吡啶类及含吡啶结构的化合物在天然产物、药物、配位化学和材料化学领域中有着广泛而重要的应用。为此，吡啶衍生物的合成一直受到化学家们的关注。由易得的卤代吡啶通过偶联反应对吡啶进行衍生化，其中过渡金属催化反应起到了重要的作用。到目前为止，绝大多数的偶联反应主要依赖Pd、Ni的催化，但Pd为贵金属，价格高；而Ni虽为廉价金属，但毒性大，所以人们一直在探寻更为理想的替代物。Fe作为一种廉价低毒的过渡金属，也是Pd和Ni的理想替代品，但Fe催化的偶联反应多用于脂肪族卤代烃（或类卤物）参与的偶联反应，对于卤代吡啶参与的Csp²?Csp²型偶联仍存在很大的挑战。同时，由于吡啶类化合物特殊的络合行为，尤其是二联或多联吡啶，对Pd、Ni和Fe等的催化有毒化作用，所以吡啶类的偶联反应，特别是制备联吡啶的偶联反应还具有特殊的挑战性。此外，像其他Kumada偶联反应一样，由于格氏试剂活性较高，很难耐受敏感官能团，导致吡啶类的这类偶联范围非常有限。偶联反应中另一类是由锌试剂参与的Negishi偶联反应，尽管因锌试剂的活性较低而表现出较好的官能团耐受性，但在参与催化的过渡金属的种类与配体，吡啶类底物适用范围等方面也同样面临着前述的问题。为此，寻找一种条件温和、适用范围广、催化金属价格低、毒性小且配体简单的吡啶卤代物的偶联反应具有重要的意义。

基于以上背景，同时又基于我们实验室长期从事Fe/Ti和Co/Ti协同的偶联反应，我们认为Ti作为一种廉价、低毒的前过渡金属，是一种很理想的Pd、Ni替代品。然而Ti参与的偶联反应已有记载，而Ti催化的偶联反应却未见报道。本论文在本课题组以往研究的基础上对Ti催化吡啶卤代物与金属试剂的偶联反应进行了深入探索，首次建立催化量Ti的催化机制，建立了吡啶卤代物与金属试剂的Kumada/Negishi偶联反应。结果表明，两类反应都具有条件温和、适用范围广、区域选择性高等优点。具体总结如下：

1. 探索并建立了条件温和、操作简便的Ti催化下吡啶卤代物Kumada偶联反应：对于不带敏感官能团的底物，Ti催化体系仅为10 mol% Ti-2或20 mol% Ti(OEt)₄；对于带有敏感官能团化底物，Ti催化体系为20 mol% Ti-2或20 mol% Ti(OEt)₄。

2. 探索并建立了条件温和、操作简便的Ti催化下吡啶卤代物Negishi偶联反应：Ti催化体系仅为10 mol% Ti-2或10 mol% Ti(OEt)₄。实验表明：锌试剂范围十分广泛，涵盖芳族和脂肪族两大类，且表现很好的官能团耐受性。对于脂肪族锌试剂，克服了Pd、Ni催化中直链或支链异构化问题。

3. 利用Kumada偶联反应，实现了高化学选择性（官能团耐受）、高区域选择性（2-卤代吡啶优先3-卤代吡啶）偶联反应，并利用这些反应合成了一个DNA-嵌入剂的前体和两个特性联吡啶。

4. 利用Kumada偶联反应，探索并建立了一种无需外加配体、操作简单、条件温和且收率良好的新型联吡啶合成方法，并合成特殊的三联吡啶。

5. 利用Negishi偶联反应解决了一直以来Pd、Ni 催化下2-卤代芳烃金属试剂与2-卤代吡啶偶联的难题，即产物中2'-卤素的进一步偶联和2-卤代金属试剂易于形成苯炔等副反应。实验表明，采用10 mol% Ti-2或10 mol% Ti(OEt)₄催化由格氏试剂衍生化的2-卤代锌试剂，可以完全避免卤素的进一步偶联，并抑制了生成苯炔的副反应。

Pyrididines and pyridine-containing compounds have extensive and important applications in the fields of natural products, pharmaceuticals, coordination chemistry and materials chemistry. For this reason, the search for efficient synthesis of pyridine derivatives has been the focus of chemists. Transition metal-catalyzed couplings play an important role in derivatizing pyridines through the coupling reactions from readily available halopyridines. So far, the vast majority of coupling reactions mainly rely on the catalysis of Pd and Ni. However, Pd is a precious metal with high price while Ni is a cheap metal with high toxicity, therefore, great effort has been devoted to the search for ideal substitutions. As a cheap and low-toxic transition metal, Fe is an ideal substitution for Pd and Ni, but Fe-catalyzed coupling reactions are mostly used in coupling reactions involving aliphatic halides and the corresponding Fe-catalyzed Csp²?Csp²-type coupling remains a great challenge. At the same time, the special complexation behavior of pyridine compounds, especially bi- or polypyridines usually poisoned the catalysis of Pd, Ni, Fe, etc., thus the coupling reactions of pyridines, especially the couplings of bipyridines also present a great challenge. Besides, due to the high activity of Grignard reagents, Kumada coupling reactions can hardly tolerate sensitive functional groups, resulting in a very limited range of such couplings of halopyridines. Another type of Negishi coupling reaction using organozinc reagents, although it shows better functional group tolerance due to the lower activity of organozinc reagents, the transition metal species and ligands in catalytic systems for pyridine substrates also face the aforementioned problems. Therefore, it is of great significance to find a coupling reaction of pyridine halides with mild conditions, wide application range, simple ligand and catalytic metal of low toxicity and low price.

Based on the above background and the long-term studies of Fe/Ti and Co/Ti synergistic coupling reactions in our laboratory, we think that Ti, as an inexpensive and low-toxic early transition metal, is an ideal substitution for Pd and Ni. Although a few of the coupling reactions mediated by Ti have been documented, but the coupling reaction catalyzed by Ti has not been reported. In this thesis, the novel Ti-catalyzed coupling reactions of pyridine halides and organometal reagents have been explored on the base of previous studies of our group and the Ti catalysis in the couplings of halopyridines has been discovered for the first time, and the Kumada/Negishi couplings of pyridine halides and organometal reagents have been established as well. The results show that both types of these reactions have the advantages of mild conditions, wide application range and high regioselectivity.

The results can be summarized as follows:

1. Exploring and establishing a titanium-catalyzed Kumada coupling reaction of pyridine halides with mild conditions and easy operation: for substrates without sensitive functional groups, the titanium-catalyzed system is only 10 mol% Ti-2 or 20 mol% Ti(OEt)₄; for substrates with sensitive functional groups, the titanium catalyst system is 20 mol% Ti-2 or 20 mol% Ti(OEt)₄.  

2. Exploring and establishing a titanium-catalyzed Negishi coupling reaction of pyridine halides with mild conditions and easy operation: the titanium-catalyzed system is only 10 mol% Ti-2 or 10 mol% Ti(OEt)₄. Experiments show that the range of organozinc reagents is very wide, covering both aromatic and aliphatic categories, and shows good functional group tolerance. For aliphatic zinc reagents, the problem of linear or branched isomerization in Pd and Ni catalysis is overcome.

3. High chemoselectivity (functional group tolerance) and high regioselectivity (2-halopyridine preferentially over 3-halopyridine) coupling reaction was achieved in the Kumada coupling reaction, and a precusor for DNA-intercalation reagent and two bipyridines of special features were efficiently synthesized by means of these selectivities.

4. Using the Kumada coupling reaction, a new method for synthesizing bipyridine with no additional ligands, simple operation, mild conditions and good yield was explored and established, and a special terpyridine was synthesized.

5. The present Negishi coupling reaction provided a solution to the problem of coupling between 2-haloaromatic metal reagents and 2-halopyridines under the catalysis of Pd and Ni, namely, the side couplings of the 2'-halogen in the product and side reactions related to the formation of benzyne resulted from 2-haloaromatic metal reagents. Experiments show that the use of 10 mol% Ti-2 or 10 mol% Ti(OEt)₄ to catalyze the 2-halogenated zinc reagents derived from Grignard reagents can completely avoid the further coupling of halogens in desired products and inhibit the formation of benzynes and related side reactions.