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Review: Synthetic Methods for Amphetamine

Review: Synthetic Methods for Amphetamine

Review: Synthetic Methods for

A. Allen1 and R. Ely2

1Array BioPharma Inc., Boulder, Colorado 80503 2Drug Enforcement Administration, San Francisco, CA

Abstract: This review focuses on synthesis of amphetamine. The chemistry of these methods will be discussed, referenced and precursors highlighted. This review covers the period 1985 to 2009 with emphasis on stereoselective synthesis, classical non-chiral synthesis and bio-enzymatic reactions. The review is directed to the Forensic Community and thus highlights precursors, reagents, stereochemistry, type and name reactions. The article attempts to present, as best as possible, a list of references covering amphetamine synthesis from 1900 -2009. Although this is the same fundamental ground as the recent publication by K. Norman; “Clandestine Laboratory Investigating Chemist Association” 19, 3(2009)2-39, this current review offers another perspective.

Keywords: Review, Stereoselective, Amphetamine, Syntheses, references,

Introduction: It has been 20 years since our last review of the synthetic literature for the manufacture of amphetamine and . Much has changed in the world of organic transformation in this time period. Chiral (stereoselective) synthetic reactions have moved to the forefront of organic transformations and these stereoselective reactions, as well as regio-reactions and biotransformations will be the focus of this review. Within the synthesis of amphetamine, these stereoselective transformations have taken the form of organometallic reactions, enzymatic reactions, ring openings, - aminooxylations, alkylations and amination reactions. The earlier review (J. Forensic Sci. Int. 42(1989)183-189) addressed for the most part, the ―reductive‖ synthetic methods leading to this drug of abuse. It could be said that the earlier review dealt with ―classical organic transformations,‖ roughly covering the period from 1900-1985. This time-line is graphically illustrated below in Figure 1. As illustrated in this figure, certain categories have been historically active. Early synthetic organic transformations such as aldol condensations, the Hofmann rearrangement [105, 116], the [118, 110, 80], the Schmidt rearrangement [80], the [118], the [111], the Wolff rearrangement [109], the Friedel-Craft alkylation [102, 105] together with catalytic reductions; populated the literature from 1900-1985. Of course, overlap has occurred between these categories as the field of organic chemistry has progressed. Interestingly, organic synthetic transformations have entered, in the last 20 years, a period of ―stereoselective organic transformation”. This is graphically illustrated in Figure 1a. The multiplicity of these transformations and their unique starting precursors and reagents may come as a challenge to the forensic community to keep up with the latest organic modifications and ―off-precursor-watch-list‖ circumventions. Herein, we hope to summarize as exhaustively as possible, the chemistry pictorially and compose a list of (IUPAC nomenclature, see supplemental material) that address these transformations to amphetamine.

The Era of Classical Organic Chemistry Stereoselective syn. Organometalic Aldo Condensations: Rearrangements: Reductions: chiral reduction 1. methyl ethyl Lossen 1. metal catayltic red. alkylations 2. Curtius 2. disolved metal red. aminations Hofmann 3. -nitroethane 3. non metalic red. Mitsunobu Wolf Enzymic

Time-Line of Synthetic Routes to Amphetamine

2009 1900 1930 1970 Figure 1

As best as possible, we have attempted to keep the needs of the forensic chemist and law enforcement personnel in mind when creating the categories for retrieving the information on a particular synthetic route. This has added a degree of difficulty to our task since in many cases, the chemist thinks visually (synthetic routes) and the law enforcement investigator works texturally (list of precursors). The categories of this review are listed below and are not without their limitations.

Outline: Review of amphetamine syntheses 1985 – 2009 (Schema 2, 3, 4) 1. Stereoselective syntheses (Scheme 2) 2. Non-Chiral Syntheses (Scheme 3) 3. Biotransformation (Scheme 4) Review of classical amphetamine syntheses 1900 – 1985 (Schema 5 and 6) 1. Classical Organic Transformations (Scheme 5) 2. Summary Routes to Amphetamine (Scheme 6)

Overview: In this reviewing period (1985-2009), with progress in stereoselective syntheses and organometallic transformations, academia, along with private industry have been motivated to explore new approaches to the synthesis of amphetamine. These numerous publications have undoubtedly been prompted more by the introduction of a chiral center to a primary than the desire to add yet another synthetic approach to the multitude of synthetic routes to amphetamine. Organometallic chemistry has been used in creative region-constructions of amphetamine, not only with magnesium metal [21, 15], but also with cerium [49], titanium [26], iridium [1] and [1]. Similarly, in the area of organometallic reductions to amphetamine, the field of reagents has expanded to include samarium iodide [4, 6, 9], ruthenium-(chiral-ligands) [18, 20, 36, 41], rhodium-(chiral ligands) [51], titanium-ligands [26], copper [32, 17], magnesium [32] and novelties with borane [33, 42, 56], lithium aluminum hydride [12, 35, 47], L-Selectride [25], Red-Al® [46], palladium [11, 14, 16, 23, 27, 40, 50, 53] and [33, 49 50]. Creative synthetic routes that do not employ a reductive step have also been published [15, 17, 21, 28, 31, 37, 55, 58]. Ring opening strategies have been developed against phosphorylated aziridines [31] and Sharpless epoxides [5] to yield amphetamine. Mitsunobu transformations [5, 8, 14, 19, 34] have been exploited in a variety of approaches to swap an alcohol precursor to the amine complement toward amphetamine. Hofmann, Curtius [37, 80], Lossen[37] and Schmidt rearrangement [80] continue to be used in synthetic schemes to produce amphetamine. The ―classical‖ Friedel-Craft alkylation [105] of with iron or aluminum trichloride has been improved with the use of N- (trifluoroacetyl)-- chloride as a chiral F-C reagent to manufacture amphetamine [55]. Intermediates of nitrostyrene have been reduced chirally and non- chirally to amphetamine [4, 12, 18, 20, 35, 41, 42, 56]. Likewise, hydroxylamine via chiral hydrosilylation [51] and hydrazines [8, 52] have been exploited in routes to amphetamine. Reductive aminations via phenyl-2-propanone; P-2-P [19, 40, 51, 54] have appeared in these years, as well as other creative approaches like -amination [5], -amination [26], alkene-amination [27], -aminooxylation [5], electrophilic aminations [15], and sulfinyl-imine amination [17]. Photochemical-induced racemization has been utilized for the transformation of the less pharmacologically active R to an equilibrium mix of R,S-amphetamine [2]. Improved resolution from of amphetamine to a single isomer has been achieved with ―enzymatic transformations‖ [3, 10, 22, 24, 43] and ―classical organic salts resolutions‖ [37, 47]. Illustrated in Figure 1a and 1b are the histograms and citations for some of the active categories within the transformations to amphetamine between 1985-2009. The activities of stereoselectivity, resolutions and enzymatic transformations are expressly evident.

Histograms for amphetamine reaction types 1985-2009 (#-reference)

2 Photochemical

55 Friedel-Craft Alkylation Figure 1a.

8, 34 Hydrazine 21, 37 Hofmann rearrangement

8, 13, 28 Mitsunobu 5, 31, 16 Ring Opening

1, 15, 17, 31 Organometalic

1, 5, 15, 21, 31 Alkylations 36, 45, 46, 51, 54 17, 26, 27, 58, 15 Amination

1, 15, 19, 26, 49, 50, 52 Imine 2, 3, 10, 22, 24, 37, 38, 43, Resolutions

2, 3, 10, 14, 22, 24, 29, 39, 43, 48 Enzymic

4, 7, 12, 18, 20, 35,41,42, 46, 47, 56 Nitrostyrene 1, 2, 3, 5, 6, 8, 9, 11, 14, 16, 17, 18, 19, 20, 21, 22, 23 25, 28, 29, 33, 34, 36, 37, 40, 41, 48, 49, 50, 51, 53, 54, 55 Stereoselective 1, 4, 6, 9, 5, 11, 12, 14, 16, 18, 19, 20, 22, 23, 25, 26, 27, 32, 33, 34, 35, 39, 41, 42, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57 Reductions

Literature Citations for the Synthesis of Amphetamine 1985-2009

Enzymatic (Bio Transformations) Stereoselective Synthesis (see Scheme 4) (see Scheme 2) 2. J. Org. Chem., JOC 73(2008)364 3. J. Org. Chem., JOC 72(2007)6918 1. J. American Chem. Soc. JACS 131(2007)9882 10. Indian J. Chem. Soc. B., IJCS 44B(2005)1312 5. Tetrahedron, Tetra. 63(2007)9758 14. J. Chemical Research, JCR 10(2004)681 6. Chemistry A European J., JEC 12(2006)4197 22. Tetrahedron Asymmetry, TA 13(2002)1315 8. Biological Med. Chem. Letter, BMCL 15(2005)3039 24. Synthetic Comm., SC 31(2001)569 9. FZSGS patent # 1673210 (2005) 39. Chem. & Pharm. Bull., CPB 38(1990)3449 11. J. Medicinal Chem., JMC 48(2005)1229 43. US Patent 04950606B1 (1990) 14. J. Chem. Research, JCR 10(2004)681 16. Tetrahedron Asymmetry, TA 15(2004)3111 17. J. Combinatorial Chem. 5(2003)590 Non-Chiral Organic Synthesis 18. J. Chem. Research, JCR 3(2003)128 (see Scheme 3) 19. Tetrahedron Asymmetry, TA 14(2003)2119 4. Tetrahedron Letter, TL 48(2007)5707 20. J. Chinese Chem. Soc. 49(2002)505 12. J. Organic Chem., JOC 70(2005)5519 21. J. Chem. Soc. Perkin I, JCSP1 16(2002)1869 13. Organic & Biomol. Chem., OBC 3(2005)1049 22. Tetrahedron Asymmetry, TA 13(2002)1315 15. Organic Letters, OL 6(2004)4619 23. US patent #6399828(2002) 26. Organic Letters, OL 2(2000)1935 25. J. Organic Chem., JOC 65(2000)5037 27. Tetrahedron, Tetra. 56(2000)5157 28. Tetrahedron Letters, TL 41(2000)6537 31. Tetrahedron, Tetra. 53(1997)4935 33. Tetrahedron Letters, TL 36(1995)1223 32. J. Chem. Soc. Perkin I, JCSP1 1(1996)265 34. Tetrahedron Asymmetry, TA 4(1993)1619 37. J. Labeled Comp. Rad., JLCR 31(1992)891 36. Tetrahedron Asymmetry, TA 3(1992)1283 38. J. Medicinal Chem., JMC 34(1991)1094 37. Acta. Chimica Scan. 45(1991)431 40. J. Chromatographic Sci., JCS 28(1990)529 41. Tetrahedron, Tetra 46(1990)7403 41. Tetrahedron, Tetra 46(1990)7403 44. Angew Chem. Int. 28(1989)218 42. Tetrahedron, Tetra 46(1990)7743 49. J. American Chem. Soc. JACS 109(1987)2224 45. Coll. Czech. Chem. Comm., 54(1989)1995 51. Organometallics, 5(1986)739 48. Organic Reactions, Vol 36 (book, 1988) 53. Analytical Chem. 58(1986)1642 57. J. Medicinal Chem., JMC 31(1988)1558 54. Khimja Geter. Soed. 12(1985)1648 52. J. Chem. Soc. Chem. Comm. 2(1986)176 55. J. Organic Chem., JOC 50(1985)3481 54. Khimya Geter. Soed #12,1648(1985) 56. Synthetic Comm., SC 15(1985)843 22. Tetrahedron Asymmetry, TA 13(2002)1315 # = Reference Figure 1b.

Amphetamine Review (1989 – 2009)

Time-Line of Synthetic Routes to Amphetamine Stereoselective syn.

1985 2009 1900 1930 1970 Stereoselective Synthesis of Amphetamine 1985--2009

Chiral Chiral Scheme 2. N R Chiral Tetra. 63(39) 9758 (2007) JACS 131(29) 9882 (2009) Chiral JOC 50(19) 3481 Tetra Asy 3(10) 1283 (1992) Ph Tetra. 63(39) 9758 (2007) (1985) Organometallics 5, 739 (1986) O TA 4(7)1619(1993) OH KGS #12,1648 (1985) Ph OH Chiral 2Q. 2A. 2B. ONHPh Chiral Ph OH 54 . Tetra. 63(39) 9758 (2007) 2P. Ph OH Chiral NH2 JOC 65(16) 5037 (2000) 51 OH O Tetra. Let. 36(8) 1223 (1995) 2D. Chiral Angew chem. Int. 28(2) 218 (1989) 36 COOH 55 Ph H Ph 1 5 Tetra. 63(39) 9758 (2007) 2O. 44 5 NH 34 2E. 2 33 5 NO 25 Ph 2 Chiral 5 Chiral Ph Br 28. Amphetamine 21 JCS, Perkin T.I, 16 2N. 18 20 41 2F. J.C. Res. Syn. 3, 128 (2003) 1869 (2002) J. Chinese C S 49, 505 (2002) NH2 Tetra. 46(21) 7403 (1990) 21 6 (S)-1-phenylpropan 9 O -2-amine Chiral 2G. 11 Ph I H N Ph 2M. 19 23 Chiral 2 40 HN 8 40 BOC 51 17 53 Chem. Eur.J. 12, 4191 2006 JCS, Perkin T.I, 16 16 1869 (2002) 54 14 FZSGS #1673210 (2005) 49 2H. 19 OH 2L. 5 Ph NH Ph 2 Chiral O 2I. JMC 48(4) Chiral Tetra. Asy. 14, 2119 (2003) 2K. 1229 (2205) Organometallics 5, 739 (1986) 2J. Anal. Chem. 58(8) 1642(1986) J. Chrom. Sci. 28,529 (1990) H Ph US # 6,399,828 (2002) KGS #12,1648 (1985) Chiral Ph OH Chiral OH J. Chrom. Sci. 28,529 (1990) J.Comb.C. 5(5) O HO Org. Biomol. Chem. 3,1049(2005) 590 (2003) Ph B.M.C.L. 15(12) 3039 (2005) JACS 109(7) Chiral J. Chem. Res. 10, 681 (2004) 2224 (1987) TA 15(19)3111(2004) T.L. 41(34) 6537 (2000)

Discussion of Stereoselective Syntheses of Amphetamine 1985-2009:

Illustrated in Scheme 2, routes 2A-2Q, repressent the multitude of stereoselective approaches to amphetamine published between 1985 –2009. Within this illustrated pinwheel of reaction routes, we have arranged references in reverse chronological order – clockwise [#‘s]. As a starting point for discussion, take the Schiff (1-phenylpropan- 2-imine, route 2A) as a chiral approach to amphetamine [1, 36, 51, 54]. This approach has been facilitated by the improvements of chiral organometallic ligands with transition metals in order to effect chiral catalytic reductions [1, 36, 51, 54, route 2A]. Similarly, armed with chiral organometallic ligands with ruthenium and rhodium, the reduction of nitrostyrenes [(E)-(2-nitroprop-1-enyl)benzene] have been achieved stereoselectively [18, 20, 41; route 2F]. A completely different approach was taken by Talluri, S. et. al.; [routes 2B-E], wherein they initiated the route to amphetamine from 1-phenylpropanal [5, route 2E]. Starting from this one-carbon extended aldehyde as opposed to the typical 2- [17, 49; route 2K] or [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 workers 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]. Reductive ring opening of the epoxide produced the alcohol, (S)-1-phenylpropan-2- ol; [see structure in route 2I]. This was followed by swapping the alcohol moiety for azide. The final step was catalytic (PtO2) reduction to amphetamine [5]. Although a lengthy process to amphetamine, its potential importance to forensic chemists lies in the fact that each intermediate is a potential starting precursor for a chiral synthesis to amphetamine. Closely allied to the alcohol-azide swap in the previous route are the variations achieved 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 starting materials like [11, 23, 29, 40, 53; route 2H] and [33, 25, 6, 9, 44; route 2O and route 2G] have been easy targets for precursors to the stereoselective synthesis of amphetamine. The routes from phenylalanine are variations on J.W. Wilson‘s original article from 1977 [84; route 6BB] utilizing alternative reagents for the reduction of the carboxylic acid, alcohol to halide swap, reduction of the halide and BOC deprotection. In the case of phenylpropanolamine as precursor, earlier literature [40,53, route 6P] make use of the chloro-pseudonorephedrine intermediate, as most typically seen in clandestine laboratories, however more recent literature [11, 23, route 6P] makes use of to yield the for catalytic reductive removal of the OH moiety to amphetamine. Creative chiral scaffolding has been used to introduce stereoselectivity early in the amphetamine synthesis [17, 49, 21; routes 2M, 2N and 2K]. These unique approaches start with the achiral, off-listed precursors, benzylbromide [21, route 1N] or 2-phenylacetaldehyde [17, 49, route 2K]. The stereoselectivity is introduced and controlled by simpler commercially available chiral directors. Interestingly, the Hofmann rearrangement, which retains stereoselectivity, was utilized at the end of route 2M [21] with the modern uses of hypervalent iodine [21]. Another older ―classical synthesis‖ improvement 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].

Time-Line of Synthetic Routes to Amphetamine non-chiral syntheses

1985 2009 1900 1930 1970 Non-Chiral Synthesis of Amphetamine 1985--2009 non-Chiral Tetra. Let. 48(32) 5707 (2007) Scheme 3 non-Chiral JOC 70(14)5519 (2005) Org. Biomol. Chem 3(6) 1049 (2005) J. Labelled Comp. Rad. 31(11) 891 (1992) Tetra. 46(21) 7443 (1990) Angew Chem. Int. 28(2) 218 (1989) J M C 31(8) 1558 (1988) non-Chiral Syn. Comm. 15(9) 843 (1985) JCS, Chem. Comm. OH 2, 176 (1986) 3A. NO2 non-Chiral NH Br SO 2 Org. Let. 6(24) 4619 (2004) 2 3B. NO2 46. 3N.H3C LiAlH 4 47 Mg N Br non-Chiral NH Ph 42 56 O 3C. Org. Rea. 36(book) (1988) 35 non-Chiral N N O O 28 Tetra. Let. 41, 6537 (2000) Ph 12 O 3M. Ts 52 13 4 15 O O OH O N O tBu 48 17 H 3D. O non-Chiral 27 47 58 Ph Tetra. 56, 5157 (2000) H 3L. Pd/H NH2 NH2 2 n-BuLi non-Chiral 3E. JMC 31(8) 1558 (1988) 45 Amphetamine 26 NH2 Ph Ph 31 37 Cp2TiMe2 32 non-Chiral S 37 O.L.. 2(13) 1935 (2000) Ph 3K. 22 3F. CN 40 O NH P Coll. Czech. Chem Comm. 3 O O 54(7) 1995 (1989) HoAc N 3G. non-Chiral MgBr 3J. Mg O O reduction 3H. 3I. O COOH T. 53(13)4935 (1997) O non-Chiral non-Chiral O Acta Chem. Scand. JCS, PTI, 265 (1996) 45, 431 (1991) Acta Chem. Scand. Tetra. Asy. 13(12) 1325 (2002) 45, 431 (1991) J. Chrom Sci. 28, 529 (1990) non-Chiral non-Chiral

Scheme 3.

Discussion of Non-Chiral Syntheses of Amphetamine 1985-2009:

Non-chiral syntheses of amphetamine (Scheme 3, routes 3A-N) have also appeared in the literature; 1985-2009. These variations are graphically illustrated in Scheme 3 and represent 25 individual citations. As described above with regards to chiral routes, the Mitsunobu type reaction chemistry has been exploited in 3 different non-chiral routes, each starting from racemic 1-phenylpropan-2-ol [13, 17, 28; route 3A and 3D]. Achiral reductions of nitrostryene to amphetamine were the most popular approaches in this time period [4, 12, 35, 42, 46, 47, 56; route 3B]. These citations are primarily in the course of building pharmaceutical analogs / research. Organo-metallic (Grignard or lithium alkylation) reactions were used in a variety of alkylation reactions to amphetamine [15, 31, 52; route 3C, 3G and 3N]. These variations include 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 -amino carbanion equivalent reaction [52; route 3N]. The amination of allylbenzene was affected in a base-catalyzed hydroamination reaction [27; route 3E]. This reaction is similar in precursor and product, however different in mechanism to the 1982 phosphoramidomercuration-demercuration of allylbenzene to amphetamine [58; route 6U]. Amination with a commercially available -aminodiphenylmethane, which serves as an equivalent, was used for the hydroamination of 1-phenyl-1-propyne to amphetamine [26; route 3F]. Several citations occurred in the literature for the of P-2-P to amphetamine [32, 22, 40; route 3H]. The classical was used to construct 2-methyl-3-phenyl propanoic acid [37, route 3I] which was then converted to amphetamine via a Curtius rearrangement / hydrolysis [37]. A similar classical reaction, that of a Claisen / Dieckmann condensation, utilizing a benzylnitrile analog was used to construct a P-2-P complement [45; route 3K]. This analog was converted to the oxime, followed by reduction and de-sulfuration with sodium / to amphetamine [45; route 3K]. Finally, O-methoxy-oxime of P-2-P was reduced with Red-Al® to yield amphetamine with marginal success [48; route 3M].

Scheme 4.

Discussion of Enzymatic, Photo-induced and Chemical Manipulation of Amphetamine : 1985-2009

Biotransformations have increased in interest, proof of concept and patent applications from 1985-2009. Illustrated in Scheme 4 are the citations within this topic regarding 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 points to the enzymatic synthesis to amphetamine. Alternatively, biotransformations of racemic amphetamine leading to the exclusion or enhancement of one isomer (enhanced ee) have been published or patented [3, 10, 22, 24, 29, 43; route 4B]. Conversely, one citation [2; route 4D] describes the photochemically induced- mediated racemization of the single amphetamine isomer to the racemic mixture. Classical methods of chiral resolution based upon chiral organic salts have been reported 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], -amino acids [78] and optical-10-camphorsulfonyl chloride [37].

Organic Transformation from 1900 -2009: Classical Organic Transformation in the Early 1900-1950‘s:

Scheme 5.

Classical Organic Transformation in the Early 1900-1950‘s: The early literature regarding amphetamine synthesis of the 1900‘s was dominated by classical organic transformations (Scheme 5). These reactions like 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 productive routes to the synthesis of amphetamine. The non-amine component, -methylbenzylacetic acid, was constructed with carbon-carbon bond formation via a carbo-anion enolate condensed with a suitable alkylhalide. These condensations, that were classically referred to as acetoacetic ester synthesis [105, 118] and malonic ester synthesis [91], later came to be referred to as cases of the . In the case of phenylacetonitrile (benzylnitrile) [107], the acidity of the central methylene between the nitrile and aromatic ring, are used for abstraction and carbo-anion production before alkylhalide reaction. Organic Transformation in the Early 1950-1985s: Moving forward in time, from the period dominated by ―classical organic transformations‖ (1900-1950), we enter a period for amphetamine synthesis that saw expanded interest in dissolved metal reductions and early chiral constructions. This time frame (1950-1985) was the focus of our previous review (J. Forensic Sci. Int. 42, (1989) 183-189)) and hightlighted catalytic reductions, dissolving metal reductions and metal hydride reduction leading to amphetamine. It was during this period that chiral complement to the Friedel-Crafts reaction was introduced for the synthesis of amphetamine [55]. Amination of a double bond was improved with the use of diethyl phosphoramidate [58], as well as acetonitrile mercuration [69] each leading to amphetamine. Reductive amination with (R)-1-phenylethanamine on the Schiff-base of phenyl-2-propanone followed by diasteroisomeric separation allowed for a chiral synthesis of amphetamine [64]. Later (1977, 1978), two chiral syntheses to amphetamine were published starting from D-phenylalanine [84a, 84b].

Summary: As best as possible the authors have attempted to summarize the synthetic transformations published within the period 1900-2009, with emphasis upon 1985-2009. The complete visual precursor / references to amphetamine pin-wheel is illustrated in Scheme 6 and is intended for the forensic chemist as a complete map of amphetamine routes / literature. These individual reactions are broken out, expanded and illustrated with added nomenclature in the supplemental material. Furthermore, precursor names via IUPAC (ChemDraw, Cambridge Software) are tabulated for the non-chemist with cross reference to literature citations.

Time-Line of Synthetic Routes to Amphetamine non-chiral syntheses

1900 1930 1970 1985 2009 O Organic Transformations NO2 to Amphetamine H Scheme 6. 1900 - 2009 COOH 6A. 114 113 6B. NH2 54 57 62 86 6BB. O 39 4 67 87 O O 6C. 70 95 41 12 O 6AA. 94 Br 84a 18 74 42 75 6D. O 84b 20 OH 109 44 6Z. 84 22 5 NH2 O 102 25 47 85 5 72 33 56 35 89 103 H OH 122 55 60 61 6E. 110 92 37 6Y. 95 92 31 89 34 OH 80 HO Br 47 5 6F. 6X. O 21 NH2 NH2 107 1 120 21 117 CN 6G. 6W. 80 O 100 111 112 121 69 Amphetamine OH 6V. 27 45 58 6H. S 26 15 Ph 74 6I. 6U. 17 8 CN 65 13 5 49 40 52 88 64 14 13 Br 53 6J. 6T. 106 101 16 63 19 91 14 23 1 54 20 28 116 51 51 29 40 96 OH 52 22 32 66K. H 11 52 6S. 54 93 38 9049 115 36 43 O 92 79 6L. Br 116 98 59 OH 91 48 76 108 40 6R. 101 59 71 O 107 105 120 73 99 O O 6Q. 82 118 6M. 6P. 88 6N. OH 6O. O OH O NH2 N R OH

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Supplemental Material:

chiral JACS 131, 9882 (2009) Ir-(S,S)-f- N MeMgI NH binaphane NH2

H2

(S)-1-phenylpropan-2-amine 2-phenylacetonitrile 1-phenylpropan-2-imine Ref. 1.

JOC 73(2) 364 (2008) chiral Photochemical --Racemization NH2 NH2 HSCH2CO2Me

Benzene 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine Ref. 2.

chiral JOC 72(18) 6918 (2007) Biotrasformation, Enzymic, Stereoselective NH NH2 2 Lipase Lauric acid

1-phenylpropan-2-amine Ref. 3. (S)-1-phenylpropan-2-amine + amide of lauric acid

non-chiral Tetra. Let. 48(32) 5707 (2007)

NH2 NO2 SmI2 H2N Ph

1-phenylpropan-2-amine (E)-(2-nitroprop-1-enyl)benzene Ref. 4.

chiral Tetra. 63, 9758 (2007) O (R)-3-phenyl-2-(phenylaminooxy)propan-1-ol nitrosobenzene OH H OH Pd/C OH l- O NHPh NaBH 3-phenylpropanal 4 (R)-3-phenylpropane-1,2-diol TEA 1, TsCl Ref. 5. 2. NaH

LiAlH4 1. NaN3 O 2. Pd/C H2 NH OH 2 (S)-1-phenylpropan-2-amine 2-benzyloxirane (S)-1-phenylpropan-2-ol

chiral Chem. European J. 12(15)4191-7(2006) H H NH N O 2 N O SmI2 TFA

O O I (S)-1-phenylpropan-2-amine tert-butyl 1-iodo-3-phenylpropan tert-butyl 1-phenylpropan-2- -2-ylcarbamate ylcarbamate Ref. 6.

non-chiral Central Eur. J. Cehm 6(4) 526-34 (2008)

NO2 NH2 NaBH4 BF3 - Et2O

THF (E)-(2-nitroprop-1-enyl)benzene Ref. 7. 1-phenylpropan-2-amine

chiral Phth Anh. NH2-NH2 Ph P N O NH2 OH 3 MeOH O DEAD, THF amphetamine (S)-1-phenylpropan-2-amine (S)-1-phenylpropan-2-ol (S)-2-(1-phenyl propan-2-yl)isoindoline Bioorganic & Med. Chem. Letters, Ref. 8. -1,3-dione 15(12) 3039-43 (2005)

chiral Faming Zhuanli Shenqing Gongkai Shuomingshu # 1673210 (2005) H H NH N O 2 N O SmI2 TFA

O O I (S)-1-phenylpropan-2-amine tert-butyl 1-iodo-3-phenylpropan tert-butyl 1-phenylpropan-2- -2-ylcarbamate ylcarbamate Ref. 9

chiral indian J. Chem.Sec B 44B(6) 1312 (2005) Biotrasformation, Enzymic, Stereoselective NH NH2 2 Lipase Lauric acid

1-phenylpropan-2-amine Ref. 10. (S)-1-phenylpropan-2-amine + amide of lauric acid

chiral Ac OH O H NH2 N Ac2O Ac norephedrine (1R,2S)-2-amino-1- 2-acetamido phenylpropan-1-ol -1-phenylpropyl acetate / H 2 O 4 BaS Pd- Ref. 11. J. Med. Chem. 48(4) 1229-36 (2005)

H NH2 N H2SO4 Ac amphetamine

N-(1-phenylpropan-2-yl)acetamide (S)-1-phenylpropan-2-amine

non-chiral JOC 70(14) 5519 (2005)

NO2 NH LiAlH4 2

(E)-(2-nitroprop-1-enyl)benzene 1-phenylpropan-2-amine Ref. 12.

non-chiral NH2 Org. and Biomolecular Chem. 3(6) 1049 (2005) SO2 NO O PhSH, K2CO3 2 HN OH NH S o 2 O 50 C 1-phenyl DCC amphetamine O N propan-2-ol 2 1-phenylpropan-2-amine 2-nitro-N-(1-phenylpropan-2-yl) benzenesulfonamide Ref. 13.

chiral J. Chem. Research 10, 681 (2004) (S)-(2-azidopropyl)benzene NH2 Pd/C baker's yeast N H2 O sucrose OH 3 (S)-1-phenylpropan-2-amine 1-phenylpropan-2-one (S)-1-phenylpropan-2-ol Ref. 14.

non-chiral O Org. Letters, 6(24) 4619-21 (2004) S O N O MgBr N HCl O O NH2 O O 1-phenyl-N- amphetamine (1-phenylpropan-2-yl) (4,4,5,5-tetramethyl- magnesium bromide 1,3-dioxolan-2-ylidene) 1-phenylpropan-2-amine propan-2-amine Ref. 15.

OH SOCl O N3 chiral 2 NaN O S 3 O OH OH (1S,2S)-1-phenyl (1R,2S)-1-azido-1-phenylpropan-2-ol propane-1,2-diol Tetrahedron Asymmetry 15(19),3111-6 (2004) H N (S)-1-phenylpropan-2-amine Ph3P Pd-C Ref. 16. HCO2NH4 NH2 2-methyl-3-phenylaziridine amphetamine J. Combinatorial Chem. chiral 5(5) 590-6 (2003) O O O

S CuSO4 S H NH2 N 2-phenylacetaldehyde (R,E)-2-methyl (R)-2-methyl -N-(2-phenylethylidene) propane-2-sulfinamide propane-2-sulfinamide Ref. 17. O MeMgBr NH2 S HCl, MeOH N amphetamine H (R)-2-methyl-N-((S)-1-phenyl (S)-1-phenylpropan-2-amine propan-2-yl)propane-2-sulfinamide chiral J. Chem. Research (S), 128 (2003) NO NH 2 Ruthenium BINAP 2

(E)-(2-nitroprop-1-enyl)benzene Ref. 18.

chiral Tetra. Asy. 14, 2119 (2003) (S)-1-phenylpropan-2-amine

H2N O N NH2 1-phenylpropan-2-one (R)-1-phenylethanamine (S,E)-1-phenyl-N- Ref. 19. (1-phenylpropan-2-ylidene) ethanamine

chiral J. Chinese Chemical Society, 49, 505 (2002)

NO NH 2 Ru2Cl2(PPh3)3 2

H2 (E)-(2-nitroprop-1-enyl)benzene Ref. 20. (S)-1-phenylpropan-2-amine

JCS Perkin T .I 16, 1869(2002) chiral O O O O Br N N LDA, THF

1-(bromomethyl) (5R)-3,3,5-trimethyl- (R)-3,3,5-trimethyl benzene 1-(2-methyl-3-phenyl -1-propionylpyrrolidin-2-one propanoyl)pyrrolidin-2-one Ref. 21. O NH2 NH3, MeOH PhI(OOCCF3)2 NH2 amphetamine (S)-2-methyl-3-phenylpropanamide (S)-1-phenylpropan-2-amine

chiral Tetra. Asy. 13(20) 2277 (2002)

NH2 Enzymic, Resolution Ref. 22. NH2

CAL-B . 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

non-chiral

NH2 HCOO NH4 O Pd, MeOH Ref. 22. 1-phenylpropan-2-one T etrahedron Asymmetry, 13(12) amphetamine 13115-1320 (2002) 1-phenylpropan-2-amine

chiral US pat. # 6399828 2002) OH NH NH 2 HI, P4 2 HCl (1R,2S)-2-amino-1-phenylpropan-1-ol Ref. 23. BaSo4 Ac2O OAc H2 HoAc Pd NH2

(1R,2S)-2-amino-1-phenylpropyl acetate

chiral Syn. Comm. 31(4) 569 (2001)

NH2 Enzymic, Resolution NH2

Candida antarcitica Lipase 1-phenylpropan-2-amine Ref. 24. (S)-1-phenylpropan-2-amine

O chiral LiBH /TMSCl NH BOC) O NH O NH2 4 2 2

COOH OH OH (S)-2-amino-3- (S)-2-amino-3-phenylpropan-1-ol (S)-tert-butyl 1-hydroxy- phenylpropanoic acid 3-phenylpropan-2-ylcarbamate Ref. 25. J. Orgainic Chemistry 65(16) 5037-42 (2000) O O O O

NH NH NH (Ph)3P / I N-Selectride TFA 2

I (S)-tert-butyl 3-iodo-1- (S)-tert-butyl 1-phenylpropan amphetamine phenylpropan-2-ylcarbamate -2-ylcarbamate S)-1-phenylpropan-2-amine non-chiral

NH2 Cp TiMe Cp2TiMe2 2 2 N Ph NH2 H2, Pd/C diphenyl (E)-diphenyl-N- 1-phenylpropan-2-amine 1-phenyl- methanamine (1-phenylpropan-2- Ph 1-propyne ylidene)methanamine Ref. 26. amphentamine Organic Letters, 2(13) 1935-1937 (2000)

non-chiral Ref. 27. T etra. 56, 5157 (2000) NH Ph 2 H2N Pd/C H2 NH cat. n-Bu Li 1-phenylpropan-2-amine allylbenzene N-benzyl-1-phenylpropan-2-amine

non-chiral T etrahedron Letters, 41(34) tBuCO) O 6537-40 (2000) 2 TFA Ph P OH 3 NH DCM NH2 DEAD, THF 1-phenyl O amphetamine propan-2-ol tert-butyl O 1-phenylpropan Ref. 28. 1-phenylpropan-2-amine -2-ylcarbamate

chiral JP 03191797 (1991) O NH BuNH2 Enzymic, Resolution 2

C: 9031-66-1 phenylpropan-1-one Ref. 29. (S)-1-phenylpropan-2-amine

non-chiral Zhongshan Dazue Xuebao 35(5) 73-76 (1996) HOOC * OH NH O NH HO * 2 Leuckart Reaction 2 COOH d-Tartaric 1-phenylpropan-2-one acid Ref. 30.

non-chiral Ref. 31. T etrahedron, 53(13) 4935-4946, 1997 O O O O O O 1-phenylpropan- P P 2-amine MgBr N CuI NH HCl NH2

THF diethyl phenylmagnesium diethyl 2- 1-phenylpropan- bromide methylaziridin- 2-ylphosphoramidate amphetamine 1-ylphosphonate

non-chiral J.Chem.Soc., Perkin T rans I, 265 (1996) O Mg MeOH NH2

NH3 HoAc 1-phenylpropan-2-one Ref. 32. 1-phenylpropan-2-amine P-2-P

Tetra. Lett. 36(8) 1223 (1995) chiral O BOC BOC HN O NH TEA NH BH3 O CH SO Cl OH THF OH 3 2 O Ms (R)-2-(tert-butoxycarbonylamino) -3-phenylpropanoic acid CH3CH2SH NaH Ref. 33. BOC BOC NH NH NH TFA 2 Ra-Ni EtOH O S (S)-1-phenylpropan-2-amine

chiral OH I OH OH I Phth Anh. Ph)3P / I OH N O N O NH2 O O (1S,2S)-2-amino- 2-((1S,2S)- 1-phenylpropane-1,3-diol 1,3-dihydroxy- 1-phenylpropan -2-yl)isoindoline-1,3-dione 2-((1S,2S)- Ref. 34. 1,3-diiodo-1-phenyl propan-2-yl)isoindoline- 1,3-dione H / Pd-C 2 NH2-NH2 N O NH 2 T etrahedron Asymmetry O amphetamine 4(7) 1619-24, 1993 (S)-1-phenylpropan-2-amine

(S)-2-(1-phenyl propan-2-yl)isoindoline-1,3-dione

non-chiral J. Labelled Comp. and Rad. 31(11) 891 (1992)

NO NH2 2 LiAlH4

(E)-(2-nitroprop-1-enyl)benzene Ref. 35. 1-phenylpropan-2-amine

chiral Ref. 36. T etrahedron Asymmetry,3(10) 1283-8 (1992) E & Z NH2 H4Ru(arene) N OH BINAP (S)-1-phenylpropan-2-amine (E)-1-phenylpropan-2-one oxime amphetamine

Acta. Chemica Scandinavica 45, 431 (1991) non-chiral Ref. 37. O O O O O O O O NaH CH3-I DMSO methyl 2-benzyl-2-methyl -3-oxobutanoate dimethyl 2-benzylmalonate O Ph O P Ph NH2 OH 1. TEA/heat 1. NaOH +N - N N amphetamine 2. AcOH 2-methyl-3-phenyl propanoic acid 2. HCl / heat 1-phenylpropan-2-amine

chiral NH2 resolution NH2

(+)-10-camphorsulonyl chloride amphetamine amphetamine 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

chiral HOOC Tetrahedron Lett. Vol. 32, No. 49 (1991) 7325-8. NH2 * OR R = H resolution NH2 RO * Benzoyl COOH p-toluoyl amphetamine amphetamine 1-phenylpropan-2-amine Ref. 38. (S)-1-phenylpropan-2-amine

non-chiral Chem. Pharm. Bull. 38(12) 3449 (1990)

Biotransformation NO NH 2 cat. Peptostreptococcus Anaerobius 2

(E)-(2-nitroprop-1-enyl)benzene Ref. 39. 1-phenylpropan-2-amine

chiral Ref. 40. J. Chrom. Sci. 28, 529 (1990) OH Cl NH NH 2 2 SOCl2 NH2 Pd H2

(1R,2S)-2-amino-1-phenylpropan-1-ol (S)-1-phenylpropan-2-amine (1S,2S)-1-chloro-1-phenylpropan-2-amine

non-chiral Ref. 40. J. Chrom. Sci. 28, 529 (1990) NH OH Ac2)O Leuchart Red 2

O NaOAc O 2- 1-phenylpropan-2-one 1-phenylpropan-2-amine

chiral Ref. 41. Tetra. 46(21) 7403 (1990) NH2 NO2 NO2 BH3-THF Ru2Cl2[(-)-DIOP]3 H 2 amphetamine (E)-(2-nitroprop-1-enyl)benzene (2-nitropropyl)benzene (S)-1-phenylpropan-2-amine

non-chiral Ref. 42. Tetra. 46(21) 7743 (1990) NO NH2 2 BH3-THF cat. NaBH4 amphetamine (E)-(2-nitroprop-1-enyl)benzene

chiral U.S. pat. # 4950606 (1990) Enzymic, Resolution Ref. 43. NH2 NH2 amino-acid transminase from Bacilllus Megaterium 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

non-chiral Biotransformation NH amino-acid transminase from Ref. 43. 2 O Bacilllus Megaterium amphetamine 1-phenylpropan-2-one 1-phenylpropan-2-amine

non-chiral Angew Chem. Int. Ed. Engl. 28(2) 218-220 (1989)

O O O O

NH (CH3)3SiCl NH

COOH LiBH4 /THF 2-(benzyloxycarbonyl) benzyl 1-phenylpropan-2-ylcarbamate -3-phenylpropanoic acid Ref. 44.

NO NH2 2 (CH3)3SiCl LiBH4 /THF amphetamine (E)-(2-nitroprop-1-enyl)benzene 1-phenylpropan-2-amine

non-chiral Coll. Czech. Chem. Comm. 54(7) 1995 (1989) 3-oxo-2-(2-(phenylthio)phenyl)butanenitrile Ph Ph Ph S S CN S NaOEt H3PO4

CN EtOH O O 1-(2-(phenylthio)phenyl)propan-2-one 2-(2-(phenylthio)phenyl)acetonitrile Ph Ref. 45. Ph S S NH2OH Na EtOH HCl NH2 N NH2 OH 1-(2-(phenylthio)phenyl)propan-2-amine

non-chiral Ref. 46. Org. Reactions 36, book (1988)

NH2 N Red - Al, THF O

1-phenylpropan-2-amine (E)-1-phenylpropan-2-one O-methyl oxime

NO2 NH2 Red-Al THF

(E)-(2-nitroprop-1-enyl)benzene

non-chiral Ref. 47. J.Med.Chem. 31(8) 1558 (1988) O NO2 NH2 NO2 LiAlH4 H

1-phenylpropan-2-amine benzaldehyde (E)-(2-nitroprop-1-enyl)benzene

chiral JP 63219396 (1988)

NO Ref. 48. NH 2 Biotransformation / 2 Enzymic, Resolution 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

chiral N N H2N N O

H (R)-2-methyl (R,E)-2-methyl 2-phenylacetaldehyde pyrrolidin-1-amine -N-(2-phenylethylidene) pyrrolidin-1-amine Ref. 49. JACS 109(7) 2224-5 (1987)

H NH2 N N H2 / Ra-Ni CH3Li / CeCl3 375 psi / 60o amphetamine (R)-2-methyl-N-((S)- 1-phenylpropan-2-yl) (s)-1-phenylpropan-2-amine pyrrolidin-1-amine chiral O NH R or S 2 low pressure * * Hydrogenation * HN phenyl-2-propanone Raney Ni / H2 [R,R]+ or [S,S]- -methylbenzylamine US 4000,197 (1976) Ref. 50. [S,S]-(-) NH2 10% Pd-C amphetamine HN * 50 psi H2 * (S)-1-phenylpropan-2-amine

chiral Ref. 51. Organometallics, 5, 739-46 (1986) O N H-SiH(Ph)2 NH OH 2 Rh(cod)Cl2 1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime

non-chiral Ref. 52. J. Chem. Soc., Chem. Comm. 2, 176, (1986) CH H H LDA 3 1. TFA Aphetamine N N 2. Pd /C H2 O NH CH3I NH Ph 2-phenylacetaldehyde Ph Ph Ph (E)-1-(2,2-dimethyl-1,1-diphenylpropyl) (E)-1-(2,2-dimethyl-1,1-diphenylpropyl) -2-(2-phenylethylidene)hydrazine -2-(1-phenylpropan-2-ylidene)hydrazine

non-chiral Ref. 52. J. Chem. Soc., Chem. Comm. 2, 176, (1986) H CH3 H LDA 1. TFA Aphetamine N N NH 2. Pd /C H2 O NH Ph-CH2-Br Ph Ph Ph Ph

non-chiral US 2009292143 (2009) OH Cl NH NH2 2 NH2 Pd H2

(1S,2S)-2-amino-1-phenylpropan-1-ol Ref. 53. (S)-1-phenylpropan-2-amine

chiral Khimiya Geterotsiklicheskikh Soedinenii 12, 1648 (1985)

O N Na MeOH NH OH 2

1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime Ref. 54.

chiral O O H AlCl H N CF 3 N CF3 Cl 3 O O (S)-2-(2,2,2-trifluoroacetamido) benzene (S)-2,2,2-trifluoro propanoyl chloride -N-(1-oxo-1-phenyl propan-2-yl)acetamide J.Org.Chem. 50(19) Ref. 55 3481-4 (1985) OH Br H H H / Pd-C PBr N CF3 2 N CF3 3 O O (S)-2,2,2-trifluoro (S)-N-(1-bromo-1-phenylpropan -N-(1-hydroxy-1-phenyl -2-yl)-2,2,2-trifluoroacetamide propan-2-yl)acetamide

H K CO , MeOH NH2 N CF3 2 3 H2 / Pd-C O amphetamine (S)-2,2,2-trifluoro-N-(1-phenyl propan-2-yl)acetamide (S)-1-phenylpropan-2-amine

non-chiral Ref. 56. Syn. Comm. 15(9) 843 (1985) NaBH4 NH NO2 BH3 - THF 2

(E)-(2-nitroprop-1-enyl)benzene

non-chiral Syn. Comm. 14(12)1099(1984) NaBH4 NH2 NO2 BH3 / THF

Ref. 57. amphetamine

non-chiral Synthesis (4) 270-3 (1982) O 1. Hg(NO3)2 / H O H2N P 1,1-diCl-ethane N P O O O O 2. 10% NaOH / NaBH4 (E)-prop-1-enylbenzene diethyl phosphoramidate

NH2 HCl /benzene

Ref. 58. amphetamine

chiral Synthesis (4) 270-3 (1982) O N O N OH P CH2Cl2, DEA O P Cl Ph Ph Ph Ph (E)-1-phenylpropan -2-one oxime

H O HCl / ethanol NH2 N LAH O P Ph Ph (-) Quinine / THF Ref. 59. amphetamine

non-chiral J. Labelled compounds and radiopharmaceuticals 18(6) 909 (1981)

O NH2 NH3 (Sealed)

o Al, HgCl2, NH4OH, 100 C, 15min 1-phenylpropan-2-one Ref.60.

non-chiral Helvetica chimica Acta 61(2) 558 (1978)

NO NH2 NO NO2 LiAlH4

(E)-prop-1-enylbenzene Ref.61.

chiral Ref. 62. T etrahedron 32(11) 1267-76 (1976) E & Z NH2 LiAlH4 N OH 1-phenylpropan-2-amine (E)-1-phenylpropan-2-one oxime amphetamine

non-chiral J. Chem. Education 51, 671(1974)

O NH2 o Al, HgCl2, NH4OH, 100 C, 15min

1-phenylpropan-2-one Ref.63.

non-chiral (R)-1-phenylethanamine JMC 16(5) 480-3 (1973) H O H2N Raney-Ni N

H2 1-phenylpropan-2-one (+) or (-) (R)-1-phenyl-N-(1-phenylethyl)propan-2-amine (S)-1-phenyl-N-((R)-1-phenylethyl)propan-2-amine Ref.64. NH H Pd-C / H2 2 separation N MeOH of Diastereoisomers (S)-1-phenylpropan-2-amine

non-chiral JACS 93, 2897 (1971)

O NH2 NaCNBH3

NH4OH, MeOH 1-phenylpropan-2-one Ref.65.

chiral resolution OH EP 915080 (1999) OH NH2 NH2 O (s)-2-naphthylglycolic acid racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine Ref. 66.

non-chiral Ref. 67. J.Med.Chem. 13, 26(1970) NH NO2 LiAlH4 / THF 2

(E)-(2-nitroprop-1-enyl)benzene

non-chiral JACS 91, 5647 (1969)

CH3CN Hg(NO3)2 N O NO2 Ref. 69. Hg allylbenzene NO 3 H H N HCl NaBH4 N O

NaOH amphetamine 1-phenylpropan-2-amine N-(1-phenylpropan-2-yl)acetamide non-chiral Ref. 70. US Pat. 3,458,576 (1969) Pd-C / H2 NO NH2 2 Pt / H2 Raney-Ni / H2 (E)-(2-nitroprop-1-enyl)benzene

non-chiral Coll. Czech. Chem. Comm. 33(11) 3551-7(1968)

O NH2 HCl NH4 HCOO Ammonium Formate

1-phenylpropan-2-one Ref.71.

chiral Coll. Czech. Chem. Comm. 33(11) 3551-7(1968)

NH2 NH2 (+)-tartaric acid

EtOH (S)-1-phenylpropan-2-amine 1-phenylpropan-2-amine Ref.71.

non-chiral Ref. 72. J. Heterocyclic Chem._5(3)339(1968)

NH2 AlCl3

HN 1-phenylpropan-2-amine 2-methylaziridine benzene non-chiral Ref. 73. T etra. 24(16) 5677 (1968)

NH2 N R LiAlH4 O THF 1-phenylpropan-2-amine R = H or R = Ts

non-chiral Chem Pharm Bull 13(2)118(1965) Cl Cl nitrosyl chloride NO2 Pt O NO2 NOCl 2

H2 NO2Cl prop-1-ynylbenzene hypochlorous nitrous anhydride Ref.74.

non-chiral US Pat. 3,187,047 (1965)

O NH2 NH4 oAc Raney-Ni / H2

1-phenylpropan-2-one Ref.75.

non-chiral T etra. 19, 1789 (1963) LEUCKART-WALLACH Mech O NH2 NH4 Formic Acid

1-phenylpropan-2-one Ref.76.

non-chiral DE_1958-968545(1958) OH Cl NH NH2 2 NH2 Pd H2

(1S,2S)-2-amino-1-phenylpropan-1-ol Ref. 77. (S)-1-phenylpropan-2-amine

chiral US 3028430 (1962) NH2 R resolution NH2 H N 2 * -amino acid COOH amphetamine amphetamine 1-phenylpropan-2-amine Ref. 78. (S)-1-phenylpropan-2-amine

non-chiral US Pat. 2,828,343 (1958)

O NH NH3 (g) CuO and Ba(OH)2 2

H2 1-phenylpropan-2-one Ref.79.

chiral Ref. 80. Curtius rearrangement JOC_22(1)33(1957) O O O NH2 CO2Cl2 OH Cl N3 HCl

NaN3 (S)-2-methyl-3- (S)-2-methyl-3- (S)-2-methyl-3- amphetamine phenylpropanoic acid phenylpropanoyl chloride phenylpropanoyl azide (S)-1-phenylpropan-2-amine

chiral O Schmidt rearrangement NH2 OH H2SO4 NaN3

(S)-2-methyl-3- amphetamine phenylpropanoic acid Ref. 80. (S)-1-phenylpropan-2-amine

chiral HOOC Zhurnal Obshchei Khimii 28 (1958) 3323-8 NH2 * OH resolution NH2 HO * d-Tartaric COOH acid amphetamine amphetamine 1-phenylpropan-2-amine Ref. 81a (S)-1-phenylpropan-2-amine

chiral US 2,833,823 (1958) NH2 resolution NH2

H3PO4 inriched in one isomer amphetamine amphetamine Ref. 81b (S)-1-phenylpropan-2-amine 1-phenylpropan-2-amine

non-chiral Ref. 82. J_Pharm_Soc_Japan_413-416(1954)

NO2 Raney-Ni NH2

(E)-(2-nitroprop-1-enyl)benzene Raney-Ni OH N

DE_1953-870265 non-chiral NH 2 Ph HN O N NH2 N PtO2 H PhenylHydrazine H2 (E)-1-phenyl-2-(1-phenyl Ref.83. 1-phenylpropan-2-one propan-2-ylidene)hydrazine

chiral J. Labelled Comp. and Radio. 3(1) 3-9 (1977) O O HN S NH NH2 p-MeTOSCl * * 2 LiAlD4 * D C D2C COOH 2 O OH CH3 D-Phenylalanine Ref. 84. p-TOS LiAlD4 O O NH2 HN S * Naphthalene radical anion CD3 amphetamine 1-phenylpropan-2-amine CH3 non-chiral Ref. 85. JACS_74(7)1837(1952)

NO2 NH2 LiAlH4

acid (E)-(2-nitroprop-1-enyl)benzene P-2-P (Nef reaction)

non-chiral Ref. 86. US Patent 02647930B1(1953) NH NO2 Organic Acids 2

Raney-Ni / H2 (E)-(2-nitroprop-1-enyl)benzene non-chiral Ref. 87. DE_1952-848197(1952)

NO2 NH2 Raney-Ni / H2

(E)-(2-nitroprop-1-enyl)benzene

chiral Chirality 6(4) 314-20 (1994) Distillation from NH Ref. 88. NH 2 optically active acids.. 2

Resolution 1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

non-chiral Ref. 89. Helv. Chim. Acta. 33, 912 (1950)

NO2 LiAlH4 / ether NH2

(E)-(2-nitroprop-1-enyl)benzene

chiral resolution O Org. Syn. Coll. 2, 506 (1943) OH NH2 HO NH / 2 OH O l-malic acid racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine Ref. 90.

non-chiral (1,3-diethoxy O -1,3-dioxopropan-2-yl) O O magnesium ethanolate Mg O O O O O SOCl2 O O

OH Cl O O 2-phenylacetic acid 2-phenylacetyl chloride

Ref. 91. diethyl 2-(2-phenylacetyl)malonate J_Am_Pharm_Assoc_687-688(1950) OH O N NH2

1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime 1-phenylpropan-2-amine

non-chiral Bull. Soc. Chem. France 1045 (1950)

O NH2 NH3 Raney-Ni / H2

1-phenylpropan-2-one Ref.92. non-chiral NO2 Chemische Berichte 124(10) 2303-6 (1991)

NH2 Cathode Red. at Hg or C electrode N OH

(E)-1-phenylpropan-2-one oxime Ref. 93.

non-chiral Ref. 94. JOC 15, 8 (1950)

NO2 NH2 Raney-Ni / H2

(E)-(2-nitroprop-1-enyl)benzene

non-chiral GB 702985(1949)

O NH2 NH3 Raney-Ni / H2 or Pt or Pd 1-phenylpropan-2-one Ref.95. non-chiral Ref. 96. US Pat. 2,636,901(1949)

NO2 NH2 Raney-Ni / H2

(E)-(2-nitroprop-1-enyl)benzene

non-chiral JACS 70, 1187 (1948) LEUCKART-WALLACH Mech O NH2 NH4 Formic Acid

1-phenylpropan-2-one Ref.97.

non-chiral JACS 70, 1315-6(1948)

O NH2 NH3 PtO2 / H2

1-phenylpropan-2-one Ref.98.

non-chiral Y akugaku Zasshi 74, 413-16 (1954).

N NH2 OH Raney Ni / H2

(E)-1-phenylpropan-2-one oxime Ref.99.

non-chiral JACS 70, 2811-12 (1948)

O NH2 NH3 Raney-Ni / H2

1-phenylpropan-2-one Ref.100.

non-chiral Bulletin of Electrochemisty 8(6) 276-7 (1992) N NH OH Cathode Red. at Hg or C electrode 2

Ref. 101.

non-chiral 1-phenylpropan-2-ol Ritter Reaction JACS 70, 4048 (1948) OH SO3H SO3H O HCl NH HCN N 2

1-phenylpropan -2-yl sulfate Ref.102. (E)-prop-1-enylbenzene

non-chiral Ref. 103. Justus_Liebigs_Annalen_der_Chemie_215-221(1948)

NO2 NH2 Pd / H2

(E)-(2-nitroprop-1-enyl)benzene non-chiral Friedel-Crafts reactions J. Am. Chem. Soc. 68 (1946) 1009-11. NH FeCl3 Cl 2 Cl NH4OH Cl or Fuming Sulfuric Allyl Chloride Ref. 104.

non-chiral Acetoacetic Ester Synthesis Route US Patent 2,413,493B1(1946) O O O O O O Na CH3-I Na O Ph-CH2-Cl O O ethyl 3-oxobutanoate Ref. 105.

O OH O NH2 NaOH SOCl2 NH3 NaOCl NH2 Hoffman 2-methyl-3-phenylpropanoic acid 1-phenylpropan-2-amine

non-chiral JOC 9, 529 (1944) LEUCKART-Study

O NH2 NH4 Formic Acid

1-phenylpropan-2-one Ref.106.

Acetylbenzylcyanide Reaction Route non-chiral J.Applied Chem. (USSR) 14(3), 410 (1941) O O N O O N H3PO4 NaOEt 2-phenylacetonitrile 3-oxo-2-phenylbutanenitrile 1-phenylpropan-2-one Ref. 107. H O N HCl NH2 ammonium formate

+ NH- 4 O O N-(1-phenylpropan-2-yl)formamide 1-phenylpropan-2-amine

non-chiral O O O O O O Acetic Anhydride O

OH O O 2-phenylacetic acid 1-phenylpropan-2-one

LEUCKART J.Gen.Chem.(USSR) 11(4), 339 (1941) H2N O H NH Formamide N O Hydrolysis H+ 2

N-(1-phenylpropan-2-yl)formamide Ref.108.

chiral Resolution OH O Ref.108. NH HO 2 OH NH2 O OH

1-phenylpropan-2-amine d-tartaric acid (S)-1-phenylpropan-2-amine

non-chiral J. Am. Chem. Soc. 5 (1940) 267-85 Wolff Rearr. O O O O AgO

NH2 OH SOCl2 Cl Diazomethane HC NH3 N 2-phenylacetic acid Ref.109. N non-chiral Chemischen Berichte 66B, 684 (1933)

HN3 acid O O O OH Curtius Rearr. NH2 N3 -methylbenzylacetic acid Ref.110.

non-chiral J. Am. Chem. Soc. 55 (1933) 1701-5. Lossen Rearr. O O N NH C 2 acid chloride Hydroxyl amineHN Hydrolysis X OH O esters anhydride Ref.111.

non-chiral J.Am. Chem. Soc. 54, 271-4 (1933) O NO2 NH2 NO2 Hg . Cathode H electrolic Red. 1-phenylpropan-2-amine benzaldehyde (E)-(2-nitroprop-1-enyl)benzene Ref. 112. non-chiral US 1879003 (1932) NO 2 NH Cathode Red. at Hg or C electrode 2

Ref. 113. non-chiral Chemicshe Berichte, 66B, 660-666 (1932). N NH OH Na / Ethanol 2

Ref. 114.

non-chiral J. Am. Chem. Soc. 31, 1875 (1931) O OH OH Cl N NH2 NH2 NH2 Pd/C, H2 HCl Pd/C, H2

(E)-2-(hydroxyimino)- 2-amino-1-phenyl 1-chloro-1-phenyl 1-phenylpropan-1-one propan-1-ol propan-2-amine

O from O

Ref. 115. 1-phenylpropane-1,2-dione

non-chiral J. Am. Chem. Soc. 31, 2787-91 (1931) O Hofmann Rearr. NaOH NH2 Br2 NH2 2-methyl-3-phenylpropanamide O Curtius Rearr. N3 Ref. 116. 1-azido-2-methyl-3-phenylpropan-1-one

non-chiral J. Chem. Soc. 18-21 (1930) OH O NH NH2-OH N Na/Hg 2 amalgum 1-phenylpropan-2-one (Z)-1-phenylpropan-2-one oxime Ref. 117.

Precursor list to amphetamine 1985 -2009

Precursor / intermediate / essentials References…… 2-phenylacetonitrile 1. J. Am. Chem. Soc. 131, 9882 (2009) 107. J. Applied Chem. (USSR) 14(3) 410 (1941) (E)-(2-nitroprop-1-enyl)benzene 4. Tetra. Lett. 48(32) 5707 (2007) 7. Central Eur. J. Chem. 6(4) 526 (2008) and 12. J. Org. Chem. 70(14) 5519 (2005) 18. J. Chem. Research (S), 128 (2003) (Z)-(2-nitroprop-1-enyl)benzene 20. J. Chinese Chem. Soc. 49, 505 (2002) 35. J. Labelled Comp. Rad. 31(11) 891 (1992) 36. Tetra. Asym. 3(10) 1283 (1992) 39. Chem. Pharm. Bull. 38(12) 3449 (1990) 41. Tetra. 46(21) 7403 (1990) 42. Tetra. 46(21) 7403 (1990) 46. Org. Reactions 36, book (1988) 47. J. Med. Chem. 31(8) 1558 (1988) 48. JP 63219396 (1988) 56. Sym. Comm. 15(9) 843 (1985) 57. Sym. Comm. 14(12) 1099 (1984) 67. J. Med. Chem. 13, 26 (1970) 70. US 3,458,576 (1969) 82. J.Pharm. Soc. Japan, 413-6(1954) 85. J. Am. Chem. Soc. 75(7) 1837(1952) 86. US 2647930B1 (1953) 87. DE 848197 (1952) 89. Helv. Chim. Acta. 33, 912 (1950) 94. J. Org. Chem. 15, 8 (1950) 96. US 2,636,901 (1949) 103. Justus Lieb. Ann. Chem. 215 (1948) 112. J. Am. Chem. Soc. 54, 271 (1933) 113. US 1879003 (1932) 3-phenylpropanol 5. Tetra. 63, 9758 (2007) (R)-3-phenylpropane-1,2-diol 5. Tetra. 63, 9758 (2007) 2-benzyloxirane 5. Tetra. 63, 9758 (2007) (R)-3-phenyl-2-(phenylamineooxy) 5. Tetra. 63, 9758 (2007) propan-1-ol tert-butyl 1-iodo-3-phenylpropan 6. Chem. European J. 12(15)4191-7(2006) -2-ylcarbamate 9. Faming Zhuanli Shenging Gongkai Shuominshu, patent 1673210 (2005) tert-butyl 1-phenylpropan-2- 6. Chem. European J. 12(15)4191-7(2006) ylcarbamate 9. Faming Zhuanli Shenging Gongkai Shuominshu, patent 1673210 (2005) (S)-1-phenylpropan-2-ol 5. Tetra. 63, 9758 (2007) And 8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005) 1-phenylpropan-2-ol 13. Org. and Biomolecular Chem. 3(6) 1049 (2005) 14. J. Chem. Research 10, 681 (2004) 28. Tetra. Lett. 41(34) 6537 (2000) 102. J. Am. Chem. Soc. 70, 4048 (1948) (S)-2-(1-phenylpropan-2- 8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005) yl)isoindoline-1,3-dione 34. Tetra. Asym. 4(7) 1619 (1993) (1R,2S)-2-amino-1-phenylpropan-1- 11. J. Med. Chem. 48(4) 1229 (2005) ol 23. US 6399828 (2002) 40. J. Chrom. Sci. 28, 529 (1990) 53. Anal. Chem. 58(8) 1642 (1986) Norephedrine 11. J. Med. Chem. 48(4) 1229 (2005) 23. US 6399828 (2002) (1R,2S)-2-amino-1-phenylpropan-1- 40. J. Chrom. Sci. 28, 529 (1990) ol 53. Anal. Chem. 58(8) 1642 (1986) 77. DE 968545 (1958) 2-acetamido-1-phenylpropyl acetate 11. J. Med. Chem. 48(4) 1229 (2005) 2-nitro-N-(1-phenylpropan-2-yl) 13. Org. and Biomolecular Chem. 3(6) 1049 benzenesulfonamide (2005) 1-phenylpropan-2-one 14. J. Chem. Research 10, 681 (2004) 19. Tetra. Asy, 14, 2119 (2003) P-2-P = Phenyl-2-propanone 22. Tetra. Asym. 13(20) 2277 (2002) 32. J. Chem. Soc. Perkin Trans I, 265 (1996) 40. J. Chrom Sci. 28, 529 (1990) 43. US 4950606 (1990) 44. Angew Chem. Int. Ed. Engl. 28(2) 218 (1989) 47. J. Med. Chem. 31(8) 1558 (1988) 50. US 4,000,197 (1996) 51. Organometallics, 5, 739 (1986) 54. Khimiya Getero Soedinenii, 12, 1648 (1985) 60. J. Labelled Comp. Rad. 18(6) 909 (1981) 63. J. Chem. Education 51, 671 (1974) 65. J. Am. Chem. Soc. 93, 2897 (1971) 71. Coll. Czech. Chem. Comm. 33(11)3551 (1968) 75. US 3,187,047 (1965) 76. Tetra. 19, 1789 (1963) 79. US 2,828,343 (1958) 80. DE 870265 (1953) 91. J. Am. Pharm. Assoc. 687 (1950) 92. Bull. Soc. Chem. France 1045 (1950) 95. GB 702,985 (1949) 97. J. Am. Chem. Soc. 70, 1187 (1948) 98. J. Am. Chem. Soc. 70, 1315 (1948) 100. J. Am. Chem. Soc. 70, 2811 (1948) 106. J. Org. Chem. 9, 529 (1944) 107. J. Applied Chem. (USSR) 14(3) 410 (1941) 108. J. Gen. Chem. (USSR) 11(4) 339 (1941) 117. J. Chem. Soc. 18 (1930) (S)-(2-azidopropyl)benzene 14. J. Chem. Research 10, 681 (2004) (1-phenylpropan-2-yl) magnesium 15. Org. Lett. 6(24) 4619 (2004) bromide 4,4,5,5-tetramethyl-1,3-dioxolan-2- 15. Org. Lett. 6(24) 4619 (2004) one O-tosyl oxime (1S,2S)-1-phenyl propane-1,2-diol 16. Tetra. Asy, 15(19) 3111 (2004) (1R,2S)-1-azido-1-phenylpropan-2-ol 16. Tetra. Asy, 15(19) 3111 (2004) 2-methyl-3-phenylaziridine 16. Tetra. Asy, 15(19) 3111 (2004) 17. J. Combinatorial Chem. 5(5) 590 (2003) 2-phenylacetaldehyde 49. J. Am. Chem. Soc. 109(7) 2224 (1987) 52. J Chem. Soc., Chem. Comm. 2, 176 (1986) (R)-2-methyl propane-2-sulfinamide 17. J. Combinatorial Chem. 5(5) 590 (2003) (R)-1-phenylethanamine 19. Tetra. Asy, 14, 2119 (2003) 1-(bromomethyl) benzene 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) (R)-3,3,5-trimethyl-1-propionyl 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) pyrrolidin-2-one (S)-2-methyl-3-phenylpropanamide 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) (S)-2-amino-3-phenylpropanoic acid 25. J. Org. Chem. 65(16) 5037 (2000) (S)-2-amino-3-phenylpropan-1-ol 25. J. Org. Chem. 65(16) 5037 (2000) (S)-tert-butyl-1-phenylpropan-2- 25. J. Org. Chem. 65(16) 5037 (2000) ylcarbamate 1-phenyl-1-propyne 26. Org. Lett. 2(13) 1935 (2000) 74. Chem. Pharm. Bull. 13(2) 118 (1965) allylbenzene 27. Tetra. 56, 5157 (2000) 69. J. Am. Chem. Soc. 91, 5647 (1969) Phenylmagnesium bromide 31. Tetra. 53(13) 4935 (1997) Diethyl-2-methylaziridin-1- 31. Tetra. 53(13) 4935 (1997) ylphosphonate (R)-2-(tert-butoxycarbonylamino)-3- 33. Tetra. Lett. 36(8) 1223 (1995) phenylpropanoic acid (R)-tert-butyl 1-hydroxy- 33. Tetra. Lett. 36(8) 1223 (1995) 3-phenylpropan-2-ylcarbamate (S)-tert-butyl 1-phenylpropan-2- 33. Tetra. Lett. 36(8) 1223 (1995) ylcarbamate (1S,2S)-2-amino-1-phenylpropane- 34. Tetra. Asym. 4(7) 1619 (1993) 1,3-diol 36. Tetra. Asym. 3(10) 1283 (1992) (E)-1-phenylpropan-2-one oxime 51. Organometallics 5, 739 (1986) 54. Khimiya Geter Soedinenii 12, 1648 (1985) And 59. Synthesis 4, 270 (1982) 62. Tetra. 32 (11) 1267 (1976) (Z)-1-phenylpropan-2-one oxime 73. Tetra. 24(16) 5677 (1968) 82. J. Pharm. Soc. Japan, 413 (1954) 91. J. Am. Pharm. Assoc. 687 (1950) 93. Berichte 124(10) 2303 (1991) 99. Yakugaku Zasshi 74, 413 (1954) 101. Bull. 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Berichte 66B, 684 (1933) 111. J. Am. Chem. Soc. 55, 1701 (1933)

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