Monoprotected Amino Acid Research Articles

Synthesis of axially chiral biaryls via Pd(II)-catalyzed direct C(sp2)−H olefination

Herein, a protocol for the construction of axially chiral biaryls via Pd-catalyzed direct C–H olefination of 1-arylisoquinoline N-oxides through kinetic resolution have been uncovered. The atroposelective C–H olefination of 1-arylisoquinoline N-oxides is achieved with alkenes such as acrylates, styrenes, phenylvinyl sulfone, acrylonitrile, and maleimides. The commercially available, cost-effective, and bench-stable chiral mono-protected amino acid is successfully utilized as the chiral ligand to achieve atroposelective products via kinetic resolution. The high conformational stability of the axially chiral products observed from the DFT calculations, shows their excellent stability. A plausible mechanism has been proposed based on the preliminary mechanistic studies, which was further evidenced by the DFT calculations.

Synthesis of axially chiral biaryls via Pd(ii)-catalysed direct C(sp2)–H arylation

Herein, a concise protocol for the construction of axially chiral biaryls via Pd-catalysed C–H arylation of 1-arylisoquinoline N-oxides through kinetic resolution using a commercially available chiral mono-protected amino acid has been uncovered.

Selective C–H activation of unprotected allylamines by control of catalyst speciation

An outstanding challenge in the Pd-catalyzed functionalization of allylamines is the control of stereochemistry. Terminal alkenes preferentially undergo Heck-type reactions, while internal alkenes may undergo a mixture of Heck and C-H activation reactions that give mixtures of stereochemical products. In the case of unprotected allylamines, the challenge in achieving C-H activation is that facile in situ formation of Pd nanoparticles leads to preferential formation of trans rather than cis-substituted products. In this study we have demonstrated the feasibility of using mono-protected amino acid (MPAA) ligands as metal protecting groups to prevent aggregation and reduction, allowing the selective synthesis of free cis-arylated allylamines. This method complements Heck-selective methods, allowing complete stereochemical control over the synthesis of cinnamylamines, an important class of amine that can serve as therapeutics directly or as advanced intermediates. To highlight the utility of the methodology, we have demonstrated rapid access to mu opioid receptor ligands.

Cooperativity between the Substrate and Ligand in Palladium-Catalyzed Allylic Alkylation Using 1-Aryl-1-propynes.

A monoprotected amino acid Bz-Gly-OH assists in the allylic alkylation of a variety of ketones, β-keto esters, aldehydes, etc., during enamine-palladium catalysis. Density functional theory calculations reveal that Bz-Gly-OH assists in the formation of an enamine that attacks the π-allylpalladium complex via an outer sphere mechanism. The preliminary result points to an asymmetric allylic alkylation under a new mode of bifunctional catalysis.

Dual Ligand Enabled Nondirected C-H Chalcogenation of Arenes and Heteroarenes.

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.

Pd-catalyzed asymmetric oxidative C-H/C-H cross-coupling reaction between dialkylaminomethylferrocenes and indolizines

Oxidative C-H/C-H cross-coupling reactions between two (hetero)arenes through 2-fold C-H activation offer rapid assembly of diverse bi(hetero)aryls. Herein, a Pd-catalyzed asymmetric oxidative C-H/C-H cross-coupling reaction of ferrocenes with indolizines was disclosed. A palladium(II)/monoprotected amino acid (MPAA) catalytic system exhibited excellent reactivity, regioselectivity, and enantioselectivity for the coupling reaction. This approach marks the first example of direct arylation of indolizines in an enantioselective oxidative C-H/C-H cross-coupling process and offers a powerful strategy for the synthesis of highly enantioenriched planar chiral ferrocenes.

Photoinduced Decarboxylative Amino-Fluoroalkylation of Maleic Anhydride.

A photoinduced decarboxylative three-component coupling reaction involving amine, maleic anhydride, and fluorinated alkyl iodides has been developed, leading to synthetically valuable fluoroalkyl-containing acrylamides with a high E selectivity. A broad array of substrates including monoprotected amino acid are capable coupling partners. Preliminary mechanistic studies suggest a stepwise process. This reaction represents the first example of photoinduced decarboxylative difunctionalization of maleic anhydride.

Di-Palladium Complexes are Active Catalysts for Mono-N-Protected Amino Acid-Accelerated Enantioselective C–H Functionalization

The role of mono-protected amino acid (MPAA) ligands in accelerating enantioselective cyclopalladation and palladium-catalyzed C–H functionalization was investigated using kinetic, spectroscopic, a...

Copper(I)-Catalyzed Enantioselective Intramolecular Aminotrifluoromethylation of O-Homoallyl Benzimidates.

In the present paper, the Cu(I)-catalyzed intramolecular aminotrifluoromethylation of O-homoallyl benzimidates with Togni reagent I was reported. O-Homoallyl benzimidates equipped with terminal alkenes produced chiral 1,3-oxazines with high enantioselectivity in the presence of a chiral BOX ligand, and racemic tetrahydro-1,3-oxazepines were obtained in high yields from internal alkene derivatives with a monoprotected amino acid additive under similar conditions.

PdII -Catalyzed Enantioselective C(sp3 )-H Activation/Cross-Coupling Reactions of Free Carboxylic Acids.

PdII -catalyzed enantioselective C(sp3 )-H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

PdII -Catalyzed Regio- and Enantioselective Oxidative C-H/C-H Cross-Coupling Reaction between Ferrocenes and Azoles.

Asymmetric C-H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C-H/C-H cross-coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C-H bond cleavage of azoles is likely proceeding through a SE Ar process and may not be a turnover limiting step.

PdII‐Catalyzed Regio‐ and Enantioselective Oxidative C−H/C−H Cross‐Coupling Reaction between Ferrocenes and Azoles

AbstractAsymmetric C−H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C−H/C−H cross‐coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C−H bond cleavage of azoles is likely proceeding through a SEAr process and may not be a turnover limiting step.

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

AbstractPdII‐catalyzed enantioselective C(sp3)−H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

Monoprotected Amino Acid (MPAA) Ligand Enabled C-H Alkynylation of Phenyl Acetic Acid.

A weakly carboxylate-directed palladium(II)-catalyzed ortho-C-H alkynylation of diverse phenylacetic acids promoted by monoprotected amino acid ligand enabled is reported. The reaction has a broad substrate scope including α-secondary, tertiary, and quaternary phenylacetic acids. Notably, the direct ortho-C-H alkynylation of α-quaternary phenylacetic acids and chiral α-tertiary phenylacetic acids was achieved for the first time. Moreover, this method could be used for simple and efficient gram-scale synthesis and diversification of an anti-inflammatory drug.

C−H Alkenylation of Pyrroles by Electronically Matching Ligand Control

Directing group and substrate control strategies have frequently been employed for the regioselective C-H alkenylation of acid- and oxidant-sensitive pyrrole heterocycles. We developed an undirected, aerobic strategy for the C-H alkenylation of N-alkylpyrroles by ligand control. For C2-alkenylation of electron-rich N-alkylpyrroles, an electrophilic palladium catalyst derived from Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF) was used. Alternatively, a combination of Pd(OAc)2 and a mono-protected amino acid ligand, Ac-Val-OH, was useful for C5-alkenylation of N-alkylpyrroles possessing electron-withdrawing groups at the C2 position. This approach based on the electronic effects of heterocycles and catalysts can rapidly provide a wide range of alkenyl pyrroles from readily available N-alkylpyrroles and alkenes.

Dynamic Ligand Exchange as a Mechanistic Probe in Pd-Catalyzed Enantioselective C-H Functionalization Reactions Using Monoprotected Amino Acid Ligands.

A new tool for probing enantioselective reaction mechanisms is introduced. Monitoring the temporal change in product enantiomeric excess after addition of the opposite enantiomer of the ligand during the reaction provides a means of probing dynamic ligand exchange in enantioselective C-H iodination catalyzed by Pd with monoprotected amino acid ligands (MPAAs). This work has general potential to provide insights about the dynamics of catalyst and ligand molecularity and exchange.

Ligand-controlled Regiodivergent C-H Alkenylation of Pyrazoles and its Application to the Synthesis of Indazoles.

Regioselective C4-, C5-, and di-alkenylations of pyrazoles were achieved. An electrophilic Pd catalyst generated by trifluoroacetic acid (TFA) and 4,5-diazafluoren-9-one (DAF) leads to C4-alkenylation, whereas KOAc and mono-protected amino acid (MPAA) ligand Ac-Val-OH give C5-alkenylation. A combination of palladium acetate, silver carbonate, and pivalic acid affords dialkenylation products. Annulation through sequential alkenylation, thermal 6π-electrocyclization, and oxidation gives functionalized indazoles. This comprehensive strategy greatly expands the range of readily accessible pyrazole and indazole derivatives, enabling useful regiodivergent C-H functionalization of pyrazoles and other heteroaromatic systems.

Ligand‐controlled Regiodivergent C−H Alkenylation of Pyrazoles and its Application to the Synthesis of Indazoles

AbstractRegioselective C4‐, C5‐, and di‐alkenylations of pyrazoles were achieved. An electrophilic Pd catalyst generated by trifluoroacetic acid (TFA) and 4,5‐diazafluoren‐9‐one (DAF) leads to C4‐alkenylation, whereas KOAc and mono‐protected amino acid (MPAA) ligand Ac‐Val‐OH give C5‐alkenylation. A combination of palladium acetate, silver carbonate, and pivalic acid affords dialkenylation products. Annulation through sequential alkenylation, thermal 6π‐electrocyclization, and oxidation gives functionalized indazoles. This comprehensive strategy greatly expands the range of readily accessible pyrazole and indazole derivatives, enabling useful regiodivergent C−H functionalization of pyrazoles and other heteroaromatic systems.

Experimental and Computational Development of a Conformationally Flexible Template for the meta-C-H Functionalization of Benzoic Acids.

A conformationally flexible template for the meta-C-H olefination of benzoic acids was designed through both experimental and computational efforts. The newly designed template favors a silver-palladium heterodimer low barrier transition state, and demonstrates that it is feasible to lengthen templates so as to achieve meta-selectivity when the distance between the functional handle of the native substrate and target C-H bond decreases. Analysis of the ortho-, meta-, and para-C-H cleavage transition states determined that the new template conformation optimizes the interaction between the nitrile and palladium-silver dimer in the meta-transition state, enabling palladium to cleave meta-C-H bonds with moderate-to-good yields and generally high regioselectivity. Regioselectivity is governed exclusively by the template, and kinetic experiments reveal that there is a 4-fold increase in rate in the presence of monoprotected amino acid ligands. Using a Boltzmann distribution of all accessible C-H activation transition states, it is possible to computationally predict meta-selectivity in a number of investigated templates with reasonable accuracy. Structural and distortion energies reported may be used for the further development of templates for meta-C-H activation of hitherto unexplored arene substrates.

A Role for Pd(IV) in Catalytic Enantioselective C-H Functionalization with Monoprotected Amino Acid Ligands under Mild Conditions.

Kinetic and mechanistic studies of the desymmetrization of benzhydrylamine using Pd/monoprotected amino acid ligands (Pd/MPAA) via C-H functionalization with molecular iodine provide mechanistic insight into the rate-determining step and the oxidation state of Pd in the C-H functionalization step. Enantiomeric excess is strikingly insensitive to temperature from ambient temperature up to over 70 °C, and reaction rate is insensitive to the electronic characteristics of the ligand's benzoyl protecting group. The reaction is highly robust with no evidence of catalyst deactivation. Intriguingly, C-H bond breaking does not occur prior to the addition of I2 to the reaction mixture. Electrochemical experiments demonstrate the viability of oxidative addition of I2 to Pd(II). Together with 19F NMR studies, these observations suggest that iodine oxidizes Pd prior to addition of the amine substrate. This work may lead to a better general understanding of the subtle variations in the reaction mechanisms for C-H functionalization reactions that may be extant for this ligand class depending on substrate, amino acid ligand and protecting group, and reaction conditions.