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.

Transition-metal-catalyzed C–H bond functionalizations have had an enormous influence on organic synthesis in recent times. However, the use of low-abundance 4d and 5d metals is almost inevitable, and they are in high demand. This will be a cause of concern, and hence, it is important to develop methods based on 3d metals, which are widely present in the Earth’s crust. In this regard, the use of 3d metal catalysts or their precursors for catalysis, in general, and C–H bond functionalizations, in particular, has gained significant momentum in the recent times. The major development in catalytic C–H bond functionalizations with 3d metals has been achieved predominantly with strongly coordinating directing groups such as pyridyl, pyrimidinyl, pyrazolyl, and 8-amino-quinolinyl groups. Thus, prefunctionalization of substrates with these directing groups is necessary, which contradicts the step- and atom-economy of C–H bond activation. However, commonly available functional groups such as aldehyde, ketone, carboxylic acid, amide, hydroxy, and N-oxides loosely bind to metals through weak-coordination. These weakly coordinating directing groups orient the metal to activate C–H bond regioselectively without the need for preinstalled strongly coordinating directing groups. Although it is challenging, this contemporary topic has been actively pursued by many researchers in recent times. Through this article, we provide a comprehensive overview of 3d metal-catalyzed, weakly coordinating, directing-group-enabled C–H bond functionalizations reported until March 2021. 

Weak-Coordination in C–H Bond Functionalizations Catalyzed by 3d Metals

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

Selective editing of the benzenoid C-H bonds (C4-C7) in indoles/indolines has received great interest because functionalized indoles/indolines are featured in many marketed drugs and natural products. Transition-metal-catalyzed directed C-H functionalization has thus been developed to manipulate the benzenoid core through C-C and C-heteroatom bond formation. This review covers the recent advances in selective C-C bond forming reactions, alkylation, alkenylation and alkynylation, over the benzenoid ring (C4-C7) of indoles/indolines using metal catalysis.

Recent Advances in Metal-catalyzed Alkylation, Alkenylation and Alkynylation of Indole/indoline Benzenoid Nucleus.

A facile insertion of ruthenium into aromatic C-H and allylic C-N bonds are the key steps in a [Ru( p-cymene)Cl2]2-catalyzed ortho-C-H allylation of benzoic acids. This protocol allows drawing on the large pool of allylic amines for state-of-the-art ortho-functionalizations of arenes, turning neutral amines into leaving groups. Concise syntheses of biologically active compounds provide further evidence of the synthetic potential of this methodology.

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Catalytic C-N and C- H bond activation: ortho-allylation of benzoic acids with allyl amines

A new strategy for the C(7)-H functionalization of indoline derivatives using first-row transition-metal cobalt has been demonstrated wherein the pivaloyl group acts as a weakly coordinating directing group. Biologically important pyroquilon (tetrahydropyroquinolinone) derivatives have been synthesized in a one-pot manner through selective C(7)-H functionalization and concomitant cyclization. In this process, aromatic C-H and amidic C-N bonds are cleaved, and new C-C and C-N bonds are formed in a step-economical fashion. Further, selective C(7)-H alkenylation of indoline derivatives has also been accomplished using activated alkenes by varying the reaction conditions.

Cobalt-Catalyzed One-Step Access to Pyroquilon and C-7 Alkenylation of Indoline with Activated Alkenes Using Weakly Coordinating Functional Groups.

O-Directed C-H functionalization via cobaltacycles: a sustainable approach for C-C and C-heteroatom bond formations.

Hydroxylamine‐O‐Sulfonic Acid (HOSA) as a Redox–Neutral Directing Group: Rhodium Catalyzed, Additive Free, One‐Pot Synthesis of Isoquinolines from Arylketones

Strain-driven palladium/N-heterocyclic carbene-catalyzed C–C bond activation of diphenylcyclopropenone (DPC) has been explored for one-step access to trisubstituted α,β-unsaturated esters and amide...

Palladium-Catalyzed C-C Bond Activation of Cyclopropenone: Modular Access to Trisubstituted α,β-Unsaturated Esters and Amides.

Co(III)-catalyzed alkenylation of 2-pyridones by using terminal alkyne as a reaction partner with high regioselectivity has been demonstrated for the first time. The reaction conditions are mild and compatible with a wide range of substrate combinations. It also shows good functional group tolerance. It proceeds through cyclometalation followed by alkyne insertion and protodemetalation steps. The formation of five- and seven-membered cobaltacycle intermediates was also detected through high-resolution mass spectrometry.

Pragati Biswal

Papers

Cobalt-Catalyzed One-Step Access to Pyroquilon and C-7 Alkenylation of Indoline with Activated Alkenes Using Weakly Coordinating Functional Groups.

O-Directed C-H functionalization via cobaltacycles: a sustainable approach for C-C and C-heteroatom bond formations.

Hydroxylamine‐O‐Sulfonic Acid (HOSA) as a Redox–Neutral Directing Group: Rhodium Catalyzed, Additive Free, One‐Pot Synthesis of Isoquinolines from Arylketones

Palladium-Catalyzed C-C Bond Activation of Cyclopropenone: Modular Access to Trisubstituted α,β-Unsaturated Esters and Amides.

Cobalt(III)-Catalyzed C-6 Alkenylation of 2-Pyridones by Using Terminal Alkyne with High Regioselectivity.