N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P-O bond

N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P-O bond was investigated and a series of N3-ethoxymethylated heterocyclic compounds were synthesized. A mechanism in which diethyl phosphite acts as an efficient surrogate of ethanol was proposed and supported by several evidences.     

Experimental and computational study of intermolecular migration of N,N-dimethylcarbamoyl group from N(7) to N(1) on a 7-azaindoline derivative

N,N-Dimethylcarbamoylation of the anilinic nitrogen atom N(1) on the spiro 7-azaindoline consists of two steps. The first step is N,N-dimethylcarbamoylation of the pyridyl nitrogen atom N(7), leading to the formation of an isolable intermediate. The second step is intermolecular migration of the N,N-dimethylcarbamoyl group from the pyridyl nitrogen atom N(7) to the anilinic nitrogen atom N(1). We accomplished optimization of the reaction conditions based on the revealed reaction mechanism and a large scale synthesis of compound 3 in quantitative yield.     

Regioselective reactions of β-aminovinyl trifluoromethyl ketones with tosyl isocyanate

The NH- and α-CH-insertion reactions of tosyl isocyanate with N-monosubstituted and N,N-disubstituted trifluoromethyl-containing enaminones have been studied. The regioselectivity of N-tosylcarbomoylation of N-monosubstituted β-aminovinyl trifluoromethyl ketones depends on the structure of enaminones, the reaction temperature, the nature of solvent and catalyst. The Z configuration of fluorinated vinylogous sulphonylurea 3e was deduced from X-ray analysis. The reaction of N,N-disubstituted enaminone 5a with tosyl isocyanate gave the product mixture of electrophilic attack on either the α-CH- or the oxygen atom of COCF₃ group—vinylog of sulfonylurea 6a and tosylamide 7a, correspondingly.     

Lewis acid mediated nucleophilic ring opening followed by cycloaddition of 2-aryl-N-tosylaziridines with carbonyl compounds: further support towards an SN2-type mechanism

A highly regioselective S_N2-type ring opening of 2-aryl-N-tosylaziridines with carbonyl compounds in the presence of a Lewis acid to afford various 1,3-oxazolidines and 1,2-amino alcohols in excellent yields and moderate to high enantioselectivity is described. The formation of non-racemic products provides convincing evidence for the S_N2-type ring opening mechanism.     

The chemistry of carbazole. VI. On the formation of N-ethylcarbazoles in the cadogan reaction

Reaction of 2′,6-dimethyl-2-nitrobiphenyl with triethyl phosphite gave 4,5-dimethyl-9-ethylcarbazole besides 4,5-dimethylcarbazole. In this reaction, 4,5-dimethylcarbazole was ethylated by triethyl N-(2′,6-dimethybiphenyl-2-yl)phosphorimidate and diethyl N-(2′,6-dimethylbiphenyl-2-yl)phosphoramidate, which arose from a nitrene-intermediate and triethyl phosphite. Analogous ethylations of carbazole with other phosphorimidate and phosphoramidates were investigated.     

The use of N-sulfenylimines in the β-lactam synthon method: Staudinger reaction, oxidation of the cycloadducts and ring opening of β-lactams

Selected N-sulfenylimines act as good nucleophilic partners in the Staudinger reaction with methoxy- and benzyloxy-ketenes. The choice of diisopropylethylamine as a non-nucleophilic Lewis base for the generation of ketenes from acid chlorides is a determining factor for the success of the reaction. N-Sulfenyl-β-lactams are obtained in good to excellent yields and with moderate cis/trans diastereoselectivity. Then, they are quantitatively and selectively transformed to N-sulfinyl- or N-sulfonyl-β-lactams, by adjusting the oxidation state of the sulfur atom. The oxidation process induces an inversion of polarity of the nitrogen atom's substituent and allows a subsequent smooth ring opening by reaction of N-thiolated-β-lactams with various nucleophiles. The overall sequence provides straightforward and efficient route to highly functionalized-β-amino acid derivatives.     

Dialkylzinc mediated radical additions to chiral N-enoyloxazolidinones in the presence of benzaldehyde. Mechanistic investigation, structural characterization of the resulting γ-lactones

Diethylzinc was used in the presence of oxygen to mediate radical additions to chiral N-enoyloxazolidinones derived from fumaric acid. The synthesis of sterically crowded trisubstituted γ-lactones was achieved through a multicomponent reaction involving t-butyl iodide and benzaldehyde in addition to the above mentioned reagents. The domino process includes successively: iodine atom transfer, radical addition, homolytic substitution at zinc, aldol condensation, and lactonization. The diastereoselectivity of the reaction and the structural features of the resulting lactones were investigated. A tentative rationalization is discussed. Comparative experiments carried out with diisopropylzinc were performed.     

Limitations of the Wittig-Horner-type annulation of fluorobutenolide moiety to 3-hydroxyquinoline-2,4(2H,3H)-diones. Novel modifications of the Perkow reaction including fluorinated acyloxy leaving groups

3-(Fluoroacyloxy)quinoline-2,4(1H,3H)-diones react with triethyl phosphite to afford either the product of the Perkow reaction or the corresponding 4-ethoxyquinolin-2(1H)-one. In both reactions, the fluorocarboxylate anion acts as the leaving group. For the corresponding 3-(fluoroiodoacetoxy) derivative this observation precludes the application of the intramolecular Wittig-Horner synthesis to modify quinoline-2,4(1H,3H)-diones by the annulation of a fluorinated but-2-enolide moiety.     

Copper-based reverse ATRP process of styrene in mixed solvents

Xylene/N,N-dimethylformamide (DMF) and xylene/ethanol were employed as mixed solvents, respectively, for the reverse atom transfer radical polymerization (R-ATRP) of styrene with the azobisisobutyronitrile (AIBN)/CuBr₂/N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA) initiating system. With a limited amount of DMF added in, CuBr₂/PMDETA complex could dissolve well in the reaction system, so the control of polymerization was enhanced compared with the one in which simplex xylene was used as solvent. But the polarity of DMF leaded kinetics to deviation from first order. Ethanol could also improve the solubility of catalyst and be scavenged quickly by argon at 110°, therefore the impact of polarity of solvent on kinetics was negligible. Induction periods were not observed here indicating rapidly establishment of equilibrium between Cu(I) and Cu(II). This method that adding a little amount of polar solvent with low boiling point into non-polar solvent gives a new way to solve the problem of poor solubility of the catalyst in R-ATRP.     

Synthesis,spectral characterization of the zinc(II) mixed-ligand complexes of N(4)-allyl thiosemicarbazones and N,N,N′,N′-tetramethylethylenediamine,and crystal structure of the novel [ZnL2(tmen)] compound

Mixed-ligand zinc complexes with N,N,N′,N′-tetramethylethylenediamine (tmen) and R-salicylaldehyde N(4)-allyl thiosemicarbazones (R: 3-OCH₃ (L₁), 5-Br(L₂)), [ZnL_1,2(tmen)], were synthesized and the complexes were characterized by elemental analysis, atomic absorption spectrometer, magnetic susceptibility, molar conductivity, electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) mass spectra and IR, UV–Vis, ¹H NMR and ¹⁵N spectroscopies. Crystal of [ZnL₂(tmen)] have a slightly distorted square pyramid involving O, N, S atoms of thiosemicarbazone and one N atom of tmen in basal plane and the other N atom of tmen in apex of the pyramid. The non-coordinated allyl group is disordered.     

3-Halomethylated cyclic nitronates: synthesis and nucleophilic substitution

A method for the introduction of a halogen atom into the methyl group attached to the C-3 atom of five- and six-membered cyclic nitronates (isoxazoline N-oxides and oxazine N-oxides, respectively) has been studied. The process involves silylation of starting 3-methyl-substituted cyclic nitronates followed by halogenation of the resulting N-(silyloxy)enamines. While five- and six-membered cyclic enamines behave similarly toward elemental bromine and iodine, their reactions with NBS give different products, that were rationalized by stereoelectronic effects. The obtained halogenated nitronates were coupled with various nucleophiles affording new nitronates functionalized at the C-3 position.     

Facile synthesis of C-phosphanylformamidines via a carbene pathway

A direct synthetic approach to C-phosphanyl-N,N-dialkyl-N′-aryl(alkyl)-formamidines was developed. It was shown that phosphorylation of the formamidines proceeds at the nitrogen atom affording N-phosphanylformamidinium salts. Upon deprotonation, these salts gave C-phosphanylformamidines via formation of carbenes followed by a 1,2-phosphorus shift.     

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.     

Acyclic tertiary diamines and 1,4,7,10-tetraazacyclododecane with fluorine-containing β-diketones: Leading to low melting ionic adducts

N,N,N′,N′-Tetramethylmethanediamine (1a), N,N,N′,N′-tetramethylethanediamine (1b), N,N,N′,N′-tetramethyl-1,3-propanediamine (1c), and N,N,N′,N′-tetramethyl-1,6-hexanediamine (1d) were reacted at 25 °C with 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (2a), 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedione (2b), 2-thenoyltrifluoroacetone (2c), and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2d) to form the ionic adducts 3-18. 1,4,7,10-Tetraazacyclododecane (1e) reacted at 25 °C with β-diketones (2a-d) and 1,1,1-trifluoro-2,4-pentanedione (2e) to give ionic solids 19-23 in good yields. Some of the products are liquid at 25 °C and are thermally stable over long liquid ranges as determined by thermal gravimetric analyses. Single-crystal X-ray structure determinations show that compounds 9 and 21 crystallize in the monoclinic space groups P2(1)/c and P2(1)/n, respectively. All the new compounds were characterized by ¹H, ¹⁹F and ¹³C NMR, electrospray MS and/or elemental analyses.     

Probing the metal complexing ability of bis-quinolizidine N-oxides: Synthesis, spectroscopy and crystal structures

New ZnX₂ (X = Cl, Br) complexes with sparteine N1-oxide, sparteine epi-N16-oxide, lupanine (2-oxosparteine) N-oxide and α-isosparteine N-oxide were obtained and characterized by spectroscopic and crystallographic methods. Complexation with N1-oxides involves inversion of the configuration at the N16 atom of sparteine, converting its C ring from a boat into a chair form, whereas the structure of sparteine epi-N16-oxide, typified by the trans boat/chair C/D quinolizidine moiety, remains unchanged upon complexation. Coordination of zinc salts in the above compounds is realized solely through the oxygen atom of the N-O group and is accompanied by protonation of the “not-N-oxide” nitrogen atom. At variance lupanine N-oxide forms bis-monodentate complexes with ZnX₂ utilizing both the N-oxide and the lactam carbonyl oxygen atoms to bridge the neighboring ZnX₂ units, while reaction of α-isosparteine N-oxide with ZnX₂ leads to formation of complex salts of the general formula [H(−)α-Sp(N-oxide)][(ZnX₃)(H₂O)].     

Naryl-substituted anthranilamides with intramolecular hydrogen bonds

Hydrogen bonding interaction as one type of non-covalent force has proven itself to be highly efficient for constructing structurally unique artificial secondary structures. Here, the structure of N_aryl-substituted anthranilamide in solution is demonstrated by various NMR technique, the intramolecular hydrogen bonds between amide attached to arylamine of the same ring is proposed, which is supported by its crystal structure in the solid phase. The substituent on the nitrogen atom of arylamine plays an important role in forming the presence of intramolecular hydrogen bonds. The chemical shift of the N_aryl-H downfield changes obviously, due to the formation of intramolecular hydrogen bonds and the deshielding effect of oxygen, and the neighboring C–H is activated and shows downfield protonic signal too. The presence of intramolecular hydrogen bonds probably provides the explanation for the transformation from N_aryl-substituted anthranilamide to imine, which could be converted into 2-aryl quinazolinone finally.     

A simple and efficient biphasic method for the preparation of 4-nitrophenyl N-methyl- and N-alkylcarbamates

Treatment of 4-nitrophenyl chloroformate with alkylammonium hydrochloride salts and solid anhydrous Na₂CO₃ in either CH₂Cl₂ or CH₃CN gave 4-nitrophenyl N-methylcarbamate and other N-alkylcarbamate analogues in excellent yields. Of particular interest is the observation that 4-nitrophenyl N-methylcarbamate, a safer alternative to the highly toxic methyl isocyanate, is obtained in quantitative yield (?95% pure as determined by ¹H NMR) after simple filtration and solvent evaporation.     

An efficient synthetic route to substituted tetrahydropyrimidines by Cu(OTf)2-mediated nucleophilic ring-opening followed by the [4+2] cycloaddition of N-tosylazetidines with nitriles

A highly efficient strategy for Cu(OTf)₂-mediated S_N2 type nucleophilic ring-opening followed by the [4+2] cycloaddition reactions of a number of 2-aryl-N-tosylazetidines with nitriles to afford a variety of substituted tetrahydropyrimidines in excellent yields is reported. The resulting tetrahydropyrimidines could easily be transformed into synthetically important 1,3-diamines by acid-catalyzed hydrolysis. The strategy has been extended to the synthesis of enantiomerically pure tetrahydropyrimidines from enantiopure disubstituted azetidines. The reaction proceeds through an S_N2 type mechanism as proposed by us earlier.     

N-Hydroxyphthalimide in combination with Cu(II), Co(II) or Mn(II) salts as catalytic systems for the oxidation of isopropyl-aromatic hydrocarbons with oxygen

Catalytic systems consisting of N-hydroxyphthalimide in combination with copper(II), cobalt(II) and manganese(II) acetylacetonate, acetate or chloride were applied to the oxidation of cumene with oxygen. The use of these catalytic systems decreases cumyl hydroperoxide selectivity as a result of the decomposition reaction of hydroperoxide to 2-phenyl-2-propanol and acetophenone. It has been demonstrated that the use of N-hydroxyphthalimide in combination with copper salts at 60 °C results in high alcohol content whereas ketone is the major product at 90 °C. The results can be used to develop a method for alcohol or ketone synthesis from other isopropyl-aromatic hydrocarbons.