Umpolung Reactivity of Diazo Arylidene Succinimides: Distal C-H Functionalization of α-Thiocarbonyls from the Reactive Carbenoid Center.

Herein, for the first time we have explored the umpolung reactivity of the vinylogous carbon center of diazo arylidene succinimide (DAS) through rhodium catalysis to achieve [2,3]-Stevens rearrangement of α-thioether esters. The protocol has successfully demonstrated the distal C-H bond functionalization of the α-thioether esters. Alongside, the carbenoid reactivity of DAS has also been achieved with Doyle-Kirmse reaction of allyl/propargyl phenyl sulfides. The protocol proved to be practical to synthesize a wide variety of [2,3]-Stevens rearrangement products exclusively and the possible side products emanating from Pummerer rearrangement and [1,2]-Stevens rearrangement were not observed. This catalytic protocol works smoothly in environmentally benign solvent under open air to afford the corresponding desired products with excellent diastereo-, regio- and chemo-selectivities in good to excellent yields. The protocol also proved to be scalable on gram quantity.

A visible light-driven direct synthesis of industrially relevant glutaric acid diesters from aldehydes.

A straightforward and practical method has been developed to access α-substituted glutaric diesters from acrylates and aldehydes using visible light, with Eosin Y facilitating hydrogen atom transfer (HAT) and subsequent Giese-type addition. Also, sunlight has been successfully used as an alternative sustainable light source. The method has also been explored to access substituted 4,5-dihydro-2H-pyridazinones, which have potential biological and industrial applications. Comprehensive mechanistic investigations have been carried out.

Direct Access to Strained Fused Dihalo-Aziridino Quinoxalinones via C3-Alkylation Followed by Tandem Cyclization.

Quinoxalinones are a privileged class of compounds, and their structural framework is found in many bioactive compounds, natural compounds, and pharmaceuticals. Quinoxalinone is a promising scaffold for different types of functionalization, and the slight modification of the quinoxalinone skeleton is known to offer a wide range of compounds for drug discovery. Owing to the importance of the quinoxalinone scaffold, we have developed a base-mediated protocol for the C3-alkylation of quinoxalinone followed by tandem cyclization to access novel types of strenuous and fused dihalo-aziridino-quinoxalinone heterocycles via the construction of C-C and C-N bonds. The protocol proved to be simple and practical to access desired fused quinoxalinone heterocycles in excellent yields (up to 98% yield). As an application, the highly functionalized fused dihalo-aziridino-quinoxalinone molecule has been further utilized for mono-dehalogenation under visible light irradiation and selective amide reduction. Moreover, the protocol has also been demonstrated on a gram scale.

Base Dependent Rearrangement of Dithiane and Dithiolane under Visible-light Photoredox catalysis.

The rearrangement of dithiolanes and dithianes to access disulfide-linked-dithioesters under visible-light photoredox catalysis via controlled C-S bond cleavage has been disclosed. Unlike, the usual deprotection of dithioacetals to corresponding aldehydes under the oxidative conditions, we observed unique regioselective oxidative reactivity of five and six membered cyclic dithioacetals to form disulfide-linked-dithioesters by exchanging DMAP and imidazole bases. The generality of the protocol has been demonstrated by exploring a wide range of substrates. As an application, in situ generated thiyl radical has been trapped with disulfides to prepare hetero-disulfides of potential utility. The protocol proved to be practical on gram scale quantity and relied on clean energy source for the transformation. Based on the series of control experiments, cyclic voltammetry and Stern-Volmer studies the plausible mechanism has been proposed.

Highly Site-Selective Direct C-H Bond Functionalization of Unactivated Arenes with Propargyl α-Aryl-α-diazoacetates via Scandium Catalysis.

Highly chemo- and regio-selective C-H bond functionalization of unactivated arenes with propargyl α-aryl-α-diazoacetates has been developed using scandium catalysis. A variety of unactivated, mildly deactivated, and electronically activated arenes have been functionalized using this protocol. The synergistic combination of scandium triflate as a catalyst and propargyl α-aryl-α-diazoacetate as a reagent played a pivotal role in the effective C-H bond functionalization of arenes without the assistance of any directing group or ligand. The practicality of the protocol has been demonstrated by the gram-scale synthesis of very useful α,α-diarylacetates including antispasmodic drug-adiphenine. Based on the experimental observations, labeling experiment, and density functional theory calculations, a plausible reaction mechanism has been outlined.

Direct Access to Thiocyano-Thioesters from Cyclic Thioacetals via Photoredox Catalysis: An Introduction of Two Functional Groups in One Pot.

The cyanation of organic compounds is an important synthetic transformation and mainly relies on a toxic CN source. Undeniably, thiocyanate salt has emerged as a very mild and environmentally benign CN source, yet its synthetic utility for cyanation is highly limited to very few types of organic compounds. Herein, we report the direct cyanation of cyclic thioacetals for accessing compounds with two different functional groups (thiocyano-thioesters) in one pot using sodium thiocyanate via photoredox catalysis. The protocol has been further extended for the direct cyanation of disulfides and diselenide to access aryl thiocyanates and aryl selenocyanate. A plausible mechanism has been proposed based on a series of control experiments, cyclic voltammetry and Stern-Volmer studies.

Direct synthesis of 1,3-dithiolanes from terminal alkynes via visible light photoredox catalysis.

A visible light-mediated, metal-free, regioselective dihydrothionation of terminal aromatic as well as heteroaromatic alkynes has been achieved using Eosin Y as a photoredox catalyst at room temperature. The protocol gives direct access to different 1,3-dithiolanes under neutral and mild reaction conditions without the use of any base or additives. The electron-donating, electron-withdrawing and electron-deactivating groups tolerated the photocatalytic reaction conditions. The control experiments, cyclic voltammetry, and Stern-Volmer experiment were carried out to gain an insight into the mechanistic pathway. The protocol proved to be scalable at the gram level and also for practicality the deprotection of 1,3-dithiolanes has been demonstrated. The method uses clean energy under sustainable conditions.

An easy and practical approach to access multifunctional cylcopentadiene- and cyclopentene-spirooxindoles via [3 + 2] annulation.

A highly regioselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates of isatin with aurone/thioaurone is developed. Spiroheterocycles such as spirooxindole cyclopentadiene and spirooxindole fused hydroxy cyclopentene derivatives are constructed in one pot by exploring the reactivity of Lewis bases. Combined experimental and density functional theory (DFT) calculations offered an insight into the reaction mechanism.

Access to Hetero-Benzyl Scaffolds via Transient-Ligand-Enabled Direct γ-C(sp3)-H Arylation of 3-Methylheteroarene-2-Carbaldehydes.

An efficient and straightforward method has been developed for the synthesis of ß-benzyl-substituted 5-membered heterocyclic carbaldehydes via transient directing-group-enabled direct γ-C(sp3)-H arylation of 3-methylheteroarene-2-carbaldehydes. A wide range of 3-methylheteroarene carbaldehydes undergo coupling with a variety of aryl iodides, including less reactive iodo pyridine derivatives to provide a library of highly selective functionalized products in good to excellent yields. Some of these products have been successfully utilized in synthesizing useful synthetic intermediates.

Access to highly enantioselective and diastereoselective spirooxindole dihydrofuran fused pyrazolones.

A tertiary amine catalyzed highly diastereoselective and enantioselective [3 + 2] annulation between Morita-Baylis-Hillman (MBH) carbonates derived from isatin and pyrazolone 4,5-diones has been developed. A series of structurally diverse and multifunctional spirooxindole dihydrofuran fused pyrazolone derivatives with two adjacent quaternary spirocenters has been achieved in excellent yields with good to excellent enantioselectivity. Further synthetic utility of this protocol has been successfully demonstrated by employing the bromo derivative of spirooxindole dihydrofuran fused pyrazolone to Suzuki coupling.

Multicomponent synthesis of pyroglutamic acid derivatives via Knoevenagel-Michael-hydrolysis-lactamization-decarboxylation (KMHL-D) sequence.

A novel and practical method for the synthesis of 3-substituted pyroglutamic acid derivatives is described. One pot multicomponent reaction of Meldrum's acid, aldehyde and Schiff's base followed an unprecedented chemoselective Knoevenagel-Michael-hydrolysis-lactamization domino sequence to afford 4-carboxy 3-substituted pyroglutamic acid derivatives under mild conditions. A carboxy intermediate formed appears to accelerate its own formation. The generality of the synthesis is exemplified by the use of a wide variety of aldehydes including enolizable aliphatic aldehydes, while substrates are stable under reaction conditions.

An Adverse Effect of Higher Catalyst Loading and Longer Reaction Time on Enantioselectivity in an Organocatalytic Multicomponent Reaction.

An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona-based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ-keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results.

Chemoselective N-deacetylation under mild conditions.

A mild and efficient chemoselective N-deacetylation using the Schwartz reagent at room temperature in rapid time is described. The mild and neutral conditions enable orthogonal N-deacetylation in the presence of some of the common protecting groups (viz. Boc, Fmoc, Cbz, Ts). The deprotection conditions did not induce any epimerization at the chiral amino centre.

A practical and convenient protocol for the synthesis of (E)-α,ß-unsaturated acids.

α,ß-Unsaturated acids are very useful and versatile reagents in organic synthesis. A novel, practical, and convenient catalytic protocol comprising FeCl3·6H2O (0.5 mol %) and H2O (1 equiv) in CH3NO2 is described for the rapid synthesis of α,ß-unsaturated acids with high E-stereoselectivity under both microwave and conventional heating conditions with high TON and TOF values. This powerful approach efficiently demonstrated the utility of biomass derived aldehydes to build chemical agents used as fuel additives. The method proved to be scalable to gram scale synthesis.

Stereoselective approach to cis-2,3-disubstituted piperidines via reduction of N-acyliminium ion intermediate: enantioselective synthesis of (+)-(2S,3S)-CP-99,994.

A very simple and efficient stereoselective approach to cis-2,3-disubstituted piperidines via the reduction of N-acyliminium ion intermediates is described. Application of this methodology is exemplified by the enantioselective total synthesis of (+)-(2S,3S)-CP-99,994.

Enantiopure synthesis of side chain-modified α-amino acids and 5-cis-alkylprolines.

A short, concise synthesis of enantiopure, side chain-modified α-amino acids such as 4-oxo-L-norvaline, 6-oxo-L-homonorleucine, and 5-cis-alkyl prolines is described. Knoevenagel condensation of l-aminocarboxylate-derived ß-ketoesters with aldehydes followed by reductive decarboxylation results in unnatural α-amino acids in good yield. A fluorescent amino acid is synthesized using a similar protocol. These studies show that aminocarboxylate-derived ß-ketoesters are very useful intermediates and the method employed is both general and practical for the preparation of γ(δ)-oxo α-amino acids and alkylprolines.

Synthesis of 2-amido, 2-amino, and 2-azido derivatives of the nitrogen analogue of the naturally occurring glycosidase inhibitor salacinol and their inhibitory activities against O-GlcNAcase and NagZ enzymes.

Seven 2-substituted derivatives of the nitrogen analogue of salacinol, a naturally occurring glycosidase inhibitor, were synthesized for structure-activity studies with hexosaminidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the 2-azido-1,4-dideoxy-1,4-imino-D-arabinitol at the least hindered carbon atom of 2,4-O-benzylidene-L-erythritol-1,3-cyclic sulfate. Hydrogenation of the azido zwitterionic compound in methanol resulted in the reduction of the azide and subsequent methylation of the resulting amine in one pot. A similar reaction, with ethanol as the solvent, gave the N-ethyl derivative. The 2-amino analogues were finally obtained by the reduction of the azide function using triphenylphosphine. Acylation of the amine using acetic, propionic, or valeric anhydride afforded the corresponding 2-amido derivatives. Deprotection of the acylated, coupled products using 80% trifluoroacetic acid proceeded smoothly. Unlike their sulfonium ion counterparts, these compounds were stable and did not undergo ring opening. We also report the synthesis of the parent nitrogen heterocycles, N-Boc-1,2,4-trideoxy-2-amino-1,4-imino-D-arabinitol, and 1,2,4-trideoxy-2-acetamido-1,4-imino-D-arabinitol and its corresponding N-Boc protected compound. The 2-substituted analogues and the parent iminoalditol showed marginal activity (<33% at 250 microM) against human O-GlcNAcase and Vibrio cholerae NagZ enzymes.

Synthesis of phosphate derivatives related to the glycosidase inhibitor salacinol.

The syntheses of polyhydroxylated imino- and anhydro thio-alditol compounds related to the naturally occurring glycosidase inhibitor, salacinol, containing a phosphate group in the side chain are described. The compounds lack hydroxyl groups on the acyclic side chain and are prototypes of the exact salacinol analogue. The synthetic strategy relies on the Mitsunobu reaction of N- and S-hydroxyalkyl derivatives of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-anhydro-2,3,5-tri-O-benzyl-1-thio-D-arabinitol with dibenzyl phosphate to yield the corresponding protected heteroalditol phosphates. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective inhibitors of MGA and demonstrates the importance of the hydroxyl and/or sulfate substituents present on the side chain for effective inhibition. The attempted synthesis of the exact analogue of salacinol by opening of cyclic phosphates is also described.

Highly selective deblocking of propargyl carbonates in the presence of propargyl carbamates with tetrathiomolybdate.

Propargyloxycarbonyl chloride, 1, has been used to protect the hydroxyl and amino functionalities of amino alcohols and aminophenols in one pot using triethylamine or pyridine as a base. The increased reactivity of benzyltriethylammonium tetrathiomolybdate, 2, toward propargyl carbonates over propargyl carbamates is studied in detail and has been exploited further to develop an orthogonal protection strategy for the hydroxyl and amino functionalities. For example, 2-amino-1-butanol, 6a, was treated with 1 to get the N,O-diPoc compound 7a in 90% yield, which when treated with 1.1 equiv of 2 at room temperature removes the Poc group attached to oxygen while leaving the one attached to nitrogen intact to yield compound 8a in 85% yield. This particular observation offers a new protecting strategy where an amine and an alcohol group can be protected simultaneously in one pot, and in a later synthetic step, if the alcohol group has to be deprotected selectively, it can be achieved with 1 equiv of 2.

Propargyloxycarbonyl (Poc) amino acid chlorides as efficient coupling reagents for the synthesis of 100% diastereopure peptides and resin bound tetrathiomolybdate as an effective deblocking agent for the Poc group.

Synthesis of short peptides using propargyloxycarbonyl amino acid chlorides as effective coupling reagents and polymer supported tetrathiomolybdate as an efficient deblocking agent are reported.