Friedel-Crafts acylation with keto-acids

Reaction of the keto acid 7, obtained through Friedel-Crafts acylation, with ammonium acetate in acetic acid gives the yellow pyridone 8 as the major product. Compound 8 is amphoteric, forming both a sodium salt and a stable hydrochloride. Alkylation with methyl iodide in alkaline methanol affords a mixture of the N- and 0-methylated products 9 and The iV-methyl-pyridone 9 is unstable and oxidized by air to the bicyclic keto imide... 

Octahydrodibenzothiophene (73) has been prepared by the following sequence. Friedel-Crafts acylation of 4,5,6,7-tetra-hydrobenzo[6]thiophene with succinic anhydride (87%) or with the ester chloride of succinic acid followed by hydrolysis (80%), yields the keto acid (74). Huang-Minlon reduction of 74 followed by cyclization of the derived acid chloride with stannic chloride yields l-keto-1,2,3,4,6,7,-8,9-octahydrodibenzothiophene (53) (Section V,A). Reduction of 53 gives 73 as a solid (overall yield 32%). 

Friedel-Crafts acylation of dibenzothiophene with succinic anhydride is known to occur in the 2-position, yielding y-oxo-2-dibenzothiophene-but3Tic acid (135a). Subsequent Wolff-Kishner reduction and internal cyclization yields 7-keto-7,8,9,10-tetrahydrobenzo[6]naphtho[2,3-d]thio-phene (136a). - This reaction has been extended to 4-methyldibenzo-... 

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]. 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

The commercial preparation of anthraquinone dyes begins with the synthesis of anthraquinone itself. In this regard, the three-step synthesis involves (1) the oxidation of naphthalene to phthalic anhydride, (2) Friedel-Crafts acylation of benzene to give a keto acid, and (3) cyclodehydration using H2S04. See Fig. 13.110. The preparation of 1,4-disubstituted anthraquinones utilizes the intermediates... 

The most important method for the preparation of aryl ketones is known as Friedel-Crafts acylation. The reaction is of wide scope. Reagents other than acyl halides can be used," including carboxylic acids," anhydrides, and ketenes. Oxalyl chloride has been used to give diaryl 1,2-diketones." Carboxylic esters usually give alkylation as the predominant product (see 11-11)." A-Carbamoyl p-lactams reacted with naphthalene in the presence of trifluoromethanesulfonic acid to give the keto-amide." ... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The synthesis of nonsymmetric cyclopentenes, containing both thien-3-yl and benzo[Z7]thien-3-yl units, was aimed at more sophisticated photochromic molecules (Scheme 54) [73]. By the application of glutaric anhydride with 2-chloro-5-methylthiophene and 5-bromo-2-methylbenzo[h]thiophene in the presence of AICI3, keto acids 52 and 53 were obtained. Conversion of the keto acids into acid anhydrides then Friedel-Crafts acylations produced the desired diketone albeit in only 31% yield (over 2 steps) in the first case and in 14% yield (over two steps) in the second case (Scheme 54) [73]. 

Preparation by Friedel-Crafts acylation of 2,5-dimethyl-phenyl benzoate with benzoyl chloride in the presence of zinc chloride, followed by saponification of the p-keto ester so obtained with sodium hydroxide in boiling ethanol (quantitative yield) [725]. Preparation by reaction of hydriodic acid with 4-methoxy-2,5-dimethylbenzo-phenone in boiling acetic acid (56%) [719]. 

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... 

Cagniant and Cagniant have reported that succinoylation of benzo[6]thiophene under Friedel-Crafts conditions yields a separable mixture of the y-ketobutyric acids 42a and 43a in a ratio of 9 1 (combined yield 85%). Huang-Minlon reduction of 42a to the butyric acid (90%) followed by cyclization of the derived acid chloride (90%) was reported to yield 4-keto-l,2,3,4-tetrahydrodibenzothiophene (44a) (69% overall). Likewise, acylation of benzo[6]thiophene with the ester chloride of succinic acid in carbon disulfide-aluminum chloride gave a separable mixture (80%) of the 2- and 3-y-ketobutyric esters. Two alternative... 

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... 

Cyclization of Anhydrides. Instead of the acid chloride, an intramolecular anhydride of the type LXXIX may be used for cyclization by the Friedel-Crafts reaction (Table VII, examples marked by h ). This resembles the intermolecular acylation with succinic anhydride, and a similar procedure is generally followed. The product of ring closure is a keto acid LXXX. Nitrobenzene 9i 6,1120 is a generally effective solvent for the reaction sym-tetrachloroethane also may be used.121... 

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