High‐performance liquid chromatography tandem mass spectrometry method for the determination of 2CC‐NBOMe and 25I‐NBOMe in human serum

2CC‐NBOMe {4‐chloro‐2,5‐dimethoxyphenethyl‐N‐[(2‐methoxyphenyl) methyl] ethanamine} and 25I‐NBOMe {2‐(4‐iodo‐2,5‐dimethoxyphenyl)‐N‐[(2‐methoxyphenyl) methyl] ethanamine} are of a class of N‐benzyl phenethylamine derivatives whose synthesis was first reported in the scientific literature in 2011. Recent reports from ‘personal drug experience websites’ and in the popular press indicate these drugs are the latest in a series of designer ‘Bath Salt’ drugs of abuse. The presented high‐performance liquid chromatography triple quadrupole mass spectrometry (HPLC/MS/MS) method was developed for the detection and quantification of 2CC‐NBOMe and 25I‐NBOMe in serum of intoxicated emergency department patients. The assay applies 2‐?(2,?5‐?dimethoxyphenyl)‐?N‐?(2‐?methoxybenzyl) ethanamine (25H‐NBOMe) as the internal standard. Samples were extracted using solid‐phase extraction columns. The chromatographic separation was performed on a Luna 3 µ C₈(2) 100 Å, 100 × 2.0 mm, column. Detection was accomplished by multiple‐reaction monitoring via an electrospray ionization source operating in the positive ionization mode. The calibration curves were linear over the investigated concentration range, 30–2000 pg/mL, with a lower limit of detection of 10 pg/mL for both 2CC‐NBOMe and 25I‐NBOMe. The method proved suitable for serum clinical toxicology testing. Two severely intoxicated emergency department patients were determined to have serum concentrations of 250 and 2780 pg/mL of 25I‐NBOMe using the presented method. Copyright © 2013 John Wiley & Sons, Ltd.     

Fragmentation Mechanism of Trans—α—Aryl—β—enamino Esters

Electron impact-induced fragmentation mechanism of Trans-α-Aryl-β-enamino esters were investigated using mass-analyzed ion kinetic energy (MIKE) spectrometry and high resolution accurate mass data It was found that the main characteristic fragmentations of compounds studied were:an odd electron ion M^ -EtOH was formed by losing a neutral molecule of ethanol;and the skeletal rearrangements took place;and the ring opening reaction happened after losing a carbon monoxide;and the typical McLafferty rearrangement underwent in ester group.The cycliztion reation caused by losing neutral molecule of TsNH2 due to the ortho-effects of substituted group of gromatic ring was also observed.     

Synthesis and Supramolecular Assemblies of Tripodal 1,3,5‐Tris(phenoxymethyl)‐2,4,6‐triethylbenzene Analogues

Tripodal 1,3,5‐tris(phenoxymethyl)‐2,4,6‐triethylbenzene analogues have been synthesized and structurally characterized by IR, ¹H NMR and ¹³C NMR spectroscopy and HRMS, and additionally, the single crystal structures of compounds bearing ortho‐ ( 7 ), meta‐ ( 9 ) and para‐hydroxymethyl ( 11 ) functions have been determined by X‐ray diffraction analysis. The structural study revealed that compounds 7 , 9 , and 11 do not adopt the expected 1,3,5‐alternate conformation in the solid state. The packing diagrams of compounds 7 , 9 , and 11 revealed that six hydrophilic hydroxymethyl groups from six individual molecules ( 7 , 9 and 11 ) were arranged in close contact via intermolecular hydrogen‐bond interactions. For compounds 7 and 9 , the six hydroxyl groups formed a distorted hexagonal ring; however, formation of such a hexagonal ring was not clear in the case of compound 11 . Compounds 9 and 11 were found to form hydrophobic cavities via intermolecular hydrogen‐bond interactions in the solid state, and the cavities were occupied by two ethyl groups from the two cavity‐forming molecules.     

Synthesis of (3,5‐Aryl/methyl‐1H‐Pyrazol‐1‐yl)‐(5‐Arylamino‐2H‐1,2,3‐Triazol‐4‐yl)Methanone

Some new (3,5‐aryl/methyl‐1H‐pyrazol‐1‐yl)‐(5‐arylamino‐2H‐1,2,3‐triazol‐4‐yl)methanones were synthesized and characterized by ¹HNMR, ¹³C NMR, MS, IR spectra data and elemental analyses or high resolution mass spectra (HRMS). During the procedure, Dimroth rearrangement was used in this synthesis.     

15N NMR spectra and reactivity of 2,4,6‐triazidopyridines, 2,4,6‐triazidopyrimidine and 2,4,6‐triazido‐s‐triazine

2,4,6‐Triazido‐s‐triazine, 2,4,6‐triazidopyrimidine and six different 2,4,6‐triazidopyridines were studied by ¹⁵N NMR spectroscopy. The assignment of signals in the spectra was performed using the gauge‐independent atomic orbital (GIAO)–Tao‐Perdew‐Staroverov‐Scuseria exchange‐correlation functional (TPSS)h/6‐311+G(d,p) calculations on the M06‐2X/6‐311+G(d,p) optimized molecular geometries. The Truhlar and coworkers' continuum solvation model called SMD was applied to treat solvent effects. With this approach, the root mean square error in estimations of the ¹⁵N chemical shifts for the azido groups was just 1.9 ppm. It was shown that the different reactivity of the α‐ and γ‐azido groups in pyridines correlates well with the chemical shifts of the N_α signals of these groups. Of two nonequivalent azido groups of azines, the azido group with the most shielded N_α signal is the most electron‐deficient and reactive toward electron‐rich reagents. By contrast, the azido group of azines with the most deshielded N_α signal is the most reactive toward electron‐poor reagents. Copyright © 2013 John Wiley & Sons, Ltd.     

Combined 1H, 13C and 11B NMR and mass spectral assignments of boronate complexes of D‐(+)‐glucose,D‐(+)‐mannose,methyl‐α‐D‐glucopyranoside,methyl‐β‐D‐galactopyranoside and methyl‐α‐D‐mannopyranoside

Complex formation between N‐butylboronic acid and D ‐(+)‐glucose, D ‐(+)‐mannose, methyl‐α‐D ‐glucopyranoside, methyl‐β‐D ‐galactopyranoside and methyl α‐D ‐mannopyranoside under neutral conditions was investigated by ¹H, ¹³C and ¹¹B NMR spectroscopy and gas chromatography–mass spectrometry (GC–MS) D ‐(+)‐Glucose and D ‐(+)‐mannose formed complexes where the boronates are attached to the 1,2:4,6‐ and 2,3:5,6‐positions of the furanose forms, respectively. On the other hand, the boronic acid binds to the 4,6‐positions of the two methyl derivatives of glucose and galactose. Methyl α‐D ‐mannopyranoside binds two boronates at the 2,3:4,6‐positions. ¹¹B NMR was used to show the ring size of the complexed sugars and the boronate. GC–MS confirmed the assignments. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and Antimicrobial Activity of Some Condensed [4‐(2,4,6‐Trimethylphenyl)‐1(2H)‐oxo‐phthalazin‐2‐yl]acetic Acid Hydrazide

Some new 1,2,4‐triazolo‐, 1,3,4‐oxadiazolo‐, 1,3,4‐thiadiazol‐, and pyrazolo‐2,4,6‐trimethylphenyl‐1(2H)‐oxo‐phthalazine derivatives were synthesized and identified by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The new compounds were synthesized with the objective of studying their antimicrobial activity.     

N‐(X‐Methylphenyl)‐2‐{(Z)‐[(2,3,4‐trimethoxyphenyl)methylidene]amino}‐4,5,6,7‐tetrahydro‐1‐benzothiophene‐3‐carboxamide,where X = 2 and 3

The title isomers, viz. the N‐(3‐methylphenyl)‐, (I), and N‐(2‐methylphenyl)‐, (II), derivatives, both C₂₆H₂₈N₂O₄S, adopt an E configuration that places the thiophene and trimethoxyphenyl groups on opposite sides of the C=N double bond, providing a suitable orientation for formation of an intramolecular N—H...N hydrogen bond. However, while the molecule in (I) is close to being planar, the N‐methylphenyl group in (II) is twisted significantly from the plane of the remainder of the molecule. Both crystal structures are essentially layered and there are no intermolecular N—H...O hydrogen bonds. Compound (I) has a significantly higher calculated density than (II) (1.340 cf 1.305 Mg m⁻³), indicating that the molecular packing in the meta isomer is overall more efficient than that in the ortho isomer.     

2,2‐Di­methyl‐1‐(2,4,6‐tri­nitro­phenyl)­hydrazine

The title mol­ecule (DMPH‐H), C₈H₉N₅O₆, was investigated to provide comparison with 2,2‐di­phenyl‐1‐picryl­hydrazine, which unlike DMPH‐H is readily oxidizable to form a well known stable free radical (DPPH). The structure shows essential differences in the configuration of the hydrazine‐N atoms, the ortho‐nitro group orientations and the crystal packing. The bond angles of the di­methyl­amino N atom [107.90 (13), 108.96 (12) and 112.21 (13)°] are consistent with a tetrahedral N atom and sp³ hybridization.     

Alkylations of N4‐(4‐Pyridyl)‐3,5‐di(2‐pyridyl)‐1,2,4‐triazole: First Observation of Room‐Temperature Rearrangement of an N4‐Substituted Triazole to the N1 Analogue

Attempts to use alkylation to introduce a positive charge at the nitrogen atom of the 4‐pyridyl ring in the bis(bidentate) triazole ligand N⁴‐(4‐pyridyl)‐3,5‐di(2‐pyridyl)‐1,2,4‐triazole ( pydpt ) were made to ascertain what effect a strongly electron‐withdrawing group would have on the magnetic properties of any subsequent iron(II) complexes. Alkylation of pydpt under relatively mild conditions led in some cases to unexpected rearrangement products. Specifically, when benzyl bromide is used as the alkylating agent, and the reaction is carried out in refluxing acetonitrile, the N⁴ substituent moves to the N¹ position. However, when the same reaction is performed in dichloromethane at room temperature, the rearrangement does not occur and the desired product containing an alkylated N⁴ substituent is obtained. Heating a pure sample of N⁴‐Bzpydpt?Br to reflux in MeCN resulted in clean conversion to N1Bzpydpt.Br . This is consistent with N4‐Bzpydpt.Br being the kinetic product whereas N1Bzpydpt.Br is the thermodynamic product. When methyl iodide is used as the alkylating agent, the N⁴ to N¹ rearrangement occurs even at room temperature, and at reflux pydpt is doubly alkylated. The observation of the lowest reported temperatures for an N⁴ to N¹ rearrangement is due to this particular rearrangement involving nucleophilic aromatic substitution: a possible mechanism for this transformation is suggested.     

GC‐MS of amaryllidaceous galanthamine‐type alkaloids

Galanthamine‐type alkaloids produced by plants of the Amaryllidaceae family are potent acetylcholinesterase inhibitors. One of them, galanthamine, has been marketed as a hydrobromide salt for the treatment of Alzheimer's disease. In the present work, gas chromatography with electron impact mass spectrometry (GC‐EIMS) fragmentation of 12 reference compounds isolated from various amaryllidaceous plants and identified by spectroscopic methods (1D and 2D nuclear magnetic resonance, circular dichroism, high‐resolution MS (HRMS) and EIMS) was studied by tandem mass spectrometry (GC‐MS/MS) and accurate mass measurements (GC‐HRMS). The studied compounds showed good peak shape and efficient GC separation with a GC‐MS fragmentation pattern similar to that obtained by direct insertion probe. With the exception of galanthamine‐N‐oxide and N‐formylnorgalanthamine, the galanthamine‐type compounds showed abundant [M]^+. and [M‐H]⁺ ions. A typical fragmentation pattern was also observed, depending on the substituents of the skeleton. Based on the fragmentation pathways of reference compounds, three other galanthamine‐type alkaloids, including 3‐O‐(2′‐butenoyl)sanguinine, which possesses a previously unelucidated structure, were identified in Leucojum aestivum ssp. pulchelum, a species endemic to the Balearic islands. GC‐MS can be successfully applied to Amaryllidaceae plant samples in the routine screening for potentially new or known bioactive molecules, chemotaxonomy, biodiversity and identification of impurities in pharmaceutical substances. Copyright © 2012 John Wiley & Sons, Ltd.     

[μ3‐cis‐N‐(2‐Aminoethyl)‐N′‐(2‐carboxylatophenyl)oxamidato(3−)]bis(2,2′‐diamino‐4,4′‐bi‐1,3‐thiazole)tetracopper(II) bis(2,4,6‐trinitrophenolate)

The title complex, [Cu₄(C₁₁H₁₀N₃O₄)₂(C₆H₆N₄S₂)₂](C₆H₂N₃O₇)₂, consists of a circular tetracopper(II) cation with an embedded inversion centre and two uncoordinated picrate (2,4,6‐trinitrophenolate) anions. The Cu^II cations at the inner sites of N‐(2‐aminoethyl)‐N′‐(2‐carboxylatophenyl)oxamidate(3−) (oxbe) have square‐planar environments and those at the outer sites are in square‐pyramidal geometries. The separations of pairs of Cu^II cations bridged by cis‐oxamide and carboxylate groups are 5.2217 (5) and 5.2871 (5) Å, respectively. The tetracopper(II) cations and picrate anions are connected by N—H...O hydrogen bonds into a two‐dimensional network parallel to the (010) plane, and these two‐dimensional networks are assembled by two types of π–π stacking interactions into a three‐dimensional supramolecular structure.     

Electron ionization and electrospray ionization mass spectrometric study of a series of isomeric N‐chloro(or bromo)benzyl‐substituted (E)‐2′(3′‐ or 4′)‐hydroxy‐4‐stilbazole halides

The electron ionization (EI) mass spectra and electrospray ionization (ESI) mass spectra of a series of isomeric N‐chlorobenzyl‐ and N‐bromobenzyl‐substituted (E)‐2′(3′ or 4′)‐hydroxy‐4‐stilbazole chlorides and bromides (1–12) were recorded. The fragmentation pathways of all of the compounds and the characteristic fragment ions formed by EI‐MS were studied by means of B/E and B²/E constant linked‐scanning techniques. The formation of ions originating from preionization reactions, characteristic of quaternary halides under EI‐MS conditions, such as the elimination of chloro‐ or bromobenzyl halides, dehydrohalogenation or substitution reactions, is explained. As soft ionization methods cause no such degradation reactions, the ESI‐MS spectra of the studied compounds were also obtained for comparison. We thus demonstrated the applicability of EI‐MS even in cases when preionization takes place, as long as such secondary processes are properly accounted for. Copyright © 2010 John Wiley & Sons, Ltd.     

A Synthesis Detour to Planar‐Diastereoisomeric Ferrocene Derivatives around an Unexpected Rearrangement of ortho‐Lithiated Kagan's Template [S(S)]‐(p‐Tolylsulfinyl)ferrocene

Usually, ortho lithiation of Kagan's template 1 and quenching with electrophiles leads highly diastereoselectively to planar‐chiral 1,2‐disubstituted ferrocenes. Surprisingly, lithiation of 1 with lithium diisopropylamide (LDA) followed by addition of paraformaldehyde afforded regioisomer (+)‐{[S(S)]‐[4‐(2‐hydroxyethyl)phenyl]sulfinyl}ferrocene ( 2 ), which was converted to (+)‐{[S(S)]‐{4‐{2‐[(methylsulfonyl)oxy]ethyl}phenyl}sulfinyl}ferrocene ( 3 ) (Scheme 1). The desired diastereoisomer (l)‐1‐(hydroxymethyl)‐2‐(p‐tolylsulfinyl)ferrocene ( 5 ) in turn could also be obtained by ortho lithiation of 1 with LDA but by quenching with DMF to yield aldehyde 4 first, which then was reduced with NaBH₄ to 5 . Finally, target compound (l)‐1‐[(dimethylamino)methyl]‐2‐(p‐tolylsulfinyl)ferrocene ( 6 ) was obtained by substitution of the OH group of 5 under mild conditions or directly by ortho lithiation of 1 with lithio‐2,4,6‐triisopropylbenzene (=2,4,6‐triisopropylphenyl)lithium; LTP) followed by quenching with N,N‐dimethylmethyleneiminium chloride. At low temperatures, reaction of 1 with LDA leads, via the preferred diastereoisomeric transition state ‘exo’‐ 7 and under extrusion of a (diisopropylamine)lithium complex of type 8 , in a highly selective manner, to diastereoisomeric ortho‐lithiated chelate (l)‐ 9 (Scheme 2). The reaction of 1 to 2 is explained by a rearrangement of (l)‐ 9 to {[S(S)] [4‐(lithiomethyl)phenyl]sulfinyl}ferrocene 10 , which is acid‐catalyzed by coordinated diisopropylamine in complexes of type 8 . This rearrangement is not observed if LTP is used as base or, in case LDA is applied, if the electrophile is sufficiently reactive at low temperatures.     

Synthesis and Bioactivities of Novel N‐(4‐(2‐Aryloxythiazol‐5‐yl)but‐3‐yn‐2‐yl)benzamides

A series of novel N‐(4‐(2‐aryloxythiazol‐5‐yl)but‐3‐yn‐2‐yl)benzamide derivatives were designed and synthesized. Their structures were identified by ¹H NMR and elemental analyses. Preliminary bioassays indicated that some title compounds provided >80% control of Sclerotinia sclerotiorum at 50 µg/mL and >70% herbicidal activities against B. campestris at 100 µg/mL. Their structure‐activities relationships were also discussed.     

Synthesis of novel rhodium‐xylyl linked N‐heterocyclic carbene complexes as hydrosilylation catalysts

Reaction of ortho‐xylylbis(N‐2,4,6‐trimethylbenzylimidazolinium); xylylbis(N‐butylimidazolinium) and para‐xylylbis(N‐2,4,6‐trimethylbenzylimidazolinium); xylylbis(N‐butylimidazolinium) salts with KOBu^t and [RhCl(COD)]₂ yields ortho‐ and para‐xylylbis{(N‐alkylimidazolidin‐2‐ylidene)chloro(η⁴‐1,5‐cyclooctadiene) rho dium(I)} complexes (2a–d). All compounds synthesized were characterized by elemental analysis and NMR spectroscopy, and the molecular structures of the 2a and 2d were determined by X‐ray crystallography. Triethylsilane reacts with acetophenone derivatives in the presence of catalytic amount of the new rhodium(I)–carbene complexes (2a–d), to give the corresponding silylethers in good yields (83–99%). Copyright © 2008 John Wiley & Sons, Ltd.     

A Facile and Efficient Synthesis of Arylsulfonamido‐Substituted 1,5‐Benzodiazepines and N‐[2‐(3‐Benzoylthioureido)aryl]‐3‐oxobutanamide Derivatives

A facile and efficient synthesis of 1,5‐benzodiazepines with an arylsulfonamido substituent at C(3) is described. 1,5‐Benzodiazepine, derived from the condensation of benzene‐1,2‐diamine and diketene, reacts with an arylsulfonyl isocyanate via an enamine intermediate to produce the title compounds of potential synthetic and pharmacological interest in good yields (Scheme 1). In addition, reaction of benzene‐1,2‐diamine and diketene in the presence of benzoyl isothiocyanate leads to N‐[2‐(3‐benzoylthioureido)aryl]‐3‐oxobutanamide derivatives (Scheme 2). This reaction proceeds via an imine intermediate and ring opening of diazepine. The structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 3).     

Fragmentation of oxime and silyl oxime ether odd‐electron positive ions by the McLafferty rearrangement: new insights on structural factors that promote α,β fragmentation

The McLafferty rearrangement is an extensively studied fragmentation reaction for the odd‐electron positive ions from a diverse range of functional groups and molecules. Here, we present experimental and theoretical results of 12 model compounds that were synthesized and investigated by GC‐TOF MS and density functional theory calculations. These compounds consisted of three main groups: carbonyls, oximes and silyl oxime ethers. In all electron ionization mass spectra, the fragment ions that could be attributed to the occurrence of a McLafferty rearrangement were observed. For t‐butyldimethylsilyl oxime ethers with oxygen in a β‐position, the McLafferty rearrangement was accompanied by loss of the t‐butyl radical. The various mass spectra showed that the McLafferty rearrangement is relatively enhanced compared with other primary fragmentation reactions by the following factors: oxime versus carbonyl, oxygen versus methylene at the β‐position and ketone versus aldehyde. Calculations predict that the stepwise mechanism is favored over the concerted mechanism for all but one compound. For carbonyl compounds, C–C bond breaking was the rate‐determining step. However, for both the oximes and t‐butyldimethylsilyl oxime ethers with oxygen at the β‐position, the hydrogen transfer step was rate limiting, whereas with a CH₂ group at the β‐position, the C–C bond breaking was again rate determining. n‐Propoxy‐acetaldehyde, bearing an oxygen atom at the β‐position, is the only case that was predicted to proceed through a concerted mechanism. The synthesized oximes exist as both the (E)‐ and (Z)‐isomers, and these were separable by GC. In the mass spectra of the two isomers, fragment ions that were generated by the McLafferty rearrangement were observed. Finally, fragment ions corresponding to the McLafferty reverse charge rearrangement were observed for all compounds at varying relative ion intensities compared with the conventional McLafferty rearrangement. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of Isoxazole, 1, 2, 4‐Oxadiazole and (1H‐Pyrazol‐4‐yl)‐methanone Oxime Derivatives from N‐Hydroxy‐1H‐pyrazole‐4‐carbimidoyl Chloride and their Biological Activity

Some novel isoxazole‐, 1,2,4 oxadiazole‐, and (1H‐pyrazol‐4‐yl)‐methanone oxime derivatives were synthesized from N‐hydroxy‐1H‐pyrazole‐4‐carbimidoyl chloride and the structures of all products were identified by spectral data (¹H‐NMR, ¹³C‐NMR, IR, MS, and HRMS) and evaluated their antibacterial activity.     

Z/E‐Isomerism of 3‐[4‐(dimethylamino)phenyl]‐2‐(2,4,6‐tribromophenyl)acrylonitrile: crystal structures and secondary intermolecular interactions

The Z and E isomers of 3‐[4‐(dimethylamino)phenyl]‐2‐(2,4,6‐tribromophenyl)acrylonitrile, C₁₇H₁₃Br₃N₂, ( 1 ), were obtained simultaneously by a Knoevenagel condensation between 4‐(dimethylamino)benzaldehyde and 2‐(2,4,6‐tribromophenyl)acetonitrile, and were investigated by X‐ray diffraction and density functional theory (DFT) quantum‐chemical calculations. The (Z)‐( 1 ) isomer is monoclinic (space group P2₁/n, Z′ = 1), whereas the (E)‐( 1 ) isomer is triclinic (space group P, Z′ = 2). The two crystallographically‐independent molecules of (E)‐( 1 ) adopt similar geometries. The corresponding bond lengths and angles in the two isomers of ( 1 ) are very similar. The difference in the calculated total energies of isolated molecules of (Z)‐( 1 ) and (E)‐( 1 ) with DFT‐optimized geometries is ∼4.47 kJ mol⁻¹, with the minimum value corresponding to the Z isomer. The crystal structure of (Z)‐( 1 ) reveals strong intermolecular nonvalent Br…N [3.100 (2) and 3.216 (3) Å] interactions which link the molecules into layers parallel to (10). In contrast, molecules of (E)‐( 1 ) in the crystal are bound to each other by strong nonvalent Br…Br [3.5556 (10) Å] and weak Br…N [3.433 (4) Å] interactions, forming chains propagating along [110]. The crystal packing of (Z)‐( 1 ) is denser than that of (E)‐( 1 ), implying that the crystal structure realized for (Z)‐( 1 ) is more stable than that for (E)‐( 1 ).