Thioxanthene

Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above Grignard condensation followed by dehydration gives thiothixine (42). 

Reduction of the exocyclic double bond generally decreases neuroleptic activity in this series. Some of these compounds, however, show other activities. Methixene (44), for example, is used as an antispasmodic agent. It is prepared by alkylation of the sodium salt of thioxanthene (43) with w-methyl-3-chloromethyl-piperidine. ... 

Chemical Name 3-(2-chloro-9H-thioxanthen-9-vlidene)-N,N-dimethyl-1-propanamine... 

Trans-2-chloro-9-(aj-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in U.S. Patent 3,115,502, which describes procedures for conversion of the cis to the trans form. 

Chemical Name 4-[3-(2-Chloro-9H-thioxanthen-9-ylidene)propyl] -1-piperazineethanol Common Name —... 

Chemical Name 4-[3- [2-(trifluoromethyl)-9H-thioxanthen-9-ylidenel propyl] -1-piperazine-ethanol... 

Chemical Name 1-methyl-3-(9H-thioxanthen-9-yl-methyl)piperidine hydrochloride Common Name —... 

The aqueous hydrochloric solution is made alkaline by adding dilute sodium hydroxide, and the thioxanthene base is isolated by extraction with ether. This results in 22 g of a slightly yellow, viscous base of BP 171° to 175°C/0.07 mm. 

Chemical Name (Z)-N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)propylidene] thioxanthene-2-sulfonamide... 

Thioxanthene Thionyl chloride n-Butyllithium Pa raformaldehyde Sodium borohydride... 

Dimethy/su/famy/thioxanthene To a slurry of dry sodium thioxanthene-2-sulfonate (33.3 grams, 0.111 mol) in 50 ml of N,N-dimethylformamide was added thionyl chloride (14.3 grams, 0.122 mol) in divided portions. An exothermic reaction ensued with complete dissolution being effected in minutes. Treatment of the reaction mixture with crushed ice precipitated a gum which crystallized after a short period of stirring. The sulfonyl chloride was filtered, washed with water, and stirred with 100 ml of liquid dimethylamine. 

Substituted dibenzo[6,/]thiepins can be generated from thioxanthene derivatives by the rearrangement of carbocation 1. Compared with other possible cations, the tropylium ion type 1C is favored because of its resonance energy. Depending on the reaction conditions, the thiepin cation can react to give thiepins by loss of a proton, or by trapping a nucleophile, followed by elimination. 

Lithiation of thioxanthene by butyllithium and condensation with formaldehyde gives thioxanthene-9-methanol. The p-toluenesulfonyl derivative 2, on treatment with refluxing formic acid, rearranges to a dibenzotropylium ion, which gives the elimination product 3 in 44% yield.20... 

The thioxanthene ligand is oxidized to thioxanthone and sulfone ligands, the ratio of which depends on the amount of KMn04 Eq. (37) ... 

Ternay and coworkers examined the conformations of thioxanthene-10-oxide (186) and related compounds. They found that oxygen preferred the pseudoequatorial position, 186e, but that the amount of pseudoaxial conformer, 186a, increased when the oxygen was complexed with iodine monochloride or trifluoroacetic acid171. 

Table 3 presents the hyperfme splitting constants of some sulfur-containing aromatic radical anions. The series studied included the monoxides and dioxides of dibenzothio-phene 1, thioxanthene 2, thioxanthone 3, dibenzo[b,/] thiepin 4 and dithienothiophene dioxide 5. 

The ESR spectrum of the thioxanthene S, S-dioxide radical anion itself shows that the two possible conformers coexist, since the two methylene protons are not equivalent. In the case of the 9-monoalkyl derivatives, the large coupling constant observed for the 9-proton leads to the conclusion that the 9-substituent is in the boat equatorial position as in II1 F Thus the radical anions and the neutral molecule display different conformations. The protons in the 9-position of the radical anions of cis-9-methylthioxanthene S-oxides (2, n — 1, R1 = H, R2 = CH3) have an appreciable coupling constant10 which suggests that these radical anions have the substituent in the pseudo-axial position. Furthermore, in the radical anions the S—O bond is pseudo-axial. These situations are exactly the opposite of that observed for the neutral compound. 

CN (Z)-3-(2-chloro-9f/-thioxanthen-9-ylidene)-M(V-ciimethyl-l-propanamine hydmhloride... 

CN 4-[3-[2-(trifluoromethyl)-9//-thioxanthen-9-ylidene]propyl]-l-piperazineethanol dihydrochloride... 

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