Isomerization of anacardic acid: A possible route to the synthesis of an unsaturated benzolactone and a kairomone

2.1 Materials and instruments

All reagents and solvents were purchased from Sigma–Aldrich and used as received. Silica for chromatography was Davisil Grade 62. The cashew nuts were collected from Tanga, Tanzania and shelled. CNSL was obtained from the shells by the solvent extraction method 20. All reactions were carried out using standard Schlenk lines and glove box techniques with nitrogen gas for maintaining an air free environment. GC–MS analyses were carried out using a Hewlett-Packard 6890 series gas chromatograph instrument equipped with a FID for quantitative analysis and a Hewlett-Packard 5973 series mass selective detector fitted with hp1 film for mass spectral identification of products. The temperature program used was 50°C (4 min), 20°C/min to 130°C (2 min), 20°C/min to 220°C (15.5 min). Helium was used as the carrier gas with initial flow of 1 mL/min. ¹H and ¹³C NMR spectra were recorded at 298 K on a Bruker 300 MHz or 400 and 75 MHz or 100 MHz spectrometers for ¹H NMR and ¹³C NMR, respectively. Samples for NMR analysis were dissolved in deuterated solvents, the peaks of which were used to reference the spectra to tetramethylsilane at δ 0 ppm. The IR spectra were recorded on Perkin Elmer Spectrum GX FT-IR spectrometer using KBr discs.

2.2 Extraction of CNSL and isolation of anacardic acid

Fresh and dry cashew nuts were scrub washed, sun dried, and shelled to obtain clean shells. The shells (2000 g) were soaked in petroleum ether (5000 mL) for 4 days. The resulting solution was concentrated at 40°C under reduced pressure using a rotary evaporator to afford a brownish oil, CNSL. The recovered solvent was used to re-extract the oil to ensure maximum yield (362 g, 18%). Isolation of anacardic acid followed the procedure reported by Paramashivappa et al. 1 starting with 50 g of CNSL to yield 29 g (58%) of anacardic acid. ¹H NMR (400 Hz; CDCl₃): δ 11.06 (s, 1H, COOH), 7.40 (t, J = 8.0, 1H, ArH), 6.92 (d, J = 8.8, 1H, ArH), 6.82 (d, J = 8.0, 1H, ArH), 5.94–5.77 (m, 0.4H, CHCH), 5.52–5.31 (m, 3.2H, CHCH), 5.14–4.97 (m, 0.8H, CHCH), 3.03 (t, J = 7.6, 2H, ArCH₂), 2.90–2.75 (m, 2H, CH₂), 2.17–1.95 (m, 3.4H, CCCH₂), 1.74–1.56 (m, 2H, ArCCH₂), 1.49–1.24 (m, 14H, alkyl chain), 1.0–0.86 (m, 2.1H, terminal CH₃/CH₂). ¹³C NMR (100 Hz; CDCl₃): δ 14.7 (CH₃), 23.2, 26.0, 27.6, 30.0, 32.4, 37.1 (CH₂), 115.2 (ArCCOOH), 116.4 (ArCH), 127.5, 128.2, 128.6, 129.8, 130.4 (CH), 136.1 (ArCH), 148.4 (ArCR), 164.13 (ArCOH), 176.91 (ArCOOH). IR: 914.4 cm⁻¹ (m), 1233.3 cm⁻¹ (s), 1447.4 (m), 1644.7 cm⁻¹ (s), 2924 cm⁻¹ (m), 3016.4 cm⁻¹ (m), 3430 cm⁻¹ (s, b).

2.3 Unsaturated benzolactone, 8-hydroxy-3-tridecyl-1H-isochromen-1-one (6)

Anacardic acid (2 g, monoene 52.6%, diene 18.3%, triene 28.9%, and saturated 1.1%) was dissolved in methanol (2 mL) followed by addition of toluene (10 mL). The Schlenk tube containing the solution was connected to a Schlenk line and left under nitrogen for 10 min. In the glove box, Pd₂(dba)₃ (0.28 g, 0.00030 mol) and DTBPMB (1.23 g, 0.0026 mol) were put into an autoclave charged with a magnetic stirrer. The autoclave was connected to the Schlenk line and degassed three times. By means of a 20 mL syringe, the whole solution of anacardic acid was transferred into the autoclave followed by addition of methane sulfonic acid (0.2 mL). The isomerization reaction was left to proceed under nitrogen atmosphere at 80°C for 96 h. Separation of the products was done by column chromatography using hexane/ethyl acetate (90/10) to separate 8-hydroxy-3-tridecyl-1H-isochromen-1-one (6, 0.3 g, 15%) followed by hexane/ethyl acetate (80/20) to separate (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid, 8 contaminated with other double bond positional isomers (0.2 g, 10%; 67% (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid, 33% other positional isomers. This corresponds to a yield of (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid of 6.7%) (Fig. 6). Crystals of 6 suitable for structure determination were obtained by layering a dichloromethane solution with methanol and slow diffusion. Found C 73.49, H 9.14%; C₂₂H₃₂O₃ · 0.2CH₂Cl₂ requires C 73.76, H 9.03%. ¹H NMR (400 Hz; CDCl₃): δ 0.91 (t, J = 6.7, 3H, CH₃), 1.22–1.44 (m, 20H, CH₂), 1.68–1.79 (m, 2H, CH₂), 2.54 (t, J = 7.8, 2H, CH₂), 6.29 (s, 1H, CH), 6.84 (d, J = 7.9, 1H, ArH), 6.95 (d, J = 8.7, 1H,ArH), 7.58 (t, J = 7.8, 1H, ArH), 11.06 (s, 1H, ArOH). ¹³C NMR (100 Hz; CDCl₃): δ 14.5 (CH₃), 23.2, 27.4, 29.9, 32.7, 33.8 (CH₂), 104.4 (CH), 114.8 (ArCH, ArCCOOH), 116.1 (ArCH), 137.8 (ArCH), 138.7 (ArCR), 158.0 (ArCOOH), 161.9 (CCO), 167.4 (ArCOH). IR: 725 (m), 1146.9 (s), 1233.5 (s), 1470.3 (m), 1574.3 (m), 1649.3 (s), 1689.8 (s), 2856.4 (m), 2920 (s), 3445 (s, b). (E)-2-Hydroxy-6-(pentadec-1-enyl)benzoic acid; Found C 76.09, H 10.01%; C₂₂H₃₄O₃ requires C 76.26, H 9.89% ¹H NMR (400 Hz; CDCl₃): δ 0.81 (t, J = 6.6, 3H, CH₃), 1.11–1.48 (m, 22H, CH₂, alkyl chain), 2.17 (q, J = 7.1, 2H, CH₂), 5.89–6.0 (m, 1H, CCH), 6.84 (d, J = 8.1, 1H, ArH), 6.9 (d, J = 7.6, 1H, ArH), 7.01, 6.96 (s, 2H, ArCCHC), 7.33 (t, J = 8.1, 1H, ArH), 10.93 (s, 1H, COOH). ¹³C NMR (100 Hz; CDCl₃): δ 14.1 (CH₃), 22.7, 29.5, 31.3, 33.1, 36.1 (CH₂), 110.4 (ArCCOOH), 116.1 (ArCH), 120.6 (ArCH), 123.1 (ArCHCH), 130.3 (CCH), 135.8 (ArCH), 143.3 (ArC), 163.4 (ArCOH), 176.1 (ArCCOOH).

2.4 Saturated benzolactone, 8-hydroxy-3-tridecyl-3,4-dihydroisochromen-1-one (7)

8-Hydroxy-3-tridecyl-1H-isochromen-1-one (0.3 g) was dissolved in ethyl acetate (10 mL). The solution was transferred into the autoclave charged with a magnetic stirrer followed by addition of Pd-C (0.03 g). The autoclave was pressurized with hydrogen to 30 bar. The reaction was left to proceed at 80°C for 12 h. The product was filtered using a sintered funnel with the aid of celite powder to remove the catalyst. Ethyl acetate was removed under vacuum to yield a white solid, saturated benzolactone (0.291 g, 97%). Found C 76.17, H 9.84%; C₂₂O₃₄ requires C 76.26, H 9.89%. ¹H NMR (400 Hz; CDCl₂): δ 0.91 (t, J = 6.6, 3H, CH₃), 1.3 (m, 22H, CH₂, alkyl chain), 1.69–1.81, 1.85–1.97 (m, CH₂), 2.96 (2H, ArCCH₂R), 4.54–4.65 (m, 1H, RCO(H)R), 6.71 (d, J = 7.5, 1H, ArH), 6.91 (d, J = 8.4, 1H, ArH), 7.43 (t, J = 8.4, 1H, ArH), 11.06 (s, 1H, ArOH). ¹³C NMR (100 Hz; CDCl₃): δ 14.5 (CH₃), 23.1, 25.2, 29.9, 32.3, 33.4, 35.2 (CH₂), 80.16 (CH, RCO(H)R), 116.49 (ArCH), 118.37 (ArCH), 136.48 (ArCH), 139.9 (ArCR). IR: 738.9 cm⁻¹ (m), 1035 cm⁻¹ (m), 1127.6 cm⁻¹ (m), 1245.5 cm⁻¹ (s), 1467.1 cm⁻¹ (m), 1585 cm⁻¹ (w), 1660 cm⁻¹ (s), 2854 cm⁻¹ (m), 2923.5 cm⁻¹ (s), 2958.1 cm⁻¹ (m), 3441.6 cm⁻¹ (b).

2.5 Monoene anacardic acid

The procedure follows that developed by Perdriau et al. 8 for cardanol. Anacardic acid (2.5 g, monoene 52.6%, diene 18.3%, triene 28.9%, and saturated 1.1%) was dissolved in propan-2-ol (20 mL) in a 100 mL round bottomed flask to which ruthenium trichloride (0.075 g, 0.36 mmol) was added. The reaction mixture was refluxed for 18 h. Propan-2-ol was removed from the product under reduced pressure using the rotary evaporator. The concentrated product was eluted through a silica column using dichloromethane to remove the catalyst. The final appearance of monoene anacardic acid was a grayish semi solid (1.7 g, 68%). The gray color presumably arises from Ru residues, which we have not been able to remove, but which do not appear to affect the subsequent reactions. Found C 76.12, H 9.80%; C₂₂O₃₄ requires C 76.26, H 9.89%. ¹H NMR (400 Hz; CDCl₂): δ 0.91 (t, J = 6.9, 3H, CH₃), 1.21–1.48 (m, 15H, CH₂, alkyl chain), 1.58–1.70 (m, 2H, ArCCCH₂), 1.94–2.1 (m, 4H, CH₂CC), 3.02 (t, J = 7.7, 2H, ArCCH₂), 5.33–5.50 (m, 2H, CHCH), 6.81 (d, J = 7.7, 1H, ArH), 6.91 (d, J = 8.6, 1H, ArH), 7.40 (t, J = 8.2, 1H, ArH), 11.04 (s, 1.4H, COOH). For this compound, as for anacardic acid itself, the signal at δ 11.04 consists of a reasonably sharp singlet with a very broad resonance underneath it. There is no resonance observed in the position expected for the phenolic OH proton (ca. 5 ppm). We assume that the phenolic proton is hydrogen bonded to the carbonyl O atom of the carboxylic acid, as seen in the crystal structure, moving the resonance to δ 11.4 ppm. The integration for this signal is still low, however, corresponding to ca. 1.5 protons. We note that the phenolic OH protons of the lactones, 6 and 7 also resonate near δ 11 ppm. ¹³C NMR (100 Hz; CDCl₃): δ 14.1 (CH₃), 22.7, 27.2, 29.5, 32.0, 36.5 (CH₂), 110.6 (ArCCOOH), 116 (ArCH), 122.6 (ArCH), 130.1 (CC), 135.6 (ArCH), 148.0 (ArCR), 163.7 (ArCOH), 176.6 (ArCCOOH). IR: 725.2 cm⁻¹ (m), 825.1 cm⁻¹(m), 910.9 cm⁻¹(m), 970.3 cm⁻¹ (m), 1254.1 cm⁻¹ (s), 1452.1 cm⁻¹ (s), 1663.3 cm⁻¹ (s), 2862.2 (s), 2937.3 (s), 3000.3 (s, b).

2.6 (E)-2-Hydroxy-6-(pentadec-1-enyl)benzoic acid (8)

The synthesis of (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid from monoene anacardic acid was as for the synthesis of unsaturated benzolactone (Section 2.3). The column chromatography separation employed ethyl acetate/hexane (20/80) as the eluting system from which a white solid (0.8 g, 40%) comprising of the desired (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid (67%) and other double bond positional isomers (33%) was obtained. The product was recrystallized from warm hexane in a freezer. Crystals of 8 suitable for structure determination were obtained by layering a methanol solution with petroleum ether and slow diffusion. Found C 76.09, H 10.01%; C₂₂H₃₄O₃ requires C 76.26, H 9.89%. ¹H NMR (400 Hz; CDCl₃): δ 0.81 (t, J = 6.6, 3H, CH₃), 1.11–1.48 (m, 22H, CH₂, alkyl chain), 2.17 (q, J = 7.1, 2H, CH₂), 5.89–6.0 (m, 1H, CCH), 6.84 (d, J = 8.1, 1H, ArH), 6.9 (d, J = 7.6, 1H, ArH), 7.01, 6.96 (s, 2H, ArCCHC), 7.33 (t, J = 8.1, 1H, ArH), 10.93 (s, 1H, COOH). ¹³C NMR (100 Hz; CDCl₃): δ 14.1 (CH₃), 22.7, 29.5, 31.3, 33.1, 36.1 (CH₂), 110.4 (ArCCOOH), 116.1 (ArCH), 120.6 (ArCH), 123.1 (ArCHCH), 130.3 (CCH), 135.8 (ArCH), 143.3 (ArC), 163.4 (ArCOH), 176.1 (ArCCOOH).

2.7 Cis-2-butene metathesis of (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid

(E)-2-Hydroxy-6-(pentadec-1-enyl)benzoic acid (0.6 g, 1.73 mmol) was dissolved in dichloromethane (5 mL) in a Schlenk tube where it was bubbled with nitrogen for 10 min. Hoveyda-Grubbs 2nd generation catalyst, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxyphenylmethylene)ruthenium) (0.01 g, 0.016 mmol) was measured and put into the autoclave charged with a magnetic stirrer. (E)-2-Hydroxy-6-(prop-1-enyl)benzoic acid solution was transferred by means of a syringe to the autoclave under nitrogen followed by addition of cis-2-butene (6 mL). The reaction was left under stirring at RT for 24 h. Analysis by GC–MS of the product mixture showed poor conversion of (E)-2-hydroxy-6-(prop-1-enyl)benzoic acid.

2.8 Decarboxylation of (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid

Isoanacardic acid, (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid (0.5 g) was placed in a 10 mL Schlenk tube. It was heated at 190°C in a graphite bath for 3 h to produce a brownish oil, (E)-3-(pentadec-1-enyl)phenol(isocardanol) (0.43 g, 98%; isocardanol 66%, other double bond positional isomers 32%). ¹H NMR (400 Hz; CDCl₃): δ 0.91 (t, J = 6.8, 3.8H, CH₃), 1.16–1.42 (m, 24H, CH₂), 1.46–1.73 (m, 2H, CH₂), 1.90–2.11 (m, 1.5H, CH₂), 2.17–2.28 (q, J = 7.0, 0.6H, CH₂), 2.57 (t, J = 8.4, 0.7H, CH₂), 5.31–5.5 (m, 0.7H, CH₂), 6.17–6.40 (m, 0.5H, CH), 6.69 (s,1H, ArH), 6.78 (d, J = 8.7, 0.5H, ArH), 6.86 (s, 0.5H), 6.93 (d, J = 8.0, 0.5H, CH), 7.17 (t, J = 6.5, 1H, ArH). ¹³C NMR (100 Hz; CDCl₃): δ 14.7 (CH₃), 23.2, 29.9, 31.7, 32.4, 33.3, 36.6, (CH₂), 112.9 (ArCH), 115.7 (ArCH), 119.4 (ArCH), 121.4 (ArCHCH), 129.7 (CHCH), 132.2 (ArCH), 156.2 (ArCOH).

2.9 Synthesis of 3-prop-1-enylphenol

Monounsaturated anacardic acid (2 g) was isomerized as in Section 2.6, above. After the 96 h reaction time, the solution was filtered through celite to remove the catalyst and evaporated to dryness. The oil was then treated as in Section 2.8 to effect decarboxylation. The (E)-3-(pentadec-1-enyl)phenol so formed was dissolved in dichloromethane (5 mL) in a Schlenk tube where it was bubbled with nitrogen for 10 min. Hoveyda-Grubbs 2nd generation catalyst, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxyphenylmethylene)ruthenium) (0.02 g, 0.032 mmol) was measured and put into the autoclave charged with a magnetic stirrer. The (E)-3-(pentadec-1-enyl)phenol solution was transferred by means of a syringe to the autoclave under nitrogen followed by addition of cis-2-butene (6 mL). The reaction was left stirring at RT for 24 h. The product mixture was analyzed by GC–MS (Fig. 9). Separation of the products was by column chromatography using hexane/ethyl acetate (90/10) to isolate the desired product (though still contaminated with about 15% other chain length products); (E)-3-(prop-1-enyl)phenol (137 mg, 18%) ¹H NMR (400 Hz; CDCl₃): δ 1.79 (d, J = 6.6, 2.5H, CH₃), 6.07–6.30 (m, 1.6H, CH), 6.53–6.63 (m, 1.5H, ArH, CH), 6.73 (s, 0.9H, ArH), 6.82 (d, J = 7.8, 0.9H, ArH), 7.07 (t, J = 7.8, 1H, ArH). ¹³C NMR (100 Hz; CDCl₃): δ 19.0 (CH₃), 112.9 (ArCH), 114.4 (ArCH), 119.0 (ArCH), 126.7 (CH), 130.2 (ArCH), 131.1 (ArCR), 156.4 (ArCOH).

2.10 X-ray crystallography

XRD data for compounds 6 and 8 were collected at 173 K by using either a Rigaku MM-007HF High intensity microfocus RA generator/confocal optics (Cu Kα radiation, λ = 1.5406 Å) and Rigaku XtaLAB P100 system (6), or a Rigaku MM-007 High brilliance RA generator/confocal optics (Cu Kα radiation, λ = 1.5406 Å) and Saturn92 CCD system (8). Intensity data were collected using ω and ϕ steps (6) or ω steps (8) accumulating area detector images spanning at least a hemisphere of reciprocal space. All data were corrected for Lorentz polarization effects. A multiscan absorption correction was applied by using CrystalClear 21. Structures were solved by direct methods (SHELXD-2013 22 or SIR2004) 23 and refined by full-matrix least-squares against F² (SHELXL-2013) 22. Non-hydrogen atoms were refined anisotropically, and carbon-bound hydrogen atoms were refined using a riding model. In 8, hydrogen atoms bound to oxygen were located from the difference Fourier map and refined isotropically subject to a distance restraint. In 6, the hydrogen atom bound to oxygen could not be located from the difference Fourier map, so was placed in calculated position and refined using a riding model. All calculations were performed using the CrystalStructure 24 interface. Crystallographic data for CCDC 1009987–1009988 can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

3.1 Double bond isomerization of anacardic acid

We have previously shown 7 that the maximum yield of the conjugated isomer of cardanol, (E)-3-(pentadec-1-enyl)phenol, that can be obtained by isomerization of cardanol is 40% and we believe this to be the thermodynamic limit because the stabilization by conjugation is insufficient. This belief has been confirmed by de Vries and co-workers using monounsaturated cardanol approaching the equilibrium from the isomer with the double bond predominantly in the 8 position and from the isomer with the conjugated double bond made by a Wittig reaction 25.

Inspired by the work of Goossen et al. 26, who showed that the double bond of oleic acid can be trapped in a lactone in the presence of silver triflate as an isomerization catalyst (Fig. 3), we reasoned that this type of trapping might also be possible for anacardic acid. Subsequent ring opening and decarboxylation would then lead to (E)-3-(pentadec-1-enyl)phenol, which we desired for further metathesis reactions.

Two major products could be isolated from the Pd/BDTBPMB/H⁺1 catalyzed double bond isomerization of anacardic acid possessing a mixture of mono-, di-, and tri-unsaturation in the C₁₅ side chain. One of the products isolated was 8-hydroxy-3-tridecyl-1H-isochromen-1-one (6, Figs. 4-6). The compound was white, crystalline and insoluble in methanol with a molecular mass of 344 g/mol, which is the same as the molecular mass of diene anacardic acid. The NMR spectra and crystal structure revealed that the compound was 6. Formation of unsaturated lactones by palladium-catalyzed cyclization of alkenoic acids is not a new concept and has been reported to proceed with good yields 28.

The other isolated product (10%) from this reaction is a white crystalline solid, which NMR studies suggest consists of double bond positional isomers of anacardic acid. The main component is isoanacardic acid, (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid (8, 67%) with other positional isomers making up 33%. We propose that these products are formed from monounsaturated anacardic acid by double bond isomerization. As indicated above, the maximum amount of (E)-3-(pentadec-1-enyl)phenol (9) among the monounsaturated isomers that we have been able to obtain by isomerization of cardanol is 40%.

However, starting from anacardic acid, the conjugated isomerized product makes up 67% of the mixture of isomers, which are isolated in 10% yield from this reaction. We assume that this is because the carboxylic acid in the ortho position relative to the chain increases the conjugation length and hence the stabilization of the conjugated isomer. Somewhat surprisingly, no saturated lactone, 8-hydroxy-3-tridecyl-3,4-dihydroisochromen-1-one (7), the product expected from trapping the conjugated monounsaturated isomer by lactonization, could be detected in the product from isomerization of anacardic acid containing mixed mono-, di-, and tri-unsaturated sidechains.

According to other workers 23, 2-vinylbenzoic acid forms isocoumarin (unsaturated lactone) in the presence of palladium (II) salts via an intramolecular carboxylate palladium complex, followed by elimination of HPdCl. 2-Vinylbenzoic acid has a double bond and carboxylic group at the same relative positions as in isoanacardic acid, 8, but the reaction of 2-vinylbenzoic acid was carried out under oxidative conditions.

Di-unsaturated anacardic acid is the most probable component in the starting mixture to lead to the formation of the unsaturated lactone, 6. The low yield of the lactone (15%) based on anacardic acid would also be consistent with its coming from the diene, which represents only 18.3% of the total anacardic acid. However, we were unable to detect any products, which obviously arise from tri-unsaturated anacardic acid (28.9% of the starting material) by GCMS analysis of the crude reaction product. This together with the observation that dibenzylideneacetone (dba) from the palladium catalyst precursor appears as dibenzylacetone with the double bonds of dba saturated, suggests that some transfer hydrogenation is occurring in this system, perhaps converting the tri-unsaturated chains of the starting material into chains with lower degrees of unsaturation. We do not see any increase in the fully saturated anacardic acid at the end of the reaction, so we propose that the triene is susceptible to hydrogenation, while the diene undergoes isomerizing lactonization and the monoene undergoes isomerization. The source of hydrogen is unknown, but could possibly be methanol in a transfer hydrogenation reaction.

A possible reason for the ability of diene anacardic acid to form unsaturated lactone is that, the two double bonds isomerize together within the alkyl chain (Fig. 5). When they are in conjugation with the aromatic ring and the carboxyl group, the second double bond will reduce the electron density at C2 of the chain, making it a better electrophile and favoring lactone formation. The second double bond must then isomerize further to form the lactone with unsaturation in the ring. Hydrogenation of 8-hydroxy-3-tridecyl-1H-isochromen-1-one to form saturated lactone (7) was easily achieved using Pd/C. The X-ray structure of 6 is shown in Fig. 6.

3.2 Isomerization of monoene anacardic acid

Realizing that higher yields of the desired iso-anacardic acid, 8 might be available from monounsaturated anacardic acid than from cardanol 7, we investigated the isomerization of monounsaturated anacardic acid, obtained by transfer hydrogenation of anacardic acid using ⁱPrOH catalyzed by RuCl₃. H₂O, a system that had proved effective for cardanol 8 and also proved effective for anacardic acid.

As expected the isomerization of monoene anacardic acid led smoothly to a mixture of positional isomers of 3-pentadecenylphenol with the desired isomer (8) making up 67% of the product. After chromatography, the product can be crystallized, apparently still as a mixture of isomers, but crystals of 8 suitable for X-ray analysis (see Fig. 7) could be selected from the batch.

3.3 Synthesis of 3-propenylphenol (10)

Two possible routes are available for converting isoanacardic acid, (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid, 8, into 3-propylphenol (Fig. 8). One route is metathesis of 8 with cis-2-butene followed by decarboxylation and hydrogenation reactions. The other route is by decarboxylation of 8 to form isocardanol, (E)-3-(pentadec-1-enyl)phenol (9) followed by metathesis of isocardanol with cis-2-butene and hydrogenation to form 3-propylphenol. We attempted both approaches but found that the but-2-enolysis of 8 was very poor compared with that of 9.

3.4 Decarboxylation of (E)-2-hydroxy-6-(pentadec-1-enyl)benzoic acid

The fact that the metathesis reaction of isoanacardic acid (8) with 2-butene is poor compared with isocardanol (9) makes decarboxylation of 8 an important step. The decarboxylation process proceeded smoothly on heating 8 to 190°C under N₂ for 3 h. Interestingly, the heating had no effect on the ratio of the conjugated isomer to other double bond positional isomers. In our case, the sample for decarboxylation had the desired isomer (67%) and other isomers (33%). After decarboxylation reaction, these ratios remained the same.

3.5 But-2-enolysis of isocardanol

In our previous study 7, the two main problems with forming 3-prop-1-enylphenol and hence 3-propylphenol from cardanol were the low percentage of isocardanol, 9, after the isomerization reaction and the self-metathesis of 3-propenylphenol, 10, during butenolysis of 9. The overall yield of 10 from isomerized cardanol was only 4.4%. Having in hand isomerized cardanol with a higher proportion of the conjugated isomer, 9 (67% compared with 40%), we also adopted the suggestion 7 that a larger amount of 2-butene would suppress the self-metathesis of (E)-3-(prop-1-enyl)phenol. GCMS analysis of the crude reaction mixture clearly shows that (E)-3-(prop-1-enyl)phenol and 2-hexadecene, dominate over the other products (Fig. 9 and Supporting Information Fig. S11). Isolation by column chromatography afforded (E)-3-(prop-1-enyl)phenol (137 mg, 18%) contaminated with ca 15% of longer chain isomers). The overall yield starting from CNSL is 10.4%.

3.6 X-ray structures of 6 and 8

Both the structures of 6 and 8 adopt an extended conformation of their tridecyl chains, although in 6 this chain lies close to the plane of the isochromene-1-one ring system, whereas in 8 the pentadec-1-enyl chain is twisted further from the plane of the 2-hydroxybenzoic acid. Both compounds pack to give regions of the crystal comprising solely aliphatic or solely aromatic groups, but how they do so differs. Compound 6 is arranged in a strictly head-to-tail manner, giving wide aliphatic regions separated by narrow aromatic regions. In contrast, compound 8 packs with the pentadec-1-enyl chains interdigitating, and also with the 2-hydroxybenzoic acid groups overlapping. These packing motifs arise from the very different sets of weak interactions that occur in each compound. The predominant interaction in compound 6 is an intermolecular CHπ interaction that links adjacent isochromene-1-one rings, supported by weak CHO hydrogen bonds. The only OHO hydrogen bonds occurring in compound 6 are intramolecular, between the alcohol and carbonyl. In compound 8, in contrast, the primary interaction is the formation of hydrogen-bonded benzoic acid dimers. No π-interactions occur; both CHO and OHO hydrogen bonds are intramolecular.