Quaternary Carbon Centers Research Articles

Direct Vinylation of Activated Methines by a Vinylsulfonium Salt

Abstract: Vinylation of activated methines is a synthetically useful and challenging transformation. Traditional methods for this transformation always encounter multiple steps, limited generality and/or handling gaseous substrates. Herein, we report by using diphenyl(vinyl)sulfonium triflate as a vinylation component, a one-step direct vinylation of activated methines can be realized under mild conditions. This reaction, compatible with several kinds of activated methines, can lead to the construction of vinylated quaternary carbon centers concisely.

Synthesis of β-Ketonitriles via N-Heterocyclic-Carbene-Catalyzed Radical Coupling of Aldehydes and Azobis(isobutyronitrile)

Herein, an NHC (N-heterocyclic carbene)-catalyzed radical coupling reaction between aldehydes and azobis(isobutyronitrile) (AIBN) has been developed. This method provides an efficient and convenient approach for the synthesis of β-ketonitriles containing a quaternary carbon center (31 examples, up to >99% yield) utilizing commercially available substrates. This protocol features broad substrate scope, good functional group tolerance, and high efficiency under metal-free and mild reaction conditions.

Asymmetric redox benzylation of enals enabled by NHC/Ru cooperative catalysis

The development of general methods for asymmetric benzylation of prochiral carbon nucleophiles remains a challenge in organic synthesis. The merging of ruthenium catalysis and N-heterocyclic carbene (NHC) catalysis for asymmetric redox benzylation of enals has been achieved, which opens up strategic opportunities for the asymmetric benzylation reactions. A wide range of 3,3'-disubstituted oxindoles with a stereogenic quaternary carbon center widely existing in natural products and biologically interesting molecules is successfully obtained with excellent enantioselectivities [up to 99% enantiomeric excess (ee)]. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of oxindole skeletons. Furthermore, the linear correlation between ee values of NHC precatalyst and the product elucidated the independent catalytic cycle of either the NHC catalyst or the ruthenium complex.

Divergent Synthesis of Highly Substituted Tetrahydroquinolines and Cyclopentenes via Lewis Base Catalyzed Switchable [4 + 2] and [3 + 2] Annulations of MBH-Carbonates with Activated Olefins

A highly selective and divergent synthesis which enabled access to various complex compounds is highly attractive in organic synthesis and medicinal chemistry. Herein, we developed an effective method for divergent synthesis of highly substituted tetrahydroquinolines via Lewis base catalyzed switchable annulations of Morita-Baylis-Hillman carbonates with activated olefins. The reaction displayed switchable [4 + 2] or [3 + 2] annulations via catalyst or substrate control, providing a diverse range of architectures which contained highly substituted tetrahydroquinolines or cyclopentenes with three contiguous stereocenters bearing a quaternary carbon center in high yields with excellent diastereoselectivities and regioselectivities. Furthermore, synthetic utility of this strategy was further highlighted by gram-scale experiments and simple transformations of the products.

Synthesizing Complex Quaternary Carbons by the Sequence-Regulated Additions of tert-Alkyl Radicals to Two Different Olefins.

We report the sequence-regulated radical additions of tert-alkyl radicals to two different olefins controlled by a Cu catalyst, which we term the "atom-transfer radical addition-substitution" reaction. The reactions of α-bromocarbonyl compounds, such as tert-alkyl radical sources, with methacrylates and styrenes occur in a sequence-regulated manner to give the corresponding three-component product possessing skipped quaternary carbon centers. Our method provides new insight into how to control the reactivities of tert-alkyl radicals during the synthesis of regulated aliphatic chains.

Metal‐Free Synthesis of Pyrimidine and Naphthoquinone‐Fused Pyrroles from Arylglyoxal‐Based Domino Reactions

AbstractHerein we report acid mediated two and three‐component domino reactions of cyclic enamines such as 2‐amino‐1,4‐naphthoquinone, and 6‐amino‐1,3‐dimethyluracil with arylglyoxals for the synthesis of diverse fused pyrroles. The two‐component reaction of arylglyoxal and 2‐amino‐1,4‐naphthoquinone in the acetic acid medium provided substituted naphthoquinone‐fused pyrroles tethered with hydroxyl and aryl substituents. On the other hand, under similar reaction conditions, the reaction of phenylglyoxal with 6‐amino‐1,3‐dimethyluracil provided an unusual bipyrrolopyrimidine with a quaternary carbon center following a domino reaction involving the formation of five new sigma bonds in one‐pot. Interestingly, the reaction of arylglyoxals with 6‐amino‐1,3‐dimethyluracil in ethanol medium in the presence of 10‐mol% PTSA provided a three‐component product having pyrimidine fused pyrrole linked with 6‐aminouracil moiety. We have also developed a three‐component reaction of 2‐amino‐1,4‐naphthoquinone, arylglyoxals, and 4‐hydroxy‐1‐methylquinolin‐2(1H)‐one for the synthesis of naphthoquinone‐fused pyrroles linked with hydroxyquinoline derivatives.

Rhodium(II)-Catalyzed Desaturative [3+2] Tandem Cyclization of Arylcycloalkanes with β-Dicarbonyls.

Synthetically important scaffolds, fused tricyclic frameworks containing a 2,3-cyclo[b]dihydrofuran unit, play a crucial role in drug discovery. In this study, we demonstrate that rhodium(II)/N-fluorobenzenesulfonimide can catalyze the in situ generation of highly reactive alkene intermediates from commonly accessible alkanes, which undergo intermolecular [3+2] tandem cyclization with the simultaneously generated β-dicarbonyl radical to synthesize a series of fused tricyclic frameworks containing a 2,3-cyclo[b]dihydrofuran unit with a quaternary carbon center.

Pd-catalyzed cascade cyclization of allenylethylene carbonates and indandiones: Synthesis of tetracyclic dihydrocyclopentaindenofuranone derivatives

A palladium-catalyzed cascade cyclization of allenylethylene carbonates with 1,3-indandiones was developed, providing biologically interesting tetracyclic dihydrocyclopentaindenofuranone derivatives having three contiguous quaternary carbon centers in moderate to high yields with excellent diastereoselectivities. In this reaction, the allene moiety was fully fused into the cyclopentene ring.

Catalytic Asymmetric Friedel–Crafts Alkylation of Indole via In Situ Generated Indol‐2‐one

AbstractAn asymmetric Friedel–Crafts alkylation of indole with in situ generated indol‐2‐one from functionalized 3‐bromooxinidole catalyzed by chiral N,N’‐dioxide/Ni(BF4)2 has been developed. This protocol provides an efficient route to stereoselective construction of a series of 3‐substituted 3’‐indolyloxindoles bearing a quaternary carbon center in excellent yields and enantioselectivities (up to 99 % ee). In addition, the conversion of the resulted 3‐substituted 3’‐indolyloxindole to the key intermediate for the formal synthesis of (+)‐folicanthine was also demonstrated.

Construction of CF<sub>3</sub>-containing Tetrasubstituted Carbon Frameworks by Way of <i>p</i>-Quinone Methides

Development of a new synthetic method for the construction of quaternary carbon centers with a trifluoromethyl group was realized by way of smooth 1,6-addition of various active methylene compounds to highly reactive δ-trifluoromethylated p-quinone methides generated in situ only with a catalytic amount of a base. A variety of aldehydes also behaved as nice nucleophiles with the aid of a NHC catalyst and the resultant products were further converted to such congested structures as the consecutive quaternary-tetrasubstituted carbons in a highly stereoselective manner. This method was also extended for the incorporation of heteroatoms like nitrogen, oxygen, and sulfur atoms.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A

AbstractKopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure‐unit‐based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza‐Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all‐carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α‐hydroxyketone moiety, and a bioinspired retro‐Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A.

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Transition-Metal-Free Dehydrogenative Cyclization via α-Csp3–H Activation of Ethers and Thioethers

AbstractWe report herein the tetraethylammonium bromide catalyzed intramolecular oxidative cyclization of O- or S-alkylated salicylic or thiosalicylic acid derivatives to access 4H-benzo[d][1,3]dioxin-4-ones or 4H-benzo[d][1,3]oxathiin-4-ones, respectively. The oxidative cyclization of salicylic acid derivatives proceeds through a radical pathway at 110 °C. In contrast, the cyclization of the thiosalicylic acids proceeds smoothly at room temperature via an ionic pathway. Notably, the overall reactions are fast, completed within short reaction times, furnishing the products in high yields and with smooth formation of quaternary carbon centers.

Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals

Transition metal-catalyzed enantioselective free radical substitution reactions have recently attracted attention as convenient and important building tools in synthetic chemistry, although construction of stereogenic carbon centers at the propargylic position of propargylic alcohols by reactions with free radicals remains unchallenged. Here we present a strategy to control enantioselective propargylic substitution reactions with alkyl radicals under photoredox conditions by applying dual photoredox and diruthenium catalytic system, where the photoredox catalyst generates alkyl radicals from 4-alkyl-1,4-dihydropyridines, and the diruthenium core with a chiral ligand traps propargylic alcohols and alkyl radicals to guide enantioselective alkylation at the propargylic position, leading to high yields of propargylic alkylated products containing a quaternary stereogenic carbon center at the propargylic position with a high enantioselectivity. The result described in this paper provides the successful example of transition metal-catalyzed enantioselective propargylic substitution reactions with free alkyl radicals.

Nickel-Catalyzed Negishi Cross-Coupling of Alkyl Halides, Including Unactivated Tertiary Halides, with a Boron-Stabilized Organozinc Reagent.

Nickel-catalyzed cross-coupling of unactivated tertiary alkyl electrophiles with alkylmetal reagents is still a challenge. We report herein a nickel-catalyzed Negishi cross-coupling of alkyl halides, including unactivated tertiary halides, with boron-stabilized organozinc reagent BpinCH2ZnI, yielding versatile organoboron products with high functional-group tolerance. Importantly, the Bpin group was found to be indispensable for accessing the quaternary carbon center. The synthetic practicability of the prepared quaternary organoboronates was demonstrated by their conversion to other useful compounds.

Photoredox-Enabled Dearomatization of Protected Anilines: Access to Cyclohexadienone Imines with Contiguous Quaternary Centers

A photoredox-enabled alkylative dearomatization of protected anilines is reported. Under Ir catalysis and light irradiation, an N-carbamoyl-protected aniline and an α-bromocarbonyl compound could be simultaneously activated, and the two resulting radical species then recombine with each other to afford a dearomatized cyclohexadienone imine as the major product. A series of such imines with contiguous quaternary carbon centers were prepared, which can be further converted into cyclohexadienones, cyclohexadienols, and cyclohexyl amines.

Nickel-Catalyzed Direct Substitution of Allylic Alcohols with Nitriles: A General Tool for the Construction of Acyclic C2-Tertiary or Quaternary Benzyl Nitriles

A nickel-catalyzed direct reaction of allylic alcohols with benzyl nitrile derivatives has been developed. The method provides an efficient route for the synthesis of nitriles bearing an α-tertiary or quaternary carbon center in good to excellent yields with high regioselectivity, wide substrate scope, and functional group compatibility. BSA was identified as the effective additive for facilitating the coupling process mainly for alkyl allylic alcohols.

Generation of Allylmagnesium Reagents by Hydromagnesiation of 2-Aryl-1,3-dienes.

A protocol for the generation of allylmagnesium reagents from 2-aryl-1,3-dienes was developed using magnesium hydride (MgH2 ) that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2 ) in tetrahydrofuran (THF). Downstream functionalization of the resulting allylmagnesium reagents with carbonyl compounds or alkyl (pseudo)halides delivers branched products having an allylic quaternary carbon center, whereas that with chlorosilanes resulted in formation of linear allylsilanes in regio and stereoselective manners. Further derivatizations of the homoallylic alcohols and allylsilanes were also demonstrated.

Generation of Allylmagnesium Reagents by Hydromagnesiation of 2‐Aryl‐1,3‐dienes

AbstractA protocol for the generation of allylmagnesium reagents from 2‐aryl‐1,3‐dienes was developed using magnesium hydride (MgH2) that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2) in tetrahydrofuran (THF). Downstream functionalization of the resulting allylmagnesium reagents with carbonyl compounds or alkyl (pseudo)halides delivers branched products having an allylic quaternary carbon center, whereas that with chlorosilanes resulted in formation of linear allylsilanes in regio and stereoselective manners. Further derivatizations of the homoallylic alcohols and allylsilanes were also demonstrated.

β‐ and γ‐C(sp3)−H Heteroarylation of Free Carboxylic Acids: A Modular Synthetic Platform for Diverse Quaternary Carbon Centers

AbstractPdII‐catalyzed C(sp3)−H activation of free carboxylic acids represents a significant advance from conventional cyclopalladation initiated reactions. However, developing a modular synthetic platform for diverse quaternary and tertiary carbon centers based on this reactivity, two challenges remain to be addressed: mono‐selectivity in each consecutive C−H functionalization step; compatibility with heteroatoms. While the exclusive mono‐selectivity was achieved by β‐lactonization/nucleophilic attack, the latter limitation remains to be overcome. Herein, we report the PdII‐catalyzed β‐ and γ‐C(sp3)−H heteroarylation of free carboxylic acids using pyridine‐pyridone ligands capable of overcoming these limitations. A sequence of three consecutive C(sp3)−H activation reactions of pivalic acid provides an unique platform for constructing diverse quaternary carbon centers containing heteroaryls which could serve as an enabling tool for escaping the flat land in medicinal chemistry.