A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki-Miyaura cross-coupling reaction.

A series of differently substituted 3,5-diaryl-2,4,6-trimethylpyridines were prepared and characterized using the Suzuki-Miyaura coupling reaction with accordingly selected bromo-derivatives and arylboronic acids. The reaction conditions were carefully optimized allowing high yield of isolated products and also the construction of unsymmetrically substituted diarylpyridines, difficult to access by other methods.

Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method.

The synthesis of the designer drug 4-methylthioamphetamine (4-MTA) has been carried out using the well-known Leuckart reaction in four versions. The treatment of 4-methylthiophenylacetone with formamide, mixture of formamide/formic acid, ammonium formate, and mixture of ammonium formate and formic acid followed by acid hydrolysis brought about the formation of 4-MTA contaminated with a number of impurities. The gas chromatography mass-spectrometry (GC-MS) analysis of the reaction mixtures allowed identification of the most prominent impurities, such as diasteromers of N,N-di-[ß-(4-methylthiophenyl)isopropyl]amine, N,N-di-[ß-(4-methylthiophenyl)isopropyl]methylamine, N,N-di-[ß-(4-methylthiophenyl)isopropyl]formamide, the Schiff bases derived from 4-MTA and 4-methylbenzaldehyde (benzaldimine) and 4-methylthiophenylacetone (ketimine) as well as some heterocycles: 4-methyl-5-(4'-methylthiophenyl)pyrimidine, 4-(4'-methylthiobenzyl)pyrimidine, 2,6-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine, 2,4-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine. The correctness of identification was confirmed by independent synthesis of these compounds. Each synthesized reference compound was characterized by means of MS, (1)H and (13)C NMR, and IR methods. The stereochemistry of (RR/SS) diasteromer of N,N-di-[ß-(4-methylthiophenyl)isopropyl]amine was confirmed by a crystallographic method.

Identification of common impurities present in the synthetic routes leading to 4-methylthioamphetamine (4-MTA). Part II: Reductive amination and nitropropene route.

In this paper the by-products arising during the synthesis of 4-methylthioamphetamine (4-MTA) by LiAlH(4) reduction of 1-(4-methylthiophenyl)-2-nitropropene (nitropropene route) and reductive amination of 4-methylthiophenyl-2-propanone in the presence of NaCNBH(4) are investigated. The identification of 4-methylthio derivatives of N-(ß-phenylisopropyl)benzaldimine, 4-methylthio derivative of N-(ß-phenylisopropyl)benzyl methyl ketimine, 1-(4-methylthiophenyl)-N-(4-methylthiobenzyl)-2-propanamine, (RS) and (SS/RR)-N,N-di-[ß-(4-methylthiophenyl)isopropyl]amine, 4-methylthiobenzyl ether and methylthiobenzoic acid methyl ester as most prominent impurities in crude 4-MTA synthesised by reductive amination of 4-methylthiophenyl-2-propanone, is reported. Methylthio derivatives of 2-methyl-3-phenylaziridine, 2-benzylaziridine, and 4-methylthio derivative of BMK oxime as route-specific markers of nitropropene route leading to 4-MTA, were also characterized. The identity of these compounds was confirmed by their independent synthesis.

The synthesis, mass spectrometric properties and identification of some N,N-di-(ß-arylisopropyl)formamides related to the synthesis of ring-modified amphetamines.

This study examines the electron impact (EI) induced mass spectrometric behavior of several N,N-di-(ß-arylisopropyl)formamides, which are connected to the Leuckart synthesis of some amphetamine analogues. Emphasis is laid on the fragmentation paths, which are common for all compounds under investigation and may be used in construction of the prediction scheme useful for identification of similar impurities, especially in absence of desirable authentic material. On the basis of this scheme several new N,N-di-(ß-arylisopropyl)formamides have been identified in selected amphetamine analogues synthesized by the Leuckart method, including 4-methylthioamphetamine (4-MTA), 4-fluoroamphetamine (4-FA), 4-methylamphetamine, 3-trifluoromethylamphetamine, 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxyamphetamine (2,5-DMA), 2,4,5- and 3,4,5-trimethoxyamphetamines (2-TMA and 3-TMA).

The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues.

The 4-methylthioamphetamine (4-MTA) is a sulphur-containing amphetamine-type stimulant (ATS), which appeared on the illicit market in Europe at the end of 90s. For the purpose of this study, several N-alkyl homologues of 4-MTA, including 4-methylthiomethamphetamine (4-MTMA), 4-methylthioethylamphetamine (4-MTEA), 4-methylthiodimethamphetamine (4-MTDMA), 4-methylthiopropylamphetamine (4-MTPA) and 4-methylthiobutylamphetamine (4-MTBA) were synthesized. The homologues were characterized by means of gas chromatography/mass spectrometry (GC-MS), infrared (IR) spectroscopy and the magnetic resonance spectroscopy ((1)H and (13)C NMR). The gas chromatography and mass spectrometry properties of their acetyl, trifluoroacyl (TFA), pentafluoropropionyl (PFP) and heptafluorobutyryl (HFB) derivatives were also investigated and discussed.

Some pyridine derivatives as "route-specific markers" in 4-methoxyamphetamine (PMA) prepared by the Leuckart Method Studies on the role of the aminating agent in their distribution in the final product.

The two previously unknown isomeric aryl-methylpyridines were prepared and analysed. Both 2,6-dimethyl-3,5-(4'-methoxyphenyl)pyridine and 2,4-dimethyl-3,5-di-(4'-methoxyphenyl)pyridine have been identified as a new by-product in the crude 4-methoxyamphetamine (PMA) obtained via the Leuckart method. The synthesis of 2,6-dimethyl-3,5-diphenylpyridine, which is connected to amphetamine chemistry, is also reported. It was also found that different reagents (formamide, formamide/HCOOH, ammonium formate) used in the course of the Leuckart synthesis of PMA significantly affected the impurity content. The presented results point out on the "high-boiling pyridines" as compounds especially useful in the comparative analysis, since their profile seems to be independent on the purification procedure and may be conveyed from the crude reaction mixture even into a carefully purified final product.

Electron ionization mass spectrometry as a tool for the investigation of the ortho effect in fragmentation of some Schiff bases derived from amphetamine analogs.

The electron ionization-induced fragmentation patterns of three forensically relevant Schiff bases, originating from the condensation between 2-, 3- and 4-methoxyamphetamine and the corresponding ketones, were studied. The proposed fragmentation routes and ion structures are supported by high-resolution data and B/E linked-scan and mass-analyzed ion kinetic energy spectra. The rationalization of the ortho effect, which is responsible for the formation of the [M-OCH3] fragment in the case of the imine bearing ortho-substituted methoxy group, is given.

Identification and synthesis of some contaminants present in 4-methoxyamphetamine (PMA) prepared by the Leuckart method.

The clandestine synthesis of ring and side chain modified phenylisopropylamines continues to be a major source of these drugs of abuse. One method used for the synthesis of the amphetamine and related compounds involves the treatment of the appropriate ketone with formamide or ammonium formate followed by acid hydrolysis of intermediate N-formyl derivative. In this paper the synthesis of 4-methoxyamphetamine (PMA, 1) by the Leuckart method is investigated. The identification by means of gas chromatography-mass spectrometry (GC-MS) of methoxy derivative of N-(beta-phenylisopropyl)benzaldimine 9, methoxy derivative of N-(beta-phenylisopropyl)benzyl methyl ketimine 5, 1-(4-methoxyphenyl)-N-(4-methoxybenzyl)-2-propanamine 10, (RR/SS) and (RS) 1-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 6a-6c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-methyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 7a-7c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-formyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 8a-8c in crude PMA, are reported. The identity of these compounds was confirmed by independent synthesis of reference compounds. The NMR, MS, IR data, stereochemistry and some chromatographic properties of synthesized compounds are discussed. Finally, the results of the GC-MS analysis of illicitly prepared tablets, containing PMA 1 and 4-methoxymethamphetamine (PMMA, 2), are outlined. The presence of 4-methoxydimethylamphetamine 11, 4-methoxyethylamphetamine 12, and 4-hydroxymethamphetamine 13 are reported in these tablets. The identity of 2, 11, and 12 was confirmed by their independent synthesis.