Unusual Regioselectivity Research Articles

Regioselective Hydroboration of Unsymmetrical Internal Alkynes Catalyzed by a Cobalt Pincer-NHC Complex.

Highly regioselective hydroboration of unsymmetrical internal alkynes remains a significant challenge for synthesizing valuable alkenylboronate esters. Herein, we describe an easily synthesizable pincer NHC-based Co complex as a catalyst for the cis-α selective hydroboration of unactivated internal alkynes and the cis-β selective hydroboration of activated internal alkynes with pinacolborane. The reaction showcases high chemo-, regio-, and stereoselectivity, and the catalyst displays high efficiency and very low loading under base-free reaction conditions. The reaction scope was demonstrated by alkynes having a variety of functional groups. The mechanistic studies suggest a feasible Co-boryl intermediate to explain the unusual regioselectivity.

Reversible [4 + 1] Cycloaddition of Arenes by a "Naked" Acyclic Aluminyl Compound.

The large steric profile of the N-heterocyclic boryloxy ligand, -OB(NDippCH)2, and its ability to stabilize the metal-centered HOMO, are exploited in the synthesis of the first example of a "naked" acyclic aluminyl complex, [K(2.2.2-crypt)][Al{OB(NDippCH)2}2]. This system, which is formed by substitution at AlI (rather than reduction of AlIII), represents the first O-ligated aluminyl compound and is shown to be capable of hitherto unprecedented reversible single-site [4 + 1] cycloaddition of benzene. This chemistry and the unusual regioselectivity of the related cycloaddition of anthracene are shown to be highly dependent on the availability (or otherwise) of the K+ countercation.

Cobalt‐Catalyzed Enantio‐ and Regioselective C(sp3)−H Alkenylation of Thioamides

AbstractAn enantioselective cobalt‐catalyzed C(sp3)−H alkenylation of thioamides with but‐2‐ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

Cobalt-Catalyzed Enantio- and Regioselective C(sp3 )-H Alkenylation of Thioamides.

An enantioselective cobalt-catalyzed C(sp3 )-H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

Unusual regioselectivity in [3+2] cycloaddition reactions between (E)-3-nitroacrylic acid derivatives and (Z)-C,N-diphenylimine N-oxide

[3+2] cycloaddition reactions of -COOMe and -CN trans-substituted nitroethenes with (Z)-C,N-diphenylimine N-oxide were tested. For the contrast to most known nitroalkene/nitrone cycloaditions, the reactions studied realized with the formation of 5-nitroisoxazolidines

Temperature-controlled S vs N selective alkylation of 1-phenyl tetrazole-5-thione with α,β-unsaturated systems in solvent-free organic salt media

In this work, a novel series of N and S-alkylated derivatives of 1-phenyl tetrazole-5-thione were synthesized by Michael addition in organic salt media TBAB (Tetrabutylammonium bromide) using inorganic base K2CO3 under solvent-free conditions. The new and conveniently synthesized products showed unusual regioselectivity during the reaction. S-Michael adducts via reaction between 1-phenyl tetrazole-5-thione and acrylic esters as well as acrylonitrile were afforded at room temperature and N-Michael adducts obtained at 70°C. Both reactions occurred within 24 h. Surprisingly, using fumarate esters as Michael acceptor proceeded a SN2 reaction at 100°C due to steric effects. The structures of products all were confirmed by 1H and 13C NMR spectra and target compound yields were good to excellent.

Synthesis of [60]- and [70]Fullerene-Fused Tetrahydroquinoxaline Derivatives by Oxidative [4 + 2] Cycloaddition with Unusual Reactivity and Regioselectivity.

The oxidative [4 + 2] reaction of o-phenylenediamine-derived disulfonamides with fullerene C60 and C70 is reported, in which electron-deficient reactants showed high reactivity. The reaction of C70 exhibited unusual regioselectivity, yielding a [5,6]-adduct as the major product, which was characterized by 1H, 13C NMR and single-crystal X-ray diffraction. DFT calculations revealed the reaction is an inverse-electron-demand Diels-Alder (IEDDA) reaction, and the [5,6]-adduct of C70 is a kinetic product.

Highly Regioselective Cobalt‐Catalyzed Hydroboration of Internal Alkynes

Highly Regioselective Cobalt‐Catalyzed Hydroboration of Internal Alkynes

Highly Regioselective Cobalt-Catalyzed Hydroboration of Internal Alkynes.

Herein, we report the development of new Co complexes that have cyclopropane-based diphosphine ligands and can catalyze highly chemo-, regio-, and stereoselective hydroboration reactions of unsymmetrical internal alkynes. These reactions exhibited unusual regioselectivity: specifically, reactions of aryl alkyl internal alkynes showed excellent cis-β-addition selectivity, and reactions of dialkyl internal alkynes gave excellent cis-α-addition selectivity. Highly regioselective hydroboration of unsymmetrical dialkyl internal alkynes cannot be achieved by other known methods. The reactions described herein are highly synthetically useful, particularly for the stereoselective synthesis of trisubstituted alkenylborates and alkenes. Mechanistic studies indicate that a CoI -H species is a plausible active catalyst and the rigid structure of the cyclopropane skeleton of the ligands and the crowded reaction pocket were responsible for the unprecedented regioselectivity.

Enzymatic Enantioselective anti-Markovnikov Hydration of Aryl Alkenes.

The addition of water to alkenes is an important method for the synthesis of alcohols, but the regioselectivity of acid-catalyzed hydration of terminal alkenes yields secondary alcohols according to Markovnikov's rule, making it difficult to obtain primary alcohols. Here we report a styrene monooxygenase that catalyzes the anti-Markovnikov hydration of the terminal aryl alkenes under anaerobic conditions. This hydration provides primary alcohols in good yields (up to 100 %), excellent anti-Markovnikov regioselectivity (>99 : 1), and good enantiomeric purity (60-83 % ee). Residues Asn46, Asp100, and Asn309 are essential for catalysis suggesting an acid-base mechanism with a carbanion-like intermediate that could account for the anti-Markovnikov regioselectivity. Our work reveals a new enzymatic tool with unusual regioselectivity based on the promiscuous catalytic activity of a monooxygenase.

Enzymatic Enantioselective anti‐Markovnikov Hydration of Aryl Alkenes

AbstractThe addition of water to alkenes is an important method for the synthesis of alcohols, but the regioselectivity of acid‐catalyzed hydration of terminal alkenes yields secondary alcohols according to Markovnikov's rule, making it difficult to obtain primary alcohols. Here we report a styrene monooxygenase that catalyzes the anti‐Markovnikov hydration of the terminal aryl alkenes under anaerobic conditions. This hydration provides primary alcohols in good yields (up to 100 %), excellent anti‐Markovnikov regioselectivity (>99 : 1), and good enantiomeric purity (60–83 % ee). Residues Asn46, Asp100, and Asn309 are essential for catalysis suggesting an acid–base mechanism with a carbanion‐like intermediate that could account for the anti‐Markovnikov regioselectivity. Our work reveals a new enzymatic tool with unusual regioselectivity based on the promiscuous catalytic activity of a monooxygenase.

Photochemical graft of γ-cyclodextrin’s interior leading to in-situ charge-transfer complexes with unusual regioselectivity and its application in 3D photo-printing

Photochemical graft of γ-cyclodextrin’s interior leading to in-situ charge-transfer complexes with unusual regioselectivity and its application in 3D photo-printing

Optimization Strategies for the Anodic Phenol‐Arene Cross‐Coupling Reaction

AbstractDehydrogenative phenol‐arene cross‐coupling by direct anodic oxidation is a promising alternative to reductive cross‐coupling, especially for construction of smaller molecules. The reaction pathway via phenoxyl radicals allows for unusual regioselectivity. Nevertheless, the numerous electrolysis parameters pose a challenge for optimization, as they determine the yield and selectivity of the reaction. Using design of experiments, we present optimization strategies for two example reactions to improve the space‐time yield. In particular, coupling reactions with 2,6‐dimethoxyphenol (syringol) were found to be very robust in the electrolysis at high current densities of up to 150 mA/cm2. Cyclic voltammetry was used to classify combinations of phenols and arenes, on the basis of which the various clusters were optimized. Based on this classification, various biaryls were synthesized and isolated in yields of up to 85 %.

Ring size and nothing else matters: unusual regioselectivity of alkyne hydration by NHC gold(I) complexes.

We have investigated the role of ring sizes and substituents in NHC ligands in some (NHC)Au(i) complexes in the hydration of internal alkynes. Despite the fact that using (NHC)Au(i) complexes in the hydration of diarylacetylenes leads to Markovnikov-type products, the precise tuning of ligands allows changing the regioselectivity in arylalkylacetylene hydration to the anti-Markovnikov-type.

EPR Studies on the Addition of Ligated Boryl Radicals to Carbonyl Compounds

The boron-centered radicals derived from alkenyl N-heterocyclic carbene (NHC)-boranes bearing ester substituents were recently found to ring close in 5-endo mode by addition to the oxygen atoms of the ester substituents. The inference from this was that NHC-boryl radicals might add intermolecularly to carbonyl-containing substrates. Several different NHC-boryl radicals were generated by H-atom abstraction from NHC-ligated trihydroborates. Electron paramagnetic resonance (EPR) spectroscopy proved that these did indeed add to the oxygen atoms of diaryl ketones with production of the corresponding bora-ketyl radicals. The same unusual regioselectivity of addition was observed with monoaryl ketones, but no bora-ketyls were observed with dialkyl ketones. Similarly, no bora-ketyl adduct radicals were observed with esters, even esters of benzoic acid. EPR spectroscopic evidence suggested that NHC-boryl radicals were also added to the O-atoms of aromatic aldehydes. Amine-boryl and phosphine-boryl radicals were also observed to add to the O-atom of benzophenone with production of the corresponding ketyl radicals.

Radical-mediated C-C cleavage of unstrained cycloketones and DFT study for unusual regioselectivity

The C-C σ-bond activation of unstrained cycloketones represents an ingenious and advanced technique in synthetic chemistry, but it remains a challenging area which has been largely underexplored. Herein we report an efficient strategy for the direct C-C cleavage of cyclohexanones and cyclopentanones. The cyclic C-C σ-bond is readily cleaved under mild conditions with the aid of an in situ formed side-chain aryl radical. Density functional theory calculations are carried out to shed light on the unusual regioselectivity of C-C bond cleavage. The reaction affords a variety of structurally diverse 3-coumaranones and indanones that widely exist in natural products and bioactive molecules, illustrating the synthetic value of this method.

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)-Peroxo Complex.

Mononuclear nonheme MnIII -peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side-on MnIII -peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C-H by C-D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)–Peroxo Complex

AbstractMononuclear nonheme MnIII‐peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side‐on MnIII‐peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C−H by C−D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Remote 1,5-Stereoselectivity Control by an N-Ligand Switch in the Pd(0)/InI-Promoted Reactions of 4-Ethynyl-β-lactams with Aldehydes.

Configurationally stable ε-amido-propargylindiums, generated in situ from N-Ts-4-ethynylazetidin-2-ones in the presence of InI, catalytic amounts of Pd(PPh3)4, and N-methylimidazole or pyridine ligand react with unusual regioselectivity with aromatic and aliphatic aldehydes to afford 2,6- syn- or 2,6- anti-allenediols with excellent central-to-axial chirality transfer and useful levels of acyclic remote 1,5-stereocontrol.

Regio- and stereoselective synthesis of tetra- and triarylethenes by N-methylimidodiacetyl boron-directed palladium-catalysed three-component coupling

The flexible synthesis of tetra- and triarylethenes bearing different aryl groups has been a long-standing challenge in organic synthesis. Here we report a palladium-catalysed syn-diarylation of arylethynyl N-methyliminodiacetyl (MIDA) boronates. The products, triarylalkenyl N-methyliminodiacetyl boronates, allow a step-economic and modular synthesis of tetra- or triarylethenes via a subsequent stereospecific Suzuki-Miyaura coupling reaction or base-promoted protodeborylation, respectively. Use of the sp3-B(MIDA) masked aryl alkyne is the key factor for success by offering an exceptionally good regioselectivity for the boron-retentive coupling. The unusual regioselectivity is believed to arise from the stabilization due to the strong electron donation from the C−Pd σ bond to the p-orbital of boron in the transition state of migratory insertion. A broad range of differently substituted tetra- and triarylethenes are constructed in good yields and geometrical control. Synthetic manipulation of the C-B bond also enables the facile construction of several other types of tetra-substituted alkenes.