The Houben-Hoesch reaction

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles ... 

The synthetic importance of the Houben-Hoesch reaction is even more limited by the fact that aryl ketones are also available by application of the Friedel-Crafts acylation reaction. 

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

A method for the preparation of 1-hydroxypyrrolizidine was published by Adams et al.7i Cyclization of 1 -(/ -cyanoethyl)pyrrole under the conditions of the Houben-Hoesch reaction gave rise to l-oxo-3/f-l,2-dihydropyrrolo(l,2-a)pyrrole (123) (cf. refe. 48 and 73), which can be converted into 1-hydroxypyrrolizidine by either direct hydrogenation over rhodium on alumina or hydrogenation of the corresponding hydroxy derivative 124. This route has some interest as a potential... 

The Houben-Hoesch Reaction refers specifically to phenols as substrates, where the reaction is generally most useful. 

More recent studies with superacidic systems (TfOH, TfOH—SbF5), used also in the Gattermann reaction, indicated that strong acids significantly increase reactivities of benzene with benzonitrile.33 104 It is concluded that the superelectrophilic 14 dication formed as a results of protonation of 13 is the reactive species in the Houben-Hoesch reaction. 

Highly activated aromatic compounds such as dihydric phenols can be acylated by reaction with an aliphatic nitrile in the presence of a Lewis acid, usually zinc chloride, and hydrogen chloride (Scheme 6.24). The Houben-Hoesch reaction is a variation of the Gattermann formylation and proceeds via an iminium salt, which is isolated and subsequently hydrolysed. 

The synthesis of 11-hydroxy O-methylsterigmatocystin (HOMST) was carried out in the laboratory of C.A. Townsend by utilizing the alkyinitrilium ion variant of the Houben-Hoesch reaction The alkyinitrilium salt was prepared by reacting the aryl nitrile with 2-chloropropene in the presence of SbCIs. Next, the phenol was added in a 2.5 1 excess. Alkaline hydrolysis then afforded the xanthone, which was subsequently converted to HOMST in few more steps. 

In the presence of both aluminium chloride and boron trifluoride, chloromethyl cyanide reacts wKh phenols to give exclusively 2-chloroacylphenols whereas the Houben-Hoesch reaction predominantly results in 4-hydroxy ketones (ref. 16). 

Friedel-Crafts acylation with nitriles and HCl is known as the Hoesch or the Houben-Hoesch reaction ... 

The generation of imidoyl chlorides from nitriles and hydrogen halides in the presence of a suitable Lewis acid accounts for the formation of ketones in the Houben-Hoesch reaction (see Section IVD). 

Other references related to the Houben-Hoesch reaction are cited in the literature. 

The Houben-Hoesch reaction proceeds via a straightforward electrophilic aromatic substitution mechanism. Following protonation or Lewis acid activation of the alkyl nitrile, nucleophilic attack by the electron-rich pyrrole selectively at C(2) produces the resonance stabilized intermediate 1. Elimination of H" reestablishes the aromaticity of the pyrrole, resulting in imine 2, which is rapidly hydrolyzed to produce the ketone 3. ... 

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. 

The electrophilic substitution of an activated nitrile onto an aromatic ring is known as the Houben-Hoesch reaction. The resulting imine is immediately hydrolyzed to yield the corresponding ketone. The reaetion requires a Lewis acid and/or a protic acid, and results in arylketone produets analogous to those which might be obtained under related Friedel-Crafts acylation conditions. 

For a complete description of synthetic utility of the Houben-Hoesch reaction before 1970 as well as some mechanistic discussions, the reader is directed to an excellent review on the subject. The Houben-Hoesch reaction has been widely used for the synthesis of a number of interesting... 

The Houben-Hoesch reaction of phloroglucinol has been elegantly used by Rama Rao and co-workers in a concise synthesis of the chromanol... 

As long as the nucleophilic partner is substituted with electron-donating substituents, the Houben-Hoesch reaction has broad scope. This is most directly illustrated by the work of Parmar and co-workers who used Houben-Hoesch conditions for the synthesis of a large number of benzyl phenyl ketones. ... 

An alkylnitrilium variant of the Houben-Hoesch reaction was used in the synthesis of 11-hydroxy-O-methylsterigmatocystin (34). The preparation of 34 was sought to investigate the role of cytochrome P-450 in the biosynthesis of aflatoxin, a widespread food contaminant and environmental carcinogen. As demonstrated below, nitrilium salt 31 is coupled with 32 to produce 33 in high yield. 

The intramolecular attack of a nitrilium ion is a key step in the Meerwein quinazoline synthesis. A recent example of this reaction can be seen in the synthesis of 4-(A -dimethylamino)-2-arylquinazolines, as demonstrated below. Treatment of imidoyl chloride 39 with NJ -dimethylcyanamide (40) followed by TiCU results in the formation of intermediate 41. Mechanistically, after the production of the likely intermediate nitrilium ion 41, the Houben-Hoesch reaction occurs to give quinazoline 42. A related procedure has been utilized for the synthesis of... 

Aliphatic nitriles react slowly with phenols and phenyl ethers in the presence of trifluoromethanesulphonic acid to give ketones after hydrolysis, in a variation of the Houben-Hoesch reaction. The crystalline complex of copper(i) triflate and benzene induces the acylation of aromatic substrates with selenol esters, affording a transition-metal mediated version of the Friedel-Crafts reaction. Aromatic carboxylic acids can be converted into symmetrical diaryl ketones in good yield by treatment of their 5-(2-pyridyl)thioesters with bis-(l,5-cyclo-octadiene)nickel [equation (15)]. In contrast to other methods for preparing symmetrical aromatic ketones, this method allows their preparation from a single starting material. 

Several name reactions are promoted by AICI3. For example, the Darzens-Nenitzescu reaction is simply the acylation of alkenes. The Ferrario reaction generates phenoxathiins from diphenyl ethers (eq 19) The rearrangement of acyloxy aromatic systems is known as the Fries rearrangement (eq 20). Aryl aldehydes are produced by the Gatterman aldehyde synthesis (eq 21). The initial step of the Haworth phenanthrene synthesis makes use of a Friedel-Crafts acylation. The acylation of phenolic cort tounds is called the Houben-Hoesch reaction (eq 22). The Leuckart amide s)oithesis generates aryl amides from isocyanates (eq 23). ... 

Another approach to the synthesis of the dihydrobenzofurancarboxylic acid 1 is outlined in Scheme 4. The key reaction in this alternative is the Houben-Hoesch reaction on methyl-4-amino-2-methoxy-5-chloro benzoate 10. Houben-Hoesch reaction on anilines, giving exclusively ortho amino ketones has been described by Sugasawa.[i3] Under these reaction conditions, the ether function is demethylated to provide the keto-phenol 11. Compound 11 can then be cyclized under very mild conditions to the furanone 12 which, after reduction... 

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