25° C. Ethoxyethene (5.40 g, 74.9 mmol) was added dropwise over 20 min at 30-35° C. and the reaction was stirred for 30 min. NaHCO.sub.3 (1.0 g) and H.sub.2O (0.50 mL) were added with stirring over 2 min, then stirring was stopped. The clean solution was decanted, and methanesulfonic acid (0.090 g, 0.94 mmol) in H.sub.2O (5.0 ml) was added. The reaction mixture was heated to reflux and volatiles were distilled off until the pot temperature reached 105° C. The reaction was cooled to 90° C. and toluene (40 ml) was added. The resulting mixture was washed successively with aq. solution of H.sub.2SO.sub.4 (63%), brine and H.sub.2O. The org. layer was dried (MgSO.sub.4), filtered and concentrated. The crude product was purified by column chromatography followed by Kugelrohr distillation to give (E)-3-(2-isobutyl-4-methylphenyl)acrylaldehyde (6, 7.50 g, 59% yield) as a colorless liquid.

(23) Boiling point: 145-150° C./0.15 mbar. .sup.1H NMR (CDCl.sub.3, 300 MHz): δ=9.70 (d, J=7.7 Hz, 1H), 7.76 (d, J=15.7 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.64 (dd, J=15.7, 7.7 Hz, 1H), 2.62 (d, J=7.2 Hz, 2H), 2.36 (s, 3H), 1.88-1.77 (m, 1H), 0.93 (d, J=6.6 Hz, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz): δ=193.9 (d), 150.5 (d), 141.9 (s), 141.2 (s), 132.2 (d), 129.8 (s), 128.5 (d), 127.5 (d), 126.8 (d), 42.3 (t), 30.7 (d), 22.4 (q), 22.4 (q), 21.5 (q) ppm. MS: m/z (%)=77 (3), 91 (13), 105 (3), 115 (20), 131 (23), 145 (100), 159 (20), 171 (2), 187 (3), 202 (6) [M.sup.+].

(24) Odour description: green, floral.

(25) D) A mixture of Pd/C (5% wt, 0.30 g), sodium acetate (2.00 g, 24.4 mmol) and (E)-3-(2-isobutyl-4-methyl phenyl)acrylaldehyde (6, 7.00 g, 34.6 mmol) in EtOAc (35 mL) was stirred under H.sub.2 (1 atm) at 25° C. overnight. The reaction mixture was filtered through a pad of SiO.sub.2 and washed with MTBE. The filtrate was concentrated. The crude product was purified by column chromatography followed by Kugelrohr distillation to give 3-(2-isobutyl-4-methylphenyl)propanal (7, 3.50 g, 17.1 mmol, 50% yield, purity >99%) as a colorless liquid.

(26) Boiling point: 145-150° C./0.15 mbar. .sup.1H NMR (CDCl.sub.3, 300 MHz): δ=9.83 (s, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.94 (s, 1H), 2.92 (t, J=7.7 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 2.45 (d, J=7.2 Hz, 2H), 2.29 (s, 3H), 1.91-1.77 (m, 1H), 0.93 (d, J=6.5 Hz, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 75 MHz): δ=201.8 (d), 139.3 (s), 135.6 (s), 135.2 (s), 131.1 (d), 128.7 (d), 126.9 (d), 45.2 (t), 41.9 (t), 29.9 (d), 24.4 (t), 22.6 (q), 22.6 (q), 21.0 (q) ppm. MS: m/z (%)=77 (6), 91 (15), 105 (18), 119 (100), 133 (12), 143 (28), 161 (30), 171 (2), 186 (10), 204 (5) [M.sup.+].

(27) Odour description: green floral, animalic costus.

EXAMPLE 3

Synthesis of 2-(2-isobutyl-4-methylphenyl)propanal (11)

(28) Compound 11 was prepared in two steps according to Scheme 3.

(29) ##STR00015##

(30) A) 1-Bromo-2-isobutyl-4-methylbenzene (12, 182 g, 0.80 mol, 75%) in Et.sub.2O (550 ml) was added to Mg (22.4 g, 0.92 mol) in Et.sub.2O (50 ml) to form the Grignard reagent. CuI (9.06 g, 48.1 mmol) was added at 25° C. and the mixture stirred for 40 min. Propargyl alcohol (18.0 g, 0.32 mol) in Et.sub.2O (100 ml) was added dropwise over 30 min, maintaining the temperature below 30° C. Following reflux for 80 min, the mixture was stirred overnight and then quenched into sat. aq. NH.sub.4Cl (400 ml) and iced H.sub.2O (400 ml). The aq. phase was extracted with Et.sub.2O (2×) and the comb. org. phases were washed with H.sub.2O (2×, to pH 6-7). The org. phase was dried (MgSO.sub.4), filtered and evaporated down to yield crude 2-(2-isobutyl-4-methylphenyl)prop-2-en-1-ol (13, 126 g) which was purified by fractionation through a vigreux column, collecting fractions boiling at 108-111° C. at 0.07 mbar (25.5 g, 39% yield).

(31) B) 2-(4-Isobutyl-2-methylphenyl)prop-2-en-1-ol (13, 11.9 g, 58.3 mmol) was dissolved in CH.sub.2Cl.sub.2 (500 ml) under Ar. CBr.sub.4 (5.17 g, 15.6 mmol) and PPh.sub.3 (4.09 g, 15.6 mmol) were jointly added portionwise to control the temperature below 25° C. After stirring for 125 h, the mixture was quenched with iced water and the aq. phase was extracted with CH.sub.2Cl.sub.2. The org. phase was washed with H.sub.2O, dried (MgSO.sub.4), filtered and the solvent evaporated to yield a crude product (18.2 g). The crude product was purified by Kugelrohr distillation (115° C., 0.07 mbar) followed by flash chromatography on SiO.sub.2, eluting with hexane/MTBE, yielding 2-(2-isobutyl-4-methylphenyl)propanal (11, 3.40 g, 29% yield, purity 93%).

(32) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=9.64 (d, J=1.0 Hz, 1H), 7.03 (dd, J=7.8, 1.2 Hz, 1H), 7.01 (br. s, 1H), 6.91 (d, J=7.8 Hz, 1H), 3.84 (qd, J=6.9, 1.0 Hz, 1H), 2.57-2.46 (m, 2H), 2.32 (s, 3H), 1.82 (nonet, J=6.9 Hz, 1H), 1.37 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H) ppm. .sup.13C NMR (CDCl3, 100 MHz): δ=201.4 (d), 140.0 (s), 136.7 (s), 133.2 (s), 131.9 (d), 127.8 (d), 127.5 (d), 48.2 (d), 42.2 (t), 30.3 (d), 22.5 (q), 22.5 (q), 21.1 (q), 15.5 (q) ppm. MS: m/z (%)=55 (20), 77 (5), 91 (14), 105 (14), 115 (15), 119 (21), 133 (100), 161 (9), 175 (39), 204 (12) [M.sup.+].

EXAMPLE 4

2-(4-isobutyl-2-methylphenyl)propanal (14)

(33) ##STR00016##

(34) 1-Bromo-4-isobutyl-2-methylbenzene was converted according to the procedure described in example 3 via 2-(2-isobutyl-4-methylphenyl)prop-2-en-1-ol to 2-(4-isobutyl-2-methylphenyl)propanal (14).

(35) .sup.1H NMR (CDCl.sub.3, 400 MHz): δ=9.64 (d, J=1.2 Hz, 1H), 7.01 (br. s, 1H), 7.00 (dd, J=7.8, 1.7 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 3.80 (qd, J=7.1, 1.2 Hz, 1H), 2.43 (d, J=7.3 Hz, 2H), 2.33 (s, 3H), 1.85 (nonet, J=6.9 Hz, 1H), 1.39 (d, J=7.1 Hz, 3H), 0.92 (d, J=6.6 Hz, 6H) ppm. .sup.13C NMR (CDCl.sub.3, 100 MHz): δ=201.3 (d), 141.0 (s), 136.3 (s), 133.5 (s), 131.8 (d), 127.4 (d), 127.3 (d), 49.0 (d), 45.0 (t), 30.2 (d), 22.4 (q), 22.4 (q), 19.7 (q) 14.3 (q) ppm. MS: m/z (%)=57 (12), 77 (5), 91 (14), 105 (14), 117 (17), 133 (26), 175 (100), 204 (9) [M.sup.+].

EXAMPLE 5

In Vitro Metabolism Study

(36) A comparison of compounds of the present invention and Lilial™.

(37) Cryopreserved hepatocytes from male rats (Sprague Dawley; Lifetechnologies) were defrozen, washed in Cyropreserved Hepatocytes Recovery Medium (CHRM; Lifetechnologies) and suspended in Williams E Medium (WEM; Lifetechnologies). Lilial™, or the compounds of the present invention (final concentration: 100 μM) were added to the cells (1×106 viable cells/ml) and suspensions were incubated up to 4 hours at 37° C. on a shaker in duplicate. Metabolism of testosterone was monitored as positive control. Decrease of the test compounds and formation of the corresponding benzoic acid derivative was determined by GC-MS analysis of methyl esters formed after derivatisation with trimethylsilyl diazomethane (Sigma-Aldrich) in methanol. The test compounds react with diazomethane yielding a methyl ketone which was used for the quantification of Lilial™ and the compound of formula (I). Metabolism was stopped with ice cold 1 M HCl, samples were extracted with tert-butyl methyl ether (MTBE) and analysed by GC-MS. Incubations containing testosterone as control were also stopped with ice cold 1 M HCl, centrifuged to separate the cells, filtrated and the decrease of testosterone analysed by LC-MS. To quantify decrease of the test substances and formation of benzoic acid metabolites, calibration curves of reference materials (Lilial™ and the compounds of the present invention, tert-butyl benzoic acid (Fluka) was prepared in hepatocyte incubation medium and analysed like the hepatocyte samples.

(38) A rapid decrease of testosterone as positive control was observed indicating that the hepatocytes were metabolically active. The compounds of the present invention and Lilial™ were metabolised rapidly in rat hepatocytes and no residual compound except for 2% with one compound was measured after 4 h. Whereas tert-butyl benzoic acid was detected as metabolite of Lilial™ (3.4-3.9 μM) no benzoic acid derivatives were formed from compounds of the present invention (Table 1). Limit of detection was <1 μM.

(39) Table 1 (below), shows the concentrations of Lilial™ and compounds of the present invention as well as corresponding benzoic acid metabolites in rat hepatocytes within 4 hours incubation. Initial test concentration at 0 hours incubation was 100 μM.

(40) It is clear from the data presented in Table 1 that the ortho or meta substituent at the benzene ring of the compounds of the present invention does affect the formation of the corresponding benzoic acid derivative in vitro. Since benzoic acid derivatives such as tert-butyl benzoic acid from Lilial™ cause reproductive toxicity in male rats, these toxic effects in male rats are prevented by the ortho-substituent and are reduced by the meta-substituent of the compounds of the present invention.

(41) TABLE-US-00001 TABLE 1 Residual conc. Benzoic acid concentration Test compound (μM) derivative (μM) 0 3.5-3.9 0 0 not found 1.5 0.7-1.0