Richter cinnoline reaction

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

This reaction is related to the Widman-Stoermer Synthesis and von Richter Cinnoline... 

In the first reported solid-phase Richter reaction, cinnolines 143 were prepared through a two step sequence of a Heck-type coupling to give intermediates 142 followed by intramolecular ring formation and release of ciimolines 143 <99TL6201>. 

Particularly useful is a synthetic approach utilizing the diazotization of 0-alkynylanilines 222 followed by cyclization of intermediate diazonium salts 223 (the Richter method) (Scheme 128) . In this reaction a nucleophile attacks the C(l) of the alkyne moiety in the diazonium intermediate 223, allowing substitution in the C(4) position of the cinnoline 224. Classically, water was used as the attacking species in the Richter reaction but more recently chloride and bromide nucleophiles have been successfully utilized <1995LA775, 2004T7983>. 

Some of us (94SC1733) have demonstrated that the classical Richter reaction (79MI1), the intramolecular cyclization of 2-alkynylaryldiazonium salts to give cinnolines, can be applied to the synthesis of not only 4-hydroxy- but also... 

The cinnoline ring system was first prepared by Richter via diazotization and subsequent cyclization of o-aminophenylpropionic acid. Subsequent efforts by Widman, and later Stoermer, demonstrated access to the cinnoline ring system via subjection of o-vinyl anilines to diazotization conditions. Other than the observation by Stoermer that o-aminocinnamic acid does not undergo cyclization when exposed to diazotization conditions, initially, little attention was paid to the influence of Ri and R2 on the cyclization of 1 to 2. Sixty years after Widman s first disclosure, Simpson and Schofield " began to address the role of Ri and R2 vide infra). There is a remarkable dearth of literature featuring the title reaction beyond the efforts of Simpson and Schofield, owing, in part, to many other useful methods to prepare cinnolines. 

Regitz reaction 263 Reissert reaction 409 Reissert synthesis (indole) 135 Remfiy-Hull synthesis (pyrimidine) 468 von Richter synthesis (cinnoline) 493 Ritter reaction 442... 

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