Direct synthesis of 2-(aminomethyl)indoles through copper(I)-catalyzed domino three-component coupling and cyclization reactions
Direct synthesis of 2-(aminomethyl)indoles through copper(I)-catalyzed domino three-component coupling and cyclization reactions
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DOI：
10.1002/anie.200604342
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Fujii, Nobutaka
中科院分区：
文献类型：
--
作者：
Ohno, Hiroaki;Ohta, Yusuke;Fujii, Nobutaka
吲哚核是存在于许多具有重要生物活性的天然产物和合成化合物中的一个重要的结构基序，因此合成高度功能化的吲哚衍生物的通用、灵活和选择性的方法受到了相当大的关注。[1]在官能化的吲哚中，2-(氨甲基)吲哚基序是存在于几种生物活性化合物中的关键结构，[2]包括钙调素。[3]大多数合成2-(氨甲基)吲哚的路线都依赖于官能化的吲哚，如吲哚-2-羧酸或其衍生物，[2-4]这限制了易于合成的目标分子的结构。现代合成化学的一个重要领域是开发有效的实用方法，将所需的试剂、溶剂、成本、时间和分离过程降至最低，并将废物的形成降至最低。虽然多组分反应(MCR)方法被认为是实现这一目标的有效方法，但包括MCR的催化多米诺反应将更有吸引力实现这一目标。在我们致力于开发有用的烯类化合物转化的过程中，[6，7]我们发现，在溴化铜存在下，用多聚甲醛(2)和二异丙胺(3a)与多聚甲醛(2)和二异丙胺(3a)处理N-保护的乙炔基苯胺1a，得到2-(氨甲基)吲哚衍生物4a，产率为92%(方案1)，而没有生成预期的[2-(N-甲苯基氨基)苯基]丙烯。该反应可能通过Mannich型MCR反应进行，然后从看似合理的中间体7形成吲哚环。这是第一个通过三组分反应形成吲哚环系而不产生任何盐的例子，尽管通过催化多米诺骨牌合成吲哚衍生物包括索诺加希拉型交叉反应。
The indole nucleus is a prominent structural motif found in numerous natural products and synthetic compounds with important biological activities, and thus considerable attention has been directed toward general, flexible, and selective methods for the synthesis of highly functionalized indole derivatives.[1] Among the functionalized indoles, the 2-(aminomethyl) indole motif is a key structure that exists in several biologically active compounds,[2] including calindol.[3] Most of the synthetic routes to 2-(aminomethyl) indoles rely upon functionalized indoles such as indole-2-carboxylic acid or its derivatives as the starting materials,[2–4] which limit the structure of the target molecules that can be readily synthesized.One current important area of modern synthetic chemistry is the development of efficient practical methods that minimize the requisite reagents, solvents, cost, time, and separation processes for the desired transformation and also minimize the formation of waste.[5] While the multicomponent reaction (MCR) approach is recognized as a powerful method toward this end, a catalytic domino reaction including a MCR would be more attractive to achieve this goal. During the course of our efforts directed toward the development of useful transformations of allenic compounds,[6, 7] we found that treatment of N-protected ethynylaniline 1a with paraformaldehyde (2) and diisopropylamine (3a) in the presence of copper (I) bromide (CrabbØ conditions)[8] gave 2-(aminomethyl) indole derivative 4a in 92% yield (Scheme 1) without formation of the expected [2-(N-tosylamino) phenyl] allene. This reaction would proceed presumably through a Mannichtype MCR followed by formation of the indole ring from the plausible intermediate 7. This is the first example of the formation of an indole ring system by a three-component reaction without producing any salts as by-products, although the synthesis of indole derivatives by catalytic domino threecomponent reactions including Sonogashira-type cross-cou-