Lithiated imines: solvent-dependent aggregate structures and mechanisms of alkylation

We describe efforts to understand the structure and reactivity of lithiated cyclohexanone N-cyclohexylimine. The lithioimine affords complex solvent-dependent distributions of monomers, dimers, and trimers in a number of ethereal solvents. Careful selection of solvent provides exclusively monosolvated dimers. Rate studies on the C-alkylations reveal chronic mixtures of monomer- and dimer-based pathways. We explore the factors influencing reactants and alkylation transition structures and the marked differences between lithioimines and isostructural lithium dialkylamides with the aid of density functional theory calculations.     

Chemo- and regioselectivity-tunable Pd-catalyzed allylic alkylation of imines

α-Carbanions of cyclic and acyclic imines have been successfully applied as nucleophiles in the Pd-catalyzed allylic alkylation reaction. Tuning of chemo- and regioselectivity has been realized by using t-BuOK/THF and LDA/toluene to give branched and linear products, respectively, with high regio- and diastereoselectivities. A plausible mechanism is proposed on the basis of the experimental results and DFT calculations.     

The selective reductive acylation of a-keto imines

Reaction of α-keto imines with the $\text{in}$$\text{situ}$ generated acetylcobalt tetracarbonyl occurs only at the carbon—nitrogen double bond to give β-keto amides. An unexpected by-product was formed in several instances.     

Regioselectivity of Birch reductive alkylation of biaryls

[reaction: see text] The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, providing that the acidic proton has been removed prior to the Li/NH3 reduction.     

Quinolinophane-derived alkyldiphenylphosphines: two homologous P,N-planar chiral ligands for palladium-catalysed allylic alkylation

Two novel homologous [2]paracyclo[2](5,8)quinolinophane-derived P,N-bidentate planar chiral ligands have been synthesised and their effectiveness in asymmetric catalysis tested in palladium-catalysed allylic malonylation of 1,3-diphenylpropenyl acetate. The extent of asymmetric induction depends linearly on the ligand/metal molar ratio, indicating the involvement of P,P-type and chelate P,N-type π-allylpalladium complexes in equilibrium. The length of the chain that binds the diphenylphosphine group to the quinolinophane moiety, while appreciably affecting the P,N-complex stability, has little effect on the extent of asymmetric induction, which is due to the greater reactivity of the [PN]-exo–syn–syn– ([PN]_xss) with respect to the [PN]-endo–syn–syn– ([PN]_nss) π-allylpalladium complex.     

Zirconium-mediated metathesis of imines: a study of the scope, longevity, and mechanism of a complicated catalytic system

By kinetically stabilizing imidozirconocene complexes through the use of a sterically demanding ligand, or by generating a more thermodynamically stable resting state with addition of diphenylacetylene, we have developed transition metal-catalyzed imine metathesis reactions that are mechanistically analogous to olefin metathesis reactions catalyzed by metal carbene complexes. When 5 mol % of Cp*Cp(THF)Zr=N(t)Bu is used as the catalyst precursor in the metathesis reaction between PhCH=NPh and p-TolCH=N-p-Tol, a 1:1:1:1 equilibrium mixture with the two mixed imines p-TolCH=NPh and PhCH=N-p-Tol is generated in C(6)D(6) at 105 degrees C. The catalyst was still active after 20 days with an estimated 847 turnovers (t(1/2) 170 m; TON = 1.77 h(-1)). When the azametallacyclobutene Cp(2)Zr(N(Tol)C(Ph)=C(Ph)) is used as the catalyst precursor under similar reaction conditions, a total of 410 turnovers are obtained after 4 days (t(1/2) 170 m; TON = 4.3 h(-1)). An extensive kinetic and equilibrium analysis of the metallacyclobutene-catalyzed metathesis of PhCH=N-p-Tol and p-F-C(6)H(4)CH=N-p-F-C(6)H(4) was carried out by monitoring the concentrations of imines and observable metal-containing intermediates over time. Numerical integration methods were used to fit these data to a detailed mechanism involving coordinatively unsaturated (16-electron) imido complexes as critical intermediates. Examination of the scope of reaction between different organic imines revealed characteristic selectivity that appears to be unique to the zirconium-mediated system. Several zirconocene complexes that could generate the catalytically active "CpCp'Zr=NAr" (Cp' = Cp or Cp*) species in situ were found to be effective agents in the metathetical exchange between different N-aryl imines. N-Alkyl aldimines were found to be completely unreactive toward metathesis with N-aryl aldimines, and metathesis reactions involving the two N-alkyl imines TolCH=NPr and PhCH=NMe gave slow or erratic results, depending on the catalyst used. Metathesis was observed between N-aryl ketimines and N-aryl aldimines, but for N-aryl ketimine substrates, the catalyst resting state consists of zirconocene enamido complexes, generated by the formal C-H activation of the alpha position of the ketimine substrates.     

The Pd-catalysed asymmetric allylic alkylation reactions of sulfamidate imines

The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5H-oxathiazole 2,2-dioxides has been developed. Various 4,5-disubstituted and 4-substituted cyclic sulfamidate imines have participated in the transformation with a range of allyl carbonates—as well as 2-vinyl oxirane, 2-vinyl-N-tosylaziridine, and 2-vinyl-1,1-cyclopropane dicarboxylate—to furnish the desired C-allylated products in moderate to high yields, with high regioselectivites and generally high enantioselectivities. Conversion between N- and C-allyl products was observed, with the N-allylated products converting to the C-allylated products over time. The resulting high-value allylated heterocyclic products all bear a tetrasubstituted stereogenic centre and can be reduced to an allylated chiral sulfamidate or an amino alcohol.

The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5H-oxathiazole 2,2-dioxides has been developed.     

Indium-copper-mediated barbier-grignard-type alkylation reaction of imines in aqueous media

An efficient system of In/CuI/InCl3 was developed for Barbier-Grignard-type alkylation reactions of simple imines, using a one-pot condensation of various aldehydes, amines (including aliphatic and chiral version), and alkyl iodides in water or aqueous media. The reactions proceeded efficiently at room temperature to give the desired products in moderate to good yields. Good diastereoselectivities were obtained when using L-valine methyl ester as substrate.     

A practical nickel-catalyzed reductive alkylation of amidophenyl bromides

A modified Weix's reductive coupling for alkylation of amidoaryl bromides based on Ni(COD)₂ precatalyst and 2,2′-dipyridyl ligand was developed. This reaction is reliable for amidophenyl bromides and gives yields up to 87%, and is potentially useful in the synthesis of amidophenyl-containing molecules.     

Tandem base-promoted ring-opening/Brook rearrangement/allylic alkylation of O-silyl cyanohydrins of beta-silyl-alpha,beta-epoxyaldehyde: scope and mechanism

Metalated O-silyl cyanohydrins of beta-silyl-alpha,beta-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem sequence involving base-promoted ring opening of the epoxide, Brook rearrangement, and alkylation of the resulting allylic anion. On the basis of mechanistic studies involving competitive experiments using the diastereomeric cyanohydrins, we propose a reaction pathway involving a silicate intermediate 36 formed by a concerted process via an anti-opening of the epoxide followed by the formation of an O-Si bond.     

Expanded scope of heterocyclic biaryl synthesis via a palladium-catalysed thermal decarboxylative cross-coupling reaction

The palladium-catalysed decarboxylative cross-coupling of heterocyclic aromatic carboxylates and aryl halides is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and tetrabutylammonium bromide (TBAB). Utilizing a mixed solvent system consisting of N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), the cross-coupling system operated at temperatures ranging from 80 to 140 °C.     

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.     

Ruthenium-catalyzed azide-alkyne cycloaddition: scope and mechanism

The catalytic activity of a series of ruthenium(II) complexes in azide-alkyne cycloadditions has been evaluated. The [Cp*RuCl] complexes, such as Cp*RuCl(PPh 3) 2, Cp*RuCl(COD), and Cp*RuCl(NBD), were among the most effective catalysts. In the presence of catalytic Cp*RuCl(PPh 3) 2 or Cp*RuCl(COD), primary and secondary azides react with a broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-disubstituted 1,2,3-triazoles; tertiary azides were significantly less reactive. Both complexes also promote the cycloaddition reactions of organic azides with internal alkynes, providing access to fully-substituted 1,2,3-triazoles. The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling of the azide and alkyne reactants to give a six-membered ruthenacycle intermediate, in which the first new carbon-nitrogen bond is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic nitrogen of the azide. This step is followed by reductive elimination, which forms the triazole product. DFT calculations support this mechanistic proposal and indicate that the reductive elimination step is rate-determining.     

Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation

The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.     

Stereoselective synthesis of trans beta-lactams through iridium-catalyzed reductive coupling of imines and acrylates

[reaction: see text] Iridium-catalyzed reductive coupling of acrylates and imines provides trans beta-lactams with high diastereoselection. The optimal catalyst allows for the synthesis of trans beta-lactams bearing aromatic, alkenyl, and alkynyl side chains. This reaction appears to proceed through a reductive Mannich addition-cyclization mechanism. Examination of substituent effects reveals a linear Hammett correlation for both the N-aryl group on the imine and the aryloxy group on the acrylate, thereby pointing to rate-determining cyclization in the reaction mechanism.     

Iridium-catalyzed allylic alkylation reaction with N-aryl phosphoramidite ligands: scope and mechanistic studies

A series of N-aryl phosphoramidite ligands has been synthesized and applied to iridium-catalyzed allylic alkylation reactions, offering high regio- and enantioselectivities for a wide variety of substrates. These ligands feature the synthetic convenience and good tolerance of the ortho-substituted cinnamyl carbonates. Mechanistic studies, including DFT calculations and X-ray crystallographic analyses of the (π-allyl)-Ir complexes, reveal that the active iridacycle is formed via C(sp(2))-H bond activation.     

Synthesis of P-chirogenic diarylphosphinoacetic acids and their proline derivatives for palladium-catalysed allylic alkylation reactions

The synthesis of P-chirogenic diarylphosphinocarboxylic acids was achieved, from which a new class of amido- and amino-diphosphine ligands (PNP*) were derived, containing an l-proline backbone. The catalytic activities of the novel ligands were evaluated in the palladium-catalysed allylic alkylation reaction of 1,3-diphenylpropenyl acetate.