Bifunctional Ligand Enables Efficient Gold-Catalyzed Hydroalkenylation of Propargylic Alcohol.
ABSTRACT: Using the previously designed biphenyl-2-ylphosphine ligand, featuring a remote tertiary amino group, the first gold-catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general-base catalyst for promoting this novel gold catalysis with good efficiency.
Project description:Inductive perturbations of C-C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C-C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of ?-alkoxy-?,?-unsaturated ketones (up to >50/1 selectivity) via ?-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a ?-phenyl-?-alkoxy-?,?-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.
Project description:A formal, metal-free, [2 + 2 + 2] cycloaddition strategy is described based on a cascade of two pericyclic processes. The first step involves an intramolecular propargylic ene reaction of a 1,6-diyne to generate a vinylallene, which then reacts in an inter- or intramolecular Diels-Alder reaction with an alkenyl or alkynyl dienophile. Reactions involving unsymmetrical alkenyl and alkynyl dienophiles proceed with good to excellent regioselectivity, and the diastereoselectivity in the Diels-Alder step is also high, with endo cycloadducts produced as the exclusive products of the reaction. In the case of alkynyl dienophiles, [4 + 2] cycloaddition initially generates an isotoluene-type intermediate that isomerizes to the isolated aromatic product upon exposure to a catalytic amount of DBU at room temperature. The mechanism of several earlier fully intramolecular related transformations have been shown to involve an analogous process rather than the diradical-mediated pathways proposed previously.
Project description:Gold(I)-chloride-catalyzed synthesis of ?-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated ?-sulfenylated aldehydes and ketones in 60-97% yield. Secondary aliphatic propargylic alcohols generated ?-sulfenylated ketones in yields of 47-71%. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3-position, and that the hydride from the alcohol was transferred to the 2-position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2-position of propargylic alcohol was determined by a low-energy, five-membered cyclic protodeauration transition state instead of the strained, four-membered cyclic transition state found for attack at the 3-position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2-hydride shift, generating the final product of the reaction.
Project description:Gold-catalyzed intermolecular oxidation of carboxylates of primary or secondary propargylic alcohols are realized with excellent regioselectivity, which is ascribed to inductive polarization of the C-C triple bond by the electron-withdrawing carboxy group. The gold carbene intermediates thus generated undergo selective 1,2-acyloxy migration over a 1,2-C-H insertion, and the selectivities could be dramatically improved by the use of a P,S-bidentate ligand, which is proposed to enable the formation of tris-coordinated and hence less electrophilic gold carbene species. ?-Carboxy ?,?-unsaturated ketones/aldehydes can be obtained with fair to excellent yields.
Project description:A general solution for the synthesis of various oxetan-3-ones is developed. This reaction uses readily available propargylic alcohols as substrates and proceeds without the exclusion of moisture or air ("open flask"). Notably, oxetan-3-one, a highly valuable substrate for drug discovery, can be prepared in one step from propargyl alcohol in a fairly good yield. The facile formation of the strained oxetane ring provides strong support for the intermediacy of alpha-oxo gold carbenes. This safe and efficient generation of gold carbenes via intermolecular alkyne oxidation offers a potentially general entry into alpha-oxo metal carbene chemistry without using hazardous diazo ketones.
Project description:The regioselective gold-catalysed hydration of propargylic alcohols to ?-hydroxy ketones can be achieved by diverting the gold-catalysed Meyer-Schuster rearrangement through the addition of a protic additive with a pKa of 7-9 such as p-nitrophenol, boric acid or a boronic acid. This provides an interesting alternative to an aldol reaction when combined with the straightforward addition of an alkyne to an aldehyde or ketone. The gold-catalysed reaction of an electron-deficient, sterically hindered propargylic alcohol with a boronic acid led to the formation of an unusually stable cyclic boron enolate.
Project description:Although chiral allene preparation via formal SN2' nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown. Here, we show that a highly enantioselective synthesis of tetrasubstituted allenes from racemic propargylic alcohols has been realized by organocatalysis with good efficiency (up to 96% yield and 97% ee). The intermolecular C-C and C-S bond formation was achieved efficiently with simultaneous stereocontrol over the axial chirality. Furthermore, an adjacent quaternary stereocenter could also be constructed. Mechanistically, the reaction may involve efficient stereocontrol on the propargylic cation by its chiral counter anion or 1,8-conjugate addition of para-quinone methides. In sharp contrast to previous central chirality construction, this process employs quinone methides for axial chirality construction.Axially chiral allenes that are normally present in natural products, bioactive molecules, organocatalysts, and functional materials are usually produced from propargylic derivatives. Here, the authors show direct use of propargylic alcohols for catalytic asymmetric allene synthesis.
Project description:Conditions have been developed for the palladium-catalyzed cross-coupling of 3-bromo-2,1-borazaronaphthalenes with potassium alkenyltrifluoroborates. Twenty-seven alkenyl-substituted azaborines have been synthesized through this method, providing access to a family of 2,1-borazaronaphthalenes with alkenyl substitution at the C3 position.
Project description:The hydration of propargylic alcohols is a green route to synthesize ?-hydroxy ketones. Herein a CO2-reactive ionic liquid (IL), [Bu4P][Im], was found to display high performance for catalyzing the hydration of propargylic alcohols in the presence of atmospheric CO2, and a series of propargylic alcohols could be converted into the corresponding ?-hydroxy ketones in good to excellent yields. In the IL/CO2 reaction system, CO2 served as a cocatalyst by forming ?-alkylidene cyclic carbonates with propargylic alcohols, and was released via the rapid hydrolysis of the carbonates catalysed by the IL. This is the first example of the efficient hydration of propargylic alcohols under metal-free conditions.
Project description:By functionalizing the privileged biphenyl-2-ylphosphine with a basic amino group at the rarely explored 3' position, the derived gold(I) complex possesses orthogonally positioned "push" and "pull" forces, which enable for the first time soft propargylic deprotonation and permit the bridging of a difference of >26 pK(a) units (in DMSO) between a propargylic hydrogen and a protonated tertiary aniline. The application of this design led to efficient isomerization of alkynes into versatile 1,3-dienes with synthetically useful scope under mild reaction conditions.