Rotational Behavior about the N3-Pyridyl Bond in 3-(Pyridin-2-yl)quinazolin-4-one and 4-Thione Derivatives.

The rotational barriers about the N3-(2-pyridyl) bond in 2-iso-propyl-3-(pyridin-2-yl)quinazolin-4-one and the thione analogue were evaluated though VT-NMR measurement of a diastereotopic iso-propyl group followed by a line-shape simulation. In 3-(pyridin-2-yl)quinazoline-4-thione bearing a chiral center as the C2 substituent, the formation of dynamic diastereomers was detected by NMR. The rotational pathway about the N3-(2-pyridyl) bond and the stereochemistries of dynamic diastereomers were revealed through a computational study.

Regio- and Stereoselective α-Allylation with Enolates Prepared from N-C Axially Chiral Thiolactam and Lactam.

The reaction of allyl bromide derivatives with the enolate prepared from enantioenriched N-C axially chiral N-(2,5-di-tert-butylphenyl)-3,4-dihydroquinolin-2-one (lactam) and -thione (thiolactam) proceeded in a completely regio- and stereoselective manner to afford SN2 and SN2'-like products, respectively. Furthermore, through the conversion of thiolactam to lactam, the regiodivergent and stereoselective synthesis of N-C axially chiral lactams bearing a chiral tertiary α-carbon was achieved.

Synthesis of Isotopic Atropisomers Based on 12C/13C Discrimination.

Quinazolin-4-one derivatives possessing an isotopic atropisomerism (isotopic N-C axial chirality) based on ortho-12CH3/13CH3 discrimination were prepared. The diastereomeric quinazolin-4-ones bearing an asymmetric carbon as well as an isotopic atropisomerism were clearly discriminated by 1H and 13C NMR spectra and revealed to possess high rotational stability and stereochemical purity.

Chiral Pd-Catalyzed Enantioselective Syntheses of Various N-C Axially Chiral Compounds and Their Synthetic Applications.

Biaryl atropisomers are key structural components in chiral ligands, chiral functional materials, natural products, and bioactive compounds, and their asymmetric syntheses have been reported by many groups. In contrast, although the scientific community has long been aware of atropisomers due to rotational restriction around N-C bonds, they have attracted scant attention and have remained an unexplored research area. In particular, their catalytic asymmetric synthesis and the synthetic applications were unknown until recently. This Account describes studies conducted by our group on the catalytic enantioselective syntheses of N-C axially chiral compounds and their applications in asymmetric reactions.In the presence of a chiral Pd catalyst, the reactions of achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene proceeded in a highly enantioselective manner (up to 96% ee), affording N-C axially chiral N-arylated ortho-tert-butylanilides in good yields. The application of the present chiral Pd-catalyzed N-arylation reaction to an intramolecular version gave N-C axially chiral lactams with high optical purity (up to 98% ee). These reactions were the first highly enantioselective syntheses of N-C axially chiral compounds with a chiral catalyst. Since the publication of these reactions, N-C axially chiral compounds have been widely accepted as new target molecules for catalytic asymmetric reactions. Furthermore, chiral-Pd-catalyzed intramolecular N-arylations were applied to the enantioselective syntheses of N-C axially chiral quinoline-4-one and phenanthridin-6-one derivatives. We also succeeded in the enantioselective syntheses of various N-C axially chiral compounds using other chiral Pd-catalyzed reactions. That is, optically active N-C axially chiral N-(2-tert-butylphenyl)indoles, 3-(2-bromophenyl)quinazolin-4-ones, and N-(2-tert-butylphenyl)sulfonamides were obtained through chiral Pd-catalyzed 5-endo-hydroaminocyclization, monohydrodebromination (reductive asymmetric desymmetrization), and Tsuji-Trost N-allylation, respectively. The study of the catalytic asymmetric synthesis of axially chiral indoles has contributed to the development of not only N-C axially chiral chemistry but also the chemistry of axially chiral indoles. Subsequently, the catalytic asymmetric syntheses of various indole derivatives bearing a C-C chiral axis as well as an N-C chiral axis have been reported by many groups. Moreover, axially chiral quinazlolin-4-one derivatives, which were obtained through chiral Pd-catalyzed asymmetric desymmetrization, are pharmaceutically attractive compounds; for example, 2-methyl-3-(2-bromophenyl)quinazolin-4-one product is a mebroqualone possessing GABA agonist activity.Most of the N-C axially chiral products have satisfactory rotational stability for synthetic applications, and their synthetic utility was also demonstrated through application to chiral enolate chemistry. That is, the reaction of various alkyl halides with the enolate prepared from the optically active anilide, lactam, and quinazolinone products proceeded with high diastereoselectivity by asymmetric induction due to the N-C axial chirality.At the present time, N-C axially chiral chemistry has become a popular research area, especially in synthetic organic chemistry, and original papers on the catalytic asymmetric syntheses of various N-C axially chiral compounds and their synthetic applications have been published.

Asymmetric Synthesis of Isotopic Atropisomers based on ortho-CH3/CD3 Discrimination and Their Structural Properties.

N-C axially chiral 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-ethylquinazolin-4-ones and 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-(1-phenylpropan-2-yl)quinazolin-4-ones were prepared in high enantio- and diastereomeric purities (98% ee). These quinazolinone derivatives are isotopic atropisomers based on ortho-CH3/CD3 discrimination and were revealed to possess a slight optical rotation and high rotational stability.

Rotational Behavior of N-(5-Substituted-pyrimidin-2-yl)anilines: Relayed Electronic Effect in Two N-Ar Bond Rotations.

N-Methyl-2-methoxymethylanilines 1 bearing various 5-substituted-pyrimidin-2-yl groups were prepared, and their rotational behaviors were explored in detail. It was revealed that the rotational barriers around two N-Ar bonds increase in proportion to the electron-withdrawing ability of substituents X at the 5-position.

Intermolecular Halogen Bond Detected in Racemic and Optically Pure N-C Axially Chiral 3-(2-Halophenyl)quinazoline-4-thione Derivatives.

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities.

Catalytic Enantioselective Synthesis of N-C Axially Chiral N-(2,6-Disubstituted-phenyl)sulfonamides through Chiral Pd-Catalyzed N-Allylation.

Recently, catalytic enantioselective syntheses of N-C axially chiral compounds have been reported by many groups. Most N-C axially chiral compounds prepared through a catalytic asymmetric reaction possess carboxamide or nitrogen-containing aromatic heterocycle skeletons. On the other hand, although N-C axially chiral sulfonamide derivatives are known, their catalytic enantioselective synthesis is relatively underexplored. We found that the reaction (Tsuji-Trost allylation) of allyl acetate with secondary sulfonamides bearing a 2-arylethynyl-6-methylphenyl group on the nitrogen atom proceeds with good enantioselectivity (up to 92% ee) in the presence of (S,S)-Trost ligand-(allyl-PdCl)2 catalyst, affording rotationally stable N-C axially chiral N-allylated sulfonamides. Furthermore, the absolute stereochemistry of the major enantiomer was determined by X-ray single crystal structural analysis and the origin of the enantioselectivity was considered.

Thionation of Optically Pure N-C Axially Chiral Quinazolin-4-one Derivatives with Lawesson's Reagent.

The reaction of various optically pure N-C axially chiral quinazolin-4-one derivatives with Lawesson's reagent proceeded without a marked decrease in optical purity to give optically active quinazoline-4-thione derivatives (93-99% ee) possessing a high rotational barrier in good yields.

Relayed Proton Brake in N-Pyridyl-2-iso-propylaniline Derivative: Two Brakes with One Proton.

The addition of methanesulfonic acid to N-(2,6-dimethylpyridin-4-yl)-N-methyl-2-iso-propylaniline led to the selective protonation of the pyridine nitrogen atom, resulting in a significant deceleration of the rotation rates around both N-pyridyl and N-(i-Pr)phenyl bonds through a relayed brake mechanism.

The self-disproportionation of enantiomers (SDE) of α-amino acid derivatives: facets of steric and electronic properties.

α-Amino acids (α-AAs) are in extremely high demand in nearly every sector of the food and health-related chemical industries and continue to be the subject of intense multidisciplinary research. The self-disproportionation of enantiomers (SDE) is an emerging and one of the least studied areas of α-AA or enantiomeric properties, critically important for their production and application. In the present work, we report a detailed study of the SDE via achiral, gravity-driven column chromatography for a set of N-acylated, N-carbonylated, N-fluoroacylated, and N-thioacylated α-amino acid esters. As well as thioacylation, attention was paid to the effect of altering the R group of the ester functionality, the side chain, or that of the acyl group attached to the amide nitrogen, whereby it was found that electron-withdrawing groups in the latter moiety had a pronounced effect on the magnitude and behavior of the resulting SDE phenomenon. Intriguingly, in the case of N-fluoroacylated derivatives, by favoring the formation of dimeric associates and effecting a strong bias toward homochiral associates over heterochiral associates, the SDE magnitude was greatly reduced contrary to intuitive expectations. Energy estimates resulted from DFT calculations.

Catalytic Enantioselective Synthesis of N-C Axially Chiral Sulfonamides through Chiral Palladium-Catalyzed N-Allylation.

In the presence of ( S,S)-Trost ligand and (allyl-Pd-Cl)2 catalyst, the reaction of allyl acetate with the anionic species prepared from various N-(2- tert-butylphenyl)sulfonamides and NaH proceeded in an enantioselective manner (up to 95% ee) to give optically active N-allylated sulfonamide derivatives possessing an N-C axially chiral structure in high yields.

N-C Axially Chiral Compounds with an ortho-Fluoro Substituent and Steric Discrimination between Hydrogen and Fluorine Atoms Based on a Diastereoselective Model Reaction.

The fluorine atom is the second smallest atom; nevertheless, the ortho-fluoro group may lead to stable N-aryl atropisomers when the steric demand of the flanking substituents is large enough. 2-Alkyl-3-(2-fluorophenyl)quinazolin-4-ones and 3-(2-fluorophenyl)-4-methylthiazoline-2-thione were found to be the first N-aryl axially chiral compounds bearing an ortho-fluoro group whose enantiomers were isolated at ambient temperature. The reaction of alkyl halides with the anionic species prepared from 2-ethyl-3-(2-fluorophenyl)quinazolin-4-one presenting an N-C axial chirality provided a model reaction for quantitative evaluation of the steric discrimination (slight difference of steric factor) between hydrogen and fluorine atoms. In the case of low steric demand (allylation reaction) no diastereoselectivity was detected, while in the case of high steric demand (isopropylation reaction) the diastereoselectivity became significant.

N-C Axially Chiral Anilines: Electronic Effect on Barrier to Rotation and A Remote Proton Brake.

N-Aryl-N-methyl-2-tert-butyl-6-methylaniline derivatives exhibit a rotationally stable N-C axially chiral structure and the rotational barriers around an N-C chiral axis increased with the increase in electron-withdrawing character of para-substituent on the aryl group. X-ray crystal structural analysis and the DFT calculation suggested that the considerable change of the rotational barriers by the electron effect of para-substituents is due to the disappearance of resonance stabilization energy caused by the twisting of para-substituted phenyl group in the transition state. This structural property of the N-C axially chiral anilines was employed to reveal a new acid-decelerated molecular rotor caused by the protonation at the remote position (remote proton brake).

Possible Case of Halogen Bond-Driven Self-Disproportionation of Enantiomers (SDE) via Achiral Chromatography.

The major breakthrough reported in this work is the discovery of likely halogen bond-driven self-disproportionation of enantiomers (SDE). Taking into account that the halogen-bonding interactions can be rationally designed and can match, or even exceed, the strength of the more familiar hydrogen bond, this discovery clearly opens an unexpected new direction of research in the areas of molecular chirality and the SDE phenomenon.

Catalytic Enantioselective Synthesis of N-C Axially Chiral Phenanthridin-6-one Derivatives.

N-C axially chiral phenanthridin-6-one derivatives bearing various ortho-substituted phenyl groups on the nitrogen atom were enantioselectively prepared through (R)-DTBM-SEGPHOS-Pd(OAc)2-catalyzed intramolecular Buchwald-Hartwig amination. The enantioselectivity strongly depended on solvents, bases, and reaction temperature as well as on the bulkiness of ortho-substituents.

Unique structural properties of 2,4,6-tri-tert-butylanilide: isomerization and switching between separable amide rotamers through the reaction of anilide enolates.

Herein, we report a unique structural property of 2,4,6-tri-tert-butylanilide, which can be separated into its amide rotamers at room temperature. Interconversion between the rotamers of anilide enolates occurs readily at room temperature and their reaction with electrophiles gives mixtures of the rotamers in a ratio that depends on the reactivity of the corresponding electrophile. That is, the reaction of the 2,4,6-tri-tert-butylacetanilide enolate with reactive electrophiles, such as allyl bromide or protic acids, gives mixtures of the anilide rotamers in which the E rotamer is the major component, whereas less-reactive electrophiles, such as 1-bromopropane and 2-iodopropane, yield mixtures of the rotamers in which the Z rotamer is the major component. The rotameric ratio of the product is also strongly dependent on the reactivity of the anilide enolate. Switching between the anilide rotamers can be achieved through protonation of a less-reactive enolate by a less-reactive protic acid and thermal isomerization of the anilide.

Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications.

This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral-phase chromatography.

Chirality Transfer Intramolecular Pauson-Khand Reaction with N-C Axially Chiral Sulfonamides Bearing an Ene-Yne Structure.

An intramolecular Pauson-Khand reaction with enantioenriched N-C axially chiral N-allyl-N-(2-alkynylphenyl)sulfonamide derivatives proceeded with complete chirality transfer from axial chirality (P configuration) to central chirality (R configuration), affording chiral nitrogen-containing tricyclic compounds (tetrahydrocyclopentaquinolin-2-one derivatives).

Detection of Isotopic Atropisomerism Based on ortho-H/D Discrimination.

Racemic and optically active 3-(2-deuteriophenyl)-2-(1-phenylpropan-2-yl)quinazoline-4-thiones were prepared. The nuclear magnetic resonance spectra clearly show that they exist as a 1:1 mixture of diastereomers due to the isotopic atropisomerism based on ortho-H/D discrimination (N-C axial chirality) and a chiral carbon.