Catalyst and base controlled site-selective sp and sp direct arylation of azine N-oxides

Site-selective direct arylation of both sp² and sp³ sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner. The sp³ arylation reaction is applied to the synthesis of the natural products, papaverine and crykonisine, and a rationale for low reactivity of electron-deficient aryl halides is provided. Mechanistic investigations point toward the intimate involvement of the base in the mechanism of these reactions.     

Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents

Addition of i-PrMgCl to pyridine N-oxides in THF at −78 °C generates selectively an ortho-metallated species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides. Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine N-oxides is achieved.     

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.     

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.     

Cu(OAc)2-catalyzed direct radical C2 arylation of quinoline N-oxide with arylamines

A Cu(OAc)₂-catalyzed synthesis of 2-arylquinoline N-oxides with easily available arylamines is described. The main features of this reaction are mild reaction conditions, high functional-group tolerance, excellent regioselectivity, and good to excellent yields. This procedure is mild, operationally simple, and constitutes a greener approach to the arylation of quinoline N-oxides.     

Synthesis of N‐alkyl‐N′‐aryl or Alkenylpiperazines: A Copper‐Catalyzed C–N Cross‐Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward, direct arylation and alkenylation of 1,4‐diaza‐bicyclo[2.2.2]octane would obviate the inefficiencies associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or alkenyl triflates, and 1,4‐diaza‐bicyclo[2.2.2]octane for the synthesis of N‐alkyl‐N ′‐aryl or alkenylpiperazines. The optimum conditions are developed using CuCl, t‐BuOL i in NMP . Alkenyl triflates requires N ,N ′‐dimethylethylenediamine and higher temperature to afford the desired cross‐coupled product. Substrates bearing electron‐deficient and electron‐rich groups were successfully coupled under the optimum reaction conditions.     

Palladium-catalysed C–C coupling reactions in the enantioselective synthesis of 2,4-disubstituted 4,5-dehydropiperidines using galactosylamine as a stereodifferentiating auxiliary

Stereoselective synthesis of enantiomerically pure 2,4-disubstituted piperidine derivatives, which are considered interesting pharmacophoric structures, was achieved starting with a tandem Mannich–Michael reaction sequence on O-pivaloylated N-galactosyl aldimines. Subsequent conversion of the thus formed 2-substituted dehydropiperidinones into the corresponding enol triflates was carried out by conjugate hydride addition and trapping the enolate with N,N-bis(trifluoromethanesulfonyl)aniline. Their Suzuki–Miyaura coupling with aryl and heteroaryl boronic acids was performed under conditions compatible with the carbohydrate structure, in particular, with the sensitive N-glycosidic bond.     

Localization of N-oxide groups by means of nitrogen chemical shifts

The applicability of nitrogen chemical shifts to the localization of N-oxide groups in azine ring systems is exemplified by 1,2,4-triazine systems. The average excitation energy approximation in the theory of magnetic shielding gives a good linear correlation with the nitrogen shieldings in azine N-oxides.     

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.     

Expeditious synthesis of 1,1-diarylethylenes related to isocombretastatin A-4 (isoCA-4) via palladium-catalyzed arylation of N-tosylhydrazones with aryl triflates

A quick and efficient entry to 1,1-diarylethylenes via the reaction of polyoxygenated aryl N-tosylhydrazones with aryl triflates is described. The reaction employs the catalytic system Pd(OAc)₂/XPhos, tBuOLi as the base and dioxane as the solvent. A variety of substituents on both the coupling partners’ hydrazones and triflates are tolerated. This procedure provides a complementary route to the existing methods for the access to 1,1-diarylethylenes of biological interest.     

N‐Arylation of Diketopyrrolopyrroles with Aryl Triflates

A new methodology for the double N‐arylation of diketopyrrolopyrroles with aryl triflates has been developed. It is now possible to prepare diketopyrrolopyrroles bearing N‐substituents derived from naphthalene, anthracene and coumarin in two steps from commercially available phenols. This represents the first time arenes lacking strong electron‐withdrawing groups were inserted onto lactamic nitrogen atoms via arylation. The ability to incorporate heretofore unprecedented substituents translates to increased modulation of the resulting photophysical properties such as switching‐on/off solvatofluorochromism. TD‐DFT calculations have been performed to explore the nature of the relevant excited states. This new synthetic method made it possible to elucidate the influence of such substituents on the absorption and emission properties of tetraaryl substituted diketopyrrolopyrroles.     

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.     

Carbon-13 NMR study of some acetylenic amines,the N-oxides and their rearrangement products

Carbon-13 NMR chemical shifts of some N, N-dialkyl-4-acetoxybut-2-ynylamines and their corresponding N-oxides have been analysed. These N-oxides undergo thermal rearrangement to O-allenyl hydroxylamine for which the ¹³C NMR spectral assignments were also carried out. The effect of N-oxidation on the chemical shifts is calculated.     

Scope of direct arylation of fluorinated aromatics with aryl sulfonates

The scope and limitations of direct arylation of fluorinated aromatics with aryl sulfonates was examined. Pd(OAc)(2), in the presence of MePhos and KOAc in THF, efficiently catalyzed the direct arylation of fluoro aromatics with aryl triflates under ambient conditions. Sterically hindered triflates and heteroaryl triflates gave good to excellent yields of the cross coupled products using a modified catalyst system which involves Pd(OAc)(2)-RuPhos at 100 °C. The direct arylation of electron deficient arenes with aryl mesylates is also established using Pd(OAc)(2)-SPhos as the catalyst in toluene-(t)BuOH at 120 °C.     

A practical and mild chlorination of fused heterocyclic N-oxides

Fused azine N-oxides were selectively chlorinated at C2 in moderate to excellent yields, employing Vilsmeier reagent as both the activating agent and the nucleophilic chloride source. Remarkable features of the method include simple operation, mild reaction conditions, a wide substrate scope, and the use of only stoichiometric amount of POCl_3. The potential extension of this method to a one-pot oxidation/chlorination sequence that obviates the need for isolation of the N-oxide intermediates is also validated.     

Synthesis of N-aryl-d-glucosamines through copper-catalyzed C–N coupling

A catalytic protocol was developed to synthesize N-aryl-d-glucosamines from the corresponding aryl halides. Cross-coupling of 1,3,4,6-tetra-O-benzyl-β-d-glucosamine with aryl iodides or bromides was catalyzed with copper. Subsequent deprotection of the benzyl group gave the arylation product N-aryl-d-glucosamines.     

The first example of atropisomeric amide-derived P,O-ligands used for an asymmetric Heck reaction

Atropisomeric N,N-diisopropyl 2-diphenylphosphino- and 2-di(tert-butyl)phosphino-1-naphthamides were used, for the first time, as bidentate P,O-ligands for intermolecular asymmetric Heck reactions of 2,3-dihydrofuran with aryl triflates. The reactions were carried out in the presence of 4 mol% Pd(OAc)₂, 8 mol% of the axially chiral ligand, and 3 equiv. of (i-Pr)₂NEt in THF at 60 °C for 3 days. Optically active 2-aryl-2,5-dihydrofurans were obtained as the major products along with the rearranged 2-aryl-2,3-dihydrofurans. Enantioselectivity up to 55.2% ee was obtained for the major product.     

Redox initiated cationic polymerization: Silane‐N‐aryl heteroaromatic onium salt redox couples

In this article, a new route for the synthesis of N‐aryl heteroaromatic onium salts by the direct copper catalyzed arylation of pyridine, substituted pyridines, isoquinoline, and acridine with diaryliodonium salts is described. It was demonstrated that these N‐aryl heteroaromatic onium salts undergo facile platinum or rhodium‐catalyzed reduction by silanes bearing Si? H groups. The reduction of N‐aryl heteroaromatic onium salts generates Brønsted acids. When this redox reaction was carried out in situ in the presence of an appropriate monomer, cationic polymerization was observed. Using this approach, the cationic polymerizations of epoxides, oxetanes, 1,3,5‐trioxane, styrene, and vinyl ethers were carried out. The use of optical pyrometry to monitor the redox initiated cationic polymerizations of some representative multifunctional monomers is described. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Natural abundance 17O NMR spectroscopy of heterocyclic N-oxides and Di N-oxides. Structural effects

The ¹⁷O chemical shift data for a series of azine N-oxides, diazine N-oxides and di-N-oxides at natural abundance are reported. Isomeric methyl substituted quinoline N-oxides exhibited chemical shifts which are interpreted in terms of electronic and compressional effects. The ¹⁷O chemical shift for 8-methylquinoline N-oxide (370 ppm) is deshielded by 25 ppm more than predicted, based upon electronic considerations. The ¹⁷O chemical shift for the N-oxide of 8-hydroxyquinoline (289 ppm) is substantially shielded as a result of intramolecular hydrogen bonding. The relative ¹⁷O chemical shifts for diazine N-oxides of pyrazine, pyridazine and pyrimidine follow predictions based on back donation considerations. Because of solubility limitations, spectra of only two N,N′-dioxides were obtained. The chemical shift of benzopyrazine di N-oxide in acetonitrile was shielded by 18 ppm compared to that of its mono N-oxide.     

One-pot two-step synthesis of 1-position arylated 1,3-disubstituted isoquinoline N-oxides

A one-pot two-step reaction of 2-alkynylbenzaldoximes with aryl halides has been developed, which offers the 1-position arylated 1,3-disubstituted isoquinoline N-oxides in moderate to good yields in most cases. The isoquinoline N-oxide intermediate was prepared in situ without isolation.