Correlation between pKa and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction:: Discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope
Correlation between pKa and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction:: Discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope
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DOI：
10.1021/jo026671s
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发表时间：
2003-02-07
影响因子：
3.6
通讯作者：
Fulford, SY
中科院分区：
文献类型：
--
作者：
Aggarwal, VK;Emme, I;Fulford, SY
对多种喹啉基催化剂在Baylis-Hillman反应中的反应性进行了研究，并建立了碱的碱度与反应性之间的直接相关性，无一例外。用括号中所示的共轭酸（在水中测得）的pk(a) s建立了反应性的顺序：喹啉（11.3）、3-羟基喹啉（9.9）、DABCO（8.7）、3-乙酰氧基喹啉（9.3）、3-氯喹啉（8.9）和喹啉酮（7.2）。通过比较DABCO和3-乙酰氧基喹啉在DMSO中的相对碱度，分析了DABCO的pK(a)高于预期的反应活性。在非质子溶剂中，DABCO比3-乙酰氧基喹啉碱性高0.6 pK(a)单位，从而建立了该胺的pK(a)与其反应性之间的直接联系。与以往的文献报道相反，研究发现，具有最高pK(a)的喹那定是最活跃的催化剂。与喹那定的反应表现出明显的自催化作用，这表明质子供体的存在可能进一步提高了反应速率。因此，研究了一系列带有极性x -氢键的添加剂，发现甲醇、三乙醇胺、甲酰胺和水都能提供额外的加速度。甲醇被发现是最佳的，并且用一系列醛和迈克尔受体测试了喹啉与甲醇的强大组合。不仅反应比以前报道的更有效和更快，而且现在可以使用以前不反应的新底物。值得注意的例子包括乙炔醛的使用和乙烯基砜、丙烯酰胺、-内酯，甚至含有-取代基的-、-不饱和酯。
The reactivity of a variety of quinuclidine-based catalysts in the Baylis-Hillman reaction has been examined, and a straightforward correlation between the basicity of the base and reactivity has been established, without exception. The following order of reactivity was established with pk(a)'s of the conjugate acids (measured in water) given in parentheses: quinuclidine (11.3), 3-hydroxy-quinuclidine (9.9), DABCO (8.7), 3-acetoxyquinuclidine (9.3), 3-chloroquinuclidine (8.9), and quinuclidinone (7.2). The higher than expected reactivity of DABCO, based on its pK(a), was analyzed by comparing the relative basicity of DABCO and 3-acetoxyquinuclidine in DMSO. It was found that in aprotic solvent, DABCO was 0.6 pK(a) units more basic than 3-acetoxyquinuclidine, thus establishing a direct link between pK(a) of the amine and its reactivity. In contrast to previous literature work that reported the contrary, quinuclidine, which has the highest pK(a), was found to be the most active catalyst. The reaction profile with quinuclidine showed significant autocatalysis, which suggested that the presence of proton donors might further enhance rates. Thus, a series of additives bearing polar X-H bonds were investigated and it was found that methanol, triethanolamine, formamide, and water all provided additional acceleration. Methanol was found to be optimum, and the powerful combination of quinuclidine with methanol was tested with a host of aldehydes and Michael acceptors. Not only were the reactions more efficient and faster than previously reported, but now new substrates that were previously unreactive could be employed. Notable examples include the use of acetylenic aldehydes and the employment of vinyl sulfones, acrylamides, delta-lactones, and even alpha,beta-unsaturated esters bearing a beta-substituent.