Organic molecules containing the biaryl motif make up an important class of organic compounds. Many are of natural origin, such as the antibiotic vancomycin. Others are valuable drugs for the treatment of hypertension. Some of the drugs containing the biaryl grouping include valsartan, losartan, irbesartan and their congeners. They are among the most prescribed drugs of today. Formation of aryl-aryl bonds has been the subject of numerous papers over the last century and several efficient processes for the synthesis of biaryls are available, such as the Ullmann, Suzuki-Miyaura and Negishi reactions. In connection with our development project on the discovery of drug candidates with thienyl-aryl and furyl-aryl structural features, we required simple and efficient methods for the large scale synthesis of o-(5-formyl-2-thienyl)benzonitrile and o-(5-formyl-2furyl)benzonitrile. Currently, reported methods for the preparation of these target compounds or the corresponding intermediates, o-(2-thienyl)benzonitrile and o-(2-furyl) benzonitrile, employ the Stille coupling from the respective organotin reagents, manganese-catalyzed oxidative cross-coupling of Grignard reagents, palladium-catalyzed arylation of thiophene, cycloaddition reactions with construction of the thiophene or aryl rings, Ullmann condensation of respective aryl iodides and SuzukiMiyaura reactions. However, the main and most important drawbacks of all the published methods are that they are performed on small scale in different solvents at high dilution, use expensive starting materials or toxic or moisture-sensitive reagents. None of the reported methods were convenient for multigram synthesis of the target compounds. We then decided to explore one of the oldest methods for the preparation of such compounds, namely the Gomberg-Bachmann-Hey reaction. An example of the synthesis of o-(2-thienyl)benzoic methyl ester (3b) by an improved Gomberg-Bachmann-Hey procedure has been tested to afford the product in 41% yield on 3.97 g scale. Somewhat better yields of unsymmetrical biaryls have been obtained under phase-transfer conditions but the method has not been tested in the preparation of our target molecules.

中文翻译：

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邻(5-甲酰基-2-噻吩基)苄腈和邻(5-甲酰基-2-呋喃基)苄腈的简单高效大规模无金属合成

含有联芳基序的有机分子构成了一类重要的有机化合物。许多是天然来源的，例如抗生素万古霉素。其他是治疗高血压的有价值的药物。一些含有联芳基的药物包括缬沙坦、氯沙坦、厄贝沙坦及其同系物。它们是当今处方最多的药物之一。在上个世纪，芳基-芳基键的形成一直是许多论文的主题，并且可以使用几种有效的联芳合成方法，例如 Ullmann、Suzuki-Miyaura 和 Negishi 反应。关于我们发现具有噻吩基-芳基和呋喃基-芳基结构特征的候选药物的开发项目，我们需要简单有效的方法来大规模合成 o-(5-formyl-2-thienyl) benzonitrile 和 o-(5-formyl-2furyl)benzonitrile。目前，报道的制备这些目标化合物或相应中间体邻-(2-噻吩基)苄腈和邻-(2-呋喃基)苄腈的方法采用来自各自有机锡试剂、锰催化氧化交叉的Stille偶联。格氏试剂的偶联、钯催化的噻吩芳基化、环加成反应与噻吩或芳环的构建、各自芳基碘化物的 Ullmann 缩合和 SuzukiMiyaura 反应。然而，所有已发表方法的主要和最重要的缺点是它们是在不同溶剂中以高稀释度小规模进行的，使用昂贵的起始材料或有毒或对湿气敏感的试剂。报道的方法均不便于目标化合物的多克合成。然后我们决定探索一种最古老的制备此类化合物的方法，即 Gomberg-Bachmann-Hey 反应。已测试通过改进的 Gomberg-Bachmann-Hey 程序合成邻-(2-噻吩基)苯甲酸甲酯 (3b) 的一个实例，以 3.97 g 的规模以 41% 的产率提供产物。在相转移条件下获得了更好的不对称联芳基产率，但该方法尚未在我们的目标分子的制备中进行测试。然后我们决定探索一种最古老的制备此类化合物的方法，即 Gomberg-Bachmann-Hey 反应。已测试通过改进的 Gomberg-Bachmann-Hey 程序合成邻-(2-噻吩基)苯甲酸甲酯 (3b) 的一个实例，以 3.97 g 的规模以 41% 的产率提供产物。在相转移条件下获得了更好的不对称联芳基产率，但该方法尚未在我们的目标分子的制备中进行测试。然后我们决定探索一种最古老的制备此类化合物的方法，即 Gomberg-Bachmann-Hey 反应。已测试通过改进的 Gomberg-Bachmann-Hey 程序合成邻-(2-噻吩基)苯甲酸甲酯 (3b) 的实例，以 3.97 g 的规模以 41% 的产率提供产物。在相转移条件下获得了更好的不对称联芳基产率，但该方法尚未在我们的目标分子的制备中进行测试。