Name: facile preparation of 4-substituted quinazoline derivatives
Uploaded: 2016-02-15T14:00:00.000+00:00
Duration: 11 min 51 s
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.

注意:使用前请咨询所有相关的材料安全数据表（MSDS）。虽然2-aminobenzophenones是无臭，在该反应中产生一些含硫分子。因此，应始终使用通风良好的条件。在温度超过140℃时进行反应时，请使用所有适当安全的做法，因为压力可能会高于5条微波辐射下的记录。当温度被设定在160℃，记录的最高压力为21巴，这几乎是上限微波反应器可以处理。尽管压力没有时，反应在回流下油浴中进行的问题，应始终使用良好的通风。 1.微波小型辐射四苯基喹唑啉的制备<ol><li>反应液的制备<ol><li>兼容的磁性搅拌棒添加至2-5毫升微波反应管中。 </li><li&gt;使用分析天平，称量0.0866克2-氨基二苯酮（黄色粉末），0.0988克硫脲（白水晶，3当量）的入上述反应管中。 注意:2-氨基二苯甲酮和硫脲之间的最佳比例为1:3。 </li><li>将5毫升DMSO到反应管中。 注意:DMSO的量是相当灵活5毫升DMSO中仅有约足以满足体积为根据制造商的指导微波的正确吸收的最小要求。然而，热条件下，需要少得多的溶剂这种规模的反应。 </li><li>密封用含有橡胶隔片入口兼容铝盖的反应管中。 </li><li>大力摇晃管上的涡旋1-2分钟，以溶解反应物。 注意:硫脲可能无法在DMSO在室温下完全溶解，但加热时它会完全溶解。 </li><li>使用微型注射器向撤回5微升反应混合物，以2毫升玻璃小号ampling含0.35毫升的乙酸乙​​酯（EtOAc）为气相色谱/质谱分析（GC / MS）分析在反应开始前管。 </li></ol></li><li>四苯基喹唑啉的形成微波辐射<ol><li>打开微波反应器，将微波反应管中的八个管持有者之一。 </li><li>设置反应通过触摸屏的参数，如管的位置（ 例如，从井1到8），一种类型的管（例如，2-5毫升）中，反应温度（150℃），预搅拌的持续时间（1分），微波的吸收水平（高），搅拌速度（600转），反应时间（5小时）。 </li><li>一旦所有的参数都是正确设置，单击"运行"按钮，机器人就会自动拿起从管夹（或井水）的反应管中，并把它加热孔内。然后，在微波反应器将根据设置先前的参数运行反应。 </li><li>当微波辐射完成后，WAIT直到温度下降到接近30ºC，机器人将拿起反应管，并把它回到原来的持有者。 </li><li>使用微型注射器向撤回5微升反应混合物（透明黄色溶液，没有观察到不溶性物质），并把它添加到含0.35毫升EtOAc中用于GC / MS分析另外2毫升玻璃采样管。 </li><li>作为GC / MS分析表明反应只完成一半，设置相同管子在相同温度下另外5小时微波反应。 注意:反应时间根据起始原料的使用量而不同，反应溶液中的浓度，对2- aminobenzophenones的取代基，以及更重要的是，反应温度。例如，0.3克2-氨基二苯甲酮在3ml DMSO中的反应将在6小时，在160℃下完成的，但两者在微波辐射和热板加热下持续在140℃以上的14小时。此外，还建议监测反应periodically用GC或GC / MS分析。得不到的GC或GC / MS的人应该再使用薄层色谱（TLC）监测反应，尽管它不是最好的工具。 </li></ol></li><li>反应混合物的GC / MS分析<ol><li>确保的GC / MS是正确根据制造商的协议设置。 </li><li>放在自动进样器托盘玻璃取样管。 </li><li>点击屏幕上"GCMS_3"快捷方式启动控制和协调注射器，GC和质谱仪职能的数据采集程序。通过点击"方法"下拉菜单并强调加载适当的方法"加载方法"。所选择的方法包含所有必要的参数为GC和四倍质谱仪分析目标样品。如果不存在这样的方法中，创建一个必要方法。 <ol><li>为一个新的样品，如果修改一些GC参数的以适应特定的样本，突出"编辑EntirE法"通过点击"方法"从下拉菜单，并相应改变它的相关参数。，常常改变GC的参数是初始温度，并保持该温度的持续时间，温度升高的速率，最终温度和持续时间，以保持温度，喷射量，该次注射时，平衡时间之前和之后洗注射针和后运行时间，以及运行后的温度。 </li><li>对于本实验，设置初始的GC温度在70℃（1分钟），在20℃/分钟的温度增加速率，并在250℃（5分钟）的最终温度。使用15分钟的总运行时间。使用2微升的注射体积，用后洗涤针4预洗和4。用纯氦作为在此条件下所使用的载气。 注意:用于GC / MS分析法包含预先设定的参数同时运行的GC和MS仪器。参数FOřGC包括烘箱的起始温度加热GC柱和分钟数保留该温度下，以提高微波炉的温度的速率，烘箱的最终温度和分钟数保留前的最终温度GC分析完成;样品的注入量;载气的分割率;的次数以洗涤针样品被注入之前;和的次数洗针的样品被注入之后; 等等初始温度和最终温度的选择，以及提高温度的速率取决于分析样品的性质。在一般情况下，低沸点的非极性分子在相对低的初始温度进行分析。 </li></ol></li><li>调整质谱仪根据制造商的协议。 <ol><li>一旦选择了一个正在运行的方法，请点击"乐器"的下拉菜单顶部，并突出显示"调谐MSD"。然后另一个窗口出现在数据采集窗口的前面。人们可以选择"调谐MSD"或"其QuickTune"，并单击"确定"按钮，启动质谱仪的调整过程。该"其QuickTune"选项大约需要3分钟即可完成，而"调谐MSD"选项，运行约10分钟。在正常情况下，"其QuickTune"选项是不够好，校准精度达0.1道尔顿质谱仪。在调整过程将测量的峰值69，219和全氟三丁胺（PFTBA），以及作为N 2，O 2量502的相对丰度，H 2 O，CO 2 等 。 注意:质谱仪必须以具有质量的精确测量每隔一天进行校准。调谐是调整参数用于质谱仪能正常工作，如四倍的电压时，真空质量检测器的，背景噪声，标准峰来衡量质谱仪，等。其中可以选择自动调谐或手动调谐模式选择"其QuickTune"或"调谐MSD"选项来校准质谱仪，也就是说，。 </li></ol></li><li>获得GC / MS的数据<ol><li>编辑数据采集序列。点击下拉菜单顶部的"顺序"，以突出"编辑序列"，一个新的窗口弹出，其中关于样本的信息必须填写，如样品（样品，空白，校准，QC的类型等 ），样品瓶（从1到100），样品名称，数据文件的名称，样品的意见等的位置。当所有样品的信息已经被输入，点击"OK"按钮。然后点击下拉菜单顶部的"顺序"，以突出"保存序列为.."，并输入了正确的文件夹序列名。 </li><li>获取的GC / MS的数据。点击下拉菜单顶部的"顺序"，以突出"运行顺序"，选择一个适当的"数据文件目录"保存采集的数据，然后单击"运行序列"按钮开始数据采集过程。 </li></ol></li><li>分析GC / MS的结果 注意:分子可以通过它们从GC柱上洗脱的分钟来表征，即所谓的保留时间。在相同的GC条件（即，上面提到的气相色谱参数），特定分子的保留时间是非常可重复的。该化合物可通过其质谱进一步证实。人们可以很容易识别的化合物在保留时间和质谱条件，并检查化合物的纯度为好。 <ol><li>双击显示器上的"GCMS_3数据分析"的快捷方式，打开了特意从GC / MS机处理采集数据的软件。 </li><li>在数据采集过程中，看到了分析样品的即时结果，单击"文件"，从下拉菜单，highligHT"拍摄快照"来获得样品的同步GC谱。通常情况下，在收购过程完成后，人们会处理数据。在这种情况下，从下拉菜单中单击"文件"突出"加载数据文件"，并选择正确的数据文件，或浏览数据目录，然后双击该数据文件，以显示样品的全光谱GC。一条垂直线出现在哪里鼠标指向GC频谱的窗口内的位置。 </li><li>将鼠标移动到垂直线命中峰的最高点峰值的中心，并双击鼠标右键，弹出样本的质谱，气相色谱光谱窗口下方的新窗口。一个可以通过按住左键放大的质谱，并选择区域放大为质谱的细节。 </li><li>通过双击质谱窗口内的鼠标右键以获得两个新视窗鉴定的化合物。小前窗与"PBM搜索结果:C:数据库 W8N08.L"的名字带来了从最有可能的匹配分析质谱数据库20的分子，并名列20分子在他们的相似之处顺序。大的背窗口包含两个板，其中前面板显示的GC光谱内所分析的峰的原始质谱，和底面板显示从小前窗的列表中所选择的分子的质谱。通常，常见的有机化合物可以通过其质谱与数据库中收集的标准质谱进行比较来确认。虽然新的化合物或在数据库中未收集的分子不能直接确认他们的身份可以通过预期分子量，并与它们的结构可能片段的匹配来获得。 </li><li>由GC上的频谱比较其保留时间识别不同的样品在同一化合物。根据数据acqu相同的条件isition，相同的化合物应显示在GC光谱相同的保留时间。 </li><li>通过点击"色谱"的下拉菜单中，突出无论是"集成"或"AutoIntegrate"，然后选择"百分比报告"分析样品的纯度。 </li><li>打印选择"打印机设置"时，点击"文件"在下拉菜单对应于纵向或横向格式GC光谱内的峰值都GC谱和质谱。此外，通过选择PDF转换直接打印谱成PDF格式。 </li></ol></li></ol></li><li>反应液提取 注意:隔离工艺已在通风柜进行的，与令人不快的气味的含硫分子的少量在该反应中生成的。 <ol><li>与制造商提供的钳打开微波反应管中，将反应混合物转移到125毫升的分液漏斗中。一个DD20毫升的EtOAc此漏斗，接着用10毫升水。 注意:如果该反应溶液在一天在室温下放置，长针形晶体可以取决于溶液中的浓度出现在该溶液中。因此，这是明智在室温下离开大型反应混合物以形成晶体和分离晶体直接的产品，如果时间不是一个因素。 </li><li>摇动分液漏斗大力，漏底水层。然后另外的10毫升的水加入到分液漏斗中，并重复此过程。 </li><li>集中剩余EtOAc溶液降至约1ml由旋转蒸发。 </li></ol></li><li>通过制备TLC -4-苯基喹唑啉的纯化<ol><li>用巴斯德吸管的浓缩EtOAc溶液转移到20×20cm的制备TLC板以这样的方式，在TLC板样品的条纹宽小于1厘米，距离边缘约1厘米。这浸板到GLA含有150mM毫升己烷和EtOAc的分类室（2:1）。观看溶剂前沿接近TLC板的顶部的运动，并取出盘时溶剂前沿从顶部边缘约1厘米。 <ol><li>借鉴薄层板上，以铅笔两条直线装载样品之前标记的地方。另外，浸在玻璃室中的TLC板在这样一种方式，样品的条纹是在底部，但仍高于溶剂水平约2mm。 </li></ol></li><li>在紫外线（UV）光，用铅笔标记与绿色荧光带，刮开对薄层板上显着的波段称量纸（有R F = 0.68，己烷/乙酸乙酯= 2的相对流动性:1）。 注:由于紫外线吸收灵敏度高，可以在平板上观察多弱带。然而，最顶部条带通常对应于含硫分子，如二甲基二硫化物，二甲基三硫化物;其他乐队低于4 - 苯基喹唑啉是visiblÈ但其量是太少进行分离和表征。 </li><li>填充有玻璃棉玻璃吸管，由对角折叠称量纸上，以允许硅胶的粉末落入吸管划伤硅胶粉末转移到吸移管，挖掘吸管对硬表面包装硅胶紧。洗用丙酮（8-15毫升）吸移管到2鼓闪烁瓶中。 </li><li>转移0.35毫升洗脱丙酮溶液来进行GC / MS分析另外2毫升玻璃采样管，并直接干燥在旋转蒸发器中残留的丙酮溶液。把含在真空干燥器进一步干燥纯化的化合物在整个闪烁瓶中。 注意:直到此步骤，该产品是纯化的和可用于进一步表征（例如，核磁共振（NMR）谱）或其他变换。 </li></ol></li></ol> 2. 4-苯基喹唑啉的制备ⅰ通过加热盘N个小规模注意:反应混合物中，反应混合物的萃取物的GC / MS分析的程序，和反应产物的纯化是非常类似于在第1（1.1.1-1.3.4，1.4.1-1.4.3中所述的那些和1.5.1-1.5.5，分别），使大部分的这些步骤将在下面被删去。 <ol><li>反应混合物为热板加热制备<ol><li>权衡0.0240克2-氨基二苯甲酮和0.0280克硫脲到2ml玻璃小瓶中，然后添加0.5毫升DMSO中转移到相同的小瓶中，并用螺旋盖关闭小瓶中。 注意:DMSO中在此条件下所用的量小于在微波辐射下一个小得多。由于该反应的规模小，则不需要磁力搅拌了，所以为将溶液的旋涡搅拌，以溶解反应物。然而，在一个相对大的反应规模，例如，在2-鼓闪烁瓶中或圆底烧瓶中，磁力搅拌仍然是必要的。 </li></ol></li><li>通过加热盘四苯基喹唑啉的制备<ol><li>里面通风柜，把一个加热块上加热板的顶部，并设定温度至160℃。 </li><li>当温度达到160℃，将玻璃小瓶入加热块的孔中的一个。约一个半小时的时间间隔，取出小瓶并用手摇晃2-3秒，并把它回再次好。 6小时后，取出药瓶，并离开它通风柜内冷却下来。 </li><li>转移5μl反应混合物与含0.35毫升EtOAc中另外2毫升玻璃采样管，并提交样品用于GC / MS分析。 </li></ol></li><li>一旦反应完成，对于GC / MS分析制定出产品如第1说明详见第1.1.1-1.3.4，1.4.1-1.4.3细节，1.5.1-1.5.5，分别反应混合物的提取，和产品的纯化。 </li></ol>

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K., 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=Antibacterial+Activity+of+Quinoxalines,+Quinazolines,+and+1,5-Naphthyridines.">Antibacterial Activity of Quinoxalines, Quinazolines, and 1,5-Naphthyridines.</a> Bioorg. Med. Chem. Lett. 23 (17), 4968-4974 (2013).</li><li>Brown, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Chemistry of Heterocyclic Compounds, Volume 55: Quinazolines, Supplement I. , (1996).</li><li>Yang, C. -. H., 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=Color+Tuning+of+Iridium+Complexes+for+Organic+Light-Emitting+Diodes:+The+Electronegative+Effect+and+-Conjugation+Effect.">Color Tuning of Iridium Complexes for Organic Light-Emitting Diodes: The Electronegative Effect and -Conjugation Effect.</a> J. Organomet. Chem. 691 (12), 2767-2773 (2006).</li><li>Byford, A., Goadby, P., Hooper, M., Kamath, H. V., Kulkarni, S. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=O-Aminophenyl+Alkyl/Aralkyl+Ketones+and+Their+Derivatives.+Part+V.+An+Efficient+Synthetic+Route+to+Some+Biologically+Active+4-Substituted+Quinazolines.">O-Aminophenyl Alkyl/Aralkyl Ketones and Their Derivatives. Part V. An Efficient Synthetic Route to Some Biologically Active 4-Substituted Quinazolines.</a> Ind. J. Chem. 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. 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.

作为该产品的分子量仅相对于该起始材料（ 见图3和图4）的增加9此洁净反应（如在图2中示出 ）出现在开始非常有趣。这听起来不可能的，因为碳的原子量为12非常有可能的，引进一个碳原子的进入的分子将至少12增加分子量如果未包括在所附的氢原子。因此，反应混淆我们相当多的时间。 在2-氨基二苯甲酮和硫脲之间的反应...

取代的喹唑啉，为一种独特类型的杂环的，已被公知用于多种生物活性，包括除其他抗生素，1抗抑郁，2-抗炎，3,4-抗高血压，3抗疟药，5和抗肿瘤，6 。更重要的是，4-取代的喹唑啉，例如，4-芳基喹唑啉，用抗疟原虫活性7已被确认为表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，8中枢神经系统抑制剂，9和对耐甲氧西林金黄色葡萄球菌抗生素金黄色葡萄球菌和由于它的生物活性广谱的抗万古霉素肠球菌 。10，为取代的喹唑啉的合成方法已经在很大程度上探索。作为一个例子，25个以上的合成方法已被报道用于4- phenylquinazolines制备11代表余丹丹方法包括4- phenylquinazolines由2- aminobenzophenones在三氟化硼醚合物的存在下形成和甲酰胺（BF 3·Et 2 O等）12或甲酸，13或从2- aminobenzophenones与乌洛托品和溴乙酸乙酯反应， 14，或在氧化剂的存在下的醛和乙酸铵进行反应。15 使用湿度敏感的试剂，上述反应不同（例如，BF 3·Et 2 O等）或昂贵的试剂（ 如 ，乌洛托品和溴乙酸乙酯），一个浅显的方法，可以很容易地转换2 aminobenzophenones成二甲基亚砜相应的4-phenylquinazolines（ DMSO）中的硫脲的存在下已探索。关于该反应中广泛机理研究表明它是一个互补的反应，其中的硫脲发生热分解，以形成碳化二亚胺和硫化氢，其中碳二亚胺与2-氨基二苯甲酮反应，形成4- phenylquinazolin -2（1H） - 亚胺中间体，同时使用的DMSO不仅作为溶剂，而且还产生了试剂还原试剂，当它与氢反应含硫硫醚（也由硫脲产生的）。然后，将含硫还原剂减少4- phenylquinazolin -2（1H） - 亚胺中间体，以形成4-苯基-1,2-二氢喹唑啉-2-胺该经过消除氨以形成4-苯基喹唑啉。此反应通常在温度从135-160℃下进行，并且可以通过上热板或在微波辐射下的传统油浴中加热的方法容易地进行。该反应在下面的图1大致示出。 <img alt="图1" src="/files/ftp_upload/53662/53662fig1.jpg" /> 图1:2-氨基二苯甲酮和之间的一般反应硫脲在DMSO。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53662/53662fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

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

facile preparation of 4-substituted quinazoline derivatives

本文报道，是从在二甲基亚砜（DMSO）的存在下取代的2- aminobenzophenones和硫脲的反应直接制备4-取代的喹唑啉衍生物的一个非常简单的方法。这是一种独特的互补反应系统，其中的硫脲发生热分解而形成的碳二亚胺和硫化氢，其中用2-氨基二苯甲酮前者反应形成4- phenylquinazolin -2（1H） - 亚胺中间体，而硫化氢用DMSO反应，得到甲硫醇或其它含硫分子，其然后用作补充还原剂减少4- phenylquinazolin -2（1H） - 亚胺中间体入4-苯基-1,2-二氢喹唑啉-2-胺。接着，氨从4-苯基-1,2-二氢喹唑啉-2-胺的消除，得到取代的喹唑啉衍生物。该反应通常给出喹唑自2-氨基二苯甲酮所产生的单品衍生物的GC / MS所监测分析，含硫分子例如二甲基二硫化物，二甲基三硫化物等 。反应通常完成在160ºC在小规模4-6小时，但是当在大规模进行的可能持续超过24小时的少量的沿。该反应产物可容易地通过洗涤的方式以水，接着用柱色谱法或薄层色谱法关闭DMSO中。

在反应前反应混合物的GC分析，在微波辐射下反应后5小时，并在150℃微波辐射下反应后10小时在图2中，它清楚地说明了这种整齐反应的过程中提出的。 2-氨基二苯酮和4-苯基喹唑啉的质谱示于图3和图4分别给出。对于与有机化学良好的知识的人可以在图5假定如图2所示氨基二苯甲酮和硫脲之间的反?...

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.

的4-取代喹唑啉衍生物简便制备

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

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Chemistry

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

视频: 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.

修改和胍集团的官能通过量身定制的前兆

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

科研

生物化学

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.

通过中级过氧化物的抗病毒四氢咔唑衍生物的合成光化学和酸催化CH官能（筹）

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 ...

化学

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.

准备n-(2-alkoxyvinyl) 磺胺从n-tosyl-1,2,3-triazoles 和随后转换为取代 Phthalans 和 Phenethylamines

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.

稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成

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.

[4.4] 刺环氧基的固相合成

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.

功能化单有机硼化合物共轭法高效合成全碳第四纪中心

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%.

微波辅助制备1-Aryl-1 H-pyrazole-5胺

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.

神经素-光催化 [4]1]- 和 [4]2]- 在轻度条件下对阿佐尔克内斯的无效

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.

用于区域选择性开环反应的连续双氮丙啶的制备

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

<meta charset="utf8"></head><body>用于抗菌应用的基于喹啉的离子液体的合成

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.

<meta charset="utf8"></head><body>作者聚焦：利用创新方法和合成化合物推进抗菌素耐药性研究

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.