Dasheng Leow

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.

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.

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, β-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.

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.

Hydroxyl-directed C–H carbonylation enabled by mono-N-protected amino acid ligands: An expedient route to 1-isochromanones

A Pd(II)-catalyzed C–H carbonylation protocol of phenethyl alcohols has been developed using amino acid ligands to promote the reaction. This transformation provides an expedient route to 1-isochromanone motifs, which are common structural elements in natural products and other biologically active compounds. A concise synthesis of a histamine release inhibitor showcases the utility of this transformation.

Ether‐Directed ortho‐C–H Olefination with a Palladium(II)/Monoprotected Amino Acid Catalyst

Cyclopalladation reactions promoted by strong σ-chelation have served as a fruitful platform for studying and developing redox chemistry to establish catalytic cycles for C–H functionalization processes.[1] However, these well-established C–H activation reactivities have several limitations from the viewpoint of both catalysis and synthetic applications.[1f] First, the cyclopalladated intermediates are thermodynamically stable and less reactive in the subsequent functionalization step thereby making early discovery of suitable conditions for a diverse range of catalytic reactions difficult. Second, the substrates are typically limited to molecules containing nitrogen-, sulfur- or phosphorus-chelating groups.[1a] Third, the strongly coordinating directing groups either outcompete ligands for vacant coordination sites or dominate the electronic properties of the metal centers, both of which are not desirable for developing ligand-controlled reactions. In response to these challenges, we and others have recently established weak coordination as a powerful means for directing catalytic C–H activation with PdII, RhIII and RuII catalysts.[2–3] The interplay between a suitable ligand and these types of weak coordination on PdII centers was also shown to accelerate C–H activation.[4] Herein, we demonstrate for the first time that mono-protected amino acid ligands (MPAA) promote ether-directed C–H olefination,[1e] which provides a method to functionalize readily available arylethyl ethers to afford novel cinnamate derivatives. Arylether directed benzylic C–H activation:[6a] (1) Alkylether directed aryl C–H activation: (2) Ether is one of the most common functional groups in natural products and drug molecules.[5] The development of ether directed C–H functionalization reactions would be very useful and important. However, such reports are very rare in literatures,[6,7] presumably due to the poor coordination of ethers to late transition metal centers. To the best of our knowledge, only one example of ether directed C–H functionalization with PdII catalyst is documented to date and it is arylether directed benzylic C–H amidation reported by Alvarez and et al. [Eq. (1)].[6a] While this reaction is an intriguing example of using arylether directing groups to promote activation of benzylic C–H bonds, the use of simple alkylethers to direct aryl C–H activation via a six-membered cyclopalladation represents a distinct and unanswered challenge. Since alkylethers are widespread in natural products and drug molecules,[5] we set out to develop C–H activation reactions using a combination of weak coordination of the alkylether moiety and ligand acceleration[2h] to provide a new method for the functionalization of a major class of ethers, namely arylethyl ethers [Eq. (2)]. Taking into consideration the weakly coordinating ability of the ether moiety, we began to develop the olefination of ether 1a using a weakly coordinating solvent hexafluoroisopropanol (HFIP).[2h] Thus a mixture of ether 1a (0.2mmol), ethyl acrylate (2a) (0.3 mmol), 10 mol% Pd(OAc)2 and Ag2CO3 (0.4 mmol) was stirred in 2 mL HFIP under 90 °C for 24 h (Table 1, entry 1). 1H NMR analysis detected the formation of the mono-olefinated product 3a in 11% yield. Guided by previous studies on PdII-catalyzed C–H activation using MPAA ligands,[2h,4] we screened these ligands and observed significant improvement of the reaction with several ligands (entries 2–4).[8] The olefinated products were formed in 92% total yield (mono/di = 1.9/1) when Ac-Gly-OH was used (entry 4). Other solvents except CF3CH2OH drastically decreased the yields (entries 5–7). Among the oxidants tested, Ag2CO3 was shown to be the most effective one, which was consistent with our previous report on PdII/Pd0 catalysis (entries 8–11).[9] It is worth noting that the use of O2 as the terminal oxidant was also possible with catalytic amount of Cu(OAc)2 (entry 12). To improve the mono-selectivity, reaction conditions were further optimized (entries 13–16). Either lowering the reaction temperature or stopping the reaction at lower conversion led to improved mono-selectivity while maintaining good yields (entries 13 and, 14). The mono- and di-olefinated products were easily separated by silica gel chromatography. Table 1 Optimization of reaction conditions.[a,b] To examine the substrate scope of this reaction, we methylated a wide range of readily available arylethanols with MeI to give the corresponding ethers. Ethers derived from primary, secondary and tertiary alcohols were olefinated to give the desired cinnamates in 55–96% yields (3a–h) (Table 2). It is worth noting that the corresponding hydroxyl-directed olefination reaction with primary and secondary arylethyl alcohols suffered from partial oxidation of the alcohols to aldehydes and ketones and decomposition of the substrates, resulting in an unproductive reaction.[4b] Both electron-donating (3i–k) and withdrawing groups (3l–p) on the arenes were tolerated. Except for a highly reactive arene (3j), meta-substituted arenes were typically olefinated in greater than 95% mono-selectivities (3f, 3k, and 3o). Olefination of the methyl ether of the diol also proceeded to give 3q in 66% total yield. Not surprisingly, the replacement of the methyl group by a benzyl group in the ether substrates resulted in olefination on both arenes to give an inseparable mixture. However, olefination of meta-trifluoromethylbenzyl ether proceeded selectively to give the desired product 3r in 51% yield, suggesting alkylethers other than methyl ethers are also reactive. Moreover, when a hydroxyl group is desired for further functionalization, the methyl ether products can be demethylated with BBr3 using a literature procedure (Scheme 1).[10] Scheme 1 Demethylation of the olefinated product. Table 2 PdII-catalyzed ortho-C–H olefination of ethers.[a,b] The scope of the olefin coupling partners was also examined (Table 3). Olefination of ether 1e or 1f with various olefin coupling partners such as α,β-unsaturated ester, amide, phosphonate and ketone gave corresponding cinnamates in good yields (5a–5d). Although the di- or tri-substituted olefins are usually not compatible with ortho-C–H olefination,[4a] modest yields (47%, 34%) were obtained with the ether directing group (5e, 5f). Table 3 Scope of olefins.[a,b] In summary, we have developed an ether-directed C–H olefination with PdII/MPAA catalysts, further demonstrating the potential of weak coordination as a useful tool for promoting C–H activation. This reaction can provide a new method for chemically modifying readily available and synthetically useful ethers. We are currently developing the asymmetric variant of this reaction by tuning the chiral MPAA ligands.

Organic dye photocatalyzed α-oxyamination through irradiation with visible light

Rose Bengal, an organic dye, was used as a visible light photocatalyst to investigate novel α-oxyamination reactions between 1,3-dicarbonyl compounds and a free radical (TEMPO). Compounds that are difficult to obtain such as quaternary fluorinated compounds were synthesized using this method. This visible light photocatalytic reaction can also be performed in water.

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.

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.