Houben—Hoesch cyclization

Various intramolecular reactions are widely used to prepare this type of heterocycle. Intramolecular acylation has been used frequently (84AHC(37)i). Houben-Hoesch cyclization of I -(3-cyanoethylpyrrole (4a) gives l-oxo-2,3-dihydropyrrolizine (5a). The methyl group in (4b) selectively activates C-2 so that only the isomer (5b) is formed (66JA1305). 

Intramolecular acylation has been used frequently. Houben-Hoesch cyclization of 1 -/ -cyanoethylpyrrole (2a) gives l-oxo-2,3-dihydropyrrolizine (3a).9-17 Difficulties occur because polymerization of the nitrile (2a) can be a side reaction. Addition of boron trifluoride [3a (33%)]11 or its ethyl ether complex [3a (60-80%)]15 has been recommended. Treatment of nitrile 2a with a molten aluminum chloride-potassium chloride-sodium chloride mixture yields 70% of ketone 3a but the experimental conditions are highly critical.13 A reproducible procedure that is based mainly on Clemo s specification9,10 gave 22% of ketone 3a.17 Purification of 3a should be carried out in an efficient fume hood because it appears to induce analgesia.1 ... 

Friedel-Crafts reactions have found application to form the 1,2-bond of pyrrolizines. Treatment of anhydride 78 with aluminum chloride gave 93% of acid 79, which on heating in the presence of copper gave a 91% yield of 2,3-benzo-1 H-pyrrolizin-1 -one (17).55 Benzopyrrolizinones (81) have been obtained from acid chlorides (80) by a similar route.56,57 Houben-Hoesch cyclization of nitrile 82 gave 2,3-benzo-lf/-pyrrolizin-l-one (17) in a reaction that resembles the formation of 17 from 16a.58... 

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). 

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... 

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). 

The first intramolecular Houben-Hoesch acylation of pyrrole was reported by Clemo and Ramage, and later used by Adams and co-workers in their efforts to prepare 1-hydroxypyrrolizidine and related compounds. Treatment of cyanopyrrole 7 under standard conditions provided 8, albeit with inconsistent yields presumably due to a nonproductive polymerization reaction that accompanies product formation. A short time later. Gabel provided a modified procedure, using BF3-OEt2 as the solvent." Formation of a somewhat stable BF3-pyrrole complex is suggested to prevent polymerization, while still allowing for cyclization. 

An interesting variant of the above reaction, in which unsaturation was present in the newly formed ring, was used by Flitsch and co-workers. Following a low-yielding Wittig reaction to produce the E -isomer 12 as the separable minor component, cyclization was effected under standard Houben-Hoesch conditions to give 13. 

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... 

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