# Review: Synthetic Methods for Amphetamine



## HIGGS BOSSON

I would love to represent to your attention a curious analysis of amphetamine syntheses, which unfortunately hasn't a lot of practical application, whereas all the benefits are expressed in research interest. Beginner chemists can clearly sight the diversity of variations for the amphetamine synthesis. In the same time, more experienced chemists can adopt modern chirality selective or enzyme syntheses, relying on enormous number of patents references.

The amphetamine molecule is rather simple, and there are numerous ways to produce it. A lot of chemistry specialists have invented different approaches to synthesis since 1900 to the present days. In the old days, simple amphetamine syntheses were common in underground and home laboratories, and currently as well. Precursors for such methods are mostly 1-phenyl-2-nitropropene (P2NP) and phenylacetone (P2P). With the chemistry since development, the techniques became more elaborated, firstly to produce the more essential dextroamphetamine, a molecule in which pharmacological activity is more potent. In short, modern enzyme biotransformations of precursors are of more scientific than pragmatic interest.​





Spoiler: Organic Transformation from 1900 -2009












Typical Organic Transformation in the Early 1900-1950‘s:​The early amphetamine synthesis concerning literature of the 1900'ss was prevailed by classical organic transformations (Scheme 5). The following reactions such as the Friedel-Crafts reaction [105,], Ritter Reaction [102], Leuckart reductive amination reaction [106, 97, 76, 71], nitro-aldol dehydration reaction, also called the Henry Reaction [116, 96, 94, 89, 87, 86, 85, 82, 70, 67] and rearrangement reactions that came to be known as the Hofmann rearrangement[105, 116], Curtius rearrangement [118, 110, 80], Schmidt rearrangement [80], Lossen rearrangement [118], Beckmann rearrangement [111] and the Wolff rearrangement [109], were effective paths to the synthesis of amphetamine. The amine-free compound, a-methylbenzylacetic acid, was built with С-С bond formation through a carbanion enolate condensed with a suitable alkylhalide. These condensations, that were traditionally referred to as acetoacetic ester synthesis [105, 118] and malonic ester synthesis [91], later began to call as cases of the Claisen condensation. In the instance of phenylacetonitrile (benzylnitrile) [107], the central methylene hydrogens acidity between the nitrile and aromatic ring, are used for elimination and carbo-anion production prior to alkylhalide reaction.​Organic Transformation in the Early 1950-1985s:​Moving further down the timeline, from the time prevailed by traditional organic transformations (1900-1950), we go in a period of amphetamine synthesis that saw extended interest in dissolved metal reductions and early chiral formations. This time interval (1950-1985) was highlighted catalytic reductions, dissolving metal reductions and metal hydride reduction heading to amphetamine. It was within this period that chiral complement to the Friedel-Crafts reaction was involved for the synthesis of amphetamine [55]. Double bond amination was improved with the diethyl phosphoramidate using [58] and acetonitrile mercuration [69], which are leaded to amphetamine. Chiral amphetamine synthesis was reached by reductive amination with (R)-1-phenylethanamine on the Schiff-base of phenyl-2-propanone, followed by diasteroisomeric separation [64]. After, two chiral syntheses to amphetamine were published starting from D-phenylalanine [84a, 84b] (1977, 1978).​*Summary:*​The authors have summarized the synthetic transformations published within the period 1900-2009 as goof as possible, with underline upon 1985-2009. The full graphic precursor/references to amphetamine pinwheel is illustrated in Scheme 6 and is created for the forensic scientist as a complete map of amphetamine ways and literature. These individual reactions are broken out, extended and illustrated with added nomenclature in the supplemental material.​

Spoiler: Non-Chiral Syntheses of Amphetamine 1985-2009








*Consideration of Non-Chiral Amphetamine Syntheses 1985-2009:*​Non-chiral amphetamine syntheses (Scheme 3, routes 3A-N) have either emerged in the literature; 1985-2009. These types are shown in Scheme 3 and represent 25 individual citations. As concerns chiral routes described above, the Mitsunobu reaction type chemistry has been operated in 3 different non-chiral ways, each of them start from racemic 1-phenylpropan-2-ol [13, 17, 28; route 3A and 3D]. Nitrostyrene achiral reductions to amphetamine were the most sought-after methods in this period of time [4, 12, 35, 42, 46, 47, 56; route 3B]. These citations are first during of creating pharmaceutical analogs / research. Organo-metallic (Grignard or lithium alkylation) reactions were used in a diversity of alkylation reactions to amphetamine [15, 31, 52; route 3C, 3G and 3N]. These methods comprise Grignard ring opening of a phosphorylated-aziridine (nucleophilic ring-opening of N-phosphorylated aziridines) [31; route 3G], reaction with an electron deficient oxime (electrophilic amination of Grignard reagent) [15; route 3C], and lithium alkylation of an a-amino carbanion equivalent reaction [52; route 3N]. A base-catalyzed hydroamination reaction affects to allylbenzene amination [27; route 3E]. This reaction is akin in precursor and product, however, has different mechanism to the 1982 phosphoramidomercuration-demercuration of allylbenzene to amphetamine [58; route 6U]. A commercially available a-aminodiphenylmethane amination, which works as an ammonia equivalent, was used for the hydroamination of 1-phenyl-1-propyne to amphetamine [26; route 3F]. Several citations emerged in the literature for the reductive amination of P2P to amphetamine [32, 22, 40; route 3H]. The typical malonic ester synthesis was used to make 2-methyl-3-phenyl propanoic acid [37, route 3I] which was then transformed to amphetamine through a Curtius rearrangement/hydrolysis [37]. A corresponding reaction, that of a Claisen/Dieckmann condensation, utilizing a benzylnitrile analog was used to create a P2P complement [45; route 3K]. This analog was transformed to the oxime, followed by reduction and de-sulfuration with sodium/ethanol to amphetamine [45; route 3K]. In addition, O-methoxy-oxime of P2P was reduced with Red-Al® to yield amphetamine with minor yield [48; route 3M].​

Spoiler: Enzymic, Photo-induced and Chemical Manipulation of Amphetamine Isomers: 1985-2009








*Discussion of Enzymatic, Photo-induced and Chemical Manipulation of Amphetamine Isomers: 1985-2009:*​An interest in biotransformations was increased, proof of concept and patent applications from 1985-2009. Illustrated in Scheme 4 is the quotations within this topic concerning amphetamine isomers. Both phenyl-2-propanone [14, 43; route 4A] and the nitrostyrene, (E)-1-(2-nitroprop-1-enyl)benzene [39,48; route 4C] have been used as starting lines to the amphetamine enzymatic synthesis. Otherwise, racemic amphetamine biotransformations leading to the exclusion or enhancement of one isomer (enhanced ee) have been announced or patented [3, 10, 22, 24, 29, 43; route 4B]. Vice versa, one citation [2; route 4D] describes the photochemically induced-radical mediated racemization of the single amphetamine isomer to the racemic mixture. Typical methods of chiral separation based upon chiral organic salts have been shown in the time frame of 1900-2009, with the use of D-(-)-tartaric acid [30, 47, 38, 71, 81a, 88, 90, 108], benzoyl-d-tartaric acid [38], di-p-toluoyl-d-tartaric acid [38], (S)-2-naphthylglycolic acid [66], a-amino acids [78] and optical-10-camphorsulfonyl chloride[37].​

Spoiler: Stereoselective Syntheses of Amphetamine 1985-2009








*Discussion of Stereoselective Amphetamine Syntheses 1985-2009:*​Illustrated routes 2A-2Q in Scheme 2, introduce the multiplicity of stereo selective approaches to amphetamine published in 1985 –2009. We have arranged references in reverse chronological order – clockwise [#'s] within this illustrated reaction routes pinwheel. For the starting of our discussion, we take the Schiff base (1-phenylpropan-2-imine, route 2A) as a chiral approach to amphetamine [1, 36, 51, 54]. This approach has been facilitated by the enhancements of chiral organometallic ligands with transition metals with an eye to effect chiral catalytic reductions [1, 36, 51, 54, route 2A]. In a like manner, the reduction of nitrostyrenes [(E)-(2-nitroprop-1-enyl)benzene] have been achieved stereoselectively with help of chiral organometallic ligands with ruthenium and rhodium [18, 20, 41; route 2F]. An entirely different approach was taken by Talluri, S. et al.; [routes 2B-E], wherein they initiated the amphetamine route from 1-phenylpropanal [5, route 2E].
Beginning with this one-carbon extended aldehyde rather than the classical 2-phenylacetaldehyde [17, 49; route 2K] or benzaldehyde [47, 80, 89, 92, 95, 110; route 5Z, also implicit in 18, 20, 41, 42, 44, 56, 60, 39, 54, 61, 35, 22, 20, 18, 12, 4.57, 85, 84, 75, 74, 70, 67, 62, 94, 87, 86, 113, 114; route 5A] precursor, these chemists preformed a chiral oxy-alkylation with nitrosobenzene to (R)-3-phenylpropan-1,2-diol [5, route 2C-2D]. Tosyl chloride assisted ring closure lead to the epoxide, 2-benzyloxirane [5, route 2B]. The epoxide reductive ring opening produced the alcohol, (S)-1-phenylpropan-2-ol; [see structure in route 2I]. Then followed, swapping the alcohol moiety for azide. The last stage was catalytic (PtO2) reduction to amphetamine [5]. Although a lengthy process to amphetamine, its potential importance to forensic chemists arranges in the fact that each intermediate is a potential starting precursor for a chiral amphetamine synthesis. Closely connected to the alcohol-azide exchange in the previous route are the variations reached by Mitusnobu reaction-type exchanges from (R)-1-phenylpropan-2-ol to (S)-1-phenylpropan-2-NX, wherein inversion of configuration is complete to the amine compliment [8, 14, 19, 5, 34; route 2I and route 2P]. Chiral predecessors such as phenylpropanolamine [11, 23, 29, 40, 53; route 2H] and phenylalanine [33, 25, 6, 9, 44; route 2O and route 2G] have been easy aims for precursors to the stereo selective amphetamine synthesis. The ways from phenylalanine are varieties of J.W. Wilson's original article from 1977 [84; route 6BB] using another reagents for the reduction of the carboxylic acid, alcohol to halide swap, reduction of the alkyl halide and BOC deprotection. In phenylpropanolamine as precursor applying case, earlier literature [40,53, route 6P] utilize the chloro-pseudonorephedrine intermediate, as most typically seen in underground laboratories, nevertheless, more recent data [11, 23, route 6P] makes use of acetic anhydride to yield the ester for catalytic reductive elimination of the OH group to amphetamine. Creative chiral skeleton has been used to introduce stereo selectivity early in the amphetamine synthesis [17, 49, 21; routes 2M, 2N and 2K]. These distinctive approaches start with the achiral, off-listed precursors, benzylbromide [21, route 1N] or 2-phenylacetaldehyde [17, 49, route 2K]. The stereo selectivity is introduced and controlled by simpler commercially available chiral directors. The stereo selectivity is established and controlled by simpler commercially available chiral substances. Remarkable that the Hofmann rearrangement, which keeps stereo selectivity, was used at the end of route 2M [21] with the modern utilizes of hypervalent iodine [21]. Different older ― "classical synthesis" enhancement was profiled in the Friedel-Crafts alkylation of benzene through the use of chiral (s)-2-(2,2,2-trifluoroacetamido)propanoyl chloride [55, route 2Q].​
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