Tapas Kumar Achar

A rhodium catalyzed C(aryl)−C(allyl) bond‐forming reaction is achieved via a combination of C−H and C−C activation. Gem‐difluorinated cyclopropanes can be employed as highly reactive allyl surrogates, enabling C−H allylation of a variety of simple arenes under mild conditions.

Abstract

Herein, we report a rhodium catalyzed directing‐group free regioselective C−H allylation of simple arenes. Readily available gem‐difluorinated cyclopropanes can be employed as highly reactive allyl surrogates via a sequence of C−C and C−F bond activation, providing allyl arene derivatives in good yields with high regioselectivity under mild conditions. The robust methodology enables facile late‐stage functionalization of complex bioactive molecules. The high efficiency of this reaction is also demonstrated by the high turnover number (TON, up to 1700) of the rhodium catalyst on gram‐scale experiments. Preliminary success on kinetic resolution of this transformation is achieved, providing a promising access to enantio‐enriched gem‐difluorinated cyclopropanes.

C–N coupling of aryl halides with nitroarenes is achieved by nickel catalysis under light irradiation and mild basic conditions, with no need for any external photosensitizers, offering a nitro version for the Buchwald–Hartwig C–N coupling reaction.

Abstract

A photochemical C–N coupling of aryl halides with nitroarenes is demonstrated for the first time. Catalyzed by a Ni^II complex in the absence of any external photosensitizer, readily available nitroarenes undergo coupling with a variety of aryl halides, providing a step‐economic extension to the widely used Buchwald–Hartwig C–N coupling reaction. The method tolerates coupling partners with steric‐congestion and functional groups sensitive to bases and nucleophiles. Mechanistic studies suggest that the reaction proceeds via the addition of an aryl radical, generated from a Ni^I/Ni^III cycle, to a nitrosoarene intermediate.

A concise total synthesis of (−)‐berkelic acid in eight linear steps was developed. This synthesis features a Catellani reaction/oxa‐Michael cascade for the construction of the isochroman scaffold, a one‐pot deprotection/spiroacetalization operation for the formation of tetracyclic core structure, and a late‐stage Ni‐catalyzed reductive coupling for the introduction of the lateral chain.

Abstract

Reported here is a concise total synthesis of (−)‐berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa‐Michael cascade for the construction of the isochroman scaffold, a one‐pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late‐stage Ni‐catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.

The non‐noble metal‐catalyzed asymmetric hydrogenation of N‐heteroaromatics, quinolines, has been realized by using a well‐defined chiral pincer manganese catalyst, with up to 97 % ee and 3840 TON.

Abstract

The non‐noble metal‐catalyzed asymmetric hydrogenation of N‐heteroaromatics, quinolines, is reported. A new chiral pincer manganese catalyst showed outstanding catalytic activity in the asymmetric hydrogenation of quinolines, affording high yields and enantioselectivities (up to 97 % ee). A turnover number of 3840 was reached at a low catalyst loading (S/C=4000), which is competitive with the activity of most effective noble metal catalysts for this reaction. The precise regulation of the enantioselectivity were ensured by a π–π interaction.

A photoinduced C(sp³)−H trifluoromethylation reaction of alkanes was developed by employing bpyCu(CF₃)₃ as a multifunctional reagent: photoinduced‐reaction initiator, precursor of the hydrogen‐atom‐transfer reagent, and trifluoromethyl anion source (see scheme). The operatively simple reaction enables the direct, late‐stage trifluoromethylation of complex molecules under mild reaction conditions.

Abstract

A mild and operationally simple C(sp³)−H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench‐stable Cu^III complex, bpyCu(CF₃)₃, as the initiator of the visible‐light photoinduced reaction, the source of a trifluoromethyl radical as a hydrogen atom transfer reagent, and the source of a trifluoromethyl anion for functionalization. The reaction was initiated by the generation of reactive electrophilic carbon‐centered CF₃ radical through photoinduced homolytic cleavage of bpyCu(CF₃)₃, followed by hydrogen abstraction from an unactivated C(sp³)−H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C−CF₃ bond formation was enabled by radical–polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF₃ source. The methylene‐selective reaction can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules.

A new concept for asymmetric hydroboration of ketones is shown, in which an ammonium halide initiates a hydride transfer to a Lewis acid activated ketone. Advantages of the bifunctional catalyst include remarkable turnover numbers (up to 15 400, 50 ppm catalyst) and high enantioselectivity. The catalyst was recycled 10 times still providing high efficiency. Mechanistic and DFT studies confirm the cooperative mechanism.

Abstract

Enantiopure secondary alcohols are fundamental high‐value synthetic building blocks. One of the most attractive ways to get access to this compound class is the catalytic hydroboration. We describe a new concept for this reaction type that allowed for exceptional catalytic turnover numbers (up to 15 400), which were increased by around 1.5–3 orders of magnitude compared to the most active catalysts previously reported. In our concept an aprotic ammonium halide moiety cooperates with an oxophilic Lewis acid within the same catalyst molecule. Control experiments reveal that both catalytic centers are essential for the observed activity. Kinetic, spectroscopic and computational studies show that the hydride transfer is rate limiting and proceeds via a concerted mechanism, in which hydride at Boron is continuously displaced by iodide, reminiscent to an S_N2 reaction. The catalyst, which is accessible in high yields in few steps, was found to be stable during catalysis, readily recyclable and could be reused 10 times still efficiently working.

Nature Reviews Chemistry, Published online: 21 December 2020; doi:10.1038/s41570-020-00247-0

An electrosynthetic coupling of olefins with ketones provides an alternative approach to synthesize tertiary alcohols traditionally prepared through Grignard addition to ketones, providing a forward path for an unusual disconnection.

Nature Reviews Chemistry, Published online: 08 January 2021; doi:10.1038/s41570-021-00250-z

Bio-othogonal chemistry lets us determine the fate of a lignin monomer using a radical tag and EPR spectroscopy.

Nature Reviews Chemistry, Published online: 02 February 2021; doi:10.1038/s41570-020-00249-y

The diverse manifestations of mechanochemistry probably share a similar mechanism, whereby mechanical motion drives otherwise endergonic reactions. This Review discusses what reactions of stretched polymers and model macrocycles have taught us about this mechanism.

A mild copper‐mediated protocol has been developed that allows for dichotomic borylation of alkynyl‐substituted carbonates, affording either 1,2‐diborylated 1,3‐dienes or α‐hydroxy allenes as the principal products, depending on the nature of the diboron(4) reagent. A mechanistic rationale is presented that reveals the crucial role of the relative kinetics of the second borylation step versus i‐PrOH‐assisted protodemetalation.

Abstract

A mild copper‐mediated protocol has been developed for borylation of alkynyl cyclic carbonates. Depending on the nature of the borylating reaction partner, either stereoselective diborylation of the propargylic surrogate takes place, providing convenient access to (E)‐1,2‐borylated 1,3‐dienes, or traceless monoborylation occurs, which leads to α‐hydroxyallenes as the principal product. The dichotomy in this borylation protocol has been scrutinized by several control experiments, illustrating that a relatively small change in the diboron(4) reagent allows for competitive alcohol‐assisted protodemetalation to forge an α‐hydroxyallene product under ambient conditions.

A SO₂ surrogate (SOgen) is reported, which is cheap, bench‐stable, and accessible in just two steps from bulk chemicals. SOgen releases SO₂ in just a few minutes when heated in the presence of a styrene. The compatibility of this gas‐releasing method with eight previously reported sulfonylation reactions was demonstrated in a two‐chamber system. Direct aminosulfonylation between aryl iodides and amines is reported.

Abstract

A new SO₂ surrogate is reported that is cheap, bench‐stable, and can be accessed in just two steps from bulk chemicals. Essentially complete SO₂ release is achieved in 5 minutes. Eight established sulfonylation reactions proceeded smoothly by ex situ formation of SO₂ by utilizing a two‐chamber system in combination with the SO₂ surrogate. Furthermore, we report the first direct aminosulfonylation between aryl iodides and amines. Broad functional group tolerance is demonstrated, and the method is applicable to pharmaceutically relevant substrates, including heterocyclic substrates.

CHieF₂ cyclopropanes: A biocatalytic method was developed for the highly diastereo‐ and enantioselective synthesis of CHF₂‐substituted cyclopropanes via myoglobin‐catalyzed carbene transfer. These biocatalysts offer broad substrate scope, enantiodivergent selectivity and could be applied to produce a difluoromethyl bioisostere of a drug candidate.

Abstract

The difluoromethyl (CHF₂) group has attracted significant attention in drug discovery and development efforts, owing to its ability to serve as fluorinated bioisostere of methyl, hydroxyl, and thiol groups. Herein, we report an efficient biocatalytic method for the highly diastereo‐ and enantioselective synthesis of CHF₂‐containing trisubstituted cyclopropanes. Using engineered myoglobin catalysts, a broad range of α‐difluoromethyl alkenes are cyclopropanated in the presence of ethyl diazoacetate to give CHF₂‐containing cyclopropanes in high yield (up to >99 %, up to 3000 TON) and with excellent stereoselectivity (up to >99 % de and ee). Enantiodivergent selectivity and extension of the method to the stereoselective cyclopropanation of mono‐ and trifluoromethylated olefins was also achieved. This methodology represents a powerful strategy for the stereoselective synthesis of high‐value fluorinated building blocks for medicinal chemistry, as exemplified by the formal total synthesis of a CHF₂ isostere of a TRPV1 inhibitor.

Z-Olefins are challenging synthetic targets owing to their relative thermodynamic instability. Transition metal–catalyzed asymmetric allylic substitution reactions are well known for installing stereocenters adjacent to branched or E-linear olefins. However, analogous reactions for the synthesis of optically active Z-olefin products are rare. Here we report iridium-catalyzed asymmetric allylic substitution reactions that retain Z-olefin geometries while establishing an adjacent quaternary stereocenter. The formation of transient anti--allyl-iridium intermediates and their capture by external nucleophiles before isomerization to the thermodynamically more stable syn--allyl-iridium counterparts have been observed. These results provide a promising method for preparing chiral Z-olefinic compounds.

Nature Chemistry, Published online: 29 January 2021; doi:10.1038/s41557-020-00621-x

In an effort to extend the important hydroformylation reaction, a palladium-catalysed carboformylation reaction has now been developed in which two new carbon–carbon bonds are created across an alkyne. This modular reaction relies on a CO shuffling process and uses an acid chloride as a dual carbon and CO source.