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Chemistry writing project

7/30/2015

Reabetsoe Dube DBXREA001

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1 Part A ............................................................................................................................................... 2

1.1 Natural products as lead structures in the synthesis of smart drugs ........................................ 2

1.1.1 Introduction ..................................................................................................................... 2

1.1.2 Hedonism versus societal control ................................................................................... 2

1.1.3 Classes of smart drugs and the mimicking of nature ...................................................... 4

1.1.4 Legislation versus the creative adaptation linking with availability versus innovation 10

1.1.5 Analytical aspects with respect to toxicity, risk and evasion ........................................ 12

1.1.6 Synthetic landscape – Scope, opportunity and limitations ............................................ 13

1.1.7 Conclusion .................................................................................................................... 18

1.2 Table ..................................................................................................................................... 19

1.3 The contribution of Alexander Shulgin and Horbart Huson (Strike) .................................... 20

1.3.1 Alexander Shulgin......................................................................................................... 20

1.3.2 Hobart Huson (Strike) ................................................................................................... 22

2 Part B ............................................................................................................................................. 24

2.1 The role of reductive amination in drug synthesis ................................................................ 24

2.1.1 Leuckart reaction........................................................................................................... 24

2.1.2 Henry reaction ............................................................................................................... 28

2.1.3 Nagai method ................................................................................................................ 35

2.2 Mechanisms and reaction designations for selected reactions .............................................. 35

2.2.1 The conversion of safrole into MDMA (Ecstasy) ......................................................... 35

2.2.2 The Speeter-Anthony method for tryptamine synthesis ................................................ 36

2.2.3 The conversion of 1-bromonaphthalene and indole into the synthetic cannabinoid,

naphthoylindole ............................................................................................................................. 37

2.3 The chemistry behind the enantioselectivity ......................................................................... 39

2.3.1 The synthesis of the dextro (2S) methamphetamine enantiomer .................................. 39

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1 Part A

1.1 Natural products as lead structures in the synthesis of smart

drugs

1.1.1 Introduction

For many years humans have taken pleasure, and even regarded as sacred, a variety of mind-

altering substances. According to Ethan Nadelmann (the founder and executive director of

the Drug Policy Alliance) in a persuasive and informative TED talk entitled ‘Why we need to

end the War on Drugs’ and I quote, “Our desire to alter our consciousness may be as

fundamental as our desires for food, companionship and sex.”1 There is ample evidence that

suggests that Homo sapiens are not the only species that seek mind-altering plants and

substances in their habitats. Pigs are known to dig up truffles that contain cannabinoids;

horses seek out locoweed for its intoxicating effect; and elephants eat the marula tree’s

fermented fruit to get drunk (see Figure 1).2 Natural products have always featured and still

feature prominently among drugs of abuse. The reasons for the use of psychoactive

substances by human beings are countable; however hedonistic bases for the use of mind-

altering substances by humans might have been the lead impelling force to the practice of the

synthesis and development of nootropics, also known as smart drugs, and recreational drug

use. Smart drugs are drug supplements, nutraceuticals and functional foods that are used to

enhance the three cognitive domains of the brain – memory, attention and creativity.3 This

practice follows from the inspiration and idea-impingement by nature’s method. The mimicry

of nature by humans to synthesize mind-altering drugs has led to the complementing and

even the replacement of natural pharmacopoeia by synthetic drugs for countable reasons – the

pharmacodynamics, pharmacokinetics and the safety of synthetic drugs compared to their

natural prototypes.4 The resistance to authority for the sheer pursuit of pleasure has also led to

the plantations of clandestine laboratories (in this document, a clandestine drug laboratory

will be referred to simply as a clandestine laboratory) all over the world. Psychonauts (see

Section 1.1.2) with and without a chemistry background have contributed to this ever-

growing drug culture.

1.1.2 Hedonism versus societal control

Psychonautics refers to the approach and explaining of the subjective effects of psychoactive

substances, and to the long established research paradigm in which the psychonaut

voluntarily alters his or her mind by using psychoactive substances for the purpose of

exploring the accompanying experience.5 Zoophoria, the use of intoxicating substances by

animals, compels us to think that altering one’s state of mind for the purpose of experiencing

that altered state of mind is a natural drive common in the animal kingdom.

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Figure 1 A herd of young elephants spotted drunk after an overdose of the Marula fruit. Picture by Ross

Couper, a field guide at Singita Kruger National Park 6

In fact, professional chemists and chemistry students have occasionally used intoxicating

substances that has surely inspired the synthesis of recreational compounds in the later years.

From their usage as medicine and in religious ceremonies, the use and misuse of

psychoactive substances has whelped other usage reasons today that are quite different from

long ago. A sheer pursuit of pleasure impinges drug cultures nowadays, making usage of

psychoactive substances prominently hedonistic. A school of thought that claims only

pleasure and pain motivates us and that pleasure has worth or value is termed as Hedonism.7

This bias has made societal control of especially illegal drugs difficult. The hedonistic drive

to usage can be subjective and psychological, and neglecting the concerns over acute and/or

long term detrimental health effects. This provides support to the banning policies of certain

drugs since the hedonistic use of intoxicants can easily be rendered intrinsically non-natural

on the evolutionary basis that eating provides energy, sex creates offspring but psychotropic

compounds perturb these associations and short-circuit thousands of years of evolution.4

Drug subcultures (or rather countercultures) exist by a common understanding of the

significance of the ingestion of the psychoactive substance in question. The unity in drug

cultures might impel members to adhere to any covenants made and rules of etiquette; to

assist each other in obtaining the drugs; and to help each other avoid arrests. This power force

that aims to get ahead of the law makes societal control difficult. The use of intoxicants has

ventured into recreational usage over the past years and even non-members of drug

subcultures have adopted the recreational use of intoxicants. The underground synthetic drug

industry has boomed calling for desperate measures and perpetual debate over the appropriate

legal status of psychoactive drugs as a means of regulating their usage. The debate involves a

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complex focal point of empirical and psychological issues. Psychological issues are difficult

to resolve since they pertain to differences in core values and empirical issues are ultimately

questions about behaviour – behavioural impact on drug laws.8 The reason to believe an

altered state of mind brings about physical fitness and health benefits in drug subcultures has

made humans addicted to and/or dependent on psychoactive drugs, promoting growth of

clandestine laboratories and making the regulation of illegal drugs more difficult.

1.1.3 Classes of smart drugs and the mimicking of nature

1.1.3.1 Classes of smart drugs

Smart drugs are nowadays commercialized as natural despite their synthetic origin; they are

developed from natural products. This echoes the mimicking of nature humans do,

complementing and even replacing agents in nature. There are five classes of recreational

natural-based drugs: Ephedrine, cathinone, mescaline, tryptamines and cannabinoids.

1.1.3.1.1 Ephedrine

Ephedrine (1) is an alkaloid with a phenethylamine skeleton found in various plants of the

genus Ephedra. It is commonly used as a stimulant; a nasal decongestant by its diastereomer

pseudoephedrine (2); an appetite suppressant; an anti-depressant like methcathinone (5); and

an asthma treating agent.

The first analogue of ephedrine to be commercialized is amphetamine (3) that had a raging

success as a nasal decongestant. Hundreds of ephedrines have been manufactured since then

and still have medicinal purposes today as treatments for the attention deficit hyperactivity

disorder (ADHD), narcolepsy and obesity. Amphetamine and its analogues became either

totally banned as medicine or heavily regulated because of their danger and the potential of

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users being dependent on them. Ephedrine is either regulated or replaced by analogues to

curb supply chains – phenylephrine (6) is the example of replacement of pseudoephedrine in

commercialized products that can be used to manufacture methamphetamine (5).

Ephedrine is mostly active at the epinephrine (adrenal) system while amphetamine and its

analogues show dopaminergic activity which release dopamine-related activity in the brain.

While mimicking nature to come up with these before-mentioned analogues, it is also very

important to get the enantiomerism right. The D-(2S)-enantiomer of amphetamine is a more

potent CNS stimulant than its enantiomer however; synthesizing illicit amphetamine gives

one a racemic mixture. Developments in industrial chemical processes have made it

economical for pharmaceutical manufacturers to take drugs that were marketed as racemic

mixtures and market them as individual enantiomers. It is possible that both enantiomers are

active; these drugs will be marketed as individual enantiomers. In cases where the more

potent enantiomer is desired, like in the case of methamphetamine where the more potent D-

form can easily be obtained, an individual enantiomer can be synthesized (referred to as

enantioselectivity, see Section 2.3).

1.1.3.1.2 Cathinone

Cathinone (benzoylethanamine, 7) is a stimulant agent that can be found from the Khat bush

in the Horn of Africa and Yemen. The leaves of the Khat bush are consumed in the same way

cocoa leaves are chewed in South America and acts as a social drug by causing people to

relax. The leaves must be consumed fresh since cathinone is quickly degraded upon drying

because it is a primary aminoketone that is unstable in the leaves (the predictable self-

condensation and the enzymatic reductive depotentiation to the corresponding alcohol [8]

makes it unstable). Cathinone has milder dopaminergic activity and slower brain penetration

compared to amphetamines. It is thus considered as being less adverse and addictive.

The synthetic analogues of cathinone are among the most successful recreational drugs used

today. Mephedrone (9) is the most successful designer cathinone to be introduced in the illicit

market. Cathinones became popular because of the facility of their synthesis from commonly

available and legal items and their biological activity resembling that of ecstasy, cocaine and

hallucinogenic piperidines (which were all in short supply at the time Mephedrone was

becoming known).

Cathinones can be synthesized from phenones via a process involving, among other steps, the

treatment of a solution of a phenone in acetic acid with bromine. See Scheme 1.

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Scheme 1 Synthesis of designer cathinones (11) from phenones (10)

From the knowledge of how the structure of cathinone looks, previously known structures

can be used to attempt to mimic nature and therefore get the desired psychoactive effects

initially encountered in nature.

1.1.3.1.3 Mescaline

Another class of smart drugs can be made from the naturally occurring psychedelic alkaloid,

known for its hallucinogenic effects similar to those of LSD. Mescaline (12) is found

abundant in peyote, the San Pedro cactus, the Peruvian torch cactus and a few other plants in

the Eastern desserts and South America. These plants have been used in religious ceremonies

by Native Americans, used as teas or chewed dried for centuries.

Mescaline has a wide range of suggested medical usage, including treating alcoholism and

depression. A psychedelic research pioneer Alexander Shulgin (see Section 1.3.1) was first

inspired to explore more psychedelic compounds after having an experience with mescaline.

MDMA, a mescaline analogue, appeared on the scene being used as a meditative and relaxing

drug before it was used as a party drug and was eventually banned. Shulgin is a classic

example of a human being inspired by nature and as a result mimicking nature. Shulgin

remembered that nutmeg consumption has been associated with psychotropic effects, he

wondered if myristicin (major constituent of its essential oil, 13), the closely related

phenylpropanoids apiol (14) and isomeric dillapiol (15) could be metabolically altered to

resemble mescaline and amphetamine analogues. Indeed, Shulgin is a success story; he

reported the discovery of more than two hundred psychedelic compounds.

1.1.3.1.4 Tryptamines

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Tryptamines are a broad class of serotonergic hallucinogens capable of producing profound

changes in sensory perception, mood and thought in humans. The most well-known

tryptamines include N,N-dimethyltryptamine (DMT. 16),found in the South American

psychoactive beverage ayahuscua, and psilocybin (17), contained in Aztec sacred

mushrooms, which have been used since the ancient times in sociocultural and ritual context.

The lack of structural sophistication of many of the natural tryptamines has impelled their

replacement with synthetic analogues. Tryptamines came to be used recreationally by young

people upon the discovery of the hallucinogenic properties of lysergic acid diethylamide

(LSD) in the mid-1900s. However, new synthetically produced tryptamine hallucinogens like

alpha-methyltryptamine (AMT, 18), 5-methoxydimethyltryptamine (5-MeO-DMT, 19) and 5-

methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, 20) are emerging in the illicit market.

The lack of literature on tryptamine derivatives pertaining to pharmacological and

toxicological properties clouds the assessment of their actual harm to the general public.9

1.1.3.1.5 Cannabinoids

Cannabinoids are a class of diverse chemical compounds secreted by cannabis flower which

are active on cannabinoid receptors in cells that repress neurotransmitter release in the brain.

The primary psychoactive compound in cannabis is the phytocannabinoid

tetrahydrocannabinol (THC, 21) which is the most notable cannabinoid. The class of

synthetic cannabinoids includes more than a hundred compounds that are structurally

heterogenous. The most notable synthetic cannabinoids can be classed into four groups:

Classical cannabinoids (e.g. HU-210, 22), cyclohexylphenols (e.g. cannabicyclohexanol, 23),

phenylacetylindoles (e.g. JWH-250, 24) and naphthoylindoles (e.g. JWH-073, 25).

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1.1.3.2 Mimicking of nature

Nature tends to inspire our most creative and most excellent work. In fact, to get it almost

right, nature has to steer us in the right direction. Humans have mimicked nature for

millennia; natural product-based drugs are the perfect example of this mimicry. Mimicking

nature in drug synthesis can lead to new developments and even the complementing of

nature. However, it can also go terribly amiss in terms of comprehending the science mother-

nature attempted to bestow.

The synthesis of the reverse ester of meperidine (1-methyl-4-phenyl-4-

propionyloxypiperidine, MPPP, 26) is a classic example of anarchy encountered by humans

in mimicking nature. An easier and more effective attempt to replace heroin as a result of

heroin shortage a long time ago became nasty very quickly. MPPP resembles heroin as it

closely mimics the effects of it. Synthesized from morphine and found naturally in opium

poppy, heroin is a recreational drug (also an analgesic and cough suppressant) that provides

euphoria. A University of Maryland chemistry graduate started an underground synthesis of

MPPP, street name China White, for personal and recreational purposes. The lack of quality

control in clandestine laboratories led to a failure in the detection of a contaminant (an

elimination product of MPPP, MPTP, 27) in MPPP which rapidly induced Parkinson’s

disease (see Scheme 1). For many years the sudden occurrence of the disease in a young adult

coupled with the rarity of juvenile Parkinson’s perplexed neurologists and psychiatrists. This

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tragedy was later elucidated by a neurologist at Stanford University who decided to

investigate the linkage between heroin addicts and juvenile Parkinson’s disease.

In other cases, the mimicry of nature is not so bad, for example in the case of ephedrine

analogues. Ephedrine can be found naturally in various plants of the genus Ephreda.

Pseudoalkaloid ephedrine can be found in the medicinal plant, ma huang.

Scheme 2 MPTP (27), an elimination product of MPPP (26)

The scarcity of ephedrine in China in the 1930s provoked the synthesis of ephedrine

analogues that were much simpler and cheaper to synthesize. Amphetamine (3), the first

commercialized analogue of ephedrine, has an increased brain penetration compared to its

parent compound because of the lack of the benzylic hydroxyl. The increased brain

penetration makes it an archetypical stimulant. For this reason, there are thousands of

amphetamines synthesized and used extensively for many medical reasons such as treating

attention deficit hyperactivity disorder (ADHD), narcolepsy and obesity. Amphetamines were

used during World War II to overcome combat fatigue and promote wakefulness in the

combat. Their usage extended to professionals, students, truck drivers and even housewives

for various purposes. A more potent and quicker acting analogue of amphetamine is

methamphetamine (4) which has better brain penetration and increased resilience against the

degradation by metabolic enzymes. Amphetamine and methamphetamine have a far broader

usage scope than the parent compound ephedrine and they have more of the desired effects in

recreational drugs such as energy, sense of well-being, euphoria and wakefulness. However,

these ephedrine analogues still come with adverse health effects. Methamphetamine is

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generally accepted as the most addictive recreational drug; the most popular adverse health

effects of it being dental decay and vision loss.

The thalidomide tragedy has had synthetic organic chemists on their toes regarding

enantiomeric purity. A great need is thus felt to create enantiomerically pure compounds

since nature elaborates chiral organic molecules in one of the enantiomeric forms with a very

few exceptions. We are yet to discover enantiomeric pairs of particular enzymes. This is not

even possible because of the homochirality of building blocks.10

Enantiomeric purity is the

fractional excess of one enantiomer over another. Thus, a racemic mixture would have an

enantiomeric purity of zero.11

Enantiomeric purity in medicine is very crucial because

enantiomers differ qualitatively in their activities and they show different bioactivities at the

same and different receptors. In general, a racemate mixture of a compound would exhibit

different behaviour to that of either enantiomer alone. For isomers that are both equally

active, no stereoselectivity of interaction is observed and this means a detrimental isomer can

interact uninterrupted in the body. Synthetic organic chemists are now investing their time in

methodologies such as asymmetric synthesis. The enantioselective synthesis of the dextro

(2S) methamphetamine enantiomer from (-)-ephedrine or (+)-pseudoephedrine, using the

Nagai method (see Section 2.3) is a classic example of humans mimicking nature with the

goal attaining of enantiomeric purity.

1.1.4 Legislation versus the creative adaptation linking with availability

versus innovation

Illicit drug abuse is a global issue that can possibly be tackled through international

interactions.12

There is a perpetual American policy debate about the appropriate legal status

for psychoactive drugs. It is believed that the Prohibition, decriminalization, and legalization

positions are based on the assumptions of how law enforcements affect behaviour in the

society.8Clandestine laboratories are becoming more ahead of legislation and even science in

terms of adapting to law enforcements and creating new synthesis methods that make the

substances transparent to forensic methods for example. Regulating the availability of

precursors of a particular illicit drug sometimes leads to new innovation of making the drug

and that is a pressing issue for law enforcers.

1.1.4.1 Drug law enforcement and the creative adaptation of smart drug producers

thereof

President Barrack Obama signed the Synthetic Drug Abuse Prevention Act in July 2012,

banning compounds that are frequently detected in synthetic marijuana. However,

mainstream forensic detection methodologies cannot keep up with the ever-changing or

rather ever-adapting designer drug methodologies. For example, smart drug producers are

now introducing chemical differences in psychoactive substances that are compatible with the

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activity of being invisible having the knowledge that forensic detection is for specific

compounds. A classic example of this occurrence of smart drug producers being ahead of the

law and science is the replacement of prohibited JWH-018 (a napthoylindole derivative that

has very high potency, 28) by its non-regulated analogue JWH-073 (25). The protocol for the

detection of JWH-018 was developed soon after its prohibition but JWH-073 was unable to

be detected by this developed detection system since JWH-018 and JWH-073 have different

molecular weights and chromatographic properties. A cocktail of synthetic cannabinoids

lowers the concentration of each substituent and therefore lowers detection levels. The

detection of new smart drugs is therefore a challenging and pressing issue because of the

ability of smart drug designers to rapidly replace closely related analogues for prohibited

substances. There is a pressing need to develop and validate the analytical methods capable

of detecting synthetic substances via biological fluids since highly refined analytical

techniques identify the metabolites1 of recreational drugs in the fluids of the consumers. A

detailed study of the metabolism of each compound in classes of smart drugs is needed since

no unchanged compound, in general, is ever found in the urine of the consumer.

Synthetic tryptamines are sometimes confused with natural ones because their UV spectra is

similar. Forensic toxicologists therefore often overlook the possibility of synthetic

tryptamines being consumed. An example of a synthetic tryptamine that resembles its

naturally occurring analogue is 5- MeO-DALT (29).

1 The product that remains after a drug has been metabolized by the body.

2 A naturally occurring compound with a vanilla and cherry aroma, hence mainly used in perfumery

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1.1.4.2 Linking availability versus innovation

One of the innovations that were inspired by the limiting conditions of law enforcements was

the synthesis of methamphetamine. The North Carolina legislation was passed to regulate the

purchase of pseudoephedrine (a precursor of methamphetamine, 31) which is contained in

previously over-the-counter medicine.13

This regulation included the restriction of the number

of purchases and the tracking of the purchaser. The legislation was a raging success as the

lack of availability of the precursor compound reduced the number of methamphetamine (4)

underground laboratories – as evidenced by a conspicuous decline of methamphetamine

laboratory busts. However, the scarcity of the precursor compound inspired innovations in

underground chemistry. The one-pot shake-and-bake method (see Scheme 2) synthesizes

methamphetamine directly from crushed pseudoephedrine pills (from nasal decongestants).

This uses far less ephedrine and can be made in something as small as a two litres soda bottle.

Compounded with readily available “reagents” (cold compress packs or fertilizers as a source

of ammonia; lithium photo batteries as a source of lithium; and other household reagents),

this method caused the ascending number of methamphetamine laboratory busts. The shake-

and-bake method also has improvised “laboratories” that are easier to hide such as in cars and

small enclosed spaces.

Scheme 2 The shake-and-bake method for the synthesis of dextro- methamphetamine (4) from ephedrine (30)

and pseudoephedrine (31)

The lack of availability of precursor compounds is not the only way for innovation. The

readily available alternatives can also inspire some innovation in drug synthesis. There are a

number of designer drugs that can be synthesized from common and readily available

chemicals (even household chemicals). One of the examples of this is mephedrone, a

designer cathinone, which was initially synthesized from chemicals like plant feeders and

bath salts. This generates security and non-infringement of the law in consumers.

1.1.5 Analytical aspects with respect to toxicity, risk and evasion

1.1.5.1 Toxicity

A major problem associated with clandestinely prepared substances is the quality of the

substance that is finally sold on the street. Since the clandestine laboratories generally do not

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follow the Current Good Manufacturing Practice (CGMP) regulations,14

the substance used

on the street is generally impure as well as misbranded and adulterated.15

The additional

substances are classified as diluents, adulterants, impurities from the manufacturing process

and impurities by origin. The contaminants of these substances have been of interest to

toxicologists, medicinal chemists and pharmacologists since they are likely to modify and/or

enhance the activity of the parent drug, and show an activity or toxicity not related to the

parent drug. A toxic substance produces local or systemic detrimental effects to the human

body. These effects may be chronic or temporary, mild or severe. Toxic substances injure

various organs including the lungs and kidneys and it does damage to the central nervous

system. Some toxic substances are carcinogens.

Toxicity is the degree to which a substance can produce adverse health effects in an organism

resulting from exposure to the substance.16

The natural intoxicating pharmacopoeia is

continually being complemented and even replaced by designer drugs. Designer drugs

combine the toxicity, of distinct chemotypes, creating new blends of psychotropic activity

that are appealing to users. The toxicity of a few designer drugs like the chronic toxicity of

ecstasy, which led to the retraction of an academic paper that claimed a neurotoxicity

induction after a single dosage of the substance in primates, and the toxicity of mephedrone

in cellular and animal experiments is still being debated. Although designer drugs have the

reputation of being safe, several experimental studies in rats and humans have shown risks in

humans including life-threatening serotonin syndrome, hepatoxicity, and neurotoxicity.17

1.1.5.2 Risk and evasion

New blends of psychotropic activity and toxicity of designer drugs pose as an analytical

challenge to forensic science, especially since the toxicity of a few drugs is not elucidated.

Mainstream forensic detection is focused on the detection of specific compounds and this

continues the race between designer drug manufacturers and regulatory laws. These new

blends of psychotropic activity introduce chemical differences that are compatible with

activity and this typically makes them invisible to forensic detection. This perpetual race

between drug design and the regulation of compounds used to make these drugs is a risk of

evasion of the law. An improvement of the detection techniques of designer drugs is urgently

required.

1.1.6 Synthetic landscape – Scope, opportunity and limitations

A clandestine laboratory is a crude mini-chemical laboratory designed for the purpose of

making illicit drugs quickly and at a low cost. A clandestine laboratory is as dangerous as the

drugs being made in them. There is virtually no quality control in clandestine laboratories and

amateur chemists with little formal chemistry lead these. Toxic chemicals, explosions, fires

and damage to the environment are inevitable in these laboratories. For every pound of

finished product, five to six pounds of chemical waste is produced. 16

Despite the dangers of

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clandestine laboratories and their limitations, the synthetic landscape of underground

chemistry provides some opportunity for new ideas in chemistry.

Figure 2 A clandestine methamphetamine laboratory in South Dakota seized by the federal Drug Enforcement

Agency

1.1.6.1 The Scope

Clandestine laboratories can be used to synthesize a wide variety of illicit drugs, 3, 4-

methylenedioxy-methamphetamine (MDMA), lysergic acid diethylamide (LSD),

phencyclidine (PCP), etc.; however methamphetamine has been the primary drug that is

being synthesized at the majority of clandestine laboratories seized. Clandestine laboratories

come in different shapes and sizes. The education and imagination of the clandestine

laboratory operator limits the level of sophistication of the lab. The use of accurate apparatus

and exotic chemicals is not a requirement in these labs. Different processes can be used to

synthesize a controlled substance. The process employed will depend on the starting

materials to be used, the end product desired, and the availability of the starting materials to

be used. Multiple manufacturing processes can be employed to get to the end product. There

are four basic manufacturing processes in clandestine laboratories: Extraction, conversion,

synthesis and tableting.18

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1.1.6.1.1 Extraction

The extraction manufacturing process isolates raw materials from a mixture by using the

physical and chemical properties of the raw materials (see Figure 3). The chemical structure

of the raw material is typically not changed during the process. Examples of extraction labs

include the hashish production and the extraction of active ingredients from pharmaceutical

products.

Figure 3 Extraction manufacturing process

1.1.6.1.2 Conversion

In the conversion process, raw materials are changed into the desired product. Minor

structural changes occur in the molecule of the compound – functional groups may be added

or removed from the compound. The drug of interest may be changed from salt form to the

free base form (the pure basic form of an amine as opposed to its salt form) or vice versa (see

Figure 4). An example of a conversion process would be the conversion of ephedrine or

pseudoephedrine into methamphetamine.

1.1.6.1.3 Synthesis

Synthesis refers to a chemical reaction or a series of chemical reactions in which molecules

or parts of molecules are combined to create the end product desired. The skeleton of the

desired product is the sum of the molecules or significant parts of the molecules that were

involved in the synthesis process and this fact distinguishes synthesis from conversion.

Examples of drugs manufactured via a synthesis process are methamphetamine and MDMA.

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Figure 4 The conversion process

Figure 5 The synthesis process

1.1.6.1.4 Tableting

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Clandestine tableting labs place finished products into dosage forms or into portable and

saleable units for distribution. Since these products are usually put into tablet forms, the

process is called ‘tableting’.

The size and the scope of the operation will determine how many processes are witnessed at

the clandestine lab.

1.1.6.1.5 Apparatus

The apparatus used in clandestine labs include reflux, distillation and conversions. Reflux

(controlled boiling of a liquid in which the evaporated liquid is condensed and returned into

the reaction mixture) is used mostly in synthesis and conversion. Ordinary household

material can be used to create the reflux apparatus (see Figure 6). In clandestine labs, glass

cookware can be used as reaction vessels; condensers can be made from copper or polyvinyl

chloride pipes and countertop deep fryers can be used as oil baths. A chemical reaction can

be carried out in a bucket – at a later point extraction might be required to separate the final

product from the reaction mixture – and heating is not required. This is known as ‘bucket

chemistry’.

Figure 6 A diagram showing the proper reflux apparatus used in a proper chemistry laboratory

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1.1.6.2 Opportunity and limitation

Regardless of the location and sophistication of the clandestine lab, operators usually have

little chemistry training and knowledge, the operations are makeshift and no two operations

are alike.

1.1.6.2.1 Little chemistry training and knowledge

Clandestine lab operators usually have little chemical background or training. Their formal

education is limited either in years or content. The chemical and physical principles involved

in the chemical reaction are not understood and therefore the hazards involved are not

understood either. The lack of content leads to hazards within the lab and to unsuspecting

citizens outside the lab (fires, explosions and toxic fumes). The insufficient chemistry

knowledge of the clandestine operator is a limitation with regards to safety, and

understanding the underlying principles of chemical reactions to improve them.

1.1.6.2.2 Makeshift operations

Clandestine lab operators are usually creative, making the limitations of the operations

dependent on the imagination of the operator. With their basic understanding of how the lab

equipment works, they design alternative apparatus that allows them to avoid detection and

suspension from the scientific supply houses. The cost of the simple household items used in

the lab is at a much lower price than proper scientific glassware. However, the operator does

not usually take into consideration the interactions of the chemicals involved and the material

out of which the makeshift equipment is made. Common kitchen glassware cannot operate at

high temperatures like Pyrex™ glassware and can therefore not be simply substituted.

1.1.6.2.3 No two operations are alike

There are many methods that can be used to manufacture controlled substances in clandestine

labs. Even if the same method is encountered during lab-busts, here are still enough

differences within each clandestine lab to make it unique. The methods used in these labs can

contribute to science one way or another. There is virtually no quality control in these labs

and purity is not a stressed issue. This is also a limitation but the toxicities of the impurities

are of great interest to toxicologists and forensic scientists. New ideas can actually be born

from these informal settings.

1.1.7 Conclusion

Humans have been intrigued by mind-altering drugs for millennia suggesting a fundamental

reason for a desire to alter a state of consciousness. The exploration of the altered state of

consciousness has led to new beneficial developments in terms of drug development; it has

also led to drug cultures (recreational drug usage) and clandestine drug laboratories that are

harmful to the society. With a lot that nature has to offer, inspiration is one of them, even in

drug design. Natural products are a vast source of this inspiration in pharmacology and

19

recreational smart drug design. This vast source of inexhaustible possibilities of ground-

breaking discoveries has also led to mimicking, or rather attempts to mimic, nature. The

endeavour by the government (and science) to regulate the abuse of recreational drugs has

birthed new developments, both in the science field and underground drug world. The

inexhaustible source of material – both legal and illegal – for illicit drug making has led to a

perpetual race between authority and illicit drug manufacturers. Forensic drug detection is

still currently been pressed to grow with the ever-growing and unpredictable underground

chemistry. Extensive studies of analytic aspects and the synthetic landscape of clandestine

laboratories still have to be carried out to alleviate and eventually end the war on drugs.

1.2 Table

Ephredine Mescaline Tryptamines

(DMT)

Canabinoids

(Tetrahydrocannabino

l) Class +

structure

Show

configuration

(-)-Alkaloid

Alkaloid

Alkaloid

(-)-Terpenoid

Source

Various plants in the

genus Ephedra –

Ephedraceae family

Lophophora williamsii

Plant (peyote cactus);

Echinopsis pachanoi

(San Pedro cactus);

Echinopsis peruviana

(Peruvian torch) –

Cactaceae family

Mimosa hostilis

Plant (Jurema) –

Fabaceae family;

Psychotria viridis

plant - Rubiaceae

family;

Banisteriopsis

caapi plant -

Malpighiaceae

family

Insects

Amphibians - toad

Bufus marinus’s

skin

Humans – Human

plasma and brain

Cannabis plant –

Cannabaceae family

Biosynthetic

precursor(s) +

biosynthesis

Benzaldehyde +

pyruvate followed by

reductive amination,

reduction and N-

methylation.

Tyrosine + phenylaniline,

decarboxylation via

tyrosine decarboxylase,

followed by oxidation

monophenol hydroxylase

and methylation

L-tryptophan,

decarboxylation by

amino acid

decarboxylase,

followed by a

transmethylation

that happens twice

Tetrahydrocannabinolic

acid + heat/drying, is

followed by

decarboxylation

20

Example of

smart drug ( +

any

configurations)

‘’Tik’’ (or ‘’crystal

meth’’)

Ecstasy

AMT

Cannabis (or

‘’Marijuana’’)

1.3 The contribution of Alexander Shulgin and Horbart Huson

(Strike)

1.3.1 Alexander Shulgin

1.3.1.1 A chemical love story

The late Alexander Theodore Shulgin (see Figure 7), also known as the father of

psychedelics, was a pharmacologist and chemist known for his active interest in mind-

altering drugs and the systematic study of their effect in humans. Shulgin is a Berkeley

graduate who received his Ph.D. in Biochemistry in 1956. In 1960, Shulgin tried mescaline

for the first time and claimed that mescaline made him aware of a spirit world that was only

available when psychoactive chemicals are used. He then started experimenting with

synthesizing compounds that are similar in structure to mescaline, like DOM. Shulgin left

Dow chemicals (a multinational chemical corporation) in 1965 to pursue his research

interests as a psychonaut. He then set up a home-made laboratory where he studied

phenylalkylamines and indolylamines, and investigated their synthesis and psychotropic

properties. His findings on phenylalkylamines and indolylamines were published in the

nineties in two cult books, “PiHKAL (Phenylethylamines I have known and loved): a

chemical love story”, and “TiHKAL (Tryptamines I have known and loved): the

continuation.” The second part of PiKHAL contains close to two hundred psychedelic

compounds, including their detailed synthesis instructions, bioassays (determination of the

biomedical activity of a substance), dosages and other valuable information. TiHKAL is a

continuation of this masterpiece.

21

Figure 7 Alexander Theodore Shulgin (1925 - 2014), at his home-made laboratory behind his Lafayette home

1.3.1.2 Shulgin and MDMA (Ecstasy)

Even though he did not discover ecstasy (methylendioxymetamphetamine, MDMA), Shulgin

and ecstasy are closely associated names. An undergraduate that was Shulgin’s student at San

Francisco State University described the effects of MDMA to Shulgin in 1976. This student

was a stutterer who benefited greatly from this compound, and also praised its psychotropic

properties. However, Shulgin first synthesized MDMA eleven years earlier (under the name

methylsafranylamine,as it was mentioned as an intermediate in a patent by a German

company, Merck). Shulgin was so impressed by the activity of this compound that he went on

to cook himself a batch which he began to test on himself in September of the year 1976. He

found it worthwhile to introduce the compound to Leo Zeff, an Oakland psychologist who

worked with psychedelics in his therapy sessions. Zeff also went on to introduce the

compound to hundreds of therapists, including underground psychotherapists that used

MDMA to relax patients and impel communication (Shulgin described MDMA as “his low-

calorie martini”), and word about this rapidly spread outside the therapist community.

Ecstasy went from being a meditative and relaxing agent for psychologists to being used as

an euphoric clubber drug in US clubs and eventually in Europe clubs. Ecstasy was perceived

as perfect dance party substance providing euphoria and energy necessary to dance for long.

It combined properties of amphetamines and hallucinogens making its properties valuable on

the dance scene.

Among many psychoactive substances Shulgin discovered – synthesized and bioassayed –

DOM (2,5-dimethoxy-4-methylamphetamine, 33) was one of them. Using 2,5-dimethoxy-4-

methylbenzaldehyde, (32) as the starting material and capitalizing on Henry reaction,

followed by a nitro-to-amine reduction, Shulgin synthesized DOM and published his work in

1970. See Scheme 3.

22

Scheme 3 Synthesis of DOM (33) from 32

Shulgin has made major contributions to pharmacology and chemistry as a psychonaut. He

has been synthesizing and bioassay-ing hundreds of self-tested psychoactive chemicals,

recording his work in five published books and hundreds of papers. In his frequently granted

interviews and talks at conferences, he instilled a sense of rational scientific insight into the

world of self-experimentation and psychoactive ingestion.19

1.3.2 Hobart Huson (Strike)

Hobart Huson, also known as Strike, is another explorer of the “inner spirit” who has

achieved stellar status in the underground chemistry community. Strike is the founder and

designer of the website Hive, dedicated to the manufacture of illicit drugs. He wrote several

famous books including Synthesis I and Total Synthesis II and Sources, in which he shared

information about the synthesis of several amphetamines, mostly illicit; obtaining apparatus

and chemicals; and shunning prosecution. Strike was mostly compelled by MDMA, which he

described as the most benign drug he has ever encountered in his book Total Synthesis II.

1.3.2.1 The Hive

The hive was a website serving as an information-sharing forum for people interested in the

synthesis, chemistry, political and legal aspects of psychoactive, typically illicit, drugs. The

participants of this online forum consisted of pure theorists, self-declared organized crime

chemists as well as forensic chemists all contributing to the development of clandestine drug

chemistry. Participants’ number ascended to thousands from all over the world. Under the

pseudonym Strike, Strike remained anonymous from 1997 until 2001 when the Hive started

getting broader attention following the investigation aired on a Dateline NBC special The

“X” files (see Figure 8). This investigation featured the Hive and its founder, Strike who

instructed readers how to synthesize a variety of amphetamines clandestinely and avoid

prosecution. The program led to the arrest and imprisonment of Hobart Huson while

maintaining the growth of the Hive.

Additionally, Strike pleaded guilty and was convicted of being involved in a federal case

involving a clandestine lab capable of producing up to 1.5 million ecstasy pills per month and

guilty of distributing chemicals from his Texas chemical distribution company to his eager

customers in underground chemistry. This earned him an eight-year long sentence. Todd

23

Robinson, a federal prosecutor in the case, described Huson as having an extremely well-

developed sense of how chemicals react. Huson was regarded as an expert in the ecstasy

underground.20

1.3.2.2 Total Synthesis II

Total Synthesis II is one of the three first MDMA cookbooks which is described by its author

as, “The most comprehensive and detailed book on the underground production of ecstasy

and amphetamines ever published.” It is written, in an informal style, by Hobart Huson, who

claims ecstasy is the most benign drug he has ever encountered and that it is passive yet

powerful (able to evoke a total sensory bath of tactile, visual and mental enhancement). The

book has details on the synthesis of amphetamines like meth, MDMA, MDEA and PEA,

including ‘hot tips’ advising readers on the best alternative methodologies. The book also

gave tips on how to go about starting a clandestine drug laboratory.

Like Alexander Shulgin, Huson is/was a psychonaut at heart, impressed and intrigued by the

activity of psychoactive compounds, especially his personal favourite, MDMA. Although

Huson and Shulgin received very different treatment from the society, they both were

contributors to science and an eye-opener to the forensic science about the operations of

underground chemistry. Their knowledge can be used for war on drugs.

Figure 8 Hobart Huson (Strike) during an

interview on The “X” Files in 2001.

24

2 Part B

2.1 The role of reductive amination in drug synthesis

2.1.1 Leuckart reaction

The conversion of aldehydes and ketones to the corresponding amines by heating the

aldehyde or ketone with formamide, ammonium formate, or formamide and formic acid or

rather the reductive amination of aldehydes and ketones by formamide, ammonium formate

or formic acid and formamide is generally called the Leuckart reaction.21

The reaction can be

represented by the general formula below.

Scheme 1 The general chemical reaction for the Leuckart reaction.21

The reaction, named after Carl Louis Rudolf Alexander Leuckart (1854 - 1889), was first

described by Leuckart and later stimulated other work – Wallach applied the method and

succeeded to show its general application. It can proceed via two mechanisms: using either

ammonium formate (1) or formamide (6) as the reducing agent; although the reaction of

formamide and formic acid (2) gives the best yield according to Crossley and Moore.22

The biosynthesis of amphetamine (4) and methamphetamine (5) can proceed via the Leuckart

reaction. In the biosynthesis of amphetamine and methamphetamine, phenyl-2-propanone

(phenylacetone, P2P, 3) is the common starting material.4 With formamide, in the presence of

formic acid (2), P2P can be converted to the corresponding amine (in this case amphetamine

or methamphetamine) by reductive amination. See Scheme 2 and Scheme 3 below.

25

Scheme 2 The synthesis of amphetamine (3) from P2P via the Leuckart reaction.4

Scheme 3 The synthesis of rac – methamphetamine (5) from P2P via the Leuckart reaction.4

2.1.1.1 The biosynthesis of amphetamine

The illegal synthesis of amphetamine (4) produces the racemic mixture.4 The mechanism of

the reaction is as follows:

Scheme 4 The leuckart reaction with formamide (6) and formic acid as the reactants.23

Step I in Scheme 4 happens at the temperature of the reaction.24

The product of step II has a

conjugated system of two double bonds and should therefore have canonical forms. The

canonical form of the product of step II further takes part in step III of Scheme 5. The water

molecule obtained in step II hydrolyses formamide (6) to give a small amount of ammonium

formate that is required for the reaction – the ammonium formate acts as a reducing agent.

26

Scheme 5 The formation of N-(2-Phenylethyl) formamide (7)

In Scheme 5, water hydrolyses formamide to give ammonium formate (side reaction). The

ammonium formate acts as the reducing agent that adds onto the N-formyl derivate (step III).

A hydride shift occurs resulting in the loss of carbon dioxide. N-(2-Phenylethyl) formamide

(7), an imine, is formed after a reaction with ammonium and there is a resultant release of

ammonia. The imine formed then goes through hydrolysis to form the amine desired –

amphetamine (3) in this case:

Scheme 6 The hydrolysis of the imine.

27

Step I and step II would essentially be the same if the reactant was only formamide. Yields

are increased when formic acid is added to a reaction mixture containing a ketone and

formamide. This can be accounted for on the basis that the presence of formic acid in the

reaction mixture increases the concentration of the effective reducing agent. As a result of

this increase, step III and step IV proceed more rapidly, than in the case where formic acid

not being a reactant, and the yield is thereby improved.24

2.1.1.2 The biosynthesis of methamphetamine

The synthesis of methamphetamine is similar to the one of amphetamine; the existing

difference is that N-methylformamide (8) instead of formamide is the precursor. As in the

case of amphetamine, the illegal synthesis of amphetamine produces the racemic mixture.

The mechanism for the synthesis of methamphetamine is as shown in Scheme 7, Scheme 8

and Scheme 9 below:

Scheme 7 The conversion of phenylacetone (P2P) to the iminium cation (9)

One phenylacetone (P2P, 3) is reacted with two equivalents of N-methylformamide (8) to

produce N-methyl-N-(2-phenylethyl) formamide (methamphetamine formamide, 10) and

carbon dioxide (see Scheme 8). The iminium cation (9) in Scheme 7 is formed as an

intermediate and it is reduced by the second equivalent of N-methylformamide (the second

equivalent is actually hydrolysed as shown in the side reaction of Scheme 8). Scheme 9

shows the hydrolysis of methamphetamine formamide that happens under acidic and aqueous

conditions to finally yield methamphetamine.

28

Scheme 8 The reduction of the iminium cation to methamphetamine formamide.

Scheme 9 The hydrolysis of N-methyl-N-(2-phenylethyl) formamide (methamphetamine formamide, 10).

2.1.2 Henry reaction

29

Also known as the Henry nitro-aldol reaction, the Henry reaction is the C-C bond-forming

reaction between nitroalkanes and aldehydes or ketones to form nitro alcohols – more

specifically, β-nitro alcohol (11).25

Scheme 10 shows the general equation of the Henry

reaction:

Scheme 10 The Henry reaction.

2.1.2.1 The biosynthesis of amphetamine

The biosynthesis of amphetamine can also proceed via the Henry reaction, although the

synthesis of amphetamine from P2P has substantially superseded the one that proceeds via

the Henry reaction.4 The mechanism of the synthesis of amphetamine via the Henry reaction

is as shown in Scheme 11.

Scheme 11 The synthesis of the β-nitro alcohol (11) from benzaldehyde (13) and nitroethane (12).

The nitroethane (12) gets deprotonated by the sodium hydride base to form a resonance

stabilized anion in Scheme 11. The nitroethane is then alkylated using benzaldehyde (13) to

form the β-nitro alkoxide that can be protonated to form the β-nitro alcohol. If the nitroalkane

30

started off with has acidic hydrogen (as in in this case), the β-nitro alcohol can undergo

dehydration to form nitroalkenes – see Scheme 12.

Scheme 12 The dehydration of the β-nitro alcohol to form a nitroalkene (14).

`The nitroalkene formed is then reduced with lithium aluminium hydride to amphetamine (3)

– see Scheme 13.

Scheme 13 The reduction of the nitroalkene to form amphetamine (4).

2.1.2.2 The biosynthesis of 3, 4-methylenedioxy-methamphetamine (MDMA)

Since the synthesis of phenethylamines, many methods have been developed to synthesize

them. Among the many methods, the Henry reaction finds itself enlisted for the synthesis of

3, 4-methylenedioxy-methamphetamine (MDMA, 21). A common starting material for the

synthesis of MDMA is piperonal2 (15).

2 A naturally occurring compound with a vanilla and cherry aroma, hence mainly used in perfumery

31

Figure 9 Piperonal (15), the starting material for the synthesis of MDMA (18).

The mechanism of the synthesis of MDMA (21) via the Henry reaction is as shown in

Scheme 14, Scheme 15 and Scheme 16.26

Scheme 14 shows the first step of the synthesis

which involves the Henry reaction, followed by the dehydration of the alcohol group. The

starting reagents are cyclohexylamine (16) and nitroethane (17). The cyclohexylamine acts as

base. Scheme 15 shows the second step of the synthesis which involves the reduction of the

nitroalkene formed (19) to (3,4-methylendioxyphenyl-2-propanone, MDP2P, 20). Scheme 16

involves the reduction of MDP2P (20) to MDMA (21) via the Eschweiler-Clarke reaction.26

The Eschweiler reaction allows the preparation of tertiary methylamines from secondary

amines via the treatment with formaldehyde in the presence of formic acid.27

The formate

anion reduces the imine or the iminium salt formed and therefore the whole process is

reductive amination – see Scheme 16. The synthesis of MDMA via the Henry reaction

affords a racemic mixture.

Scheme 14 Step I: The Henry reaction, followed by the dehydration of the β-nitro alcohol (18) to 19.

32

Scheme 15 The reduction of 19 to MDP2P (20).

Scheme 16 Eschweiler-Clarke reaction: Converting MDP2P (20) to MDMA (21)

2.1.2.3 The biosynthesis of 2,5-dimethoxy-4-methylamphetamine (DOM)

DOM (25), known by its street name STP which stands for Serenity, Tranquillity and Peace,

can be synthesized by capitalizing on a Henry reaction.4 The starting material for the

synthesis of DOM via the Henry reaction is 2,5-dimethoxy-4-methylbenzaldehyde (23) and

nitroethane (17), with ammonium acetate (22) acting as a weak base. The mechanism of the

synthesis of DOM (25) is as shown in Scheme 17 and Scheme 18. Scheme 17 involves the

conversion of 2,5-dimethoxy-4-methylbenzaldehyde into the corresponding alkene. Scheme

18 involves the reduction of the alkene formed in Scheme 17 to DOM.

33

Scheme 17 The conversion of 2,5-dimethoxy-4-methylbenzaldehyde (23) to a corresponding nitroalkene (24)

Scheme 18 The reduction of the nitroalkene to DOM (25).4

2.1.2.4 The biosynthesis of tryptamines

There are a number of ways for synthesizing tryptamines. The Henry reaction is amongst

many alternatives. Tryptamines (28) can be made from 3-indole carboxaldehyde (s) which

can be condensed with nitromethane (or nitroethane to give alpha methyltryptamine),

catalysed by a weak base, to give nitrothenyl indoles (27). Nitroethenyl indoles can then be

reduced to tryptamines (28). Scheme 19 shows the first part of the reaction – conversion of 3-

34

indole carboxaldehyde (26) to a nitroethenyl indole in the presence of ammonium acetate (a

weak base).

Scheme 19 The conversion of 3-indole carboxaldehyde (26) to a nitroethenyl indole (27) in the presence of

ammonium acetate (22).

Scheme 20 shows the reduction of the nitroethenyl indole formed (27) to a tryptamine (28).

Scheme 20 The reduction of nitroethenyl indole (27) to a tryptamine (28).

35

2.1.3 Nagai method

2.1.3.1 The synthesis of methamphetamine

The facile reductive deoxygenation of ephedrine or pseudoephedrine is named the Nagai

method. Treating ephedrine or pseudoephedrine with hydroiodic acid and red phosphorus

leads to reductive deoxygenation which eventually forms methamphetamine (4). Scheme 21

shows the mechanism of this method.4

Scheme 21 The Nagai method: The synthesis of the dextro (2S) methamphetamine (5) enantiomer.

2.2 Mechanisms and reaction designations for selected reactions

2.2.1 The conversion of safrole into MDMA (Ecstasy)

36

Scheme 22 A Scheme showing the conversion of safrole (31) to MDMA (21)

Step I shows the hydrobomination of an alkene (safrole, 31) to give a homoallylic secondary

bromide. Step II shows the alkylation of the amine to give MDMA (33). Step I is designated

as an electrophilic addition and step II as a first-order nucleophilic substitution.

2.2.2 The Speeter-Anthony method for tryptamine synthesis

Scheme 23 Friedel-Crafts acylation (step I) followed by a substitution of chloride with amine to end up with 34

Step I shows the acylation of the indole (33) via Friedel-Craft acylation. Step II shows the

substitution of chloride with an amine. The reaction designation of step I is an aromatic

electrophilic substitution and step II can be designated as a first-order nucleophilic

substitution.

37

Scheme 24 The reduction of 34 to a tryptamine (28)

2.2.3 The conversion of 1-bromonaphthalene and indole into the synthetic

cannabinoid, naphthoylindole

Scheme 25 The conversion of 1-bromo naphthalene (35) into 1-naphthoyl chloride (38) via aromatic

electrophilic substitution

38

Step I of Scheme 25 involves the aromatic metal-halogen exchange of 1-bromo naphthalene

(35) to give 1-naphthoic acid (37). The step proceeds via a radical chain reaction for the

production of the carbanion naphthalene-1-ide (36), which is reactive with a range of

functional groups. The reaction can be designated as an aromatic electrophilic addition. Step

II proceeds via a nucleophilic substitution reaction with internal return (there would have

been retention of stereochemistry if the carbon at which the hydroxyl group is attached was

chiral). The thionyl chloride coordinates with the alcohol with loss of HCl and formation of a

good leaving group (chlorosulfite). The chlorosulfite departs forming a carbocation. The

chlorine can then acts as a nucleophile – attacking the carbocation at the same face from

which it was expelled. The expulsion of SO2 then gives the desired 1-naphthoyl chloride (38).

Scheme 26 N-alkylation of 1-H-indole (39) to form a 1-butyl-R-1-H-indole (40) via electrophilic aromatic

substitution

Indoles can readily undergo aromatic electrophilic substitution. The C-3 position is the most

nucleophilic followed by the N and then the C-2 position. Indoles can be deprotonated at the

nitrogen with a strong enough base in an aprotic solvent. The 1-H-indole is N-alkylated using

a strong base, potassium hydroxide, in the aprotic polar solvent, dimethyl sulfoxide (DMSO)

via aromatic electrophilic substitution. See Scheme 26.

In Scheme 27, 1-naphthoyl chloride (38) formed in Scheme 25 and the 1-R-1-H-indole (40)

formed in Scheme 26 react via aromatic electrophilic substitution where the indole acts as the

nucleophile, the aryl chloride acts as the electrophile and the chloride acts as a leaving group.

The product is (1-butyl-R-1H-indol-3-yl)(naphthalen-1-yl)methanone.28

39

Scheme 27 Aromatic electrophilic substitution to give a (1-butyl-R-1H-indol-3-yl)(naphthalen-1-yl)methanone

(41)

2.3 The chemistry behind the enantioselectivity

2.3.1 The synthesis of the dextro (2S) methamphetamine enantiomer

The synthesis of a compound by a method that favours a specific enantiomer over another is

known as enantioselectivity. The manufacture of methamphetamine via the Nagai method

(Scheme 21) from the diastereoisomers, (-)-ephedrine or (+)-pseudoephedrine, yield (+)-

methamphetamine instead of (-)-methamphetamine. Likewise, the diastereoisomers, (+)-

ephedrine or (-)-pseudoephedrine, yield (-)-methamphetamine instead of (+)-

methamphetamine.29

This is an example of enantioselectivity.

In Scheme 21, the hydroiodic acid reacts with ephedrine to form iodo-methamphetamine via

an aziridine ion (the aziridine gets attacked by the iodide anion via nucleophilic addition that

preserves the stereochemistry at the carbon to which the amine is bonded to). Since this

attack preserves the stereochemistry at C-2, the enantiomer of the methamphetamine product

depends solely on the enantiomer of the ephedrine precursor. The final step involves the

elimination of the iodide to get to a specific enantiomer; this step gets rid of one of two chiral

40

centres giving us a case of enantiomerism. The enantioselectivity arises when there is this

possibility of forming the R enantiomer over the S enantiomer. (-)-Ephedrine or (+)-

pseudoephedrine are diastereoisomers; (+)-ephedrine or (-)-pseudoephedrine are the

respective enantiomers thereof. See figure 10.

Figure 10 A diagram that shows the relationships between the different possible precursors for the synthesis of

a specific methamphetamine compound

Figure 11 A diagram showing the relationship between the methamphetamine compounds that could have been

formed.

The deoxygenation of either (-)-ephedrine (1R, 2S Ephedrine) or (+)-pseudoephedrine (1S,

2S Ephedrine) that is shown in figure 10 will form the S enantiomer shown in figure 11 since

deoxygenation gets rid of the chiral centre on C-1. By other experimental methods, the S

enantiomer is determined to be dextro or (+) (it rotates polarised light to the right). Likewise,

the deoxygenation of either (+)-ephedrine (1S, 2R Ephedrine) or (-)-pseudoephedrine (1R, 2R

Ephedrine) shown in figure 10 gets rid of the C-1 chiral centre to give the R enantiomer

which is levo or (-) and rotates polarised light to the left.

41

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