Review: Synthetic Methods for Amphetamine

Review: Synthetic Methods for Amphetamine A. Allen1 and R. Ely2 1

2

Array BioPharma Inc., Boulder, Colorado 80503 Drug 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 methamphetamine. 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 Curtius rearrangement [118, 110, 80], the Schmidt rearrangement [80], the Lossen rearrangement [118], the Beckmann rearrangement [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 precursor chemicals (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 Lossen 1. metal catayltic red. alkylations 1. methyl ethyl ketone Curtius 2. disolved metal red. aminations 2. ethyl acetoacetate Hofmann 3. non metalic red. Mitsunobu 3. aldehyde -nitroethane Wolf Enzymic Time-Line of Synthetic Routes to Amphetamine

1900

1930

1970

2009

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 alpha to a primary amine 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 lithium [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 Raney nickel [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 benzene with iron or aluminum trichloride has been improved with the use of N(trifluoroacetyl)--amino acid chloride as a chiral F-C reagent to manufacture amphetamine [55]. Intermediates of nitrostyrene have been reduced chirally and nonchirally 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], alkyne-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 isomer to an equilibrium mix of R,S-amphetamine [2]. Improved resolution from racemic mixture 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

8, 34

Figure 1a.

Hydrazine

21, 37 Hofmann rearrangement 8, 13, 28

Mitsunobu

5, 31, 16 1, 15, 17, 31

Ring Opening Organometalic

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

Oxime Amination

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

Imine Resolutions

2, 3, 10, 14, 22, 24, 29, 39, 43, 48 4, 7, 12, 18, 20, 35,41,42, 46, 47, 56

Enzymic 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) 2. 3. 10. 14. 22. 24. 39. 43.

(see Scheme 4) J. Org. Chem., JOC 73(2008)364 J. Org. Chem., JOC 72(2007)6918 Indian J. Chem. Soc. B., IJCS 44B(2005)1312 J. Chemical Research, JCR 10(2004)681 Tetrahedron Asymmetry, TA 13(2002)1315 Synthetic Comm., SC 31(2001)569 Chem. & Pharm. Bull., CPB 38(1990)3449 US Patent 04950606B1 (1990)

Non-Chiral Organic Synthesis (see Scheme 3)

4. 12. 13. 15. 26. 27. 31. 32. 37. 38. 40. 41. 42. 45. 48. 57. 52. 54. 56. 22.

Tetrahedron Letter, TL 48(2007)5707 J. Organic Chem., JOC 70(2005)5519 Organic & Biomol. Chem., OBC 3(2005)1049 Organic Letters, OL 6(2004)4619 Organic Letters, OL 2(2000)1935 Tetrahedron, Tetra. 56(2000)5157 Tetrahedron, Tetra. 53(1997)4935 J. Chem. Soc. Perkin I, JCSP1 1(1996)265 J. Labeled Comp. Rad., JLCR 31(1992)891 J. Medicinal Chem., JMC 34(1991)1094 J. Chromatographic Sci., JCS 28(1990)529 Tetrahedron, Tetra 46(1990)7403 Tetrahedron, Tetra 46(1990)7743 Coll. Czech. Chem. Comm., 54(1989)1995 Organic Reactions, Vol 36 (book, 1988) J. Medicinal Chem., JMC 31(1988)1558 J. Chem. Soc. Chem. Comm. 2(1986)176 Khimya Geter. Soed #12,1648(1985) Synthetic Comm., SC 15(1985)843 Tetrahedron Asymmetry, TA 13(2002)1315

Stereoselective Synthesis (see Scheme 2)

1. 5. 6. 8. 9. 11. 14. 16. 17. 18. 19. 20. 21. 22. 23. 25. 28. 33. 34. 36. 37. 41. 44. 49. 51. 53. 54. 55.

J. American Chem. Soc. JACS 131(2007)9882 Tetrahedron, Tetra. 63(2007)9758 Chemistry A European J., JEC 12(2006)4197 Biological Med. Chem. Letter, BMCL 15(2005)3039 FZSGS patent # 1673210 (2005) J. Medicinal Chem., JMC 48(2005)1229 J. Chem. Research, JCR 10(2004)681 Tetrahedron Asymmetry, TA 15(2004)3111 J. Combinatorial Chem. 5(2003)590 J. Chem. Research, JCR 3(2003)128 Tetrahedron Asymmetry, TA 14(2003)2119 J. Chinese Chem. Soc. 49(2002)505 J. Chem. Soc. Perkin I, JCSP1 16(2002)1869 Tetrahedron Asymmetry, TA 13(2002)1315 US patent #6399828(2002) J. Organic Chem., JOC 65(2000)5037 Tetrahedron Letters, TL 41(2000)6537 Tetrahedron Letters, TL 36(1995)1223 Tetrahedron Asymmetry, TA 4(1993)1619 Tetrahedron Asymmetry, TA 3(1992)1283 Acta. Chimica Scan. 45(1991)431 Tetrahedron, Tetra 46(1990)7403 Angew Chem. Int. 28(1989)218 J. American Chem. Soc. JACS 109(1987)2224 Organometallics, 5(1986)739 Analytical Chem. 58(1986)1642 Khimja Geter. Soed. 12(1985)1648 J. Organic Chem., JOC 50(1985)3481

# = Reference

Figure 1b.

Amphetamine Review (1989 – 2009) Time-Line of Synthetic Routes to Amphetamine

1985

1970

1930

1900

Stereoselective syn.

2009

Stereoselective Synthesis of Amphetamine 1985--2009 Chiral

N R

Chiral

JACS 131(29) 9882 (2009) JOC 50(19) 3481 Tetra Asy 3(10) 1283 (1992) Ph Organometallics 5, 739 (1986) (1985) TA 4(7)1619(1993) KGS #12,1648 (1985) OH Chiral 2Q. 2A. 2B.

Ph

OH

51 55

2O.

NH2

44 33

Chiral

Ph

Ph 2M.

Ph 18 20 41

NH2 (S)-1-phenylpropan -2-amine

11

40 17

54

2G. 40

49 2L.

14 19 5

53 2H.

Ph

O

Tetra. Asy. 14, 2119 (2003) Organometallics 5, 739 (1986) J. Chrom. Sci. 28,529 (1990) KGS #12,1648 (1985) Chiral

2I. 2K. Ph

2J.

H

J.Comb.C. 5(5) O 590 (2003) JACS 109(7) 2224 (1987)

OH

I Chiral HN BOC

Chem. Eur.J. 12, 4191 2006 FZSGS #1673210 (2005)

Ph Chiral

OH

NH2

JMC 48(4) Chiral 1229 (2205) Anal. Chem. 58(8) 1642(1986) US # 6,399,828 (2002) J. Chrom. Sci. 28,529 (1990)

Org. Biomol. Chem. 3,1049(2005) Ph B.M.C.L. 15(12) 3039 (2005) Chiral J. Chem. Res. 10, 681 (2004) T.L. 41(34) 6537 (2000) TA 15(19)3111(2004)

HO

Ph

OH

Ph Chiral

Chiral

J. Chinese C S 49, 505 (2002) Tetra. 46(21) 7403 (1990)

23

8 16

NO2

2F. J.C. Res. Syn. 3, 128 (2003)

6 9

19 51

JCS, Perkin T.I, 16 1869 (2002)

2E. 5

Amphetamine

21

2N.

H

Tetra. 63(39) 9758 (2007)

5

25

Chiral

H2N

5

5

21 O

1

Ph

34

28.

Br

JCS, Perkin T.I, 16 1869 (2002)

Chiral

36

COOH

Ph

Chiral

O Tetra. 63(39) 9758 (2007) Ph OH Chiral ONHPh Tetra. 63(39) 9758 (2007) 2C. Ph OH OH O 2D.

54

2P.

Chiral NH2 JOC 65(16) 5037 (2000) Tetra. Let. 36(8) 1223 (1995) Angew chem. Int. 28(2) 218 (1989)

Scheme 2.

Chiral Tetra. 63(39) 9758 (2007)

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 base (1-phenylpropan2-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 2phenylacetaldehyde [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 workers preformed a chiral oxy-alkylation with nitrosobenzene to (R)-3-phenylpropan-1,2-diol [5, route 2C2D]. 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-2ol; [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 phenylpropanolamine [11, 23, 29, 40, 53; route 2H] and phenylalanine [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 alkyl 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

acetic anhydride to yield the ester 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

1985

1970

1930

1900

non-chiral syntheses

2009

Non-Chiral Synthesis of Amphetamine 1985--2009

non-Chiral Tetra. Let. 48(32) 5707 (2007) 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) Syn. Comm. 15(9) 843 (1985) OH

Scheme 3 non-Chiral JCS, Chem. Comm. 2, 176 (1986)

Br

NO2

3N. H3C

N

O

NH Ph

N

non-Chiral Org. Rea. 36(book) (1988)

28

Ph

3M.

52

13

48

O H

NO2

3A. NH2 SO2

non-Chiral Org. Let. 6(24) 4619 (2004)

3B. 46. LiAlH4 Mg 47 Br 42 56 3C. O 35 non-Chiral N O Tetra. Let. 41, 6537 (2000) 12 O Ts 4 O O 15 OH N O tBu3D. O 17 H 27 58

47

3L.

45

Ph CN

32 22 40 NH3 HoAc

Coll. Czech. Chem Comm. 54(7) 1995 (1989) non-Chiral

3J. O

Mg reduction

O O

non-Chiral O Acta Chem. Scand. 45, 431 (1991)

NH2

n-BuLi

non-Chiral Tetra. 56, 5157 (2000)

3E.

NH2 Ph Ph

31 37

3K.

26

Amphetamine 37

S

Pd/H2

NH2

non-Chiral JMC 31(8) 1558 (1988)

Ph

Cp2TiMe2

3F. O P O O N

3G.

non-Chiral O.L.. 2(13) 1935 (2000)

MgBr

3H.

3I. COOH Acta Chem. Scand. 45, 431 (1991) non-Chiral

O

T. 53(13)4935 (1997) non-Chiral

JCS, PTI, 265 (1996) Tetra. Asy. 13(12) 1325 (2002) J. Chrom Sci. 28, 529 (1990) 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 ammonia equivalent, was used for the hydroamination of 1-phenyl-1-propyne to amphetamine [26; route 3F]. Several citations occurred in the literature for the reductive amination of P-2-P to amphetamine [32, 22, 40; route 3H]. The classical malonic ester synthesis 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 / ethanol 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 Isomers: 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 inducedradical 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)-2naphthylglycolic 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 Claisen condensation. In the case of phenylacetonitrile (benzylnitrile) [107], the acidity of the central methylene hydrogens 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

1900

Organic Transformations to Amphetamine 1900 - 2009

non-chiral syntheses

1985

1970

1930

NO2

H COOH

NH2 6BB.

6A. 113 114 54 57 62 86

107

O

39

6D.

OH

6E.

37 34 5

O NH2

21 117

Amphetamine

26

O

112 121

OH

45

27

6H. S

15 6I.

6U.

17 49 52

6T.

88 106 101

23 40

116 H 6S.

53

11 115 116

Br 6R. 6Q.

O

O

6P. OH NH2

8 5 65 13 40 64 14 13 6J. 63 19 14 16 91 1 54 20 28 51 29 51 52 96 22 32 66K. 52 38 54 93 9049 43 92 36 6L. 9879 59 91 48 76 40 108 71 101 59 107 99 105 120 73 82 118 6M. 88 6N. 6O. O OH N OH

OH

HO 6F.

6G.

74

O

OH

103

80 111 69

O

O

NH2 5

100

58

O O

NH2

1 120

O

6C.

6W.

6V.

Scheme 6.

6B.

4 67 87 95 41 12 70 94 Br 6AA. 84a 18 74 42 75 84b 20 109 44 84 6Z. 5 25 102 O 47 22 85 72 56 35 89 33 H 122 55 60 61 92 110 6Y. 95 92 31 89 80 47 Br 6X. 21 CN

2009

O

R

Ph CN Br

OH

OH O

References: [1.] G. Hou, F. Gosselin, W. Li, J.C. McWilliams, Y. Sun, M. Weisel, P.D. O‘Shea, C. Chen, I.W. Davies, X. Zhang, Enantioselective Hydrogenationof N-H imines, J. Am. Chem. Soc. Vol.131, No 29, (2009) 9882-3. [2] L. Routaboul, N. Vanthuyne, S. Gastaldi, G. Gil, M. Bertrand, Highly Efficient Photochemically Induced Thiyl Radical-Mediated Racemization of Aliphatic Amines at 30 deg C., J. Org. Chem., Vol 73, No 2, (2008) 364-8. [3] M. Nechab, N. Azzi, N. Vanthuyne, M. Bertrand, S. Gastaldi, G. Gil, Highly Selective Enzymatic Kinetic Resolution of Primary Amines at 80 deg.C: A comparative Study of Carboxylic Acids and Their Ethyl Esters as Acyl Donors, J. Org. Chem. Vol 72, No 18, (2007) 6918-23. [4] T. Ankner, G. Hilmersson, Instantaneous SmI2/H2O/amine mediated reduction of nitroalkanes and a,b-unsaturated nitroalkenes, Tetrehedron Lett. 48 (2007) 5707-10. [5] S. K. Talluri, A. Sudalai, An organo-catalytic approach to the enantioselective synthesis of (R)-selegiline, Tetrahedron, Vol 63, No 39, 9758-62. [6] J. Granander, R. Sott, G. Hilmersson, Correlation between the 6Li, 15N Coupling Constant and the Coordination Number at Lithium, Chem. Eur. J. 12, (2006) 4191-7. [7] M. Guy, S. Freeman, J.F. Alder, S.D. Brandt, The Henry reaction: Spectroscopic Studies of Nitrile and Hydroxylamine by-products formed during synthesis of psychoactive phenylalkylamines, Central European J. Chem. Vol. 6, No. 4, (2008) 526534. [8] D.G. Barrett, D.N. Deation, A.M. Hassell, R.B. McFadyen, A.B.Miller, L.R. Miller, J.A. Payne, L.M. Shewchuk, D.H. Willard, Jr., L.L. Wright, Acyclic Cyanamide-Based Inhibitors of Cathepsin K, BioOrg. Med. Chem. Lett., 15 (2005) 3039-43. [9] B. Zhong, J. Zheng, H. Liu, K. Liu, J. Xie, L. Liu, W. Li, L. Chen, W. Liu, Y. Wang, X. Ge, X. Weng, Preparation of levorotatory R-(-)-phencynonate as anticholinergic angents, Faming Zhuanli Shenqing Gongkai Shuomingshu, patent 1673210, 28 Sept. (2005).

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Supplemental Material: JACS 131, 9882 (2009)

chir al MeMgI

N

NH

Ir-(S,S)-fbinaphane

NH2

H2 (S)-1-phenylpropan-2-amine

2-phenylacetonitrile

1-phenylpropan-2-imine

Ref. 1. JOC 73(2) 364 (2008)

chir al Photochemical --Racemization

NH2

NH2

HSCH2CO2Me Benzene

1-phenylpropan-2-amine

(S)-1-phenylpropan-2-amine

Ref. 2. chir al

JOC 72(18) 6918 (2007) NH2

Biotrasformation, Enzymic, Stereoselective Lauric acid Lipase


NH2

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

Ref. 3.

Tet r a. Let. 48(32) 5707 (2007)

non-chir al

NH2 NO2

H 2N

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

Ph

SmI2 1-phenylpropan-2-amine

Ref. 4.

chir al

Tet r a. 63, 9758 (2007)

O

(R)-3-phenyl-2-(phenylaminooxy)propan-1-ol H nitrosobenzene l-proline NaBH 4

3-phenylpropanal

O

1, TsCl

OH

NHPh

(R)-3-phenylpropane-1,2-diol

TEA

Ref. 5.

2. NaH 1. NaN3

LiAlH4

O


(S)-1-phenylpropan-2-ol

chir al H N

O

H N

SmI2

O I t er t-butyl 1-iodo-3-phenylpropan -2-ylcarbamate

NH 2

2. Pd/C H2

OH 2-benzyloxirane

OH

Pd/C

OH

O

Chem. Eur opean J. 12(15)4191-7(2006) NH2 TFA

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

ter t -butyl 1-phenylpropan-2ylcarbamate

non-chir al

Ref. 6.

Centr al Eur. J. Cehm 6( 4) 526-34 (2008) NO2

NaBH4

NH2

BF3 - Et2O

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


Ref. 7.

chir al Phth Anh. OH

NH2 -NH 2 N

Ph3 P DEAD, THF

O

O

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

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

Ref. 8. chir al H N

NH 2

MeOH

Bioor ganic & Med. Chem. Lett er s, 15( 12) 3039-43 ( 2005)

Faming Zhuanli Shenqing Gongk ai Shuomingshu # 1673210 (2005) H N O TFA SmI2 O

O I t er t-butyl 1-iodo-3-phenylpropan -2-ylcarbamate

NH2

O ter t -butyl 1-phenylpropan-2ylcarbamate


Ref. 9

chir al

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

NH2


chir al

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

Ref. 10.

Ac

OH NH 2

O

Ac 2O

H N

norephedrine

2-acetamido -1-phenylpropyl acetate

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

H 2 / aS O 4 B Pd-

H N

Ac

Ref. 11.

J . Med. Chem. 48( 4) 1229-36 ( 2005) NH 2

H2 SO4

Ac


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

non-chir al

J OC 70( 14) 5519 (2005) NO2

NH2

LiAlH4


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

Ref. 12. non-chir al

NH2 SO 2 NO2

OH 1-phenyl propan-2-ol

Or g. and Biomolecular Chem. 3( 6) 1049 ( 2005)

HN

O

PhSH, K2CO3

S DCC

O O2 N 2-nitro-N-(1-phenylpropan-2-yl) benzenesulfonamide

NH2

50o C

amphetamine 1-phenylpropan-2-amine

Ref. 13.

J. Chem. Research 10, 681 (2004)

chir al

(S)-(2-azidopropyl)benzene Pd/C baker's yeast O

1-phenylpropan-2-one

O S O O N

Or g. Letters, 6( 24) 4619-21 ( 2004)

MgBr

HCl

N O

O O

OH

O

SOCl2 O

S

NH 2

O

1-phenyl-N (4,4,5,5-tetramethyl1,3-dioxolan-2-ylidene) propan-2-amine

(1-phenylpropan-2-yl) magnesium bromide

chir al


Ref. 14.

(S)-1-phenylpropan-2-ol

non-chiral

H2

N3

OH

sucrose

NH2

amphetamine

Ref. 15.


N3

NaN3

O

OH

OH (1R,2S)-1-azido-1-phenylpropan-2-ol

(1S,2S)-1-phenyl propane-1,2-diol

Tet r ahedron Asy mmet ry 15(19),3111-6 (2004) H N

Ph 3P

Pd-C


Ref. 16.

HCO2 NH 4

NH2

2-methyl-3-phenylaziridine

amphetamine J. Combinator ial Chem. 5(5) 590-6 (2003)

chir al O S

O H

NH2

CuSO4

(R)-2-methyl propane-2-sulfinamide

MeMgBr

N

(R,E)-2-methyl -N-(2-phenylethylidene) propane-2-sulfinamide

2-phenylacetaldehyde

O S

O S

Ref. 17. HCl, MeOH N H

(R)-2-methyl-N-((S)-1-phenyl propan-2-yl)propane-2-sulfinamide

NH 2 amphetamine (S)-1-phenylpropan-2-amine

chir al

J. Chem. Resear ch ( S), 128 (2003) NO2

NH2

Ruthenium BINAP


Ref. 18.

Tet r a. Asy . 14, 2119 (2003)

chir al

(S)-1-phenylpropan-2-amine H2 N

O

NH 2

N

1-phenylpropan-2-one (R)-1-phenylethanamine

Ref. 19.

(S,E)-1-phenyl-N(1-phenylpropan-2-ylidene) ethanamine

chir al

J. Chinese Chemical Societ y, 49, 505 ( 2002) NO2

NH2

Ru2Cl2(PPh3)3 toluene

H2 (E)-(2-nitroprop-1-enyl)benzene

Ref. 20.


JCS Per k in T .I 16, 1869(2002)

chir al O Br

1-(bromomethyl) benzene

O

O

O

N

LDA, THF

N

(R)-3,3,5-trimethyl -1-propionylpyrrolidin-2-one

(5R)-3,3,5-trimethyl1-(2-methyl-3-phenyl propanoyl)pyrrolidin-2-one

Ref. 21. O NH 3, MeOH

NH2 NH 2

PhI(OOCCF3) 2

(S)-2-methyl-3-phenylpropanamide


chir al

Tetr a. Asy. 13( 20) 2277 ( 2002) NH2

Enzymic, Resolution


Ref. 22.

NH2

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

non-chiral NH 2

HCOO NH 4 O

Pd, MeOH

Ref. 22. amphetamine

T etr ahedr on Asymmetr y, 13( 12) 13115-1320 ( 2002)


chir al


US pat . # 6399828 2002) OH NH 2

NH 2

HI, P4 HCl

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

Ref. 23. BaSo4 Ac 2O HoAc

H2

OAc

Pd

NH 2

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

chir al

Syn. Comm. 31(4) 569 (2001) NH 2

Enzymic, Resolution

NH 2

Candida antarcitica Lipase 1-phenylpropan-2-amine

Ref. 24.


O

chir al NH 2

LiBH4 /TMSCl

COOH (S)-2-amino-3phenylpropanoic acid

BOC) 2O

NH 2

NH

OH (S)-t er t-butyl 1-hydroxy3-phenylpropan-2-ylcarbamate

OH (S)-2-amino-3-phenylpropan-1-ol

Ref. 25. O

O

O

NH

(Ph) 3P / I

I ( S)-tert -butyl 3-iodo-1phenylpropan-2-ylcarbamate

J . Or gainic Chemistr y 65(16) 5037-42 ( 2000)

O NH

N-Selectride

O

NH 2

TFA

( S)-tert -butyl 1-phenylpropan amphetamine -2-ylcarbamate S)-1-phenylpropan-2-amine

non-chir al NH 2

Cp2 TiMe 2

Cp2 TiMe2

NH2 Ph H 2 , Pd/C (E)-diphenyl-N1-phenylpropan-2-amine (1-phenylpropan-2- Ph ylidene)methanamine amphentamine N

diphenyl methanamine

1-phenyl1-propyne

Ref. 26.

Or ganic Let ter s, 2( 13) 1935-1937 ( 2000) T et ra. 56, 5157 ( 2000)

Ref. 27.

non-chir al H 2N

Ph

Pd/C H2 NH

cat. n-Bu Li


allylbenzene

N-benzyl-1-phenylpropan-2-amine T et rahedron Letters, 41( 34) 6537-40 ( 2000)

non-chir al tBuCO) 2O OH 1-phenyl propan-2-ol

NH2

TFA

Ph 3P

NH

DEAD, THF O ter t-butyl 1-phenylpropan -2-ylcarbamate

O

DCM

NH2 amphetamine

Ref. 28.


chir al

JP 03191797 (1991) O NH 2

Enzymic, Resolution

BuNH 2

C: 9031-66-1 phenylpropan-1-one

Ref. 29.

non-chir al O


Zhongshan Dazue Xuebao 35( 5) 73-76 (1996) HOOC * OH NH 2 NH 2 HO * COOH

Leuckart Reaction ammonium formate

d-Tartaric acid


Ref. 31.

non-chir al O MgBr

O P N

T et rahedron, 53(13) 4935-4946, 1997 O

O CuI

phenylmagnesium diethyl 2bromide methylaziridin1-ylphosphonate

HCl

diethyl 1-phenylpropan2-ylphosphoramidate

non-chir al

1-phenylpropan2-amine NH2

amphetamine

J.Chem.Soc., P er kin T rans I , 265 ( 1996) O

1-phenylpropan-2-one P-2-P

O O P NH

THF

Ref. 30.

Mg

MeOH

NH3

HoAc

NH 2

Ref. 32.


chir al

Tet r a. Lett . 36( 8) 1223 (1995)

O

BOC

BOC HN

O BH 3

O

OH

THF

(R)-2-(t er t-butoxycarbonylamino) -3-phenylpropanoic acid

NH

TEA

OH

CH 3SO2 Cl

CH 3CH2 SH

NH O Ms

Ref. 33.

NaH BOC

BOC

NH

NH EtOH

O S

NH 2

TFA

Ra-Ni


chiral

OH OH OH

Phth Anh.

N

NH 2 (1S,2S)-2-amino1-phenylpropane-1,3-diol

O

Ref. 34. H 2 / Pd-C

I OH O

Ph) 3P / I N

2-((1S,2S)1,3-dihydroxy1-phenylpropan -2-yl)isoindoline-1,3-dione

I O

O

2-((1S,2S)1,3-diiodo-1-phenyl propan-2-yl)isoindoline1,3-dione

NH2 -NH2 N

O

NH 2

O

amphetamine

T etr ahedr on Asymmetr y 4( 7) 1619-24, 1993

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

non-chir al

J. Labelled Comp. and Rad. 31(11) 891 ( 1992) NO2

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

NH2

LiAlH4

Ref. 35.


Ref. 36.

chir al

T etr ahedr on Asymmetr y,3( 10) 1283-8 ( 1992)

E&Z

NH 2

H 4Ru(arene) N

BINAP

OH

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

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

non-chir al O O O

Acta. Chemica Scandinavica 45, 431 ( 1991) O O

Ref. 37. NaH

O

O

CH3-I

O

DMSO

methyl 2-benzyl-2-methyl -3-oxobutanoate

dimethyl 2-benzylmalonate O OH

1. NaOH 2. AcOH

chir al

1. -N

2-methyl-3-phenyl propanoic acid

NH2

Ph O P Ph TEA/heat N N+

NH2


2. HCl / heat

resolution

NH2

(+)-10-camphorsulonyl chloride amphetamine



Tetr ahedr on Lett . Vol. 32, No. 49 ( 1991) 7325-8.

HOOC

chir al NH 2

* * COOH OR

RO

R=H resolution Benzoyl p-toluoyl

amphetamine


Ref. 38.


non-chir al

NH 2

Chem. Pharm. Bull. 38(12) 3449 (1990) NO2

Biotransf ormation cat. Peptostr eptococcus Anaer obius


Ref. 39.

NH2


chir al

Ref. 40.

OH NH2

J. Chr om. Sci. 28, 529 ( 1990) Cl

SOCl2

NH2

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-chir al

J. Chr om. Sci. 28, 529 ( 1990)

Ref. 40. OH

Ac2)O

NaOAc O 2-phenylacetic acid

O 1-phenylpropan-2-one

Ref. 41.

chir al NO2

BH3-THF


Tet r a. 46( 21) 7403 (1990) NH 2 NO2 Ru Cl [(-)-DIOP] 2 2 3 H2


(2-nitropropyl)benzene

non-chiral

Ref. 42.

NO2

NH2

Leuchart Red


Tet r a. 46( 21) 7743 ( 1990) NH 2

BH3-THF cat. NaBH4

amphetamine


chir al

U.S. pat . # 4950606 (1990)

Enzymic, Resolution NH2

Ref. 43.


non-chiral

NH2

amino-acid transminase f rom Bacilllus Megat er ium


Biotransf ormation O


amino-acid transminase f rom Bacilllus Megater ium

Ref. 43.

NH 2


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

non-chiral O

O

O

NH

(CH3)3SiCl

NH COOH 2-(benzyloxycarbonyl) -3-phenylpropanoic acid

LiBH4 /THF benzyl 1-phenylpropan-2-ylcarbamate

Ref. 44.

NO2

NH2

(CH3)3SiCl LiBH4 /THF



Coll. Czech. Chem. Comm. 54( 7) 1995 ( 1989)

non-chir al

3-oxo-2-(2-(phenylthio)phenyl)butanenitrile Ph S CN H3PO4 NaOEt

Ph S

O

2-(2-(phenylthio)phenyl)acetonitrile

Ref. 45.

S

NH2OH

Ph

Na EtOH N OH

N

S

1-(2-(phenylthio)phenyl)propan-2-one

S HCl

NH 2 1-(2-(phenylthio)phenyl)propan-2-amine

Ref. 46.

non-chir al

Ph

O

EtOH

CN

Ph

O

O

Red - Al, THF

(E )-1-phenylpropan-2-one O-methyl oxime NO 2 Red-Al THF


NH2

Or g. React ions 36, book ( 1988) NH 2

1-phenylpropan-2-amine NH 2

Ref. 47.

non-chir al O

J.Med.Chem. 31( 8) 1558 (1988) NO2

NO 2

H



benzaldehyde

NH2

LiAlH4

chir al

JP 63219396 (1988) NO2

Ref. 48.

Biotransf ormation /

NH2

Enzymic, Resolution 1-phenylpropan-2-amine


chir al

N N

H 2N N

O H

(R,E )-2-methyl -N-(2-phenylethylidene) pyrrolidin-1-amine

(R)-2-methyl 2-phenylacetaldehyde pyrrolidin-1-amine

Ref. 49.

JACS 109(7) 2224-5 (1987) H N N

CH3 Li / CeCl3

NH 2

H 2 / Ra-Ni 375 psi / 60 o amphetamine

(R)-2-methyl-N -((S)1-phenylpropan-2-yl) pyrrolidin-1-amine

(s)-1-phenylpropan-2-amine

chir al O

R or S

phenyl-2-propanone

NH 2

low pressure

*

Hydrogenation Raney Ni / H2

*

HN

*

[R,R]+ or [S,S]-

 -methylbenzylamine U S 4000,197 ( 1976)

Ref. 50. [S,S]-(-) 10% Pd-C

*

HN

*

NH 2 amphetamine

50 psi H2


chir al

Or ganometallics, 5, 739-46 (1986)

Ref. 51. N

O

OH

NH2

Rh(cod)Cl2 (E)-1-phenylpropan-2-one oxime


Ref. 52.

non-chir al

H-SiH(Ph)2

H

H N

O

LDA

NH

CH3I

J. Chem. Soc., Chem. Comm. 2, 176, ( 1986) CH 3 1. TFA Aphetamine N NH 2. Pd /C H2 Ph Ph

Ph Ph

2-phenylacetaldehyde

(E)-1-(2,2-dimethyl-1,1-diphenylpropyl) (E )-1-(2,2-dimethyl-1,1-diphenylpropyl) -2-(1-phenylpropan-2-ylidene)hydrazine -2-(2-phenylethylidene)hydrazine

Ref. 52.

non-chir al

H

H N

O

LDA

NH

Ph-CH2-Br

Ph Ph

acetaldehyde

non-chir al

J. Chem. Soc., Chem. Comm. 2, 176, ( 1986) CH 3 1. TFA Aphetamine N 2. Pd /C H2 NH Ph Ph

OH

US 2009292143 (2009)

Cl NH 2

NH 2

NH 2

Pd H2

Ref. 53.

(1S,2S)-2-amino-1-phenylpropan-1-ol


Khimiy a Get er ot siklicheskikh Soedinenii 12, 1648 (1985)

chir al O


N

OH

Na MeOH


NH2

Ref. 54.

chiral

O Cl

benzene

O

H N

CF3

O (S)-2-(2,2,2-trifluoroacetamido) propanoyl chloride J .Org.Chem. 50(19) 3481-4 (1985)

Ref. 55 OH H 2 / Pd-C

PBr 3

CF3

H N

CF3 O

O

(S)-N-(1-bromo-1-phenylpropan -2-yl)-2,2,2-trif luoroacetamide

(S)-2,2,2-trifluoro -N-(1-hydroxy-1-phenyl propan-2-yl)acetamide H N

H 2 / Pd-C

CF3

O (S)-2,2,2-trifluoro -N -(1-oxo-1-phenyl propan-2-yl)acetamide Br

H N

H N

AlCl3

CF3

K2 CO 3, MeOH

NH2

O amphetamine (S)-1-phenylpropan-2-amine

(S)-2,2,2-trifluoro-N-(1-phenyl propan-2-yl)acetamide

non-chiral

Ref. 56. NO2

Syn. Comm. 15(9) 843 (1985) NaBH4 BH3 - THF

NH2


Sy n. Comm. 14( 12)1099(1984)

non-chir al

NaBH 4 NO2

NH 2

BH 3 / THF

Ref. 57. non-chir al

amphetamine

Sy nt hesis ( 4) 270-3 (1982) O H 2N P O O

1. Hg(NO 3) 2 / 1,1-diCl-ethane

2. 10% NaOH / NaBH 4 (E )-prop-1-enylbenzene diethyl phosphoramidate

H N

O P O O

NH 2 HCl /benzene

Ref. 58.

amphetamine

chir al

Sy nt hesis ( 4) 270-3 (1982) N

O P Cl Ph Ph

OH

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

H N

LAH (-) Quinine / THF

N

CH2Cl2, DEA

HCl / ethanol

O O P Ph Ph

Ref. 59.

O O P Ph Ph

NH 2

amphetamine

J. Labelled compounds and radiophar maceuticals 18(6) 909 ( 1981)

non-chir al

NH2

O NH3 (Sealed) 1-phenylpropan-2-one

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

non-chir al

Ref.60.

Helvet ica chimica Acta 61( 2) 558 ( 1978) NO NO2 LiAlH4

NO (E)-prop-1-enylbenzene

NH2

Ref.61.

Ref. 62.

chir al

T etr ahedr on 32( 11) 1267-76 (1976)

E&Z NH 2

LiAlH 4 N

OH


non-chir al

1-phenylpropan-2-amine amphetamine J. Chem. Education 51, 671(1974) NH 2

O Al, HgCl2, NH4OH, 100 oC, 15min 1-phenylpropan-2-one

Ref.63.

non-chir al

JMC 16(5) 480-3 ( 1973) H N

(R)-1-phenylethanamine O

H2 N

Raney-Ni H2


(+) or (-)

(R)-1-phenyl-N-(1-phenylethyl)propan-2-amine (S)-1-phenyl-N-((R)-1-phenylethyl)propan-2-amine

Ref.64. H N

separation

NH 2

Pd-C / H2 MeOH


of Diastereoisomers

non-chir al

JACS 93, 2897 ( 1971) NH 2

O NaCNBH3 NH 4OH, MeOH


OH

chiral resolution NH2

Ref.65.

EP 915080 (1999) OH

NH2 O (s)-2-naphthylglycolic acid racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

non-chiral

Ref. 67. NO2


Ref. 66.

J.Med.Chem. 13, 26( 1970) LiAlH4 / THF

NH2

JACS 91, 5647 ( 1969)

non-chir al Hg(NO 3) 2

CH3CN

N

NO3 H N

NaBH4


NaOH N-(1-phenylpropan-2-yl)acetamide

non-chiral

Ref. 70. NO2

H N

HCl

O

NO 2

Hg

Ref. 69.

allylbenzene

O

US Pat. 3,458,576 (1969) Pd-C / H2

NH2

Pt / H2 Raney-Ni / H2


non-chir al

Coll. Czech. Chem. Comm. 33( 11) 3551-7(1968) O NH4 HCOO Ammonium Formate

HCl


NH 2

Ref.71.

chir al

Coll. Czech. Chem. Comm. 33( 11) 3551-7(1968) NH 2

NH 2

(+)-tartaric acid EtOH

Ref.71.


non-chir al

Ref. 72. AlCl3

benzene

HN 2-methylaziridine


J. Het er ocy clic Chem._5( 3)339( 1968) NH 2


Ref. 73.

non-chir al N

O

T etr a. 24(16) 5677 ( 1968) NH 2

LiAlH4

R

THF 1-phenylpropan-2-amine R = H or R = Ts

Chem Phar m Bull 13( 2)118( 1965)

non-chir al

Cl

Cl nitrosyl chloride NOCl

NO2

NO2

Pt2O H2

NO2Cl prop-1-ynylbenzene hypochlorous nitrous anhydride

Ref.74.

non-chir al

US Pat. 3,187,047 ( 1965) O

NH2

Raney-Ni / H2

NH4 oAc


Ref.75.

non-chir al

T etr a. 19, 1789 (1963) LEUCKART-WALLACH Mech O

NH 2

Formic Acid

NH4


non-chir al

Ref.76.

OH

DE_1958-968545(1958)

Cl NH 2

NH 2

Pd

NH 2

H2 (1S,2S)-2-amino-1-phenylpropan-1-ol

Ref. 77.


chir al NH 2

R H2 N

*

COOH

resolution  -amino acid


US 3028430 (1962) NH 2

Ref. 78.


non-chir al

US Pat. 2,828,343 ( 1958) O

NH 2

NH3 (g) CuO and Ba(OH)2 H2


Ref.79.

chir al

Ref. 80.

O

O

OH CO2Cl2 (S)-2-methyl-3phenylpropanoic acid chir al

Curtius rearrangement O

JOC_22( 1)33(1957) NH 2

N 3 HCl

Cl

NaN 3 (S)-2-methyl-3(S)-2-methyl-3phenylpropanoyl chloride phenylpropanoyl azide

Schmidt rearrangement

O

(S)-2-methyl-3phenylpropanoic acid


Ref. 80. HOOC

chir al

NH 2 NaN 3

H 2SO4

OH

Zhur nal Obshchei Khimii 28 ( 1958) 3323-8 NH 2 resolution d-Tartaric COOH acid amphetamine Ref. 81a (S)-1-phenylpropan-2-amine

*

NH 2 HO amphetamine 1-phenylpropan-2-amine

*


OH

US 2,833,823 (1958)

chir al NH 2

resolution

NH 2

H 3 PO 4 inriched in one isomer amphetamine 1-phenylpropan-2-amine

Ref. 81b


non-chiral

J_Phar m_Soc_Japan_413-416( 1954)

Ref. 82. NO 2

Raney-Ni NH 2


Raney-Ni

OH N

non-chir al

DE_1953-870265

NH 2

Ph

HN

O

N

PhenylHydrazine

N H

NH 2 PtO2 H2

Ref.83.

(E)-1-phenyl-2-(1-phenyl propan-2-ylidene)hydrazine

1-phenylpropan-2-one chir al

J. Labelled Comp. and Radio. 3( 1) 3-9 ( 1977) NH 2

*

*

LiAlD4

NH 2

*

p-MeTOSCl

D2 C

D2 C

COOH

O

OH

D-Phenylalanine

Ref. 84.

O O HN S

CH 3 p-TOS

LiAlD4

NH 2

*

Naphthalene radical anion

CD 3


CH 3

non-chiral

O O HN S

JACS_74( 7)1837(1952)

Ref. 85. NO 2

NH 2

LiAlH 4 acid


non-chiral

P-2-P (Nef reaction)

US Patent 02647930B1( 1953)

Ref. 86. NO 2

Organic Acids Raney-Ni / H 2


NH 2

non-chiral

DE_1952-848197( 1952)

Ref. 87. NO 2

NH 2

Raney-Ni / H 2


chir al

Chir ality 6(4) 314-20 ( 1994)

Ref. 88.

Distillation from optically active acids..

NH2

NH2

Resolution 1-phenylpropan-2-amine

non-chiral

(S)-1-phenylpropan-2-amine Helv. Chim. Act a. 33, 912 ( 1950)

Ref. 89. NO 2

NH 2

LiAlH4 / ether


O

chiral resolution NH 2

Or g. Syn. Coll. 2, 506 (1943) OH

HO OH

racemic-1-phenylpropan-2-amine

NH 2

/ water

O

l-malic acid


Ref. 90.

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

non-chiral

O O

SOCl2

OH

O

O O

O

Cl

2-phenylacetic acid

Ref. 91.

O

O O

2-phenylacetyl chloride

diethyl 2-(2-phenylacetyl)malonate J_Am_Phar m_Assoc_687-688( 1950) O


N

OH

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

NH2 1-phenylpropan-2-amine

non-chir al

Bull. Soc. Chem. Fr ance 1045 ( 1950) O

NH3

NH2

Raney-Ni / H2


Ref.92.

non-chir al

Chemische Ber icht e 124(10) 2303-6 ( 1991)

NO 2

NH 2 N

Cathode Red. at Hg or C electrode OH


non-chiral

JOC 15, 8 (1950)

Ref. 94. NO 2

Ref. 93.

Raney-Ni / H 2

NH 2


non-chir al

GB 702985( 1949) O

NH3

Raney-Ni / H2

NH2

or Pt or Pd 1-phenylpropan-2-one

non-chiral

Ref.95. US Pat. 2,636,901(1949)

Ref. 96. NO 2

Raney-Ni / H 2

NH 2


non-chir al

JACS 70, 1187 (1948) LEUCKART-WALLACH Mech O


NH4

Formic Acid

NH2

Ref.97.

non-chir al

JACS 70, 1315-6(1948) O

NH2

PtO2 / H 2

NH3


Ref.98.

non-chir al

Y ak ugak u Zasshi 74, 413-16 ( 1954). N

NH 2

Raney Ni / H2

OH

Ref.99.


non-chir al

JACS 70, 2811-12 (1948) O

NH3

NH2

Raney-Ni / H2


Ref.100.

non-chir al Bullet in of Electr ochemist y 8(6) 276-7 (1992) N

OH

NH 2

Cathode Red. at Hg or C electrode

Ref. 101. non-chir al 1-phenylpropan-2-ol OH

Ritter Reaction SO 3H O

HCN

1-phenylpropan -2-yl hydrogen sulfate (E )-prop-1-enylbenzene

JACS 70, 4048 (1948) SO 3H N

HCl

NH2

Ref.102.

non-chiral

Justus_Liebigs_Annalen_der_Chemie_215-221( 1948)

Ref. 103. NO 2

NH 2

Pd / H2


non-chiral

Friedel-Crafts reactions

J. Am. Chem. Soc. 68 (1946) 1009-11.

FeCl3

Cl

Cl

or Fuming Sulf uric

Cl

NH 2

NH4 OH

Allyl Chloride

non-chiral O

Ref. 104.

U S P atent 2,413,493B1( 1946)

Acetoacetic Ester Synthesis Route

O Na

O

CH3-I

O

O

O

Na

Ph-CH2-Cl

O

ethyl 3-oxobutanoate

O O

Ref. 105. NaOH

O

OH

SOCl2

NH 3

O

NH 2

NaOCl

NH 2

Hoffman 1-phenylpropan-2-amine

2-methyl-3-phenylpropanoic acid

non-chir al

LEUCKART-Study O


NH4

Formic Acid

JOC 9, 529 ( 1944) NH 2

Ref.106.

Acetylbenzylcyanide Reaction Route non-chiral N

J.Applied Chem. ( USSR) 14(3), 410 (1941)

O

O ethyl acetate

N

O

O

H3 PO4

NaOEt 2-phenylacetonitrile


3-oxo-2-phenylbutanenitrile

Ref. 107. H N

O

NH- 4+ O

NH 2

HCl

ammonium formate

N-(1-phenylpropan-2-yl)f ormamide

O

O

non-chir al

O


O

O Acetic Anhydride

O OH

O O

O

sodium acetate

O

2-phenylacetic acid

1-phenylpropan-2-one J.Gen.Chem.(USSR) 11( 4), 339 (1941)

LEUCKART H N

H2 N O Formamide

O

NH2

Hydrolysis H+

Ref.108.

N -(1-phenylpropan-2-yl)formamide

chir al

Resolution NH2

OH

NH2

OH O


Ref.108.

O

HO OH

d-tartaric acid


J . Am. Chem. Soc. 5 (1940) 267-85

non-chir al

Wolf f Rearr. O OH SOCl2 2-phenylacetic acid

O Cl

Diazomethane

O

O AgO NH 3

HC N

N

NH 2

Ref.109.

Chemischen Ber icht e 66B, 684 ( 1933)

non-chiral

acid

HN3

O

O

O

OH

N3

-methylbenzylacetic acid

Curtius Rearr.

NH2

Ref.110. J . Am. Chem. Soc. 55 ( 1933) 1701-5.

non-chir al Lossen Rearr. O

O

Hydroxyl amineHN

acid chloride X esters anhydride

N

OH

C

NH 2 O Hydrolysis

Ref.111.

J.Am. Chem. Soc. 54, 271-4 (1933)

non-chir al O

NO2

NO 2

H

Hg . Cathode electrolic Red.


benzaldehyde

non-chir al

NH2


Ref. 112. U S 1879003 (1932)

NO 2 Cathode Red. at Hg or C electrode

NH 2

Ref. 113. non-chir al Chemicshe Ber icht e, 66B, 660-666 (1932). N

OH

Na

/ Ethanol

NH 2

Ref. 114.

non-chiral O

OH N

J. Am. Chem. Soc. 31, 1875 (1931) Cl NH2 NH2 Pd/C, H2

OH NH2 HCl

Pd/C, H2 (E)-2-(hydroxyimino)1-phenylpropan-1-one

2-amino-1-phenyl propan-1-ol

1-chloro-1-phenyl propan-2-amine

O from

O

Ref. 115.

1-phenylpropane-1,2-dione

non-chir al O

J. Am. Chem. Soc. 31, 2787-91 (1931)

Hofmann Rearr. NaOH

NH2

Br 2 NH 2

2-methyl-3-phenylpropanamide O Curtius Rearr. N3

Ref. 116.

1-azido-2-methyl-3-phenylpropan-1-one

non-chir al

J . Chem. Soc. 18-21 ( 1930)

OH O

N

NH2-OH

Na/Hg

NH2

amalgum 1-phenylpropan-2-one

(Z)-1-phenylpropan-2-one oxime

Ref. 117.

Precursor list to amphetamine 1985 -2009 Precursor / intermediate / essentials 2-phenylacetonitrile (E)-(2-nitroprop-1-enyl)benzene and (Z)-(2-nitroprop-1-enyl)benzene

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3-phenylpropanol (R)-3-phenylpropane-1,2-diol

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2-benzyloxirane (R)-3-phenyl-2-(phenylamineooxy) propan-1-ol

5. Tetra. 63, 9758 (2007) 5. Tetra. 63, 9758 (2007)

tert-butyl 1-iodo-3-phenylpropan -2-ylcarbamate

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tert-butyl 1-phenylpropan-2ylcarbamate (S)-1-phenylpropan-2-ol And 1-phenylpropan-2-ol

(S)-2-(1-phenylpropan-2yl)isoindoline-1,3-dione (1R,2S)-2-amino-1-phenylpropan-1ol

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Norephedrine (1R,2S)-2-amino-1-phenylpropan-1ol 2-acetamido-1-phenylpropyl acetate 2-nitro-N-(1-phenylpropan-2-yl) benzenesulfonamide 1-phenylpropan-2-one P-2-P = Phenyl-2-propanone

(S)-(2-azidopropyl)benzene (1-phenylpropan-2-yl) magnesium bromide 4,4,5,5-tetramethyl-1,3-dioxolan-2-

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one O-tosyl oxime (1S,2S)-1-phenyl propane-1,2-diol (1R,2S)-1-azido-1-phenylpropan-2-ol 2-methyl-3-phenylaziridine 2-phenylacetaldehyde (R)-2-methyl propane-2-sulfinamide (R)-1-phenylethanamine 1-(bromomethyl) benzene (R)-3,3,5-trimethyl-1-propionyl pyrrolidin-2-one (S)-2-methyl-3-phenylpropanamide (S)-2-amino-3-phenylpropanoic acid (S)-2-amino-3-phenylpropan-1-ol (S)-tert-butyl-1-phenylpropan-2ylcarbamate 1-phenyl-1-propyne allylbenzene Phenylmagnesium bromide Diethyl-2-methylaziridin-1ylphosphonate (R)-2-(tert-butoxycarbonylamino)-3phenylpropanoic acid (R)-tert-butyl 1-hydroxy3-phenylpropan-2-ylcarbamate (S)-tert-butyl 1-phenylpropan-2ylcarbamate (1S,2S)-2-amino-1-phenylpropane1,3-diol (E)-1-phenylpropan-2-one oxime And (Z)-1-phenylpropan-2-one oxime

Dimethyl 2-benylmalonate

16. 16. 16. 17. 49. 52. 17. 19. 21. 21.

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21. 25. 25. 25.

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26. 74. 27. 69. 31. 31.

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Methyl-2-benyl-2-methyl-3oxobutanoate 2-methyl-3-phenyl propanoic acid 1-(2-(phenylthio)phenyl)propan-2amine 1-(2-(phenylthio)phenyl)propan-2one 3-oxo-2-(2(phenylthio)phenyl)butanenitrile 2-(2-(phenylthio)phenyl)acetonitrile Benzaldehyde (E)-1-phenylpropan-2-one O-methyl oxime (R)-2-methyl pyrrolidin-1-amine (2,2-dimethyl-1,1diphenylpropyl)diazene benzene 2-(2,2,2-trifluoroacetamido) propanoyl chloride 2,2,2-trifluoro-N-(1-oxo-1-phenyl propan-2-yl)acetamide 2-(2,2,2-trifluoro-N-(1-hydroxy-1phenyl propan-2-yl)acetamide N-(1-bromo-1-phenylpropan-2-yl)2,2,2-trifluoroacetamide 2-(2,2,2-trifluoro-N-(1-phenyl propan-2-yl)acetamide (E)-prop-1-enylbenzene

1-(bromomethyl)benzene Or benzylbromide Phenylpropan-1-one Bromobenzene Or Phenylmagnesium bromide 2-phenylacetic acid Or Phenylacetic acid Prop-1-ynylbenzene (S)-2-methyl-3-phenylpropanoic acid D-phenylalanine Diethyl 2-(2-phenylacetyl)malonate

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2-phenylacetyl chloride Chlorobenzene Allyl Chloride Ethyl 3-oxobutanoate Ethyl acetoacetate 2-methyl-3-phenylpropanoic acid 3-oxo-2-phenylbutanenitrile N-(1-phenylpropan-2-yl)formamide 2-methyl-3-phenylpropanoic acid

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