ACS Acta Chemica Scandinavica
AP Archiv der Pharmazie
BCSJ Bulletin of the Chemical Society of Japan
BER Berichte der Deutsche Chemische Gesellschaft
BSC Bulletin de la Société Chimique de France
CA Chemical Abstracts
CCCC Collection of Czechoslovakian Chemical Communications
CJC Canadian Journal of Chemistry
CPB Chemical and Pharmaceutical Bulletin
CT Chimie Thérapeutique (Chimica Therapeutica)
GCI Gazzetta Chimica Italiana
HCA Helvetica Chimica Acta
JACS Journal of the American Chemical Society
JBC Journal of Biological Chemistry
JCS Journal of the Chemical Society
JGC Journal of General Chemistry (English translation of
Zhurnal Obschei Kimii)
JHC Journal of Heterocyclic Chemistry
JMC Journal of Medicinal Chemistry
JOC Journal of Organic Chemistry
JPS Journal of Pharmaceutical Science
LAC Leibigs Annalen der Chemie
MON Monatshefte fur Chemie
REC Recueil Travaux Chemiques
TL Tetrahedron Letters
Much useful information can be found in any lab text in organic chemistry such as that of Wiberg.
Shake the solution with an anhydrous salt such as MgS04, Na2S04, etc. and filter out the salt. Solids can be dried by spreading on a filter paper at room temperature or drying in an oven at low heat.
All solvents should be anhydrous unless otherwise specified. This can sometimes be done by drying as above and is to be attended to especially in the case of ethanol which is available in 95% or 100% (100% takes up water from the air very rapidly).
Whenever apparatus with ground glass joints is used, Dow silicone grease provides excellent lubrication and airtight seal.
This usually refers to the light boiling fraction (60°-80° C) of petroleum ether which must not be confused with "ether," which refers to diethyl ether.
This requires a heavy-walled flask. Ordinary lab vacuums are about 15mm Hg. A simple water-forced suction vacuum requires only a water source to produce a vacuum of about 25mm Hg, which is satisfactory for most purposes. Evaporation causes the temperature to drop which slows evaporation. Running a stream of warm water over the flask or putting it in a warm water bath avoids this. To avoid difficulties in getting residues out of the
bottom of the flask, it is useful to do the evaporation in a vacuum exsiccator shaped as shown or in a flat dish in the exsiccator. Whenever a forced water vacuum is used, it is wise to place a water trap between the vacuum and the solvent being evaporated to prevent water from entering when the pressure fluctuates.
This can be done in the old way with a stirring propeller entering through one of the necks of the flask, attached to a non-sparking motor. It is easier to sit the flask on a magnetic stirrer, and drop a magnetic stirring bar (preferably Teflon coated and egg shaped for round-bottom flask) in the solution.
Heating and Refluxing
Do not smoke or have any flames (such as a pilot light on gas appliances) around when using organic solvents, especially ether. Bunscn or other types of gas burners are generally outmoded. Much better are electric heating mantles available for each size of round-bottom flask. Put a rheostat in the circuit to regulate the temperature of the mantle. For refluxing, adjust the rheostat so that the vapor level in the water-cooled condenser is about a quarter of the way up the condenser. Heating plates or combination heating plate-magnetic stirrer is also useful.
If a lab hood is not available, some forced air ventilation such as a large fan near a window is advisable, especially if ether is used.
Lithium Aluminum Hydride
Lithium aluminum hydride is expensive and often difficult to obtain. It can be synthesized [JACS 69,1197(1947)], but this is rather tricky. Its use can usually be circumvented by using a different reducing method or a different synthetic route.
An explosion shield, asbestos gloves, face mask and tongs are desirable.
A Substitute for Raney-Nickel, JACS 85,1004(1963) 5 mMoles Ni acetate in 50 ml water in 125 ml erlenmeyer flask;
connect as below to Hg pressure outlet. Flush with N2, stir and add over 30 seconds with the syringe, 10 ml 1M NaBH4in water. After hydrogen evolution ceases, add 5 ml more of NaBH4. Decant the aqueous phase, wash solid with 2X50 ml ethanol to get the Ni-boride catalyst as a black, granular solid. Hydrogénation can then be done as described below at room temperature and atmospheric pressure.
A Highly Active Raney-Nickel Catalyst, JOC 26,1625(1961) Add with stirring, in small portions over one-half hour, 40g 50% Raney-Ni to 600 ml 10% NaOH in a 1L three-neck flask and continue stirring one hour. Let the Ni settle and decant the solution. Wash residue with 5X200 ml water, 5X50 ml ethanol, always keeping the Ni covered with liquid. Store under ethanol in refrigerator. Hydrogénation with this catalyst can be carried out in a low pressure Parr bottle (e.g., 30-80 ml ethanol, 5-1 Og Ni suspension, 1-2 ml 20% NaOH, 40°-50° and 40-60 PSI H2).
A New Method for Hydrogenating at Room Temperature and Atmospheric Pressure
Method 1 : External Generation of Hydrogen
JACS 75,215(1953) This method reduces the solvent volume in the reducing flask for large-scale work. Add 1M NaBH4 in water to an aqueous HCl or acetic acid solution containing a little CoCl2, if necessary for a rapid rate.
Method 2: Internal Generation of Hydrogen
JACS «4,1494-5,2827-30(1962) Three-necked flask fitted with a graduated dropping funnel or a 50 ml burette, an inlet port fitted with a rubber serum cap, and an Hg manometer which allows gas to escape when the pressure exceeds about 25 mm above atmospheric pressure. At room temperature (25° C water bath) with stirring, add 1 ml 0.2M chloroplatinic acid (commercial 10% is about 0.2M) to 40 ml ethanol and lg decolorizing carbon (e.g., Darco KB—may omit this but the reaction is slower). Flush with N2 if possible and add 5 ml 1M NaBH4 (prepared from 3.8g NaBH4, 95 ml ethanol, 5 ml 2N NaOH) rapidly to a vigorously stirred solution (black precipitate forms). After about one minute inject about 4 ml concentrated HCl or glacial acetic acid to initiate hydrogen generation. Then inject about 0.02M of the unsaturated compound. Add NaBH4 dropwise so that flask pressure remains about atmospheric pressure. Reaction is over when uptake ceases. NaBH4 addition can be made automatic by putting a syringe full of it in an Hg-filled tube (about 15mm Hg, with holes so that as the pressure drops, more solution enters). This apparatus is available from Delmar Scientific Labs. Can also use PdCl2, PtCl4, Ni, Rhodium, Pt02, platinum-carbon catalyst, palladium-carbon catalyst in place of chloroplatinic acid, but the last three are poor. Other salts can be used in place of the chlorides.
Note that the above procedures permit hydrogenation without the use of hydrogen tanks or special hydrogenation apparatus (Parr bottles, etc.).
Other references on the use of boron compounds for reduction: Org. Rxns. 28(1963); JACS 86,3566(1964); JOC 28, 3261(1963); JCS 371(1962).
l"-Meihylociyl homolog r,2"-Dimelhylheplyl homolog of d'-THC (MOP) of J'-THC
Fig. 24. Some widely tested synthetic cannabinoids l"-Meihylociyl homolog r,2"-Dimelhylheplyl homolog of d'-THC (MOP) of J'-THC
Fig. 24. Some widely tested synthetic cannabinoids
IS IT LEGAL?
The A1 and A1 (6) THC's with the n-pentyl in the 5' position (obtained by using olivetol in the syntheses) are naturally occurring and hence illegal, but the A3 THC's and the numerous isomers, homologs and analogs of the A1 and A1 <6) compounds are probably legal.
Apparently, recent federal legislation outlaws delta-1, delta-1(6), delta-3,4-THC's, both cis and trans and D and L and compounds. This still leaves hundreds of legal cannabinoids.
THC refers to tetrahydrocannabinol, and A refers to the position of the double bond. Various numbering systems are used, so the following equivalences should be noted: A1 THC = A1 3,4-trans-THC = A9THC and A6THC = A1 (6,THC = A8THC = A6-3, 4-trans-THC.
Little careful human testing has been done, so data given here and elsewhere on the relative psychedelic activity of various cannabinoids is often only a rough guess. A1 THC and A6 THC have about the same activity which is about five times that of A3 THC. Cannabidiol, cannabidiolic acid, cannabinol, cannabigerol and cannabichromene all have very little or no activity. Only the C (-) isomer of THC seems to be active. When the n-pentyl at the 5' position is replaced by 1,2-dimethylhep-tyl, potency and duration of action increases about five times, giving the most active THC analog yet tested.
It should be noted that recent testing has indicated that a 1,1-dimethylheptyl or 1-methyloctyl and probably similar side chains give THC's of equal or greater activity than the 1,2-di-methylheptyl cpd. However, the difficulty of synthesizing these compounds plus their very long action (up to several days or more) makes it doubtful whether they deserve all the interest they have generated among psychedelic enthusiasts. More concern should be devoted to the shorter side chains, since they would presumably allow one to get very stoned but to be straight again within a few hours, thus allowing the drug to be more easily manipulated.
Substituting N, O, or S atoms at various places or saturating the double bond to produce hexahydrocannabinol probably retains activity. [See CA 74,125667(1971) for S analogs.] Alkoxy side chains at 5' retain activity. Unsaturated side chains arc as active as saturated ones. Ether moieties at the 5' position, but not as the 3', retain activity. Activity is retained if an additional alkyl is placed at 4' but lost if placed at 6'. Activity is greatly decreased or lost if the H at the 4' or 6' positions is replaced by carboxyl, carbomethoxyl, acetyl or acetoxyl; if the hydroxyl is replaced by H; if the OH is at 5' and the side chain at 4'. Methyl and/or ethyl at 1 and 5 retains activity, as does removal of the methyl at 1. An hydroxyl in the side chain is active, but not on the first carbon of the side chain. Esterifying the OH retains activity, but etherifying eliminates activity.
THC can be synthesized via cannabigerol and cannabichro-mene in low yield [TET 24,4830(1968), TL 5349,5353(1969), Proc. Chem. Soc. 82,(1964)]. For several moderately difficult routes leading to A1 THC via cannabinol in about 10% yield, see LAC 685,126(1965). For a synthesis of A1 (6) THC from cinnamyl derivatives and isoprene see JACS 59,4551(1967). A rather difficult synthesis of A1 and A1,6) THC is given in JACS 59,5934(1967). For a variety of THC analogs of unknown activity see BSC 1374, 1384(1968); JCS 952(1949); JACS 63, 1971,1977,2766(1941), 64,694,2031,2653(1942), 67,1534 (1945), 70,662(1948), 71,1624(1949), 52,5198(1960); CA 75,48910(1971); TL 3405(1967); JMC 11,377(1968); CT 2, 167(1967); CA 76,126783(1972).
Since 0 or 1 and perhaps 2 double bonds anywhere in the lefthand ring above, as well as changes in the size and position of the alkyl groups will probably all produce compounds with THC activity, many compounds similar to menthadieneol, men-thatriene, verbenol, epoxycarene, pulegone and 4-carbethoxy-l-Me-3-cyclohexanone can be used in the methods below to get active THC analogs (e.g., isopiperitinol will work [TL 945 (1972)]). Also, 5-chlororesorcinol and 5-methylresorcinol (orcinol) have been shown to give weakly active THC's [see CA 76,33946(1972), US Patent 3,028,410(1962), and TET 23, 3435(1967) for syntheses of orcinol and related compounds]. Unfortunately, recent data indicate that orcinol gives a THC with very low activity. It appears that delta-5 and delta-7 THC have very little activity. If the methyl groups at carbon 8 in THC are changed to longer alkyl groups, the activity decreases, but the replacement of the alkyl groups by hydrogen or other groups has not been carried out. Open chain analogs also have activity [see CT 2,167(1967)].
For new information on the structure-activity relationships of cannabinoids see JMC 16,1200(1973), Arzneim, Forsch 22, 1995(1972), and Chem. Revs. 76,75(1976).
For THC analogs see JMC ¿9,445-71,549-53(1976); Eur. JMC 10,79(1975); Phytochem. 14,213(1975); CA 52,57564, 170672-3(1975); Diss. Abst. 345,1442(1973); J. Labelled Cpds.
11,551(1975); Compt. Rend. Acad. Sci. 281C, 197(1975).
For THC in one step from chrysanthenol see Experientia 31,16(1975).
Fig. 25. Two commonly used numbering systems for the same molecule
The following gives the synthesis of a water soluble THC derivative which is equipotent with THC and perhaps more rapidly acting (see Science 1 77,442(1972)). Stir equimolar amounts of THC, dicyclohexylcarbodiimide and gamma-morpholinobuty-ric acid hydrochloride (or gamma-piperidinobutyric acid hydrochloride) [JACS 53,2891(1961)] in methylene chloride at room temperature for 16 hours and filter, evaporate in vacuum (can triturate with ether and filter). The cost of synthetic THC will vary greatly depending on many factors, but high quality grass can probably be produced for under $20 a kilo.
For good reviews of marijuana chemistry see Prog. Chem. Natural Prod. 25,175(1967), Science 168,1159(1970), C. Joyce and J. Curry (Eds.), Botany and Chemistry of Cannabis (1970), JACS 93,217(1971), JPS 60,1433(1971), Ann. N.Y. Acad. Sci. 191(1971), Prog. Org. Chem. 5,78(1973), Marijuana-R. Mech-oulam (Ed.) (1973), and Chemical Reviews 76,75(1976).
Only the first three methods below give the natural S. (-) isomer of THC. The other methods give the racemic product and consequently their yields of active THC are actually one-half that indicated.
SYNTHESES OF THC AND ANALOGS
C(-)-A'(6) THC HCA 52,1123(1969), cf. JACS 96,5860(1974). Method 1
This method gives about 50% yield for THC and about 90% for the l',l'-dimethylpentyl analog.
Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or trans p-methadien (2,8)-ol-l (the racemic compound can be used but yield will be one-half), 0.8 g p-toluenesulfonic acid in 250 ml benzene; reflux two hours (or use 0.004 Moles tri-fluoroacetic acid and reflux five hours). Cool, add ether, wash with NaHC03 and dry, evaporate in vacuum to get about 9 g of mixture (can chromatograph on 350 g silica gel- benzene elutes the THC; benzene: ether 98:2 elutes an inactive product; then benzene: ether 1:1 elutes unreacted olivetol; evaporate in vacuum to recover olivetol).
Dissolve the olivetol or analog and p-menthadienol or p-metha-triene (1,5,8) in 8 ml liquid S02 in a bomb and fuse 70 hours at room temperature. Proceed as above to get about 20% yield.
C(-)-AJ (6) THC JACS «9,4552(1967), JCS (C) 579(1971), cf. Diss. Abst. 35B,3843(1974), and Phytochemistry 14,213(1975). Convert (-) alpha-pinene to (-) verbenol (sec precursors section). Add 1M (-) verbenol (racemic verbenol will give one-half yield), 1M olivetol or analog with methylene chloride as solvent. Add BF3 etherate and let stand at room temperature one-half hour to get approximately 35% yield after evaporating in vacuum or purifying as above to recover unreacted olivetol. Solvent and catalyst used in method 1 above will probably also work. Either cis or trans verbenol can be used. The JCS paper adds lg BF3-etherate to a solution of lg olivetol and l.lg verbenol in 200 ml methylene chloride and let stand two hours at room temperature. JACS 94,6164(1972) recommends two hours at -10° C, thdn one-half hour at room temperature and the use of cis rather than trans verbenol (the latter gradually decomposes at room temperature). The reaction is also carried out under nitrogen, using twice as much verbenol as olivetol, 0.85ml BF3 etherate and 85 ml methylene chloride/g verbenol (both freshly distilled over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972) for the use of citral and Arzneim. Forsch. 22,19 9 5 (19 7 2) for use of p-TSA.
In the synthesis of THC with verbenol, the cis isomer is preferable to the trans since the latter decomposes at room temperature. Pinene or carvone give active THC's [JMC 17,287(74)].
«(-)-A1 and A1 (6) THC JACS 92,6061(1970), U.S. Patent 3,734,930
1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog, 0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and evaporate in vacuum (or can separate the unreacted olivetol as above) to get about 30% yield THC. Olivetol can also be separated as described below. For synthesis of 2-epoxycarene (A4 carene oxide) from A4 carene (preparation given later) see p-methadieneol preparation (method 2). 3-carene oxide gives 20% yield of A1'61 THC.
1M pulegone, 1M olivetol or analog, 0.3 M POCl3; reflux four hours in 1 L benzene and evaporate in vacuum or pour into excess saturated NaHC03 and extract with dilute NaOH to recover unreacted olivetol. Dry, and evaporate in vacuum the benzene layer to get the THC.
A1161 THC from Cannabidiol HCA 52,1123(1969)
Reflux lg cannabidiol, 60 mg p-toluenesulfonic acid (or 0.003 M trifluoroacetic acid) in 50 ml benzene for 1 Vi hours. Evaporate in vacuum to get about 0.7 g THC. Alternatively, add 1.8 g cannabidiol to 100 ml 0.005N HCl and reflux four hours. Proceed as above to get about 0.5 g THC [cf. JACS 94,6159(1972)].
Nitrogen Analogs of A3 THC CA 72,66922(1970); JACS 88, 3664(1966), TL 545(1972)
5.4 g olivetol or 0.03 M analog, 5.8 g 4-carbethoxy-N-benzyl-3-piperidone hydrochloride or 0.03 M analog [JACS 71,896 (1949) and 55,1239(1933) give an old and clumsy synthesis, and Heterocyclic Compounds, Klingenberg (Ed.), part 3, chaps. IX-X1I (1962) gives information on related compounds] in 10 ml concentrated sulfuric acid. The concentrated sulfuric acid should be added dropwise, with cooling (cf. U.S. Patent 3,429, 889). Add 3 ml POCl3 and stir at room temperature for 24 hours. Neutralize with NaHC03 to precipitate 2.3 g (I). Filter; wash precipitate with NaHC03 and recrystallize from acetoni-trile. Dissolve 4.3 g (I) in 30 ml anisole and add 0.1 M methyl Mgl in 50 ml anisole. Stir 12 hours and evaporate in vacuum or acidify with sulfuric acid, neutralize with NaHC03 and filter;
wash to get 2.4 g N-benzyl analog of THC. For other N-analogs of unknown activity see JOC 33,2995(1968). Recover unreacted olivetol as usual.
The 5-aza analogs given in the JOC ref. seem to be active but they use the pyrone intermediate from certain routes of THC synthesis for a precursor. See U.S. Patent 3,493,579(03 Feb. 1970) for quinuclidine analogs and JOC 38,440(1973) for a different approach to N-analogs. See JOC 39,1546(1974) and HCA 56,519(1973) for other N-analogs.
This synthetic route allows one to proceed from the alkylresor-cinol dimethyl ether without using a compound of the verbenol or cyclohexanone type.
Synthesis of olivetol aldehyde [Aust. J. Chem. 21,2979 (1968)].To a stirred solution of phenyllithium (1.6g bromoben-zene and 0.16g Li) in 50 ml ether, add 0.01M olivetol dimethyl ether (or analog—see elsewhere here for preparation) in 5 ml ether and reflux 4 hours. Add 5 ml N-methylformanilidc, reflux 1 hour and wash with 2X50 ml dilute sulfuric acid, 50 ml water, 25 ml saturated NaCl and dry, evaporate in vacuum the ether (can dissolve in benzene and filter through lOOg of alumina) to get 60% yield of the dimethylolivetol aldehyde (1) (recrystallize from ether-pentane). Can recover unreacted starting material by refluxing the vacuum distillate 3 hours with excess 10% HCl, removing the organic layer and extracting the aqueous layer with ether: wash and dry, evaporate in vacuum the combined ether layers.
An alternative method for (I) [JACS 65,361(1943)] In a 200 ml 3 neck round bottom flask with a stirrer, a reflux condenser, a dropping funnel and a nitrogen inlet tube, introduce a rapid stream of nitrogen and in the stream issuing from the central neck, cut 1.5g of lithium into ca. 70 picccs and drop into the flask containing about 25 ml dry ether. Place the fittings in position, slow the nitrogen stream and add % of the solution of 9.2g n-butyl-chloride in 25 ml dry ether. Start the stirring and add the rest of the n-butyl-chloride at a rate giving a gentle reflux. Continue stirring and reflux 2 hours and add 15 ml olivetol dimethyl ether in 25 ml dry ether. Reflux 2 hours and add drop-wise a solution of 15 ml N-methylformanilide in 25 ml dry ether with stirring at a rate sufficient to produce refluxing. Continue stirring 1 hour, treat with 3% sulfuric acid and then pour into excess of this acid. Remove upper layer and extract aqueous layer twice with ether. Wash combined ether layers with dilute aqueous NaHC03 and water and dry, evaporate in vacuum the ether (can distill 148-52/0.3) to get 78% (I).
JACS 65,361(1943). A mixture of 6.5g (I) (or analog), 20 ml pyridine, 1 ml piperidine and 9g malonic acid is warmed on a steam bath 1 hour. Add another lg malonic acid and heat another V2 hour. Reflux V2 hour and pour into excess iced 10% HCl, stirring occasionally over 2 hours. Filter and dry to get 6g 2,6-dimethoxy-4-n-amylcinnamic acid (II) (recrystallize from ethanol).
lOg (II), 40 ml 80% isoprene and 40 ml dry xylene or toluene is heated in an autoclave at 185° C for 15 hours. Cool, dilute with 160 ml petroleum ether and shake with 100 ml saturated aq. Na2C03. Let stand and separate the middle layer. Wash the middle layer with a mixture of petroleum ether and dilute aq. Na2C03 and again separate the middle layer and treat with 75 ml 10% HCl and 75 ml ether. Shake, separate the aqueous layer and wash the ether 3 times with water. Dry and evaporate in vacuum the ether and dissolve the residue in petroleum ether. The solid which ppts. after about 10 minutes is unchanged (II). Filter and let stand in refrigerator overnight and dry and evaporate in vacuum to ppt. about 7g of the l-methyl-5(2,6-dimethoxy-4-n-amylphenyl)-l-cyclohexene-4-COOH (III) (re-crystallize from petroleum ether).
lg (III) in 5 ml dry ether is added to 10 ml 3M MeMgl (from 0.21g Mg and 1.2g methyl iodide) in ether, heated to 130° C to evaporate the solvent and the oil kept at a bath temperature of 165° C for Vi hour. Cool in dry ice-acetone bath and cautiously add ammonium chloride-ice water mix to decompose the excess Grignard reagent. Acidify with dilute HCl and extract with ether. Wash with NaCl, dilute K2C03, NaCl and dry, evaporate in vacuum to get the dimethyl derivative (IV). Reflux (IV) in 25 ml benzene with 100 mg p-toluenesulfonic acid for 1 hour with a Dean-Stark trap and dry, evaporate in vacuum (or wash with NaHC03, NaCl first) to get the THC or analog.
Hydrolysis of benzopyrones (for synthesis see elsewhere here) will produce compounds of type (III) which will work in this synthesis. The hydrolysis proceeds as follows f JCS 926 (1927)]: Add lOg of the benzopyrone to 20g 30% NaOH, cool and shake 1 hour with 19 ml methylsulfate. Extract the oil with ether and dry, evaporate in vacuum to get the ester. Acidify the aqueous solution and filter, wash, dissolve ppt. in sodium carbonate and acidify, filter to get the free acid. Both the acid and the ester will work in this synthesis.
For a possible route to benzopyrones via condensation of isoprene and 3-CN-5-OH-7-alkyl-coumarin see JACS 82,5198 (1960). See JMC ¿6,1200(1973) for another ref. on the pyrone route to THC.
A3 THC Analogs TET 25,77(1967)
11.6 g 5-(l,2-dimethyl)-heptyl resorcinol or equimolar amount of olivetol or other analog, 9.2 g 2-carbethoxy-5-methyl cyclo-hexanone(4-carbethoxy-l-methyl-3-cyclohexanone), 5 gPOCl3, 70 ml dry benzene (protect from moisture with CaCl2 tube). Boil 5 minutes (HCl evolution) and let stand at room temperature 20 hours. Pour into 10% NaHC03, separate the benzene layer and wash with 3X50 ml 10% NaHC03. Dry and evaporate in vacuum the benzene and recrystallize from 50 ml ethyl acetate to get 6.6 g of the pyrone (I). 4.5g(I), 150 ml benzene; a.dd dropwise to a solution prepared from 7.8 g Mg, 18 ml methyl iodide, and 90 ml ether. Reflux 20 hours and add 45 ml saturated NH4Cl. Separate the organic layer and extract the aqueous phase with benzene. Combine the organic layer and benzene and dry, evaporate in vacuum to get the THC analog.
A3 THC Analogs from Resorcinol TET 25,83(1967) 22g resorcinol, 36 g 4-carbethoxy-l-methyl-3-cyclohexanone, 20 g polyphosphoric acid; heat to 105° C and when the exothermic reaction which occurs subsides, heat at 140° C for one-half hour. Pour onto ice-water; filter; wash with water and recrys-tallize-ethanol to get 34 g of the pyrone (I). 6.4 g (I), 8 ml cap-royl-Cl or analog (for preparation see above reference, page 84); heat on oil bath (can use mineral oil) at 120° C until the exothermic reaction subsides (HCl evolution). Cool and pour into ethanol. Filter to get 8 g precipitate (II). 3.2 g (II), 4.4 g dry AlCl3; heat on oil bath at 170° C for one hour. Cool and add
HCl; filter and dissolve precipitate in 7 ml 2N NaOH. Filter and acidify with HCl to precipitate 1.4 g (III) (recrystallize-ethanol). Test this for activity. Use benzoyl-Cl or benzoic anhydride to esterify the OH group (this may not be necessary), methyl MgBr or methyl Mgl to methylate the keto group, and sulfuric acid to dehydrate and hydrogenate as described elsewhere here to get the THC analog. Since the resulting THC analog has the side chain at the 6' position, it may not be active. This paper also gives a synthesis for THC analogs with the side chain in the 4' position, but again their activity in man is unknown. Verbenol, etc., should work in this synthesis, thus obviating the need for the methylation step.
1M olivetol or analog, 1M citral in 10% BF3 cthcrate in benzene about eight hours at 5-10° C. Extract unreacted olivetol with dilute NaOH and evaporate in vacuum the ether to get about 20% yield of the trans THC, and 20% of the cis THC which can be converted to the active trans isomer by reacting with BBr3 in methylene chloride at -20° C for lYi hours. [TL 4947(1969)]. Alternatively, the reaction can be carried out in 1% BF3 etherate in methylene chloride to get 20% A1 THC.
A3 THC Analogs JACS 63,1971(1941) cf. CA 52,170672-3 (1975)
7.6 g 5-n-heptyl resorcinol or equimolar amount analog, 6.6 g (0.037M) 4-carbethoxy-l-methyl-3-cyclohexanone or analog, 5.8 g POCl3 in 60 ml benzene. Reflux 5 hours, cool and pour into NaHC03 to get about 6 g THC analog and 1 g more by concentrating the mother liquor, or proceed as described elsewhere here to recover unreacted resorcinol. 3-carbethoxy-l-methyl-2 or 4-cyclohexanone, 2-carbethoxy-cyclohexanone, etc. will probably also give active THC analogs.
A3 THC Analogs JCS 952(1949)
1.75 g 2-Br-4-methyl-benzoic acid. 1.5 g olivetol or analog, 10 ml IN Na OH and heat to boiling; add 0.5ml CuS04. Filter; wash with ethanol and recrystallize from ethanol to get (I). 10 g (1) in 150 ml benzene; add to methyl-Mgl prepared from 47.5 g methyl iodide, 8 g Mg, 1 20 ml ether. Reflux fifteen hours, cor>l and pour on ice. Add saturated NH4Cl and separate the ether.
Wash two times with water and dry and evaporate in vacuum the ether to get the THC.
PRECURSORS FOR THC SYNTHESIS
p-Menthatriene (1,5,8) BER 59,2493(1956)
90 g d(+) carvone [i (-) carvone or racemic carvone probably will work also] in 150 ml ether; add dropwise with stirring to 7.5 g lithium aluminum hydride in ether. Heat one hour on water bath; cool and carefully add water and then ice cold dilute sulfuric acid. Separate the ether and extract the aqueous layer with ether; dry and evaporate in vacuum the combined ether to get about 60 g product (can distill 65/14).
Method 1: LAC 6 74,93(1964) cf. BSC 3961(1971), JOC 38,
136 g (+) limonene in 2 liters methanol; 2g bengal rose dye. Illuminate with a high voltage Hg lamp (e.g., HgH 5000) for fourteen hours or until about 1M of 02 is taken up. Evaporate the methanol at 0-10° C to about 500 ml and then stir with ice cooling and add this solution dropwise to solution of 250 g Na2S03 in 1.5 liters water and continue stirring for twelve hours. Heat two hours at 70° C and extract with ether and dry, evaporate in vacuum (can distill with addition of Na2 C03 at 40-70/0.2) to get about 100 g mixture containing about 40% product which can be purified by fractional distillation.
Method 2: HCA 45,1665(1965)
Convert (+) A3 carene to (+) trans-4-acetoxycarane (I) via (+) trans-4-OH-carane. Reflux 50 g (I) for 45 minutes (180° C oil bath under N2 or Argon). Cool and can distill (57/10) to get about 25 g mixture of A3 and A4 carene (residue is unchanged starting material) containing about 60% A4 isomer.
Alternatively, to 150 ml ethylene diamine add portionwise with stirring at 110° C under Argon or N2 , 5.3 g Li metal; after one hour add dropwise 110 g (+) A3 carene. After one hour cool to 4° C and add water. Extract with ether, wash the ether five times with water and dry, evaporate in vacuum to get 100 g of a mix containing about 40% (+) A4 carene (can separate by fractional distillation).
A4 carene can also be obtained from A3 carene as follows: [JCS (C) 46(1966)]: Dissolve 1 g A3 carene in 50 ml propionic acid and heat at a suitable temperature (e.g., one-half hour at room temperature may do) in presence of Vi g Palladium-Carbon catalyst (5%) in ethanol and filter, evaporate in vacuum (can distill 63.5/19.5). See J. Soc. Cosmet. Chem. 22,249(1971) for a review of (+) A3 carene chemistry.
A2 Carene oxide (2-epoxy carene) LAC 687,22(1965), [cf. TL 2335(1966), and CA 68:22063(1968)]
To 136 g A4 carene in 330 ml methylene chloride and 120 g anhydrous sodium acetate, add dropwise with vigorous stirring in an ice bath, 167 g of 50% peracetic acid and continue stirring for ten hours. Heat to boiling for two hours, cool, wash with water, sodium carbonate, water, and dry, evaporate in vacuum the methylene chloride to get about 100 g p-menthadieneol. Apparently [CA ¿£,22063(1968)] substituting sodium carbonate for sodium acetate results in the production of A2 carene oxide (2-epoxycarene) in about 50% yield (can distill 63/7).
4-Carbethoxy-l-methyl-cyclohexanone LAC 630,78(1960) Cool 20 g of sodium metal in 325 ml ethanol to -15° C in an ice-salt bath and add in small amounts over one hour a solution of 100 g 3-methyl-cyclohexanone and 150 g diethyloxalate (keep temperature below -10° C). Keep three hours in cold and then twelve hours at room temperature. Add solution of 1.3 L of water, 60 ml 2N sulfuric acid. Separate the yellow-brown oil and extract the water with ether or CHCl3 until the yellow is removed. Combine the oil and the extract and distill the solvent and the unchanged starting material (100° C bath, 13 mm). Slowly heat the residue in a one-half liter flask with air cooling. C02 evolution starts at 160° C. Continue heating to 220° C and keep at this temperature for IV2 hours or until a test with 1% ethanol-FeCl3 solution shows the end of the reaction by a violet color (unconverted material gives a brown color). Can distill two times on Vigreux column to give about 83 g of oily colorless product.
(-) Verbenol JCS 2232(1961)
Racemic alpha-pinene will yield racemic verbenol which will give one-half the yield of (-) verbenol.
27 g (-) alpha-pinene in 500 ml dry benzene; heat and keep temperature at 60-65° C throughout. Add with stirring over 20 minutes 84 g dry (dry over PjOj) lead tetra-acctate. Stir one-half hour; cool and filter and add filtrate to water. Filter and evaporate in vacuum the benzene layer (can distill 96-7/9) to get 21.2 g cis-2-acetoxy-pin-3-ene(I)). 5 g (I) in 25 ml glacial acetic acid; keep at 20° C for one-half hour and add water and extract with ether. Wash the extract with aqueous Na2C03 and evaporate in vacuum the ether (can distill 97-8/9) to get 4.3 g trans verbenyl acetate (II). Hydrolyze (II) with NaOH to give the (-) cis and trans verbenol. For other methods of producing verbenol see CA 57,361(1943), CA 57,16772(1962) and BSC 2184(1964), JCS (B) 1259(1967). The last paper also gives a method for converting (-) beta-pinene to (-) alpha-pinene. See also CA 65,2312(66).
5-Alkyl Resorcinols from Acyl Resorcinols CA 72,66922(1970) Compounds I-III may be able to give active THC analogs if used in place of olivetol for synthesis.
45 g l-(3,5-dimethoxyphenyl)-1 -hexanone(I) or analog (for preparation see the following methods) in 400 ml ether and 0.3 M methyl-Mgl in 150 ml ether react to give 49 g 2-(3,5-di-methoxyphenyl)-2-heptanol(II). Heat 49g (II) with 1 ml 20% sulfuric acid to 105-125° C/30 mm for \Vi hours to get 34 g of the 2-heptene compound (III). 33g (III) in 100 ml ethanol, 6g Raney-Ni, 1500 PSI hydrogen, 150° C to get 26 g of the 2-hep-tane (IV). 26 g (IV), 118 ml 57% hydrogen iodide; add 156 ml acetic anhydride and heat at 155° C for two hours to get 22 g of the resorcinol.
5-Alkyl Resorcinols BER 69,1644(1936)
25 g ethyl-3,4,5-trimethoxybenzoyl acetate and 2.1 g Na in 100 ml ethanol; warm to react. Add 2 g n-propyl iodide (or n-amyl iodide, etc.) and heat twelve hours on steam bath; neutralize and distill off the ethanol. Extract with ether and dry, evaporate in vacuum to get about 32 g of the alkyl acetate (I). Heat 22 g (I) in 5% KOH in ethanol for one hour at 50° C to get 14 g 3,4,5-trimethoxyvalerophenone (II), which crystallizes on standing. 11 g (II), 600 ml ethanol, 60 g Na; warm and after Na is dissolved, add 2 L water. Acidify with HCl, distill off the ethanol and extract with ether. Dry, evaporate in vacuum the ether to get 7.8 g olivetol dimethyl ether (or analog) (III). 7.2 g (III), 70 ml hydrogen iodide; boil two hours and distill (164/760) to get olivetol.
Olivetol HCA 52,1132(1969)
Reduce 3,5-dimethoxybenzoic acid with lithium aluminum hydride to 3,5-dimethoxybenzyl alcohol (I). To 10.5 g(I) in 100 ml methylene chloride at 0° C add 15 g PBr3; warm to room temperature and stir for one hour. Acid a little ice water and then more methylene chloride. Separate and then dry, evaporate in vacuum the methylene chloride. Add petroleum ether to precipitate about 11.5 g of the benzyl bromide (II). To 9.25 g (II), 15 g Cul, 800 ml ether at 0° C, add butyl (or other alkyl)-Li (16% in hexane), and stir for four hours at 0° C. Add saturated NH4Cl and extract with ether. Dry and evaporate in vacuum the ether (can distill 100/0.001) to get about 4.5 g olivetol dimethyl ether (III) or analog. Distill water from a mixture of 90 ml pyridine, 100 ml concentrated HCl until temperature is 210° C. Cool to 140° C and add 4.4 g (III); reflux two hours under N2. Cool and pour into water. Extract with ether and wash with NaHC03. Make pH 7 and dry, evaporate in vacuum to get 3.8 g olivetol which can be chromatographed on 200 g silica gel (elute with CHCl3) or distill (130/0.001) to purify.
5-Alkyl Resorcinols TET 23,77(1967)
Since the method as given originally leads to 4-alkyl resorcinols which do not produce an active THC, it is here modified to give the 5-alkyl isomers. The method is illustrated for 1.2-dimethyl-heptyl resorcinol which gives a much more active THC than olivetol.
Convert 3,5-dihydroxyacetophenone (5-acetyl resorcinol) to 3,5-dimethoxyacetophenone(I) in the usual way with di-methylsulfate.
To 24 g Mg, 1 crystal I2, 100 ml ether, add dropwise under N2,180 g 2-Br-heptane in 100 ml ether over one hour and then reflux two hours. Add over 1 Vi hours a solution of 90g (I) in 200 ml tetrahydrofuran and reflux 10 hours. Cool and add 180 ml saturated NH4Cl; decant the solvents and extract the residue with tetrahydrofuran. Combine the solvents and the tetrahydrofuran and dry, evaporate in vacuum. Add a few drops 20% sul-
furic acid to the residual oil and evaporate in vacuum the water (oil bath temperature 120-130° C/10 mm). Distill the oil at oil bath temperature 285° C/0.2. Fraction boiling 128-140/0.2 yields about 60 g 2-(3,5-dimethoxyphenyl)-3-methyl-2-octene
(II). If saponified and used to synthesize a THC, this might give an active product, thus disposing of the necessity of the next step. Hydrogenate 50 g (II) in 100 ml ethanol, 2-3 atmospheres H2, 0.6 g 10% Palladium-Carbon catalyst for two hours, or until no more H2 uptake (or use the NaBH4-Ni method described at the start). Filter and dry, evaporate in vacuum, and distill the residual oil (110-17/0.1) to get 42 g of the octane (III). 40 g
(III), 100 ml 48% HBr, 320 ml glacial acetic acid and reflux four hours. Pour on ice and take pH to 4.5 with 10 N NaOH and extract with ether. Extract the ether with 3X150 ml 2N NaOH; acidify the combined NaOH extracts with glacial acetic acid and extract with ether. Dry and evaporate in vacuum, and distill the oil (159/0.1) to get 20 g 5-1, 2-dimethylheptyl resor-cinol.
S-Alkyl Resorcinols JACS 61,232(1939)
Convert benzoic acid to 3,5-dihydroxybenzoic acid (alpha-resor-cylic acid) (I). 50 g (I), 134 g dimethylsulfate, 60 g NaOH, 300 ml water; add 35 g NaOH and reflux to obtain about 50 g 3,5-dimethoxybenzoic acid (II) which is converted to dimeth-oxybenzoyl chloride (III) with PCl5. Extract the (III) with ether and filter. Saturate the ether with NH3 at 0° C and filter. Wash with ether and water and recrystallize from hot water to get 3,5-dimethoxybenzamide (IV). To a solution of 1 M of n-hexyl bromide (or 1,2-dimethylheptyl bromide, etc.) add 24.3 g Mg in 200 ml ether to prepare the Grignard reagent. Then rapidly add 46 g (IV); add 300 ml ether and reflux and stir two days, excluding moisture and air. Add a mixture of ice and water and 80 ml concentratcd sulfuric acid. Separate and dry, evaporate in vacuum the ether layer to get about 50 g of the dimethoxyyalkyl benzyl ketone (V). Recrystallizc from dilute ethanol. Add 0.2 M (V), 20.8 g 100% hydrazine hydrate, 75 ml ethanol; reflux six hours. Evaporate in vacuum and heat the residual oil with 82 g powdered KOH in oil bath about 225° C until N2 evolution ceases. Can distill or recrystallize from 95% ethanol to get the dimethoxyalkyl benzene (VI). 0.025 M (VI),
40 ml glacial acetic acid, 15 ml 48% HBr; reflux four hours and pour into ice water; decolorize with a little Na bisulfite, neutralize with NaHC03 and extract with ether. Wash the extract with 10% NaOH and separate and acidify the basic solution. Extract with ether and dry, evaporate in vacuum the extract to get the 5-alkyl resorcinol. Distill or recrystallize from water to purify. Dry, evaporate in vacuum the first ether extract to recover starting material.
Olivetol LAC 630,77(1960), JCS 311(1945), cf. JACS «9,6734 (1967)
Dissolve 100 g malonic acid in 360 g dry pyridine and heat 48-52° C for forty hours with 100 g n-hcxaldehyde (n-capronaldc-hyde) or homolog. Cool in ice bath and with good stirring add dropwise 150 ml ice cold concentrated sulfuric acid (keep temperature below 5° C). After addition add water to dissolve the precipitate and extract with ether two times. Dry, evaporate in vacuum the ether and distill (70/0.7 or 102/5) to get about 98 g 2-octenoic acid (I). 95 g (I) in 300 ml ether; cool to -5° C and slowly add a solution of an excess of diazomethane in ether dried over KOH and let react for about one hour. Let stand twelve hours, evaporate in vacuum and distill (91/17) to get about 94 g clear methyl-2-octenoate (11).
To 16.3 g Na in 210 ml ethanol add 93 g ethyl-acetoacetate (ethyl-3-oxo-butanoate), heat to boil and add dropwise 92 g (II) over 20 minutes. Stir and reflux five hours and cool to precipitate. Filter, wash with ethanol and dissolve precipitate in 800 ml water. Cool to 0° C and slowly add 80 ml ice cold concentrated HCl to precipitate. Filter, wash with water and ligroin to get about 108 g 6-carbethoxy-4,5-dihydro-olivctol (III) (recrystallize from petroleum ether). To 104 g (III) in 260 ml glacial acetic acid at room temperature with good stirring, add drop-wise over one hour 69 ml Bromine. Heat four to five hours at 60° C, cool and add 300 ml water and let stand twelve hours. Oil separates which will precipitate on agitation and rubbing. Filter, wash with water until colorless (recrystallize from ligroin, recrystallize from glacial acetic acid and precipitate with water) to get about 86 g 6-carbethoxy-2,4-dibromo-olivetol (IV). 0.035 g Palladium-Carbon catalyst in 25 ml hydrogenation bottle. Saturate with H2 (pressure - 2.8 Kg/cm2) and add 0.33g
(IV) in 5 ml glacial acetic acid, which takes up 39.5 cm3 H2 at atmospheric pressure over IV2 hours at 60-70° C. Filter and acidify at 0° C with ice cold 6N HCl. Extract with ether and dry, evaporate in vacuum. Recrystallize the oil from ligroin and then from glacial acetic acid by adding water to get about 0.2 g 6-carbethoxyolivetol (V). (IV) can also be hydrogenated at room temperature and atmospheric pressure over Vzg Palladium-Car-bon catalyst by dissolving 70 g in 500 ml IN NaOH. Heat 35 g
(V) with 45 g NaOH in 1 70 ml water for two hours or until no more C02 is evolved. Cool, acidify with 6N HCl and boil 3 minutes. Extract the oil with ether and dry, evaporate in vacuum the ether (can distill on Vigreux column 123/0.01, oil bath 160° C) and let oil stand in refrigerator until crystalline to get about 21 g olivetol. See CA 70,77495t(1969) for another variant of this procedure.
1 ',1'-Dimethylolivetol HCA 52,1127(1969)
Prepare 3,5-dimethoxy benzyl alcohol by reducing the acid with lithium aluminum hydride as described elsewhere here, by hy-drogenating the aldehyde (2-3 atmospheres H2 , room temperature, Pt02 in ethanol—or by the NaBH4 method), in five steps as described in JACS 70,666(1948), or prepare (II) directly by the diborane procedure.
Add with stirring 22.5 g SOCl2 in 100 ml ether in 20 ml portions to a solution of 15 g 3,5-dimethoxybenzyl alcohol, 1 ml pyridine and 200 ml ether. Let stand and wash with 2X100 ml cold water; separate and dry, evaporate in vacuum the ether to get 16 g 3,5-dimethoxybenzyl chloride (I). Recrystallize from petroleum ether. 16 g (I), 300 ml ethanol, 30 g NaCN, 75 ml water; reflux three hours and pour onto 400 g ice. After ice melts, filter and recrystallize precipitate from petroleum ether to get about 14 g 3,5-dimethoxybenzyl CN (II). 5g 50% NaH in mineral oil; wash three times with pentane or hexane; fill flask with N2 or argon and add dimethoxyethane or dimethylforma-mide (freshly distilled from K if possible). Stir and add 9 ml methyl iodide. Carefully add 8 g (II) and stir twelve hours. Add ice water and neutralize with NaHC03 to pH 7-8. Extract with ether and dry, evaporate in vacuum the ether (can distill 1 70/ 0.1) to get about 9 g alpha, alpha-dimethyl-3,5-dimethoxyphen-ylacetonitrile (III). Add 1.5 g (III) to a solution of 0.45 g Mg,
2.5 g n-propyl Br (freshly distilled if possible) in 30 ml ether. Reflux sixty-five hours. Add 2N sulfuric acid and heat two hours on water bath. Cool and extract with ether and dry, evaporate in vacuum (can distill 135/0.001) to get about 1.75 g 2-methyl-2-(3,5-dimethoxyphenyl) hexanone-3 (IV). Dissolve 4 g (IV) in 50 g ethane dithiol and saturate at 0° C with HCl gas (take care to exclude water). Stir the solution in a sealed container forty-eight hours at room temperature and then basify with NaHC03. Extract with ether and dry, evaporate in vacuum (or dry and evaporate in vacuum two hours at 70/12 and distill at 130/0.001) to get about 5 g of the thioketal (V). Reflux 5.3 g (V), 100 g Raney-Ni, 2 L ethanol (or use NaBH4 procedure) for thirty hours. Cool and filter (Celite), evaporate in vacuum and distill residue (115/0.001) to get 3.7 g of the hexane which is saponified as described for the dimethyl ether of olivetol above to give about 2.5 g of the title compound (can distill 150/0.001).
Olivetol ACS 24,716(1970)
Prepare 3,5-dimcthoxybenzoic acid as described elsewhere here, and to a solution of 18.2 g in 250 ml dry tetrahydrofuran under N2, add 1 g 85% LiH, stir for fourteen hours and then reflux for one-half hour. Add a solution of about 1.3 M butyllithium in ether [Org. Rxns. 6,352(1957)] with stirring and ice cooling until the reaction mixture gives a positive Gilman test f JACS 47, 2002(1925)]. Then add 500 ml ice water, extract with ether and dry, evaporate in vacuum the organic phase to get a yellow oil which is dissolved in an equal amount of absolute ethanol; left in refrigerator twelve hours to precipitate. Filter and evaporate in vacuum the ethanol to one-half volume to give more precipitate for a total of 18 g l-(3,5-dimethoxyphenyl)-l penta-none (I). 5.64 g(I) in 200 ml methanol; 0.66 g 20% Pd(OH)2 on carbon [TL 1663(1967)] and hydrogenate at room temperature and atmospheric pressure over two to three hours (or use other reducing method as described here). Filter and evaporate in vacuum to get olivetol dimethyl ether (II). 4.88 g (II), 40 ml HI (density 1.7, decolorized with red phosphorous) and stir three hours at 115-125° C under N2. Dry, evaporate in vacuum or pour into 100 ml ice water and extract with methylene chloride; wash methylene chloride with water and dry, evaporate in vacuum (can distill 160-170/3-4) to get 3.5 g olivetol.
5-Alkyl Resorcinols JOC 35,687(1968), JACS 71,1624,1628 (1949)
Illustrated for 1,2-dimethylheptyl compound.
110 g powdered 3,5-dimethoxybcnzamide (preparation given elsewhere here), five times excess of methylMgl and reflux sixteen hours. Add 1.2 L concentrated HCl and 1200 g ice and let stand sixteen hours with occasional shaking. Extract with ether, dry, evaporate in vacuum and distill (115-128/0.3). Let stand in refrigerator to precipitate. Wash precipitate with petroleum ether and recrystallize from petroleum ether to get about 60 g 3,5-dimethoxyacetophenone (I). 83 g (I) in 50 ml methanol. Add dropwise with stirring to solution of 18 g NaBH4 in 300 ml methanol and 1 g NaOH. Reflux 30 minutes and concentrate by distilling. Add about 100 ml water during distillation. Evaporate the methanol, cool and extract with ether. Dry, filter, concentrate, and distill (124/0.65) to get about 80 g 3,5-dimethoxy-phenyl ethanol (II). 18 ml PBr3 in 70 ml ether; add dropwise with stirring over one hour to 28.5 g (II) in 70 ml ether cooled in an ice bath. Warm to room temperature; reflux two hours on steam bath; cool and pour into 200 g ice. Shake and extract with ether 3 times; wash ether with 10% NaHC03 and water and dry, filter. Concentrate on steam bath and then add with stirring under anhydrous conditions to 42 g diethyl-n-amylmalonate in 300 ml ethanol in which has been dissolved 4.6 g Na metal. Stir 1 Vi hours at room temperature and then heat to distill off the ether and complete the reaction. When the distillation head temperature reaches 78°C add water and continue distilling until temperature reaches 99° C. Cool, and extract with 3X250 rnl ether and evaporate in vacuum the ether. Dissolve residue in 180 ml ethylene glycol and 35 g NaOH by stirring six hours at 160° C. Cool and add 1500 ml water and wash with ether. Acidify the aqueous phase and extract with 4X200 ml ether. Evaporate in vacuum the ether or evaporate on steam bath and dissolve the residue in 150 ml xylene. Evaporate residual ether and water until head temperature reaches 140° C and reflux six hours. Evaporate in vacuum to get about 30 g oily alpha-amyl-beta-methyl-hydrocinnamic acid (III). 14.5 g (III), 5 g lithium aluminum hydride, 250 ml ether; reflux 6 hours. Cool and carefully add methanol, water and dilute HCl. Separate the aqueous layer, saturate with NaCl and extract with ether. Wash ether with NaHCOa (acidify NaHC03 extract to precipitate starting material) and dry, evaporate in vacuum the ether to get about 12 g 2-amyl-3(3,5-dimethoxyphenyl)-butanol (IV). 11.7 g (IV) and 8.5 g p-tolucncsulfonyl Cl each dissolved in 20 ml pyridine. Cool in ice bath and combine. Place in freezer about sixteen hours, pour over ice and extract with ether. Wash ether with cool, dilute HCl until HCl extract is acidic. The combined HCl extracts are then acidified and extracted with ether. Wash the ether with NaHC03, dry and then add dropwise with stirring to 3 g lithium aluminum hydride in 75 ml ether. Reflux 4Yi hours and work up as for (IV). (Can chromatograph the undistilled product on activated alumina and elute with 600 ml petroleum ether, then 200 ml methanol; concentrate and distill (94/0.001) the petroleum ether to get product; concentrate the methanol to give starting material). Yield is about 8 g 2-(3,5-dimethoxy-phenyl)-3-methyl-octane (V). Convert (V) to the title compound by refluxing in 48% HBr in glacial acetic acid as described elsewhere here.
An alternative route from (II) to (V) involves adding (II) and diethylmethylmalonate to prepare dimethyl-3,5-dimethoxyhy-drocinnamic acid as described for the preparation of (III). Then dehydrate and hydrolyze to dimethyl-3,5-dimethoxycinnamic acid which is hydrogenated to the alcohol and converted in several steps to (V).
5-/4Ikylresorcinols Aust. J. Chem. 21,2979(1968) Reflux 6.9 g triphenylphosphine and 6.6g 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 llg lauryl triphenylphosphonium bromide(I). To a stirred suspension of 5.6g(0.011M)(I) in 50 ml ether add 0.01M butyllithium solution [sec Organic Reactions 8,258 (1954) for preparation] .Stir Yi hour at room temperature and slowly add 1.66g 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 recrystallized from pentane and demethylated as described elsewhere here.
5-AlkyIresorcinoIs Aust. J. Chem. 21,2979(1968) Add 2.17g 3,5-dimethoxybenzoyl chloride [see BER 4/, 1329 (1908) or elsewhere here for preparation] in 2.5 ml ether over 10 minutes to a stirred solution of 0.42g diazomethane and 1.01 g triethylamine in ether at -5° C. Keep 10 hours at 0° C, filter, wash precipitate with 20 ml ether and evaporate in vacuum the combined filtrates to get 1.9g diazo-3,5-dimethoxyace-tophenone(I). Recrystallize from benzene-cyclohexane. To 1.5g(I) in 15 ml ethanol add 1.23g pyridinium perchlorate in 2 ml pyridine. Reflux 2 hours, cool and add 5 ml water. Filter to get 1.5g 3,5-dimethoxyphenylacyl pyridinium perchlorate (II). Recrystallize from ethanol. To a stirred suspension of 0.13 g Na hydride in 10 ml dry, acid free dimethylacetamide at 10° C under nitrogen, add 1.79g (II) in 10 ml dimethylacetamide and shake for 15 minutes. Add 0.0075M propyl iodide or homolog and keep 12 hours at room temperature. Heat 2 hours at 90° C and cool to room temperature. Add 3g zinc dust and 5 ml glacial acetic acid; stir at room temperature four hours and filter. Add 20 ml water to filtrate and extract with 50 ml ether. Wash the ether layer with 2X50 ml 10% K2C03 , 50 ml water and 20 ml saturated NaCl. Dry and evaporate in vacuum to get oily 3, 5-dimethoxyphenylbutyl ketone (can chromatograph on 50g alumina and elute with 3:1 petroleum ether:ether). Recrystallize from methanol. Hydrogenolysis [see Aust. J. Chem. 18, 2015(1965) or elsewhere here] gives the olivetol dimethyl ether.
5-AIkylresorcinols Aust. J. Chem. 24,2655(1971) The method is illustrated for olivetol preparation, but substituted thiophens can be used to get olivetol homologs.
To a stirred solution of 45g 3,5-dimethoxybenzoyl chloride and 17.4g thiophen in 300 ml benzene at 0° C, add dropwise 10.5g freshly distilled stannic chloride. Stir one hour at room temperature and add 200 ml 3% aqueous HCl. Separate the benzene layer and wash the aqueous layer with benzene. Dry and evaporate in vacuum the combined benzene layers and distill the red residue (250° C bath/4.5) to get 45g 2-(3,5-dimethoxy-
benzoyl) thiophen(I). Recrystallize from petroleum ether. Add a solution of 21g AlCl3 in 160 ml ether to a stirred suspension of 6.1g lithium aluminum hydride in 140 ml ether. After 5 minutes add a solution of 39g (I) in 300 ml ether at a rate giving a gentle reflux. Reflux and stir 1 hour; cool in an ice bath and treat dropwise with 50 ml water, then 50 ml 6N aqueous sulfuric acid. Separate the layers, extract the aqueous layer with 3X 100 ml ether and dry, evaporate in vacuum the combined ether layers. Can distill the residue (230° C bath/5mm) to get 27g oily 2-(3,5-dimethoxybenzyl) thiophen(II). Recrystallize from petroleum ether. Reflux a solution of 5g (II) in 700 ml ethanol with W-7 Raney Nickel prepared from Ni-Al alloy [see Org. Synthesis Coll. Vol. Ill, 176(1955)] for 6 hours. Filter, evaporate in vacuum and can distill (140/0.01) to get about 2.2g oily olivetol dimethyl ether which can be reduced to olivetol 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-AIkylresorcinols German Patent 2,002,815 (30 July 1970)
In a 2 liter, 3 necked flask with a stirrer, dropping funnel, thermometer, reflux head, nitrogen stream and mercury manometer (if available) stir 230 ml dry methanol and 32.4g sodium meth-oxide under nitrogen until dissolved. Add 110g diethylmalonate and stir 10 minutes. Add portionwise 75g 90% pure 3-nonene-2-one (for olivetol-preparation below) keeping the temperature below the boiling point (50-60° C). Stir and reflux 3 hours, then cool to room temperature, neutralize with about 50 ml concentrated HCl and let stand overnight. Evaporate in a vacuum and dissolve the residue in 200 ml IN HCl and 800 ml ethyl-acetate. Separate and wash the ethylacetate with 2X300 ml water and extract with saturated NaHC03 until a small portion gives no turbidity upon acidification (about 5X200 ml). Carefully acidify the combined NaHC03 extracts and then extract with 3X300 ml ether. Dry and evaporate in vacuum the ether (can dry under vacuum several days) to get 6-n-pentyl-2-OH-4-oxo-cyclohex-2-ene-l-methyl-carboxylate (I). 4.8g (I) and 100 ml glacial acetic acid are stirred vigorously at 75° C until dissolved. Cool and keep temperature between 5 and 10° C while adding a solution of 3.9g bromine in 10 ml glacial acetic acid dropwise over 1 hour. Stir 1 hour at room temperature then 3 hours on a steam bath. Evaporate in vacuum and dissolve the residual oil in 200 ml ether. Wash with 2X25 ml 10% sodium dithionite, 2X25 ml saturated NaHCOj and water and dry, evaporate in vacuum to get olivetol (or analog) (can distill at 125-130/0.05).
Alternatively, to 4.8g (I) add 5.6g iodine in 200 ml glacial acetic acid. Stir and reflux 10 hours, evaporate in vacuum, dissolve residue in 250 ml ether and proceed as above to get olivetol.
A third alternative is to stir 12.2g (I) in 100 ml glacial acetic acid at 25° C with vigorous stirring until well suspended. Cool and keep temperature at 5-10° C while adding dropwise 22.4g cupric bromide dissolved in 25 ml glacial acetic acid over 1 hour. Stir 1 hour at room temperature then 3 hours on a steam bath and evaporate in vacuum. Dissolve the residue in 200 ml water and 300 ml ether. Wash the ether layer with 2X50 ml 10% sodium dithionite, 2X35 ml saturated NaHC03 and 75 ml water and dry, evaporate in vacuum to get olivetol (or analog).
For the 1,2-dimethylheptyl homolog proceed as follows. Combine 15g 5,6-dimethylundec-3-ene-2-one with 19g diethyl-malonate as described above to get (1). Brominate 20.2g (I) with 12g bromine over 2 hours as described and stir 1 hour at room temperature. Add 500 ml water and let stand overnight at 5-10° C. Filter, wash precipitate with about 4X75 ml cold water and dry in vacuum at 50° C to get 26g 3-bromo-2-OH-4-oxo-6 (l,2-dimethylheptyl)-cyclohex-2-ene-l-methylcarboxyl-ate (II). In a 3 liter 3 necked flask with a stirrer, thermometer, reflux head and Dean-Stark trap, add 350g (II) and 522g pyridine hydrochloride and heat on oil bath at 90° C 4 hours. Heat with the heating mantle (removing volatiles with the Dean-Stark trap) until the internal temperature reaches 190-200° C and hold at this temperature 2 hours. Cool to room temperature and shake with 3 liters ether and 660 ml 1.2N HCl. Separate and wash the ether layer with 300 ml 1.2N HCl and then 2X300 ml water. Extract the ether solution with 4X350 ml 10% NaOH and then extract the combined NaOH extracts with 2X300 ml ether. Acidify the alkaline solution with about 700 ml concentrated HCl and extract with 3X800 ml ether. Wash the combined ether extracts with 3X300 ml 10% sodium dith-
ionite, 2X300 ml saturated NaHC03 and 300 ml water and dry, evaporate in vacuum the ether to get the 5-(l,2-dimethyl-heptyl) resorcinol.
To prepare the 3-nonene-2-one condense excess acetone with n-hexaldehyde (or 2,3-dimethyloctanal for 5,6-dimethyl-undec-3-ene-2-one) in the presence of NaOH in an inert medium if desired (benzene, toluene, xylene, etc.), at 10-70° C to get (I). Dehydrate (I) with sodium sulfate or cupric sulfate in an inert medium at reflux temperature or simply reflux in benzene, xylene or toluene.
5-AIkylresorcinols JOC 37,2901(1972)
For 5-alkylresorcinols see Chem. and Ind. 685(1973) also.
This is an improved version of a previously given synthesis (LAC 630,71(1960)). The cthanol used is distilled from Ca ethoxide; dimethoxyethane from potassium. Cupric bromide is produced from cupric oxide and 5% excess of HBr, plus sufficient bromine to remove the milkiness on addition of a drop of the mixture to water; concentrate and dry, evaporate in vacuum over KOH flakes.
650g (5.3M) ethyl chloroacetate and 880g (5.3M) triethyl phosphite are mixed and placed in a 3 liter flask fitted with a thermometer and condenser under nitrogen. Heat and stir and slowly bring to 125° C. Discontinue heating as ethyl chloride evolution proceeds over Vi hour. Heat to 160° C over a 75 minute period and keep at 160° C 8 hours. Cool, distill (e.g., through 12" Vigrcux column) (74-7/0.03) to get 96% yield of triethylphosphonoacctate (I). In a 3 liter flask fitted with a stirrer, dropping funnel and condenser, place 45.3g NaH (1M in mineral oil) and 1 liter of dry ether. Flush with nitrogen and keep at positive nitrogen pressure. Stir in ice bath while 224 g (1M) (I) is added dropwise over 75 min. Stir and reflux 1 hour (H2 evolution stops). Cool in ice-salt bath and add 1M of aldehyde (e.g., hexaldehyde for olivetol) over 1 hour. Continue to cool and stir an additional 10 minutes and then slowly bring to reflux and reflux for 10 minutes (ppt. prevents stirring). Decant the ether and dissolve the oil layer in 500 ml warm water and separate the upper organic layer. Extract the aqueous layer with 200 ml ether and extract the combined organic solutions with 200 ml saturated NaHC03. Dry and evaporate in vacuum (can distill) to get the ethyl-j3-alkylacrylates in about 90% yield (II).
In a flask with nitrogen and fittings as in preceding step, add 156 g ethyl acetoacetate to Na ethoxide from 25.3g Na and 500 ml dry ethanol, and stir and reflux Vi hour. Add 1M of (II) dropwise over 90 minutes and reflux 20 hours. Cool in ice, filter, wash ppt with 500 rnl ice cold absolute ethanol and several times with portions of ether and dry, evaporate in vacuum to get the dione Na salt (III) in about 80% yield (for olivetol precursor). In a 250 ml flask place 0.1M (III), 100 ml 1,2-dimeth-oxyethane and flush with nitrogen and stir at room temperature while 45g of cupric bromide is added portionwise over 5 minutes, under a nitrogen stream. Stir Vi hour and then reflux and stir 1 hour. Cool and evaporate (keep temperature below 50° C) but do not remove more than about 65 ml dimethoxyethane. Dilute the remaining solution with 200 ml benzene and filter. Wash the ppt. with 50 ml benzene and evaporate the combined benzene filtrates (keep temperature below 50° C). Dissolve the bromodione in 100 ml dimethylformamide and put in 500 ml flask under nitrogen. Stir and heat slowly until reflux and then Heat to 150° C and reflux 4 hours. Cool, pour into 500 rnl water, extract with 3X100 ml dichloromethane and dry, evaporate in vacuum to get the ethyl-6-alkyl-2,4-dihydroxybenzoate (IV). Add a solution of 24g NaOH in 200 ml water to (IV) and stir and reflux under nitrogen in hood for 3 hours. Cool in icc bath, acidify carefully with a cold solution of 20 ml concentrated sulfuric acid in 80 ml water while stirring under nitrogen in ice bath. Reflux under nitrogen 5 minutes, cool, extract 3 times with ether and dry, evaporate in vacuum the combined extracts to get about 80% yield of olivetol (or analog). The last step may not be necessary since (IV) may yield an active THC.
Dimethylheptylresorcinol CA 65,20062(1966)
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.
Mix 294g (1.6M) 1,3,5-trichlorobenzene, 184g (3.4M) Na methoxide and 450g (3.3M) diglyme and reflux at 162° C for
42 hours. Cool to room temperature, filter and distill the solvent to get 70% yield of l-Cl-3,5-dimethoxybcnzene (I). 43.2g (I) in 540 ml tetrahydrofuran is added dropwise to 7.3g Mg, a small crystal of iodine and a few drops of ethyl bromide (under nitrogen if possible) over Yi hour while the mixture is heated to 75° C. R
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