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MONOMETHYLATION
BY

OF

AMPHETAMINES

RHODIUM

INTRODUCTION
There are many procedures out there for the production of Nmethylamphetamines (methamphetamines) from
various starting materials, such as phenyl2propanone (P2P) or ephedrine, but what if you already have an
amphetamine(orphenethylamine)andwantedtoaddamethylgrouptothenitrogenatom?Ifyouwouldusethe
first reaction that comes to mind for the conversion, to alkylate the amphetamine with methyl iodide or
dimethylsulfate, you would be disappointed, as you would get a mixture of products, most important the N,N
dimethylamphetamine(ofverylowactivity),asoncetheamphetaminehasbeenmethylatedtomethamphetamine,
themoleculeismuchmoresucceptibletoanotheralkylation,andthusthedimethylamphetamineisformedmuch
fasterthantheremainingamphetamineisalkylatedtomethamphetamine.Actually,inthereactionmixyouwould
findunreactedamphetamine,Nmethylamphetamine, N,Ndimethyl amphetamine and even some of a quaternary
N,N,Ntrimethylamphetammoniumsalt.
Toavoidthishappening,wemustusuallyresorttoindirectmethodsofintroducingthemethylgroup.Onewayisto
react the amphetamine with formaldehyde (either as an aqueous solution, or as paraformaldehyde) to get the
amphetamine formaldehyde imine, which can then be reduced to the Nmethylamphetamine using a several
differentreducingagents,forexampleAl/HgorPt/H2.

Amphetaminecanalsofromanamidewithformicacid,Nformylamphetamine,ifboiledinaDeanStarkapparatus
wheretheformedwaterinthereactioniscontinouslyremoved,thusdrivingtheformationoftheamideforward.The
amidecanthenbereducedbyforexamplelithiumaluminumhydride.

Another way is to react the amine with benzaldehyde to form an imine, which then can safely be alkylated with
methyliodideordimethylsulfate,andafterhydrolysisoftheresultingcompound,NMethylamphetamineisformed.

Finally,itmustbesaidthatusingexoticreagentslikecesiumsalts,itmightbepossibletodirectlymonomethylate
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amphetaminewithouttoomuchoveralkylatingtakingplace.Yougetanapproximate9:1ratioofsecondaryamineto
tertiaryamine,whilenotperfectitisprettygoodforonestepwithnoreductionnecessary.Theselectivitymightbe
somewhatlowerwithmethylationsthanwiththebutylationdescribedinthelastsynthesisofthisdocument.

FORMALDEHYDE

AND

ALUMINUM AMALGAM1

NMethylamphetamines were prepared by the reaction of the corresponding amphetamine with

formaldehyde and reduction in the absence of acid. Thus, a mixture of 1 mole amphetamine freebase
(136g)and1moleaqueousformaldehyde(81ml37%or75ml40%)in350mlalcoholandanexcessof
aluminum amalgam was reduced for several hours, water added, aluminum hydroxide filtered off, the
solution acidified and evaporated, and the freebase separated by means of alkali yielding phenylN
methylisopropylamine, converted to the hydrochloride, mp 140C. Similarly, 70g damphetamine in
alcoholwithaluminumand1moleformaldehydegavedmethamphetamine,whichwasconvertedto the
phosphatesalt.1Phenyl2aminopropanolsimilarlyyieldedephedrine.

PARAFORMALDEHYDE, PLATINUM OXIDE

AND

HYDROGEN2

Thisprocedureisforthemethylationof2phenethylamine,butitcaneasilybeadaptedforusewithany
amphetamine.
A solution of 30.25 g (0.25 mole) of 2phenylethylamine and 7.5 g. (0.25 mole) of paraformaldehyde
(Note1) in 50 ml of 95% ethanol was allowed to stand for a short period (Note2). Additional ethanol
(100ml),15g.(0.25mole)ofglacialaceticacid(Note3),and0.5g.ofplatinumoxide(Note4)were
added, and hydrogenation was carried out at room temperature and 3 atm. When hydrogen absorption
was complete, the catalyst was removed, and the filtrate and washings concentrated to dryness. The
residuewastreatedwithsodiumhydroxidesolution(Note5),extractedwithether,driedanddistilledto
givean8090%yieldofNmethyl2phenethylamine(Note6).
Notes:

1. Originallyabout20mlof37%formaldehydesolutionwasadded(0.25mole).Inviewofthereported
2.

3.

4.
5.
6.

danger of dimethylation of primary amines when formaldehyde is used, it appeared safer to use
paraformaldehyde,sinceanexactamountcouldbeweighed.
When the aldehyde and base were mixed, the solution became warm. The solution was allowed to
stand for 0.250.5 hr. for complete reaction. In some cases the mixture was allowed to stand
overnight, but this gave no improvement in yield after reduction. When no heat developed in the
reaction of aldehyde and amine, the mixture was warmed slightly and allowed to stand before
reduction.Whenlowboilingcomponentsaretobemixed,itisbesttocoolthesolutionofaminewhile
the aldehyde is added to prevent loss of amine or aldehyde from the exothermic reaction. After
standing,themixturecanthenbehydrogenated.Hydrogenuptakewasusuallycompletewithin2hror
less.
Thereactionrateinthisreductionwasslowerintheabsenceofaceticacid.Otheracidsshouldalsobe
satisfactoryaslongatheydonotcausereversaloftheformationofimine.Strongacidsshouldnotbe
usedwithrhodiumbecausetheyactasinhibitorsofitsactivity.Manyreductivealkylationswerecarried
out successfully with platinum or palladium in the absence of acid. When reduction was too slow,
interruptionforadditionoftherequiredamountofaciddidspeedhydrogenuptake.
Palladium on carbon was not used in this experiment, but 5 g of 5% rhodium on carbon did prove
satisfactory. Freifelder states there is little doubt that 5 g of 5% palladium on carbon or an equal
amountof5%platinumoncarbonwouldworkastheyhadinotherreductivealkylations.
Whenacidisnotused,additionofalkaliandextractionofbaseareunnecessary.
Areactionsuchasthisisactuallyareductionoftheimineinsitu,averyusefulprocedurethatmaybe
usedinalkylationswithotheraldehydes.

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FORMIC

ACID

AND

LITHIUM ALUMINUM HYDRIDE3

Asolutionof6.55gof3,4methylenedioxyamphetamine(MDA)asthefreebaseand2.8mLformicacidin
150mLbenzenewasheldatrefluxunderaDeanStarktrapuntilnofurtherH2Owasgenerated(about20
hwassufficient,and1.4mLH2O was collected). Removal of the solvent gave an 8.8 g of an amber oil
which was dissolved in 100 mL CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally
onceagainwithdiluteacid.Thesolventwasremovedundervacuumgiving7.7gofanamberoilthat,on
standing, formed crystals of Nformyl3,4methylenedioxyamphetamine. An alternate process for the
synthesisofthisamideinvolvedholdingatrefluxfor16hasolutionof10gofMDAasthefreebasein20
mLfreshethylformate.Removalofthevolatilesyieldedanoilthatsetuptowhitecrystals,weighing7.8
g.
A solution of 7.7 g Nformyl3,4methylenedioxyamphetamine in 25 mL anhydrous THF was added
dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL anhydrous THF under an inert
atmosphere.Thereactionmixturewasheldatrefluxfor4days.Afterbeingbroughttoroomtemperature,
theexcesshydridewasdestroyedwith7.4mLH2OinanequalvolumeofTHF,followedby7.4mLof15%
NaOHandthenanother22mLH2O.Thesolidswereremovedbyfiltration,andthefiltercakewashedwith
additionalTHF.Thecombinedfiltrateandwasheswerestrippedofsolventundervacuum,andtheresidue
dissolved in 200 mL CH2Cl2. This solution was extracted with 3x100 mL dilute HCl, and these extracts
pooledandmadebasicwith25%NaOH.Extractionwith3x75mLCH2Cl2 removed the product, and the
pooled extracts were stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white
residuewhichwasdistilledat100110Cat0.4mm/Hgtogive5.0gofacolorlessoil.Thiswasdissolved
in25mLIPA,neutralizedwithconcentratedHCl,followedbytheadditionofsufficientanhydrousEt2Oto
produce a lasting turbidity. On continued stirring, there was the deposition of fine white crystals of 3,4
methylenedioxyNmethylamphetamine hydrochloride (MDMA) which were removed by filtration, washed
withEt2O,andairdried,givingafinalweightof4.8g.

BENZALDEHYDE

AND

DIMETHYLSULFATE4

pMethoxyphenethylamine,generatedfrom100g(0.536mole)ofthehydrochloridebystirringwithconc.
aq NaOH, was treated with 100 ml of benzene (toluene could be substituted) and 70 g (0.66 mole) of
benzaldehyde. A mildly exothermic reaction began at once. The mixt was heated under reflux until no
moreH2Owaspresentinthecondensate(ca.1hr),then,withoutcooling,anattachedDeanStarktrap
was removed and a soln of 82 g (0.65 mole) of Me2SO45 in 200 ml of benzene (toluene could be
substituted)wasaddedthroughthecondenseratsucharateastomaintainreflux(15min).The2phase
mixtwasheatedfor90minonthesteambath,cooledslightly,treatedwith200mlofH2O,andheatedfor
anaddn20min.Aftercoolinginice,theaqueouslayerwaswashedtwicewithEt2Otoremoveunreacted
benzaldehyde and made strongly basic with 50% aq NaOH. Two Et2O exts of the basic aqueous phase
wereaddedtotheaminelayerwhichseparated,andtheresultingsolutionwasevacuatedattheaspirator
for 30 min, leaving 90 g (102%) of crude Nmethylpmethoxyphenethylamine. This material was
dissolvedin500mlof20%absEtOHEt2Oandtreatedwith50mlofconcHClwithswirlingandcoolingto
yield the white, cryst hydrochloride, which was washed thoroughly with icecold 20% EtOHEt2O and
dried,mp185.5186.5C.Theyieldwas83g(77%).

CESIUM HYDROXIDE PROMOTED MONOALKYLATION6,7

Selective Nalkylation of primary amines was developed using cesium hydroxide to prepare various secondary
amines efficiently. A cesium base not only promoted monoalkylations of primary amines but also suppressed
overalkylations. Various amines and alkyl bromides were examined, and the preliminary results demonstrated this
methodology was highly chemoselective, favoring monoNalkylation over dialkylation. In particular, use of amino
acidderivativesaffordedthedesiredsecondaryaminesexclusively.
Among the cesium bases examined, cesium hydroxide monohydrate, in general, gave the highest yields and
selectivitiesalthoughcesiumcarbonatealsoworkedwell,dependingonsubstrates.Toconfirmthepossiblecesium
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effect, defined by the enhanced reactivities in the presence of cesium salts, comparative studies between cesium
bases and other bases were performed, demonstrating that cesium hydroxide was superior to other alkali bases
tried with the regard to the observed chemoselectivities. Other alkali hydroxides produced moderate yields of the
desired product along with a considerable amount of the tertiary amine, whereas cesium hydroxide allowed for a
greater selectivity of 9:1 in preference for the monoalkylation product. It was apparent that an unprecedented
"cesium effect" in Nalkylation was observed as seen in Oalkylation. Interestingly, the next comparative study
impliedthatthecesiumbasenotonlypromotedNalkylationofprimaryamines,butalsoinhibitedtheformationof
tertiary amines. According to our experiments, the intended alkylation of a secondary amine (Nbutyl
phenethylamine)wasverysluggishunderourconditions,affordingthetertiaryamine(N,Ndibutylphenethylamine)
inonly10%yield,whereas72%ofN,Ndibutylphenethylaminewasobtainedalongwiththerecoveryof25%ofN
butylphenethylamineinabsenceofcesiumhydroxideafterthesameduration.UnderourcesiumbasepromotedN
alkylation conditions, primary and secondary amines exhibited opposing reactivities, suggesting that the
improvement of chemoselectivity would stem mainly from the retarded overalkylation or reversal of normally
observedalkylationrates.

RepresentativeExperimentalProcedure
To activated powdered 4 molecular sieves (500 mg) in anhydrous N,Ndimethylformamide (8.3 mL),
was added cesium hydroxide monohydrate (280 mg, 1.7 mmol), and then the white suspension was
vigorously stirred for 10 min. After phenethylamine (0.21 mL, 1.7 mmol) was added and followed by
additional30minofstirring,1bromobutane(0.21mL,2.0mmol)wasaddedintothewhitesuspension.
Thereactionwasstirredfor20h,filteredtoremovethemolecularsievesandundissolvedinorganicsalts,
andrinsedseveraltimeswithEtOAc.Afterthefiltratewasconcentratedtoanominalvolumebyblowing
air,theresiduewastakenupin1NNaOH,andextractedwithEtOAc(4x20mL).Thecombinedorganic
layerswerewashedwithbrine,driedoveranhydroussodiumsulfate,filtered,andconcentratedinvacuo.
Flash column chromatography (EtOAcEtOH, 9:1 v/v) afforded the secondary amine, Nbutyl
phenethylamine (260 mg, 1.5 mmol 89%) as a colorless oil as well as tertiary amine, N,Ndibutyl
phenethylamine(40mg,0.17mmol10%)asapaleyellowoil.

REFERENCES
1.
2.
3.
4.
5.
6.
7.

Keiletal.,NMonomethylphenylethylamines,GermanPat.871,155(1953)CA52:20055e.
Freifelder,CatalyticHydrogenationinOrganicSynthesis:ProceduresandCommentary,98101.
AlexanderShulgin,Pihkal#109(MDMA)
EdgarF.Kiefer,J.Med.Chem.15(2),214(1972)
J.J.Lucier,A.D.Harris,andP.S.Korosec,Org.Syn.,44,72(1964)
Org.Lett.1(12),18931896(1999)
PatentWO50377

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