Synthetic Amphetamine

Review: Synthetic Methods for Amphetamine Amphetamine 1

2

A. Allen and R. Ely 1

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

2

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, precursors, reagents, stereochemistry, 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 pe rspective. 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 transformation in this time period. Chiral (stereoselective) (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 stereoselective transformations have taken the form of organometallic reactions, enzymatic reactions, ring openings, aminooxylations, alkylations alkylations and amination reactions. The earlier review J. (J. Forensic Sci. Int. 42(1989)183-189) addressed 42(1989)183-189) addressed for the most part, the ―reductive ―reductive‖‖ synthetic methods leading to this this drug of abuse. It could be said that the earlier review dealt with ―classical ―classical organic transformations,‖ transformations,‖ roughly roughly covering the period from 1900-1985. This time-line is graphically illustrated illustrated below in Figure 1. As illustrated in this figure, 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 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 stereoselective organic transformation”. transformation”. This is graphically illustrated in Figure 1a. The multiplicity of these transformations and their unique starting precursors 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‖ -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 Stereosele ctive s yn.

Ald o Condensations: Cond ensations:

Rearrangements: Rearrangeme nts: Reductions Redu ctions:: Lossen 1. metal catayltic red. 1. methyl ethyl k etone etone Curtius 2. disolved metal r ed. 2. ethyl acetoacetate Hofmann 3. non metalic r ed. 3. aldehyde -nitroethane Wolf

Organometalic chiral reduction alkylations aminations Mitsunobu Enzymic

Time-Line Time-Lin e of Synthetic Routes 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: 2009 (Schema 2, 3, 4) Review of amphetamine syntheses 1985 – 2009 4) 1. Stereoselective syntheses (Scheme 2) 2) 2. Non-Chiral Syntheses (Scheme 3 ) 3. Biotransformation (Scheme (Scheme 4) 4) 1985 (Schema Review of classical amphetamine syntheses 1900 – 1985 (Schema 5 and 6 ) 1. Classical Organic Transformations (Scheme 5) 5) 2. Summary Routes to Amphetamine (Scheme (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 undo ubtedly been prompted more b y the introduction of a chiral center cente r 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]. [1]. Similarly, in 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],

list of precursor chemicals (IUPAC nomenclature, see supplemental material ) that address these transformations to amphetamine. The Era of Classical Organic Chemistry

Stereoselective Stereosele ctive s yn.

Ald o Condensations: Cond ensations:

Rearrangements: Rearrangeme nts: Reductions Redu ctions:: Lossen 1. metal catayltic red. 1. methyl ethyl k etone etone Curtius 2. disolved metal r ed. 2. ethyl acetoacetate Hofmann 3. non metalic r ed. 3. aldehyde -nitroethane Wolf

Organometalic chiral reduction alkylations aminations Mitsunobu Enzymic

Time-Line Time-Lin e of Synthetic Routes 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: 2009 (Schema 2, 3, 4) Review of amphetamine syntheses 1985 – 2009 4) 1. Stereoselective syntheses (Scheme 2) 2) 2. Non-Chiral Syntheses (Scheme 3 ) 3. Biotransformation (Scheme (Scheme 4) 4) 1985 (Schema Review of classical amphetamine syntheses 1900 – 1985 (Schema 5 and 6 ) 1. Classical Organic Transformations (Scheme 5) 5) 2. Summary Routes to Amphetamine (Scheme (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 undo ubtedly been prompted more b y the introduction of a chiral center cente r 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]. [1]. Similarly, in 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 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 Friedel-Craft alkylation [105] of benzene with iron or aluminum trichloride has been improved with the use of N (trifluoroacetyl)- (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 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 active R isomer isomer to an equilibrium mix of R,S of R,S -amphetamine -amphetamine [2]. Improved resolution resolution from racemic mixture of amphetamine to a single isomer has been achieved with ―enzymat ―enzymatic ic transformations‖ [3, 10, 22, 24, 43] and ―classical organic salts resolutions‖ [37, [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 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, 5 0, 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 Citations for the Synthesis of Amphetamine 1985-2009 Enzymatic (Bio Transformations) 2. 3. 10. 14. 14. 22. 24. 39. 43.

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

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

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

Stereoselective Stereoselectiv e Synthesis (see Scheme 2) 2) 1. J. American Chem. Soc. JACS 131(2007)9882 131(2007)9882 5. Tetrahedron, Tetra. 63(2007)9758 6. Chemistry A European J., JEC 12(2006)4197 12(2006)4197 8. Biological Med. Chem. Letter, BMCL 15(2005)3039 15(2005)3039 9. FZSGS patent # 1673210 (2005) 11. J. Medicinal Chem., JMC 48(2005)1229 48(2005)1229 14. 14. J. Chem. Research, JCR 10(2004)681 10(2004)681 16. Tetrahedron Asymmetry, TA Asymmetry, TA 15(2004)3111 17. J. Combinatorial Chem . 5(2003)590 18. J. Chem. Research, JCR 3(2003)128 19. Tetrahedron Asymmetry, TA 14(2003)2119 14(2003)2119 20. J. Chinese Chem. Soc . 49(2002)505 21. J. Chem. Soc. Perkin I, JCSP1 I, JCSP1 16(2002)1869 22. Tetrahedron Asymmetry, TA 13(2002)1315 13(2002)1315 23. US patent #6399828(2002) 25. J. Organic Chem., JOC 65(2000)5037 28. Tetrahedron Letters, TL 41(2000)6537 41(2000)6537 33. Tetrahedron Letters, TL 36(1995)1223 36(1995)1223 34. Tetrahedron Asymmetry, TA 4(1993)1619 36. Tetrahedron Asymmetry, TA 3(1992)1283 3(1992)1283 37. Acta. Chimica Chimica Scan . 45(1991)431 41. Tetrahedron, Tetra 46(1990)7403 46(1990)7403 44. Angew Chem. Int . 28(1989)218 49. J. American Chem. Soc. JACS Soc. JACS 109(1987)2224 51. Organometallics , 5(1986)739 53. Analytical Chem. Chem. 58(1986)1642 58(1986)1642 54. Khimja Geter. Soed . 12(1985)1648 55. J. Organic Chem., JOC 50 (1985)3481 (1985)3481

# = Reference

Figure 1b .

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

1900

1930

Stereoselective syn.

1985

1970

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) Organometallics 5, 739 (1986) (1985) TA 4(7)1619(1993) KGS #12,1648 (1985) OH Chiral 2Q. 2A.

Ph

OH

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

Ph

55 44 33

Chiral

Ph

5

11

54

49

40 14

53 2H.

2I.

Ph

2J.

H

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

OH

Ph Chiral

OH

Ph

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) 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

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

OH Ph

2K.

Chiral

HN BOC

19 5

O

I

Ph

23

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

Chiral

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

2G.

8 16

NO2

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

6 9

(S)-1-phenylpropan -2-amine

40

Chiral

H

Ph

NH2

17

O

5

Amphetamine

2L. Chiral

OH

2E.

19 51

OH

Tetra. 63(39) 9758 (2007)

18 20 41

Chiral

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

Ph

Ph 5

25

2M.

Tetra. 63(39) 9758 (2007)

2D.

21

2N.

Ph

1

Chiral

ONHPh

5

21

H2N

OH

2C.

34

28.

Br

O

Ph 2B.

36

2O.

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

O Tetra. 63(39) 9758 (2007)

51

COOH NH2

Chiral

Ph

54

2P.

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 2 phenylacetaldehyde [17, 49; route 2K] or benzaldehyde [47, 80, 89, 92, 95, 110; route 5Z, also implicit in 18, 20, 41, 42, 44, 56, 60, 39, 54, 61, 35, 22, 20, 18, 12, 4.57, 85, 84, 75, 74, 70, 67, 62, 94, 87, 86, 113, 114; route 5A] precursor, these 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

1900

1930

non-chiral syntheses

1985

1970

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

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

N

O

NO2

3A. NH2 SO2

NH Ph 28

Ph

3M.

52

13

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

3B. 46. LiAlH4 47 42 56 O 35 N O 12 O Ts 4 15 17

48

O H

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

45

Ph

32 22 40

CN

NH3 HoAc

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

O

3J.

Mg reduction

O O

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

O O O N O tBu3D. H

3I. COOH

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

Ph

NH2

n-BuLi

OH

non-Chiral Tetra. 56, 5157 (2000)

3E.

NH2 Ph Ph

31 37

3K.

26

Amphetamine 37

S

non-Chiral Tetra. Let. 41, 6537 (2000)

Pd/H2

NH2

Br

3C.

27 58

47

3L.

Mg

Cp2TiMe2

O P O O N

3F. 3G.

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

MgBr

3H. 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

1930

non-chiral syntheses

1985

1970

NO2 COOH

NH2 6BB.

H

6A. 113 114 54 57 62 86

CN

Scheme 6.

6B. O

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

2009

O

39

O

O

6C. O 6D.

O

OH NH2

5

103

OH

6E.

37 34

6F.

5

O

21 107 6W.

Amphetamine

69

26

OH 6H. S 6I.

6U.

17 49 52

6T.

88 106 101

53 23 40

116 H 6S.

11 115

Br

116 6R.

O

O

112 121

15

74

O

6G.

45

27

58

21 117 80 111

100 6V.

NH2

NH2

1 120

6Q.

O

O

6P. OH NH2

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

OH

HO

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).

[10] B. Yang, Y. Zhang, S. Zhang, T. Izumi, Amidation of amines with esters catalyzed by Candida Antarctica Lipase (CAL), Indian J. Chem., Sec. B: Org – Med. Chem. 44B, No 6, (2005) 1312-16. [11] F.A. Fecik, R. Devasthale, S. Pillai, A. Keschavarz-Shokri, L. Shen, L.A. Mitscher, Chiral DNA Gyrase Inhibitors. 3. Probing the Chiral Preference of the Active Site of DNA Gyrase. Synthesis of 10-Fluoro-6-mehyl-6,7-dihydro-9-piperazinyl-2H benzo[a]quinolizin-20-one-3-carboxylic Acid Analogues, J. Med. Chem. 48 (2005) 1229-36. [12] S.S. Kinderman, M.M.T. Wekking, J.H.van Maarseveen, H.E. Schoemaker, H. Hiemstra, F.P.J.T. Rutjes, Catalytic N-Sulfonyliminium Ion-Mediated Cyclizations to Vinyl-Substituted Isoquinolines and -Carbolines and Applications in Metathesis, J. Org. Chem. Vol. 70, No. 14, (2005) 5519-27. [13] C. Guisado, J.E. Waterhouse, W.S. Price, M.R. Jorgensen, A.D. Miller, The facile preparation of primary and secondary amines via an improved Fukuyama-Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent, Organic and Biomolecular Chem. Vol 3 No 6, (2005) 1049-57. [14] X, Shi, J. Yao, L. Kang, C. Shen, F. Yei, Asymmetric syntheses of both enantiomers of amphetamine hydrochloride via bakers‘ yeast reduction of phenylacetone, J. Chem. Research, 10 (2004) 681-83. [15] M. Kitamura, T. Suga, S. Chiba, K. Narasaka, Synthesis of primary amines by the electrophilic amination of Grignard Reagent with 1,3-Dioxolan-2-one O-Sulfonlyoxime, Org. Lett. Vol 6, No. 24, (2004) 4619-21. [16] I.A. Sayyed, A.Sudalai, Asymmetric synthesis of L-DOPA and ( R)-selegiline via, OsO4-catalyzed asymmetric dihydroxylation, Tetrahedron Asym. 15 (2004) 3111-6. [17] T. Mukade, D.R. Dragoli, J.A. Ellman, Parallel Solution-Phase Asymmetric Synthesis of a-Branched Amines, J. Comb. Chem. 5 (2003) 590-6. [18] Y. Li, T. Izumi, A novel asymmetric reduction of nitroolefin 2-nitro-1-phenyl-1 propene by using BINAP-ruthenium(II) complexes , J. Chem Research, Synopses, 3 (2003) 128-9. [19] J.M. Wagner, C.J. McElhinny, Jr., A.H. Lewin, F.I. Carroll, Stereospecific synthesis of amphetamines, Tetrahedron: Asym. 14 (2003) 2119-25. [20] Y. Li, T. Izumi, Low-valent Ruthenium Induced Simultaneous reduction of Nitro Group and C=C Double Bond in Nitroolefin 1-phenyl-2-nitropropene-1, J. Chinese Chem. Soc. 49 (2002) 505-8.

[21] S.G. Davies, D.J. Dixon, N -Acyl ‗Quat‘ pyrrolidinone auxiliary as a chiral amide equivalent via direct aminolysis, J. Chem. Soc., Perkin Trans. I , 16 (2002) 1869-76. [22] J. Gonzales-Sabin, V. Gotor, F. Rebolledo, CAL-B-catalyzed resolution of some pharmacologically interesting -substituted isopropylamines, Tetrahedron: Asym. 13 (2002) 1325-20. [23] R.F. Boswell, Y.S. Lo, Boehringer Ingelheim Chemicals, patent no. US 6,399,828 B1, Jun. 4, 2002. [24] B.A. Davis and D.A. Durden, Resolution of chiral aliphatic and arylalkylamines using immobilized Candida Antarctica Lipase and isolation of the ir R- and S enantiomers, Syn. Comm. Vol. 31, No. 4, (2001) 569-78. [25] D.A. Quagliato, P.M. Andrae, E.M. Matelan, Efficient Procedure for the reduction of -amino acids to enantiomerically pure a-methylamines, J. Org. Chem. 65 (2000) 5037-42. [26] E. Haak, H. Siebeneicher, S. Doye, An Ammonia Equivalent for the Dimethyltitanocene-Catalyzed Intermolecular Hydroamination of Alkynes, Org. Lett . Vol. 2, No. 13, (2000) 1935-7. [27] C.G. Hartung, C. Breindl, A. Tillack, M. Beller, A base-catalyzed DominoIsomerization — Hydroamination Reaction – A new synthetic route to Amphetamines, Tetrahedron, 56 (2000) 5157-62. [28] C. Subramanyam, Polymer bound iminodicarbonate: a new ammonia equivalent for solid-phase synthesis of primary amines, Tetrahedron Lett. 41 (2000) 6537-40. [29] I. Ito, R. Nemori, Enzymic resolution of racemic amines, (Fuji Photo Film Co., Ltd., Japan) Jpn. Kokai Tokkyo Koho (1991), patent # JP 03191797. [30] H. Liu, B. Wang, F. Ji, Z. Xu, Synthesis and Enantiomeric resolution of Racemic Amines, Zhongshan Daxue Xuebao, Vol. 35, No. 5 (1996) 73-76. [31] T. Gajda, A. Napleraj, K. Osowska-Pacewicka, S. Zawadzki, A. Zwierzak, Synthesis of Primary sec-Alkylamines via Nucleophilic Ring-opening of NPhosphorylated Aziridines, Tetrahedron, Vol 53, No 13, (1997) 4935-46. [32] I.V. Micovic, M.D. Ivanovic, G.M. Roglic, V.D. Kiricojevic, J.B. Popovic, Preparation of secondary amines by reductive am ination with metallic magnesium, J. Chem. Soc. Perkin Trans. I , (1996) 265-9. [33] B.G. Donner, Conversion of Chiral Amino Acids to Enantiomerically Pure Methylamines, Tetrahedron Lett . Vol 36, No. 8, (1995) 1223-6.

[34] M.D. Rozwadowska, An Efficient Synthesis of S -(+)-Amphetamine, Tetrahedron Asym. Vol. 4, No. 7, (1993) 1619-24. 11

[35] K.O. Schoeps, C. Halldin, Synthesis of racemic [- C] amphetamine and [11 11 C]phenethylamine from [ C]nitroalkanes, J. Labelled Compounds and Radiopharmaceuticals, Vol 31, No 11, (1992) 891-901. [36] P. Krasik, H. Alper, The Ruthenium Catalyzed Asymmetric Hydrogenation of Oximes using BINAP as the Chiral Ligand, Tetrahedron: Asym. Vol 3, No. 10, (1992) 1283-8. [37] A. Gee, B. Langstrom, Synthesis of Racemic (S )-(+)- or ( R)-(-)-[Methyl11 C]Amphetamine, Acta Chemica Scandinavica, Vol 45, No. 4, (1991) 431-5. [38] M. Acs, T. Szili, E. Fogassy, New Method of Optical Activation for Racemic Bases, Tetrahedron Lett . Vol. 32, No. 49 (1991) 7325-8. [39] A. Mori, I. Ishiyama, H. Akita, K. Suzuki, T. Mitsuoka, T. Oishi, Reduction of Nitroolefin using Microorganisms, Chem Pharm. Bull , Vol. 38, No. 12, (1990) 3449-51. [40] F.T. Noggle, Jr., J. DeRuiter, C.R. Clark, Methods for the Analysis and Characterization of Forensic Samples Containing Amphetamines and Related Amines, J. Chromatographic Sci. Vol 28, No. 10 (1990) 529-36. [41] S.G. Harsy, Homogeneous Hydrogenation of Nitroaliphatic Compounds Catalyzed by Group VIII Transition Metal Phosphine Complexes, Tetrahedron, Vol 46, No. 21, (1990) 7403-12. [42] G.W. Kabalka, L.H.M. Guindi, R.S. Varma, Selected Reductions of Conjugated Nitroalkenes, Tetrahedron, Vol 46, No. 21, (1990) 7443-57. [43] D.I. Stirling, A.I. Zeitlin, G.W. Matcham, Celgene Corporation, Enantiomeric Enrichment and Stereoselective Synthesis of Chiral Amines, patent # US 4950606, Aug. 21, 1990. [44] A. Giannis, K. Sandhoff, LiBH4(NaBH4)Me3SiCl, an Unusually Strong and Versatile Reducing Agent, Angew. Chem. Int. Ed. Engl Vol 28, No. 2, (1989) 218-20. [45] J. Jilek, J. Urban, P. Taufmann, J. Holubek, A. Diabac, M. Valchar, M. Protiva, Potential Antidepressants. 2-(phenylthio)aralkylamines, Collection of Czechoslovak Chemical Comm. Vol. 54, No. 7 (1989) 1995-2008. [46] J. Malek, Reduction by Metal Alkoxyaluminum Hydrides, in Organic Reactions, A.S. Kende, ed. Wiley Publication, Hoboken, NJ, USA) Vol 36, (1988).

[47] R.A. Smith, R.L. White, A. Krantz, Stereoisomers of Allenic Amines as inactivators of Monoamine Oxidase Type B. Stereochemical Probes of the Active Site, J. Med. Chem. 31 (1988) 1558-66. [48] A. Ishiyama, T. Oishi, T. Mitsuoka, M. Tomotari, H. Mori, H. Akita, K. Suzuki, Manufacture of Optically active amine with enterobacteria from aliphatic nitro compounds, assigned to Institute of Physical and Chem. Res., Japan. JP 63219396 (1900) [49] S.E. Denmark, T. Weber, D.W. Piotrowski, Organocerium Addition to SAMPHydrazones: General Synthesis of Chiral Amines, J. Am. Chem. Soc., 109 (1987) 22245. [50] C.F. Barfknecht, D.E. Nichols, Asymmetric Synthesis of Phenylisopropylamines, assigned to Univ. of Iowa Res. Foundation, USA, patent US 4000197 (1976). [51] H. Brunner, R. Becker, S. Gauder, Asymmetric Catalysis.29 Optically Active Primary Amines by Enantioselective Calalytic Hydrosilylation of Ketoximes, Organometallics, 5 (1986) 739-46. [52] J.E. Baldwin, R.M. Adlington, I.M. Newington, Azo Anions in Synthesis: -Amino Carbanion Equivalents from t-Butyldiphenylmethylhydrazones, J. Chem. Soc. Chem. Comm., 2 (1986) 176-8. [53] G. Buenger, J. Douglas, P. Jass, E. Michalson, M. Schiesher, Process for preparation of amphetamines from crude chlorinated phenylpropanolamines via treatment with carbon and hydrogenolysis, patent US 2009292143 (2009). [54] G.V. Grishina, V.M. Potapov, S.A. Abdulganeeva, E.Y. Korchagina, Steric directivity in asymmetric synthesis of N-substituted 2-methyl-4-piperidones, Khimiya Geterotsiklicheskikh Soedinenil , 12 (1985) 1648-55. [55] J.E. Nordlander, F.G. Njoroge, M.J. Payne, D. Warman, N -(Trifluoroacetyl)-aamino Acid Chlorides as Chiral Reagents for Friedel-Crafts Synthesis, J. Org. Chem. Vol 50, No 19, (1985) 3481-4. [56] R.S. Varma, G.W. Kabalka, A Simple route to alkylamines via the reduction of nitroalkenes, Synthetic Communications, Vol. 15, No. 9, (1985) 843-7. [57] M.S. Mourad, R. Varma, G.W. Kabalka, A Convenient Reduction of a,bunsaturated Nitroalkenes to Alkylamines using Boron Hydrides, Synthetic Comm. Vol. 14, No. 12. (1984) 1099-104. [58] A. Koziara, B. Olejniczak, K. Osowska, A. Zwierzak, Phosphoramido mercuration-Demercuration: A Simple, Two-step Conversion of Alkenes into alkanamines, Synthesis, 11 (1982) 918-20.

[59] B. Krzyzanowska, W.J. Stec, A Study of the synthesis of Optically Active Amines from Prochiral N-Phosphinylimines, Synthesis, 4 (1982) 270-3. [60] R.D. Finn, D.R. Christman, A.P. Wolf, A rapid synthesis of nitrogen-13 labeled amphetamine, J. Labelled Comp. and Radiopharmaceuticals, Vol. 18, No. 6. (1981) 90913. [61] J. Tuaillon, R. Perrot, Action du monoxide d‘azote sur le phenylethylene et sur quelques arylalcenes, Helvetica Chimica Acta, Vol 61. No. 2 (1978) 558-66. [62] A.H. Beckett, G.R. Jones, R.T. Coutts, Synthesis and Properties of Aryalkylamine C-Nitroso Dimers, Tetrahedron, Vol. 32. No. 11. (1976) 1267-76. [63] B.H.G. Wassink, A. Duijndam, A.C.A. Jansen, A Synthesis of Amphetamine, J. Chem. Education, 51 (1974) 671. [64] D.E. Nichols, C.F. Barfknecht, D.B. Rusterholz, Asymmetric Synthesis of Psychotomimetic Phenylisopropylamines, J. Med. Chem. Vol. 16. No. 5 (1973) 480-3. [65] R.F. Borch, M.D. Bernstein, H.D. Durst, The Cyanohydridoborate Anion as a Selective Reducing Agent, J. Am. Chem. Soc. 93 (1971) 2897-2907. [66] K. Saigo, Y. Hashimoto, K. Kazushi, Y. Harada, K. Sakai, Optical resolution of Arylalkylamines, assigned to Yamakawa Chem. Ind. Co., Ltd., Japan, EP 915080 (1999). [67] B.T. Ho, W.M. McIsaac, R. An, W. Tansey, K.E. Walker, L.F. Englert, Jr., M.B. Noel, Analogs of a-Methylphenethylamine (amphetamine). I. Synthesis and Pharmacological Activity of Some Methoxy and/or Methyl Analo gs, J. Med. Chem. 13 (1970) 26-30. [68] R. Foreman, F.P. Siegel, R.G. Mrtek, Synthesis of (-)amphetamine--d Sulfate, J. Pharmaceutical Sci. Vol. 58, No. 2., (1969) 189-92. [69] H.C. Brown, J.T. Kurek, The Solvomercuration-Demercuration of Representative Olefins in the Presence of Acetonitrile. A Convenient Procedure for the Synthesis of Amines, J. Am. Chem. Soc. 91 (1969) 5647-9. [70] L.A. Bryan, Reduction of Arylnitroalkenes, to Great Lakes Carbon Corp. New Youk, NY, patent # US 3458576 july 29, 1969. [71] O. Cervinka, E. Kroupova, O. Belovsky, Asymmetric reactions. XXIX. Absolute configuration of -phenyl-2-alkyl amines and their N-methyl derivatives, Coll. Czechosiovak Chem. Comm. Vol. 33, No. 11, (1968) 3551-7.

[72] N. Milstein, Friedel Crafts Reactions of Three-Member Heterocycles II. Alkylation of Aromatic Compounds with Aziridines, J. Heterocyclic Chem. Vol 5, No. 3, (1968) 339-41. [73] K. Kotera, T. Okada, S. Miyazaki, Stereochemistry of Aziridine Formation by Reduction of Oximes with Lithium Aluminum Hydride on Aralkyl Alkyl Ketox imes and their Tosylates, Tetrahedron, Vol 24, No. 16, (1968) 5677-90. [74] I. Iwai, K. Tomita, J. Ide, Studies on Aceylenic Compounds, XL. The Addition Reaction of Nitrosyl Chloride and Nitryl Chloride to Acetylenic Compounds, Chem. Pharm. Bull. Vol. 13, No. 2, (1965) 118-129. [75] M. Green, Reductive Amination of Ketones, assigned to Polaroid Corp., Cambridge, Mass. Patent US 3187047. [76] A. Lukasiewicz, A Study of the Mechanism of certain Chemical Reactions, I. The Mechanism of the Leuckart-Wallach Reaction and of the Reduction of Schiff Bases by Formic Acid, Tetrahedron, Vol. 19, (1963) 1789-99. [77] H. Metzger, Bases of the 1-phenyl-2-aminopropane series, assigned to Knoll A.G. Chemische Fabriken, Germany patent DE_968545 (1958). [78] J.M. Gillingham, Resolution of dl-amphetamine, assigned to Parke, Davis and CO., patent US 3028430 (1962). [79] J.B. Tindall, Process for the Production of Secondary Amines, assigned to Commercial Solvents Corp., Terre Haute, Ind. Patent US 2828343. [80] A.W. Schrecker, Resolution and Rearrangement of a-Methylhydrocinnamic Acid and of Its 3,4-Dimethoxy derivative, J. Org. Chem. Vol.22, No. 1 (1957) 33-5. [81a] V.M. Potapov, A.P. Terent‘ev, Stereochemical studies. IV. Schiff bases from optically active a-benzylethylamine, Zhurnal Obshchei Khimii 28, 3323-9 (1958). [81b] M.F. Zienty, Separation of optically active isomers of amphetamine, assigned to Miles Lab., Inc. USA, patent US 2833823 (1958). [82] T. Kametani, Y. Nomura, Reduction of Nitrogen Compounds by Raney Nickel Alloy and Alkali Solution. I. Synthesis of Amines by Reduction of Oximes, J. Pharm. Soc. Japan, Vol 74., No. 4, (1954) 413-6. [83] T.H. Temmler, Reduction of Hydrazones, assigned to Temmler-Werke Vereinigte Chemische Fabriken, Germany, patent DE 870265 (1953) [84a] J. Gal, Synthesis of (R)- and (S)-amphetamine-d3 from the corresponding pheylalanies, J. Labelled Comp. Radiopharmaceuticals Vol. 13, No. 1. (1977) 3-9. [84b] R.B. Repke, D.K. Bates, W.J. Ferguson, J. Pharm. Sci., 67 (1978) 11681169.

[85] R.T. Gilsdorf, F.F. Nord, Reverse Addition of Lithium Aluminum Hydride to Nitroolefins, J. Am. Chem. Soc. Vol. 74, No. 7, (1952) 1837-43. [86] J.B. Tindall, Catalytic Reduction of Nitroolefins, assigned to Commercial Solvents Corp., Terre Haute, Ind. Patent US 2647930. [87] G. Stochdorph, O. von Schickh, Verfahren zur Herstellung von gesattigten Aminen, assigned to Badishe Anilin and Soda Fabrik, Ludwigshafen/Rhein, German, DE 848197. [88] M. Acs, A. Mravik, E. Fogassy, Z. Bocskei, New Technique in Optical Resolutions, Chirality Vol. 6, No. 4, (1994) 314-20. [89] E. Max, F. Ramirez, Uber die Reduktion von b-Nitrostyrolen mit Lithiumaluminiumhydrid, Helv. Chim. Acta. 33 (1950) 912-916. [90] A.W. Ingersoll, d- and l--phenylethylamine, Organic Synthesis, Coll, Vol. 2 (1943) 506-7; Vol 17, (1937) 80-81. 14

[91] J.W. Wilson, III, Synthesis of dl-Amphetamine Sulfate Labeled with C, J. Am. Pharm. Assoc. (1950) 687-88. [92] P. Mastagli, M. Metayer, A. Bricard, Study of the Aminolysis of some Ketones and Aldehydes, Bull. Soc. Chim. France, (1950) 1045. [93] H.J. Schaefer, Electroorganic synthesis. 49. Cathodic reduction of 1-nitroalkenes to oximes and primary amines, Chemische Berichte, Vol. 124, No. 10 (1991) 2303-6. [94] H.B. Hass, A.G. Susie, R.L. Heider, Nitro Alkene Derivatives, J. Org. Chem. 15 (1950) 8-14. [95] American Home Prod., Improvements in and relating to imines and amino compounds prepared there from, patent GB 702985 (1949). [96] J.B. Tindall, Process for Reduction of Nitroolefins, assigned to Commercial Solvents Corp., Terre Haute, Ind. Patent US 2636901 (1949). [97] E.R. Alexander, R.B. Wildman, Studies on the Mechanism of the Leuckart Reaction, J. Am. Chem. Soc. 70, (1948) 1187-9. [98] E.R. Alexander, A.L. Misegades, A Low Pressure Reductive Alkylation Method for the Conversion of Ketones to Primary Amines, J. Am. Chem. Soc. 70, (1948) 13156.

[99] J. Kametani, Y. Nomura, Raduction of nitrogen compounds by Raney Nickel Alloy and Alkali Solution. I. Syntheses of amines by reduction of oximes, Yakugaku Zasshi 74 (1954) 413-16. [100] L. Haskelberg, Aminative Reduction of Ketones, J. Am. Chem. Soc. 70, (1948) 2811-12. [101] A. Muthukumaran, V. Krishnan, Electrosysthesis of Amphetamine, Bulletin of Electrochemisty, Vol. 8, No. 6, (1992). 276-7.

[102] J.J. Ritter, J. Kalish, A New reaction of Nitriles. II. Synthesis of t-Carbinamines, J. Am. Chem. Soc. 70, (1948) 4048-50. [103] Von K. Kindler, B. Hedemann, E. Scharfe, Studien uber den Mechanismus Chemischer Reaktionen. X. Phenyl- und Cyclohexyl-alkylamine durch Hydrierung, Justus Liebigs Annalen der Chemie, 560 (1948) 215-21. [104] T.M. Patrick, Jr., E.T. McBee, H.B. Hass, Synthesis of Arylpropylamines. I. From Allyl Chloride, J. Am. Chem. Soc. 68, (1946) 1009-11. [105] A.C. Flisik, L. Nicholl, W.P. Bitler, Synthesis of Isomer-Free Benzyl Methyl Acetoacetic Methyl Ester, assigned to Kay-Fries Chemicals, Inc., Haverstraw, NY, patent US 2413493 (1946). [106] F.S. Crossley, M.L. Moore, Studies on the Leuckart Reaction, J. Org. Chem. 9 (1944) 529-36. [107] B.R. Bobranski, Y.V. Drabik, A New Method of 1-phenyl-2-aminopropane preparation, J. Applied Chem. Vol. 14, No. 3. (1941) 410-414. [108] O.Y. Magidson, G.A. Garkusha, Synthesis of -Phenyl-isopropyl-amine (phenamine), J. General Chem. Vol. 11, No. 4, (1941) 339-343. [109] J.F. Lane, J. Willenz, A. Weissberger, E.S. Wallis, Molecular Rarrangements Involving Optically Active Radicals. VIII. The Wolff Rearrangement of Optically Active Diazoketones, J. Am. Chem. Soc. 5 (1940) 267-85. [110] J.V. Braun, E. Friehmelt, Carboxylc acids with Hydrazoic Acids, Chemicshe Berichte, 66B (1933) 684-5. [111] E.S. Wallis, R.D. Dripps, Molecular Rarrangements Involving Optically Active Radicals. III. The Lossen Rearrangement of Optically Active Hydroxamic Acids, J. Am. Chem. Soc. 55 (1933) 1701-1705.

[112] A.A. Gordon, dl-Beta-phenylisopropylamines, J. Am. Chem. Soc. 54 (1932) 2714. [113] A.A. Gordon, Salts of 1-phenyl-2-aminopropane, assigned to Monterey Park, CA., patent US 1879003 (1932). [114] W. Leithe, Die Konfiguration der Ephedrin-Basen, Chemicshe Berichte, 66B (1932) 660-666. [115] W.H. Hartung, J.C. Munch, Amino Alcohols. VI. The Preparation and Pharmacodynamic Activity of four Isomeric Phenylpropylamines, J. Am. Chem. Soc. 53 (1931) 1875-79. [116] E.S. Wallis, S.C. Nagel, Molecular Rarrangements Involving Optically Active Radicals. II. The Hofmann rearrangement of Optically Active Acid Amides, J. Am. Chem. Soc. 55 (1933) 2787-91. [117] D.H. Hey, V. dl --Pheylisopropylamine and Related Compounds, J. Chem. Soc. 18 (1930). [118] W.H. Hartung, Catalytic Reduction of Nitriles and Oximes, J. Am. Chem. Soc. 50 (1928) 3370-4.

Supplemental Material: JACS 131, 9882 (2009)

chiral

N

MeMgI

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)

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, E nzymic, Ster eoselective NH2

Lipase


NH2

Lauric acid

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

Ref. 3.

Tetr a. Let. 48(32) 5707 (2007)

non-chiral

NH2 NO2

H2N

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

Ph

SmI2 1-phenylpropan-2-amine

Ref. 4.

chiral

Tetra. 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

NH2

2. Pd/C H2

OH 2-benzyloxirane

OH

Pd/C

OH


(S)-1-phenylpropan-2-ol

chiral

Chem. Eur opean J . 12(15)4191-7(2006) H N

O

H N

SmI2

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

O

NH2

TFA

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

tert -butyl 1-phenylpropan-2ylcarbamate

non-chiral

Ref. 6.

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

NaBH4

NH2

BF3 - Et2O

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


Ref. 7.

chiral Phth Anh. OH

NH2-NH 2 N

Ph3P 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. chiral H N

NH2

MeOH

Bioorganic & Med. Chem. Letters, 15( 12) 3039-43 ( 2005)

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

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

NH2

O tert -butyl 1-phenylpropan-2ylcarbamate


Ref. 9

chiral

indian J. Chem.Sec B 44B(6) 1312 (2005) Biotrasformation, E nzymic, Ster eoselective NH2


chiral

NH2

Lauric acid

Lipase

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

Ref. 10.

Ac

OH NH2

O

Ac 2O

H N

norephedrine

2-acetamido -1-phenylpropyl acetate

(1R ,2S)-2-amino-1phenylpropan-1-ol / H 2 a S O 4 - B P d

H N

Ac

Ref. 11.

J . Med. Chem. 48(4) 1229-36 (2005) NH2

H2 SO4

Ac


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

non-chiral

JOC 70(14) 5519 (2005) NO2

NH2

LiAlH4



Ref. 12. non-chiral

NH2 SO2 NO 2

OH 1-phenyl propan-2-ol

Org. and Biomolecul ar Chem. 3(6) 1049 ( 2005)

HN

O

PhSH, K2CO3

S DCC

O O2N 2-nitro-N -(1-phenylpropan-2-yl) benzenesulfonamide

NH2

50oC

amphetamine 1-phenylpropan-2-amine

Ref. 13.

J. Chem. Research 10, 681 (2004)

chiral

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

1-phenylpropan-2-one

O N

O

Org. Letters, 6(24) 4619-21 (2004)

S O

MgBr O

HCl

N 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

chiral


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

Tetrahedron Asymmetry 15(19),3111-6 (2004) H N

Ph3P

Pd-C


Ref. 16.

HCO2NH4

NH2

2-methyl-3-phenylaziridine

amphetamine J. Combinatorial Chem. 5(5) 590-6 (2003)

chiral O

O

S

H

O NH2

CuSO4

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

Ref. 17.

O S

N

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

2-phenylacetaldehyde

MeMgBr

S

HCl, MeOH N H

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

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

chiral

J. Chem. Research (S), 128 (2003) NO2

NH2

Ruthenium BINAP


Ref. 18.

Tetr a. Asy. 14, 2119 (2003)

chiral

(S)-1-phenylpropan-2-amine H2N

O

NH2

N

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

Ref. 19.

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

chiral

J. Chinese Chemical Society, 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)

chiral 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 NH3, MeOH

NH2 NH2

(S)-2-methyl-3-phenylpropanamide

PhI(OOCCF3) 2 amphetamine (S)-1-phenylpropan-2-amine

chiral

Tet r a. Asy. 13( 20) 2277 ( 2002) NH2

Enzymic, Resolution


Ref. 22.

NH2

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

non-chiral NH2

HCOO NH 4 O

Pd, MeOH

Ref. 22. amphetamine

T etrahedron Asymmetr y, 13( 12) 13115-1320 ( 2002)


chiral


US pat. # 6399828 2002) OH NH2

NH2

HI, P4 HCl

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

Ref. 23. BaSo4 Ac 2O HoAc

H2

OAc

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.


O

chiral NH 2

LiBH4 /TMSCl

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

Ref. 25. O NH

O

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

O

J. Or gainic Chemistry 65(1 6) 5037-42 ( 2000)

O NH

N-Selectride

NH

OH (S)-tert -butyl 1-hydroxy3-phenylpropan-2-ylcarbamate

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

O (Ph) 3P / I

BOC) 2O

NH 2

NH 2

TFA

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

non-chiral NH2

Cp2 TiMe2

Cp2 TiMe2 N

diphenyl methanamine

1-phenyl1-propyne

Ref. 26.

NH2

Ph H 2 , Pd/C

(E )-diphenyl-N (1-phenylpropan-2- Ph ylidene)methanamine

1-phenylpropan-2-amine amphentamine

Org anic Let ters, 2( 13) 1935-1937 ( 2000) T etra. 56, 5157 ( 2000)

Ref. 27.

non-chiral Ph

H 2N

Pd/C H2 NH

cat. n-Bu Li


allylbenzene

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

non-chiral tBuCO) 2O OH 1-phenyl propan-2-ol

NH2

Ph 3P

TFA NH

DCM

DEAD, THF

O tert -butyl 1-phenylpropan -2-ylcarbamate

O

NH2 amphetamine

Ref. 28.


chiral

JP 03191797 (1991) O NH2

Enzymic, Resolution

BuNH 2

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

Ref. 29.

non-chiral O


Zhongshan Dazue Xu ebao 35( 5) 73-76 ( 1996) HOOC * OH NH2 NH2 HO * COOH

Leuckart R eaction ammonium formate

d-Tartaric acid


Ref. 31.

non-chiral O MgBr

O P

T etrahedr on, 53(13) 4935-4946, 1997 O

O CuI

N

phenylmagnesium diethyl 2bromide methylaziridin-

O P

O

NH

THF

Ref. 30.

1-phenylpropan2-amine HCl

diethyl 1-phenylpropan2-ylphosphoramidate

NH2

amphetamine

1-ylphosphonate

non-chiral

J.Chem.Soc., Perki n T rans I, 265 (1996) O

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

Mg

M eOH

NH3

HoAc

NH2

Ref. 32.


chiral

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

O

BOC

BOC HN

O BH3

O

OH

THF

(R )-2-(tert -butoxycarbonylamino) -3-phenylpropanoic acid

NH

TEA

OH

CH3SO2 Cl

CH3CH2 SH

O Ms

Ref. 33.

NaH BOC

BOC

NH

NH EtOH

S

NH 2

TFA

Ra-Ni O

NH


chiral

OH OH Phth Anh.

OH

NH2 (1S,2S)-2-amino1-phenylpropane-1,3-diol

N O

Ref. 34. H 2 / Pd-C

I OH O

I

Ph) 3P / I N

O

O

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

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

NH2-NH2 N

O

NH2

O

amphetamine

T etrahedr on Asymmetry 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) NO2


NH2

LiAlH4

Ref. 35.


Ref. 36.

chiral

Tetrahedron Asymmetry,3(10) 1283-8 ( 1992)

E & Z

NH2

H 4Ru(arene) N

BINAP

OH

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

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

non-chiral O

O

O

Acta. Che mica Sc andinavica 45, 4 31 ( 1991) O O

Ref. 37. NaH

O

O

CH3-I

O

DMSO

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

dimethyl 2 -benzylmalonate Ph

O OH

1. NaOH

1. -

N

2. AcOH

chiral

2-methyl-3-phenyl propanoic acid

NH2

NH2

O P Ph TEA/heat +N N

amphetamine

2. HCl / heat


resolution

NH2

(+)-10-camphorsulonyl chloride amphetamine



chiral

HOOC NH2 RO

* OR * COOH

amphetamine

Tetr ahedr on Lett. Vol. 32, No. 49 ( 1991) 7325-8. R=H resolution Benzoyl p-toluoyl


Ref. 38.

1-phenylpropan-2-amine non-chiral

NH2

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

Biotransformation cat. Peptostreptococcus Anaerobius


Ref. 39.

NH2


chiral

Ref. 40.

OH NH2

J. Chrom. 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-chiral

J. Chrom. Sci. 28, 529 (1990)

Ref. 40. OH

Ac2)O

NaOAc O 2-phenylacetic acid

O 1-phenylpropan-2-one

Ref. 41.

chiral NO2

BH3-THF


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

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

non-chiral

Ref. 42.

NO2

NH2

Leuchart Red

BH3-THF


Tetr a. 46(21) 7743 (1990) NH 2

cat. NaBH4

amphetamine


chiral

U.S. pat. # 4950606 (1990)

Enzymic, Resolution NH2

Ref. 43.


non-chiral

NH2

amino-acid transminase f rom Bacilllus Megaterium


Biotransformation amino-acid transminase f rom O


Ref. 43.

NH2

Bacilllus Megaterium amphetamine 1-phenylpropan-2-amine

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. C zech. Chem. Comm. 54( 7) 1995 (1989)

non-chiral

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

Ph S

O

2-(2-(phenylthio)phenyl)acetonitrile Ph

Ref. 45.

S

NH2OH

Na N OH

Ph

EtOH

N

S

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

S HCl

NH2 1-(2-(phenylthio)phenyl)propan-2-amine

Ref. 46.

non-chiral

Ph

O

EtOH

CN

O

Red - Al, THF

O

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


Red-Al THF

NH2

Org . Reactions 36, book ( 1988) NH2

1-phenylpropan-2-amine NH2

Ref. 47.

non-chiral O NO2

H

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



benzaldehyde

NH2

LiAlH4

chiral

JP 63219396 (1988) NO2

Ref. 48.

Biotransformation /

NH2

Enzymic, Resolution 1-phenylpropan-2-amine


chiral

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

NH2

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

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

(s)-1-phenylpropan-2-amine

chiral O

R or S

phenyl-2-propanone 

NH 2

low pressure

*

Hydrogenation Raney Ni / H2

*

HN

*

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

-methylbenzylamine US 4 000,197 ( 1976)

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

*

HN

*

NH2 amphetamine

50 psi H2


chiral

Organometall ics, 5, 739-46 (1986)

Ref. 51. N

O

H-SiH(Ph)2

OH

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


Ref. 52.

non-chiral

H

H N

O

J. Chem. Soc., Chem. Comm. 2, 176, (19 86) CH3 1. TFA Aphetamin e N NH 2. Pd /C H2

LDA

NH

CH3I

Ph Ph

Ph Ph

2-phenylacetaldehyde

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

Ref. 52.

non-chiral

H

H N

O

J. Chem. Soc., Chem. Comm. 2, 176, (19 86) CH3 1. TFA Aphetamin e N 2. Pd /C H2 NH

LDA

NH

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

Ph-CH2-Br

Ph Ph

Ph Ph

acetaldehyde

non-chiral

NH2

OH

US 2009292143 (2009)

Cl NH2

NH2

NH2

Pd H2

Ref. 53.

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


Khimiya Get erotsikli cheskikh Soedi nenii 12, 1648 ( 1985)

chiral O


N

OH

Na MeOH


NH2

Ref. 54.

chiral

O

O

H N

Cl

CF 3

O (S)-2-(2,2,2-trifluoroacetamido) benzene propanoyl chloride J .Org .Chem. 50( 19) 3481-4 (19 85)

Ref. 55 OH H 2 / Pd-C

PBr 3

CF 3

H N

CF 3 O

O

(S)-N -(1-bromo-1-phenylpropan -2-yl)-2,2,2-trifluoroacetamide

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

H 2 / Pd-C

CF 3

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

H N

H N

AlCl 3

CF 3

K2CO3, MeOH

NH2

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

non-chiral


Syn. Comm. 15(9) 843 (1985)

Ref. 56.

NaBH4 BH3 - THF

NO2

NH2


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

non-chiral

NaBH4 NO2

NH 2

BH3 / THF

Ref. 57. non-chiral

amphetamine

Sy nthesis ( 4) 270-3 (1982) O H 2N

P O

1. Hg(NO3) 2 / 1,1-diCl-ethane

O

2. 10% NaOH / NaBH4

H N

O P O

O

(E )-prop-1-enylbenzene diethyl p hosphoramidate NH 2 HCl /benzene

Ref. 58.

amphetamine

chiral

Sy nthesis ( 4) 270-3 (1982) N

O OH Cl

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

P Ph

CH2Cl2, DEA Ph

H N

LAH (-) Quinine / THF

N

HCl / ethanol

O

O O P Ph Ph

NH 2

O P Ph Ph

Ref. 59.

amphetamine

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

non-chiral

NH2

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

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

non-chiral

Ref.60.

Helvetica chimica Acta 61(2) 558 (1978) NO NO2 LiAlH4

NO (E )-prop-1-enylbenzene

NH2

Ref.61.

Ref. 62.

chiral

T etrahedron 32(11) 1267-76 (1 976)

E & Z NH2

LiAlH 4 N

OH

1-phenylpropan-2-amine amphetamine


non-chiral

J. Chem. Education 51, 671(1974) NH2

O o

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

Ref.63.

non-chiral

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

(R )-1-phenylethanamine O

H2N

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

NH2

Pd-C / H2 MeOH


of Diastereoisomers

non-chiral

JACS 93, 2897 ( 1971) NH2

O NaCNBH3 NH 4OH, M eOH


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-chiral CH3CN

allylbenzene

Hg(NO 3) 2

N

Ref. 69.

Hg

O

NO3 H N

NaBH4


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

non-chiral

Ref. 70. NO2

H N

HCl

O

NO 2

US Pat. 3,458,576 (1 969) Pd-C / H2

NH2

Pt / H2 Raney-Ni / H2


non-chiral

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

HCl


NH2

Ref.71.

chiral

Coll. Czech. Chem. Comm. 33(11) 3551-7(1968) NH2

NH2

(+)-tartaric acid EtOH

Ref.71.


non-chiral

Ref. 72. AlCl 3

benzene

HN 2-methylaziridine


J. Heterocyclic Chem._5(3)339(1968) NH2


Ref. 73.

non-chiral N

O

T etra. 24(16) 5677 (1968) NH2

LiAlH4

R

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

Chem Pharm Bull 13(2)118(1965)

non-chiral

Cl

Cl nitrosyl chloride NOCl

NO2

NO2

Pt 2O H2

NO2 Cl prop-1-ynylbenzene hypochlorous nitrous anhydride

Ref.74.

non-chiral

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

NH2

Raney-Ni / H2

NH4 oAc


Ref.75.

non-chiral

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

NH2

Formic Acid

NH4


non-chiral

Ref.76.

OH

DE_1958-968545(1958)

Cl NH2

NH2

Pd

NH2

H2

Ref. 77.

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


US 3028430 ( 1962)

chiral NH2

R H2N


*

resolution 

COOH

NH2

-amino acid

Ref. 78.


non-chiral

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

NH2

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


Ref.79.

chiral

Ref. 80.

O

O

OH CO 2Cl 2 (S)-2-methyl-3phenylpropanoic acid

chiral

Curtius rearrangement O

JOC_22(1)33(1957)

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

chiral NH2

HO amphetamine 1-phenylpropan-2-amine

*

*


NH2

NaN 3

H 2SO4

OH

NH2

Zhurnal Obshchei Khimii 28 (1958) 3323-8 OH

resolution

NH2

d-Tartaric acid

COOH

Ref. 81a

amphetamine (S)-1-phenylpropan-2-amine US 2,833,823 (1958)

chiral NH2

resolution

NH2

H 3 PO4 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 NH2


Raney-Ni

OH N

non-chiral

NH2

DE_1953-870265 Ph

HN

O

N

PhenylHydrazine

N H

NH2

PtO2 H2

Ref.83.

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


chiral

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

*

*

LiAlD4

NH 2

*

p-MeTOSCl

D2C

D2C

COOH

O

OH

D-Phenylalanine

Ref. 84.

O O HN S

CH3 p-TOS

LiAlD4

NH 2

*

Naphthalene radical anion

CD3


CH3

non-chiral

O O HN S

Ref. 85. NO2

JACS_74(7)1837(1952) NH2

LiAlH4 acid


non-chiral

P-2-P (Nef reaction)

US Patent 02647930B1(1953)

Ref. 86. NO2

Organic Acids Raney-Ni / H 2


NH2

non-chiral

Ref. 87. NO2

DE_1952-848197(1952) NH2

Raney-Ni / H 2


chiral

Chirali ty 6( 4) 314-20 (1994)

Ref. 88.

Distillation from optically a ctive acids..

NH2

NH2

Resolution 1-phenylpropan-2-amine

non-chiral

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

Ref. 89. NO2

NH2

LiAlH4 / ether

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

chiral resolution NH2

Org . Syn. Coll. 2, 506 (1 943) OH

HO OH

racemic-1-phenylpropan-2-amine

NH2

/ water

O

l-malic acid


Ref. 90.

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

non-chiral

O O

O O

O

Cl

2-phenylacetic acid

Ref. 91.

O

SOCl2

OH

O

O O

2-phenylacetyl chloride

diethyl 2-(2-phenylacetyl)malonate J_Am_Pharm_Assoc_687-688(1950) O


N

OH


NH2 1-phenylpropan-2-amine

non-chiral

Bull. Soc. Chem. France 1045 (1950) O

NH3

NH2

Raney-Ni / H2


Ref.92.

non-chiral

Chemische Berichte 124(10) 2303-6 (1991)

NO2

NH2 N

Cathode Red. at Hg or C e lectrode OH


non-chiral

JOC 15, 8 (1 950)

Ref. 94. NO2

Ref. 93.

Raney-Ni / H 2

NH2


non-chiral

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. NO2

Raney-Ni / H 2

NH2


non-chiral

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


NH4

Formic Acid

NH2

Ref.97.

non-chiral

JACS 70, 1315-6( 1948) O

NH2

PtO 2 / H2

NH3


Ref.98.

non-chiral

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

NH2

Raney Ni / H2

OH

Ref.99.


non-chiral

JACS 70 , 2811-12 (1948) O

NH3

NH2

Raney-Ni / H2


Ref.100.

non-chiral Bulletin of Electr ochemisty 8 (6) 276-7 (1 992) N

OH

NH2

Cathode Red. at Hg or C e lectrode

Ref. 101. non-chiral 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

Ref. 103. NO2

Justus_Liebigs_Annalen_der_Chemie_215-221(1948) NH2

P d / H2

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

Friedel-Crafts reactions

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

FeCl3

Cl

Cl

or Fuming Sulfur ic

Cl

NH2

NH4 OH

Allyl Chloride

non-chiral O

Ref. 104.

US Patent 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

NH3

O

NH2

NaOCl

NH2

Hoffman 1-phenylpropan-2-amine

2-methyl-3-phenylpropanoic acid

non-chiral

LEUCKART-Study O


NH4

Formic Acid

JOC 9 , 529 ( 1944) NH2

Ref.106.

Acetylbenzylcyanide Reaction Route non-chiral O ethyl acetate

N

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

O

N

O

O

H3PO4

NaOEt 2-phenylacetonitrile

3-oxo-2-phenylbutanenitrile


Ref. 107. H N

O

NH- 4+ O

NH2

HCl

ammonium formate

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

O

O

non-chiral

O


O

O Acetic Anh ydride

O OH

O O

O

sodium acetate

O

2-phenylacetic acid

1-phenylpropan-2-one J.Gen.Chem.(USSR) 11( 4), 339 (1 941)

LEUCKART H2N O Formamide

H N

O

NH2

Hydrolysis H+

Ref.108.

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

chiral

Resolution NH2

OH

HO

NH2

OH O


Ref.108.

O

OH

d-tartaric acid


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

non-chiral

Wolff Rearr. O OH SOCl2 2-phenylacetic acid

O Cl

Diazomethane

O

O AgO NH 3

HC N

N

NH2

Ref.109.

Chemischen Ber ichte 66B, 684 ( 1933)

non-chiral

HN3

O

acid

O

O

OH

N3

Curtius Rearr.

NH2

Ref.110.

-methylbenzylacetic acid



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

non-chiral Lossen Rearr. O

O

Hydroxyl amineHN

acid chloride X esters anhydride

N

OH

C

NH2 O Hydrolysis

Ref.111.

J.Am. Chem. Soc. 5 4, 271-4 ( 1933)

non-chiral O

NO2

NO2

H

Hg . Cathode electrolic Red.


benzaldehyde

non-chiral

NH2


Ref. 112.

US 1879003 (1932) NO2 Cathode Red. at Hg or C electrode

NH2

Ref. 113. non-chiral Chemicshe Berichte, 66B, 660-666 (1932). N

OH

Na

/ Ethanol

NH2

Ref. 114.

non-chiral O

OH

J. Am. Chem. Soc. 31, 1875 (1931) Cl

OH

N

NH2 HCl

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

NH2 Pd/C, H2

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

NH2

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

O from

O

Ref. 115.

1-phenylpropane-1,2-dione

non-chiral O

J. Am. Ch em. Soc . 31, 2787 -91 (1 931)

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-chiral

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

OH O

NH2-OH

N

Na/Hg

NH2

amalgum 1 -p hen ylp ro pa n-2 -o ne

(Z )-1-phenylpropan-2-one ox ime

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

References…… 1. J. Am. Chem. Soc. 131, 9882 (2009) 107. J. Applied Chem. (USSR) 14(3) 410 (1941) 4. Tetra. Lett. 48(32) 5707 (2007) 7. Central Eur. J. Chem. 6(4) 526 (2008) 12. J. Org. Chem. 70(14) 5519 (2005) 18. J. Chem. Research (S), 128 (2003) 20. J. Chinese Chem. Soc. 49, 505 (2002)

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

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

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

6. Chem. European J. 12(15)4191-7(2006) 9. Faming Zhuanli Shenging Gongkai Shuominshu, patent 1673210 (2005) 6. Chem. European J. 12(15)4191-7(2006) 9. Faming Zhuanli Shenging Gongkai Shuominshu, patent 1673210 (2005) 5. Tetra. 63, 9758 (2007) 8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)

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

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) 8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005) 34. Tetra. Asym. 4(7) 1619 (1993) 11. J. Med. Chem. 48(4) 1229 (2005) 23. US 6399828 (2002)

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-

40. J. Chrom. Sci. 28, 529 (1990) 53. Anal. Chem. 58(8) 1642 (1986) 11. J. Med. Chem. 48(4) 1229 (2005) 23. US 6399828 (2002) 40. J. Chrom. Sci. 28, 529 (1990) 53. Anal. Chem. 58(8) 1642 (1986) 77. DE 968545 (1958) 11. J. Med. Chem. 48(4) 1229 (2005) 13. Org. and Biomolecular Chem. 3(6) 1049 (2005) 14. J. Chem. Research 10, 681 (2004) 19. Tetra. Asy, 14, 2119 (2003) 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) 14. J. Chem. Research 10, 681 (2004) 15. Org. Lett. 6(24) 4619 (2004) 15. Org. Lett. 6(24) 4619 (2004)

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)-3 phenylpropanoic 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. Tetra. Asy, 15(19) 3111 (2004) 16. Tetra. Asy, 15(19) 3111 (2004) 16. Tetra. Asy, 15(19) 3111 (2004) 17. J. Combinatorial Chem. 5(5) 590 (2003) 49. J. Am. Chem. Soc. 109(7) 2224 (1987 ) 52. J Chem. Soc., Chem. Comm. 2, 176 (1986) 17. J. Combinatorial Chem. 5(5) 590 (2003) 19. Tetra. Asy, 14, 2119 (2003) 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002) 25. J. Org. Chem. 65(16) 5037 (2000) 25. J. Org. Chem. 65(16) 5037 (2000) 25. J. Org. Chem. 65(16) 5037 (2000) 26. Org. Lett. 2(13) 1935 (2000) 74. Chem. Pharm. Bull. 13(2) 118 (1965) 27. Tetra. 56, 5157 (2000) 69. J. Am. Chem. Soc. 91, 5647 (1969) 31. Tetra. 53(13) 4935 (1997) 31. Tetra. 53(13) 4935 (1997) 33. Tetra. Lett. 36(8) 1223 (1995) 33. Tetra. Lett. 36(8) 1223 (1995) 33. Tetra. Lett. 36(8) 1223 (1995) 34. Tetra. Asym. 4(7) 1619 (1993) 36. Tetra. Asym. 3(10) 1283 (1992) 51. Organometallics 5, 739 (1986) 54. Khimiya Geter Soedinenii 12, 1648 (1985) 59. Synthesis 4, 270 (1982) 62. Tetra. 32 (11) 1267 (1976) 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. Electrochem. 8(6) 276 (1992) 114. Berichte, 66B, 660 (1932) 117. J. Chem. Soc. 18 (1930) 37. Acta. Chemica Scandinavica 45, 431 (1991)

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-1 phenyl 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

37. Acta. Chemica Scandinavica 45, 431 (1991) 37. Acta. Chemica Scandinavica 45, 431 (1991) 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989) 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989) 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989) 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989) 47. J. Med. Chem. 31(8) 1558 (1988) 112. J. Am. Chem. Soc. 54, 271 (1933) 48. Org. Reactions 36, book (1988) 49. JACS 109(7) 2224-5 (1987) 52. J. Chem. Soc., Chem. Comm. 2, 176 (1986) 55. J. Org. Chem 50(19) 3481 (1985) 72. J. Heterocyclic Chem. 5(3) 339 (1968) 55. J. Org. Chem 50(19) 3481 (1985) 55. J. Org. Chem 50(19) 3481 (1985) 55. J. Org. Chem 50(19) 3481 (1985) 55. J. Org. Chem 50(19) 3481 (1985) 55. J. Org. Chem 50(19) 3481 (1985) 58. Synthesis 4, 270 (1982) 61. Hetvetica Chimica Acta 61(2) 558 (1978) 102. J. Am. Chem. Soc. 70, 4048 (1948) 21. J. Chem. Soc. Perkin T. I 16, 1869 (2002)

29. JP 2002142793 (2002) 31. Tetra. 53(13) 4935 (1997) 105. US 2,413,494 B1 (1946) 118. J. Am. Chem. Soc. 48, 169 (1928) 40. J. Chrom Sci. 28, 529 (1990) 91. J. Am. Chem. Soc. 687 (1950) 108. J. Gen. Chem. (USSR) 11(4) 339 (1941) 74. Chem. Pharm Bull. 13(2) 118 (1965) 80. J. Org. Chem. 22(1) 33 (1957) 84. J. Labelled Comp. Radio 3(1) 3 (1977) 84. J. Labelled Comp. Radio 3(1) 3 (1977)

Synthetic Amphetamine

Recommend Documents