Preparation of Aromatic Geraniol Analogues via a Cu ( I )-Mediated Grignard Coupling

Terpenos alílicos difuncionais constituem-se em importantes blocos de construção sintéticos. A funcionalização de derivados geranílicos protegidos por SeO 2 /t-BuO 2 H adsorvido em SiO 2 , propicia uma rota conveniente para tais compostos. Os grupos protetores escolhidos efetivamente influenciam o processo de oxidação. Também, desenvolveu-se uma eficiente síntese de derivados 2-geranilfenóis através de um acoplamento de Grignard mediado por Cu(I) entre derivados de 2-lítiofenóis e substratos geranílicos.


Introduction
A wide variety of phenolic natural products contain isoprenoid residues. 1It has been suggested that the biosynthetic origin of phenolic isoprenoids involves initial C-alkylation of a preformed phenol or its poly-β-ketonic precursor by an active isoprenoid allylic alcohol derivative. 2 For example, C-geranyl compounds may arise by nucleophilic attack of a phenol on the resonance stabilized allylic cation or by an S N 2-type displacement of pyrophosphate from geranylpyrophosphate.
C-geranyl and C-farnesyl phenols have been prepared by reaction of geranyl or farnesyl bromide with the sodium salt of the phenol.Alkylation of sodium salts, however, invariably leads to complex mixtures containing both ring and oxygen substituted products. 3C-alkylation has been obtained by acid-catalyzed condensation of geraniol or farnesol with phenols in aprotic solvents in the presence of Lewis acids, 4 mineral acids such as p-toluenesulfonic acid, 5 Friedel-Crafts alkylation, 6 copper-induced isomerization to 2-alkenyl 2-lithiophenyl ethers, 7 or Cu(I)-mediated Grignard coupling of THP ethers. 8As part of our continuing interest in phenolic oxidative coupling mediated for iodine hypervalent reagents, 9 we describe the preparation of 2geranylphenolic intermediates that will be necessary for future studies on synthesis of cyclic isoprenoids.

Results and Discussion
The Sharpless conditions for oxidation of geranyl acetate employs 0.5 equiv. of SeO 2 and 2 equiv. of t-BuO 2 H, and the reaction was complete after 8 h 10 with formation of colloidal selenium by-products in small amounts that were difficult to eliminate after column chromatography or distillation.Using lower molar quantities of SeO 2 should reduce selenium by-products, facilitating the purification of selenium-free products.Our efforts with 1-2 mol% of SeO 2 , reproducing literature conditions of these reactions, failed to proceed to completion. 11Very recently, improvement of the oxidation procedure using 5 mol% of SeO 2 and 3.6 equiv. of t-BuO 2 H led to complete consumption of the geranyl acetate, giving allylic alcohol (43%) and aldehyde (9%) in 52% yield. 12We were able to improve those conditions and obtain complete conversion of geranyl acetate after 24 h at room temperature into alcohol 2 and aldehyde 3 in 70% and 30% yield, respectively (  groups. 13In our hands, this methodology (SeO 2 /SiO 2 , 10% m/m, dichloromethane as solvent) gave after 24h at room temperature a 75% yield of 2 and a 25% yield of 3, but the reaction was cleaner without by-products of organoselenium and the work up was carried out easier (entry 2).
The crude mixture was reduced with NaBH 4 /EtOH to give the alcohol 2 in 75% after the two steps.
Singh et al. observed a faster reaction when SeO 2 and t-BuO 2 H were adsorbed on silicagel without solvents and exposed to microwave irradiation for the oxidation of allylic methyl groups. 14Using this condition for the oxidation of geranyl acetate, with 10 min of microwave irradiation (640 W), we obtained exclusively the aldehyde 3. The reduction of crude mixture gave the alcohol 2 in 75% yield (Table 1, entry 3).
Geranyl bromide 4 was necessary in the next steps and its preparation (although it is commercially available) was achieved after some attempts in order to optimize the conditions for getting high yield.Bromination of geraniol 15 with phosphorus tribromide (0.5 equiv.) in hexane under argon at -30 °C followed by a slow increased of the temperature to -10 °C gave, after 45 min, pure geranyl bromide 4 in 98% yield.
Our target was to obtain 2-[(2E,6E)-3,7-dimethyl-8hydroxy-2,6-octadienyl]phenol 9 by optimizing the coupling of geranyl acetate derivatives with more appropriate reagent O-protected 2-iodophenol.Scheme 2 shows the first attempt.Treating (2-iodophenyl)-2tetrahydropyranyl ether 6 with butyllithium in THF-TMEDA at low temperature and then adding the geranyl bromide 4 gave the phenol derivative 7, which was isolated after the usual work up in 95% yield.2-Geranylphenol 8 was obtained in 93% yield after deprotection of precursor 7 with pyridinium p-toluenesulfonate (PPTS).This compound was identified by comparison of its NMR, IR and MS spectra with literature data. 16Oxidation of the geranyl moiety with SeO 2 /SiO 2 , t-BuO 2 H and then reduction with NaBH 4 of the intermediate aldehyde using the optimized protocol described above gave alcohol 9, which was isolated in low yield (47%).
To improve the low yield that was obtained for the oxidation of 8, we investigated a new route to reach 9. Protected geranyl phenol 7 was oxidized under our optimized selenium oxide/silica gel and t-butylhydroperoxide methodology, and allylic alcohol 10 was obtained in 58% yield, a yield superior when compared with the sequence 8 to 9, described earlier.After usual deprotection, phenol 9 was isolated in 92% yield (Scheme 3).A new sequence was investigated with another substrate in an attempt to improve the yield of the desired phenolalcohol 9 (Scheme 4).Using a modified Mechelke-Wiemer protocol, 8 the transmetalation of the lithium derivative of the O-protected 2-iodophenol 11 with magnesium bromide was performed at low temperature to give the Grignard intermediate and then with CuI to afford the intermediate organocuprate which was alkylated with geranyl 2tetrahydropyranyl ether 12 to give 13 in 88% yield.Oxidation of the geranyl moiety with SeO 2 /SiO 2 , t-BuO 2 H and then with NaBH 4 reduction of the intermediate aldehyde using the optimized protocol described above gave the allylic alcohol 14 in 43% yield.This result was still not satisfactory so we tried a different approach.The O-protected 2-iodophenol 11 was treated with n-BuLi in THF at low temperature and then with MgBr 2 .After allowing the reaction mixture to reach ambient temperature, CuI was added followed by the addition of allylic alcohol 2. The reaction mixture was then heated to 50 °C and after usual work-up, monoterpenylphenol 9 was isolated with significative improvement of the overall yield (83% yield).

Conclusion
In brief, we optimized a selective oxidation of allylic methyl groups in geraniol derivatives over a solid support to the corresponding trans-α,β-unsaturated alcohols and aldehydes, using selenium dioxide and t-butylhydroperoxide adsorbed on silica gel as oxidants.The chosen protecting groups clearly influence the oxidation process.Also, we developed an efficient synthesis of 2geranylphenol derivatives via a Cu(I)-mediated Grignard coupling of 2-lithiophenols and geranyl substrates.Further studies on phenolic oxidation of these synthetic intermediates to achieve the synthesis of cyclic isoprenoids will be reported in due course.

Experimental
The IR spectra were recorded on a Hartmann & Braun BOMEM MB SERIES spectrometer.The 1 H NMR and 13 C NMR were recorded on a VARIAN-INOVA spectrometer.Mass spectra were recorded on a SHIMADZU GC-MS QP 5000 gas chromatograph/mass spectrometer and with helium as carrier gas.A 30 m x 0.25 mm I.D. capillary column of fused silica, SUPELCO SIMPLICITY 1 TM , was used.An injector temperature of 230 °C and a detector temperature of 280 °C, with the column at 50 °C for 3 min; then using a rate of 20 °C min -1 up to 280 °C, with a pressure of 100 kPa and gas flow of 80 mL min -1 , was used.HMRS were obtained on a Fison VG Autospec.Preparative column chromatography was carried using silica gel 60 (Merck 7734, 70-230 mesh).Completion of the reactions was established by TLC analysis.Geraniol was purchased from Aldrich Chem.Co. (purity >98%), othres reagents were analytical (Aldrich or Acros) and we employed 230-400 mesh silica gel for flash chromatography.

(2E,6E)-3,7-Dimethyl-8-hydroxy-2,6-octadienyl acetate (2)
A suspension of selenium oxide (0.44 g, 5 mmol) and t-butylhydroperoxide (2.75 mL, 70% m/m, 20 mmol) in anhydrous dichloromethane (30 mL, ethanol free) was stirred for 20 min at room temperature and then silica gel (230-400 mesh, 5.55 g) was added.After 30 min the temperature was decreased to 0 °C and geranyl acetate (10 mmol) was slowly added.The mixture was stirred for 48 h.The solvent was stripped off until a yellow powder was obtained that was transferred to a fibrous glass frit Büchner funnel equipped with a layer of celite and neutral alumina, and washed with ethyl acetate/hexane (2/3, v/v, 3x50 mL).The extracts were washed with a saturated aqueous solution of FeSO 4 .2H 2 O (3x30 mL), acidified with conc H 2 SO 4 , then washed with brine (2x30 mL) and dried with anhydrous MgSO 4 .After the solvent was removed, the oily residue was dissolved in methanol/THF (1/20, v/v, 25 mL) while keeping the temperature at -10 °C (ice-water/NaCl bath 1:1, m/m) and then NaBH 4 was added (0.30 g, 80 mmol) in four portions.After 30 min, a cold saturated solution of NH 4 Cl (30 mL) was added, and the mixture was extracted with CH 2 Cl 2 (3x30 mL), washed with water and brine, and dried over MgSO 4 .The solvent was removed and the residue was purified by flash chromatography eluting with AcOEt/hexane (3/7, v/v), to give pure 2 as an yellow oil (1.59 g, 75% yield); IR (film) ν max /cm
(2-iodophenyl)-2-tetrahydropyranyl ether (6)   A solution of 2.2 g (10 mmol) of 2-iodophenol 5 in dichloromethane (10 mL) was stirred at room temperature under nitrogen and 23 mg (0.9 mmol%) of pyridinium p-toluenesulfonate was added, followed by drop wise addition of dihydropyran (1.13 mL, 12 mmol).The mixture was stirred at ambient temperature for 8 h and then diluted with 30 mL of ether.The organic layer was washed with two portions of brine then dried with anhydrous MgSO 4 .The solvent was removed under vacuum and the residue was purified by flash chromatography, eluting with AcOEt/ hexane (1/19, v/v), to give 2.89 g (95%) of the tetrahydropyranyl ether 6 as an oil; IR (film) ν max /cm -
Method B. From 10.To a solution of 10 (3.30g, 10 mmol) in methanol (30 mL) pyridinium p-toluenesulfonate (PPTS, 0.025g, 0.1 mmol) was added and then heated to 50 °C for 6 h.The solvent was removed under reduced pressure and the residue was diluted with ether (50 mL) and water (30 mL) and extracted with ether (2x50 mL).The ether phase was washed with water (30 mL), then with brine (2x30 mL), dried over MgSO 4 , filtered and the solvent was removed under reduced pressure by rotatory evaporation.The residue was purified by flash chromatography, eluting with AcOEt/hexane (3/7 v/v) to give 9 (2.27 g, 92%).
Method C. From 14.To a stirred solution of 14 (3.61 g, 10 mmol) in anhydrous THF (20 mL) under argon atmosphere, a solution of tetrabutylammonium fluoride (TBAF, 5.23 g, 20 mmol) in THF (20 mL) was added.After the disappearance of the starting material, water (30 mL) was added and the mixture was extracted with dichloromethane (2x30 mL).The extracts were dried over MgSO 4 , filtered and the solvent was removed under reduced pressure by rotatory evaporation.The crude residue was purified by column chromatography with silica gel using AcOEt/hexane to give pure 9 (2.29 g, 93%) as a yellow oil.

Table
1, entry 1).By making certain changes in above methods and employing SeO 2 /t-BuO 2 H adsorbed on silica gel, Chhabra et al. found this to be a highly selective reagent for the oxidation of allylic methyl