A base-catalyzed domino-isomerization-hydroamination reaction - A new synthetic route to amphetamines

Article abstract of DOI:10.1016/S0040-4020(00)00436-1

An efficient synthesis of pharmaceutically interesting amphetamines by a base-catalyzed domino-isomerization- hydroamination reaction is presented. Starting from allylbenzene and various primary or secondary amines, the basic structural pattern of amphetamines is synthesized directly in yields of up to 91% in the presence of catalytic amounts of n-butyllithium. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00436-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5157±5162
A Base-Catalyzed Domino-Isomerization±Hydroamination
ReactionÐA New Synthetic Route to Amphetamines
Christian G. Hartung,a Claudia Breindl,b Annegret Tillacka and Matthias Bellera,
*
a
È
È
Institut fur Organische Katalyseforschung (IfOK) an der Universitat Rostock e.V., Buchbinderstraûe 5-6, D-18055 Rostock, Germany
b
È È È
Institut fur Anorganische Chemie der Technischen Universitat Munchen, Lichtenbergstraûe 4, D-85747 Garching, Germany
Received 28 March 2000; accepted 18 May 2000
AbstractÐAn ef®cient synthesis of pharmaceutically interesting amphetamines by a base-catalyzed domino-isomerization±hydroamination
reaction is presented. Starting from allylbenzene and various primary or secondary amines, the basic structural pattern of amphetamines is
synthesized directly in yields of up to 91% in the presence of catalytic amounts of n-butyllithium. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
Most of these reactions have disadvantages because they
require complicated substrates as starting materials in
combination with a hydrogen donor, they use stoichiometric
amounts of toxic mercury salts or they produce at least one
equivalent of a salt as a by-product.
New amination reactions are of general interest in synthetic
organic and industrial chemistry because of the importance
of amines and their derivatives as natural products, pharma-
cological agents, ®ne chemicals and dyes. The direct addi-
tion of N-nucleophiles to alkenesÐthe hydroamination
reactionÐis the most atom economic and elegant way to
synthesize amines, since in principle no by-products are
formed.1 The low prices and ubiquitous availability of the
substrates are further advantages of the hydroamination in
contrast to classical amination reactions. Although transi-
tion metal complexes,1 lanthanide catalysts2 and traditional
acids3 as well as bases4 have been used as catalysts for the
hydroamination of ole®ns, so far no ef®cient general
methodology has been developed. Therefore, a general
hydroamination reaction is still one of the major goals in
catalysis research.5
Results and Discussion
Â
In 1998, Seijas and Vazquez-Tato et al. demonstrated that
the synthesis of 2-phenylethylamines can be performed by
the addition of lithium amides to styrene derivatives.11 In
the ®rst step the lithium amide was prepared in a stoichio-
metric reaction of the amine with n-butyllithium. The subse-
quent addition to the styrene derivative is performed with a
2.5-fold excess of the lithium amide. For instance, the
conversion of b-methylstyrene and different amines leads
to amphetamine derivatives in yields of 33±58%. In earlier
work we showed that styrene derivatives are hydroaminated
with amines, even in the presence of only catalytic amounts
of bases, in excellent yields of up to 99%.12 Consequently,
we were interested in developing an ef®cient method for
preparing amphetamines in a catalytic hydroamination
reaction.
Derivatives of 2-amino-1-phenylpropane (amphetamines)
belong to the psychopharmacologically active class of
sympathomimetic drugs and are of pharmacological interest
not only because of the stimulating and inhibiting effect on
the central nervous system, but also due to their anti-in¯am-
matory activity and ability to inhibit several enzymes.6 In
general, classical methods for synthesizing the C±N bond in
amphetamines are the reductive amination reactions of the
appropriate ketones,7 reactions of aryl aldehydes with
nitroalkanes and subsequent reduction,8 amidomercura-
tion±demercuration of ole®ns9 or N-alkylation of ammonia,
primary and secondary amines using alkylating agents.10
In view of our earlier work,12 the base-catalyzed conversion
of alkenes and amines with n-butyllithium seemed to be a
promising approach to this goal. Due to the considerably
lower price of allylbenzene compared to b-methylstyrene
(ca. 5-fold)13 we were interested in the direct synthesis of
amphetamines via base-catalyzed domino-reaction14 of
allylbenzenes. Preliminary studies revealed that under the
reaction conditions required for base-catalyzed hydro-
amination, it should be possible to isomerize allylbenzene
to yield b-methylstyrene.15 Thus, as a model reaction to
generate amphetamine derivatives we studied the reaction
Keywords: domino-isomerization±amination reaction; base-catalysis;
hydroamination; amphetamines.
* Corresponding author. Tel.: 149-381-4669313; fax: 149-381-4669324;
e-mail: matthias.beller@ifok.uni-rostock.de
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00436-1

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C. G. Hartung et al. / Tetrahedron 56 (2000) 5157±5162
Table 1. n-Butyllithium-catalyzed hydroamination of allylbenzene (1) with piperidine (2) (allylbenzene±piperidine ratio 2:1; 20 mol% n-BuLi refers to
piperidine)
Entry
Temperature (8C)
Solvent
Additive (mol%)
Yield of 3 (%)a
1
2
3
4
5
6c
7
8
9
Room temperature
278 to room temperature
50
THF
THF
THF
THF
THF
THF
Toluene
Toluene
Pentane
±
±
±
±
89
91
85
60
88
68
20
88
60
100
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
TMEDAb (20)
±
±
TMEDAb (20)
TMEDAb (20)
a Yields refer to piperidine and were determined by GC with internal standard (hexadecane).
b TMEDA: tetramethylethylenediamine.
c Allylbenzene±piperidine ratio 1:1.
of allylbenzene (1) and piperidine (2) (Table 1). Indeed, in
the presence of catalytic amounts of n-butyllithium
(0.2 equiv.) a fast isomerization of allylbenzene to the
thermodynamically more stable isomer b-methylstyrene is
observed at room temperature. The subsequent hydroamina-
tion of b-methylstyrene proceeds regioselectively (.99%)
to yield N-2-(1-phenyl)propyl-piperidine 3. As shown in
Table 1 the reaction gave the best yields of product 3
(89±91%) using an allylbenzene±piperidine ratio of 2:1 in
tetrahydrofuran as the solvent at room temperature.
Oligomers of b-methylstyrene are obtained as side-
products by an anionic polymerization reaction. The
amount of oligomers increases at higher reaction
temperature. Using an equimolar amount of allyl-
benzene and piperidine, product 3 is obtained in 68%
yield (entry 6). In general, the hydroamination of allyl-
benzene can also be performed in nonpolar solvents
such as toluene or pentane in the presence of tetra-
methylethylenediamine (TMEDA) as the co-catalyst.
TMEDA is needed for the solvation and deaggregation
of n-butyllithium and the resulting lithium amides
(entries 7, 8, 9). Remarkably, no oligomers of b-methyl-
styrene were detected applying these nonpolar solvents.
The scope of the new domino-isomerization±hydroamina-
tion reaction is demonstrated in the reaction of allylbenzene
and 4-phenyl-1-butene with various primary and secondary
amines (Table 2 and Scheme 1).
Table 2. n-Butyllithium-catalyzed hydroamination of allylbenzene (1) with primary and secondary amines (allylbenzene±amine ratio 2:1; 20 mol% n-BuLi
refers to the amine)
Entry
Amine
Product
Temperature (8C)
Solvent
Additive (mol%)
Yield of amphetamine (%)a
1
2
3
4
Room temperature
50
100
THF
THF
Toluene
±
±
44
88
38
TMEDAb (20)
4
5
5
6
50
50
THF
Toluene
±
65
22
TMEDAb (20)
6
7
50
100
THF
Toluene
TMEDAb (20)
TMEDAb (20)
32 (de 8%)
36 (de 0%)
8
9
7
8
9
50
100
THF
Toluene
±
62
41
TMEDAb (20)
10
11
12c
Room temperature
50
THF
Toluene
±
66
36
TMEDAb (20)
120
THF
KOtBu (30)
54
a Yields refer to the amine and were determined by GC with internal standard (hexadecane).
b TMEDA: tetramethylethylenediamine.
c Allylbenzene±aniline ratio 1:1; mixture of 30 mol% n-BuLi and 30 mol% KOtBu.

C. G. Hartung et al. / Tetrahedron 56 (2000) 5157±5162
5159
Scheme 1.
As shown in Table 2 most of the applied amines give
improved yields of hydroamination products at higher
reaction temperatures compared to piperidine. As an
example morpholine reacts with allylbenzene at 508C to
give the corresponding amphetamine in 88% yield, while
the reaction at room temperature leads to only a 44% yield
(Table 2, entries 1, 2). With toluene as the solvent, in
general higher temperatures are required, however, the
yields are lower compared to tetrahydrofuran (22±41%
yield, entries 3, 5, 9, 11); but advantageously no oligomers
of the alkene are formed. Apart from cyclic and acyclic
secondary amines primary amines such as benzylamine or
n-butylamine produce the corresponding products in tetra-
hydrofuran as the solvent in yields of 65 and 62%, respec-
tively. (Table 2, entries 4, 8). The catalytic hydroamination
reaction with the chiral amine S-(2)-a-methylbenzylamine
only resulted in the formation of diastereomeric mixtures
(diastereomeric excess ,10%) in yields of 32 and 36%
(Table 2, entries 6, 7). Interestingly, anilines may be used
successfully in this new domino-amination reaction. Due to
the lower nucleophilicity of lithium anilides compared to
aliphatic amides the addition of KOtBu as the second base
is needed to generate the more ionic and therefore more
reactive potassium anilides in situ in low concentrations.12a
Hence, in the presence of a mixture of 0.3 equiv. n-butyl-
lithium and 0.3 equiv. KOtBu, aniline reacts with allyl-
benzene to give the amphetamine derivative in 54% yield
(Table 2, entry 12).
benzenes. The reaction is easily performed and does not
require expensive reagents. Further investigations on stereo-
selective variants of this method are currently under
investigation.
Experimental
Chemicals were obtained from Aldrich and Fluka and used
without further puri®cation. All operations were carried out
under an argon atmosphere. Solvents and amines were dried
according to standard procedures. NMR spectra (1H, 13C)
were recorded with a 400 MHz Bruker ARX 400 instrument
(1H: 400.1 MHz, 13C: 100.6 MHz). 1H and 13C NMR chemi-
cal shift were referenced to tetramethylsilane (0 ppm) and
CDCl3 (77.0 ppm), respectively. Coupling constants are
reported in Hertz. Elemental analyses were performed by
the Microanalytical Laboratory at IfOK Rostock. GC±MS
spectra were measured with a Hewlett±Packard gas chro-
matograph GC 5890 equipped with a mass-selective detec-
tor MS 5989 A. Quantitative analyses were performed with
a Hewlett±Packard GC 6890 instrument using a HP-5 capil-
lary column in conjunction with a ¯ame ionization detector
(GC/FID). Column chromatography was carried out using
silica gel 60 (0.063±0.2 mm Fluka). The hydroamination
reactions were performed in Aldrich Ace-pressure tubes
(30 ml). (Caution: The required safety measures should be
taken when performing reactions under pressure.)
We would like to emphasize that tertiary (double alkylated)
amines were produced in yields ,1% in the reactions of
allylbenzene with primary amines. This makes the method
especially attractive for the selective synthesis of `second-
ary amphetamines' because typical nucleophilic substitu-
tion procedures with primary amines gave mixtures of
secondary, tertiary and even quaternary amines. Further-
more, the reaction of benzylamine is noteworthy, since the
benzyl group is easily removed by hydrogenation with H2/
Pd/C to give 1-phenyl-2-aminopropane in 65% overall yield
by GC analysis.
General procedure
The amine (2.5 mmol) and 100 ml hexadecane (internal
standard) were dissolved in 5 ml dry tetrahydrofuran in an
Ace-pressure tube under an argon atmosphere. 20 mol%
n-butyllithium (1.6 M n-BuLi solution in hexane) was
added slowly at room temperature. The solution was stirred
for 10 min and then allylbenzene (5 mmol) was added. The
intensive coloured solutions were reacted for 20 h at the
de®ned temperature. After cooling to room temperature,
the solution was quenched with 2 ml water, whereby a
discolouration of the solution was observed. The products
were isolated by acidi®cation of the mixture with 5 ml of
1 M HCl followed by addition of 5 ml dichloromethane.
The resulting aqueous phase was collected and the organic
phase was extracted three times with 5 ml of 1 M HCl. The
combined aqueous phases were neutralized with solid
Na2CO3 and were extracted ®ve times with 5 ml dichloro-
methane. The organic phases were washed with water and
dried over MgSO4. After removal of the solvent in vacuo the
products were isolated by column chromatography.
The presented domino-isomerization±hydroamination reac-
tion has also been expanded to aryl ole®ns whereby the
double bond is separated from the aryl group by two CH2-
units. In the reaction of 4-phenyl-1-butene 10 with piper-
idine 2, the 2-amino-1-phenylbutane derivative 11 is
produced in 59% yield in tetrahydrofuran as the solvent at
508C (Scheme 1). In toluene 11 can be obtained in 50%
yield without any formation of oligomers.
In conclusion, we have found that amphetamine derivatives
can be produced atom-ef®ciently by a new base-catalyzed
domino-isomerization±hydroamination reaction of allyl-
N-2-(1-Phenyl)propyl-piperidine (3). According to the
general procedure piperidine (2.5 mmol; 247 ml) and allyl-

5160
C. G. Hartung et al. / Tetrahedron 56 (2000) 5157±5162
benzene (5 mmol; 662 ml) were reacted in the presence of
20 mol% n-BuLi solution (0.5 mmol; 313 ml) at room
temperature. The residue was puri®ed by column chromato-
graphy (n-hexane/ethyl acetateˆ3:1) to afford 3 as a colour-
less oil.ÐYield: 89% (GC); 84% (isolated).Ð1H NMR
(CDCl3, 258C, dˆppm): 7.24 (m, 2H, phenyl); 7.15 (m,
662 ml) were reacted in the presence of 20 mol% n-BuLi
solution (0.5 mmol; 313 ml) and 20 mol% tetramethylethyl-
enediamine (0.5 mmol, 75 ml) at 508C. The residue was
puri®ed by column chromatography (n-hexane/ethyl
acetateˆ2:1) to afford the diastereomeric mixture of 6 as
a colourless oil.ÐYield: 32% (GC); 30% (isolated).Ð1H
NMR (CDCl3, 258C, dˆppm): 7.36±6.94 (m, 2£10H,
phenyl); 3.93, 3.88 (2£q, 3J(H,H)ˆ6.6 Hz, 2£1H,
Ph±CHMe±N); 2.88, 2.66 (2£dd, 2J(H,H)ˆ12.9 Hz,
3J(H,H)ˆ 5.0 Hz, 2£1H, Ph±CH2); 2.77, 2.65 (2£m,
2
3
3H, phenyl); 3.00 (dd, J(H,H)ˆ12.9 Hz, J(H,H)ˆ3.8 Hz,
1H, Ph±CH2); 2.76 (ddq, 3J(H,H)ˆ10.1 Hz, 3J(H,H)ˆ
3
6.5 Hz, J(H,H)ˆ3.8 Hz, 1H, Ph±CH2±CH); 2.54 (m, 4H,
N±CH2); 2.36 (dd, 2J(H,H)ˆ12.9 Hz, 3J(H,H)ˆ10.1 Hz,
2
1H, Ph±CH2); 1.59 (m, 4H, N±CH2±CH2); 1.43 (m, 2H,
2£1H, Ph±CH2±CH); 2.59, 2.50 (2£dd, J(H,H)ˆ12.9 Hz,
3
N±CH2±CH2±CH2); 0.91 (d, J(H,H)ˆ6.5 Hz, 3H, CH3).
3J(H,H)ˆ7.5 Hz, 2£1H, Ph±CH2); 1.46 (2£s, 2£1H, NH);
13C NMR (CDCl3, 258C, dˆppm): 141.0, 129.2, 128.1,
125.7, 62.1, 49.6, 39.1, 26.4, 24.9, 14.2. GC±MS:
m/zˆ203 [M1], 112 [M12C6H5±CH2], 91, 69. MS (CI,
isobutane): 204 [M11H], 112 [M12C6H5±CH2], 86.
Anal. Calcd for C14H21N: C 82.70, H 10.41, N 6.89.
Found: C 82.68, H 10.42, N 6.85.
1.31, 1.27 (2£d, 3J(H,H)ˆ6.7 Hz, 2£3H, Ph±CH(CH3)±N);
3
1.05, 0.92 (2£d, J(H,H)ˆ6.3 Hz, 2£3H, Ph±CH2±CH±
CH3). 13C NMR (CDCl3, 258C, dˆppm): 146.1, 145.4,
139.5, 139.3, 129.4, 129.2, 128.4, 128.3, 128.3, 128.2,
126.8, 126.6, 126.5, 126.3, 126.1, 125.9, 55.3, 54.8, 51.9,
50.8, 44.2, 42.5, 25.0, 24.5, 21.1, 19.9. GC±MS: m/zˆ239
[M1], 148 [M12C6H5±CH2], 105 [C6H5±CH±CH3], 91,
79. Anal. Calcd for C17H21N: C 85.30, H 8.84, N 5.85.
Found: C 85.20, H 8.88, N 5.86.
N-2-(1-Phenyl)propyl-morpholine (4). According to the
general procedure morpholine (2.5 mmol; 218 ml) and allyl-
benzene (5 mmol; 662 ml) were reacted in the presence of
20 mol% n-BuLi solution (0.5 mmol; 313 ml) at 508C. The
residue was puri®ed by column chromatography (n-hexane/
ethyl acetateˆ1:1) to afford 4 as a colourless oil.ÐYield:
88% (GC); 80% (isolated).Ð1H NMR (CDCl3, 258C,
dˆppm): 7.26 (m, 2H, phenyl); 7.16 (m, 3H, phenyl);
3.72 (m, 4H, O±CH2); 2.99 (dd, 2J(H,H)ˆ13.1 Hz,
3J(H,H)ˆ4.4 Hz, 1H, Ph±CH2); 2.75 (ddq, 3J(H,H)ˆ
N-n-Butyl-N-2-(1-phenyl)propyl-amine (7). According to
the general procedure n-butylamine (2.5 mmol; 247 ml) and
allylbenzene (5 mmol; 662 ml) were reacted in the presence
of 20 mol% n-BuLi solution (0.5 mmol; 313 ml) at 508C.
The residue was puri®ed by column chromatography (n-
hexane/ethyl acetateˆ1:2) to afford 7 as a colourless
oil.ÐYield: 62% (GC); 54% (isolated).Ð1H NMR
(CDCl3, 258C, dˆppm): 7.27 (m, 2H, phenyl); 7.17 (m,
3H, phenyl); 2.87 (sext, 3J(H,H)ˆ3J(H,H)ˆ6.5 Hz, 1H,
Ph±CH2±CH); 2.73 (dd, 2J(H,H)ˆ13.3 Hz, 3J(H,H)ˆ
6.5 Hz, 1H, Ph±CH2); 2.65 (ddd, 2J(H,H)ˆ11.1 Hz,
3
3
9.7 Hz, J(H,H)ˆ6.5 Hz, J(H,H)ˆ4.4 Hz, 1H, Ph±CH2±
2
CH); 2.60 (m, 4H, N±CH2); 2.39 (dd, J(H,H)ˆ13.1 Hz,
3
3J(H,H)ˆ9.7 Hz, 1H, Ph±CH2); 0.94 (d, J(H,H)ˆ6.5 Hz,
3H, CH3). 13C NMR (CDCl3, 258C, dˆppm): 140.3, 129.2,
128.2, 125.8, 67.3, 61.6, 49.0, 39.1, 14.2. GC±MS:
m/zˆ114 [M12C6H5±CH2], 91, 70. MS (CI, isobutane):
206 [M11H], 114 [M12C6H5±CH2]. Anal. Calcd for
C13H19NO: C 76.06, H 9.33, N 6.82. Found: C 76.06, H
9.19, N 6.88.
3
3J(H,H)ˆ8.1 Hz, J(H,H)ˆ6.5 Hz, 1H, N±CH2); 2.58 (dd,
2J(H,H)ˆ13.3 Hz, 3J(H,H)ˆ6.5 Hz, 1H, Ph±CH2); 2.51
(ddd, 2J(H,H)ˆ11.1 Hz, 3J(H,H)ˆ7.6 Hz, 3J(H,H)ˆ
6.7 Hz, 1H, N±CH2); 1.40 (m, 2H, N±CH2±CH2); 1.37 (s,
3
1H, NH); 1.25 (sext, J(H,H)ˆ3J(H,H)ˆ7.4 Hz, 2H, CH2±
3
CH2±CH3); 1.04 (d, J(H,H)ˆ6.5 Hz, 3H, CH±CH3); 0.85
N-2-(1-Phenyl)propyl-N-benzylamine (5). According to
the general procedure benzylamine (2.5 mmol; 273 ml)
and allylbenzene (5 mmol; 662 ml) were reacted in the
presence of 20 mol% n-BuLi solution (0.5 mmol; 313 ml)
at 508C. The residue was puri®ed by column chromato-
graphy (n-hexane/ethyl acetateˆ4:1) to afford 5 as a colour-
less oil.ÐYield: 65% (GC); 60% (isolated).Ð1H NMR
(CDCl3, 258C, dˆppm): 7.29±7.12 (m, 10H, phenyl); 3.83
(d, 2J(H,H)ˆ13.3 Hz, 1H, Ph±CH2±N); 3.72 (d,
2J(H,H)ˆ13.3 Hz, 1H, Ph±CH2±N); 2.92 (sext, 1H,
3J(H,H)ˆ3J(H,H)ˆ6.3 Hz, 1H, Ph±CH2±CH); 2.76 (dd,
2J(H,H)ˆ13.3 Hz, 3J(H,H)ˆ6.3 Hz, 1H, Ph±CH2±CH);
2.62 (dd, 2J(H,H)ˆ13.3 Hz, 3J(H,H)ˆ6.3 Hz, 1H, Ph±
(t, 3J(H,H)ˆ7.4 Hz, 3H, CH2±CH3). 13C NMR (CDCl3,
258C, dˆppm): 139.5, 129.2, 128.3, 126.1, 54.7, 47.0,
43.6, 32.3, 20.4, 20.2, 13.9. GC±MS: m/zˆ191 [M1], 176
[M12CH3], 100 [M12C6H5±CH2], 91, 77. Anal. Calcd for
C13H21N: C 81.61, H 11.06, N 7.32. Found: C 81.44, H
10.99, N 7.20.
N-n-Butyl-N-methyl-N-2-(1-phenyl)propyl-amine
(8).
According to the general procedure n-butylmethylamine
(2.5 mmol; 296 ml) and allylbenzene (5 mmol; 662 ml)
were reacted in the presence of 20 mol% n-BuLi solution
(0.5 mmol; 313 ml) at room temperature. The residue was
puri®ed by column chromatography (n-hexane/ethyl
acetateˆ3:1) to afford 8 as a colourless oil.ÐYield: 66%
(GC); 61% (isolated).Ð1H NMR (CDCl3, 258C, dˆppm):
7.26 (m, 2H, phenyl); 7.17 (m, 3H, phenyl); 2.94 (dd,
2J(H,H)ˆ12.5 Hz, 3J(H,H)ˆ4.0 Hz, 1H, Ph±CH2); 2.89
(m, 1H, Ph±CH2±CH); 2.44 (m, 2H, N±CH2); 2.38 (dd,
3
CH2±CH); 1.54 (s, 1H, NH); 1.08 (d, J(H,H)ˆ6.3 Hz,
3H, CH3). 13C NMR (CDCl3, 258C, dˆppm): 140.4,
139.4, 129.3, 128.3, 128.3, 127.9, 126.8, 126.1, 53.7, 51.2,
43.5, 20.1. GC±MS: m/zˆ134 [M12C6H5±CH2], 91, 65.
MS (CI, isobutane): 226 [M11H], 134 [M12C6H5±CH2].
Anal. Calcd for C16H19N: C 85.28, H 8.50, N 6.22. Found: C
85.19, H 8.51, N 6.19.
3
2J(H,H)ˆ12.5 Hz, J(H,H)ˆ9.5 Hz, 1H, Ph±CH2); 2.28 (s,
3H, N±CH3); 1.46 (m, 2H, N±CH2±CH2); 1.31 (m, 2H,
CH2±CH2±CH3); 0.91 (t, 3J(H,H)ˆ7.3 Hz, 3H, CH2±
3
N-(S)-1-Phenylethyl-N-2-(1-phenyl)propyl-amine
(6).
CH3); 0.90 (d, J(H,H)ˆ6.9 Hz, 3H, CH±CH3). 13C NMR
According to the general procedure S-(2)-a-methylbenzyl-
amine (2.5 mmol; 318 ml) and allylbenzene (5 mmol;
(CDCl3, 258C, dˆppm): 140.8, 129.2, 128.2, 125.7, 60.3,
53.2, 39.0, 37.1, 30.4, 20.7, 14.1, 13.9. GC±MS: m/zˆ205

C. G. Hartung et al. / Tetrahedron 56 (2000) 5157±5162
5161
[M1], 190 [M12CH3], 162 [M12CH2CH2CH3], 114
[M12C6H5±CH2], 91, 72, 58. Anal. Calcd for
C14H23N: C 81.89, H 11.29, N 6.82. Found: C 81.31,
H 11.19, N 6.76.
metallics 1998, 17, 1452. (b) Li, Y.; Marks, T. J. J. Am. Chem.
Soc. 1996, 118, 9295. (c) Li, Y.; Marks, T. J. J. Am. Chem. Soc.
1996, 118, 707. (d) Li, Y.; Marks, T. J. Organometallics 1996, 15,
3770. (e) Haar, C. M.; Stern, C. L.; Marks, T. J. Organometallics
1996, 15, 1765. (f) Giardell, M. A.; Conticello, V. P.; Brard, L.;
Â
Gagne, M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241.
N-2-(1-Phenyl)propyl-aniline (9). According to the
general procedure aniline (2.5 mmol; 228 ml) and allyl-
benzene (2.5 mmol; 331 ml) were reacted in the presence
of 30 mol% n-BuLi solution (0.75 mmol; 469 ml) and
30 mol% KOtBu (0.75 mmol, 84 mg) at 1208C. The residue
was puri®ed by column chromatography (n-hexane/ethyl
acetateˆ15:1) to afford 9 as a colourless oil.ÐYield: 54%
(GC); 50% (isolated).Ð1H NMR (CDCl3, 258C, dˆppm):
7.28 (m, 2H, phenyl); 7.18 (m, 3H, phenyl); 7.16 (m, 2H,
phenyl); 6.68 (m, 1H, phenyl); 6.62 (m, 2H, phenyl); 3.75
(m, 1H, Ph±CH2±CH); 3.61 (s, 1H, NH); 2.93 (dd,
2J(H,H)ˆ13.4 Hz, 3J(H,H)ˆ4.8 Hz, 1H, Ph±CH2); 2.68
(dd, 2J(H,H)ˆ13.4 Hz, 3J(H,H)ˆ7.3 Hz, 1H, Ph±CH2);
(g) Giardello, M. A.; Conticello, V. P.; Brard, L.; Sabat, M.;
Rheingold, A. L.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc.
1994, 116, 10212. (h) Li, Y.; Fu, P. F.; Marks, T. J. Organo-
Â
metallics 1994, 13, 439. (i) Gagne, M. R.; Stern, C. L.; Marks,
Â
T. J. J. Am. Chem. Soc. 1992, 114, 275. (j) Gagne, M. R.; Nolan,
Â
S. P.; Marks, T. J. Organometallics 1990, 9, 1716. (k) Gagne,
M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108. (l) Li,
Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757. (m) Molander,
G. A.; Dowdy, E. D. J. Org. Chem. 1999, 64, 6515. (n) Arredondo,
V. M.; McDonald, F. E.; Marks, T. J. Organometallics 1999, 18,
1949. (o) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J.
J. Am. Chem. Soc. 1999, 121, 3633.
3
1.13 (d, J(H,H)ˆ6.3 Hz, 3H, CH3). 13C NMR (CDCl3,
3. (a) Brunet, J.-J.; Neibecker, D.; Niedercorn, F. J. Mol. Catal.
1989, 49, 235. (b) Deeba, M.; Ford, M. E.; Johnson, T. A. In
Catalysis of Organic Reactions; Blackburn, D. W., Ed.; Marcel
Dekker: New York, 1990; p 241.
258C, dˆppm): 147.1, 138.5, 129.5, 129.3, 128.3, 126.2,
117.2, 113.4, 49.4, 42.2, 20.1. GC±MS: m/zˆ211 [M1],
120 [M12C6H5±CH2], 91, 77. Anal. Calcd for C15H17N:
C 85.26, H 8.11, N 6.63. Found: C 85.41, H 8.10, N 6.64.
4. (a) Wegler, R.; Pieper, G. Chem. Ber. 1950, 83, 1. (b) Howk,
B. W.; Little, E. L.; Scott, S. L.; Whitman, G. M. J. Am. Chem. Soc.
1954, 76, 1899. (c) Closson, R. D.; Napolitano, J. P.; Ecke, G. G.;
Kolka, A. J. J. Org. Chem. 1957, 22, 646. (d) Lehmkuhl, H.;
Reinehr, D. J. Organomet. Chem. 1973, 55, 215. (e) Pez, G. P.;
Galle, J. E. Pure Appl. Chem. 1985, 57, 1917. (f) Steinborn, D.;
Thies, B.; Wagner, I.; Taube, R. Z. Chem. 1989, 29, 333.
(g) Schlott, R. J.; Falk, J. C.; Narducy, K. W. J. Org. Chem.
1972, 37, 4243. (h) Narita, T.; Yamaguchi, T.; Tsuruta, T. Bull.
Chem. Soc. Jpn 1973, 46, 3825. (i) Asahara, T.; Seno, M.; Tanabe,
S.; Den, N. Bull. Chem. Soc. Jpn 1969, 42, 1996. (j) Fujita, T.;
Suga, K.; Watanabe, S. Aust. J. Chem. 1974, 27, 531. (k) Imai, N.;
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T.; Imai, N.; Tsuruta, T. Bull. Chem. Soc. Jpn 1973, 46, 1242.
5. Haggin, J. Chem. Eng. News 1993, May 31, 23.
N-2-(1-Phenyl)butyl-piperidine (10). According to the
general procedure piperidine (2.5 mmol; 247 ml) and
4-phenyl-1-butene (5 mmol; 746 ml) were reacted in the
presence of 20 mol% n-BuLi solution (0.5 mmol; 313 ml)
at 508C. The residue was puri®ed by column chromato-
graphy (n-hexane/ethyl acetateˆ4:1) to afford 10 as a
colourless oil.ÐYield: 59% (GC); 57% (isolated).Ð1H
NMR (CDCl3, 258C, dˆppm): 7.25 (m, 2H, phenyl); 7.16
(m, 3H, phenyl); 2.94 (dd, 2J(H,H)ˆ12.9 Hz, 3J(H,H)ˆ
4.0 Hz, 1H, Ph±CH2); 2.66±2.40 (m, 5H, N±CH2, Ph±
2
3
CH2±CH); 2.33 (dd, J(H,H)ˆ12.9 Hz, J(H,H)ˆ9.0 Hz,
1H, Ph±CH2); 1.54 (m, 4H, N±CH2±CH2); 1.49±1.38 (m,
3H, N±CH2±CH2±CH2, Ph±CH2±CH±CH2); 1.32 (m, 1H,
3
Ph±CH2±CH±CH2); 0.81 (t, J(H,H)ˆ7.3 Hz, 3H, CH3).
6. (a) Pelletier, S. W. Chemistry of Alkaloids; Van Nostrand-
Reinhold: New York, 1970. (b) Leake, C. D. The Amphetamines:
Their Actions and Uses; Charles C. Thomas Co.: Spring®eld, 1958.
(c) Testa, B.; Salvesen, B. J. Pharm. Sci. 1980, 69, 497. (d) Laske,
R.; Meindl, W.; Holler, E.; SchoÈnenberger, H. Arch. Pharm.
(Weinheim Germany) 1989, 322, 297, 847. (e) Mutschler, E.
Arzneimittelwirkungen, 7th ed.; Wissenschaftliche Verlagsge-
sellschaft: Stuttgart, 1996.
13C NMR (CDCl3, 258C, dˆppm): 141.7, 129.2, 128.1,
125.4, 68.6, 49.6, 35.5, 26.6, 25.1, 23.3, 11.7. GC±MS:
m/zˆ217 [M1], 188 [M12CH2CH3], 126 [M12C6H5±
CH2], 91, 69. Anal. Calcd for C15H23N: C 82.89, H 10.67,
N 6.44. Found: C 82.80, H 10.62, N 6.33.
Acknowledgements
7. (a) Novelli, A. An. Asoc. Quim. Argent. 1939, 27, 169.
(b) Glennon, R. A.; Smith, J. D.; Ismaiel, A. M.; El-Ashmawy,
M.; Battaglia, G.; Fisher, J. B. J. Med. Chem. 1991, 34, 1094.
(c) Nicols, D. E. J. Med. Chem. 1973, 16, 480. (d) Jacobsen
Skand. Arch. Physiol. 1938, 79, 258, 279. (e) Freifelder, M.;
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Perkin Trans. 1 1996, 265.
We thank Dr Martin Hateley (IfOK, Rostock) for helpful
comments on the manuscript and the Deutsche Forschungs-
gemeinschaft (BE 1931/3-1) and FORKAT-II for ®nancial
support.
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