Cinnolines Borsch synthesis

For example, the cinnoline 8 was synthesized for evaluation as an inhibitor of the twosine kinase domain of the epidermal growth factor receptor (EGFR). This was prepared from l//-4-cinnolone 6 by chlorination and subsequent displacement of chlorine by 3-bromoaniline, as shown in the previous page. The l//-4-cinnolone 6 was prepared in turn from (2-amino)acetophenone by the Borsche synthesis. 

Similarly, cinnoline inhibitors of the tyrosine kinase of the vascular endothelial growth factor receptor (VEGF), such as 10, have also been described. Again, the Borsche synthesis was used to construct the appropriately functionalized l//-4-cinnolone 9, which was then further elaborated to afford 10. ... 

More recently, a cinnoline containing inhibitor of protein kinase B (13) has been prepared through the use of the Borsche cinnoline synthesis. The origin of this product in the Borsche synthesis may not be immediately apparent, because there is no functional group at the 4-position of the cinnoline. In this case, the l/f-4-cinnolone product 11 of the Borsche synthesis was reduced to afford the desired intermediate 6-bromocinnoline 12, which was subjected to a Stille coupling to afford 13. 

A review of cinnolines with biological activity, not limited to those prepared by the Borsche synthesis, has been published recently. ... 

Bischler-Napieralski synthesis (isoquinoline) 413 Bltimlein-Lewy synthesis (oxazole) 172 B oekelheide reaction 362 Bonnemann synthesis (pyridine) 373 Bohlmann-Rahtz synthesis (pyridine) 369 Borsche synthesis (cinnoline) 494 von Braun degradation 432 Brederek synthesis... 

Borsche cinnoline synthesis 141 Bromo-de-diazoniation 194, 230ff., 270, 301... 

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. 

See the Borsche Cinnoline Synthesis and the von Richter Cinnoline Synthesis for other preparations of cinnolines. 

Bart Reaction Borsche (Cinnoline) Synthesis Demianov Rearranement Diazo Reaction Gattermann Reaction Gattermann Method Pschorr Arvlation Sandmever Reaction Schiemann Reaction (Bak-Schiemann JRxn) Tiffeneau-Demianov Reaction fVidman-Stoermer ([Pg.847]

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) ... 

Other references related to the Borsche-Koelsch cinnoline synthesis are cited in the literature. ... 

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. 

Walther Borsche and Alfred Herbert first reported the spontaneous cyclization of an ort/io-diazonium acetophenone in 1941, as part of a larger study on the synthetic transformations of 2-bromo-5-nitroacetophenone carried out at the University of Frankfurt am Main. The authors did not draw especial attention to this observation, and it was not until four years later that Schofield and Simpson suggested that this reaction might offer a general route to 4-cinnolones. After 70 years, this general reaction yielding 4-cinnolones remains one of the most useful methods for the synthesis of cinnolines. 

A deficiency of the Borsche cinnoline synthesis lies in the fact that the orthoacyl aniline starting materials are sometimes not available by convenient means. In the older literature, the starting materials were prepared by the nitration of acetophenones, followed by a difficult separation of the ortho-and meta-nxiro isomers, followed last by reduction of the nitro group to afford the aniline. ... 

---