Diversity oriented synthesis of 6-nitro- and 6-aminoquinolones and their activity as alkaline phosphatase inhibitors

Abstract

During the optimization of the conditions of the cyclization, we were able to isolate sideproducts 9 and 10 (Scheme 2). The quantity of these compounds strongly depends on the conditions (see legend of Table 2). The formation of products 9 can be explained by reaction of 6 with two molecules of the amine, i.e. conjugate addition to the ynone and nucleophilic substitution at the arene. Products 10 are formed by conjugate addition of the amine to the alkynone moiety. Under the standard conditions applied for the synthesis of quinolones 7, sideproducts 9 and 10 were formed only in very small quantities (1-2%). However, 9a-d could be isolated and spectroscopically characterized when the reaction was carried out at lower temperature. Reduction of the reaction time during the synthesis of nitroquinolone derivatives allowed us to isolate intermediates 10a and 10b. In general, the yields of unwanted side-products 9 and 10 increased when potassium fluoride was employed instead of standard K 2 CO 3 and K 3 PO 4 . Scheme 2. Side-products 9 and 10. Yields of isolated compounds obtained in reaction conditions specified in footnotes g, h, and i of Table 2.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489

“…The synthesis of 5 took its inspiration from the method of Bernini et al, in which the 4‐quinolone core is assembled by means of a copper‐catalysed heterocyclisation of 1‐(2‐halophenyl)‐2‐en‐3‐amin‐1‐ones, which are in turn synthesised from α,β‐ynones and primary amines . Several similar methodologies exist;, however, the use of these to attain 1,2‐dialkyl‐4‐quinolones has been limited thus far.…”

Conjugated Ynones in Organic Synthesis

“…366 Intermolecular hydroamination of conjugated ynones followed by cyclization has been applied by Langer and co-workers to synthesize aminoquinolones. 152 The substrates were four 2chloro-5-nitrophenyl 1-alkynyl ketones 150, which suffered Michael addition and formation of enaminones 340 when treated with primary amines at elevated temperature. Subsequent intramolecular nucleophilic substitution at the chlorinesubstituted carbon gave 6-nitro-4-quinolones 341 in up to 90% yield (Scheme 155).…”

A review of the syntheses of (thio)flavones, 4‐quinolones, (thio)aurones, and azaaurones from 2′‐substituted alkynones

“…The reaction involved 1,4-addition of amines to 68, nitrogen attack to chlorosubstituted carbon atom with the assistance of p-nitro group, elimination of chloride, and 6-endo cyclization to give 6-nitro-4-quinolone derivatives (69) (Scheme 39). 64 In general, the cyclization proceeded in low yields for anilines than aliphatic amines, which are more nucleophilic.…”