Cyclization of a cysteine conjugate of N-(3,5-Dichlorophenyl)succinimide

N-(3,5-Dichlorophenyl)-2-cysteinylsuccinimide methyl ester hydrochloride ( 5 ) was prepared from N-(3,5-dichlorophenyl)maleimide ( 3 ) and cysteinyl methyl ester hydrochloride. Attempted neutralization of the cysteine conjugate salt with triethylamine resulted in spontaneous cyclization of 5 to form the more stable 2-(N-3,5-dichlorophenylcarbamoylmethyl)-5-carbomethoxy-1,4-thiazine- 3-one ( 6 ). Similar results might be expected in vivo should these metabolites of succinimides be formed.     

Reaction of N-(2-pyridylmethyl)-3,5-dimethylbenzamide and N-(3-pyridylmethyl)-3,5-dimethylbenzamide N-oxides with acetic anhydride

As a continuation of our work on the reaction of N-pyridylmethyl-3,5-dimethylbenzamide N-oxides with acetic anhydride, we now report a study of the reaction of N-(2-pyridylmethyl)-3,5-dimethylbenzam.de N-oxide ( 5 ) and N-(3-pyridylmethyl)-3,5-dimethylbenzamide N-oxide ( 6 ) with acetic anhydride. Compound 5 gave N,N′-di(3,5.dimethylbenzoyl)-1,2-di(2.pyridyl)ethenediamine ( 7 ) and 3,5-dimethylbenzamtde ( 8 ). Compound 6 afforded three products formulated as 2-acetoxy-3-(3,5-dimethylbenzoylaminomethyl)pyridine ( 12 ), 3-(3,5-dimethylbenzoylaminomethyl)-2-pyridone ( 13 ) and 5-(3,5-dimethylbenzoylaminomethyl)-2-pyridone ( 14 ). Analytical and spectral data are presented which support the structures proposed.     

The synthesis and reagent properties of tetrakis-(3,5-dichlorophenyl)borate

Cesium tetrakis(3,5-dichlorophenyl)borate shows similar precipitation and gravimetric properties as tetrakis(m-chlorophenyl)- and tetrakis(p-chlorophenyl)borates. Its overall stability is worse than those of the chloro-substituted borates but it is more stable toward acid attack.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to N-(3,5-dichlorophenyl)itaconimide

Summary The regioselectivity of the nitrile oxide cycloaddition with 3,3-methylene-1-(3,5-dichlorophenyl)-2,5-pyrrolidindione (1) is discussed. Arylnitrile oxides add regioselectively to the carboncarbon double bond of1, giving exclusively spiro-isoxazolines3a–k, whereas acetonitrile oxide gives both adducts3l and4l. AM1 calculations of the reactants and cycloadducts were performed, the regiochemistry of the cycloaddition seems to be controlled by steric effects. Reduction of3a with NaBH₄ in the presence of magnesium perchlorate at –20 °C was regio-and stereoselective to yield the hydroxylactams9a and10a, whereas hydroxymethylisoxazoline14a was obtained in the absence of Mg(ClO₄)₂.Part XXX in the series 1,3-Dipolar Cycloaddition on Heterocycles. Part XXIX [27]     

Diels-Alder reaction of fulvenes with N-(3,5-dichlorophenyl)-maleimide

Summary N-(3,5-Dichlorophenyl)-maleimide reacts smoothly with a variety of substituted fulvenes (1) to give onlyendo adducts (3) independent of the nature of fulvene substituent,Lewis acid catalyst, and reaction solvent and temperature. The structure of theDiels-Alder adduct3f was determined by X-ray crystallography. Semi-empirical quantum methods (AM1) were used to rationalize theendo stereoselectivity.Dedicated to Professor Fritz Sauter on the occasion of his 65^th birthday     

Synthesis of 3-(2-guanidinoethyl) and 3-[2-(S-methylisothioureidoethyl)] analogs of 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate as a respective releaser of nitric oxide and inhibitor of nitric oxide synthase

The Hantzsch condensation of 2-azidoethyl acetoacetate with 2,3-dichlorobenzaldehyde and isopropyl 3-aminocrotonate afforded 3-(2-azidoethyl) 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate ( 7 ). Reduction of the 3-(2-azidoethyl) moiety of 7 using 5% palladium-on-calcium carbonate and hydrogen gas gave the 3-(2-aminoethyl) derivative 8 , which was subjected to guanylation using 1H-pyrazole-1-carboxamidine hydrochloride to yield the target 3-(2-guanidinoethyl) analog 9 . The 3-(2-aminoethyl) product 8 was elaborated to the title compound 3-[2-(S-methylisothioureidoethyl)] 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate hydrochloride ( 12 ) via the intermediate 3-(2-thioureidoethyl) compound 10 . The 3-(2-guanidinoethyl 9 and 3-[2-(S-methylisothioureidoethyl)] 12 compounds were about 116- and 23-fold less potent calcium channel antagonists, respectively relative to the reference drug nifedipine.     

Synthèse de N-2 alkyl (aryl) dioxo-3,5 oxadiazolidine-1,2,4

The synthesis of new 3,5 dioxo-1,2,4 oxadiazolidines whixh are N-2 substituted bioisosters of biologically active carboxylic compounds was studies. Nitro compounds were used as starting materials, and triton B as the cyclizing base. The expected N-2 allyl and aryl substituted derivatives were obtained in satisfactory yields.     

Determination of the site of glucuronidation in an N-(3,5-dichlorophenyl)succinimide metabolite by electrospray ionization tandem mass spectrometry following derivatization to picolinyl esters

Derivatization using 3-pyridylcarbinol coupled with liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) was used to characterize a novel Phase II metabolite of the nephrotoxic agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS). A glucuronide conjugate of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) was identified in the urine from a rat dosed with [14C]NDPS. However, 2-NDHSA contains an aliphatic hydroxyl group and a carboxylic acid group, both of which are potential sites for glucuronidation. Mass spectrometry alone was unable to distinguish between these possibilities. Since the position of glucuronidation may be important in the mechanism of NDPS-induced nephrotoxicity, chemical derivatization in conjunction with mass spectrometry was used to characterize the glucuronide. The 2-NDHSA glucuronide conjugate was isolated from rat urine, derivatized with 3-pyridylcarbinol, and the derivatized metabolite was then analyzed by LC/MS/MS. Two known NDPS metabolites, 2-NDHSA and N-(3,5-dichlorophenyl)succinamic acid (NDPSA), were also isolated from rat urine and derivatized similarly. 3-Pyridinylcarbinol reacted rapidly with the carboxylic acid groups and formation of the picolinyl esters increased the ionization potential under positive ion conditions. The urinary glucuronide of 2-NDHSA was identified as an alcohol-linked glucuronide by examination of the molecular ions and the collision-induced dissociation (CID) product ion spectra of the derivatized products. When used in combination with mass spectrometry, derivatization of carboxylic acids with 3-pyridylcarbinol provided useful mass fragmentations and is a rapid way to obtain structural information about the position of glucuronidation of NDPS metabolites.     

Reaction of N-[(α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide with alkyl isocyanates

Reaction of N-(α-acetoxy)4-pyridylmethyl]-3,5-dimethylbenzamide 3 with methyl and ethyl isocyanates afforded 1,3-dimethyl and 1,3-diethyl-4-(3,5-dimethylbenzoylamino)-2-oxoimidazolidine-5-spiro-4′-[1′,4′-dihydro-1′-acetyl]pyridine 6a,b , respectively. However, the reaction of 3 with isopropyl, t-butyl and phenyl isocyanates gave the corresponding N,N′-diurea and the dimerization compound 8 . The structure of 6a was confirmed by crystal X-ray diffraction analysis.     

Reaction of N-(4-pyridylmethyl)-3,5-dimethylbenzamide N-oxide with acidic compounds in the presence of acetic anhydride: Discussion of the mechanism

The mechanism of N-(4-pyridylmethyl)-3,5-dimethylbenzamide N-oxide with acidic compounds in the presence of acetic anhydride is presented.     

Synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides

This paper describes the synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides by ¹H, ¹³C, and ¹⁵N. The presence of intra- and intermolecular hydrogen bonds were studied by variable temperature NMR spectroscopy. The molecular structure of two amides in the solid state was determined by X-ray diffraction experiments. The results show that tert-butyl substituents in the phenolic ring have important effects in the nature of hydrogen bonds and conformation of these amides. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:114–120, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10223     

Computational chemical studies of chiral stationary-phase models: The nature of the Pi interaction in complexes of methyl N-(2-naphthyl) alaninate with N-(3,5-dinitrobenzoyl)leucine n-propylamide

The pi interaction in complexes of (S)-methyl N-(2-naphthyl)alaninate with (S)- and (R)-N-(3,5-dinitrobenzoyl)leucine n-propylamide was investigated with Hartree–Fock and second-order Møller–Plesset perturbation theory calculations using the STO -3G basis set. For each complex, the geometry of the model of the pi interaction (i.e., naphthalene and 1,3-dinitrobenzene) was derived directly from the complex geometry which was relaxed by the semiempirical quantum-mechanical AM 1 method. At the level of treatment used herein, our results are in agreement with our earlier AM 1 interaction energy calculations in which the pi interaction, one of the three primary interactions proposed in models of the aforementioned complexes, is attractive and of equal strength (ca. 0.8 kcal/mol) in both complexes.     

1-(Cyanoacetyl)-3,5-dimethylpyrazole as Active Methylene Compound in Hantzsch-type Pyridine Synthesis: A Convenient and Highly Effective Approach to 3,5-Dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates

Summary. Reaction of 1-(cyanoacetyl)-3,5-dimethylpyrazole with (E)-2-cyano-3-(het)arylprop-2-enethioamides was used for the synthesis of N-methylmorpholinium 3,5-dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates for the first time. The latter were also obtained in a multicomponent one-pot mode via the condensation of cyanothioacetamide with corresponding aldehydes and above 1-cyanoacetylpyrazole in the presence of N-methylmorpholine under mild conditions. Thiolates 1 exist as a pair of cis/trans-diastereomers in different ratios (from 3:4 to 2:1). Last author was Deceased on February 26, 2007     

Synthesis and reactivity of N-[α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide

The synthesis of N-[(α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide (4) and its reactivity are described. Since the acetoxy is a good leaving group, 4 gives S_N processes easily.     

Synthesis of 4-substituted 1,4-benzodiazepine-3,5-diones

Synthetic routes leading to the preparation of 4-substituted 1,4-benzodiazepine-3,5-diones are described. Thus, 2-carbobenzoxyaminobenzoic acid was converted to its p-nitrobenzyl ester (I) and the decarbobenzoxylated product (II) gave, with ethyl α-bromoacetate, N-(2-carboxy p-nitrobenzylate)phenylglycine ethyl ester (III). The latter was hydrogenolyzed to N-(2-car-boxy)phenylglycine ethyl ester (IV), which was coupled with benzylamine to give N-(2-carboxy-benzylamido)phenylglycine ethyl ester (VIa). Saponification of VIa afforded N-(2-carboxy-benzylamido)phenylglycine (VIIa) which was cyclized with DCCI to produce 4-benzyl-2H-1,4-benzodiazepine-3,5(lH,4H)dione (VIIIa). Alternatively, 2-nitro-N-phenylbenzamide (Xb) was reduced to 2-amino-N-phenylbenzamide (XIb) which was converted to N-(2-carboxanih'do)-phenylglycine ethyl ester (VIb). The latter was converted to 4-phenyl-2H-1,4-benzodiazepine-3,5(1H,4H)dione (VIIIb) in an analogous fashion described for VIIIa.     

Nitropyrazoles 15. Synthesis and some transformations of 1-(2,4-dinitrophenyl)-4-methyl-3,5-dinitropyrazole

The method for preparation of 1-(2,4-dinitrophenyl)-4-methyl-3,5-dinitropyrazole has been developed. Due to the larger CH-acidity of 4-Me-group compared to 1,4-dimethyl-3,5-dinitropyrazole, 1-(2,4-dinitrophenyl)-4-methyl-3,5-dinitropyrazole is capable of reacting with substituted benzaldehydes to afford 4-[(E)-2-arylvinyl]-1-(2,4-dinitrophenyl)-3,5-dinitropyrazoles. Under the action of nucleophiles, dinitrophenyl group is detached from the former compounds leading to previously unknown N-unsubstituted 4-[(E)-2-arylvinyl]-3,5-dinitropyrazoles.     

N-(2-tetrahydrofuranyl)azole nucleoside analogs by reactions of azoles with dihalomethanes in tetrahydrofuran

The reactions of the mono-N-substituted bispyrazolylpyridine 2-(1-methyl-4,5,6,7-tetxahydroindazol-3-yl)-6-(2H-4,5,6,7-tetrahydroindazol-3-yl)pyridine, 3,5-dimethylpyrazole and benzimidazole with sodium hydride and diiodomethane or dibromomethane in tetrahydrofuran produced the unexpected N-tetrahydrofuran-2-yl adducts as well as the expected diazolylmethanes. These side-reactions are thought to involve the 2-halo tetrahydrofuran derivative resulting from a free-radical halogenation by the dihalomethane.     

Synthesis and polymerization of 1-(2,4,6-tricyanophenylthio)-3-[3,5-bis(n,n-dimethylamino)phenoxy]-2-propyl methacrylate; polymer effect on intramolecular charge–transfer interaction

1-[3,5-Bis(N,N-dimethylamino)phenoxy]-ω-(2,4,6-tricyanophenylthio)alkanes ( 1a–c ), where an electron-accepting 2,4,6-tricyanophenylthio group and an electron-donating 3,5-bis(N,N-dimethylamino)phenoxy one are linked with a spacer such as ethylene, trimethylene, and tetramethylene, were prepared in order to examine an effect of the spacer chain length on intramolecular charge–transfer interaction between the 2,4,6-tricyanophenylthio and 3,5-bis(N,N-dimethylamino)phenoxy groups. From the UV-vis spectra measurements of 1a–c , 1-[3,5-bis(N,N-dimethylamino)phenoxy]-3-(2,4,6-tricyanophenylthio)Propane ( 1b ) carrying the trimethylene chain as a spacer was found to have the strongest intramolecular charge–transfer interaction. A new methacrylate-type monomer carrying the 1b unit as a side chain, 1-(2,4,6-tricyanophenylthio)-3-[3,5-bis(N,N-dimethylamino)phenoxy]-2-propyl methacrylate ( 2 ), was prepared successfully in 9.2% total yield in seven steps. The monomer 2 homopolymerized in benzene, tetrahydrofuran, acetone, and dimethyl sulfoxide in the presence of 2,2′-azobis(isobutyronitrile) at 60°C to give polymers [poly( 2 )] with molecular weights of 6,000 to 98,000. An intramolecular charge–transfer interaction in the poly( 2 ) was found to be larger than that in the monomer 2 and to increase with an increase in the degree of polymerization of the poly( 2 ), suggesting that there is an existence of polymer effect other than the polymer effect due to the high local concentration of the donor-acceptor pair. © 1995 John Wiley & Sons, Inc.     

2-Nitroguanidine Derivatives: V. Synthesis and Structure of 3,5-Bis(nitroamino)-1,2,4-triazole Salts. Acid–Base Properties of 3,5-Bis(nitroamino)-1,2,4-triazole

Heterocyclization of hydrazine-1,2-bis(N ²-nitrocarboximidamide) and salts derived therefrom provides a procedure for the synthesis of 3,5-bis(nitroamino)-1,2,4-triazole salts. The presence of two acceptor nitroamino groups conjugated with the triazole ring considerably enhances the acidity of 3,5-bis(nitroamino)-1,2,4-triazole (pK a¹= –2.0, pKa² = 4.8, pKa³ = 10.6) as compared to mononitroaminotriazole, so that formation of salts with the corresponding dianion becomes possible.     

Pseudosymmetry in the crystal structure of 2,6-dimethyl-3,5-dicarbomethoxy-4-(2′,3′-dichlorophenyl)-1,4-dihydropyridine

Within the framework of a detailed crystallochemical analysis a comparison of the structures of symmetrically independent molecules was performed and the energy of intermolecular interaction was calculated for a triclinic bisystem crystal, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2′,3′-dichlorophenyl)-1,4-dihydropyridine. Pseudosymmetrical operations were detected and identified. The presence of highly efficient layers with pseudomonoclinic symmetry was disclosed in this structure.