Richter cyclization

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). 

Because of the much lower reactivity of the diazonium salt with respect to the Richter cyclization, the same sequence could also be carried out starting with aminopyrazole 88 (R = Ph). The azodiazonium salt 89 (R = Ph) was thus obtained by sequential diazotization and neutralization of the resulting mixture at 5-10°C. The salt 89 (R = Ph) could be smoothly cyclized in boiling ethanol in the presence of triethylamine to afford the pyrazolo[4,3-c]pyrazole 90 (R = Ph) [96MC190 99JCS(P1)3721],... 

This method is suitable only for the preparation of 4-substituted and/or 3,4-disubstituted derivatives, the substituents being only alkyl, aryl or heteroaryl groups. The presence of electron-withdrawing groups in the unsaturated side chain prevents the cyclization step. This is understandable if the influence of such groups on the stability of the intermediate carbonium ion is considered. Of more limited application is the analogous cyclization of diazotized o-aminophenylpropiolic acids, the reaction being referred to as the Richter synthesis (Scheme 70). A related synthesis (also referred to as the Neber-Bossel synthesis)... 

The thermal cyclization of 2-alkynylbenzenediazonium salts represented by 2 to provide the 4-hydroxycinnoline derivatives 3 respectively is regarded as the von Richter cinnoline synthesis. " ... 

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

The intramolecular cyclization of 2-alkynylaryldiazonium salts (Richter reaction) leads not only to 4-hydroxy- but also to 4-bromo- and 4-chlorocinnolines. The behavior of alkynylpyrazolediazonium chlorides differs from that of their benzene analogs. The Richter reaction of the series of alkynylaminopyrazoles gives only 4-halo derivatives of l//-pyrazolo[3,4-c]pyridazines and l//-pyrazolo[4,3-c] pyridazines, and mainly hydroxy derivatives of 2//-pyrazolo[3,4-c]pyridazines. 

Dialkyltriazenes ortho to an acetylene substituent on an aryl ring as in 184, undergo ring closure in modified Richter-type cyclizations, forming substituted cinnolines 185 and isoindazoles 186 in fair to very good yields . 

The recent impact of solid-phase synthesis on medicinally relevant benzoaime-lated nitrogen heterocycles has been recently reviewed [16], therefore in this section only recent publications are included. Benzoannelated heterocycles can be prepared efficiently through cyclization on solid supports employing classical heterocycle forming reactions such as the Fischer [425], the Bischler-Napieralski [426], Tsuge [427], Nenitzescu [428], and Richter [140] reactions. In addition, the... 

This approach is important for the synthesis of cinnolines. CHEC(1984) <1984CHEC(2)1> already covered several examples. The methodology used starts with an aniline ortho substituted with an alkene (Widman-Stoermer type), alkyne (Richter type), or enolisable ketone (Borsche type) which is diazotisized, delivering the sixth atom, allowing cyclization. CHEC-II(1996) <1996CHEC-II(6)1> gave more examples. 

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>. 

Richter, L. S., Tom, J. Y. K., and Burnier, J. P. (1994) Peptide-cyclizations on sohd support—a fast and efficient route to small cyclopeptides. Tetrahedron Lett. 35, 5547-5550. 

Cinnolines are prepared by an intramolecular cyclization of o-alkenyl or o-alkynyl aryldiazonium salts. For instance, (o-aminophenyl)alkynes 6 or alkyl(o-aminophenyl)ketones 8 (via the enol form) yield 4-hydroxycinnolines 7 (the v. Richter and Borsche syntheses, respectively), o-Aminostyrenes 10 afford 3,4-disubstituted cinnolines 11 (Widman-Stoermer synthesis) ... 

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 Borsche (or Borsche-Herbert) cinnoline synthesis constitutes the cyclization of an ort/zo-diazonium aryl ketone to form a 4-cinnolone, or 4-hydroxycinnoline. It is mechanistically related to the Widman-Stoermer and Richter cinnoline syntheses, which involve the cyclization of ortho-diazonium aryl olefins and ortho-diazomnm aryl alkynes, respectively. 

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. 

Richter M, Busch B, Ishida K, Moore BS, Hertweck C (2012) Pyran formation by an atypical CYP-mediated four-electron oxygenation-cyclization cascade in an engineered aureothin pathway. Chembiochem 13 2196-2199... 

Vinogradova OV, Sorokoumov VN, Balova lA (2009) A short route to 3-alkynyl-4-bromo (chloro)cinnolines by Richter-type cyclization of OTtho-(dodeca-l,3-diynyl)aryltriaz-l-enes. Tetrahedron Lett 50 6358-6360... 

Ricl994b Richter, L.S., Tom, J.Y.K. and Bumier, J.P., Peptide-Cyclizations on Solid Support A Fast and Efficient Route to Small Cyclopeptides, Tetrahedron Lett., 35 (1994) 5547-5550. 

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