Succinic anhydride, Friedel-Crafts acylation

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

Friedel-Crafts acylation of unsaturated fatty acids can be carried out with succinic anhydride ia the presence of alkyl aluminium haUde (104). 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

Friedel-Crafts acylation can be carried out with cyclic anhydrides, in which case the product contains a carboxyl group in the side chain. When succinic... 

Almost every major structural class discussed to date has featured at least one nonsteroidal antiinflammatory carboxylic acid. It is thus perhaps not surprising to find a dibenzoheterocycle serving as the nucleus for one of these agents, furobufen (34). Straightforward Friedel-Crafts acylation of dibenzo-furan (33) with succinic anhydride affords a mixture of 2- and 3-acylated products, with the latter predominating. The mixture is esterified with methanol, and the methyl ester of the 3-isomer is separated by fractional crystallization. Hydrolysis back to the... 

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 first agent of this class to be introduced in the clinic, haloperidol (18-8), interestingly shares the 4-phenylpiperidine structural fragment found in the central analgesic agent meperidine and its derivatives (see Chapter 7). The former compound may well have been discovered in the course of further SAR studies on the opiate [20]. An unusual synthesis of haloperidol starts with the product (18-1) from Friedel-Crafts acylation of 4-fluorobenzene with succinic anhydride. Successive protection of the... 

Friedel-Crafts acylation can be carried out with cyclic anhydrides,272 in which case the product contains a carboxyl group in the side chain. When succinic anhydride is used, the product is ArCOCH2CH2COOH. This can be reduced (9-37) to A1CH2CH2CFLCOOH, which can then be cyclized by an internal Friedel-Crafts acylation. The total process is called the Haworth reaction 173... 

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). 

Succinic anhydride, the structure of which is shown, is a cyclic anhydride often used in Friedel-Crafts acylations. Give the structure of the product obtained when benzene is acylated with succinic anhydride in the presence of aluminum chloride. 

Friedel-Crafts acylation of 2,3-dihydrobenzo[6]thiophene using succinic anhydride 426 or acetyl chloride 427 affords the 5-substituted... 

In a third microreactor, the anion of 4-ferf-butyl l-ethyl-2-(diethox-yphosphoryl)succinate was prepared in situ using sodium ethoxide 237 (in EtOH) and the Wittig-Horner olefination with benzaldehyde 116 performed using a residence time of 47 min to afford (E)-ferf-butyl-l-ethyl-2-benzylidenesuccinate 238 in excellent selectivity (89% yield). In a fourth reactor, the acid-catalyzed (TFA 239) ferf-butyl ester deprotection was achieved using a residence time of 5 min at 34 °C and employing DCM as the reaction solvent to afford (E)-3-(ethoxycarbonyl)-4-phenylbut-3-enoic acid 246 in 82% yield. The deprotection was subsequently followed by a Friedel-Crafts acylation, using triethylamine 14 and acetic anhydride 37, to afford 4-acetoxy-naphthalene-2-carboxylic acid ethyl ester 241 in quantitative yield when conducted at 130 °C (residence time = 47 min). 

FRIEDEL-CRAFTS ACYLATION OF AROMATIC COMPOUNDS USING SUCCINIC ANHYDRIDE... 

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 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. ... 

Friedel-Crafts acylation is a well-known reaction. For example, one can react benzene with succinic anhydride using a Lewis acid, aluminum chloride, to synthesize... 

This paper deals with a novel approach of functionalizing poly (IB-PMS) copolymers using the Friedel-Crafts acylation reaction. Poly (IB-PMS) copolymer was reacted with an acylating agent, succinic anhydride, using aluminum chloride as a Lewis acid. The reaction involves the aluminum chloride-catdyzed substitution of an acyl group on the aromatic ring. 

The Haworth reaction is a classical method for the synthesis of tetralone, beginning with benzene and succinic anhydride. The three-step protocol involves a Friedel-Crafts acylation, followed by reduction of the arylketone, and an intramolecular Friedel-Crafts acylation. The tetralone analog may be further reduced and dehydrogenated to form new aromatic species, in what is known as the Haworth phenanthrene synthesis. 

The Haworth phenanthrene synthesis has been extensively used in the synthesis of derivatives of chrysene,an environmental pollutant which exhibits tumorigenic and mutagenic properties. For example Harvey and coworkers treated 61 with succinic anhydride under Friedel-Crafts conditions to produce 62. Reduction of the ketoacid under Wolff-Kishner conditions is followed by esterification to yield 63. Dehydrogenation of 63 is followed by saponification to yield carboxylic acid 64. Intramolecular Friedel-Crafts acylation produces tetralone derivative 65, which undergoes carbonyl reduction and dehydrogenation to produce 66. 

Scheme 9.137. A representation of the Friedel-Crafts acylation of benzene (CeHe) by butane-1,4-dioic anhydride (succinic anhydride) in the presence of an aluminum trichloride (AICI3) catalyst. Generation of the 4-phenyl-4-oxobutanoic acid and hydrolysis of the catalyst are shown as the last step.

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