Palladium-Catalyzed Domino Direct Arylation/N-Arylation: Convenient Synthesis of Phenanthridines
Palladium-Catalyzed Domino Direct Arylation/N-Arylation: Convenient Synthesis of Phenanthridines
复制标题
DOI：
10.1002/anie.200902400
复制
发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Lautens, Mark
中科院分区：
文献类型：
--
作者：
Candito, David A.;Lautens, Mark
菲啶单元代表了天然产物和生物相关化合物中发现的重要结构基序（方案1）。含有该基序的分子作为有效的抗肿瘤剂、抗微生物剂和抗病毒剂是相当感兴趣的主题。[1]人们在这些化合物的衍生物的合成方面投入了大量的精力，以推断结构-活性关系并发现具有改进性质的新类似物。[1]尽管有许多方法可用于合成这些菲啶，但由于缺乏通用性、有限的官能团耐受性和冗长的合成序列，许多方法受到限制。[1-3]钯催化的方法已经解决了官能团耐受性的问题，然而，冗长的合成序列仍然与官能化偶联配偶体的产生有关。采用直接芳基化的方法允许使用简化的起始材料，并且相对于传统的金属催化的交叉偶联反应提供更原子经济的方法。[4]Catellani及其同事报道了一种强有力的策略，该策略涉及一系列多米诺邻位官能化，随后进行末端交叉偶联过程，用于合成二硫代取代的芳族化合物。[5]我们的团队已经采用这种策略设计了有效构建杂环化合物的替代方法。[6]我们设想将C13 H活化/交叉偶联方法应用于合成二硫代取代的菲啶衍生物，由此邻位芳基化和随后的N-芳基化的顺序将在一个步骤中提供所需的化合物（方案1）。①]。[7a]在这些研究期间，研究了许多不同的亚胺衍生物，并且当使用N-二苯基膦酰亚胺（N-Dpp亚胺）时观察到有趣的副产物。使用这些亚胺衍生物，在预期的α-位发生芳基化[Eq. (1)，a]伴随少量的N-芳基化产物[Eq. (1)，B]。据推测，甲硅烷基亚胺有利于N-芳基化的产物，因为它们在氮原子上是亲核的，并且甲硅烷基在反应条件下可以容易地裂解。[8a为了测试该假设，合成甲硅烷基亚胺2a（表1），并在我们先前开发的反应条件下与碘萘反应，以72%的产率顺利地提供所需的苯并[c]菲啶3a。[7b]在这里，我们报告了我们的努力，对发展一个高效的方法，用于建设二氮杂取代的菲啶衍生物，采用N-未取代的和N-甲硅烷基亚胺的基础上，这个反应协议。据我们所知，这份报告是第一次应用这些亚胺衍生物在金属介导的杂环合成。此外，我们还介绍了N-硅基脒的N-芳基化反应，从而扩大了反应的范围。
The phenanthridine unit represents an important structural motif found in natural products and biologically relevant compounds (Scheme 1). Molecules containing this motif are the subject of considerable interest as potent antitumor, antimicrobial, and antiviral agents.[1] Much effort has been invested in the synthesis of derivatives of these compounds to deduce structure-activity relationships and discover new analogues with improved properties.[1] Although a number of methods are available for the synthesis of these phenanthridines, many are limited because of the lack of generality, limited functional group tolerance, and lengthy synthetic sequences.[1–3] Palladium-catalyzed approaches have addressed issues of functional group tolerance, however, lengthy synthetic sequences are still associated with the generation of functionalized coupling partners. Methods employing direct arylation allow for the use of simplified starting materials and offer a more atom economical approach relative to traditional metal-catalyzed crosscoupling reactions.[4] Catellani and co-workers have reported a powerful strategy involving a sequence of domino ortho functionalization with subsequent terminal cross-coupling processes for the synthesis of diversely substituted aromatic compounds.[5] Our group has employed this strategy in devising alternative processes for the efficient construction of heterocyclic compounds.[6] We envisioned applying a CÀH activation/cross-coupling approach toward the synthesis of diversely substituted phenanthridine derivatives, whereby a sequence of ortho arylation and subsequent N-arylation would provide the desired compounds in one step (Scheme 1).The feasibility of this approach was suggested by the unexpected reactivity observed during our previous investigations [Eq.(1)].[7a] During these studies a number of different imine derivatives were investigated and an interesting side-product was observed when N-diphenylphosphinoylimines (N-Dpp imines) were employed. With these imine derivatives, arylation occurred at the expected α-position [Eq.(1), a] accompanied by a small amount of an N-arylated product [Eq.(1), b]. It was reasoned that silylimines would favor the product of N-arylation because they are nucleophilic at the nitrogen atom and the silyl group can be easily cleaved under the reaction conditions.[8a, 9] To test this hypothesis silylimine 2a (Table1) was synthesized and reacted with iodonaphthalene under our previously developed reaction conditions, smoothly providing the desired benzo [c] phenanthridine 3a in 72% yield.[7b] Herein we report our efforts toward the development of a highly efficient method for the construction of diversely substituted phenanthridine derivatives employing N-unsubstituted and N-silylimines based on this reaction protocol. To the best of our knowledge this report represents the first application of these imine derivatives in the metal-mediated synthesis of heterocycles. Furthermore, we introduce the N-arylation of N-silylamidines, thereby expanding the range of