synthetic amphetamine
TRANSCRIPT
Review: Synthetic Methods for Amphetamine
A. Allen1 and R. Ely
2
1Array BioPharma Inc., Boulder, Colorado 80503
2Drug Enforcement Administration, San Francisco, CA
Abstract: This review focuses on synthesis of amphetamine. The chemistry of these
methods will be discussed, referenced and precursors highlighted. This review covers
the period 1985 to 2009 with emphasis on stereoselective synthesis, classical non-chiral
synthesis and bio-enzymatic reactions. The review is directed to the Forensic Community
and thus highlights precursors, reagents, stereochemistry, type and name reactions. The
article attempts to present, as best as possible, a list of references covering amphetamine
synthesis from 1900 -2009. Although this is the same fundamental ground as the recent
publication by K. Norman; “Clandestine Laboratory Investigating Chemist Association”
19, 3(2009)2-39, this current review offers another perspective.
Keywords: Review, Stereoselective, Amphetamine, Syntheses, references,
Introduction: It has been 20 years since our last review of the synthetic literature for the
manufacture of amphetamine and methamphetamine. Much has changed in the world of
organic transformation in this time period. Chiral (stereoselective) synthetic reactions
have moved to the forefront of organic transformations and these stereoselective
reactions, as well as regio-reactions and biotransformations will be the focus of this
review. Within the synthesis of amphetamine, these stereoselective transformations have
taken the form of organometallic reactions, enzymatic reactions, ring openings, -
aminooxylations, alkylations and amination reactions. The earlier review (J. Forensic
Sci. Int. 42(1989)183-189) addressed for the most part, the ―reductive‖ synthetic methods
leading to this drug of abuse. It could be said that the earlier review dealt with ―classical
organic transformations,‖ roughly covering the period from 1900-1985. This time-line is
graphically illustrated below in Figure 1. As illustrated in this figure, certain categories
have been historically active. Early synthetic organic transformations such as aldol
condensations, the Hofmann rearrangement [105, 116], the Curtius rearrangement [118,
110, 80], the Schmidt rearrangement [80], the Lossen rearrangement [118], the
Beckmann rearrangement [111], the Wolff rearrangement [109], the Friedel-Craft
alkylation [102, 105] together with catalytic reductions; populated the literature from
1900-1985. Of course, overlap has occurred between these categories as the field of
organic chemistry has progressed.
Interestingly, organic synthetic transformations have entered, in the last 20 years,
a period of ―stereoselective organic transformation”. This is graphically illustrated in
Figure 1a. The multiplicity of these transformations and their unique starting precursors
and reagents may come as a challenge to the forensic community to keep up with the
latest organic modifications and ―off-precursor-watch-list‖ circumventions. Herein, we
hope to summarize as exhaustively as possible, the chemistry pictorially and compose a
list of precursor chemicals (IUPAC nomenclature, see supplemental material) that
address these transformations to amphetamine.
1900 1930 1970 2009
LossenCurtiusHofmannWolf
1. methyl ethyl ketone2. ethyl acetoacetate3. aldehyde -nitroethane
1. metal catayltic red.2. disolved metal red.3. non metalic red.
Stereoselective syn.
Organometalicchiral reductionalkylationsaminationsMitsunobuEnzymic
Time-Line of Synthetic Routes to Amphetamine
The Era of Classical Organic Chemistry
Rearrangements: Reductions:Aldo Condensations:
Figure 1
As best as possible, we have attempted to keep the needs of the forensic chemist
and law enforcement personnel in mind when creating the categories for retrieving the
information on a particular synthetic route. This has added a degree of difficulty to our
task since in many cases, the chemist thinks visually (synthetic routes) and the law
enforcement investigator works texturally (list of precursors). The categories of this
review are listed below and are not without their limitations.
Outline: Review of amphetamine syntheses 1985 – 2009 (Schema 2, 3, 4)
1. Stereoselective syntheses (Scheme 2)
2. Non-Chiral Syntheses (Scheme 3)
3. Biotransformation (Scheme 4)
Review of classical amphetamine syntheses 1900 – 1985 (Schema 5 and 6)
1. Classical Organic Transformations (Scheme 5)
2. Summary Routes to Amphetamine (Scheme 6)
Overview: In this reviewing period (1985-2009), with progress in stereoselective syntheses
and organometallic transformations, academia, along with private industry have been
motivated to explore new approaches to the synthesis of amphetamine. These numerous
publications have undoubtedly been prompted more by the introduction of a chiral center
alpha to a primary amine than the desire to add yet another synthetic approach to the
multitude of synthetic routes to amphetamine.
Organometallic chemistry has been used in creative region-constructions of
amphetamine, not only with magnesium metal [21, 15], but also with cerium [49],
titanium [26], iridium [1] and lithium [1]. Similarly, in the area of organometallic
reductions to amphetamine, the field of reagents has expanded to include samarium
iodide [4, 6, 9], ruthenium-(chiral-ligands) [18, 20, 36, 41], rhodium-(chiral ligands) [51],
titanium-ligands [26], copper [32, 17], magnesium [32] and novelties with borane [33,
42, 56], lithium aluminum hydride [12, 35, 47], L-Selectride [25], Red-Al® [46],
palladium [11, 14, 16, 23, 27, 40, 50, 53] and Raney nickel [33, 49 50]. Creative
synthetic routes that do not employ a reductive step have also been published [15, 17, 21,
28, 31, 37, 55, 58]. Ring opening strategies have been developed against phosphorylated
aziridines [31] and Sharpless epoxides [5] to yield amphetamine. Mitsunobu
transformations [5, 8, 14, 19, 34] have been exploited in a variety of approaches to swap
an alcohol precursor to the amine complement toward amphetamine. Hofmann, Curtius
[37, 80], Lossen[37] and Schmidt rearrangement [80] continue to be used in synthetic
schemes to produce amphetamine. The ―classical‖ Friedel-Craft alkylation [105] of
benzene with iron or aluminum trichloride has been improved with the use of N-
(trifluoroacetyl)--amino acid chloride as a chiral F-C reagent to manufacture
amphetamine [55]. Intermediates of nitrostyrene have been reduced chirally and non-
chirally to amphetamine [4, 12, 18, 20, 35, 41, 42, 56]. Likewise, hydroxylamine via
chiral hydrosilylation [51] and hydrazines [8, 52] have been exploited in routes to
amphetamine. Reductive aminations via phenyl-2-propanone; P-2-P [19, 40, 51, 54] have
appeared in these years, as well as other creative approaches like -amination [5],
alkyne-amination [26], alkene-amination [27], -aminooxylation [5], electrophilic
aminations [15], and sulfinyl-imine amination [17]. Photochemical-induced racemization
has been utilized for the transformation of the less pharmacologically active R isomer to
an equilibrium mix of R,S-amphetamine [2]. Improved resolution from racemic mixture
of amphetamine to a single isomer has been achieved with ―enzymatic transformations‖
[3, 10, 22, 24, 43] and ―classical organic salts resolutions‖ [37, 47]. Illustrated in Figure
1a and 1b are the histograms and citations for some of the active categories within the
transformations to amphetamine between 1985-2009. The activities of stereoselectivity,
resolutions and enzymatic transformations are expressly evident.
Reductions
Stereoselective
Nitrostyrene
Enzymic
Ring Opening
Organometalic
Amination
Mitsunobu
Resolutions
Oxime
Hydrazine
Friedel-Craft Alkylation
Photochemical
Histograms for amphetamine reaction types 1985-2009 (#-reference)
Alkylations
Hofmann rearrangement21, 37
2
55
1, 5, 15, 21, 31
1, 15, 17, 31
4, 7, 12, 18, 20, 35,41,42, 46, 47, 56
5, 31, 16
1, 2, 3, 5, 6, 8, 9, 11, 14, 16, 17, 18, 19, 20, 21, 22, 23 25, 28, 29, 33, 34, 36, 37, 40, 41, 48, 49, 50, 51, 53, 54, 55
1, 4, 6, 9, 5, 11, 12, 14, 16, 18, 19, 20, 22, 23, 25, 26, 27, 32, 33, 34, 35, 39, 41, 42, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57
8, 13, 28
2, 3, 10, 22, 24, 37, 38, 43,
17, 26, 27, 58, 15
36, 45, 46, 51, 54
2, 3, 10, 14, 22, 24, 29, 39, 43, 48
8, 34
1, 15, 19, 26, 49, 50, 52 Imine
Figure 1a.
Literature Citations for the Synthesis of Amphetamine 1985-2009
Enzymatic (Bio Transformations) (see Scheme 4)
2. J. Org. Chem., JOC 73(2008)364 3. J. Org. Chem., JOC 72(2007)6918 10. Indian J. Chem. Soc. B., IJCS 44B(2005)1312 14. J. Chemical Research, JCR 10(2004)681 22. Tetrahedron Asymmetry, TA 13(2002)1315 24. Synthetic Comm., SC 31(2001)569 39. Chem. & Pharm. Bull., CPB 38(1990)3449 43. US Patent 04950606B1 (1990)
Non-Chiral Organic Synthesis (see Scheme 3)
4. Tetrahedron Letter, TL 48(2007)5707 12. J. Organic Chem., JOC 70(2005)5519 13. Organic & Biomol. Chem., OBC 3(2005)1049 15. Organic Letters, OL 6(2004)4619 26. Organic Letters, OL 2(2000)1935 27. Tetrahedron, Tetra. 56(2000)5157 31. Tetrahedron, Tetra. 53(1997)4935 32. J. Chem. Soc. Perkin I, JCSP1 1(1996)265 37. J. Labeled Comp. Rad., JLCR 31(1992)891 38. J. Medicinal Chem., JMC 34(1991)1094 40. J. Chromatographic Sci., JCS 28(1990)529 41. Tetrahedron, Tetra 46(1990)7403 42. Tetrahedron, Tetra 46(1990)7743 45. Coll. Czech. Chem. Comm., 54(1989)1995 48. Organic Reactions, Vol 36 (book, 1988) 57. J. Medicinal Chem., JMC 31(1988)1558 52. J. Chem. Soc. Chem. Comm. 2(1986)176 54. Khimya Geter. Soed #12,1648(1985) 56. Synthetic Comm., SC 15(1985)843 22. Tetrahedron Asymmetry, TA 13(2002)1315
Stereoselective Synthesis (see Scheme 2)
1. J. American Chem. Soc. JACS 131(2007)9882 5. Tetrahedron, Tetra. 63(2007)9758 6. Chemistry A European J., JEC 12(2006)4197 8. Biological Med. Chem. Letter, BMCL 15(2005)3039 9. FZSGS patent # 1673210 (2005) 11. J. Medicinal Chem., JMC 48(2005)1229 14. J. Chem. Research, JCR 10(2004)681 16. Tetrahedron Asymmetry, TA 15(2004)3111 17. J. Combinatorial Chem. 5(2003)590 18. J. Chem. Research, JCR 3(2003)128 19. Tetrahedron Asymmetry, TA 14(2003)2119 20. J. Chinese Chem. Soc. 49(2002)505 21. J. Chem. Soc. Perkin I, JCSP1 16(2002)1869 22. Tetrahedron Asymmetry, TA 13(2002)1315 23. US patent #6399828(2002) 25. J. Organic Chem., JOC 65(2000)5037 28. Tetrahedron Letters, TL 41(2000)6537 33. Tetrahedron Letters, TL 36(1995)1223 34. Tetrahedron Asymmetry, TA 4(1993)1619 36. Tetrahedron Asymmetry, TA 3(1992)1283 37. Acta. Chimica Scan. 45(1991)431 41. Tetrahedron, Tetra 46(1990)7403 44. Angew Chem. Int. 28(1989)218 49. J. American Chem. Soc. JACS 109(1987)2224 51. Organometallics, 5(1986)739 53. Analytical Chem. 58(1986)1642 54. Khimja Geter. Soed. 12(1985)1648 55. J. Organic Chem., JOC 50(1985)3481
# = Reference Figure 1b.
Amphetamine Review (1989 – 2009)
1900 1930 1970 2009
Stereoselective syn.Time-Line of Synthetic Routes to Amphetamine
1985
Ph
OHPh
H2N
O
Ph
HOPh
OH
Ph
NH2
OH
OH
TA 4(7)1619(1993)
TA 15(19)3111(2004)
PhCOOH
NH2
Ph
OH
NH2
JCS, Perkin T.I, 161869 (2002)
JCS, Perkin T.I, 161869 (2002)
JOC 50(19) 3481(1985)
J.Comb.C. 5(5)590 (2003)
JACS 109(7)2224 (1987)
JMC 48(4)1229 (2205)
B.M.C.L. 15(12) 3039 (2005)
JOC 65(16) 5037 (2000)
H
O
T.L. 41(34) 6537 (2000)
Chiral
Chiral
Chiral
Chiral
Chiral
Chiral
Chiral
Chiral
Chiral
Org. Biomol. Chem. 3,1049(2005)
Chiral
NJACS 131(29) 9882 (2009)
Chiral
Ph H
O
Ph OH
Ph OH
ONHPh
OH
PhO
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
Tetra. 63(39) 9758 (2007)
PhNO2
Ph Br
Ph
HN BOC
I
Chem. Eur.J. 12, 4191 2006
FZSGS #1673210 (2005)
J. Chem. Res. 10, 681 (2004)
J.C. Res. Syn. 3, 128 (2003)
Ph
OTetra. Asy. 14, 2119 (2003)
J. Chinese C S 49, 505 (2002)
Tetra. Let. 36(8) 1223 (1995)
Tetra. 46(21) 7403 (1990)
Anal. Chem. 58(8) 1642(1986)Organometallics 5, 739 (1986)
Chiral
Chiral
Chiral
Chiral
Chiral
Chiral
NH2
Amphetamine28.
Stereoselective Synthesis of Amphetamine 1985--2009
Scheme 2.
(S)-1-phenylpropan-2-amine
36
51
1 55
5
5
18 20 41
6 9
1123
4053
8
14
19
1617
49
1940
5154
21
21
2533
34
55
Tetra Asy 3(10) 1283 (1992)
Organometallics 5, 739 (1986)
KGS #12,1648 (1985)
US # 6,399,828 (2002)
J. Chrom. Sci. 28,529 (1990)
J. Chrom. Sci. 28,529 (1990)
54
KGS #12,1648 (1985)
5
44
Angew chem. Int. 28(2) 218 (1989)
R
2A. 2B.
2C.
2D.
2E.
2F.
2G.
2H.
2J.2K.
2L.
2M.
2N.
2O.
2P.
2Q.
2I.
Discussion of Stereoselective Syntheses of Amphetamine 1985-2009:
Illustrated in Scheme 2, routes 2A-2Q, repressent the multitude of stereoselective
approaches to amphetamine published between 1985 –2009. Within this illustrated
pinwheel of reaction routes, we have arranged references in reverse chronological order –
clockwise [#‘s]. As a starting point for discussion, take the Schiff base (1-phenylpropan-
2-imine, route 2A) as a chiral approach to amphetamine [1, 36, 51, 54]. This approach
has been facilitated by the improvements of chiral organometallic ligands with transition
metals in order to effect chiral catalytic reductions [1, 36, 51, 54, route 2A]. Similarly,
armed with chiral organometallic ligands with ruthenium and rhodium, the reduction of
nitrostyrenes [(E)-(2-nitroprop-1-enyl)benzene] have been achieved stereoselectively [18,
20, 41; route 2F].
A completely different approach was taken by Talluri, S. et. al.; [routes 2B-E],
wherein they initiated the route to amphetamine from 1-phenylpropanal [5, route 2E].
Starting from this one-carbon extended aldehyde as opposed to the typical 2-
phenylacetaldehyde [17, 49; route 2K] or benzaldehyde [47, 80, 89, 92, 95, 110; route
5Z, also implicit in 18, 20, 41, 42, 44, 56, 60, 39, 54, 61, 35, 22, 20, 18, 12, 4.57, 85, 84,
75, 74, 70, 67, 62, 94, 87, 86, 113, 114; route 5A] precursor, these workers preformed a
chiral oxy-alkylation with nitrosobenzene to (R)-3-phenylpropan-1,2-diol [5, route 2C-
2D]. Tosyl chloride assisted ring closure lead to the epoxide, 2-benzyloxirane [5, route
2B]. Reductive ring opening of the epoxide produced the alcohol, (S)-1-phenylpropan-2-
ol; [see structure in route 2I]. This was followed by swapping the alcohol moiety for
azide. The final step was catalytic (PtO2) reduction to amphetamine [5]. Although a
lengthy process to amphetamine, its potential importance to forensic chemists lies in the
fact that each intermediate is a potential starting precursor for a chiral synthesis to
amphetamine. Closely allied to the alcohol-azide swap in the previous route are the
variations achieved by Mitusnobu reaction-type exchanges from (R)-1-phenylpropan-2-ol
to (S)-1-phenylpropan-2-NX, wherein inversion of configuration is complete to the amine
compliment [8, 14, 19, 5, 34; route 2I and route 2P].
Chiral starting materials like phenylpropanolamine [11, 23, 29, 40, 53; route 2H]
and phenylalanine [33, 25, 6, 9, 44; route 2O and route 2G] have been easy targets for
precursors to the stereoselective synthesis of amphetamine. The routes from
phenylalanine are variations on J.W. Wilson‘s original article from 1977 [84; route 6BB]
utilizing alternative reagents for the reduction of the carboxylic acid, alcohol to halide
swap, reduction of the alkyl halide and BOC deprotection.
In the case of phenylpropanolamine as precursor, earlier literature [40,53, route
6P] make use of the chloro-pseudonorephedrine intermediate, as most typically seen in
clandestine laboratories, however more recent literature [11, 23, route 6P] makes use of
acetic anhydride to yield the ester for catalytic reductive removal of the OH moiety to
amphetamine.
Creative chiral scaffolding has been used to introduce stereoselectivity early in
the amphetamine synthesis [17, 49, 21; routes 2M, 2N and 2K]. These unique
approaches start with the achiral, off-listed precursors, benzylbromide [21, route 1N] or
2-phenylacetaldehyde [17, 49, route 2K]. The stereoselectivity is introduced and
controlled by simpler commercially available chiral directors. Interestingly, the Hofmann
rearrangement, which retains stereoselectivity, was utilized at the end of route 2M [21]
with the modern uses of hypervalent iodine [21]. Another older ―classical synthesis‖
improvement was profiled in the Friedel-Crafts alkylation of benzene through the use of
chiral (s)-2-(2,2,2-trifluoroacetamido)propanoyl chloride [55, route 2Q].
1900 1930 1970 2009
non-chiral synthesesTime-Line of Synthetic Routes to Amphetamine
1985
NH2
Ph Ph
NH2
MgBr
T. 53(13)4935 (1997)
O.L.. 2(13) 1935 (2000)
NP
Cp2TiMe2
non-Chiral
O
O O
OH
SO2
NO2
NH2
Org. Biomol. Chem 3(6) 1049 (2005)
NO2
LiAlH4
JOC 70(14)5519 (2005)
MgBr
O
ON
O
Org. Let. 6(24) 4619 (2004)
non-Chiral
non-Chiral
non-Chiral
OHO
ONH
O
O tBu
Tetra. Let. 41, 6537 (2000)
non-Chiral
n-BuLi
Ph NH2Pd/H2
Tetra. 56, 5157 (2000)
O
Mgreduction
NH3
HoAc
JCS, PTI, 265 (1996)
J. Labelled Comp. Rad. 31(11) 891 (1992)Tetra. 46(21) 7443 (1990)
Angew Chem. Int. 28(2) 218 (1989)J M C 31(8) 1558 (1988)
TsPh
PhNH
N
H3C
JCS, Chem. Comm.2, 176 (1986)
Syn. Comm. 15(9) 843 (1985)non-Chiral
non-Chiral
non-Chiral
non-Chiral
Non-Chiral Synthesis of Amphetamine 1985--2009
Scheme 3
4
28
1315
27
26
31
32
COOH
OO
O
O
Acta Chem. Scand.45, 431 (1991)
CN
SPh
Coll. Czech. Chem Comm.54(7) 1995 (1989)
H
O
NO
Tetra. Asy. 13(12) 1325 (2002)J. Chrom Sci. 28, 529 (1990)
Acta Chem. Scand.45, 431 (1991)
JMC 31(8) 1558 (1988)
Org. Rea. 36(book) (1988)non-Chiral
non-Chiral
22
40
48
47
37
Amphetamine
12
35
4247
56
37
non-Chiral
non-Chiral
non-Chiral
45
52
58
17
Br
46.
Tetra. Let. 48(32) 5707 (2007)
3A.
3B.
3C.
3D.
3E.
3F.
3G.
3H.3I.
3J.
3K.
3L.
3M.
3N.
Scheme 3.
Discussion of Non-Chiral Syntheses of Amphetamine 1985-2009:
Non-chiral syntheses of amphetamine (Scheme 3, routes 3A-N) have also
appeared in the literature; 1985-2009. These variations are graphically illustrated in
Scheme 3 and represent 25 individual citations. As described above with regards to
chiral routes, the Mitsunobu type reaction chemistry has been exploited in 3 different
non-chiral routes, each starting from racemic 1-phenylpropan-2-ol [13, 17, 28; route 3A
and 3D]. Achiral reductions of nitrostryene to amphetamine were the most popular
approaches in this time period [4, 12, 35, 42, 46, 47, 56; route 3B]. These citations are
primarily in the course of building pharmaceutical analogs / research. Organo-metallic
(Grignard or lithium alkylation) reactions were used in a variety of alkylation reactions to
amphetamine [15, 31, 52; route 3C, 3G and 3N]. These variations include Grignard ring
opening of a phosphorylated-aziridine (nucleophilic ring-opening of N-phosphorylated
aziridines) [31; route 3G], reaction with an electron deficient oxime (electrophilic
amination of Grignard reagent) [15; route 3C], and lithium alkylation of an -amino
carbanion equivalent reaction [52; route 3N].
The amination of allylbenzene was affected in a base-catalyzed hydroamination
reaction [27; route 3E]. This reaction is similar in precursor and product, however
different in mechanism to the 1982 phosphoramidomercuration-demercuration of
allylbenzene to amphetamine [58; route 6U]. Amination with a commercially available
-aminodiphenylmethane, which serves as an ammonia equivalent, was used for the
hydroamination of 1-phenyl-1-propyne to amphetamine [26; route 3F].
Several citations occurred in the literature for the reductive amination of P-2-P to
amphetamine [32, 22, 40; route 3H]. The classical malonic ester synthesis was used to
construct 2-methyl-3-phenyl propanoic acid [37, route 3I] which was then converted to
amphetamine via a Curtius rearrangement / hydrolysis [37]. A similar classical reaction,
that of a Claisen / Dieckmann condensation, utilizing a benzylnitrile analog was used to
construct a P-2-P complement [45; route 3K]. This analog was converted to the oxime,
followed by reduction and de-sulfuration with sodium / ethanol to amphetamine [45;
route 3K]. Finally, O-methoxy-oxime of P-2-P was reduced with Red-Al® to yield
amphetamine with marginal success [48; route 3M].
Scheme 4.
Discussion of Enzymatic, Photo-induced and Chemical Manipulation of
Amphetamine Isomers: 1985-2009
Biotransformations have increased in interest, proof of concept and patent
applications from 1985-2009. Illustrated in Scheme 4 are the citations within this topic
regarding amphetamine isomers. Both phenyl-2-propanone [14, 43; route 4A] and the
nitrostyrene, (E)-1-(2-nitroprop-1-enyl)benzene [39,48; route 4C] have been used as
starting points to the enzymatic synthesis to amphetamine. Alternatively,
biotransformations of racemic amphetamine leading to the exclusion or enhancement of
one isomer (enhanced ee) have been published or patented [3, 10, 22, 24, 29, 43; route
4B]. Conversely, one citation [2; route 4D] describes the photochemically induced-
radical mediated racemization of the single amphetamine isomer to the racemic mixture.
Classical methods of chiral resolution based upon chiral organic salts have been reported
in the time frame of 1900-2009, with the use of D-(-)-tartaric acid [30, 47, 38, 71, 81a,
88, 90, 108], benzoyl-d-tartaric acid [38], di-p-toluoyl-d-tartaric acid [38], (S)-2-
naphthylglycolic acid [66], -amino acids [78] and optical-10-camphorsulfonyl chloride
[37].
Organic Transformation from 1900 -2009: Classical Organic Transformation in the Early 1900-1950‘s:
Scheme 5.
Classical Organic Transformation in the Early 1900-1950‘s:
The early literature regarding amphetamine synthesis of the 1900‘s was
dominated by classical organic transformations (Scheme 5). These reactions like the
Friedel-Crafts reaction [105,], Ritter Reaction [102], Leuckart reductive amination
reaction [106, 97, 76, 71], nitro-aldol dehydration reaction, also called the Henry
Reaction [116, 96, 94, 89, 87, 86, 85, 82, 70, 67] and rearrangement reactions that came
to be known as the Hofmann rearrangement[105, 116], Curtius rearrangement [118, 110,
80], Schmidt rearrangement [80], Lossen rearrangement [118], Beckmann rearrangement
[111] and the Wolff rearrangement [109], were productive routes to the synthesis of
amphetamine. The non-amine component, -methylbenzylacetic acid, was constructed
with carbon-carbon bond formation via a carbo-anion enolate condensed with a suitable
alkylhalide. These condensations, that were classically referred to as acetoacetic ester
synthesis [105, 118] and malonic ester synthesis [91], later came to be referred to as cases
of the Claisen condensation. In the case of phenylacetonitrile (benzylnitrile) [107], the
acidity of the central methylene hydrogens between the nitrile and aromatic ring, are used
for abstraction and carbo-anion production before alkylhalide reaction.
Organic Transformation in the Early 1950-1985s:
Moving forward in time, from the period dominated by ―classical organic
transformations‖ (1900-1950), we enter a period for amphetamine synthesis that saw
expanded interest in dissolved metal reductions and early chiral constructions. This time
frame (1950-1985) was the focus of our previous review (J. Forensic Sci. Int. 42, (1989)
183-189)) and hightlighted catalytic reductions, dissolving metal reductions and metal
hydride reduction leading to amphetamine. It was during this period that chiral
complement to the Friedel-Crafts reaction was introduced for the synthesis of
amphetamine [55]. Amination of a double bond was improved with the use of diethyl
phosphoramidate [58], as well as acetonitrile mercuration [69] each leading to
amphetamine. Reductive amination with (R)-1-phenylethanamine on the Schiff-base of
phenyl-2-propanone followed by diasteroisomeric separation allowed for a chiral
synthesis of amphetamine [64]. Later (1977, 1978), two chiral syntheses to amphetamine
were published starting from D-phenylalanine [84a, 84b].
Summary: As best as possible the authors have attempted to summarize the synthetic
transformations published within the period 1900-2009, with emphasis upon 1985-2009.
The complete visual precursor / references to amphetamine pin-wheel is illustrated in
Scheme 6 and is intended for the forensic chemist as a complete map of amphetamine
routes / literature. These individual reactions are broken out, expanded and illustrated
with added nomenclature in the supplemental material. Furthermore, precursor names
via IUPAC (ChemDraw, Cambridge Software) are tabulated for the non-chemist with
cross reference to literature citations.
1900 1930 1970
non-chiral synthesesTime-Line of Synthetic Routes to Amphetamine
1985
Br
H
O
Br
CN
H
Br
OH
OHO
O
N
OH
NH2
R
OHOOH
NH2
OH
OH
NH2
O
NH2
Amphetamine
O
O
Br
O
COOH
NH2
NO2
H
O
O O
O
O
OH
O
S
CN
Ph
O
HOOH
Scheme 6.
Organic Transformationsto Amphetamine1900 - 2009
2009
12
18
20
39
22
4
35
41
42
5
5
37
5
34
21
15
8
1314
28
1419
2029
32
384336
116
11
17
26
27
1
21
25
33
31
44
45
47
48
49
51
5222
23
40
40
40
47
49
51
52
52
53
54
54
5556
513
54 57
58
59
59
60 61
62
6364
65
67
70
69
71
72
73
74
74
75
7679
80
80
82
84
85
86
87
88
88
89
89
92
92
91
91
9092
95
95
94
93
96
98
99
100
101
101
103
102
105
106
108
107
107
109
110
111112
113 114
115
117
116
116
118
120
120
121
122
6A.
6B.
6C.
6D.
6E.
6F.
6G.
6H.
6I.
6J.
66K.
6L.
6M.
6N.6O.
6P.6Q.
6R.
6S.
6T.
6U.
6V.
6W.
6X.
6Y.
6Z.
6AA.
6BB.
84a
84b
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Pharmacodynamic Activity of four Isomeric Phenylpropylamines, J. Am. Chem. Soc. 53
(1931) 1875-79.
[116] E.S. Wallis, S.C. Nagel, Molecular Rarrangements Involving Optically Active
Radicals. II. The Hofmann rearrangement of Optically Active Acid Amides, J. Am.
Chem. Soc. 55 (1933) 2787-91.
[117] D.H. Hey, V. dl--Pheylisopropylamine and Related Compounds, J. Chem. Soc.
18 (1930).
[118] W.H. Hartung, Catalytic Reduction of Nitriles and Oximes, J. Am. Chem. Soc. 50
(1928) 3370-4.
Supplemental Material:
N MeMgI NH NH2
Ir-(S,S)-f-binaphane
H2
(S)-1-phenylpropan-2-amine1-phenylpropan-2-imine2-phenylacetonitrile
JACS 131, 9882 (2009)
Ref. 1.
chiral
NH2
(S)-1-phenylpropan-2-amine
NH2
1-phenylpropan-2-amine
Ref. 2.
HSCH2CO2Me
Benzene
Photochemical --Racemization
JOC 73(2) 364 (2008)chiral
NH2
1-phenylpropan-2-amine
NH2
(S)-1-phenylpropan-2-amine
Lipase Lauric acid
+ amide of lauric acid
Biotrasformation, Enzymic, Stereoselective
JOC 72(18) 6918 (2007)
Ref. 3.
chiral
NO2
NH2
1-phenylpropan-2-amine
PhH2NSmI2
(E)-(2-nitroprop-1-enyl)benzene
Tetra. Let. 48(32) 5707 (2007)
Ref. 4.
non-chiral
H
O
OH
ONHPh
OH
OH
OHO NH2
3-phenylpropanal
(R)-3-phenyl-2-(phenylaminooxy)propan-1-ol
(R)-3-phenylpropane-1,2-diol
2-benzyloxirane (S)-1-phenylpropan-2-ol(S)-1-phenylpropan-2-amine
nitrosobenzene
l-proline
NaBH4
Pd/C
TsClTEA
NaH1,
2.
LiAlH4 1. NaN3
2. Pd/C H2
Tetra. 63, 9758 (2007)
Ref. 5.
chiral
HN
ter t-butyl 1-iodo-3-phenylpropan-2-ylcarbamate
I
O
O
HN O
O
NH2
(S)-1-phenylpropan-2-amineter t -butyl 1-phenylpropan-2-
ylcarbamate
chiral Chem. European J. 12(15)4191-7(2006)
Ref. 6.
SmI2 TFA
NO2 NH2
(E)-(2-nitroprop-1-enyl)benzene
NaBH4
1-phenylpropan-2-amine
Central Eur. J. Cehm 6(4) 526-34 (2008)non-chiral
Ref. 7.
BF3 - Et2O
THF
OHN
Phth Anh.
O
O NH2
NH2-NH2
amphetamine
Ref. 8.
Ph3P
DEAD, THF
MeOH
Bioorganic & Med. Chem. Letters,15(12) 3039-43 (2005)
(S)-1-phenylpropan-2-ol
(S)-2-(1-phenylpropan-2-yl)isoindoline
-1,3-dione
(S)-1-phenylpropan-2-amine
chiral
HN
ter t-butyl 1-iodo-3-phenylpropan-2-ylcarbamate
I
O
O
HN O
O
NH2
(S)-1-phenylpropan-2-amineter t -butyl 1-phenylpropan-2-
ylcarbamate
chiral Faming Zhuanli Shenqing Gongkai Shuomingshu # 1673210 (2005)
Ref. 9
SmI2 TFA
NH2
1-phenylpropan-2-amine
NH2
(S)-1-phenylpropan-2-amine
Lipase Lauric acid
+ amide of lauric acid
Biotrasformation, Enzymic, Stereoselective
indian J. Chem.Sec B 44B(6) 1312 (2005)
Ref. 10.
chiral
OH
NH2
norephedrine
OHNAc2O
Ac
Ac
HN
Ac
H 2/
Pd-BaSO4
NH2H2SO4
amphetamine
J. Med. Chem.48(4) 1229-36 (2005)
2-acetamido-1-phenylpropyl acetate
N-(1-phenylpropan-2-yl)acetamide
chiral
Ref. 11.
(S)-1-phenylpropan-2-amine
(1R,2S)-2-amino-1-phenylpropan-1-ol
NO2 NH2
(E )-(2-nitroprop-1-enyl)benzene
LiAlH4
1-phenylpropan-2-amine
JOC 70(14) 5519 (2005)non-chiral
Ref. 12.
OH NH2
amphetamine1-phenylpropan-2-ol 1-phenylpropan-2-amine
SO2
NO2
NH2
DCC
HNS
O
O2N
O
2-nitro-N-(1-phenylpropan-2-yl)benzenesulfonamide
non-chiral Org. and Biomolecular Chem. 3(6) 1049 (2005)
PhSH, K2CO3
50oC
Ref. 13.
NH2
(S)-1-phenylpropan-2-amineO
1-phenylpropan-2-one
OHN3
baker's yeast
sucrose
Pd/C
H2
(S)-1-phenylpropan-2-ol
(S)-(2-azidopropyl)benzene
J. Chem. Research 10, 681 (2004)chiral
Ref. 14.
MgBrO O
NO
S
O O
N
NH2
HCl
amphetamine
Org. Letters, 6(24) 4619-21 (2004)
(1-phenylpropan-2-yl)magnesium bromide
O
O
1-phenyl-N -(4,4,5,5-tetramethyl-
1,3-dioxolan-2-ylidene)propan-2-amine
1-phenylpropan-2-amine
non-chiral
Ref. 15.
OH
OH
SOCl2O
O
S
O N3
OH
NaN3
NH2
HN
Ph3P Pd-C
HCO2NH4
amphetamine
Tetrahedron Asymmetry15(19),3111-6 (2004)
(1S,2S)-1-phenylpropane-1,2-diol
(1R,2S)-1-azido-1-phenylpropan-2-ol
2-methyl-3-phenylaziridine
Ref. 16.(S)-1-phenylpropan-2-amine
chiral
O
HS
NH2
O
CuSO4 SN
O
MeMgBrS
NH
OHCl, MeOH
NH2
amphetamine
J. Combinator ial Chem.5(5) 590-6 (2003)
2-phenylacetaldehyde(R)-2-methyl
propane-2-sulfinamide
(R,E)-2-methyl-N-(2-phenylethylidene)propane-2-sulfinamide
(R)-2-methyl-N-((S)-1-phenylpropan-2-yl)propane-2-sulfinamide
(S)-1-phenylpropan-2-amine
chiral
Ref. 17.
NO2
J. Chem. Research (S), 128 (2003)
NH2Ruthenium BINAP
(E)-(2-nitroprop-1-enyl)benzene
chiral
Ref. 18.
O
1-phenylpropan-2-one
H2NN
(R)-1-phenylethanamine (S,E)-1-phenyl-N-(1-phenylpropan-2-ylidene)
ethanamine
NH2
(S)-1-phenylpropan-2-amine
Tetra. Asy. 14, 2119 (2003)chiral
Ref. 19.
NO2
J. Chinese Chemical Society, 49, 505 (2002)
NH2
H2(E)-(2-nitroprop-1-enyl)benzene
Ru2Cl2(PPh3)3
toluene(S)-1-phenylpropan-2-amine
chiral
Ref. 20.
BrN
OO
LDA, THFN
OO
NH3, MeOHNH2
O NH2
PhI(OOCCF3)2
amphetamine
JCS Perk in T .I 16, 1869(2002)
1-(bromomethyl)benzene
(R)-3,3,5-trimethyl-1-propionylpyrrolidin-2-one
(5R)-3,3,5-trimethyl-1-(2-methyl-3-phenyl
propanoyl)pyrrolidin-2-one
(S)-1-phenylpropan-2-amine(S)-2-methyl-3-phenylpropanamide
chiral
Ref. 21.
NH2
amphetamine
OPd, MeOH
T etrahedron Asymmetry, 13(12)13115-1320 (2002) 1-phenylpropan-2-amine
1-phenylpropan-2-one
HCOO NH4
NH2
Tetra. Asy. 13(20) 2277 (2002)
NH2
1-phenylpropan-2-amine
chiral
Ref. 22.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
CAL-B cat.
non-chiral
Ref. 22.
NH2
US pat. # 6399828 2002)
NH2
OH
Ac2O
NH2
OAcPd
BaSo4H2
(1R,2S)-2-amino-1-phenylpropan-1-ol
(1R,2S)-2-amino-1-phenylpropyl acetate
chiral
Ref. 23.
HoAc
HI, P4
HCl
NH2
Syn. Comm. 31(4) 569 (2001)
NH2
1-phenylpropan-2-amine
chiral
Ref. 24. (S)-1-phenylpropan-2-amine
Enzymic, Resolution
Candida antarcitica Lipase
NH2
COOH
LiBH4/TMSCl NH2
OH
NH
OH
BOC)2O
O
O
NH
I
(Ph)3P / I N-Selectride NH NH2
amphetamine
TFA
J. Orgainic Chemistry65(16) 5037-42 (2000)
OO OO
(S)-tert -butyl 3-iodo-1-phenylpropan-2-ylcarbamate
(S)-tert -butyl 1-phenylpropan-2-ylcarbamate S)-1-phenylpropan-2-amine
(S)-2-amino-3-phenylpropanoic acid
(S)-2-amino-3-phenylpropan-1-ol (S)-ter t-butyl 1-hydroxy-3-phenylpropan-2-ylcarbamate
chiral
Ref. 25.
NH2 Cp2TiMe2
N
Ph
Ph NH2
1-phenyl-1-propyne
amphentamine
Organic Let ters, 2(13) 1935-1937 (2000)
Ref. 26.
diphenylmethanamine
(E)-diphenyl-N-(1-phenylpropan-2-
ylidene)methanamine
1-phenylpropan-2-amine
non-chiral
Cp2TiMe2
H2, Pd/C
NH2
1-phenylpropan-2-amine
H2N
cat. n-Bu Li
Ph
NH
Pd/C H2
non-chiral T etra. 56, 5157 (2000)Ref. 27.
allylbenzeneN-benzyl-1-phenylpropan-2-amine
OH NH
O
NH2
TFA
amphetamine
Ph3P
DEAD, THF
DCM
T etrahedron Letters, 41(34)6537-40 (2000)tBuCO)2O
O1-phenyl
propan-2-ol ter t-butyl1-phenylpropan-2-ylcarbamate
1-phenylpropan-2-amine
non-chiral
Ref. 28.
JP 03191797 (1991)
NH2
phenylpropan-1-one
chiral
Ref. 29. (S)-1-phenylpropan-2-amine
Enzymic, Resolution
C: 9031-66-1
O
BuNH2
d-Tartaricacid
O
Ref. 30.
NH2
1-phenylpropan-2-one
non-chiral
Leuckart Reaction
ammonium formate
NH2 COOH
OHHO *
HOOC*
Zhongshan Dazue Xuebao 35(5) 73-76 (1996)
MgBr N
PO O
O
NH
POO
O
CuI
THF
NH2HCl
amphetamine
T etrahedron, 53(13) 4935-4946, 1997
diethyl 2-methylaziridin-
1-ylphosphonate
phenylmagnesiumbromide
diethyl1-phenylpropan-
2-ylphosphoramidate
1-phenylpropan-2-amine
non-chiral Ref. 31.
NH2
O
NH3
P-2-P
J.Chem.Soc., Perkin T rans I , 265 (1996)
Mg MeOH
HoAc1-phenylpropan-2-one
1-phenylpropan-2-amine
non-chiral
Ref. 32.
HN
OH
O
O
Tetra. Lett . 36(8) 1223 (1995)
O
NH
OH
NH
O
BH3
THF CH3SO2Cl
TEA
Ms
NH
O S
NaH
CH3CH2SH
NHRa-Ni
EtOH
NH2
BOC BOC
BOC BOC
(R)-2-(ter t-butoxycarbonylamino)-3-phenylpropanoic acid
chiral
TFA
Ref. 33.
(S)-1-phenylpropan-2-amine
OH
NH2
OH
OH
N
OHPhth Anh.
O
OPh)3P / I
I
I
H2 / Pd-C
NH2
NH2-NH2
amphetamine
T etrahedron Asymmetry4(7) 1619-24, 1993
(1S,2S)-2-amino-1-phenylpropane-1,3-diol
2-((1S,2S)-1,3-dihydroxy-
1-phenylpropan-2-yl)isoindoline-1,3-dione
N
O
O
N
O
O
2-((1S,2S)-1,3-diiodo-1-phenyl
propan-2-yl)isoindoline-1,3-dione
(S)-2-(1-phenylpropan-2-yl)isoindoline-1,3-dione
(S)-1-phenylpropan-2-amine
chiral
Ref. 34.
NO2
J. Labelled Comp. and Rad. 31(11) 891 (1992)
NH2
(E )-(2-nitroprop-1-enyl)benzene
LiAlH4
non-chiral
1-phenylpropan-2-amineRef. 35.
NH2
amphetamine
N
T etrahedron Asymmetry,3(10)1283-8 (1992)
OH
E & Z
H4Ru(arene)
BINAP
(E)-1-phenylpropan-2-one oxime
chiral
(S)-1-phenylpropan-2-amine
Ref. 36.
O
O
O
O
O
O
O
O
OH
O
2. AcOH
NH2
Acta. Chemica Scandinavica 45, 431 (1991)
amphetamine
methyl2-benzyl-2-methyl-3-oxobutanoate
2-methyl-3-phenylpropanoic acid 1-phenylpropan-2-amine
dimethyl 2-benzylmalonate
CH3-INaH
DMSO
1. NaOH
PO
Ph
Ph
NN+
-N
1. TEA/heat
2. HCl / heat
non-chiral Ref. 37.
NH2
amphetamine
1-phenylpropan-2-amine
NH2
amphetamine(S)-1-phenylpropan-2-amine
(+)-10-camphorsulonyl chloride
resolutionchiral
Tetrahedron Lett . Vol. 32, No. 49 (1991) 7325-8.
NH2
amphetamine
1-phenylpropan-2-amine
NH2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chiral HOOC
COOH
ORRO
*
* R = HBenzoylp-toluoyl
Ref. 38.
NO2
Chem. Pharm. Bull. 38(12) 3449 (1990)
NH2
(E)-(2-nitroprop-1-enyl)benzene
Biotransformationcat. Peptostreptococcus Anaerobius
1-phenylpropan-2-amine
non-chiral
Ref. 39.
NH2
J. Chrom. Sci. 28, 529 (1990)
NH2
(1R,2S)-2-amino-1-phenylpropan-1-ol
OH
NH2
Cl
Pd H2SOCl2
(1S,2S)-1-chloro-1-phenylpropan-2-amine(S)-1-phenylpropan-2-amine
chiral
OH
J. Chrom. Sci. 28, 529 (1990)
O
NH2
2-phenylacetic acidO
1-phenylpropan-2-amine
non-chiral
Ac2)O
NaOAc
Leuchart Red
1-phenylpropan-2-one
Ref. 40.
Ref. 40.
NH2
amphetamine(S)-1-phenylpropan-2-amine
NO2 NO2BH3-THF Ru2Cl2[(-)-DIOP]3
H2
(E)-(2-nitroprop-1-enyl)benzene (2-nitropropyl)benzene
Tetra. 46(21) 7403 (1990)chiral Ref. 41.
NH2
amphetamine
NO2 BH3-THF
(E)-(2-nitroprop-1-enyl)benzene
Tetra. 46(21) 7743 (1990)Ref. 42.
cat. NaBH4
non-chiral
NH2
amphetamine
O
1-phenylpropan-2-amine1-phenylpropan-2-one
NH2
U.S. pat . # 4950606 (1990)
NH2
1-phenylpropan-2-amine
chiral
Ref. 43.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
Bacill lus Megater ium
non-chiral Biotransformation
amino-acid transminase from
Bacil llus Megater ium
amino-acid transminase from
Ref. 43.
NH2
amphetamine1-phenylpropan-2-amine
NO2
LiBH4 /THF
(E)-(2-nitroprop-1-enyl)benzene
Angew Chem. Int. Ed. Engl. 28(2) 218-220 (1989)non-chiral
Ref. 44.
(CH3)3SiCl
NH
COOH
OO
2-(benzyloxycarbonyl)-3-phenylpropanoic acid
NH
OO
benzyl 1-phenylpropan-2-ylcarbamate
(CH3)3SiCl
LiBH4 /THF
S
CN
PhS CN
Ph
O
SPh
O
SPh
NOH
SPh
NH2
NH2
NaOEt
EtOH
H3PO4
NH2OH Na EtOH HCl
Coll. Czech. Chem. Comm. 54(7) 1995 (1989)non-chiral
Ref. 45.2-(2-(phenylthio)phenyl)acetonitrile
3-oxo-2-(2-(phenylthio)phenyl)butanenitrile
1-(2-(phenylthio)phenyl)propan-2-one
1-(2-(phenylthio)phenyl)propan-2-amine
N
Org. React ions 36, book (1988)
NH2
(E )-1-phenylpropan-2-one O-methyl oxime
Red - Al, THF
non-chiral
1-phenylpropan-2-amine
Ref. 46.
O
NO2
(E)-(2-nitroprop-1-enyl)benzene
Red-Al THFNH2
NO2
J.Med.Chem. 31(8) 1558 (1988)
NH2
(E)-(2-nitroprop-1-enyl)benzene
H
O
benzaldehyde
NO2 LiAlH4
non-chiral
1-phenylpropan-2-amine
Ref. 47.
NO2
JP 63219396 (1988)
NH2
1-phenylpropan-2-amine
chiral
Ref. 48.
(S)-1-phenylpropan-2-amine
Enzymic, Resolution
Biotransformation /
NH2N
NH2
Ref. 49.
amphetamine
O
NN
H
CH3Li / CeCl3N
HN H2 / Ra-Ni
375 psi / 60o
JACS 109(7) 2224-5 (1987)
2-phenylacetaldehyde(R)-2-methyl
pyrrolidin-1-amine
(R,E )-2-methyl-N-(2-phenylethylidene)
pyrrolidin-1-amine
(s)-1-phenylpropan-2-amine
chiral
(R)-2-methyl-N -((S)-1-phenylpropan-2-yl)
pyrrolidin-1-amine
O NH2
NH2
amphetamine
US 4000,197 (1976)
chiral
Ref. 50.
(S)-1-phenylpropan-2-amine
phenyl-2-propanone
HN*
*low pressure
Hydrogenation
HN*
*
[R,R]+
R or S
[S,S]-orRaney Ni / H2
[S,S]-(-)
10% Pd-C
50 psi H2
*
-methylbenzylamine
O
Ref. 51. Organometall ics, 5, 739-46 (1986)
NH2NOH
H-SiH(Ph)2
1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime
Rh(cod)Cl2
chiral
H
O
H
NNH
Ph
Ph
CH3
NNH
Ph
Ph
LDA
CH3I
Aphetamine
2-phenylacetaldehyde
J. Chem. Soc., Chem. Comm. 2, 176, (1986)
(E)-1-(2,2-dimethyl-1,1-diphenylpropyl)-2-(2-phenylethylidene)hydrazine
(E )-1-(2,2-dimethyl-1,1-diphenylpropyl)-2-(1-phenylpropan-2-ylidene)hydrazine
non-chiral Ref. 52.
H
O
H
NNH
Ph
Ph
CH3
NNH
Ph
Ph
LDAAphetamine
1. TFA
J. Chem. Soc., Chem. Comm. 2, 176, (1986)non-chiral Ref. 52.
acetaldehyde
Ph-CH2-Br2. Pd /C H2
1. TFA
2. Pd /C H2
NH2NH2
US 2009292143 (2009)
(S)-1-phenylpropan-2-amine
non-chiral
Ref. 53.
OH
(1S,2S)-2-amino-1-phenylpropan-1-ol
NH2
Cl
Pd
H2
O
Ref. 54.
Khimiya Geterotsikl icheskikh Soedinenii 12, 1648 (1985)
NH2NOH
Na MeOH
1-phenylpropan-2-one (E)-1-phenylpropan-2-one oxime
chiral
Cl
OHN CF3
O
AlCl3
OHN CF3
O
H2 / Pd-COH
HN CF3
O
PBr3
BrHN CF3
O
H2 / Pd-C
HN CF3
O
NH2
amphetamine
K2CO3, MeOH
Ref. 55J.Org.Chem. 50(19)3481-4 (1985)
benzene(S)-2-(2,2,2-trifluoroacetamido)
propanoyl chloride(S)-2,2,2-trifluoro
-N -(1-oxo-1-phenylpropan-2-yl)acetamide
(S)-2,2,2-trifluoro-N-(1-hydroxy-1-phenylpropan-2-yl)acetamide
(S)-N-(1-bromo-1-phenylpropan-2-yl)-2,2,2-trif luoroacetamide
(S)-2,2,2-trifluoro-N-(1-phenylpropan-2-yl)acetamide (S)-1-phenylpropan-2-amine
chiral
NO2
Ref. 56. Syn. Comm. 15(9) 843 (1985)
NH2
(E)-(2-nitroprop-1-enyl)benzene
BH3 - THF
non-chiral
NaBH4
NH2
amphetamine
NO2
non-chiral
BH3 / THF
Syn. Comm. 14(12)1099(1984)
Ref. 57.
NaBH4
NH2
amphetamine
non-chiral Synthesis (4) 270-3 (1982)
Ref. 58.
PO
O
H2N
O
HN P
O
O
O
HCl /benzene
Hg(NO3)2
1,1-diCl-ethane
1. /
2. 10% NaOH / NaBH4
(E )-prop-1-enylbenzene
diethyl phosphoramidate
NH2
amphetamine
chiral Synthesis (4) 270-3 (1982)
Ref. 59.
NOH P
Ph
O
ClPh
CH2Cl2, DEAN
PPh
O
O
Ph(E)-1-phenylpropan
-2-one oxime
LAH
(-) Quinine / THF
HN
PPh
O
O
Ph
HCl / ethanol
O
Ref.60.
J. Labelled compounds and radiopharmaceuticals 18(6) 909 (1981)
NH2
1-phenylpropan-2-one
non-chiral
NH3 (Sealed)
Al, HgCl2, NH4OH, 100oC, 15min
Ref.61.
Helvet ica chimica Acta 61(2) 558 (1978)
NH2
(E)-prop-1-enylbenzene
non-chiral
NO NO2
NO
LiAlH4
NH2
amphetamine
N
T etrahedron 32(11) 1267-76 (1976)
OH
E & Z
(E)-1-phenylpropan-2-one oxime
chiral
1-phenylpropan-2-amine
Ref. 62.
LiAlH4
O
Ref.63.
J. Chem. Education 51, 671(1974)
NH2
1-phenylpropan-2-one
non-chiral
Al, HgCl2, NH4OH, 100oC, 15min
O
JMC 16(5) 480-3 (1973)
HN
1-phenylpropan-2-one
non-chiral
Ref.64.
NH2
H2N
(R)-1-phenylethanamine
(+) or (-)
Raney-Ni
H2
HN
(R)-1-phenyl-N-(1-phenylethyl)propan-2-amine
(S)-1-phenyl-N-((R)-1-phenylethyl)propan-2-amine
separationPd-C / H2
MeOH(S)-1-phenylpropan-2-amineof Diastereoisomers
O
Ref.65.
JACS 93, 2897 (1971)
NH2
1-phenylpropan-2-one
non-chiral
NaCNBH3
NH4OH, MeOH
O
OH
Ref. 66.
EP 915080 (1999)chiral resolution
NH2 NH2
racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine
OH
(s)-2-naphthylglycolic acid
NO2
Ref. 67. J.Med.Chem. 13, 26(1970)
NH2
(E)-(2-nitroprop-1-enyl)benzene
LiAlH4 / THF
non-chiral
HN
amphetamine1-phenylpropan-2-amine
JACS 91, 5647 (1969)non-chiral
Ref. 69.
NCH3CN Hg(NO3)2 ONO2
Hg
NO3
HN ONaBH4
NaOH
HCl
allylbenzene
N-(1-phenylpropan-2-yl)acetamide
NO2
Ref. 70. US Pat. 3,458,576 (1969)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Pd-C / H2
Pt / H2
Raney-Ni / H2
O
Ref.71.
Coll. Czech. Chem. Comm. 33(11) 3551-7(1968)
NH2
1-phenylpropan-2-one
non-chiral
NH4 HCOO Ammonium FormateHCl
Ref.71.
Coll. Czech. Chem. Comm. 33(11) 3551-7(1968)
NH2
chiral
NH2 (+)-tartaric acid
EtOH
1-phenylpropan-2-amine(S)-1-phenylpropan-2-amine
J. Heterocyclic Chem._5(3)339(1968)
NH2
non-chiral
1-phenylpropan-2-amine
Ref. 72.
HN
AlCl3
2-methylaziridinebenzene
N
T etra. 24(16) 5677 (1968)
NH2LiAlH4
non-chiral
1-phenylpropan-2-amine
Ref. 73.
OR
R = H or R = Ts
THF
Ref.74.
Chem Pharm Bull 13(2)118(1965)
NO2
prop-1-ynylbenzene
non-chiral
NOClnitrosyl chloride
NO2Clhypochlorous nitrous anhydride
Cl
NO2
Cl
Pt2O
H2
O
Ref.75.
US Pat. 3,187,047 (1965)
NH2
1-phenylpropan-2-one
non-chiral
NH4 oAc Raney-Ni / H2
O
Ref.76.
T etra. 19, 1789 (1963)
NH2
1-phenylpropan-2-one
non-chiral
NH4 Formic Acid
LEUCKART-WALLACH Mech
NH2NH2
DE_1958-968545(1958)
(S)-1-phenylpropan-2-amine
non-chiral
Ref. 77.
OH
(1S,2S)-2-amino-1-phenylpropan-1-ol
NH2
Cl
Pd
H2
US 3028430 (1962)
NH2
amphetamine
1-phenylpropan-2-amine
NH2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chiral
COOH
RH2N
*
Ref. 78.
-amino acid
O
Ref.79.
US Pat. 2,828,343 (1958)
NH2
1-phenylpropan-2-one
non-chiral
NH3 (g) CuO and Ba(OH)2
H2
OH
ONH2
JOC_22(1)33(1957)
amphetamine
chiralRef. 80.
Cl
O
N3
O
(S)-2-methyl-3-phenylpropanoic acid
(S)-2-methyl-3-phenylpropanoyl chloride
(S)-2-methyl-3-phenylpropanoyl azide (S)-1-phenylpropan-2-amine
CO2Cl2
NaN3
HCl
Curtius rearrangement
OH
O
(S)-2-methyl-3-phenylpropanoic acid
NH2
amphetamine(S)-1-phenylpropan-2-amine
H2SO4 NaN3
Schmidt rearrangementchiral
Ref. 80.
US 2,833,823 (1958)
NH2
amphetamine1-phenylpropan-2-amine
NH2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chiral
Ref. 81binriched in one isomer
H3PO4
Zhurnal Obshchei Khimii 28 (1958) 3323-8
NH2
amphetamine
1-phenylpropan-2-amine
NH2
amphetamine
(S)-1-phenylpropan-2-amine
resolution
chiral
COOH
OHHO
*
Ref. 81a
HOOC
*d-Tartaricacid
NO2
Ref. 82. J_Pharm_Soc_Japan_413-416(1954)
NH2
(E)-(2-nitroprop-1-enyl)benzene
Raney-Ni
non-chiral
N
OH
Raney-Ni
O
Ref.83.
NH2
1-phenylpropan-2-one
non-chiral DE_1953-870265
NNH
(E)-1-phenyl-2-(1-phenylpropan-2-ylidene)hydrazine
PtO2
H2PhenylHydrazine
HN
NH2 Ph
NH2
amphetamine1-phenylpropan-2-amine
J. Labelled Comp. and Radio. 3(1) 3-9 (1977)chiral
Ref. 84.
NH2
COOH
NH2
D2COH
*
D-Phenylalanine
LiAlD4 * p-MeTOSClHN
D2CO
*S
O
CH3
O
p-TOSLiAlD4
HN
CD3
*S
O
CH3
O
Naphthalene radical anion
NO2
Ref. 85. JACS_74(7)1837(1952)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
LiAlH4
acidP-2-P (Nef reaction)
NO2
Ref. 86. US Patent 02647930B1(1953)
NH2
(E)-(2-nitroprop-1-enyl)benzene
Organic Acids
non-chiral
Raney-Ni / H2
NO2
Ref. 87. DE_1952-848197(1952)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H2
NH2
Chirali ty 6(4) 314-20 (1994)
NH2
1-phenylpropan-2-amine
chiral
Ref. 88.
(S)-1-phenylpropan-2-amine
Resolution
Distillation fromoptically active acids..
NO2
Ref. 89. Helv. Chim. Acta. 33, 912 (1950)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
LiAlH4 / ether
l-malic acid
OH
O
HO
O
OH
Ref. 90.
Org. Syn. Coll. 2, 506 (1943)chiral resolution
NH2 NH2
racemic-1-phenylpropan-2-amine (S)-1-phenylpropan-2-amine
/ water
OH
O
Cl
OO
O O
O
(1,3-diethoxy-1,3-dioxopropan-2-yl)magnesium ethanolate
2-phenylacetic acid 2-phenylacetyl chloride
SOCl2
O
O
O
O
O
diethyl 2-(2-phenylacetyl)malonate
O
1-phenylpropan-2-one
NOH
(E)-1-phenylpropan-2-one oxime
NH2
1-phenylpropan-2-amine
Mg
Onon-chiral
Ref. 91.J_Am_Pharm_Assoc_687-688(1950)
O
Ref.92.
NH2
1-phenylpropan-2-one
non-chiral
NH3 Raney-Ni / H2
Bull. Soc. Chem. France 1045 (1950)
NO2
NH2
(E)-1-phenylpropan-2-one oxime
non-chiralChemische Ber ichte 124(10) 2303-6 (1991)
Ref. 93.
NOH
Cathode Red. at Hg or C electrode
NO2
Ref. 94. JOC 15, 8 (1950)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H2
O
Ref.95.
NH2
1-phenylpropan-2-one
non-chiral
NH3 Raney-Ni / H2
GB 702985(1949)
or Pt or Pd
NO2
Ref. 96. US Pat. 2,636,901(1949)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Raney-Ni / H2
O
Ref.97.
JACS 70, 1187 (1948)
NH2
1-phenylpropan-2-one
non-chiral
NH4 Formic Acid
LEUCKART-WALLACH Mech
O
Ref.98.
JACS 70, 1315-6(1948)
NH2
1-phenylpropan-2-one
non-chiral
NH3 PtO2 / H2
N
Ref.99.
NH2
(E)-1-phenylpropan-2-one oxime
non-chiralY akugaku Zasshi 74, 413-16 (1954).
OH Raney Ni / H2
O
Ref.100.
NH2
1-phenylpropan-2-one
non-chiral
NH3 Raney-Ni / H2
JACS 70, 2811-12 (1948)
NH2
non-chiralBullet in of Electrochemisty 8(6) 276-7 (1992)
Ref. 101.
NOH Cathode Red. at Hg or C electrode
OH
Ref.102.
NH2
1-phenylpropan-2-ol
non-chiralJACS 70, 4048 (1948)
(E )-prop-1-enylbenzene
O
SO3H
1-phenylpropan-2-yl hydrogen sulfate
HCN
SO3H
N HCl
Ritter Reaction
NO2
Ref. 103. Justus_Liebigs_Annalen_der_Chemie_215-221(1948)
NH2
(E)-(2-nitroprop-1-enyl)benzene
non-chiral
Pd / H2
NH2
non-chiral J. Am. Chem. Soc. 68 (1946) 1009-11.
Ref. 104.
ClCl
FeCl3
orFuming Sulfuric
Cl NH4OH
Allyl Chloride
Friedel-Crafts reactions
O O
O
NH2
1-phenylpropan-2-amine
non-chiral
Ref. 105.
US Patent 2,413,493B1(1946)
ethyl 3-oxobutanoate
Acetoacetic Ester Synthesis Route
Na CH3-IO O
O
Na Ph-CH2-Cl
O O
O
OHOSOCl2 NH3
NH2O
2-methyl-3-phenylpropanoic acid
NaOCl
Hoffman
NaOH
O
Ref.106.
JOC 9, 529 (1944)
NH2
1-phenylpropan-2-one
non-chiral
NH4 Formic Acid
LEUCKART-Study
N
2-phenylacetonitrile
non-chiral
Ref. 107.
J.Applied Chem. (USSR) 14(3), 410 (1941)
N
O
OH3PO4O
O ethyl acetate
NaOEt
3-oxo-2-phenylbutanenitrile 1-phenylpropan-2-one
N-(1-phenylpropan-2-yl)formamide
HN O
ammonium formate
NH4+
O-O
HCl NH2
1-phenylpropan-2-amine
Acetylbenzylcyanide Reaction Route
O
OH
2-phenylacetic acid
non-chiral
HN
Ref.108.
J.Gen.Chem.(USSR) 11(4), 339 (1941)
NH2
N -(1-phenylpropan-2-yl)formamide
LEUCKART
Acetic Anhydride
OO
O
sodium acetate
O
O
O
O
O
1-phenylpropan-2-one
Formamide
OH2NO Hydrolysis H+
NH2
1-phenylpropan-2-amine
NH2
(S)-1-phenylpropan-2-amined-tartaric acid
OH
OHO
HO
O
OH
Ref.108.chiral Resolution
O
OH
2-phenylacetic acid
non-chiral
O
Cl
O
HC
N
N
O
NH2DiazomethaneSOCl2 NH3
AgO
Wolf f Rearr.
J. Am. Chem. Soc. 5 (1940) 267-85
Ref.109.
O
OH
non-chiral
O
NH2
Chemischen Ber ichte 66B, 684 (1933)
Ref.110.
Curtius Rearr.
O
N3
HN3 acid
-methylbenzylacetic acid
O
X
non-chiral
O
HN
NH2
J. Am. Chem. Soc. 55 (1933) 1701-5.
Ref.111.OH
Lossen Rearr.
NC
O HydrolysisHydroxyl amineacid chlorideestersanhydride
NO2
J.Am. Chem. Soc. 54, 271-4 (1933)
NH2
(E)-(2-nitroprop-1-enyl)benzene
H
O
benzaldehyde
NO2
non-chiral
1-phenylpropan-2-amine
Ref. 112.
Hg . Cathode
electrolic Red.
NH2
non-chiralUS 1879003 (1932)
Ref. 113.
NO2
Cathode Red. at Hg or C electrode
NH2
non-chiralChemicshe Ber ichte, 66B, 660-666 (1932).
Ref. 114.
NOH Na / Ethanol
NH2
non-chiral J. Am. Chem. Soc. 31, 1875 (1931)
Ref. 115.
N
OHO
NH2
OH
NH2
Cl
1-chloro-1-phenylpropan-2-amine
2-amino-1-phenylpropan-1-ol
(E)-2-(hydroxyimino)-1-phenylpropan-1-one
O
Ofrom
1-phenylpropane-1,2-dione
Pd/C, H2 HCl Pd/C, H2
NH2
non-chiral J. Am. Chem. Soc. 31, 2787-91 (1931)
Ref. 116.
NH2 Br2
O
NaOH
N3
O
1-azido-2-methyl-3-phenylpropan-1-one
Hofmann Rearr.
2-methyl-3-phenylpropanamide
Curtius Rearr.
NH2
non-chiral J . Chem. Soc. 18-21 (1930)
Ref. 117.
O N
OH
NH2-OH Na/Hg
amalgum
1-phenylpropan-2-one (Z)-1-phenylpropan-2-one oxime
Precursor list to amphetamine 1985 -2009
Precursor / intermediate / essentials References……
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107. J. Applied Chem. (USSR) 14(3) 410 (1941)
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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)
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67. J. Med. Chem. 13, 26 (1970)
70. US 3,458,576 (1969)
82. J.Pharm. Soc. Japan, 413-6(1954)
85. J. Am. Chem. Soc. 75(7) 1837(1952)
86. US 2647930B1 (1953)
87. DE 848197 (1952)
89. Helv. Chim. Acta. 33, 912 (1950)
94. J. Org. Chem. 15, 8 (1950)
96. US 2,636,901 (1949)
103. Justus Lieb. Ann. Chem. 215 (1948)
112. J. Am. Chem. Soc. 54, 271 (1933)
113. US 1879003 (1932)
3-phenylpropanol 5. Tetra. 63, 9758 (2007)
(R)-3-phenylpropane-1,2-diol 5. Tetra. 63, 9758 (2007)
2-benzyloxirane 5. Tetra. 63, 9758 (2007)
(R)-3-phenyl-2-(phenylamineooxy)
propan-1-ol
5. Tetra. 63, 9758 (2007)
tert-butyl 1-iodo-3-phenylpropan
-2-ylcarbamate
6. Chem. European J. 12(15)4191-7(2006)
9. Faming Zhuanli Shenging Gongkai
Shuominshu, patent 1673210 (2005)
tert-butyl 1-phenylpropan-2-
ylcarbamate
6. Chem. European J. 12(15)4191-7(2006)
9. Faming Zhuanli Shenging Gongkai
Shuominshu, patent 1673210 (2005)
(S)-1-phenylpropan-2-ol
And
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8. BioOrg. Med. Chem Lett. 15(12) 3039 (2005)
34. Tetra. Asym. 4(7) 1619 (1993)
(1R,2S)-2-amino-1-phenylpropan-1-
ol
11. J. Med. Chem. 48(4) 1229 (2005)
23. US 6399828 (2002)
40. J. Chrom. Sci. 28, 529 (1990)
53. Anal. Chem. 58(8) 1642 (1986)
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(1R,2S)-2-amino-1-phenylpropan-1-
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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)
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benzenesulfonamide
13. Org. and Biomolecular Chem. 3(6) 1049
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P-2-P = Phenyl-2-propanone
14. J. Chem. Research 10, 681 (2004)
19. Tetra. Asy, 14, 2119 (2003)
22. Tetra. Asym. 13(20) 2277 (2002)
32. J. Chem. Soc. Perkin Trans I, 265 (1996)
40. J. Chrom Sci. 28, 529 (1990)
43. US 4950606 (1990)
44. Angew Chem. Int. Ed. Engl. 28(2) 218
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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
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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
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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)
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(1-phenylpropan-2-yl) magnesium
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15. Org. Lett. 6(24) 4619 (2004)
4,4,5,5-tetramethyl-1,3-dioxolan-2- 15. Org. Lett. 6(24) 4619 (2004)
one O-tosyl oxime
(1S,2S)-1-phenyl propane-1,2-diol 16. Tetra. Asy, 15(19) 3111 (2004)
(1R,2S)-1-azido-1-phenylpropan-2-ol 16. Tetra. Asy, 15(19) 3111 (2004)
2-methyl-3-phenylaziridine 16. Tetra. Asy, 15(19) 3111 (2004)
2-phenylacetaldehyde
17. J. Combinatorial Chem. 5(5) 590 (2003)
49. J. Am. Chem. Soc. 109(7) 2224 (1987)
52. J Chem. Soc., Chem. Comm. 2, 176 (1986)
(R)-2-methyl propane-2-sulfinamide 17. J. Combinatorial Chem. 5(5) 590 (2003)
(R)-1-phenylethanamine 19. Tetra. Asy, 14, 2119 (2003)
1-(bromomethyl) benzene 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
(R)-3,3,5-trimethyl-1-propionyl
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21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
(S)-2-methyl-3-phenylpropanamide 21. J. Chem. Soc., Perkin T. I, 16, 1869 (2002)
(S)-2-amino-3-phenylpropanoic acid 25. J. Org. Chem. 65(16) 5037 (2000)
(S)-2-amino-3-phenylpropan-1-ol 25. J. Org. Chem. 65(16) 5037 (2000)
(S)-tert-butyl-1-phenylpropan-2-
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25. J. Org. Chem. 65(16) 5037 (2000)
1-phenyl-1-propyne 26. Org. Lett. 2(13) 1935 (2000)
74. Chem. Pharm. Bull. 13(2) 118 (1965)
allylbenzene 27. Tetra. 56, 5157 (2000)
69. J. Am. Chem. Soc. 91, 5647 (1969)
Phenylmagnesium bromide 31. Tetra. 53(13) 4935 (1997)
Diethyl-2-methylaziridin-1-
ylphosphonate
31. Tetra. 53(13) 4935 (1997)
(R)-2-(tert-butoxycarbonylamino)-3-
phenylpropanoic acid
33. Tetra. Lett. 36(8) 1223 (1995)
(R)-tert-butyl 1-hydroxy-
3-phenylpropan-2-ylcarbamate
33. Tetra. Lett. 36(8) 1223 (1995)
(S)-tert-butyl 1-phenylpropan-2-
ylcarbamate
33. Tetra. Lett. 36(8) 1223 (1995)
(1S,2S)-2-amino-1-phenylpropane-
1,3-diol
34. Tetra. Asym. 4(7) 1619 (1993)
(E)-1-phenylpropan-2-one oxime
And
(Z)-1-phenylpropan-2-one oxime
36. Tetra. Asym. 3(10) 1283 (1992)
51. Organometallics 5, 739 (1986)
54. Khimiya Geter Soedinenii 12, 1648 (1985)
59. Synthesis 4, 270 (1982)
62. Tetra. 32 (11) 1267 (1976)
73. Tetra. 24(16) 5677 (1968)
82. J. Pharm. Soc. Japan, 413 (1954)
91. J. Am. Pharm. Assoc. 687 (1950)
93. Berichte 124(10) 2303 (1991)
99. Yakugaku Zasshi 74, 413 (1954)
101. Bull. Electrochem. 8(6) 276 (1992)
114. Berichte, 66B, 660 (1932)
117. J. Chem. Soc. 18 (1930)
Dimethyl 2-benylmalonate 37. Acta. Chemica Scandinavica 45, 431 (1991)
Methyl-2-benyl-2-methyl-3-
oxobutanoate
37. Acta. Chemica Scandinavica 45, 431 (1991)
2-methyl-3-phenyl propanoic acid 37. Acta. Chemica Scandinavica 45, 431 (1991)
1-(2-(phenylthio)phenyl)propan-2-
amine
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
1-(2-(phenylthio)phenyl)propan-2-
one
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
3-oxo-2-(2-
(phenylthio)phenyl)butanenitrile
45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
2-(2-(phenylthio)phenyl)acetonitrile 45. Coll. Czesh. Chem. Comm. 54(7)1995(1989)
Benzaldehyde 47. J. Med. Chem. 31(8) 1558 (1988)
112. J. Am. Chem. Soc. 54, 271 (1933)
(E)-1-phenylpropan-2-one O-methyl
oxime
48. Org. Reactions 36, book (1988)
(R)-2-methyl pyrrolidin-1-amine 49. JACS 109(7) 2224-5 (1987)
(2,2-dimethyl-1,1-
diphenylpropyl)diazene
52. J. Chem. Soc., Chem. Comm. 2, 176 (1986)
benzene 55. J. Org. Chem 50(19) 3481 (1985)
72. J. Heterocyclic Chem. 5(3) 339 (1968)
2-(2,2,2-trifluoroacetamido)
propanoyl chloride
55. J. Org. Chem 50(19) 3481 (1985)
2,2,2-trifluoro-N-(1-oxo-1-phenyl
propan-2-yl)acetamide
55. J. Org. Chem 50(19) 3481 (1985)
2-(2,2,2-trifluoro-N-(1-hydroxy-1-
phenyl propan-2-yl)acetamide
55. J. Org. Chem 50(19) 3481 (1985)
N-(1-bromo-1-phenylpropan-2-yl)-
2,2,2-trifluoroacetamide
55. J. Org. Chem 50(19) 3481 (1985)
2-(2,2,2-trifluoro-N-(1-phenyl
propan-2-yl)acetamide
55. J. Org. Chem 50(19) 3481 (1985)
(E)-prop-1-enylbenzene 58. Synthesis 4, 270 (1982)
61. Hetvetica Chimica Acta 61(2) 558 (1978)
102. J. Am. Chem. Soc. 70, 4048 (1948)
1-(bromomethyl)benzene
Or
benzylbromide
21. J. Chem. Soc. Perkin T. I 16, 1869 (2002)
Phenylpropan-1-one 29. JP 2002142793 (2002)
Bromobenzene
Or
Phenylmagnesium bromide
31. Tetra. 53(13) 4935 (1997)
105. US 2,413,494 B1 (1946)
118. J. Am. Chem. Soc. 48, 169 (1928)
2-phenylacetic acid
Or
Phenylacetic acid
40. J. Chrom Sci. 28, 529 (1990)
91. J. Am. Chem. Soc. 687 (1950)
108. J. Gen. Chem. (USSR) 11(4) 339 (1941)
Prop-1-ynylbenzene 74. Chem. Pharm Bull. 13(2) 118 (1965)
(S)-2-methyl-3-phenylpropanoic acid 80. J. Org. Chem. 22(1) 33 (1957)
D-phenylalanine 84. J. Labelled Comp. Radio 3(1) 3 (1977)
Diethyl 2-(2-phenylacetyl)malonate 84. J. Labelled Comp. Radio 3(1) 3 (1977)
2-phenylacetyl chloride 84. J. Labelled Comp. Radio 3(1) 3 (1977)
Chlorobenzene 104. J. Am. Chem. Soc. 68, 1009 (1946)
Allyl Chloride 104. J. Am. Chem. Soc. 68, 1009 (1946)
Ethyl 3-oxobutanoate
Ethyl acetoacetate
105. US 2,413,494 B1 (1946)
118. J. Am. Chem. Soc. 48, 169 (1928)
2-methyl-3-phenylpropanoic acid 106. US 2,413,494 B1 (1946)
3-oxo-2-phenylbutanenitrile 107. J. Applied Chem (USSR) 14(3) 410 (1941)
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