One-Pot Synthesis of Highly Substituted Nicotinic Acid Derivatives Based on a Formylation Strategy of Enamino Keto Esters

Abstract

A facile one-pot synthesis of 4-chloro or 4-bromonicotinic acid esters with optional 2- and 2,5-disubstitution on the pyridine ring has been developed from easily accessible enamino keto esters by a formylation followed by in situ intramolecular cyclization strategy under optimized Vilsmeier reaction conditions. The effect of the substituents on the β-carbon and the nature of the keto functionality were explored in detail to understand the mechanism of pyridine ring formation under the described conditions.

Synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones: Rearrangement of pyrrolo[1,2-d][1,3,4]oxadiazines and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles

“…3) [20–28]. For example, it is not reasonable to consider Mazurkiewicz’s acid-promoted rearrangement [20–21], because oxadiazine is not stable under acidic conditions.…”

“…This is highlighted by the observation that the N -imidoylation product (triazinone) 12 was preferentially obtained when a chlorine-halogen source and electron-donating alkyl groups were used. While further studies are required, we suggest the intermediates are N -acylnitrenium ions [26] and halogen-imine structures (the Vilsmeier type) [27–28]. …”

One Pot Synthesis and Biological Evaluation of Some New Pyridine‐3,5‐dicarbonitrile Derivatives

“…Various methodologies have been described for the synthesis of 3,5‐dicarbonitrile pyridine derivatives . However, the existing methods suffered from some drawbacks, such as; the % yield, time, product isolation and purification . We have applied green chemistry principles for de novo synthesis of novel cyanopyridine derivatives.…”

Expanding Blaise‐Type Reactions towards Indium‐Mediated Transformations of α‐Bromo‐β‐keto Esters with Nitriles

“…In this case the primary intermediate 1 was deprotonated with a strong base ( n BuLi) and quenching of the anion with an acyl chloride was reported to generate the formal product 2 of a Blaise reaction starting from an α‐bromo‐β‐keto ester with a nitrile . Shortly thereafter, the Lee group reported the reaction of aminoacrylates with hydrazine derivatives to generate pyrazoles, whereas the Thomas group used the formylation of the aminoacrylates and subsequent cyclisation to generate interesting pyridine derivatives . Additionally, the reaction of the aminoacrylates with alkynes was reported to generate polysubstituted 1‐amino‐substituted 1,3‐dienes, which led to a number of promising follow‐up reactions .…”