Tuhin Patra

Oxidative Trifluoromethylation of Unactivated Olefins: An Efficient and Practical Synthesis of α-Trifluoromethyl-Substituted Ketones†

The incorporation of a CF3 group in a compound of pharmacological relevance usually results in significant enhancement of its lipophilicity, binding selectivity, and metabolic stability. A number of highly effective methods for the incorporation of a CF3 moiety into commonly used synthetic scaffolds have been reported. In this context, the synthesis of a-CF3-substituted carbonyl compounds [10–14] has recently drawn significant attention, owing to their importance for both pharmaceutical and synthetic research. Generally, a-CF3-substituted carbonyl compounds are prepared from silyl enol ethers and enolates by using various radical and electrophilic trifluoromethylating agents (Scheme 1). Strong bases, such as lithium diisopropylamide (LDA), are often employed in the synthesis of these precursors, thus limiting the available methods by extra

Remote para-C–H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

A general and efficient aldehyde decarbonylation reaction by using a palladium catalyst

A facile decarbonylation reaction of aldehydes has been developed by employing Pd(OAc)(2). A wide variety of substrates are decarbonylated, without using any exogenous ligand for palladium as well as CO-scavenger.

Meta-selective arene C-H bond olefination of arylacetic acid using a nitrile-based directing group.

A nitrile-based template attached with a phenylacetic acid framework promoted meta-selective C-H bond olefination. This palladium-catalyzed protocol is applicable to a wide range of substituted phenylacetic acids and tolerates a variety of functional groups. The versatility of this operationally simple method has been demonstrated through drug diversification.

Palladium‐Catalyzed Directed para C−H Functionalization of Phenols

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

Decarboxylation as the Key Step in C-C Bond-Forming Reactions

C-C bond forming reactions incarnate the core of organic synthesis because of their fundamental applications to molecular diversity and complexity. In recent years, use of carboxylic acid as one of the coupling partners in place of conventional organometallic reagents has seen an upsurge due to its potency to generate similar organometallic intermediates after decarboxylation. This Review provides an overview on the most recent progress in the field of C-C bond formation involving decarboxylation as a key step. Different important developments, which are not included in earlier Reviews in this area, have been summarized with representative examples and discussions on their reaction mechanisms.

Metal‐Mediated Deformylation Reactions: Synthetic and Biological Avenues

Methods for the removal of functional groups from organic molecules are immensely important in synthesis and biology. Synthetically, the utility of functional groups is mainly due to their ability to act as directing groups as well as their high reactivity and selectivity in a wide variety of transformations. In this regard, metal-mediated deformylation reactions have attracted the attention of chemists for decades since such processes enable temporary use of the beneficial features of the CHO functionality. Also the majority of C!C bondcleavage reactions catalyzed by cytochrome P450 (CYP) in nature are deformylation reactions. Interestingly, the biosynthesis of alkanes and alkenes from cyanobacteria has been recently suggested to occur through deformylation as one of the key steps. In 2008, Madsen and co-workers reported detailed mechanistic studies on the decarbonylation of aldehydes catalyzed by a bidentate phosphine ligated rhodium complex (Scheme 1). Linear Hammett plots having positive slopes of+ 0.79 and+ 0.43 were obtained for both the benzaldehyde derivatives and the phenyl acetaldehyde derivatives, respectively. These values suggest that there is a build up of a negative charge in the selectivity determining steps in both cases. The observed kinetic isotope effect values of 1.73 for benzaldehyde and 1.77 for phenyl acetaldehyde indicate a similarity in their reaction mechanisms. A detailed density functional theory (DFT; B3LYP) study of the catalytic cycle suggested a rapid oxidative addition into the C(O)!H bond followed by the rate-limiting elimination of CO and product formation. Furthermore, the theoretical kinetic isotope effects matched well with the observed experimental values for both benzaldehyde and phenyl acetaldehyde, provided removal of carbon monoxide was selected as the ratedetermining step. Based on this information, the deformylation mechanism by rhodium complexes are suggested to be as follows: 1) coordination of the aldehyde substrate to the metal complex, 2) oxidative addition of the aldehydic C!H bond to form a metal acyl complex (Rh!Rh), 3) migratory extrusion of carbon monoxide, 4) reductive elimination of the product (Rh!Rh). For the case of cytochrome-P450-catalyzed deformylation, methyl group hydroxylation occurs first to generate an alcohol and then a geminal diol. The diol intermediate then dehydrates to the aldehyde, which is removed by the enzyme. Sen and Hackett demonstrated the deformylation mechanism of the sterol 14a-demethylase (CYP51) from Mycobacterium tuberculosis by using a molecular dynamics simulation, DFT, and hybrid quantum mechanics/molecular mechanics methods. A heme/peroxo intermediate has been established as the key active species in CYP-catalyzed deformylation (Scheme 2). Molecular dynamics simulations indicate that the hydrogen-bonded proton shuttle in this enzyme is diverted to the aldehyde oxygen atom from the peroxo intermediate, thus allowing the peroxo species to accumulate. In turn, the peroxo intermediate is trapped by the preorganized aldehyde substrate, thus resulting in a peroxohemiacetal without an apparent barrier. A transition state for the concerted rearrangement to produce the formate and the triene steroid was found; however, a stepwise mechanism involving heterolytic C!C bond cleavage is favored as a result of its lower energy, and thus a carbanion at C14 is generated along the way. The researchers also show that a homolytic C! C cleavage is favorable in the absence of the protein electrostatic background. According to them, this fact clearly Scheme 1. Catalytic cycle for the rhodium-catalyzed decarbonylation of aldehydes.

Four-Center Oxidation State Combinations and Near-Infrared Absorption in [Ru(pap)(Q)2]n (Q=3,5-Di-tert-butyl-N-aryl-1,2-benzoquinonemonoimine, pap=2-Phenylazopyridine)

The complex series [Ru(pap)(Q)2](n) ([1](n)-[4](n); n = +2, +1, 0, -1, -2) contains four redox non-innocent entities: one ruthenium ion, 2-phenylazopyridine (pap), and two o-iminoquinone moieties, Q = 3,5-di-tert-butyl-N-aryl-1,2-benzoquinonemonoimine (aryl = C6H5 (1(+)); m-(Cl)2C6H3 (2(+)); m-(OCH3)2C6H3 (3(+)); m-(tBu)2C6H3 (4(+))). A crystal structure determination of the representative compound, [1]ClO4, established the crystallization of the ctt-isomeric form, that is, cis and trans with respect to the mutual orientations of O and N donors of two Q ligands, and the coordinating azo N atom trans to the O donor of Q. The sensitive C-O (average: 1.299(3) Å), C-N (average: 1.346(4) Å) and intra-ring C-C (meta; average: 1.373(4) Å) bond lengths of the coordinated iminoquinone moieties in corroboration with the N-N length (1.292(3) Å) of pap in 1(+) establish [Ru(III)(pap(0))(Q(·-))2 ](+) as the most appropriate electronic structural form. The coupling of three spins from one low-spin ruthenium(III) (t2g(5)) and two Q(·-) radicals in 1(+)-4(+) gives a ground state with one unpaired electron on Q(·-), as evident from g = 1.995 radical-type EPR signals for 1(+)-4(+). Accordingly, the DFT-calculated Mulliken spin densities of 1(+) (1.152 for two Q, Ru: -0.179, pap: 0.031) confirm Q-based spin. Complex ions 1(+)-4(+) exhibit two near-IR absorption bands at about λ = 2000 and 920 nm in addition to intense multiple transitions covering the visible to UV regions; compounds [1]ClO4-[4]ClO4 undergo one oxidation and three separate reduction processes within ±2.0 V versus SCE. The crystal structure of the neutral (one-electron reduced) state (2) was determined to show metal-based reduction and an EPR signal at g = 1.996. The electronic transitions of the complexes 1(n)-4(n) (n = +2, +1, 0, -1, -2) in the UV, visible, and NIR regions, as determined by using spectroelectrochemistry, have been analyzed by TD-DFT calculations and reveal significant low-energy absorbance (λmax >1000 nm) for cations, anions, and neutral forms. The experimental studies in combination with DFT calculations suggest the dominant valence configurations of 1(n)-4(n) in the accessible redox states to be [Ru(III)(pap(0))(Q(·-))(Q(0))](2+) (1(2+)-4(2+))→[Ru(III)(pap(0))(Q(·-))2](+) (1(+)-4(+))→[Ru(II)(pap(0))(Q(·-))2] (1-4)→[Ru(II)(pap(·-))(Q(·-))2](-) (1(-)-4(-))→[Ru(III)(pap(·-))(Q(2-))2](2-) (1(2-)-4(2-)).

Nickel-catalyzed hydrogenolysis of unactivated carbon–cyano bonds

Selective hydrogenolysis of C-CN bonds can allow chemists to take advantage of ortho-directing ability, α-C-H acidity and electron withdrawing ability of the cyano group for synthetic manipulations. We have discovered hydrogenolysis of aryl and aliphatic cyanides under just 1 bar of hydrogen by using a nickel catalyst. This protocol was applied in the aryl cyanide directed functionalization reaction and α-substitution of benzyl cyanides.

Highly Enantioselective [5 + 2] Annulations through Cooperative N-Heterocyclic Carbene (NHC) Organocatalysis and Palladium Catalysis

The highly enantioselective [5 + 2] annulation of enals with vinylethylene carbonates through a cooperative N-heterocyclic carbene (NHC)/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the NHC organocatalyst to the active Pd catalyst. The complementary and matched combination of the chiral NHC catalyst and chiral phosphine ligand promotes high levels of both reactivity and enantioselectivity (mostly ≥99% ee).