有机钛试剂在金属催化交叉偶联反应中的应用

The exploration of new and efficient catalytic protocols for organic synthesis remains at the core of modern organic chemistry because of its versatile applications, from the total synthesis of natural products to the preparation of diversified compounds in pharmaceutical industry. Most of the pharmaceuticals containing C-C, C-N and C-O bond hence the ability to construct those bonds in high selectivites under mild conditions is highly valued. Cross-coupling between organometals and organic electrophiles is undoubtedly one of the most straightforward methods for bond construction. Before 1960s, the scope of cross-coupling was limited to magnesium and lithium reagents. Starting from late 1960s, a vast amount of efforts were put on the development of cross-coupling reactions and variety of metals counter-cations as nucleophilic partners for transmetalltion processes were report such as Zn (Negishi cross-coupling), B (Suzuki-Miyaura cross-coupling), Sn (Stille cross-coupling), Mg(Kumada-Corriu cross-coupling), Si (Hiyama cross-coupling), Al, Zr etc. However， the applications of Ti-nucleophiles in cross-coupling process remain less studied. In fact the reduced nucleophilicity of organotitanium reagents compared to that of organomagnesium or organolithium reagents is one of the synthetic advantages of organotitanium chemistry. But the application of organotitanium mainly focused on its unique selectivities in the nucleophilic addition to carbonyl groups and related carbotitanium reactions. Until 2009 Kwong et al. and Gau et al. reported Pd-catalyzed cross-coupling between aryl halides and organtitanium in good yields. And it is undoubtedly a milestone for the development of cross-coupling reaction with organotitanium reagents as nucelophiles. Inspired by the fruitful results the PI would like to probe and explore this novel cross-coupling reactions and attempt to apply the organotitanium reagents on the cross-coupling reactions with aryl sulfonates. In addition to the exploration of substrate scope, the PI would also investigate the possibilities of others metal catalysts for this novel reaction instead of Pd and Ni catalysts. And the PI finally would attempt to explore the asymmetric cross-coupling of organotitanium.

从1960年后期开始经过近数十年间的研究和探索，不单镁能作为非过渡金属有机化合物应用于转移金属化和有机亲电子体构建碳-碳键，其他非过渡金属有机化合物如锌、硼、锡、铝、锆、矽等亦能用作转移金属化试剂进行交叉偶联反应。 事实上以有机钛与有机镁或有机锂试剂相比，有机钛的亲核性较弱以使它在化学合成的应用上有一定的优点。但有机钛的报导多年来则集中于与羰基化合物的加成反应上, 有关应用于交叉偶联反应上的报导则很少。 至2009年Kwong和Gau两研究小组报导了利用钯-膦配体络合物催化芳基卥与有机钛进行偶联反应合成并联芳基化合物, 为偶联反应增加了另一路径。 在催化芳基卥与有机钛进行偶联反应取得成果后, 本研究计划探索利用钯-膦配体络合物催化芳基磺酸盐, 以扩大底物应用范围。此外亦将探索其他金属催化该偶联反应的可行性以及研究实现不对称偶联反应。

背景.虽然不少研究已发现锌、硼、 锡、镁、铝、锆、矽等能用作转移金属化试剂和有机亲电子体进行交叉偶联反应构建碳-碳键。但它们于催化反应中有不同的局限性例如： 有机镁进行Kumada-Corriu交叉偶联反应时，不温和的反应条件使官能团兼容性差, Stille交叉偶联反应中的有机锡试剂毒性强以致它不被广泛应用。 Negishi交叉偶联反应及Suzuki-Miyaura 交叉偶联反应为现时有机合成反应中最常用的交叉偶联反应, 但某些底物在Negishi 交叉偶联反应和Suzuki-Miyaura 交叉偶联反应下产能不高, 所以开发新的高效及高官能团兼容性的偶联反应仍然十分重要。..研究内容、重要结果.我們发现钯- 吲哚类膦配体络合物能进行催化芳基磺酸酯类底物与有机钛进行交叉偶联反应，及后测试及调节了不同反应条件， 探索出加入K3PO4 (0.25倍)能提高催化效能。利用经调较的反应条件,不同的芳基磺酸酯类底物以及环芳基磺酸酯类底物能高效地跟有机钛合成出联芳基化合物(70 %-95%)。 .我們透过调节吲哚类膦配体的电子特性和空间因素, 研发出新的吲哚类膦配体，NMe2-CMPhos并利用0.2 -4mol% 钯－NMe2-CMPhos催化芳基/杂芳基／烯基甲磺酸与有机钛进行偶合反应生成联芳基化合物/联芳基杂环化合物。另外这是首次在没有加入碱及溶剂的反应条件下，非过渡金属有机化合物和芳基磺酸酯类底物之间的碳-碳成键反应。有助开拓探索非过渡金属有机化合物作为碱，溶剂及亲核体的研究，降低交叉偶联反应的成本以提高其实用性。.在探索不同金属去催化芳基碘与有机钛进行偶合反应，在测试及调节不同的反应条件后，我們利用碘化铜和吲哚类膦配体，在温和的反应条件下高效催化3-甲氧基碘和4-甲基钛生成联芳基化合物（85%）。..科学意义.1)首次催化有机钛和芳基及甲基磺酸酯等活性低的有机亲电子体进行交叉偶联反应,高效生成多样联芳基化合物/联芳基杂环化合物。..2)发现有机钛在进行交叉偶联反应中作为溶剂，碱及亲核体的特性,能减少反应工骤，降低成本，其概念有助开发简易的交叉偶联反应以提高应用性。..3) 首次利用平价金属如铜去催化有机钛跟芳基碘反应生成联芳化合物, 有助开拓低成本的交叉偶联反应。