Recent Advances in Chiral Guanidine-Catalyzed Enantioselective Reactions.

Chiral guanidines have been widely used as Brønsted base catalysts and phase transfer catalysts in enantioselective reactions. Due to their amendable structure and powerful catalytic ability, they have attracted much interest. Several new catalysts containing a guanidinium moiety have been reported over the past decade and many promising outcomes have been achieved. This article illustrates the progress of chiral guanidine catalysis in asymmetric synthesis from 2009 to 2018. It is an update of a review of the same title published in 2009.

Metal-catalysed reactions enabled by guanidine-type ligands.

Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. As ligands, guanidines can have different coordination modes with the metal center. However, the exploitation of these guanidine complexes as catalysts has been much less successful. The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. The catalytic activities of metal-guanidinate complexes are of great interest to chemists. The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. This field is currently being pursued with great interest by synthetic organic chemists. In this review, the representative reactions enabled by guanidine and guanidinate metal complexes are highlighted.

Remazol-Catalyzed Hydroperoxyarylation of Styrenes.

A mild photocatalytic hydroperoxyarylation of styrenes has been developed, in which a novel photocatalyst, remazol brilliant blue R (RBBR), is employed at low catalytic loading (1 mol %). The operationally easy procedure uses air as the dioxygen source. Simple mono-substituted styrenes react with aryl hydrazines in moderate-to-good yields. RBBR is proposed to act as a photosensitizer for the generation of singlet oxygen.

Pd(II)-catalyzed C-H functionalizations directed by distal weakly coordinating functional groups.

Ortho-C(sp(2))-H olefination and acetoxylation of broadly useful synthetic building blocks phenylacetyl Weinreb amides, esters, and ketones are developed without installing an additional directing group. The interplay between the distal weak coordination and the ligand-acceleration is crucial for these reactions to proceed under mild conditions. The tolerance of longer distance between the target C-H bonds and the directing functional groups also allows for the functionalizations of more distal C-H bonds in hydrocinnamoyl ketones, Weinreb amides, and biphenyl Weinreb amides. Mechanistically, the coordination of these carbonyl groups and the bisdentate amino acid ligand with Pd(II) centers provides further evidence for our early hypothesis that the carbonyl groups of the potassium carboxylate are responsible for the directed C-H activation of carboxylic acids.

Phenazinium salt-catalyzed aerobic oxidative amidation of aromatic aldehydes.

Amides are prevalent in organic synthesis. Developing an efficient synthesis that avoids expensive oxidants and heating is highly desirable. Here the oxidative amidation of aromatic aldehydes is reported using an inexpensive metal-free visible light photocatalyst, phenazine ethosulfate, at low catalytic loading (1-2 mol %). The reaction proceeds at ambient temperature and uses air as the sole oxidant. The operationally easy procedure provides an economical, green, and mild alternative for the formation of amide bonds.

Palladium-catalyzed meta-selective C-H bond activation with a nitrile-containing template: computational study on mechanism and origins of selectivity.

Density functional theory investigations have elucidated the mechanism and origins of meta-regioselectivity of Pd(II)-catalyzed C-H olefinations of toluene derivatives that employ a nitrile-containing template. The reaction proceeds through four major steps: C-H activation, alkene insertion, ß-hydride elimination, and reductive elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation (CMD) pathway, is found to be the rate- and regioselectivity-determining step. For the crucial C-H activation, four possible active catalytic species-monomeric Pd(OAc)2, dimeric Pd2(OAc)4, heterodimeric PdAg(OAc)3, and trimeric Pd3(OAc)6-have been investigated. The computations indicated that the C-H activation with the nitrile-containing template occurs via a Pd-Ag heterodimeric transition state. The nitrile directing group coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta-selectivity. The Pd2(OAc)4 dimeric mechanism also leads to the meta-C-H activation product but with higher activation energies than the Pd-Ag heterodimeric mechanism. The Pd monomeric and trimeric mechanisms require much higher activation free energies and are predicted to give ortho products. Structural and distortion energy analysis of the transition states revealed significant effects of distortions of the template on mechanism and regioselectivity, which provided hints for further developments of new templates.

Synthesis of indolines via Pd(II)-catalyzed amination of C-H bonds using PhI(OAc)2 as the bystanding oxidant.

The Pd(II)-catalyzed intramolecular C-H amination of 2-pyridinesulfonyl-protected phenethylamine derivatives has been achieved using PhI(OAc)2 as a bystanding oxidant, providing access to a variety of substituted indoline derivatives in good yields. The use of the 2-pyridinesulfonyl protecting group allows for facile deprotection following C-H functionalization.

Activation of remote meta-C-H bonds assisted by an end-on template.

Functionalization of unactivated carbon-hydrogen (C-H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C-H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C-H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C-H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C-H activation to a weak 'end-on' interaction between the linear nitrile group and the metal centre. The 'end-on' coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C-H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

Pd(II)-catalyzed para-selective C-H arylation of monosubstituted arenes.

Pd-catalyzed highly para-selective C-H arylation of monosubstituted arenes (including toluene) is developed for the first time using an F(+) reagent as a bystanding oxidant. This finding provides a new retrosynthetic disconnection for para-substituted biaryl synthesis via C-H/C-H cross-coupling.

Enantioselective protonation of itaconimides with thiols and the rotational kinetics of the axially chiral C-N bond.

Bicyclic guanidines are able to catalyze the protonation reactions of 2-phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition-enantioselective protonation of N-substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C-N axis of N-2-tert-butyl phenylitaconimide is also studied, both experimentally and computationally.

Enantioselective synthesis of chiral allenoates by guanidine-catalyzed isomerization of 3-alkynoates.

We report that chiral bicyclic guanidine 1 is found to catalyze the isomerization of alkynes to chiral allenes with high enantioselectivities. This Brønsted base catalyzed 1,3-proton shift reaction, an efficient and atom economical reaction, proceeds through deprotonation and protonation sequences. The axial chirality of the allenes is efficiently transferred to functionalized butenolides and cycloaddition products. We also successfully demonstrate the stereospecific synthesis of butenolide through allenoate cyclization with a catalytic cationic Au(I) complex.

Chiral guanidine catalyzed enantioselective reactions.

Chiral guanidine catalysts share common characteristics such as high pK(a) values and dual hydrogen-bonding modes of activation, and high catalytic activities and enantioselectivities can often be achieved. The utilization of guanidines as catalysts has been growing at a steady pace. In the past few years, it has attracted tremendous attention through several landmark achievements. This article highlights the development of chiral guanidine catalysis in asymmetric synthesis.