Solid-phase synthesis of substituted cinnolines by a Richter type cleavage protocol

Methods for the synthesis of cinnolines (review)

“…The presence of donating groups in the phenyl substituent at the triple bond promoted the formation of the fivemembered products whereas the presence of accepting groups promoted the production of the six-membered products (Scheme 24), which may favor the formation of a cationic intermediate in the course of the cyclization. An interesting modification of the Richter reaction is the use of ortho-ethynyl-substituted phenyltriazenes, in which the triazine fragment acts as a masked diazonium cation, for cyclization [82,83]. This method of synthesis was used for the creation of combinatorial libraries [84].…”

“…Thus, Brase realized the synthesis of 4-halocinnolines during the treatment of alkynyl-substituted triazines with solutions of hydrohalic acids (Scheme 25) [82,83]. The reaction was conducted in a solid-phase version on a polystyrene support, which significantly simplified the isolation and purification of the final products.…”

Tracelessness Unmasked: A General Linker Nomenclature

“…Bräse et al applied such thinking to the cyclization and release of cinnolines (Table 7, entry 5), wherein triazene-bound orthoalkynylarenes were cyclized with aqueous HCl or HBr. [28] Not dissimilar is the acid-mediated cyclorelease of 3-aminobenzisoxazoles which has been shown to take place from the aryloxime polymeric precursor shown in Table 7, entry 6. [29] The system depicted in Table 7, entry 7 allows for the liberation of tetrasubstituted furans by means of a cycloreversion/aromatization process.…”

Solid phase synthesis of 6-acylamino-1-alkyl/aryl-4-oxo-1,4-dihydrocinnoline-3-carboxamides

“…The first cinnolines were synthesized by von Richter 5 and a method based on that initial synthesis was shown to provide cinnolines with various substitution patterns on the allocycle, that is, C5-8, as well as on C3 and C4. 6 Unfortunately, N1-substituted cinnolines are not accessible by this route unless at least one derivatization step would be performed in solution phase. We also attempted to avoid Pd-mediated couplings, 6 that are often oxygen sensitive and may lead to Pd-contaminations in the final products.…”

“…6 Unfortunately, N1-substituted cinnolines are not accessible by this route unless at least one derivatization step would be performed in solution phase. We also attempted to avoid Pd-mediated couplings, 6 that are often oxygen sensitive and may lead to Pd-contaminations in the final products. The principle of our solid-phase approach, allowing to exploit three diversity points on a cinnolinescaffold is presented below (Scheme 1).…”