Chiral pyridine N-oxides derived from monoterpenes as organocatalysts for stereoselective reactions with allyltrichlorosilane and tetrachlorosilane

The synthesis of enantiomerically pure C₂-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C₂-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.     

New pyridine N-oxides as chiral organocatalysts in the asymmetric allylation of aromatic aldehydes

Asymmetric allylation of aromatic aldehydes 1 with allyltrichlorosilane (2) can be catalyzed by new terpene-derived bipyridine N,N′-dioxides 12-15 and an axially chiral biisoquinoline dioxide 17b with good enantioselectivities. Dioxides have been found to be more reactive catalysts than their monooxide counterparts.     

Enantioselective cyanosilylation of ketones catalyzed by double-activation catalysts with N-oxides

Enantioselective addition of trimethylsilyl cyanide to ketones by a catalytic double-activation method is described. By combinatorially using 2.0 mol% of a chiral salen-titanium complex and 1.0 mol% of an achiral tertiary amine N-oxide, aromatic, aliphatic and α,β-unsaturated ketones are converted into corresponding cyanohydrin trimethylsilyl ethers with 50-93% yield and 59-86% ee. The effects of ligand structure, catalyst loading and substrate concentration, solvents, the nature of Lewis base, counter ion and other additives, temperature, and substrate structure on the enantioselectivity are discussed. Three possible paths to achieve the asymmetric version of double-activation catalysis and two independent examples of it are proposed.     

A novel method for the reduction of sulfoxides and pyridine N-oxides with the system silane/MoO2Cl2

A novel method for the reduction of sulfoxides and pyridine N-oxides using a silane and a catalytic amount of MoO₂Cl₂ in excellent yields and with a wide functional group tolerance is reported. A green protocol for this reaction was developed in water with the air-stable catalytic system PMHS/MoO₂Cl₂(H₂O)₂.     

A novel reagent combination for the oxidation of highly electron deficient pyridines to N-oxides: trifluoromethanesulfonic anhydride/sodium percarbonate

A novel reagent combination, Tf₂O/Na₂CO₃·1.5H₂O₂, has been developed for the oxidation of highly electron deficient pyridines to their corresponding N-oxides. The N-oxidation reaction, utilizing the in situ generated peracid, proceeds under mild conditions that allow for a number of functional groups and substitution patterns on the pyridine ring.     

Access to lincomycin N-oxide isomers controlled by reaction conditions

Oxidation of lincomycin with H₂O₂ in alkaline media leads to N-oxides, besides the conversion of thiomethyl group into sulfoxides and sulfones. NH₄OH favors formation of the S-isomer; both R- and S-isomers of the N-oxide are formed in the presence of NaOH. Addition of acetonitrile markedly accelerates the reaction.     

Synthesis of 7-aryl-1,8-naphthyridines via addition of aryl boronic acids to 1,8-naphthyridine N-oxides

Simply combining aryl boronic acids with 1,8-naphthyridine N-oxides and heating at 110 °C in toluene or dimethylformamide affords the corresponding 7-aryl-1,8-naphthyridines. The reaction is not sensitive to air or moisture and the process can be extended to other electron-deficient heteroaromatic N-oxides.     

Cu(I)-mediated deoxygenation of N-oxides to amines

A mild and highly efficient deoxygenation of variety of N-oxides using an inexpensive CuX, or a CuX-Zn or CuX-Al couple is described.     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Efficient iodine catalyzed chemoselective synthesis of aminals—an access to N,N-acetals by the addition of lactams to N-acyl imines

A highly efficient protocol has been developed for the synthesis of aminals from γ-butyrolactam and benzaldehyde using iodine as Lewis acid catalyst. The attack of γ-butyrolactam nucleophile to intermediate N-acyliminium ion was more favorable, when aryl aldehyde bears the electron donating group (EDG). Iodine plays a key role in these reaction transformations. This current mild protocol is environmentally benign and cost-effective method for the synthesis of industrially and pharmaceutically useful scaffolds.     

Nickel-catalysed addition of dialkylzinc reagents to N-phosphinoyl- and N-sulfonylimines

A catalytic amount of a nickel complex (0.1-5.3 mol %) extraordinarily increases the reaction rate of the addition of dialkylzinc reagents to N-(diphenylphosphinoyl)- or N-(benzenesulfonyl)imines. The reaction of imines derived from both aromatic and aliphatic aldehydes with various dialkylzinc reagents in the presence of several nickel complexes gives the expected addition products in most cases in 1 h and in very good yields. In general, the formation of reduction by-products was not an important side reaction. The process represents a great improvement, with regard to the reaction rate and the yield of the addition products, in comparison with the reactions performed in the absence of the nickel catalyst, and reaction times are much shorter than the ones reported so far using other catalysts.     

Copper powder-catalyzed N-arylation of imidazoles in water using 2-(hydrazinecarbonyl)pyridine N-oxides as the new ligands

2-(2-Hydrazinecarbonyl)pyridine N-oxides, which were derived from pyrrole-2-carbohydrazides and pyridine N-oxides, were synthesized and utilized as the ligands for copper powder-catalyzed N-arylation of imidazoles with aryl halides in water. Imidazoles could be arylated smoothly with various aryl halides to provide the title products in preferable yields without the need of an inert atmosphere.     

N-Polyfluoro(trimethylsilyl)ethyl azole derivatives

A facile synthetic route to N-polyfluoro(trimethylsilyl)ethyl azole derivatives was developed starting from N-bromo(chloro)polyfluoroethyl-substituted azoles. The silanes thus obtained were reacted with various electrophiles in the presence of the fluoride ion to yield the corresponding fluorinated carbinols, ketones, carboxylic acids, and methyl dithiocarboxylates as well as N-pentafluoroethylbenzimidazole.     

Catalytic photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine and carbon dioxide

Photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine (TMB) in MeCN under bubbling of CO₂ proceeded with high catalytic efficiency, giving 3,3-diphenylacrylic acid (DPA) and 3-hydroxy-3,3-diphenylpropionic acid (20). The turnover number (TON=(DPA+20)/TMB) reached 17. Similarly, 1-phenyl-1-cyclohexene yielded cis-2-acetamido-2-phenylcyclohexanecarboxylic acid with TON 5.9. As compared with related N,N-dimethylaniline derivatives, TMB is more resistant to photodecomposition, has the much larger absorbance in the S₀→S₁ transition, and has the lower quenching efficiency by CO₂. Probably these factors are partly responsible for the high TON observed for TMB.     

Synthesis and reactions of 3-halomethyl-substituted oxazine N-oxides

A series of 3-halomethyl-5,6-dihydro-1,2-oxazine N-oxides (halogen = Cl, Br, I) is prepared from 4-phenyl-3,6,6-trimethyl-5,6-dihydro-4H-oxazine N-oxide by means of a silylation/halogenation sequence. The obtained halogenated N-oxides undergo reactions typical of cyclic six-membered nitronates including 1,3-dipolar cycloaddition, addition of nucleophiles, and substitution of the halogen by C-, S-, and N-nucleophiles.     

Solid-phase synthesis of benzimidazole N-oxides on SynPhase™ Lanterns

A solid-phase synthesis of benzimidazole N-oxides was developed while attempting to synthesize 1,5-benzodiazepine-2,4-diones. The key step of the synthesis involves the reduction of an arylnitro to a hydroxyamino intermediate which subsequently condenses with an internal carbonyl group to give a benzimidazole N-oxide. A library of nine benzimidazole N-oxides was prepared on SynPhase™ Lanterns using this reduction-cyclization methodology.     

Aerobic alcohol oxidation using a PdCl2/N,N-dimethylacetamide catalyst system under mild conditions

A new and simple PdCl₂/DMA catalytic system for the alcohol oxidation has been developed using molecular oxygen as the sole oxidant under mild conditions. The catalytic system could be reused for three runs without significant loss of catalytic activity. A variety of active and non-active alcohols were oxidized to their corresponding carbonyl compounds in good to excellent yields. Gas-uptake kinetics for the catalytic system was also investigated. The ca. 1:1 molar ratio of O₂ uptake to product yield is observed, suggesting the in situ formation of H₂O₂.     

Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by chiral N,N-dioxides and monodentate N-oxides

Chiral N,N^′-dioxides and monodentate N-oxides were employed as catalysts in catalytic, enantioselective aldol reactions of trichlorosilyl enol ethers. The reactions of acyclic enol ethers using N,N^′-dioxides resulted in the anti-adducts from (E)-enol ethers and the syn-adducts from (Z)-enol ethers. The reactions of cyclic (E)-enol ethers using N,N^′-dioxides gave the anti-adducts, whereas monodentate N-oxides predominantly gave the syn-adducts.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.     

Electrochemical fluorination of N,N-dimethylperfluoroacylamides

The electrochemical fluorination (ECF) of N,N-dimethylperfluoroacylamides gives the corresponding perfluoro-N,N-dimethylacylamides in low yield. With increase of the number of carbon atoms in the perfluoroacyl radical the yield of the required perfluoro-N,N-dimethylacylamides is slightly increased.