Directing Group Strategy Research Articles

Copper(II)‐Catalyzed [2+2+2] Annulation of Enaminones with Maleimides Using a Traceless Directing Group Strategy

AbstractA copper‐catalyzed annulation of enaminones with maleimides was developed to synthesize various pyrrolo[3,4‐e]isoindoles. In this strategy, 2‐aminopyridine served as a traceless directing group, and target products were obtained in 54–72% yields. Moreover, a plausible mechanism for this reaction was proposed based on several control experiments, deuterium exchange experiments, and previous reports.

Highly Regio- and Stereoselective Dehydration of Allylic Alcohols to Conjugated Dienes via 1,4-syn-Elimination with H2 Evolution.

Dehydration of alcohols is one of the most fundamental transformations in the organic chemistry class and one of the most widely used methods for producing alkenes in synthetic research. Numerous methods and reagents have been developed to control the regio- and stereoselectivity as well as the dehydration efficiency of normal alcohols. Despite these achievements, regio- and stereoselective and predictable dehydration of allylic alcohol has seldom been reported, except for limited substrates with a native preferred elimination position, as a result of the challenges that many potential dienes could be formed via 1,2- or 1,4-syn- or anti-elimination. Here, we report a tBuOK/potassium 2,2-difluoroacetate-mediated 1,4-syn-dehydration of allylic alcohol for the synthesis of regio- and stereodefined conjugated dienes via an in situ generated directing group strategy. This reaction exhibits a broad substrate scope and good functional group compatibility for primary-tertiary alcohols. The simple and scalable (up to 0.6 mol) procedure with readily available and inexpensive reagents makes it a practical method for conjugated diene synthesis. Mechanistic studies reveal that an acetate with tert-butoxide and allyloxide acetal moiety is formed as an intermediate, in which the acetate and the acetal act as the directing group for the base-promoted elimination. An unusual H2 evolution is also involved in the reaction.

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.

Rhodium-catalyzed three-component C(sp3)/C(sp2)-H activation enabled by a two-fold directing group strategy.

Rh-catalyzed three-component C(sp3)/C(sp2)-H activation has been achieved through a two-directing group strategy. This protocol provides a convenient and efficient pathway for the construction of diverse 8-alkyl quinoline derivatives in one-pot. Furthermore, mechanistic studies revealed that the first C-H amidation was significantly faster than the sequential C-H alkylation.

Ligand-controlled regiodivergent Ni-catalyzed trans-hydroboration/carboboration of internal alkynes with B2pin2

With the aid of the directing group strategy, an approach for the synthesis of alkenyl and 1-naphthyl boronates with stereo- and regioselectivity via ligand-controlled Ni-catalyzed trans-hydroboration/carboboration of internal alkynes was developed.

Directing Group Strategy for the Isolation of Organoselenium(VI) Benzoselenonates: Metal-Free Catalysts for Hydrogen Evolution Reaction.

The exploration of fourth-period organoelements, particularly organoseleniums in their highest VI oxidation state, is limited owing to their stability and synthesis. Herein, the isolation of a new class of quinolinyl-embedded, hexavalent selenium(VI) benzoselenonates has been discussed and further evaluated for a metal-free electrocatalytic hydrogen evolution reaction (HER). The Se(VI) benzoselenonates exhibited high Faradaic efficiency (F.E.) of metal-free H2 gas production up to 86% with a very good turnover number (TON) up to 43 and moderate overpotential (η) of 500 mV; in the presence of mild acetic acid source in a less deprotonating DMF solvent. Taken together with various (NMR, UV-vis, and EPR) spectroscopic and DFT computation studies, a plausible HER pathway is proposed, which suggests that the electrochemical reduction of quinolinyl ring is the initiation step and Se(VI) acts as the reaction site by involving a hydridic type of intermediate for the electrochemical H2 gas generation.

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.

A Fujiwara-Moritani-Type Alkenylation Using a Traceless Directing Group Strategy: A Rare Example of C-C Bond Formation towards the C2-Carbon of Terminal Alkenes.

Herein we report, a rhodium-catalyzed Fujiwara-Moritani-type reaction of unactivated terminal alkenes and benzoic acid derivatives bearing electron donating residues under mild conditions. The acid functionality acts as a traceless directing group delivering products alkenylated in meta-position to the electron donating substituent in contrast to the usually obtained ortho- and para-substitution in Friedel-Crafts-type reactions. Remarkably, the new C-C bond is formed to the C2 of the terminal olefin, in contrast to similar reported transformations. Initially formed mixtures of exo- and endo-double bond isomers can be efficiently isomerized to the more stable endo-products.

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.

Palladium-Catalyzed Vinylation of Cyclopentenes with Inverted Z,E-Isomerism of Vinylic Substrates.

A palladium-promoted Mizoroki-Heck type reaction employing a directing-group strategy to efficiently produce the coupled vinyl cyclopentenes with excellent regio- and stereoselectivity is reported. Typically, a Pd-catalyzed reaction of 2-(cyclopent-2-en-1-yl)-N-tosylacetamide (1a) with (E)-styryl bromides gave cis-2-((Z)-styryl)cyclopent-3-en-1-yl-N-tosylacetamide (3e), an allylic substitution product. Interestingly, we have found that the E,Z-stereochemistry of vinylic substrates is inverted in those products. The mechanism of this catalytic reaction is discussed.

Nickel(0)-catalysed linear-selective hydroarylation of 2-aminostyrenes with arylboronic acids by a bifunctional temporary directing group strategy

We report a nickel(0)-catalyzed linear-selective hydroarylation of 2-aminostyrenes with arylboronic acids using a bifunctional temporary directing group strategy.

Synthesis of 2-trifluoromethylquinolines through rhodium-catalysed redox-neutral [3 + 3] annulation between anilines and CF3-ynones using traceless directing groups

Rhodium-catalysed [3 + 3]-cycloaddition of acetanilides with CF3-ynones was achieved through a traceless directing-group strategy, which delivered 2-trifluromethylquinolines exhibiting favorable blue emissions.

Photocatalytic Sulfonylcarbocyclization of Alkynes Using SEt as a Traceless Directing Group: Access to Cyclopentenes and Indenes.

Cyclopentenes and indenes are important structural scaffolds in synthetic, medical, and material chemistry. Cyclization of alkynes via remote C-H functionalization is an appealing approach to construct these motifs due to its high efficiency and step-economy. Herein, a traceless directing group strategy was designed to reverse the regioselectivity of radical addition which enabled an unprecedented photocatalytic sulfonylcarbocyclization of terminal alkynes by forming C-C bond on inert C(sp3 )-H bond. It offers a facile access to decorated cyclopentenes and indenes under mild conditions. The resultant products could be converted into a set of valuable molecular scaffolds, including a key intermediate of AM-6226. Mechanistic experiments suggest a radical cascade pathway comprising a Markovnikov-type sulfonylation, 1,5-hydrogen atom transfer, 5-endo-trig cyclization, and β-elimination. This study lays further groundwork for the use of anti-Baldwin 5-endo-trig radical cyclization in rapidly assembling five-membered carbocycles.