Divergent Synthesis of Quinazolines Using Organocatalytic Domino Strategies under Aerobic Conditions

Abstract

An easy and efficient organocatalytic approach to the synthesis of 2‐substituted quinazolines is described based on the reaction between 2‐aminobenzylamines and aldehydes or alcohols or amines. Three organocatalytic platforms were investigated, using 3‐nitropyridine, pyridine N‐oxide, and vitamin B3. Having established the new catalytic systems, the tandem transformations of 2‐aminobenzylamines to give substituted quinazolines were achieved in excellent yields and with a broad substrate scope, with no formation of toxic side‐products. The investigated conditions are not restricted to the use of aldehydes; the protocol also works well with alcohols or amines as substrates. These are oxidized in situ to the corresponding aldehydes to achieve the successful transformation. A mechanistic proposal has been drawn up based on control experiments. We found that under aerobic conditions, catalytic amounts of H2O2 can be generated; this plays a key role in the efficacy of the described approach. The green chemistry metrics of the developed method are also presented. The E factor of 8.18 mg/1 mg demonstrates that the reported method is an excellent complement to previous protocols.

Recent Advances in Pyridine‐Based Organocatalysis and its Application towards Valuable Chemical Transformations

“…The developed reaction conditions showed good compatibility with broad range of functional groups by delivering moderate to excellent yields. The mechanistic pathway resembles the earlier reported method towards the synthesis of 2‐substituted quinazolines . The difference between the two protocol being the use of base to generate t BuOOH by auto‐oxidation, where as in earlier report aerial oxidation could produce catalytic amount of H 2 O 2 (Scheme ).…”

“…The protocol was realized using 3 different organocatalysts, namely vitamin B 3 ( 4 p ), 3‐nitropyridine ( 4 q ) and pyridine‐ N ‐oxide ( 4 r ) for the successful conversion of 2‐aminobenzylamines 52 and aldehydes 41 , 55 or alcohols 53 or amines 54 into 2‐substituted quinazolines 56 a ‐ e . The developed reaction conditions showed applicability over variety of substrates with good functional group tolerance (Scheme ) …”

Organocatalytic Decarboxylation and Dual C(sp3)−H Bond Functionalization Toward Facile Access to Divergent 2,6‐Diarylpyridines

“…With an objective of devising a coherent organocatalytic strategy for the decarboxylation of amino acids and C(sp 3 )−H bond functionalization of aromatic ketones toward the synthesis of pyridines, we began our explorations by choosing acetophenone ( 1 a ) and glycine ( 2 a ) as our model substrates. With the experience of working on the similar cores and organocatalysts, we initiated our experimental studies by screening established organocatalysts [2g,m–o] towards the effective conversion of acetophenone ( 1 a ) and glycine ( 2 a ) in to 2,6‐diphenylpyridine ( 3 aa ) (Table 1). To our surprise, all tested organocatalysts responded fairly under the reaction conditions by giving 2,6‐diarylpyridine ( 3 aa ) in yields ranging from 46–72% (Table 1, entries 1–5).…”

Metal-Free Synthesis of 2-Substituted Quinazolines via Green Oxidation of o-Aminobenzylamines: Practical Construction of N-Containing Heterocycles Based on a Salicylic Acid-Catalyzed Oxidation System

“…Since many byproducts could be generated from this multistep synthesis of quinazolines, several previous studies used an excess amount of benzylamine to selectively obtain the desired products. From the viewpoint of green chemistry, the development an eco-friendly synthesis method for quinazolines with excellent environmental factor (E-factor (%) = kg waste/kg product) and reaction mass efficiency (RME (%) = kg product/kg all reactants × 100) remains challenging (see the Supplementary Information , Han et al, 2011 ; Saha et al, 2017 ; Yamaguchi et al, 2016 ; Yamaguchi et al, 2017 ; Gujjarappa et al, 2018 .). The availability of quinazolines for large-scale synthesis under metal-free conditions is also an important factor in pharmaceutical and industrial chemistry; however, previous methods achieved synthesis only up to the 1 mmol scale ( Tiwari and Bhanage, 2016 ; Gopalaiah, et al, 2017 ; Deshmukh and Bhanage, 2018 ).…”