Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation

The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C-H bond functionalization and represents the first application of this C-H activation method to natural product synthesis. Furthermore, a challenging deprotection of a late-stage permethylated lithospermic acid was achieved.     

Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan

A new asymmetric entry of the 1,2-aza-Friedel-Crafts reaction catalyzed by a chiral phosphoric acid is described. The present reaction has provided an atom-economical route to furan-2-ylamine derivatives in a highly enantioselective fashion. The synthetic utility of these products was displayed by oxidative cleavage of the furan ring (aza-Achmatowicz reaction) to form a 1,4-dicarbonyl compound that could be further derivatized to a chiral gamma-butenolid.     

Rhodium-catalyzed alkylation of aromatic azines with alkenes via C-H bond activation

The aromatic azines reacted with terminal alkenes under a rhodium catalyst [RhCl(coe)₂]₂ and Cy₃P to give the alkylated products with good to high isolated yields. The azines bearing H and o-CH₃, p-CH₃ and p-CH₃O groups have high reactivities, but m-CH₃O, p-Cl, p-F exhibit low reactivities.     

Rhodium-catalyzed alkylation of terephthaldialdimine with terminal alkenes via C-H bond activation

Terephthaldialdimine 1a reacted with alkenes to give 2,6-dialkylated products selectively in moderate to high isolated yields. In the case of terephthaldialdimine 1b having a substituent at site 2 in the phenyl ring, the alkylation takes place selectively at site 6 in the phenyl ring. In this alkylation, a meta-substituent affected the reactivity significantly because of the steric hindrance.     

Pd-Catalyzed C-3 functionalization of indolizines via C-H bond cleavage

New transition metal-catalyzed methods for the arylation of indolizines by the direct cleavage of C-H bonds have been developed. A wide range of aryltrifluoroborate salts react with indolizines in the presence of Pd(OAc)(2) catalyst and AgOAc oxidant to give the arylated indolizines in high yields. Both electron-donating and electron-withdrawing groups perform smoothly while bromide and chlorine substituents are tolerated. In addition, the indolizines display similar reactivities in the Pd-catalyzed reaction with 3-phenylpropiolic acid to afford the corresponding C-3 alkynylated indolizines. These methods allow the direct functionalization of indolizines in one step.     

Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation

The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.     

Organocatalytic chemoselective asymmetric N-allylic alkylation of enamides

The first Lewis base-catalysed chemoselective asymmetric N-allylic alkylation of enamides with Morita-Baylis-Hillman carbonates has been developed, which affords multifunctional products in moderate to high enantioselectivity (up to 92% ee).     

Nickel-catalyzed alkenylation and alkylation of fluoroarenes via activation of C-H bond over C-F bond

Nickel/P(c-C(5)H(9))(3) (PCyp(3)) catalyst effects the addition reactions of fluoroarenes across alkynes, 1,3-dienes, and vinylarenes via the activation of C-H bonds over C-F bonds. The acidic C-H bonds located ortho to fluorine are exclusively activated to afford a range of alkenylated and alkylated fluoroarenes.     

Organocatalytic asymmetric allylic carbon-carbon bond formation

Organocatalytic allylic C-C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit gamma-selectivity in the C-C bond forming step. The reactions proceed with up to >99:1 syn:anti ratio for both the alkyl- and aryl nitroalkenes with up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are difficult to access via alternative methods.     

Palladium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzosiloles via enantioselective C-H bond functionalization

A Pd-catalyzed asymmetric synthesis of Si-stereogenic dibenzosiloles is developed through enantioselective C-H bond functionalization of prochiral 2-(arylsilyl)aryl triflates. High chemo- and enantioselectivities are achieved by employing a Josiphos-type ligand under mild conditions.     

Cobalt-catalyzed arylation of azole heteroarenes via direct C-H bond functionalization

[reaction: see text] We herein report a new cobalt-catalyzed method for arylation of azole heteroarenes, including thiazole, oxazole, imidazole, benzothiazole, benzoxazole, and benzimidazole. The direct arylation of thiazole and oxazole was achieved both with iodo- and bromoarenes as the aryl donors in the presence of cobalt catalyst [Co(OAc)(2)/IMes] and cesium carbonate, while imidazole required the use of zinc oxide as the base. A complete reversal of arylation from C-5 to C-2 was accomplished using the bimetallic Co/Cu/IMes system. A direct comparison of the new cobalt method and the previously developed palladium protocol revealed significant differences, in terms of both chemical yield and selectivity.     

Palladium catalyzed alkylation of indole via aliphatic C-H bond activation of tertiary amine

Alkylation of indoles has been achieved via Pd-catalyzed aliphatic C-H bond activation of tertiary amine coupling with indole followed by C-N bond cleavage and subsequent addition of indole. This method involves the migration of alkane chain from tertiary amine to indole.     

Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C-H bond functionalization

A novel protocol for nickel-catalyzed direct sp(2) C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach provides new access to a variety of alkylated N-aromatic heterocycles which are potentially of great importance in medicinal chemistry.     

Palladium-catalysed asymmetric arylation of tert-cyclobutanols via enantioselective C-C bond cleavage

Palladium-catalysed arylation of tert-cyclobutanols with aryl bromide involving enantioselective C-C bond cleavage affords chiral ketones with moderate to good enantioselectivity.     

Organocatalytic asymmetric allylic alkylation of sulfonylimidates with Morita-Baylis-Hillman carbonates

The asymmetric allylic alkylation reaction of sulfonylimidates with various Morita-Baylis-Hillman (MBH) carbonates was accomplished by the catalysis of commercially available cinchona alkaloids catalyst (DHQD)2AQN.The corresponding allylic alkylation products were obtained in good yields with high stereoselectivities (up to 99% ee,89:11 dr).     

Organocatalytic asymmetric direct alpha-alkynylation of cyclic beta-ketoesters

The first organocatalytic enantioselective direct alpha-alkynylation of beta-ketoesters and 3-acyl oxindoles is described. It is demonstrated that activated beta-halo-alkynes undergo nucleophilic acetylenic substitution catalyzed by chiral phase-transfer compounds to afford the alkynylated products in high yields and excellent enantioselectivities. The potential of the reaction is first demonstrated for various alkynylating reagents having chloride and bromide as the leaving groups and substituents such as allyl and alkyl esters, amides, ketones, and sulfones. These reactions proceed with 74-99% yield and 88-97% ee. Then the scope in nucleophile is demonstrated for a large number of cyclic beta-ketoesters with various ring-sizes and for oxindoles as well. The corresponding optically active products are formed in high yields and with enantioselectivities up to 98% ee. The procedure allows for the stereocontrolled attachment of an ethynyl unit in the alpha-position to the carbonyl compound by facile removal of the activating group, and this has been demonstrated for a number of the optically active allyl esters. Furthermore, the synthesis of optically active 1,4-enynes is also shown. The isolation and characterization by X-ray analysis of the catalyst with p-nitrophenolate as the counterion allowed us to propose a model of the catalyst-substrate intermediate which might account for the observed enantioselectivity of the organocatalytic enantioselective alpha-alkynylation reaction. Furthermore, it is suggested that this intermediate is also the reactive species for a number of other electrophiles adding to beta-ketoesters giving enantioselectivities in the range of 90-98% ee.     

Organocatalytic direct asymmetric aldol reactions in water

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol products in excellent yield with high enantiomeric excess, even when only an equal molar ratio of the donor and acceptor was used. These results reveal an effective design strategy for the development of aqueous organocatalytic systems.     

Palladium-catalyzed C-N bond formation via direct C-H bond functionalization. Recent developments in heterocyclic synthesis

The formation of carbon-nitrogen bonds by reaction between a nitrogen atom and an unactivated carbon-hydrogen bond is a highly atom-economical process that attracted the attention of the chemists in the last two decades. The widely useful amination and hydroamination reactions, which furnish acyclic or cyclic products, give access to various nitrogen-containing basic and fine chemicals. This review highlights recent progress in the development of palladium-catalyzed reactions that occur by direct functionalization of simple carbon-hydrogen bonds to give heterocyclic products. Pd(0)- and Pd(II)-catalyzed reactions are described separately, emphasizing the different behavior of the metal in these two oxidation states.     

Ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes via regioselective C-H bond cleavage

The ruthenium-catalyzed oxidative vinylation of thiophene-2-carboxylic acids with alkenes efficiently proceeds through directed C-H bond cleavage to give the corresponding 3-vinylated products. Similarly, benzothiophene-, benzofuran-, pyrrole-, and indolecarboxylic acids also undergo regioselective vinylation.