Keto acids from Friedel-Crafts acylation

Keto-4-arylbutanoic acid derivatives resulting from Friedel-Crafts acylation reaction are prepared in high yields and purity using AICI3. Such compounds are useful structural moieties in the synthesis of several biologically active compounds such as Fenbufen, a nonsteroidal anti-inflammatory drug (eq 48). 4... 

The structure of the pyridazine-based antidepressant agent minaprine (34-6) departs markedly from both the older tricyclic drugs and the more recent selective serotonin re-uptake inhibitors. There is evidence that the compound acts via a dopa-mimetic route. Friedel-Crafts acylation of benzene with itaconic anhydride (34-1) leads to the keto-acid (34-2). Condensation with hydrazine leads to the formation of the hydrazine and hydrazide bonds the double bond shifts into the ring to give the fully unsaturated pyridazinone (34-3) this is then converted to the chloride (34-4) in the usual way. The displacement of halogen by the amine on 3-(A -morpho-lino)propylamine (34-5) affords (34-6) [36]. 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

Dibenzothiophene derivatives are available from benzo[Z> jthiophenes by this procedure. In this case the major product of Friedel-Crafts acylation is the 3-substituted derivative cf. Chapter 3.14) and reaction of succinic anhydride gives as the major product the keto acid (319), which is then reduced and cyclized via the acid chloride to 4-keto-l,2,3,4-tetrahydrodibenzothiophene (320). Better yields were obtained when 3-methoxycar-bonylpropionyl chloride was substituted for succinic anhydride in the first step (69JHC771). 

The synthesis of estrone from anisole and glutaric anhydride was first described by Johnson and coworkers [225, 563, 564] in 1951 and was perfected by Kipriyanov and Kutsenko [565] in 1961 (yields and reagents in Scheme 46 are given in accordance with [565]). The Friedel—Crafts acylation of anisole (82) with glutaric anhydride and subsequent esterification led to the keto ester (474) which was converted by the Stobbe reaction into a mixture of tricarboxylic acids isomeric with respect to the position of the... 

Alkynes are readily acylated with acid chlorides under Friedel-Crafts conditions to form, in most cases, fram-p-chlorovinyl ketones through the corresponding vinyl cation intermediate [Eq. (8.16)]. The first study in 1935 reported low yields.11 Later in acylations with acyl triflates, p-keto vinyl triflates were obtained in satisfactory yields.123 When aroyl derivatives are used, the intermediate can undergo cyclization to form indenones. Chlorovinyl ketones formed from terminal alkynes may also react further losing hydrogen chloride to yield conjugated acetylenic ketones 11,13... 

---