Unified Approach to Diverse Heterocyclic Synthesis: Organo-Photocatalyzed Carboacylation of Alkenes and Alkynes from Feedstock Aldehydes and Alcohols.

We report an organo-photocatalyzed carboacylation reaction that offers a springboard to create chemical complexity in a diversity-driven approach. The modular one-pot method uses feedstock aldehydes and alcohols as acyl surrogates and commercially available Eosin Y as the photoredox catalyst, making it simple and affordable to introduce structural diversity. Several biologically relevant skeletons have been easily synthesized under mild conditions in the presence of visible light irradiation by fostering a radical acylation/cyclization cascade. The proposed reaction mechanism was further illuminated by a number of spectroscopic studies. Furthermore, we applied this protocol for the late-stage functionalization of pharmaceuticals and blockbuster drugs.

Synergistic Effect of Cerium in Dual Photoinduced Ligand-to-Metal Charge Transfer and Lewis Acid Catalysis: Diastereoselective Alkylation of Coumarins.

We report the dual role of cerium to promote the photoinduced ligand-to-metal charge transfer (LMCT) process for the generation of the alkyl radical and subsequent Lewis acid catalysis to construct stereodefined C-C bonds. This paradigm utilized ubiquitous carboxylic acids as alkyl radical surrogates and offers excellent diastereoselectivity for the formation of C-4 alkylated coumarins in good to excellent yield. UV-vis spectroscopy studies in combination with in situ Fourier transform infrared spectroscopy are consistent with the proposed mechanism, supporting the participation of the CeIV-carboxylate complex in photoinduced LMCT and its subsequent homolysis to generate the alkyl radial through the exclusion of CO2. Finally, the oxophilicity of cerium enables a two-point complexation with the in situ generated enolate intermediate and facilitates the diastereoselective protonation to form the desired product. Furthermore, this mild and atom-economical catalytic manifolds allow the late-stage modification of pharmaceuticals.

Electrochemical Activation of the C-X Bond on Demand: Access to the Atom Economic Group Transfer Reaction Triggered by Noncovalent Interaction.

An atom economic method demonstrates the involvement of noncovalent interaction via hydrogen or halogen bonding interaction in triggering paired electrolysis for the group transfer reactions. Specifically, this method demonstrated the bromination of several aromatic and heteroaromatic compounds through the activation of the C(sp3)-Br bond of organic-bromo derivatives on demand. This electrochemical protocol is mild, and mostly no additional electrolyte is needed, which makes the workup process straightforward. Unlike the existing regioselective monobromination methods, this work utilizes a relatively small amount (1.2 equiv) of bromine surrogates that releases bromine on demand under the electrochemical condition and after completion of the reaction generates acetophenone as a useful byproduct. Green metrics indicate this protocol has a very good atom efficiency with an E-factor of 26.86 kg of waste/1 kg of product. In addition to the scale-up process, this strategy could be extended to the transfer of chlorine and thioaryl units. An extensive mechanistic study is accomplished to validate the hypothesis of noncovalent interaction using computational, spectroscopic, and cyclic voltammetry studies. Finally, the applicability of this newly developed nonbonding interaction to trigger paired electrolysis was extended to the chemoselective debromination of several dihalo organic compounds.

Visible-Light-Mediated Cross Dehydrogenative Coupling of Thiols with Aldehydes: Metal-Free Synthesis of Thioesters at Room Temperature.

Thioesters play a crucial role in biological systems and serve as important building blocks for organic synthesis. Herein, Eosin Y and TBHP mediated photochemical cross dehydrogenative coupling (PCDC) between feedstock aldehydes and thiols has been described at room temperature to synthesize thioesters. This thioesterification protocol proceeds smoothly to give the desired products in good to excellent yields by the suitable PCDC of both alkyl/aryl- aldehydes with a variety of alkyl/aryl-thiols and generates water and tBuOH as green byproducts. This method is also found to be scalable with good efficiency. Mechanistic investigations reveal that under this photochemical condition, the formation of acyl radical can be achieved from aldehyde. This acyl radical was further intercepted with an intermediate disulfide, generated in situ via the dehydrogenation of thiol to give the desired thioester. Moreover, disulfides, which are relatively easier to handle, also provided good to excellent yields in the optimized reaction condition. This protocol was further extended toward the more challenging direct transformation of alcohols to thioesters.

Direct functionalization of quinoxalin-2(1H)-one with alkanes: C(sp2)-H/C(sp3)-H cross coupling in transition metal-free mode.

Considering the significance of pharmaceutically important heterocycles, efficient and highly versatile protocols for the functionalization of diverse heterocycles with easily accessible feedstock are crucial. Here, we have reported selective alkylation of quinoxalin-2(1H)-one with a broad class of hydrocarbons having different C(sp3)-H bonds with varying bond strengths using di-tert-butyl peroxide (DTBP) as an alkoxyl radical mediator for hydrogen atom transfer (HAT). This dehydrogenative coupling approach utilizes feedstock chemicals such as cycloalkanes, cyclic ethers and alkyl arenes as coupling partners. This protocol exhibits good functional group compatibility and selectivity regarding both heterocycles and unactivated alkanes. Moreover, this methodology allows functionalization of relatively strong C-H bonds of adamantane and exclusive selectivity towards 3° C(sp3)-H bonds is observed. We also illustrate the applicability of this C(sp2)-H/C(sp3)-H cross-coupling for practical access to bioactive pharmaceuticals.

Probing the versatility of metallo-electro hybrid catalysis: enabling access towards facile C-N bond formation.

The development of versatile and mild methodologies for C-N bond construction has always been a hot topic of interest in synthetic organic chemistry. In recent years, electrochemistry has emerged as a promising green and sustainable environmentally benign approach to carry out these transformations under mild conditions utilizing electrons as oxidizing/reducing agents. The current state-of-the-art in combining electrocatalysis with transition metal catalysis has gained significant attention. This hybrid synthetic methodology has increasingly become a common tool and offers many potential advantages compared to direct electrolysis. This review comprehensively highlights recent developments in the merging of transition metal catalysis in electro-organic synthesis for the facile construction of C-N bonds. In this review major emphasis is given to mechanistic investigations and their synthetic applications of this hybrid catalysis.

Photochemical Asymmetric Nickel-Catalyzed Acyl Cross-Coupling.

Photochemical enantioselective nickel-catalyzed cross-coupling reactions are difficult to implement. We report a visible-light-mediated strategy that successfully couples symmetrical anhydrides and 4-alkyl dihydropyridines (DHPs) to afford enantioenriched α-substituted ketones under mild conditions. The chemistry does not require exogenous photocatalysts. It is triggered by the direct excitation of DHPs, which act as a radical source and as a reductant, facilitating the turnover of the chiral catalytic nickel complex.

Catalytic π-π Interactions Triggered Photoinduced Synthesis of Biaryls.

A highly regioselective photocatalytic method to access a variety of biaryl motifs under metal-free conditions has been developed. The organophotocatalyst is involved in π-π stacking interactions with the alkyne species, which promotes this photocatalytic process with thiophene. Mechanistic studies have shed light on these interactions and the overall process. Along with a broad functional-group tolerance and excellent regioselectivity, this protocol has been utilized in the late-stage functionalization of pharmaceuticals and other natural products.

Photocatalytic Proficiency of Cinnoline Moiety for Cross-Coupling Reactions: A Two in One Photocatalyst.

Herein, we have developed a new class of organic photocatalysts that can mimic transition metals for several oxidative and reductive organic cross-coupling transformations. Due to its wide potential window in both the oxidation and reduction ranges, cinnoline exhibits dual catalytic activity under visible light illumination, acting as both a photoreductant and photooxidant.

Light-Induced Activation of C-X Bond via Carbonate-Assisted Anion-π Interactions: Applications to C-P and C-B Bond Formation.

We have presented a carbonate anion assisted photochemical protocol for the C-X bond activation. Anion-π interactions have been leveraged to generate aryl radicals from easily accessible aryl halides that are further utilized in C-P and C-B bond formation reactions with excellent reactivity and broad functional group tolerance. Spectroscopic investigations and DFT studies were conducted for mechanistic insights. This inexpensive method alleviates the use of a photocatalyst and the need of preactivation of the substrate for the light-induced activation of C-X bonds.

Making and Breaking of C-N Bonds: Applications in the Synthesis of Unsymmetric Tertiary Amines and α-Amino Carbonyl Derivatives.

An operationally simple process has been developed for the synthesis of unsymmetrical amines and α-amino carbonyl derivatives in the absence of a catalyst, ligand, oxidant, or any additives. Contrary to known reductive amination methods, this protocol is amenable to substrates containing other reducible groups. This process effectively results in consecutive cleavage and formation of C-N bonds. DFT studies and Hammett analysis provide useful insight into the mechanism. The role of noncovalent interactions as a stabilizing factor have been examined in the protocol. A wide range of alkyl-bromides have been coupled efficiently with a variety of dimethyl anilines to get unsymmetric tertiary amines with yields up to 90%. This methodology was further extended to the synthesis of α-amino carbonyl derivatives with yields up to 93%.

Skeletal rearrangement through photocatalytic denitrogenation: access to C-3 aminoquinolin-2(1H)-ones.

The addition of an amine group to a heteroaromatic system is a challenging synthetic process, yet it is an essential one in the development of many bioactive molecules. Here, we report an alternative method for the synthesis of 3-amino quinolin-2(1H)-one that overcomes the limitations of traditional methods by editing the molecular skeleton via a cascade C-N bond formation and denitrogenation process. We used TMSN3 as an aminating agent and a wide variety of 3-ylideneoxindoles as synthetic precursors for the quinolin-2(1H)-one backbone, which demonstrates remarkable tolerance of sensitive functional groups. The control experiments showed that the triazoline intermediate plays a significant role in the formation of the product. The spectroscopic investigation further defined the potential reaction pathways.

Lack of correlation between catalytic efficiency and basicity of amines during the reaction of aryl methyl ketones with DMF-DMA: an unprecedented supramolecular domino catalysis.

1-Methylimidazole exhibits an unusually high efficiency in promoting the reaction of aryl methyl ketones with DMF-DMA to form (2E)-1-aryl-3-dimethylamino-2-propenones which lacks correlation between the catalytic efficiency and the basicity of 1-methylimidazole in comparison to other amines. An unprecedented supramolecular domino catalysis rationalises the lack of correlation between the catalytic efficiency and basicity of the amines. The supramolecular assemblies have been characterized by mass-spectrometric ion fishing. The time-dependent increase/decrease in the concentration (ion current) of the supramolecular species consolidated the mechanism.

Synchronous double C-N bond formation via C-H activation for a novel synthetic route to phenazine.

A novel synthetic strategy for phenazine formation is reported following self-coupling of anilines by Pd-Ag binary nanocluster-catalysed synchronous double C-N bond formation via non-radical mode of ortho-aryl C-H activation.