03-03-03 19:17
No 413367
      tetra- and penta-methoxy-beta-phenethylamines
(Rated as: excellent)

the following is taken from J.Org.Chem. 20, 102-108 (1955):

All of the tetramethoxy-beta-phenethylamines and pentamethoxy-beta-phenethylamine were synthesized from the corresponding polymethoxybenzenes through the routes and intermediates which are shown in Chart I.

Both 1,2,3,5-tetramethoxybenzene (I) and pentamethoxybenzene (IX) were prepared by the elegant methods which have been described by Baker (*). Modifications in Baker's procedure (**) were developed for the preparation of 1,2,3,4-tetramethoxybenzene (V) from gallacetophenone through 2-hydroxy-3,4-dimethoxyacetophenone and 1,2-dihydroxy-3,4-dimethoxybenzene as intermediates. 1,2,4,5-tetramethoxybenzene (XIII) was prepared from p-benzoquinone via 2,5-dimethoxy-1,4-benzoquinone and 2,5-dimethoxyhydroquinone.

Both the 2,3,4,6- and 2,3,4,5-tetramethoxy-beta-phenethylamines (IV and VIII) were prepared according to Route A. The synthesis of 2,3,4,6-tetramethoxybenzaldehyde (II) was carried out by subjecting the corresponding tetramethoxybenzene (I) to a Gatterman reaction crazy. Although 1,2,3,4-tetramethoxybenzene (V) failed to undergo this reaction, it was readily formylated by N-phenyl-N-methylformamide in the presence of POCl3 to the desired aldehyde (VI).

(then the article goes on with the well-known MeNO2 condensation of these aldehydes and LiAlH4 reduction of their corresponding beta-nitrostyrenes )

Route B proved to be advantageous for the synthesis of the pentamethoxy- and 2,3,5,6-tetramethoxy-beta-phenethylamines (XII and XVI). The attempted conversion of pentamethoxybenzene (IX) to the corresponding benzaldehyde by the Gatterman reaction with hydrogen cyanide and hydrogen chloride in the presence of anhydrous zinc chloride failed, and the starting material was recovered unchanged. Also, the addition of a small quantity of aluminium chloride to the ZnCl2 catalyst did not bring about the desired reaction. However, chloromethylation of pentamethoxybenzene proceeded readily in good yield in the absence of any catalyst. Smith and Opie (***) reported similar results for the chloromethylation of several other penta-substituted benzenes.

The chloromethylation of 1,2,4,5-tetramethoxybenzene (XIII) with aqueous formaldehyde and conc. hydrochloric acid resulted chiefly in the formation of tarry products. However, a satisfactory procedure was developed for the preparation of XIV through the reaction of 1,2,4,5-tetramethoxybenzene with chloromethyl ether in glacial acetic acid as solvent.

The chloromethylation of 1,2,3,4-tetramethoxybenzene failed to give a monochloromethylation product. Reaction of V with aq. formaldehyde and conc. hydrochloric acid resulted in bischloromethylation. Action of chloromethyl ether on V resulted in the formation of a halogen-free product, m.p. 163-164C, which was not further investigated.


Route A.

Compounds I-IV,    R = 2,3,4,6-(CH3O)4C6H-
Compounds V-VIII,  R = 2,3,4,5-(CH3O)4C6H-

RH __> RCHO __> RCH=CH-NO2 __> RCH2CH2NH2

I __> II __> III__> IV
V __> VI __> VII __> VIII

Route B.

Compounds IX-XII,    R = (CH3O)5C6-
Compounds XIII-XVI,  R = 2,3,5,6-(CH3O)4C6H-

RH __> RCH2Cl __> RCH2CN __> RCH2CH2NH2

IX __> X __> XI__> XII
XIII __> XIV __> XV __> XVI


All melting points are uncorrected.

2,3,4,6-tetramethoxybenzaldehyde (II). 1,2,3,5-tetramethoxybenzene was obtained in 50% over-all yield from pyrogallol trimethyl ether via 2,6-dimethoxybenzoquinone and 2,6-dimethoxyhydroquinone following the procedure of Baker (*). Purification of the tetramethoxybenzene was best achieved by vacuum distillation, collecting the fraction boiling at 109-110C/0.9mm.

The Gattermann reaction to introduce the aldehyde group was carried out essentially as described by Herzig et al. (****).

(I'll skip this part, there are probably few people who want to work with liquid HCN to achieve their goal.)

1,2,3,4-tetramethoxybenzene (V). The method reported by Baker (**) for partial methylation of gallacetophenone to 3,4-dimethoxy-2-acetophenone was unsuccesful in our hands. After considerable experimentation, the following procedure was developed.

To a well-stirred solution of 84 gr. of gallacetophenone in 500 ml. of dry acetone was added 250 gr. of finely divided anhydrous K2CO3 and 62.5 ml. (exactly 2 equiv.) of redistilled methyl iodide.  The mixture was refluxed for 6 hours with stirring, and then filtered hot from the inorganic salts, which were washed thorougly with some fresh acetone. The acetone solution was concentrated under reduced pressure until solids began to separate. Dilution with water and seeding caused the product to crystallize. The buff-coloured crystals were collected, washed with water, and with cold MeOH, and air-dried; yield, 46.2 grams (47%); m.p. 78-79C; reported 77C.

This material was used without any further purification. Oxidation to 1,2-dihydroxy-3,4-dimethoxybenzene by the  Dakin reaction as described by Baker (*) proceeded in 64% yield; the vicious liquid product boiled at 122-124C/0.7mm.
1,2,3,4-tetramethoxybenzene was obtained in 96% yield by treatment of 1,2-dihydroxy-3,4-dimethoxybenzene with Me2SO4 and aq. NaOH; m.p. 89.9-90C; reported 89C

(This compound is then formylated by the abovementioned Vilsmeyer procedure)

pentamethoxybenzyl chloride (X). Pentamethoxybenzene (IX) was obtained from 1,2,3,5-tetramethoxybenzene in 46% over-all yield via 2-hydroxy-3,4,6-trimethoxyacetophenone and 1,2-dihydroxy-3,4,6-trimethoxybenzene as described by Baker (*).

A rapid stream of hydrogen chloride gas was passed into a well-stirred mixture of 20 gr. of pentamethoxybenzene, 62 ml. of 35% aq. formaldehyde solution and 75 ml. of conc. HCl. The temp. of the mixture rose to 55-58C, remained there for 0.75 hour, and then started to fall. The temp. was maintained at 51-53C with genle heating for an additional 1.25 hours while continuing passage of HCl gas into the mixture. The reaction mixture was poured into 150 ml. ice-water, and the nearly pure product slowly solidified when seeded; yield 23.5 g. (97%); m.p. 46-48C. b.p. 145-147C/2.2mm.

2,5-dimethoxy-1,4-benzoquinone The reaction of methanol with p-benzoquinone in the presence of fused anhydrous ZnCl2, as described by Knoevenagel gave somewhat erratic results. Investigation of the reaction conditions showed that the time of reluxing is critical and must be controlled carefully. The following procedure gave reproducible results in repeated runs.
To a solution of 24 grams of freshly fused and powdered ZnCl2 in 120 ml. absolute MeOH was added 21.6 gr of purified or freshly prepared p-benzoquinone. The mixture was heated under reflux on a steam-bath; during about the first ten minutes the condensate was yellow, indicating the presence of unchanged quinone. After about 15 min. a red-brown solid was deposited.The mixture was refluxed for a total of 30 minutes and then cooled to 0C for at least 2 hours. the crude 2,5-dimethoxy-1,4-benzoquinone was collected, washed with cold MeOH, and air-dried; the yield of the brown crystalline solid product was 10.8 gr. (64%). This material was used in the next step without purification.

2,5-dimethoxyhydroquinone To a mixture of 10.8 gr. of crude 2,5-dimethoxy-1,4-benzoquinone and 20 gr. sodium hydrosulfite was added 100 ml. of boiling water as described by Baker (*) for a similar compound. A nearly colorless solid was formed which was collected and washed after cooling the mixture to 5C; yield, 8.5 gr. (78%). The crude 2,5-dimethoxyhydroquinone melted at 169-171C (reported 166C) and was used directly in the next step

1,2,4,5-tetramethoxybenzene To a stirred mixture of 10 gr. 2,5-dimethoxyhydroquinone, 24 ml. alcohol, 35 ml. Me2SO4 and 1 gr NaHSO3 was added a solution of 14.4 gr. of NaOH in 32 ml. H2O during 30 min. while maintaining the temp. at 15-20C with an ice-bath. The mixture was warmed to 70-80C for 20 min., diluted with 100 ml. of water, and cooled to 5C. The 1,2,4,5-tetramethoxybenzene was obtained as a nearly colorless solid melting at 102-13C; yield, 10 gr. (86%) (reported 102.5C)


(*)     Baker, J.Chem.Soc, 665 (1941)
(**)    Baker, J.Chem.Soc, 1683 (1934)
(***)   Smith and Opie, J.Am.Chem.Soc, 92, 2782 (1950)
(****)  Herzig et al., Monatsh. 24, 886 (1903)


I didn't find much about the pharmacological activity of these compounds, I know that 2,3,4,5-tetramethoxyamphetamine which has been described in PiHKaL (#145 TA) has some activity.

If people are interested I'll go dig up that Baker ref this week and post it.

"There are many things under the sun."
(Chief Bee)
03-03-03 21:21
No 413394
      yes & ref     

Yes! Very interested!

BTW, the correct Ramirez & Burger ref is J. Am. Chem. Soc.; 1950; 72(6); 2781-2782. (../rhodium/chemistry /lah.phenolic.nitrostyrenes.html)
03-03-03 23:50
No 413436
      your wish is my command!     

Will dig them up first thing tomorrow.

Oops, that Smith & Opie ref should have been J. Am. Chem. Soc. 63, 939 (1941)

"There are many things under the sun."
(Chief Bee)
03-04-03 01:42
No 413475
      Almost correct     

Eh... Actually, to be really precise, the proper ref is J. Am. Chem. Soc. 63, 937-940 (1941) crazy
(Hive Addict)
03-04-03 01:48
No 413478

Are we finally decided on the actual Reference numbers? 
(Chief Bee)
03-04-03 01:55
No 413484     

The ones I have posted has been verified through
(Hive Addict)
03-04-03 01:56
No 413486

thank you, i hate marring up my printouts with excessive changes. 
03-05-03 01:02
No 413838
(Rated as: excellent)

This is taken from J. Chem. Soc. p.662-670 (1941):

Pentamethoxybenzene (IV) is best prepared in quantity from the very accessible 1,2,3,5-tetramethoxybenzene (I) via the compounds 2-hydroxy-3,4,6-trimethoxyacetophenone (II) and 1,2-dihydroxy-3,4,6-trimethoxybenzene (III).

In the present work a very simple synthesis of pentahydroxybenzene derivatives has been developed starting from pyrogallol. This was converted by known methods into 1,2,3,5-tetramethoxybenzene (I), and with improvements described in the experiment section the over-all yield of (I) was rather over 50%. Compound (I), when treated with acetyl chloride and anhydrous AlCl3 in dry ethereal solution at room temperature, gave a 70% yield of (II), the highest yield previously claimed in this much investigated reaction being 42% (Wesseley and Kallab, Monatsh., 1932, 60, 26); the increase is due to the use of ether as a solvent, and employment of low temperature. When 2-hydroxy-3,4,6-trimethoxyacetophenone (II) was oxidised by hydrogen peroxide in alkaline solution under the conditions of the Dakin reaction, it yielded 1,2-dihydroxy-3,4,6-trimethoxybenzene (III). Methylation of (III) with Me2SO4 and alkali readily gave pentamethoxybenzene (IV), identical with that described by Aulin and Erdtman (Svensk Kem. Tidskr., 1937, 49, 208). By this route it is possible to prepare just over 50 gr. of pentamethoxybenzene from 126 gr. of pyrogallol.

An alternative route to pentamethoxybenzene started from gallacetophenone, which was converted into its dimethyl ether (V) (improved preparation), and oxidation of this with alkaline potassium persulfate gave 2,5-dihydroxy-3,4-dimethoxyacetophenone (VI) in 36% yield. Partial methylation of (VI) with Me2SO4 and K2CO3 in benzene gave 2-hydroxy-3,4,5-trimethoxyacetophenone (VII), which was then oxidised with H2O2 in alkaline solution to give 1,2-dihydroxy-3,4,5-trimethoxybenzene (VIII). Methylation of (VIII) again gave pentamethoxybenzene (IV).

A considerable less convenient way to prepare (VIII) is from 2,6-dimethoxyquinol diacetate, which is converted first by the action of AlCl3 into 2,5-dihydroxy-4,6-dimethoxyacetophenone (IX) (Mauthner, J. pr. Chem., 1933, 147, 287), and then by monomethylation with Me2SO4 and anhydrous K2CO3 in benzene into the bright yellow 2-hydroxy-4,5,6-trimethoxyacetophenone (X). Oxidation of (X) with H2O2 then gave 1,2-dihydroxy-3,4,5-trimethoxybenzene (VIII), identical with that prepared by the oxidation of the isomer (VII).

Two routes leading to the preparation of pentahydroxyacetophenone derivatives have been investigated. In the first, (II) was oxidised by potassium persulfate in alkaline solution to give 2,5-dihydroxy-3,4,6-trimethoxyacetophenone (XVI), and this readily yielded 2,3,4,5,6-pentamethoxyacetophenone (XVII) on treatment with excess Me2SO4 and alkali.

in the second route pentamethoxybenzene (IV) was treated with acetyl chloride and AlCl3 in ethereal solution and yielded the bright yellow 2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XIX), and important intermediate for the synthesis of flavones and related compounds; it yielded pentamethoxyacetophenone (XVII) on methylation with methyl sulfate and alkali.

The partial methylation of 2,5-dihydroxy-3,4,6-trimethoxyacetophenone (XVI) to give 2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XIX), under conditions which converted (IX) into (X), gave only traces of the desired product.


1,2,3,5-tetramethoxybenzene (I).
Considerable quantities of this substance have been made from pyrogallol via the stages (1) pyrogallol methyl ether, (2) 2,6-dimethoxy-1,4-benzoquinone, and (3) 2,6-dimethoxyquinol, and the yields represent a very considerable improvement over those previously described. The modifications of recorded conditions are described in the following notes, and enable over 100 gr. of the tetramethoxybenzene to be obtained from 126 gr. of pyrogallol.

(1) Pyrogallol trimethyl ether : The methylation of pyrogallol (126 gr) is carried out as described by Chapman, Perkin and Robinson (J.Chem.soc., 1927, 3028) but it is essential that the reaction mixture should be cooled in a trough of water so that the temp. keeps between 18 and 22, and the addition of NaHSO3 (10 gr) as recommended by Kohn and Grn (Monatsh., 1925,  46, 27) ensures a water-white product. After stirring for a total of 6 hours, crushed ice (1 kg) is added, and the product collected, washed and dried. Yield: 155 gr.

(2) 2,6-dimethoxybenzoquinone (see Graebe and Hess, Annalen, 1905, 340, 237) : The above pyrogallol trimethyl ether (155 gr), alcohol (775 cc), and nitric acid (775 cc; d 1.2) are warmed to 35 crazy and allowed to stand until the vigorous reaction sets in, and the temp. then kept just below 50 till the main heat evolution ceases (15 min). After 4 hours with occasional shaking the quinone is collected, drained, washed with alcohol (400 cc), then water (800 cc) and dried on the water bath. Yield : 124 gr.

(3) 2,6-dimethoxyquinol : To the above quinone (124 gr) and NaHSO3 was quickly added boiling water (1250 cc), and the mixture vigorously shaken till a clear solution was obtained (less than 1 min.) and then cooled rapidly under the tap with shaking. After 30 min. the product was collected, drained, washed with ice-water (600 cc) and dried on the steam-bath (local darkening). Yield : 110 gr. If the filtrate and the washings from the quinol are saturated with NaCl and extracted with EtOAc at 40-50, a further 8 gr of the quinol are obtained, but the labour involved is hardly justified.

(4) 1,2,3,5-tetramethoxybenzene : To a continually stirred mixture of 2,6-dimethoxyquinol (55 gr), alcohol (130 cc), Me2SO4 (250 gr) and NaHSO3 (4 gr) in an atmosphere of coal gas was added dropwise during 4 hours a solution of NaOH (80 gr) in water (180 cc), the temp. being kept at 15-20C. The mixture was then heated on the water bath for 30 min. with frequent shaking, diluted with water (500 cc), cooled and seeded, and the solid product collected, thoroughly washed, and dried. Yield : 54 gr, mp. 35-40 (mp. of pure material : 47)

2-hydroxy-3,4,6-trimethoxyacetophenone (II).
Anhydrous AlCl3 (50 gr) was dissolved in absolute ether (250 cc) with cooling, and then 1,2,3,5-tetramethoxybenzene (50 gr as obtained from the above reaction) added. To the mixture ,which was vigorously stirred and cooled in a vessel of water, acetyl chloride (25 gr) was added during 1 hour, and stirring continued for a further 6 hours. During this time the yellow, solid Al-complex of (II) began to separate. After standing overnight, water (350 cc) and conc. HCl (50 cc) were cautiously added and the mixture was heated on the water bath for 30 min., the ether being allowed to distill away, and, while hot, extracted with benzene (200 cc). The benzen layer was washed with dil. HCl and shaken with an excess of 10% aq. NaOH, and the aqueous layer acidified. The rather dark, solid product was collected, washed (dry weight 46.5 gr; mp. 101-104) and crystallised from dilute alcohol (charcoal), giving a light fawn, crystalline powder (42.5 gr; 70% yield) mp. 103-105

1,2-dihydroxy-3,4,6-trimethoxybenzene (III).
2-hydroxy-3,4,6-trimethoxyacetophenone (22.6 gr) was dissolved in a solution of NaOH (8 gr) in water (160 cc) with heating, and cooled to 20, and a 3% solution of H2O2 (142 cc; 1.25 mol) at 20 added. The temp rose gradually at first, then rapidly to 54, and then fell. After 2 hours the solution was acidified with H2SO4, and unchanged material collected by filtration, washed and dried (2.2 gr). The filtrate was saturated with NaCl and extracted 3x with ether (100 cc each time) and the extracts shaken with an excess of NaHCO3 suspension and water to remove AcOH, dried over Na2SO4 and distilled, leaving 1,2-dihydroxy-3,4,6-trimethoxybenzene as an oil which completely solidified on scratching (yield : 12.3 gr)
Recrystallize from benzene/light petroleum, mp. 82

Pentamethoxybenzene (IV).
The preceding compound (III) (10 gr; not crystallised), alcohol (10 cc) and NaHSO3 (1 gr) were vigorously shaken during the alternate portionwise addition of methyl sulphate (25 gr) and a solution of NaOH (50 cc containing 10gr). The temp was allowed to rise to about 50, and the reaction was completed by heating on the water-bath for 30 min. The alkaline solution was extracted 3x with benzene, and the extracts dried and distilled, leaving a viscious brown oil (10.2 gr) which solidified on cooling (mp. ca 45-53). The compound separated from light petroleum (bp. 40-60) in which it was easily soluble, in colourless, nacreous, rhombic plates, mp. 58-59. It is most easily purified by vacuum distillation; bp. 150/14mm.; 167/21mm.

"There are many things under the sun."
03-05-03 02:10
No 413881
      pentamethoxybenzene : alternative route
(Rated as: excellent)

2-hydroxy-3,4-dimethoxyacetophenone (V)
The following method, based on that described by Baker et al. (J. Chem. Soc., 1934, 1682), gives an increased yield and enables the compound to be prepared easily and in quantity.
Crude gallacetophenone (62.7 gr.; 1 mol; prepared according to Badhwar and Venkataraman, Organic Syntheses, 1934, 14, 40, but not recrystallised), benzene (800 cc), anhydrous K2CO3 (220 gr), and Me2SO4 (104 gr.; 2.05 mols) were refluxed for 8 hours with occasional shaking. Hot water (1L) was now added, the mixture acidified with conc. HCl (250 cc) (much CO2!), and whilst still hot the benzen layer was separated, washed 4x with 10 cc of water, shaken with charcoal (10 gr) and filtered with the aid of a pump, the residue being washed with a little benzene. The benzen solution was now shaken once with 300 cc and 4x with 50 cc of 10% aq. NaOH, the united alkaline solutions acidified with HCl and cooled, and the precipitated 2-hydroxy-3,4-dimethoxyacetophenone collected, washed, and dried at gentle heat. The pale brown product (51 gr), mp. 71-73, is readily purified, if desired, by crystallisation from light petroleum (bp. 80-100) and then forms yellow prisms, mp. 77.

Some 2,3,4-trimethoxyacetophenone is also produced in this reaction and may be isolated by heating the alkali-washed benzene solution with aq. alkali to remove methyl sulphate shocked, drying and distilling; the trimethyl ether is isolated as a colourless oil, bp. 178/20mm. (yield, 10 gr.)

2,5-dihydroxy-3,4-dimethoxyacetophenone (VI).
This reaction was studied in considerable detail, and the following method gives the maximum yield. The use of the equivalent of KOH diminishes the yield by 20%, and the addition of a little ferrous sulphate as recommonded by Barghellini (Gazetta, 1916, 46, i, 249) reduces the yield by 5%.
2-hydroxy-3,4-dimethoxyacetophenone (20 gr.; prepared as described above but not recrystallised) was dissolved in a solution of NaOH (30 gr) in water (200 cc) and, with continual stirring, oxidised by the addition during 4 hours of a solution of potassium persulphate (40 gr) in water (800 cc), the reaction vessel being cooled in a trough of water. After standing for 48 hours, the mixture was made distinctly acid to Congo-Red paper with conc. HCl, anhydrous Na2SO3 (5 gr) and powdered charcoal (10 gr) stirred in, and the liquid filtered and extracted with benzene (100 cc) (this benzene extract was heated with the charcoal, filtered, and distilled, leaving a residue of crude 2-hydroxy-3,4-dimethoxyacetophenone, which, after crystallisation from light petroleum weighed 3.2 gr). To the solution were now added conc. HCl (200 cc) and benzene (400 cc), the mixture gently refluxed on the water bath for 6 hours, partially cooled, and shaken, and the benzene layer separated. The aqueous solution was now extracted twice with benzene (100 cc each), the benzene extracts united, dried over Na2SO4 and distilled under slightly diminished pressure, leaving (VI) as a pale brown, crystalline mass, mp. 105-110C (yield 6.6 gr). It separated from water (charcoal) in small, pale yellow prisms, mp. 119

2-hydroxy-3,4,5-trimethoxyacetophenone (VII).
A mixture of 2,5-dihydroxy-3,4-dimethoxyacetophenone (VI) (21.2 gr.; 1 mol), anhydrous benzene (200 cc), freshly ignited K2CO3, and anhydrous acid-free Me2SO4 (12.6 gr.; 1 mol) was refluxed with occasional shaking for 14 hours. Water (200 cc) was now added, the mixture shaken, the benzen layer separated and the aqueous layer extracted twice with benzene (100 cc each). The united extracts were dried over Na2SO4 and distilled, leaving an oil which solidified on scratching, and which was extracted 3x with boiling light petroleum (bp. 60-80; 200 + 50 + 50 cc). On cooling, the extracts deposited 2-hydroxy-3,4,5-trimethoxyacetophenone as pale yellow, large, flat, rhombic, crystalline aggregates (total yield, 16.5 gr). mp. 86 after 2x crystallisation from light petroleum.

1,2-dihydroxy-3,4,5-trimethoxybenzene (VIII).
2-hydroxy-3,4,5-trimethoxyacetophenone (11.3 gr) was oxidised in the same manner as (II), but in an atmosphere of coal gas, the temp. rising to 53. Recovered starting material (0.2 gr) and the crude catechol derivative (7.8 gr) were obtained, the latter as a light brown oil which solidified on scratching. After 2x crystallising from benzene contained a little light petroleum, the 1,2-dihydroxy-3,4,5-trimethoxybenzene was obtained in colourless, thin, elongated, hexagonal plates, mp. 90-91 The mp. of a mixture with the isomeride (III) was 50-60 The compound was easily oxidised and turned pinkish on exposure to the air.
Treatment of the alkaline solution with methyl sulphate in the usual way (see methylation of the isomeride III) gave pentamethoxybenzene, mp. and mixed mp. 58-59

"There are many things under the sun."
03-05-03 02:46
No 413913

2,5-dihydroxy-3,4,6-trimethoxyacetophenone (XVI).
To a stirred mixture of 2-hydroxy-3,4,6-trimethoxyacetophenone (II) (11.2 gr) and a solution of NaOH (20 gr) in water (120 cc) was added during 4 hours a solution of potassium persulphate (17.6 gr) in water (360 cc); stirring was continued for a further 2 hours. After standing overnight, the solution was acidified to Congo-Red, filtered from a crystalline deposit, extracted with benzene (100 cc) (the benzene extract and solid yielded 1.3 gr of crude starting material), and refluxed for 4 hours after the addition of benzene (200 cc) and conc. HCl (100 cc). The benzene layer was separated, dried over Na2SO4, and distilled, leaving a yellow, crystalline mass (3.5 gr). (XVI) separated from water in fine, yellow needles, mp. 116-117

2,3,4,5,6-pentamethoxyacetophenone (XVII).
2,5-dihydroxy-3,4,6-trimethoxyacetophenone (5.5 gr) was shaken in dilute acetone with a large excess of Me2SO4 and aq. KOH, added alternately, and the alkaline mixture was finally heated on the water-bath for 30 min. Light petroleum (bp. 40-60) then extracted a colourless oil which became crystalline on cooling, and the product was distilled under diminished pressure (bp. 163/13mm) (yield : 4.8 gr) and then crystallised 2x from light petroleum (bp. 35-50) at 0, giving fine needles, mp. 43. It was extremely easily soluble in all organic solvents.


2-hydroxy-3,4,5,6-tetramethoxyacetophenone (XIX).
To a solution of AlCl3 (5 gr) in anhydrous ether (25 cc) were added pentamethoxybenzene (5 gr) and then acetyl chloride (5gr) in portions during 30 min. The mixture was kept at RT with occasional shaking for 16 hours. Water (35 cc) and conc. HCl (5 cc.) were then cautiously added, the mixture heated on the water-bath for 30 min, the ether being allowed to distill away, and the residual liquid extracted with benzene (20 cc). The benzene was washed with dil. HCl and shaken with excess of 10% NaOH-solution, the alkaline layer acidified and extracted with benzene, and the benzene layer finally dried and distilled, leaving a residue (1.7 gr) which distilled as a bright yellow oil (1.4 gr) bp. 183/14mm. It's very slightly volatile in steam.

Methylation of this gives 2,3,4,5,6-pentamethoxyacetophenone.

"There are many things under the sun."
(Hive Bee)
12-20-03 03:25
No 477919
      References from Clark Leland C. Jr.
(Rated as: excellent)

Clark Leland C. Jr. was the man who wrote the above article on the polymethoxy mescaline analogs. He and his group did a lot of researchs on this subject, here is a quick compilation of their work. Link in red are articles that didn't show in TFSE, link in green are posted or downloadable.

Mescaline analogs.

Part I of this paper is on the 2,4,6-trimethoxy pattern, and was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. I. 2,4,6-Trialkoxyphenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry (1954),19 11-16.

Part II was the paper Vitus posted at the top of the thread Post 413367 (Vitus_Verdegast: "tetra- and penta-methoxy-beta-phenethylamines", Novel Discourse) and the PDF was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. II. Tetra- and pentamethoxyphenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry (1955), 20 102-8.

Part III was posted by Vitus there Post 414105 (Vitus_Verdegast: "preparation of adrenochrome analogs", Chemistry Discourse) and the PDF was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. III. 2,4,6-Trialkyl- and 3,4-dihydroxy-5-methoxyphenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry  (1955), 20 1292-6.

Part IV was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. IV. Substituted 4,5,6-trimethoxyindoles.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry (1955), 20 1454-7.

Part V was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. V. p-Dialkylamino-b-phenethylamines and 9-(b-aminoethyl)julolidine.
Bennington, F.; Morin, R. D.; Clark, L. C., Jr.

J. Org. Chem. (1956), 21 1470-2.

Part VI was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. VI. Mescaline homologs.  
Bennington, F.; Morin, R. D.; Clark, L. C., Jr.

J. Org. Chem. (1956), 21 1545-6.

Part VII use a Willgerodt-Kindler reaction and was cited by vitus in Post 414469 (Vitus_Verdegast: "alternative routes to mescaline", Novel Discourse) and PDF posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. VII. 3,4,5-Trimethyl-b-phenethylamine.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry  (1957),  22  332-3.

Part VIII was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. VIII. Substituted 5-methoxy- and 5,6,7-trimethoxyindoles.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry  (1958),  23  19-23.

Part IX was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. IX. Tetra- and pentamethyl-b-phenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry  (1958),  23  2034-5. 

Part X is the last one, and was posted in Post 480428 (merbst: "Mescaline analogs - 10 part article series", Novel Discourse):

Mescaline analogs. X. 3,4-Dimethyl-, 3,4-dichloro-, and 3,5-dimethoxy-4-methyl-b-phenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry  (1960),  25  2066-7.


Effects of psychotomimetic compounds on certain oxidative and hydrolytic enzymes in mammalian brain.
Clark, Leland C., Jr.; Fox, R. Phyllis; Morin, Richard; Benington, Frederick.

J. Nervous Mental Disease  (1956),  124  466-72.

The effect of 19 b-phenethylamines (I), related to mescaline, and 30 closely related analogs on alk. phosphatase activity (AP) and pyruvate (II) utilization by homogenates of rat brain tissue, or supernatant fluids from such homogenates, was studied.  The position of substitution in I was more important than the nature of the substituent in effect on AP.  In general, compds. substituted in the 3,4,5 positions had only slight effects on AP, whereas unsubstituted I exerted a definite inhibition.  Compds. having alkyl or alkyloxy substituents in the 2 and 6 positions were more inhibitory than 3,4,5-substituted amines.  In 2,4,6-substituted compds. inhibition was related to the groups as follows: CH3 > C2H5O > C2H5 > CH3O.  The same compds. had quite different effects on II utilization; increasing the no. of substituents caused increased inhibition, and the nature of the substituent had a great influence, e.g. replacement of OH- by CH3O- or CH3- by CH3O- increased inhibition.  Max. AP in glycine buffer (0.05M) at pH 10.4 was 54% of that in 0.1M 2-amino-2-methyl-1-propanol (III).  In 1MM III, AP was about 20% higher than in 0.1M III.  The effect of 10 compds. with psychotomimetic or tranquilizing activity on AP and lactic and malic dehydrogenase (IV) activities of brain prepns. was studied.  Bufotenin and the tranquilizers (e.g., reserpine, chlorpromazine, frenquel), significantly increased AP.  IV was relatively resistant to the compds. tested.  

Synthesis of 5,6,7-trimethoxyindole, a possible intermediary metabolite of mescaline.
Morin, R. D.; Benington, F.; Clark, L. C., Jr.

Journal of Organic Chemistry  (1957),  22  331-2.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

Psychotomimetic substances may owe physiol. activity to the presence of an indole nucleus.  Similar activity of b-phenethylamines such as mescaline could be explained on the same basis provided they are capable of oxidative cyclization in vivo to the corresponding indole.  5,6,7-Trimethoxyindole was synthesized as a possible intermediary metabolite of mescaline.  Only one of seven alternate routes explored was practical.  The critical step was introducing a nitro group in 2-position of a suitably 1-substituted 3,4,5-trimethoxybenzene.  2-Nitro-3,4,5-trimethoxy-b-nitrostyrene (I), m. 177-8, was obtained in 9% yield by the nitration of 3,4,5-trimethoxy-b-nitrostyrene in Ac2O with red fuming HNO3.  Reductive cyclization of I to 5,6,7-trimethoxyindole (II), m. 71-2, was accomplished with Fe powder and HOAc (cf. Ek and Witkop, C.A. 49, 12437i).  The ultraviolet spectrum of II in MeOH-PrOH showed l 268 (log e 3.52), 287 mm(3.34). 

Psychopharmacological activity of ring- and side chainsubstituted b-phenethylamines.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.; Fox, R. Phyllis.

Journal of Organic Chemistry  (1958),  23  1979-84. 

Synthesis of a no. of ring substituted b-phenethylamines contg. alkyl, halogen, and alkoxy substituents by various methods is described.  The influence of these ring substituents on the psychotomimetic activity of substituted b-phenethylamines was examd. by observing the effect of these compds. on cat behavior.  Addnl. information was thus required on the influence of both the nature and position of substituents on the psychotomimetic activity.  The procedure developed for the synthesis of 4-ethyl-b-phenethylamine (I) is representative of that used to obtain related compds.

A link to the full text was provided by Rhodium in Post 433309 (Rhodium: "3,5-Dimethoxyphenethylamine Activity", Chemicals & Equipment).

The effects of ring-methoxyl groups on biological deamination of phenethylamines.
Clark, Leland C., Jr.; Benington, Frederick; Morin, Richard D.

Journal of Medicinal Chemistry  (1965),  8(3),  353-5.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

The oxidative deamination of all tongue the possible ring-methoxylated b-phenethylamines by the amine oxidase systems present in rabbit liver has been investigated.  The effects of the no. and position of the methoxyl groups on ease of deamination of this series of mescaline congeners were detd. 

The enzymatic oxidative deamination and effect on cat behavior of mescaline and structurally-related b-phenethylamines.
Clark L. C., Jr.; Benington, F.; Morin, R. D.

Alabama J. Med. Sci.  (1964),  1(4),  417-29.

The paper was posted by Vitus (again wink) in Post 458113 (Vitus_Verdegast: "mescaline: deamination & effect on cat behaviour", General Discourse).

Structure-activity relation studies on mescaline.  III.  The influence of the methoxy groups.
Smythies, John R.; Bradley, Ronald J.; Johnston, Victor S.; Benington, Frederick; Morin, Richard D.; Clark, Leland Charles, Jr.

Psychopharmacologia  (1967),  10(5),  379-87.

Psychotomimetic activity of a series of mescaline analogs was examd. in rats; 2 behavioral indexes were used to elucidate the probable role of methoxy group configuration in the mescaline mol.: discrete trial avoidance technique in a shuttle box and a continuous avoidance schedule in a Skinner box.  Of 18 compds. tested, only an i.p. injection of 2,3,4,5 - tetramethoxyphenylethylamine and 2,3,4,5,6 - pentamethoxyphenylethylamine (12.5 and 3.125 mg./kg., resp.) produced an effect similar to mescaline (25 mg./kg.).  All the mono-, di-, and trisubstituted compds. tested, except mescaline, were inactive; since none of these inactive compds., nor the inactive tetrasubstituted compds. possessed the 3,4,5-configuration, this is required for activity; the addn. of other methoxy groups to this configuration further increased the activity.  The greater activity of the pentamethoxy compd. may be due to its not being metabolized by mescaline oxidase.  18 references. 

New behavior-disrupting amphetamines and their significance.
Smythies, John R.; Johnston, Victor S.; Bradley, Ronald J.; Benington, Frederick; Morin, Richard D.; Clark, Leland Charles, Jr.

Nature (London) (1967), 216(5111), 128-9.

The effect of a series of 12 amphetamines on hallucinogenic behavior was investigated in rats.  A typical Bovet-Gatti hallucinogenic profile, with activity in decreasing order, was obtained for 2,4,5-, 3,4,5-, and 2,4,6-trimethoxyphenylisopropylamine, while 2,3,4-trimethoxyphenylisopropylamine was almost inactive.  2,3-, 2,5-, and 3,5-Dimethoxyphenylisopropylamine were inactive, but 3,4-dimethoxyphenylisopropylamine was highly active, 12.5 mg./kg. being roughly equiv. to 25 mg. of mescaline/kg.  o-Methoxyphenylisopropylamine was moderately active but p-methoxyamphetamine (PMA) proved to be the most potent hallucinogen so far tested with the exception of LSD.  At 3.1 mg./kg., it produced a typical "low dose hallucinogenic" Bovet-Gatti profile, quite distinct from that for amphetamine; at 6.2 mg./kg. it disrupted bar-pressing behavior completely and induced bizarre behavior.  Substitution in the para position apparently is the essential feature for hallucinogenic properties.  Behavior was completely disrupted and toxic effects appeared rapidly after the pretreatment of an animal with 50 mg. of iproniazid/kg. 3 hrs. before the injection of 6.2 mg. of p-methoxyphenylethylamine/kg. but not when either drug was given alone.


New synthesis of trichocereine.    
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

J. Org. Chem. (1957), 22 227-8.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

Synthesis of O- and N-methylated derivatives of 5-hydroxytryptamine.
Benington, F.; Morin, R. D.; Clark, Leland C., Jr.

Journal of Organic Chemistry (1958), 23 1977-9.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

Several new methylated derivs. of serotonin (I) and bufotenine (II) having potential physiol. interest were prepd.  Convenient syntheses of 1-methylbufotenine (III), 5-methoxy-N,N-dimethyltryptamine (IV), and 1 methyl-5-methoxy-N,N-dimethyltryptamine (V) from 5-benzyloxyindole (VI) are described.  The wide study made on I and II in relation to mental disorders prompted the present work.

Synthesis of 2,3-dihydro-5,6,7-trimethoxyindole and 6,7-dimethoxyindole.
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

Journal of Organic Chemistry (1959), 24 917-19.

Also describe the synthesis of 2-Bromo-Mescaline, a link to the article is in Post 470662 (Rhodium: "2,6-Dichloromescaline", Newbee Forum).

Synthesis of 5- and 6-chloro, 5-methyl, and 5,6,7-trimethyl derivatives of tryptamine.
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

Journal of Organic Chemistry (1960), 25  1542-7.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

cf. CA 53, 11342c.  Ring-chlorinated indoles, RC6H3.NH.CH:CH (I), were converted through the corresponding glyoxalyl chlorides and glyoxalamides, RC6H3.NH.CH:CCOCONR'2 (II), to ring-substituted tryptamines, RC6H3.NH.CH:CCH2CH2NR'2 (III), to obtain compds. with psychopharmacol. activities comparable to the corresponding substituted b-phenethylamines.

Synthesis of vicinal trimethoxyphenyl derivatives of heterocyclic nitrogen bases.
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

Journal of Organic Chemistry (1960), 25 1912-16.
Posted in Post 480583 (Rhodium: "More from Leland C. Clark", Novel Discourse)

v-Trimethoxy analogs of compds. possessing psychopharmacol. activity were synthesized to exam. the influence of v-trimethoxy groups on this type of activity.

Pharmacological activity of phenylisopropylhydroxylamine and its O-methyl ether.
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

Nature (London, United Kingdom)  (1964),  202(4934), 813.

N-(2-Phenylisopropyl)hydroxylamine (I) and its O-Me ether (II) were prepd. by the method of Vavon and Krajcinovic (CA 22, 2745) and injected into cats as the HCl salts.  I at concns. of 25 mg./kg. by muscle induces rage and other symptoms in cats similar to amphetamine and is inhibited by chlorpromazine.  II does not have an observable effect in cats.  I has an E.D.200 = 20 mg./kg. in mice compared with amphetamine with E.D.200 = 100 mg./kg. II was inactive for 0.5 hr. after injection into mice but spontaneous motor activity developed in 2 hrs., producing death.  I antagonized hexabarbital but II increased the action of hexabarbital.  In cats I resembles b-phenylethylamine and II does not.

5-Methoxy-N,N-dimethyltryptamine, a possible endogenous psychotoxin.
Benington, F.; Morin, R. D.; Clark, L. C., Jr.

Alabama J. Med. Sci.  (1965),  2(4),  397-403.

A review of plant sources of substituted tryptamine alkaloids, their use as hallucinogens, and the occurrence of tryptamines as urinary metabolites.  The possible role of the title compd. as an endogenous psychotoxin in schizophrenia is discussed.  25 references.

There are a bunch of very interesting articles in the references above, feel free to post them. wink
(Chief Bee)
01-05-04 22:49
No 480583
      More from Leland C. Clark
(Rated as: excellent)

Notes - New Synthesis of Trichohocereine
F. Benington, R. Morin, L. Clark, Jr.
J. Org. Chem. 22, 227-228 (1957) (../rhodium/pdf /archive/leland.c.clark/trichocereine.pdf)

Notes - Synthsesis of 5,6,7-Trimethoxyindole Possible Intermediary Metabolite of Mescaline
R. Morin, F. Benington, L. Clark, Jr.
J. Org. Chem. 22, 331-332 (1957) (../rhodium/pdf /archive/leland.c.clark/567-meo-indole.pdf)

Synthesis of O- and N-Methylated Derivatives of 5-Hydroxytryptamine
F. Benington, R. D. Morin, Leland C. Clark, Jr.
J. Org. Chem. 23, 1977-1979 (1958) (../rhodium/pdf /archive/leland.c.clark/o-n-methylated.5ht.pdf)

Synthesis of Some Vicinal Trimethoxyphenyl Derivatives of Heterocyclic Nitrogen Bases
F. Benington, R. D. Morin, L. C. Clark, Jr.
J. Org. Chem. 25, 1912-1916 (1960) (../rhodium/pdf /archive/leland.c.clark/trimethoxyphenyl.derivs.pdf)

Synthesis of Some 5- and 6-Chloro, 5-Methyl, and 5,6,7-Trimethyl Derivatives of Tryptamine
F. Benington, R. D. Morin, L. C. Clark, Jr.
J. Org. Chem. 25, 1542-1547 (1960) (../rhodium/pdf /archive/leland.c.clark/chloro.methyl.tryptamines.pdf)

The Effects of Ring-Methoxyl Groups on Biological Deamination of Phenethylamines
Leland C. Clark, Jr. Frederick Benington, Richard D. Morin
J. Med. Chem. 8, 353-355 (1965) (../rhodium/pdf /archive/leland.c.clark/pea-biological.deamination.pdf)

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
03-22-04 17:33
No 496641
      Only one more from Leland Clark
(Rated as: excellent)

This is very far from the first topic of this thread but is on topic of the latest two posts due to the authors of this old paper (this one is missing from the above Clark's bibliography). Besides I thought somebee might bee interested in the pharmacological activity (in animal tests) of phenylisopropylhydroxylamines and related stuff:

Behavioral and Neuropharmacological Actions of N-Aralkylhydroxylamines and their O-Methyl Ethers.
Benington F., Morin R.D., Clark L. C. Jr.
J. Med. Chem. 8, 100-104 (1965) (../rhodium/pdf /archive/leland.c.clark/n-aralkylhydroxylamine.ethers.pdf)

Abstract: The syntheses of a number of ring-substituted l-aryl-2-hydroxyamino- and l-aryl-2-methoxyaminopropanes are described. These compounds are compared pharmacologically with the corresponding 1-aryl-2-arnino-propanes. The hydroxyamino compounds are, in general, central stimulants, and O-methylation diminishes this activity. Two compounds within this series were found to be monoamine oxidase inhibitors.

The real drug-problem is that we need more and better drugs. J. Ott
(Chief Bee)
08-02-04 15:50
No 523232
      Synthesis of Escaline and Homosyringylamine
(Rated as: good read)

Here is another forgotten article by Benington & Clark, dealing with the synthesis of Escaline and Homosyringylamine from syringaldehyde:

Synthesis of 4-Hydroxy- and 4-Ethoxy-3,5-dimethoxy-β-phenethylamines
F. Benington, R. D. Morin, Leland C. Clarke, Jr.
J. Am. Chem. Soc.; 1954; 76(21); 5555-5556 (1954) (../rhodium/pdf /escaline.homosyringylamine.pdf)

The Hive - Clandestine Chemists Without Borders