Mild and efficient syntheses of diverse isoindolinones from ortho-phthaldehydic acid methylthiomethyl ester

A mild and efficient method for the synthesis of diverse isoindolinones from o-phthaldehydic acid methylthiomethyl ester and aliphatic/aromatic amines has been developed. A number of nucleophiles including a hydride ion were successfully added to the intermediate Schiff's base providing isoindolinones, with or without substitution at 3-position. Conditions have also been developed for amines with an integrated nucleophilic group to react in a diverse fashion either to give isoindolinones or tricyclic γ-lactams as single diastereoisomers in very good yield.     

Novel one-step synthesis of 2-carbonyl/thiocarbonyl isoindolinones and mechanistic disclosure on the rearrangement reaction of o-phthalaldehyde with amide/thioamide analogs

A rearrangement reaction of o-phthalaldehyde with urea/thiourea analogs or amides/thioamides under the catalysis of TMSCl (trimethylchlorosilane) is described, whereby a series of 2-carbonyl isoindolinones and 2-thiocarbonyl isoindolinones are afforded. This is the first time that the N-carbonyl/thiocarbonyl isoindolinones are synthesized in a single step from o-phthalaldehyde. Similar reactions using primary amines also proceed smoothly to give corresponding N-alkyl or N-aryl isoindolinones in this mild catalytic system. The mechanism of this kind of rearrangement is discussed based on new evidences observed from the ESI-MS time-interval monitoring of the full reaction course and deuterium exchange experiments.     

An unexpected three-component condensation leading to amino- (3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)- acetonitriles

The reaction of 2-carboxybenzaldehyde with primary amines in the presence of cyanide leads to the formation of 2-substituted amino(3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)acetonitriles. These compounds originate from the condensation of 2-carboxybenzaldehyde with the amine and two molecules of hydrogen cyanide and represent a novel class of isoindolinones.     

Catalyst-free Mannich-type reactions in water: Expedient synthesis of naphthol-substituted isoindolinones

An environmentally benign while efficient approach to the synthesis of isoindolinones by three-component reactions of 2-formylbenzoic acids, primary amines, 2-naphthols via a Mannich-cyclization reaction sequence in water under catalyst-free conditions is described here. This protocol features wide substrate scope, ease of operation, the use of naturally abundant while enviromentally benign water as a reaction medium and the formation of only water as the sole byproduct in the transformation.     

Highly efficient synthesis of N-substituted isoindolinones and phthalazinones using Pt nanowires as catalysts

A series of N-substituted isoindolinones have been successfully synthesized through the reductive C-N coupling and intramolecular amidation of 2-carboxybenzaldehyde and amines. This one-pot synthesis gives excellent yields using ultrathin Pt nanowires as catalysts under 1 bar of hydrogen. These unsupported catalysts can also be used for the synthesis of phthalazinones in high yield when hydrazine or phenyl hydrazine is used instead of amines.     

Isoindolinones via a room temperature palladium nanoparticle-catalysed 3-component cyclative carbonylation-amination cascade

A room temperature 3-component cascade process involving nucleophilic substitution/carbonylation/amination, catalysed by palladium nanoparticles generated in situ from palladacycle 5, affords isoindolinones in good yields. The conversions correlate with the pK_a values of the amines.     

Solid-phase synthesis of isoindolinones and naturally-occurring benzobutyrolactones (phthalides) using a cyclative-cleavage approach

Starting from Merrifield resin, 2-formylbenzoic acids were immobilized on solid supports. Reactions between immobilized 2-formylbenzoic acids and different organometallic reagents (Grignard reagents, zinc reagents, allyl silanes via Sakurai type reactions) furnished secondary alcohols which cyclized depending on the metal counter ion and reaction conditions, forming benzoannelated lactones. Asymmetric synthesis was possible on the resin using chiral [2.2]paracyclophane ligands. While the reaction of immobilized ortho-carboxy benzaldehydes with primary amines at elevated temperatures yielded 3-hydroxyisoindolinones, a reaction at ambient temperature allowed imine formation, which underwent 1,2-addition-cleavage reaction with various nucleophiles, yielding isoindolinones with three points of diversity.     

A practical synthesis of functionalized isoindolinones via [3 + 3] benzannulation of 1,3-bissulfonylpropenes and 4-arylmethylene-2,3-dioxopyrrolidines

A straightforward synthesis of isoindolinones has been developed via a [3?+?3] benzannulation of 4-arylmethylene-2,3-dioxopyrrolidines and 1,3-bissulfonylpropenes (or 4-sulfonylcrotonates). A series of functionalized isoindolinones were obtained in excellent yields. The reaction could be carried out under mild conditions without transition metal catalyst. The finding provides a practical approach for the preparation of isoindolinone derivatives with potential biological activities.     

Preparation of isoindolinones via a palladium-catalyzed diamination

A Pd(II)-catalyzed cyclization using oxidative olefin diamination was developed for the preparation of isoindolinones from ortho-olefinic N-methoxybenzamides. Using the optimized reaction conditions, the desired products were obtained in up to 90% yield using NFSI as the oxidant. This reaction provides an efficient and direct access to isoindolinones with amine functionality, an important drug skeleton.     

Palladium‐Catalyzed Carbonylation of 2‐Bromoanilines with 2‐Formylbenzoic Acid and 2‐Halobenzaldehydes: Efficient Synthesis of Functionalized Isoindolinones

A concise and highly versatile method for the synthesis of functionalized isoindolinones is reported. Various 2‐bromoanilines undergo palladium‐catalyzed carbonylation with 2‐formylbenzoic acid under a convenient and mild procedure to give good to excellent yields of the corresponding isoindolinones. Additionally, 2‐halobenzaldehydes can be applied as substrates in palladium‐catalyzed double‐carbonylation to provide identical compounds in moderate to good yields.     

Mg-catalyzed enantioselective benzylic C-H bond functionalization of isoindolinones: addition to imines

Access to chiral isoindolinones: The Mg-catalyzed enantioselective benzylic C-H bond functionalization of isoindolinones is described. A Bu(2) Mg/Schiff base catalyst (1:1) promoted the enantioselective addition of N-Boc-isoindolinones to aryl, heteroaryl, alkenyl, and alkyl imines, giving 3-substituted isoindolinones in 84-99?%?ee and 50:50-91:9?d.r. (see scheme).     

Cesium effect: high chemoselectivity in direct N-alkylation of amines

A novel method for the mono-N-alkylation of primary amines, diamines, and polyamines was developed using cesium bases in order to prepare secondary amines efficiently. A cesium base not only promoted alkylation of primary amines but also suppressed overalkylations of the produced secondary amines. Various amines, alkyl bromides, and alkyl sulfonates were examined, and the results demonstrated this methodology was highly chemoselective to favor mono-N-alkylation over dialkylation. In particular, use of either sterically demanding substrates or amino acid derivatives afforded the secondary amines exclusively, offering wide applications in peptidomimetic syntheses.     

Supported Palladium Nanoparticles that Catalyze Aminocarbonylation of Aryl Halides with Amines using Oxalic Acid as a Sustainable CO Source

Polystyrene-supported palladium (Pd@PS) nanoparticles (NPs) have been used to catalyze the aminocarbonylation of aryl halides with amines using oxalic acid as a CO source for the first-time for the synthesis of amides. Furthermore, o-iodoacetophenones participated in amidation and cyclization reactions to give isoindolinones in a single step following a concerted approach. Oxalic acid has been used as a safe, environmentally benign and operationally simple ex situ sustainable CO source under double-layer-vial (DLV) system for different aminocarbonylation reactions. Catalyst stability under a CO environment is a challenging task, however, Pd@PS was found to be recyclable and applicable for a vast substrate scope avoiding regeneration steps. Easy handling of oxalic acid, additive and base-free CO generation, catalyst stability and effortless catalyst separation from the reaction mixture by filtration and introduce of DLV are the added advantages to make the overall process a sustainable approach.     

Enantiopure Isoindolinones through Viedma Ripening

Here we demonstrate that deracemization of isoindolinones using Viedma ripening is possible starting from a racemic mixture of conglomerate crystals. Crystals of the enantiopure isoindolinones lose their chiral identity upon dissolution even without the need for a catalyst. This enabled complete deracemization of the reported isoindolinones without a catalyst.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

RhIII-Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Rh^III-catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.     

A direct arylation-oxidation route to 3-arylisoindolinone inhibitors of MDM2-p53 interaction

A route to the MDM2-p53 inhibitor isoindolinone pharmacophore from a pre-formed phthalimide is detailed. The route involves treatment of 3-hydroxy-2-(n-propyl)isoindolinone with a substituted benzene in the presence of triflic acid. The resulting 3-aryl-2-(n-propyl)isoindolinones are then oxidized to the corresponding 3-hydroxy-3-aryl-2-(n-propyl) isoindolinones by treatment with 2,2’-bipyridinium chlorochromate. The benzylic oxidation represents a rather rare oxochromium (VI)-mediated reaction in which a selective C-H to C-OH transformation occurs.     

Catalytic Asymmetric Synthesis of Isoindolinones

As important reactive species, isoindolinones represent a cluster of valuable building blocks for the construction of natural‐product‐like compounds. In particular, chiral isoindolinones are the key structural feature of naturally occurring bioactive molecules. During the past decade, great advances have been made in the asymmetric synthesis of isoindolinone skeleton compounds. Hence, recent progress in catalytic asymmetric synthesis of isoindolinones is reviewed here, with emphasis on chiral organocatalysis and transition metal complexes enabled transformations. Different organocatalysts (chiral phosphoric acids, phase transfer catalysts, chiral thioureas) and chiral transition‐metal complexes (Rh, Pd, Ir, Cu, Mg, and Ni) are included in this transformation.     

Visible‐Light‐Promoted Metal‐Free Aerobic Oxidation of Primary Amines to Acids and Lactones

A unique metal‐free aerobic oxidation of primary amines via visible light photocatalytic double carbon–carbon bonds cleavage and multi carbon–hydrogen bonds oxidation was observed. Aerobic oxidation of primary amines could be controlled to afford acids by using dioxane with 18 W CFL, and lactones by using DMF with 8 W green LEDs, respectively. A plausible mechanism was proposed based on control experiments. This observation showed direct evidences for the fragmentation in the aerobic oxidation of aliphatic primary amines.     

Tris(2,6-dimethoxyphenyl)methyl carbenium ion as a charge derivatization agent for the analysis of primary amines by MALDI mass spectrometry

A novel derivatization method for the analysis of primary amines by MALDI mass spectrometry is proposed. Tris(2,6-dimethoxyphenyl) methyl carbenium cation reacts smoothly with primary amines, forming permanently charged adducts with the mass increment +359 Da and absorbance in the UV region. The approach was tested on a number of amines, including biologically active compounds and therapeutic agents.