Novel Base‐Free Catalytic Wittig Reaction for the Synthesis of Highly Functionalized Alkenes

A highly efficient catalyst system for base‐free catalytic Wittig reactions has been developed and optimized. Initially, several potential (pre)catalysts as well as different silanes as reducing agents were screened. A system based on a readily available phosphine oxide as precatalyst and trimethoxy silane as reducing agent proved to be optimal. The effect of various Brønsted acidic additives was studied. Subsequently, the reaction conditions were optimized and standard reaction conditions were determined. Under these conditions the scope of this new protocol was evaluated. Nine activated olefins and 33 aldehydes were converted into 42 highly functionalized alkenes. Notably, aromatic, aliphatic as well as heteroaromatic aldehydes could be converted, giving the desired products in isolated yields up to 99 % and with good to excellent E/Z selectivities. These results underline the remarkable efficiency of this protocol considering the complexity of the reaction mixture and the four reaction steps that proceed in parallel in one pot.     

Part I: The Development of the Catalytic Wittig Reaction

We have developed the first catalytic (in phosphane) Wittig reaction (CWR). The utilization of an organosilane was pivotal for success as it allowed for the chemoselective reduction of a phosphane oxide. Protocol optimization evaluated the phosphane oxide precatalyst structure, loading, organosilane, temperature, solvent, and base. These studies demonstrated that to maintain viable catalytic performance it was necessary to employ cyclic phosphane oxide precatalysts of type 1 . Initial substrate studies utilized sodium carbonate as a base, and further experimentation identified N,N‐diisopropylethylamine (DIPEA) as a soluble alternative. The use of DIPEA improved the ease of use, broadened the substrate scope, and decreased the precatalyst loading. The optimized protocols were compatible with alkyl, aryl, and heterocyclic (furyl, indolyl, pyridyl, pyrrolyl, and thienyl) aldehydes to produce both di‐ and trisubstituted olefins in moderate‐to‐high yields (60–96 %) by using a precatalyst loading of 4–10 mol %. Kinetic E/Z selectivity was generally 66:34; complete E selectivity for disubstituted α,β‐unsaturated products was achieved through a phosphane‐mediated isomerization event. The CWR was applied to the synthesis of 54 , a known precursor to the anti‐Alzheimer drug donepezil hydrochloride, on a multigram scale (12.2 g, 74 % yield). In addition, to our knowledge, the described CWR is the only transition‐/heavy‐metal‐free catalytic olefination process, excluding proton‐catalyzed elimination reactions.     

Synthesis of Nonsymmetric Divinylarenes by a Heck/Wittig Reaction Combination

A protocol for a one-pot Heck reaction/Wittig olefination to divinylarenes has been developed.     

Phosphine‐Relayed Aldehyde‐Olefination and Aza‐Wittig Reaction with 2,2,2‐Trifluorodiazoethane

Phosphine‐relayed olefination and aza‐Wittig reactions of readily available aldehydes with 2,2,2‐trifluorodiazoethane (CF₃CHN₂) have been realized. This protocol enables the facile construction of a series of trifluoromethylated alkenes and hydrazones in good to high yield under mild conditions.     

Unexpected course of Wittig reaction when using cinnamyl aldehyde as a substrate

When trans-cinnamyl aldehyde was used as a substrate of the Wittig reaction, instead of the olefination product, formation of four products with (E)-1,3-diphenylprop-2-en-1-ol and cinnamyl alcohol was observed being quite unexpected ones. The possible mechanism of this unusual reaction has been considered.     

改良的Wittig 反应

本文对改良的Wittig反应进行了综述,并讨论了膦酸酯类与羰基化合物反应的各种机理。还介绍了此反应在有机合成上的应用。     

Wittig reactions of moderate ylides with heteroaryl substituents at the phosphorus atom

The influence of various heteroaryl substituents at the phosphorus atom to the stereoselectivity of Wittig reactions of allylic and benzylic ylides has been studied. In the case of nitrogen bearing heteroaromatic ligands at the phosphorous atom of benzylidenephosphoranes high E-alkene selectivity's of up to 90:10 could be observed. NMR spectroscopic investigations revealed that substituents at the phosphorus have influences on the reactivity of ylides as well as the stability of reaction intermediates. Indications for chelation of lithium ions with ylides could also be detected and will be discussed in this article.     

二苯基甲基烯丙基型膦烷与醛的Wittig反应的立体化学研究

利用3-甲氧基羰基-2-稀丙基二苯基甲基膦叶立德与醛(脂肪醛、芳香醛、杂环醛)的Wittig反应合成了5-取代-2,4-戊二烯酸甲酯(ABA酯类似物),研究了碱对Wittig反应立体化学的影响,发现了该类型季鏻盐的Wittig反应具有很好的4E选择性,并提出了可能的反应机理.     

Catalytic Wittig Reactions of Semi‐ and Nonstabilized Ylides Enabled by Ylide Tuning

The first examples of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert‐butyl carbonate, and/or ylide tuning. The acidity of the ylide‐forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.     

S-甘油醛缩丙酮的合成及其Wittig反应

以L-抗坏血酸为原料合成了S-甘油醛缩丙酮;研究了S-甘油醛缩丙酮的Wittig反应立体选择性.     

Diversity‐Oriented Synthesis of Furo[3,2‐c]coumarins and Benzofuranyl Chromenones through Chemoselective Acylation/Wittig Reaction

A highly efficient and chemoselective one‐pot protocol for the diversity‐oriented synthesis of two types of coumarin‐based formal cross‐coupling adducts, furo[3,2‐c]coumarins and 3‐benzofuranyl chromenones, is described. Key attributes of the methodology are an initial chemoselective acylation of functionalized phosphorus zwitterions and a subsequent chemoselective intramolecular Wittig reaction that preferentially resulted in one of the two coumarin derivatives in high yield, depending on relative reactivities and the addition sequence of the acylating agents.     

Wittig反应在天然产物合成中的应用

综述了近十年来Wittig反应、Wittig－Horner反应及其它类型Wittig反应在天然产物合成中的应用。参考文献33篇。     

卡宾的钨配合物与二氯甲基Wittig试剂的反应

卡宾的过渡金属配合物是一个十分活跃的研究领域,有关它们的制备方法及性质的研究工作正日益引起人们的注意。Burkhardt等发现,卡宾的钨配合物能与Witting试剂反应,生成烷氧基取代烯烃。本文将卡宾的钨配合物进一步用于与二氯甲基Wittig试剂的反应,合成1,1-二氯-2-烷氧基烯烃。众所周知,1,1-二卤代烯烃是一类产生不饱和卡宾的前体化合物。因此,通过对卡宾的钨配合物与二氯代Wittig试剂之间的反应研究,还可以为进一步研究烷氧基取代不饱和卡宾的性质提供方便。