Transient Directing Group Strategy Research Articles

Rhodium-Catalyzed Two-Fold, Regioselective and Enantioselective C-H Activation: an Efficient Strategy to Chiral Single-Benzene-Based Fluorophores.

A Rh-catalyzed two-fold, regioselective and enantioselective C-H activation via chiral transient directing group strategy has been demonstrated in moderate to good yields with commendable enantioselectivities. The newly synthesized chiral fluorophores exhibit favorable photophysical properties, including large Stokes shifts, good fluorescence quantum yields, aggregation-induced emission in aqueous solution, and intense emission and circularly polarized luminescence in the solid state, indicating great potential applications as chiral fluorescent probes or optoelectronic materials.

Palladium-Catalyzed β-C(sp3)-H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands.

2-Pyridone ligand-facilitated palladium-catalyzed direct C-H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct β-C(sp3)-H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.

Chiral Transient Ligand Enabled Enantioselective Synthesis of Atropisomers Decorated with Unactivated Olefins via a Palladium-Catalyzed C-H Olefination.

Herein, atroposelective synthesis of axially chiral biaryls with unactivated olefins by a palladium-catalyzed C-H olefination using a chiral transient directing group strategy has been disclosed. This protocol is well compatible with a variety of biaryl-2-aldehydes as well as various olefins such as allyl sulfonamides and allyl sulfones to provide the atroposelective olefinated products in synthetically useful yields with excellent enantioselectivities up to >99% ee. In addition, a wide number of axially chiral biaryl alcohols were synthesized by the simple diversification of the products in excellent enantioselectivity.

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

AbstractIn order to directly functionalize C−H bonds of complex molecules and, in particular, to control the regioselectivity of the reaction, a wide range of directing groups has been used. However, these directing groups need to be installed and removed for further applications, which may limit the use of C−H activation in synthesis. Concerning aldehydes and ketones, a transient directing group strategy has recently emerged to overcome this drawback. The addition of an additive, in general an amine, allowed the in situ formation of the real directing group to achieve C−H activation. This review presents the latest developments in the field over the period 2020–2023.

Synthesis of Naphthalimides through Tandem Pd(II)-Catalyzed C(sp3)-H Oxidation and Diels-Alder Reaction Using a Transient Directing Group Strategy.

Naphthalimides have found extensive applications in materials science and pharmaceuticals. It is still highly desirable to develop efficient methods for the synthesis of naphthalimides with structural diversity. In this work, we developed a new approach for the synthesis of naphthalimides via a tandem reaction of o-methylbenzaldehydes and maleimides. The tandem reaction involves Pd(II)-catalyzed benzylic C(sp3)-H oxidation using an amino acid as the transient directing group and Diels-Alder reaction. The subsequent dehydration forms naphthalimides. The reaction introduces the imide moiety and constructs a benzene ring simultaneously, allowing for easy access to a range of naphthalimides with a variety of substituents.

Iridium-Catalyzed Direct Ortho-C-H Amidation of α-Ketoesters with Sulfonyl Azides Using a Transient Directing Group Strategy.

Direct C-H amidation of α-ketoesters was accomplished using various organic azides as the amino source through the combination of transient directing group strategy and iridium catalysis. Excellent functional group tolerance and wide substrate scope were explored under simple and mild conditions. Importantly, it was found that the steric hindrance of the ester moiety played a pivotal role for the reaction efficacy. In addition, the reaction could be enlarged to gram scale, and several useful heterocycles were readily constructed via one-step late-stage derivatization.

Palladium-Catalyzed ortho-C-H Alkoxycarbonylation of Aromatic Aldehydes via a Transient Directing Group Strategy.

Transient directing groups (TDGs) can be a powerful strategy for directly functionalizing C-H bonds of aldehydes. We report a palladium-catalyzed o-C-H alkoxycarbonylation of benzaldehydes using a catalytic amount of aromatic amine to form a transient imine that plays the role of a monodentate TDG. The reaction conditions were applied to a broad range of aldehydes, and the corresponding 2-formyl benzoates were used as direct precursors for the synthesis of phthalides and 1-isoindolinones.

Rhodium-Catalyzed Tandem C-H Annulation Enabled by Transient Directing Group Strategy and Sequential Nucleophilic Substitution.

A novel protocol of rhodium-catalyzed tandem C-H annulation of aldehyde and aniline with diazonaphthalen-1(2H)-one via transient directing group strategy and sequential nucleophilic substitution has been demonstrated in moderate to excellent yields. This reaction proceeds smoothly via intramolecular cyclization to form 6H-benzo[c]chromen-6-ol and is followed by nucleophilic substitution of para-carbon of aniline to construct 6-aryl-6H-benzo[c]chromene derivatives. A series of 6-aryl-6H-benzo[c]chromenes were synthesized in one-pot via the tandem C-H annulation.

Palladium‐catalyzed Atroposelective Interannular C−H Arylation of Biaryl Aldehydes with Aryl Iodides Enabled by a Transient Directing Group Strategy

AbstractA concise synthesis of axially chiral biaryl aldehydes through Pd/amino acid‐catalyzed atroposelective interannular C−H arylation of biaryl aldehydes with aryl iodides is developed. This reaction proceeds smoothly involving excellent enantiocontrol and accomplishes with good tolerance of functional groups. Moreover, the readily accessible scale‐up synthesis and further transformation of products has highlighted the potential utility of this asymmetric catalytic protocol.magnified image

Monodentate transient directing group promoted Pd-catalyzed direct ortho-C‒H arylation and chlorination of α-ketoesters for three-step synthesis of Cloidogrel racemate

An unprecedented direct ortho C–H arylation and chlorination of α-ketoesters were successfully accomplished by using a combination of monodentate transient directing group strategy and palladium catalysis. The in situ formed imine changed the bidentate coordination model of α-ketoesters to monodentate, so as to fulfill the ortho C–H activation. Importantly, the key binuclear cyclopalladium intermediate bridged by acetate anion was unambiguously characterized by X-ray diffraction, which solidly supports the proposed mechanism. The practical utility was further depicted as facile access to oral antiplatelet agent Clopidogrel racemate via subsequent two-step derivatization.

Transient Directing Group Strategy as a Unified Method for Site Selective Direct C4-H Halogenation of Indoles.

A unified method for direct C4-H halogenation of indoles has been accomplished with the assistance of anthranilic acids as suitable transient directing groups. Exclusive site selectivity (one out of five potential reactive sites) as well as good functional group tolerance was obtained to install three kinds of halogen atoms (Cl, Br and I, respectively) by using inexpensive N-halosuccinimides (NXS) as halogen sources under mild conditions. Taking advantage of the rich functional groups in the product, a diversity of nitrogen-containing heterocycles were facily constructed via one-step late-stage derivations.

Frontispiece: Transient Directing Groups in Metal−Organic Cooperative Catalysis

The direct functionalization of C−H bonds is among the most important transformations in organic synthesis, but its efficiency depends on its selectivity that can be controlled by the innate reactivity of the substrate or a directing group. We review and discuss in a comprehensive manner C−H functionalization processes based on the transient directing group strategy. For more information, see the Review by Gwilherm Evano et al. on page 13899.

Transient Directing Groups in Metal-Organic Cooperative Catalysis.

The direct functionalization of C-H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C-H bond, this selective C-H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C-H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C-H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C-H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

A Transient Directing Group Strategy Enables Enantioselective Multicomponent Organofluorine Synthesis.

The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catalyzed three-component coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a transient directing group. The synthetically enabling methodology constructs vicinal stereocenters with excellent regio-, diastereo-, and enantioselectivities, forging products that map onto bioactive compounds.

Palladium-Catalyzed Dehydrogenative Fluoroalkoxylation of Benzaldehydes

A direct and efficient palladium-catalyzed oxidative dehydrogenative fluoroalkoxylation of benzaldehydes is reported here for the first time. The method features mild reaction conditions, good tolerance of functional groups, and a broad substrate scope. The protocol employs the transient directing group strategy, thereby avoiding the additional installation and removal of directing groups, endowing the method with great advantages of atom and step economy. The approach should find broad applications in drug synthesis and discovery processes.

Manganese-catalyzed selective C-H activation and deuteration by means of a catalytic transient directing group strategy.

A novel manganese-catalyzed C-H activation methodology for selective hydrogen isotope exchange of benzaldehydes is presented. Using D2O as a cheap and convenient source of deuterium, the reaction proceeds with excellent functional group tolerance. High ortho-selectivity is achieved in the presence of catalytic amounts of specific amines, which in situ form a transient directing group.

Chiral Transient Directing Group Strategies in Asymmetric Synthesis.

The development of novel methodologies for catalytic enantioselective functionalization reactions enabled by chiral transient directing groups is accompanying in a paradigm shift in the field of asymmetric synthesis. In particular, these highly atom- and step-economic enantioinduction processes commonly proceed either via enantioselective C-H functionalization, or via enantioselective hydroarylation of the pro-chiral substrates generating point, axial or planar chirality. The use of the transient directing group strategy in C-H functionalizations precludes the stoichiometric installations and removal of directing groups and enables efficient, more compatible and economical chemical routes. This minireview highlights asymmetric transition-metal-catalyzed methodologies involving chiral transient directing groups together with the scope, utility and future perspective of the field.

Ir-Catalyzed C-H Amidation Using Carbamoyl Azides for the Syntheses of Unsymmetrical Ureas.

An iridium-catalyzed C-H amidation for the syntheses of unsymmetrical urea was developed using carbamoyl azides (R(R')N-C(O)-N3) as the nitrogen source. A combination of iridium and silver gave an active catalyst for C-N bond formation. A variety of urea derivatives were synthesized using carbamoyl azides with only dinitrogen byproducts. Finally, the use of the transient directing group strategy with carbamoyl azides extended the substrate scope of the catalytic C-H amidation to yield aldehyde-containing unsymmetrical ureas.

Cp*Co(III)‐Catalyzed o‐Amidation of Benzaldehydes with Dioxazolones Using Transient Directing Group Strategy

AbstractTransition metal‐catalyzed ortho‐selective C(sp2)−H amidation of weakly coordinating aldehydes remains limited to precious metals such as Ir, Rh, Ru, etc. Herein, we put forward a novel report on ortho‐amidation of benzaldehydes employing user‐friendly dioxazolones under cost‐effective and air‐stable Cp*Co(III) catalysis. This catalytic transformation involves transient directing group strategy to enhance the ligating capability of weakly chelating aldehydes.magnified image

Transition Metal-Catalyzed C-H Activation via Imine-Based Transient Directing Group Strategy

Transition Metal-Catalyzed C-H Activation via Imine-Based Transient Directing Group Strategy