Bathophenanthroline-promoted C(sp3)-H alkylation of N-heteroarenes using alcohols: a practical approach
Sankar V., Sakthiganapathi R., Singh Baghel A., Sivakumar B., Mannathan S.
Organic and Biomolecular Chemistry, 2025, DOI Link
View abstract ⏷
We present a transition-metal-free and environmentally friendly method for the alkylation of C(sp3)-H bonds in methyl-substituted N-heteroarenes using alcohols, mediated by bathophenanthroline. This straightforward and practical protocol employs readily available alcohols as alkylating agents, affording the desired alkylated N-heteroarenes in good to excellent yields using a broad range of aliphatic, aromatic, and heteroaromatic alcohols. The method also exhibits broad compatibility with various substituted methyl-N-heteroarenes, affording C-alkylated products in moderate to good yields. Mechanistic investigations, including deuterium-labeling and intermediate analysis, confirm that the reaction proceeds via a borrowing-hydrogen (BH) pathway.
Organophotoredox-Catalyzed CDC Reactions for the Synthesis of Diverse Heterocycles via C─N and C─O Bond Formation under Visible Light Irradiation
Selvaraj E., Thulasidaran P., Mannathan S., Baskar B.
Asian Journal of Organic Chemistry, 2025, DOI Link
View abstract ⏷
An efficient construction of C═N and C─O bonds by the metal-free organophotoredox catalyzed intramolecular cross-dehydrogenative coupling of tertiary amines with amides, amines, and acids as nucleophiles is described. A series of 12,13-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-one, 5,6-dihydrobenzo[4,5]imidazo [2,1-a]isoquinoline, and 4b,13-dihydro-6H,12H-benzo[4,5] [1,3]oxazino[2,3-a]isoquinolin-6-one derivatives were prepared in good to excellent yields. All the transformations proceeded smoothly under an oxygen atmosphere, serving as a clean oxidant. Moreover, the current approach was extended for the synthesis of the biologically active natural product, rutaecarpine.
Visible Light-Driven Heterogeneous Cu─Ti─gCN Photoredox Catalyzed Synthesis of Diverse N-Heterocyclic Derivatives via ODH and CDC Reactions
Preety J., Shanmugam M., Lekshmi Priya S.L., Baskar B., Li W., Mannathan S., Sekar K.
Asian Journal of Organic Chemistry, 2025, DOI Link
View abstract ⏷
Visible light-mediated oxidative dehydrogenation (ODH) of partially saturated heterocycles and different cross dehydrogenative coupling (CDC) reactions using heterogeneous photoredox catalyst is described in this paper. A systematic study led to an ODH of partially saturated heterocycles and different CDC reactions in very good-to-excellent yields. Oxygen is used as a clean oxidant in both ODH and CDC reactions. The methodology is atom economic and exhibits excellent tolerance toward various functional groups, and broad substrate scopes. This methodology was found to be suitable for scale-up and reusability.
Synthesis of N-Aryl and N-Alkyl Phthalimides via Denitrogenative Cyanation of 1,2,3-Benzotriazin-4(3H)-ones
Korivi R., Rana J., Baskar B., Mannathan S.
Journal of Organic Chemistry, 2025, DOI Link
View abstract ⏷
An efficient metal-free approach for synthesizing N-aryl- and N-alkyl phthalimide derivatives from 1,2,3-benzotriazin-4(3H)-ones is described. The reaction likely proceeds via a denitrogenative cyanation pathway, utilizing TMSCN as the cyanide source. This method is straightforward as well as scalable and supports a wide range of substrates with high functional group tolerance, yielding diverse phthalimide derivatives in good to excellent yields. The utility of this method is further highlighted by the successful synthesis of a tyrosinase inhibitor analogue in good yield.
Synthesis of Diverse Imidazole and Quinoxaline Derivatives via Iodine-Mediated Cyclization Reactions
Panneerselvam S., Selvaraj E., Mannathan S., Saravanan T., Baskar B.
Journal of Organic Chemistry, 2025, DOI Link
View abstract ⏷
A novel approach for the synthesis of diverse substituted imidazoles and quinoxalines via an iodine-promoted cyclization reaction is described. The methodology showcases a broad substrate scope, achieving moderate to very good yields for biologically relevant imidazoles and quinoxalines. Notably, iodine serves as both an iodinating agent and an oxidizing agent, as shown by a mechanistic study. The current methodology is capable of being scaled up to gram quantities, operates in a metal-free environment under mild reaction conditions, and utilizes readily available substrates.
Denitrogenative Transformations of Benzotriazinones and Related Compounds
Korivi R., Sureshbabu P., Sharma D.K., Mannathan S.
Denitrogenative Transformation of Nitrogen Heterocycles: Synthesis, Reactions and Applications, 2025, DOI Link
View abstract ⏷
This chapter will emphasize the recent advancements focusing on (i) transition-metal-based organic transformations of 1,2,3-benzotriazin-4(3 H)-ones, (ii) reactions of 1,2,3-benzotriazin-4(3 H)-ones under thermal and photolytic conditions, as well as (iii) acid mediated or metal-free reactions of 1,2,3-benzotriazin-4(3 H)-ones to fabricate highly functionalized five, six-membered N-heterocycles and ortho -functionalized benzamides. Further, this book chapter also discusses the denitrogenative reactions of 1,2,3,4-benzothiatriazine-1,1(2 H)-dioxides with suitable reaction mechanisms of the developed protocols.
Photoredox/Nickel Dual Catalysis for Regio- and Stereoselective Reductive Coupling of Alkynes with Vinyl Phosphonates
Sakthiganapathi R., Sharma D.K., Dutta R., Chakrabortty S., Baskar B., Mannathan S.
Journal of Organic Chemistry, 2025, DOI Link
View abstract ⏷
An efficient nickel-photoredox dual-catalyzed intermolecular reductive coupling reaction of alkynes with vinyl phosphonates is described. The reaction is highly regio- and stereoselective, affording the homoallylic phosphonates in good to high yields. The present protocol is also successfully applied to other activated alkenes such as enones, acrylates, and vinyl sulfone. The reaction is believed to proceed via the nickelacyclopentene intermediate. Mechanistic investigations, including control experiments and isotopic labeling studies, revealed that methanol serves as a proton source rather than a reducing agent.
Visible light-induced denitrogenative annulation reaction of 1,2,3-benzotriazin-4(3H)-ones with alkenes and alkynes via electron donor-acceptor (EDA) complex formation: a sustainable approach to isoindolinone and isoquinolinone synthesis
Organic Chemistry Frontiers, 2024, DOI Link
View abstract ⏷
An efficient method for the synthesis of isoindolinones and isoquinolinones from 1,2,3-benzotriazin-4(3H)-ones under visible light is described. The reaction of 1,2,3-benzotriazin-4(3H)-ones with activated alkenes such as acrylonitrile, vinyl ketone, acrylates and vinyl sulfones in the presence of DIPEA under blue LED light irradiation gave isoindolinones in good to high yields. In a similar manner, the reaction of aromatic terminal alkynes with 1,2,3-benzotriazin-4(3H)-ones gave 3-substituted isoquinolinones. This method avoids the use of any metal or external photocatalysts and is believed to proceed via electron donor-acceptor (EDA) complex formation facilitated by DIPEA and 1,2,3-benzotriazin-4(3H)-ones. The practical applicability of these reactions is also demonstrated by performing gram-scale synthesis of isoquinolinones and isoindolinones. Moreover, the utility of this method was showcased through the synthesis of an anxiolytic drug pazinaclone analogue in high yield.
Regioselective Synthesis of 3-Substituted Isocoumarin-1-imines via Palladium-Catalyzed Denitrogenative Transannulation of 1,2,3-Benzotriazin-4(3H)-ones and Terminal Alkynes
Balakrishnan M.H., Sureshbabu P., Korivi R., Mannathan S.
Chemistry - An Asian Journal, 2023, DOI Link
View abstract ⏷
A palladium-catalyzed denitrogenative transannulation strategy to access various 3-substituted isocoumarin-1-imine frameworks using 1,2,3-benzotriazin-4(3H)-ones and terminal alkynes is described. The reaction is highly regioselective and tolerates a wide range of functional groups. The reaction is believed to proceed via a five-membered palladacycle intermediate extruding environmentally benign molecular nitrogen as a by-product. The utility of this method was showcased through the one-pot synthesis of biologically relevant 3-substituted isocoumarin scaffolds.
Convenient Synthesis of Salicylanilide Sulfonates from 1,2,3-Benzotriazin-4(3 H)-ones and Organosulfonic Acids via Denitrogenative Cross-Coupling
Korivi R., Madasamy K., Sureshbabu P., Mannathan S.
ACS Omega, 2023, DOI Link
View abstract ⏷
An efficient and straightforward approach to synthesize salicylanilide aryl and alkyl sulfonates from 1,2,3-benzotriazin-4(3H)-ones and organosulfonic acids is described. This protocol is operationally simple and scalable, exhibits a broad substrate scope with high functional group tolerance, and affords the desired products in good to high yield. Application of the reaction is also demonstrated by converting the desired product to synthetically useful salicylamides in high yields.
Sustainable Bioengineering of Gold Structured Wide-Area Supported Catalysts for Hand-Recyclable Ultra-Efficient Heterogeneous Catalysis
Bhatt C.S., Parimi D.S., Bollu T.K., Madhura H.U., Jacob N., Korivi R., Ponugoti S.S., Mannathan S., Ojha S., Klingner N., Motapothula M., Suresh A.K.
ACS Applied Materials and Interfaces, 2022, DOI Link
View abstract ⏷
Metal nanoparticles grafted within inert and porous wide-area supports are emerging as recyclable, sustainable catalysts for modern industry applications. Here, we bioengineered gold nanoparticle-based supported catalysts by utilizing the innate metal binding and reductive potential of eggshell as a sustainable strategy. Variable hand-recyclable wide-area three-dimensional catalysts between ∼80 ± 7 and 0.5 ± 0.1 cm2 are generated simply by controlling the size of the support. The catalyst possessed high-temperature stability (300 °C) and compatibility toward polar and nonpolar solvents, electrolytes, acids, and bases facilitating ultra-efficient catalysis of accordingly suspended substrates. Validation was done by large-volume (2.8 liters) dye detoxification, gram-scale hydrogenation of nitroarene, and the synthesis of propargylamine. Moreover, persistent recyclability, monitoring of reaction kinetics, and product intermediates are possible due to physical retrievability and interchangeability of the catalyst. Finally, the bionature of the support permits ∼76.9 ± 8% recovery of noble gold simply by immersing in a royal solution. Our naturally created, low-cost, scalable, hand-recyclable, and resilient supported mega-catalyst dwarfs most challenges for large-scale metal-based heterogeneous catalysis.
Trifluoroacetic Acid-Mediated Denitrogenative ortho-Hydroxylation of 1,2,3-Benzotriazin-4(3 H)-ones: A Metal-Free Approach
Madasamy K., Balakrishnan M.H., Korivi R., Mannathan S.
Journal of Organic Chemistry, 2022, DOI Link
View abstract ⏷
An efficient trifluoroacetic acid-mediated denitrogenative hydroxylation of 1,2,3-benzotriazin-4(3H)-ones is described. This metal-free approach is compatible with a wide range of 1,2,3-benzotriazin-4(3H)-ones, affording ortho-hydroxylated benzamides in good to high yields with a short reaction time. The reaction is believed to proceed via a benzene diazonium intermediate. The synthetic utility of the reaction was successfully demonstrated by the preparation of an antimicrobial drug, Riparin C, and benzoxazine-2,4(3H)-diones in good yields.
Synthesis ofortho-arylated and alkenylated benzamides by palladium-catalyzed denitrogenative cross-coupling reactions of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids
Balakrishnan M.H., Kanagaraj M., Sankar V., Ravva M.K., Mannathan S.
New Journal of Chemistry, 2021, DOI Link
View abstract ⏷
An efficient palladium-catalyzed denitrogenative Suzuki-Miyaura type cross-coupling of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acid is described. The reaction is compatible with various aryl and alkenyl boronic acids affordingortho-arylated and alkenylated benzamides in good to high yields. Heteroaromatic boronic acids were also successfully employed. Along with this, a coupling reaction was established by using phenyl boronate ester as the coupling partner. The reaction is believed to proceedviaa five-membered aza-palladacyclic intermediate. DFT calculations were studied comparing the reactivity of palladium and nickel complexes in the five-membered aza-metallacycle formation from 1,2,3-benzotriazin-4(3H)-ones. The application of the reaction was successfully demonstrated by convertingortho-alkenylated products toortho-alkylated products in high yieldsviaa reduction reaction.
Quaternary ammonium hydroxide-functionalized g-C3N4 catalyst for aerobic hydroxylation of arylboronic acids to phenols
Muhammad I., Mannathan S., Sasidharan M.
Journal of the Chinese Chemical Society, 2020, DOI Link
View abstract ⏷
A new and efficient metal-free approach toward the synthesis of phenols via an aerobic hydroxylation of arylboronic acids by using a novel quaternary ammonium hydroxide g-C3N4 catalyst has been described. The functionalized quaternary ammonium hydroxide (g-C3N4-OH) has been prepared from graphitic carbon nitride (g-C3N4) scaffold by converting the residual –NH2 and –NH groups to quaternary methyl ammonium iodide by performing a methylation reaction with methyl iodide followed by ion-exchange with 0.1 N KOH or anion exchange resin Amberlyst A26 (OH- form) by post-synthetic modification. The resultant g-C3N4-OH was characterized by XRD, FTIR, field-emission scanning electron microscope (FESEM), high-resolution transmission electron microscope (HRTEM), N2 adsorption/desorption isotherms, and acid–base titration. Tested as solid-base catalysts, the g-C3N4-OH showed excellent catalytic activity in the aerobic hydroxylation reaction by converting a variety of arylboronic acids to the corresponding phenols in high yields. More importantly, the g-C3N4-OH solid-base has been successfully reused four times with the minor loss of initial catalytic activity (10.5%).
Zinc-Catalyzed N-Alkylation of Aromatic Amines with Alcohols: A Ligand-Free Approach
Sankar V., Kathiresan M., Sivakumar B., Mannathan S.
Advanced Synthesis and Catalysis, 2020, DOI Link
View abstract ⏷
An efficient zinc-catalyzed N-alkylation reaction of aromatic amines was achieved using aliphatic, aromatic, and heteroaromatic alcohols as the alkylating reagent. A variety of aniline derivatives, including heteroaromatic amines, underwent the N-alkylation reaction and furnished the corresponding monoalkylated products in good to excellent yields. The application of the reaction is also further demonstrated by the synthesis of a 2-phenylquinoline derivative from acetophenone and 2-aminobenzyl alcohol. Deuterium labeling experiments show that the reaction proceeds via a borrowing hydrogen process. (Figure presented.).
Palladium/Copper-Catalyzed Denitrogenative Alkylidenation and ortho-Alkynylation Reaction of 1,2,3-Benzotriazin-4(3 H)-ones
Organic Letters, 2020, DOI Link
View abstract ⏷
An efficient palladium-catalyzed approach to access various functionalized (Z)-3-benzylidene-isoindoline-1-ones and (Z)-3-benzylidene(imino)isobenzofuranones via a denitrogenative tandem alkynylation/cyclization reaction of 1,2,3-benzotriazin-4(3H)-ones with aromatic terminal alkynes is described. Furthermore, a denitrogenative ortho-alkynylation reaction of 1,2,3-benzotriazinones with aliphatic terminal alkynes is also developed. The reaction proceeds through a five-membered azapalladacyclic intermediate with the extrusion of a nitrogen molecule. The significance of the reaction is also demonstrated by a one-pot synthesis of (Z)-3-benzylideneisobenzofuran-1(3H)-one derivatives in good to high yields.
A Zn based metal organic framework as a heterogeneous catalyst for C-C bond formation reactions
Madasamy K., Kumaraguru S., Sankar V., Mannathan S., Kathiresan M.
New Journal of Chemistry, 2019, DOI Link
View abstract ⏷
Herein, we report the synthesis and application of a Zn-Bp-BTC MOF (Bp-4,4′-bipyridine; BTC-1,3,5-benzene tricarboxylic acid; MOF-metal organic framework) as a heterogeneous catalyst for mediating organic reactions. Initially, conditions were optimized for the Knoevenagel condensation reaction using Zn-Bp-BTC as a heterogeneous catalyst by varying the solvent, temperature and catalyst loading. Although the reaction proceeded at room temperature using methanol as the solvent, 60 °C offered the best yield in a shorter duration. Under optimized reaction conditions, a wide range of α,β-unsaturated dicyano compounds were prepared from the corresponding carbonyl precursor and malononitrile, the active methylene counterpart. Systematic investigation was also carried out to assess the role of the ligand and metal salt in the Knoevenagel condensation reaction. It was found that the Zn-Bp-BTC MOF catalyzed the reaction efficiently in comparison to its analogue Zn-BTC MOF and precursor Zn(NO3)2·6H2O. Finally, catalytic recycling and stability studies showed that the catalyst is able to mediate the reaction for up to five consecutive cycles without undergoing any significant chemical or morphological changes. Further, the catalyst was tested for its efficacy in a multi-component reaction (MCR). A MCR with the Zn-Bp-BTC MOF as the catalyst afforded good yields and there was no reaction in the absence of the catalyst. Similarly, the catalyst was tested for its efficiency in benzimidazole synthesis.
Potassium: Tert -butoxide mediated aerobic hydroxylation of arylboronic acids: An application towards the synthesis of (E)-phenoxy acrylates
Muhammad I., Balakrishnan M.H., Sasidharan M., Mannathan S.
New Journal of Chemistry, 2019, DOI Link
View abstract ⏷
The first example of potassium tert-butoxide mediated aerobic hydroxylation of arylboronic acids is described. A variety of arylboronic acids bearing both electron donating and withdrawing substituents successfully participated in the reaction and furnished phenols in good yields. This strategy also provides access to one pot synthesis of (E)-3-phenoxy acrylates from arylboronic acids and propiolates. The solvent plays an important role and a binary solvent system comprising CH3CN/THF is found to be the best.
Importance of the Reducing Agent in Direct Reductive Heck Reactions
Raoufmoghaddam S., Mannathan S., Minnaard A.J., de Vries J.G., de Bruin B., Reek J.N.H.
ChemCatChem, 2018, DOI Link
View abstract ⏷
The role of the reductant in the palladium N-heterocyclic carbene (NHC) catalyzed reductive Heck reaction and its effect on the mechanism of the reaction is reported. For the first time in this type of transformation, the palladium-NHC-catalyzed reductive Heck reaction was shown to proceed in the presence of LiOMe and iPrOH even at 10 °C to give the products very efficiently in excellent yields and with exceptional chemoselectivities. This study shows that the reaction proceeds through two distinct mechanisms that depend on the nature of the reducing agent. In the presence of a protic solvent or acidic medium the reaction undergoes protonation to yield the reduced product, whereas in the absence of proton source, it proceeds through the insertion of the reductant followed by reductive elimination. The kinetic data reveal that the oxidative addition is the rate-determining step in the reaction. The reaction profiles show first-order kinetics in aryl iodide and Pd and zero-order kinetics in LiOMe, benzylideneacetone, and the excess amount of NHC ligand. In addition, the reaction progress kinetic analysis shows that neither catalyst decomposition nor product inhibition occurs during the reaction. DFT calculations of the key steps confirm that the oxidative addition step is the rate-determining step in the reaction. Deuterium-labeling experiments indicate that the product is formed by the protonation of the Pd−Calkyl bond of the intermediate formed after enone insertion into the Pd−CAr bond. Application of chiral NHC ligands in the asymmetric reductive Heck reaction only results in poor enantioselectivities (enantiomeric excess up to 20 %) and is also substrate specific. DFT calculations suggest that the migration of the aryl group to the alkene of the substrate is the enantioselectivity-determining step of the reaction. It is further shown that if the steric bulk at the enone is small (a methyl group), the two transition state barriers from [PdII(L2)(ArI)(enone)] species Cre and Csi, which have the re and si face of the enone substrate coordinated to Pd, are very similar, in line with the experimental results. With a slightly larger group (an isopropyl substituent) a significant difference in energy barriers is calculated (2.6 kcal mol−1), and in the experiment this product is formed with a modest enantiomeric excess (up to 20 %).
Nickel-Catalyzed Denitrogenative Cross-Coupling Reaction of 1,2,3-Benzotriazin-4(3 H)-ones with Organoboronic Acids: An Easy Access to Ortho-Arylated and Alkenylated Benzamides
Hari Balakrishnan M., Sathriyan K., Mannathan S.
Organic Letters, 2018, DOI Link
View abstract ⏷
A novel nickel-catalyzed approach to synthesize ortho-arylated and alkenylated benzamides in good to high yields via a denitrogenative cross-coupling reaction of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids is described. The reaction proceeds through a five-membered azanickelacyclic intermediate with the extrusion of a nitrogen molecule. Moreover, the resulting ortho-arylated benzamides were successfully converted into synthetically useful substituted fluorenones and ortho-arylated benzylamine derivatives in high yields.
Nickel-catalyzed highly chemo- and stereoselective borylative cyclization of 1,6-enynes with bis(pinacolato)diboron
Hsieh J.-C., Hong Y.-C., Yang C.-M., Mannathan S., Cheng C.-H.
Organic Chemistry Frontiers, 2017, DOI Link
View abstract ⏷
A highly chemo- and stereoselective nickel-catalyzed borylative cyclization of 1,6-enynes with bis(pinacolato)diboron is described. Enynes containing an electron-deficient alkene such as a vinyl ketone provided alkenylboronates while enynes containing a terminal alkene gave homoallylic boronates. A plausible mechanism involving a nickelacyclopentene intermediate is proposed. In addition, the resulted alkenyl- or homoallylic boronates can be transformed to the corresponding ketones and alcohols via oxidation. Application to a palladium-catalyzed cross coupling reaction of alkenylboronates with aromatic halides has been demonstrated as well.
Enantioselective Intramolecular Reductive Heck Reaction with a Palladium/Monodentate Phosphoramidite Catalyst
Mannathan S., Raoufmoghaddam S., Reek J.N.H., de Vries J.G., Minnaard A.J.
ChemCatChem, 2017, DOI Link
View abstract ⏷
A palladium-catalyzed enantioselective reductive Heck reaction of enones using monodentate phosphoramidite ligands is described. α,α,α’,α’-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites with palladium(II) acetate, and N-methyl dicyclohexylamine as reducing agent gives the reductive Heck product in high yields and enantioselectivities of up to 90 %. The solvent plays an important role and in diethyl carbonate, the chemo- and enantioselectivity appeared to be the highest.
Corrigendum to: Palladium(II) Acetate Catalyzed Reductive Heck Reaction of Enones; A Practical Approach (ChemCatChem, (2015), 7, (3923–3927), 10.1002/cctc.201500760)
Mannathan S., Raoufmoghaddam S., Reek J.N.H., de Vries J.G., Minnaard A.J.
ChemCatChem, 2016, DOI Link
View abstract ⏷
The following part of the text needs to replaced: Mechanistic studies by Friestad and Branchaud[16] on the Cacchi system suggested that the absence of acid would result in the initial formation of the Mizoroki–Heck product 4a, followed by its reduction to 3a by accumulated Pd-H species formed from NBu3. To study this hypothesis in our present catalyst system, we carried out a reaction with deuterated benzylidene acetone ([D1]-1 a) under the optimized reaction conditions (Scheme 2). Either the absence of deuterium or deuterium scrambling at the b-carbon of 3a, will support the reaction pathway via Heck reaction followed by reduction. However, the reaction gave reductive Heck product [D1]-3 a in 80% yield with=97% remaining deuteration at the b-carbon. This rejects the hypothesis of Friestad and Branchaud and supports the pathway in which the Pd-alkyl complex A (Scheme 1) is reduced by DIPEA to a palladium hydride species followed by reductive elimination. Alternatively A tautomerizes to an O-bound palladium enolate that is subsequently reduced by DIPEA.[20] This part should be replaced by the following: We have performed a deuterium labelling experiment to shed more light on the mechanism of the reaction (Scheme 2). Thus, reaction of 4-d-phenyl-3-buten-2-one ([D1]-1 a) with 2a and 5 eq. of DIPEA catalyzed by 1 mol% of Pd(OAc)2 gave the reductive arylation product [D1]-3a in 80% yield with 97% retention of deuterium. This conclusively shows a reductive arylation mechanism is active and it excludes the possibility of a Heck reaction followed by a hydrogenation, as in this case all deuterium would be lost. However, the final stages of the mechanism remain obscure. We see two possible mechanisms: protonation of the formed palladium enolate species and reduction of the palladium(II) to palladium(0) with the trialkylamine. The second mechanism: reaction of the palladium alkyl intermediate with the trialkylamine to form the palladium alkylhydride complex seems quite plausible. Reductive elimination of this will lead to the reductive arylation product. A third mechanistic possibility, previously proposed by Friestad and Branchaud, suggested reduction of the palladium enolate by XPdII(Ln)H, EtNHX, or other reductants.[16] However, we have shown in later work that upon use of [D15]Et1N 55% of deuterium is incorporated a to the ketone in the 3-position, providing strong support for the second mechanism.[20].
Palladium(0)/NHC-Catalyzed Reductive Heck Reaction of Enones: A Detailed Mechanistic Study
Raoufmoghaddam S., Mannathan S., Minnaard A.J., De Vries J.G., Reek J.N.H.
Chemistry - A European Journal, 2015, DOI Link
View abstract ⏷
We have studied the mechanism of the palladium-catalyzed reductive Heck reaction of para-substituted enones with 4-iodoanisole by using N,N-diisopropylethylamine (DIPEA) as the reductant. Kinetic studies and in situ spectroscopic analysis have provided a detailed insight into the reaction. Progress kinetic analysis demonstrated that neither catalyst decomposition nor product inhibition occurred during the catalysis. The reaction is first order in the palladium and aryl iodide, and zero order in the activated alkene, N-heterocyclic carbene (NHC) ligand, and DIPEA. The experiments with deuterated solvent ([D7]DMF) and deuterated base ([D15]Et3N) supported the role of the amine as a reductant in the reaction. The palladium complex [Pd0(NHC)(1)] has been identified as the resting state. The kinetic experiments by stopped-flow UV/Vis also revealed that the presence of the second substrate, benzylideneacetone 1, slows down the oxidative addition of 4-iodoanisole through its competing coordination to the palladium center. The kinetic and mechanistic studies indicated that the oxidative addition of the aryl iodide is the rate-determining step. Various scenarios for the oxidative addition step have been analyzed by using DFT calculations (bp86/def2-TZVP) that supported the inhibiting effect of substrate 1 by formation of resting state [Pd0(NHC)(1)] species at the cost of further increase in the energy barrier of the oxidative addition step.
Palladium(II) Acetate Catalyzed Reductive Heck Reaction of Enones; A Practical Approach
Mannathan S., Raoufmoghaddam S., Reek J.N.H., De Vries J.G., Minnaard A.J.
ChemCatChem, 2015, DOI Link
View abstract ⏷
A surprisingly practical Pd(OAc)2 or Pd(TFA)2-catalyzed reductive Heck reaction between aryl iodides and α,β-unsaturated ketones is described using N,N-diisopropylethylamine (DIPEA, Hünigs base) as the reductant. In general, 1 mol % of Pd(OAc)2 is sufficient to afford good yields using electron-rich or halogen-substituted aryl iodides. Electron-deficient aryl iodides preferentially give homocoupling. Enones containing aryl or bulky substituents on the β-carbon react smoothly, producing mainly reductive Heck product, whereas enones with alkyl substituents on the β-carbon afford a mixture of reductive Heck and Heck product. Deuterium labeling experiments show that the reaction is a bona fide reductive Heck reaction and exclude a Heck reaction-conjugate reduction cascade. Deeply DIPEA about... A palladium-catalyzed reductive Heck reaction of aryl iodides to α,β-unsaturated ketones is described using N,N diisopropylethylamine (DIPEA, Hünigs base) as the reductant. A deuterium labeling study shows that the reaction is a bona fide reductive Heck reaction and excludes a Heck reaction-conjugate reduction cascade.
Ligand-Controlled Divergent C-H Functionalization of Aldehydes with Enynes by Cobalt Catalysts
Santhoshkumar R., Mannathan S., Cheng C.-H.
Journal of the American Chemical Society, 2015, DOI Link
View abstract ⏷
We describe a highly step and atom economical cobalt-catalyzed cyclization of 1,6-enynes with aldehydes to synthesize functionalized pyrrolidines and dihydrofurans with high chemo- and stereoselectivity. The catalytic reaction plausibly proceeds via the cobaltacycle intermediate generated from the reaction of enyne substrate with cobalt catalyst, followed by switchable C-H functionalization of weakly coordinating aldehydes depending on the electronic nature of the ligand.
Cobalt-catalyzed hydroarylative cyclization of 1,6-enynes with aromatic ketones and esters via C-H activation
Santhoshkumar R., Mannathan S., Cheng C.-H.
Organic Letters, 2014, DOI Link
View abstract ⏷
A highly chemo- and stereoselective cobalt-catalyzed hydroarylative cyclization of 1,6-enynes with aromatic ketones and esters to synthesize functionalized pyrrolidines and dihydrofurans is described. A mechanism involving cobaltacycle triggered C-H activation of aromatic ketones and esters was proposed. © 2014 American Chemical Society.
Nickel-catalyzed regio- and stereoselective reductive coupling of Oxa- and azabicyclic alkenes with enones and electron-rich alkynes
Advanced Synthesis and Catalysis, 2014, DOI Link
View abstract ⏷
A nickel-catalyzed regio- and stereoselective reductive coupling of oxa- and azabicyclic alkenes with activated alkenes and electron-rich alkynes is described. Thus, 7-oxabenzonorbornadienes underwent reductive coupling with various vinyl ketones such as ethyl, methyl, propyl and α-methyl- substituted vinyl ketones, in the presence of a nickel(II) iodide (NiI 2), zinc (Zn), and water catalyst system in acetonitrile at 50 °C for 14 h to afford 2-alkylnaphthalenes in good to excellent yields. Under similar reaction conditions, 7-azabenzonorbornadiene derivatives provided cis-2-alkyl-1,2-dihydronaphthalene derivatives in high yields. On the other hand, the nickel(II) iodide, tris(4-fluorophenyl)phoshine [P(4-FC 6H4)3] and zinc catalyst system successfully catalyzed the reductive coupling reaction of electron-rich alkynes, with 7-aza- and 7-oxabenzonorbornadienes to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives in good to excellent yields. In the reaction, a mild reducing agent (zinc) and simple hydrogen source (water) were used. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Alkene-assisted nickel-catalyzed regioselective 1,4-addition of organoboronic acid to dienones: A direct route to all-carbon quaternary centers
Hong Y.-C., Gandeepan P., Mannathan S., Lee W.-T., Cheng C.-H.
Organic Letters, 2014, DOI Link
View abstract ⏷
A nickel-catalyzed highly regioselective 1,4-addition reaction of boronic acids to dienones to form products with an all-carbon quaternary center is described. The 3-alkenyl group of dienones is the key for the reaction to proceed smoothly. A mechanism involving the coordination of the dienyl group to the nickel center is proposed. © 2014 American Chemical Society.
Ene-carbonyl reductive coupling for the synthesis of 3,3-disubstituted phthalide, 3-hydroxyisoindolin-1-one and 3-hydroxyoxindole derivatives
Yeh C.-H., Lin Y.-C., Mannathan S., Hung K., Cheng C.-H.
Advanced Synthesis and Catalysis, 2014, DOI Link
View abstract ⏷
An efficient method for the synthesis of three classes of heterocyclic derivatives such as 3,3-disubstituted phthalides, 3-hydroxyisoindolin-1-ones and 3-hydroxyoxindoles, is reported. In the presence of the simple reductive system, zinc (Zn)/ammonia (NH3) [or zinc-copper (Zn-Cu)/ammonia], a wide range of alkenes including acrylates, acrylonitrile, acrylamide and vinyl sulfoxide underwent reductive coupling with methyl 2-acylbenzoates and subsequent lactonization to provide 3,3-disubstituted phthalides in good to high yields at ambient temperature. In a similar manner, 3-hydroxyisoindolin-1-one and 3-hydroxyoxindole derivatives could also be easily prepared by direct reductive coupling of phthalimides and N-substituted isatins with activated alkenes, respectively. Application of this methodology towards the synthesis of 1-naphthol derivatives on a gram scale is also depicted. Furthermore, the intramolecular phthalimides-ene reductive coupling afforded the respective cyclization products with high diastereoselectivity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
[4+2] vs [3+2] annulations in the nickel- and cobalt-catalyzed reaction of ortho-haloimines with alkynes: Differential reactivity towards the synthesis of isoquinolines and aminoindenes
Journal of the Chinese Chemical Society, 2014, DOI Link
View abstract ⏷
Metal-catalyzed annulation reactions to synthesize carbo- and heterocycles have been an attractive field of research for many years. The development of new cyclization reactions utilizing readily available less expensivemetal catalyst is one of the important tasks. In this regard, this review summerizes and discusses about nickel- and cobalt-catalyzed [4+2] and [3+2] annulation reactions of ortho-halo substituted imines and alkynes. Nickel complexes under suitable reaction conditions underwent [4+2] annulation to form six-membered isoquinoline (salts) derivatives. However, cobalt complexes afforded aminoindenes via [3+2] annulation reactions. Both reactions proceed through a five membered metallacycle. The regioselective insertion of alkyne containing keto or ester groups into the metallacycle further demonstrates the difference in selectivity of these metal complexes. © 2014 The Chemical Society Located in Taipei &Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim.
Nickel-catalyzed chemo- and stereoselective alkenylative cyclization of 1,6-enynes with alkenyl boronic acids
Yang C.-M., Mannathan S., Cheng C.-H.
Chemistry - A European Journal, 2013, DOI Link
View abstract ⏷
Discover nickel! A nickel-catalyzed alkenylative cyclization of 1,6-enynes and alkenyl boronic acids affording substituted pyrrolidines and dihydrofurans is described (see scheme; cod=1,5-cyclooctadiene, Ts = p-toluene sulfonate). The reaction is highly chemo- and stereoselective. A possible reaction mechanism involving a nickelacyclopentene intermediate is proposed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Nickel-catalyzed regio- and diastereoselective intermolecular three-component coupling of oxabicyclic alkenes with alkynes and organoboronic acids
Chemical Communications, 2013, DOI Link
View abstract ⏷
Reaction of oxabicyclic alkenes with alkynes and organoboronic acids in the presence of Ni(cod)2, P(t-Bu)3, and CsF in a binary solvent toluene–methanol (1 : 3) at 75 to 85°C provided exo-5,6-disubstituted 7-oxanorbornene derivatives in good to excellent yields. © 2013 The Royal Society of Chemistry.
Cobalt(II)-catalyzed 1,4-addition of organoboronic acids to activated alkenes: An application to highly cis-stereoselective synthesis of aminoindane carboxylic acid derivatives
Chen M.-H., Mannathan S., Lin P.-S., Cheng C.-H.
Chemistry - A European Journal, 2012, DOI Link
View abstract ⏷
It all adds up: The 1,4-addition of organoboronic acids to activated alkenes catalyzed by [Co(dppe)Cl2] is described. A [3+2]-annulation reaction of ortho-iminoarylboronic acids with acrylates to give various aminoindane carboxylic acid derivatives with cis-stereoselectivity is also demonstrated (see scheme; dppe=1,2-bis(diphenylphosphino)ethane). © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Regio- and enantioselective cobalt-catalyzed reductive [3+2] cycloaddition reaction of alkynes with cyclic enones: A route to bicyclic tertiary alcohols
Angewandte Chemie - International Edition, 2012, DOI Link
Synthesis of trans-disubstituted alkenes by cobalt-catalyzed reductive coupling of terminal alkynes with activated alkenes
Chemistry - A European Journal, 2012, DOI Link
View abstract ⏷
A cobalt-catalyzed reductive coupling of terminal alkynes, RC≡CH, with activated alkenes, R'CH=CH2, in the presence of zinc and water to give functionalized trans-disubstituted alkenes, RCH=CHCH2CH 2R', is described. A variety of aromatic terminal alkynes underwent reductive coupling with activated alkenes including enones, acrylates, acrylonitrile, and vinyl sulfones in the presence of a CoCl2/P(OMe) 3/Zn catalyst system to afford 1,2-trans-disubstituted alkenes with high regio- and stereoselectivity. Similarly, aliphatic terminal alkynes also efficiently participated in the coupling reaction with acrylates, enones, and vinyl sulfone, in the presence of the CoCl2/P(OPh)3/Zn system providing a mixture of 1,2-trans- and 1,1-disubstituted functionalized terminal alkene products in high yields. The scope of the reaction was also extended by the coupling of 1,3-enynes and acetylene gas with alkenes. Furthermore, a phosphine-free cobalt-catalyzed reductive coupling of terminal alkynes with enones, affording 1,2-trans-disubstituted alkenes as the major products in a high regioisomeric ratio, is demonstrated. In the reactions, less expensive and air-stable cobalt complexes, a mild reducing agent (Zn) and a simple hydrogen source (water) were used. A possible reaction mechanism involving a cobaltacyclopentene as the key intermediate is proposed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Enantioselective synthesis of β-substituted cyclic ketones via cobalt-catalyzed asymmetric reductive coupling of alkynes with alkenes
Journal of the American Chemical Society, 2011, DOI Link
View abstract ⏷
A CoI2/(R)-BINAP, Zn, ZnI2, H2O system efficiently catalyzes the intermolecular asymmetric reductive coupling of alkynes with cyclic enones to afford highly regioand enantioselective β-alkenyl cyclic ketones. A possible mechanism that involves the formation of a cobaltacyclopentene intermediate from the alkyne and cyclic enone is proposed. © 2011 American Chemical Society.
Cobalt-catalyzed regio- and stereoselective intermolecular enyne coupling: An efficient route to 1,3-diene derivatives
Chemical Communications, 2010, DOI Link
View abstract ⏷
The reaction of alkynes with vinyl arenes or vinyl trimethyl silane in the presence of a cobalt(II) complex, Zn and ZnI2 in CH 2Cl2 at rt to 50 °C provides 1,3-dienes in good to excellent yields. © The Royal Society of Chemistry 2010.
Nickel-catalyzed borylative coupling of alkynes, enones, and bis(pinacolato)diboron as a route to substituted alkenyl boronates
Mannathan S., Jeganmohan M., Cheng C.-H.
Angewandte Chemie - International Edition, 2009, DOI Link
View abstract ⏷
(Chemical Equation Presented) Three-component coupling reactions of an alkyne, an enone, and a diboron reagent provide access to highly substituted alkenyl boronates in good to excellent yields (see scheme). The coupling is highly regio- and stereoselective, and the products are amenable to further functional-group transformations. R1,R2=H, alkyl, aryl, CO2Me; R3=alkyl, Ph; R4,R5=H, alkyl. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
