Asymmetric synthesis of axially chiral benzamides and anilides utilizing planar chiral arene chromium complexes

Optically active axially chiral 2,6-disubstituted benzamides and anilides were stereoselectively prepared by utilizing planar chiral (arene)chromium complexes. Nucleophilic addition to enantiomerically pure planar chiral tricarbonyl(N,N-diethyl-2-methyl-6-formyl- (or 6-acyl)benzamide)chromium complex gave axially chiral 2-methyl-6-substituted N,N-diethyl benzamide chromium complexes with high selectivity. An alternative method for the preparation of axial chiral benzamides or anilides is an enantiotopic lithiation at the benzylic methyl of prochiral tricarbonylchromium complexes of N,N-diethyl-2,6-dimethylbenzamide and N-methyl-N-acyl-2,6-dimethylaniline with a chiral lithium amide followed by electrophilic substitution. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized in air to give chromium-free axially chiral benzamides and anilides in enantiomerically enriched form without axial bond rotation at room temperature.     

Asymmetric Synthesis of Axially Chiral Anilides by Enantiotopic Lithiation of Tricarbonyl(N-methyl-N-acyl-2,6-dimethylanilide)chromium Complex

Axially chiral N-methylanilides were synthesized by enantioselective lithiation of prochiral tricarbonyl(N-methyl-N-pivaloyl-2,6-dimethylaniline)chromium (1) with the lithium amide of the 4-methylpiperazinylethylamine derivative 13 followed by electrophilic quenching up to 97% ee in good yields. The resulting axially chiral chromium-complexd anilides 2 were oxidized under air to give the axially chiral anilides 14 in enantiomerically active form without axial bond rotation at room temperature.     

Enantioselective synthesis of axially chiral anilides through rhodium-catalyzed [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides

We have developed a rhodium-catalyzed enantioselective intermolecular [2+2+2] cycloaddition of 1,6-diynes with trimethylsilylynamides for the synthesis of axially chiral anilides. The axial chirality is constructed at the formation of benzene rings with high enantioselectivity (up to 98% ee). It should be noted that the present reaction employs the readily prepared trimethylsilylynamides starting from commercially available bis(trimethysilyl)acetylene and the trimethylsilyl group of the product anilides is expected to be utilized for further functionalization.     

Phase‐Transfer‐Catalyzed Asymmetric Synthesis of Axially Chiral Anilides

Catalytic asymmetric synthesis of axially chiral o‐iodoanilides and o‐tert‐butylanilides as useful chiral building blocks was achieved by means of binaphthyl‐modified chiral quaternary ammonium‐salt‐catalyzed N‐alkylations under phase‐transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N‐allyl‐o‐iodoanilide was transformed to 3‐methylindoline by means of radical cyclization with high chirality transfer from axial chirality to C‐centered chirality. Furthermore, stereochemical information on axial chirality in o‐tert‐butylanilides could be used as a template to control the stereochemistry of subsequent transformations. The transition‐state structure of the present phase‐transfer reaction was discussed on the basis of the X‐ray crystal structure of ammonium anilide, which was prepared from binaphthyl‐modified chiral ammonium bromide and o‐iodoanilide. The chiral tetraalkylammonium bromide as a phase‐transfer catalyst recognized the steric difference between the ortho substituents on anilide to obtain high enantioselectivity. The size and structural effects of the ortho substituents on anilide were investigated, and a wide variety of axially chiral anilides that possess various functional groups could be synthesized with high enantioselectivities. This method is the only general way to access a variety of axially chiral anilides in a highly enantioselective fashion reported to date.     

Synthesis of Axially Chiral Anilides Enabled by a Palladium/Ming-Phos-Catalyzed Desymmetric Sonogashira Reaction

Atropisomeric anilides are one of important C—N axially chiral compounds.Compared with the N-terminal functionalization to pre-pare such compounds,C-terminal fu...     

Synergistic effect of palladium and copper catalysts: catalytic cyclizative dimerization of ortho-(1-alkynyl)benzamides leading to axially chiral 1,3-butadienes

Two is better than one: In the presence of Pd(OAc)(2) and Cu(OAc)(2), o-(1-alkynyl)benzamides 1 were converted into bis-iminobenzoisofurans with an axially chiral 1,3-diene 2 unit. The coexistence of both Pd and Cu?catalysts was found to be essential for both the cyclizative dimerization process and for the observed unusual cyclization mode.     

Asymmetric Synthesis of Axially Chiral C−N Atropisomers

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C−C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C−N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C−N axes. The preparation of different families of C−N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.     

Rhodium-Catalyzed ortho-Olefination of Sterically Demanding Benzamides: Application to the Asymmetric Synthesis of Axially Chiral Benzamides

It has been established that an unsubstituted cyclopentadienyl rhodium(III) (CpRh^III) complex is a highly active catalyst for the aerobic oxidative ortho C−H bond olefination of sterically demanding ortho-substituted benzamides with alkenes. This catalysis was successfully applied to the diastereoselective synthesis of axially chiral N,N-dialkylbenzamides. The combination of the ruthenium(II)-catalyzed enantioselective hydrogenation and the CpRh^III-catalyzed diastereoselective ortho C−H bond olefination enabled the asymmetric synthesis of axially chiral N,N-dialkylbenzamide derivatives with high ee values.     

Stereoselective synthesis of both enantiomers of N-aryl indoles with axially chiral N-C bonds

N-Aryl indoles with axially chiral N-C bonds were synthesized by stereoselective nucleophilic aromatic substitution reactions of planar chiral tricarbonyl(2,6-disubstituted-1-fluorobenzene)chromium complexes. The stereochemistry of the products is highly dependent on the position of the substituent in the indole. When indoles devoid of a substituent at the 2-position were used, N-aryl indole chromium complexes having anti orientation with respect to the tricarbonylchromium fragment were obtained diastereoselectively. In contrast, 2-substituted indoles gave the N-aryl indoles with syn orientation between the tricarbonylchromium fragment and the benzene ring of the indole. These results demonstrate that we have succeeded in synthesizing both enantiomers of N-aryl indoles utilizing an identical planar chiral arene chromium complex.     

Axial Chirality in Alkylidene-Cyclic Molecules

Axial chirality is an interesting stereoisomeric phenomenon in organic chemistry and a key structural feature of several organic compounds. Atropisomers such as biaryls, anilides and diaryl ethers are one type of axially chiral compounds, whose axial chirality is resulted from rotationally blocked single bond. Allenes, spiranes and alkylidenecycloalkanes are another type of axially chiral compounds and their axial chirality come from the perpendicular geometry of two pairs of substituents. The axial chirality in atropisomers, allenes and spiranes has been widely investigated and well developed, while the similar chirality in alkylidene-cyclic molecules gained very limited attentions. This concept focuses on summarizing recent advances of axial chirality in alkylidene-cyclic molecules and arouses the research interests to this promising field.     

Ruthenium-catalyzed oxidative C-H alkenylations of anilides and benzamides in water

A cationic ruthenium(II) complex enabled efficient oxidative alkenylations of anilides in water as a green solvent and proved applicable to double C-H bond functionalizations of (hetero)aromatic amides with ample scope. Detailed studies provided strong support for a change of ruthenation mechanism in the two transformations, with an irreversible metalation as the key step in cross-dehydrogenative alkenylations of benzamides.     

Iron‐Catalyzed C(sp2)H and C(sp3)H Methylations of Amides and Anilides

The so‐called magic methyl effect significantly boosts the bioactivities and physical properties of pharmacologically active drugs. Direct introduction of the methyl group by C?H activation was accomplished with a versatile iron catalyst, which enabled the C?H methylation of (hetero)benzamides, anilides, alkenes, and even alkanes by triazole assistance in a chemo‐, site‐ and diastereo‐selective fashion.     

NCN pincer palladium complexes: their preparation via a ligand introduction route and their catalytic properties

A wide range of NCN pincer palladium complexes, [4-tert-butyl-2,6-bis(N-alkylimino)phenyl]chloropalladium (alkyl = n-butyl, benzyl, cyclohexyl, tert-butyl, adamantyl, phenyl, 4-methoxyphenyl), were readily prepared from trans-(4-tert-butyl-2,6-diformylphenyl)chlorobis(triphenylphosphine)palladium via dehydrative introduction of the corresponding alkylimino ligand groups (ligand introduction route) in excellent yields (71-98%). NMR studies on this route for forming pincer complexes revealed the intermediacy of [4-tert-butyl-2,6-bis(N-alkylimino)phenyl]chlorobis(triphenylphosphine)palladium which is in equilibrium with the corresponding NCN pincer complexes via coordination/dissociation of the intramolecular imino groups and triphenylphosphine ligands. A series of chiral NCN pincer complexes bearing pyrroloimidazolone units as the trans-chelating donor groups, [4-tert-butyl-2,6-bis{(3R,7aS)-2-phenylhexahydro-1H-pyrrolo[1,2-c]imidazol-1-on-3-yl}phenyl]chloropalladium, were also prepared from the same precursor via condensation with proline anilides in high yields. The catalytic properties of the NCN imino and the NCN pyrroloimidazolone pincer palladium complexes were examined in the Heck reaction and the asymmetric Michael reaction to demonstrate their high catalytic activity and high enantioselectivity.     

Structural optimization of a chiral selector for use in preparative enantioselective chromatography

Utilizing the immobilized-target strategy, the structure of a proline-derived chiral stationary phase was optimized for use in the preparative chromatographic separation of the enantiomers of two chiral selectors used in commercial chiral stationary phases. In this study, various N-acylated proline anilides were prepared and chromatographed on the commercial Pirkle-1J and -Burke 2 chiral stationary phases. The analyte which displayed the greatest retention without sacrifice of enantioselectivity (the 3,5-dimethoxyanilide of N-undecenoyl proline) was chosen for incorporation into the preparative chiral stationary phase. Once prepared, this phase shows increased analyte retention and enantioselectivity comparable to that of earlier phases derived from 3,5-dimethyl anilides of proline. The increased retention allows one to use mobile phases in which the target analytes are more soluble, hence greatly facilitating an increase in the through-put of a column of a given size.     

Asymmetric synthesis of axially chiral biaryls: inversion of planar chirality vs axial isomerization and functionalization at the side chain of biaryl chromium complexes

Axially chiral syn-biaryl chromium complexes having a coordinating heteroatom substituent at the benzylic position gave anti-biaryl chromium complexes 5 with inversion of the planar chirality by heating in a nonaromatic solvent, while syn-biaryl chromium complexes with an o-methyl or formyl substituent afforded axially isomerized anti-biaryl chromium complexes under heating in an aromatic solvent. syn-biaryl and both enantiomeric anti-biaryl chromium complexes with the o-formyl group were stereoselectively prepared from an identical planar chiral arene chromium complex as chiral source. The formyl group of the axially chiral chromium complexes was functionalized by radical cyclization and beta-lactam formation, and hetero-Diels-Alder reaction.     

Reaction of 2-polyfluoroalkylchromones with 1,3,3-trimethyl-3,4-dihydroisoquinolines and methylketimines as a direct route to zwitterionic axially chiral 6,7-dihydrobenzo[a]quinolizinium derivatives and 2,6-diaryl-4-polyfluoroalkylpyridines

[reaction: see text] 2-Polyfluoroalkylchromones react with 1,3,3-trimethyl-3,4-dihydroisoquinolines to give zwitterionic axially chiral 6,7-dihydrobenzo[a]quinolizinium derivatives in high yields. In addition, performing this reaction with aromatic methylketimines is a simple and convenient synthesis of 2,6-diaryl-4-polyfluoroalkylpyridines.     

Palladium-catalyzed asymmetric synthesis of axially chiral (allenylmethyl)silanes and chirality transfer to stereogenic carbon centers in S(E)' reactions

[reaction: see text] Novel stereoselective reactions of 4-substituted-1-trimethylsilyl-2,3-butadienes ((allenylmethyl)silanes) were developed. The axially chiral (allenylmethyl)silanes were prepared from (3-bromopenta-2,4-dienyl)trimethylsilane by a Pd-catalyzed asymmetric reaction with soft nucleophiles with up to 88% enantioselectivity. The (allenylmethyl)silanes reacted with acetals in the presence of a TiCl(4) promoter to give 1,3-diene derivatives via an S(E)' pathway. The 1,3-dienyl products have (E)-geometry exclusively and up to 88%( )()chirality transfer from the axially chiral allenes to the centrally chiral 1,3-dienes was observed in the S(E)' reaction.     

Characteristics of lithium iodide-containing poly(ethylene glycol) as a gas chromatographic stationary phase, and its application to analysis of amidic drugs

The characteristics of lithium iodide-containing poly(ethylene glycol) as a gas chromatographic stationary phase have been evaluated in terms of partial free energy of transfer (delta G t0) from poly(ethylene glycol) to the lithium iodide-poly(ethylene glycol) system for a variaty of amides (n-fatty acid amides, lactams, benzamides, anilides, nicotinamides, isonicotinamides, barbiturates, pyrazolones) and several amines. The changes in relative retention and resolution of two solute peaks caused by the addition of lithium iodide to poly)ethylene glycol) are correlated with the difference in their delta Gt0 values. The application to the specific separation of some amidic drugs is demonstrated.     

Stereochemical control of both C-C and C-N axial chirality in the synthesis of chiral N,O-biaryls

A Rh(I)-catalyzed asymmetric [2 + 2 + 2] cycloaddition of achiral ynamides is described here. This work demonstrates a unique concept of stereochemical control of both the C-C and C-N axial chirality and provides an approach to the synthesis of chiral N,O-biaryls as well as chiral anilides.     

Rhodium-Catalyzed Atroposelective Access to Axially Chiral Olefins via C−H Bond Activation and Directing Group Migration

Axially chiral open-chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C?H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N-aminocarbonyl directing group afforded C–N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a β-nitrogen elimination–reinsertion pathway for the directing group migration. Meanwhile, the employment of N-phenoxycarboxamide delivered C?C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well-defined orientation during the C?H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.