Identification of thermolabile positional isomers of N-(2-hydroxybenzyl)-2-(dimethoxyphenyl)ethanamines (NBOH series) using chromatography and mass spectrometry methods.

Among N-((2-substituted)benzyl)phenylethanamines, N-(2-hydroxybenzyl)phenylethanamines are a special type of compounds which are thermolabile and degrade in the course of analysis by means of gas chromatography-mass spectrometry (GC-MS). This can lead to substantial errors, in the identification of legally controlled compounds of this series containing methoxy groups at positions 2 and 5 of the benzene ring of the phenylethyl fragment by GC-MS, which is commonly used in forensic and toxicological laboratories. Exemplified by the five isomeric 2-(dimethoxyphenyl)-N-(2-hydroxybenzyl)ethanamines, it was shown that their derivatization with trifluoroacetic anhydride (same as in the case of the N-(2-methoxybenzyl)-, N-(2-fluorobenzyl)-, N-(2-chlorobenzyl)-, and N-(2-bromobenzyl)substitutes phenylethanamines [NBOMe, NBF, NBCl, and NBBr, respectively] series described earlier) results in only one product, N-monosubstituted derivative, for each positional isomer within a series, which makes it possible to reliably identify each compound by the GC-MS method. In addition, chromatographic conditions for sufficient separation of trifluoroacetyl derivatives of these positional isomers of the NBOH series in 25 min are proposed, which is an important aspect for analysis in forensic laboratories engaged in the determination of narcotic drugs and new psychoactive substances. As an alternative approach, a method for identifying positional isomers of the NBOH series by the high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) method without derivatization is proposed.

Potential of chromatography and mass spectrometry for the differentiation of three series of positional isomers of 2-(dimethoxyphenyl)-N-(2-halogenobenzyl)ethanamines.

N-(2-substituted benzyl)-2,5-dimethoxyphenethylamines often cause severe poisonings which has led to their legal prohibition in many countries. At the same time, their positional isomers can be studied as potential therapeutic drugs. In this regard, the search for various approaches to differentiate these isomers is an important practical task, the solution of which would guarantee from identification errors during laboratory analysis. In this paper, the possibilities of differentiation of isomers varying in the position of two methoxy groups in the phenylethyl part of the molecule are considered on the example of compounds of NBF, NBCl, and NBBr series by chromatography-mass spectrometry methods. Gas or liquid reverse-phase chromatography in the proposed chromatographic separation modes has demonstrated their ability to resolve this problem reliably. Data on retention indices of isomeric compounds and their derivatives can serve as an additional identification criterion for gas chromatography-mass spectrometry (GC-MS) analysis. Differentiation of NBF and NBCl isomers using electron ionization (EI) mass spectra is feasible only if both the spectrum of the compound and its N-trifluoroacetyl derivative are registered; differentiation of NBBr positional isomers under these conditions does not require obtaining the derivatives. Using electrospray ion source, the compounds can easily be differentiated based on the distinctive features of their collision induced dissociation (CID) spectra recorded at low energy values, which also does not require the synthesis of derivatives. The data presented in current paper will be useful for analysis in laboratories providing the determination of narcotic drugs.

Selective Synthesis of Azoloyl NH-1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights.

Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.

Synthesis and determination of analytical characteristics and differentiation of positional isomers in the series of N-(2-methoxybenzyl)-2-(dimethoxyphenyl)ethanamine using chromatography-mass spectrometry.

N-(2-Methoxybenzyl)-2,5-dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5-HT2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H-NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography-mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature-programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H-NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography-tandem mass spectrometry could distinguish the isomers of 25H-NBOMe without the need for any derivatization.

Rh(II)-mediated domino [4 + 1]-annulation of α-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes.

A new approach towards the synthesis of multisubstituted thiophenes is elaborated based on Rh(II)-catalyzed domino reactions of acyclic diazoesters with α-cyanothioacetamides. It provides a way for the preparation of 5-amino-3-(alkoxycarbonylamino)thiophene-2-carboxylates, 2-(5-amino-2-methoxycarbonylthiophene-3-yl)aminomalonates and (2-cyano-5-aminothiophene-3-yl)carbamates with the preparative yields of up to 67%. It was also shown that α-cyanothioacetamides easily interact with dirhodium carboxylates to give rather stable 2:1 complexes, resulting in an evident decrease in the efficiency of the catalytic process at moderate temperatures (20-30 °C).

Distinguishing of 2-MAPB and 6-MAPB: Solution of the problem.

Differentiation of new psychoactive substance (NPS), 6-(2-methylaminopropyl)benzofuran (6-MAPB), and its positional isomer, 2-(2-methylaminopropyl)benzofuran (2-MAPB), by means of gas chromatography/mass spectrometry (GC/MS) with quadrupole detection is ambiguous. Reliable distinguishing of the two isomers could be achieved by MS/MS spectra recorded after collision-induced dissociation (CID) of precursor ions. Both electron ionization (EI) and electrospray ionization (ESI) methods could be used for these purposes.

Mass spectrometric properties of N-(2-methoxybenzyl)-2-(2,4,6-trimethoxyphenyl)ethanamine (2,4,6-TMPEA-NBOMe), a new representative of designer drugs of NBOMe series and derivatives thereof.

Emergence of new psychoactive substances, hallucinogenic phenethylamines in particular, in illicit market is a serious threat to human health in global scale. We have detected and identified N-(2-methoxybenzyl)-2-(2,4,6-trimethoxyphenyl)ethanamine (2,4,6-TMPEA-NBOMe), a new compound in NBOMe series. Identification was achieved by means of gas chromatography/mass spectrometry (GC/MS), including high-resolution mass spectrometry with tandem experiments (GC/HRMS and GC/HRMS2 ), ultra-high performance liquid chromatography/high-resolution mass spectrometry with tandem experiments (UHPLC/HRMS and UHPLC/HRMS2 ), and 1 H and 13 C nuclear magnetic resonance spectroscopy. The peculiarities of fragmentation of the compound under electron ionization (EI) and collision-induced dissociation were studied. Despite of the empirical rule denying migration of the hydrogen atom in McLafferty rearrangement to the benzene ring with substituents in the both ortho-positions, it easily occurs for 2,4,6-TMPEA-NBOMe in EI conditions. We have noticed that electron-donating substituents, e.g. methoxy groups in the both ortho-positions and para-positions favor the rearrangement. For specially synthesized N-methyl and N-acyl derivatives McLafferty rearrangement is not observed. N-Acyl derivatives demonstrate McLafferty rearrangement, but the charge retains at the alternative fragment involving N-acyl carbonyl group. We have also showed that the hydrogen atoms in 2,4,6-trimethoxybenzene ring may be easily substituted for deuterium or for strong electrophiles like trifluoroacetyl. Analytical characteristics of 2,4,6-TMPEA-NBOMe and of some derivatives thereof which enable their determination in various criminal seizures are given. Copyright © 2016 John Wiley & Sons, Ltd.

Synthetic cannabinoid 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]-1,2,4-oxadiazole. The first detection in illicit market of new psychoactive substances.

We were the first to detect 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]-1,2,4-oxadiazole (given name BzODZ-EPyr) as a new synthetic cannabinoid, in illegal market of new psychoactive compounds (NPS). The compound was known only from pharmaceutical literature so far. BzODZ-EPyr was identified by means of gas chromatography/mass spectrometry (GC/MS) including high resolution mass spectrometry (GC/HRMS), ultra-high performance liquid chromatography/high resolution tandem mass spectrometry (UHPLC/HRMS(2)), Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR) (1)H and (13)C. The peculiarities of mass-spectral fragmentation in experiments in electronic ionization (EI) and collision-induced dissociation (CID) modes were studied. Herewith we report analytical characteristics of BzODZ-EPyr enabling its (and possible analogues thereof) determination in criminal seizures.

Identification and analytical characteristics of synthetic cannabinoids with an indazole-3-carboxamide structure bearing a N-1-methoxycarbonylalkyl group.

Illicit new psychoactive substances (NPS) are a serious threat to health throughout the world. Such NPS do not usually pass preliminary pharmacological trials. In 2014, we identified a series of five new synthetic cannabinoids with an indazole-3-carboxamide structure bearing an N-1-methoxycarbonylalkyl group. The compounds have very high cannabimimetic activity which has caused mass severe intoxication and deaths. The compounds were identified by means of gas chromatography-mass spectrometry (GC-MS), including high-resolution mass spectrometry (GC-HRMS), ultra-high-performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HRMS(2)), and (1)H and (13)C nuclear magnetic resonance spectroscopy (NMR). The peculiarities of mass-spectral fragmentation of the compounds after electron ionization (EI) ionization and collision-induced dissociation (CID) were studied. The analytical characteristics reported for the compounds will enable their identification in a variety of materials seized from criminals.Graphical Abstract.

Synthetic cannabinoids as designer drugs: new representatives of indol-3-carboxylates series and indazole-3-carboxylates as novel group of cannabinoids. Identification and analytical data.

By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of new synthetic cannabinoids, representatives of indol- and indazole-3-carboxylates groups, used in smoke mixtures, was determined. Obtained analytical data make reliable identification of these compounds in a course of analysis of criminal seizures possible.

3-Naphthoylindazoles and 2-naphthoylbenzoimidazoles as novel chemical groups of synthetic cannabinoids: chemical structure elucidation, analytical characteristics and identification of the first representatives in smoke mixtures.

By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of novel synthetic cannabinoids, namely, 1-(5-fluoropentyl)-1H-indazol-3-yl(naphthalen-1-yl)methanone, naphthalen-1-yl(1-pentyl-1H-benzo[d]imidazol-2-yl)methanone and 1-(5-fluoropentyl)-1H-benzo[d]imidazol-2-yl(naphthalen-1-yl)methanone was established. Analytical data obtained in the paper enable reliable identification of these compounds during qualitative analysis of seizures, including smoke mixtures.

Analytical characterization of some synthetic cannabinoids, derivatives of indole-3-carboxylic acid.

By means of gas chromatography with high resolution mass spectrometry (GC-HRMS), ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of a series from a novel synthetic cannabinoids, derivatives of indole-3-carboxylic acid, was established. Methods for determination of the compounds in mixtures, involving chromatographic separation with mass-spectroscopic determination, were elaborated. Analytical data obtained in the paper will make reliable identification of synthetic cannabinoids of the new type during forensic examination possible.

Identification and analytical properties of new synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety.

By means of gas chromatography with mass spectrometry detector (GC-MS), liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy (NMR), structure of a series from a novel class of synthetic cannabimimetics bearing 2,2,3,3-tetramethylcyclopropanecarbonyl moiety was established. It was found that this fragment could undergo thermal ring-opening into isomeric structures. The title compounds under action of hydrochloric acid can transform into new compounds which structure is discussed in the paper. The compounds identified could be referred to a new class of 'designer drugs' and are in illegal turnover in Russia and Belarus since the summer of 2011. Analytical data obtained in the paper will make possible reliable identification of such new 'designer drugs' during forensic examination.

Self condensation of enamines mediated by acetylation. A novel approach to 1-(azol-5-yl)-(1E,3Z)-butadiene-4-N,N-dimethylamines.

Novel self-condensation of 3-(azol-5-yl)-1,1-dimethylenamines has been found to form new C-C bonds leading to 2,4-(1,2,3-triazole-1,2,3-thiadiazole-3-phenylisothiazole)-(1E,3Z)-5-yl-butadiene-1-amines. The discovered reaction represents a new example of C-H functionalization in unsaturated systems and can serve an efficient synthetic approach to rational design of new 2,4-(diazole-5-yl)-dieneamines.