醇的可控活化策略机理研究及其在碳-碳和碳-杂键绿色构建中的应用

Alcohols are considered as a class of comparatively greener chemicals for their ready availability, abundance, low cost, low toxicity, high stability, easy storage, and easy handling. Traditionally, they are widely used as synthetic precursors by firstly transformed into more active and toxic organohalides or carbonyl compounds via stoichiometric halogenation or oxidation. However, these methods have severe drawbacks regarding the multi-step processes, low reaction efficiencies, harsh conditions, low yields, and waste production. Hence, developing effective protocols for in situ activation of alcohols and direct applications in synthesis are promising and significant topics in organic synthesis, organometallic chemistry, pharmaceutical chemistry, green chemistry, and even the chemical industry. However, known methods for alcohol activation are mainly limited to dehydrogenation methods using expensive and toxic noble transition metal complexes under anaerobic conditions, which are in effect not practical and thus difficult to be applied in large scale synthesis and the industry due to their inherent limitations. In contrast, researches using the cheaper metal catalysts under aerobic conditions or other potentially promising protocols such as autocatalysis have not been intensively investigated. There are still many critical issues remained to be solved, mechanisms to be elucidated more clearly, more controllable activation methods to be developed, and the theory of alcohol activation to be consummated. .In previous studies, we have developed a more advantageous and practical method for alcohol activation and proposed, for the first time in the field, a concept of general alcohol activation and an aerobic “relay race” method for the reactions. In this project, based on our own proposal of the general alcohol activation and the “relay race” methods, we wish to develop new protocols for alcohol activation and study their mechanisms, which will then be used to predict and guide the exploration in possible protocols for controllable alcohol activation such as the autocatalytic and aerobic oxidative methods. The new activation protocols will then be adopted to direct the studies to achieve highly active, multifunctional, lowly toxic even non-toxic catalytic systems and greener methods for construction of carbon-carbon and carbon-heteroatom bonds under mild conditions. Thus, by effectively utilizing alcohols as alkyl, cabinol, acyl, and alkylenyl synthons respectively, alcohols can be transformed into various versatile organic and pharmaceutical intermediates and bioactive bifunctional molecules such as poly-substituted alcohols, long-chain carbonyl compounds, esters, functionalized alkenes, amide and amine derivatives. These new methods can shorten the synthetic processes, save time, resources and energy, and reduce waste production. By studying the proposed projects, protocols for alcohol activation may be broadened, the theory of general alcohol activation improved and consummated, and it may also promote the synthetic applications of alcohols as green reagents in many fields especially the synthesis of complex molecules and pharmaceutically and biochemically active compounds. This project may not only provide a series of efficient and straightforward green synthetic models but also theoretical principles and research ideas for pharmaceutical synthesis and even the chemical industry. This project is thus of high significance in research and have potentially broad utilities in many fields.

廉价易得稳定低毒的醇类是相对绿色的有机物，作为前体广泛用于各类合成中,因此醇活化应用研究对有机药物合成、绿色化学化工都有极其重要的意义。以往醇活化多采用贵金属催化惰性体系，而廉价金属催化有氧体系、自催化等富有潜力的新方法尚未很好地研究，很多难点尚待解决，活化策略和理论有待进一步丰富完善。本项目以前期研究提出的广义醇活化概念和接力方法为基础，通过研究醇活化反应本质规律，探索发展自催化或氧化等方式的可控活化新策略，用于指导高活性催化体系和低毒无毒新方法研发，实现温和条件下碳碳和碳杂键的绿色构建，利用醇为烷基、羟甲基、羰基、亚甲基等的有效合成子用于取代醇、取代酮、酯、硫代酯、酰胺、官能团化烯烃等有用的有机药物中间体的绿色合成。本研究可完善和提升醇活化理论、拓展醇可控活化策略、促进醇类作为绿色试剂在复杂分子或药物合成等领域的应用，为医药合成和化学化工提供绿色高效的合成方法、研究思路及相关理论基础。

廉价易得稳定低毒的醇类是相对绿色的一类有机化合物，是各类合成反应中的重要原料。但醇活性不高，通常需转化为更活泼的醛酮等才能有效利用，因此醇的原位活化及其应用对有机药物合成、绿色化学化工都有重要意义。已知醇活化多采用贵金属催化方法，存在很多缺点。因此醇的绿色活化新方法及其理论研究有待进一步丰富提高和完善。在前期研究中提出的广义醇活化概念及接力方法的基础上，本项目进一步研究了醇活化反应的本质规律，发展了自催化、类似自催化或氧化等方式的可控活化新策略，开发了一系列低毒无毒高效的醇活化新方法，实现了无过渡金属参与条件下的碳-碳和碳-杂键的绿色构建方法，例如，通过醇与亚磷酸酯的酯交换实现了醇活化进而开发了醇为原料、碘离子催化的高效Michaelis-Arbuzov反应构建C-P(O)键，可进一步用于单齿多齿有机膦配体制备；外加活泼醛酮或卤代烃中间体的醇活化方式实现了芴的高选择性C-烷基化反应和硫酚硫醇的S-烷基化反应；利用CsOH的铯效应及其良好的催化氧化活性促使醇氧化活化从而实现了喹唑啉、喹唑啉酮等杂环骨架的构建；利用TBN/TEMPO温和的催化氧化活性促进醇氧化活化实现了咔啉、四氢咔啉等杂环的构建，该方法还可用于重要药物原料2,4,6-三甲基苯甲酰基-二苯基氧化膦的温和高效制备；利用无机硫源如硫脲或硫代硫酸钠与卤代杂芳烃现场反应生成的中间体硫酚和副产物氢卤酸可实现醇的卤化活化进而发展了包含硫转移过程的非对称硫醚的直接合成方法；实现了无外加催化剂的羟基活化从而发展了苯并二氮杂卓杂环骨架的绿色构建新方法；等等。上述新反应中，醇作为烷基、羰基、亚甲基、次甲基等的绿色合成子成功被用于各种官能团化的有机药物中间体或杂环结构的绿色合成。综上所述，本项目的研究成果可在一定程度上完善广义醇活化概念、拓展醇可控活化策略、促进醇类作为绿色试剂在复杂分子或药物合成等领域的应用，因此可为某些医药合成和化工生产提供一定的理论基础或合成策略借鉴。