Houben—Hoesch reaction

Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 139, Springer International Publishing Switzerland 2014 

(a) Hoesch, K. Ber. 1915, 48, 1122-1133. Kurt Hoesch (1882-1932) was bom in Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family business. (b) Houben, J. Ber. 1926, 59, 2878-2891. 

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To explain the experimentally observed high reactivity of HCN and alkyl nitriles under snperacidic condition, Shndo found that in the Gat-terman and Houben-Hoesch reactions, diprotonated HCN (or nitriles) are involved as the de facto reagents (HC N H2, RC N H2). 

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. 

Houben-Hoesch reaction, 12 179 Household appliances, virtual two-way SMA devices in, 22 348 Household laundering, 4 45-46 detersive systems for, <5 413t Household products emulsion use in, 10 129 organic esters in, 10 518-519 Household uses, sodium sulfates in,... 

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. 

In a study involving an intramolecular Houben-Hoesch reaction (eq. 19),... 

Kinetic evidence suggests the involvement of gitonic superelectrophiles also in superacid-promoted Houben-Hoesch reactions.44 As discussed previously, 4-phenylbutyronitrile (6) is found to cyclize at an appreciable rate only in solutions more acidic than Hq —10 (eq 28). 

A modified Houben-Hoesch reaction of the nitrile 84 gave 31% of the azaazulenone 85, which was transformed to 63 by Wolff-Kishner reduction (62JOC1652). Similarly, 86 has been converted into 87 (78CB2407). Acid 88 gave ketone 89 with polyphosphoric acid (69JCS(C)1028) as was 91 formed from 90 (79JHC1443). 

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. 

In the laboratory of D.W. Cameron the total synthesis of the azaanthraquinone natural product bosttycoidin was undertaken using the Minisci reaction and the intramolecular Houben-Hoesch reaction as the key steps. It is worth noting that the synthesis of specific di- and trihydroxyazaanthraquinones by the Friedel-Crafts acylation is very limited due to the lack of orientational specificity and the lack of reactivity of pyridine derivatives in acylation reactions. 

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. 

Houben-Hoesch reaction Synthesis of aromatic ketones from activated aromatic compounds (e.g. phenols) and nitriles. 216... 

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