Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles by a Gold-Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition
Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles by a Gold-Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition
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DOI：
10.1002/adsc.201500905
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发表时间：
2016-01-21
影响因子：
5.4
通讯作者：
Davies, Paul W.
中科院分区：
文献类型：
--
作者：
Gillie, Andrew D.;Reddy, Raju Jannapu;Davies, Paul W.
恶唑类化合物是生物活性和功能材料中的重要模体。复杂的、完全取代的和官能化的4-氨基恶唑是在金催化剂的存在下，通过氰胺和N-酰基吡啶N-氨化物之间的有效分子间反应来获得的。形式上的[3+2]偶极环加成反应采用亲核的类硝基方法，以可控的方式获得1，3-N，O-偶极性质。环加成途径的选择性与亲电的酰基腈的不分青红皂白的反应性形成了鲜明对比。报道了从包括羧酸酯和酸在内的可获得的前体中形成酰基官能化胺的方案。探索了这些胺化物在恶唑形成反应中的作用，结果表明，尽管靠近反应中心，但仍能进行大量的精制。因此，基于恶唑的功能性基序，例如具有生物相关取代模式的手性恶唑，很容易获得。评价了未被开发或很少使用的氰化亚胺在金催化中的应用。恶唑周围不寻常的全杂原子取代模式被证明可以使用硫代氰胺来实现。研究表明，在实际的多摩尔规模反应中，接近化学计量比的反应物与相对较低负载的台架稳定的预催化剂是合适的。这种区域选择性分子间制备的有效性和灵活性在具有显著结构和官能团变化的恶唑的现成合成中得到了证明。
Oxazoles are important motifs within bioactive and functional materials. Complex, fully substituted and functionalised 4-aminooxazoles are accessed by an efficient intermolecular reaction between an ynamide and an N-acylpyridinium N-aminide in the presence of a gold catalyst. The formal [3+2] dipolar cycloaddition employs a nucleophilic nitrenoid approach to access the 1,3-N,O-dipole character in a controllable fashion. The selectivity for a cycloaddition pathway provides a stark contrast against the indiscriminate reactivity of electrophilic acyl nitrenes. Protocols for the formation of acyl-functionalised aminides are reported from accessible precursors including carboxylic esters and acids. The function of these aminides in the oxazole-forming reaction has been explored and it is shown that substantial elaboration is accommodated despite proximity to the reactive centre. As a result functional oxazole-based motifs, such as chiral oxazoles with biologically pertinent substitution patterns, are readily accessible. The use of ynamide types that are unexplored or little used in gold catalysis has been evaluated. Unusual all-heteroatom substitution patterns around the oxazole are shown to be accessible using thio-ynamides. The study shows that a close stoichiometry of reactants is suitable alongside relatively low loadings of the bench-stable precatalysts in practically straightforward multi-mmol scale reactions. The efficiency and flexibility of this regioselective intermolecular preparation is demonstrated in the ready synthesis of oxazoles with substantial structural and functional group variation.