Review: Synthetic Methods for Amphetamine

A. Allen1 and R. Ely2

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.

The Era of Classical Organic Chemistry Stereoselective syn.

Organometalic
Aldo Condensations: Rearrangements: Reductions: chiral reduction
1. methyl ethyl ketone Lossen 1. metal catayltic red. alkylations
2. ethyl acetoacetate Curtius 2. disolved metal red. aminations
Hofmann 3. non metalic red. Mitsunobu
3. aldehyde -nitroethane Wolf
Enzymic

Time-Line of Synthetic Routes to Amphetamine

1970 2009
1900 1930
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.
 Histograms for amphetamine reaction types 1985-2009 (#-reference)
2 Photochemical

55 Friedel-Craft Alkylation Figure 1a.

8, 34 Hydrazine
21, 37 Hofmann rearrangement
8, 13, 28 Mitsunobu
5, 31, 16 Ring Opening
1, 15, 17, 31 Organometalic
1, 5, 15, 21, 31 Alkylations

36, 45, 46, 51, 54 Oxime

17, 26, 27, 58, 15 Amination
1, 15, 19, 26, 49, 50, 52 Imine
2, 3, 10, 22, 24, 37, 38, 43, Resolutions

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

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

1, 2, 3, 5, 6, 8, 9, 11, 14, 16, 17, 18, 19, 20, 21, 22, 23
25, 28, 29, 33, 34, 36, 37, 40, 41, 48, 49, 50, 51, 53, 54, 55 Stereoselective

1, 4, 6, 9, 5, 11, 12, 14, 16, 18, 19, 20, 22, 23, 25, 26, 27, 32, 33,
34, 35, 39, 41, 42, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57 Reductions
 Literature Citations for the Synthesis of Amphetamine 1985-2009
Enzymatic (Bio Transformations) Stereoselective Synthesis
(see Scheme 4) (see Scheme 2)
2. J. Org. Chem., JOC 73(2008)364
3. J. Org. Chem., JOC 72(2007)6918 1. J. American Chem. Soc. JACS 131(2007)9882
10. Indian J. Chem. Soc. B., IJCS 44B(2005)1312 5. Tetrahedron, Tetra. 63(2007)9758
14. J. Chemical Research, JCR 10(2004)681 6. Chemistry A European J., JEC 12(2006)4197
22. Tetrahedron Asymmetry, TA 13(2002)1315 8. Biological Med. Chem. Letter, BMCL 15(2005)3039
24. Synthetic Comm., SC 31(2001)569 9. FZSGS patent # 1673210 (2005)
39. Chem. & Pharm. Bull., CPB 38(1990)3449 11. J. Medicinal Chem., JMC 48(2005)1229
43. US Patent 04950606B1 (1990) 14. J. Chem. Research, JCR 10(2004)681
16. Tetrahedron Asymmetry, TA 15(2004)3111
Non-Chiral Organic Synthesis 17.
18.
J. Combinatorial Chem. 5(2003)590
J. Chem. Research, JCR 3(2003)128
(see Scheme 3) 19. Tetrahedron Asymmetry, TA 14(2003)2119
4. Tetrahedron Letter, TL 48(2007)5707 20. J. Chinese Chem. Soc. 49(2002)505
12. J. Organic Chem., JOC 70(2005)5519 21. J. Chem. Soc. Perkin I, JCSP1 16(2002)1869
13. Organic & Biomol. Chem., OBC 3(2005)1049 22. Tetrahedron Asymmetry, TA 13(2002)1315
15. Organic Letters, OL 6(2004)4619 23. US patent #6399828(2002)
26. Organic Letters, OL 2(2000)1935 25. J. Organic Chem., JOC 65(2000)5037
27. Tetrahedron, Tetra. 56(2000)5157 28. Tetrahedron Letters, TL 41(2000)6537
31. Tetrahedron, Tetra. 53(1997)4935 33. Tetrahedron Letters, TL 36(1995)1223
32. J. Chem. Soc. Perkin I, JCSP1 1(1996)265 34. Tetrahedron Asymmetry, TA 4(1993)1619
37. J. Labeled Comp. Rad., JLCR 31(1992)891 36. Tetrahedron Asymmetry, TA 3(1992)1283
38. J. Medicinal Chem., JMC 34(1991)1094 37. Acta. Chimica Scan. 45(1991)431
40. J. Chromatographic Sci., JCS 28(1990)529 41. Tetrahedron, Tetra 46(1990)7403
41. Tetrahedron, Tetra 46(1990)7403 44. Angew Chem. Int. 28(1989)218
42. Tetrahedron, Tetra 46(1990)7743 49. J. American Chem. Soc. JACS 109(1987)2224
45. Coll. Czech. Chem. Comm., 54(1989)1995 51. Organometallics, 5(1986)739
48. Organic Reactions, Vol 36 (book, 1988) 53. Analytical Chem. 58(1986)1642
57. J. Medicinal Chem., JMC 31(1988)1558 54. Khimja Geter. Soed. 12(1985)1648
52. J. Chem. Soc. Chem. Comm. 2(1986)176 55. J. Organic Chem., JOC 50(1985)3481
54. Khimya Geter. Soed #12,1648(1985)
56. Synthetic Comm., SC 15(1985)843
22. Tetrahedron Asymmetry, TA 13(2002)1315
# = Reference Figure 1b.
Amphetamine Review (1989 – 2009)
Time-Line of Synthetic Routes to Amphetamine Stereoselective syn.

1985 2009
1900 1930 1970

Stereoselective Synthesis of Amphetamine 1985--2009

Chiral
Chiral
Scheme 2.
N R Tetra. 63(39) 9758 (2007)
Chiral
JACS 131(29) 9882 (2009)
Chiral
JOC 50(19) 3481 Tetra Asy 3(10) 1283 (1992) Ph
(1985) Organometallics 5, 739 (1986) O Tetra. 63(39) 9758 (2007)
TA 4(7)1619(1993)
OH Chiral
KGS #12,1648 (1985) Ph OH
2Q. 2A. 2B. ONHPh Chiral
Ph OH 54 Tetra. 63(39) 9758 (2007)
2C.
2P. Ph OH
Chiral NH2
JOC 65(16) 5037 (2000) 51
Tetra. Let. 36(8) 1223 (1995) 2D. OH O
Chiral
Angew chem. Int. 28(2) 218 (1989) 36
COOH 55 Ph H
Ph 1 5 Tetra. 63(39) 9758 (2007)
2O. 44 34 5 2E.
NH2
33 5 NO2
25 Ph
Chiral 5 Chiral
Ph Br 28. Amphetamine
21 2F. J.C. Res. Syn. 3, 128 (2003)
JCS, Perkin T.I, 16 2N. 18 20 41
1869 (2002) J. Chinese C S 49, 505 (2002)
NH2 Tetra. 46(21) 7403 (1990)
21 6 9
(S)-1-phenylpropan
O -2-amine
Chiral 2G.
11 Ph I
H2N Ph 2M. 19 23 HN BOC
Chiral
40 40
51 8
JCS, Perkin T.I, 16 17 53 Chem. Eur.J. 12, 4191 2006
54 16 14
1869 (2002) FZSGS #1673210 (2005)
49 2H.
19
OH
2L. 5
Ph NH2
Chiral
Ph
O JMC 48(4)
2I. 1229 (2205)
Chiral
Tetra. Asy. 14, 2119 (2003)
2K.
Organometallics 5, 739 (1986) 2J. Anal. Chem. 58(8) 1642(1986)
J. Chrom. Sci. 28,529 (1990) H Ph US # 6,399,828 (2002)
KGS #12,1648 (1985) Chiral Ph OH Chiral OH J. Chrom. Sci. 28,529 (1990)
J.Comb.C. 5(5) O Org. Biomol. Chem. 3,1049(2005)
590 (2003)
HO
Ph B.M.C.L. 15(12) 3039 (2005)
JACS 109(7) Chiral J. Chem. Res. 10, 681 (2004)
2224 (1987)
TA 15(19)3111(2004) T.L. 41(34) 6537 (2000)
 Discussion of Stereoselective Syntheses of Amphetamine 1985-2009:
Illustrated in Scheme 2, routes 2A-2Q, repressent the multitude of stereoselective
approaches to amphetamine published between 1985 –2009. Within this illustrated
pinwheel of reaction routes, we have arranged references in reverse chronological order –
clockwise [#‘s]. As a starting point for discussion, take the Schiff 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].
 Time-Line of Synthetic Routes to Amphetamine non-chiral syntheses

1985 2009
1900 1930 1970
Non-Chiral Synthesis of Amphetamine 1985--2009
non-Chiral
Tetra. Let. 48(32) 5707 (2007)
Scheme 3 non-Chiral JOC 70(14)5519 (2005)
Org. Biomol. Chem 3(6) 1049 (2005) J. Labelled Comp. Rad. 31(11) 891 (1992)
Tetra. 46(21) 7443 (1990)
Angew Chem. Int. 28(2) 218 (1989)
J M C 31(8) 1558 (1988)
non-Chiral
OH Syn. Comm. 15(9) 843 (1985)
JCS, Chem. Comm.
2, 176 (1986) 3A. NO2 non-Chiral
NH2 Org. Let. 6(24) 4619 (2004)
Br SO2
3B.
NO2 46.
3N. H3C LiAlH4 Mg
47
NH Ph 42 56 3C. Br
N

non-Chiral O
Org. Rea. 36(book) (1988) 35 non-Chiral
N N O Tetra. Let. 41, 6537 (2000)
O Ph 28 12
3M. O
13 4 Ts
52 O O
15 OH
O N O tBu3D.
48 17 H
O
non-Chiral
27 58 Tetra. 56, 5157 (2000)
H 47 Ph
NH2
3L. Pd/H2
NH2 n-BuLi
non-Chiral 3E.
JMC 31(8) 1558 (1988) 45 Amphetamine 26 NH2
Ph Ph
37 31 Cp2TiMe2
non-Chiral
S 37 32 O.L.. 2(13) 1935 (2000)
Ph 3K. 22 3F.
CN 40 O
Coll. Czech. Chem Comm. NH3 P
54(7) 1995 (1989) O O
HoAc N 3G.
non-Chiral MgBr
3J. Mg
O O reduction
3H.
3I.
O T. 53(13)4935 (1997)
COOH
O non-Chiral
non-Chiral O
Acta Chem. Scand. JCS, PTI, 265 (1996)
45, 431 (1991) Acta Chem. Scand. Tetra. Asy. 13(12) 1325 (2002)
45, 431 (1991) J. Chrom Sci. 28, 529 (1990)
non-Chiral non-Chiral

Scheme 3.

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

Non-chiral syntheses of amphetamine (Scheme 3, routes 3A-N) have also
appeared in the literature; 1985-2009. These variations are graphically illustrated in
Scheme 3 and represent 25 individual citations. As described above with regards to
chiral routes, the Mitsunobu type reaction chemistry has been exploited in 3 different
non-chiral routes, each starting from racemic 1-phenylpropan-2-ol [13, 17, 28; route 3A
and 3D]. Achiral reductions of nitrostryene to amphetamine were the most popular
approaches in this time period [4, 12, 35, 42, 46, 47, 56; route 3B]. These citations are
primarily in the course of building pharmaceutical analogs / research. Organo-metallic
(Grignard or lithium alkylation) reactions were used in a variety of alkylation reactions to
amphetamine [15, 31, 52; route 3C, 3G and 3N]. These variations include Grignard ring
opening of a phosphorylated-aziridine (nucleophilic ring-opening of N-phosphorylated
aziridines) [31; route 3G], reaction with an electron deficient oxime (electrophilic
amination of Grignard reagent) [15; route 3C], and lithium alkylation of an -amino
carbanion equivalent reaction [52; route 3N].
The amination of allylbenzene was affected in a base-catalyzed hydroamination
reaction [27; route 3E]. This reaction is similar in precursor and product, however
different in mechanism to the 1982 phosphoramidomercuration-demercuration of
allylbenzene to amphetamine [58; route 6U]. Amination with a commercially available
-aminodiphenylmethane, which serves as an 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.
 Time-Line of Synthetic Routes to Amphetamine non-chiral syntheses

1900 1930 1970 1985 2009

O
Organic Transformations NO2
to Amphetamine H Scheme 6.
1900 - 2009 COOH 6A.
113 114 6B.
NH2 54 57 62 86
6BB. O
4 67 87 39 O O
95 6C.
41 12 70 O
Br 6AA. 84a 18 74
94
42 75 6D. O
109 84b 20 OH
44 84
6Z. 5 NH2
O 102 25 47 22 85
72 5
33 56 35 89 103
H 6E. OH
122 55 60 61 92 37
110
6Y. 95 92 31
89 34 OH
80 HO
Br 47
5 6F. O
6X.
21
NH2
NH2
107 1 120 21 117
CN 6G.
6W. O
80 111
100 112 121
69
Amphetamine OH
6V. 27 45
58 6H.
26 15 S
Ph
74 6I.
6U. 17 8 CN
65 13 5
49 40
52 88 64 14 13 Br
6T. 106 101 53 63 19 14 6J.
16 91
23 1 54 20 28
116 51 51 29
40 OH
52 96 22 32 66K.
H 6S. 11 52 38
54 93
115 9049 43
O 92 36
Br 116 9879 59 6L. OH
91 48 76 40
6R. 108
101 59 71 O
107 99 105
O 6Q. 120 73
O 82 118 6M.
6P.
88 6N.
OH 6O. O
OH
O NH2
N
R
OH
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Supplemental Material:

chir al JACS 131, 9882 (2009)

Ir-(S,S)-f-
N MeMgI NH binaphane NH2
H2

(S)-1-phenylpropan-2-amine
2-phenylacetonitrile 1-phenylpropan-2-imine
Ref. 1.
JOC 73(2) 364 (2008)
chir al
Photochemical --Racemization NH2
NH2
HSCH2CO2Me
Benzene 1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
Ref. 2.

chir al JOC 72(18) 6918 (2007)

Biotrasformation, Enzymic, Stereoselective
NH2 NH2
Lipase Lauric acid

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

non-chir al Tet r a. Let. 48(32) 5707 (2007)

NH2
NO2 SmI2
H 2N Ph

1-phenylpropan-2-amine
(E)-(2-nitroprop-1-enyl)benzene
Ref. 4.
 chir al
Tet r a. 63, 9758 (2007)
O (R)-3-phenyl-2-(phenylaminooxy)propan-1-ol
H nitrosobenzene OH Pd/C OH
OH
l-proline O
NHPh
NaBH 4 (R)-3-phenylpropane-1,2-diol
3-phenylpropanal
TEA
1, TsCl Ref. 5.
2. NaH

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

chir al Chem. Eur opean J. 12(15)4191-7(2006)

H H NH2
N O SmI2 N O TFA

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

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

NO2 NaBH4 NH2

BF3 - Et2O

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

chir al
Phth Anh. NH2 -NH 2
Ph3 P N O NH 2
OH MeOH
DEAD, THF O
amphetamine
(S)-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-ol
(S)-2-(1-phenyl
propan-2-yl)isoindoline Bioor ganic & Med. Chem. Lett er s,
Ref. 8. -1,3-dione 15( 12) 3039-43 ( 2005)

chir al Faming Zhuanli Shenqing Gongk ai Shuomingshu # 1673210 (2005)

H H NH2
N O SmI2 N O TFA

O O
I (S)-1-phenylpropan-2-amine
t er t-butyl 1-iodo-3-phenylpropan ter t -butyl 1-phenylpropan-2-
-2-ylcarbamate ylcarbamate
Ref. 9
 chir al indian J. Chem.Sec B 44B(6) 1312 ( 2005)
Biotrasformation, Enzymic, Stereoselective
NH2 NH2
Lipase Lauric acid

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

chir al
OH Ac
O
H
NH 2 N
Ac 2O Ac
norephedrine
(1R,2S)-2-amino-1- 2-acetamido
phenylpropan-1-ol -1-phenylpropyl acetate

H 2 / aS O 4
B
Pd-
Ref. 11. J . Med. Chem.
48( 4) 1229-36 ( 2005)

H NH 2
N H2 SO4
Ac
amphetamine

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

non-chir al J OC 70( 14) 5519 (2005)

NO2 LiAlH4 NH2

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

Ref. 12.

non-chir al NH2 Or g. and Biomolecular Chem. 3( 6) 1049 ( 2005)

SO 2
NO2 O PhSH, K2CO3
HN
OH S NH2
O 50o C
1-phenyl DCC amphetamine
propan-2-ol O2 N
1-phenylpropan-2-amine
2-nitro-N-(1-phenylpropan-2-yl)
benzenesulfonamide Ref. 13.
 chir al J. Chem. Research 10, 681 (2004)
(S)-(2-azidopropyl)benzene NH2
Pd/C
baker's yeast
N3 H2
O sucrose OH
(S)-1-phenylpropan-2-amine
1-phenylpropan-2-one (S)-1-phenylpropan-2-ol Ref. 14.

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

OH SOCl2 O N3
chir al NaN3
O S
O
OH OH

(1S,2S)-1-phenyl (1R,2S)-1-azido-1-phenylpropan-2-ol
propane-1,2-diol
Tet r ahedron Asy mmet ry
15(19),3111-6 (2004)
H
N
Ph 3P Pd-C (S)-1-phenylpropan-2-amine
Ref. 16.
HCO2 NH 4
NH2
2-methyl-3-phenylaziridine amphetamine

J. Combinator ial Chem.

chir al 5(5) 590-6 (2003)
O O O
S CuSO4 S
H NH2 N
2-phenylacetaldehyde (R,E)-2-methyl
(R)-2-methyl -N-(2-phenylethylidene)
propane-2-sulfinamide propane-2-sulfinamide

Ref. 17.
O
MeMgBr NH 2
S HCl, MeOH
N amphetamine
H
(R)-2-methyl-N-((S)-1-phenyl (S)-1-phenylpropan-2-amine
propan-2-yl)propane-2-sulfinamide
chir al J. Chem. Resear ch ( S), 128 (2003)
NO2 NH2
Ruthenium BINAP

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

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

(S)-1-phenylpropan-2-amine

O H2 N
N NH 2
1-phenylpropan-2-one
(R)-1-phenylethanamine (S,E)-1-phenyl-N- Ref. 19.
(1-phenylpropan-2-ylidene)
ethanamine

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

NO2 NH2
Ru2Cl2(PPh3)3

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

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

O
O O
O N
Br LDA, THF
N

1-(bromomethyl) (5R)-3,3,5-trimethyl-
(R)-3,3,5-trimethyl 1-(2-methyl-3-phenyl
benzene
-1-propionylpyrrolidin-2-one propanoyl)pyrrolidin-2-one
Ref. 21.
O NH2
NH 3, MeOH PhI(OOCCF3) 2
NH 2
amphetamine
(S)-2-methyl-3-phenylpropanamide (S)-1-phenylpropan-2-amine
 chir al Tetr a. Asy. 13( 20) 2277 ( 2002)

NH2 Enzymic, Resolution Ref. 22. NH2

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

non-chiral
NH 2
HCOO NH 4
O
Pd, MeOH Ref. 22.
1-phenylpropan-2-one T etr ahedr on Asymmetr y, 13( 12) amphetamine
13115-1320 ( 2002) 1-phenylpropan-2-amine

chir al US pat . # 6399828 2002)

OH
NH 2 HI, P4 NH 2

HCl
(1R,2S)-2-amino-1-phenylpropan-1-ol
Ref. 23.
BaSo4
Ac 2O OAc H2
HoAc Pd
NH 2

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

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

NH 2 Enzymic, Resolution NH 2

Candida antarcitica Lipase

1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine
Ref. 24.
 O
chir al
NH 2 LiBH4 /TMSCl NH 2 BOC) 2O NH O

COOH OH OH
(S)-2-amino-3- (S)-2-amino-3-phenylpropan-1-ol (S)-t er t-butyl 1-hydroxy-
phenylpropanoic acid 3-phenylpropan-2-ylcarbamate
Ref. 25. J . Or gainic Chemistr y
65(16) 5037-42 ( 2000)
O O O O

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

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

non-chir al
NH 2 Cp2 TiMe 2
Cp2 TiMe2
N
Ph H 2 , Pd/C NH2
diphenyl (E)-diphenyl-N- 1-phenylpropan-2-amine
1-phenyl- methanamine (1-phenylpropan-2- Ph
1-propyne ylidene)methanamine
Ref. 26. amphentamine
Or ganic Let ter s, 2( 13) 1935-1937 ( 2000)

T et ra. 56, 5157 ( 2000)

non-chir al Ref. 27.
NH2
H 2N Ph Pd/C H2
NH
cat. n-Bu Li
1-phenylpropan-2-amine
allylbenzene
N-benzyl-1-phenylpropan-2-amine

non-chir al T et rahedron Letters, 41( 34)

tBuCO) 2O 6537-40 ( 2000)
TFA
OH Ph 3P DCM NH2
NH
DEAD, THF O
1-phenyl amphetamine
propan-2-ol ter t-butyl O
1-phenylpropan Ref. 28. 1-phenylpropan-2-amine
-2-ylcarbamate
 chir al JP 03191797 (1991)
O
BuNH 2 Enzymic, Resolution NH 2

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

non-chir al Zhongshan Dazue Xuebao 35( 5) 73-76 (1996)

HOOC
* OH
O NH 2
Leuckart Reaction NH 2 HO *
COOH
ammonium formate
d-Tartaric
1-phenylpropan-2-one acid Ref. 30.

non-chir al Ref. 31. T et rahedron, 53(13) 4935-4946, 1997

O O
O O O O 1-phenylpropan-
P P 2-amine
MgBr N CuI NH HCl NH2

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

non-chir al J.Chem.Soc., P er kin T rans I , 265 ( 1996)

O
Mg MeOH NH 2

NH3 HoAc
1-phenylpropan-2-one
Ref. 32. 1-phenylpropan-2-amine
P-2-P
chir al Tet r a. Lett . 36( 8) 1223 (1995)
O
BOC BOC
HN O NH NH
BH 3 TEA

O OH THF CH 3SO2 Cl
OH O Ms
(R)-2-(t er t-butoxycarbonylamino)
-3-phenylpropanoic acid CH 3CH2 SH
NaH Ref. 33.
BOC BOC
NH NH NH 2
TFA
Ra-Ni
O S EtOH
(S)-1-phenylpropan-2-amine

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

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

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

NO2 LiAlH4 NH2

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

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

Acta. Chemica Scandinavica 45, 431 ( 1991)

non-chir al
Ref. 37. O O
O O
O O
O O NaH CH3-I
DMSO
methyl
2-benzyl-2-methyl
-3-oxobutanoate
dimethyl 2-benzylmalonate
O Ph
O P Ph NH2
OH 1. N TEA/heat
1. NaOH
-N N+
2. AcOH amphetamine
2-methyl-3-phenyl
propanoic acid 2. HCl / heat 1-phenylpropan-2-amine

chir al NH2 resolution NH2

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

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

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

Biotransf ormation NH2

NO2
cat. Peptostr eptococcus Anaer obius

(E)-(2-nitroprop-1-enyl)benzene
Ref. 39. 1-phenylpropan-2-amine
 chir al Ref. 40. J. Chr om. Sci. 28, 529 ( 1990)
OH Cl
NH2
NH2 SOCl2 NH2 Pd H2

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

non-chir al J. Chr om. Sci. 28, 529 ( 1990)

Ref. 40.
NH2
OH Ac2)O Leuchart Red

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

chir al Ref. 41. Tet r a. 46( 21) 7403 (1990)

NO2 NH 2
BH3-THF NO2 Ru Cl [(-)-DIOP]
2 2 3

H2
amphetamine
(E)-(2-nitroprop-1-enyl)benzene (2-nitropropyl)benzene (S)-1-phenylpropan-2-amine

non-chiral Tet r a. 46( 21) 7743 ( 1990)

Ref. 42. NH 2
NO2
BH3-THF
cat. NaBH4
amphetamine
(E)-(2-nitroprop-1-enyl)benzene

chir al U.S. pat . # 4950606 (1990)

Enzymic, Resolution
NH2 Ref. 43. NH2
amino-acid transminase f rom
Bacilllus Megat er ium
1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

non-chiral Biotransf ormation

amino-acid transminase f rom Ref. 43. NH 2

O Bacilllus Megater ium

amphetamine
1-phenylpropan-2-one 1-phenylpropan-2-amine
 non-chiral Angew Chem. Int. Ed. Engl. 28(2) 218-220 (1989)

O O O O

NH (CH3)3SiCl NH

COOH LiBH4 /THF

2-(benzyloxycarbonyl) benzyl 1-phenylpropan-2-ylcarbamate
-3-phenylpropanoic acid Ref. 44.

NO2 NH2
(CH3)3SiCl
LiBH4 /THF
amphetamine
(E)-(2-nitroprop-1-enyl)benzene 1-phenylpropan-2-amine

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

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

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

non-chir al Ref. 46. Or g. React ions 36, book ( 1988)

NH 2
N Red - Al, THF
O

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

(E)-(2-nitroprop-1-enyl)benzene
 non-chir al Ref. 47. J.Med.Chem. 31( 8) 1558 (1988)
O NH2
NO2
NO 2 LiAlH4
H

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

chir al JP 63219396 (1988)

NO2 Ref. 48. NH2

Biotransf ormation /
Enzymic, Resolution
1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine

chir al
N N
H 2N N
O

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

Ref. 49. JACS 109(7) 2224-5 (1987)

H NH 2
CH3 Li / CeCl3 N N H 2 / Ra-Ni

375 psi / 60 o
amphetamine
(R)-2-methyl-N -((S)-
1-phenylpropan-2-yl) (s)-1-phenylpropan-2-amine
pyrrolidin-1-amine
chir al
O NH 2 low pressure
R or S

* Hydrogenation HN *
Raney Ni / H2
*
phenyl-2-propanone [R,R]+ or [S,S]-
 -methylbenzylamine

U S 4000,197 ( 1976)

Ref. 50.
[S,S]-(-)
NH 2
10% Pd-C
amphetamine
HN * 50 psi H2
* (S)-1-phenylpropan-2-amine
 chir al Or ganometallics, 5, 739-46 (1986)
Ref. 51.
O N H-SiH(Ph)2 NH2
OH
Rh(cod)Cl2
1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime

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

H CH 3
H LDA
1. TFA Aphetamine
N N
O NH CH3I NH 2. Pd /C H2
Ph Ph
2-phenylacetaldehyde
Ph Ph

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

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

H CH 3
H LDA 1. TFA
N Aphetamine
N 2. Pd /C H2
O NH NH
Ph-CH2-Br
acetaldehyde Ph Ph
Ph Ph

non-chir al US 2009292143 (2009)

OH Cl
NH 2 NH 2 Pd NH 2

H2

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

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

O N Na MeOH NH2
OH

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

Ref. 54.
 chiral O O
H AlCl3 H
N CF3 N CF3
Cl
O O
(S)-2-(2,2,2-trifluoroacetamido) (S)-2,2,2-trifluoro
benzene
propanoyl chloride -N -(1-oxo-1-phenyl
propan-2-yl)acetamide
J .Org.Chem. 50(19)
Ref. 55 3481-4 (1985)
OH Br
H H
H 2 / Pd-C N CF3 PBr 3 N CF3

O O

(S)-2,2,2-trifluoro (S)-N-(1-bromo-1-phenylpropan
-N-(1-hydroxy-1-phenyl -2-yl)-2,2,2-trif luoroacetamide
propan-2-yl)acetamide

H K2 CO 3, MeOH NH2
H 2 / Pd-C N CF3

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

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

Ref. 56.
NaBH4
NO2 NH2
BH3 - THF

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

non-chir al Sy n. Comm. 14( 12)1099(1984)

NaBH 4
NH 2
NO2 BH 3 / THF

amphetamine
Ref. 57.

non-chir al Sy nt hesis ( 4) 270-3 (1982)

O 1. Hg(NO 3) 2 / O
H
H 2N P 1,1-diCl-ethane N P
O O
O O
2. 10% NaOH / NaBH 4
(E )-prop-1-enylbenzene
diethyl phosphoramidate
NH 2
HCl /benzene

Ref. 58. amphetamine

 chir al Sy nt hesis ( 4) 270-3 (1982)

O O
N N
OH P CH2Cl2, DEA O P
Cl Ph Ph
Ph Ph
(E)-1-phenylpropan
-2-one oxime

H O HCl / ethanol NH 2
LAH N
O P
Ph
Ph
(-) Quinine / THF
Ref. 59. amphetamine

non-chir al J. Labelled compounds and radiophar maceuticals 18(6) 909 ( 1981)

O NH2
NH3 (Sealed)

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

1-phenylpropan-2-one Ref.60.

non-chir al Helvet ica chimica Acta 61( 2) 558 ( 1978)

NO
NH2
NO NO2 LiAlH4

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

chir al Ref. 62. T etr ahedr on 32( 11) 1267-76 (1976)

E&Z
NH 2
LiAlH 4
N
OH
1-phenylpropan-2-amine
(E)-1-phenylpropan-2-one oxime amphetamine

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

O NH 2
Al, HgCl2, NH4OH, 100 oC, 15min

1-phenylpropan-2-one Ref.63.
 non-chir al (R)-1-phenylethanamine JMC 16(5) 480-3 ( 1973)
H
O H2 N N
Raney-Ni

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

non-chir al JACS 93, 2897 ( 1971)

O NH 2
NaCNBH3

NH 4OH, MeOH
1-phenylpropan-2-one Ref.65.

chiral resolution OH EP 915080 (1999)

OH
NH2 NH2
O
(s)-2-naphthylglycolic acid
racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine Ref. 66.

non-chiral
Ref. 67. J.Med.Chem. 13, 26( 1970)
NO2 NH2
LiAlH4 / THF

(E)-(2-nitroprop-1-enyl)benzene
 non-chir al JACS 91, 5647 ( 1969)

CH3CN Hg(NO 3) 2 N O
NO 2

Hg
allylbenzene
Ref. 69.
NO3
H
H N
N O HCl
NaBH4

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

non-chiral
Ref. 70. US Pat. 3,458,576 (1969)
Pd-C / H2
NO2 NH2
Pt / H2
Raney-Ni / H2
(E)-(2-nitroprop-1-enyl)benzene

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

O NH 2
HCl
NH4 HCOO Ammonium Formate

1-phenylpropan-2-one Ref.71.

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

NH 2
NH 2 (+)-tartaric acid

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

non-chir al Ref. 72. J. Het er ocy clic Chem._5( 3)339( 1968)

NH 2
AlCl3

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

non-chir al Chem Phar m Bull 13( 2)118( 1965)

Cl Cl
nitrosyl chloride NO2 Pt2O NO2
NOCl
H2
NO2Cl
prop-1-ynylbenzene hypochlorous nitrous anhydride Ref.74.

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

O NH2
NH4 oAc Raney-Ni / H2

1-phenylpropan-2-one Ref.75.

non-chir al T etr a. 19, 1789 (1963)

LEUCKART-WALLACH Mech
O NH 2
NH4 Formic Acid

1-phenylpropan-2-one Ref.76.

non-chir al DE_1958-968545(1958)
OH Cl
NH 2 NH 2 Pd NH 2

H2

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

chir al US 3028430 (1962)

NH 2 R resolution NH 2
H2 N
*  -amino acid
COOH
amphetamine amphetamine
1-phenylpropan-2-amine Ref. 78. (S)-1-phenylpropan-2-amine
 non-chir al US Pat. 2,828,343 ( 1958)

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

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

chir al Curtius rearrangement JOC_22( 1)33(1957)

O Ref. 80. O
O
NH 2
OH CO2Cl2 Cl N 3 HCl
NaN 3
(S)-2-methyl-3- (S)-2-methyl-3- (S)-2-methyl-3- amphetamine
phenylpropanoic acid phenylpropanoyl chloride phenylpropanoyl azide (S)-1-phenylpropan-2-amine

chir al O Schmidt rearrangement

NH 2
OH H 2SO4 NaN 3

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

chir al HOOC Zhur nal Obshchei Khimii 28 ( 1958) 3323-8

NH 2 * OH resolution NH 2
HO d-Tartaric
* COOH acid
amphetamine amphetamine
1-phenylpropan-2-amine Ref. 81a (S)-1-phenylpropan-2-amine

chir al US 2,833,823 (1958)

NH 2 resolution NH 2
H 3 PO 4
inriched in one isomer amphetamine
amphetamine Ref. 81b (S)-1-phenylpropan-2-amine
1-phenylpropan-2-amine
non-chiral J_Phar m_Soc_Japan_413-416( 1954)
Ref. 82.
NO 2 Raney-Ni
NH 2

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

non-chir al DE_1953-870265
NH 2
Ph
O HN NH 2
N
N PtO2
H
PhenylHydrazine H2

1-phenylpropan-2-one
(E)-1-phenyl-2-(1-phenyl Ref.83.
propan-2-ylidene)hydrazine

chir al J. Labelled Comp. and Radio. 3( 1) 3-9 ( 1977) O O

HN S
* NH 2 LiAlD4 * NH 2 p-MeTOSCl *
D2 C D2 C
COOH O
OH CH 3
D-Phenylalanine p-TOS
Ref. 84. LiAlD4
O O NH 2
HN S
* Naphthalene radical anion
CD 3 amphetamine
CH 3 1-phenylpropan-2-amine

non-chiral JACS_74( 7)1837(1952)

Ref. 85.
NO 2 NH 2
LiAlH 4

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

non-chiral US Patent 02647930B1( 1953)

Ref. 86.
NO 2 NH 2
Organic Acids
Raney-Ni / H 2
(E)-(2-nitroprop-1-enyl)benzene
 non-chiral DE_1952-848197( 1952)
Ref. 87.
NO 2 NH 2
Raney-Ni / H 2

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

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

NH2
Distillation from Ref. 88. NH2
optically active acids..

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

non-chiral Helv. Chim. Act a. 33, 912 ( 1950)

Ref. 89.
NO 2 LiAlH4 / ether NH 2

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

chiral resolution O Or g. Syn. Coll. 2, 506 (1943)

OH
NH 2 HO NH 2
/ water
OH O

racemic-1-phenylpropan-2-amine l-malic acid

(S)-1-phenylpropan-2-amine Ref. 90.

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

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

diethyl 2-(2-phenylacetyl)malonate
Ref. 91. J_Am_Phar m_Assoc_687-688( 1950)
OH
O N NH2

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

 non-chir al Bull. Soc. Chem. Fr ance 1045 ( 1950)

O NH2
NH3 Raney-Ni / H2

1-phenylpropan-2-one Ref.92.

non-chir al
NO 2 Chemische Ber icht e 124(10) 2303-6 ( 1991)

NH 2
Cathode Red. at Hg or C electrode
N
OH

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

non-chiral JOC 15, 8 (1950)

Ref. 94.
NO 2 NH 2
Raney-Ni / H 2

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

non-chir al GB 702985( 1949)

O NH2
NH3 Raney-Ni / H2

or Pt or Pd
1-phenylpropan-2-one Ref.95.

non-chiral US Pat. 2,636,901(1949)

Ref. 96.
NO 2 NH 2
Raney-Ni / H 2

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

non-chir al JACS 70, 1187 (1948)

LEUCKART-WALLACH Mech
O NH2
NH4 Formic Acid

1-phenylpropan-2-one Ref.97.
 non-chir al JACS 70, 1315-6(1948)

O PtO2 / H 2 NH2
NH3

1-phenylpropan-2-one Ref.98.
non-chir al
Y ak ugak u Zasshi 74, 413-16 ( 1954).

N NH 2
OH Raney Ni / H2

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

non-chir al JACS 70, 2811-12 (1948)

O NH2
NH3 Raney-Ni / H2

1-phenylpropan-2-one Ref.100.

non-chir al
Bullet in of Electr ochemist y 8(6) 276-7 (1992)
N
OH NH 2
Cathode Red. at Hg or C electrode

Ref. 101.

non-chir al
1-phenylpropan-2-ol Ritter Reaction JACS 70, 4048 (1948)
OH SO 3H
SO 3H
O N HCl NH2
HCN

1-phenylpropan
-2-yl hydrogen sulfate Ref.102.
(E )-prop-1-enylbenzene
 non-chiral Justus_Liebigs_Annalen_der_Chemie_215-221( 1948)
Ref. 103.
NO 2 NH 2
Pd / H2

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

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

Friedel-Crafts reactions
NH 2
Cl FeCl3 Cl NH4 OH
Cl or
Fuming Sulf uric
Allyl Chloride
Ref. 104.

non-chiral Acetoacetic Ester Synthesis Route U S P atent 2,413,493B1( 1946)

O O O O
O O
Na CH3-I Na Ph-CH2-Cl
O O
O
ethyl 3-oxobutanoate

Ref. 105.
O OH O NH 2
NaOH SOCl2 NH 3 NaOCl NH 2
Hoffman
2-methyl-3-phenylpropanoic acid 1-phenylpropan-2-amine

non-chir al JOC 9, 529 ( 1944)

LEUCKART-Study
O NH 2
NH4 Formic Acid

1-phenylpropan-2-one Ref.106.
 Acetylbenzylcyanide Reaction Route
non-chiral J.Applied Chem. ( USSR) 14(3), 410 (1941)
O ethyl acetate O
N O
O N H3 PO4

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

Ref. 107.
H
N O NH 2
HCl
ammonium formate

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

non-chir al O O
O O
O
O Acetic Anhydride O

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

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

H2 N O H
N O Hydrolysis H+ NH2
Formamide

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

chir al Resolution OH O Ref.108.

NH2 HO NH2
OH
O OH

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

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

Wolf f Rearr.
O O
O O AgO

OH SOCl2 Cl NH 3 NH 2
Diazomethane HC
2-phenylacetic acid N
N Ref.109.
 non-chiral Chemischen Ber icht e 66B, 684 ( 1933)

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

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

Lossen Rearr.
O
O N NH 2
C
acid chloride X Hydroxyl amineHN O Hydrolysis
OH
esters
anhydride Ref.111.

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

O NH2
NO2
NO 2 Hg . Cathode
H
electrolic Red.

(E)-(2-nitroprop-1-enyl)benzene 1-phenylpropan-2-amine
benzaldehyde
Ref. 112.

non-chir al
U S 1879003 (1932)
NO 2
NH 2
Cathode Red. at Hg or C electrode

Ref. 113.
non-chir al
Chemicshe Ber icht e, 66B, 660-666 (1932).
N
OH / Ethanol NH 2
Na

Ref. 114.
 non-chiral J. Am. Chem. Soc. 31, 1875 (1931)
O OH OH Cl
N NH2 NH2 NH2
Pd/C, H2 HCl Pd/C, H2

(E)-2-(hydroxyimino)- 2-amino-1-phenyl 1-chloro-1-phenyl

1-phenylpropan-1-one propan-1-ol propan-2-amine

O
from O

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

non-chir al O J. Am. Chem. Soc. 31, 2787-91 (1931)

Hofmann Rearr.
NH2 NaOH
Br 2
NH 2
2-methyl-3-phenylpropanamide
O
Curtius Rearr.
N3
Ref. 116.
1-azido-2-methyl-3-phenylpropan-1-one

non-chir al J . Chem. Soc. 18-21 ( 1930)

OH
O N NH2
NH2-OH Na/Hg
amalgum
1-phenylpropan-2-one (Z)-1-phenylpropan-2-one oxime Ref. 117.

Precursor list to amphetamine 1985 -2009

Precursor / intermediate / essentials References……

2-phenylacetonitrile
(E)-(2-nitroprop-1-enyl)benzene
and
(Z)-(2-nitroprop-1-enyl)benzene
1. J. Am. Chem. Soc. 131, 9882 (2009)
107. J. Applied Chem. (USSR) 14(3) 410 (1941)
4. Tetra. Lett. 48(32) 5707 (2007)
7. Central Eur. J. Chem. 6(4) 526 (2008)
12. J. Org. Chem. 70(14) 5519 (2005)
18. J. Chem. Research (S), 128 (2003)
20. J. Chinese Chem. Soc. 49, 505 (2002)

3-phenylpropanol
(R)-3-phenylpropane-1,2-diol
2-benzyloxirane
(R)-3-phenyl-2-(phenylamineooxy)
propan-1-ol
tert-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
tert-butyl 1-phenylpropan-2-
ylcarbamate
(S)-1-phenylpropan-2-ol
And
1-phenylpropan-2-ol
(S)-2-(1-phenylpropan-2-
yl)isoindoline-1,3-dione
(1R,2S)-2-amino-1-phenylpropan-1-
ol
35. J. Labelled Comp. Rad. 31(11) 891 (1992)
36. Tetra. Asym. 3(10) 1283 (1992)
39. Chem. Pharm. Bull. 38(12) 3449 (1990)
41. Tetra. 46(21) 7403 (1990)
42. Tetra. 46(21) 7403 (1990)
46. Org. Reactions 36, book (1988)
47. J. Med. Chem. 31(8) 1558 (1988)
48. JP 63219396 (1988)
56. Sym. Comm. 15(9) 843 (1985)
57. Sym. Comm. 14(12) 1099 (1984)
67. J. Med. Chem. 13, 26 (1970)
70. US 3,458,576 (1969)
82. J.Pharm. Soc. Japan, 413-6(1954)
85. J. Am. Chem. Soc. 75(7) 1837(1952)
86. US 2647930B1 (1953)
87. DE 848197 (1952)
89. Helv. Chim. Acta. 33, 912 (1950)
94. J. Org. Chem. 15, 8 (1950)
96. US 2,636,901 (1949)
103. Justus Lieb. Ann. Chem. 215 (1948)
112. J. Am. Chem. Soc. 54, 271 (1933)
113. US 1879003 (1932)
5. Tetra. 63, 9758 (2007)
5. Tetra. 63, 9758 (2007)
5. Tetra. 63, 9758 (2007)
5. Tetra. 63, 9758 (2007)
6. Chem. European J. 12(15)4191-7(2006)
9. Faming Zhuanli Shenging Gongkai
Shuominshu, patent 1673210 (2005)
6. Chem. European J. 12(15)4191-7(2006)
9. Faming Zhuanli Shenging Gongkai
Shuominshu, patent 1673210 (2005)
5. Tetra. 63, 9758 (2007)
8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)
13. Org. and Biomolecular Chem. 3(6) 1049
(2005)
14. J. Chem. Research 10, 681 (2004)
28. Tetra. Lett. 41(34) 6537 (2000)
102. J. Am. Chem. Soc. 70, 4048 (1948)
8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)
34. Tetra. Asym. 4(7) 1619 (1993)
11. J. Med. Chem. 48(4) 1229 (2005)
23. US 6399828 (2002)

Norephedrine
(1R,2S)-2-amino-1-phenylpropan-1-
ol
2-acetamido-1-phenylpropyl acetate
2-nitro-N-(1-phenylpropan-2-yl)
benzenesulfonamide
1-phenylpropan-2-one
P-2-P = Phenyl-2-propanone
(S)-(2-azidopropyl)benzene
(1-phenylpropan-2-yl) magnesium
bromide
4,4,5,5-tetramethyl-1,3-dioxolan-2-
40. J. Chrom. Sci. 28, 529 (1990)
53. Anal. Chem. 58(8) 1642 (1986)
11. J. Med. Chem. 48(4) 1229 (2005)
23. US 6399828 (2002)
40. J. Chrom. Sci. 28, 529 (1990)
53. Anal. Chem. 58(8) 1642 (1986)
77. DE 968545 (1958)
11. J. Med. Chem. 48(4) 1229 (2005)
13. Org. and Biomolecular Chem. 3(6) 1049
(2005)
14. J. Chem. Research 10, 681 (2004)
19. Tetra. Asy, 14, 2119 (2003)
22. Tetra. Asym. 13(20) 2277 (2002)
32. J. Chem. Soc. Perkin Trans I, 265 (1996)
40. J. Chrom Sci. 28, 529 (1990)
43. US 4950606 (1990)
44. Angew Chem. Int. Ed. Engl. 28(2) 218
(1989)
47. J. Med. Chem. 31(8) 1558 (1988)
50. US 4,000,197 (1996)
51. Organometallics, 5, 739 (1986)
54. Khimiya Getero Soedinenii, 12, 1648
(1985)
60. J. Labelled Comp. Rad. 18(6) 909 (1981)
63. J. Chem. Education 51, 671 (1974)
65. J. Am. Chem. Soc. 93, 2897 (1971)
71. Coll. Czech. Chem. Comm. 33(11)3551
(1968)
75. US 3,187,047 (1965)
76. Tetra. 19, 1789 (1963)
79. US 2,828,343 (1958)
80. DE 870265 (1953)
91. J. Am. Pharm. Assoc. 687 (1950)
92. Bull. Soc. Chem. France 1045 (1950)
95. GB 702,985 (1949)
97. J. Am. Chem. Soc. 70, 1187 (1948)
98. J. Am. Chem. Soc. 70, 1315 (1948)
100. J. Am. Chem. Soc. 70, 2811 (1948)
106. J. Org. Chem. 9, 529 (1944)
107. J. Applied Chem. (USSR) 14(3) 410 (1941)
108. J. Gen. Chem. (USSR) 11(4) 339 (1941)
117. J. Chem. Soc. 18 (1930)
14. J. Chem. Research 10, 681 (2004)
15. Org. Lett. 6(24) 4619 (2004)
15. Org. Lett. 6(24) 4619 (2004)
one O-tosyl oxime
(1S,2S)-1-phenyl propane-1,2-diol
(1R,2S)-1-azido-1-phenylpropan-2-ol
2-methyl-3-phenylaziridine
2-phenylacetaldehyde
(R)-2-methyl propane-2-sulfinamide
(R)-1-phenylethanamine
1-(bromomethyl) benzene
(R)-3,3,5-trimethyl-1-propionyl
pyrrolidin-2-one
(S)-2-methyl-3-phenylpropanamide
(S)-2-amino-3-phenylpropanoic acid
(S)-2-amino-3-phenylpropan-1-ol
(S)-tert-butyl-1-phenylpropan-2-
ylcarbamate
1-phenyl-1-propyne
allylbenzene
Phenylmagnesium bromide
Diethyl-2-methylaziridin-1-
ylphosphonate
(R)-2-(tert-butoxycarbonylamino)-3-
phenylpropanoic acid
(R)-tert-butyl 1-hydroxy-
3-phenylpropan-2-ylcarbamate
(S)-tert-butyl 1-phenylpropan-2-
ylcarbamate
(1S,2S)-2-amino-1-phenylpropane-
1,3-diol
(E)-1-phenylpropan-2-one oxime
And
(Z)-1-phenylpropan-2-one oxime
Dimethyl 2-benylmalonate
16. Tetra. Asy, 15(19) 3111 (2004)
16. Tetra. Asy, 15(19) 3111 (2004)
16. Tetra. Asy, 15(19) 3111 (2004)
17. J. Combinatorial Chem. 5(5) 590 (2003)
49. J. Am. Chem. Soc. 109(7) 2224 (1987)
52. J Chem. Soc., Chem. Comm. 2, 176 (1986)
17. J. Combinatorial Chem. 5(5) 590 (2003)
19. Tetra. Asy, 14, 2119 (2003)
21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
25. J. Org. Chem. 65(16) 5037 (2000)
25. J. Org. Chem. 65(16) 5037 (2000)
25. J. Org. Chem. 65(16) 5037 (2000)
26. Org. Lett. 2(13) 1935 (2000)
74. Chem. Pharm. Bull. 13(2) 118 (1965)
27. Tetra. 56, 5157 (2000)
69. J. Am. Chem. Soc. 91, 5647 (1969)
31. Tetra. 53(13) 4935 (1997)
31. Tetra. 53(13) 4935 (1997)
33. Tetra. Lett. 36(8) 1223 (1995)
33. Tetra. Lett. 36(8) 1223 (1995)
33. Tetra. Lett. 36(8) 1223 (1995)
34. Tetra. Asym. 4(7) 1619 (1993)
36. Tetra. Asym. 3(10) 1283 (1992)
51. Organometallics 5, 739 (1986)
54. Khimiya Geter Soedinenii 12, 1648 (1985)
59. Synthesis 4, 270 (1982)
62. Tetra. 32 (11) 1267 (1976)
73. Tetra. 24(16) 5677 (1968)
82. J. Pharm. Soc. Japan, 413 (1954)
91. J. Am. Pharm. Assoc. 687 (1950)
93. Berichte 124(10) 2303 (1991)
99. Yakugaku Zasshi 74, 413 (1954)
101. Bull. Electrochem. 8(6) 276 (1992)
114. Berichte, 66B, 660 (1932)
117. J. Chem. Soc. 18 (1930)
37. Acta. Chemica Scandinavica 45, 431 (1991)
Methyl-2-benyl-2-methyl-3-
oxobutanoate
2-methyl-3-phenyl propanoic acid
1-(2-(phenylthio)phenyl)propan-2-
amine
1-(2-(phenylthio)phenyl)propan-2-
one
3-oxo-2-(2-
(phenylthio)phenyl)butanenitrile
2-(2-(phenylthio)phenyl)acetonitrile
Benzaldehyde
(E)-1-phenylpropan-2-one O-methyl
oxime
(R)-2-methyl pyrrolidin-1-amine
(2,2-dimethyl-1,1-
diphenylpropyl)diazene
benzene
2-(2,2,2-trifluoroacetamido)
propanoyl chloride
2,2,2-trifluoro-N-(1-oxo-1-phenyl
propan-2-yl)acetamide
2-(2,2,2-trifluoro-N-(1-hydroxy-1-
phenyl propan-2-yl)acetamide
N-(1-bromo-1-phenylpropan-2-yl)-
2,2,2-trifluoroacetamide
2-(2,2,2-trifluoro-N-(1-phenyl
propan-2-yl)acetamide
(E)-prop-1-enylbenzene
1-(bromomethyl)benzene
Or
benzylbromide
Phenylpropan-1-one
Bromobenzene
Or
Phenylmagnesium bromide
2-phenylacetic acid
Or
Phenylacetic acid
Prop-1-ynylbenzene
(S)-2-methyl-3-phenylpropanoic acid
D-phenylalanine
Diethyl 2-(2-phenylacetyl)malonate
37. Acta. Chemica Scandinavica 45, 431 (1991)
37. Acta. Chemica Scandinavica 45, 431 (1991)
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
47. J. Med. Chem. 31(8) 1558 (1988)
112. J. Am. Chem. Soc. 54, 271 (1933)
48. Org. Reactions 36, book (1988)
49. JACS 109(7) 2224-5 (1987)
52. J. Chem. Soc., Chem. Comm. 2, 176 (1986)
55. J. Org. Chem 50(19) 3481 (1985)
72. J. Heterocyclic Chem. 5(3) 339 (1968)
55. J. Org. Chem 50(19) 3481 (1985)
55. J. Org. Chem 50(19) 3481 (1985)
55. J. Org. Chem 50(19) 3481 (1985)
55. J. Org. Chem 50(19) 3481 (1985)
55. J. Org. Chem 50(19) 3481 (1985)
58. Synthesis 4, 270 (1982)
61. Hetvetica Chimica Acta 61(2) 558 (1978)
102. J. Am. Chem. Soc. 70, 4048 (1948)
21. J. Chem. Soc. Perkin T. I 16, 1869 (2002)
29. JP 2002142793 (2002)
31. Tetra. 53(13) 4935 (1997)
105. US 2,413,494 B1 (1946)
118. J. Am. Chem. Soc. 48, 169 (1928)
40. J. Chrom Sci. 28, 529 (1990)
91. J. Am. Chem. Soc. 687 (1950)
108. J. Gen. Chem. (USSR) 11(4) 339 (1941)
74. Chem. Pharm Bull. 13(2) 118 (1965)
80. J. Org. Chem. 22(1) 33 (1957)
84. J. Labelled Comp. Radio 3(1) 3 (1977)
84. J. Labelled Comp. Radio 3(1) 3 (1977)
2-phenylacetyl chloride
Chlorobenzene
Allyl Chloride
Ethyl 3-oxobutanoate
Ethyl acetoacetate
2-methyl-3-phenylpropanoic acid
3-oxo-2-phenylbutanenitrile
N-(1-phenylpropan-2-yl)formamide
2-methyl-3-phenylpropanoic acid
84. J. Labelled Comp. Radio 3(1) 3 (1977)
104. J. Am. Chem. Soc. 68, 1009 (1946)
104. J. Am. Chem. Soc. 68, 1009 (1946)
105. US 2,413,494 B1 (1946)
118. J. Am. Chem. Soc. 48, 169 (1928)
106. US 2,413,494 B1 (1946)
107. J. Applied Chem (USSR) 14(3) 410 (1941)
107. J. Applied Chem (USSR) 14(3) 410 (1941)
108. J. Gen. Chem. (USSR) 11(4) 339 (1941)
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)