Tetrasubstituted Alkenes Research Articles

Stereoselective Electrochemical Synthesis of E-Tetrasubstituted Haloalkenyl Chalcogenides.

Herein, we describe an electrochemical method for the synthesis of haloalkenyl chalcogenides from internal alkynes using hydrobromic and hydrochloric acids as halogenating agents, with the sole byproduct being hydrogen gas. This e-halochalcogenation protocol generates electrophilic chalcogenium species under mild conditions in a simple, undivided cell setup, enabling the synthesis of 25 examples of chloro- and bromovinyl selenides and sulfides with yields ranging from 10 % to 94 %, predominantly as the E-isomer. The synthetic utility of the halovinyl chalcogenides was demonstrated through various transformations, yielding densely functionalized tetra-substituted olefins. This underscores the versatility and efficiency of our method in assembling intricate molecular frameworks.

Cobalt-Catalyzed Divergence in C(sp3)-H Functionalization of 9H-Fluorene: A Streamlined Approach Utilizing Alcohols.

Sustainable chemical production demands the creation of innovative catalysts and catalytic technologies. While the development of coherent and robust catalytic systems using earth-abundant transition metals is essential, it remains a significant challenge. Herein, an expedient divergence strategy for tandem dehydrogenative C(sp3)-H alkylation and cyclization reactions of 9H-fluorene using a newly developed N,N-bidentate cobalt catalytic system is developed. This method capitalizes on the use of abundant and readily accessible alcohol. Demonstrating wide-ranging applicability, the catalytic protocol successfully integrated a diverse array of fluorenes and alcohols. This includes benzylic, heteroaromatic, and aliphatic primary and secondary alcohols, amassing a total of 75 distinct examples. When applied to sterically bulky alcohols, the reaction preferentially undergoes alkenylation, yielding a tetrasubstituted olefin as the main product. In the case of diols, the expected outcome is Dual-fluorescence at both terminal positions. This process leads to difluorination, followed by a cyclization step, culminating in the formation of a relatively unprecedented spiro compound. The scalability of this method has been validated through gram-scale synthesis. Control experiments have shed light on the reaction mechanism, indicating that it progresses through an unsaturated intermediate and adheres to the borrowing hydrogen pathway.

Interception and Synthetic Application of Diradical and Diene Forms of Dual-Nature Azabicyclic o-Quinodimethanes Generated by 6π-Azaelectrocyclization.

We demonstrate that 2-alkenylarylaldimines and ketimines undergo thermal 6π-azaelectrocyclization to generate a wide range of azabicyclic o-quinodimethanes (o-QDMs). These o-QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H-atom donor, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o-QDMs by H-atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4+2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o-QDMs can be generated for [4+2] cycloaddition from a wide range of electronically and sterically varied 2-alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc-amine.

Unprecedented synthesis of indole-linked tetra-substituted alkenes by catalyst-free domino reaction

Herein, we report a simple, efficient catalyst-free green domino reaction of indole, arylglyoxal, and cyclic 1,3-dicarbonyls such as barbituric acid derivatives/dimedone at 100oC in dimethylformamide medium in open air condition. In this reaction, one C-C and one C=C bonds have been formed in one-pot without using any additive or metal based reagent. Considering the presence of indole, benzoyl and cyclic 1,3-dicarbonyl moieties in the products, it is expected that they will exhibit interesting medicinal properties. All the synthesized products were characterized by recording FTIR, 1H NMR, 13C NMR, and HRMS. Moreover, a single crystal XRD of compound 4i was recorded to confirm the structure of the product. Operational simplicity, gram-scale synthesis, mild reaction conditions, good yields, and wide substrate scope are the salient features of this methodology.

C−S‐Selektive Stille‐Kupplung zur Synthese stereodefinierter Alkene

AbstractIn dieser Arbeit wird eine Palladium‐katalysierte, hochselektive C−S‐Stille‐Kreuzkupplung zwischen Arylthianthreniumsalzen und tri‐ oder tetrasubstituierten Alkenylstannanen präsentiert. Dabei werden Herausforderungen wie die Kontrolle der Positions‐ und Chemoselektivität durch C−H‐Thianthrenierung und C−S‐Alkenylierung erfolgreich gelöst, wodurch ein nützlicher Zugang zu stereodefinierten tri‐ und tetrasubstituierten Alkenen stereoretentiv ermöglicht wird. Die Palladium‐katalysierte Stille‐Alkenylierung von poly(pseudo)halogenierten Arenen zeigt die privilegierte Fähigkeit, C−S‐ über C−I‐, C−Br‐ und C−Cl‐Bindungen sowie Triflate (C−OTf), Tosylate (C−OTs), Carbamate und Sulfamate unter milden Reaktionsbedingungen zu differenzieren. Sequenzielle und mehrfache Kreuzkupplungen durch selektive C−X‐Funktionalisierung sollten bei zunehmender funktioneller Molekülkomplexität breit einsetzbar sein. Der modulare Einbau von stereospezifischen Alken‐Motiven in Pharmazeutika veranschaulicht die synthetische Anwendung in der Arzneimittelforschung.

C-S-Selective Stille-Coupling Enables Stereodefined Alkene Synthesis.

A palladium-catalyzed highly C-S-selective Stille cross-coupling between aryl thianthrenium salts and tri- or tetrasubstituted alkenyl stannanes is described. Herein, critical challenges including site- and chemoselectivity control are well addressed through C-H thianthrenation and C-S alkenylation, thereby providing an expedient access to stereodefined tri- and tetrasubstituted alkenes in a stereoretentive fashion. Indeed, the palladium-catalyzed Stille-alkenylation of poly(pseudo)halogenated arenes displays privileged capability to differentiate C-S over C-I, C-Br, C-Cl bonds, as well as oxygen-based triflates (C-OTf), tosylates (C-OTs), carbamates and sulfamates under mild reaction conditions. Sequential and multiple cross-couplings via selective C-X functionalization should be widely applicable for increasing functional molecular complexity. Modular installation of stereospecific alkene motifs into pharmaceuticals illustrated the synthetic application of the present protocol in drug discovery.

Interception and Synthetic Application of Diradical and Diene Forms of Dual‐Nature Azabicyclic o‐Quinodimethanes Generated by 6π‐Azaelectrocyclization

AbstractWe demonstrate that 2‐alkenylarylaldimines and ketimines undergo thermal 6π‐azaelectrocyclization to generate a wide range of azabicyclic o‐quinodimethanes (o‐QDMs). These o‐QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H‐atom donor, 2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o‐QDMs by H‐atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4+2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o‐QDMs can be generated for [4+2] cycloaddition from a wide range of electronically and sterically varied 2‐alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc‐amine.

Regio- and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Regio‐ and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical‐Catalyzed (4+2) Cycloaddition

AbstractPiperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results.

Radical Cation Alkene Functionalization Using Anodic Oxidation

Oxidative functionalization of alkenes is a promising molecular transformation technique, where intramolecular reactions enable the synthesis of saturated heterocycles1), which are often found in natural products and pharmaceuticals. In addition to the widely studied palladium-catalyzed oxidative functionalization of alkenes2), electrochemical3), 4) and photocatalytic5) methods have recently been developed. These one-electron oxidation-based methods have been applied to trisubstituted and tetrasubstituted alkenes with large steric hindrance, which is difficult to achieve with conventional palladium-catalyzed reactions. In many cases, these methods reported previously form rings as neutral radicals under basic conditions. On the other hand, radical cationic cyclization is relatively rare and have not yet been fully discussed. In this study, we developed an alkene oxidative functionalization using electrolysis for radical cationic cyclization.After optimizing the reaction conditions using trisubstituted alkene (1a) as a model substrate, we succeeded in obtaining the target compound (2a) in 90% yield (Scheme 1). In this reaction, a six-membered ring is formed as a byproduct, but the anion species of the supporting salt affects the reaction selectivity, and it was found that a five-membered ring was formed with high selectivity when ClO4- or TfO- were used. Furthermore, using a 1:9 mixture of highly polar CH3CN and low-polar 1,2-DCE as the reaction solvent improved the solubility and conductivity of the supporting salt, resulting in a significant increase in yield. The use of carbon felt, which has a large surface area, as the working electrode also contributed to the yield improvement by suppressing the voltage increase.For sulfonamides (1b-d) with various substituents on the aromatic ring, we were able to obtain five-membered ring compounds (2b-d) in good yields in all cases. In addition to these results, the details of the condition studies and other substrates will be discussed.1) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198.2) McDonald, R. I.; Liu, G.; Stahl, S, S. Chem. Rev. 2011, 111, 2981-3019.3) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2010, 132, 2839–2844.4) Huang, C.; Li, Z.-Y.; Song, J.; Xu, H.-C. Angew. Chem. Int. Ed. 2021, 60, 11237–11241.5) Reed, N. L.; Lutovsky, G. A.; Yoon, T. P. J. Am. Chem. Soc. 2021, 143, 6065-6070. Figure 1

Cobalt-Catalyzed Chemo- and Stereoselective Transfer Semihydrogenation of 1,3-Dienes with Water as a Hydrogen Source.

(Z)-1,2-Disubstituted, trisubstituted, and tetrasubstituted alkenes are not only important units in medicinal chemistry, natural product synthesis, and material science but also useful intermediates in organic synthesis. Development of catalytic stereoselective transformations to access multisubstituted alkenes with various substitution patterns from easily accessible modular starting materials and readily available catalysts is a crucial goal in the field of catalysis. Water is an ideal hydrogen source for catalytic transfer hydrogenation despite of the high difficulty to activate water. Here, we report a cobalt-catalyzed protocol for regio- and stereoselective transfer semihydrogenation of 1,3-dienes to construct a broad scope of (Z)-1,2-disubstituted, (Z)-, (E)-trisubstituted, and tetrasubstituted alkenes in high stereoselectivity with H2O as the hydrogen source. Mechanistic studies revealed that the reactions proceeded through a unique Co(I)/Co(III) cycle and involved a 1,4-cobalt shift process, which is an unprecedented reaction pathway, providing a new platform for modular synthesis of multisubstituted alkenes as well as opportunities for designing novel reaction modes and pushing forward the advancement in organocobalt chemistry.

Solvent-Controlled, Atom-Economic, and Highly Regio- and Stereoselective Halo-Chalcogenations of Ynamides: Green Synthesis of Stereodefined Tetrasubstituted Alkenes Bearing Four Different Functional Groups.

The synthesis of stereodefined tetrasubstituted alkenes bearing four different functional groups is challenging. Herein, we disclose a 100% atom-economic and highly regio- and stereoselective halo-chalcogenations, in particular, chlorosulfenylation, bromosulfenylation, chloroselenation, and bromoselenation, of ynamides in toluene at room temperature under an aerobic atmosphere for the synthesis of a wide variety of stereodefined tetrasubstituted alkenes bearing four different functional groups in excellent yields. Notably, all the reactions are highly efficient and furnished the desired products in excellent yield (average yield >96%) and stereoselectivity (Z/E = 90:10 to >99:1) within a short time (15-30 min). Interestingly, the high (Z)-stereoselectivity (syn-addition) is controlled by the solvent. The transformation does not require any catalyst, oxidizing or reducing reagent, or external energy. The products were obtained pure by evaporating the solvent after the reaction and washing the crude product with either pentane or ethanol (column-chromatography-free protocol). Moreover, the solvent toluene was recovered and reused in subsequent reactions, which makes the protocol highly sustainable. The protocol is efficiently scalable (96% yield) on a gram scale. Notably, the products were synthetically diversified to other new classes of stereodefined tetrasubstituted alkenes. Significantly, the green chemistry metrics of the protocol are found to be excellent.

Synthesis of Z-gem-Cl,CF3-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes.

Stereochemically defined organofluorine compounds are central to drug discovery and development. Here, we present a catalytic cross-metathesis method for the synthesis of Z-trisubstituted olefins that contain a Cl- and a CF3-bound carbon terminus. Notably, the process is stereoselective, which is in contrast to the existing stereoretentive strategies that also involve a trisubstituted olefin as starting material. Reactions are catalyzed by a Mo monoaryloxide pyrrolide alkylidene, involve a trisubstituted alkene and gem-Cl,CF3-substituted alkene, and are fully Z-selective. Catalytic cross-coupling can be used to convert the C-Cl bond of the trisubstituted olefin to C-B, C-D, and different C-C bonds. We elucidate the role of Cl,CF3-disubstituted Mo alkylidenes. Experimental and computational (DFT) data show that in some instances a disubstituted alkylidene is formed and then transformed to a more active complex. In other cases, the Cl,CF3-disubstituted alkylidene is a direct participant in a catalytic cycle. The studies described shed new light on the chemistry of high oxidation-state disubstituted alkylidenes-scarcely investigated entities likely to be pivotal to approaches for stereocontrolled synthesis of tetrasubstituted alkenes through olefin metathesis.

Enantioselective Total Synthesis of (+)‐Propolisbenzofuran B†

Comprehensive SummaryThe first catalytic asymmetric total synthesis of (+)‐propolisbenzofuran B, enabled by a highly enantioselective rhodium‐catalyzed hydrogenation of a tetrasubstituted olefin, was described. Other noteworthy aspects include the construction of the central hydrodibenzo[b,d]furan core through a sequence of Zn(II)‐mediated regioselective benzofuran formation and Dieckmann condensation, as well as C‐H oxidations, involving a visible light‐induced Fe(III)‐catalyzed benzylic C(sp3)‐H oxidation. Additionally, the absolute configuration was confirmed by X‐ray analysis of a carbonate intermediate.

Hydrosilylation of Olefins Activated on Highly Lewis-Acidic Calcium Cation.

The report introduces simple yet highly reactive calcium salt, Ca[Al(ORF)4]2 (RF=C(CF3)3), 1, which effectively catalyses olefin hydrosilylation through an unusual mechanism involving the activation of the alkene molecule. Upon dissolution in o-difluorobenzene (oDFB), 1 forms a highly Lewis acidic [Ca(oDFB)6]2+ complex. Our DFT calculations reveal that fluoride ion affinity is comparable to SbF5. Reactivity tests show that it effectively catalyses the hydrosilylation of olefins with high regioselectivity, also in reactions involving sterically demanding substrates like (iPr)3SiH or tetrasubstituted olefins. Experimental and computational results point to the mechanism where the olefin molecule forms a complex with Ca2+, which significantly facilitates the attack of H-SiR3 on the C=C double bond.

Publisher Correction: Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Publisher Correction: Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Mild Photochemical Reduction of Alkenes and Heterocycles via Thiol-Mediated Formate Activation.

The reduction of alkenes to their respective alkanes is one of the most important transformations in organic chemistry, given the abundance of natural and commercial olefins. Metal-catalyzed hydrogenation is the most common way to reduce alkenes; however, the use of H2 gas in combination with the precious metals required for these conditions can be impractical, dangerous, and expensive. More complex substrates often require extremely high pressures of H2, further emphasizing the safety concerns associated with these hydrogenation reactions. Here we report a safe, cheap, and practical photochemical alkene reduction using a readily available organophotocatalyst, catalytic thiol, and formate. These conditions reduce a variety of di-, tri-, and tetra-substituted alkenes in good yield as well as dearomatize pharmaceutically relevant heterocycles to generate sp3-rich isosteres of benzofurans and indoles. These formal-hydrogenation conditions tolerate a broad range of functionalities that would otherwise be sensitive to typical hydrogenations and are likely to be important for industry applications.

Visible Light-Induced Copper-Catalyzed Regio- and Stereoselective Difluoroalkylthiocyanation of Alkynes.

The first regio- and stereoselective difluoroalkylthiocyanation of alkynes with BrCF2R and KSCN has been disclosed under visible light-induced copper catalysis. The copper complex photosensitizer formed in situ not only promotes the generation of CF2-alkyl radicals but also facilitates the construction of C-SCN bonds, allowing the reaction to proceed smoothly without any additional photocatalysts or radical initiators. Moreover, the challenging internal alkynes can also be transformed to deliver CF2-derived tetrasubstituted olefins with potential applications in agricultural and medicinal chemistry.

Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Cyclolignan synthesis streamlined by enantioselective hydrogenation of tetrasubstituted olefins

Rhodium-Catalyzed Highly Enantioselective Hydroboration of Acyclic Tetrasubstituted Alkenes Directed by an Amide.

Although progress has been made in enantioselective hydroboration of di- and trisubstituted alkenes over the past decades, enantioselective hydroboration of tetrasubstituted alkenes with high diastereo- and enantioselectivities continues as an unmet challenge since the 1950s due to its extremely low reactivity and the difficulties to simultaneously control the regio- and stereoselectivity of a tetrasubstituted alkene. Here, we report highly regio-, diastereo-, and enantioselective catalytic hydroboration of diverse acyclic tetrasubstituted alkenes. The delicate interplay of an electron-rich rhodium complex and coordination-assistance forms a highly adaptive catalyst that effectively overcomes the low reactivity and controls the stereoselectivity. The generality of the catalyst system is exemplified by its efficacy across various tetrasubstituted alkenes with diverse steric and electronic properties.