synthetic amphetamine

Review: Synthetic Methods for Amphetamine

A. Allen1 and R. Ely

2

1Array BioPharma Inc., Boulder, Colorado 80503

2Drug Enforcement Administration, San Francisco, CA

Abstract: This review focuses on synthesis of amphetamine. The chemistry of these

methods will be discussed, referenced and precursors highlighted. This review covers

the period 1985 to 2009 with emphasis on stereoselective synthesis, classical non-chiral

synthesis and bio-enzymatic reactions. The review is directed to the Forensic Community

and thus highlights precursors, reagents, stereochemistry, type and name reactions. The

article attempts to present, as best as possible, a list of references covering amphetamine

synthesis from 1900 -2009. Although this is the same fundamental ground as the recent

publication by K. Norman; “Clandestine Laboratory Investigating Chemist Association”

19, 3(2009)2-39, this current review offers another perspective.

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

Introduction: It has been 20 years since our last review of the synthetic literature for the

manufacture of amphetamine and 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.

1900 1930 1970 2009

LossenCurtiusHofmannWolf

1. methyl ethyl ketone2. ethyl acetoacetate3. aldehyde -nitroethane

1. metal catayltic red.2. disolved metal red.3. non metalic red.

Stereoselective syn.

Organometalicchiral reductionalkylationsaminationsMitsunobuEnzymic

Time-Line of Synthetic Routes to Amphetamine

The Era of Classical Organic Chemistry

Rearrangements: Reductions:Aldo Condensations:

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 non-

chirally to amphetamine [4, 12, 18, 20, 35, 41, 42, 56]. Likewise, hydroxylamine via

chiral hydrosilylation [51] and hydrazines [8, 52] have been exploited in routes to

amphetamine. Reductive aminations via phenyl-2-propanone; P-2-P [19, 40, 51, 54] have

appeared in these years, as well as other creative approaches like -amination [5],

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.

Reductions

Stereoselective

Nitrostyrene

Enzymic

Ring Opening

Organometalic

Amination

Mitsunobu

Resolutions

Oxime

Hydrazine

Friedel-Craft Alkylation

Photochemical

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

Alkylations

Hofmann rearrangement21, 37

2

55

1, 5, 15, 21, 31

1, 15, 17, 31

4, 7, 12, 18, 20, 35,41,42, 46, 47, 56

5, 31, 16

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

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

8, 13, 28

2, 3, 10, 22, 24, 37, 38, 43,

17, 26, 27, 58, 15

36, 45, 46, 51, 54

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

8, 34

1, 15, 19, 26, 49, 50, 52 Imine

Figure 1a.

Literature Citations for the Synthesis of Amphetamine 1985-2009

Enzymatic (Bio Transformations) (see Scheme 4)

2. J. Org. Chem., JOC 73(2008)364 3. J. Org. Chem., JOC 72(2007)6918 10. Indian J. Chem. Soc. B., IJCS 44B(2005)1312 14. J. Chemical Research, JCR 10(2004)681 22. Tetrahedron Asymmetry, TA 13(2002)1315 24. Synthetic Comm., SC 31(2001)569 39. Chem. & Pharm. Bull., CPB 38(1990)3449 43. US Patent 04950606B1 (1990)

Non-Chiral Organic Synthesis (see Scheme 3)

4. Tetrahedron Letter, TL 48(2007)5707 12. J. Organic Chem., JOC 70(2005)5519 13. Organic & Biomol. Chem., OBC 3(2005)1049 15. Organic Letters, OL 6(2004)4619 26. Organic Letters, OL 2(2000)1935 27. Tetrahedron, Tetra. 56(2000)5157 31. Tetrahedron, Tetra. 53(1997)4935 32. J. Chem. Soc. Perkin I, JCSP1 1(1996)265 37. J. Labeled Comp. Rad., JLCR 31(1992)891 38. J. Medicinal Chem., JMC 34(1991)1094 40. J. Chromatographic Sci., JCS 28(1990)529 41. Tetrahedron, Tetra 46(1990)7403 42. Tetrahedron, Tetra 46(1990)7743 45. Coll. Czech. Chem. Comm., 54(1989)1995 48. Organic Reactions, Vol 36 (book, 1988) 57. J. Medicinal Chem., JMC 31(1988)1558 52. J. Chem. Soc. Chem. Comm. 2(1986)176 54. Khimya Geter. Soed #12,1648(1985) 56. Synthetic Comm., SC 15(1985)843 22. Tetrahedron Asymmetry, TA 13(2002)1315

Stereoselective Synthesis (see Scheme 2)

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

# = Reference Figure 1b.

Amphetamine Review (1989 – 2009)

1900 1930 1970 2009

Stereoselective syn.Time-Line of Synthetic Routes to Amphetamine

1985

Ph

OHPh

H2N

O

Ph

HOPh

OH

Ph

NH2

OH

OH

TA 4(7)1619(1993)

TA 15(19)3111(2004)

PhCOOH

NH2

Ph

OH

NH2

JCS, Perkin T.I, 161869 (2002)

JCS, Perkin T.I, 161869 (2002)

JOC 50(19) 3481(1985)

J.Comb.C. 5(5)590 (2003)

JACS 109(7)2224 (1987)

JMC 48(4)1229 (2205)

B.M.C.L. 15(12) 3039 (2005)

JOC 65(16) 5037 (2000)

H

O

T.L. 41(34) 6537 (2000)

Chiral

Chiral

Chiral

Chiral

Chiral

Chiral

Chiral

Chiral

Chiral

Org. Biomol. Chem. 3,1049(2005)

Chiral

NJACS 131(29) 9882 (2009)

Chiral

Ph H

O

Ph OH

Ph OH

ONHPh

OH

PhO

Tetra. 63(39) 9758 (2007)

Tetra. 63(39) 9758 (2007)

Tetra. 63(39) 9758 (2007)

Tetra. 63(39) 9758 (2007)

PhNO2

Ph Br

Ph

HN BOC

I

Chem. Eur.J. 12, 4191 2006

FZSGS #1673210 (2005)

J. Chem. Res. 10, 681 (2004)

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

Ph

OTetra. Asy. 14, 2119 (2003)

J. Chinese C S 49, 505 (2002)

Tetra. Let. 36(8) 1223 (1995)

Tetra. 46(21) 7403 (1990)

Anal. Chem. 58(8) 1642(1986)Organometallics 5, 739 (1986)

Chiral

Chiral

Chiral

Chiral

Chiral

Chiral

NH2

Amphetamine28.

Stereoselective Synthesis of Amphetamine 1985--2009

Scheme 2.

(S)-1-phenylpropan-2-amine

36

51

1 55

5

5

18 20 41

6 9

1123

4053

8

14

19

1617

49

1940

5154

21

21

2533

34

55

Tetra Asy 3(10) 1283 (1992)

Organometallics 5, 739 (1986)

KGS #12,1648 (1985)

US # 6,399,828 (2002)

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

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

54

KGS #12,1648 (1985)

5

44

Angew chem. Int. 28(2) 218 (1989)

R

2A. 2B.

2C.

2D.

2E.

2F.

2G.

2H.

2J.2K.

2L.

2M.

2N.

2O.

2P.

2Q.

2I.

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-phenylpropan-

2-imine, route 2A) as a chiral approach to amphetamine [1, 36, 51, 54]. This approach

has been facilitated by the improvements of chiral organometallic ligands with transition

metals in order to effect chiral catalytic reductions [1, 36, 51, 54, route 2A]. Similarly,

armed with chiral organometallic ligands with ruthenium and rhodium, the reduction of

nitrostyrenes [(E)-(2-nitroprop-1-enyl)benzene] have been achieved stereoselectively [18,

20, 41; route 2F].

A completely different approach was taken by Talluri, S. et. al.; [routes 2B-E],

wherein they initiated the route to amphetamine from 1-phenylpropanal [5, route 2E].

Starting from this one-carbon extended aldehyde as opposed to the typical 2-

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 2C-

2D]. Tosyl chloride assisted ring closure lead to the epoxide, 2-benzyloxirane [5, route

2B]. Reductive ring opening of the epoxide produced the alcohol, (S)-1-phenylpropan-2-

ol; [see structure in route 2I]. This was followed by swapping the alcohol moiety for

azide. The final step was catalytic (PtO2) reduction to amphetamine [5]. Although a

lengthy process to amphetamine, its potential importance to forensic chemists lies in the

fact that each intermediate is a potential starting precursor for a chiral synthesis to

amphetamine. Closely allied to the alcohol-azide swap in the previous route are the

variations achieved by Mitusnobu reaction-type exchanges from (R)-1-phenylpropan-2-ol

to (S)-1-phenylpropan-2-NX, wherein inversion of configuration is complete to the amine

compliment [8, 14, 19, 5, 34; route 2I and route 2P].

Chiral starting materials like 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].

1900 1930 1970 2009

non-chiral synthesesTime-Line of Synthetic Routes to Amphetamine

1985

NH2

Ph Ph

NH2

MgBr

T. 53(13)4935 (1997)

O.L.. 2(13) 1935 (2000)

NP

Cp2TiMe2

non-Chiral

O

O O

OH

SO2

NO2

NH2

Org. Biomol. Chem 3(6) 1049 (2005)

NO2

LiAlH4

JOC 70(14)5519 (2005)

MgBr

O

ON

O

Org. Let. 6(24) 4619 (2004)

non-Chiral

non-Chiral

non-Chiral

OHO

ONH

O

O tBu

Tetra. Let. 41, 6537 (2000)

non-Chiral

n-BuLi

Ph NH2Pd/H2

Tetra. 56, 5157 (2000)

O

Mgreduction

NH3

HoAc

JCS, PTI, 265 (1996)

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)

TsPh

PhNH

N

H3C

JCS, Chem. Comm.2, 176 (1986)

Syn. Comm. 15(9) 843 (1985)non-Chiral

non-Chiral

non-Chiral

non-Chiral

Non-Chiral Synthesis of Amphetamine 1985--2009

Scheme 3

4

28

1315

27

26

31

32

COOH

OO

O

O

Acta Chem. Scand.45, 431 (1991)

CN

SPh

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

H

O

NO

Tetra. Asy. 13(12) 1325 (2002)J. Chrom Sci. 28, 529 (1990)

Acta Chem. Scand.45, 431 (1991)

JMC 31(8) 1558 (1988)

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

non-Chiral

22

40

48

47

37

Amphetamine

12

35

4247

56

37

non-Chiral

non-Chiral

non-Chiral

45

52

58

17

Br

46.

Tetra. Let. 48(32) 5707 (2007)

3A.

3B.

3C.

3D.

3E.

3F.

3G.

3H.3I.

3J.

3K.

3L.

3M.

3N.

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 induced-

radical mediated racemization of the single amphetamine isomer to the racemic mixture.

Classical methods of chiral resolution based upon chiral organic salts have been reported

in the time frame of 1900-2009, with the use of D-(-)-tartaric acid [30, 47, 38, 71, 81a,

88, 90, 108], benzoyl-d-tartaric acid [38], di-p-toluoyl-d-tartaric acid [38], (S)-2-

naphthylglycolic acid [66], -amino acids [78] and optical-10-camphorsulfonyl chloride

[37].

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

Scheme 5.

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

The early literature regarding amphetamine synthesis of the 1900‘s was

dominated by classical organic transformations (Scheme 5). These reactions like the

Friedel-Crafts reaction [105,], Ritter Reaction [102], Leuckart reductive amination

reaction [106, 97, 76, 71], nitro-aldol dehydration reaction, also called the Henry

Reaction [116, 96, 94, 89, 87, 86, 85, 82, 70, 67] and rearrangement reactions that came

to be known as the Hofmann rearrangement[105, 116], Curtius rearrangement [118, 110,

80], Schmidt rearrangement [80], Lossen rearrangement [118], Beckmann rearrangement

[111] and the Wolff rearrangement [109], were productive routes to the synthesis of

amphetamine. The non-amine component, -methylbenzylacetic acid, was constructed

with carbon-carbon bond formation via a carbo-anion enolate condensed with a suitable

alkylhalide. These condensations, that were classically referred to as acetoacetic ester

synthesis [105, 118] and malonic ester synthesis [91], later came to be referred to as cases

of the 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.

1900 1930 1970

non-chiral synthesesTime-Line of Synthetic Routes to Amphetamine

1985

Br

H

O

Br

CN

H

Br

OH

OHO

O

N

OH

NH2

R

OHOOH

NH2

OH

OH

NH2

O

NH2

Amphetamine

O

O

Br

O

COOH

NH2

NO2

H

O

O O

O

O

OH

O

S

CN

Ph

O

HOOH

Scheme 6.

Organic Transformationsto Amphetamine1900 - 2009

2009

12

18

20

39

22

4

35

41

42

5

5

37

5

34

21

15

8

1314

28

1419

2029

32

384336

116

11

17

26

27

1

21

25

33

31

44

45

47

48

49

51

5222

23

40

40

40

47

49

51

52

52

53

54

54

5556

513

54 57

58

59

59

60 61

62

6364

65

67

70

69

71

72

73

74

74

75

7679

80

80

82

84

85

86

87

88

88

89

89

92

92

91

91

9092

95

95

94

93

96

98

99

100

101

101

103

102

105

106

108

107

107

109

110

111112

113 114

115

117

116

116

118

120

120

121

122

6A.

6B.

6C.

6D.

6E.

6F.

6G.

6H.

6I.

6J.

66K.

6L.

6M.

6N.6O.

6P.6Q.

6R.

6S.

6T.

6U.

6V.

6W.

6X.

6Y.

6Z.

6AA.

6BB.

84a

84b

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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:

N MeMgI NH NH2

Ir-(S,S)-f-binaphane

H2

(S)-1-phenylpropan-2-amine1-phenylpropan-2-imine2-phenylacetonitrile

JACS 131, 9882 (2009)

Ref. 1.

chiral

NH2


NH2

1-phenylpropan-2-amine

Ref. 2.

HSCH2CO2Me

Benzene

Photochemical --Racemization

JOC 73(2) 364 (2008)chiral

NH2


NH2


Lipase Lauric acid

+ amide of lauric acid

Biotrasformation, Enzymic, Stereoselective

JOC 72(18) 6918 (2007)

Ref. 3.

chiral

NO2

NH2


PhH2NSmI2

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

Tetra. Let. 48(32) 5707 (2007)

Ref. 4.

non-chiral

H

O

OH

ONHPh

OH

OH

OHO NH2

3-phenylpropanal

(R)-3-phenyl-2-(phenylaminooxy)propan-1-ol

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

2-benzyloxirane (S)-1-phenylpropan-2-ol(S)-1-phenylpropan-2-amine

nitrosobenzene

l-proline

NaBH4

Pd/C

TsClTEA

NaH1,

2.

LiAlH4 1. NaN3

2. Pd/C H2

Tetra. 63, 9758 (2007)

Ref. 5.

chiral

HN

ter t-butyl 1-iodo-3-phenylpropan-2-ylcarbamate

I

O

O

HN O

O

NH2

(S)-1-phenylpropan-2-amineter t -butyl 1-phenylpropan-2-

ylcarbamate

chiral Chem. European J. 12(15)4191-7(2006)

Ref. 6.

SmI2 TFA

NO2 NH2


NaBH4


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

Ref. 7.

BF3 - Et2O

THF

OHN

Phth Anh.

O

O NH2

NH2-NH2

amphetamine

Ref. 8.

Ph3P

DEAD, THF

MeOH

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

(S)-1-phenylpropan-2-ol

(S)-2-(1-phenylpropan-2-yl)isoindoline

-1,3-dione


chiral

HN

ter t-butyl 1-iodo-3-phenylpropan-2-ylcarbamate

I

O

O

HN O

O

NH2

(S)-1-phenylpropan-2-amineter t -butyl 1-phenylpropan-2-

ylcarbamate

chiral Faming Zhuanli Shenqing Gongkai Shuomingshu # 1673210 (2005)

Ref. 9

SmI2 TFA

NH2


NH2


Lipase Lauric acid

+ amide of lauric acid

Biotrasformation, Enzymic, Stereoselective

indian J. Chem.Sec B 44B(6) 1312 (2005)

Ref. 10.

chiral

OH

NH2

norephedrine

OHNAc2O

Ac

Ac

HN

Ac

H 2/

Pd-BaSO4

NH2H2SO4

amphetamine

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

2-acetamido-1-phenylpropyl acetate

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

chiral

Ref. 11.


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

NO2 NH2

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

LiAlH4


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

Ref. 12.

OH NH2

amphetamine1-phenylpropan-2-ol 1-phenylpropan-2-amine

SO2

NO2

NH2

DCC

HNS

O

O2N

O

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

non-chiral Org. and Biomolecular Chem. 3(6) 1049 (2005)

PhSH, K2CO3

50oC

Ref. 13.

NH2

(S)-1-phenylpropan-2-amineO

1-phenylpropan-2-one

OHN3

baker's yeast

sucrose

Pd/C

H2


(S)-(2-azidopropyl)benzene

J. Chem. Research 10, 681 (2004)chiral

Ref. 14.

MgBrO O

NO

S

O O

N

NH2

HCl

amphetamine

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

(1-phenylpropan-2-yl)magnesium bromide

O

O

1-phenyl-N -(4,4,5,5-tetramethyl-

1,3-dioxolan-2-ylidene)propan-2-amine


non-chiral

Ref. 15.

OH

OH

SOCl2O

O

S

O N3

OH

NaN3

NH2

HN

Ph3P Pd-C

HCO2NH4

amphetamine

Tetrahedron Asymmetry15(19),3111-6 (2004)

(1S,2S)-1-phenylpropane-1,2-diol

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

2-methyl-3-phenylaziridine

Ref. 16.(S)-1-phenylpropan-2-amine

chiral

O

HS

NH2

O

CuSO4 SN

O

MeMgBrS

NH

OHCl, MeOH

NH2

amphetamine

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

2-phenylacetaldehyde(R)-2-methyl

propane-2-sulfinamide

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

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


chiral

Ref. 17.

NO2

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

NH2Ruthenium BINAP


chiral

Ref. 18.

O


H2NN

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

ethanamine

NH2


Tetra. Asy. 14, 2119 (2003)chiral

Ref. 19.

NO2

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

NH2

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

Ru2Cl2(PPh3)3

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

chiral

Ref. 20.

BrN

OO

LDA, THFN

OO

NH3, MeOHNH2

O NH2

PhI(OOCCF3)2

amphetamine

JCS Perk in T .I 16, 1869(2002)

1-(bromomethyl)benzene

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

(5R)-3,3,5-trimethyl-1-(2-methyl-3-phenyl

propanoyl)pyrrolidin-2-one

(S)-1-phenylpropan-2-amine(S)-2-methyl-3-phenylpropanamide

chiral

Ref. 21.

NH2

amphetamine

OPd, MeOH

T etrahedron Asymmetry, 13(12)13115-1320 (2002) 1-phenylpropan-2-amine


HCOO NH4

NH2

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

NH2


chiral

Ref. 22.


Enzymic, Resolution

CAL-B cat.

non-chiral

Ref. 22.

NH2

US pat. # 6399828 2002)

NH2

OH

Ac2O

NH2

OAcPd

BaSo4H2


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

chiral

Ref. 23.

HoAc

HI, P4

HCl

NH2

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

NH2


chiral

Ref. 24. (S)-1-phenylpropan-2-amine

Enzymic, Resolution

Candida antarcitica Lipase

NH2

COOH

LiBH4/TMSCl NH2

OH

NH

OH

BOC)2O

O

O

NH

I

(Ph)3P / I N-Selectride NH NH2

amphetamine

TFA

J. Orgainic Chemistry65(16) 5037-42 (2000)

OO OO

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

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

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

(S)-2-amino-3-phenylpropan-1-ol (S)-ter t-butyl 1-hydroxy-3-phenylpropan-2-ylcarbamate

chiral

Ref. 25.

NH2 Cp2TiMe2

N

Ph

Ph NH2

1-phenyl-1-propyne

amphentamine

Organic Let ters, 2(13) 1935-1937 (2000)

Ref. 26.

diphenylmethanamine

(E)-diphenyl-N-(1-phenylpropan-2-

ylidene)methanamine


non-chiral

Cp2TiMe2

H2, Pd/C

NH2


H2N

cat. n-Bu Li

Ph

NH

Pd/C H2

non-chiral T etra. 56, 5157 (2000)Ref. 27.

allylbenzeneN-benzyl-1-phenylpropan-2-amine

OH NH

O

NH2

TFA

amphetamine

Ph3P

DEAD, THF

DCM

T etrahedron Letters, 41(34)6537-40 (2000)tBuCO)2O

O1-phenyl

propan-2-ol ter t-butyl1-phenylpropan-2-ylcarbamate


non-chiral

Ref. 28.

JP 03191797 (1991)

NH2

phenylpropan-1-one

chiral

Ref. 29. (S)-1-phenylpropan-2-amine

Enzymic, Resolution

C: 9031-66-1

O

BuNH2

d-Tartaricacid

O

Ref. 30.

NH2


non-chiral

Leuckart Reaction

ammonium formate

NH2 COOH

OHHO *

HOOC*

Zhongshan Dazue Xuebao 35(5) 73-76 (1996)

MgBr N

PO O

O

NH

POO

O

CuI

THF

NH2HCl

amphetamine

T etrahedron, 53(13) 4935-4946, 1997

diethyl 2-methylaziridin-

1-ylphosphonate

phenylmagnesiumbromide

diethyl1-phenylpropan-

2-ylphosphoramidate


non-chiral Ref. 31.

NH2

O

NH3

P-2-P

J.Chem.Soc., Perkin T rans I , 265 (1996)

Mg MeOH

HoAc1-phenylpropan-2-one


non-chiral

Ref. 32.

HN

OH

O

O

Tetra. Lett . 36(8) 1223 (1995)

O

NH

OH

NH

O

BH3

THF CH3SO2Cl

TEA

Ms

NH

O S

NaH

CH3CH2SH

NHRa-Ni

EtOH

NH2

BOC BOC

BOC BOC

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

chiral

TFA

Ref. 33.


OH

NH2

OH

OH

N

OHPhth Anh.

O

OPh)3P / I

I

I

H2 / Pd-C

NH2

NH2-NH2

amphetamine

T etrahedron Asymmetry4(7) 1619-24, 1993

(1S,2S)-2-amino-1-phenylpropane-1,3-diol

2-((1S,2S)-1,3-dihydroxy-

1-phenylpropan-2-yl)isoindoline-1,3-dione

N

O

O

N

O

O

2-((1S,2S)-1,3-diiodo-1-phenyl

propan-2-yl)isoindoline-1,3-dione

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


chiral

Ref. 34.

NO2

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

NH2

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

LiAlH4

non-chiral

1-phenylpropan-2-amineRef. 35.

NH2

amphetamine

N

T etrahedron Asymmetry,3(10)1283-8 (1992)

OH

E & Z

H4Ru(arene)

BINAP

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

chiral


Ref. 36.

O

O

O

O

O

O

O

O

OH

O

2. AcOH

NH2

Acta. Chemica Scandinavica 45, 431 (1991)

amphetamine

methyl2-benzyl-2-methyl-3-oxobutanoate

2-methyl-3-phenylpropanoic acid 1-phenylpropan-2-amine

dimethyl 2-benzylmalonate

CH3-INaH

DMSO

1. NaOH

PO

Ph

Ph

NN+

-N

1. TEA/heat

2. HCl / heat

non-chiral Ref. 37.

NH2

amphetamine


NH2

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

(+)-10-camphorsulonyl chloride

resolutionchiral

Tetrahedron Lett . Vol. 32, No. 49 (1991) 7325-8.

NH2

amphetamine


NH2

amphetamine


resolution

chiral HOOC

COOH

ORRO

*

* R = HBenzoylp-toluoyl

Ref. 38.

NO2

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

NH2


Biotransformationcat. Peptostreptococcus Anaerobius


non-chiral

Ref. 39.

NH2

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

NH2


OH

NH2

Cl

Pd H2SOCl2

(1S,2S)-1-chloro-1-phenylpropan-2-amine(S)-1-phenylpropan-2-amine

chiral

OH

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

O

NH2

2-phenylacetic acidO


non-chiral

Ac2)O

NaOAc

Leuchart Red


Ref. 40.

Ref. 40.

NH2


NO2 NO2BH3-THF Ru2Cl2[(-)-DIOP]3

H2

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

Tetra. 46(21) 7403 (1990)chiral Ref. 41.

NH2

amphetamine

NO2 BH3-THF


Tetra. 46(21) 7743 (1990)Ref. 42.

cat. NaBH4

non-chiral

NH2

amphetamine

O

1-phenylpropan-2-amine1-phenylpropan-2-one

NH2

U.S. pat . # 4950606 (1990)

NH2


chiral

Ref. 43.


Enzymic, Resolution

Bacill lus Megater ium

non-chiral Biotransformation

amino-acid transminase from

Bacil llus Megater ium

amino-acid transminase from

Ref. 43.

NH2

amphetamine1-phenylpropan-2-amine

NO2

LiBH4 /THF


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

Ref. 44.

(CH3)3SiCl

NH

COOH

OO

2-(benzyloxycarbonyl)-3-phenylpropanoic acid

NH

OO

benzyl 1-phenylpropan-2-ylcarbamate

(CH3)3SiCl

LiBH4 /THF

S

CN

PhS CN

Ph

O

SPh

O

SPh

NOH

SPh

NH2

NH2

NaOEt

EtOH

H3PO4

NH2OH Na EtOH HCl

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

Ref. 45.2-(2-(phenylthio)phenyl)acetonitrile

3-oxo-2-(2-(phenylthio)phenyl)butanenitrile

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

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

N

Org. React ions 36, book (1988)

NH2

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

Red - Al, THF

non-chiral


Ref. 46.

O

NO2


Red-Al THFNH2

NO2

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

NH2


H

O

benzaldehyde

NO2 LiAlH4

non-chiral


Ref. 47.

NO2

JP 63219396 (1988)

NH2


chiral

Ref. 48.


Enzymic, Resolution

Biotransformation /

NH2N

NH2

Ref. 49.

amphetamine

O

NN

H

CH3Li / CeCl3N

HN H2 / Ra-Ni

375 psi / 60o

JACS 109(7) 2224-5 (1987)

2-phenylacetaldehyde(R)-2-methyl

pyrrolidin-1-amine

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

pyrrolidin-1-amine

(s)-1-phenylpropan-2-amine

chiral

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

pyrrolidin-1-amine

O NH2

NH2

amphetamine

US 4000,197 (1976)

chiral

Ref. 50.


phenyl-2-propanone

HN*

*low pressure

Hydrogenation

HN*

*

[R,R]+

R or S

[S,S]-orRaney Ni / H2

[S,S]-(-)

10% Pd-C

50 psi H2

*

-methylbenzylamine

O

Ref. 51. Organometall ics, 5, 739-46 (1986)

NH2NOH

H-SiH(Ph)2

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

Rh(cod)Cl2

chiral

H

O

H

NNH

Ph

Ph

CH3

NNH

Ph

Ph

LDA

CH3I

Aphetamine

2-phenylacetaldehyde

J. Chem. Soc., Chem. Comm. 2, 176, (1986)

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

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

non-chiral Ref. 52.

H

O

H

NNH

Ph

Ph

CH3

NNH

Ph

Ph

LDAAphetamine

1. TFA

J. Chem. Soc., Chem. Comm. 2, 176, (1986)non-chiral Ref. 52.

acetaldehyde

Ph-CH2-Br2. Pd /C H2

1. TFA

2. Pd /C H2

NH2NH2

US 2009292143 (2009)


non-chiral

Ref. 53.

OH

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

NH2

Cl

Pd

H2

O

Ref. 54.

Khimiya Geterotsikl icheskikh Soedinenii 12, 1648 (1985)

NH2NOH

Na MeOH

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

chiral

Cl

OHN CF3

O

AlCl3

OHN CF3

O

H2 / Pd-COH

HN CF3

O

PBr3

BrHN CF3

O

H2 / Pd-C

HN CF3

O

NH2

amphetamine

K2CO3, MeOH

Ref. 55J.Org.Chem. 50(19)3481-4 (1985)

benzene(S)-2-(2,2,2-trifluoroacetamido)

propanoyl chloride(S)-2,2,2-trifluoro

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

(S)-2,2,2-trifluoro-N-(1-hydroxy-1-phenylpropan-2-yl)acetamide

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

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

chiral

NO2

Ref. 56. Syn. Comm. 15(9) 843 (1985)

NH2


BH3 - THF

non-chiral

NaBH4

NH2

amphetamine

NO2

non-chiral

BH3 / THF

Syn. Comm. 14(12)1099(1984)

Ref. 57.

NaBH4

NH2

amphetamine

non-chiral Synthesis (4) 270-3 (1982)

Ref. 58.

PO

O

H2N

O

HN P

O

O

O

HCl /benzene

Hg(NO3)2

1,1-diCl-ethane

1. /

2. 10% NaOH / NaBH4

(E )-prop-1-enylbenzene

diethyl phosphoramidate

NH2

amphetamine

chiral Synthesis (4) 270-3 (1982)

Ref. 59.

NOH P

Ph

O

ClPh

CH2Cl2, DEAN

PPh

O

O

Ph(E)-1-phenylpropan

-2-one oxime

LAH

(-) Quinine / THF

HN

PPh

O

O

Ph

HCl / ethanol

O

Ref.60.

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

NH2


non-chiral

NH3 (Sealed)

Al, HgCl2, NH4OH, 100oC, 15min

Ref.61.

Helvet ica chimica Acta 61(2) 558 (1978)

NH2

(E)-prop-1-enylbenzene

non-chiral

NO NO2

NO

LiAlH4

NH2

amphetamine

N

T etrahedron 32(11) 1267-76 (1976)

OH

E & Z


chiral


Ref. 62.

LiAlH4

O

Ref.63.

J. Chem. Education 51, 671(1974)

NH2


non-chiral

Al, HgCl2, NH4OH, 100oC, 15min

O

JMC 16(5) 480-3 (1973)

HN


non-chiral

Ref.64.

NH2

H2N

(R)-1-phenylethanamine

(+) or (-)

Raney-Ni

H2

HN

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

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

separationPd-C / H2

MeOH(S)-1-phenylpropan-2-amineof Diastereoisomers

O

Ref.65.

JACS 93, 2897 (1971)

NH2


non-chiral

NaCNBH3

NH4OH, MeOH

O

OH

Ref. 66.

EP 915080 (1999)chiral resolution

NH2 NH2

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

OH

(s)-2-naphthylglycolic acid

NO2

Ref. 67. J.Med.Chem. 13, 26(1970)

NH2


LiAlH4 / THF

non-chiral

HN


JACS 91, 5647 (1969)non-chiral

Ref. 69.

NCH3CN Hg(NO3)2 ONO2

Hg

NO3

HN ONaBH4

NaOH

HCl

allylbenzene

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

NO2

Ref. 70. US Pat. 3,458,576 (1969)

NH2


non-chiral

Pd-C / H2

Pt / H2

Raney-Ni / H2

O

Ref.71.

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

NH2


non-chiral

NH4 HCOO Ammonium FormateHCl

Ref.71.

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

NH2

chiral

NH2 (+)-tartaric acid

EtOH

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

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

NH2

non-chiral


Ref. 72.

HN

AlCl3

2-methylaziridinebenzene

N

T etra. 24(16) 5677 (1968)

NH2LiAlH4

non-chiral


Ref. 73.

OR

R = H or R = Ts

THF

Ref.74.

Chem Pharm Bull 13(2)118(1965)

NO2

prop-1-ynylbenzene

non-chiral

NOClnitrosyl chloride

NO2Clhypochlorous nitrous anhydride

Cl

NO2

Cl

Pt2O

H2

O

Ref.75.

US Pat. 3,187,047 (1965)

NH2


non-chiral

NH4 oAc Raney-Ni / H2

O

Ref.76.

T etra. 19, 1789 (1963)

NH2


non-chiral

NH4 Formic Acid

LEUCKART-WALLACH Mech

NH2NH2

DE_1958-968545(1958)


non-chiral

Ref. 77.

OH

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

NH2

Cl

Pd

H2

US 3028430 (1962)

NH2

amphetamine


NH2

amphetamine


resolution

chiral

COOH

RH2N

*

Ref. 78.

-amino acid

O

Ref.79.

US Pat. 2,828,343 (1958)

NH2


non-chiral

NH3 (g) CuO and Ba(OH)2

H2

OH

ONH2

JOC_22(1)33(1957)

amphetamine

chiralRef. 80.

Cl

O

N3

O

(S)-2-methyl-3-phenylpropanoic acid

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

(S)-2-methyl-3-phenylpropanoyl azide (S)-1-phenylpropan-2-amine

CO2Cl2

NaN3

HCl

Curtius rearrangement

OH

O

(S)-2-methyl-3-phenylpropanoic acid

NH2


H2SO4 NaN3

Schmidt rearrangementchiral

Ref. 80.

US 2,833,823 (1958)

NH2


NH2

amphetamine


resolution

chiral

Ref. 81binriched in one isomer

H3PO4

Zhurnal Obshchei Khimii 28 (1958) 3323-8

NH2

amphetamine


NH2

amphetamine


resolution

chiral

COOH

OHHO

*

Ref. 81a

HOOC

*d-Tartaricacid

NO2

Ref. 82. J_Pharm_Soc_Japan_413-416(1954)

NH2


Raney-Ni

non-chiral

N

OH

Raney-Ni

O

Ref.83.

NH2


non-chiral DE_1953-870265

NNH

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

PtO2

H2PhenylHydrazine

HN

NH2 Ph

NH2


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

Ref. 84.

NH2

COOH

NH2

D2COH

*

D-Phenylalanine

LiAlD4 * p-MeTOSClHN

D2CO

*S

O

CH3

O

p-TOSLiAlD4

HN

CD3

*S

O

CH3

O

Naphthalene radical anion

NO2

Ref. 85. JACS_74(7)1837(1952)

NH2


non-chiral

LiAlH4

acidP-2-P (Nef reaction)

NO2

Ref. 86. US Patent 02647930B1(1953)

NH2


Organic Acids

non-chiral

Raney-Ni / H2

NO2

Ref. 87. DE_1952-848197(1952)

NH2


non-chiral

Raney-Ni / H2

NH2

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

NH2


chiral

Ref. 88.


Resolution

Distillation fromoptically active acids..

NO2

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

NH2


non-chiral

LiAlH4 / ether

l-malic acid

OH

O

HO

O

OH

Ref. 90.

Org. Syn. Coll. 2, 506 (1943)chiral resolution

NH2 NH2

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

/ water

OH

O

Cl

OO

O O

O

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

2-phenylacetic acid 2-phenylacetyl chloride

SOCl2

O

O

O

O

O

diethyl 2-(2-phenylacetyl)malonate

O


NOH


NH2


Mg

Onon-chiral

Ref. 91.J_Am_Pharm_Assoc_687-688(1950)

O

Ref.92.

NH2


non-chiral

NH3 Raney-Ni / H2

Bull. Soc. Chem. France 1045 (1950)

NO2

NH2


non-chiralChemische Ber ichte 124(10) 2303-6 (1991)

Ref. 93.

NOH

Cathode Red. at Hg or C electrode

NO2

Ref. 94. JOC 15, 8 (1950)

NH2


non-chiral

Raney-Ni / H2

O

Ref.95.

NH2


non-chiral

NH3 Raney-Ni / H2

GB 702985(1949)

or Pt or Pd

NO2

Ref. 96. US Pat. 2,636,901(1949)

NH2


non-chiral

Raney-Ni / H2

O

Ref.97.

JACS 70, 1187 (1948)

NH2


non-chiral

NH4 Formic Acid

LEUCKART-WALLACH Mech

O

Ref.98.

JACS 70, 1315-6(1948)

NH2


non-chiral

NH3 PtO2 / H2

N

Ref.99.

NH2


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

OH Raney Ni / H2

O

Ref.100.

NH2


non-chiral

NH3 Raney-Ni / H2

JACS 70, 2811-12 (1948)

NH2

non-chiralBullet in of Electrochemisty 8(6) 276-7 (1992)

Ref. 101.

NOH Cathode Red. at Hg or C electrode

OH

Ref.102.

NH2

1-phenylpropan-2-ol

non-chiralJACS 70, 4048 (1948)

(E )-prop-1-enylbenzene

O

SO3H

1-phenylpropan-2-yl hydrogen sulfate

HCN

SO3H

N HCl

Ritter Reaction

NO2

Ref. 103. Justus_Liebigs_Annalen_der_Chemie_215-221(1948)

NH2


non-chiral

Pd / H2

NH2

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

Ref. 104.

ClCl

FeCl3

orFuming Sulfuric

Cl NH4OH

Allyl Chloride

Friedel-Crafts reactions

O O

O

NH2


non-chiral

Ref. 105.

US Patent 2,413,493B1(1946)

ethyl 3-oxobutanoate

Acetoacetic Ester Synthesis Route

Na CH3-IO O

O

Na Ph-CH2-Cl

O O

O

OHOSOCl2 NH3

NH2O

2-methyl-3-phenylpropanoic acid

NaOCl

Hoffman

NaOH

O

Ref.106.

JOC 9, 529 (1944)

NH2


non-chiral

NH4 Formic Acid

LEUCKART-Study

N

2-phenylacetonitrile

non-chiral

Ref. 107.

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

N

O

OH3PO4O

O ethyl acetate

NaOEt

3-oxo-2-phenylbutanenitrile 1-phenylpropan-2-one

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

HN O

ammonium formate

NH4+

O-O

HCl NH2


Acetylbenzylcyanide Reaction Route

O

OH

2-phenylacetic acid

non-chiral

HN

Ref.108.

J.Gen.Chem.(USSR) 11(4), 339 (1941)

NH2

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

LEUCKART

Acetic Anhydride

OO

O

sodium acetate

O

O

O

O

O


Formamide

OH2NO Hydrolysis H+

NH2


NH2

(S)-1-phenylpropan-2-amined-tartaric acid

OH

OHO

HO

O

OH

Ref.108.chiral Resolution

O

OH

2-phenylacetic acid

non-chiral

O

Cl

O

HC

N

N

O

NH2DiazomethaneSOCl2 NH3

AgO

Wolf f Rearr.

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

Ref.109.

O

OH

non-chiral

O

NH2

Chemischen Ber ichte 66B, 684 (1933)

Ref.110.

Curtius Rearr.

O

N3

HN3 acid

-methylbenzylacetic acid

O

X

non-chiral

O

HN

NH2

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

Ref.111.OH

Lossen Rearr.

NC

O HydrolysisHydroxyl amineacid chlorideestersanhydride

NO2

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

NH2


H

O

benzaldehyde

NO2

non-chiral


Ref. 112.

Hg . Cathode

electrolic Red.

NH2

non-chiralUS 1879003 (1932)

Ref. 113.

NO2

Cathode Red. at Hg or C electrode

NH2

non-chiralChemicshe Ber ichte, 66B, 660-666 (1932).

Ref. 114.

NOH Na / Ethanol

NH2

non-chiral J. Am. Chem. Soc. 31, 1875 (1931)

Ref. 115.

N

OHO

NH2

OH

NH2

Cl

1-chloro-1-phenylpropan-2-amine

2-amino-1-phenylpropan-1-ol

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

O

Ofrom

1-phenylpropane-1,2-dione

Pd/C, H2 HCl Pd/C, H2

NH2

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

Ref. 116.

NH2 Br2

O

NaOH

N3

O

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

Hofmann Rearr.

2-methyl-3-phenylpropanamide

Curtius Rearr.

NH2

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

Ref. 117.

O N

OH

NH2-OH Na/Hg

amalgum

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

Precursor list to amphetamine 1985 -2009

Precursor / intermediate / essentials References……

2-phenylacetonitrile 1. J. Am. Chem. Soc. 131, 9882 (2009)

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


and

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

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)

35. J. Labelled Comp. Rad. 31(11) 891 (1992)

36. Tetra. Asym. 3(10) 1283 (1992)

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

41. Tetra. 46(21) 7403 (1990)

42. Tetra. 46(21) 7403 (1990)

46. Org. Reactions 36, book (1988)

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

48. JP 63219396 (1988)

56. Sym. Comm. 15(9) 843 (1985)

57. Sym. Comm. 14(12) 1099 (1984)

67. J. Med. Chem. 13, 26 (1970)

70. US 3,458,576 (1969)

82. J.Pharm. Soc. Japan, 413-6(1954)

85. J. Am. Chem. Soc. 75(7) 1837(1952)

86. US 2647930B1 (1953)

87. DE 848197 (1952)

89. Helv. Chim. Acta. 33, 912 (1950)

94. J. Org. Chem. 15, 8 (1950)

96. US 2,636,901 (1949)

103. Justus Lieb. Ann. Chem. 215 (1948)

112. J. Am. Chem. Soc. 54, 271 (1933)

113. US 1879003 (1932)

3-phenylpropanol 5. Tetra. 63, 9758 (2007)

(R)-3-phenylpropane-1,2-diol 5. Tetra. 63, 9758 (2007)

2-benzyloxirane 5. Tetra. 63, 9758 (2007)

(R)-3-phenyl-2-(phenylamineooxy)

propan-1-ol

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)

tert-butyl 1-phenylpropan-2-

ylcarbamate

6. Chem. European J. 12(15)4191-7(2006)

9. Faming Zhuanli Shenging Gongkai

Shuominshu, patent 1673210 (2005)


And

1-phenylpropan-2-ol

5. Tetra. 63, 9758 (2007)

8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)

13. Org. and Biomolecular Chem. 3(6) 1049

(2005)

14. J. Chem. Research 10, 681 (2004)

28. Tetra. Lett. 41(34) 6537 (2000)

102. J. Am. Chem. Soc. 70, 4048 (1948)

(S)-2-(1-phenylpropan-2-

yl)isoindoline-1,3-dione

8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)

34. Tetra. Asym. 4(7) 1619 (1993)

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

ol

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)

Norephedrine

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

ol

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)

2-acetamido-1-phenylpropyl acetate 11. J. Med. Chem. 48(4) 1229 (2005)

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

benzenesulfonamide

13. Org. and Biomolecular Chem. 3(6) 1049

(2005)


P-2-P = Phenyl-2-propanone

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)

(S)-(2-azidopropyl)benzene 14. J. Chem. Research 10, 681 (2004)

(1-phenylpropan-2-yl) magnesium

bromide

15. Org. Lett. 6(24) 4619 (2004)

4,4,5,5-tetramethyl-1,3-dioxolan-2- 15. Org. Lett. 6(24) 4619 (2004)

one O-tosyl oxime

(1S,2S)-1-phenyl propane-1,2-diol 16. Tetra. Asy, 15(19) 3111 (2004)

(1R,2S)-1-azido-1-phenylpropan-2-ol 16. Tetra. Asy, 15(19) 3111 (2004)

2-methyl-3-phenylaziridine 16. Tetra. Asy, 15(19) 3111 (2004)

2-phenylacetaldehyde

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)

(R)-2-methyl propane-2-sulfinamide 17. J. Combinatorial Chem. 5(5) 590 (2003)

(R)-1-phenylethanamine 19. Tetra. Asy, 14, 2119 (2003)

1-(bromomethyl) benzene 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)

(R)-3,3,5-trimethyl-1-propionyl

pyrrolidin-2-one

21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)

(S)-2-methyl-3-phenylpropanamide 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)

(S)-2-amino-3-phenylpropanoic acid 25. J. Org. Chem. 65(16) 5037 (2000)

(S)-2-amino-3-phenylpropan-1-ol 25. J. Org. Chem. 65(16) 5037 (2000)

(S)-tert-butyl-1-phenylpropan-2-

ylcarbamate

25. J. Org. Chem. 65(16) 5037 (2000)

1-phenyl-1-propyne 26. Org. Lett. 2(13) 1935 (2000)

74. Chem. Pharm. Bull. 13(2) 118 (1965)

allylbenzene 27. Tetra. 56, 5157 (2000)

69. J. Am. Chem. Soc. 91, 5647 (1969)

Phenylmagnesium bromide 31. Tetra. 53(13) 4935 (1997)

Diethyl-2-methylaziridin-1-

ylphosphonate

31. Tetra. 53(13) 4935 (1997)

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

phenylpropanoic acid

33. Tetra. Lett. 36(8) 1223 (1995)

(R)-tert-butyl 1-hydroxy-

3-phenylpropan-2-ylcarbamate

33. Tetra. Lett. 36(8) 1223 (1995)

(S)-tert-butyl 1-phenylpropan-2-

ylcarbamate

33. Tetra. Lett. 36(8) 1223 (1995)

(1S,2S)-2-amino-1-phenylpropane-

1,3-diol

34. Tetra. Asym. 4(7) 1619 (1993)


And

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

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)

Dimethyl 2-benylmalonate 37. Acta. Chemica Scandinavica 45, 431 (1991)

Methyl-2-benyl-2-methyl-3-

oxobutanoate

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

2-methyl-3-phenyl propanoic acid 37. Acta. Chemica Scandinavica 45, 431 (1991)

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

amine

45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)

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

one


3-oxo-2-(2-

(phenylthio)phenyl)butanenitrile


2-(2-(phenylthio)phenyl)acetonitrile 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)

Benzaldehyde 47. J. Med. Chem. 31(8) 1558 (1988)

112. J. Am. Chem. Soc. 54, 271 (1933)

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

oxime

48. Org. Reactions 36, book (1988)

(R)-2-methyl pyrrolidin-1-amine 49. JACS 109(7) 2224-5 (1987)

(2,2-dimethyl-1,1-

diphenylpropyl)diazene

52. J. Chem. Soc., Chem. Comm. 2, 176 (1986)

benzene 55. J. Org. Chem 50(19) 3481 (1985)

72. J. Heterocyclic Chem. 5(3) 339 (1968)

2-(2,2,2-trifluoroacetamido)

propanoyl chloride

55. J. Org. Chem 50(19) 3481 (1985)

2,2,2-trifluoro-N-(1-oxo-1-phenyl

propan-2-yl)acetamide

55. J. Org. Chem 50(19) 3481 (1985)

2-(2,2,2-trifluoro-N-(1-hydroxy-1-

phenyl propan-2-yl)acetamide

55. J. Org. Chem 50(19) 3481 (1985)

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

2,2,2-trifluoroacetamide

55. J. Org. Chem 50(19) 3481 (1985)

2-(2,2,2-trifluoro-N-(1-phenyl

propan-2-yl)acetamide

55. J. Org. Chem 50(19) 3481 (1985)

(E)-prop-1-enylbenzene 58. Synthesis 4, 270 (1982)

61. Hetvetica Chimica Acta 61(2) 558 (1978)

102. J. Am. Chem. Soc. 70, 4048 (1948)

1-(bromomethyl)benzene

Or

benzylbromide

21. J. Chem. Soc. Perkin T. I 16, 1869 (2002)

Phenylpropan-1-one 29. JP 2002142793 (2002)

Bromobenzene

Or

Phenylmagnesium bromide

31. Tetra. 53(13) 4935 (1997)

105. US 2,413,494 B1 (1946)

118. J. Am. Chem. Soc. 48, 169 (1928)

2-phenylacetic acid

Or

Phenylacetic acid

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

91. J. Am. Chem. Soc. 687 (1950)

108. J. Gen. Chem. (USSR) 11(4) 339 (1941)

Prop-1-ynylbenzene 74. Chem. Pharm Bull. 13(2) 118 (1965)

(S)-2-methyl-3-phenylpropanoic acid 80. J. Org. Chem. 22(1) 33 (1957)

D-phenylalanine 84. J. Labelled Comp. Radio 3(1) 3 (1977)

Diethyl 2-(2-phenylacetyl)malonate 84. J. Labelled Comp. Radio 3(1) 3 (1977)

2-phenylacetyl chloride 84. J. Labelled Comp. Radio 3(1) 3 (1977)

Chlorobenzene 104. J. Am. Chem. Soc. 68, 1009 (1946)

Allyl Chloride 104. J. Am. Chem. Soc. 68, 1009 (1946)

Ethyl 3-oxobutanoate

Ethyl acetoacetate

105. US 2,413,494 B1 (1946)

118. J. Am. Chem. Soc. 48, 169 (1928)

2-methyl-3-phenylpropanoic acid 106. US 2,413,494 B1 (1946)

3-oxo-2-phenylbutanenitrile 107. J. Applied Chem (USSR) 14(3) 410 (1941)

N-(1-phenylpropan-2-yl)formamide 107. J. Applied Chem (USSR) 14(3) 410 (1941)

108. J. Gen. Chem. (USSR) 11(4) 339 (1941)

2-methyl-3-phenylpropanoic acid 118. J. Am. Chem. Soc. 48, 169 (1928)

109. J. Am. Chem. Soc. 5, 267 (1940)

110. Berichte 66B, 684 (1933)

111. J. Am. Chem. Soc. 55, 1701 (1933)

synthetic amphetamine

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