Claisen’s alkali

B. 2-Nitro-4-metfwxyaniline. A mixture of 160 g. of 2-nitro-4-methoxyacetanilide and 250 ml. of cold Claisen s alkali (Note 4) in a 2-1. beaker is stirred and warmed on a steam bath for 15 minutes it first becomes liquid and then sets to a thick, red paste. After the addition of 250 ml. of hot water the mixture is stirred and digested on a steam bath for an additional 15 minutes and then cooled to 0-5°. The product is collected on a 19-cm. Buchner funnel, washed with three 160-ml. portions of ice-cold water, and pressed as dry as possible with a rubber dam. The yield of vacuum-dried product melting at 122.5-123° is 122-4 g. (95-97%). 

Claisen s alkali is prepared by dissolving 88 g. of potassium hydroxide in 63 ml. of water, cooling, and diluting to 250 ml. with methanol. 

After 36 hours the furnace is allowed to cool, the bomb is removed, cooled to dry-ice temperatures, and opened carefully as there may be residual pressure. The golden brown liquid is poured into a 200-ml. flask, and the methyl iodide is removed on a rotary evaporator (iCautionI Hood). The residue from the flask and the bomb is washed into a 500-ml. separatory funnel with 100 ml. each of ether and 1 1 solution of Claisen s alkali and water (Note 8). The funnel is shaken, and the alkali layer is removed. The ether layer is extracted four additional times with 100 ml. portions of the alkali (Note 9), washed twice with 75-ml. portions of water, once with saturated aqueous salt solution, and... 

Sufficient Claisen s alkali for one run is made by dissolving 175 g. of potassium hydroxide pellets in 125 ml. of distilled water, cooling to room temperature, adding 500 ml. of methanol, and again cooling this gives 655-665 ml. of solution. 

The reaction mixture is usually worked up by removing the basic solvent, if present, by extraction with dilute mineral add, solution of the residue in petroleum ether, and extraction with aqueous alkali to separate the phenolic product from any neutral by-products and unchanged ether. When the phenols are highly substituted, espedally the 2,6-disubstituted ones, their acidity may be so greatly diminished that they are practically insoluble in aqueous alkali Claisen s alkali (p. 28) has proved of great service in isolating weakly acidic phenols.11 101 Petroleum ether or benzene should be the solvent for the organic material when Claisen s alkali is used for an extraction. 

The problem of lipophiles remained and here again we could make use of the acid functionality of the phenols. With less lipid soluble phenols such as the steroids, simple back extraction from organic solvent into strong base would have been sufficient. However, the high lipid solubility of A9-THC necessitated that extraction be carried out with Brodie s solvent (hexane and isoamyl alcohol) and that back extraction be done with Claisen s alkali, which is a mixture of KOH, methanol, and water. After acidification of the Claisen s alkali, A9-THC could be recovered by extraction. The external standard and the trimethylanilinium hydroxide were added and the extracted phenol (i.e. A9-THC) was converted to the 1-0-methyl derivative in the injector port and the determination carried out... 

We had shown that it was possible to extract both A9-THC and ll-hydroxy-A9-THC from plasma with toluene. The next question was the problem of lipophiles. Again we found that in order to remove interferences to A9-THC determinations it was necessary to fractionate the toluene extract with Claisen s alkali in order to obtain the phenol fraction of plasma. We found that the extractions of A9-THC from toluene with Claisen s alkali is not quantitative, but it is reproducible. The loss of A9-THC in this reaction however, is compensated for by removal of interferences which were the limiting factors in the single extraction step. 

The final analytical method for the simultaneous determination of A9-THC and its metabolites consists of the following sequence the cannabinoids are extracted from plasma with toluene they are then back extracted from toluene into Claisen s alkali the Claisen s alkali is diluted with water, tetrahexyl ammonium hydroxide is added and the alkaline solution is extracted with methylene chloride containing ethyl iodide. The overall recoveries were 45% for A9-THC and 83% for 11-hydroxy-A9-THC. External standards (l-0-ethyl-A9-THC and l-0-ethyl-ll-hydroxy-A9-THC) were added to the methylene chloride phase followed by a small amount of Florosil, which absorbed the tetra-hexylammonium hydroxide and tetrahexylammonium iodide. The methylene chloride was decanted and evaporated. 

Four ml plasma are extracted twice with 4 ml of the following solvent methyl acetate/petroleum ether/ ethanol (66 33 1.5 v/v). After centrifugation, the organic extracts are evaporated to dryness, dissolved into 4 ml hexane and again extracted twice with 2 ml Claisen s alkali reagent. The alkaline solutions are acidified with 1 ml N HC1 (pH = 1.5) and then extracted twice with 4 ml hexane. This last solution is evaporated to dryness and the residue dissolved in the necessary amount of acetone and then transferred into a hemolysis tube. 

Claisen s alkali is prepared by dissolving 360 g. of potassiiim hydroxide in 260 cc. of water and diluting to lOOO cc. with methanol. 

Claisen s alkali as long as the extracts are colored yellow by enolate affords a simple means of isolating the total enedione present (yield 40%). 

SapoHification. TarbeU and co-workers saponified ethyl 3,5-dichloro-4-hydroxy-benzoate by heating it with Claisen s alkali for 1 hr. on the steam bath (93-97% yield) 2-nitro-4-methoxyacetamlide was hydrolyzed similarly in 15 min. of heating. L. Claisen,v /in.,418,96 (1919)... 

Bases, strong Choline. Claisen s alkali. Lithium (potassium, sodium) amide (ethoxide, hydroxide, methoxide). Lithium nitride. Phenyllithium (potassium, sodium). Potassium r-butoxide. Potassium (sodium) 2-methyl-2-butoxide. Resins Amberlite IRA-dOO. Dowex... 

Claisen s alkali. Preparation dissolve 35 g. of potassium hydroxide in 25 ml. of water, cool, add 100 ml. of methanol, and cool. 

Extraction of cryptophenois and enok. Phenols insoluble in aqueous alkali, for example 2,4,6-triallylphenol, can be extracted from petroleum ether with Claisen s alkali. Vitamin K, is easily isolated from a 3-5% alfalfa concentrate by shaking an alcoholic suspension of the oil with aqueous sodium hydrosulfite, extracting with petroleum ether, and extracting the Kj hydroquinone from petroleum ether with Claisen s alkali. The yellow extract is diluted with water and Ki hydroquinone OH CHj CH, CHj CH,... 

Reagents (a) MeS-C(=NCOOMe)NHCOOMe (b) i) HNO3-AC2O ii) Claisen s alkali (c), SnCl2-Ha... 

Bromocodeinone (115) is unstable to Claisen s alkali, which converts it, presumably through the enolised intermediate (116), into the a-diketone (117 R = H), which can be methylated to salutaridine (117 R = Me). Electrolytic reduction of 14-bromocodeinone has long been known to give dihydrodeoxycodeine-E, which has recently been shown to be the phenolic 8,(i4) compound. ... 

This compound undergoes rearrangement to 6-O-demethylsalutaridine (139) in the presence of Claisen s alkali.147 The product has been correlated with salutari-dine and a mechanism involving SN2 attack by base on the allylic bromide function to form the intermediate (140 X = OH) has been proposed. Compound (139) has also been obtained independently by treatment of 7-bromoneopinone (140 X = Br) perchlorate with sodium acetate-acetic acid and several pertinent mechanistic observations on this reaction have been presented.149 Attempts to prepare the proposed intermediate (140 X = OH) from (140 X = Br) perchlorate by treatment with aqueous silver nitrate at room temperature gave no reaction, while under reflux a quantitative yield of (139) perchlorate was obtained. Compound (140 X = Br) perchlorate was stable to base in the cold while at reflux temperature a Hofmann degradation product was obtained.150 It is interesting to... 

Ckisen rearrangements A recent review stresses the value of Claisen s alkali for separation of neutral and phenolic products of Claisen rearrangements. Extraction with aqueous sodium hydroxide is effective for fairly acidic phenols, but incomplete for weakly acidic phenols. 

Rapoport el al. described a simple preparation of 6-O-demethyl-salutaridine (43e) from thebaine with sodium bisulfite in an oxygen atmosphere (494). In another synthesis, 14-bromocodeinone (47b) in Claisen s alkali yields 6-O-demethylsalutaridine (495). Methylation of this compound with diazomethane gives rise to O-methylsalutaridine (43d). The following reaction sequence appears to account for the production of... 

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