Unusual Sterically Controlled Regioselective Lithiation of 3-Bromo-5-(4,4‘-dimethyl)oxazolinylpyridine. Straightforward Access to Highly Substituted Nicotinic Acid Derivatives

Abstract

[Structure: see text] Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4'-dimethyl)oxazoline with lithium amides is reported. The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'-dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic acids.

On study of sterically controlled regioselective lithiation of meta-halopyridocarboxamides derivatives

“…Indeed, we previously verified this assumption by examining the lithiation of the less hindered 3-bromo-5-oxazolinylpyridine which occurs mainly at the more hindered position 4 (Scheme 1 and Table 1, entry 7). 4 Thus, the present extended study on chlorooxazolinylpyridines 11 and 12 is gaining more support for the sterically controlled regioselective lithiation model depicted in Figure 1. The fact that the nitrogen atom onto the oxazoline DMG versus the oxygen atom onto the alkylamide or dialkylamide DMG is the main chelating-base approach site prior to metallation process is highlighted by experiments for the first time.…”

“…To this end, we recently selected from the 3-bromonicotinic acid model the 4,4 0 -dimethyloxazoline (5) versus bulky amides (1-4) as carboxylic acid modulation to indifferently drive lithiation at both C-2 and C-4 positions using 2,2 0 ,6,6 0 -tetramethylpiperidinyl lithium (LTMP) and lithium diisopropylamide (LDA) bases, respectively (Scheme 1 and Table 1, entries 1-6). 4 In this Letter, we further study the extension of the sterically controlled regioselective lithiation methodology using deuterated probes on the meta-chloro picolinic and isonicotinic series using both (4,4 0 -dimethyl)oxazoline and the structurally related secondary N-alkoxyamide as carboxylic acid DMG-moduling.…”

Opposing actions of TRPV4 channel activation in the lung vasculature

“…Following the protocols of several previous studies (Menendez et al, 2013;Xia et al, 2013), we used serotonin (10 -6 mol/L) to precontract the lung vascular bed. To study TRPV4 channels in the function of pulmonary circulation, GSK1016790A was used to directly contract perfused lung without serotonin ( Figure 6A), GSK1016790A retains normal potency towards its target across a variety of species making it an attractive for investigating TRPV4 channel pharmacology and physiology (Robert et al, 2006). Our data show that TRPV4-dependent mechanisms are responsible for increased pulmonary vascular resistance induced by GSK1016790A in the perfused lung with constant flow at concentrations lower than 10 -6 mol/L.…”

Step by step palladium mediated syntheses of new 2-(pyridin-2-yl)-6-R-nicotinic acids and esters

“…Functionalized nicotinic acid derivatives, including amide, ester, and oxazoline, are of paramount biological and pharmaceutical interest. In addition they also find application in quite different fields [11].…”