5- Alkylresorcinols

Preparation of l-Hydroxy-2,6-dimethoxy-4-(tertiary alkyl)benzene 

It has now been discovered that 2,6-dimethoxyphenol surprisingly is alkylated almost exclusively at the 4-position by reaction with a tertiary carbinol in the presence of an acid. Such alkylation provides a l-hydroxy-2,6-dimethoxy-4-(tertiary alkyDbenzene which can readily be converted to a 5-(tertiary alkyl)resorcinol. Such process affords high 5rields of the desired 5-(tertiary alkyl)resorcinol... starting from relatively inexpensive starting materials. 

6- dimethoxyphenol with an alkenyl bromide to provide a 1-alkenoxy- 

6- dimethoxybenzene, which compound is then rearranged, generally by heating, to provide a l-hydroxy-2,6-dimethoxy-4-alkenylbenzene. 

A solution containing 15.4 g. of l-hydroxy-2,6-dimethoxybenzene and 14.4 g. of 1,1-dimethyl-1-hydroxyheptane in 20 mL. of methane-sulfonic acid was heated at 50° C. and stirred for three and one-half hours. The reaction mixture next was poured over 50 g. of ice, and the resulting aqueous solution was extracted several times with dichloromethane. The organic extracts were combined, washed with water and with saturated aqueous sodium bicarbonate solution, and dried. Removal of the solvent by evaporation under reduced pressure provided 27.4 g. of l-hydroxy-2,6-dimethoxy-4-(l,1-dimethyl-heptyl)benzene as an oil. Source Dominianni 1978 

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Table 2. DNA protection efficiency in comparision with the control (%) in the presence of various alkylresorcinols at UV-irradiation for 300 seconds. - P<0.05.

Vagel, A., Roo, E. Alkylresorcinols - rare chemicals available in bulk. Innov. Pharm. Tech. (2004), pp. 94-95... 

Zarnowski, R., Kozubek, A., Pietr, S. Effect of rye 5-n-alkylresorcinols on in vitro growth of phytopathogenic Fusarium and Rhizoctonia fungi. Bulletin of the Polish Academy of Sciences, Vol.47, No.2-4, (1999), pp. 231-235, ISSN 0239-7269... 

Gqsiorowski K, Szyba K, Brokos B and Kozubek A (1996), Antimutagenic activity of alkylresorcinols from cereal grains , Cancer Lett, 106, 109-115. 

Ross A B, Aman P, Andersson R and Kamal-Eldin A (2004), Chromatographic analysis of alkylresorcinols and their metabolites J Chromatogr A, 1054, 157-164. 

This synthetic route allows one to proceed from the alkylresorcinol dimethyl ether without using a compound of the verbenol or cyclohexanone type. 

Reflux 6.9 g triphenylphosphine and 6.6 g lauryl bromide (or equimolar amount of homolog) in 40 ml xylene for 60 hours. Remove solvent and wash residue with 5X20 ml ether (by decanting) to get 11 g lauryl triphenylphosphonium bromide (I). To a stirred suspension of 5.6 g (0.011M)(I) in 50 ml ether add 0.01M butyllithium solution (see Organic Reactions 8,258(1954) for preparation). Stir Vz hour at room temperature and slowly add 1.66 g 3,5-dimethoxybenzaldehyde (preparation given elsewhere here) in 10 ml ether over Vi hour. After 15 hours, filter, wash filtrate with water and dry, evaporate in vacuum. Dilute residue with pentane, filter and remove solvent. Dissolve the residual oil in 25 ml ethyl acetate and hydrogenate over O.lg Adams catalyst at one atmosphere and room temperature for 2 hours. Filter and evaporate in vacuum to get the 5-alkylresorcinol dimethyl ether which can be reciystallized from pentane and demethylated as described elsewhere here. 

The use of the novel reduction methods described at the beginning of this section would render this method much simpler. 5-Alkylresorcinols German Patent 2,002,815 (30 July 1970)... 

This method is specifically designed to produce good yields of dimethylheptylresorcinol, which provides, after synthesis by any of the various routes, one of the most active THC analogs yet discovered. Note that the synthesis may not have to be carried all the way to the alkylresorcinol since the intermediate ketones etc. may give an active THC analog. 

As an alternative process for getting from (III) to (VI), combine 64.2g (0.18M) methyltriphenylphosphonium bromide in dry benzene with 11.6g (0.18M) (in 14% solution) butyllithium in benzene. Heat to 60° C and cool. 49.Og (0.176M) (III) in 40 ml dry benzene is added (keep temperature below 40° C) and then reflux 2 hours. Cool, filter and evaporate in vacuum to get the octene, which after catalytic hydrogenation as described for (V) yields (VI). 5-Alkylresorcinols Aust. J. Chem. 21,2979(1968)... 

Aust. J. Chem. 26,799(1973) gives a 2 step synthesis of 5-alkylresorcinols by condensation of beta-ketosulphones with 3,5-dimethoxybenzyl bromide and then reduction. Aust. J. Chem. 26,183(1973) gives a synthesis from 3,5-dimethoxy-N,N-dimeth-ylbenzylamine in 7 steps (but perhaps only 4 will reach a cpd. that can give an active THC analog). 

Figure 2. Relationship between hot-press time and wet-bond adhesion strength for lignin-resol resin adhesives with and without alkylresorcinol. Legend Q without alkylresorcinol 0 with 10 parts alkylresorcinol. Note Numerical values in parentheses are percentages of wood failure phenola-tion 200°C, 60 min, without catalyst hot-press 120°C, 6 min.

Suzuki, Y., Esumi, Y., Saito T, Kishimoto Y, MoritaT. Identification of 5-n-(2.-oxo)alkylresorcinols from etiolated rice seedlings. Phytochemistry 1998 47 1247-1252. 

A portion (30.5 g) of the residue collected above was subjected to fractional distillation under reduced pressure (0.1-0.15 mm/Hg). The temperature was slowly raised to 125°C and the materials collected were kept separate. The temperature was then raised between 140°-160°C where the major fraction was collected (14 g). GC analysis showed >96% THC. Further purification on a silica gel column gives THC with at least 98% purity. An improvement of this process includes the use of high pressure liquid chromatography (HPLC). The preparation of dronabinol and related compounds have employed acid-catalyzed electrophilic condensation of a 5-alkylresorcinol such as 5-n-pentylresorcinol (commonly known as olivetol) and a menthadienol, followed by cyclization yield of desired product is about 17-22% (Petrzilka et al., Helv. Chim. Acta, 52, 1102 (1969)). 

The mass spectra and pyrolysis of alkyl resorcinols are also subject to nonquantitative correlations. 3 > Lille and Kundel reported that the mass spectra of 2, 4 and 5 alkyl (C4 or larger) resorcinols were all dominated by jS-cleavage (benzylic) ions. The pyrolysis of the 2 or 4 alkylresorcinols at 700 °C was consistent with their mass spectra however, pyrolysis of 5-alkylresorcinols gave in addition to the anticipated / -cleavage products, 5,7-dihydroxyindene or an alkenylresorcinol. The yield of the unique olefin was of the same order as the peld of the 5-methylresorcinol. The basis for this reactivity discrepancy may be the scrambling of positions in the resorcinol on electron impact. 

The resorcinols used as starting materials in the present process are either resorcinol itself (III, R=H) or a 5-alkylresorcinol (III, R=alkyl). The alkyl group may have up to twelve carbon atoms and it may be either branched or straight-chained. Examples of such alkyl groups are methyl, ethyl, propyl, sec-butyl, pentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, l-ethyl-2-methylpropyl, isohexyl, heptyl, 1-methylhexyl, 1,2-dimethylhexyl, 1,2-dimethylheptyl, 1-methyloctyl, and 1-methylnonyl. 

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