Development of one-pot benzylic amination reactions of azine N-oxides

An efficient one-pot synthetic methodology has been developed for the benzylic amination reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction was found to tolerate quinoline and isoquinoline N-oxides with electron donating and withdrawing substituents as the electrophilic reaction partners as well as a broad range of nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products in up to 82% yield.     

Examination of the mechanism of the intramolecular amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines: a Pd-catalyzed amination and/or a base-assisted nucleophilic aromatic substitution?

The intramolecular amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines was investigated. In this way we unraveled the mechanism of the ring closure reaction in the auto-tandem amination (inter- and intramolecular Pd-catalyzed amination) of 2,3-dibromopyridine with amino(benzo)(di)azines and 2-chloro-3-iodopyridine with amino(benzo)(di)azines, respectively. Depending on the substrate a Pd-catalyzed amination, a base-assisted nucleophilic aromatic substitution or a combination of both is occurring. An explanation based on the aromaticity of the amidine, supported by theoretical calculations, is provided. In addition we gained evidence that the intramolecular metal-catalyzed amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines indeed involves a nitrogen atom that is not substituted with a hydrogen atom.     

Electrophilic amination of enolates with oxaziridines: effects of oxaziridine structure and reaction conditions

A range of N-alkoxycarbonyl- and N-carboxamido-oxaziridines has been prepared to test the effects of oxaziridine structure on yields of enolate amination product. Side-products arising from reaction of aldehyde-derived oxaziridines with base were identified, while a ketone-derived oxaziridine afforded moderate yields of amination product with stabilised carbanions.     

A concise synthesis of (−)-cytoxazone and (−)-4-epi-cytoxazone using chlorosulfonyl isocyanate

A concise synthesis of (−)-cytoxazone and its stereoisomer (−)-4-epi-cytoxazone, novel cytokine modulators, has been accomplished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include the regioselective and diastereoselective amination of anti- and syn-1,2-dimethyl ethers with chlorosulfonyl isocyanate and the subsequent regioselective cyclization of the diol to construct the oxazolidin-2-one core. The diastereoselectivity of amination reaction using CSI was explained by the Cieplak electronic model via S_N1 mechanism and neighboring group effect, leading to the retention of the configuration.     

Enantioselective amination of silylketene acetals with (N-arylsulfonylimino)phenyliodinanes catalyzed by chiral dirhodium(II) carboxylates: asymmetric synthesis of phenylglycine derivatives

The first catalytic enantioselective amination of silylketene acetals with (N-arylsulfonylimino)phenyliodinanes is described. The reaction of silylketene acetals derived from methyl phenylacetates with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN = IPh) under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, proceeds in benzene at room temperature to give N-(2-nitrophenylsulfonyl)phenylglycine derivatives in high yields and with enantioselectivities of up to 99% ee.     

Electrophilic amination of diorganozinc reagents by oxaziridines

Electrophilic amination of organozinc reagents by oxaziridines has been studied. Diorganozinc reagents R₂Zn (R = alkyl or aryl) react with N-Boc oxaziridine to afford N-Boc protected primary amines BocNHR in moderate to good yields. No additives are needed in this reaction, which proceeds at 0 °C. We suggest that the presence of two heteroatoms in oxaziridine allows Lewis base activation of the diorganozinc reagent.     

An efficient palladium-catalyzed synthesis of 1-heteroaryl-4-aminopiperidine derivatives from heteroaryl chlorides

An efficient protocol for the synthesis of 1-heteroaryl-4-(N-methyl)aminopiperidines starting from heteroaryl chloride derivatives is described. A broad range of 1-heteroaryl-4-(N-Boc-N-methyl)aminopiperidine derivatives were obtained in good to excellent yields using DavePhos as optimal ligand for Pd-catalyzed Buchwald-Hartwig amination reaction. After a mild and efficient acidolysis the amination products could be obtained successfully.     

Thermal 1,3-proton shift reaction and its application for operationally convenient and improved synthesis of α-(trifluoromethyl)benzylamine

This paper describes a synthesis of α-(trifluoromethyl)benzylamine via a novel base-free biomimetic reductive amination of α,α,α-trifluoroacetophenone with benzylamine. When the corresponding imine, derived from α,α,α-trifluoroacetophenone and benzylamine was heated at 200 °C under N₂ for 1 day, the thermal 1,3-proton shift reaction took place giving rise to the N-(benzylidene)-α-(trifluoromethyl)benzylamine in quantitative yield. This thermal 1,3-proton shift reaction was used a key step in the development of new and substantially simplified, practical and operationally convenient procedure for preparation of the target α-(trifluoromethyl)benzylamine on large scale.     

Polymer-supported N-benzyl- and N-benzhydryl-2-nitrobenzenesulfonamides as alternative to aldehyde linkers

Polymer-supported N-benzyl- and N-benzhydryl-2-nitrobenzenesulfonamides 1 were N-alkylated using three different routes: via Fukuyama reaction with alcohols, by N-alkylation with electrophiles, and by Michael addition reaction with α,β-unsaturated carbonyl compounds. The N-alkylated products were obtained in excellent purity and high yield. The 2-nitrobenzenesulfonyl (Nos) group was then cleaved to yield polymer-supported N-alkylated benzylamines and benzhydrylamines. N-alkylation of polymer-supported 2-nitrobenzenesulfonamide linkers 1 described herein represents an alternative route to reductive amination of aldehyde linkers.     

Synthesis of substituted 5-aminomethyl tetrahydro-isoquinolines and dihydro-isoindoles

The synthesis of ten substituted aminomethylene tetrahydro-isoquinolines is described, proceeding in eight steps from 5-hydroxyisoquinoline via reductive amination of N-Boc tetrahydro-isoquinoline 5-carboxaldehyde. Likewise, reductive amination was used to prepare four substituted dihydro-isoindoles from the corresponding aldehyde. The dihydro-isoindole ring system was conveniently accessed via a 2+2+2 cycloaddition reaction.     

Synthesis of optically active trifluoromethyl substituted diaziridines and oxaziridines

(E)-Trifluoromethyl imines were considered as ideal substrates to be transformed into the corresponding diaziridines by a direct amination reaction with nosyloxycarbamates. The diastereoselective induction was strongly controlled by the N-substituent. Similar results were obtained in the epoxidation reactions performed on the same substrates using m-CPBA as oxidant. Starting from enantiopure imines chiral diaziridines or oxaziridines were obtained with very high enantiopurity.     

Reductive amination of cyclohexanol/cyclohexanone to cyclohexylamine using SBA-15 supported copper catalysts

Amination of cyclohexanol was investigated in vapour phase over copper catalysts supported on mesoporous SBA-15. The different products identified during reductive amination of cyclohexanol reaction were cyclohexanone, cyclohexylamine, along with small amounts of N-Cyclohexylidinecyclohexylamine and dicyclohexylamine. Among several catalysts tested for the reductive amination, 5% Cu supported on SBA-15 exhibited better catalytic performance than other catalysts with 36% selectivity towards cylclohexylamine at 80% cyclohexanol conversion. The optimum reaction conditions employed to achieve the best catalyst performance were at 250 °C, 0.1 MPa of H₂/NH₃, TOS-10h. The active Cu sites, acidity of the catalyst, and effect of reaction parameters play a pivotal role in the reductive amination reaction. The prepared catalysts were characterized by XRD, BET, SEM, H₂-TPR and NH₃-TPD. The dispersion of Cu, particle size, and metal surface area (m²/g) calculated from pulse N₂O decomposition method. TPR findings reveal the presence of substantially dispersed copper oxide species at lower loadings which is easily reducible than the bulk copper oxide species found at higher Cu loadings. The acidity measurements by NH₃-TPD analysis suggest that the maximum acidic strength was obtained at 5 wt% copper on porous SBA-15, and decreased with Cu loadings. The catalytic properties are well in agreement with the findings of catalysts characterization.     

Investigation of amination in 4-chloro-2-phenylquinoline derivatives with amide solvents

Novel 4-amino-2-phenylquinoline derivatives were synthesized by reacting various 4-chloro-2-arylquinoline compounds having activated chloro group with the corresponding amide solvents at reflux for overnight. The activity of amination by the amide solvents depended on the competition between the steric and electronic effect of the N-substituents on the amino group. Their activities were shown as N,N-dimethylformamide>N,N-diethylformamide>N-methylformamide>formamide>N,N-dimethylacetamide>N,N-dimethylpropionamide. The yields for the amination products seemed proportional to the ease of the dissociation of the amides.     

A new method for the synthesis of N-substituted 1,3,5-dithiazinanes via the catalytic recyclization of 1,3,5-trithiane with aryl(benzyl) hydrazines and aryl amines

An efficient method for the synthesis of N-substituted 1,3,5-dithiazinanes based on the amination reaction of 1,3,5-trithiane with aryl(benzyl) hydrazines and N-aryl amines in the presence of Ti and Fe catalysts has been developed.     

A reusable polymer supported copper catalyst for the C–N and C–O bond cross-coupling reaction of aryl halides as well as arylboronic acids

A simple and industrially viable protocol for C–N and C–O coupling was reported here. The polymer supported heterogeneous copper catalyst was prepared from chloromethyl polystyrene using a simple procedure. O-Arylation of substituted phenols with various aryl halides was achieved using this copper catalyst in DMSO medium. This heterogeneous copper catalyst, also efficiently works for the N-arylation of N–H heterocycles with aryboronic acids in methanol. This catalyst was also effective in amination reaction of primary amines with aryl halides as well as arylboronic acids in DMSO medium. The effects of solvent, base and temperature for the O-Arylation and amination reactions were reported. Further, the catalyst can be easily recovered quantitatively by simple filtration and reused up to several times without sufficient loss of its catalytic activity.     

Solid-phase synthesis of 2-imidazolidinethiones via Mitsunobu reaction of N-(2-hydroxyethyl)thioureas

This letter reports the solid-phase synthesis of 2-imidazolidinethiones via the N-cyclization of N-(2-hydroxyethyl)thioureas using the Mitsunobu reaction in good yield and purity. This process employed the reductive amination of an ArgoGel-MB-CHO resin to anchor the aminoalcohols, followed by a reaction with isothiocyanates to give the resin-attached N-(2-hydroxyethyl)thioureas. Cleavage of the 2-imidazolidinethiones was performed with trifluoroacetic acid.     

Reductive alkylation of thioureas: a highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas

A highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas by the reductive alkylation of N-monosubstituted thioureas with aldehydes is described. N-Monosubstituted thioureas can in turn be synthesized by the reductive amination of thiourea with an appropriate aldehyde. This reductive alkylation methodology was also extended to carbamates.     

Metal-free remote oxidative benzylic C−H amination of 4-methylanilides with N-fluorobenzenesulfonimide

A metal-free remote oxidative benzylic C?H amination of 4-methylanilides with N-fluorobenzenesulfonimide was reported. The reaction was promoted by a hypervalent iodine reagent and can be handled under mild and neutral conditions, providing the highly regioselective benzylic C?H amination products even with multi-substituted 4-methylanilides. It provided a novel and facile method for the construction of C(sp³)–N bonds.     

Furan- and thiophene-functionalised bis-carbene ligands: Synthesis,silver(I) complexes,and catalysis

New furan- and thiophene-functionalised nucleophilic heterocyclic carbene (NHC) complexes of Ag(I) were prepared via the reaction of novel furan- and thiophene-functionalised bis-imidazolium salts with Ag₂O. Samples of both the N-methyl substituted furan- and thiophene-functionalised Ag(I) complexes suitable for single crystal X-ray studies were obtained following anion metathesis to the tetrafluoroborate salts. The structural characterisations revealed dinuclear [Ag₂(_MeCEC)₂](BF₄)₂ (E = O, S) formulations with discrete twenty-membered dimetallacycles present in both instances; however, the overall molecular conformation varies considerably, notably in the orientations of the two bridging furan or thiophene heterocycles to the silver coordination plane. The functionalised bis-imidazolium salts were tested as in situ additives in a Pd(0)-catalysed aryl amination coupling reaction, with the best observed activities around 20% of those seen with 1,3-bis(2,6-di-iso-propylphenyl)imidazolium chloride under identical conditions. The bulkier N-^tBu and N-mesityl substituted salts were found to be more active than the N-methyl substituted analogues.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.