Reactions between Grignard reagents and heterocyclic N-oxides: Stereoselective synthesis of substituted pyridines, piperidines, and piperazines

Abstract

In this perspective we discuss the recent developments of stereoselective synthesis of substituted pyridines, piperidines, and piperazines from cheap and commercially readily available starting materials. Pyridine N-oxides and pyrazine N-oxides are reacted with alkyl, aryl, alkynyl and vinyl Grignard reagents to give a diverse set of heterocycles in high yields. Optically active substituted piperazines are obtained by an asymmetric reaction from pyrazine N-oxides using sparteine as chiral ligand. In addition, a stereoselective synthesis of dienal-oximes from the reaction between pyridine N-oxides and Grignard reagents is presented, which results in a useful intermediate for the synthesis of a diverse set of compounds.

Synthesis of 2,6‐Dialkyl(aryl)purine Nucleosides by Exploiting the Reactivity of Nebularine N1‐Oxide towards Grignard Reagents

“…The latter step is similar to the one hypothesized for the transformation of acetylated 3 to 4 . A similar ring‐closing procedure has been previously reported for the transformation of dienal‐oximes to α‐substituted pyridines 11a,11c. It is reasonable to assume that the formation of 8 follows the same pathway, even though it has never been observed for purines.…”

“…However, contrary to what had been observed for the first Grignard addition at C‐6, ring‐opened adducts 7a – g were now formed as a consequence of N1–C2 bond scission; ring‐closed forms 6a – g were not obtained in this case. This behaviour parallels that of formation of dienal‐oximes from pyridine N ‐oxide independently observed by Kellog,11e and Almqvist 11a. Compounds 7a – g proved to be unstable decomposing in a few hours even in dry conditions.…”

Recent Advances in Cycloaddition Reactions of Heterocyclic N-Oxides

“…General and useful synthetic methods exploiting N-oxides as starting materials have been developed, such as cine [6][7][8][9][10][11][12] and other types [13][14][15] of nucleophilic substitution, metalation with organometallic reagents [16], or, more recently, transition metal-catalyzed C-H activation of N-oxides of azines [17][18][19][20][21][22][23][24][25][26][27][28][29] and azoles [30][31][32][33]. The main focus of this review are useful and general synthetic approaches to the preparation of C-2 functionalized azines and azoles based on 1,3-dipolar cycloaddition that has been developed in recent years.…”

On the nonadditivity of the substituent effect in homo-disubstituted pyridines

“…The pyridine ring also constitutes a variety of natural products such as (tobacco) alkaloids . Now, the synthesis of pyridine derivatives is remarkably well documented . The disubstituted pyridines (Scheme ) find application in multitude chemical disciplines and materials: light‐emitting devices, versatile and flexible coordination chemistry ligands, perfuming ingredients, and medicines in which probably only 3,4‐substituted pyridines did not yet have a wide application.…”

“…[40][41][42] Now, the synthesis of pyridine derivatives is remarkably well documented. [43][44][45] The disubstituted pyridines (Scheme 1) find application in multitude chemical disciplines and materials: light-emitting devices, [46] versatile and flexible coordination chemistry ligands, [47] perfuming ingredients, [48] and medicines [49][50][51][52][53][54][55][56][57][58][59][60][61] in which probably only 3,4-substituted pyridines [62,63] did not yet have a wide application.…”