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A protocol for facile preparation of 4-substituted quinazoline derivatives from 2-aminobenzophenones, thiourea and dimethyl sulfoxide is presented.
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.
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 Enterococcus faecalis.10 Because of its wide spectrum of biological activities, synthetic methods for substituted quinazolines have been largely explored. As an example, more than 25 synthetic methods have already been reported for the preparation of 4-phenylquinazolines.11 Representative methods include the formation of 4-phenylquinazolines from 2-aminobenzophenones and formamide in the presence of boron trifluoride etherate (BF3·Et2O)12 or formic acid,13 or from the reaction of 2-aminobenzophenones with urotropine and ethyl bromoacetate,14 or the reaction with aldehyde and ammonium acetate in the presence of an oxidizing agent.15
Different from the above reactions using moisture sensitive reagent (e.g., BF3·Et2O) or expensive reagent (e.g., urotropine and ethyl bromoacetate), a facile method that can easily convert 2-aminobenzophenones into corresponding 4-phenylquinazolines in dimethyl sulfoxide (DMSO) in the presence of thiourea has been explored. Extensively mechanistic studies on this reaction indicate that it is a complementary reaction in which thiourea undergoes thermal decomposition to form carbodiimide and hydrogen sulfide, where carbodiimide reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, whilst DMSO is used not only as a solvent, but also the reagent to generate sulfur-containing reducing reagent when it reacts with hydrogen sulfide (also arising from thiourea). Then, the sulfur-containing reducing agents reduce the 4-phenylquinazolin-2(1H)-imine intermediate to form 4-phenyl-1,2-dihydroquinazolin-2-amine that undergoes elimination of ammonia to form 4-phenylquinazoline. This reaction is usually carried out at temperature from 135-160 °C, and can be easily performed by means of traditional oil bath heating on hotplate or under microwave irradiation. This reaction is generally illustrated in Figure 1 below.
Figure 1: A general reaction between 2-aminobenzophenone and thiourea in DMSO. Please click here to view a larger version of this figure.
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 under refluxing, good ventilation should always be used.
1. Preparation of 4-Phenylquinazoline in Small Scale Under Microwave Irradiation
2. Preparation of 4-Phenylquinazoline in Small Scale via Hotplate Heating
Note: The procedures for the GC/MS analysis of reaction mixture, extraction of reaction mixture, and purification of reaction product are very similar to the ones described in section 1 (1.1.1-1.3.4, 1.4.1-1.4.3, and 1.5.1-1.5.5, respectively), so that most of these steps will be omitted below.
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...
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...
Except for the contents described in patent (pending), the authors have nothing else to disclose.
The financial support from the National Science Foundation (NSF, grant number 0958901), the Robert Welch Foundation (Welch departmental grant BC-0022 and the Principal Investigator grant BC-1586), and the University of Houston-Clear Lake (FRSF grant) are greatly appreciated.
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 |
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