4-arylbutyric acids

Several other synthetic sequences have been developed that lead to the production of potentially useful intermediates for the total synthesis of galanthamine-type alkaloids. For example, the 4-arylbutyric acid 348 has been converted to the tetrahydrobenzazepine 349 by a modified Curtius reaction followed by cycliza-tion of the intermediate isocyanate with polyphosphoric acid (168). N-Methyla-tion of 349 and photooxidation of the resulting tertiary lactam in the presence of NBS gave 350. 

Irie and co-workers have described an improved synthesis of the alkaloid elwesine (dihydrocrinine) (14).8 Application of Tsuda s two-stage method for the preparation of lactams (POCl3, then SnCl4) to the isocyanate that was derived from the 4-arylbutyric acid derivative (12) gave the benzazepinone (13) in 70% yield this compound has already been converted into elwesine. 

In addition to the works previously reported [50] Bi(0Tf)3 x H20 proved to be as active as scandium triflate in the EC acylation of aromatic compounds with carboxylic acids in the presence of perfluoroalkanoic anhydrides using solvent-free conditions (Equation 31) [60]. Under these conditions no reactions were reported with aromatics less activated than benzene. As previously reported [21], Bi(0Tf)3 xH20 was shown to be recoverable in good yields with no loss of activity. In addition, Bi(NTf2)3 [61] is proved to be an excellent catalyst for the intramolecular EC cyclization of 4-arylbutyric acids [62]. 

Cyclizations meta to an ortho, para directing substituent are known. For example, the 7-substituted tetralones XXIV were prepared16 from the corresponding arylbutyric acids XXIII. 

Polycyclic Nuclei. In general, arylpropionic and arylbutyric acids in which the aryl group is a polycyclic aromatic nucleus cyclize readily. Cyclization into the a-position of the naphthalene nucleus, for example, takes place more easily than into the benzene ring. The ring closure of the substituted naphthylpropionic acids XXXIII and XXXV proceeded smoothly. 

Procedure V. Ring Closure with Sulfuric Acid.198 For the conversion of Y-arylbutyric acids into cyclic ketones, the finely powdered acid (1 part) is added gradually with stirring to a mixture of concentrated sulfuric acid (3 volumes) and water (1 volume). After one hour s heating on the water bath the colored solution is cooled, diluted with water by pouring onto ice, and extracted with ether. The extract is washed with water, which removes traces of colored sulfonation product, then with dilute aqueous ammonia, and dried over anhydrous potassium carbonate the solvent is removed, the residue distilled under reduced pressure, and the distillate crystallized from a suitable solvent. 

CycKzation of f-arylbutyric acids, Eisenbraun et al. greatly prefer use of PPA to the acid chloride-AICI3 procedure for cyclizalion of 4-(2,5-dimethylphenyl)-2-mcthyl-butyric acid (I) to 2,5.8-trimelhyl-l-tetralone (2). 

There seems to be some indication that a-substituted 7-arylbutyric acids can be cyclized by sulfuric acid in better yields than the unsubstituted acids. Thus, whereas 7-phenylbutyric acid has not been cyclized in yields exceeding 50% with sulfuric acid (Table III), the a-methyl and a-ethyl homologs have been converted to the tetralones in 98% and 86% yields respectively. Similarly a-methyl-7-l-naphthylbutyric acid was cyclized in 91% yield, althou in the case of the unsubstituted acid yields over 75% could not be obtained. This peculiarity may be explained by the fact that ring closure of acids containing a substituent in the a-position gives rise to ketones lacking the usual reactive methyl-... 

In the laboratory of K. Krohn, the total synthesis of phytoalexine (+)-lacinilene C methyl ether was completed. In order to prepare the core of the natural product, an intermolecular Friedel-Crafts acylation was carried out between succinic anhydride and an aromatic substrate, followed by an intramolecular acylation. After the first acylation, the 4-keto arylbutyric acid was reduced under Clemmensen reduction conditions (to activate the aromatic ring for the intramolecular acylation). 

The liquid reagent has high solvent power, particularly for oxygen-containing substances and for aromatic compounds. It is an effective dehydrating and condensing agent comparable to coned, sulfuric acid but less prone to permit secondary reactions such as enolization and aromatic substitution. Treatment with liquid HF at room temperature provides a simple and efficient method for the cyclization of /3-arylpropionic acids and y-arylbutyric acids to 1-indanones and 1-tetralones, as shown by the yields cited under the formulas of typical ketones. It is far superior... 

Haworth phenanthrene synthesis. Acylation of aromatic compounds with aliphatic dibasic acid anhydrides to (i-aroylpropionic acids, reduction of the carbonyl group according to Clemmensen or Wolff-Kishner procedures, cyclization of the y-arylbutyric acid with 85% sulfuric acid, and conversion of the cyclic ketone to polycyclic hydroaromatic and subsequently to aromatic compounds. 

The following directions for reducing substituted benzoylpropionic acids to the corresponding arylbutyric acids illustrates the technique devized by Martin501 for effecting Clemmensen reduction in the presence of toluene. 

Z-Arginine hydrochloride, 12, 4 Arsanilic acid, 16, 85 Arsonoacetic acid, 10,108 Arylarsonic acid, preparation, IS, 59 y-Arylbutyric esters, 18, 25 Arylsulfur chlorides, preparation, 15, 45... 

The conditions just discussed apply, in general, in the cyclization of arylbutyric and arylpropionic acids by the Friedel-Craffs method. Although other factors may enter, it is significant that a higher incidence of good yields is found under milder reaction conditions. This may be seen by arranging the results of a cyclization in the order of increasing yields as in Tables II, III, and IV. 

It has been known for some time190 that sulfuric add can be used as an agent for dehydrating y-arylbutyric and /3-arylpropionic acids to... 

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