Yuya Hu

Hydroxylation of aryl carbon–hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon–hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

The first enantioselective addition of pyrazoles to 1,3-dienes is reported. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity.

Abstract

We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd⁰-catalyzed ligand-to-ligand hydrogen transfer (LLHT). This hydroamination tolerates a range of functional groups and advances the field of diene hydrofunctionalization.

We report access to an Fe⁰ PC_carbeneP pincer complex that proceeds via an isolated α-hydroxylalkyl hydrido complex. Reversible carbonyl migration to the carbene position is found to allow coordination chemistry and E−H bond addition (E=H, B, Cl) across the iron–carbene linkage, representing a unique mechanism for metal–ligand cooperativity. The PC_carbeneP pincer ligand is also found to stabilize formal Fe^II, Fe^I and Fe^−I oxidation states.

Abstract

Despite their promising metal–ligand cooperative reactivity, PC_carbeneP pincer ligands are rarely reported for first-row transition-metal centres. Using a dehydration methodology, we report access to an Fe⁰ PC_carbeneP pincer complex (1) that proceeds via an isolated α-hydroxylalkyl hydrido complex (3). Reversible carbonyl migration to the carbene position in 1 is found to allow coordination chemistry and E−H bond addition (E=H, B, Cl) across the iron–carbene linkage, representing a unique mechanism for metal–ligand cooperativity. The PC_carbeneP pincer ligand is also found to stabilize formal Fe^II, Fe^I, and Fe^−I oxidation states, as demonstrated with synthesis and characterization of the complexes [11-X][BAr^F ₂₀] (X=Br, I), 12, and K[13]. Compound K[13] is found to be highly reactive, and abstracts hydrogen from a range of aliphatic C−H sources. Computational analysis by DFT suggests that the formal Fe^I and Fe^−I complexes contain significant carbene radical character. The ability of the PC_carbeneP ligand scaffold to partake in metal–ligand cooperativity and to support a range of iron oxidation states renders it as potentially useful in many catalytic applications.

Copper catalysts bearing cyclic (alkyl)(amino)carbene (CAAC) ligands exhibit remarkably high Markovnikov selectivity in the protoboration and -silylation of terminal alkynes. This work demonstrates the ability of this strongly σ-donating family of ligands to perturb regioselectivity in the addition of copper−boryl species to C−C π-bonds.

Abstract

Regioselective hydrofunctionalization of alkynes represents a straightforward route to access alkenyl boronate and silane building blocks. In previously reported catalytic systems, high selectivity is achieved with a limited scope of substrates and/or reagents, with general solutions lacking. Herein, we describe a selective copper-catalyzed Markovnikov hydrofunctionalization of terminal alkynes that is facilitated by strongly donating cyclic (alkyl)(amino)carbene (CAAC) ligands. Using this method, both alkyl- and aryl-substituted alkynes are coupled with a variety of boryl and silyl reagents with high α-selectivity. The reaction is scalable, and the products are versatile intermediates that can participate in various downstream transformations. Preliminary mechanistic experiments shed light on the role of CAAC ligands in this process.

Synlett
DOI: 10.1055/a-1523-3336

Deuterium incorporation can effectively stabilize the chiral centers of drug and agrochemical candidates that hampered by rapid in vivo racemization. In this work, the synthetically challenging chiral-center deuteration of alcohols has been achieved via a single-electron umpolung reductive-deuteration protocol using benign D2O as deuterium source and mild SmI2 as electron donor. The broad scope and excellent functional group tolerance of this method has been showcased by the synthesis of 43 respective α-deuterioalcohols in high yields and ≥98% deuterium incorporations. The potential application of this versatile method has been exemplified in the synthesis of 6 deuterated drug derivatives, 1 deuterated human hormone, and 3 deuterated natural products. This method using D2O is greener and more efficient compared to traditional pyrophoric-metal-deuteride-mediated reductive deuterations.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Synthesis
DOI: 10.1055/a-1509-6078

The facile synthesis of highly functionalized building blocks with potential biological activity is of great interest to medicinal chemistry. The benzoxepinone core structures commonly exhibit biological activity. Thus, a short and efficient synthetic route towards benzoxepine containing scaffold, which enables late stage modification was developed. Namely, base-free catalytic Wittig reactions enabled the synthesis of bromobenzoxepinones from readily available starting materials. Subsequent, Suzuki–Miyaura and Stille reactions proved to be suitable methods to access a variety of benzoxepinone diaryl derivatives by late stage modification in only three steps. This three-step reaction sequence is suitable for high throughput applications and gives facile access to highly complex molecular structures, which are suitable for further functionalization. The antiproliferative properties of selected arylbenzoxepinones­ were tested in vitro on monolayer tumor cell line A549. Notably, in this initial screening, these compounds were found to be active in the micromolar range.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Bridged bicyclic nitrogen scaffolds are conformationally restricted analogues of important aminocarbo- and aminoheterocycles. Fixation of functional groups in a biologically active conformation provides efficient and selective ligands for various targets, featuring improved ADME parameters. Long synthetic sequences relying on traditional organic chemistry currently limit the drug discovery process. New step-economic synthetic procedures are therefore highly sought after.

Abstract

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed γ-C(sp³)-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed γ-C(sp³)-H olefination is achieved.

Under cooperative ruthenium and Lewis acid catalysis, readily available anilines and 1,2-diols (as a mixture of diastereomers) couple to forge two C−N bonds in an efficient and diastereoselective fashion. By identifying an effective chiral iridium/phosphoric acid co-catalyzed procedure, enantioconvergent double amination of racemic 1,2-diols has also been achieved, resulting in a practical access to highly valuable enantioenriched vicinal diamines.

Abstract

We present herein an unprecedented diastereoconvergent synthesis of vicinal diamines from diols through an economical, redox-neutral process. Under cooperative ruthenium and Lewis acid catalysis, readily available anilines and 1,2-diols (as a mixture of diastereomers) couple to forge two C−N bonds in an efficient and diastereoselective fashion. By identifying an effective chiral iridium/phosphoric acid co-catalyzed procedure, the first enantioconvergent double amination of racemic 1,2-diols has also been achieved, resulting in a practical access to highly valuable enantioenriched vicinal diamines.

In the presence of co-modulator alcohol, the putative strong σ donor, CDC is reshaped into frustrated Lewis pair-like reactivity. The unique synergistic FLP behavior of CDC; unachievable by its counterpart NHCs, is shown to have beneficial and complementary effects on isocyanate cyclotrimerization, LA polymerization, MMA polymerization and dehydrosilylation of alcohols.

Abstract

Carbodicarbene (CDC), unique carbenic entities bearing two lone pairs of electrons are well-known for their strong Lewis basicity. We demonstrate herein, upon introducing a weak Brønsted acid benzyl alcohol (BnOH) as a co-modulator, CDC is remolded into a Frustrated Lewis Pair (FLP)-like reactivity. DFT calculation and experimental evidence show BnOH loosely interacting with the binding pocket of CDC via H-bonding and π-π stacking. Four distinct reactions in nature were deployed to demonstrate the viability of proof-of-concept as synergistic FLP/Modulator (CDC/BnOH), demonstrating enhanced catalytic reactivity in cyclotrimerization of isocyanate, polymerization process for L-lactide (LA), methyl methacrylate (MMA) and dehydrosilylation of alcohols. Importantly, the catalytic reactivity of carbodicarbene is uniquely distinct from conventional NHC which relies on only single chemical feature of nucleophilicity. This finding also provides a new spin in diversifying FLP reactivity with co-modulator or co-catalyst.

The strategic use of alkene isomerization has enabled the first systematic study of the [3,3]-sigmatropic rearrangement of allylic vinyl acetals, first discovered by Coates nearly forty years ago and rarely applied since. We explore the mediation of this rearrangement by Lewis and Brønsted acids and demonstrate the synthetic utility of the products through a concise synthesis of the iridoid natural product isoneomatatabiol.

Abstract

The [3,3]-sigmatropic rearrangement of allylic vinyl acetals, first investigated by Coates nearly four decades ago, is set apart from other variants of the Claisen rearrangement owing to the versatile monoprotected 1,5-dicarbonyl motif featured in the products. Unfortunately, the synthetically elusive nature of the substrates has thus far precluded the widespread application of this attractive transformation. Herein, we show that the key allylic vinyl acetals can be efficiently generated through alkene isomerization of their readily available regioisomeric counterparts (derived from allylic alcohols and α,β-unsaturated aldehydes), thus enabling the first systematic study of the substrate scope of this rearrangement, as well as the discovery of exceptionally mild conditions for its mediation by Lewis and Brønsted acids.

We report an enantioselective Ir-catalyzed hydrocarbonation towards pyrrole and indole polycyclic scaffolds featuring five-, six- or seven-membered rings, with tertiary and all-carbon quaternary stereocenters. The process can be coupled with the desymmetrization of prochiral centers to obtain pyrrole- and indole-fused scaffolds with either vicinal or skipped stereocenters. DFT studies shed light on the mechanism and key stereodetermining factors.

Abstract

We report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five-, six- and seven-membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non-covalent interactions as key factors to control the enantioselectivity.

A highly efficient site-selective desymmetric mono-hydrogenation of 1,4-dienes is reported. This protocol allows rapid access to a wide range of chiral allylic alcohols and amides bearing two vicinal chiral centers adjacent to the alkene. The utility of this method is further highlighted by the synthesis of the alkyl side chain of zaragozic acid A and the formal total synthesis of (+)-invictolide.

Abstract

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

This Minireview summarizes recent developments in which both noble and non-noble metal-based heterogeneous catalysts are used to synthesize N-heterocycles from alcohols and N-nucleophiles via acceptorless dehydrogenation or borrowing hydrogen methodologies. The strategies for the preparation and functionalization of heterogeneous catalysts, reaction mechanisms, and the roles of heterogeneous catalysts in these reactions are also discussed.

Abstract

N-Heterocycles, such as pyrroles, pyrimidines, quinazolines, and quinoxalines, are important building blocks for organic chemistry and the fine-chemical industry. For their synthesis, catalytic borrowing hydrogen and acceptorless dehydrogenative coupling reactions of alcohols as sustainable reagents have received significant attention in recent years. To overcome the problems of product separation and catalyst reusability, several metal-based heterogeneous catalysts have been reported to achieve these transformations with good yields and selectivity. In this Minireview, we summarize recent developments using both noble and non-noble metal-based heterogeneous catalysts to synthesize N-heterocycles from alcohols and N-nucleophiles via acceptorless dehydrogenation or borrowing hydrogen methodologies. Furthermore, this Minireview introduces strategies for the preparation and functionalization of the corresponding heterogeneous catalysts, discusses the reaction mechanisms and the roles of metal electronic states, and the influence of support Lewis acid–base properties on these reactions.

The application of earth abundant Mn, Fe, Co, and Ni complexes for various heterocycle synthesis using alcohol as a coupling partner is discussed in the present review.

Abstract

Development in the area of acceptorless dehydrogenation (AD) and borrowing hydrogen (BH) catalysis emerge as one of the potential tools for various C−C and C-heteroatom bond forming reactions. Alcohols, which are important lignocellulosic biomass products, act as pivotal electrophilic coupling partners in such processes and interestingly only H₂ or H₂O is eliminated as a byproduct. Initially, the area was developed by the use of noble metal catalysts. Recently, base metals such as Mn, Fe, Co, and Ni proved to be environmentally benign and inexpensive alternatives for the noble metals in the application of AD and BH methods. This transition metal catalyzed AD and BH approaches also allow access toward a plethora of structurally important heterocyclic molecules via environmentally benign and atom economical strategy. Herein, we summarize the current and rising expansion of base metal catalyzed heterocycles synthesis through acceptorless dehydrogenation and borrowing hydrogenation strategy.

In this review, a profound revision on the latest advances on the organocatalytic asymmetric inverse-electron demand hetero-Diels-Alder reaction is shown.

Abstract

Cycloaddition reactions, in particular Diels-Alder reactions, have attracted a lot of attention from organic chemists since they represent one of the most powerful methodologies for the construction of carbon-carbon bonds. In particular, inverse-electron-demand hetero-Diels-Alder reactions have been an important breakthrough for the synthesis of heterocyclic compounds. Among all their variants, the organocatalytic enantioselective version has been widely explored since the asymmetric construction of diversely functionalized scaffolds under reaction conditions encompassed within the green chemistry field is of great interest. In this review, a profound revision on the latest advances on the organocatalytic asymmetric inverse-electron demand hetero-Diels-Alder reaction is shown.

The production of synthetically valuable ArCF₂X and ArCX₃ compounds from ArCF₃ using catalytic iron(III)halides is described, which constitutes the first iron-catalyzed halogen exchange of non-aromatic C−F bonds. Theoretical calculations suggest direct activation of C−F bonds by iron coordination. To optimize for mono-exchange, a statistical analysis called Design of Experiments was used. Optimized parameters were successfully applied to both electron-rich and electron-deficient aromatic substrates, and to the late-stage diversification of flufenoxuron, a commercial insecticide.

Abstract

The facile production of ArCF₂X and ArCX₃ from ArCF₃ using catalytic iron(III)halides is reported, which constitutes the first iron-catalyzed halogen exchange for non-aromatic C−F bonds. Theoretical calculations suggest direct activation of C−F bonds by iron coordination. ArCX₃ and ArCF₂X products of the reaction are synthetically valuable due to their diversification potential. In particular, chloro- and bromodifluoromethyl arenes (ArCF₂Cl, ArCF₂Br respectively) provide access to a myriad of difluoromethyl arene derivatives (ArCF₂R). To optimize for mono-halogen exchange, a statistical method called Design of Experiments was used. Optimized parameters were successfully applied to electron rich and electron deficient aromatic substrates, and to the late stage diversification of flufenoxuron, a commercial insecticide. These methods are highly practical, being run at convenient temperatures and using inexpensive common reagents.

Nature Communications, Published online: 18 June 2021; doi:10.1038/s41467-021-24094-9

Chiral alkyne motifs bearing an α stereocentre are often found in many bioactive compounds, chemical probes, and functional materials. Here the authors show NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that form benzylic alkynylation products in high yield and with excellent regioselectivity.

Nature Communications, Published online: 17 June 2021; doi:10.1038/s41467-021-23971-7

The direct deoxygenative coupling of aldehydes or ketones to construct C(sp3)−C(sp3) bond remains a scientific challenge. Here the authors use a nickel−catalyzed reductive homo-coupling of moisture- and air-stable hydrazones generated in-situ from naturally abundant aldehydes and ketones to construct challenging C(sp3)−C(sp3) bonds.