Direct Synthesis of Diphenylamines from Phenols and Ammonium Formate Catalyzed by Palladium.

Arylamines are commercially and synthetically useful compounds with a wide variety of applications. Their preparation has been traditionally achieved using metal-catalyzed C-N coupling reactions with aryl halides. In this work, 17 different diarylamines are prepared from phenols by using ammonium formate as the aminating reagent. Phenolic compounds are more desirable feedstocks, owing to their availability from lignin, making them valuable biorenewable alternatives to aryl halides. Ammonium formate is found to be a convenient surrogate for ammonia and a useful aminating reagent for phenols. Diarylamine products are obtained in good to excellent yields while only water and CO2 are generated as byproducts of the transformation.

Copper-catalyzed asymmetric sp3 C-H arylation of tetrahydroisoquinoline mediated by a visible light photoredox catalyst.

This report describes a highly enantioselective oxidative sp3 C-H arylation of N-aryltetrahydroisoquinolines (THIQs) through a dual catalysis platform. The combination of the photoredox catalyst, [Ir(ppy)2(dtbbpy)]PF6, and chiral copper catalysts provide a mild and highly effective sp3 C-H asymmetric arylation of THIQs.

Stabilizing and Activating Nitrogen Catenates.

The remarkably stable catenated hexa-nitrogen chain in bis(benzotriazene-4-one) is structurally, theoretically, and spectroscopically characterized to illustrate the durability of the central N-N bond in this hexaazo chain. The reactions of this species illustrate the potential of these nitrogen catenates for the preparation of other condensed heterocycles, such as bispyrazolones, by thermal nitrogen exclusion or by trapping the single ring-opened Dimroth intermediates. In these latter reactions, 2-naphtholate anion condenses with bis(benzotriazene-4-one) to trap and retain a zwitterionic diazonium intermediate as an isolated diazo product, whereas transition metals ring effect ring-extrusion of dinitrogen from the Dimroth intermediate to generate chelating σ-aryls. The catenated nitrogen species can be stabilized by incorporating strong formal sp(2)-sp(2) N-N σ bonds with orthogonal orientations. Extending these stabilization and activation principles may allow these types of nitrogen catenates to be useful synthons for other polyaza species.

Efficient merging of copper and photoredox catalysis for the asymmetric cross-dehydrogenative-coupling of alkynes and tetrahydroisoquinolines.

A highly efficient catalytic asymmetric alkynylation of prochiral CH2 groups in tetrahydroisoquinoline was developed using copper catalyzed cross-dehydrogenative-coupling of sp(3) and sp C-H bonds with the assistance of a photocatalyst and visible light.

E/Z oxime isomerism in PhC(NOH)CN.

The reaction of nitric oxide with benzyl cyanide in the presence of potassium methoxide at low temperature gave the dipotassium salt of a bis-diazeniumdiolate 2 in excellent yield. Two new stereospecific syntheses of E or Z 2-(hydroxyimino)-2-phenylacetonitrile from 2 have been found. The thermodynamics of the E/Z isomerization has been investigated spectroscopically in solution, in the solid state by differential scanning calorimetry (DSC), and theoretically in the gas phase. Evidence of catalysis by NO of E/Z oxime isomerization has been observed.

Facile NN Activation in Benzotriazole: Capturing the Dimroth Azo/Triazole Intermediate by Complexation to Iridium.

The in situ observation of benzotriazole ring and ring-opened isomers, which result from the Dimroth equilibrium for 1-[(nonafluorobutane)sulfonyl]benzotriazole, 1, in solution by 19 F NMR and UV/Vis spectroscopy is reported. Two benzotriazoles, compound 1 and 1,1'-sulfonylbis(benzotriazole) (3), undergo Dimroth triazole ring opening and coordination to an iridium(I) metal center to give either linear diazo [IrI (η1 -NNPhNSO2 C4 F9 )(Cl)(PPh3 )2 ] (2) or an unusual double bent diazene [IrIII (η3 -NNPhNSO2 Btz)(Cl)(PPh3 )2 ] (4; Btz=benzotriazole) complex.

E versus Z diazeniumdiolation of acetoacetate-derived carbanions.

Nitric oxide adds to methyl acetoacetate in the presence of KOH in methanol at room temperature to form potassium acetylsydnonate N-oxide (K1) with an (E)-diazeniumdiolation and potassium acetate diazenium diolate (K(2)2) from a (Z)-diazeniumdiolation. A study of the reaction with LiOH, NaOH, and NMe(4)OH and with ethyl acetate substrate reveals that the temperature of the reaction greatly influences the nitric oxide reactivity. At 23 °C, nitric oxide adds to give both E and Z products, whereas at -5 °C the gas reacts almost exclusively to give Z addition. The (Z)-diazeniumdiolation products, namely, the alkali metal and NMe(4)(+) salts of methyl and ethylbutenoate-2-diazeniumdiolate-3-hydroxylate (3(2-) and 4(2-)), are isolated in good yields. The alkali metal salts are not amenable for recrystallization because of their ready decomposition in aqueous solutions. However, [NMe(4)](2)[MeC(O)C(N(2)O(2))CO(2)Me] is readily recrystallized from a methanol/acetonitrile solvent mixture. The crystals are unambiguously characterized by X-ray crystallography. NMR spectra for all of the 3(2-) and 4(2-) salts reveal the presence of two isomers in aq solutions. But the structure of the NMe(4)(+) salt contains only one of the isomers. Our attempts to cyclize the isolated and purified butenoatediazeniumdiolates from the (Z)-diazeniumdiolation to the E-containing sydnonate products were unsuccessful. TGA/DSC data for all of the products demonstrate the thermal instability of the salts at high temperatures. The salts decompose exothermally possibly with the release of N(2)O among other gases.

Interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX, a solid state spectroscopy study.

To investigate the nature of binding of quinoline antimalarial drugs to heme and to extract experimental evidence for this binding, the interaction of ferriprotoporphyrin IX (FP) with chloroquine and quinacrine (both of which have a similar side chain) and quinoline methanol antimalarials quinine and mefloquine has been studied using IR and NIR-Raman spectroscopy in the solid state. Attenuated total reflectance infrared spectroscopic data clearly show that heme in chloroquine-FP complex is not µ-oxo dimeric indicating that the hypothesis that chloroquine binds to FP µ-oxo dimer with a stoichiometry of 1 chloroquine:2 µ-oxo dimers is not valid in the solid state. Moreover, the first vibrational spectroscopy evidence is presented for the formation of hydrogen bonding between a propionate group of heme and the tertiary amino nitrogen of chloroquine and quinacrine. Raman spectroscopy data does not provide any evidence to support the formation of a similar salt bridge in the complexes of FP with quinine and mefloquine; however, it suggests that the interaction of these drugs with FP happens through coordination of the Fe(III) center of the porphyrin to the 9-hydroxy group of the drug.

A new synthetic route to 3-oxo-4-amino-1,2,3-oxadiazole from the diazeniumdiolation of benzyl cyanide: stable sydnone iminium N-oxides.

Treating benzylcyanide with nitric oxide in basic methanol returns 3-oxo-4-phenyl-5-amino-1,2,3-oxadiazole (a 5-iminium-sydnone N-oxide), 5, in addition to the known 2-(hydroxyimino)-2-phenylacetonitrile, 6, and the bisdiazeniumdiolate imidate salt, 7. Conditions for the separation and purification of the new 1,2,3-oxadiazole 5 are described along with its theory, structure, spectroscopy, and reactivity which demonstrate the predominance of the amino tautomer over the N-hydroxide tautomer. New derivatives of 5 include a Schiff base, from the condensation with salicylaldehyde, 8, and a dimethylamino analogue of 5, from its reaction with methyliodide and NaH. As with other related 3-oxo-1,2,3-oxadiazoles 5 has pronounced acid/base stability. Theoretical calculations demonstrate that the only other prior sydnone N-oxides prepared were misformulated as the N-hydroxide imines and are better described as 3-oxo-5-amino-derivatives of 1,2,3-oxadiazoles.

Fluorescent diethylcarbamazine analogues: sites of accumulation in Brugia malayi.

New fluorescein and rhodamine B-labeled antifilarial drug DEC analogues for use in drug localization studies with confocal microscopy have been prepared by a high-yield three-step synthesis. The resulting beta-amine-substituted DEC analogue has a single ethyl substituent which is beta-aminated to accommodate the fluorophore of either fluorescein isothiocyananate or rhodamine B. Confocal microscopy is used to show that the drug accumulates in the adult filarial worms in the pharynx, esophagus, and near the nerve ring of all adults, as well as in the uteri and vulva and the testes of the females and males.

Methylation of sydnone N-oxides: kinetic and thermodynamic control in the alkylation site of an electron-rich heterocycle.

Methylation of the anionic 4-methylcarboxy 1,2,3-oxadiazolate 3-oxide occurs at either the disubstituted ring nitrogen or the oxygen of the N-oxide depending upon the conditions and reagents employed. Alkylation with methyl iodide leads to N-alkylation, while dimethyl sulfate gives O-alkylation and trifluoromethanemethylsulfonate gives a mixture of the two products. The regioselectivity of these methylations has been confirmed by X-ray diffraction of the two products, and these are in turn correlated with their theoretically predicted (B3LYP//6-311++G**) relative energies and vibrational spectra. Theoretically, N-alkylation is expected to give an isomer that is over 10 kcal mol-1 more stable than the O-alkylated product. As a neat melt the kinetic O-alkylation product cleanly isomerizes in 2 h when heated to 140 degrees C to give the thermodynamic N-methylated isomer. Taken together the results illustrate the remarkable new sydnone N-oxide derivatives which are readily accessed in this chemistry, with the N-alkylation of the sydnone N-oxide, corresponding to the first case of such an N-alkylation for a diazenium diolate.