Synthetic cathinones are related to the parent compound cathinone (Figure 1), one of the psychoactive principals in ( Forsk). Cathinone derivatives are the β-keto (βk) analogues of a corresponding . The group includes several substances that have been used as of medicinal products, e.g. amfepramone (diethylpropion; Figure 2). Since the mid-2000s, unregulated ring-substituted cathinone derivatives have appeared in the European recreational drugs market. The most commonly available cathinones sold on the recreational market in the period up to 2010 appear to be mephedrone (Figure 3) and methylone (Figure 4). These products are usually encountered as highly pure white or brown powders. Ring-substituted cathinone derivatives are claimed to have effects similar to those of , or (ecstasy), but little is known of their detailed pharmacology. Apart from cathinone (Figure 1), methcathinone (Figure 5) and two ’s amfepramone (Figure 2) and pyrovalerone, cathinone derivatives are not under international control.
A method for the synthesis of diazepam has been described (Sternbach et al., 1961). Benzoyl chloride reacts with p-chloroaniline to produce 2-amino-5-chlorobenzophenone. This is converted to the oxime with hydroxylamine. After cyclization with chloroacetyl chloride and ring enlargement with alkali treatment, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide is reduced and methylated to diazepam.
Up until the introduction of control measures in the UK in April 2010, mephedrone and other synthetic cathinones were readily available either from Internet suppliers or retail outlets. An EMCDDA snapshot of the availability of mephedrone on the Internet in March 2010 showed that at least 77 websites, would sell and ship the substance to a user in the EU. In July 2011, 18 websites were identified claiming to sell mephedrone.
Although not controlled in many countries, synthetic cathinones are regularly submitted to forensic laboratories by police and customs for identification. The number of such submissions increased rapidly during the second half of 2009. Methylone was one of the first ring-substituted synthetic cathinones to be reported in the EU (Netherlands, Sweden, 2005), but mephedrone has become the most commonly seen derivative. Information on seizures and samples from the Netherlands indicate that tablets sold as ecstasy, but actually containing mephedrone (sometimes in combination with ), appeared on the market for the first time in 2009. However, the absence of systematic data makes it difficult to comment with confidence on the availability of different cathinone products, although reports do suggest that availability varies over time and place.
Probably the winner for the gassiest sequence described is from a Movassaghi paper that I remember from last year. Although the reaction hasn't actually been used to make a natural product yet, it looks like a useful way to access hetero cyclotryptamine natural products, of which there are many. The idea is to synthesise an unsymmetrical sulfamide, where the two amines are connected to the two units to be linked. Oxidation of this with NCS then generated a thiadiaziridine dioxide in some bizarre Aza-Myers-Ramberg-Bäcklund-type reaction. This then lost sulfur dioxide as expected to give a diazene that was decomposed photolytically with loss of nitrogen to give a pair of radicals that recombined quickly. Amazingly this recombination occurred sufficiently to prevent the formation of homodimeric products. Neat reaction - I love the fact that the linker is completely traceless!
Synthetic cathinones have only recently appeared on the recreational drugs market, and few formal epidemiological studies have been published. There are no nationwide studies within the EU on the prevalence of mephedrone use in any given population. In an online survey conducted in late 2010 in collaboration with the United Kingdom’s dance music magazine Mixmag, mephedrone was the fourth most-commonly used drug in the past year (after , and ) and had been tried by 61 % of respondents. 25 % of respondents had tried it within the last month, which was a decrease compared to 33.6% in late 2009. It should be noted that mephedrone was scheduled in the UK mid-april 2010.
The ring-substituted -methylcathinone derivatives are best synthesised by reacting the suitably substituted bromopropiophenone with methylamine; the result is always . In the case of methylone, for example, 2-bromo-3,4-methylenedioxy-propiophenone can be prepared by reacting 3,4-methylenedioxypropiophenone with bromine. These precursor substances are readily available and none of them is under international control. Other methods are required to produce the derivatives, but apart from MDPV, substances such as PPP, MPHP, MOPPP and MDPPP, which briefly appeared in Germany in 2004 (see Table 1), have since been rarely observed.
In the absence of convulsions, diazepam administration at doses of 5-10 mg intravenously in adults has also been recommended in cases of organophosphate poisoning accompanied by anxiety and restlessness (Johnson & Vale, 1992) or muscle fasciculation. If large doses of diazepam are required to suppress seizure activity, barbiturates should be considered as an alternative.
Simple derivatives such as methcathinone and -dimethylcathinone can be synthesised by oxidation of ephedrine (or pseudoephedrine) and-methylephedrine (or -methylpseudoephedrine) respectively. This requires reacting the precursor with a solution of potassium permanganate in dilute sulfuric acid. The precursors can be obtained as specific enantiomers, thereby ensuring that the synthesis is stereoselective. Cathinone itself can be made in a similar way, starting from phenylpropanolamine (norephedrine). One of the hazards of the permanganate process is that users can suffer manganese poisoning if the product is not purified.
This week saw another brilliant synthesis from the still fairly new Reisman group over at Caltech, this time an epidithiodiketopiperazine (ETP), the group's first. These interesting secondary metabolites have so far only been isolated from fungi, and owe their toxicity to their disulfide bridges that generate reactive oxygen species by redox cycling. Although ETPs have been popular targets for the last 40 years, and the field has seen some impressive chemistry from Kishi in the 70s to more recent efforts by Movassaghi, Overman and Nicolaou. More challenging still are the dihydrooxepine containing ETPs such as acetylaranotin, which has stood unconquered since its isolation 1968, and in fact no synthesis of such a compound has been reported, until now.
Synthetic cathinones are mostly encountered as white or brown amorphous or crystalline powders, occasionally encapsulated. Unlike many phenethylamine derivatives (, etc.), tablets are less common but are sometimes available on the illicit market, presumably as a replacement for .
Near-infrared (NIR) cyanine dyes are increasingly employed as fluorescent probes for interrogating biological processes such as enzyme activity, nitric oxide, calcium, , zinc, and proton concentration., The key idea is to incorporate different functionalities into a cyanine molecular framework to obtain environment-sensitive fluorophores where the spectral properties are influenced by the presence of specific compounds or ions in complex samples. This requires a precise choice of functionalities as well as a feasible synthetic methodology. A majority of these dyes are constructed via a well-established SN1 mechanistic pathway where the meso-chlorine atom of heptamethine dye is substituted with various nucleofugal functionalities. This route renders an array of fluorophores that contain highly functional aminoalkyl-, , hydroxyalkyl-, hydroxyaryl-, thioalkyl-, thioaryl- substituents that can be further conjugated to biomolecules or other metal ligands. Recently we reported the first C-C bond formation by Suzuki-coupling approach at the meso-position to give functionalized aryl-substituted fluorophores with reinforced chemical stability.