的4-取代喹唑啉衍生物简便制备
Summary
A protocol for facile preparation of 4-substituted quinazoline derivatives from 2-aminobenzophenones, thiourea and dimethyl sulfoxide is presented.
Abstract
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。
Introduction
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。
图1：2-氨基二苯甲酮和之间的一般反应硫脲在DMSO。 请点击此处查看该图的放大版本。
Protocol
Representative Results
Discussion
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…
Divulgations
The authors have nothing to disclose.
Acknowledgements
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.
Materials
| 2-Aminobenzophenone | Alfa Aesar | A12580 | 98% purity, with tiny impurity as seen on Figure 1(A) in the manuscript. |
| Thiourea | Acros | 138910010 | 1 KG package, 99%, extra pure |
| Dimethyl Sulfoxide | Acros | 326880010 | Methyl sulfoxide, 99.7+%, Extra Dry, AcroSeal® |
| N,N-Dimethylformamide | Acros | 348430010 | N,N-Dimethylformamide, 99.8%, Extra Dry over Molecular Sieve, AcroSeal® |
| Ethyl Acetate | Acros | 610170040 | Ethyl acetate, used as solvent for GC/MS analysis |
| Preparative TLC plate | Sigma-Aldrich | Z740216 SIGMA | PTLC (Preparative TLC) Glass Plates from EMD/Merck KGaA |
| Rotavapor | Buchi | Rotavapor R-205 | Use to dry solvent |
| Microwave Reactor | Biotage | Initiator+ | Use to carry out chemical reaction under microwave irradiation |
| Hotplate | IKA | RCT basic | use to carry out thermal chemical reaction |
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