Facile Preparation of 4-Substituted Quinazoline Derivatives

Summary

A protocol for facile preparation of 4-substituted quinazoline derivatives from 2-aminobenzophenones, thiourea and dimethyl sulfoxide is presented.

Abstract

Reported in this paper is a very simple method for direct preparation of 4-substituted quinazoline derivatives from a reaction between substituted 2-aminobenzophenones and thiourea in the presence of dimethyl sulfoxide (DMSO). This is a unique complementary reaction system in which thiourea undergoes thermal decomposition to form carbodiimide and hydrogen sulfide, where the former reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, whilst hydrogen sulfide reacts with DMSO to give methanethiol or other sulfur-containing molecule which then functions as a complementary reducing agent to reduce 4-phenylquinazolin-2(1H)-imine intermediate into 4-phenyl-1,2-dihydroquinazolin-2-amine. Subsequently, the elimination of ammonia from 4-phenyl-1,2-dihydroquinazolin-2-amine affords substituted quinazoline derivative. This reaction usually gives quinazoline derivative as a single product arising from 2-aminobenzophenone as monitored by GC/MS analysis, along with small amount of sulfur-containing molecules such as dimethyl disulfide, dimethyl trisulfide, etc. The reaction usually completes in 4-6 hr at 160 ºC in small scale but may last over 24 hr when carried out in large scale. The reaction product can be easily purified by means of washing off DMSO with water followed by column chromatography or thin layer chromatography.

Introduction

Substituted quinazolines, as a unique type of heterocycles, have been known for a variety of biological activities, including antibiotic,¹ antidepressant,² anti-inflammatory,^3,4 anti-hypertensive,³ antimalarial,⁵ and anti-tumoral,⁶ among others. What is more, 4-substituted quinazolines, e.g., 4-aryl-quinazolines, with anti-plasmodial activity⁷ have been recognized as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors,⁸ CNS depressants,⁹ and antibiotics against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enter....

Protocol

Caution: Please consult all relevant material safety data sheets (MSDS) before use. Whilst 2-aminobenzophenones are odorless, some sulfur-containing molecules are generated in this reaction. Therefore, good condition of ventilation should always be used. Please use all appropriate safety practice when performing the reactions at temperature higher than 140 °C, as pressure may go above 5 bars as recorded under microwave irradiation. When the temperature is set at 160 °C, the highest pressure recorded is 21 bars, which is almost the upper limit the microwave reactor can handle. Although pressure is not an issue when the reaction is carried out in oil bath unde....

Results

The GC analysis of reaction mixture before the reaction, 5 hr after reaction under microwave irradiation, and 10 hr after reaction under microwave irradiation at 150 °C are presented in Figure 2, which clearly illustrates the process of this neat reaction. The mass spectra of 2-aminobenzophenone and 4-phenylquinazoline are presented in Figure 3 and Figure 4, respectively. An apparent mechanism for the reaction between 2-aminobenzophe.......

Discussion

This clean reaction (as shown in Figure 2) appears very intriguing at beginning as molecular weight of the product is only increased by 9 with respect to that of starting material (as shown in Figure 3 and Figure 4). This sounds impossible because the atomic weight of carbon is 12. Very likely, introduction of one carbon atom into a molecule will increase the molecular weight by at least 12 if the accompanying hydrogen atom(s) were not included. Therefore, the reaction h.......

Materials

Name	Company	Catalog Number	Comments
2-Aminobenzophenone	Alfa Aesar	A12580	98% purity, with tiny impurity as seen on Figure 1(A) in the manuscript.
Thiourea	Acros	138910010	1 KG package, 99%, extra pure
Dimethyl Sulfoxide	Acros	326880010	Methyl sulfoxide, 99.7+%, Extra Dry, AcroSeal®
N,N-Dimethylformamide	Acros	348430010	N,N-Dimethylformamide, 99.8%, Extra Dry over Molecular Sieve, AcroSeal®
Ethyl Acetate	Acros	610170040	Ethyl acetate, used as solvent for GC/MS analysis
Preparative TLC plate	Sigma-Aldrich	Z740216 SIGMA	PTLC (Preparative TLC) Glass Plates from EMD/Merck KGaA
Rotavapor	Buchi	Rotavapor R-205	Use to dry solvent
Microwave Reactor	Biotage	Initiator+	Use to carry out chemical reaction under microwave irradiation
Hotplate	IKA	RCT basic	use to carry out thermal chemical reaction