Intermolecular Friedel-Crafts acylation

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). 

Anderson, K. W. and Tepe, J. J. 2002. The first intermolecular Friedel-Crafts acylation with P-lactams. Org. Lett. 4 459M61. 

Intermolecular Friedel-Crafts acylation of various substituted alkyl alkoxyben-zenes 1257 with oxalyl chloride using 1,2-dichloroethane [942] or carbon disulfide [943] as solvent gives rise to benzils 1258. 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

The reaction leading to compound A is an intramolecular Friedel-Crafts acylation. Since cyclization to form an eight-membered ring is difficult, it must be carried out in dilute solution to minimize competition with intermolecular acylation. 

All of the Friedel-Crafts reactions discussed thus far have resulted from intermolecular reaction of a benzene ring with an electrophile. Starting materials that contain both units are capable of intramolecular reaction, and this forms a new ring. For example, treatment of compound A, which contains both a benzene ring and an acid chloride, with AICI3, forms a-tetralone by an intramolecular Friedel-Crafts acylation reaction. 

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... 

The influence of the above factors on the course of the reaction has been demonstrated for intermolecular acylation. Changing the solvent from benzene to nitrobenzene in the Friedel-Crafts acetylation of naphthalene makes it possible to obtain principally the /3-isomer instead... 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

For a complete description of the synthetic utility of the Houben-Hoesch reaction as it applies to other aromatic systems, as well as some mechanistic discussions, the reader is directed to two reviews on the subject. Due to the diminished electrophilic reactivity of nitriles compared to other carboxylic acid derivatives as well as the broad number of Friedel-Crafts substrates, most Houben-Hoesch pyrrole acylation reactions are conducted intramolecularly. However, an impressive intermolecular example was delineated by Chang and co-workers in efforts directed toward the synthesis of novel 2-[5-aroylpyrrolo]alkanoic acids, for evaluation of their potential analgesic and anti-inflammatory activities. Treatment of substituted pyrrole 4 and 3-cyanopyridine (5) with acid in dry chloroform resulted in the preparation of 6 in good yield. 

Generalized Friedel-Crafts Intermolecular Acylation Reaction... 

An interesting one-pot tandem Lewis Acid Friedel-Crafts intermolecular acylation method with concomittant in situ reduction of the aryl ketone product has been reported by Jaxa-Chamiec. Treatment of toluene (13) with 4-chlorobutanoyl chloride and AICI3 gave an intermediate ketone 15 which was reduced in situ by use of either of EtsSiH of PMSH (polymethylhydroxysilane) to afford 16 in an impressive 85% yield from 13. 

The Friedel-Crafts reaction we have discussed in this section is an intermolecular reaction between an aromatic compound and an acyl halide. However, if the acyl halide also contains an aromatic ring, an intramolecular reaction can easily occur. Such a unimolecular reaction is favored over a bimolecular reaction when the ring formed contains either five or six atoms. This is a Friedel-Crafts reaction in which the acyl chloride acylates the ortho position. 

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