Pd/SadPhos Enabled Modular and Enantioselective Assembly of Triarylmethanes.

Artificial intelligence (AI) has grown widely into diverse areas of research over the last decade. Publications distributed over the years disclose that biochemistry and analytical chemistry are incorporating AI to the utmost level. Enormous complex data sets are produced by analytical instruments comprising a treasure of information which is very helpful to analytical chemists in characterization. Despite this, we lack capabilities in data analysis and algorithms, which restricts our aptitude to discover and employ this data entirely. Machine learning and AI are being instigated to deal with this current challenge by accelerating several other applications in analytical chemistry. A critical valuation of illustrative reports amalgamating AI with analytical chemistry, spectroscopies, and several sensors has been discussed widely. This comprehensive review evaluates the AI advancement in data interpretation, the assistance of AI in analyte identification and quantification in proteomics and metabolomics, AI databases for primary and secondary metabolites information, regulatory and ethical guidelines in analytical chemistry incorporating AI, machine learning applications in drug discovery, agriculture, cosmetic, and food and separation techniques. In summary, this current review puts forward a thorough examination concerning the advancements of AI in different domains of chemistry and strives to facilitate comprehension of its forthcoming trajectories.

Active Pd intermediates of the Suzuki-Miyaura reaction with low reactive aryl chlorides under “ligand-free” conditions

Cyclic sulfones have demonstrated important applications in drug discovery. However, the catalytic and enantioselective synthesis of chiral cyclic sulfones remains challenging. Herein, we develop nickel-catalyzed regiodivergent and enantioselective hydroalkylation of sulfolenes to streamline the synthesis of chiral alkyl cyclic sulfones. The method has broad scope and high functional group tolerance. The regioselectivity can be controlled by ligands only. A neutral PYROX ligand favors C3-alkylation whereas an anionic BOX ligand favors C2-alkylation. This control is kinetic in origin as the C2-bound Ni intermediates are always thermodynamically more stable. Reactivity study of a wide range of relevant Ni intermediates reveal a NiI/NiIII catalytic cycle with a NiII-H species as the resting state. The regio- and enantio-determining step is the insertion of this NiII-H species into 2-sulfolene. This work provides an efficient catalytic method for the synthesis of an important class of organic compounds and enhances the mechanistic understanding of Ni-catalyzed stereoselective hydroalkylation.

Two novel cross-linked polystyrene-supported N-sulfonylated β-aminoalcohol resins 94 and 95 have been prepared from radical co-polymerizations of styrene, divinylbenzene, and styrenes bearing a para-substituent of N-sulfonylated aminoalcohol. Resins 94 and 95 were obtained in high yields of 85.8 and 84.7%, and were characterized by IR and solid state 13C NMR spectroscopy. Elemental analyses reveal that one gram of the resin 94 contains 0.93 mmol bidentate N-sulfonylated β-aminoalcohol. The ligand content in the tridentate resin 95 is calculated to be 0.95 mmol/g. The Ti(O-i-Pr)4/94 catalytic system works excellently in asymmetric ZnEt2 additions to aldehydes affording secondary alcohols in ≥90% ee. The resin 94 can be reused 9 times without losing any activity, giving the product with enantioselectivities ≥87% ee. The Ti(O-i-Pr)4/95 system was used only once in asymmetric AlEt3 additions to a variety of aldehydes affording secondary alcohols in good to excellent enantio- selectivities from 73 to 92% ee. Novel asymmetric aryl additions of AlAr3(THF) to ketones catalyzed by the titanium catalyst of (S)-BINOL are reported. A wide variety of ketones are examined to afford products, in general, in excellent enantioselectivities of ≥90% ee for aromatic ketones bearing either an electron-donating or an electron-withdrawing substituent at 2’-, 3’-, or 4’-position on the aromatic ring. Steric effects are found for additions to ortho-substituted aromatic ketones with longer reaction times required to give products in higher yields. The catalytic system applies also to α,β-unsaturated ketones and 2-acetylfuran to give products in good to excellent enantioselectivities. More importantly, aluminum reagents with different aryl nucleophiles can be easily prepared for additions to aromatic ketones furnishing tertiary diaryl alcohols in both absolute configurations. Asymmetric AlPh3(THF) additions to ketones catalyzed by the titanium catalyst of 20 mol% trans-1,2-bis(hydroxycamphorsulfonylamino)cyclohexane (116) are now reported. Several important features were demonstrated in this study. First, a novel aspect of inorganic salt of MgBr2 as a key additive to promote the phenyl addition of AlPh3(THF) to ketones was demonstrated. Second, the catalytic system worked excellently for aromatic ketones bearing either an electron-withdrawing or an electron-donating substituent on the aromatic group to afford tertiary alcohols in enantioselectivities of ≥90% ee except for 2’-methoxyacetophenone. Third, longer reactions times were required for ortho-substituted aromatic ketones to furnish products in good yields. Based on these results, we propose that MgBr2 binds to the sulfonamide oxygen atom, thereby freeing a coordination site for the ketone substrate. A series of background, stoichiometric, and catalytic phenyl addition reactions are tested for aldehydes and ketones. TiPh(O-i-Pr)3 exists in the catalytic system, as confirmed by 1H NMR study and X-ray diffraction. These results indicate that TiPh(O-i-Pr)3 plays a key role in the catalytic reactions, yielding high enantio- selectivities. Ti2Ph(BINOLate)(O-i-Pr)5 (176) is synthesized by mixing Ti(BINOLate)- (O-i-Pr)2 and TiPh(O-i-Pr)3, and characterized by X-ray diffraction. Observation of the structure of complex 176 reveals a pocket on the same side of the bridging isopropoxide. Aldehydes and ketones apparently access the Ti(1) metal center from the top of the pocket to form a six-coordinate metal center, and the substrates then would appear to be placed in the proper orientation for achieving the excellent enantioselectivities. Thus, a catalytic cycle is depicted to illustrate the Ti(O-i-Pr)4/AlPh3(THF) asymmetric catalytic addition reactions with aldehydes or ketones.

The mechanism of the Suzuki–Miyaura cross-coupling reaction between pyridine and phenylboronic acid catalyzed by the complex of iron salt combined with macrocyclic polyamine (iron–MCPA) was investigated theoretically and experimentally. It was found that the overall reaction includes three steps: C–H activation, transmetalation, and reductive elimination. The results indicate that the rate-determining step is the transmetalation step. The C–H activation of a different position on pyridine is the origin of the regioselectivity. The transmetalation step is the regio-determining step. Both the C–H activation and the transmetalation steps favor the regioselective formation of the ortho product. The oxoiron complex is predicted to be the active species theoretically and is confirmed by experiments. The calculations correctly reproduce the major product, 2-phenylpyridine, which is consistent with the experimental observation.

The field of nickel catalysis has witnessed remarkable growth in recent years. However, the use of nickel catalysts in enantioselective C–H activation remains a daunting challenge because of their variable oxidation states, intricate coordination chemistry, and unpredictable reactivity patterns. Herein, we report an enantioselective C–H activation reaction catalyzed by commercially available and air-stable nickel(II) catalyst. Readily available and simple (S)-BINOL is used as a chiral ligand. This operationally simple protocol enables the synthesis of planar chiral metallocenes in high yields with excellent enantioselectivity through desymmetrization and kinetic resolution. Air-stable planar chiral nickelacycle intermediates are first synthesized via enantioselective C–H nickelation and shown to be possible intermediates of the reaction. Deuterium-labeling studies, alongside the characterization and transformation of chiral nickel(II) species, suggest that C–H cleavage is the enantio-determining step. Moreover, the large-scale synthesis and diverse synthetic transformations underscore the practicality of this protocol.

Graph-based molecular representation learning is essential for predicting molecular properties in drug discovery and materials science. Despite its importance, current approaches struggle with capturing the intricate molecular relationships and often rely on limited chemical knowledge during training. Multimodal fusion, which integrates information from graph and other data sources together, has emerged as a promising approach for enhancing molecular property prediction. However, existing studies explore only a narrow range of modalities, and the optimal integration stages for multimodal fusion remain largely unexplored. Furthermore, the reliance on auxiliary modalities poses challenges, as such data is often unavailable in downstream tasks. Here, we present MMFRL (Multimodal Fusion with Relational Learning), a framework designed to address these limitations by leveraging relational learning to enrich embedding initialization during multimodal pre-training. MMFRL enables downstream models to benefit from auxiliary modalities, even when these are absent during inference. We also systematically investigate modality fusion at early, intermediate, and late stages, elucidating their unique advantages and trade-offs. Using the MoleculeNet benchmarks, we demonstrate that MMFRL significantly outperforms existing methods with superior accuracy and robustness. Beyond predictive performance, MMFRL enhances explainability, offering valuable insights into chemical properties and highlighting its potential to transform real-world applications in drug discovery and materials science.

Theoretical insight into phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones

Good to excellent yields of aryl trifluoromethyl sulfides, which are an important class of compounds in both the pharmaceutical and agrochemical areas, can be achieved under mild conditions by the Pd-catalyzed reaction of aryl bromides with a trifluoromethylthiolate nucleophile (see scheme). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Transition-metal-catalyzed asymmetric C-H functionalization has emerged as a powerful strategy for constructing planar-chiral ferrocenes (PCFs). However, current methods typically require preinstallation of a directing group (DG) and are usually limited to monofunctionalization. Herein, we report a "de novo" construction of PCFs via Pd/NBE* cooperative catalysis, employing a unique bulky (C1,C4)-bridgehead-modified chiral norbornene as the cocatalyst as well as the only chiral source. This approach enables the formation of two new chemical bonds in a single step from simple iodoferrocenes. A series of planar-chiral isoquinolone-fused ferrocenes are quickly obtained with up to >99% ee. Mechanistic studies reveal that the ortho-C-H activation step serves as the enantio-determining step, while the reductive elimination is not only the rate-determining step but also plays a pivotal role in further enhancing the enantioselectivity. The synthetic utility is highlighted by diverse transformations of products and the development of a powerful NAD(P)H coenzyme for biomimetic asymmetric hydrogenation of olefins.

A highly efficient gold and palladium combined methodology for the Sonogashira coupling of a wide array of electronically and structurally diverse aryl and heteroaryl halides is described. The orthogonal reactivity of the two metals shows high selectivity and extreme functional group tolerance in Sonogashira coupling. A brief mechanistic study reveals that the gold acetylide intermediate enters into the palladium catalytic cycle at the transmetalation step.

With the aid of DFT calculations, we have examined the mechanism of the widely employed Pd-catalyzed borylation of aryl halides using HBpin (pin = OCMe2CMe2O) developed by Masuda et al. In contrast to their original proposed mechanism involving an ammonium boride ion pair in the transmetalation step that follows aryl halide oxidative addition to Pd(0), our calculations support a transmetalation process that involves σ-bond metathesis between HBpin and a cationic [L2Pd(Ar)]+ species as the ArBpin product generating step. The new mechanism is also applicable to the related boration reaction employing R2NBH2 reagents developed by Alcaraz et al.

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf-stable and easy-to-prepare bilateral disulfurating platform molecule, N-(morpholine-4-dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron-rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C-S bond-forming reactions.

This review explores recent advancements in synthesizing quinoid heteroaryls, namely quinazoline and quinoline, vital in chemistry due to their prevalence in natural products and pharmaceuticals. It emphasizes the rapid, highly efficient, and economically viable synthesis achieved through gold-catalyzed cascade protocols. By investigating methodologies and reaction pathways, the review underscores exceptional yields attainable in the synthesis of quinoid heteroaryls. It offers valuable insights into accessing these complex structures through efficient synthetic routes. Various strategies, including cyclization, heteroarylation, cycloisomerization, cyclo-condensation, intermolecular and intramolecular cascade reactions, are covered, highlighting the versatility of gold-catalyzed approaches. The comprehensive compilation of different synthetic approaches and elucidation of reaction mechanisms contribute to a deeper understanding of the field. This review paves the way for future advancements in synthesizing quinoid heteroaryls and their applications in drug discovery and materials science.

Multicomponent reactions, which involve the reaction of three or more components in a single step to efficiently produce a new molecular structure, have received growing attention in a range of research areas. In this study, four- and five-component reactions incorporating alkenes, carboxylic acids, alkyl radicals, and nitriles are developed for the imidoalkylation of alkenes with perfect regioselectivity. More specifically, this approach involves a photoredox reaction based on a catalytic indirect reductive quenching system. Various drug molecules and amino acids were demonstrated to be compatible substrates for this reaction, thereby enabling the synthesis of multifunctionalized derivatives. Notably, five individual components were assembled with perfect regioselectivity via the reaction of a radical species in the presence of a polarity-matched alkene. Mechanistic studies and density functional theory calculations suggested that this multicomponent reaction involves a cascade of Ritter-type substitutions and Mumm rearrangements. This method exhibits immense potential for use in the creation of structurally diverse and biologically relevant molecules with defined connectivities, thereby holding promise for applications in drug discovery and materials science.