Name: facile preparation of 4-substituted quinazoline derivatives
Uploaded: 2016-02-15T14:00:00
Description: Watch this Scientific Journal Video about Facile Preparation of 4-Substituted Quinazoline Derivatives at JoVE.com

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.

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 &#176;C, as pressure may go above 5 bars as recorded under microwave irradiation. When the temperature is set at 160 &#176;C, the highest pressure recorded is 21 bars,...

<ol>
	<li>Kamal, A., Reddy, K. L., Devaiah, V., Shankaraiah, N., Rao, M. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+Advances+in+the+Solid-Phase+Combinatorial+Synthetic+Strategies+for+the+Quinoxaline,+Quinazoline+and+Benzimidazole+Based+Privileged+Structures.">Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Quinoxaline, Quinazoline and Benzimidazole Based Privileged Structures.</a> Mini-Rev. Med. Chem. 6 (1), 71-89 (2006).</li><li>Spirkova, K., Stankovsky, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Some+Tricyclic+Annelated+Quinazolines.">Some Tricyclic Annelated Quinazolines.</a> Khim. Geterotsikl. Soedin. (10), 1388-1389 (1995).</li><li>Connolly, D. J., Cusack, D., O'Sullivan, T. P., Guiry, P. 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B. 27 (4), 396-397 (1988).</li><li>Blazevic, N., Oklobdzija, M., Sunjic, V., Kajfez, F., Kolbah, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+Ring+Closures+of+Quinazoline+Derivatives+by+Hexamine.">New Ring Closures of Quinazoline Derivatives by Hexamine.</a> Acta Pharmaceut. Jugo. 25 (4), 223-230 (1975).</li><li>Panja, S. K., Saha, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recyclable,+Magnetic+Ionic+Liquid+Bmim[Fecl4]-Catalyzed,+Multicomponent,+Solvent-Free,+Green+Synthesis+of+Quinazolines.">Recyclable, Magnetic Ionic Liquid Bmim[Fecl4]-Catalyzed, Multicomponent, Solvent-Free, Green Synthesis of Quinazolines.</a> RSC Adv. 3 (34), 14495-14500 (2013).</li><li>Wang, Z. D., Eilander, J., Yoshida, M., Wang, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanistic+Study+of+a+Complementary+Reaction+System+That+Easily+Affords+Quinazoline+and+Perimidine+Derivatives.">Mechanistic Study of a Complementary Reaction System That Easily Affords Quinazoline and Perimidine Derivatives.</a> Eur. J. Org. Chem. (34), 7664-7674 (2014).</li><li>Wang, D. Z., Yoshida, M., George, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Theoretical+Study+on+the+Thermal+Decomposition+of+Thiourea.">Theoretical Study on the Thermal Decomposition of Thiourea.</a> Comput. Theoret. Chem. 1017, 91-98 (2013).</li><li>Zhang, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhibitory+Effect+of+Hydrogen+Sulfide+on+Ozone-Induced+Airway+Inflammation,+Oxidative+Stress,+and+Bronchial+Hyperresponsiveness.">Inhibitory Effect of Hydrogen Sulfide on Ozone-Induced Airway Inflammation, Oxidative Stress, and Bronchial Hyperresponsiveness.</a> Am. J. Respir. Cell Mol. Biol. 52 (1), 129-137 (2015).</li><li>Yan, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-Pot+Synthesis+of+Cdxzn1-Xs-Reduced+Graphene+Oxide+Nanocomposites+with+Improved+Photoelectrochemical+Performance+for+Selective+Determination+of+Cu2+.">One-Pot Synthesis of Cdxzn1-Xs-Reduced Graphene Oxide Nanocomposites with Improved Photoelectrochemical Performance for Selective Determination of Cu2+.</a> RSC Adv. 3 (34), 14451-14457 (2013).</li><li>Keith, J. D., Pacey, G. E., Cotruvo, J. A., Gordon, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+Results+from+the+Reaction+of+Bromate+Ion+with+Synthetic+and+Real+Gastric+Juices.">Experimental Results from the Reaction of Bromate Ion with Synthetic and Real Gastric Juices.</a> Toxicology. 221 (2-3), 225-228 (2006).</li><li>Timchenko, V. 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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...

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&#183;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&#183;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 &#176;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.
<img alt="Figure 1" src="/files/ftp_upload/53662/53662fig1.jpg" />
Figure 1: A general reaction between 2-aminobenzophenone and thiourea in DMSO. <a href="https://www.jove.com/files/ftp_upload/53662/53662fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<table border="0" cellpadding="0" cellspacing="0" width="811">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">2-Aminobenzophenone</td>
			<td style="width:95px;">Alfa Aesar</td>
			<td style="width:105px;">A12580</td>
			<td style="width:395px;">98% purity, with tiny impurity as seen on Figure 1(A) in the manuscript.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Thiourea</td>
			<td style="width:95px;">Acros</td>
			<td style="width:105px;">138910010</td>
			<td>1 KG package, 99%, extra pure</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Dimethyl Sulfoxide</td>
			<td style="width:95px;">Acros</td>
			<td style="width:105px;">326880010</td>
			<td>Methyl sulfoxide, 99.7+%, Extra Dry, AcroSeal&#174;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">N,N-Dimethylformamide</td>
			<td style="width:95px;">Acros</td>
			<td style="width:105px;">348430010</td>
			<td>N,N-Dimethylformamide, 99.8%, Extra Dry over Molecular Sieve, AcroSeal&#174;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Ethyl Acetate</td>
			<td style="width:95px;">Acros</td>
			<td style="width:105px;">610170040</td>
			<td>Ethyl acetate, used as solvent for GC/MS analysis</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Preparative TLC plate</td>
			<td style="width:95px;">Sigma-Aldrich</td>
			<td style="width:105px;">Z740216 SIGMA</td>
			<td>PTLC (Preparative TLC) Glass Plates from EMD/Merck KGaA</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Rotavapor</td>
			<td style="width:95px;">Buchi</td>
			<td style="width:105px;">Rotavapor R-205</td>
			<td>Use to dry solvent</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Microwave Reactor</td>
			<td style="width:95px;">Biotage</td>
			<td style="width:105px;">Initiator+</td>
			<td>Use to carry out chemical reaction under microwave irradiation</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Hotplate</td>
			<td style="width:95px;">IKA</td>
			<td style="width:105px;">RCT basic</td>
			<td>use to carry out thermal chemical reaction</td>
		</tr>
	</tbody>
</table>

facile preparation of 4-substituted quinazoline derivatives

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 &#186;C 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.

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 &#176;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...

Watch this Scientific Journal Video about Facile Preparation of 4-Substituted Quinazoline Derivatives at JoVE.com

Facile Preparation of 4-Substituted Quinazoline Derivatives

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 ...

The overall goal of this experiment is to provide a simple and clean procedure to form four-phenylquinazoline from the reaction between two-aminobenzophenone, and the urea and dimethyl sulfoxide. This method can help answer key questions in the chemistry-field, such as miniscale preparation of chemical compounds and the associated purification techniques. The main advantage of this technique are that the reaction is very clean, as demonstrated by gas chromatography-mass spectroscopy, or GC-mass analysis, and the product can be easily purified by means of preparative or chromatography, or TLC.To prepare the reaction mixture, add a compatible magnetic stir bar to a two to five milliliter microwave reaction tube. Use an analytical balance and weigh point-zero-eight-six-six grams of two-aminobenzophenone, and point-zero-nine-eight-eight grams of the urea into the reaction tube. Then, transfer five milliliters of DMSO to the reaction tube.Seal the reaction tube with a compatible aluminum cap containing a rubber septum-inlet. Vigorously shake the tube on a vortexer for one to two minutes to dissolve the reactants. Next, turn on the microwave reactor and put the microwave reaction tube in one of the eight tube holders.Set up the reaction parameters through the display screen on the microwave reactor, such as the location of tube, the type of tube, the reaction temperature, pre-stirring duration, microwave absorption level, stirring speed, and reaction time. Once all the parameters are set up correctly, click the Run"button. The robot will automatically pick up the reaction tube from the tube holder and put it inside the heating hole.Then, the microwave reactor will run the reaction according to the parameters. When the microwave irradiation completes, wait until the temperature drops to close it to 30 degrees Celsius. The robot will pick up the reaction tube and put it back in the original holder.To perform gas chromatography-mass spectroscopy analysis, first put the glass sampling tubes on the auto-sampler tray. Click the GC-MS-three shortcut on the monitor to initiate the data acquisition program that controls and coordinates the functions of injector GC and mass spectrometer. Load a proper method by clicking Method"on the drop-down menu, and high-lighting Load Method.For this experiment, set the initial GC temperature at 70 degrees Celsius, with an increasing rate of temperature at 20 degrees Celsius per minute, and a final temperature at 250 degrees Celsius. Adjust hold time to set the total running time of 15 minutes, then switch to adjust the injection volume to two-microliters, with four pre-washes by two different solvents each, for two times, and four after-washes with two different solvents each for two times. Use pure helium as the carrier gas under this condition.To edit the data acquisition sequence, click Sequence"on top of the drop-down menu, to highlight Edit Sequence. A new window pops up. Input the information about the samples, such as the type of sample, the location of the sample vial, the sample name, the data file name, and comments.When all the sample information has been input, click the Okay"button. Then click Sequence"on top of the drop-down menu to highlight Save Sequence As"and input the sequence name in a proper folder. Acquire the GC-MS data by clicking Sequence"on top of the drop-down menu, to highlight Run Sequence, choosing a proper data file directory to save the acquired data, and then clicking the Run Sequence"button to start the data acquisition process.To analyze the GC-MS results, double-click the GS-MS-three data analysis shortcut on the monitor to bring up the software that deliberately processes the acquired data from the GC-MS machine. To see this instant results of the analyzed sample during the data acquisition process, click File"from the drop-down menu, and highlight Take Snapshot"to get the synchronized GC spectrum of sample. Process the data after the acquisition process completes by clicking File"from the drop-down menu to highlight Load Data File.Then select the correct data file to show the whole GC spectrum of the sample. A vertical line appears at the position where the mouse is pointed inside the window of the GC spectrum. Move the mouse to the center of a peak where the vertical line hits the highest point and double-click the right button of the mouse to bring up the mass spectrum of the sample in a new window below the GC spectrum.One can zoom the mass spectrum by holding the left button and selecting the region to zoom to visualize the detailed spectrum. Identify the same compound in different samples by comparing its retention time on the GC spectrum. Under the same condition of data acquisition, the same compound should appear with the same retention time on the GC spectrum.Identify the compounds by double-clicking the right button of the mouse inside the mass spectrum window to obtain two new windows. Analyze the purity of the sample by clicking Chromatogram"on the drop-down menu, highlighting either Integrate"or Auto-Integrate, and selecting Percent Report. Before purification, extract the reaction mixture.Open the microwave reaction tube with the manufacture-provided plier and transfer the reaction mixture into a 125-milliliter separating funnel. Add 20-milliliters of ethyl acetate to this funnel, followed by 10-milliliters of water. Shake the separating funnel vigorously, and drain the bottom aqueous layer.Then add another 10-milliliters of water to the separating funnel and repeat this process. Concentrate the remaining ethyl acetate solution down to about one-milliliter by rotary evaporation. Use a pasteur pipette to transfer the concentrated ethyl acetate solution to a 20-centimeter by 20-centimeter preparative TLC plate, in such a way that the stripe of sample on the TLC plate is less than one-centimeter wide, and is about one-centimeter from the edge.Dip this plate into a glass chamber containing 150-milliliters of hexane and ethyl acetate. Watch the movement of the solvent frontier approaching the top of the TLC plate, and take out the plate when the solvent frontier is about one-centimeter from the top edge. Under ultraviolet light, use a pencil to mark the band with green fluorescence.Scratch off the marked band on the TLC plate to a weighing paper. To a glass pipette filled with glass wool, transfer the scratched silica gel powder to the pipette using a diagonally folded weighing paper. Allow the powder of silica gel to fall into the pipette from the weighing paper, and then tap the pipette against a hard surface to pack the silica gel tight.Wash the pipette with acetone into a two-drum scintillation vial. Then transfer point-35 milliliters of the eluted acetone solution to another two-milliliter glass sampling tube, for GC-MS analysis. Directly dry the remaining acetone solution on a rotary evaporator.As a final step, put the whole scintillation vial containing the purified compound in the vacuum desiccator for further drying. Shown here is a GC analysis of the reaction mixture before heat is applied. The peaks of DMSO, ethyl acetate, thiourea, and two-aminobenzophenone, are labeled.Also, the mass spectrum of two-aminobenzophenone in electron ionization mode is shown below the GC spectrum. Shown here is the GC spectrum of the reaction mixture at 150 degrees Celsius after being heated for five hours. The peak of four-phenylquinazoline is almost the same amount of the starting material.The tract reaction intermediate is labeled. Here, the mass spectrum of four-phenylquinazoline in electron ionization mode is shown. The GC spectrum of the reaction mixture after being heated for 10 hours clearly shows the disappearance of the starting material, indicating the completion of the reaction.Shown here, are GC spectra of a reaction heated on a hotplate before the heat is applied. And after the reaction has been heated for six hours. Also shown is the mass spectrum of the reaction side-product.The mass spectra of dimethyl disulfide, and dimethyl trisulfide, is also tracked by GC-MS analysis. While attempting this procedure, it is important to remember that the reaction time varies depending on the scale of the reaction. The larger the reaction scale, the longer the time it takes to complete.After watching this video, you should have a good understanding of how to track a reaction with a GC-mass instrument, and how to purify the reaction product with a preparative of TLC. Don't forget that the side products such as dimethyl disulfide, and possibly methane are strong smelling, so that the reaction should always be wrong in the fume hood.

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Preparation of Carbon Nanosheets at Room Temperature

Amphiphilic molecules equipped with a reactive, carbon-rich "oligoyne" segment consisting of conjugated carbon-carbon triple bonds self-assemble into ...

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

Preparation of Biopolymer Aerogels Using Green Solvents

Although the first reports on aerogels made by Kistler1 in the 1930s dealt with aerogels from both inorganic oxides (silica and others) and biopolymers ...

Facile Synthesis of Worm-like Micelles by Visible Light Mediated Dispersion Polymerization Using Photoredox Catalyst

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins ...

Self-assembling Morphologies Obtained from Helical Polycarbodiimide Copolymers and Their Triazole Derivatives

A facile method for the preparation of polycarbodiimide-based secondary structures (e.g., nano-rings, &#34;craters,&#34; fibers, looped fibers, fibrous ...

Facile Preparation of Ultrafine Aluminum Hydroxide Particles with or without Mesoporous MCM-41 in Ambient Environments

An aqueous suspension of nanogibbsite was synthesized via the titration of aluminum aqua acid [Al(H2O)6]3+ with L-arginine to pH 4.6. Since the hydrolysis ...

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high ...