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Author
del Barrio Aliaga, Inés
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Abstract
The hypervalent iodine Chemistry has become a go-to tool in organic synthesis. In the last decade, the common applications of organo-iodanes as oxidants and group transfer agents have been amplified with new reactivity patterns exploiting the iodoarene fragment itself as a building block. In this context, our research group has developed a series of processes for introducing unsaturated organic units into the Ar-I ring via the C-H coupling guided by the hypervalent fragment –I(OAc)2. As of today, efforts from various research groups, including ours, have led to C-C bond formation with fragments such as propargyl, allyl, cyanoalkyl, as well as with enolates, phenolates and formal benzylic anions. For the methods leading to the C-C bond formation ortho to the iodine, the regioselectivity has been rationalized via the cyclic transition state in a [3,3]-sigmatropic rearrangement model. The resulting functionalized iodoarenes are valuable building blocks, and have been used as precursors to improve the synthesis of experimental antitumor agents such as Dosabuline, or the antiinflamatory drugs such as Diclorofenal. The group’s most recent studies on the reactivity of silylated dienic substrates with hypervalent reagents have led to the unexpected observation of a selective C-H coupling in position para to iodine. However, given the difficulties to access the penta-dienyl substrates of this type, a study has now been undertaken to uncover efficient methods to form of such silylated substrates in a stereodefined manner.
This work is directed, in the first place, to the preparation of the 6-trimethylsilyl-2,4-hexadienoic acid through the ring opening of pyran-2-one. As a prior enabling study, in the last months we developed a new method of synthesizing pyran-2-one from coumalic acid through a palladium-catalyzed decarboxylation, by adapting a catalytic procedure reported recently by Szostak et al. for aromatic carboxylic acids. This new process, the first avoiding heating to >300 oC, has allowed for the pyran-2-one to be obtained reliably, albeit in yields that indicate the need for further process optimization. The following study of the iron-catalyzed ring opening of pyran-2-one, following a precedent from the group of A. Fürstner, has allowed us to generate the (2E,4E) isomer of 6-trimethylsilyl-2,4-hexadienoic acid, albeit with moderate selectivity levels. In addition, a study was undertaken to explore the viability of the photochemical ring closing of the pyran-2-one to form the Dewar lactone using the monochromatic 365 nm light source. The tests revealed the need to improve the efficiency of the processes, e.g. by using a shorter wavelength, or by introducing a redox photocatalyst. Finally, as an alternative strategy the synthesis of the thermodynamically favored trans,trans isomer of the 6-trimethylsilyl-2,4-hexadienoic acid was accomplished via the deprotonation/silylation route of the sorbic acid, a commercially available low cost precursor.
The second part of this work was devoted to the iodane-guided para C-H coupling reactions using the model reagent λ3-PhI(OAc)2. Following the initial process validation using benzyl(trimethyl)silane, the coupling of the 6-trimethylsilyl-2,4-hexadienoic acid was tackled. As was hoped for, reaction was found to be highly selective for the para C-H position, and led predominantly to the product with a final trans,trans configuration of the olefinic chain.
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