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, 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
<ol>
	<li>Preparation of Reaction Mixture
	<ol>
		<li>Add a compatible magnetic stir bar to a 2-5 ml microwave reaction tube.</li>
		<li>Use analytical balance and weigh 0.0866 g of 2-aminobenzophenone (yellow powder), 0.0988 g of thiourea (white crystal, 3 equivalents) into the above reaction tube. 
		Note: The optimal ratio between 2-aminobenzophenone and thiourea is 1:3.</li>
		<li>Transfer 5 ml of DMSO to the reaction tube. 
		Note: The amount of DMSO is quite flexible, 5 ml of DMSO is just about enough to meet the minimal requirement of volume for correct absorption of microwave according to manufacturer&#39;s guide. However, under thermal condition, much less solvent is needed for reaction of this scale.</li>
		<li>Seal the reaction tube with a compatible aluminum cap containing rubber septum inlet.</li>
		<li>Vigorously shake the tube on a vortexer for 1-2 min to dissolve the reactants. 
		Note: Thiourea may not completely dissolve in DMSO at room temperature, but it will fully dissolve when heat is applied.</li>
		<li>Use a micro-syringe to withdraw 5 &#956;l of reaction mixture to a 2 ml glass sampling tube containing 0.35 ml of ethyl acetate (EtOAc) for gas chromatography/mass spectroscopy (GC/MS) analysis before the reaction starts.</li>
	</ol>
	</li>
	<li>Formation of 4-phenylquinazoline Under Microwave Irradiation
	<ol>
		<li>Turn on microwave reactor, put the microwave reaction tube in one of the eight tube holders.</li>
		<li>Setup reaction parameters through touch screen, such as the location of tube (e.g., from well 1 to 8), type of tube (e.g., 2-5 ml), reaction temperature (at 150 &#176;C), pre-stirring duration (1 min), microwave absorption level (high), stirring speed (600 rpm), and reaction time (5 hr).</li>
		<li>Once all parameters are setup correctly, click &#34;run&#34; button, the robot will automatically pick up the reaction tube from the tube holder (or well) and put it inside the heating hole. Then, the microwave reactor will run the reaction according to the parameters set up previously.</li>
		<li>When microwave irradiation completes, wait until temperature drops to close to 30 &#186;C, the robot will pick up the reaction tube and put it back to the original holder.</li>
		<li>Use micro-syringe to withdraw 5 &#956;l of reaction mixture (clear yellow solution, no insoluble substance observed) and add it to another 2 ml glass sampling tube containing 0.35 ml of EtOAc for GC/MS analysis.</li>
		<li>As GC/MS analysis indicates that the reaction is only half completed, set up the microwave reaction of the same tube for another 5 hr at the same temperature. 
		Note: Reaction time varies depending on the amount of starting material used, the concentration of reaction solution, the substituting groups on 2-aminobenzophenones, and more importantly, the reaction temperature. For example, a reaction of 0.3 g 2-aminobenzophenone in 3 ml of DMSO will complete in 6 hr at 160 &#176;C, but lasts more than 14 hr at 140 &#176;C under both microwave irradiation and hotplate heating. It is also recommended to monitor the reaction periodically with GC or GC/MS analysis. People without access to GC or GC/MS should then use thin layer chromatography (TLC) to monitor the reaction, although it is not the best tool.</li>
	</ol>
	</li>
	<li>GC/MS Analysis of Reaction Mixture
	<ol>
		<li>Make sure GC/MS is setup properly according to manufacturer&#39;s protocol.</li>
		<li>Put the glass sampling tubes on auto-sampler tray.</li>
		<li>Click &#34;GCMS_3&#34; 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 the &#34;Method&#34; on the drop down menu and highlighting &#34;Load Method.&#34; The selected method contains all necessary parameters for both GC and quadruple mass spectrometer to analyze the target samples. If there is no such method, create a necessary method.
		<ol>
			<li>For a new sample, if modify some of the GC parameters to suit a particular sample, highlight the &#34;Edit Entire Method&#34; by clicking &#34;Method&#34; from the drop down menu and change the relevant parameters accordingly. The GC parameters that are often changed are the initial temperature and the duration to hold that temperature, the rate of increasing temperature, the final temperature and the duration to maintain the temperature, the injection amount, the times to wash the injection needle before and after the injection, the equilibration time and post run time, and the post run temperature.</li>
			<li>For this experiment, set the initial GC temperature at 70 &#176;C (1 min), with an increasing rate of temperature at 20 &#176;C/min, and the final temperature at 250 &#176;C (5 min). Use a total running time of 15 min. Use an injection volume of 2 &#956;l, with 4 pre-wash and 4 after-washes of needle. Use pure helium as the carrier gas used under this condition. 
			Note: A method for GC/MS analysis contains the pre-set parameters to run both GC and MS instruments. The parameters for GC include the initial temperature of oven to heat the GC column and the number of minutes to retain that temperature, the rate to raise the temperature of oven, the final temperature of the oven and the number of minutes to retain the final temperature before the GC analysis completes; the amount of sample injected; the split rate of the carrier gas; the number of times to wash the needle before sample is injected; and the number of times to wash the needle after the sample is injected; etc. The choice of initial and final temperatures as well as the rate of raising temperature depends on the nature of analyzed sample. In general, non-polar molecules of low boiling points are analyzed at relatively low initial temperature.</li>
		</ol>
		</li>
		<li>Tune the Mass Spectrometer According to Manufacturer&#39;s Protocol.
		<ol>
			<li>Once a running method is selected, click &#34;Instrument&#34; on top of the drop down menu, and highlight &#34;Tune MSD.&#34; Then another window appears in front of the data acquisition window. One can select either &#34;Tune MSD&#34; or &#34;QuickTune&#34;, and click &#34;OK&#34; button to start the tuning process of mass spectrometer. The &#34;QuickTune&#34; option takes about 3 min to complete, whereas the &#34;Tune MSD&#34; option runs about 10 min. Under normal circumstance, &#34;QuickTune&#34; option is good enough to calibrate the mass spectrometer with accuracy up to 0.1 Dalton. The tuning process will measure the relative abundance of peak 69, 219 and 502 of perfluorotributylamine (PFTBA) as well as the amount of N2, O2, H2O, CO2, etc. 
			Note: The mass spectrometer must be calibrated every other day in order to have an accurate measurement of mass. The tuning is to adjust the parameters for the mass spectrometer to work properly, such as the voltage of quadruple, vacuum of mass detector, the background noise, the standard peaks to gauge the mass spectrometer, etc. One can choose either autotune or manual tune mode to calibrate the mass spectrometer, i.e., by selecting &#34;QuickTune&#34; or &#34;Tune MSD&#34; option.</li>
		</ol>
		</li>
		<li>Acquire the GC/MS Data
		<ol>
			<li>Edit data acquisition sequence. Click the &#34;Sequence&#34; on top of the drop down menu to highlight &#34;Edit Sequence&#34;, and a new window pops up, in which the information about samples should be input, such as the type of sample (sample, blank, calibration, QC, etc.), the location of sample vial (from 1 to 100), sample name, data file name, comments of sample, etc. When all sample information has been input, click &#34;OK&#34; button. Then click the &#34;Sequence&#34; on top of the drop down menu to highlight &#34;Save Sequence As..&#34; and input the sequence name in a proper folder.</li>
			<li>Acquire the GC/MS data. Click the &#34;Sequence&#34; on top of the drop down menu to highlight &#34;Run Sequence&#34;, choose a proper &#34;Data File Directory&#34; to save the acquired data, and then click the &#34;Run Sequence&#34; button to start the data acquisition process.</li>
		</ol>
		</li>
		<li>Analyze the GC/MS Results 
		Note: Molecules can be characterized by the minutes they are eluted from the GC column, so-called the retention time. Under the same GC condition (i.e., the above mentioned GC parameters), the retention time of a particular molecule is very reproducible. The compound can be further confirmed by its mass spectrum. One can easily identify a compound in terms of retention time and mass spectrum, and check the purity of a compound as well.
		<ol>
			<li>Double click the &#34;GCMS_3 Data Analysis&#34; shortcut on the monitor to bring up the software that deliberately processes the acquired data from the GC/MS machine.</li>
			<li>During the data acquisition process, to see the instant result of the analyzed sample, click &#34;File&#34; from the drop down menu and highlight &#34;Take Snapshot&#34; to get the synchronized GC spectrum of sample. Often, people will process the data after the acquisition process completes. In this case, click &#34;File&#34; from the drop down menu to highlight &#34;Load Data File&#34; and select the correct data file, or browse the data directory and double click the data file, to show the whole GC spectrum of the sample. A vertical line appears at the position where mouse is pointed to inside the window of GC spectrum.</li>
			<li>Move mouse to the center of a peak where the vertical line hits the highest point of the peak, and double click the right button of mouse to bring up the mass spectrum of the sample in a new window below the window of GC spectrum. One can zoom the mass spectrum by holding the left button and select the region to zoom for the detail of mass spectrum.</li>
			<li>Identify the compounds by double clicking the right button of mouse inside the mass spectrum window to obtain two new windows. The small front window with a name of &#34;PBM Search Results: C:\Database\W8N08.L&#34; brings up 20 molecules from the database that most likely match the analyzed mass spectrum, and ranks the 20 molecules in order of their similarities. The large back window contains two panels, of which the top panel displays the original mass spectrum of the analyzed peak inside the GC spectrum, and the bottom panel displays the mass spectrum of the selected molecule from the list of small front window. Often, common organic compounds can be confirmed by comparing its mass spectrum with the standard mass spectrum collected in the database. Although new compounds or molecules not collected in the database cannot be directly confirmed, their identities can be obtained through the matching of expected molecular weight and possible fragments with their structures.</li>
			<li>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.</li>
			<li>Analyze the purity of sample by clicking the &#34;Chromatogram&#34; on the drop down menu, highlighting either &#34;Integrate&#34; or &#34;AutoIntegrate&#34;, and selecting &#34;Percent Report&#34;.</li>
			<li>Print both GC spectrum and mass spectra corresponding to the peaks inside the GC spectrum in either portrait or landscape format by selecting &#34;Printer Setup&#34; when one click &#34;File&#34; on the drop down menu. Also, print the spectra directly into pdf format by selecting a pdf converter.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Extraction of Reaction Mixture 
	Note: The isolation process has been carried out in fume hood, as small amount of sulfur-containing molecules with unpleasant smell are generated in this reaction.
	<ol>
		<li>Open the microwave reaction tube with manufacturer provided plier, and transfer the reaction mixture into a 125 ml separating funnel. Add 20 ml of EtOAc to this funnel followed by 10 ml of water. 
		Note: If the reaction solution is left at room temperature over one day, long needle shape crystals may appear in the solution depending on the concentration of solution. Thus, it is wise to leave the large-scale reaction mixture at room temperature to form crystal and isolate the product of crystal directly if time is not a factor.</li>
		<li>Shake the separating funnel vigorously, and drain the bottom aqueous layer. Then add another 10 ml of water to the separating funnel, and repeat this process.</li>
		<li>Concentrate the remaining EtOAc solution down to about 1 ml by rotatory evaporation.</li>
	</ol>
	</li>
	<li>Purification of 4-phenylquinazoline by Preparative TLC
	<ol>
		<li>Transfer the concentrated EtOAc solution with Pasteur pipette to a 20 cm x 20 cm preparative TLC plate in such a way that the stripe of sample on the TLC plate is less than 1 cm wide and is about 1 cm from the edge. Dip this plate to a glass chamber containing 150 ml of hexane and EtOAc (2:1). Watch the movement of solvent frontier approaching the top of the TLC plate, and take out the plate when solvent frontier is about 1 cm from the top edge.
		<ol>
			<li>Draw two straight lines on the TLC plate with pencil to mark the place before sample is loaded. Also, dip the TLC plate in glass chamber in such a way that the stripe of sample is at the bottom but still about 2 mm above the solvent level.</li>
		</ol>
		</li>
		<li>Under ultra-violet (UV) light, use a pencil to mark the band with green fluorescence, and scratch off the marked band on the TLC plate to a weighing paper (with a relative mobility of Rf = 0.68, Hexane/EtOAc = 2:1). 
		Note: Due to high sensitivity of UV absorption, one may observe multiple weak bands on the plate. However, the very top bands often correspond to sulfur-containing molecules, such as dimethyl disulfide, dimethyl trisulfide; others bands below 4-phenylquinazoline are visible but their amount are too little to be isolated and characterized.</li>
		<li>To a glass pipette filled with glass wool, transfer the scratched silica gel powder to the pipette by folding the weighing paper diagonally to allow the powder of silica gel falls into the pipette, and tap the pipette against a hard surface to pack the silica gel tight. Wash the pipette with acetone (8-15 ml) into a 2-drum scintillation vial.</li>
		<li>Transfer 0.35 ml of the eluted acetone solution to another 2 ml glass sampling tube for GC/MS analysis, and directly dry the remaining acetone solution on a rotatory evaporator. Put the whole scintillation vial containing the purified compound in vacuum desiccator for further drying. 
		Note: Up to this step, the product is purified and can be used for further characterization (e.g., nuclear magnetic resonance (NMR) spectroscopy) or additional transformations.</li>
	</ol>
	</li>
</ol>
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.
<ol>
	<li>Preparation of reaction mixture for hotplate heating
	<ol>
		<li>Weigh 0.0240 g of 2-aminobenzophenone and 0.0280 g of thiourea into a 2 ml glass vial, then transfer 0.5 ml of DMSO to the same vial, and close the vial with a screw cap. 
		Note: The amount of DMSO used under this condition is much less than the one under microwave irradiation. Due to small scale of this reaction, magnetic stirring is not needed anymore, so for the vortex stirring of the solution to dissolve the reactants. However, in a relative large reaction scale, for example, in 2-drum scintillation vial or round-bottomed flask, magnetic stirring is still needed.</li>
	</ol>
	</li>
	<li>Preparation of 4-phenylquinazoline via Hotplate Heating
	<ol>
		<li>Inside fume hood, put a heating block on top of hotplate, and set temperature to 160 &#176;C.</li>
		<li>When temperature reaches 160 &#176;C, insert the glass vial into one of the wells in heating block. With about half an hour interval, take out of the vial and hand shake it for 2-3 sec, and put it back to the well again. After 6 hr, take out of the vial and leave it inside the fume hood to cool down.</li>
		<li>Transfer 5 &#956;l of the reaction mixture to another 2 ml glass sampling tube containing 0.35 ml of EtOAc, and submit the sample for GC/MS analysis.</li>
	</ol>
	</li>
	<li>Once the reaction completes, work out the product as described in section 1. See the details in section 1.1.1-1.3.4, 1.4.1-1.4.3, and 1.5.1-1.5.5 for GC/MS analysis, extraction of reaction mixture, and purification of product, respectively.</li>
</ol>

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P., Novozhilov, A. L., Slepysheva, O. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Kinetics+of+Thermal+Decomposition+of+Thiourea.">Kinetics of Thermal Decomposition of Thiourea.</a> Russ. J. Gen. Chem. 74 (7), 1046-1050 (2004).</li><li>Wang, S., Gao, Q., Wang, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thermodynamic+Analysis+of+Decomposition+of+Thiourea+and+Thiourea+Oxides.">Thermodynamic Analysis of Decomposition of Thiourea and Thiourea Oxides.</a> J. Phys. Chem. B. 109 (36), 17281-17289 (2005).</li></ol>

Except for the contents described in patent (pending), the authors have nothing else to disclose.

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 has confused us for quite a bit of time.
In a quick glimpse of the reaction between 2-aminobenzophenone and thiourea, one may postulate that a simple addition of the amino group of 2-aminobenzophenone to the thiocarbonyl group of thiourea followed by addition of the amino group connecting to thiocarbonyl group to the carbonyl group inside the 2-aminobenzophenone will form a structure with a molecular weight of 238 (Figure 5). However, as shown in Figure 2, thiourea decomposes quickly because it cannot be detected after the reaction mixture is heated for 5 hr; under this condition, almost 50% of starting material still remains. If thiourea is the real species to react with 2-aminobenzophenone as postulated in Figure 5, then there will always be starting material remaining in the reaction solution because no more thiourea is available to react with the residual starting material. Thus, this sound mechanism does not represent the real reaction path and is also inconsistent with the change of molecular weight from 197 of starting material to 206 of the product. It is well known that an even number of molecular weight suggests an even number of nitrogen atom inside the molecule. Thus, the product either does not have nitrogen atom at all or contains even number of nitrogen atoms, most likely with two nitrogen atoms in this case; otherwise, the molecular weight of the product cannot be just increased by 9.
After extensive structural characterizations, including 1H NMR, 13C NMR, and especially X-ray crystallography, it is clear that the product is 4-phenylquinazoline.16 But how is it formed? Computational study shows that hydrogen sulfide and carbodiimide can be formed from thermal decomposition of thiourea.17 If the carbodiimide is the species to react with 2-aminobenzophenone, even though thiourea disappears in the reaction solution, carbodiimide would remain in the solution. With this knowledge, it is possible that the amino group inside 2-aminobenzophenone initially reacts with carbodiimide to form 1-(2-benzoylphenyl)guanidine intermediate, which cyclizes to form 4-phenylquinazolin-2(1H)-imine intermediate. However, such intermediate is unstable, and can be hydrolyzed to 4-phenylquinazolin-2(1H)-one, as shown in Figure 6C, under the condition of heating on hotplate. In addition, the decomposition of this intermediate does not lead to the formation of 4-phenylquinazoline either, because the direct transformation of this intermediate to 4-phenylquinazoline would require the removal of a nitrogen atom. This is impossible, as both bonds connecting to this nitrogen atom must break to get rid of a fragment of NH, a highly unstable reactive species. However, if 4-phenylquinazolin-2(1H)-imine intermediate were reduced, then the elimination of ammonia under high temperature would take place very easily (Figure 7). Then, there must be a reducing reagent that participates in the reaction and reduces 4-phenylquinazolin-2(1H)-imine to 4-phenyl-1,2-dihydroquinazolin-2-amine. As mentioned early, thermal decomposition of thiourea generates hydrogen sulfide, along with carbodiimide. Hydrogen sulfide may react with solvent DMSO to generate organic sulfur-containing molecules that function as reducing reagents, although hydrogen sulfide itself has been applied as the reducing agent as well.18-20 The most possible sulfur-containing organic reducing agent might be methanethiol, as supported by detection of dimethyl disulfide (retention time = 3.287 minutes in Figure 2, Mass spectra in Figure 8) and dimethyl trisulfide (retention time = 3.691 minutes in Figure 2, Mass spectra in Figure 9).
<img alt="Figure 2" src="/files/ftp_upload/53662/53662fig2highres.jpg" width="700" /> 
Figure 2: GC analysis of reaction between 2-aminobenzophenone and thiourea in DMSO at 150 &#186;C under microwave irradiation. The GC conditions are: initial temperature at 70 &#176;C (1 min), increasing temperature rate at 20 &#176;C/min, final temperature at 250 &#176;C (5 min). Total running time is 15 min. The injection amount is 2 &#956;l, with 4 pre-wash and 4 after-wash of needle. (A) Reaction mixture before heat is applied; (B) reaction mixture after being heated at 150 &#186;C for 5 hr(imine intermediate observable); (C) reaction mixture after being heated at 150 &#186;C for 10 hr. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig2highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/53662/53662fig3.jpg" /> 
Figure 3: Mass spectrum of 2-aminobenzophenone (EI mode, quadruple). Molecular formula: C13H11NO, molecular weight: 197. Typical fragments are 198, M++1 (9.8%), 197: M+ (68.6%), 196, M+-1 (100.0%), 180: M+-17 (NH3 lost, 8.3%), 120: M+-77 (phenyl C6H5 lost, 35.9%), 105: benzoyl cation (C6H5CO+, 11.4%), 92: M+-benzoyl (M+-C6H5CO, 18.0%), 77: phenyl cation (22.4%). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" src="/files/ftp_upload/53662/53662fig4.jpg" /> 
Figure 4: Mass spectrum of 4-phenylquinazoline (EI mode, quadruple). Molecular formula: C14H10N2, molecular weight: 206.25. Typical fragments are 207: M++1 (7.2%), 206: M+ (50.8%), 205: M+-1 (100.0%), 177: M+-1-HCN-1 (6.6%), 151: M+-1-C4H4-H2 (8.9%), 129: M+-C6H5 (1.6%), 102: M+-C4H4-C4H4 (5.3%). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" src="/files/ftp_upload/53662/53662fig5.jpg" /> 
Figure 5: The apparent mechanism for reaction between 2-aminobenzophenone and thiourea. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" src="/files/ftp_upload/53662/53662fig6highres.jpg" width="700" /> 
Figure 6: GC/MS analysis of reaction between 2-aminobenzophenone and thiourea in DMSO on hotplate at 160 &#186;C. (A) A mixture of 0.0240 g 2-aminobenzophenone and 0.0280 g of thiourea in 0.5 ml DMSO before heat is applied; (B) reaction mixture after being heated at 160 &#186;C for 6 hr; (C) mass spectrum of 4-phenylquinazolin-2(1H)-one byproduct after the solution was heated at 160 &#186;C for 6 hr. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig6highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" src="/files/ftp_upload/53662/53662fig7.jpg" /> 
Figure 7: The true reaction mechanism for the formation of 4-phenylquinazoline from 2-aminobenzophenone and thiourea. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig7large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" src="/files/ftp_upload/53662/53662fig8.jpg" /> 
Figure 8: Mass spectrum of dimethyl disulfide (EI mode, quadruple). Molecular formula: C2H6S2, molecular weight: 94.19. Typical fragments are 95.9: M++2 (2.9%), 94: M+ (62.0%), 79: M+-CH3 (100.0%). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig8large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 9" src="/files/ftp_upload/53662/53662fig9.jpg" /> 
Figure 9: Mass spectrum of dimethyl trisulfide (EI mode, quadruple). Molecular formula: C2H6S3, molecular weight: 126.25. Typical fragments are 128: M++2 (13.7%), 126: M+ (100.0%), 110.9: M+-CH3 (14.6%). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig9large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
For this simple reaction, the critical steps are the control of heating temperature and afterwards purification. As the carbodiimide is the real species that reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, the formation of carbodiimide from thermal decomposition of thiourea is very important. Early study indicated that thiourea starts to decompose at temperature between 140 and 180 &#176;C,21 which is also consistent with computational study of thiourea.17 However, when thiourea is dissolved in polar solvent like DMSO, it starts to decompose at a lower temperature. This temperature has been observed around 120 &#176;C or above in order to have a reasonable reaction rate for the formation of 4-phenylquinazoline from 2-aminobenzophenone. On the other hand, this reaction cannot be setup at a very high temperature either. The upper limit of reaction temperature depends on the boiling point of solvent, and possibly the temperature at which additional side products from thermal decomposition of thiourea are generated. For example, it has been reported that carbon disulfide is the primary product when thiourea is heated at temperature between 182 and 240 &#176;C.22 Also, under condition of microwave irradiation, the whole reaction system is sealed in a reaction tube of limited space, too high temperature can cause very high pressure and potential explosion. Therefore, the ideal reaction temperature is recommended between 150 and 165 &#176;C. While the pressure may not be an issue under thermal refluxing, a high reaction temperature will cause the evolving of hydrogen sulfide that is required to generate reducing reagents from the reaction with DMSO. Another critical step in this protocol is the purification of product. As 4-phenylquinazoline is less polar than starting material, the solubility of product in DMSO is less than that of the starting material. When the reaction is completed, often product of crystal appears if the reaction solution is left at room temperature for a day or longer. In this case, the crystal can be simply filtrated and washed with solvent to obtain pure product. In addition, the concentration of reactants also influences the way to purify the products. At the same reaction temperature, the higher the concentration of solution is, the longer time the reaction takes to complete. Particularly, when the reaction solution is too concentrated, an oil layer of product forms and floats on top of DMSO solution. This is the case when 3 g of 2-aminobenzophenone and 3.5 g of thiourea react in a 20 ml microwave tube with 7 to 8 ml of DMSO. In this case, no crystal forms, and the product can only be separated from solvent through extraction. Meanwhile, the product can be contaminated with sulfur-containing molecules such as dimethyl disulfide and dimethyl trisulfide, which will be removed by column chromatography. This is the procedure recommended for purification of large-scale reaction.
Regarding the modification of this reaction, it can be carried out in a different polar solvent, such as N,N-dimethylformamide (DMF), in the presence of DMSO. In this case, small amount of DMSO is used as the reagent rather than the solvent, for the purpose of generating reducing agent. Under this condition, besides DMSO, less sulfur-containing molecules are present so that unpleasant smell can be well handled. However, this modification will slow down the overall reaction rate. Also, a tiny amount of byproduct originating from DMF is noticeable by GC/MS analysis, although it may not affect the overall purification process. On the other hand, a reaction of large scale can be performed in a round-bottomed flask under refluxing. As it is open to air in the fume hood during refluxing, low volatile molecules including dimethyl disulfide and dimethyl trisulfide will evolve from the reaction system, so that less unpleasant smell will be detected. It should be pointed out that this reaction is very reproducible that has been repeated in multiple times. If the starting materials are mixed correctly in DMSO, and the solution is heated between 150 and 165 &#176;C, it is guaranteed to have the expected final product, so that almost no trouble-shooting is necessary. However, the reaction rate does change when a different 2-aminobenzophenone is used, due to the substituent effect and steric effect.
The significance of this reaction is its simplicity and neatness, with very few minor byproducts. As shown in Figure 2, almost no other side products arising from 2-aminobenzophenone can be observed by GC analysis. Although one peak appears at a retention time (i.e., 10.553 min) higher than 4-phenylquinazoline, such peak is very small and disappears as the reaction proceeds to completion. Spectroscopy study on this peak indicates that it is 4-phenylquinazolin-2(1H)-imine intermediate.16 In addition, very cheap starting material such as thiourea is used in this reaction, instead of other expensive reagents like urotropine or ethyl bromoacetate. Besides the preparation of 4-phenylquinazolines from 2-aminobenzophenones, this reaction can be easily extended to prepare other aromatically fused molecules containing quinazoline scaffold, such as perimidines that have important industrial applications as dyes and pigments. Moreover, this reaction can also be extended to 2-aminophenyl alkyl ketones to prepare quinazolines with an alkyl group at position 4, instead of an aryl group. But it is limited to only those 2-aminophenyl alkyl ketones without active &#945;-hydrogen(s) on the carbon atom adjacent to the carbonyl group, because if an active hydrogen exists at this &#945;-carbon atom, potential tautomerization can occur to form enol that undergoes Aldol condensation to form other side products, instead of quinazoline derivatives.
For this reaction, the optimal ratio between 2-aminobenzophenone and thiourea is 1:3. Computational study of thermal decomposition for thiourea shows that besides a pair of hydrogen sulfide and carbodiimide, ammonia and thiocyanic acid are generated as well, indicating that not all thiourea will be converted into carbodiimide.17 Therefore, at least one equivalent of thiourea is needed for this reaction. On the other hand, as small sulfur-containing molecule will be generated from this reaction, it is wise not to use too much thiourea for this reaction due to the unpleasant smell of sulfur-containing by-products.
It is clear that the reaction between 2-aminobenzophenone and thiourea in DMSO is a unique complementary reaction system, in which thermal decomposition of thiourea produces the required reactive species (i.e., carbodiimide) that couples with 2-aminobenzophenone to form the imino intermediate (i.e., 4-phenyl-quinazolin-2(1H)-imine), whereas hydrogen sulfide reacts with DMSO to generate organic sulfur-containing molecule that functions as reducing agent to reduce the imino intermediate. Then, elimination of ammonia from 4-phenyl-1,2-dihydroquinazolin-2-amine affords 4-phenylquinazoline. The reaction has been tested in other aprotic polar solvents, such as DMF, ethylene glycol, but the reaction is not as good as the one in DMSO. For example, the reaction between 2-aminobenzophenone and thiourea in ethylene glycol affords primarily (5Z,11Z)-6,12-diphenyl-dibenzo[b,f][1,5]-diazocine, the dimerization product of 2-aminobenzophenone.16 While the reaction between 2-aminobenzophenone and thiourea in DMF can afford 4-phenylquinazoline, this reaction is not as clean as the one in DMSO, as shown by the unknown byproducts in Figure 10B. Apparently, this reaction is not as fast as the one in DMSO either. However, the addition of small amount of DMSO into DMF solution certainly improves the reaction in terms of both reaction rate and reduction of side products (Figure 10D and Figure 10E). This result clearly shows the role of DMSO in this reaction, not only as a solvent, but also as a reagent to generate reducing reagent. Therefore, this is a complementary reaction system. As a simple and clean reaction to make quinazoline derivatives, the reported protocol can be applied to the preparation of heterocycles containing the fused pyrimidine scaffold in the future. Many heterocyclic molecules containing the pyrimidine moiety have been used in medicines as well as colorants.
<img alt="Figure 10" src="/files/ftp_upload/53662/53662fig10.jpg" /> 
Figure 10: GC/MS analysis of the reaction between 2-aminobenzophenone and thiourea in DMF and in DMF with DMSO present. (A) A mixture of 0.0318 g of 2-aminobeznophenone and 0.0382 g of thiourea in 2 ml of DMF before heated is applied; (B) the DMF solution after being heated at 165 &#186;C for 11 hr under microwave irradiation; (C) a mixture of 0.0663 g of 2-aminobenzophenone, 0.0767 g of thiourea, 0.5 ml of DMSO and 5.0 ml of DMF before heated is applied; (D) the solution in (C) after being heated at 160 &#186;C for 6 hr under microwave irradiation; (E) the solution in (C) after being heated at 160 &#186;C for 18 hr under microwave irradiation. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53662/53662fig10large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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.remotexs.ntu.edu.sg/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-aminobenzophenone and thiourea that a person with good knowledge of Organic Chemistry may postulate is shown in Figure 5. In comparison, the reaction in DMSO on hotplate at 160 &#186;C is similarly tracked by GC/MS as shown in Figure 6, along with the mass spectrum of 4-phenylquinazolin-2(1H)-one byproduct. Based on many experimental facts, a full explanation for the generation of 4-phenylquinazoline is illustrated in Figure 7. The mass spectra of dimethyl disulfide (MeSSMe) and dimethyl trisulfide (MeSSSMe) are shown in Figure 8 and Figure 9, respectively. The comparison of the reaction between 2-aminobenzophenone and thiourea in DMF and in DMF but with a small amount of DMSO is illustrated in Figure 10.
On the basis of GC/MS analysis, it is quite clear that the conversion of starting material into product is nearly quantitative (Figure 2). Due to small difference of molecular weight between the starting material (e.g., 2-aminobenzophenone, MW = 197, retention time = 9.673 min) and the product of substituted quinazoline derivative (e.g., 4-phenylquinazoline, MW = 206, retention time = 9.962 min), the retention times of starting material and product on GC are very similar, but still separable. More than 10 different 2-aminobenzophenones have been tested for this reaction and similar results are obtained.16

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 ...

facile-preparation-of-4-substituted-quinazoline-derivatives

Nanyang Technological University

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Chemistry

11.8K Views.  University of Houston-Clear Lake. A protocol for facile preparation of 4-substituted quinazoline derivatives from 2-aminobenzophenones, thiourea and dimethyl sulfoxide is presented.

Video: Facile Preparation of 4-Substituted Quinazoline Derivatives

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes &#945;v and &#945;5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document. The modifications described here involve terminally (N&#969;) alkylated and acetylated guanidine groups. For the synthesis, tailor-made precursor molecules are synthesized, which are then subjected to a reaction with an orthogonally deprotected amine to transfer the pre-modified guanidine group. For the synthesis of alkylated guanidines, precursors based on N,N&#8242;-Di-Boc-1H-pyrazole-1-carboxamidine are used to synthesize acylated compounds, the precursor of choice being a correspondingly acylated derivative of N-Boc-S-methylisothiourea, which can be obtained in one- and two-step reactions.

A protocol for the synthesis of alkyl-modified guanidines based on the use of the corresponding precursors is presented.

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. ...

Biochemistry

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Preparation of N-2-alkoxyvinylsulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Representative experimental procedures for the synthesis of N-(2-alkoxyvinyl)sulfonamides and subsequent conversion to phthalan and phenethylamine derivatives are presented in detail.

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines

A synthetic process for the preparation of a variety of 1-aryl-1H-pyrazole-5-amines was developed. The microwave-mediated nature of this method makes it efficient in both time and resources and utilizes water as the solvent. 3-Aminocrotononitrile or an appropriate &#945;-cyanoketone is combined with an aryl hydrazine and dissolved in 1 M HCl. The mixture is then heated in a microwave reactor at 150 &#176;C, typically for 10-15 min. The product can be readily obtained by basifying the solution with 10% NaOH and isolating the desired compound with a simple vacuum filtration. The use of water as a solvent in this reaction lends to its ease and utility in production, and this method is easily reproducible with a variety of functional groups. Typical isolated yields range from 70-90%, and reactions can be performed on the milligram to gram scale with little to no change in observed yields. Some of the applications of these molecules and their derivatives include pesticides, anti-malarials, and chemotherapeutics, among many others.

Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines

1-Aryl-1H-pyrazole-5-amines are prepared from aryl hydrazines combined with either 3-aminocrotononitrile or an &#945;-cyanoketone in a 1 M HCl solution using a microwave reactor. Most reactions are done in 10-15 minutes and pure product can be obtained via vacuum filtration with typical isolated yields of 70-90%.

A synthetic process for the preparation of a variety of 1-aryl-1H-pyrazole-5-amines was developed. The microwave-mediated nature of this method makes it ...

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. Traditionally, they were synthesized through thermal cycloaddition reactions, whereas today, photocatalysis is preferred due to the mild and efficient conditions. With this focus, a new photocatalytic method for the synthesis of nitrogen-containing heterocycles is highly desired. Here, we report a protocol for the biosynthesis of cercosporin, which could function as a metal-free photocatalyst. We then illustrate cercosporin-photocatalyzed protocols for the synthesis of nitrogen-containing heterocycles 1,2,3-thiadiazoles through annulation of azoalkenes with KSCN, and synthesis of 1,4,5,6-tetrahydropyridazines [4+2] through cyclodimerization of azoalkenes under mild conditions, respectively. As a result, there is a new bridge between the microbial fermentation method and organic synthesis in a mild, cost-effective, environmentally friendly and sustainable manner.

New routes for the synthesis of nitrogen-containing heterocycles utilizing cercosporin as a metal-free photocatalyst were developed.

The interest on nitrogen-containing heterocycles has expanded rapidly in the synthetic community since they are important motifs for new drugs. ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of ...

Synthesis of Quinoline-Based Ionic Liquids for Antimicrobial Applications

Green Synthesis of Quinoline-Based Ionic Liquid

The ever-growing menace of Antimicrobial Resistance (AMR) jeopardizes the potency of the prevailing antibiotics against the relentlessly sprouting infections spawned by bacteria, viruses, parasites as well as fungi, posing a great threat to human health and well-being. In this regard, several novel molecules have proved their mettle, with Ionic Liquids (ILs) being one of the most eco-friendly, non-volatile, and thermally stable alternatives to the existing antimicrobials, possessing high solvating potential as well as low vapor pressure. Moreover, the utilization of these entities in both stabilizing as well as destabilizing protein structures and enhancing enzymatic activity has further raised their potential in the biomedical industry. With this in view, we present the green synthesis and characterization of quinoline-based IL, owing to its immense antimicrobial potency, with low cytotoxicity and great artificial chaperone activity. Here, maneuvering the one-pot synthesis approach in solvent-free, greener reaction conditions not only ameliorated the reaction efficiency but also augmented the chemical yield. The purity of the synthesized IL was corroborated using 1H Nuclear Magnetic Resonance (NMR), 13C NMR, and Infrared (IR) spectroscopy. The biological potential of the synthesized compound is further validated by analyzing its Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties and authenticated using disc diffusion assay.

Author Spotlight: Advancing Antimicrobial Resistance Research with Innovative Approaches and Synthetic Compounds

In the present work, we elucidate the green synthesis of quinoline-based Ionic Liquid (IL), namely, 1-Hexadecylquinolin-1-ium bromide {[C16quin]Br} by mixing quinoline with an excess of 1-Bromohexadecane, along with its detailed characterization using Nuclear Magnetic Resonance and Infrared spectroscopic measurements.

Facile Preparation of 4-Substituted Quinazoline Derivatives

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Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

Microwave-Assisted Preparation of 1-Aryl-1H-pyrazole-5-amines

Cercosporin-Photocatalyzed [4+1]- and [4+2]-Annulations of Azoalkenes Under Mild Conditions

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Green Synthesis of Quinoline-Based Ionic Liquid