Benzylation of nitroalkanes using copper-catalyzed thermal redox catalysis: toward the facile C-alkylation of nitroalkanes

The C-alkylation of nitroalkanes under mild conditions has been a significant challenge in organic synthesis for more than a century. Herein we report a simple Cu(I) catalyst, generated in situ, that is highly effective for C-benzylation of nitroalkanes using abundant benzyl bromides and related heteroaromatic compounds. This process, which we believe proceeds via a thermal redox mechanism, allows access to a variety of complex nitroalkanes under mild reaction conditions and represents the first step toward the development of a general catalytic system for the alkylation of nitroalkanes.     

Palladium-catalyzed monoarylation of nitroalkanes.

A general protocol for the Pd-catalyzed-arylation of nitroalkanes is described. Substituted aryl bromides as well as aryl chlorides can be coupled efficiently with a variety of nitroalkanes under mild conditions to selectively yield the monoarylated products. This method tolerates a number of functional groups including ketones, esters, and olefins. Notably, the arylation of nitroalkanes can be effected chemoselectively over ketone and ester arylation.     

Addition-elimination of nitroalkanes to 3-phenacylideneoxindoles—direct method for the synthesis of 3-alkenylphenacylidene-oxindoles

The first addition-elimination of nitroalkanes to 3-phenacylideneoxindoles was developed, affording the corresponding 3-alkenylphenacylidene-oxindoles with high yields.The addition-elimination mechanism of 3-phenacylideneoxindoles with nitroalkanes and removable NO₂ group in concert guarantees the high regioselectivity.     

Asymmetric multifunctional organocatalytic Michael addition of nitroalkanes to alpha,beta-unsaturated ketones

Cinchona alkaloid derived primary amine thioureas organocatalyzed Michael addition of nitroalkanes to enones in good yield and up to 98% ee and offered a new way to construct quaternary stereocenters from enones and nitroalkanes.     

Organic synthesis by means of noble metal compound—LI : Palladium-catalyzed addition of butadiene to nitroalkanes

Butadiene reacts with nitroalkanes in the presence of triphenylphosphine complexes of palladium, α-Hydrogens of nitroalkanes are displaced with 2,7-octadienyl groups to give nitroolefins. The nitroolefins thus obtained are reduced to give novel long chain amines, which have a primary amino group at the middle of the carbon chain.     

Synthesis of 5-alkyl-5-aryl-1-pyrroline N-oxides from 1-aryl-substituted nitroalkanes and acrolein via Michael addition and nitro reductive cyclization

A general method for accessing 5-alkyl-5-aryl-1-pyrroline N-oxides (AAPOs) has been established using readily available aryl bromides, nitroalkanes, and acrolein as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the Et₃N-catalyzed Michael addition with acrolein at room temperature to afford the 4-aryl-4-nitroaldehydes. The latter were then subjected to the nitro reductive cyclization using Zn–HOAc in EtOH at 0 °C followed by warming the reaction mixture to room temperature for 24 h, furnishing the 5-alkyl-5-aryl-1-pyrroline N-oxides in good overall yields. Selected examples of 1,3-dipolar cycloaddition of the cyclic nitrones with methyl methacrylate were also described.     

Asymmetric reduction of nitroalkenes with baker's yeast

Various α,β-disubstituted and trisubstituted nitroalkenes were chemoselectively reduced with baker's yeast to the corresponding nitroalkanes. Stereoselectivities of the reduction of α,β-disubstituted nitroalkenes were modest to low, and e.e.s up to 52% were obtained. Trisubstituted nitroalkenes could be reduced to the corresponding nitroalkanes with excellent enantioselectivities, moderate diastereoselectivities and in good yield.     

Pd-Catalyzed allylic alkylation of secondary nitroalkanes

A Pd-catalyzed allylic alkylation of secondary nitroalkanes, using a catalytic amount of external base, was developed. Simple allyl carbonate and monosubstituted allyl carbonates were used as electrophiles, and bulky secondary nitroalkanes were used as nucleophiles. This is the first catalytic allylic alkylation of bulky secondary nitroalkanes, such as 2-nitroheptane. The use of the strong base DBU in the aprotic polar solvent DMSO is a key in realizing the high reactivity. In an attempt to develop an asymmetric reaction, 2-aryloxazoline ligand PHOX L1 gave excellent results for inducing chirality at the π-allyl moiety. As for asymmetric induction at the α-position of the NO₂ functionality, the free OH-group containing 2-aryloxazoline ligand L4 showed moderate selectivity.     

A mild reduction of aliphatic nitro compounds to imines for further in situ reactions : A simple synthesis of pyrroles

Tributylphosphine-diphenyldisulphide reduces nitroalkanes to imines which can be trapped intramolecularly to give pyrroles.     

Novel addition of nitroalkanes to o-quinones

A novel addition reaction of nitroalkanes to o-quinones is found to give 1,3-dioxole derivatives.     

Organocatalytic asymmetric conjugate addition of nitroalkanes to alpha,beta-unsaturated enones using novel imidazoline catalysts

A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic alpha,beta-unsaturated enones catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4-addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization. The potential of the reaction is documented by the reaction of a series of substituted alpha,beta-unsaturated enones with different nitroalkanes. Furthermore, the synthetic applicability of the reaction is demonstrated by the formation of optically active functionalized pyrrolines and pyrrolidines by reductive amination of the products. On the basis of the absolute configuration of the conjugate addition products, the mechanism for the reaction is discussed and a transition state proposed.     

Enantioselective synthesis of nitroalkanes bearing all-carbon quaternary stereogenic centers through Cu-catalyzed asymmetric conjugate additions

The first examples of catalytic asymmetric conjugate addition (ACA) of alkylzinc reagents to trisubstituted nitroalkenes, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic center, are reported. Reactions are promoted in the presence of 4 mol % of a readily available amino acid-based phosphine and 2 mol % (CuOTf).C6H6. Cu-catalyzed reactions proceed efficiently in up to 98% ee and can be carried out with a variety of dialkylzinc reagents and trisubstituted nitroolefins. We highlight the synthetic utility of the products obtained by efficient conversion of optically enriched nitroalkanes to the corresponding carboxylic acids.     

Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted nitroalkanes and methyl acrylate via Michael addition and reductive lactamization

A general method for accessing 5-alkyl-5-aryl-γ-lactams has been developed using readily available aryl bromides, nitroalkanes, and methyl acrylate as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the DBU-mediated Michael addition with methyl acrylate at room temperature to afford the methyl 4-aryl-4-nitroalkanoates. The latter were then subjected to the nitro reduction using NaBH₄–NiCl₂·6H₂O in MeOH at 0 °C to furnish, after treatment with aqueous K₂CO₃ at room temperature, the 5-alkyl-5-aryl-γ-lactams in good to excellent overall yields. Selected examples of N-alkylation of the γ-lactams were also illustrated.     

Metal-Free Deoxygenation of Chiral Nitroalkanes: An Easy Entry to α-Substituted Enantiomerically Enriched Nitriles

A metal-free, mild and chemodivergent transformation involving nitroalkanes has been developed. Under optimized reaction conditions, in the presence of trichlorosilane and a tertiary amine, aliphatic nitroalkanes were selectively converted into amines or nitriles. Furthermore, when chiral β-substituted nitro compounds were reacted, the stereochemical integrity of the stereocenter was maintained and α-functionalized nitriles were obtained with no loss of enantiomeric excess. The methodology was successfully applied to the synthesis of chiral β-cyano esters, α-aryl alkylnitriles, and TBS-protected cyanohydrins, including direct precursors of four active pharmaceutical ingredients (ibuprofen, tembamide, aegeline and denopamine).     

Gas chromatographic determination of impurities in nitromethane

Summary Impurities in commercially available nitromethane have been determined by gas-liquid chromatography using six different column packings. Besides nitromethane, 1-nitropropane, 2-nitropropane, acetonitrile, methanol, small amounts of ethanol and acetaldehyde have been detected. The presence of formaldehyde, ethyl acetate and acetone is probable. Mixtures containing comparable amounts of the four nitroalkanes could be separated on all columns, but plots of logarithms of the retention times vs. carbon number or boiling points of the nitroalkanes or column temperatures were linear only in case of columns packed with Porapak R and Q.     

Uncatalyzed reactions of α-(trihaloethylidene)nitroalkanes with push-pull enamines: a new type of ring-ring tautomerism in cyclobutane derivatives and the dramatic effect of the trihalomethyl group on the reaction pathway

A new type of ring-ring isomerism, which consists of the reversible transformation of cyclobutane derivatives into substituted 1,2-oxazine N-oxides was found and studied by NMR spectroscopy and X-ray diffraction analysis. The starting materials were prepared by the stereoselective reaction of α-(trifluoroethylidene)nitroalkanes, which react with ethyl β-morpholino- and β-piperidinocrotonates at the more nucleophilic α-position, whereas the reaction of α-(trichloroethylidene)nitroalkanes proceeds at the β-methyl group to give the corresponding linear products.     

Solid-phase synthesis of isoxazolines

The polymer-supported synthesis of isoxazolines is described via nitrile oxide intermediates, starting from primary nitroalkanes in a one-pot process.     

One-pot synthesis of polysubstituted indoles from aliphatic nitro compounds under mild conditions

Polysubstituted indoles can be prepared directly from functionalized nitroalkanes under very mildly acidic conditions in a simple, one-pot, two-stage procedure.     

Conversion of Nitroalkenes into β-(Trichloromethyl) Nitroalkanes

The cesium fluoride-catalyzed reaction of (trichloromethyl) - trimethylsilane with conjugated nitroalkenes affords β-(trichloromethyl)nitroalkanes.     

An analysis of the molecular concerted decomposition of nitroalkanes by the method of intersecting parabolas

The molecular concerted decomposition of nitroalkanes was analyzed using the model of two intersecting parabolas. Parameters describing the activation energy of decomposition as a function of the enthalpy of the reaction were obtained. These parameters were used to calculate the activation energies of unstudied reactions of the decomposition of RNO₂ and the activation energies and rate constants for reverse combination reactions between olefins and nitrous acid with the formation of the corresponding nitroalkanes. The concerted decomposition of nitroalkanes was also analyzed using another two-center model, in which decomposition was treated as two single-stage events, the transfer of H from the C-H bond to the O atom of the nitro group and the dissociation of the C-N bond accompanied by a shift of electrons in a five-membered reaction center. This approach and two elementary event models (a model of two intersecting parabolas and a model of the superposition of three parabolas) were used to calculate the spectrum of activation energies, in which each overall reaction event was characterized by an activation barrier of its own.