Silicon-Tethered Strategies for C-H Functionalization Reactions

Abstract

Selective and efficient functionalization of ubiquitous C-H bonds is the Holy Grail of organic synthesis. Most advances in this area rely on employment of strongly or weakly coordinating directing groups (DGs) which have proven effective for transition-metal-catalyzed functionalization of C(sp²)-H and C(sp³)-H bonds. Although most directing groups are important functionalities in their own right, in certain cases, the DGs become static entities that possess very little synthetic leverage. Moreover, some of the DGs employed are cumbersome or unpractical to remove, which precludes the use of this approach in synthesis. It is believed, that development of a set of easily installable and removable/modifiable DGs for C-H functionalization would add tremendous value to the growing area of directed functionalization, and hence would promote its use in synthesis and late-stage functionalization of complex molecules. In particular, silicon tethers have long provided leverage in organic synthesis as easily installable and removable/modifiable auxiliaries for a variety of processes, including radical transformations, cycloaddition reactions, and a number of TM-catalyzed methods, including ring-closing metathesis (RCM) and cross-coupling reactions. Employment of Si-tethers is highly attractive for several reasons: (1) they are easy to handle/synthesize and are relatively stable; (2) they utilize cheap and abundant silicon precursors; and (3) Si-tethers are easily installable and removable/modifiable. Hence, development of Si-tethers for C-H functionalization reactions is appealing not only from a practical but also from a synthetic standpoint, since the Si-tether can provide an additional handle for diversification of organic molecules post-C-H functionalization. Over the past few years, we developed a set of Si-tether approaches for C-H functionalization reactions. The developed Si-tethers can be categorized into four types: (Type-1) Si-tethers possessing a reacting group, where the reacting group is delivered to the site of functionalization; (Type-2) Si-tethers possessing a DG, designed for selective C(sp²)-H functionalization of arenes; (Type-3) reactive Si-tethers for C-H silylation of organic molecules; and finally, (Type-4) reactive Si-tethers containing a DG, developed for selective C-H silylation/hydroxylation of challenging C(sp³)-H bonds. In this Account, we outline our advances on the employment of silicon auxiliaries for directed C-H functionalization reactions. The discussion of the strategies for employment of different Si-tethers, functionalization/modification of silicon tethers, and the methodological developments on C-C, C-X, C-O, and C-Si bond forming reactions via silicon tethers will also be presented. While the work described herein presents a substantial advance for the area of C-H functionalization, challenges still remain. The use of noble metals are required for the C-H functionalization methods presented herein. Also, the need for stoichiometric use of high molecular weight silicon auxiliaries is a shortcoming of the presented concept.

Scheme 1

Directing Group Concept for C–H Functionalization

Scheme 2

Types of Silicon Tethers for C–H Functionalization

Scheme 3

C–H Arylation Using TBDPS and Br-TBDPS Tethers

Scheme 4

Synthesis of Biphenols via C–H Arylation Using Type 1 Silicon Tethers

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Scope of Obtained Biphenols and Binaphthols

Scheme 6

Concept of PyDipSi Directing Group

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Scope of C–H Acyloxylation of PyDipSi Arenes

Scheme 8

Further Transformations of Obtained Acyloxy PyDipSi Arenes

Scheme 9

Scope of C–H Halogenation Reaction Employing PyDipSi DG

Scheme 10

Scope of C–H Halogenation Reaction Employing PyDipSi DG

Scheme 11

Proposed Mechanism of C–H Acyloxylation Reaction Employing PyDipSi DG

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Double-Fold C–H Acyloxylation Reactions Using PyrDipSi DG

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Symmetrical Double-Fold C–H Pivaloxylation Reaction Using PyrDipSi DG

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Unsymmetrical Double-Fold C–H Pivaloxylation Reaction Using PyrDipSi DG

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Concept of Sequential C–H Halogenation/Oxygenation Using PyrDipSi DG

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Scope of Sequential C–H Halogenation/Oxygenation Using PyrDipSi DG

Scheme 17

Synthetic Utility and Further Transformations of Building Block 70

Scheme 18

Toward Multisubstituted Arenes Employing Bis-PyrDipSi Substrate 89

Scheme 19

C–H Alkylation Using PyDipSi and PyrDipSi DGs

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Scope of Sequential C–H Halogenation/Oxygenation Using PyrDipSi DG

Scheme 21

Synthetic Utility and Modification of PyrDipSi DG

Scheme 22

Methods for C–H Alkoxycarbonylation

Scheme 23

Initial Studies for C–H Alkoxycarbonylation Using PyDipSi- and PyrDipSi-DGs

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Scope for C–H Alkoxycarbonylation Using PyrDipSi-DG

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Synthetic Utility of C–H Alkoxycarbonylation Using PyrDipSi-DG

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C–H Alkenylation Using Silanol DG

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Scope of C–H Alkenylation Using Silanol DG

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C–H Oxygenation Using Silanol DG

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Mechanism of C–H Oxygenation Using Silanol DG

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C–H Carbonylation Using Silanol DG

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Scope of C–H Carbonylation Using Silanol DG

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meta- and para-C–H Functionalization Using Silicon Tethers

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One-Pot Procedure for Synthesis of Dihydrobenzosiloles

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Scope of Dihydrobenzosiloles via Hydrosilylation/Dehydrogenative Cyclization

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Hydrosilylation/Dehydrogenative Cyclization of Heteroarenes

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Synthetic Utility of Dihydrobenzosiloles, and Their Heteroaromatic Analogs

Scheme 37

δ-C(sp³)–H Silylation/Oxygenation Using TBPicSi DG

Scheme 38

Scope of δ-C(sp³)–H Silylation/Oxygenation Using TBPicSi DG

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δ-C(sp³)–H Silylation/Oxygenation of Natural Products and Derivatives Using TBPicSi DG

Scheme 40

Design of C–H Functionalization Using Tether 18 for Direct Oxidation of Silyl Ethers into Silyl Enol Ethers

Scheme 41

Scope of the Photocatalytic Oxidation of Silyl Ethers into Silyl Enol Ethers