Review: Synthetic Methods for Amphetamine
A. Allen1 and R. Ely2
1
2
Array BioPharma Inc., Boulder, Colorado 80503
Drug Enforcement Administration, San Francisco, CA
Abstract:
This review focuses on synthesis of amphetamine.
The chemistry of these
methods will be discussed, referenced and precursors highlighted. This review covers
the period 1985 to 2009 with emphasis on stereoselective synthesis, classical non-chiral
synthesis and bio-enzymatic reactions. The review is directed to the Forensic Community
and thus highlights precursors, reagents, stereochemistry, type and name reactions. The
article attempts to present, as best as possible, a list of references covering amphetamine
synthesis from 1900 -2009. Although this is the same fundamental ground as the recent
publication by K. Norman; “Clandestine Laboratory Investigating Chemist Association”
19, 3(2009)2-39, this current review offers another perspective.
Keywords: Review, Stereoselective, Amphetamine, Syntheses, references,
Introduction:
It has been 20 years since our last review of the synthetic literature for the
manufacture of amphetamine and methamphetamine. Much has changed in the world of
organic transformation in this time period. Chiral (stereoselective) synthetic reactions
have moved to the forefront of organic transformations and these stereoselective
reactions, as well as regio-reactions and biotransformations will be the focus of this
review. Within the synthesis of amphetamine, these stereoselective transformations have
taken the form of organometallic reactions, enzymatic reactions, ring openings, aminooxylations, alkylations and amination reactions. The earlier review (J. Forensic
Sci. Int. 42(1989)183-189) addressed for the most part, the ―reductive‖ synthetic methods
leading to this drug of abuse. It could be said that the earlier review dealt with ―classical
organic transformations,‖ roughly covering the period from 1900-1985. This time-line is
graphically illustrated below in Figure 1. As illustrated in this figure, certain categories
have been historically active. Early synthetic organic transformations such as aldol
condensations, the Hofmann rearrangement [105, 116], the Curtius rearrangement [118,
110, 80], the Schmidt rearrangement [80], the Lossen rearrangement [118], the
Beckmann rearrangement [111], the Wolff rearrangement [109], the Friedel-Craft
alkylation [102, 105] together with catalytic reductions; populated the literature from
1900-1985. Of course, overlap has occurred between these categories as the field of
organic chemistry has progressed.
Interestingly, organic synthetic transformations have entered, in the last 20 years,
a period of ―stereoselective organic transformation”. This is graphically illustrated in
Figure 1a. The multiplicity of these transformations and their unique starting precursors
and reagents may come as a challenge to the forensic community to keep up with the
latest organic modifications and ―off-precursor-watch-list‖ circumventions. Herein, we
hope to summarize as exhaustively as possible, the chemistry pictorially and compose a
list of precursor chemicals (IUPAC nomenclature, see supplemental material) that
address these transformations to amphetamine.
The Era of Classical Organic Chemistry
Stereoselective syn.
Organometalic
Aldo Condensations: Rearrangements: Reductions:
chiral reduction
Lossen
1. metal catayltic red.
alkylations
1. methyl ethyl ketone
Curtius
2.
disolved
metal
red.
aminations
2. ethyl acetoacetate
Hofmann
3. non metalic red.
Mitsunobu
3. aldehyde -nitroethane Wolf
Enzymic
Time-Line of Synthetic Routes to Amphetamine
1900
1930
1970
2009
Figure 1
As best as possible, we have attempted to keep the needs of the forensic chemist
and law enforcement personnel in mind when creating the categories for retrieving the
information on a particular synthetic route. This has added a degree of difficulty to our
task since in many cases, the chemist thinks visually (synthetic routes) and the law
enforcement investigator works texturally (list of precursors). The categories of this
review are listed below and are not without their limitations.
Outline:
Review of amphetamine syntheses 1985 – 2009 (Schema 2, 3, 4)
1. Stereoselective syntheses (Scheme 2)
2. Non-Chiral Syntheses (Scheme 3)
3. Biotransformation (Scheme 4)
Review of classical amphetamine syntheses 1900 – 1985 (Schema 5 and 6)
1. Classical Organic Transformations (Scheme 5)
2. Summary Routes to Amphetamine (Scheme 6)
Overview:
In this reviewing period (1985-2009), with progress in stereoselective syntheses
and organometallic transformations, academia, along with private industry have been
motivated to explore new approaches to the synthesis of amphetamine. These numerous
publications have undoubtedly been prompted more by the introduction of a chiral center
alpha to a primary amine than the desire to add yet another synthetic approach to the
multitude of synthetic routes to amphetamine.
Organometallic chemistry has been used in creative region-constructions of
amphetamine, not only with magnesium metal [21, 15], but also with cerium [49],
titanium [26], iridium [1] and lithium [1]. Similarly, in the area of organometallic
reductions to amphetamine, the field of reagents has expanded to include samarium
iodide [4, 6, 9], ruthenium-(chiral-ligands) [18, 20, 36, 41], rhodium-(chiral ligands) [51],
titanium-ligands [26], copper [32, 17], magnesium [32] and novelties with borane [33,
42, 56], lithium aluminum hydride [12, 35, 47], L-Selectride [25], Red-Al® [46],
palladium [11, 14, 16, 23, 27, 40, 50, 53] and Raney nickel [33, 49 50]. Creative
synthetic routes that do not employ a reductive step have also been published [15, 17, 21,
28, 31, 37, 55, 58]. Ring opening strategies have been developed against phosphorylated
aziridines [31] and Sharpless epoxides [5] to yield amphetamine.
Mitsunobu
transformations [5, 8, 14, 19, 34] have been exploited in a variety of approaches to swap
an alcohol precursor to the amine complement toward amphetamine. Hofmann, Curtius
[37, 80], Lossen[37] and Schmidt rearrangement [80] continue to be used in synthetic
schemes to produce amphetamine. The ―classical‖ Friedel-Craft alkylation [105] of
benzene with iron or aluminum trichloride has been improved with the use of N(trifluoroacetyl)--amino acid chloride as a chiral F-C reagent to manufacture
amphetamine [55]. Intermediates of nitrostyrene have been reduced chirally and nonchirally to amphetamine [4, 12, 18, 20, 35, 41, 42, 56]. Likewise, hydroxylamine via
chiral hydrosilylation [51] and hydrazines [8, 52] have been exploited in routes to
amphetamine. Reductive aminations via phenyl-2-propanone; P-2-P [19, 40, 51, 54] have
appeared in these years, as well as other creative approaches like -amination [5],
alkyne-amination [26], alkene-amination [27], -aminooxylation [5], electrophilic
aminations [15], and sulfinyl-imine amination [17]. Photochemical-induced racemization
has been utilized for the transformation of the less pharmacologically active R isomer to
an equilibrium mix of R,S-amphetamine [2]. Improved resolution from racemic mixture
of amphetamine to a single isomer has been achieved with ―enzymatic transformations‖
[3, 10, 22, 24, 43] and ―classical organic salts resolutions‖ [37, 47]. Illustrated in Figure
1a and 1b are the histograms and citations for some of the active categories within the
transformations to amphetamine between 1985-2009. The activities of stereoselectivity,
resolutions and enzymatic transformations are expressly evident.
Histograms for amphetamine reaction types 1985-2009 (#-reference)
2
Photochemical
55
Friedel-Craft Alkylation
8, 34
Figure 1a.
Hydrazine
21, 37 Hofmann rearrangement
8, 13, 28
Mitsunobu
5, 31, 16
1, 15, 17, 31
Ring Opening
Organometalic
1, 5, 15, 21, 31 Alkylations
36, 45, 46, 51, 54
17, 26, 27, 58, 15
Oxime
Amination
1, 15, 19, 26, 49, 50, 52
2, 3, 10, 22, 24, 37, 38, 43,
Imine
Resolutions
2, 3, 10, 14, 22, 24, 29, 39, 43, 48
4, 7, 12, 18, 20, 35,41,42, 46, 47, 56
Enzymic
Nitrostyrene
1, 2, 3, 5, 6, 8, 9, 11, 14, 16, 17, 18, 19, 20, 21, 22, 23
25, 28, 29, 33, 34, 36, 37, 40, 41, 48, 49, 50, 51, 53, 54, 55
Stereoselective
1, 4, 6, 9, 5, 11, 12, 14, 16, 18, 19, 20, 22, 23, 25, 26, 27, 32, 33,
34, 35, 39, 41, 42, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57
Reductions
Literature Citations for the Synthesis of Amphetamine 1985-2009
Enzymatic (Bio Transformations)
2.
3.
10.
14.
22.
24.
39.
43.
(see Scheme 4)
J. Org. Chem., JOC 73(2008)364
J. Org. Chem., JOC 72(2007)6918
Indian J. Chem. Soc. B., IJCS 44B(2005)1312
J. Chemical Research, JCR 10(2004)681
Tetrahedron Asymmetry, TA 13(2002)1315
Synthetic Comm., SC 31(2001)569
Chem. & Pharm. Bull., CPB 38(1990)3449
US Patent 04950606B1 (1990)
Non-Chiral Organic Synthesis
(see Scheme 3)
4.
12.
13.
15.
26.
27.
31.
32.
37.
38.
40.
41.
42.
45.
48.
57.
52.
54.
56.
22.
Tetrahedron Letter, TL 48(2007)5707
J. Organic Chem., JOC 70(2005)5519
Organic & Biomol. Chem., OBC 3(2005)1049
Organic Letters, OL 6(2004)4619
Organic Letters, OL 2(2000)1935
Tetrahedron, Tetra. 56(2000)5157
Tetrahedron, Tetra. 53(1997)4935
J. Chem. Soc. Perkin I, JCSP1 1(1996)265
J. Labeled Comp. Rad., JLCR 31(1992)891
J. Medicinal Chem., JMC 34(1991)1094
J. Chromatographic Sci., JCS 28(1990)529
Tetrahedron, Tetra 46(1990)7403
Tetrahedron, Tetra 46(1990)7743
Coll. Czech. Chem. Comm., 54(1989)1995
Organic Reactions, Vol 36 (book, 1988)
J. Medicinal Chem., JMC 31(1988)1558
J. Chem. Soc. Chem. Comm. 2(1986)176
Khimya Geter. Soed #12,1648(1985)
Synthetic Comm., SC 15(1985)843
Tetrahedron Asymmetry, TA 13(2002)1315
Stereoselective Synthesis
(see Scheme 2)
1.
5.
6.
8.
9.
11.
14.
16.
17.
18.
19.
20.
21.
22.
23.
25.
28.
33.
34.
36.
37.
41.
44.
49.
51.
53.
54.
55.
J. American Chem. Soc. JACS 131(2007)9882
Tetrahedron, Tetra. 63(2007)9758
Chemistry A European J., JEC 12(2006)4197
Biological Med. Chem. Letter, BMCL 15(2005)3039
FZSGS patent # 1673210 (2005)
J. Medicinal Chem., JMC 48(2005)1229
J. Chem. Research, JCR 10(2004)681
Tetrahedron Asymmetry, TA 15(2004)3111
J. Combinatorial Chem. 5(2003)590
J. Chem. Research, JCR 3(2003)128
Tetrahedron Asymmetry, TA 14(2003)2119
J. Chinese Chem. Soc. 49(2002)505
J. Chem. Soc. Perkin I, JCSP1 16(2002)1869
Tetrahedron Asymmetry, TA 13(2002)1315
US patent #6399828(2002)
J. Organic Chem., JOC 65(2000)5037
Tetrahedron Letters, TL 41(2000)6537
Tetrahedron Letters, TL 36(1995)1223
Tetrahedron Asymmetry, TA 4(1993)1619
Tetrahedron Asymmetry, TA 3(1992)1283
Acta. Chimica Scan. 45(1991)431
Tetrahedron, Tetra 46(1990)7403
Angew Chem. Int. 28(1989)218
J. American Chem. Soc. JACS 109(1987)2224
Organometallics, 5(1986)739
Analytical Chem. 58(1986)1642
Khimja Geter. Soed. 12(1985)1648
J. Organic Chem., JOC 50(1985)3481
# = Reference
Figure 1b.
Amphetamine Review (1989 – 2009)
Time-Line of Synthetic Routes to Amphetamine
1985
1970
1930
1900
Stereoselective syn.
2009
Stereoselective Synthesis of Amphetamine 1985--2009
Chiral
N R
Chiral
JACS 131(29) 9882 (2009)
JOC 50(19) 3481 Tetra Asy 3(10) 1283 (1992) Ph
Organometallics 5, 739 (1986)
(1985)
TA 4(7)1619(1993)
KGS #12,1648 (1985)
OH Chiral
2Q.
2A.
2B.
Ph
OH
51
55
2O.
NH2
44
33
Chiral
Ph
Ph 2M.
Ph
18 20 41
NH2
(S)-1-phenylpropan
-2-amine
11
40
17
54
2G.
40
49
2L.
14
19
5
53
2H.
Ph
O
Tetra. Asy. 14, 2119 (2003)
Organometallics 5, 739 (1986)
J. Chrom. Sci. 28,529 (1990)
KGS #12,1648 (1985) Chiral
2I.
2K.
Ph
2J.
H
J.Comb.C. 5(5) O
590 (2003)
JACS 109(7)
2224 (1987)
OH
I
Chiral
HN BOC
Chem. Eur.J. 12, 4191 2006
FZSGS #1673210 (2005)
Ph
Chiral
OH
NH2
JMC 48(4)
Chiral
1229 (2205)
Anal. Chem. 58(8) 1642(1986)
US # 6,399,828 (2002)
J. Chrom. Sci. 28,529 (1990)
Org. Biomol. Chem. 3,1049(2005)
Ph
B.M.C.L. 15(12) 3039 (2005)
Chiral
J. Chem. Res. 10, 681 (2004)
T.L. 41(34) 6537 (2000)
TA 15(19)3111(2004)
HO
Ph
OH
Ph
Chiral
Chiral
J. Chinese C S 49, 505 (2002)
Tetra. 46(21) 7403 (1990)
23
8
16
NO2
2F. J.C. Res. Syn. 3, 128 (2003)
6 9
19
51
JCS, Perkin T.I, 16
1869 (2002)
2E.
5
Amphetamine
21
2N.
H
Tetra. 63(39) 9758 (2007)
5
25
Chiral
H2N
5
5
21
O
1
Ph
34
28.
Br
JCS, Perkin T.I, 16
1869 (2002)
Chiral
36
COOH
Ph
Chiral
O Tetra. 63(39) 9758 (2007)
Ph
OH
Chiral
ONHPh
Tetra. 63(39) 9758 (2007)
2C.
Ph
OH
OH
O
2D.
54
2P.
Chiral
NH2
JOC 65(16) 5037 (2000)
Tetra. Let. 36(8) 1223 (1995)
Angew chem. Int. 28(2) 218 (1989)
Scheme 2.
Chiral
Tetra. 63(39) 9758 (2007)
Discussion of Stereoselective Syntheses of Amphetamine 1985-2009:
Illustrated in Scheme 2, routes 2A-2Q, repressent the multitude of stereoselective
approaches to amphetamine published between 1985 –2009. Within this illustrated
pinwheel of reaction routes, we have arranged references in reverse chronological order –
clockwise [#‘s]. As a starting point for discussion, take the Schiff base (1-phenylpropan2-imine, route 2A) as a chiral approach to amphetamine [1, 36, 51, 54]. This approach
has been facilitated by the improvements of chiral organometallic ligands with transition
metals in order to effect chiral catalytic reductions [1, 36, 51, 54, route 2A]. Similarly,
armed with chiral organometallic ligands with ruthenium and rhodium, the reduction of
nitrostyrenes [(E)-(2-nitroprop-1-enyl)benzene] have been achieved stereoselectively [18,
20, 41; route 2F].
A completely different approach was taken by Talluri, S. et. al.; [routes 2B-E],
wherein they initiated the route to amphetamine from 1-phenylpropanal [5, route 2E].
Starting from this one-carbon extended aldehyde as opposed to the typical 2phenylacetaldehyde [17, 49; route 2K] or benzaldehyde [47, 80, 89, 92, 95, 110; route
5Z, also implicit in 18, 20, 41, 42, 44, 56, 60, 39, 54, 61, 35, 22, 20, 18, 12, 4.57, 85, 84,
75, 74, 70, 67, 62, 94, 87, 86, 113, 114; route 5A] precursor, these workers preformed a
chiral oxy-alkylation with nitrosobenzene to (R)-3-phenylpropan-1,2-diol [5, route 2C2D]. Tosyl chloride assisted ring closure lead to the epoxide, 2-benzyloxirane [5, route
2B]. Reductive ring opening of the epoxide produced the alcohol, (S)-1-phenylpropan-2ol; [see structure in route 2I]. This was followed by swapping the alcohol moiety for
azide. The final step was catalytic (PtO2) reduction to amphetamine [5]. Although a
lengthy process to amphetamine, its potential importance to forensic chemists lies in the
fact that each intermediate is a potential starting precursor for a chiral synthesis to
amphetamine. Closely allied to the alcohol-azide swap in the previous route are the
variations achieved by Mitusnobu reaction-type exchanges from (R)-1-phenylpropan-2-ol
to (S)-1-phenylpropan-2-NX, wherein inversion of configuration is complete to the amine
compliment [8, 14, 19, 5, 34; route 2I and route 2P].
Chiral starting materials like phenylpropanolamine [11, 23, 29, 40, 53; route 2H]
and phenylalanine [33, 25, 6, 9, 44; route 2O and route 2G] have been easy targets for
precursors to the stereoselective synthesis of amphetamine.
The routes from
phenylalanine are variations on J.W. Wilson‘s original article from 1977 [84; route 6BB]
utilizing alternative reagents for the reduction of the carboxylic acid, alcohol to halide
swap, reduction of the alkyl halide and BOC deprotection.
In the case of phenylpropanolamine as precursor, earlier literature [40,53, route
6P] make use of the chloro-pseudonorephedrine intermediate, as most typically seen in
clandestine laboratories, however more recent literature [11, 23, route 6P] makes use of
acetic anhydride to yield the ester for catalytic reductive removal of the OH moiety to
amphetamine.
Creative chiral scaffolding has been used to introduce stereoselectivity early in
the amphetamine synthesis [17, 49, 21; routes 2M, 2N and 2K]. These unique
approaches start with the achiral, off-listed precursors, benzylbromide [21, route 1N] or
2-phenylacetaldehyde [17, 49, route 2K]. The stereoselectivity is introduced and
controlled by simpler commercially available chiral directors. Interestingly, the Hofmann
rearrangement, which retains stereoselectivity, was utilized at the end of route 2M [21]
with the modern uses of hypervalent iodine [21]. Another older ―classical synthesis‖
improvement was profiled in the Friedel-Crafts alkylation of benzene through the use of
chiral (s)-2-(2,2,2-trifluoroacetamido)propanoyl chloride [55, route 2Q].
Time-Line of Synthetic Routes to Amphetamine
1985
1970
1930
1900
non-chiral syntheses
2009
Non-Chiral Synthesis of Amphetamine 1985--2009
non-Chiral
Tetra. Let. 48(32) 5707 (2007)
non-Chiral
JOC 70(14)5519 (2005)
Org. Biomol. Chem 3(6) 1049 (2005) J. Labelled Comp. Rad. 31(11) 891 (1992)
Tetra. 46(21) 7443 (1990)
Angew Chem. Int. 28(2) 218 (1989)
J M C 31(8) 1558 (1988)
Syn. Comm. 15(9) 843 (1985)
OH
Scheme 3
non-Chiral
JCS, Chem. Comm.
2, 176 (1986)
Br
NO2
3N. H3C
N
O
NH Ph
N
non-Chiral
Org. Rea. 36(book) (1988)
28
Ph
3M.
52
13
48
O
H
NO2
3A.
NH2
SO2
non-Chiral
Org. Let. 6(24) 4619 (2004)
3B.
46.
LiAlH4
Mg
47
Br
42 56
3C.
O
35
non-Chiral
N O
Tetra. Let. 41, 6537 (2000)
12
O
Ts
4
O O
15
OH
N O tBu3D.
O
17
H
27 58
47
3L.
45
Ph
CN
32
22
40
NH3
HoAc
Coll. Czech. Chem Comm.
54(7) 1995 (1989)
non-Chiral
3J.
O
Mg
reduction
O
O
non-Chiral
O
Acta Chem. Scand.
45, 431 (1991)
NH2
n-BuLi
non-Chiral
Tetra. 56, 5157 (2000)
3E.
NH2
Ph Ph
31
37
3K.
26
Amphetamine
37
S
Pd/H2
NH2
non-Chiral
JMC 31(8) 1558 (1988)
Ph
Cp2TiMe2
3F.
O
P
O O
N
3G.
non-Chiral
O.L.. 2(13) 1935 (2000)
MgBr
3H.
3I.
COOH
Acta Chem. Scand.
45, 431 (1991)
non-Chiral
O
T. 53(13)4935 (1997)
non-Chiral
JCS, PTI, 265 (1996)
Tetra. Asy. 13(12) 1325 (2002)
J. Chrom Sci. 28, 529 (1990)
non-Chiral
Scheme 3.
Discussion of Non-Chiral Syntheses of Amphetamine 1985-2009:
Non-chiral syntheses of amphetamine (Scheme 3, routes 3A-N) have also
appeared in the literature; 1985-2009. These variations are graphically illustrated in
Scheme 3 and represent 25 individual citations. As described above with regards to
chiral routes, the Mitsunobu type reaction chemistry has been exploited in 3 different
non-chiral routes, each starting from racemic 1-phenylpropan-2-ol [13, 17, 28; route 3A
and 3D]. Achiral reductions of nitrostryene to amphetamine were the most popular
approaches in this time period [4, 12, 35, 42, 46, 47, 56; route 3B]. These citations are
primarily in the course of building pharmaceutical analogs / research. Organo-metallic
(Grignard or lithium alkylation) reactions were used in a variety of alkylation reactions to
amphetamine [15, 31, 52; route 3C, 3G and 3N]. These variations include Grignard ring
opening of a phosphorylated-aziridine (nucleophilic ring-opening of N-phosphorylated
aziridines) [31; route 3G], reaction with an electron deficient oxime (electrophilic
amination of Grignard reagent) [15; route 3C], and lithium alkylation of an -amino
carbanion equivalent reaction [52; route 3N].
The amination of allylbenzene was affected in a base-catalyzed hydroamination
reaction [27; route 3E]. This reaction is similar in precursor and product, however
different in mechanism to the 1982 phosphoramidomercuration-demercuration of
allylbenzene to amphetamine [58; route 6U]. Amination with a commercially available
-aminodiphenylmethane, which serves as an ammonia equivalent, was used for the
hydroamination of 1-phenyl-1-propyne to amphetamine [26; route 3F].
Several citations occurred in the literature for the reductive amination of P-2-P to
amphetamine [32, 22, 40; route 3H]. The classical malonic ester synthesis was used to
construct 2-methyl-3-phenyl propanoic acid [37, route 3I] which was then converted to
amphetamine via a Curtius rearrangement / hydrolysis [37]. A similar classical reaction,
that of a Claisen / Dieckmann condensation, utilizing a benzylnitrile analog was used to
construct a P-2-P complement [45; route 3K]. This analog was converted to the oxime,
followed by reduction and de-sulfuration with sodium / ethanol to amphetamine [45;
route 3K]. Finally, O-methoxy-oxime of P-2-P was reduced with Red-Al® to yield
amphetamine with marginal success [48; route 3M].
Scheme 4.
Discussion of Enzymatic, Photo-induced and Chemical Manipulation of
Amphetamine Isomers: 1985-2009
Biotransformations have increased in interest, proof of concept and patent
applications from 1985-2009. Illustrated in Scheme 4 are the citations within this topic
regarding amphetamine isomers. Both phenyl-2-propanone [14, 43; route 4A] and the
nitrostyrene, (E)-1-(2-nitroprop-1-enyl)benzene [39,48; route 4C] have been used as
starting points to the enzymatic synthesis to amphetamine.
Alternatively,
biotransformations of racemic amphetamine leading to the exclusion or enhancement of
one isomer (enhanced ee) have been published or patented [3, 10, 22, 24, 29, 43; route
4B]. Conversely, one citation [2; route 4D] describes the photochemically inducedradical mediated racemization of the single amphetamine isomer to the racemic mixture.
Classical methods of chiral resolution based upon chiral organic salts have been reported
in the time frame of 1900-2009, with the use of D-(-)-tartaric acid [30, 47, 38, 71, 81a,
88, 90, 108], benzoyl-d-tartaric acid [38], di-p-toluoyl-d-tartaric acid [38], (S)-2naphthylglycolic acid [66], -amino acids [78] and optical-10-camphorsulfonyl chloride
[37].
Organic Transformation from 1900 -2009:
Classical Organic Transformation in the Early 1900-1950‘s:
Scheme 5.
Classical Organic Transformation in the Early 1900-1950‘s:
The early literature regarding amphetamine synthesis of the 1900‘s was
dominated by classical organic transformations (Scheme 5). These reactions like the
Friedel-Crafts reaction [105,], Ritter Reaction [102], Leuckart reductive amination
reaction [106, 97, 76, 71], nitro-aldol dehydration reaction, also called the Henry
Reaction [116, 96, 94, 89, 87, 86, 85, 82, 70, 67] and rearrangement reactions that came
to be known as the Hofmann rearrangement[105, 116], Curtius rearrangement [118, 110,
80], Schmidt rearrangement [80], Lossen rearrangement [118], Beckmann rearrangement
[111] and the Wolff rearrangement [109], were productive routes to the synthesis of
amphetamine. The non-amine component, -methylbenzylacetic acid, was constructed
with carbon-carbon bond formation via a carbo-anion enolate condensed with a suitable
alkylhalide. These condensations, that were classically referred to as acetoacetic ester
synthesis [105, 118] and malonic ester synthesis [91], later came to be referred to as cases
of the Claisen condensation. In the case of phenylacetonitrile (benzylnitrile) [107], the
acidity of the central methylene hydrogens between the nitrile and aromatic ring, are used
for abstraction and carbo-anion production before alkylhalide reaction.
Organic Transformation in the Early 1950-1985s:
Moving forward in time, from the period dominated by ―classical organic
transformations‖ (1900-1950), we enter a period for amphetamine synthesis that saw
expanded interest in dissolved metal reductions and early chiral constructions. This time
frame (1950-1985) was the focus of our previous review (J. Forensic Sci. Int. 42, (1989)
183-189)) and hightlighted catalytic reductions, dissolving metal reductions and metal
hydride reduction leading to amphetamine. It was during this period that chiral
complement to the Friedel-Crafts reaction was introduced for the synthesis of
amphetamine [55]. Amination of a double bond was improved with the use of diethyl
phosphoramidate [58], as well as acetonitrile mercuration [69] each leading to
amphetamine. Reductive amination with (R)-1-phenylethanamine on the Schiff-base of
phenyl-2-propanone followed by diasteroisomeric separation allowed for a chiral
synthesis of amphetamine [64]. Later (1977, 1978), two chiral syntheses to amphetamine
were published starting from D-phenylalanine [84a, 84b].
Summary:
As best as possible the authors have attempted to summarize the synthetic
transformations published within the period 1900-2009, with emphasis upon 1985-2009.
The complete visual precursor / references to amphetamine pin-wheel is illustrated in
Scheme 6 and is intended for the forensic chemist as a complete map of amphetamine
routes / literature. These individual reactions are broken out, expanded and illustrated
with added nomenclature in the supplemental material. Furthermore, precursor names
via IUPAC (ChemDraw, Cambridge Software) are tabulated for the non-chemist with
cross reference to literature citations.
Time-Line of Synthetic Routes to Amphetamine
1900
Organic Transformations
to Amphetamine
1900 - 2009
non-chiral syntheses
1985
1970
1930
NO2
H
COOH
NH2
6BB.
6A.
113 114
54 57 62 86
107
O
39
6D.
OH
6E.
37
34
5
O
NH2
21 117
Amphetamine
26
O
112 121
OH
45
27
6H.
S
15
6I.
6U.
17
49
52
6T.
88
106 101
23
40
116
H 6S.
53
11
115
116
Br
6R.
6Q.
O
O
6P.
OH
NH2
8
5
65 13
40
64 14
13
6J.
63 19
14
16
91
1
54 20
28
51 29
51
52 96 22 32
66K.
52 38
54 93
9049 43
92 36
6L.
9879 59
91 48
76 40
108
71
101 59
107 99 105
120 73
82
118 6M.
88 6N.
6O.
O
OH
N
OH
OH
HO
6F.
6G.
74
O
OH
103
80 111
69
O
O
NH2
5
100
58
O
O
NH2
1 120
O
6C.
6W.
6V.
Scheme 6.
6B.
4 67 87
95
41 12 70
94
Br 6AA.
84a
18 74
42
75
84b
20
109
44
84
6Z.
5
25
102
O
47 22 85
72
56 35 89
33
H
122
55
60 61 92
110
6Y.
95 92
31
89
80
47
Br
6X.
21
CN
2009
O
R
Ph
CN
Br
OH
OH
O
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(phenamine), J. General Chem. Vol. 11, No. 4, (1941) 339-343.
[109] J.F. Lane, J. Willenz, A. Weissberger, E.S. Wallis, Molecular Rarrangements
Involving Optically Active Radicals. VIII. The Wolff Rearrangement of Optically
Active Diazoketones, J. Am. Chem. Soc. 5 (1940) 267-85.
[110] J.V. Braun, E. Friehmelt, Carboxylc acids with Hydrazoic Acids, Chemicshe
Berichte, 66B (1933) 684-5.
[111] E.S. Wallis, R.D. Dripps, Molecular Rarrangements Involving Optically Active
Radicals. III. The Lossen Rearrangement of Optically Active Hydroxamic Acids, J.
Am. Chem. Soc. 55 (1933) 1701-1705.
[112] A.A. Gordon, dl-Beta-phenylisopropylamines, J. Am. Chem. Soc. 54 (1932) 2714.
[113] A.A. Gordon, Salts of 1-phenyl-2-aminopropane, assigned to Monterey Park,
CA., patent US 1879003 (1932).
[114] W. Leithe, Die Konfiguration der Ephedrin-Basen, Chemicshe Berichte, 66B
(1932) 660-666.
[115] W.H. Hartung, J.C. Munch, Amino Alcohols. VI. The Preparation and
Pharmacodynamic Activity of four Isomeric Phenylpropylamines, J. Am. Chem. Soc. 53
(1931) 1875-79.
[116] E.S. Wallis, S.C. Nagel, Molecular Rarrangements Involving Optically Active
Radicals. II. The Hofmann rearrangement of Optically Active Acid Amides, J. Am.
Chem. Soc. 55 (1933) 2787-91.
[117] D.H. Hey, V. dl--Pheylisopropylamine and Related Compounds, J. Chem. Soc.
18 (1930).
[118] W.H. Hartung, Catalytic Reduction of Nitriles and Oximes, J. Am. Chem. Soc. 50
(1928) 3370-4.
Supplemental Material:
JACS 131, 9882 (2009)
chir al
MeMgI
N
NH
Ir-(S,S)-fbinaphane
NH2
H2
(S)-1-phenylpropan-2-amine
2-phenylacetonitrile
1-phenylpropan-2-imine
Ref. 1.
JOC 73(2) 364 (2008)
chir al
Photochemical --Racemization
NH2
NH2
HSCH2CO2Me
Benzene
1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
Ref. 2.
chir al
JOC 72(18) 6918 (2007)
NH2
Biotrasformation, Enzymic, Stereoselective
Lauric acid
Lipase
1-phenylpropan-2-amine
NH2
(S)-1-phenylpropan-2-amine
+ amide of lauric acid
Ref. 3.
Tet r a. Let. 48(32) 5707 (2007)
non-chir al
NH2
NO2
H 2N
(E)-(2-nitroprop-1-enyl)benzene
Ph
SmI2
1-phenylpropan-2-amine
Ref. 4.
chir al
Tet r a. 63, 9758 (2007)
O
(R)-3-phenyl-2-(phenylaminooxy)propan-1-ol
H nitrosobenzene
l-proline
NaBH 4
3-phenylpropanal
O
1, TsCl
OH
NHPh
(R)-3-phenylpropane-1,2-diol
TEA
Ref. 5.
2. NaH
1. NaN3
LiAlH4
O
(S)-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-ol
chir al
H
N
O
H
N
SmI2
O
I
t er t-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
NH 2
2. Pd/C H2
OH
2-benzyloxirane
OH
Pd/C
OH
O
Chem. Eur opean J. 12(15)4191-7(2006)
NH2
TFA
O
(S)-1-phenylpropan-2-amine
ter t -butyl 1-phenylpropan-2ylcarbamate
non-chir al
Ref. 6.
Centr al Eur. J. Cehm 6( 4) 526-34 (2008)
NO2
NaBH4
NH2
BF3 - Et2O
THF
(E)-(2-nitroprop-1-enyl)benzene
1-phenylpropan-2-amine
Ref. 7.
chir al
Phth Anh.
OH
NH2 -NH 2
N
Ph3 P
DEAD, THF
O
O
amphetamine
(S)-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-ol
(S)-2-(1-phenyl
propan-2-yl)isoindoline
-1,3-dione
Ref. 8.
chir al
H
N
NH 2
MeOH
Bioor ganic & Med. Chem. Lett er s,
15( 12) 3039-43 ( 2005)
Faming Zhuanli Shenqing Gongk ai Shuomingshu # 1673210 (2005)
H
N
O
TFA
SmI2
O
O
I
t er t-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
NH2
O
ter t -butyl 1-phenylpropan-2ylcarbamate
(S)-1-phenylpropan-2-amine
Ref. 9
chir al
indian J. Chem.Sec B 44B(6) 1312 ( 2005)
Biotrasformation, Enzymic, Stereoselective
NH2
Lauric acid
Lipase
NH2
1-phenylpropan-2-amine
chir al
(S)-1-phenylpropan-2-amine
+ amide of lauric acid
Ref. 10.
Ac
OH
NH 2
O
Ac 2O
H
N
norephedrine
2-acetamido
-1-phenylpropyl acetate
(1R,2S)-2-amino-1phenylpropan-1-ol
H 2 / aS O 4
B
Pd-
H
N
Ac
Ref. 11.
J . Med. Chem.
48( 4) 1229-36 ( 2005)
NH 2
H2 SO4
Ac
amphetamine
(S)-1-phenylpropan-2-amine
N-(1-phenylpropan-2-yl)acetamide
non-chir al
J OC 70( 14) 5519 (2005)
NO2
NH2
LiAlH4
1-phenylpropan-2-amine
(E )-(2-nitroprop-1-enyl)benzene
Ref. 12.
non-chir al
NH2
SO 2
NO2
OH
1-phenyl
propan-2-ol
Or g. and Biomolecular Chem. 3( 6) 1049 ( 2005)
HN
O
PhSH, K2CO3
S
DCC
O
O2 N
2-nitro-N-(1-phenylpropan-2-yl)
benzenesulfonamide
NH2
50o C
amphetamine
1-phenylpropan-2-amine
Ref. 13.
J. Chem. Research 10, 681 (2004)
chir al
(S)-(2-azidopropyl)benzene
Pd/C
baker's yeast
O
1-phenylpropan-2-one
O
S
O
O
N
Or g. Letters, 6( 24) 4619-21 ( 2004)
MgBr
HCl
N
O
O
O
OH
O
SOCl2
O
S
NH 2
O
1-phenyl-N (4,4,5,5-tetramethyl1,3-dioxolan-2-ylidene)
propan-2-amine
(1-phenylpropan-2-yl)
magnesium bromide
chir al
(S)-1-phenylpropan-2-amine
Ref. 14.
(S)-1-phenylpropan-2-ol
non-chiral
H2
N3
OH
sucrose
NH2
amphetamine
Ref. 15.
1-phenylpropan-2-amine
N3
NaN3
O
OH
OH
(1R,2S)-1-azido-1-phenylpropan-2-ol
(1S,2S)-1-phenyl
propane-1,2-diol
Tet r ahedron Asy mmet ry
15(19),3111-6 (2004)
H
N
Ph 3P
Pd-C
(S)-1-phenylpropan-2-amine
Ref. 16.
HCO2 NH 4
NH2
2-methyl-3-phenylaziridine
amphetamine
J. Combinator ial Chem.
5(5) 590-6 (2003)
chir al
O
S
O
H
NH2
CuSO4
(R)-2-methyl
propane-2-sulfinamide
MeMgBr
N
(R,E)-2-methyl
-N-(2-phenylethylidene)
propane-2-sulfinamide
2-phenylacetaldehyde
O
S
O
S
Ref. 17.
HCl, MeOH
N
H
(R)-2-methyl-N-((S)-1-phenyl
propan-2-yl)propane-2-sulfinamide
NH 2
amphetamine
(S)-1-phenylpropan-2-amine
chir al
J. Chem. Resear ch ( S), 128 (2003)
NO2
NH2
Ruthenium BINAP
(E)-(2-nitroprop-1-enyl)benzene
Ref. 18.
Tet r a. Asy . 14, 2119 (2003)
chir al
(S)-1-phenylpropan-2-amine
H2 N
O
NH 2
N
1-phenylpropan-2-one
(R)-1-phenylethanamine
Ref. 19.
(S,E)-1-phenyl-N(1-phenylpropan-2-ylidene)
ethanamine
chir al
J. Chinese Chemical Societ y, 49, 505 ( 2002)
NO2
NH2
Ru2Cl2(PPh3)3
toluene
H2
(E)-(2-nitroprop-1-enyl)benzene
Ref. 20.
(S)-1-phenylpropan-2-amine
JCS Per k in T .I 16, 1869(2002)
chir al
O
Br
1-(bromomethyl)
benzene
O
O
O
N
LDA, THF
N
(R)-3,3,5-trimethyl
-1-propionylpyrrolidin-2-one
(5R)-3,3,5-trimethyl1-(2-methyl-3-phenyl
propanoyl)pyrrolidin-2-one
Ref. 21.
O
NH 3, MeOH
NH2
NH 2
PhI(OOCCF3) 2
(S)-2-methyl-3-phenylpropanamide
amphetamine
(S)-1-phenylpropan-2-amine
chir al
Tetr a. Asy. 13( 20) 2277 ( 2002)
NH2
Enzymic, Resolution
1-phenylpropan-2-amine
Ref. 22.
NH2
CAL-B cat.
(S)-1-phenylpropan-2-amine
non-chiral
NH 2
HCOO NH 4
O
Pd, MeOH
Ref. 22.
amphetamine
T etr ahedr on Asymmetr y, 13( 12)
13115-1320 ( 2002)
1-phenylpropan-2-one
chir al
1-phenylpropan-2-amine
US pat . # 6399828 2002)
OH
NH 2
NH 2
HI, P4
HCl
(1R,2S)-2-amino-1-phenylpropan-1-ol
Ref. 23.
BaSo4
Ac 2O
HoAc
H2
OAc
Pd
NH 2
(1R,2S)-2-amino-1-phenylpropyl acetate
chir al
Syn. Comm. 31(4) 569 (2001)
NH 2
Enzymic, Resolution
NH 2
Candida antarcitica Lipase
1-phenylpropan-2-amine
Ref. 24.
(S)-1-phenylpropan-2-amine
O
chir al
NH 2
LiBH4 /TMSCl
COOH
(S)-2-amino-3phenylpropanoic acid
BOC) 2O
NH 2
NH
OH
(S)-t er t-butyl 1-hydroxy3-phenylpropan-2-ylcarbamate
OH
(S)-2-amino-3-phenylpropan-1-ol
Ref. 25.
O
O
O
NH
(Ph) 3P / I
I
( S)-tert -butyl 3-iodo-1phenylpropan-2-ylcarbamate
J . Or gainic Chemistr y
65(16) 5037-42 ( 2000)
O
NH
N-Selectride
O
NH 2
TFA
( S)-tert -butyl 1-phenylpropan
amphetamine
-2-ylcarbamate
S)-1-phenylpropan-2-amine
non-chir al
NH 2
Cp2 TiMe 2
Cp2 TiMe2
NH2
Ph H 2 , Pd/C
(E)-diphenyl-N1-phenylpropan-2-amine
(1-phenylpropan-2- Ph
ylidene)methanamine
amphentamine
N
diphenyl
methanamine
1-phenyl1-propyne
Ref. 26.
Or ganic Let ter s, 2( 13) 1935-1937 ( 2000)
T et ra. 56, 5157 ( 2000)
Ref. 27.
non-chir al
H 2N
Ph
Pd/C H2
NH
cat. n-Bu Li
1-phenylpropan-2-amine
allylbenzene
N-benzyl-1-phenylpropan-2-amine
T et rahedron Letters, 41( 34)
6537-40 ( 2000)
non-chir al
tBuCO) 2O
OH
1-phenyl
propan-2-ol
NH2
TFA
Ph 3P
NH
DEAD, THF
O
ter t-butyl
1-phenylpropan
-2-ylcarbamate
O
DCM
NH2
amphetamine
Ref. 28.
1-phenylpropan-2-amine
chir al
JP 03191797 (1991)
O
NH 2
Enzymic, Resolution
BuNH 2
C: 9031-66-1
phenylpropan-1-one
Ref. 29.
non-chir al
O
(S)-1-phenylpropan-2-amine
Zhongshan Dazue Xuebao 35( 5) 73-76 (1996)
HOOC
* OH
NH 2
NH 2 HO *
COOH
Leuckart Reaction
ammonium formate
d-Tartaric
acid
1-phenylpropan-2-one
Ref. 31.
non-chir al
O
MgBr
O
P
N
T et rahedron, 53(13) 4935-4946, 1997
O
O
CuI
phenylmagnesium diethyl 2bromide
methylaziridin1-ylphosphonate
HCl
diethyl
1-phenylpropan2-ylphosphoramidate
non-chir al
1-phenylpropan2-amine
NH2
amphetamine
J.Chem.Soc., P er kin T rans I , 265 ( 1996)
O
1-phenylpropan-2-one
P-2-P
O
O
P
NH
THF
Ref. 30.
Mg
MeOH
NH3
HoAc
NH 2
Ref. 32.
1-phenylpropan-2-amine
chir al
Tet r a. Lett . 36( 8) 1223 (1995)
O
BOC
BOC
HN
O
BH 3
O
OH
THF
(R)-2-(t er t-butoxycarbonylamino)
-3-phenylpropanoic acid
NH
TEA
OH
CH 3SO2 Cl
CH 3CH2 SH
NH
O Ms
Ref. 33.
NaH
BOC
BOC
NH
NH
EtOH
O S
NH 2
TFA
Ra-Ni
(S)-1-phenylpropan-2-amine
chiral
OH
OH
OH
Phth Anh.
N
NH 2
(1S,2S)-2-amino1-phenylpropane-1,3-diol
O
Ref. 34.
H 2 / Pd-C
I
OH
O
Ph) 3P / I
N
2-((1S,2S)1,3-dihydroxy1-phenylpropan
-2-yl)isoindoline-1,3-dione
I
O
O
2-((1S,2S)1,3-diiodo-1-phenyl
propan-2-yl)isoindoline1,3-dione
NH2 -NH2
N
O
NH 2
O
amphetamine
T etr ahedr on Asymmetr y
4( 7) 1619-24, 1993
(S)-1-phenylpropan-2-amine
(S)-2-(1-phenyl
propan-2-yl)isoindoline-1,3-dione
non-chir al
J. Labelled Comp. and Rad. 31(11) 891 ( 1992)
NO2
(E )-(2-nitroprop-1-enyl)benzene
NH2
LiAlH4
Ref. 35.
1-phenylpropan-2-amine
Ref. 36.
chir al
T etr ahedr on Asymmetr y,3( 10)
1283-8 ( 1992)
E&Z
NH 2
H 4Ru(arene)
N
BINAP
OH
(S)-1-phenylpropan-2-amine
amphetamine
(E)-1-phenylpropan-2-one oxime
non-chir al
O
O
O
Acta. Chemica Scandinavica 45, 431 ( 1991)
O
O
Ref. 37.
NaH
O
O
CH3-I
O
DMSO
methyl
2-benzyl-2-methyl
-3-oxobutanoate
dimethyl 2-benzylmalonate
O
OH
1. NaOH
2. AcOH
chir al
1.
-N
2-methyl-3-phenyl
propanoic acid
NH2
Ph
O P Ph
TEA/heat
N
N+
NH2
amphetamine
1-phenylpropan-2-amine
2. HCl / heat
resolution
NH2
(+)-10-camphorsulonyl chloride
amphetamine
amphetamine
(S)-1-phenylpropan-2-amine
1-phenylpropan-2-amine
Tetr ahedr on Lett . Vol. 32, No. 49 ( 1991) 7325-8.
HOOC
chir al
NH 2
*
* COOH
OR
RO
R=H
resolution
Benzoyl
p-toluoyl
amphetamine
amphetamine
(S)-1-phenylpropan-2-amine
Ref. 38.
1-phenylpropan-2-amine
non-chir al
NH 2
Chem. Pharm. Bull. 38(12) 3449 (1990)
NO2
Biotransf ormation
cat. Peptostr eptococcus Anaer obius
(E)-(2-nitroprop-1-enyl)benzene
Ref. 39.
NH2
1-phenylpropan-2-amine
chir al
Ref. 40.
OH
NH2
J. Chr om. Sci. 28, 529 ( 1990)
Cl
SOCl2
NH2
NH2
Pd H2
(1R,2S)-2-amino-1-phenylpropan-1-ol
(S)-1-phenylpropan-2-amine
(1S,2S)-1-chloro-1-phenylpropan-2-amine
non-chir al
J. Chr om. Sci. 28, 529 ( 1990)
Ref. 40.
OH
Ac2)O
NaOAc
O
2-phenylacetic acid
O
1-phenylpropan-2-one
Ref. 41.
chir al
NO2
BH3-THF
1-phenylpropan-2-amine
Tet r a. 46( 21) 7403 (1990)
NH 2
NO2 Ru Cl [(-)-DIOP]
2 2
3
H2
(E)-(2-nitroprop-1-enyl)benzene
(2-nitropropyl)benzene
non-chiral
Ref. 42.
NO2
NH2
Leuchart Red
amphetamine
(S)-1-phenylpropan-2-amine
Tet r a. 46( 21) 7743 ( 1990)
NH 2
BH3-THF
cat. NaBH4
amphetamine
(E)-(2-nitroprop-1-enyl)benzene
chir al
U.S. pat . # 4950606 (1990)
Enzymic, Resolution
NH2
Ref. 43.
1-phenylpropan-2-amine
non-chiral
NH2
amino-acid transminase f rom
Bacilllus Megat er ium
(S)-1-phenylpropan-2-amine
Biotransf ormation
O
1-phenylpropan-2-one
amino-acid transminase f rom
Bacilllus Megater ium
Ref. 43.
NH 2
amphetamine
1-phenylpropan-2-amine
Angew Chem. Int. Ed. Engl. 28(2) 218-220 (1989)
non-chiral
O
O
O
NH
(CH3)3SiCl
NH
COOH
2-(benzyloxycarbonyl)
-3-phenylpropanoic acid
LiBH4 /THF
benzyl 1-phenylpropan-2-ylcarbamate
Ref. 44.
NO2
NH2
(CH3)3SiCl
LiBH4 /THF
amphetamine
1-phenylpropan-2-amine
(E)-(2-nitroprop-1-enyl)benzene
Coll. Czech. Chem. Comm. 54( 7) 1995 ( 1989)
non-chir al
3-oxo-2-(2-(phenylthio)phenyl)butanenitrile
Ph
S
CN
H3PO4
NaOEt
Ph
S
O
2-(2-(phenylthio)phenyl)acetonitrile
Ref. 45.
S
NH2OH
Ph
Na EtOH
N
OH
N
S
1-(2-(phenylthio)phenyl)propan-2-one
S
HCl
NH 2
1-(2-(phenylthio)phenyl)propan-2-amine
Ref. 46.
non-chir al
Ph
O
EtOH
CN
Ph
O
O
Red - Al, THF
(E )-1-phenylpropan-2-one O-methyl oxime
NO 2
Red-Al THF
(E)-(2-nitroprop-1-enyl)benzene
NH2
Or g. React ions 36, book ( 1988)
NH 2
1-phenylpropan-2-amine
NH 2
Ref. 47.
non-chir al
O
J.Med.Chem. 31( 8) 1558 (1988)
NO2
NO 2
H
1-phenylpropan-2-amine
(E)-(2-nitroprop-1-enyl)benzene
benzaldehyde
NH2
LiAlH4
chir al
JP 63219396 (1988)
NO2
Ref. 48.
Biotransf ormation /
NH2
Enzymic, Resolution
1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
chir al
N N
H 2N N
O
H
(R,E )-2-methyl
-N-(2-phenylethylidene)
pyrrolidin-1-amine
(R)-2-methyl
2-phenylacetaldehyde pyrrolidin-1-amine
Ref. 49.
JACS 109(7) 2224-5 (1987)
H
N N
CH3 Li / CeCl3
NH 2
H 2 / Ra-Ni
375 psi / 60 o
amphetamine
(R)-2-methyl-N -((S)1-phenylpropan-2-yl)
pyrrolidin-1-amine
(s)-1-phenylpropan-2-amine
chir al
O
R or S
phenyl-2-propanone
NH 2
low pressure
*
Hydrogenation
Raney Ni / H2
*
HN
*
[R,R]+ or [S,S]-
 -methylbenzylamine
U S 4000,197 ( 1976)
Ref. 50.
[S,S]-(-)
10% Pd-C
*
HN
*
NH 2
amphetamine
50 psi H2
(S)-1-phenylpropan-2-amine
chir al
Or ganometallics, 5, 739-46 (1986)
Ref. 51.
N
O
OH
NH2
Rh(cod)Cl2
(E)-1-phenylpropan-2-one oxime
1-phenylpropan-2-one
Ref. 52.
non-chir al
H-SiH(Ph)2
H
H
N
O
LDA
NH
CH3I
J. Chem. Soc., Chem. Comm. 2, 176, ( 1986)
CH 3
1. TFA
Aphetamine
N
NH 2. Pd /C H2
Ph
Ph
Ph
Ph
2-phenylacetaldehyde
(E)-1-(2,2-dimethyl-1,1-diphenylpropyl) (E )-1-(2,2-dimethyl-1,1-diphenylpropyl)
-2-(1-phenylpropan-2-ylidene)hydrazine
-2-(2-phenylethylidene)hydrazine
Ref. 52.
non-chir al
H
H
N
O
LDA
NH
Ph-CH2-Br
Ph
Ph
acetaldehyde
non-chir al
J. Chem. Soc., Chem. Comm. 2, 176, ( 1986)
CH 3
1. TFA
Aphetamine
N
2. Pd /C H2
NH
Ph
Ph
OH
US 2009292143 (2009)
Cl
NH 2
NH 2
NH 2
Pd
H2
Ref. 53.
(1S,2S)-2-amino-1-phenylpropan-1-ol
(S)-1-phenylpropan-2-amine
Khimiy a Get er ot siklicheskikh Soedinenii 12, 1648 (1985)
chir al
O
1-phenylpropan-2-one
N
OH
Na MeOH
(E)-1-phenylpropan-2-one oxime
NH2
Ref. 54.
chiral
O
Cl
benzene
O
H
N
CF3
O
(S)-2-(2,2,2-trifluoroacetamido)
propanoyl chloride
J .Org.Chem. 50(19)
3481-4 (1985)
Ref. 55
OH
H 2 / Pd-C
PBr 3
CF3
H
N
CF3
O
O
(S)-N-(1-bromo-1-phenylpropan
-2-yl)-2,2,2-trif luoroacetamide
(S)-2,2,2-trifluoro
-N-(1-hydroxy-1-phenyl
propan-2-yl)acetamide
H
N
H 2 / Pd-C
CF3
O
(S)-2,2,2-trifluoro
-N -(1-oxo-1-phenyl
propan-2-yl)acetamide
Br
H
N
H
N
AlCl3
CF3
K2 CO 3, MeOH
NH2
O
amphetamine
(S)-1-phenylpropan-2-amine
(S)-2,2,2-trifluoro-N-(1-phenyl
propan-2-yl)acetamide
non-chiral
Ref. 56.
NO2
Syn. Comm. 15(9) 843 (1985)
NaBH4
BH3 - THF
NH2
(E)-(2-nitroprop-1-enyl)benzene
Sy n. Comm. 14( 12)1099(1984)
non-chir al
NaBH 4
NO2
NH 2
BH 3 / THF
Ref. 57.
non-chir al
amphetamine
Sy nt hesis ( 4) 270-3 (1982)
O
H 2N P
O
O
1. Hg(NO 3) 2 /
1,1-diCl-ethane
2. 10% NaOH / NaBH 4
(E )-prop-1-enylbenzene
diethyl phosphoramidate
H
N
O
P
O
O
NH 2
HCl /benzene
Ref. 58.
amphetamine
chir al
Sy nt hesis ( 4) 270-3 (1982)
N
O
P
Cl
Ph
Ph
OH
(E)-1-phenylpropan
-2-one oxime
H
N
LAH
(-) Quinine / THF
N
CH2Cl2, DEA
HCl / ethanol
O
O P
Ph
Ph
Ref. 59.
O
O P
Ph
Ph
NH 2
amphetamine
J. Labelled compounds and radiophar maceuticals 18(6) 909 ( 1981)
non-chir al
NH2
O
NH3 (Sealed)
1-phenylpropan-2-one
Al, HgCl2 , NH4OH, 100o C, 15min
non-chir al
Ref.60.
Helvet ica chimica Acta 61( 2) 558 ( 1978)
NO
NO2 LiAlH4
NO
(E)-prop-1-enylbenzene
NH2
Ref.61.
Ref. 62.
chir al
T etr ahedr on 32( 11) 1267-76 (1976)
E&Z
NH 2
LiAlH 4
N
OH
(E)-1-phenylpropan-2-one oxime
non-chir al
1-phenylpropan-2-amine
amphetamine
J. Chem. Education 51, 671(1974)
NH 2
O
Al, HgCl2, NH4OH, 100 oC, 15min
1-phenylpropan-2-one
Ref.63.
non-chir al
JMC 16(5) 480-3 ( 1973)
H
N
(R)-1-phenylethanamine
O
H2 N
Raney-Ni
H2
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.
H
N
separation
NH 2
Pd-C / H2
MeOH
(S)-1-phenylpropan-2-amine
of Diastereoisomers
non-chir al
JACS 93, 2897 ( 1971)
NH 2
O
NaCNBH3
NH 4OH, MeOH
1-phenylpropan-2-one
OH
chiral resolution
NH2
Ref.65.
EP 915080 (1999)
OH
NH2
O
(s)-2-naphthylglycolic acid
racemic-1-phenylpropan-2-amine
(S)-1-phenylpropan-2-amine
non-chiral
Ref. 67.
NO2
(E)-(2-nitroprop-1-enyl)benzene
Ref. 66.
J.Med.Chem. 13, 26( 1970)
LiAlH4 / THF
NH2
JACS 91, 5647 ( 1969)
non-chir al
Hg(NO 3) 2
CH3CN
N
NO3
H
N
NaBH4
amphetamine
1-phenylpropan-2-amine
NaOH
N-(1-phenylpropan-2-yl)acetamide
non-chiral
Ref. 70.
NO2
H
N
HCl
O
NO 2
Hg
Ref. 69.
allylbenzene
O
US Pat. 3,458,576 (1969)
Pd-C / H2
NH2
Pt / H2
Raney-Ni / H2
(E)-(2-nitroprop-1-enyl)benzene
non-chir al
Coll. Czech. Chem. Comm. 33( 11) 3551-7(1968)
O
NH4 HCOO Ammonium Formate
HCl
1-phenylpropan-2-one
NH 2
Ref.71.
chir al
Coll. Czech. Chem. Comm. 33( 11) 3551-7(1968)
NH 2
NH 2
(+)-tartaric acid
EtOH
Ref.71.
1-phenylpropan-2-amine
non-chir al
Ref. 72.
AlCl3
benzene
HN
2-methylaziridine
(S)-1-phenylpropan-2-amine
J. Het er ocy clic Chem._5( 3)339( 1968)
NH 2
1-phenylpropan-2-amine
Ref. 73.
non-chir al
N
O
T etr a. 24(16) 5677 ( 1968)
NH 2
LiAlH4
R
THF
1-phenylpropan-2-amine
R = H or R = Ts
Chem Phar m Bull 13( 2)118( 1965)
non-chir al
Cl
Cl
nitrosyl chloride
NOCl
NO2
NO2
Pt2O
H2
NO2Cl
prop-1-ynylbenzene hypochlorous nitrous anhydride
Ref.74.
non-chir al
US Pat. 3,187,047 ( 1965)
O
NH2
Raney-Ni / H2
NH4 oAc
1-phenylpropan-2-one
Ref.75.
non-chir al
T etr a. 19, 1789 (1963)
LEUCKART-WALLACH Mech
O
NH 2
Formic Acid
NH4
1-phenylpropan-2-one
non-chir al
Ref.76.
OH
DE_1958-968545(1958)
Cl
NH 2
NH 2
Pd
NH 2
H2
(1S,2S)-2-amino-1-phenylpropan-1-ol
Ref. 77.
(S)-1-phenylpropan-2-amine
chir al
NH 2
R
H2 N
*
COOH
resolution
 -amino acid
amphetamine
1-phenylpropan-2-amine
US 3028430 (1962)
NH 2
Ref. 78.
amphetamine
(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
Ref. 80.
O
O
OH CO2Cl2
(S)-2-methyl-3phenylpropanoic acid
chir al
Curtius rearrangement
O
JOC_22( 1)33(1957)
NH 2
N 3 HCl
Cl
NaN 3
(S)-2-methyl-3(S)-2-methyl-3phenylpropanoyl chloride phenylpropanoyl azide
Schmidt rearrangement
O
(S)-2-methyl-3phenylpropanoic acid
amphetamine
(S)-1-phenylpropan-2-amine
Ref. 80.
HOOC
chir al
NH 2
NaN 3
H 2SO4
OH
Zhur nal Obshchei Khimii 28 ( 1958) 3323-8
NH 2
resolution
d-Tartaric
COOH acid
amphetamine
Ref. 81a
(S)-1-phenylpropan-2-amine
*
NH 2
HO
amphetamine
1-phenylpropan-2-amine
*
amphetamine
(S)-1-phenylpropan-2-amine
OH
US 2,833,823 (1958)
chir al
NH 2
resolution
NH 2
H 3 PO 4
inriched in one isomer
amphetamine
1-phenylpropan-2-amine
Ref. 81b
amphetamine
(S)-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
HN
O
N
PhenylHydrazine
N
H
NH 2
PtO2
H2
Ref.83.
(E)-1-phenyl-2-(1-phenyl
propan-2-ylidene)hydrazine
1-phenylpropan-2-one
chir al
J. Labelled Comp. and Radio. 3( 1) 3-9 ( 1977)
NH 2
*
*
LiAlD4
NH 2
*
p-MeTOSCl
D2 C
D2 C
COOH
O
OH
D-Phenylalanine
Ref. 84.
O O
HN S
CH 3
p-TOS
LiAlD4
NH 2
*
Naphthalene radical anion
CD 3
amphetamine
1-phenylpropan-2-amine
CH 3
non-chiral
O O
HN S
JACS_74( 7)1837(1952)
Ref. 85.
NO 2
NH 2
LiAlH 4
acid
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
P-2-P (Nef reaction)
US Patent 02647930B1( 1953)
Ref. 86.
NO 2
Organic Acids
Raney-Ni / H 2
(E)-(2-nitroprop-1-enyl)benzene
NH 2
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)
Ref. 88.
Distillation from
optically active acids..
NH2
NH2
Resolution
1-phenylpropan-2-amine
non-chiral
(S)-1-phenylpropan-2-amine
Helv. Chim. Act a. 33, 912 ( 1950)
Ref. 89.
NO 2
NH 2
LiAlH4 / ether
(E)-(2-nitroprop-1-enyl)benzene
O
chiral resolution
NH 2
Or g. Syn. Coll. 2, 506 (1943)
OH
HO
OH
racemic-1-phenylpropan-2-amine
NH 2
/ water
O
l-malic acid
(S)-1-phenylpropan-2-amine
Ref. 90.
(1,3-diethoxy
O
-1,3-dioxopropan-2-yl) O
O
magnesium ethanolate Mg
non-chiral
O
O
SOCl2
OH
O
O
O
O
Cl
2-phenylacetic acid
Ref. 91.
O
O
O
2-phenylacetyl chloride
diethyl 2-(2-phenylacetyl)malonate
J_Am_Phar m_Assoc_687-688( 1950)
O
1-phenylpropan-2-one
N
OH
(E )-1-phenylpropan-2-one oxime
NH2
1-phenylpropan-2-amine
non-chir al
Bull. Soc. Chem. Fr ance 1045 ( 1950)
O
NH3
NH2
Raney-Ni / H2
1-phenylpropan-2-one
Ref.92.
non-chir al
Chemische Ber icht e 124(10) 2303-6 ( 1991)
NO 2
NH 2
N
Cathode Red. at Hg or C electrode
OH
(E)-1-phenylpropan-2-one oxime
non-chiral
JOC 15, 8 (1950)
Ref. 94.
NO 2
Ref. 93.
Raney-Ni / H 2
NH 2
(E)-(2-nitroprop-1-enyl)benzene
non-chir al
GB 702985( 1949)
O
NH3
Raney-Ni / H2
NH2
or Pt or Pd
1-phenylpropan-2-one
non-chiral
Ref.95.
US Pat. 2,636,901(1949)
Ref. 96.
NO 2
Raney-Ni / H 2
NH 2
(E)-(2-nitroprop-1-enyl)benzene
non-chir al
JACS 70, 1187 (1948)
LEUCKART-WALLACH Mech
O
1-phenylpropan-2-one
NH4
Formic Acid
NH2
Ref.97.
non-chir al
JACS 70, 1315-6(1948)
O
NH2
PtO2 / H 2
NH3
1-phenylpropan-2-one
Ref.98.
non-chir al
Y ak ugak u Zasshi 74, 413-16 ( 1954).
N
NH 2
Raney Ni / H2
OH
Ref.99.
(E)-1-phenylpropan-2-one oxime
non-chir al
JACS 70, 2811-12 (1948)
O
NH3
NH2
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
OH
Ritter Reaction
SO 3H
O
HCN
1-phenylpropan
-2-yl hydrogen sulfate
(E )-prop-1-enylbenzene
JACS 70, 4048 (1948)
SO 3H
N
HCl
NH2
Ref.102.
non-chiral
Justus_Liebigs_Annalen_der_Chemie_215-221( 1948)
Ref. 103.
NO 2
NH 2
Pd / H2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Friedel-Crafts reactions
J. Am. Chem. Soc. 68 (1946) 1009-11.
FeCl3
Cl
Cl
or
Fuming Sulf uric
Cl
NH 2
NH4 OH
Allyl Chloride
non-chiral
O
Ref. 104.
U S P atent 2,413,493B1( 1946)
Acetoacetic Ester Synthesis Route
O
Na
O
CH3-I
O
O
O
Na
Ph-CH2-Cl
O
ethyl 3-oxobutanoate
O
O
Ref. 105.
NaOH
O
OH
SOCl2
NH 3
O
NH 2
NaOCl
NH 2
Hoffman
1-phenylpropan-2-amine
2-methyl-3-phenylpropanoic acid
non-chir al
LEUCKART-Study
O
1-phenylpropan-2-one
NH4
Formic Acid
JOC 9, 529 ( 1944)
NH 2
Ref.106.
Acetylbenzylcyanide Reaction Route
non-chiral
N
J.Applied Chem. ( USSR) 14(3), 410 (1941)
O
O ethyl acetate
N
O
O
H3 PO4
NaOEt
2-phenylacetonitrile
1-phenylpropan-2-one
3-oxo-2-phenylbutanenitrile
Ref. 107.
H
N
O
NH- 4+
O
NH 2
HCl
ammonium formate
N-(1-phenylpropan-2-yl)f ormamide
O
O
non-chir al
O
1-phenylpropan-2-amine
O
O
Acetic Anhydride
O
OH
O
O
O
sodium acetate
O
2-phenylacetic acid
1-phenylpropan-2-one
J.Gen.Chem.(USSR) 11( 4), 339 (1941)
LEUCKART
H
N
H2 N
O
Formamide
O
NH2
Hydrolysis H+
Ref.108.
N -(1-phenylpropan-2-yl)formamide
chir al
Resolution
NH2
OH
NH2
OH
O
1-phenylpropan-2-amine
Ref.108.
O
HO
OH
d-tartaric acid
(S)-1-phenylpropan-2-amine
J . Am. Chem. Soc. 5 (1940) 267-85
non-chir al
Wolf f Rearr.
O
OH SOCl2
2-phenylacetic acid
O
Cl
Diazomethane
O
O AgO
NH 3
HC
N
N
NH 2
Ref.109.
Chemischen Ber icht e 66B, 684 ( 1933)
non-chiral
acid
HN3
O
O
O
OH
N3
-methylbenzylacetic acid
Curtius Rearr.
NH2
Ref.110.
J . Am. Chem. Soc. 55 ( 1933) 1701-5.
non-chir al
Lossen Rearr.
O
O
Hydroxyl amineHN
acid chloride X
esters
anhydride
N
OH
C
NH 2
O Hydrolysis
Ref.111.
J.Am. Chem. Soc. 54, 271-4 (1933)
non-chir al
O
NO2
NO 2
H
Hg . Cathode
electrolic Red.
(E)-(2-nitroprop-1-enyl)benzene
benzaldehyde
non-chir al
NH2
1-phenylpropan-2-amine
Ref. 112.
U S 1879003 (1932)
NO 2
Cathode Red. at Hg or C electrode
NH 2
Ref. 113.
non-chir al
Chemicshe Ber icht e, 66B, 660-666 (1932).
N
OH
Na
/ Ethanol
NH 2
Ref. 114.
non-chiral
O
OH
N
J. Am. Chem. Soc. 31, 1875 (1931)
Cl
NH2
NH2
Pd/C, H2
OH
NH2
HCl
Pd/C, H2
(E)-2-(hydroxyimino)1-phenylpropan-1-one
2-amino-1-phenyl
propan-1-ol
1-chloro-1-phenyl
propan-2-amine
O
from
O
Ref. 115.
1-phenylpropane-1,2-dione
non-chir al O
J. Am. Chem. Soc. 31, 2787-91 (1931)
Hofmann Rearr.
NaOH
NH2
Br 2
NH 2
2-methyl-3-phenylpropanamide
O
Curtius Rearr.
N3
Ref. 116.
1-azido-2-methyl-3-phenylpropan-1-one
non-chir al
J . Chem. Soc. 18-21 ( 1930)
OH
O
N
NH2-OH
Na/Hg
NH2
amalgum
1-phenylpropan-2-one
(Z)-1-phenylpropan-2-one oxime
Ref. 117.
Precursor list to amphetamine 1985 -2009
Precursor / intermediate / essentials
2-phenylacetonitrile
(E)-(2-nitroprop-1-enyl)benzene
and
(Z)-(2-nitroprop-1-enyl)benzene
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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
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4,4,5,5-tetramethyl-1,3-dioxolan-2-
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one O-tosyl oxime
(1S,2S)-1-phenyl propane-1,2-diol
(1R,2S)-1-azido-1-phenylpropan-2-ol
2-methyl-3-phenylaziridine
2-phenylacetaldehyde
(R)-2-methyl propane-2-sulfinamide
(R)-1-phenylethanamine
1-(bromomethyl) benzene
(R)-3,3,5-trimethyl-1-propionyl
pyrrolidin-2-one
(S)-2-methyl-3-phenylpropanamide
(S)-2-amino-3-phenylpropanoic acid
(S)-2-amino-3-phenylpropan-1-ol
(S)-tert-butyl-1-phenylpropan-2ylcarbamate
1-phenyl-1-propyne
allylbenzene
Phenylmagnesium bromide
Diethyl-2-methylaziridin-1ylphosphonate
(R)-2-(tert-butoxycarbonylamino)-3phenylpropanoic acid
(R)-tert-butyl 1-hydroxy3-phenylpropan-2-ylcarbamate
(S)-tert-butyl 1-phenylpropan-2ylcarbamate
(1S,2S)-2-amino-1-phenylpropane1,3-diol
(E)-1-phenylpropan-2-one oxime
And
(Z)-1-phenylpropan-2-one oxime
Dimethyl 2-benylmalonate
16.
16.
16.
17.
49.
52.
17.
19.
21.
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51. Organometallics 5, 739 (1986)
54. Khimiya Geter Soedinenii 12, 1648 (1985)
59. Synthesis 4, 270 (1982)
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37. Acta. Chemica Scandinavica 45, 431 (1991)
Methyl-2-benyl-2-methyl-3oxobutanoate
2-methyl-3-phenyl propanoic acid
1-(2-(phenylthio)phenyl)propan-2amine
1-(2-(phenylthio)phenyl)propan-2one
3-oxo-2-(2(phenylthio)phenyl)butanenitrile
2-(2-(phenylthio)phenyl)acetonitrile
Benzaldehyde
(E)-1-phenylpropan-2-one O-methyl
oxime
(R)-2-methyl pyrrolidin-1-amine
(2,2-dimethyl-1,1diphenylpropyl)diazene
benzene
2-(2,2,2-trifluoroacetamido)
propanoyl chloride
2,2,2-trifluoro-N-(1-oxo-1-phenyl
propan-2-yl)acetamide
2-(2,2,2-trifluoro-N-(1-hydroxy-1phenyl propan-2-yl)acetamide
N-(1-bromo-1-phenylpropan-2-yl)2,2,2-trifluoroacetamide
2-(2,2,2-trifluoro-N-(1-phenyl
propan-2-yl)acetamide
(E)-prop-1-enylbenzene
1-(bromomethyl)benzene
Or
benzylbromide
Phenylpropan-1-one
Bromobenzene
Or
Phenylmagnesium bromide
2-phenylacetic acid
Or
Phenylacetic acid
Prop-1-ynylbenzene
(S)-2-methyl-3-phenylpropanoic acid
D-phenylalanine
Diethyl 2-(2-phenylacetyl)malonate
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)
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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)
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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)