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Review
. 2020 Jun 17;142(24):10571-10591.
doi: 10.1021/jacs.0c04074. Epub 2020 Jun 5.

Achieving Site-Selectivity for C-H Activation Processes Based on Distance and Geometry: A Carpenter's Approach

Guangrong Meng  1 , Nelson Y S Lam  1 , Erika L Lucas  1 , Tyler G Saint-Denis  1 , Pritha Verma  1 , Nikita Chekshin  1 , Jin-Quan Yu  1
Affiliations
Review

Achieving Site-Selectivity for C-H Activation Processes Based on Distance and Geometry: A Carpenter's Approach

Guangrong Meng et al. J Am Chem Soc. .

Abstract

The ability to differentiate between highly similar C-H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C-H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C-H bond and a coordinating functional group, along with the geometry of the cyclic transition state in directed C-H activation, as core molecular recognition parameters to differentiate between multiple C-H bonds. In this Perspective, we discuss the advent and recent advances of this concept. We cover a wide range of transition-metal-catalyzed, template-directed remote C-H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates, and amines. Additionally, we review eminent examples which take advantage of non-covalent interactions to achieve regiocontrol. Continued advancement of this distance- and geometry-based differentiation approach for regioselective remote C-H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic molecules at any site, in any order.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Classical approaches for achieving regioselectivity
Figure 2.
Figure 2.
Central challenges in regioselective remote C–H activation and early pioneering work in this field
Figure 3.
Figure 3.
Free energy comparison between an ortho-and meta-palladacycle arising from the cyclopalladation of hydrocinnamic acid
Scheme 1.
Scheme 1.
Incorporating ‘distance’ and ‘geometry’ as key design parameters leads to the highly selective meta-olefination of hydrocinnamic acid
Scheme 2.
Scheme 2.
Template-mediated remote meta-C–H olefination of benzyl alcohols
Scheme 3.
Scheme 3.
Modulating site-selectivity through template attachment demonstrated by the tunable ortho or meta-C–H olefination of phenolic substrates
Scheme 4.
Scheme 4.
Template-enabled meta-C–H olefination of biaryl phenols
Scheme 5.
Scheme 5.
Silyl ether-anchored nitrile template as applied to the remote meta-olefination of benzyl alcohols
Scheme 6.
Scheme 6.
Template-directed remote meta-C–H olefination of benzyl silanes
Scheme 7.
Scheme 7.
meta-C–H functionalizations facilitated by a pyridine-containing directing group
Scheme 8.
Scheme 8.
meta-C–H cyanation of arenes enabled by a pyrimidine template
Scheme 9.
Scheme 9.
Achieving selectivity in a range of distally directed meta-C–H olefination reactions for substrates containing flexible alkyl tethers
Scheme 10.
Scheme 10.
meta-C–H functionalization of arenes across different linker lengths enabled by a pyrimidine template
Scheme 11.
Scheme 11.
Sequential functionalization of meta-C–H and ipso-C–O bonds for phenolic substrates
Scheme 12.
Scheme 12.
meta-Selective cross-coupling of and olefination of acid derivatives enabled by a nitrile template
Scheme 13.
Scheme 13.
meta-Olefination of phenylacetic acid and biphenyl carboxylic acid derivatives
Scheme 14.
Scheme 14.
Divergent meta-selective C–H mono or diolefination of sulfonate containing substrates
Scheme 15.
Scheme 15.
Accessing a variety of meta-substituents from the selective C–H functionalization of sulfonate-containing substrates
Scheme 16.
Scheme 16.
Template-mediated remote meta-C–H functionalization of phosphonate-containing substrates
Scheme 17.
Scheme 17.
meta-Selective remote olefination, arylation and iodination of phenylacetic acid substrates enabled by a 2-fluoropyridine-containing template
Scheme 18.
Scheme 18.
A pyrimidine-containing template allows for the cyanation, alkylation, alkenylation, allylation, perfluoroalkenylation and alkynylation of sulfonate-bearing arenes
Scheme 19.
Scheme 19.
meta-C–H alkylation and cyanation of phosphonate-containing substrates mediated by a pyrimidine-containing template
Scheme 20.
Scheme 20.
meta-Deuteration of arenes bearing diverse ester-linkable functionalities enabled through a pyridine or pyrimidine-containing template
Scheme 21.
Scheme 21.
Meta-functionalization of arenes enabled by an 8-nitroquinoline-based template
Scheme 22.
Scheme 22.
meta-Olefination and arylation enabled by a carboxyl-containing template
Scheme 23.
Scheme 23.
Challenges surrounding the meta-C-H functionalization of benzoic acids relative to other aryl carboxylic acid substrates
Scheme 24.
Scheme 24.
Enabling the meta-C–H functionalization of benzoic acids through a nitrile directing group with a flexible tether
Scheme 25.
Scheme 25.
Conformation-induced meta-C–H activation of amines
Scheme 26.
Scheme 26.
meta-C–H olefination and acetoxylation of indolines mediated by a sulfonamide-tethered nitrile template
Scheme 27.
Scheme 27.
ortho and meta-C–H olefination of phenylethylamines enabled by an amide-anchored nitrile template
Scheme 28.
Scheme 28.
A single sulfonamide-tethered nitrile template enables the divergent olefination of various N-heterocycles
Scheme 29.
Scheme 29.
Rh(III)-catalyzed meta-C–H functionalizations enabled by a template-mediated strategy
Scheme 30.
Scheme 30.
Development of a template-mediated strategy to enable para-selective C–H functionalization
Scheme 31.
Scheme 31.
Employing a bifunctional template strategy for the remote functionalization of N-heteroarenes, and its application to the remote functionalization of 3-phenylpyridine and quinoline substrates
Scheme 32.
Scheme 32.
Site-selective C–H olefination of small heterocycles via a bifunctional template strategy
Scheme 33.
Scheme 33.
Remote C–H borylation mediated by a bifunctional template anchored through potassium coordination
Scheme 34.
Scheme 34.
Meta-selective C–H borylation mediated by substrate-Lewis acid interaction
Scheme 35.
Scheme 35.
Hydrogen-bonding interactions mediated by a bifunctional urea template enables a meta-selective iridium catalyzed C–H borylation of benzamides
Scheme 36.
Scheme 36.
Meta-selective C–H borylation mediated by ion-pairing interactions
Scheme 37.
Scheme 37.
Reversing conventional site-selectivity through geometric factors in C(sp3)–H arylation of alcohols
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