Propargylic Substitution Reactions Research Articles

Ruthenium-Catalyzed Enantioselective Propargylic Phosphinylation of Propargylic Alcohols with Phosphine Oxides.

The development of transition metal-catalyzed enantioselective propargylic substitution reactions has gained much progress in recent years, however, no successful example with phosphorus-centered nucleophiles has yet been reported until now. Herein, we report the first successful example of ruthenium-catalyzed enantioselective propargylic substitution reactions of propargylic alcohols with diarylphosphine oxides as phosphorus-centered nucleophiles. This synthetic approach provides a new method to prepare chiral phosphorus-containing organic compounds.

Ruthenium‐Catalyzed Enantioselective Propargylic Phosphinylation of Propargylic Alcohols with Phosphine Oxides

AbstractThe development of transition metal‐catalyzed enantioselective propargylic substitution reactions has gained much progress in recent years, however, no successful example with phosphorus‐centered nucleophiles has yet been reported until now. Herein, we report the first successful example of ruthenium‐catalyzed enantioselective propargylic substitution reactions of propargylic alcohols with diarylphosphine oxides as phosphorus‐centered nucleophiles. This synthetic approach provides a new method to prepare chiral phosphorus‐containing organic compounds.

Development of Asymmetric Propargylic Substitution Reactions Using Transition Metal Catalysts

This highlight review overviews our recent advances on enantioselective propargylic substitution reactions catalyzed by transition metal complexes including cooperative and hybrid catalysts for the last 15 years.

Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (−)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (−)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile.

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols.

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp3 -hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.

Asymmetric O-propargylation of secondary aliphatic alcohols

The asymmetric O-alkylation of secondary aliphatic alcohols remains a substantial challenge in chemistry. Such a challenge largely stems from the steric demand of each reactant, in addition to the relatively low nucleophilicity of alcohols. Here, we report the development of a base-free, Cu-catalysed propargylic substitution reaction that enables the efficient, asymmetric O-propargylation of secondary aliphatic alcohols. Mechanistic studies implied key factors to slow down the undesired decomposition process of electrophiles in this reaction, which opened up the possibility of using secondary aliphatic alcohols as nucleophilic substrates. This asymmetric O-alkylation reaction proceeds under almost neutral conditions, tolerates a broad scope of functional groups and shows remarkable chemoselectivities. This method is amenable to the modification of natural products and commercial drugs. The products obtained could be readily elaborated to various classes of enantioenriched α,α′-disubstituted ethers that are difficult to access by other methods. The asymmetric O-alkylation of alcohols is a useful route to chiral ethers, but aliphatic secondary alcohols have proven to be difficult substrates. Here the authors report a method to achieve this by developing conditions to avoid the decomposition of the alkylating agent.

Diastereo- and Enantioselective Synthesis of Quaternary α-Amino Acid Precursors by Copper-Catalyzed Propargylation.

A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.

Copper-catalysed enantioselective intramolecular etherification of propargylic esters: synthetic approach to chiral isochromans.

Enantioselective synthesis of chiral isochromans bearing a terminal alkyne moiety has been accomplished by copper-catalysed enantioselective intramolecular propargylic substitution reactions of propargylic esters with alcoholic nucleophiles. This method represents the first successful example which directly introduced a terminal alkyne group into chiral isochromans.

Diastereo‐ and Enantioselective Propargylation of 5H‐Thiazol‐4‐ones and 5H‐Oxazol‐4‐ones as Enabled by Cu/Zn and Cu/Ti Catalysis

AbstractReported is the asymmetric propargylic substitution (APS) reaction of 5H‐thiazol‐4‐ones using a Cu/Zn dual metal catalytic system and the APS reaction of 5H‐oxazol‐4‐ones using a Cu/Ti catalytic system. These reactions furnish functional‐group‐rich, terminal‐alkyne‐containing products with two vicinal stereocenters in high yields and with good to excellent diastereo‐ and enantioselectivities. This study demonstrates the use of dual metal catalytic systems as a viable approach to improve the selectivity profiles of the copper‐catalyzed APS reactions.

Diastereo- and Enantioselective Propargylation of 5H-Thiazol-4-ones and 5H-Oxazol-4-ones as Enabled by Cu/Zn and Cu/Ti Catalysis.

Reported is the asymmetric propargylic substitution (APS) reaction of 5H-thiazol-4-ones using a Cu/Zn dual metal catalytic system and the APS reaction of 5H-oxazol-4-ones using a Cu/Ti catalytic system. These reactions furnish functional-group-rich, terminal-alkyne-containing products with two vicinal stereocenters in high yields and with good to excellent diastereo- and enantioselectivities. This study demonstrates the use of dual metal catalytic systems as a viable approach to improve the selectivity profiles of the copper-catalyzed APS reactions.

Copper- and Borinic Acid-catalyzed Propargylic Etherification of Propargylic Carbonates with Benzyl Alcohols

Propargylic substitution reactions have offered useful synthetic methods because further transformations based on the alkyne moiety in the propargylic substituted products was readily achieved to construct more complex organic compounds. A large number of works have been devoted to enantioselective propargylic substitution reactions with a variety of nucleophiles. However, successful examples of the use of alcohols as nucleophiles have been quite limited until now. To achieve utilization of aliphatic alcohols, herein we report the use of combined catalysis of a copper-pybox complex and a borinic acid. In this catalytic system, aliphatic alcohols such as benzyl alcohol derivatives were successfully applied to afford the corresponding propargylic etherified products in good yields with high enantioselectivities.

Transition-Metal-Free Decarboxylative Propargylic Substitution/Cyclization with either Azolium Enolates or Acyl Anions.

Presented herein is an unprecedented transition-metal-free propargylic substitution reaction with either azolium enolates or acyl anions, which are generated from aldehydes under N-heterocyclic carbene catalysis. This new catalytic activation operates on readily available cyclic propargylic carbamates through decarboxylation, and generates reactive allene intermediates that can undergo divergent cyclization pathways to deliver skeletally diverse polycyclic compounds with high levels of efficiency and excellent enantioselectivities.

Transition‐Metal‐Free Decarboxylative Propargylic Substitution/Cyclization with either Azolium Enolates or Acyl Anions

AbstractPresented herein is an unprecedented transition‐metal‐free propargylic substitution reaction with either azolium enolates or acyl anions, which are generated from aldehydes under N‐heterocyclic carbene catalysis. This new catalytic activation operates on readily available cyclic propargylic carbamates through decarboxylation, and generates reactive allene intermediates that can undergo divergent cyclization pathways to deliver skeletally diverse polycyclic compounds with high levels of efficiency and excellent enantioselectivities.

Copper‐Catalyzed Enantioselective Synthesis of β‐Amino Alcohols Featuring Tetrasubstituted Tertiary Carbons

AbstractHere we report a copper‐catalyzed asymmetric propargylic substitution reaction to prepare tetrasubstituted β‐amino‐β‐ethynyl alcohols in high yields and with enantiomeric ratio (er) up to 94:6. This transformation generates tetrasubstituted tertiary carbons by utilizing stable cyclic carbonates and amines as substrates, economical copper catalysts, and easily accessible ligands.magnified image

Mechanism and reactivity of catalytic propargylic substitution reactions via metal–allenylidene intermediates: a theoretical perspective

The mechanism and reactivity of transition metal-catalyzed propargylic substitution reactions are summarized from a theoretical point of view.

Scope and advances in the catalytic propargylic substitution reaction

Nucleophilic displacement of the propargylic alcohol is one of the sought-after methods in the current scenario. The highly nucleophilic alkyne functional moiety along with its considerably acidic terminal hydrogen atom allows the propargylic unit to play a crucial role in organic synthesis by offering a handle for further synthetic transformations. Until 2000, the most fundamental propargylic substitution reaction was the Nicolas reaction, a multi-step transformation, developed in 1972, which involved cobalt as a stoichiometric promoter. Therefore, the direct catalytic substitution of propargylic alcohols was a highly desirable method for development. The pioneering work on the Ru-catalyzed propargylic substitution reaction in 2000 encouraged many researchers to develop several novel catalytic propargylic substitution reactions, which have made rapid progress since then. The purpose of this review is to emphasise the involvement of diverse types of Lewis acid, transition metal and Brønsted acid catalysts in the propargylic substitution reaction and provide an updated summary of the recent developments in this field. The selected examples presented here are the most significant and relevant ones and we believe that this will help the readers to comprehend the scope of the propargylic substitution reaction with diverse types of catalysts and will envisage the scientific community for the future developments in this field.

Ruthenium complexes of the general formula [RuCl2(PHOX)2] as precatalysts in propargylic substitution reactions

After activation by chloride abstraction utilizing NaBArF as an activator (BArF=tetrakis(3,5-bis(trifluoromethyl)phenyl)borate), a complex of the general formula [RuCl2(PHOX)2] was utilized as a catalyst in propargylic substitution reactions, where PHOX is a phosphinooxazoline ligand. Oxygen and nitrogen-centered nucleophiles could be employed in the substitution of a propargylic acetate to obtain the corresponding propargylic substitution products in 87% to 9% isolated yields (45°C, 16h reaction time, toluene solvent, 1–2mol% catalyst loading, 1–2mol% activator).

Copper-catalyzed propargylation of diborylmethane.

A Cu/PPh3-catalyzed propargylic substitution reaction of diborylmethane is reported. Different substituted propargyl electrophiles can be employed in this reaction, and various synthetic valuable functional groups can be tolerated. Di-deuterated diborylmethane can also be used under these conditions and generates α-deuterated alkylboronic esters in good yield.

ChemInform Abstract: Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles.

The first copper-catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.

Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles

AbstractThe first copper‐catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.