N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

Organocatalysis of asymmetric aldol reaction in water: comparison of catalytic properties of (S)-valine and (S)-proline amides

(S)-Valine amides containing (S)- or (R)-α-phenylethyl substituents at N¹ atom efficiently catalyze asymmetric aldol reactions between cyclic (heterocyclic) ketones and aromatic aldehydes in water, predominantly giving rise to the aldol anti-diastereomers in high yields (up to 98%) and enantiomeric excess (up to 94%).     

Synthesis and reactions of α-fluoro-α-amino amides

N-((S)-1-Phenylethyl)halofluoroethanamides have been investigated as precursors to N-protected α-fluoro-α-amino amides by nucleophilic displacement of halide with nitrogen nucleophiles such as potassium phthalimide, sodium succinimide, sodium glutarimide, trimethylamine and sodium azide. With single diastereoisomers of the iodofluoroethanamide, clean inversion of configuration occurs at room temperature, but subsequent epimerisation may occur as a result of the liberated iodide. The α-fluoro-α-amino amides made underwent a wide variety of reactions depending on conditions, but in many cases the carbon-fluorine bond was compromised. However, reacting trimethylamine and N-((S)-1-phenylethyl)iodofluoroethanamide gave the corresponding α-fluorobetaine amide, and subsequent acidic hydrolysis led to α-fluorobetaine as the first example of an ‘unprotected’ α-fluoroamino acid.     

Selective N-debenzylation of amides with p-TsOH

N-Benzylamides were debenzylated efficiently with 4 equiv. of p-TsOH in refluxing toluene. Good to quantitative yields of the desired primary amides were obtained within 2-4 h from a wide variety of N-2,4-dimethoxybenzylamides. N-4-Methoxylbenzyl amides and N-benzylamides were also debenzylated cleanly. In the case of N-2,4-dimethoxylbenzylamides, selective N-debenzylation was possible in the presence of N-Fmoc, N-t-BOC or N-trityl-protection. Protected amino acid amides survived these conditions without any detectable epimerization.     

Synthese des Dysidins

Synthesis of Dysidin The synthesis of dysidin ((?)- 1 ), the enantiomer of a metabolite of the marine sponge Dysidea herbacea, is described. To effect the synthesis, (±)-5-isopropyl-4-methoxy-3-pyrrolin-2-one ( 7 ) is converted to its lithium salt and reacted with (?)-(5R,2E)-3-methoxy-5-trichloromethyl-2-hexenoyl chloride ((-)- 11 ) to give (?)- 1 and its diastereoisomer (+)-5-epidysidin ((+)- 12 ) epimeric at C(5) of the pyrrolinone ring. The (?)-acyl chloride (?)- 11 has been synthesized from (+)-(R)-3-(trichloromethyl)butanoic acid ((+)- 8 ) via the intermediates (+)- 9 and (?)- 10 , the pyrrolinone 7 from N-benzyl-oxycarbonyl-L-valine via the intermediate 5 . The enantiomers of acid 8 have been resolved by fractional crystallization of their diastereoisomeric N-(1-phenylethyl)amides. The (R)-chirality of (+)- 8 was determined by comparing the ¹H-NMR spectra of the diastereoisomeric N-(1-phenylethyl)amides 16 and 17 , made from (+)- 8 by substituting deuterium for chlorine, with the spectra of the N-(1-phenylethyl)amides 14 and 15 of known absolute configuration. This correlation shows that literature value (R) for (?)- 8 is in error. Therefore, the structural formulae of (?)-dysidenin and (+)-isodysidenin, two other metabolites of D.herbacea, have to be changed to their mirror images as shown in formulae (?)- 3 and (+)- 4 , respectively.     

Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl)benzamidines by reaction of halobenzonitriles with lithium amides

3- and 4-N,N-Dialkylaminobenzonitriles and 4-chloro-(N,N-dialkyl)benzamidines were isolated by reacting 4-chlorobenzonitrile with hindered lithium amides under thermodynamic (0 °C) and kinetic control conditions (−78 °C), respectively. As previously reported, a benzyne mechanism seems to be confirmed since N,N-dialkylaminobenzonitriles are formed. Only benzamidines were isolated in fair to high yields at both 0 °C and −78 °C with non-hindered lithium amides. Exploitation and mechanistic rationale of the reaction of different halobenzonitriles are also reported.     

DFT study of the reaction sites of N,N′-substituted p-phenylenediamine antioxidants

The geometry of N,N′-diphenyl-p-phenylenediamine (DPPD), N-phenyl-N′-(1′-methylbenzyl)-p-phenylenediamine (SPPD), N-phenyl-N′-(1,3-dimethyl-butyl)-p-phenylenediamine (6PPD), N-phenyl-N′-isopropyl-p-phenylenediamine (IPPD), and N-(1-methyl-1-phenylethyl)-N′-phenyl-p-phenylenediamine (CPPD) as well as of their dehydrogenation products has been optimized at B3LYP/6-31G^∗ level of theory. Our results support the idea of formation of stable ketimine Ph-NC structures (instead of quinonediimine structures) during consecutive dehydrogenation of SPPD, 6PPD, and IPPD antioxidants despite the formation of tertiary carbon-centered radicals in the first dehydrogenation step is energetically preferred for SPPD only.     

Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium ion cyclisations with an internal alkene nucleophile

Chiral non-racemic bicyclic and tricyclic oxylactams obtained in two steps from N-(2-hydroxy-1(R)-phenylethyl)-succinimide and phthalimide are cyclised diastereoselectively in formic acid to give spiro[cyclohexane-1,2′-pyrrolidin]-5-ones and spiro[cyclohexane-1,1′-isoindolin]-3-ones, respectively.     

Palladium-catalyzed stereoselective synthesis of (E)-β,γ-unsaturated amides

A facile Suzuki type cross-coupling reaction of alkenylborane with 2-bromo-N,N-dimethylacetamide in the presence of a catalytic amount of tricyclohexylphosphine as the ligand has been demonstrated to be a convenient way for the synthesis of (E)-β,γ-unsaturated amides.     

On the easy oxidation of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid to its disulfide dimer

The physical and spectroscopic data of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid are reviewed and the synthesis of (R)-di-[2-(N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid disulfide is described. The product resulting from the conjugate addition of the dithioacid to 2(5H)-furanone is also characterised.     

Synthesis of the four enantiomers of diethyl 1,2-di(N-Boc-amino)propylphosphonates

A simple and efficient synthetic strategy to all four enantiomerically pure diethyl 1,2-di(N-Boc-amino)propylphosphonates has been elaborated starting from the corresponding N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes, employing a one-pot three-components Kabachnik-Fields reaction followed by the hydrogenolytic removal of the chiral auxiliary and aziridine ring opening with simultaneous protection of the amino groups as the N-Boc derivatives.     

Features of catalyzed hydration of 2-(dichloromethyl)-<Emphasis Type="Italic">N</Emphasis>-[(1<Emphasis Type="Italic">R</Emphasis>)-1-phenylethyl)]cyclopent-3-ene-1-carboxamides

The hydration of gem-dichloromethyl group in 2-(dichloromethyl)-N-[(1R)-1-phenylethyl)]cyclopent-3-ene-1-carboxamides in aqueous acetonitrile catalyzed by AgNO₃, FeCl₃·6H₂O, PdCl₂, and BaO was investigated. The optimum results were obtained at the use of BaO. It was demonstrated, that Pd-catalyzed reactions initiated intermolecular ether formation from the primary hydration products, bicyclic amides.     

Synthesis of four stereoisomers of protected 1,2-epiimino-3-hydroxypropylphosphonates

Enantiomerically pure protected 1,2-epiimino-3-hydroxypropylphosphonates were synthesised from hydroxy-1-{[(R)- or (S)-1-phenylethyl]aziridin-2-yl}methylphosphonates via regioselective ring opening with acetic acid followed by a stereospecific intramolecular cyclisation of 3-acetoxy-1-mesyloxy-2-(1-phenylethyl)aminopropylphosphonates and hydrogenolytic removal of the 1-phenylethyl group in the presence of Boc₂O. The trans-isomers of 3-acetoxy-[N-(1-phenylethyl)-1,2-epiimino]propylphosphonates exist as a 2:1 mixture of invertomers, which were fully structurally characterised based on their ¹H and ¹³C NMR spectroscopic data. Large differences in the ¹J_C-P values in N-(1-phenylethyl)aziridine-2-phosphonates were noticed depending on the spatial arrangement of the nitrogen lone pair and the phosphorus atom (syn-periplanar—ca. 215 Hz; anti-periplanar—182 Hz).     

Elimination of benzotriazolyl group in N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling and cross-coupling reactions with carbonyl compounds

The elimination of benzotriazolyl group from N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.     

Stereoselective fluorination of methylenecyclopropanes with N-F reagents: A modular entry to γ-fluorohomoallylic sulfonimides and γ-fluorohomoallylic amides

A convenient and efficient method for fluorination of methylenecyclopropanes is reported. This is exemplified in the stereoselective preparation of N-[(E)-3-fluorobut-3-en-1-yl]-benzenesulfonimides by the reaction of methylenecyclopropanes with N-fluorobenzenesulfonimide in good to excellent yields. Moreover, γ-fluorohomoallylic amides are synthesized using Selectfluor in R₃CN at 60 °C.     

Stereoselective synthesis of substituted 2,5-diazabicyclo[2.2.1]heptanes by iodine-mediated cyclization of optically pure compounds containing the 4,5-diamino-1,7-octadiene and 1,2-diamino-4-alkene moieties

3,7-endo-Disubstituted 2,5-diazabicyclo[2.2.1]heptanes were obtained by iodo-cyclization of N,N′-di[(S)-1-phenylethyl]-(E,E)-4,5-diamino-1,8-diphenyl-1,7-octadiene and substituted N,N′-di[(S)-1-phenylethyl]-1,2-diamino-4-alkenes. Removal of only one N-substituent of the bridged piperazines was achieved by reduction with ammonium formate and Pd/C. Unexpected cleavage of the skeleton of vinyl-substituted bridged piperazines was observed using hydrogen, leading to substituted 3-aminopyrrolidines.     

Superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids: synthesis of quinolin-2(1H)-one derivatives

The superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids by Bronsted superacids (CF₃SO₃H, HSO₃F) or strong Lewis acids AlX₃ (X=Cl, Br) results in the formation of 4-aryl quinolin-2(1H)-ones in quantitative yields. The vinyl triflates or vinyl chlorides may be formed as additional reaction products. The investigated amides in reactions with benzene give 4,4-diaryl 3,4-dihydroquinolin-2-(1H)-ones under the superelectrophilic activation. 4-Aryl quinolin-2(1H)-ones in POCl₃ are converted into 4-aryl 2-chloroquinolines. 4-Fluorophenyl-4-phenyl 3,4-dihydroquinolin-2-(1H)-one give N-formylation products in a yield of 79% under the Vilsmeier–Haack reaction conditions.     

Dithiophosphorylation of racemic and enantiomerically pure trimethyl-N-(1-phenylethyl)silanamine

Trimethylsilyl P-aryl-N-[(RS)-, (S)-(?)-, and (R)-(+)-(1-phenylethyl)]phosphonamidodithioates were synthesized by reactions of 2,4-diaryl-1,3,2λ⁵,4λ⁵-dithiadiphosphetane 2,4-disulfides with racemic and and enantiomerically pure trimethyl-N-(1-phenylethyl)silanamine.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

Reactions of <Emphasis Type="Italic">N</Emphasis>-(2,2,2-trichloroethylidene)- and <Emphasis Type="Italic">N</Emphasis>-(2,2-dichloro-2-phenylethylidene)arenesulfonamides with biuret

N-(2,2,2-Trichloroethylidene)- and N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides react with an equimolar amount of biuret to give 1-(1-arylsulfonylamino-2,2,2-trichloroethyl)- or 1-(1-arylsulfonylamino-2,2-dichloro-2-phenylethyl)biurets. The reactions with 2 equiv of N-(polychloroethylidene)arenesulfonamides involve both amino groups in the biuret molecule, yielding the corresponding 1,5-bis(1-arylsulfonylamino-2,2,2-trichloroethyl)- and 1,5-bis(1-arylsulfonylamino-2,2-dichloro-2-phenylethyl)biurets.