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Some New Psychoactive Substances

Some New Psychoactive Substances

[2] So [2] nstituteAustralia Drug Testing Drug Analysis and 2011 John Wiley & Sons, Ltd. c tional MeasurementI However, despite this care taken to 2011 John Wiley & Sons, Ltd. [3] c Little more happened until the 1980s when [4] Correspondence to: Michael Collins, Director, Australian Forensic Drugtory Labora- 1 Suakin St, Pymble, 2073, Sydney,E-mail: Australia. [email protected] Australian ForensicDrugLaboratory,Na The term ‘designer drug’ was first coined in the 1980s but s’ being encountered today by forensic scientists and law ∗ . In particular, it concentrates on new derivatives, open scientific and medical literature and the exploitation of annabinoids; ; psychoactive; precursors lesser extent phenyl-2-propanone (P-2-P)legitimate which industrial has use in some the small flavour and fragrance industries. The immediate precursor3,4-methylenedioxyphenyl-2-propanone (3,4-MDP-2-P) for which has almostvirtually all no MDMA legitimate industrial production useessential oil but is safrole or is from easily the industrial madeof chemical piperonal, from which both the are producedalso for a thriving industry illegal production in of safrole large in south-east quantities. Asia. There is analogues of drugs such as1980s fentanyl that appeared. what It is wasappeared during probably the although the the classic case compoundmany years of before. itself The substance a MDMA had had designer been known been since drug its synthesized prevent the diversion of industrial chemicals andfor pharmaceuticals illegitimate use,have clandestine no difficulty drug in sourcing manufacturers them. appear to describes a problem more commonly associatedfirst with the century. twenty- Historically, the1925 age of with the the designerthe International drug use began Opium in of Conventionalternative morphine which esters of and banned morphine, such its as dibenzoylmorphine,manufactured diacetyl in being an ester, attempt to circumvent heroin. the Opiumwhich This Convention in led turn led to to thein first controls 1930 when the passed Leagueesters of analogue of Nations morphine. resolutions extending control to all for the drugs heroin, ,and , , MDMA, thereprocedures, is and strong ready marketnoteworthy,however,thattheseprecursorchemicalsandreagents availability demand, of simple precursorare synthetic chemicals. listed It in is eitherConvention and Schedule are closely watched I by National orlaw and International II enforcement agencies. of the 1988 United Nations te research into medical conditions and the natural product the . The synthetic approaches towards [1] Similarly, the The chemicals [2] [1] drugs for illicit purposes is drawn. Copyright -methylamphetamine), N ∗ , 404–416 Copyright 3 , -Tetrahydrocannabinol and cocaine are es- 9 2011 [1] designer drugs; ; ; tryptamine; c

While these three compounds are the most commonly trafficked demand for amphetamine, methamphetamine, and MDMAvery is still high and thesesatisfy user drugs demand in are the produced United States, in Europe, and large Australia. quantities to sentially fullyfollowing cultivated harvesting drugs ofspectively, the requiring and cannabis little plantrequiring extraction. further and acetylation Heroin of work The is leaf, the amphetamine re- a morphine typeand extracted semi-cultivated from include drug opium. some arephetamine very fully itself, well-known synthetic methamphetamine substances ( drugs such as am- of the fully synthetic drugs,both there are licit other synthetic and substances, increasing illicit, trend that towardsno are so-called strict abused ‘designer definitionthey and drugs’. on are today, usually what There there moleculesway constitutes is is that that a have they an designer beencontrols. retain modified drug The psychoactivity in but main while suchabused factors circumventing a are legal determining marketof which demand, ease substances precursor of are chemicals.such synthesis, Cultivated as and and availability cocaineproduction semi-cultivated and in drugs, heroin, countries areand such always other as in politically Colombia,those demand involved unstable in Peru, their and production nations and Afghanistan, trafficking. crop is rarely a problem for and 3,4-methylenedioxymethamphetamine (MDMA). Drug Test. Analysis In addition tofrom being a popular syntheticchemicals viewpoint, with used quite for users, the simple. production theirpharmaceutical The of drugs methamphetamine production major are and precursor the is, and to a Introduction The major drugsmain of heroin, abuse cocaine,ulants trafficked cannabis, (ATS). and in amphetamine-type the stim- world today re- This paper describes someenforcement agencies of in Europe, the the newthe United tryptamines, States, new-generation classes phenethylamines, and and of Australia some of ‘designermany of drug these designerof drugs today’s including so-called a designer discussionchemistry. drugs of A link exist the between chemical as synthetic approaches precursorsthis a published research used result in by in the clandestine of manufacture the legitima of syntheses are presented. Many Keywords: chemicals and synthesis-driven end-products Michael Collins Some new psychoactive substances: Precursor (www.drugtestinganalysis.com) DOI 10.1002/dta.315 Mini review Received: 21 February 2011 Revised: 21 April 2011 Accepted: 28 April 2011 Published online in Wiley Online Library: required to convertacetic the anhydride, hydrochloric acid, crops potassium permanganate, into are produced finished for legitimate products, industrial suchdiversion use of as on comparatively a smalla large amounts major scale for problem and illegitimate for use the law is enforcement agencies.

404 405 3 CH 2 N N 3 3 C NH 3 H H N H CH N -diallyltryptamine 3 H N NHCH N , Psilocin N Drug Testing Drug Analysis and OH 3 NHCOCH Serotonin 2 CH Methamphetamine CO www.drugtestinganalysis.com 3 H NH N HO H 5'-Methoxy- H O 2 2 2 3 CO Cathinone 3 Melatonin NH α 2 NH CH 2 Chemically, cathinone is structurally similar 1 CH NH H H β N N CO 3 N 3 H C [14,15] 3 H 4 7 H N Tryptophan Amphetamine Tryptamine 5 6 Tryptamine and some related compounds. Cathinone, amphetamine, and methamphetamine. CO 3 Bufotenin -methyl derivative of cathinone, methcathinone (Figure 4), H N HO (). The plantand is has a beeneleventh century. native used to for many its pharmacological East effects African since countries the Figure 2. Figure 3. to amphetamine (Figure 3) butUnited is Nations 1971 unstable. Convention It on is Pyschotropic Substances. scheduled in the Synthesis of methcathinone The was first identified in the Soviet Union in 1982 and referred to 2011 John Wiley & Sons, Ltd. Oth- c [5] [10] 3 2 Catha edulis NH NHCH Other phenethy- OH OH Many ‘designers’ are 2 [6–9] OH OH NH Noradrenaline [11–13] 3 HO HO OCH 2 2 NH CO CO , 404–416 Copyright 3 3 NH 3 , H H 2011 OH Phenethylamine, adrenaline, dopamine, noradrenaline, and HO Since the 1990s, there has been an explosion in the number of Precursor chemicals and synthesis-driven end-products ers still are based(Figure 2) on and the its serotonin like many compound analogues. tryptamine chemical modifications ofhave currently similar controlled pharmacological effects substances andcircumvent chemically that legislation. designed to Which substancethedrug becomes abusing communityisagainbasedonanumberoffactors: popular with (1) popularity with users, i.e.(2) does will it it produce be theaddress legal; desired a effects; number and of (3) the is newtheir classes it synthesis, of and easy psychoactive precursor chemicals substances, to andin produce. some an of This their attempt effects paper towhat will demonstrate sort of how substance these may become factors popular. can determine Drug Test. Analysis Cathinones Cathinone (Figure 3) is a powerful stimulantsystem of the and central nervous occurs naturally in the fresh leaves of synthesis in 1912 at Merck Darmstadt inappetite an suppressant. attempt From to a produce structural an point ofmethamphetamine view with it a was methylenedioxy simply group on thering aromatic and it was not illegal until new legislation was enacted. Figure 1. mescaline. lamine modifications include compoundslegitimate developed chemical as and partpharmaceuticals medical of to research treat a aimed variety at of medical producing conditions. new psychoactive substances. Thehas science opened of up organic a world chemistry the of new millions psychoactive of compounds, molecules liketively and the small yet old, number most belong of of tonitrogenous. chemical a rela- classes A with quick the glancemany majority similarities at being between the the chemicalthe endogenous synthetic structures neurohormonal psychotomimetics reveals transmitters, and suchand as serotonin. dopamine Many of the new designerthe substances phenethylamine are based (Figure on 1) structuresuch and include as compounds the cathinone family analogues. The 3 [18] , 404–416 M. Collins CH 3 3 3 2 3 , 3 3 CH CH CH Propiophenone 2011 NHCH NHCH NHCH 3 [6] O O O 3 CH NHCH -Ethylcathinone H N and their synthesis of MDPV H C C O O 3 3 H H [18] Drug Test. Analysis . 3',4'-Dimethylmethcathinone HO 3',4'-Methylenedioxymethcathinone CNMRspectroscopy. et al It has some similar effects to metham- 13 [18] 3 3 -methylmethcathinone also known as 3 3 3  3 CH CH CH Hand 1 NHCH NHCH NHCH O O O Some ring- and nitrogen-substituted cathinones. 3 C F 4'-Methylmethcathinone 3 CO 3 4'-Fluoromethcathinone 4'-Methoxymethcathinone H 3 Another class of cathinone-related compounds is the py- H CH NHCH rovalerones, some ofin the Figure 8. more Pyrovalerone1964 common itself and was ones marketed synthesizedpetite legitimately being suppressant as and for in shown far the therapeutic treatment of back use chronic fatigue. as as an ap- and its ring-substituted derivativeswithout are attracting relatively too easy muchto to attention obtain and clandestinely so the produceanalogues opportunities are many and an this is indeed what entire isIn occurring the at author’s present. range laboratory alone, nine analogues of ofhave methcathinone been submitted methcathinone by law enforcement agencies duringtwo the years. last Where standards have not beenhas available been identification made by phetamine and is alsoMDPV said is to now increase widely available libido mainlywhere and through it anxiety Internet has purchases levels. been marketedan as attempt ‘bath to salts’ avoid andses medicines as of or ‘plant many other food’ in legislation.in derivatives The a have synthe- publication been by well Meltzer described ring-substituted compound 3,4-Methylenedioxypyrovalerone, or MDPV as it has come to be known,other was stimulants first in synthesized 1969. along with Figure 6. is the synthesis of 4 (Figure 7), whichsame results approach in may a be racemicmethcathinone used mixture. analogues, to The i.e. produce commence otherring-substituted with ring-substituted propiophenone. the To appropriate preparesubstituted different nitrogen- cathinone analogues,appropriate it is in necessary the to amination use step. the is shown in Figure 9.in The most syntheses cases are the comparatively starting easy materials and are commercially available H , O S This 2011 John Wiley & Sons, Ltd. c [17] 3 3 3 CH 3 CH Br Copyright NHCH CH 2 O )-ephedrine or the 1 O NH − -( S ,2 3 R ) - Methcathinone 3 2 (+ The major activity is as- Br CH NHCH A good example of this approach H 3 [9,16] OH CH )-isomer of methcathinone which may be [6,17] H − -( It was first produced in the United States in S O [6] Preparation of racemic methcathinone from propiophenone. Synthesis of methcathinone by oxidation of ephedrine or pseudoephedrine. )-pseudoephedrine with Jones reagent or potassium per- )-methcathinone. Another synthetic approach to methcathi- + − -( S -( Drug Testing Drug Analysis and sociated with the www.drugtestinganalysis.com as ‘ephedrone’. Figure 5. Figure 4. 1988 and hundredshave of been clandestine found methcathinone sincecomparatively laboratories then. simple The synthesis with of thedation methcathinone of easiest the is approach readily available being pharmaceuticalsand pseudoephedrine the ephedrine oxi- (Figure 4). Synthesis of methcathinone analogues Today there are many analogues ofthe methcathinone drug appearing scene which on is particularly dynamicof at these the moment. involve Most substitution ofgroup the (Figure aromatic 6). ring In or these atviewpoint,tobeginwithephedrineorpseudoephedrine.However, cases the it amino is not feasible,analogues from a or synthetic designersby of methcathinone using may thethe be appropriate synthesized starting ring-substituted material. propiophenones as synthesis will always produce racemicsence methcathinone of in asymmetric the influence. ab- and Despite pseudoephedrine the are factforcement that more than ephedrine propiophenone closely – for monitored example,1 they by chemicals are under law Schedule the en- United(UNODC) 1988 Nations Precursor Office Convention – of they Drugs are stillfor and easily Crime diverted illegitimate usefor as methamphetamine is manufacture. They evidenced arequantities by produced for in their use large as massive nasalgradually diversion being replaced and by although other they drugsphenylephrine, are for there this is purpose, such currently as into enough available the for clandestine diversion enough methamphetamine for methcathinone industry production. and certainly produced by the oxidation of the 1 2 manganate. Oxidation of the benzylic hydroxylremoves group chirality to at the a benzylic position but proceedstion of with stereochemistry reten- at the 2 position producing theS more active none and its analoguespropiophenones employs as propiophenone the or substituted immediate precursor (Figure 5).

406 407 It has [13,19–22] Psilocybe [23] -acetylation N a tryptamine species by the [22,24] Virola Drug Testing Drug Analysis and [19,22] 3 3 CH CH www.drugtestinganalysis.com 3 3 is the active ingredient of a number 3 CH Br , CH 2 NHCH O , acetic acid Virola, Br O 2 NH O 3 O Br Interestingly, 20 years later, it was discovered triethylamine CH [25] -dimethyltryptamine, present in several species of O O N O O , C N 3 C 3 H . The structures of psilocin and psilocybin were confirmed H -methylation of serotonin. Bufotenin, O The hallucinogenic activity of these naturally occurring mexicana tryptamines has longmost been potent exploited naturally by occurringtryptamine structure humans. is that psilocybin, One the contain phosphate ester of the found of in psilocin, the various hallucinogenic mushrooms, particularly widely in nature in both the plant and animal kingdoms. Serotonin, a naturally occurring tryptamine, isand a local neurotransmitter hormone inthe humans and of its the essential biosynthesis amino proceeds acid, by tryptophan. again by his son5-Methoxy- Theodor Wieland in toadstools. The substance many receptors in bothsystems the and central its and pharmacological thenaturally occurring effects tryptamine peripheral with an are nervous important pharmacology profound. is melatonin. Another It is biosynthesized in the pineal glandand by closely related to serotonin, wasNobel originally Chemistry found laureate, by Heinrich the Wielandof German in toads the in 1934. parotid gland of snuff powders prepared from theWaika resin Indians of of the Upperin Orinoco Brazil. in It Venezuela and isYanoama Rio also Indians Negro of a the component Upper Orinoco. of the dart poison used by the jungle trees of the genus 2 Br 4 ether pyrrolidine 2011 John Wiley & Sons, Ltd. acetic acid SO 3 2 -BuMgCl c n CH -methylpropiophenone. 2. H  1. 3 3 CH N CH O O 3 CH CN N O O O C 3 N H Methylenedioxypyrovalerone O O O -methylmethcathinone from 4  O O 3 , 404–416 Copyright 3 , CH 2011 N O Synthesis of MDPV. New-generation legal highs related to methcathinone. Synthesis of racemic 4 Pyrovalerone Precursor chemicals and synthesis-driven end-products Drug Test. Analysis Figure 9. Tryptamines Tryptamine (Figure 2)the is heterocycle a indole. The primary basic tryptamine amine structure alkaloid is found based on Figure 8. industrial chemicals that may beany concerns easily among obtained law enforcement without agencies. raising Figure 7. H 3 2 a H H H H H R CH , 404–416 M. Collins 3 3 , 3 3 3 3 3  5 R NHCH 2011 2  4 HH H HOCH HOCH HOCH HSO HH H R OH H H 2 2 3 ) 3 3 3 3 3 he phenethylamine (PEA) moiety Drug Test. Analysis 2 CH CH-CH 2 R . By extension, the PEA structure is CH CH CH CH CH 2 CH(CH CH amine 2 hyl 2 3 ) et 3 3 3 3 3 1 CH en CH-CH 2 ph 2 2 R a ethyl R α m N 1 2 R 1 If indole or an indole derivative is not available, it can be The structural relationship between compounds such as lpha- H β easily synthesized using asynthesis range of is methods. The aof Fischer indole well-known substituted procedureindole, indoles, that for although gives useortho-nitrobenzaldehyde not good as by indole yields anitromethane a itself. to precursor give 1-(2-nitrophenyl)-2-nitroethane However, nitro-aldol followed may by cyclizationtoindole.Theorganicchemistryofindole,firstprepared be condensation easily with preparedin 1866, is from comprehensive and wellof documented. the The importance pharmacology of naturallythe occurring endogenous tryptamines, molecule such as serotonin,elucidated whose in structure 1948, was isthen that first also those well with an established.connection eye between the It to psychoactive the properties is of main serotonin not chance –itsrelativesfoundincertainmushrooms or should surprising draw the – andtheeaseofsynthesisof tryptamines, andpsychoactive embark designer on drugs. The production precursorsor are of easily readily prepared a and available the synthetic new chemistry requiredtryptamines range to is prepare comparatively of simple. present in methamphetamine, MDMA, andtype stimulants. other amphetamine- mescaline, which occur naturally in peyote, and the endogenous Phenethylamines The relationship thatsuch exists as between serotonin, endogenous andpsilocin, compounds, naturally and occurring the many compounds, synthetic,be such extended psychoactive as to tryptamines the may generalas class phenethylamines of (Figure compounds 1). often T referredis to embedded in the structuresas mescaline of and many dopamine, psychoactive etc. Indeed drugscommon amphetamine such name derives its from a methyla derivative of phenethylamine, i.e. N 3 - N 4' , 7 R N 4 2011 John Wiley & Sons, Ltd. 5 c 6 5' R The dimethyl -methoxy-  Copyright [24,26,27] -N,N-dimethyltryptamine Synthetic CH ropyltryptamine Synthetic CH(CH -dimethyltryptamine (DMT) thyltryptamine Natural CH N , allyltryptamine Synthetic CH N -methyltryptamine Synthetic H H H OCH gives good yields of tryptamines. An α [27] [28–31] . in the Basel laboratories of Sandoz in et al -carboxyltryptamine Natural H H H H CO α Obviously, the easiest approach for some simple -Dimethyltryptamine, was first synthesized in 1931 N , [26] Some natural and synthetic tryptamines N [20,21] -dialkyl tryptamines is to begin with tryptamine itself and N Tryptophan 5-MeO-DMT 5-methoxy-N,N-dime DET N,N-diethyltryptamine Synthetic CH Common Name Full NameSerotoninMelatonin 5-hydroxytryptamine 5-methoxy-N-acetyltryptamine Natural Natural COCH3 Origin H R H H H OCH H OH H Table 1. Psilocin 4-hydroxy-N,N-dimethyltryptamine5-MeO-DALT5-MeO-DiPT 5-methoxy-N,N-di Sumatriptan5-MeO-AMT 5-methoxy-N,N-diisop 5-methylaminosulfonamide 5-methoxy- Natural CH Bufotenin 5-hydroxy-N,N-dimethyltryptamine Natural CH , Drug Testing Drug Analysis and example of the applicability of this synthesis is 5 www.drugtestinganalysis.com Synthesis of tryptamine analogues Many naturally occurring tryptaminesthe have course been of synthesized chemical in researchnatural into products. the A molecular structureslegitimately number produced of to of combat medical synthetic conditions, forsumatriptan analogues example, used to have treat migraines. been Other tryptamines haveclandestinely been synthesized in attempts to exploit powerful pharma- cological effects of theof tryptamine tryptamine structure analogues (Table 1). isnumber Synthesis of not successful difficult synthetic and approaches. there have been a by Albert Hoffmann 1959. derivative, N diisopropyltryptamine, whose psychoactiveknown. properties Its synthesis are by this well method ising shown the in amine used Figure in 11. the second By step, vary- abe variety of prepared. tryptamines may Generally the Speeter-Anthony approachway to is produce an various ideal tryptamines ifindole indole or is a available ring-substituted as the precursor.Nichols’ More team recently at Purdue Professor University David has prepared a numbertryptamine of derivatives novel as part of theirreceptor research sites into in the the serotonin brain. by Manske. exhaustively alkylate the primarythis approach is amino the preparation group. of An example of shown in Figure 10.iodide Tryptamine and the is intermediatereduced treated quaternary to with ammonium DMT. salt If excess is howeverdesired methyl tryptamine then to is produce not more availablecontaining or complex substituents if tryptamines, on it i.e. the is may tryptamines aromatic be tried. ring, Starting with other indole, or approaches Speeter-Anthony a synthesis ring-substituted indole, the

408 409 or 2A Drug Testing Drug Analysis and 2 www.drugtestinganalysis.com ) 3 - I 3 ) 2 3 ) 3 CH(CH Cl (CH + O O , THF 4 N N N(CH -diisopropylamine H BH N HC N 3 , H H 2 H N O N N N O C) LiEt 3 However, the psychoactive properties of these (H [37] CO receptor site has been carried out using the simple 3 CO 3 H H 2A substances are largelyweak undetermined. when Mescaline compared itselfit to is has other quite frequently psychoactivefor been substances, their used but psychicdose as of properties. a 350 means mg Itto of to has produce mescaline rate been sulfate aone compounds is determined psychic ‘mescaline the that minimum response unit’.and required a and its Considering similarity this the toadrenaline, has structure endogenous and molecules been of such serotonin,it rated mescaline as should it dopamine, at have isbeen well powerful perhaps established pharmacological that not manypharmacological effects. hallucinogenic activity drugs surprising to It owe their their that ability has to now activate the 5-HT alkaloid in peyote, 3,4,5-trimethoxyphenylethylamine is not alone with at least an additionalamounts. five alkaloids being present in smaller serotonin-2A receptor site in the brain. Manyhave drug this classes seem effect to including amphetamine derivatives,and tryptamines, some ergot alkaloids.also Amongst be the counted ergot the(LSD). alkaloids synthetic Much should drug of lysergicHT the acid diethylamide research aimed at understanding the 5- I 3 4 The and 2011 John Wiley & Sons, Ltd. LiAlH c 2 [34] ) [36] 3 Beginning Excess CH oxalyl chloride [35] CH(CH 2 N NH H HC H N 2 N H C) N in 1896 by Heffter 3 (H -diisopropyltryptamine. plant which when fermented N , Mescaline was first isolated from N CO CO 3 3 H H [32,33] -dimethyltryptamine (DMT) from tryptamine. , 404–416 Copyright N 3 , , Although the most abundant psychoactive N Lophophora williamsii [22] 2011 Agave tequilana Synthesis of 5-methoxy- Synthesis of Precursor chemicals and synthesis-driven end-products with gallic acid3,4,5,-trimethoxybenzaldehyde (3,4,5-trihydroxy which benzoic was acid) thennitromethane condensed Spath and with prepared the resulting nitrostyrenesteps was to reduced in mescaline. two Thealong the peyote Texas cactus side growswithin of the in the Chihuahuan desert. Rio a It Grande has narrow beenpeoples and used area of by into the these Mexico, indigenous lands mainly for millennia for sacramental rites. thepeyotecactus, word ‘mescal’ has been incorrectlycactus applied to where refer in to the factto peyote the refer word is toproduces only the the used famous in drink tequila. Mexicanactive So, Spanish ingredient when of Heffter the isolated peyote the name cactus. ‘mescaline’. it was given the common Drug Test. Analysis neurotransmitters, such as dopamine,and adrenaline, noradrenaline, isMexican Indians obvious practiced (Figurea a 1). small cactus religion The with based powerful hallucinogenic pre-Colombian to on properties attributed the the alkaloid worship mescaline. of Figure 11. Figure 10. its structure was confirmed byas total 3,4,5-trimethoxyphenethylamine synthesis by (Figure Ernst 12) Spath. in 1919 [42] , 404–416 M. Collins 3 , 2011 -[2-(2,5-dimethoxy- N 2 NH CHO COCl 3 3 Drug Test. Analysis 3 3 OCH OCH The analogous iodo compound, 2, OCH OCH [41] CO CO CO CO 3 3 3 3 H H H H 4 Halogenated analogues of -H are easily prepared LiAlH [40] 2 H NO 2 2 CO NO 3 5-dimethoxy-4-iodophenethylamine (2C-I) may be prepared from 2C-H by first protecting the amino group as atreating phthalimide and it then with iodine monochloride to4-iodophenyl)ethyl]phthalimide. give The protectingeasily removed group to afford is 2C-I. AlthoughKnoevenagel the then procedure, Henry i.e. variation the of so-called the ‘nitrostyrene’beenthemostcommonlyemployedmethodtopreparephenethy- route, has lamines, other routes have been explored particularly whentrostyrene the route ni- has failed to give satisfactoryreaction yields. has been The employed Mannich to create benzylamines from phenols. Nitriles have been produced via reductive alkylation ofand cyanide the ion nitriles have then been reduced to phenethylamines. Some new-generation phenethylamines These simple variationssome powerful of hallucinogenic compounds. One well the known street mescaline molecule produced gives 2,5-dimethoxyphenylethylamine (2C-H). The5-dimethoxyphenylisopropylamine analogous series may 2, beilarly prepared sim- by usingproducing nitroethane a instead rangethese synthetic of of pathways are easy ring-substituted nitromethane tolated benzaldehyde carry precursors . thereby out and nitromethane with and the nitroethane Today methoxy- being readily available. There are alsoducing an agentssuchaslithium increasing number of aluminum hydridethatmaybeeasily re- obtained. from 2C-H itself. Forbromide instance, treatment and of hydrogen 2C-Hgives with peroxide, fair hydrogen yields of or 2,5-dimethoxy-4-bromophenethylamine (2C-B; withaka elemental ‘NEXUS’) (Figure , 14). 3 OCH 3 3 OCH The OCH OCH 2011 John Wiley & Sons, Ltd. CO CO [38] c . 3 3 CO CO 3 3 H H H H 2 Copyright 2 NO NOH NH 3 H 2 CH CO 3 3 hoxy-4-substituted phenethy- OH OCH OCH tivity relationship (SAR) work has CHO 3 3 The nitrostyrene is then reduced to HO HO CO CO CO CO OCH OCH 3 3 3 3 H H H H [39] Synthesis of 2, 5-dimethoxyphenethylamine. Spath’s 1919 synthesis of mescaline from gallic acid. PIHKAL: Phenethylamines I have known and loved This similarity between the structure-activity relationships Drug Testing Drug Analysis and book also describes originalcompounds. literature Some of syntheses the synthetic of approaches for many 2,5-dimethoxy- 4-substituted of phenethylamines the and 2,5-dimethoxy-4-substituted amphetamines used chemistry similar to thatin employed by his Spath synthesis ofmatic mescaline aldehyde, (Figure with 12). methoxy If groupsavailable, in the the the appropriate molecule desired aro- positions mayphenethylamine is be or developed amphetamine. tobe An easily give condensed aromatic the with aldehyde desired derivative a may nitroalkane in to a produceas nitrostyrene variation the of Henry reaction. the Knoevenagel reaction known www.drugtestinganalysis.com Figure 13. been performed using moleculesber where of the position the andvaried methoxyl num- and groups otherIn in substituent particular the a groups mescaline rangelamines added of molecule and 2, to were 5-dimet 2, thebeen 5-dimethoxy-4-substituted carefully studied. molecule. amphetamines In the have 1980s andder 1990s, researcher Shulgin, Alexan- his wifeby and taking friends them tested personally manysults such of and their compounds describing investigations their wereentitled effects. eventually published The in re- a book amphetamine compounds presumablysynthesis/availability. because of their easy of mescaline andprompted the the endogenous synthesisstructures. of Extensive structure-ac many no phenethylamines doubt containing Figure 12. the corresponding phenylalkylamine. Figuretion 13 between shows 2,5-dimethoxybenzaldehyde the and reac- give nitromethane the to intermediate nitrostyrene derivative which on reduction

410 411 The [43] Once an [48] Drug Testing Drug Analysis and www.drugtestinganalysis.com 3 3 ]difuran was developed it then re- O  CH . 2C- O CH b 6 NH 2 NH C Br :4,5- [47] 3 NH 3 Br C b 3 H CH H O O 3 3 OCH OCH -Methyl-3C-B-FLY; N Br . 3 5 3 2 O CH In the course of the work by the Nichols research group, many -Methyl Bromo-dragonFLY 2 O CH N NH new compounds were producedpotent hallucinogens. In and particular, a some range of rigid provedcompounds benzodifuranyl were to synthesized be and very ing proved with most the useful SAR studies. in SeveralgainedadegreeofnotorietyasdrugsofabuseandareshowninFig- assist- of these compounds have since ure 14. The rigid benzodifuranylhave compounds become shown in widely Figure knownbecause 14 as of the the so-called resemblancecompounds to the of ‘FLY’ common housefly. the compounds The synthetic approaches molecular to these compounds models are published in of the scientific and these medicaltureandinvolveeasilyobtainedprecursors.Thefirststepinthepro- litera- duction of some FLY compounds isof to the produce benzodifuran the basic compounds skeleton asachieved shown by in the Figure 15. Nichols This groupbeginning was using with the benzoquinone procedures of as Parham, starting material. mained to develop theby alkylamino sidechain. This the was achieved series of reactions shown in Figure 16 involving Nichols group conducted SARmore studies about the with three-dimensional the structureceptor aim of site. the of They serotonin learning re- synthesizedwhat they many knew new about mescaline compounds andthe 2C-B based in receptor on attempts sites. to ‘probe’ including By three-dimensional conformation, building and determining molecules their potency, of they inferred knowledge known of the geometry, serotonin 5-HT3-dimensional receptor’s structure. exceeded many of the naturally occurring hallucinogens. efficient synthesis of the rigid benzodifuran7-tetrahydrobenzo[1,2- skeleton i.e. the 2,3,6, . NH 8 Br Br . DOB-FLY; [46] 4 2011 John Wiley & Sons, Ltd. O O c Serotonin 2 NH [44,45] . 2C-B-FLY; 3 . Bromo-dragonFLY; 7 receptor site. This 2 O 3 3 The Nichols research 2 O 2A NH . DOB; [43] receptor. NH 2 OCH OCH (1) (2) Br (3) (4) (5) 2A Br (6) (7) (8) O Br d naturally occurring phenethy- . 2C-B; O B-DragonFLY; 1 to the amine side chain. Based on para , 404–416 Copyright 3 , 2011 Some benzodifuranyl compounds and related phenethylamines. Professor David Nichols’s research group at Purdue Univer- Precursor chemicals and synthesis-driven end-products work was bornerties of of the mescaline and knowledge the 2,5-dimethoxylatedand of phenethylamines phenylisopropylamines the and hallucinogenicdimensional aimed prop- structure of at this receptor site. revealing the three- Drug Test. Analysis The Nichols group studiedLSD (lysergide) indole-based and psilocybin, hallucinogens an such as lamine hallucinogens such asthe mescaline potency of and synthetic quickly analogues of noted mescaline1-(2, such 5-dimethoxy-4-bromo that as phenyl) 2C-B isopropylamine and (DOB) greatly this knowledge that both mescaline, 2C-B and otherspotent like them of are the serotonin receptors researchprobing groups began deeper the affinityserotonin of receptor sites. certain-shaped molecules for the sity has produced ain range of the new course generation phenethylamines of research into the 5HT Figure 14. drug, 2,5-dimethoxy-4-bromophenethylamine (2C-B) (Figure 14), is substantially more potent than mescaline4-bromoamphetamine while 2,5-dimethoxy- isobvious rated structural at featuresphenethylamines 400 had that in common mescaline were 2C-B the primaryseparated and units. amine from moiety the other The aromatic ring psychoactive byaliphatic four carbon angstrom atoms, units, the i.e. methoxyl two groups,substituent and in a a hydrophobic position or 5-hydroxytryptamine (5-HT), a neurotransmitter withman many hu- receptors is linked to many human mental processes. group was very activephenethylamine over and several phenylisopropylamine decades analoguesstudies in in and relation to the SAR the serotonin synthesis 5-HT of ]-  b ;4,5- b , 404–416 M. Collins 3 , 2011 O 2 O 2 NH NO Drug Test. Analysis 3 R 4 3 R C LiAlH THF, reflux ° O O O 3 O NHCOCF 3 NHCOCF CH -BuLi, CH n THF, 0 , acetic acid 2 Br O O O 2 Cl Br Cl O NO 2 Br OAc O O 4 , acetic acid 2 NH RCH Br known by itsthen R street equal name,is produced, methyl i.e. 2C-B-FLY. 1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2- and If the nitroethane analogous amphetamine is series used difuran-4-yl)-2-aminopropane which is known byof its DOB-FLY. Another street of the name FLY compounds createdresearch by the Nichols group has thesynthesis street is shown name in Figure ‘Bromo-DragonFLY’ 17. Like and the other its rigid benzodifuranyl Br , toluene 1 2 4 O reflux 2 CHO C to RT in 2 Hr NH ° DDQ R , 0 CO) , CCl 2011 John Wiley & Sons, Ltd. O 2 3 2 O c 3 Cl Br 2 (CF O Cl CH Cl 2 O ]difuran.  b 2 3 NH 3 O/MeOH 3 3 NHCOCF Br NH 2 O O CH :4,5- Copyright b 4 CH CH SnCl CHOCH O 2 NaOH/H Cl O 2 O O Cl ) O 2 O 1. 2,3-Dichloro-5,6-dicyanobenzoquinone Br Br O Br(CH O ]-difuran-4-yl)-2-aminoethane better  b OH OH ;4,5- b If nitromethane is used in the second step R [44,49] A synthesis of Bromo-DragonFLY. Formylation and subsequent elaboration of the benzodifuran nucleus. Synthesis of 2,3,6,7-tetrahydrobenzo[1,2- Drug Testing Drug Analysis and www.drugtestinganalysis.com Figure 17. Figure 16. formylation to givejected the to the aldehyde samemescaline which type and of could used reactions much then laterple used by by be phenylethylamine many Spath sub- others compounds toproperties. to prepare with prepare sim- potent hallucinogenic Figure 15. will equal hydrogen and thetetrahydrobenzo[1,2- product will be 1-(8-bromo-2,3,6,7-

412 413 Nymphaea ).Theseproducts Drug Testing Drug Analysis and ),the‘BlueLotus’( www.drugtestinganalysis.com Nelumbonucifera the National Institute of Health Sciences Leonitisleonuris [50] and the Bundeskriminalamt in Wiesbaden also OH O O O N N N 3 [52,53] O )andthe‘SacredLotus’( CH O (6) (4) A large volume of medical and scientific research has been were known to have minimalto psychoactive be effects, but attractive sufficient became enough apparent for that sale userswere by really thought internet. very this excellent However, at range producingsome it of a very high, soon Spice i.e. potent drugs they psychoactive contained experiences substance or by substances.chemistry These users community and attracted lawinitial enforcement chemical attention analyses agencies. failed to However, from detect anyknowntoproducepsychoactiveeffectsandthegeneralfeelingwas of the the ‘usual suspects’ forensic that the users were overstatingHowever, the some effects suspicions of regarding the the Spice supposedof products. herbal the nature Spice drugs arose whendetect the any chemical of analyses the compounds also that failed would be to expecteda to plant be seen extract, in for example, phytosterols. Inthe late German 2008, THC chemists at Pharmaceuticals Companychemical, identified JWH-018 a (Figure research 18), andUniversity in of early Freiberg, 2009 scientists at the identified JWH-018 and another research chemical47,497 designated CP (Figure 18). Whilethese new research chemicals to had the been developedas drug-abusing part within of community, universities legitimate chemical research designed tomedical combat certain conditions. carried out over several decades intoactivity. the mechanism By of cannabis the early 1980s, two cannabinoid receptors had in Japan, Typical plants represented by theincludethe‘Lion’sEar( Spice drugs were supposedcaerulea to 2011 John Wiley & Sons, Ltd. c It was always [50,51] O OH OH N 3 THC; (2) HU-210; (3) CP 47,497; (4) WIN 55,212; (5) JWH-018; THC; (2) HU-210; (3) CP 47,497; (4) WIN 55,212; O 9 ∆ (5) (1)(3) (2) CH OH (1) (6) JWH-073 , 404–416 Copyright 3 receptor. There were many dozens of the , 2A 2011 Some cannabinoid receptor agonists. Duringtheearlytomid-2000sanewrangeofproductsappeared, Precursor chemicals and synthesis-driven end-products benzodifuranyl and benzofuranyl compounds prepared forstudies but these it is beyond the scopeof of synthesis this of article them to all. discuss the ease Drug Test. Analysis also marketed asmainly by herbal the highs Internet or as the legal ‘Spice’ highs range. and marketed Synthetic cannabinoids The synthetic cannabinoid class of drugs is some of theof most recent the so-called designer drugs.in Although this many class of were the created molecules inis the laboratory only over in the the last 20 lastthe years drug few it scene. years There that has long they beengenerally have available referred a been to range introduced as of products ‘herbal into highs’.plant materials These with products little are psychoactive effects usually andreceive have little tended attention to from law enforcementpresent agencies. as liquids, They dried may vegetable matter,contain or a live wide matter range and of may extractssalvia, and from kava. substances While such the as peyote peyote, cactuscontain some for very instance potent does substances, indeed for example,amount mescaline, present the in the herbal highs is usually very small. compounds, it wasstudies prepared and for turned structure-activity outthe relationship to serotonin have 5-HT a particularly high potency for Figure 18. maintained that these substancesherbal were highs nothing that more wereby than already law the well-known enforcement and because of largely their ignored low psychoactive potency. , 404–416 M. Collins 3 , 2011 .Athirdgroupof 9 to C 6 -, appeared. N Drug Test. Analysis 3 R 3 Probably the best known of these is -THC and other molecules that interact 9 Structurally these compounds do not [61] or -OCH 2 Ar 3 3 R 3 2 [57–60] , 2-(4-morpholino) ethyl R -THC molecule itself but many are potent cannabi- 11 9 1 O H N 5 R 11 N H 5 = -C = H or -CH = H or -CH - instead of the = H or -CH C 1 2 3 Naphthylindoles N 1 R R R Phenylacetylindoles R Ar = Phenyl substituent -THC. When it was detected along with CP 47,497-C8 as an One of the most active research teams in the field was that of While the clandestine preparation of compounds such as HU- 9 resemble the with the cannabinoid receptors might assistmedical with conditions such a as wide pain range relief of and Parkinson’s disease. Professor John Huffman atOver Clemson the University, course South oflooked two Carolina. at decades, Huffman’s the researchmolecular development structure group of the of has cannabinoid agonists pharmaceuticals andthree-dimensional explored configuration based the of the on cannabinoid receptors.the the In course of this research,ber his group of has molecules produced a thatbeen large are named num- with potent the cannabinoids letterscompounds JWH and – included for have naphthoylindoles, example, often JWH-018. naphthylmethylindoles, naphthoylpyrroles, These naphthylmethylindenes, and phenylacetylin- doles (Figure 19). cannabinoid agonists is the naphthoylindoles exemplified by55,212 (Figure WIN 18). All of these agonistsome groups were importance of interest because and it appearedthat molecules likely such to as some physicians JWH-018 (Figure 18) which is about three times as potent as range of products. German authoritiesCP then 47,497 range placed with a ban sidechains of on C the active ingredient in SpiceHowever, products within in a month Germany, of ithas the an ban, was JWH-073 banned. (Figure 18), which 210 and CP 47,497 requires enantioselective synthesisthe techniques JWH range of compounds,quite such as easy the to naphthoylindoles, are face prepare. and the There synthesis relies are on well no known synthetic stereochemistry procedures, issues to noid receptor agonists. = H 4 = H = H [55] 4 4 = R 3 2 2011 John Wiley & Sons, Ltd. = R R = R c 3 3 -THC. One 9 = R 4 = Cl, R = R 2 3 R 2 , R 2 , R , R 9 11 R 11 Copyright H H H O 2 4 5 5 R 1 N O R = -C = -C = -C 1 1 1 1 In 2009, at the University N R Naphthoylindoles Naphthoylpyrroles [56] Receptor) and the other in the 1 JWH-018: R JWH-073: R JWH-398: R = phenyl, alkyl, methoxy or halogen = Alkyl group; 2 1 R R (hence the ‘HU’). This particular synthetic Receptor). In addition to the receptor sites, 2 [54] -THC and possibly up to as much as 28 times -THC that do not contain the pyran ring moiety 9 9 This compound is reported to be at least 3 times [55] -THC itself. A, by now well-known synthetic counterpart -THC. HU-210 has been investigated for its possible use Some JWH compounds. 9 9 -THC – HU-210 (Figure 18) – was synthesized in Israel in 9 A second group of agonists are the cyclohexylphenols which are Drug Testing Drug Analysis and as potent as as potent depending onanalgesic, the motor route of depressant, administration. and It anticonvulsant displays properties. in preventing inflammation caused byto amyloid be proteins involved thought invery the potent onset analgesic properties. of However it Alzheimer’s hasSpice disease. been products detected It seized in by is US Customs. also has analogues of to www.drugtestinganalysis.com The cyclohexylphenols, or ‘CP’potential compounds analgesics were during developedhomologues the of as 1980s CP by 47,4971-dimethyloctylhomologue,orCP47,497-C8whichisseveraltimes have Pfizer. been A prepared number includingmore the potent of 1, than CP 47,497 itself. been identified bythe medical central researchers, nervous system one (CB in the brain and Figure 19. in their structuremethyloctan-2-yl)phenol such (Figure as 18), 2-[(1R, more usuallyCP 3S)-3-hydroxycyclohexyl]-5-(2- referred 47,497. to as 1988 by RaphaelHebrew Mechoulam University and his research group at the of Freiburg the CP 47,497-C8 analogue was detected in the Spice group of cannabinoid receptor agonists is the phytocannabinoids, such as immune system (CB a number of endogenous receptorThe agonists identification of were the also receptor identified. sitesto spurred investigate on the research structures of efforts the cannabinoid receptorsto and produce also molecules that might behave similarly to cannabinoid is reported tothat have of a potency of at least 100 times

414 415 , Avail- , pp. Annex. 2010 J. Forensic Sci. 2003 Annual report 2009. Drug Testing Drug Analysis and Pharmacol.Biochem.Behav. /precursors-report/2010/en/ , 10. rg/pdf/annual-report/2009/en/ 185 , 36. , www.drugtestinganalysis.com 1953 2009 V10579291.pdf [8 June 2011]. E Forensic Sci. Int. , 915. , 1109. COCl English.pdf [8 June 2011]. C nuclear magnetic resonance spectroscopy must be 36 58 , , 13 11 09 Friedel-Crafts Acylation H 11 5 1991 UNODC Bulletin on Narcotics 1997 United Nations ConventionDrugsandPsychoactiveSubstances,Vol.V.03-81665 (1988) Against Illicit Traffic in Narcotic PrecursorsReport2010 able at: http://www.incb.org/pdf Available at:AR http://www.incb.o H C 5 N Hand C [8] K. Y. Zhingel, W. Dovensky, A. Crossman, A. Allen, [5] The DEA website.[6] Available at: TheDEA.org T. [8 A. June Dal Cason, 2011]. R. Young, R. A. Glennon, [4] [7] R. P. Archer, [3] [2] International Narcotics Control Board, INCB [1] International Narcotis Control Board, 1 N O the time appropriate legislation hascan been be passed, made. small Syntheses fortunes really of quite the easy majority of andthe these drugs the compounds such precursor is methamphetamine, chemicals,very are unlike easy either to those not obtain. for scheduledproblem The or for new those designer forensicforensic compounds chemistry scientists analysis also is engaged based pose on in the a the need analysis. for ‘unknown’ comparison Most with of reference materials,identity i.e. substances and of purity. known Thiswhere is a typified retention in timecompared chromatographic with and retention analysis times mass and spectrum massof spectra reference of materials. of But what a the does large the forensic unknown range chemistnoreferencematerialisavailable?Today,thissituationisbecoming do is when a common occurrence asas more the JWH and compounds, are more appearing.be These designer easily compounds drugs, cannot purchased as such reference materials.before Today the more than first ever principlesas approach employing techniques such References used to determine the molecular structure of the unknown. JWH-018 2011 John Wiley & Sons, Ltd. 1 c I 11 H 5 C NaH / HMPA H N 1. Hexamethylphosphoramide -alkyl indole commercially, in N , 404–416 Copyright 3 , 2011 Synthesis of JWH-018 from indole. Precursor chemicals and synthesis-driven end-products Drug Test. Analysis Conclusions The modern scourge of designer drugs is ato problem that disappear is unlikely quickly. Inof the abuse twentieth century, wereand the heroin, major more drugs cocaine, latterlymajor methamphetamine, MDMA problem across cannabis, or thea ‘Ecstasy’. world. new These Today, range however, drugs ofchemistry we psychoactive are that also substance still face was abusetwentiethcentury.Whenspecificsubstanceshavebeenscheduled, a developed albeit based during on themolecular structure second variants half thatsoon appeared. of avoid Often new molecules specific the developed during legislation the course of have legitimate medical or chemical researchexploited efforts as have psychoactive later substances been for sale toa drug dilemma abusers. faced It by is scientists involvedsynthetic in such research, organic including chemistry;in that learned their journals workanyone. and will In today’s therefore be world, will published itto is be relevant very journals. open easy It to to issyntheses obtain of also Internet scrutiny compounds just access offshore in by as parts easyquestions of to the are world commission asked. where custom few Again,the the Internet final may product be for used to sale market in countries where it is not illicit. By primarily modifications of the Friedel CraftsanexampleasynthesisofJWH-018isshowninFigure acylation reaction. As either 20.Itinvolves obtaining the appropriate Figure 20. this case 1-pentylindole, orThe synthesizing compound it 1- which Naphthoic ischloride acid not and is difficult. a then Friedel converted Craftsand acylation to the between the alkyl the acid acid indole chloride that is performed if to one giveeasy member the matter to product. of produce another, It e.g. this is JWH-073by instead series clear of commencing JWH-018, is with a legislated differentindole. against alkyl indole, it in is this case an 1-butyl , , , 11 223 , , 1997 , 1931. , 1184. 29 2003 41 , 1395. , 404–416 , 1982 , 995. , , 3526. M. Collins , Churchill 3 Bioorg. Med. Tetrahedron: , 46 , 285 1w2 , 1353. , , Forensic Sci. Int. 1973 1976 73 , 2953. 2011 , Bioorg. Med. Chem. 2003 Bioorg. Med. Chem. 39 1998 2005 , J. Med. Chem. , 58. 1951 Pharmacology 191 , 1996 , 705. , 832. Tetrahedron J. Phar. Exp. 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