Palladium-catalyzed aryl-amidation. Synthesis of non-racemic N-aryl lactams

The Buchwald/Hartwig aryl amination method was used to construct a series of chiral, non-racemic N-aryl pyrrolidinones from a common pyrrolidinone precursor and the corresponding aryl bromide. The stereochemical integrity of the N-aryl lactam after cross-coupling was proven by synthesis of the racemic compounds and comparison by ¹H NMR spectroscopy using Pirkle's chiral solvating agent.     

H-N HMBC as a valuable tool for the identification and characterization of nitrones

¹H-¹⁵N HMBC has been evaluated as an efficient and high-speed method to determine ¹⁵N chemical shifts for nitrones, which can be used to identify aromatic nitrones and to extract structural information by comparison with reference data. Substituent effects have been measured on C and N aryl groups separately, showing up the influence of electronic effects on C-aryl groups rather than N-aryl groups on the ¹⁵N chemical shifts. Steric effects are remarkable in the case of C-aryl-N-alkyl nitrones. Depending on N or C substitution, chemical shift changes in such an additive way that it is possible to predict chemical shifts for unknown nitrones.     

H, C, and F NMR studies of phencyclone adducts of N-(polyhalophenyl)maleimides: evidence for dynamic NMR in maleamic acids: Ab initio calculations for optimized structures

NMR methods, including one- and two-dimensional techniques (at 7.05 T) for ¹H, ¹³C and ¹⁹F, have been applied to studies of hindered rotations and magnetic anisotropy in some crowded Diels-Alder adducts of phencyclone (1). Symmetrically substituted N-aryl maleimides (2) bearing numerous halogens on the N-aryl ring, were employed as dienophiles to form the target adducts (3). The maleimides included: N-(4-bromo-2,6-difluorophenyl)maleimide (2a); N-(2,3,5,6-tetrafluorophenyl)maleimide (2b); N-(4-bromo-2,3,5,6-tetrafluorophenyl)maleimide (2c); N-(2,3,4,5,6-pentachlorophenyl)maleimide (2d); and N-(2,4,6-tribromophenyl)maleimide (2e). Maleimides (2a-2c) were prepared from the precursor N-aryl maleamic acids (5a-5c). Ambient temperature fluorine-19 NMR of these maleamic acids in d₆-acetone showed substantial unusual peak broadening consistent with intermediate exchange rate processes, which may correspond to the N-aryl rotation process. Maleimides (2d) and (2e) were produced in one step from pentachloroaniline or 2,4,6-tribromoaniline, respectively, and maleic anhydride with anhydrous ZnCl₂ at ca. 200 °C. For the adducts (3), we observed slow exchange limit spectra on the ¹H, ¹³C, [and ¹⁹F, for (3a-3c)] NMR timescales for the rotation of the unsubstituted bridgehead phenyls about the C(sp³)C(sp²) bonds, and for the rotations of the N-aryl rings about the N(sp²)C(aryl sp²) bonds. Ab initio calculations for geometry optimizations at the Hartree-Fock level with 6-31G* (or LACVP*) basis sets were performed for the adducts. We believe that this is the first report of detailed ¹H, ¹³C, and ¹⁹F NMR data for a substantial collection of N-aryl maleamic acids, maleimides and their phencyclone adducts bearing multiple fluorines or other halogens directly on the N-aryl ring, together with complementary quantitative geometric parameters from high-level HF/6-31G* (or LACVP*) calculations.     

Hydrazines in the synthesis of N-substituted 1,5,3-dithiazocan-3-amines catalyzed by Ti and Cu compounds

Efficient preparation method was developed for N-aryl(benzyl, alkyl)-1,5,3-dithiazocan-3-amines consisting in the transamination of 3-tert-butyl-1,5,3-dithiazocane with aryl(benzyl)hydrazines, and also in the reaction of N ¹,N ¹,N ⁷,N ⁷-tetramethyl-2,6-dithiaheptane-1,7-diamine with aryl(benzyl, alkyl)hydrazines in the presence of catalytic amounts of Ti and Cu compounds.     

Chemistry of iminofurans: X. Synthesis and hydrolysis of 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2<Emphasis Type="Italic">H</Emphasis>)-ones

5-Aryl(hetaryl)furan-2,3-diones reacted with N-(triphenyl-λ⁵-phosphanylidene)-4,5,6,7-tetrahydro-1-benzothiophen-2-amines to give 5-aryl(hetaryl)-2-[(4,5,6,7-tetrahydro-1-benzothiophen-2-yl)imino]furan-3(2H)-ones whose acid hydrolysis afforded 4-aryl(hetaryl)-2-hydroxy-4-oxo-N-(4,5,6,7-tetrahydro-1-benzothiophen- 2-yl)but-2-enamides.     

A Synthetic Method to Access Symmetric and Non-Symmetric 2-(<em>N</em>,<em>N</em><em>'</em>-disubstituted)guanidinebenzothiazoles

Symmetric and non-symmetric 2-(N-H, N-methyl, N-ethylenyl and N-aryl)guanidinebenzothiazoles were synthesized from the reaction of ammonia, methylamine, pyrrolidine and aniline with dimethyl benzo[d]thiazol-2-yl-carbono-dithioimidate (5) as intermediate. The products were characterized by ¹H-, ¹³C-NMR spectroscopy and three of them by X-ray diffraction analysis. HN-phenyl protons formed intramolecular hydrogen bonds that assist the stereochemistry of the second substituent, whereas the HN-alkyl protons were involved in intermolecular hydrogen bonding.     

An efficient synthesis of α-aryl β-(N-tosyl)amino phosphonate derivatives from α-diazophosphonate

The α-diazophosphonate was added to aryl (N-tosyl)imine to give β-aryl β-(N-tosyl)amino α-diazophosphonates, which were further subjected to TsOH-catalyzed diazo decomposition to yield α-aryl β-(N-tosyl)enaminophosphonates through 1,2 aryl migration. The α-aryl β-(N-tosyl)enamino phosphonates were hydrogenated to give α-aryl β-(N-tosyl)amino phosphonates.     

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru(diamine) complexes as catalysts: the counteranion and solvent effects,and substrate scope

Asymmetric hydrogenation of N-alkyl and N-aryl ketimines catalyzed by chiral cationic η⁶-arene-(N-monosulfonylated diamine) Ru(II) complexes has been investigated. Strong counteranion and solvent effects on the enantioselectivity were observed. The ruthenium catalyst bearing non-coordinating BArF^? anion was found to be particularly effective for the hydrogenation of acyclic and exocyclic N-alkyl ketimines in the presence of (Boc)₂O in dichloromethane or even under solvent-free conditions, providing chiral amines with up to >99% ee and full conversions. Alternatively, the ruthenium catalyst bearing achiral phosphate anion together with corresponding phosphoric acid as the additive was also efficient for the hydrogenation of N-alkyl ketimines in the absence of (Boc)₂O with excellent enantioselectivities and full conversions. For N-aryl ketimines lower enantiomeric excesses were observed by using the ruthenium catalyst bearing BArF^? anion. This catalytic protocol thus provides a facile and practical access to optically active amines and has been successfully employed in the gram-scale synthesis of enantiomerically pure (+)-sertraline.     

Gas-phase acidity of sulfonamides: implications for reactivity and prodrug design

A computational study at the density functional theory level was performed on bioactive and model sulfonamides with the aim of determining the factors affecting the acidity of the sulfonamido group. The effects of introducing different substituents at either the para-aryl or the N¹-sulfonamide positions were independently analyzed. A linear correlation was found between sulfonamide acidity and the Hammett constants or charge of the SO₂ group of substituents at the para-aryl position. Most N¹-substituents were taken from bacteriostatic sulfonamide structures and presented a more complex behavior, possibly due to a conjugation of steric and electronic factors. In the latter situation, sulfonamide acidity and the charge of the SO₂ group were not linearly correlated. Interestingly, the acidity of the sulfonamido group was found to be correlated with the reactivity of sulfa drugs towards acylating agents. The implications for the design of suitable sulfonamide prodrugs are discussed.     

Synthesis of new N-aryl oxindoles as intermediates for pharmacologically active compounds

Various new N-aryl oxindoles were synthesized as intermediates for the preparation of pharmacologically active 2-(N-arylamino)-phenylacetic acids. Two novel approaches were explored for the construction of diarylamine and N-aryl oxindole core structures, in addition to Buchwald-arylamination and Smiles rearrangement. Condensation of anilines with 2-oxo-cyclohexylidene-acetic acid derivatives and subsequent dehydrogenation is a new and viable method for the preparation of N-aryl oxindoles.     

Copper-promoted Chan-Lam coupling between enaminones and aryl boronic acids

A novel copper-promoted N-arylation of enaminones with aromatic boronic acids has been developed, which provides an efficient way to synthesize N-aryl enaminones with a broad substrate scope and excellent functional group compatibility. The N-aryl enaminones could be converted into a series of highly valuable building blocks and bioactive compounds. Notably, in comparison with traditional methods, this alternative approach provides accesses to N-aryl enaminones bearing multiple aromatic rings.     

Reactions of 1-amino-2-nitroguanidine with 2-aryl(hetaryl)-1-nitro-1-ethoxycarbonyl(benzoyl)ethenes

Reactions of 1-amino-2-nitroguanidine with 2-aryl(hetaryl)-1-nitro-1-ethoxycarbonyl(benzoyl)-ethenes proceed via initial formation the aza-Michael product, are accompanied by liberation of nitroacetic ester (or nitroacetophenone), and result in N-aryl(hetaryl)methylidene-N-(2-nitroguanidino)amines.     

Lithium and sodium N,N′-di(2,6-dialkylphenyl)formamidinate complexes

A study has been undertaken of the lithium and sodium metallation of N,N′-di(aryl)formamidines with alkyl groups at the 2- and 6-aryl position. ¹H NMR and X-ray diffraction data indicate an increase in steric bulk from 2,6-dimethylphenyl to 2,6-diethylphenyl to 2,6-diisopropylphenyl incites incremental changes in amidinate binding and nuclearity. In selected instances, this invokes the first lithium and sodium amidinate/guanidinate complexes to exhibit metal-arene contacts.     

A modular approach to α,β-unsaturated N-aryl ketonitrones

A modular approach to α,β-unsaturated N-aryl ketonitrones has been developed. Specifically, condensation of anilines and enals followed by alkylation of the resulting α,β-unsaturated imines provided N-allyl anilines, which were subjected to oxidation with Oxone® to form α,β-unsaturated N-aryl ketonitrones. This modular approach is general and provides rapid access to diversely substituted α,β-unsaturated N-aryl ketonitrones with a single purification step in good yields.     

Facile synthesis of vicinal diamines via oxidation of N-phenyltetrahydroisoquinolines with DDQ

The oxidation of N-phenyltetrahydroisoquinolines occurs rapidly with DDQ. Under ambient conditions and in the presence of nitromethane, the corresponding β-nitroamine derivatives are isolated in good to excellent yields. Variation in the electronic nature of the isoquinoline and the N-phenyl substituent showed that a broad range of substituents are tolerated, with electronic communication between the isoquinoline aromatic ring and the C1 carbon being stronger than with the N-aryl ring. Reduction of the β-nitroamines to the corresponding novel chiral vicinal diamines are straightforward. Examination of the reaction by ¹H NMR spectroscopy suggested that the reaction proceeds via an iminium ion, which then reacts with nitromethane upon work-up. This information was used to shorten the required reaction time.     

Synthesis and spectral properties of 4-amino- and 4-acetylamino-N-arylnaphthalimides containing electron-donating groups in the N-aryl substituent

A method for the synthesis of N-aryl-substituted 4-amino- and 4-acetylaminonaphthalimide derivatives with mono- and dialkoxy groups or a 15-crown-5 moiety in the N-aryl substituent is described. The introduction of electron-donating alkoxy groups into the benzene ring of the N-aryl fragment results in fluorescence quenching of the naphthalimide chromophore, which is most pronounced in the spectra of N-acetyl derivatives. The photophysical properties of the synthesized 4-amino- and 4-acetylaminonaphthalimides depend on the solvent polarity and its specific solvating ability due to H-bonding. The crown-containing compounds are promising fluorescent chemosensors for metal cations.     

Coupling and cycloaddition of ynamides: homo- and Negishi coupling of tosylynamides and intramolecular [4+2] cycloaddition of N-(o-ethynyl)phenyl ynamides and arylynamides

N,N′-aryl- and N,N′-alkyl-buta-1,3-diyne-1,4-ditosylamides have been synthesized for the first time, in good to excellent yields, by copper-catalyzed dimerization of the corresponding N-aryl or N-alkyl tosylynamides. Negishi coupling of N-ethynylzinc tosylamides derivatives with (hetero)aryl iodides in the presence of Pd₂dba₃ and triphenylphosphine affords N-aryl and N-alkyl arylynamides in yields of up to 90%. Intramolecular [4+2] cycloaddition reactions of N-ethynylphenyl ynamides and arylynamides allow the synthesis of carbazoles and benzannulated and heteroannulated carbazoles in moderate-to-good yields.     

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

A one step, direct method for the synthesis of 1,5-diaryl pyridin-2(1H)-one derivatives by condensation of 2-aryl vinamidinium salts with N-aryl cyanoacetamides has been developed. This method can conveniently provide the corresponding 1,5-diaryl pyridin-2(1H)-one derivatives with various substituents in good yields and overcome the drawbacks of existing methods such as poor substrate scope, heavy metal pollution, and low yields. The formation mechanism of the products was illustrated.     

Features of the reactions of β-aryl(heteryl)-α-nitroacrylates with N,N-, N,O-, and N,S-binucleophiles

The reactions of ??-aryl(heteryl)-??-nitroacrylates with N,N-, N,O-, and N,S-binucleophiles proceed regiospecifically through the initial formation of the Ad_N products, among which only the product from o-aminothiophenol was isolated. The conditions of converting the S-adducts into 2-aryl(heteryl)benzothiazole were found. The N-adducts formed in the reaction with hydrazine, o-phenylenediamine, and o-aminophenol undergo immediately the spontaneous transformation into the linear (azine, azomethine) or heterocyclic (benzimidazole) structures.     

Synthesis and reactivity of N-aryl substituted N-heterocyclic silylenes

The synthesis of two N-aryl substituted 2-silaimidazolidenes 9a, b by metal-reduction of the appropriate silicon(IV) heterocycles is reported. Structural as well as spectroscopic data obtained for the N-aryl substituted N-heterocyclic silylenes (NHSi) are very close to those obtained previously for their N-alkyl substituted counterparts. NHSis 9a, b are used as starting materials for the synthesis of a series of dichalcogenadisiletanes 19-24 and for of a mono silylene tungsten complex 29. The reactivity studies revealed only marginally differences between the N-aryl substituted NHSis 9a, b and previously described N-alkyl substituted silylenes.