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.

Ionic Liquid-accelerated Growth of Covalent Organic Frameworks with Tunable Layer-stacking.

Layer-stacking behaviors are crucial for two-dimensional covalent organic frameworks (2D COFs) to define their pore structure, physicochemical properties, and functional output. So far, fine control over the stacking mode without complex procedures remains a grand challenge. Herein, we proposed a "key-cylinder lock mimic" strategy to synthesize 2D COFs with a tunable layer-stacking mode by taking advantage of ionic liquids (ILs). The staggered (AB) stacking (unlocked) COFs were exclusively obtained by incorporating ILs of symmetric polarity and matching molecular size; otherwise, commonly reported eclipsed (AA) stacking (locked) COFs were observed instead. Mechanistic study revealed that AB stacking was induced by a confined interlocking effect (CIE) brought by anions and bulky cations of the ILs inside pores ("key" and "cylinder", respectively). Excitingly, this strategy can speed up production rate of crystalline powders (e.g., COF-TAPT-Tf@BmimTf2N in merely 30 minutes) under mild reaction conditions. This work highlights the enabling role of ILs to tailor the layer stacking of 2D COFs and promotes further exploration of their stacking mode-dependant applications.

Interfacial Ti-S Bond Modulated S-Scheme MOF/Covalent Triazine Framework Nanosheet Heterojunctions for Photocatalytic C-H Functionalization.

Constructing photocatalyst systems to functionalize the inert C-H bonds has attracted extensive research interest. However, purposeful modulation of interfacial charge transfer in heterostructures remains a challenge, as it usually suffers from sluggish kinetics. Reported herein is an easy strategy to construct the heteroatom-induced interface for developing the titanium-organic frameworks (MOF-902) @ thiophene-based covalent triazine frameworks (CTF-Th) nanosheets S-scheme heterojunctions with controllable oxygen vacancies (OVs). Specifically, Ti atoms were first anchored onto the heteroatom site of CTF-Th nanosheets, and then grown into MOF-902 via an interfacial Ti-S linkage, generating OVs. Using in situ X-ray photoelectron spectroscopy (XPS), extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional theory (DFT) calculations, the enhanced interfacial charge separation and transfer induced by moderate OVs in the pre-designed S-scheme nanosheets was validated. The heterostructures exhibited an improved efficiency in photocatalytic C3-acylation of indoles under mild conditions with a yield 8.2 times larger than pristine CTF-Th or MOF-902 and enabled an extended scope of substrates (15 examples). This performance is superior to state-of-the-art photocatalyst and can be retained, without significant loss, after 12 consecutive cycles.

Modular and Selective Access to Functionalized Alkynes and Allenes via the Intermediacy of Propargylic Acetates.

We report an efficient one-pot, two-step procedure for the modular synthesis of α-difunctionalized alkynes and trisubstituted allenes by sequential cross-coupling of benzal gem-diacetates with organozinc or -copper reagents in the absence of external transition metals. The intermediacy of propargylic acetates enables the divergent and selective synthesis of these valuable products. This method features its readily accessible substrates, relatively mild conditions, wide scope, and scalability in practical synthesis.

Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents.

A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step SN 1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.

Preparation of Polyfunctional Biaryl Derivatives by Cyclolanthanation of 2-Bromobiaryls and Heterocyclic Analogues Using nBu2 LaCl⋠4 LiCl.

Various aryl- and heteroaryl-substituted 2-bromobiaryls are converted to cyclometalated lanthanum intermediates by reaction with nBu2 LaCl⋅4 LiCl. These resulting lanthanum heterocycles are key intermediates for the facile preparation of functionalized 2,2'-diiodobiaryls, silafluorenes, fluoren-9-ones, phenanthrenes, and their related heterocyclic analogues. X-ray absorption fine structure (XAFS) spectroscopy was used to rationalize the proposed structures of the involved organolanthanum species.

The Halogen-Samarium Exchange Reaction: Synthetic Applications and Kinetics.

Fast I/Sm and Br/Sm exchanges take place when various aromatic or heterocyclic iodides and bromides are treated with nBu2 SmCl⋅4 LiCl and nBu3 Sm⋅5 LiCl, respectively. The resulting organosamarium reagents were efficiently quenched with aldehydes, ketones, and imines. Also, they undergo acylations when treated with N,N-dimethylamides leading to ketones. The rate of the Br/Sm exchange for a typical aryl bromide was determined and found to be 8.5×105 faster than the Br/Mg exchange, indicating that the rate of a metal-exchange is related to the ionic character of the carbon-metal bond and to the metal electronegativity.

Improving the Halogen-Magnesium Exchange by using New Turbo-Grignard Reagents.

This Minireview describes the scope of the halogen-magnesium exchange. It shows that the use of the turbo-Grignard reagent (iPrMgCl⋅LiCl) greatly enhances the rate of the Br- and I-Mg exchange. Furthermore, this magnesium reagent allows the performance of a fast sulfoxide-magnesium exchange. Also, the use of sBuMgOR⋅LiOR (R=2-ethylhexyl) enables a Br-Mg exchange in toluene leading to various Grignard reagents in toluene. Additionally, the new exchange reagent sBu2 Mg⋅2 LiOR (R=2-ethylhexyl) further increases the rate of the halogen-magnesium exchange allowing one to perform a chlorine-magnesium exchange for aromatic chlorides bearing an ortho-methoxy substituent in toluene.

Well-defined styryl and biphenyl calcium complexes from dilithio compounds and calcium iodide: synthesis, structure and reactivity toward nitrous oxide.

Efficient synthesis and structure elucidation of carbon-calcium σ-bonded compounds are of remarkable interest and importance in organometallic chemistry of the heavier s-block metals. In this paper, we report that styryl and biphenyl calcium complexes with well-defined structures can be facilely obtained via metathesis reaction between their corresponding dilithio compound and calcium iodide. Single-crystal X-ray structural analysis of these calcium complexes revealed their unique iodide-bridged or dicalcium-bridged structures. Their reactivity toward nitrous oxide was disclosed.

Comparison of the expression of TGF-ß1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1α in oral squamous cell carcinoma and lymph node metastases of humans and mice.

The aim of the present study was to prove that a mouse model closely simulates human oral cancer progression by comparing the expression levels of transforming growth factor (TGF)-ß1, E-cadherin, N-cadherin, tumor protein (TP)53, RB1 inducible coiled-coil (RB1CC)1 and hypoxia inducible factor (HIF)-1α at different stages of oral squamous cell carcinoma (OSCC) in humans and mice. The expression levels of TGF-ß1, E-cadherin, N-cadherin, TP53, RB1CC1, and HIF-1α were detected by immunohistochemical staining in normal oral mucosa, oral mucosa dysplasia, OSCC primary tumor and carcinoma tissues from lymph node metastases. Tissue samples were obtained from human specimens and the Balb/c mouse model of lymphatic metastases oral carcinoma, induced by 4-nitroquinoline-1-oxide in drinking water. The results indicated no significant differences in the expression levels of TGF-ß1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1α between humans and mice, at any stage of OSCC examined (P>0.05). The expression of TGF-ß1, N-cadherin, TP53 and RB1CC1 increased in different stages of OSCC in both humans and mice. The expression of E-cadherin decreased from normal oral mucosa to OSCC, and increased in lymph node metastases in both human and mouse samples. The expression of HIF-1α increased from normal oral mucosa to OSCC, and decreased in lymph node metastases in both human and mouse samples. Additionally, the expression of p53 was positively correlated with that of RB1CC1 in human and mouse samples (r=0.971, P=0.029; r=0.97, P=0.03). Overall, the similar expression of multiple molecules in both human and mouse carcinoma prove that the mouse model of lymphatic metastases from oral carcinoma established in the present study may closely mimic human oral cancer.

Early discovery of disseminated tumor cells during carcinogenesis in a 4NQO-induced mouse model of oral squamous cell carcinoma.

OBJECTIVES: Heterogeneous cells appear in multiple organs during the same time period as the primary lesion of some tumors is clinically detected. These heterogeneous cells are also known as disseminated tumor cells (DTCs). However, the characteristics of DTCs that disseminate during oral carcinogenesis remain unclear. MATERIALS AND METHODS: A mouse 4NQO model of lymph node metastasis in oral squamous cell carcinoma was established. Tissue samples of the tongue, bone marrow and submandibular lymph node were collected. Five stages (stage 0~stage IV) of carcinogenesis in each experimental animal were classified by two pathologists. After immunohistochemical staining of cytokeratin, the DTCs were isolated from bone marrow samples (stage II) by the laser capture microdissection (LCM) technique during oral carcinogenesis. Genomic amplification of bone marrow DTCs was performed, and homozygous deletion of the RB1CC1 gene was analyzed. After confirming the presence of disseminated tumor cells in stage II bone marrow samples, a comprehensive study among various stages of lymph node tissue was conducted using the same method. RESULTS: DTCs that spread from the primary tumor were discovered in stage II bone marrow samples and in stage I, stage II and stage III submandibular lymph node samples through immunohistochemical staining. These spreading cells had different levels of homozygous exon deletion in the RB1CC1 and TP53 genes. CONCLUSION: Early spreading of epithelial cells may occur during the carcinogenesis of oral cancer. DTCs of oral carcinoma may show different chromosome aberrations from matched primary tumor cells.

Formation and ligand-based reductive chemistry of bridged bis-alkylidene scandium(iii) complexes.

The chemistry of rare-earth carbene and alkylidene complexes including their synthesis, structure and reaction is a challenging issue because of their high reactivity (or instability) and the lack of synthetic methods. In this work, we report the first synthesis of the bridged bis-alkylidene complexes which feature a 2-butene-1,1,4,4-tetraanion and four Sc-C(sp3) bonds by the reaction of 1,4-dilithio-1,3-butadienes with ScCl3. This reaction proceeds via two key intermediates: an isolable scandacyclopentadiene and a proposed scandacyclopropene. The scandacyclopentadiene undergoes ß,ß'-C-C bond cleavage to generate the scandacyclopropene, which then dimerizes to afford the bridged bis-alkylidene complex via a cooperative double metathesis reaction. Reaction chemistry study of the bridged bis-alkylidene complex reveals their ligand-based reduction reactivity towards different oxidants such as hexachloroethane, disulfide and cyclooctatetraene.

Synthesis and Structural Characterization of Butadienylcalcium-based Heavy Grignard Reagents and a Ca4 [O] Inverse Crown Ether Complex.

The structure elucidation of heavy Grignard reagents (RAeX, Ae=Ca, Sr, and Ba, X=halides) has been greatly strived after, mainly because of their inaccessibility and remarkable instability. The synthesis of a series of butadienylcalcium compounds is presented, including 1-calcio-4-lithio-1,3-butadiene, 1,4-dicalcio-1,3-butadiene, and a Ca4 [O] inverse crown ether complex, via the reaction between 1,4-dilithio-1,3-butadienes and calcium iodide in THF. Single-crystal X-ray analysis of these unprecedented heavy Grignard reagents revealed unique structural characteristics and bonding modes. Preliminary reaction chemistry was investigated. This study provides a novel class of alkenyl heavy Grignard reagents and a useful synthetic strategy for otherwise unavailable reactive organometallic compounds.

Reaction of Dilithio Reagents with PhSiH3: Formation of Siloles and 3-Silacyclopentenes.

The reaction chemistry between 1,4-dilithio-1,3-butadienes (dilithio reagents for short) and PhSiH3 has been investigated. Direct substitution of two hydride ions from PhSiH3 with the dilithio reagents led to multisubstituted siloles (silacyclopentadienes) in diethyl ether solution, with the concomitant generation of LiH. When THF was used as the solvent, the reaction between PhSiH3 and 1,4-bis(silyl) dilithio reagents afforded cis-3-silacyclopentenes stereoselectively. Experimental results demonstrated that reactive LiH was generated in situ in the reaction system. Formal syn addition of LiH to silacyclopentadiene intermediates would afford silacyclopentenes, most likely via pentavalent organosilicates.

Intramolecular C-F and C-H bond cleavage promoted by butadienyl heavy Grignard reagents.

Organomagnesium compounds (Grignard reagents) are among the most useful organometallic reagents and have greatly accelerated the advancement of synthetic chemistry and related sciences. Nevertheless, heavy Grignard reagents based on the metals calcium, strontium or barium are not widely used, mainly due to their rather inert heavy alkaline-earth metals and extremely high reactivity of their corresponding Grignard-type reagents. Here we report the generation and reaction chemistry of butadienyl heavy Grignard reagents whose extremely high reactivity is successfully tamed. Facile synthesis of perfluoro-π-extended pentalene and naphthalene derivatives is realized by the in situ generated heavy Grignard reagents via intramolecular C-F/C-H bond cleavage. These obtained perfluorodibenzopentalene and perfluorodinaphthopentalene derivatives show low-lying LUMO levels, with one being the lowest value so far among all pentalene derivatives. Our results set an exciting example for the meaningful synthetic application of heavy Grignard reagents.