Yuya Hu

Abstract

The isomerization of epoxides to aldehydes using the readily available Crabtree's reagent is described. The aldehydes were transformed into synthetically useful amines by a one‐pot reductive amination using pyrrolidine as imine‐formation catalyst. The reactions worked with low catalyst loadings in very mild conditions. The procedure is operationally simple and tolerates a wide range of functional groups. A DFT study of its mechanism is presented showing that the isomerization takes place via an iridium hydride mechanism with a low energy barrier, in agreement with the mild reaction conditions.

Cutting with air: C(sp³)−C(sp³) single bonds in amines can be cleaved using homogeneous copper‐based catalysts in the presence of air. The utility of this novel methodology is demonstrated for C_α−C_β bond scission in >70 amines with excellent functional group tolerance.

Abstract

The selective cleavage of thermodynamically stable C(sp³)−C(sp³) single bonds is rare compared to their ubiquitous formation. Herein, we describe a general methodology for such transformations using homogeneous copper‐based catalysts in the presence of air. The utility of this novel methodology is demonstrated for C_α−C_β bond scission in >70 amines with excellent functional group tolerance. This transformation establishes tertiary amines as a general synthon for amides and provides valuable possibilities for their scalable functionalization in, for example, natural products and bioactive molecules.

Palladium(II)‐catalyzed meta‐selective C−H allylation of arenes has been developed utilizing synthetically inert unactivated acyclic internal olefins as allylic surrogates. The strong σ‐donating and π‐accepting ability of pyrimidine‐based directing group facilitates the olefin insertion by overcoming inertness of the typical unactivated internal olefins. Exclusive allyl over styrenyl product selectivity as well as E‐stereoselectivity were achieved with broad substrate scope, wide functional group tolerance and good to excellent yields. Late‐stage functionalisations of pharmaceuticals were demonstrated. Experimental and computational studies shed insights on the mechanism and pointed to key palladacyclic steric control in determining product selectivities.

Put a ring on it: Morphological control synthesis of ZIF‐8 was achieved via an one‐pot heating strategy; ZIF‐8 solid spheres shows the best catalytic activity in cycloaddition between CO₂ and epoxide, owing to its highest specific surface areas, most abundant acid‐basic sites, and large mesopores.

Abstract

Morphology control synthesis of zeolitic imidazolate frameworks (ZIFs) is very important to understand its morphology, structure, and catalytic property relationships. Herein, morphology control synthesis of ZIF‐8 was achieved through an efficient and environmentally friendly one‐pot heating strategy. Different sophisticated ZIF‐8, such as solid spheres, hollow spheres, hierarchical particles, and stackable particles, were obtained by using different surfactants as templates. The sophisticated ZIF‐8 can be employed directly as a catalyst for cycloaddition reaction between CO₂ and styrene oxide. The high specific surface areas and most abundant acid‐base sites are account for the superior catalytic performance of ZIF‐8 solid spheres, and the rich mesopores provides channels for the mass transfer of large reactants or product molecules, facilitating the accessibility of reactive sites and increasing catalytic activity. ZIF‐8 solid spheres showed enhanced catalytic activity and excellent recyclability and are thus potential heterogeneous catalysts in various catalytic reactions.

Breaking aromaticity: A novel dearomative process is described using arenophile‐based chemistry and Pd catalysis. A range of arenes were readily converted exclusively into the corresponding syn‐1,4‐carboaminated products using Grignard reagents as nucleophiles. The synthetic value of this transformation was demonstrated by several elaborations of the products, including a short synthesis of sertraline from naphthalene.

Abstract

A protocol for palladium‐catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one‐pot method features a visible‐light‐mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium‐catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn‐1,4‐selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

The less the merrier: Spectroscopic comparison of hydrogen‐bonding dynamics of two isomeric diol‐based organocatalysts shows that the good catalyst forms less intermolecular bonds than the poor catalyst. The results suggest, that—rather than the strength of the intermolecular hydrogen‐bond—bonding kinetics and bonding entropy determine the catalytic efficiency.

Abstract

The catalytic efficiency of diol‐based organocatalysts has been shown to strongly depend on the diols molecular structure including hydrogen‐bonding, yet, the underlying molecular‐level origins have remained elusive. Herein a study on the inter‐ and intramolecular hydrogen‐bonding of two isomeric diol‐based catalysts (TADDOLs) in solution is presented: 1‐Naphthyl substituted TADDOL (1nTADDOL), which exhibits high catalytic efficiency, and 2‐naphthyl substituted TADDOL (2nTADDOL), which is a poor catalyst. Using nuclear magnetic resonance and infrared spectroscopy, comparable hydrogen‐bond strengths for both TADDOLs in solution were found, however, significantly slower bonding dynamics for 1nTADDOL. In aromatic solvents, 1nTADDOL forms less, but longer‐lived, intermolecular OH⋅⋅⋅π bonds to solvent molecules, as compared to 2nTADDOL. Thus, rather than previously suggested differences in intermolecular hydrogen‐bonding strengths, the results suggest that the hydrogen‐bonding kinetics and entropies differ for both TADDOLs, which also explains their vastly different catalytic activities.

Once you C1 you see them all: ruthenium catalyzed methylation using methanol as a C1 source is demonstrated to be a widely applicable synthetic strategy for the generation of β‐methyl‐branched primary and secondary alcohols.

Abstract

Selective introduction of methyl branches into the carbon chains of alcohols can be achieved with low loadings of ruthenium precatalyst [RuH(CO)(BH₄)(HN(C₂H₄PPh₂)₂)] (Ru‐MACHO‐BH) using methanol both as methylating reagent and as reaction medium. A wide range of structurally divers alcohols was β‐methylated with excellent selectivity (>99 %) in fair to high yields (up to 94 %) under standard conditions, and turnover numbers up to 18,000 could be established. The overall reaction rate of the complex catalytic network appears to be governed by interconnection of the individual subcycles through availability of the reactive intermediates. The synthetic procedure opens pathways to important structural motifs following the Green Chemistry principles.

Abstract

Described is a tetrabutylammonium fluoride‐mediated hydroxyalkylation reaction of phenols with cyclic carbonates. This operationally simple method enables the synthesis of a variety of aryl β‐hydroxyethyl ethers in good to excellent yields with a very small amount of catalyst loading (0.1–1 mol%). Of particular note is the efficient conversion of aromatic diols and phloroglucinol to the corresponding bis‐ and tris‐hydroxyethylated products. To further showcase the versatility of this protocol, guaifenesin was prepared with a single step by the condensation of guaiacol and glycerol carbonate. We also developed a flow ethoxylation process permitting the continuous synthesis of multiflorol.

Double activation required: Latent nucleophiles enlarge substrate scopes and improve selectivities in Lewis base catalysis. N‐Silyl pyrroles, indoles, and carbazoles serve as latent N‐centered nucleophiles in highly selective enantioselective Lewis base catalyzed substitutions of allylic fluorides.

Abstract

Latent nucleophiles are compounds that are themselves not nucleophilic but can produce a strong nucleophile when activated. Such nucleophiles can expand the scope of Lewis base catalyzed reactions. As a proof of concept, we report that N‐silyl pyrroles, indoles, and carbazoles serve as latent N‐centered nucleophiles in substitution reactions of allylic fluorides catalyzed by Lewis bases. The reactions feature broad scopes for both reaction partners, excellent regioselectivities, and produce enantioenriched N‐allyl pyrroles, indoles, and carbazoles when chiral cinchona alkaloid catalysts are used.

¹H NMR is not a proof of hydrogen bonds in transition metal complexes

¹H NMR is not a proof of hydrogen bonds in transition metal complexes, Published online: 09 April 2019; doi:10.1038/s41467-019-09625-9

Convincing and consistent evidence for the existence of hydrogen bonding to gold has been obtained. An ammonium or pyridinium group has been shown to be an efficient hydrogen bond donor unit for gold(I) coordination centers, and the assembly leads to the structural pattern typical for standard hydrogen bonds. This constitutes the first rigorous, scrutinizing, and comprehensive study of hydrogen bonds to a metal atom, with gold being an ideal model element because of relativistic effects.

Inside source: A nickel‐catalyzed three‐component coupling of alkyl halides and ethyl chloroformate can be used to prepare a wide range of unsymmetrical and symmetrical dialkyl ketones under mild reaction conditions. Ethyl chloroformate serves as a safe CO source relative to the toxic CO or metal carbonyl reagents used by other methods.

Abstract

Ketones are an important class of molecules in synthetic and medicinal chemistry. Rapid and modular synthesis of ketones remains in high demand. Described here is a nickel‐catalyzed three‐component reductive carbonylation method for the synthesis of dialkyl ketones. A wide range of both symmetric and asymmetric dialkyl ketones can be accessed from alkyl halides and a safe CO source, ethyl chloroformate. The approach offers complementary substrate scope to existing carbonylation methods while avoiding the use of either toxic CO or metal carbonyl reagents.

Shifting positions: Asymmetric catalytic alkoxylation/oxidative rearrangement of allylic alcohols was achieved by using a Brønsted acid and a chiral organoiodine. The reaction leads to optically active α‐arylated β‐etherized ketones in good yields and excellent stereoselectivity. Ts=4‐toluenesulfonyl.

Abstract

An enantioselective catalytic alkoxylation/oxidative rearrangement of allylic alcohols has been established by using a Brønsted acid and chiral organoiodine. The presence of 20 mol % of an (S)‐proline‐derived C ₂‐symmetric chiral iodine led to enantioenriched α‐arylated β‐alkoxylated ketones in good yields and with high levels of enantioselectivity (84–94 % ee).

Rate control: Reported here is the highly enantio‐ and diastereoselective hydrofluorination of enals by an asymmetric β‐protonation/α‐fluorination cascade catalyzed by N‐heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate are sequentially protonated and fluorinated. Controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation.

Abstract

In contrast to well‐established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox‐neutral conditions. Reported here is the highly enantio‐ and diastereoselective hydrofluorination of enals by an asymmetric β‐protonation/α‐fluorination cascade catalyzed by N‐heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.

Finding the greenest route: Bifunctional ammonium and phosphonium salts are identified as potential organocatalysts for the synthesis of glycerol carbonate methacrylate (GCMA), with three of them giving the desired product in >99 % conversion and selectivity. A life cycle assessment is conducted to identify a potential reduction of the global warming potential of 3 % for the overall process.

Abstract

Bifunctional ammonium and phosphonium salts have been identified as potential organocatalysts for the synthesis of glycerol carbonate methacrylate (GCMA). Three of these catalysts showed high efficiency and allowed the conversion of glycidyl methacrylate with CO₂ to the desired product in >99 % conversion and selectivity. Subsequently, immobilized analogues of selected catalysts were prepared and tested. A phenol‐substituted phosphonium salt on a silica support proved to be a promising candidate in recycling experiments. The same catalyst was used in 12 consecutive runs, resulting in GCMA yields of up to 88 %. Furthermore, a life cycle assessment was conducted for the synthesis of GCMA starting from epichlorohydrin (EPH) and methacrylic acid (MAA). For the functional unit of 1 kg GCMA, 15 wt % was attributed to the incorporation of CO₂, which led to a reduction of the global warming potential of 3 % for the overall process.

Abstract

The capture and utilization of CO by 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) were performed in the absence of transition‐metal complexes. The reaction of TBD with CO afforded TBD‐CO adducts, which were converted to formylated TBD (TBD‐CHO). TBD‐CO adducts may include an interaction of CO with positively charged species based on NMR and IR analysis. In the presence of amines, CO was transferred from TBD‐CO to amines, producing formylated amines with good yields. The reaction mechanism involving TBD‐CO adducts is presented based on theoretical calculations.

Urea‐lly got me: Silylamines react with CO₂ to give facile access to silylcarbamates or the corresponding aryl or alkyl ureas. This procedure also provides a convenient route to ¹³C‐labelled, chiral or macrocyclic derivatives.

Abstract

A series of thirty‐three N,N′‐diaryl, dialkyl, and alkyl‐aryl ureas have been prepared in pyridine or toluene by reaction of silylamines with CO₂. This protocol is shown to provide facile access to ¹³C‐labeled ureas, as well as chiral and macrocyclic ureas. These reactions proceed through initial generation of the corresponding silylcarbamates, which subsequently react with silylamine under thermal conditions to afford the thermodynamically favored urea and disilyl ether.

Asymmetric and site selective annulations at the γ and γ′ positions of cyclic 2‐enones with α,β‐unsaturated aldehydes were achieved. The organocatalysed [3+3]‐annulations proceeded with high levels of regio‐, diastereo‐, and enantioselectivity, affording a series of high‐value fused carbocycles. Further elaboration gave key lactones (both bridged and fused).

Abstract

A method for asymmetric and site selective annulations at the γ and γ′ positions of cyclic 2‐enones with α,β‐unsaturated aldehydes has been developed. The organocatalysed [3+3]‐annulations proceed with high levels of regio‐, diastereo‐, and enantioselectivity, affording a series of high value fused carbocycles. Further elaboration gave key lactones (both bridged and fused).

Synlett
DOI: 10.1055/s-0037-1611749

A novel and efficient method for the direct α-nitration of nitrostilbenes was developed in which NO2 was used as the nitro source. This method provided (E)-α-nitrostilbenes derivatives in moderate to good yields. A broad substrate scope, mild and convenient conditions, and high stereoselectivity are important features of this method.
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Abstract

Tris(pentafluorophenyl)borane‐catalyzed C−C bond functionalization of arylallyl alcohols using donor‐acceptor carbenes is presented. The allylic hydroxyl group is found to assist the product formation by neighboring group participation providing a clue towards mechanistic understanding. This method can also be employed to effect homologation of allyl alcohols to homoallyl alcohols. Overall, this metal‐free transformation presents a novel disconnection strategy towards carbon‐carbon bond scission and formation.