Copper-Catalyzed Tandem C-N Bond Formation: An Efficient Annulative Synthesis of Functionalized Cinnolines
Copper-Catalyzed Tandem C-N Bond Formation: An Efficient Annulative Synthesis of Functionalized Cinnolines
复制标题
DOI：
10.1002/anie.201201529
复制
发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Willis, Michael C.
中科院分区：
文献类型：
--
作者：
Ball, Catherine J.;Gilmore, Jeremy;Willis, Michael C.
过渡金属催化的芳基C3 N键的形成[1]已成为合成杂环化合物的重要工具。[2]温和的条件下，容易获得的起始材料和用户友好的程序是这样的策略相比，经典的合成提供的优势。然而，开发更广泛的杂环的通用和灵活的路线仍然是一个重要的目标。已知噌啉和噌啉衍生物具有抗癌[3]、杀真菌和杀菌[4]和抗肿瘤[5]活性以及发光和光学性质（方案1）。[6]然而，这些结构在现代有机化学中仍然相对陌生;与喹啉电子等排体相比，噌啉亚结构的利用要少得多。然而，在直接比较这两种结构的药理学特征的许多情况下，噌啉类似物通常表现出上级性质。[3d考虑到许多噌啉的有希望的生物学特性，令人困惑的是，这些结构没有被更彻底地探索。其中一个原因可能是缺乏有效和可获得的合成路线。在本通讯中，我们解决了这个问题，并报告了一个有效的和灵活的噌啉合成的基础上串联铜催化成环，采用一个简单的酰肼亲核试剂。噌啉是典型地使用苯基重氮离子环化到邻位官能团上形成的。[8]在经典的冯里希特合成[9]中，这种环化涉及活化的邻炔（1！2，方案2中的路线A）。然而，这样的路线通常存在显著的限制;需要强酸性条件，需要潜在不稳定且难以处理的重氮中间体，并且噌啉框架的构建必然导致在4位和通常3位的取代。通常需要大量的转化和苛刻的反应条件来生产缺乏这些取代基的噌啉。[10]噌啉的替代途径包括涉及芳基腙，[11]芳基肼，[12]和腈的环化，[13]和分子间环加成。[14]然而，这些途径都不代表一般合成或允许完全控制所并入的取代基模式。我们以前已经证明，2-（2-卤代烯基）-芳基卤化物3可以作为有用的前体的一些杂环，使用两个顺序的过渡金属催化的反应。例如，串联胺化，第一分子间，第二分子内，提供了一系列N-官能化吲哚的有效途径。[15]还可以并入氨基羰基化步骤以产生喹诺酮和异喹诺酮。[16]苯并呋喃也已使用相关化学方法制备。[17]考虑到这些双官能化主链的多功能性，我们设想它们也可以提供一种有效的合成噌啉的途径。我们提出的路线包括芳基烯基二卤化物3与N，N ′-二取代酰肼亲核试剂4的催化环化，得到二氢噌啉衍生物5，然后可以简单地将其转化为相应的芳族核（方案2中的路线B）。
Transition metal-catalyzed aryl CÀN bond formation [1] has become an important tool in the synthesis of heterocycles.[2] Mild conditions, readily accessible starting materials and userfriendly procedures are among the advantages that such a strategy offers compared to classical syntheses. However, the development of general and flexible routes to a wider variety of heterocycles remains an important goal. Cinnolines, and cinnoline derivatives, are known to exhibit anti-cancer,[3] fungicidal and bactericidal,[4] and antiinflammatory [5] activity as well as luminescent and optical properties (Scheme 1).[6] Yet these structures remain relatively unfamiliar in modern-day organic chemistry; when compared with their quinoline isostere, the cinnoline substructure is considerably less exploited. However, in a number of cases where the pharmacological profiles of these two structures have been directly compared, the cinnoline analogue has often exhibited superior properties.[3d, 5, 7] Given the promising biological profile of many cinnolines it is puzzling that these structures have not been explored more thoroughly. One reason for this is presumably the lack of efficient and accessible synthetic routes. In this Communication, we address this issue and report an efficient and flexible cinnoline synthesis based on a tandem copper-catalyzed annulation that employs a simple hydrazide nucleophile. Cinnolines are classically formed using cyclization of a phenyldiazonium ion onto an ortho functionality.[8] In the classic von Richter synthesis [9] this cyclization involves an activated ortho-alkyne (1! 2, route A in Scheme 2). However, such a route usually presents significant limitations; strongly acidic conditions are required, potentially unstable and difficult to handle diazonium intermediates are needed, and the construction of the cinnoline framework necessarily results in substitution at the 4-and often 3-positions. Extensive transformations and harsh reaction conditions are often required to produce cinnolines lacking these substituents.[10] Alternative routes to cinnolines include cyclizations involving aryl hydrazones,[11] aryl hydrazines,[12] and nitriles,[13] and intermolecular cycloadditions.[14] However, none of these routes represent a general synthesis or allow for complete control of the substituent pattern incorporated. We have previously demonstrated that 2-(2-haloalkenyl)-aryl halides 3 can serve as useful precursors to a number of heterocycles, using two sequential transition metal-catalyzed reactions. For example, tandem aminations, the first intermolecular, the second intramolecular, provide efficient routes to a range of N-functionalized indoles.[15] An aminocarbonylation step can also be incorporated to produce quinolones and isoquinolones.[16] Benzofurans have also been prepared using related chemistry.[17] Given the versatility of these difunctionalized backbones we envisaged that they could also provide an efficient synthetic route to cinnolines. Our proposed route involved the catalytic annulation of arylalkenyl dihalides 3 with an N, N’-disubstituted hydrazide nucleophile 4 to provide a dihydrocinnoline derivative 5, which could then be simply converted to the corresponding aromatic core (route B in Scheme 2).