Recent Advances in Halogen-Metal Exchange Reactions.

ConspectusThe halogen-metal exchange reaction is a very powerful method for preparing functionalized organometallic reagents in the fields of organic and organometallic chemistry. Since its inception, significant interest has been directed toward the on-demand development of new halogen-metal exchange reactions, primarily through the upgrading of exchange reagents. The enduring quest for optimal reactivity, superior functional group compatibility, and innovative synthetic applications of exchange reagents remains a fundamental objective. In the past several years, the emergence of some significant discoveries in halogen-metal exchange reactions has proclaimed a renaissance to this field. This Account outlines the latest advances within the domain contributed by the Knochel group, including the main points as follows.The stereoretentive I/Li exchange on stereodefined secondary alkyl iodides was developed for the synthesis of nonstabilized chiral secondary alkyllithium reagents. This provided a straightforward method to access chiral organolithium reagents, which can be trapped by various electrophiles or transmetalated with other metals such as copper, zinc, and magnesium, thus enabling the stereoselective synthesis of a series of functionalized compounds and natural products.Faster halogen-magnesium and halogen-zinc exchanges in toluene were realized using a novel kind of exchange reagent complexed with lithium alkoxide. These highly efficient exchange reactions are much faster than traditional ones and performed in an industrially friendly solvent. These advantages are of great value in practical synthesis, paving the way for new developments in this evolving area.Halogen-lanthanide exchanges and their novel applications in organic synthesis were established. These new exchanges introduced the lanthanide metals into halogen-metal exchange reactions for the first time, thereby opening new avenues in synthetic chemistry. Building on these achievements, a comparative analysis of the exchange reaction rates by kinetic study has quantified the relationship between the electronegativity of metals and the rates of halogen-metal exchanges.Br/Na exchange in continuous flow was achieved using a hexane-soluble exchange reagent, 2-ethylhexylsodium. This approach effectively circumvented the poor solubility of the organosodium reagent, which has proven to be of significant practical value and greatly enhanced the synthetic utility of the organosodium reagent in organic synthesis.These remarkable breakthroughs as mentioned above are fueled mainly by upgrading the exchange reagents, resulting in the development of new halogen-metal exchange reactions and innovative applications in organic synthesis. Given the importance of halogen-metal exchanges in synthetic chemistry, the pursuit of other types of exchange reactions, particularly those involving new metals, will be in continuous demand. This Account provides a timely summary of recent progress and will undoubtedly inspire further advances to drive this research field forward.

The Role of Base in Reaction Performance of Photochemical Synthesis of Thiazoles: An Integrated Theoretical and Experimental Study.

Artificial intelligence (AI)/machine learning (ML) is emerging as pivotal in synthetic chemistry, offering revolutionary potential in retrosynthetic analysis, reaction conditions and reaction prediction. We have combined chemical descriptors, primarily based on Density Functional Theory (DFT) calculations, with various AI/ML tools such as Multi-Layer Perceptron (MLP) and Random Forest (RF), to predict the synthesis of 2-arylbenzothiazole in photoredox reactions. Significantly, our models underscore the critical role of the molecular structure and physicochemical characteristics of the base, especially the total atomic polarizabilities, in the rate-determining steps involving cyclohexyl and phenethyl moieties of the substrate. Moreover, we validated our findings in articles through experimental studies. It showcases the power of AI/ML and quantum chemistry in shaping the future of organic chemistry.

Preparation of Aromatic and Heterocyclic Amines by the Electrophilic Amination of Functionalized Diorganozincs with Polyfunctional O-2,6-Dichlorobenzoyl Hydroxylamines.

We report a catalyst-free electrophilic amination, which enables the synthesis of aromatic and heterocyclic amines. By subjecting diarylzinc or diheteroarylzinc compounds to readily accessible O-2,6-dichlorobenzoyl hydroxylamines in the presence of MgCl2 in dioxane at a temperature of 60 °C (8-16 h). This new electrophilic amination allowed an expedited synthesis of two pharmaceutically significant compounds: vortioxetine is a key intermediate of delamanid. This approach offers opportunities for the streamlined synthesis of amine-based molecules in the pharmaceutical industry.

In Situ X-Ray Techniques Unraveling Charge Distribution Induced by Halogen Bonds in Solvates of an Iodo-Substituted Squaraine Dye.

The importance of halogen bonds (XBs) in the regulation of material properties through a variation in the electrostatic potential of the halogen atom is not attracted much attention. Herein, this study utilizes in situ single crystal X-ray diffraction and synchrotron-based X-ray techniques to investigate the cooling-triggered irreversible single-crystal-to-single-crystal transformation of the DMF solvated iodo-substituted squaraine dye (SQD-I). Transformation is observed to be mediated by solvent-involved XB formation and strengthening of electrostatic interaction between adjacent SQD-I molecules. By immersing a DMF solvate in acetonitrile a solvent exchange without loss of long-range ordering is observed. This is attributed to conservation of the molecular charge distribution of SQD-I molecules during the process. The different solvates can be used in combination for temperature-dependent image encryption. This work emphasizes the changes caused by XB formation to the electrostatic potentials of halogen containing molecules and their influence on material properties and presents the potential utility of XBs in the design of soft-porous crystals and luminescent materials.

Access to Valuable Chalcogen-Containing Biaryl Derivatives via Regioselective 2,2'-Dichalcogenation of 2-Bromobiaryls.

The regioselective installation of chalcogen atoms into biaryl scaffolds is an important synthetic task due to the great value of chalcogen-containing biaryl derivatives in many fields. Here we undertake this task by developing a regioselective 2,2'-dichalcogenation of 2-bromobiaryls with common chalcogen sources using an organolanthanum-mediated one-pot, two-step protocol. This strategy features high regioselectivity, readily available substrates, transition-metal-free conditions, and performance superior to those of previous methods, thereby demonstrating the unique advantages of organolanthanum reagents in organic synthesis.

Association of higher transient receptor potential melastatin 8 expression with higher tumor histologic grades, lymph node metastasis, risk factors, and worse survival in patients with head and neck squamous cell carcinoma.

Background/purpose: Transient receptor potential melastatin 8 (TRPM8), a thermosensitive ion channel known for its role in cold sensation and menthol response, has emerged as a potential regulator in various cancers. This study aimed to investigate expression trends of TRPM8 in head and neck squamous cell carcinoma (HNSCC) cases and oral squamous cell carcinoma (OSCC) cell lines and its association with clinicopathological features. Materials and methods: The noncancerous matched tissues and HNSCC paired tissue samples from 84 HNSCC patients were utilized to evaluate the association of TRPM8 with HNSCC clinicopathological features. TRPM8 expression was examined in HNSCC patient tissues and OSCC cell lines treated with arecoline. Results: Kaplan-Meier survival analysis of TCGA data revealed high TRPM8 expression correlated with unfavorable outcomes and higher tumor histologic grades. TRPM8 mRNA expression was upregulated in HNSCC cell lines and patients' tissue samples. Arecoline treatment led to significantly increased TRPM8 mRNA and protein expression in OSCC cell lines. Lymph node metastasis showed a significant association with upregulated TRPM8 expression in combined OSCC and oropharyngeal squamous cell carcinoma (OPSCC) cases. TRPM8 mRNA expression was upregulated in HNSCC and OSCC patients with alcohol drinking and cigarette smoking habits, but not in betel quid chewing. Conclusion: These findings reveal the involvement of TRPM8 in HNSCC's malignant development and metastasis, suggesting that high expression of TRMP8 may be mutually causal with addiction to tobacco, alcohol, and betel nut in HNSCC patients. Further investigations are needed to determine the underlying pathways of TRPM8 in HNSCC's development and progression.