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Synthesis of unsymmetrical ethers and transetherification reactions a Williamson ether synthesis. b Acid mediated transetherification reactions. c Mechanism of acid mediated transetherification for aliphatic ethers. d Mechanism of transetherification for aromatic ethers. e Transetherification of ethers and alcohols via OH activation, C–O/C–O σ-bond metathesis. f Ring-closing alkene metathesis. g Ring-closing carbonyl-olefin metathesis. h Ring-closing C–O/C–O σ-bond metathesis of aliphatic ethers. i Ring-closing C–O/C–O σ-bond metathesis via OH activation, a mechanism reversal in transetherification.
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In canonical organic chemistry textbooks, the widely adopted mechanism for the classic transetherifications between ethers and alcohols starts with the activation of the ether in order to weaken the C–O bond, followed by the nucleophilic attack by the alcohol hydroxy group, resulting in a net C–O/O–H σ-bond metathesis. In this manuscript, our exper...
Citations
... Furthermore, ring-closing σbond metathesis reactions were only reported for two C-O bonds (Fig. 1c). [24][25][26][27] Considering these limitations, further breakthrough in this eld should be characterized by following features: 1) metathesis between two different C-X bonds could be realized from easily available starting materials in a controllable way; 2) mechanism other than reversible ligand swap in the state-of-art C-X σ-bond metathesis should be veri ed to allow for more convenient substrate preparation; 3) intramolecular variant should present a general strategy for the synthesis saturated heterocycles. The rst two features of C-X bonds metathesis are exquisitely exhibited in the natural SAM cycle (Fig. 1d), in which C-O of adenosine "exchange partner" with S-C(Me) to give adenosylhomocysteine (SAH). ...
Cross metathesis reactions of multiple bonds, such as alkenes and alkynes, have undoubtedly revolutionized various fields and become one of the most efficient strategies in organic synthesis. In contrast, metathesis reactions of more naturally abundant yet less reactive σ-bond bonds remain less developed, especially for polar C–X bonds, the existing activation modes are rather limited and reactions often occur between two C–X bonds of the same type. Here, inspired by the natural S-adenosylmethionine (SAM) cycle, we devise a σ-bond metathesis between the C–O bond of alcohols with various other different C–X bonds. This reaction is realized by using a delicate mixture of commonly used Lewis acids and allows fast access to various challenging thioethers or selenoethers from easily available ones by directly editing the C component of the C–X bond with easily available alcohols as the sources of the new C component. Like multiple bond metathesis, this method could also be rendered intramolecular to provide saturated heterocycles such as cyclic ethers, cyclic thioethers, as well as cyclic amines. Mechanistic experiments and DFT calculations were carried out to show a high level of resemblance to the natural SAM cycle. We anticipate this bioinspired design of C–O/ C–X metathesis will infuse the area of a σ-bond metathesis with more insights and provide opportunities for further advances in areas that have been facilitated by traditional C–X bond forming reactions.
The hydroarylation of alkenes is arguably the most straightforward and atom-economical strategy for the construction of multi-aryl substituted alkanes, but systematic study is quite limited to transition metal catalysis. Here...
This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.
