Cyclization agents/cyclizations chloride

In the cyclization of 7-3-pyrenylbutyric acid (Table IV) the higher yields obtained by the Friedel-Crafts reaction (examples 7 and 8) again involved the use of mild conditions. Even with the mild condensing agent, stannic chloride, it was foilnd unnecessary to heat the reaction mixture in order to obtain 96% yields (example 8). 

Scheme 98) (523). Hydrogen chloride is unsatisfactory as a cyclizing agent, whereas hydrogen iodide causes further reduction and leads directly to derivatives of the previously inaccessible 4-aminothiazoles (see Section VII. 2). 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

A rather simple derivative of imidazoimidazoline has been described as an antidepressant agent. Preparation of this compound starts with the displacement of the nitramine grouping in imidazoline derivative by phenyl ethanol amine The product of this reaction is then treated with thio-nyl chloride. The probable chloro intermediate ( ) cyclizes under the reaction conditions to afford imafen (5. ... 

Starting material for the first of these agents can in principle be obtained by alkylation of phenol with benzyl chloride 89. Cyclization of the product (90) under Friedel-Crafts conditions leads directly to isoxepac (91). ... 

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of o-nitroaniline with g-fluorobenzoyl chloride, with ethylene glycol leads to acetal 48. Sequential reduction of the nitro group and cyclization of the resulting diamine (49) with N,N-dicarbomethoxy-S-methylthiourea gives the benzimidazole etibendazole (50) fl6]. 

Cyclopropyl sulfones were shown to be obtained either by cyclization of y-p-tosyloxy sulfones 232 with base or by treatment of phenylsulfonylacetonitrile 233a or ethyl phenyl sulfonyl acetate 233b with 1,2-dibromoethane in the presence of benzyltriethyl-ammonium chloride (BTEA) and alkali in good yields. Chang and Pinnick synthesized various cyclopropane derivatives 234 upon initial treatment of carbanions derived from cyclopropyl phenyl sulfone with either alkylating agents or a carbonyl compound and subsequent desulfonylation, as shown below. 

Suitable agents are chlorosulfonic acid, monohydrate, or concentrated sulfuric acid. Other methods include cyclization of phenylthioglycolic acid chlorides, which is afforded by Friedel-Crafts reaction with aluminum chloride, possibly in the presence of sulfuric acid/sodium chloride. The acid chloride is obtained from phenylthioglycolic acid with thionyl chloride or phosphorus trichloride. 

Arylamino)quinoline-3-carboxylates (693) were prepared by the cyclization of /V -aryl(arylamino)methylenemalonamates (252) on the action of phosphoryl chloride in boiling benzene or of phosphorus pentoxide in refluxing xylene (46JA1246). Phosphoryl chloride proved to be a more effective cyclization agent than phosphorus pentoxide. This method could not be applied for the preparation of 4-alkylaminoquinoline-5-carbox-ylates. 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

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