A Modular Synthesis of Functionalized Pyridines through Lewis‐Acid‐Mediated and Microwave‐Assisted Cycloadditions between Azapyrylium Intermediates and Alkynes

Abstract

In this report we describe the synthesis of differentially functionalized pyridine derivatives 3 and the related 3-bromosubstituted pyridines 11. Dissociation of 6H-1,2-oxazine precursors (1a, 1b, 5, 6, or 12) in situ, mediated by boron trifluoride-diethyl ether, generates the azapyrylium intermediates A, which undergo hetero-Diels-Alder reactions with various mono-and disubstituted alkynes 2. In general, these pyridine syntheses proceeded with high efficiencies and were very flexible with respect to all positions in the pyridine cores. For the 3-phenyl-substituted pyridine derivatives 3a-3j and 11a-11f the best results were obtained by a new microwave-assisted protocol, which is clearly superior to the previously used conventional procedure at low temperature in dichloro-

Diels–Alder Reaction in the Synthesis of Fluorinated (Hetero)Aromatic Compounds

“…Another example was published by Reissig and Zimmer, who synthesized a series of 6 H ‐1,2‐oxazines 135 and demonstrated their application for the preparation of diverse pyridines 136 (Scheme ) . The reaction is mediated by BF 3 · Et 2 O, which transforms 135 to intermediates 137 that react as heterodiene with alkynes giving bicyclic adducts 138 .…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…A wide range of practical syntheses of pyridine derivatives using MW-irradiation have been reported in the last decade [30][31][32][33][34]. In a recent work, Hu et al [30] synthesized a series of novel polyfunctionalized pyrido [2,3-b]indoles.…”

“…In both cases, the compounds were obtained in moderate to good yield; nevertheless, MW-irradiation allowed shortened reaction times (Scheme 3). Another new method allowing the preparation of highly functionalized pyridine derivatives was established by Linder et al [33]. In this synthesis, 6H-1,2-oxazines 22 and various alkynes 23 reacted in the presence of a Lewis acid catalyst and under MW-irradiation leading to polyfunctionnalized pyridines 24 (Scheme 4).…”

Pyridine synthesis by [4 + 2] cycloadditions of 1-azadienes: hetero-Diels Alder and transition metal-catalysed approaches

“…Reissig and Zimmer investigated this concept in their study of 6H-1,2-oxazine derivatives (17, eqn (6)). 22 In this case, Lewis acid-mediated ionization accesses azapyrylium intermediate 19. Cycloaddition proceeds with both electron neutral and rich dienophiles, and extrusion of carbon monoxide affords pyridine products with complete regioselectivity.…”