LiHMDS-Mediated Deprotonative Coupling of Toluenes with Ketones.

We demonstrate that lithium hexamethyldisilazide (LiHMDS) acts as an effective base for deprotonative coupling reactions of toluenes with ketones to afford stilbenes. Various functionalities (halogen, OCF3 , amide, Me, aryl, alkenyl, alkynyl, SMe, and SPh) are allowed on the toluenes. Notably, this system proved successful with low-reactive toluenes bearing a large pKa value compared to that of the conjugate acid of LiHMDS (hexamethyldisilazane, 25.8, THF), as demonstrated by 4-phenyltoluene (38.57, THF) and toluene itself (∼43, DMSO).

Versatile Reactivity of Metalloid-Substituted π-Allylpalladium Species.

π-Allylpalladium complexes can not only serve as electrophilic allylating agents for a broad range of nucleophiles, but also nucleophilic allylating agents for electrophiles depending on their electronic environments. In contrast to these typical reactivities of π-allylpalladium complexes, silylated and borylated π-allylpalladium species show unique reactivities that can allow versatile transformations in addition to simple allylation. Herein, four different types of transformations that are in principle achieved via the inherently reactive silylated and borylated π-allylpalladium species as common intermediates are described. An appropriate selection of ligands of the silylated and borylated π-allylpalladium species can allow control over the reaction pathways.

Dynamic parallel kinetic resolution of α-ferrocenyl cation initiated by chiral Brønsted acid catalyst.

The dynamic parallel kinetic resolution (DPKR) of an α-ferrocenyl cation intermediate under the influence of a chiral conjugate base of a chiral phosphoric acid catalyst has been demonstrated in an SN1 type substitution reaction of a racemic ferrocenyl derivative with a nitrogen nucleophile. The present method provides efficient access to a ferrocenylethylamine derivative in a highly enantioselective manner, which is potentially useful as a key precursor of chiral ligands for metal catalysis. The mechanism of the present intriguing resolution system was elucidated by control experiments using the enantio-pure precursor of relevant α-ferrocenyl cation intermediates and the hydroamination of vinylferrocene. Further theoretical studies enabled the elucidation of the origin of the stereochemical outcome as well as the efficient DPKR. The present DPKR, which opens a new frontier for kinetic resolution, involves the racemization process through the formation of vinylferrocene and the chemo-divergent parallel kinetic resolution of the enantiomeric α-ferrocenyl cations generated by the protonation/deprotonation sequence of vinylferrocene.

Enantioselective Acyl Migration Reactions of Furanyl Carbonates with Chiral DMAP Derivatives.

An efficient enantioselective acyl migration reaction of furanyl carbonates was developed to construct all-carbon quaternary stereogenic centers. In some cases, the reactions required only 0.05 mol % (minimum 500 ppm) of catalyst and showed a high turnover frequency value (TOF; 3640 h-1 ). Multigram-scale reactions (10 grams) also proceeded with high enantioselectivity (>99:1 e.r.) in quantitative yield. The catalyst was robust and easily recovered in 98 % yield. A wide range of functional groups were tolerated (15 examples, >98 % yield, up to >99:1 e.r.), and a variety of optically active 3,3'-disubstituted benzofuranone derivatives, which are useful intermediates for the synthesis of natural products and pharmaceuticals, were efficiently obtained. Control experiments on the catalyst structure (e.g., catalyst 1 a vs. 1 a' and 1 a'') and computational calculations revealed that both the catalytic activity and enantioselectivity should be enhanced by hydrogen bonding between catalyst and substrate. Moreover, this system was applied to the challenging γ-selective acyl migration reaction of furanyl carbonates with high γ-selectivity and high enantioselectivity (α:γ=10:90, 95:5 e.r.).

Perfluorocyclopentadienyl Radical Derivative as an Organocatalyst for Oxidative Coupling of Aryl- and Thienylmagnesium Compounds under Atmospheric Oxygen.

The oxidative homocoupling reaction of Grignard reagents in the presence of atmospheric oxygen molecules proceeded in the presence of a heptafluorotolyl-substituted perfluorocyclopentadienyl radical. The turnover number (TON) was over 30 for the coupling reactions of PhMgBr to give biphenyl. The organocatalyst could couple thienylmagnesium compounds to give bithiophene derivatives in up to 94% yield. Furthermore, a gram-scale synthesis of 6,6'-dimethoxybiphenyl-2,2'-diyl-bis(phosphonic acid diethyl ester) was demonstrated. Stabilization of the phenyl radical for the inhibition of the side reaction was also considered using DFT calculations.

Chiral Phosphoric Acid Catalyzed Enantioselective Ring Expansion Reaction of 1,3-Dithiane Derivatives: Case Study of the Nature of Ion-Pairing Interaction.

Chiral counterion controlled asymmetric catalysis via an ion-pairing interaction has attracted immense attention in recent years. Despite a number of successful studies, the mechanistic elucidation of the stereocontrolling element in the ion-pairing interaction is rarely conducted and hence its nature is still far from being well understood. Herein we report an in-depth mechanistic case study of a newly developed enantioselective ring expansion reaction of 1,3-dithiane derivatives catalyzed by chiral phosphoric acid (CPA). An unprecedented enantioselective 1,2-sulfur rearrangement/stereospecific nucleophilic addition sequence was proven to be the stereoselective pathway. More importantly, by thorough investigation of the intrinsic nature of the stereospecific nucleophilic addition to the cationic thionium intermediate, we discovered that the key interaction in this process is the nonclassical C-H···O hydrogen bonds formed between the conjugate base of the CPA catalyst and the cationic intermediate. These C-H···O hydrogen bonds not only bind the catalyst to the substrates to form energetically favored states throughout the overall processes but also firmly maintain the relative positions of these fragments as the "fixed" contact ion pair to sustain the chiral information generated at the initial sulfur rearrangement step. This mechanistic case study provides a very clear understanding of the nature of the ion-pairing interaction in organocatalysis. The conclusion encourages the further development of the research field with the focus to design new organocatalysts and cultivate novel organocatalytic transformations.

Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet Cellana toreuma.

In our previous study, unusual odd-numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2∆7,18 and 21:2∆7,20, through a common pathway involving the strategic combination of alkyne-zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2-propyn-1-ol was at first subjected to alkylation and alkyne-zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C-19 and C-21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z-alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z-alkenyl group. Total synthesis of target fatty acids, 19:2∆7,18 and 21:2∆7,20, was finally accomplished by two-step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC-MS spectra of the methyl esters of authentic and synthetic fatty acids.

Rh-Catalyzed Dehydrogenative Cyclization Leading to Benzosilolothiophene Derivatives via Si-H/C-H Bond Cleavage.

Straightforward syntheses leading to π-extended benzosilolothiophene (BST) derivatives by Rh-catalyzed dehydrogenative cyclization reactions have been developed. Electron-deficient ligands were effective for the reactions, and dppe-F20 gave the best result. This method could be applied to the synthesis of highly π-extended ladder-type BST derivatives, which exhibited fluorescence.

Enantioselective acyl transfer catalysis by a combination of common catalytic motifs and electrostatic interactions.

Catalysts that can promote acyl transfer processes are important to enantioselective synthesis and their development has received significant attention in recent years. Despite noteworthy advances, discovery of small-molecule catalysts that are robust, efficient, recyclable and promote reactions with high enantioselectivity can be easily and cost-effectively prepared in significant quantities (that is, >10 g) has remained elusive. Here, we demonstrate that by attaching a binaphthyl moiety, appropriately modified to establish H-bonding interactions within the key intermediates in the catalytic cycle, and a 4-aminopyridyl unit, exceptionally efficient organic molecules can be prepared that facilitate enantioselective acyl transfer reactions. As little as 0.5 mol% of a member of the new catalyst class is sufficient to generate acyl-substituted all-carbon quaternary stereogenic centres in quantitative yield and in up to 98:2 enantiomeric ratio (er) in 5 h. Kinetic resolution or desymmetrization of 1,2-diol can be performed with high efficiency and enantioselectivity as well.

Enantioselective Aza Michael-Type Addition to Alkenyl Benzimidazoles Catalyzed by a Chiral Phosphoric Acid.

Highly enantioselective Michael-type addition (MTA) reactions between N-protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N-protecting group of benzimidazole contributed to the resulting high enantioselectivity.

Development and Application of a Multielectron-Accepting Organic Oxidant for the Catalytic Transition-Metal-Free Oxidative Homocoupling of Grignard Reagents in Air.

Heptafluorotolyl-substituted perfluorocyclopentene acts as a four-electron oxidant for the homocoupling of Grignard reagents. It can also be used for catalytic homocoupling with a low catalyst loading (up to 2 mol %) in the presence of atmospheric oxygen. The organocatalytic cycle involves the generation of an organic radical and a perfluorocyclopentadienyl anion.

Enantioselective Steglich Rearrangement of Oxindole Derivatives by Easily Accessible Chiral N,N-4-(Dimethylamino)pyridine Derivatives.

Chiral N,N-4-(dimethylamino)pyridine (DMAP) derivatives, which can be readily prepared by the Ugi multicomponent reaction in a one-pot manner, have been efficiently applied to the enantioselective Steglich rearrangement of oxindole derivatives to give the desired products bearing a quaternary carbon center in high yield (>98% yield) and with high enantioselectivity (up to 99:1 er).

Highly electron-poor Buchwald-type ligand: application for Pd-catalysed direct arylation of thiophene derivatives and theoretical consideration of the secondary Pd(0)-arene interaction.

Highly electron-poor SPhos ligands bearing either 2,6-bis(trifluoromethyl)-4-pyridyl (BFPy) or 3,5-(CF3)2C6H3 groups were synthesised. The former ligand highly accelerated the Pd-catalysed direct arylation of 2-propylthiophene, 2-methylthiophene or benzo[b]thiophene with only 1 mol% of the catalyst. This high catalytic activity can be attributed to a combination of electronic properties and the secondary Pd-arene interaction of BFPySPhos. The secondary interactions of SPhos, PhSPhos and BFPySPhos were optimised at the oniom(mp2/lanl2dz : b3lyp/lanl2dz) level and were further evaluated using the NBO method by DFT at the M06-2X/6-31G(d) level with LanL2DZ + ECP. The deletion energy analysis showed that the transfer of electrons from Pd to aromatic ring is the dominating factor for the secondary Pd-arene interaction of SPhos-Pd(0) complexes. Although an electron-poor BFPySPhos does not particularly favour this type of interaction, this interaction is still substantial enough to sufficiently stabilise the BFPySPhos-Pd complex.

Novel One-step Synthesis of Quinoline-2(1H)-thiones and Selones by Treating 3-Aryl-3-(2-aminophenyl)-1-propyn-3-ols with a Base and Elemental Sulfur or Selenium.

A one-step conversion of 3-aryl-3-(2-aminophenyl)-1-propyn-3-ols into quinoline-2(1H)-thiones and quinoline-2(1H)-selones was achieved only by treating the substrates with n-butyllithium and either elemental sulfur or selenium, respectively. The reactions were assumed to proceed through an intramolecular nucleophilic attack of the neighboring amino group to the plausible in situ generated reactive species related to chalcogenoketenes. The subsequent mCPBA oxidation of quinoline-2(1H)-selones afforded quinolin-2(1H)-ones in high yields.

Mechanistic studies of highly enantio- and diastereoselective aza-Petasis-Ferrier rearrangement catalyzed by chiral phosphoric acid.

The precise mechanism of the highly anti- and enantioselective aza-Petasis-Ferrier (APF) rearrangement of hemiaminal vinyl ethers catalyzed by a chiral phosphoric acid was investigated by undertaking experimental and theoretical studies. The APF rearrangement is characterized by the following unique mechanistic features: (i) efficient optical kinetic resolution of the starting racemic hemiaminal vinyl ether, (ii) enantioconvergent process from racemic hemiaminal vinyl ethers to optically active ß-amino aldehyde products, and (iii) anomalous temperature effects on the enantioselectivity (enantioselectivity increases as reaction temperature increases). The following experiments were conducted to elucidate the unique mechanistic features as well as to uncover the overall scheme of the present rearrangement: (A) X-ray crystallographic analysis of the recovered hemiaminal vinyl ether to determine its absolute configuration, (B) rearrangements of enantiomerically pure hemiaminal vinyl ethers to validate the stereochemical relationship between the hemiaminal vinyl ethers and ß-amino aldehydes, (C) theoretical studies on the transition states of the C-O bond cleavage and C-C bond formation steps to gain an insight into the optical kinetic resolution of the hemiaminal vinyl ether and the origin of the stereoselectivity, as well as to elucidate the overall scheme of the present rearrangement, and (D) crossover experiments of two hemiaminal vinyl ethers having different vinyl ether and aliphatic substituents to comprehend the mechanism of the anomalous temperature effect and the enantioconvergent process. The results of experiments and theoretical studies fully support the proposed mechanism of the present anti- and enantioselective APF rearrangement.

Low-temperature Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,ß-unsaturated carbonyl compounds.

Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to α,ß-unsaturated carbonyl compounds was achieved at temperatures below 0 °C using a Rh/MeO-F12-BIPHEP catalyst. The reaction of cyclohexenone or N-R-maleimide with arylboronic acids proceeded even at -80 °C in the presence of the Rh catalyst. In the latter case, high enantioselectivity was observed because a low-temperature method was used, regardless of the type of substituent on maleimide.

Highly enantioselective and efficient synthesis of flavanones including pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition.

An efficient synthesis of bioactive chiral flavanones (1) was achieved through the Rh-catalyzed asymmetric 1,4-addition of arylboronic acid to chromone. The reaction in toluene proceeded smoothly at room temperature in the presence of 0.5% Rh catalyst with electron-poor chiral diphosphine MeO-F(12)-BIPHEP. In this reaction, the 1,2-addition to (S)-1 frequently occurred to yield (2S,4R)-2,4-diaryl-4-chromanol as a byproduct, which could be reduced by changing the reaction solvent to CH(2)Cl(2) to deactivate the Rh catalyst (3% required).

Rational electronic tuning of CBS catalyst for highly enantioselective borane reduction of trifluoroacetophenone.

α,α,α-Trifluoroacetophenone (2), which is susceptible to noncatalytic reduction by BH(3), could be reduced to chiral alcohol up to 90% ee by using electronically tuned-CBS catalyst (1) with BH(3). The enantioselectivities highly correlated with the differential orbital energies between 1-BH(3) adduct and 2, which were calculated by DFT method.