Continuous-Flow Synthesis of 1-Substituted Benzotriazoles from Chloronitrobenzenes and Amines in a CN Bond Formation/Hydrogenation/Diazotization/Cyclization Sequence
Continuous-Flow Synthesis of 1-Substituted Benzotriazoles from Chloronitrobenzenes and Amines in a CN Bond Formation/Hydrogenation/Diazotization/Cyclization Sequence
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DOI：
10.1002/anie.201300615
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Buchwald, Stephen L.
中科院分区：
文献类型：
--
作者：
Chen, Mao;Buchwald, Stephen L.
取代苯并三唑代表了具有抗菌、抗疟疾和抗真菌活性的化合物的关键结构基元。[1]它们也存在于钾通道激活剂、各种酶的[2]抑制剂、[3]和人类孤儿G蛋白偶联受体GPR109b的选择性激动剂中。[4]此外，苯并三唑是合成重要杂环的多种中间体，如咔唑、吡啶、卡波林和四氮杂戊烯。[5]它们还被广泛用作苯环和烷基化反应的合成助剂。1-取代苯并三唑是通过苯并三唑的N-烷基化/芳基化反应或叠氮化物和苯炔的[3+2]环加成反应合成的。由于不对称苯并三唑的互变异构性，烷基化/芳基化方法的区域选择性较差。[7]此外，芳基化试剂通常仅限于活化的杂芳基卤化物或具有强吸电子基团的芳基卤化物。叠氮化合物的1，3-偶极环加成反应的区域选择性在很大程度上取决于苯炔的空间性质和电子性质，经常会形成区域异构体的混合物。[8]由于1-、2-和3-取代苯并三唑的相似物理性质，1-、2-和3-取代苯并三氮唑的分离也往往不容易。此外，不稳定的苯炔中间体的产生和叠氮化合物的大规模处理也存在安全问题。因此，开发一种安全有效的方法来以区域特异性的方式制备1-取代苯并三唑是可取的。[10]在这方面，我们设计了一种由2-氯硝基苯和胺开始的C±N键formation/hydrogenation/diazotization/cyclization序列组成的多步合成方法。根据氯硝基苯的电子性质，C±N键的形成步骤可以通过亲核芳香族取代(SNAR；接近A)或通过钯催化的C±N交叉偶联反应(接近B)，然后加氢和重氮-
Substituted benzotriazoles represent key structural motifs in compounds that possess antibacterial, antimalarial, and antifungal activities.[1] They are also found in potassium channel activators,[2] inhibitors of various kinases,[3] and in selective agonists of human orphan G-protein-coupled receptor GPR109b.[4] In addition, benzotriazoles are versatile intermediates in the synthesis of important heterocycles, such as carbazoles, pyridoacridines, carbolines, and tetraazapentalenes.[5] They have also been extensively utilized as synthetic auxiliaries in benzannulation and alkylation reactions.[6] Traditionally, 1-substituted benzotriazoles have been prepared by N-alkylation/arylation of benzotriazoles or [3+ 2] cycloaddition of azides and benzynes. The alkylation/arylation approach often suffers from poor regioselectivities because of the tautomeric nature of unsymmetrical benzotriazoles.[7] Moreover, the arylation reagents are usually limited to activated heteroaryl halides or aryl halides that possess strong electron-withdrawing groups. The regioselectivity of 1, 3-dipolar cycloadditions of azides is largely dependent on the steric and electronic properties of benzynes, and mixtures of regioisomers are often formed.[8] Separation of 1-, 2-, and 3-substituted benzotriazoles is also oftentimes not trivial because of their similar physical properties.[9] In addition, the generation of unstable benzyne intermediates and the handling of azides on large scale present safety problems. Thus, the development of a safe and efficient method to prepare 1-substituted benzotriazoles in a regiospecific fashion is desirable.[10]In this regard, we have designed a multistep synthesis consisting of a CÀN bond formation/hydrogenation/diazotization/cyclization sequence starting from 2-chloronitrobenzenes and amines. Depending on the electronic properties of the chloronitrobenzene, the CÀN bond-forming step can be achieved either by nucleophilic aromatic substitution (SNAr; approachA) or by a Pd-catalyzed CÀN cross-coupling reaction (approach B) followed by hydrogenation and diazo-