A total synthesis of (±)-triophamine

Treatment of ethyl 2-pentynoate (14) with lithium (phenylthio)(tri-n-butylstannyl)cuprate (12) afforded, in 76% yield, ethyl (Z)-3-(tri-n-butylstannyl)-2-pentenoate (15). On the other hand, when compound 14 was allowed to react with the (tri-n-butylstannyl)copper reagent 13, ethyl (E)-3-(tri-n-butylstannyl)-2-pentenoate (21) was produced in 83% yield. Reduction (diisobutylaluminum hydride, ether) of the esters 15 and 21 gave the alcohols 16 and 22, respectively. Treatment of each of the latter substances with pyridine – sulfur trioxide complex, followed by further reduction of the resultant intermediates with lithium aluminum hydride, provided the geometrically isomeric alkenylstannanes 17 and 23. Conjugate addition of (E)-3-lithio-2-pentene (18) (formed by transmetalation of 17) to compound 19 produced the olefinic trimethylhydrazide 20, which was converted (diisobutylaluminum hydride, ether; pyridinium dichromate, dimethylformamide) into the corresponding carboxylic acid 2. Subjection of compound 23 to a sequence of reactions identical with that used for the conversion of 17 into 2 provided the isomeric acid 3, which was identical (infrared, 1H nmr) with the natural acid derived from triophamine (1). Conversion of 3 into the p-nitrophenyl ester 26, followed by condensation of the latter substance with guanidine, afforded a chromatographically separable mixture of (±)-triophamine (1) and the corresponding diastereomer.

Potential metabolites of tricyclic neuroleptics: 2,8-Dihydroxy and 3,8-dihydroxy derivatives of 10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin

A synthesis of the title compounds II and III, potential metabolites of the neuroleptic agent perathiepin I, was carried out. A reaction of (2-iodo-5-methoxyphenyl)acetic acid with 4-methoxythiophenol afforded the acid VI. The isomeric acid XI was obtained from 2-iodo-4-methoxybenzoic acid by reaction with 4-methoxythiophenol and via intermediates VIII-X. Both acids (VI,XI) were cyclized with polyphosphoric acid to dimethoxydibenzo[b,f]thiepin-10(11H)-onesXIIab which were transformed via the alcohols XIIIab to the chloro compounds XIVab. Substitution reactions with 1-methylpiperazine gave the piperazine derivatives IV and V and dimethoxydibenzo[b,f]thiepins XVab. The dimethoxy compounds IV and V were demethylated with boron tribromide to the diaminodiphenols II and III. The central depressant and cataleptic activity of compounds II-V is lower than that of the unsubstituted substance I.

Reaction of some 3-(phenylthioaryl)propionic acids with polyphosphoric acid; Formation of 2H-cyclopenta[k,l]thioxanthenes

The cyclization of 3-[2-(phenylthio)phenyl]propionic acid (I) with polyphosphoric acid gave equal amounts of 4-(phenylthio)indanone (III) and 2H-cyclopenta[k,l]thioxanthene (VI), accompanied with a small amount of the macrocyclic diketone V. Compound VI was evidently formed via the cation XII and 7-(phenylthio)indanone (X) which was quantitatively dehydrocyclized. Similar cyclization of the isomeric acid XIIIa yielded 5-(phenylthio)indanone (XVIII) as the main product; formation of VI could be detected only chromatographicaly. Cyclization of 3-[2-(chloro-5-(phenylthio)phenyl]propionic acid (XIIIb) gave 3-chloro-2H-cyclopenta[k,l]thioxanthene (VII) as the predominant product. From the by-products formed, only 4-chloro-7-(phenylthio)indanone (XI) could be identified, being the precursor of compound VII. Treatment of thioxanthene-9-acetic acid (XXII) with polyphosphoric acid resulted in a cleavage with thioxanthone (XXIII) and thioxanthene (XXIV) as the main products.

FLAVOUR REVERSION IN HYDROGENATED LINSEED OIL: I. THE PRODUCTION OF AN ISOMER OF LINOLEIC ACID FROM LINOLENIC ACID

Linseed oil that has been hydrogenated to a plastic consistency is subject to a type of deterioration termed "flavour reversion" when heated to temperatures used in baking or frying. Investigation of the course of hydrogenation of linseed oil by the spectral method of Mitchell, Kraybill, and Zscheile (11) has indicated that linolenic acid is converted to an isomeric linoleic acid; this acid differs from naturally occurring linoleic acid in that the double bonds are in such positions that diene conjugation is not produced by high-temperature saponification. In a typical hydrogenation, the concentration of the isomeric acid increased to a maximum, at about iodine number 120, of 18% of the total fatty acids, and at iodine number 80, at which point the plasticity was similar to that of a commercial shortening, the concentration of the isomer was 13%. Evidence is presented that the isomeric linoleic acid in partially hydrogenated linseed oil is responsible for the unpleasant flavour that develops when the oil is heated.

IV. On the synthesis of succinic and pyrotartaric acids

Succinic acid bears the same relation to the diatomic alcohol glycol that propionic acid bears to ordinary alcohol. Propionic acid can be obtained by treating the cyanide of the alcohol radical with potash. Can succinic acid be obtained by treating the cyanide of the glycol radical with the same reagent ? or is it an isomeric acid that is formed under those circumstances? C 4 H 5 Cy + O 2 { K H +2HO = O 2 Cyanide of Ethyle. { C 6 H 5 O 2 K + NH 3 Propionate Potash. C 4 H 4 Cy 2 + 2{O 2 { K H + 4HO = O 4 Cyanide of Ethylene. { C 8 H 4 O 4 K 2 + 2NH 3 Succinate of Potash? The following experiments were performed with the view of determining this point. Preparation of Cyanide of Ethylene . As a preliminary step to the formation of succinic acid in this way, it became of course necessary to prepare the cyanide of ethylene. This body I obtained by submitting bromide of ethylene to the action of cyanide of potassium. The process was thus conducted:—A mixture of two equivalents of the cyanide and one of the bromide, together with a considerable quantity of alcohol, was exposed in well-corked soda-water bottles to the temperature of a water-bath for about sixteen hours. To prevent the caking of the salt, it is advisable to have some coarsely-powdered glass in the bottles, and to agitate them occasionally. At the expiration of this time the bottles were opened, and the alcohol separated and distilled. A semifluid residue was thus obtained, which was filtered at 100° Cent. It was very dark in colour, owing to the presence of a considerable quantity of a tarry matter, which embarrassed me for a long time. This I at last succeeded in removing, by exposing the residue to a powerful freezing mixture, and pressing it, while in the mixture, between folds of bibulous paper, as long as the paper was stained. After this treatment there remained a crystalline mass, which was almost white. This was finally washed with a small quantity of ether, and dissolved in the same fluid. The residue obtained on evaporating the etherial solution is the body in question. It was dried at 100° Cent., and analysed. The nunbers obtained agree with the formula of cyanide of ethylene (C 4 H 4 Cy 2 ), as will be seen from the following Table:— Theory. Experiment. per cent. I. II. C 8 . . 48·00 60·00 59·20 —— H 4 . . 4·00 5·00 5·55 —— N 2 . . 28·00 35·00 —— 34·00* ——— ——— 80·00 100·00 This is, I believe, the first example of a diatomic cyanide. It has the following properties:-Below the temperature of 37° Cent, it is a crystalline solid of a light-brown colour, above that temperature it is a fluid oil. It cannot be distilled. Nevertheless it bears a tolerably high temperature without suffering much decomposition. Its specific gravity at 45° Cent, is 1·023. It is very soluble in water and alcohol, and sparingly soluble in ether. It has an acrid disagreeable taste. It is neutral to test-paper. Gently warmed with potassium, it is decomposed, cyanide of potassium being formed in large quantity. Its solution in water is not precipitated by nitrate of silver.

III. On cyanide of ethylene and succinic acid. —Preliminary notice

Succinic acid bears the same relation to the diatomic alcohol (glycol) that propionic acid bears to ordinary alcohol. Propionic acid can be obtained by treating the cyanide of the alcohol radical with potash. Can succinic acid be obtained by treating the cyanide of the glycol radical with the same reagent, or is it an isomeric acid that is formed under these circumstances ? The following experiments were performed with the view of determining this point:— Preparation of Cyanide of Ethylene .—As a preliminary step to the formation of succinic acid in this way, it became of course necessary to prepare the cyanide of ethylene. This body I obtained by submitting bromide of ethylene to the action of cyanide of potassium.