The Houben-Hoesch Synthesis

REACTIONS USING NITRILES — THE HOUBEN-HOESCH SYNTHESIS... 

REACTIONS USING NITRILES —THE HOUBEN-HOESCH SYNTHESIS 747... 

Houben-Hoesch synthesis orgchem Condensation of cyanides with polyhydric phenols in the presence of hydrogen chloride and zinc chloride to yield phenolic ketones. hit-ban harsh sin-tha-sas ... 

Pyrroles and furans also undergo the Gattermann aldehyde synthesis with HC1 and HCN, furan gives furfuraldehyde and 2-methylindole gives 2-methylindole-3-carboxaldehyde. The Houben-Hoesch ketone synthesis is also applicable to the preparation of acyl derivatives of furans and pyrroles, e.g. ethyl 2,4-dimethylpyrrole-3-carboxylate with MeCN and HC1 yields (81). 

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. 

Imidoyl chlorides are also intermediates in the Gattermann aldehyde synthesis and in the Houben-Hoesch ketone synthesis. The former reaction uses hydrocyanic acid, hydrogen chloride, and aluminum chloride as the catalyst, while in the latter reaction nitriles, hydrogen chloride, and zinc chloride are used. Hoesch in 1915 assumed that the nitriles combine with hydrogen chloride to form imidoyl chlorides, which undergo electrophilic substitution reaction with a wide variety of substrates. Stephen verified Hoesch s hypothesis by reacting phenylbenzimidoyl chloride with resorcinol, and he obtained the intermediate anil CLIX, which can be hydrolyzed to the corresponding ketone (CLX). 

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. 

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... 

Hao and colleagues disclosed a rapid total synthesis of ( )-tr onoliimine A via a Strecker/Houben-Hoesch sequence.The three-component Strecker-type reaction of 169, 170, and TMSCN was found to be effectively promoted by TMSOTf to furnish intermediate 171 this intermediate was unstable in basic or neutral environments and thus was treated directly with triflic acid at room temperature to effect the Houben-Hoesch cyclization and give ketone 172. Finally, the addition of hydrazine triggered deprotection of the amine and subsequent cyclization to furnish 173 (130L528). 

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... 

Prof. Hao s synthesis commenced with the copper(I) chloride-catalyzed oxidation of the tryptamine derivative to afford ketone 42 [74], A three-component Strecker-type reaction was designed to react the ketone 42 with tryptamine and TMSCN to finish the first ring closure. After examining a series of both Lewis acid and Bronsted acids, the authors found a catalytic amount of TMSOTf promoted the transformation and afforded nitrile intermediate 43, which is ready for the Houben-Hoesch-type cyclization [75]. Treatment by TfOH (trifluoromethanesulfonic acid) [76] in DCM and the... 

The intramolecular acylation of 2-aryloxybenzonitriles allowed the synthesis of molecules with dixanthone skeleton.363 The procedure, in fact, is an intramolecular Houben-Hoesch reaction364 to afford the intermediate bisiminium salts [Eq. (5.144)] which, after hydrolysis, gave the final diketo products. 

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. 

Houben-Hoesch reaction. Synthesis of acyl-phenols from phenols or phenolic ethers by the action of organic nitriles in the presence of hydrochloric acid and aluminum chloride as catalyst. 

This reaction is related to the Friedel-Crafts Acylation, Reimer-Tiemann Reaction, Houben-Hoesch Reaction, Gatterman Aldehyde Synthesis, and Vilsmeier-Haack Formylation. 

The synthesis involved a tnodihed Houben-Hoesch reaction as the key step with A(-alkylnitriliuni salt, in conjunction with the effective, if unusual, protection of a carbonyl group as an alkene i.e. via addition of n-butyllithium and elimination of H2O) (62) (Scheme 13.6). The facile removal of the butenyl group was then effected with m-chloroperbenzoic acid. 

The intramolecular Houben-Hoesch acylation of pyrroles has been used for the synthesis of a number of compounds with interesting properties. An intramolecular acylation was reported by the Meinwald group to synthesize the hairpencil secretion of the butterfly Lycorea ceres... 

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