Synthesis and regioselective alkylation of 1,6- and 1,7-naphthyridines

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis

“…These functionalized [1,6]-naphthyridines and their benzoheterofused analogues are found in many products of marine origin and possess biological activities, including antiproliferative, 306 HIV-1 integrase inhibition, 307 allosteric inhibition of Aktl and Akt2 308 and selective antagonistic activity for 5-HT4 receptors. 309 Traditionally, the synthesis of naphthyridines was carried out either using expensive catalysts [310][311][312] or multistep syntheses, 313 but these greener protocols can offer a useful alternative to synthetically important organic compounds. Indeed, the synthesis of 1,2-dihydro [1,6]naphthyridine and its derivatives using the aforementioned methodology avoids the use of expensive catalysts, toxic organic solvents, and anhydrous conditions.…”

Regioselective [5 + 1] rearrangement–annulation: a new and efficient domino route to highly functionalized [1,6]naphthyridines

“…Fortunately, the desired reaction took place successfully to afford polysubstituted 5,7-diamino-1,6naphthyridines, 4a-4c, in 81-89% yields (Scheme 3). The structures of all the products, 3a-r and 4a-4c, were deduced from their IR, mass, 1 H NMR, and 13 C NMR spectra (see the ESI3) and unambiguously confirmed by the X-ray crystal structure analysis of 3f (CCDC 903823, see the ESI 3 ).…”

“…Heterocycles of [1,6]naphthyridines containing two pyridine rings widely exist in nature; 5 they often serve as ''privileged structures'' in drug discovery and development based on their attractive activities, such as antiproliferative activity, 6 HIV-1 integrase inhibitors, 7 allosteric inhibitors of Akt1 and Akt2, 8 and selective antagonists of 5-HT4 receptors. 9 In the past several decades, many methodologies for the synthesis of [1,6]naphthyridines have been developed, which involved multistep transformations of various substrates 10 (quinolinoannulation, 11 base-promoted heterocyclization of aryl nitriles, 12 alkylation of naphthyridines, 13 hetero-Diels-Alder reactions of aldimines, 14 metal-catalyzed cyclization of dialkynylnitriles, 15 and the recent multicomponent strategy of methyl ketones). 16 In addition, the utilization of a [5 + 1] methodology for the synthesis of pyridines has been reported.…”

One‐Pot Synthesis of Densely Substituted 1,2,3,4‐Tetrahydro‐1,6‐naphthyridine Mediated by Isocyanide‐Assisted Reduction of C−C Double Bond

“…There are only a few novel unconventional routes to access this compound which includes multistep operations starting from 2‐aminopyridine, radical cyclization, reaction of aldehydes with novel HARP (halogen amine radical protocol) reagents, ortho‐alkylation of aminopyridines, intramolecular Chichibabin cyclization etc . In most of the cases, naphthyridine is formed first which is reduced to tetrahydro derivatives in subsequent steps by conventional as well as uncommon procedure using metal catalysis . Notably, a straightforward access to few tetrahydro‐1,5‐ and 1,8‐naphthyridines were afforded via an intramolecular inverse‐electron demand hetero‐Diels‐Alder (ihDA)/retro‐Diels‐Alder (rDA) sequence .…”