Unusual Regioselectivity Research Articles

Computational Study of the Ni-Catalyzed C-H Oxidative Cycloaddition of Aromatic Amides with Alkynes.

The mechanism of Ni-catalyzed ortho C(sp2)–H oxidative cycloaddition of aromatic amides with internal alkynes containing 2-pyridinylmethylamine directing group was investigated using density functional theory (DFT) calculations. The C–H cleavage step proceeds via σ-complex-assisted metathesis (σ-CAM) with an alkenyl-Ni(II) complex. This is in contrast to the more common carboxylate/carbonate-assisted concerted metalation–deprotonation mechanism in related Ni-catalyzed C–H bond functionalization reactions with N,N-bidentate directing groups. In this reaction, the alkyne not only serves as the coupling partner, but also facilitates the σ-CAM C–H metalation both kinetically and thermodynamically. The subsequent functionalization of the five-membered nickelacycle proceeds via alkyne insertion into the Ni–C bond to form a seven-membered nickelacycle. This process proceeds with high levels of regioselectivity to form a C–C bond with sterically more encumbered alkyne terminus. This unusual regioselectivity is due to steric repulsions with the directing group that is coplanar with the alkyne in the migratory insertion transition state. The C–N bond reductive elimination to form the isoquinolone cycloadduct is promoted by PPh3 complexation to the Ni center and the use of flexible 2-pyridinylmethylamine directing group. The origin of the cis–trans isomerism of alkene byproduct was also explained by computations.

C−C Bond Formation of Benzyl Alcohols and Alkynes Using a Catalytic Amount of KOtBu: Unusual Regioselectivity through a Radical Mechanism

AbstractWe report a C−C bond‐forming reaction between benzyl alcohols and alkynes in the presence of a catalytic amount of KOtBu to form α‐alkylated ketones in which the C=O group is located on the side derived from the alcohol. The reaction proceeds under thermal conditions (125 °C) and produces no waste, making the reaction highly atom efficient, environmentally benign, and sustainable. Based on our mechanistic investigations, we propose that the reaction proceeds through radical pathways.

C-C Bond Formation of Benzyl Alcohols and Alkynes Using a Catalytic Amount of KOt Bu: Unusual Regioselectivity through a Radical Mechanism.

We report a C-C bond-forming reaction between benzyl alcohols and alkynes in the presence of a catalytic amount of KOt Bu to form α-alkylated ketones in which the C=O group is located on the side derived from the alcohol. The reaction proceeds under thermal conditions (125 °C) and produces no waste, making the reaction highly atom efficient, environmentally benign, and sustainable. Based on our mechanistic investigations, we propose that the reaction proceeds through radical pathways.

Catalytic Asymmetric Dearomatization by Visible-Light-Activated [2+2] Photocycloaddition.

A novel method for the catalytic asymmetric dearomatization by visible-light-activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2-position with a chelating N-acylpyrazole moiety which permits the coordination of a visible-light-activatable chiral-at-rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.

Catalytic Asymmetric Dearomatization by Visible‐Light‐Activated [2+2] Photocycloaddition

AbstractA novel method for the catalytic asymmetric dearomatization by visible‐light‐activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2‐position with a chelatingN‐acylpyrazole moiety which permits the coordination of a visible‐light‐activatable chiral‐at‐rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.

Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins.

The cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates. A new organometallic species in the heterocyclization provides an opportunity to synthesize heterocycles that are difficult to obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position. This new type of metalated isocoumarin provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decomposition of terminal alkynes, respectively. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallographic analysis. The theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the atomic characters of indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied to organic synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.

Stereoselective Total Synthesis of Hetisine-type C20 -Diterpenoid Alkaloids: Spirasine IV and XI.

The first total synthesis of the architecturally complex hetisine-type heptacyclic C20 -diterpenoid alkaloids (±)-spirasine IV and XI is reported. The A/F/G/C tetracyclic skeleton with the challenging N-C6 and C14-C20 linkages was efficiently constructed by an intramolecular azomethine-ylide-based 1,3-dipolar cycloaddition with unusual regioselectivity. SmI2 -mediated free-radical addition to the arene moiety without prior dearomatization and a stereoselective intramolecular aldol reaction further enabled rapid access to the hetisine core, providing a bicyclo[2.2.2]octane ring with a new oxygen substitution pattern.

Stereoselective Total Synthesis of Hetisine‐type C20‐Diterpenoid Alkaloids: Spirasine IV and XI

AbstractThe first total synthesis of the architecturally complex hetisine‐type heptacyclic C20‐diterpenoid alkaloids (±)‐spirasine IV and XI is reported. The A/F/G/C tetracyclic skeleton with the challenging N−C6 and C14−C20 linkages was efficiently constructed by an intramolecular azomethine‐ylide‐based 1,3‐dipolar cycloaddition with unusual regioselectivity. SmI2‐mediated free‐radical addition to the arene moiety without prior dearomatization and a stereoselective intramolecular aldol reaction further enabled rapid access to the hetisine core, providing a bicyclo[2.2.2]octane ring with a new oxygen substitution pattern.

Understanding the Regioselectivity of Aromatic Hydroxylation over Divanadium-Substituted γ-Keggin Polyoxotungstate

The aromatic hydroxylation of pseudocumene (PC) with aqueous hydrogen peroxide catalyzed by the divanadium-substituted γ-Keggin polyoxotungstate TBA4[γ-PW10O38V2(μ-O)(μ-OH)] (TBA-1H, TBA = tetrabutylammonium) has been studied using kinetic modeling and DFT calculations. This reaction features high chemoselectivity and unusual regioselectivity, affording 2,4,5-trimethylphenol (TMP) as the main product. Then the computational study was extended to the analysis of the regioselectivity for other alkoxy- and alkylarene substrates. The protonation/deprotonation of TBA-1H in MeCN/tBuOH (1:1) was investigated by 31P NMR spectroscopy. Forms with different protonation states, [γ-PV2W10O40]5– (1), [γ-HPV2W10O40]4– (1H), and [γ-H2PV2W10O40]3– (1H2), have been identified, and the protonation equilibrium constants were estimated on the basis of the 31P NMR data. DFT calculations were used to investigate the oxygen transfer process from hydroperoxo species, [γ-PW10O38V2(μ-O)(μ-OOH)]4– (2) and [γ-PW10O38V2(μ-OH)(μ-OOH)]3...

Visible‐Light‐Driven Iron‐Promoted Thiocarboxylation of Styrenes and Acrylates with CO2

AbstractThe first thiocarboxylation of styrenes and acrylates with CO2 was realized by using visible light as a driving force and catalytic iron salts as promoters. A variety of important β‐thioacids were obtained in high yields. This multicomponent reaction proceeds in an atom‐ and redox‐economical manner with broad substrate scope under mild reaction conditions. Notably, high regio‐, chemo‐, and diasteroselectivity are observed. Mechanistic studies indicate that a radical pathway can account for the unusual regioselectivity.

Visible‐Light‐Driven Iron‐Promoted Thiocarboxylation of Styrenes and Acrylates with CO2

The first thiocarboxylation of styrenes and acrylates with CO2 was realized by using visible light as a driving force and catalytic iron salts as promoters. A variety of important β-thioacids were obtained in high yields. This multicomponent reaction proceeds in an atom- and redox-economical manner with broad substrate scope under mild reaction conditions. Notably, high regio-, chemo-, and diasteroselectivity are observed. Mechanistic studies indicate that a radical pathway can account for the unusual regioselectivity.

Diastereoselective Organocatalytic Addition of α-Angelica Lactone to β-Halo-α-ketoesters.

A quinidine-catalyzed diastereoselective addition of α-angelica lactone to β-halo-α-ketoesters is reported. The α-angelica lactone displays unusual regioselectivity in this reaction, acting as a nucleophile at the α-position to provide fully substituted glycolic esters with three contiguous stereocenters. Subsequent diastereoselective hydrogenation provides an additional stereocenter within the lactone.

ChemInform Abstract: Unusual Regioselectivity in the Gold(I)‐Catalyzed [3 + 2] Carbocycloaddition Reaction of Vinyldiazo Compounds and N‐Allenamides.

The reaction of N-allenamides with alkenyl diazo compounds in the presence of gold catalysts provided methylidenecyclopentene derivatives resulting from a formal intermolecular [3+2] carbocyclization, a rare process in the gold chemistry of allenes. The participation of the CαCβ bond of the allenamide represents a very unusual regioselectivity in gold-catalyzed cycloaddition reactions of this type of allenic scaffolds. A stepwise mechanism involving initial activation of the diazo component has been proposed.

Methoxylation of Singly Bonded 1,4-1',4'-BnC60-C60Bn Dimer: Preferential Formation of 1,4-C60 Adduct with Sterically Less Demanding Addends and Stability Difference between 1,2- and 1,4-OMe(Bn)C60.

Methoxylation of the singly bonded 1,4-1',4'-BnC60-C60Bn dimer afforded 1,4-OMe(Bn)C60, a 1,4-C60 adduct with sterically less demanding addends, as the major adduct. The situation was different from that of direct functionalization of C60, where 1,2-OMe(Bn)C60 was obtained as the major product. The reaction was studied with in situ vis-NIR spectroscopy and computational calculations to obtain a better understanding of this unusual regioselectivity. The stability difference between 1,2- and 1,4-OMe(Bn)C60 was studied.

Regioselective Acylation of Diols and Triols: The Cyanide Effect.

Central topics of carbohydrate chemistry embrace structural modifications of carbohydrates and oligosaccharide synthesis. Both require regioselectively protected building blocks that are mainly available via indirect multistep procedures. Hence, direct protection methods targeting a specific hydroxy group are demanded. Dual hydrogen bonding will eventually differentiate between differently positioned hydroxy groups. As cyanide is capable of various kinds of hydrogen bonding and as it is a quite strong sterically nondemanding base, regioselective O-acylations should be possible at low temperatures even at sterically congested positions, thus permitting formation and also isolation of the kinetic product. Indeed, 1,2-cis-diols, having an equatorial and an axial hydroxy group, benzoyl cyanide or acetyl cyanide as an acylating agent, and DMAP as a catalyst yield at -78 °C the thermodynamically unfavorable axial O-acylation product; acyl migration is not observed under these conditions. This phenomenon was substantiated with 3,4-O-unproteced galacto- and fucopyranosides and 2,3-O-unprotected mannopyranosides. Even for 3,4,6-O-unprotected galactopyranosides as triols, axial 4-O-acylation is appreciably faster than O-acylation of the primary 6-hydroxy group. The importance of hydrogen bonding for this unusual regioselectivity could be confirmed by NMR studies and DFT calculations, which indicate favorable hydrogen bonding of cyanide to the most acidic axial hydroxy group supported by hydrogen bonding of the equatorial hydroxy group to the axial oxygen. Thus, the "cyanide effect" is due to dual hydrogen bonding of the axial hydroxy group which enhances the nucleophilicity of the respective oxygen atom, permitting an even faster reaction for diols than for mono-ols. In contrast, fluoride as a counterion favors dual hydrogen bonding to both hydroxy groups leading to equatorial O-acylation.

Unusual Regioselectivity in the Gold(I)‐Catalyzed [3+2] Carbocycloaddition Reaction of Vinyldiazo Compounds and N‐Allenamides

AbstractThe reaction of N‐allenamides with alkenyl diazo compounds in the presence of gold catalysts provided methylidenecyclopentene derivatives resulting from a formal intermolecular [3+2] carbocyclization, a rare process in the gold chemistry of allenes. The participation of the CαCβ bond of the allenamide represents a very unusual regioselectivity in gold‐catalyzed cycloaddition reactions of this type of allenic scaffolds. A stepwise mechanism involving initial activation of the diazo component has been proposed.magnified image

ChemInform Abstract: Phosphine‐Catalyzed Regioselective Michael Addition to Allenoates.

The first phosphine catalysed Michael addition of arylcyanoacetates to allenoates has been developed, and the β-selective products with a quaternary center were obtained in excellent yields. This unusual regioselectivity may open new opportunities to access interesting molecular structures.

Synthesis of highly functionalized [3]dendralenes and their Diels–Alder reactions displaying unexpected regioselectivity

Sequential olefinations were applied for the synthesis of acyclic tetrasubstituted [3]dendralenes, which did not cyclodimerize and displayed unusual regioselectivity in the Diels–Alder reaction.

Alkylation of Catechol with Benzhydrol: Unusual Regioselectivity in the Synthesis of o‐Quinones and Catechols

AbstractUnusual regioselectivity occurs in the alkylation reaction of benzhydrol with catechol. The reaction proceeds to give catechols containing two vicinal diphenylmethyl substituents. 4,5‐Bis‐(diphenylmethyl)‐substituted catechol was found as the main product in more than 50 % yield. The reaction outcome is quite different to that of the reactions using bulky alkyl alcohols reported so far, in which 3,5‐ and 3,4,6‐disubstituted species were formed predominantly. The minor products this reaction are 3,5‐di‐ and 3,4,6‐trisubstituted species. Di‐ and trialkylated catechols were oxidized to give the corresponding o‐quinones. The reactivity and physicochemical properties of the new compounds were studied.

ChemInform Abstract: An Organocatalytic Cascade Reaction of 2‐Nitrocyclohexanone and α,β‐Unsaturated Aldehydes with Unusual Regioselectivity.

AbstractUnsaturated β‐alkyl aldehydes such as crotonaldehyde and trans‐2‐hexenal as well as 2‐nitrocyclopentanone and 2‐nitrocycloheptanone do not react to the desired products.