Csp3 Bond Research Articles

Synergistic Pd/Cu-Catalyzed Asymmetric Csp3–Csp3 Coupling of 1,3-Dienes with 2-Acylimidazoles

The catalytic asymmetric coupling of 1,3-dienes with carbon nucleophiles is an important process for forming Csp3–Csp3 bonds. In our report, we describe a synergistic Pd/Cu catalyzed coupling of 1,3-dienes with 2-acylimidazoles. This reaction produces 2-acylimidazole derivatives that have α, β-adjacent stereocenters in moderate yields with good to excellent stereoselectivity.

Paired Electrolysis Enables Reductive Heck Coupling of Unactivated (Hetero)Aryl Halides and Alkenes

AbstractThe formation of carbon‐carbon (C−C) bonds is a cornerstone of organic synthesis. Among various methods to construct Csp2−Csp3 bonds, the reductive Heck reaction between (hetero)aryl halides and alkenes stands out due to its potential efficiency and broad substrate availability. However, traditional reductive Heck reactions are limited by the use of precious metal catalysts and/or limited aryl halide and alkene compatibility. Here, we present an electrochemically mediated, metal‐ and catalyst‐free reductive Heck reaction that tolerates both unactivated (hetero)aryl halides and diverse alkenes such as vinyl boronates and silanes. Detailed electrochemical and deuterium‐labeling studies support that this transformation likely proceeds through a paired electrolysis pathway, in which acid generated by the oxidation of N,N‐diisopropylethylamine (DIPEA) at the anode intercepts an alkyl carbanion formed after radical‐polar crossover at the cathode. As such, this approach offers a sustainable method for the construction of Csp2−Csp3 bonds from (hetero)aryl halides and alkenes, paving the way for the development of other electrochemically mediated olefin difunctionalization reactions.

Formation of Bis‐indolylmethanes from Symmetrical Triarylmethanes via Brønsted Acid Catalyzed C−C Bond Breaking Reaction

AbstractAn alternative approach to synthesize bis‐indolylmethanes (BIMs) via a unique p‐toluenesulfonic acid (PTSA) catalyzed dual Csp3−Csp2 bond‐breaking reaction has been reported here. In the reported protocol, 1,3,5‐trimethoxybenzene (TMB), an electron‐rich and sterically bulky arene, acts as a carbon‐based leaving group which can be recovered after the completion of the reaction. In this process, several BIMs of various indole derivatives can be synthesized from symmetrical triarylmethanes (TRAMs) containing bis‐TMB motifs. By modifying the reaction conditions, we could control the sequential bond cleavage of two Csp3−Csp2 bonds in starting TRAM.

Water mediated redox-neutral cleavage of arylalkenes via photoredox catalysis

Cleavage of carbon-carbon bonds remains a challenging task in organic synthesis. Traditional methods for splitting Csp2=Csp2 bonds into two halves typically involve non-redox (metathesis) or oxidative (ozonolysis) mechanisms, limiting their synthetic potential. Disproportionative deconstruction of alkenes, which yields one reduced and one oxidized fragment, remains an unexplored area. In this study, we introduce a redox-neutral approach for deleting a Csp2 carbon unit from substituted arylalkenes, resulting in the formation of an arene (reduction) and a carbonyl product (oxidation). This transformation is believed to proceed through a mechanistic sequence involving visible-light-promoted anti-Markovnikov hydration, followed by photoredox cleavage of Csp3-Csp3 bond in the alcohol intermediate. A crucial consideration in this design is addressing the compatibility between the highly reactive oxy radical species in the latter step and the required hydrogen-atom-transfer (HAT) reagent for both steps. We found that ethyl thioglycolate serves as the optimal hydrogen-atom shuttle, offering remarkable chemoselectivity among multiple potential HAT events in this transformation. By using D2O, we successfully prepared dideuteromethylated (-CD2H) arenes with good heavy atom enrichment. This work presents a redox-neutral alternative for alkene deconstruction, with considerable potential in late-stage modification of complex molecules.

Palladium Complexes with N,O‐Bidentate Ligands Based on N‐Oxide Units from Cyclic Secondary Amines: Synthesis and Catalytic Application in Mizoroki‐Heck Reaction

Comprehensive SummaryPalladium‐catalyzed Mizoroki‐Heck reaction is a powerful and efficient method for construction of Csp2–Csp2 bonds. Herein, four palladium complexes (I—IV) with N,O‐bidentate ligands (L1—L4) based on N‐oxide units from cyclic secondary amines were easily synthesized and successfully applied in Mizoroki‐Heck reaction of aryl bromides with electron‐deficient olefins. X‐ray diffraction analyses indicated the palladium(II) atom of II took the distorted square planar geometry and was four‐coordinated by nitrogen and oxygen atoms from two ligands (L2). Two free chloride ions were presented as counter anions in complex II. But the palladium(II) center of IV was coordinated by nitrogen and oxygen atoms from one ligand (L4) as well as two chlorine atoms, which exhibited the nearly square‐planar geometry. The study on catalytic properties of palladium complexes revealed that complex II exhibited high activity superior to the other complexes. The coupling reactions of a series of aryl bromides and olefin derivatives proceeded in the presence of 2—5 mol% palladium complex II, giving the desired products in good to excellent yields. The advantages of this method such as good compatibility of functional groups, high yields, and short reaction times made it more attractive for constructing Csp2–Csp2 bonds in the synthesis of functional molecules and materials.

Sterically demanding Csp2(ortho-substitution)-Csp3(tertiary) bond formation via carboxylate-directed Mizoroki-Heck reaction under extra-ligand-free conditions.

Construction of the sterically demanding Csp2(oS)-Csp3(T) bond was achieved by carrying out the Pd-catalyzed carboxylate-directed Mizoroki-Heck reaction under extra-ligand-free aqueous conditions. The cooperative role of the presence of water with the absence of phosphine ligand was proposed to accelerate the migratory insertion process considerably, delivering a broad substrate scope.

Electrochemical NiH-Catalyzed C(sp3)-C(sp3) Coupling of Alkyl Halides and Alkyl Alkenes.

Herein, an electrochemically driven NiH-catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp3-Csp3 bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched product. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late-stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp3-carbon-halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation.

Electrochemical NiH‐Catalyzed C(sp3)−C(sp3) Coupling of Alkyl Halides and Alkyl Alkenes

AbstractHerein, an electrochemically driven NiH‐catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp3−Csp3 bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched products. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late‐stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp3‐carbon‐halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation.

Co‐Catalyzed Reductive Cross‐Couplings of Csp3−S with Callyl−O Electrophiles to form Csp3−Csp3 Bonds

AbstractCross‐electrophilic coupling of various benzyl sulfonium salts with Callyl−O electrophiles is described using a simple Co−Mn catalytic system. This catalytic system is able to activate both the stable Csp3−S bond of sulfonium salts and the Csp3−O bond of allylic acetate or ether under mild reaction conditions to form various functionalized alkyl olefinic compounds. Allyl methyl ethers were employed for the first time in transition metal‐catalyzed cross‐electrophilic coupling to build Csp3−Csp3 bonds. Preliminary mechanistic studies suggested the involvement of benzyl radicals generated from C−S bond cleavage through a single electron transfer.

KOtBu‐Mediated Regioselective Hydroxymethylation of Thiazoles and Benzothiazoles: Synthesis of Biologically Active Heteroaromatic Compounds

AbstractWe present a transition metal‐free direct C‐2 hydroxymethylation of thiazoles using ketones in the presence of KOtBu, leading to the synthesis of thiazole‐2‐diarylcarbinols. The regioselective deprotonation promotes the Csp2−Csp3 bond formation, resulting in the creation of a quaternary centre. The method offers a complementary strategy to traditional cross‐coupling technologies utilizing azole halides and organometallic reagents, thereby expanding the substrate scope. Furthermore, benzothiazoles exhibit compatibility under the mild reaction conditions. Moreover, this method enables the synthesis of thiazolyl diarylcarbinols and bioactive compounds on a multigram scale.

Iron‐Catalyzed Oxidative C−C Bond Cleavage of Unstrained Tertiary Alkyl Aromatics to Arylketones

AbstractWe present here an iron‐catalyzed oxidative Csp3−Csp3 bond cleavage of unstrained tertiary alkyl aromatics to provide a range of synthetically useful arylketones even with H2O2 as the oxidant. This method is operationally simple, scalable, and eco‐friendly, as well as suitable for the late‐stage oxidation of complex molecules bearing hydroxy groups, making it a valuable tool in organic synthesis.

Back Cover

This cover picture shows a new electrophotocatalytic intermolecular reductive 1,2‐diarylation of alkenes with aryl halides and cyanoaromatics. Upon use of a synergistic cathodic reduction and visible‐light photoredox catalysis, a magpie bridge (two new Csp3–Csp2 bonds) was built for the Niulang and the Zhinyu to meet on the Chinese Valentine's Day (Big hugs among multiple reaction components to enable alkene intermolecular reductive 1,2‐diarylation). This method features broad substrate scope, excellent functional group compatibility, and excellent selectivity, and provides a conceptually novel electrophotocatalytic alkene difuncrionalization strategy that consists of undivided cell and divided cell methodologies for highly valuable transformations of alkenes. More details are discussed in the article by Li et al. on page 1921—1930.image

Enantioselective Intramolecular Decarboxylative C-H Bond Func-tionalization of Quinazolinones with Amino Acids by Visible Light Photoredox Catalysis.

The direct visible light-mediated intramolecular decarboxylative C-H functionalization of Csp2 -H bond adjacent to the nitrogen of a heteroarene has been achieved by iridium-catalyzed photodecarboxylative radical cyclization. This method offers rapid entry to the synthesis of quinazolinone scaffolds from easily accessible starting materials. The newly developed protocol is mild, operationally simple, oxidant free and general. The utility of this unique Csp3 -Csp2 bond forming reaction has been demonstrated in the syntheses of Circumdatin, Sclerotigenine and Benzomalvin A class of quinazolinone natural products and their congeners. The present work represents an interesting example of use of memory of chirality in decarboxylative C-C bond forming enantioselective photoredox reaction.

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

Mechanistic Studies on Programmed C―O/C―H Activation with Valence‐Adjusted Ti‐Complexes

Comprehensive SummaryTwo‐electron reduction of [N2NBn]TiIVCl2 (3) gave a highly reactive [N2N]TiII species, which underwent C—O bond activation of THF (tetrahydrofuran) to generate [N2NBn]TiIV[O(CH2)4] (4) through oxidative addition. The resulted TiIV–Csp3 bond in oxametallacyclohexane was tantamount to the elaborately‐designed Ti‐alkyl complexes, competent to activate intramolecular Csp2–H bond, forming ortho‐cyclometalated complex [N2NCH2C6H4]TiIV(OnBu) (5). Key intermediates were isolated and fully characterized by X‐ray crystallography. Mechanistic studies revealed that the oxidative addition of C—O bond took place at TiII‐center via a radical intermediate, while a Csp2–H bond activation proceeded by σ‐bond metathesis with a kitelike four‐centered TiIV‐transition state.

Photoinduced α‐Alkylation of Tetrahydroisoquinolines with Organoboron Reagent Enabled by Organic Photocatalyst

AbstractWe describe an efficient method for α‐functionalization of N‐aryl‐tetrahydroisoquinolines under visible‐light‐irradiation catalyzed by organic photocatalyst. This protocol provides a concise and environmental approach for the rapid allylation and benzylation of N‐aryl‐tetrahydroisoquinolines, and shows broad substrate scope. Stable organoboron reagents have shown their ability in the construction of challenging Csp3−Csp3 bond. The load of the photocatalyst is low and the oxidant is inexpensive and less toxic.

Alkaline Transition Metal‐Free Oxidative Coupling of Benzylic and Quasi Benzylic sp3 Bonds with O2

AbstractAn in‐situ strategy is reported for the transition‐metal‐free oxidation of a benzylic H‐pair to perform Csp3−Csp3 bond formation. This study used sixteen benzylic and quasi benzylic reactants of primary and secondary alkyl aryl compounds, e. g., toluene, pyridine, and quinoline derivatives, to perform an oxidative coupling reaction via convenient air oxygen (O2) and MeOH‐KOH solution with a yield of 0–98 %. We now report using an in‐situ green transition‐metal‐free oxidative coupling strategy for C−C bond formation. In other attempts, metal‐catalyzed oxidation of the benzylic sp3 C−H bond of the methylquinoline has been done to perform the sp3 functionalization reaction. The reaction of 2‐methylqunioline with phenylacetylene in the presence of CuCl catalyst completed to isoxazole linkage product.

Electrochemically enhanced deoxygenative cross-coupling of aryl ketones with heteroarenes through in situ generated benzyl carbocations.

Triflic acids/silanes as cooperative reductants enable the convenient transformation of CO bonds through a multistep reaction pathway in one pot. Electrolysis of the acidic reaction mixture significantly improved carbonyl reduction and thus facilitated the generation of benzyl carbocations, which show high reactivity towards electron-rich heteroarenes for C-C bond formation.

Stereodivergent Construction of Csp3 -Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis.

Synergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3 -Csp3 bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3 -Csp3 coupling reactions involving stabilized nucleophiles remain challenging because of the competing single-catalysis pathway. Herein, we report a synergistic palladium/phase-transfer catalyst system that enables diastereodivergent Csp3 -Csp3 coupling reactions of 1,3-dienes with stabilized nucleophile oxindoles. Both the syn and anti coupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio- and diastereoselectivities. Non-covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Photoexcited Enzymes for Asymmetric Csp3 -Csp3 Cross-Electrophile Couplings.

Enzymes have several advantages over conventional catalysts for organic synthesis. Over the last two decades, much effort has been made to further extend the scope of biocatalytic reactions available to synthetic chemists, particularly by expanding the repertoire of enzymes for abiological transformations. In this regard, exciting new developments in the area of photobiocatalysis enable now the introduction of non-natural reactivity in enzymes to solve long-standing synthetic challenges. A recently described example from the Hyster group demonstrates in an unprecedented way how the combination of photochemistry with enzyme catalysis empowers the catalytic asymmetric construction of Csp3 -Csp3 bonds with high chemo- and enantioselectivity.