Synthesis of Alkynylated Heterocycles by Direct C-H Alkynylation or Domino Alkynylation Reactions

Heterocycles are important compounds in organic chemistry. To introduce functional groups on heterocycles or synthesize functionalized heterocycles stays a hot topic of research. Among all the functional groups, alkynes attracted a lot of attention not only because of their occurrence in organic compounds, like synthetic pharmaceuticals, natural products and organic materials, but also because of their versatile chemistry, such as metal catalyzed cyclization and [3+2] annulation reactions. Therefore, it is of great importance to introduce alkynes on heterocycles or synthesize alkynylated heterocycles in an efficient and regioselective manner. The Sonogashira reaction has dominated the introduction of alkynes on heterocycles. Even though the method is well established, there are several shortcomings such as stoichiometric waste production and poor stability or accessibility of the starting materials. To introduce alkynes on heterocycles in an efficient fashion, direct C-H alkynylation has been intensiely investigated as an alternative in the last decades. Based on the previous work in our group, direct C-H alkynylation was extended to access C2- alkynylated furans using a gold catalyst and triisopropylsilyl ethynyl benziodoxolone (TIPS-EBX). For less nucleophilic substrates like benzofurans, the use of Zn(OTf)2 was necessary to activate the EBX reagent. Although direct C-H alkynylation provides a straightforward way to access alkynylated heterocycles, it is limited to the inherently more reactive positions such as the C2 position of five-membered heterocycles or the heterocyclic ring of benzofused heterocycles. It is therefore challenging to find pathways to obtain heterocycles functionalized at other positions. Domino reactions could provide a solution to this challenge, as the metal-carbon bond could be installed on positions different from the ones obtained via a direct metallation approach. Based on this concept, unprecedented cyclization-alkynylation domino reactions were developed to access alkynylated heterocycles. Starting from easily prepared allenic ketones or ortho- ethynylated phenols or thioanisoles, C3 alkynylated furans, benzofurans and benzothiophenes can be rapidly accessed. This is a breakthrough as it allows for the introduction of alkynes on less nucleophilic positions. These products are difficult to obtain via direct C-H alkynylation as it occurred exclusively on C2 position of furans, benzofurans and benzothiophenes. Nevertheless, this approach was still limited to more reactive heterocycles. We then turned our efforts to develop domino reactions to functionalize the less reactive benzene ring. We found that with C2 or C3-substituted pyrroles as starting materials, C5 or C6 alkynylated indoles can be easily formed when combining a platinum catalyst with a bistrifluoromethyl benziodoxole reagent. In summary, a series of alkynylated heterocycles were obtained via direct alkynylation or domino reactions combining hypervalent iodine reagents and metal catalysts. This discovery is expected to find broad application to access diverse alkynylated heterocycles. It also set the bases for the development of new domino processes with different metal catalysts and electrophilic reagents in the future.

Waser, Jérôme
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis6915-0

Note: The status of this file is: EPFL only

 Record created 2016-03-07, last modified 2019-05-09

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