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Review: Synthetic Methods for Amphetamine

A. Allen
1
and R. Ely
2

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

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

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

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

1900 1930
1970
2009
Lossen
Curtius
Hofmann
Wolf
1. methyl ethyl ketone
2. ethyl acetoacetate
3. aldehyde -nitroethane
1. metal catayltic red.
2. disolved metal red.
3. non metalic red.
Stereoselective syn.
Organometalic
chiral reduction
alkylations
aminations
Mitsunobu
Enzymic
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 rearrangement
21, 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
OH
Ph
H
2
N
O
Ph
HO
Ph
OH
Ph
NH
2
OH
OH
TA 4(7)1619(1993)
TA 15(19)3111(2004)
Ph
COOH
NH
2
Ph
OH
NH
2
JCS, Perkin T.I, 16
1869 (2002)
JCS, Perkin T.I, 16
1869 (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
N
JACS 131(29) 9882 (2009)
Chiral
Ph H
O
Ph OH
Ph OH
ONHPh
OH
Ph
O
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
Ph
NO
2
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
O
Tetra. 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
NH
2
Amphetamine
28.
Stereoselective Synthesis of Amphetamine 1985--2009
Scheme 2.
(S)-1-phenylpropan
-2-amine
36
51
1
5
5
5
5
18 20 41
6
9
11
23
40
53
8
14
19
16
17
49
19
40
51
54
21
21
25
33
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 (PtO
2
) 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. Wilsons 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 syntheses Time-Line of Synthetic Routes to Amphetamine
1985
NH
2
Ph Ph
NH
2
MgBr
T. 53(13)4935 (1997)
O.L.. 2(13) 1935 (2000)
N
P
Cp
2
TiMe
2
non-Chiral
O
O
O
OH
SO
2
NO
2
NH
2
Org. Biomol. Chem 3(6) 1049 (2005)
NO
2
LiAlH
4
JOC 70(14)5519 (2005)
Mg
Br
O
O
N
O
Org. Let. 6(24) 4619 (2004)
non-Chiral
non-Chiral
non-Chiral
OH
O
O
N
H
O
O
tBu
Tetra. Let. 41, 6537 (2000)
non-Chiral
n-BuLi
Ph
NH
2
Pd/H
2
Tetra. 56, 5157 (2000)
O
Mg
reduction
NH
3
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)
Ts
Ph
Ph NH
N
H
3
C
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
13
15
27
26
31
32
COOH
O O
O
O
Acta Chem. Scand.
45, 431 (1991)
CN
S
Ph
Coll. Czech. Chem Comm.
54(7) 1995 (1989)
H
O
N
O
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
42
47
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 1900-1950s:


Scheme 5.

Classical Organic Transformation in the Early 1900-1950s:
The early literature regarding amphetamine synthesis of the 1900s 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 syntheses Time-Line of Synthetic Routes to Amphetamine
1985
Br
H
O
Br
CN
H
Br
OH
OH
O
O
N
OH
NH
2
R
OH
O
OH
NH
2
OH
OH
NH
2
O
NH
2
Amphetamine
O
O
Br
O
COOH
NH
2
NO
2
H
O
O O
O
O
OH
O
S
CN
Ph
O
HO
OH
Scheme 6.
Organic Transformations
to Amphetamine
1900 - 2009
2009
12
18
20
39
22
4
35
41
42
5
5
37
5
34
21
15
8
13
14
28
14
19
20
29
32
38
43
36
1
16
11
17
26
27
1
21
25
33
31
44
45
47
48
49
51
52
22
23
40
40
40
47
49
51
52
52
53
54
54
55
56
5
13
54 57
58
59
59
60 61
62
63
64
65
67
70
69
71
72
73
74
74
75
76
79
80
80
82
84
85
86
87
88
88
89
89
92
92
91
91
90
92
95
95
94
93
96
98
99
100
101
101
103
102
105
106
108
107
107
109
110
111
112
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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[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) 271-
4.

[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:

N MeMgI
NH
NH
2
Ir-(S,S)-f-
binaphane
H
2
(S)-1-phenylpropan-2-amine
1-phenylpropan-2-imine
2-phenylacetonitrile
JACS 131, 9882 (2009)
Ref. 1.
chir al

NH
2
(S)-1-phenylpropan-2-amine
NH
2
1-phenylpropan-2-amine
Ref. 2.
HSCH2CO2Me
Benzene
Photochemical --Racemization
JOC 73(2) 364 (2008)
chir al

NH
2
1-phenylpropan-2-amine
NH
2
(S)-1-phenylpropan-2-amine
Lipase
Lauric acid
+ amide of lauric acid
Biotrasformation, Enzymic, Stereoselective
JOC 72(18) 6918 (2007)
Ref. 3.
chir al



NO
2
NH
2
1-phenylpropan-2-amine
Ph
H
2
N
SmI
2
(E)-(2-nitroprop-1-enyl)benzene
Tet r a. Let. 48(32) 5707 (2007)
Ref. 4.
non-chi r al

H
O
OH
O
NHPh
OH
OH
OH
O
NH
2
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
NaBH
4
Pd/C
TsCl
TEA
NaH
1,
2.
LiAlH4
1. NaN3
2. Pd/C H2
Tet r a. 63, 9758 (2007)
Ref. 5.
chir al

H
N
t er t-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
I
O
O
H
N O
O
NH
2
(S)-1-phenylpropan-2-amine
ter t -butyl 1-phenylpropan-2-
ylcarbamate
chir al
Chem. Eur opean J. 12(15)4191-7(2006)
Ref. 6.
SmI
2
TFA

NO
2
NH
2
(E)-(2-nitroprop-1-enyl)benzene
NaBH
4
1-phenylpropan-2-amine
Centr al Eur. J. Cehm 6( 4) 526-34 (2008)
non-chi r al
Ref. 7.
BF
3
- Et
2
O
THF

OH
N
Phth Anh.
O
O
NH
2
NH
2
-NH
2
amphetamine
Ref. 8.
Ph
3
P
DEAD, THF
MeOH
Bioor gani c & Med. Chem. Lett er s,
15( 12) 3039-43 ( 2005)
(S)-1-phenylpropan-2-ol
(S)-2-(1-phenyl
propan-2-yl)isoindoline
-1,3-dione
(S)-1-phenylpropan-2-amine
chir al


H
N
t er t-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
I
O
O
H
N O
O
NH
2
(S)-1-phenylpropan-2-amine
ter t -butyl 1-phenylpropan-2-
ylcarbamate
chir al
Faming Zhuanl i Shenqi ng Gongkai Shuomingshu # 1673210 (2005)
Ref. 9
SmI
2
TFA

NH
2
1-phenylpropan-2-amine
NH
2
(S)-1-phenylpropan-2-amine
Lipase
Lauric acid
+ amide of lauric acid
Biotrasformation, Enzymic, Stereoselective
indian J. Chem.Sec B 44B(6) 1312 ( 2005)
Ref. 10.
chir al

OH
NH
2
norephedrine
O
H
N
Ac
2
O
Ac
Ac
H
N
Ac
H2
/
P
d
-B
a
S
O4
NH
2
H
2
SO
4
amphetamine
J. Med. Chem.
48( 4) 1229-36 ( 2005)
2-acetamido
-1-phenylpropyl acetate
N-(1-phenylpropan-2-yl)acetamide
chir al
Ref. 11.
(S)-1-phenylpropan-2-amine
(1R,2S)-2-amino-1-
phenylpropan-1-ol

NO
2
NH
2
(E)-(2-nitroprop-1-enyl)benzene
LiAlH
4
1-phenylpropan-2-amine
JOC 70( 14) 5519 (2005)
non-chi r al
Ref. 12.

OH NH
2
amphetamine 1-phenyl
propan-2-ol
1-phenylpropan-2-amine
SO
2
NO
2
NH
2
DCC
HN
S
O
O
2
N
O
2-nitro-N-(1-phenylpropan-2-yl)
benzenesulfonamide
non-chi r al
Or g. and Biomol ecul ar Chem. 3( 6) 1049 ( 2005)
PhSH, K2CO3
50
o
C
Ref. 13.

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

MgBr
O
O
N
O
S
O
O
N
NH
2
HCl
amphetamine
Or g. 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
1-phenylpropan-2-amine
non-chiral
Ref. 15.

OH
OH
SOCl
2
O
O
S
O N
3
OH
NaN
3
NH
2
H
N
Ph
3
P Pd-C
HCO
2
NH
4
amphetamine
Tet r ahedron Asymmet ry
15(19),3111-6 (2004)
(1S,2S)-1-phenyl
propane-1,2-diol
(1R,2S)-1-azido-1-phenylpropan-2-ol
2-methyl-3-phenylaziridine
Ref. 16.
(S)-1-phenylpropan-2-amine
chi r al

O
H
S
NH
2
O
CuSO
4
S
N
O
MeMgBr
S
N
H
O
HCl, MeOH
NH
2
amphetamine
J. Combi nator i al 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-phenyl
propan-2-yl)propane-2-sulfinamide
(S)-1-phenylpropan-2-amine
chir al
Ref. 17.

NO
2
J. Chem. Resear ch ( S), 128 (2003)
NH
2
Ruthenium BINAP
(E)-(2-nitroprop-1-enyl)benzene
chir al
Ref. 18.

O
1-phenylpropan-2-one
H
2
N
N
(R)-1-phenylethanamine
(S,E)-1-phenyl-N-
(1-phenylpropan-2-ylidene)
ethanamine
NH
2
(S)-1-phenylpropan-2-amine
Tet r a. Asy. 14, 2119 (2003)
chir al
Ref. 19.

NO
2
J. Chi nese Chemi cal Soci et y, 49, 505 ( 2002)
NH
2
H2
(E)-(2-nitroprop-1-enyl)benzene
Ru2Cl2(PPh3)3
toluene
(S)-1-phenylpropan-2-amine
chir al
Ref. 20.

Br
N
O
O
LDA, THF
N
O
O
NH
3
, MeOH
NH
2
O
NH
2
PhI(OOCCF
3
)
2
amphetamine
JCS Per kin 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
chi r al
Ref. 21.

NH
2
amphetamine
O
Pd, MeOH
Tetr ahedr on Asymmetr y, 13( 12)
13115-1320 ( 2002)
1-phenylpropan-2-amine
1-phenylpropan-2-one
HCOO NH
4
NH
2
Tetr a. Asy. 13( 20) 2277 ( 2002)
NH
2
1-phenylpropan-2-amine
chi r al
Ref. 22.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
CAL-B cat.
non-chiral
Ref. 22.

NH
2
US pat . # 6399828 2002)
NH
2
OH
Ac
2
O
NH
2
OAc
Pd
BaSo4
H2
(1R,2S)-2-amino-1-phenylpropan-1-ol
(1R,2S)-2-amino-1-phenylpropyl acetate
chir al
Ref. 23.
HoAc
HI, P
4
HCl

NH
2
Syn. Comm. 31(4) 569 (2001)
NH
2
1-phenylpropan-2-amine
chir al
Ref. 24.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
Candida antarcitica Lipase

NH
2
COOH
LiBH
4
/TMSCl NH
2
OH
NH
OH
BOC)
2
O
O
O
NH
I
(Ph)
3
P / I N-Selectride
NH
NH
2
amphetamine
TFA
J. Or gai ni c Chemistr y
65(16) 5037-42 ( 2000)
O O O O
( 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)-t er t-butyl 1-hydroxy-
3-phenylpropan-2-ylcarbamate
chir al
Ref. 25.

NH
2
Cp
2
TiMe
2
N
Ph
Ph
NH
2
1-phenyl-
1-propyne
amphentamine
Or gani c Let ter s, 2( 13) 1935-1937 ( 2000)
Ref. 26.
diphenyl
methanamine
(E)-diphenyl-N-
(1-phenylpropan-2-
ylidene)methanamine
1-phenylpropan-2-amine
non-chi r al
Cp
2
TiMe
2
H
2
, Pd/C
NH
2
1-phenylpropan-2-amine
H
2
N
cat. n-Bu Li
Ph
NH
Pd/C H
2
non-chi r al
Tet ra. 56, 5157 ( 2000)
Ref. 27.
allylbenzene
N-benzyl-1-phenylpropan-2-amine

OH
NH
O
NH
2
TFA
amphetamine
Ph
3
P
DEAD, THF
DCM
Tet rahedron Letters, 41( 34)
6537-40 ( 2000)
tBuCO)
2
O
O
1-phenyl
propan-2-ol
ter t-butyl
1-phenylpropan
-2-ylcarbamate
1-phenylpropan-2-amine
non-chi r al
Ref. 28.


JP 03191797 (1991)
NH
2
phenylpropan-1-one
chir al
Ref. 29.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
C: 9031-66-1
O
BuNH
2

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

MgBr
N
P
O O
O
NH
P
O O
O
CuI
THF
NH
2
HCl
amphetamine
Tet rahedron, 53(13) 4935-4946, 1997
diethyl 2-
methylaziridin-
1-ylphosphonate
phenylmagnesium
bromide
diethyl
1-phenylpropan-
2-ylphosphoramidate
1-phenylpropan-
2-amine
non-chi r al
Ref. 31.

NH
2
O
NH3
P-2-P
J.Chem.Soc., Per ki n Trans I , 265 ( 1996)
Mg MeOH
HoAc
1-phenylpropan-2-one
1-phenylpropan-2-amine
non-chi r al
Ref. 32.

HN
OH
O
O
Tet r a. Lett . 36( 8) 1223 (1995)
O
NH
OH
NH
O
BH
3
THF
CH
3
SO
2
Cl
TEA
Ms
NH
O S
NaH
CH
3
CH
2
SH
NH
Ra-Ni
EtOH
NH
2
BOC
BOC
BOC BOC
(R)-2-(t er t-butoxycarbonylamino)
-3-phenylpropanoic acid
chir al
TFA
Ref. 33.
(S)-1-phenylpropan-2-amine

OH
NH
2
OH
OH
N
OH
Phth Anh.
O
O
Ph)
3
P / I
I
I
H
2
/ Pd-C
NH
2
NH
2
-NH
2
amphetamine
Tetr ahedr on Asymmetr y
4( 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-phenyl
propan-2-yl)isoindoline-1,3-dione
(S)-1-phenylpropan-2-amine
chiral
Ref. 34.

NO
2
J. Labell ed Comp. and Rad. 31(11) 891 ( 1992)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
LiAlH
4
non-chi r al
1-phenylpropan-2-amine Ref. 35.

NH
2
amphetamine
N
Tetr ahedr on Asymmetr y,3( 10)
1283-8 ( 1992)
OH
E & Z
H
4
Ru(arene)
BINAP
(E)-1-phenylpropan-2-one oxime
chir al
(S)-1-phenylpropan-2-amine
Ref. 36.

O
O
O
O
O
O
O
O
OH
O
2. AcOH
NH
2
Acta. Chemica Scandinavi ca 45, 431 ( 1991)
amphetamine
methyl
2-benzyl-2-methyl
-3-oxobutanoate
2-methyl-3-phenyl
propanoic acid 1-phenylpropan-2-amine
dimethyl 2-benzylmalonate
CH3-I NaH
DMSO
1. NaOH
P O
Ph
Ph
N
N
+
-
N
1.
TEA/heat
2. HCl / heat
non-chi r al
Ref. 37.
NH
2
amphetamine
1-phenylpropan-2-amine
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
(+)-10-camphorsulonyl chloride
resolution
chir al

Tetr ahedr on Lett . Vol . 32, No. 49 ( 1991) 7325-8.
NH
2
amphetamine
1-phenylpropan-2-amine
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chi r al
HOOC
COOH
OR
RO
*
* R = H
Benzoyl
p-toluoyl
Ref. 38.

NO
2
Chem. Pharm. Bul l. 38(12) 3449 (1990)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
Biotransf ormation
cat. Peptostr eptococcus Anaer obi us
1-phenylpropan-2-amine
non-chi r al
Ref. 39.

NH
2
J. Chr om. Sci. 28, 529 ( 1990)
NH
2
(1R,2S)-2-amino-1-phenylpropan-1-ol
OH
NH
2
Cl
Pd H2 SOCl2
(1S,2S)-1-chloro-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
chir al
OH
J. Chr om. Sci. 28, 529 ( 1990)
O
NH
2
2-phenylacetic acid
O
1-phenylpropan-2-amine
non-chi r al
Ac2)O
NaOAc
Leuchart Red
1-phenylpropan-2-one
Ref. 40.
Ref. 40.

NH
2
amphetamine
(S)-1-phenylpropan-2-amine
NO
2 NO
2
BH3-THF Ru
2
Cl
2
[(-)-DIOP]
3
H
2
(E)-(2-nitroprop-1-enyl)benzene (2-nitropropyl)benzene
Tet r a. 46( 21) 7403 (1990)
chir al Ref. 41.

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

NH
2
amphetamine
O
1-phenylpropan-2-amine
1-phenylpropan-2-one
NH
2
U.S. pat . # 4950606 (1990)
NH
2
1-phenylpropan-2-amine
chi r al
Ref. 43.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
Baci ll lus Megat er ium
non-chiral
Biotransf ormation
amino-acid transminase f rom
Bacil ll us Megater i um
amino-acid transminase f rom
Ref. 43.


NH
2
amphetamine
1-phenylpropan-2-amine
NO
2
LiBH4 /THF
(E)-(2-nitroprop-1-enyl)benzene
Angew Chem. Int. Ed. Engl. 28(2) 218-220 (1989)
non-chiral
Ref. 44.
(CH3)3SiCl
NH
COOH
O O
2-(benzyloxycarbonyl)
-3-phenylpropanoic acid
NH
O O
benzyl 1-phenylpropan-2-ylcarbamate
(CH3)3SiCl
LiBH4 /THF

S
CN
Ph
S CN
Ph
O
S
Ph
O
S
Ph
N
OH
S
Ph
NH
2
NH
2
NaOEt
EtOH
H3PO4
NH2OH Na EtOH
HCl
Coll . Czech. Chem. Comm. 54( 7) 1995 ( 1989)
non-chi r al
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
Or g. React ions 36, book ( 1988)
NH
2
(E)-1-phenylpropan-2-one O-methyl oxime
Red - Al, THF
non-chir al
1-phenylpropan-2-amine
Ref. 46.
O
NO
2
(E)-(2-nitroprop-1-enyl)benzene
Red-Al THF
NH
2

NO
2
J.Med.Chem. 31( 8) 1558 (1988)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
H
O
benzaldehyde
NO
2
LiAlH
4
non-chi r al
1-phenylpropan-2-amine
Ref. 47.

NO
2
JP 63219396 (1988)
NH
2
1-phenylpropan-2-amine
chi r al
Ref. 48.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
Biotransf ormation /

N
H
2
N
NH
2
Ref. 49.
amphetamine
O
N
N
H
CH
3
Li / CeCl
3
N
H
N
H
2
/ Ra-Ni
375 psi / 60
o
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
chir al
(R)-2-methyl-N-((S)-
1-phenylpropan-2-yl)
pyrrolidin-1-amine
O NH
2
NH
2
amphetamine
US 4000,197 ( 1976)
chir al
Ref. 50.
(S)-1-phenylpropan-2-amine
phenyl-2-propanone
HN
*
*
low pressure
Hydrogenation
HN
*
*
[R,R]+
R or S
[S,S]- or
Raney Ni / H2
[S,S]-(-)
10% Pd-C
50 psi H
2
*
-methylbenzylamine

O
Ref. 51.
Or ganometall ics, 5, 739-46 (1986)
NH
2
N
OH
H-SiH(Ph)2
1-phenylpropan-2-one
(E)-1-phenylpropan-2-one oxime
Rh(cod)Cl2
chir al


H
O
H
N
NH
Ph
Ph
CH
3
N
NH
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-chi r al
Ref. 52.
H
O
H
N
NH
Ph
Ph
CH
3
N
NH
Ph
Ph
LDA
Aphetamine
1. TFA
J. Chem. Soc., Chem. Comm. 2, 176, ( 1986)
non-chi r al
Ref. 52.
acetaldehyde
Ph-CH2-Br
2. Pd /C H2
1. TFA
2. Pd /C H2

NH
2
NH
2
US 2009292143 (2009)
(S)-1-phenylpropan-2-amine
non-chir al
Ref. 53.
OH
(1S,2S)-2-amino-1-phenylpropan-1-ol
NH
2
Cl
Pd
H2

O
Ref. 54.
Khimiya Get er ot si kl i cheski kh Soedi neni i 12, 1648 (1985)
NH
2
N
OH
Na MeOH
1-phenylpropan-2-one
(E)-1-phenylpropan-2-one oxime
chir al



Cl
O
H
N CF
3
O
AlCl
3
O
H
N CF
3
O
H
2
/ Pd-C
OH
H
N CF
3
O
PBr
3
Br
H
N CF
3
O
H
2
/ Pd-C
H
N CF
3
O
NH
2
amphetamine
K
2
CO
3
, MeOH
Ref. 55
J.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-phenyl
propan-2-yl)acetamide
(S)-2,2,2-trifluoro
-N-(1-hydroxy-1-phenyl
propan-2-yl)acetamide
(S)-N-(1-bromo-1-phenylpropan
-2-yl)-2,2,2-trif luoroacetamide
(S)-2,2,2-trifluoro-N-(1-phenyl
propan-2-yl)acetamide
(S)-1-phenylpropan-2-amine
chiral

NO
2
Ref. 56.
Syn. Comm. 15(9) 843 (1985)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
BH3 - THF
non-chiral
NaBH
4

NH
2
amphetamine
NO
2
non-chi r al
BH
3
/ THF
Syn. Comm. 14( 12)1099(1984)
Ref. 57.
NaBH
4

NH
2
amphetamine
non-chi r al Synt hesi s ( 4) 270-3 (1982)
Ref. 58.
P
O
O
H
2
N
O
H
N
P
O
O
O
HCl /benzene
Hg(NO
3
)
2
1,1-diCl-ethane
1.
/
2. 10% NaOH / NaBH
4
(E)-prop-1-enylbenzene
diethyl phosphoramidate

NH
2
amphetamine
chir al Synt hesi s ( 4) 270-3 (1982)
Ref. 59.
N
OH
P
Ph
O
Cl
Ph
CH2Cl2, DEA
N
P
Ph
O
O
Ph
(E)-1-phenylpropan
-2-one oxime
LAH
(-) Quinine / THF
H
N
P
Ph
O
O
Ph
HCl / ethanol

O
Ref.60.
J. Labell ed compounds and radiophar maceuti cals 18(6) 909 ( 1981)
NH
2
1-phenylpropan-2-one
non-chi r al
NH3 (Sealed)
Al, HgCl
2
, NH4OH, 100
o
C, 15min

Ref.61.
Hel vet ica chi mi ca Acta 61( 2) 558 ( 1978)
NH
2
(E)-prop-1-enylbenzene
non-chi r al
NO
NO
2
NO
LiAlH4

NH
2
amphetamine
N
Tetr ahedr on 32( 11) 1267-76 (1976)
OH
E & Z
(E)-1-phenylpropan-2-one oxime
chir al
1-phenylpropan-2-amine
Ref. 62.
LiAlH
4

O
Ref.63.
J. Chem. Educati on 51, 671(1974)
NH
2
1-phenylpropan-2-one
non-chir al
Al, HgCl
2
, NH4OH, 100
o
C, 15min

O
JMC 16(5) 480-3 ( 1973)
H
N
1-phenylpropan-2-one
non-chir al
Ref.64.
NH
2
H
2
N
(R)-1-phenylethanamine
(+) or (-)
Raney-Ni
H2
H
N
(R)-1-phenyl-N-(1-phenylethyl)propan-2-amine
(S)-1-phenyl-N-((R)-1-phenylethyl)propan-2-amine
separation
Pd-C / H2
MeOH
(S)-1-phenylpropan-2-amine of Diastereoisomers

O
Ref.65.
JACS 93, 2897 ( 1971)
NH
2
1-phenylpropan-2-one
non-chir al
NaCNBH
3
NH
4
OH, MeOH


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

NO
2
Ref. 67.
J.Med.Chem. 13, 26( 1970)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
LiAlH4 / THF
non-chiral



H
N
amphetamine
1-phenylpropan-2-amine
JACS 91, 5647 ( 1969)
non-chi r al
Ref. 69.
N CH3CN Hg(NO
3
)
2 O
NO
2
Hg
NO
3
H
N O
NaBH4
NaOH
HCl
allylbenzene
N-(1-phenylpropan-2-yl)acetamide

NO
2
Ref. 70.
US Pat. 3,458,576 (1969)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Pd-C / H2
Pt / H2
Raney-Ni / H2

O
Ref.71.
Col l. Czech. Chem. Comm. 33( 11) 3551-7(1968)
NH
2
1-phenylpropan-2-one
non-chir al
NH4 HCOO Ammonium Formate
HCl
Ref.71.
Col l. Czech. Chem. Comm. 33( 11) 3551-7(1968)
NH
2
chi r al
NH
2 (+)-tartaric acid
EtOH
1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine

J. Het er ocycl ic Chem._5( 3)339( 1968)
NH
2
non-chir al
1-phenylpropan-2-amine
Ref. 72.
HN
AlCl
3
2-methylaziridine
benzene

N
Tetr a. 24(16) 5677 ( 1968)
NH
2
LiAlH4
non-chir al
1-phenylpropan-2-amine
Ref. 73.
O
R
R = H or R = Ts
THF

Ref.74.
Chem Phar m Bull 13( 2)118( 1965)
NO
2
prop-1-ynylbenzene
non-chi r al
NOCl
nitrosyl chloride
NO
2
Cl
hypochlorous nitrous anhydride
Cl
NO
2
Cl
Pt
2
O
H
2

O
Ref.75.
US Pat. 3,187,047 ( 1965)
NH
2
1-phenylpropan-2-one
non-chi r al
NH4 oAc Raney-Ni / H2

O
Ref.76.
Tetr a. 19, 1789 (1963)
NH
2
1-phenylpropan-2-one
non-chir al
NH4
Formic Acid
LEUCKART-WALLACH Mech

NH
2
NH
2
DE_1958-968545(1958)
(S)-1-phenylpropan-2-amine
non-chir al
Ref. 77.
OH
(1S,2S)-2-amino-1-phenylpropan-1-ol
NH
2
Cl
Pd
H2

US 3028430 (1962)
NH
2
amphetamine
1-phenylpropan-2-amine
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chi r al
COOH
R
H
2
N
*
Ref. 78.
-amino acid

O
Ref.79.
US Pat. 2,828,343 ( 1958)
NH
2
1-phenylpropan-2-one
non-chir al
NH3 (g) CuO and Ba(OH)2
H2

OH
O
NH
2
JOC_22( 1)33(1957)
amphetamine
chi r al
Ref. 80.
Cl
O
N
3
O
(S)-2-methyl-3-
phenylpropanoic acid
(S)-2-methyl-3-
phenylpropanoyl chloride
(S)-2-methyl-3-
phenylpropanoyl azide (S)-1-phenylpropan-2-amine
CO
2
Cl
2
NaN
3
HCl
Curtius rearrangement
OH
O
(S)-2-methyl-3-
phenylpropanoic acid
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
H
2
SO
4
NaN
3
Schmidt rearrangement chi r al
Ref. 80.

US 2,833,823 (1958)
NH
2
amphetamine
1-phenylpropan-2-amine
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chi r al
Ref. 81b
inriched in one isomer
H
3
PO
4
Zhur nal Obshchei Khimii 28 ( 1958) 3323-8
NH
2
amphetamine
1-phenylpropan-2-amine
NH
2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chi r al
COOH
OH
HO
*
Ref. 81a
HOOC
*
d-Tartaric
acid

NO
2
Ref. 82.
J_Phar m_Soc_Japan_413-416( 1954)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
Raney-Ni
non-chiral
N
OH
Raney-Ni

O
Ref.83.
NH
2
1-phenylpropan-2-one
non-chir al
DE_1953-870265
N
N
H
(E)-1-phenyl-2-(1-phenyl
propan-2-ylidene)hydrazine
PtO
2
H
2
PhenylHydrazine
HN
NH
2
Ph

NH
2
amphetamine
1-phenylpropan-2-amine
J. Labell ed Comp. and Radi o. 3( 1) 3-9 ( 1977)
chir al
Ref. 84.
NH
2
COOH
NH
2
D
2
C
OH
*
D-Phenylalanine
LiAlD
4
*
p-MeTOSCl
HN
D
2
C
O
*
S
O
CH
3
O
p-TOS
LiAlD
4
HN
CD
3
*
S
O
CH
3
O
Naphthalene radical anion

NO
2
Ref. 85.
JACS_74( 7)1837(1952)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
LiAlH
4
acid
P-2-P (Nef reaction)

NO
2
Ref. 86.
US Patent 02647930B1( 1953)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
Organic Acids
non-chiral
Raney-Ni / H
2

NO
2
Ref. 87.
DE_1952-848197( 1952)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H
2

NH
2
Chir ali ty 6(4) 314-20 ( 1994)
NH
2
1-phenylpropan-2-amine
chi r al
Ref. 88.
(S)-1-phenylpropan-2-amine
Resolution
Distillation from
optically active acids..

NO
2
Ref. 89.
Helv. Chi m. Act a. 33, 912 ( 1950)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
LiAlH4 / ether

l-malic acid
OH
O
HO
O
OH
Ref. 90.
Or g. Syn. Col l. 2, 506 (1943) chiral resolution
NH
2
NH
2
racemic-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
/ water

OH
O
Cl
O
O
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
1-phenylpropan-2-one
N
OH
(E)-1-phenylpropan-2-one oxime
NH
2
1-phenylpropan-2-amine
Mg
O
non-chiral
Ref. 91.
J_Am_Phar m_Assoc_687-688( 1950)

O
Ref.92.
NH
2
1-phenylpropan-2-one
non-chi r al
NH3 Raney-Ni / H
2
Bul l. Soc. Chem. Fr ance 1045 ( 1950)

NO
2
NH
2
(E)-1-phenylpropan-2-one oxime
non-chir al
Chemi sche Ber icht e 124(10) 2303-6 ( 1991)
Ref. 93.
N
OH
Cathode Red. at Hg or C electrode

NO
2
Ref. 94.
JOC 15, 8 (1950)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H
2

O
Ref.95.
NH
2
1-phenylpropan-2-one
non-chi r al
NH3 Raney-Ni / H
2
GB 702985( 1949)
or Pt or Pd

NO
2
Ref. 96.
US Pat. 2,636,901(1949)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H
2

O
Ref.97.
JACS 70, 1187 (1948)
NH
2
1-phenylpropan-2-one
non-chi r al
NH4
Formic Acid
LEUCKART-WALLACH Mech

O
Ref.98.
JACS 70, 1315-6(1948)
NH
2
1-phenylpropan-2-one
non-chi r al
NH3
PtO
2
/ H
2

N
Ref.99.
NH
2
(E)-1-phenylpropan-2-one oxime
non-chir al
Yakugaku Zasshi 74, 413-16 ( 1954).
OH
Raney Ni / H2

O
Ref.100.
NH
2
1-phenylpropan-2-one
non-chi r al
NH3 Raney-Ni / H
2
JACS 70, 2811-12 (1948)

NH
2
non-chir al
Bull et in of El ectr ochemi st y 8(6) 276-7 (1992)
Ref. 101.
N
OH
Cathode Red. at Hg or C electrode

OH
Ref.102.
NH
2
1-phenylpropan-2-ol
non-chi r al
JACS 70, 4048 (1948)
(E)-prop-1-enylbenzene
O
SO
3
H
1-phenylpropan
-2-yl hydrogen sulfate
HCN
SO
3
H
N
HCl
Ritter Reaction

NO
2
Ref. 103.
Justus_Li ebi gs_Annal en_der_Chemie_215-221( 1948)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Pd / H
2

NH
2
non-chi ral
J. Am. Chem. Soc. 68 (1946) 1009-11.
Ref. 104.
Cl
Cl
FeCl3
or
Fuming Sulf uric
Cl
NH
4
OH
Allyl Chloride
Friedel-Crafts reactions

O O
O
NH
2
1-phenylpropan-2-amine
non-chiral
Ref. 105.
US Patent 2,413,493B1( 1946)
ethyl 3-oxobutanoate
Acetoacetic Ester Synthesis Route
Na CH3-I
O O
O
Na Ph-CH2-Cl
O O
O
OH O
SOCl
2 NH
3
NH
2
O
2-methyl-3-phenylpropanoic acid
NaOCl
Hoffman
NaOH


O
Ref.106.
JOC 9, 529 ( 1944)
NH
2
1-phenylpropan-2-one
non-chir al
NH4
Formic Acid
LEUCKART-Study

N
2-phenylacetonitrile
non-chiral
Ref. 107.
J.Appl ied Chem. ( USSR) 14(3), 410 (1941)
N
O
O
H
3
PO
4
O
O
ethyl acetate
NaOEt
3-oxo-2-phenylbutanenitrile
1-phenylpropan-2-one
N-(1-phenylpropan-2-yl)f ormamide
H
N
O
ammonium formate
NH
4
+
O
-
O
HCl
NH
2
1-phenylpropan-2-amine
Acetylbenzylcyanide Reaction Route

O
OH
2-phenylacetic acid
non-chi r al
H
N
Ref.108.
J.Gen.Chem.(USSR) 11( 4), 339 (1941)
NH
2
N-(1-phenylpropan-2-yl)formamide
LEUCKART
Acetic Anhydride
O O
O
sodium acetate
O
O
O
O
O
1-phenylpropan-2-one
Formamide
O H
2
N
O
Hydrolysis H+
NH
2
1-phenylpropan-2-amine
NH
2
(S)-1-phenylpropan-2-amine
d-tartaric acid
OH
OH O
HO
O
OH
Ref.108.
chir al Resolution

O
OH
2-phenylacetic acid
non-chi r al
O
Cl
O
HC
N
N
O
NH
2
Diazomethane
SOCl2
NH
3
AgO
Wolf f Rearr.
J. Am. Chem. Soc. 5 (1940) 267-85
Ref.109.

O
OH
non-chi ral
O
NH
2
Chemischen Ber icht e 66B, 684 ( 1933)
Ref.110.
Curtius Rearr.
O
N
3
HN3 acid
-methylbenzylacetic acid

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

NO
2
J.Am. Chem. Soc. 54, 271-4 (1933)
NH
2
(E)-(2-nitroprop-1-enyl)benzene
H
O
benzaldehyde
NO
2
non-chi r al
1-phenylpropan-2-amine
Ref. 112.
Hg . Cathode
electrolic Red.

NH
2
non-chir al
US 1879003 (1932)
Ref. 113.
NO
2
Cathode Red. at Hg or C electrode

NH
2
non-chir al
Chemi cshe Ber icht e, 66B, 660-666 (1932).
Ref. 114.
N
OH
Na / Ethanol

NH
2
non-chiral
J. Am. Chem. Soc. 31, 1875 (1931)
Ref. 115.
N
OH O
NH
2
OH
NH
2
Cl
1-chloro-1-phenyl
propan-2-amine
2-amino-1-phenyl
propan-1-ol
(E)-2-(hydroxyimino)-
1-phenylpropan-1-one
O
O
from
1-phenylpropane-1,2-dione
Pd/C, H
2 HCl
Pd/C, H
2

NH
2
non-chi r al J. Am. Chem. Soc. 31, 2787-91 (1931)
Ref. 116.
NH
2
Br
2
O
NaOH
N
3
O
1-azido-2-methyl-3-phenylpropan-1-one
Hofmann Rearr.
2-methyl-3-phenylpropanamide
Curtius Rearr.

NH
2
non-chir al 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
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56. Sym. Comm. 15(9) 843 (1985)
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67. J. Med. Chem. 13, 26 (1970)
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82. J.Pharm. Soc. Japan, 413-6(1954)
85. J. Am. Chem. Soc. 75(7) 1837(1952)
86. US 2647930B1 (1953)
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94. J. Org. Chem. 15, 8 (1950)
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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)
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And
1-phenylpropan-2-ol
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(1R,2S)-2-amino-1-phenylpropan-1-
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40. J. Chrom. Sci. 28, 529 (1990)
53. Anal. Chem. 58(8) 1642 (1986)
Norephedrine

(1R,2S)-2-amino-1-phenylpropan-1-
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53. Anal. Chem. 58(8) 1642 (1986)
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2-nitro-N-(1-phenylpropan-2-yl)
benzenesulfonamide
13. Org. and Biomolecular Chem. 3(6) 1049
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1-phenylpropan-2-one

P-2-P = Phenyl-2-propanone
14. J. Chem. Research 10, 681 (2004)
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32. J. Chem. Soc. Perkin Trans I, 265 (1996)
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44. Angew Chem. Int. Ed. Engl. 28(2) 218
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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)
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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)

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

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