1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C-H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

HFIP in Organic Synthesis.

The use of pre-installed directing groups has become a popular and powerful strategy to control site selectivity in transition metal catalysed C–H functionalisation reactions. However, the necessity for directing group installation and removal reduces the efficiency of a directed C–H functionalisation method. To overcome this limitation, taking inspiration from organocatalytic methodologies, the use of transient directing groups has arisen. These methods allow for a transient ligand to be used, potentially in catalytic quantities, without the need for discrete installation or removal steps, enabling the discovery of more efficient, and mechanistically intriguing, dual catalytic methods. This review summarises recent developments in this fast moving field covering >70 new methodologies, highlighting new directing group designs and advances in mechanistic understanding. It covers progress since 2018, providing an update to our previous review of the field.

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Transient imine directing groups for the C–H functionalisation of aldehydes, ketones and amines: an update 2018–2020

Ester-linked, crystalline, porous covalent organic frameworks (COFs) have been synthesized and structurally characterized. Transesterification reactions between ditopic 2-pyridinyl aromatic carboxylates and tri- or tetratopic phenols gave the corresponding ester-linked COFs. They crystallize as 2D structures in kgm (COF-119) and hcb (COF-120, 121, 122) topologies with surface areas of up to 2092 m2/g. Notably, crystalline COF-122 comprises edges spanning over 10 phenylene units, an aspect that had only been achieved in metal-organic frameworks. This work expands the scope of reticular chemistry to include, for the first time, crystalline ester-linked COFs related to common polyesters.

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Ester-Linked Crystalline Covalent Organic Frameworks.

C–H activation is a ‘simple-to-complex’ transformation that nature has perfected over millions of years of evolution. Transition-metal-catalysed C–H activation has emerged as an expeditious means to expand the chemical space by introducing diverse functionalities. Notably, among the strategies to selectively cleave a particular C–H bond, the catalytic use of a small molecule as co-catalyst to generate a transient directing group, which provides a balance between step economy and chemical productivity, has gained immense attention in recent years. This allows one to convert a desired C–H bond irrespective of its geometrical or stereochemical configuration. This Review describes the various transient directing groups used in C–H activation and explains their mechanistic significance. Transient directing groups enable selective metal-catalysed C–H functionalization reactions to give diverse products. These directing groups form and dissociate in situ, such that their use is an efficient route to complex organics, examples of which are summarized in this Review.

Transient directing ligands for selective metal-catalysed C–H activation

Pd(II)-catalyzed site-selective β- and γ-C(sp3)-H arylation of primary aldehydes is developed by rational design of L,X-type transient directing groups (TDG). External 2-pyridone ligands are identified to be crucial for the observed reactivity. By minimizing the loading of acid additives, the ligand effect is enhanced to achieve high reactivities of the challenging primary aldehyde substrates. Site selectivity can be switched from the proximate to the relatively remote position by changing the bite angle of TDG to match the desired palladacycle size. Experimental and computational investigations support this rationale for designing TDG to potentially achieve remote site-selective C(sp3)-H functionalizations.

PdII-Catalyzed Site-selective β- and γ-C(sp3)-H Arylation of Primary Aldehydes Controlled by Transient Directing Groups.

The palladium catalyzed aldehyde directed acetoxylation of C(sp3)–H bonds was realized by a transient directing group approach for the first time. Crucial to the successful outcome of this reaction is the dual role of acetohydrazide as a directing group for the catalytic C(sp3)–H activation process and as a protecting group for the CHO functional group. The applicable methodology exhibits good functional group tolerance and occurs readily under mild conditions.

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A dual role for acetohydrazide in Pd-catalyzed controlled C(sp3)─H acetoxylation of aldehydes

A site-selective supported palladium nanoparticle catalyzed Suzuki–Miyaura cross-coupling reaction with heteroaryl esters and arylboronic acids as coupling partners was developed. This methodology provides a heterogeneous catalytic route for aryl ketone formation via C(acyl)–O bond activation of esters by successful suppression of the undesired decarbonylation phenomenon. The catalyst can be reused and shows high activity after eight cycles. The XPS analysis of the catalyst before and after the reaction suggested that the reaction might be performed via a Pd0/PdII catalytic cycle that began with Pd0.

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Heterogeneous Suzuki–Miyaura coupling of heteroaryl ester via chemoselective C(acyl)–O bond activation

The first [3 + 2 + 1] methodology for pyridine skeleton synthesis via cascade carbopalladation/cyclization of acetonitrile, arylboronic acids, and aldehydes was developed. This reaction proceeds via six step tandem reaction sequences involving the carbopalladation reaction of acetonitrile, a nucleophilic addition, a condensation, an intramolecular Michael addition, cyclization, and aromatization. Delightfully, both palladium acetate and supported palladium nanoparticles catalyzed this reaction with similar catalytic performance. The characterization results of the fresh and used supported palladium nanoparticle catalysts indicated that the reaction might be performed via a Pd(0)/Pd(II) catalytic cycle that began with Pd(0). Furthermore, the products showed good fluorescence characteristics. The green homogeneous/heterogenous catalytic methodologies pave a new way for constructing the pyridine skeleton.

[3 + 2 + 1] Pyridine Skeleton Synthesis Using Acetonitrile as C4N1 Units and Solvent.

Readily available and inexpensive Earth-abundant alkali metal species are used as efficient catalysts for the transesterification of aryl or heteroaryl esters with phenols which is a challenging and underdeveloped transformation The simple conditions and the use of heterogeneous alkali metal catalyst make this protocol very environmentally friendly and practical This reaction fills in the missing part in transesterification reaction of phenols and provides an efficient approach to aryl esters, which are widely used in the synthetic and pharmaceutical industry

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Chaolumen Bai

Papers

A dual role for acetohydrazide in Pd-catalyzed controlled C(sp3)─H acetoxylation of aldehydes

Heterogeneous Suzuki–Miyaura coupling of heteroaryl ester via chemoselective C(acyl)–O bond activation

[3 + 2 + 1] Pyridine Skeleton Synthesis Using Acetonitrile as C4N1 Units and Solvent.

Transesterification of (hetero)aryl esters with phenols by an Earth-abundant metal catalyst

Nano palladium catalyzed C(sp3)–H bonds arylation by a transient directing strategy