An easy three step synthesis of perfluoroalkylated amphetamines

Article abstract of DOI:10.1016/j.tetlet.2004.08.080

A general method for the synthesis of fluoroalkylated amphetamine derivatives is presented starting from commercially available arylacetylenes. The method allows the preparation of primary, secondary, and tertiary amines.

Full text of DOI:10.1016/j.tetlet.2004.08.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7703–7707
An easy three step synthesis of perfluoroalkylated amphetamines
Amit Tewari,a Martin Hein,a,* Alexander Zapfb and Matthias Bellerb,*
aUniversita¨t Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Organische Katalyse an der Universitta¨t Rostock e.V. (IfOK), Buchbinderstraße 5–6,
D-18055 Rostock, Germany
Received 2 June 2004; revised 13 August 2004; accepted 16 August 2004
Abstract—A general synthesis of perfluoroalkylated amphetamines is presented. Initially, 1-aryl-1-iodo-2-(perfluoroalkyl)ethylenes
are prepared by radical addition of perfluoroalkyl iodides to arylacetylenes. Key step of the reaction sequence is the following
dehydroiodination in the presence of n-BuLi to give 1-perfluoroalkyl-2-arylacetylenes in situ, which are reacted with secondary
amines to produce perfluoroalkylated enamines in a new one pot procedure. Final hydrogenation yields the desired products in good
yields. By using N,N-dibenzylamine or N-benzylamines the corresponding primary and secondary perfluoroalkylated amines are
easily available.
Ó 2004 Elsevier Ltd. All rights reserved.
NH2
CH3
NHCH3
1. Introduction
O
O
CH2CH3
2-Aminoprop-1-ylbenzene and its derivatives (amphet-
amines) belong to the class of sympathomimetic drugs
(Fig. 1). They are of pharmacological interest due to
their stimulating or inhibiting effect on the central nerv-
ous system, their anti-inflammatory activity and their
ability to inhibit several enzymes.1
Amphetamine
2-(Methylamino)but-1-yl-(3,4-
methylenedioxy)benzene (MBDB)
Figure 1. Biologically active amphetamines.
sponding amphetamine derivatives via an isomeriza-
tion–hydroamination sequence.7
Classic methods for synthesizing amphetamines include
reductive amination reactions of appropriate ketones,2
reactions of aromatic aldehydes with nitroalkanes and
subsequent reduction,3 amidomercuration–demercura-
tion of olefins4 or N-alkylation of ammonia, primary
and secondary amines.5 Most of these reactions have
significant drawbacks, because they require not easily
available starting materials, they use stoichiometric
amounts of toxic mercury salts or they produce at least
one equivalent of a salt as a by-product.
Based on this work we were interested in extending the
methodology to prepare more functionalized, for exam-
ple, fluorinated, amphetamines by hydroamination reac-
tions.8 Here, our studies toward a general synthesis of
perfluoroalkylated amphetamine derivatives are
described.
It is well established that the introduction of fluorine or
fluoroalkyl groups into organic molecules changes their
chemical and physical properties as well as their biologi-
cal activity. Often fluorine has been used to replace
hydrogen or hydroxyl groups, and CF2 groups were
introduced instead of carbonyl groups in order to obtain
substances with similar sterical properties but with dif-
ferent reactivity or physicochemical behavior. A signifi-
cant amount of partially fluorinated compounds is
nowadays in use or at various stages of clinical trials
as anticancer, antiviral, antibacterial, antimalarial, anti-
fungal, or CNS active agents.9 It is generally agreed on
In the past we demonstrated that simple styrenes are effi-
ciently hydroaminated with amines in the presence of
catalytic amounts of a base.6 It is also possible to
hydroaminate allylbenzenes directly to give the corre-
Keywords: Amphetamines;
Perfluoroalkylation.
Hydroamination;
Alkynes;
*
Corresponding authors. Fax: +49 381 4986412 (M.H.); tel.: +49 381
466930; fax: +49 381 4669324 (M.B.); e-mail addresses: martin.hein@
chemie.uni-rostock.de; matthias.beller@ifok.uni-rostock.de
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.080

7704
A. Tewari et al. / Tetrahedron Letters 45 (2004) 7703–7707
Table 1. Reaction of arylacetylenes with perfluoro-alkyl iodides
that the introduction of fluorine or a short fluoroalkyl
chain into specific parts of a molecule (e.g., aromatic
cores) is advantageous because of the increase in the
lipophilic character of the respective compound, which
improves its in vivo transport and absorption behav-
ior.10 On the other hand fluorine atoms proved to be
suitable markers for in vivo and in vitro 19F NMR stud-
ies of the metabolism of drugs.11
Entry
R
RF
Product
Yield (%)
1
H
C6F13
C8F17
C6F13
C8F17
1
2
3
4
75
50
45
40
2
H
3-OMe
3
44
Despite the importance of amphetamines on the one
hand and fluorinated pharmaceuticals on the other hand
until now, very little work has been done toward the
synthesis of fluorinated analogues of amphetamines.12
-CF
3
Although the introduction of longer perfluoroalkyl
groups into amphetamine analogues seems less favora-
ble from a pharmacological point of view, we decided
to introduce perfluorohexyl and perfluorooctyl chains
as model systems because of the lower volatility of the
starting materials and intermediates, which do not
require special equipment for handling.
by X-ray crystallography16 and NMR studies and is in
agreement with the literature.17
Next, we thought that olefins 1–4 should undergo in situ
dehydroiodination to produce the corresponding alky-
nes, which might react with amines to give 2-aryl-1-per-
fluoroalkyl enamines. Indeed, in the presence of 2equiv
of n-BuLi immediate formation of 1-aryl-2-(perfluo-
roalkyl)alkynes is observed, which can be trapped di-
rectly with various secondary amines to yield the
desired enamines 5–14 (Table 2).18
2. Results and discussion
Our initial attempts to synthesize [2-amino-2-(perfluo-
roalkyl)ethyl]benzenes started from b-fluoroalkylated
styrenes, which were prepared by radical addition of
fluoroalkyl halides to styrene or related reactions and
subsequent HX-elimination,13 using a base-catalyzed
hydroamination reaction (Scheme 1). Although base-
catalyzed hydroaminations work reliably with a number
of styrenes,14 the reaction did not work in the case of b-
fluoroalkylated styrenes. Here, only starting material
was recovered from the reaction mixtures.
Interestingly, this novel two step one-pot reaction is not
a simple nucleophilic substitution of the vinylic iodide
and proceeds highly regio- and stereoselectively. The
amine adds nearly exclusively (>95%) at the alkyne car-
bon, which is attached to the perfluoroalkyl group.
Despite the electron-withdrawing character of the per-
fluoroalkyl group the negative charge is better stabilized
in a-position to the aryl group. Hence, in all cases the 2-
aryl-1-perfluoroalkylenamines are formed regioselec-
tively. X-ray studies of product 10 (Table 2, entry 6)
show the morpholine and phenyl ring on the same side
of the resulting double bond confirming the (Z)-config-
uration for 10. This stereochemical assignment for the
enamines is also supported by NOE experiments.
For example, in the case of N-[3,3,4,4,5,5,6,6,
7,7,8,8,9,9,10,10,10-heptadecafluoro-1-(4-trifluorometh-
ylphenyl)dec-1-en-2-yl]morpholine (14) (Table 2, entry
10) a correlation between the ortho-proton of the
aromatic ring and N–CH2 protons of the morpho-
line ring was observed, which confirms the (Z)-
configuration.
Alternatively, we explored the possibility of hydroami-
nation reactions of 1-perfluoroalkyl-2-aryl-acetylenes.15
Fluorinated acetylenes are conveniently synthesized by
free radical addition of 1-iodoperfluoroalkanes to aryl-
acetylenes. Thus, treatment of perfluoroalkyl iodides
with three different arylalkynes in the presence of di-
tert-butyl peroxide at 110–120°C yielded 1-aryl-1-iodo-
2-(perfluoroalkyl)ethylenes in 40–75% yield (Table 1).
The addition of RFI to arylacetylenes was also per-
formed at lower temperature (0°C–rt) using sodium
dithionite as radical initiator. However, these reactions
generally resulted in lower yields due to side reactions
of dithionite.
Finally, the reduction of 5–14 was investigated with dif-
ferent reagents (LiAlH4, NaBH4, BH3, LiBH4/ClSiMe3,
and H2 with Pd/C). Here, only the catalytic hydrogena-
tion gave satisfactory results and the desired amines
15–24 could be isolated in good to excellent yields (70–
95%).19
In all cases the corresponding E-isomer is obtained
exclusively. Similar conversions of non-aryl substituted
olefines are known to give mixtures of E- and Z-ole-
fins.16 The reason for the high E-selectivity in case of
arylacetylenes is unclear, but a correlation with the dif-
ferent radical geometry is supposed. The stereochemis-
try of the resulting iodinated olefins 1–4 was confirmed
Noteworthy, in case of N-benzylated enamines 11 and
13 (Table 2, entries 7 and 9) a selective reduction of
the double bond can be achieved applying shorter reac-
tion times (6–12h) and 5mol% Pd/C, whereas enamine
reduction and cleavage of the benzyl groups is observed
using higher catalyst concentrations (10–15mol%) and
longer reaction times (2–3days, see enamines 6, 7, 9;
Table 2, entries 2, 3, and 5). This allows the selective
Scheme 1. Hydroamination of b-(perfluoroalkyl)styrenes.

A. Tewari et al. / Tetrahedron Letters 45 (2004) 7703–7707
7705
Table 2. Hydroamination of in situ generated perfluoroalkylated arylacetylenes and subsequent reduction to amphetamine
analogues
Entry Starting material Amine
Enamine
Yield (%) Amphetamine derivative
Yield (%)
95
H
N
C6F13
C6F13
N
O
N
1
2
3
4
5
1
1
1
1
1
(5)
(6)
(7)
50
51
52
4
(15)
(16)
(17)
O
O
C6F13
H
C6F13
NH2
N
N
90
96
93
70
Ph
Ph
Ph Ph
C6F13
C6F13
NH
H
N
N
Ph
Ph
C6F13
C6F13
N(C6H13 2
NH(C6H13)2
(8)
0
(18)
N(C6H13 2
)
)
C6F13
C6F13
CH2Ph
N
N
N
N
(9)
52
(19)
N
H
N
H
CH2Ph
C8F17
C8F17
H
N
N
O
N
O
6
7
2
2
(10)
(11)
53
63
(20)
(21)
97
95
O
C8F17
C8F17
H
N
N
N
Ph
Ph
Ph Ph
C6F13
Ph Ph
C6F13
H
N
N
O
N
O
8
9
3
3
(12)
55
56
(22)
92
94
OMe
OMe
O
C6F13
C6F13
H
N
(13)
(23)
N
N
Ph
Ph
OMe Ph Ph
OMe Ph Ph
C8F17
C8F17
H
N
N
O
N
O
10
4
(14) 20
(24) 96
F3C
F3C
O
preparation of primary, secondary, and tertiary fluori-
nated amphetamines.
regio- and stereoselectively. Subsequent hydrogenation
gives the desired fluoroalkylated amphetamine ana-
logues in good yield.
In conclusion, an easy and straightforward synthesis of
fluorinated amphetamine analogues has been developed.
Key step of the procedure is a novel two step one-pot
hydroamination reaction of 1-aryl-1-iodo-2-(perfluoro-
alkyl)ethylenes. In situ dehydroiodination produced
(perfluoroalkyl)arylacetylenes, which react with different
amines to yield the corresponding enamines highly
Acknowledgements
The authors thank Prof. M. Michalik (IfOK), Prof. H.
Reinke (University of Rostock) and Mrs. S. Buchholz
(IfOK) for analytical assistance. This work was funded

7706
A. Tewari et al. / Tetrahedron Letters 45 (2004) 7703–7707
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14. For a review on base-catalyzed hydroamination, see:
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15. For examples, of base-catalyzed hydroamination of aryl-
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Tetrahedron Lett. 1999, 40, 6193; (b) Rodriguez, A.;
Koradin, C.; Dohle, W.; Knochel, P. Angew. Chem. 2000,
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References and notes
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Ashmawy, M.; Battaglia, G.; Fisher, J. B. J. Med. Chem.
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Perkin Trans. 1 1996, 265.
16. X-ray analyses of 1 and 10 clearly show the supposed
configurations of the compounds, but due to the disor-
dered perfluoroalkyl chains the data are not suitable for
publication.
3. (a) Mori, A.; Ishiyama, I.; Akita, H.; Suzuki, K.;
Mitsuoka, T.; Oishi, T. Chem. Pharm. Bull. 1990, 38,
3449; (b) Iwai, I. Chem. Pharm. Bull 1965, 13, 118; (c)
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17. Baum, K.; Bedford, C. D.; Hunadi, R. J. J. Org. Chem.
1982, 47, 2251.
4. (a) Koziara, A.; Olejniczak, B.; Osowska, K.; Zwierzak, A.
´
´
Synthesis 1982, 918; (b) Barluenga, J.; Jimenez, C.; Najera,
C.; Yus, M. J. Chem. Soc., Perkin Trans. 1 1983, 591; (c)
Griffith, R. C.; Gentile, R. J.; Davidson, T. A.; Scott, F. L.
18. A representative procedure is given for (Z)-N-
(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-1-phenyloct-1-en-2-
yl)morpholine (5): To a stirred solution of morpholine
(0.158g, 1.82mmol) in dry THF, 2equiv of n-BuLi
(3.6mmol, 2.5M in toluene) were added slowly at room
temperature under argon and the reaction mixture was
´
J. Org. Chem. 1979, 44, 3580; (d) Barluenga, J.; Jimenez,
C.; Najera, C.; Yus, M. J. Chem. Soc., Chem. Commun.
´
1981, 670; (e) Larock, R. C. Angew. Chem. 1978, 90, 28; .
Angew. Chem., Int. Ed. Engl. 1978, 17, 27.
stirred for 10min. Then
a
solution of (E)-
5. (a) Kirk-Othmer Encyclopedia of Chemical Technology,
4th ed.; John Wiley and Sons: New York, 1992; p 369; (b)
Bell, F. W.; Cantrell, A. S.; Hoegberg, M.; Jaskunas, S.
R.; Johansson, N. G. J. Med. Chem. 1995, 25, 4929; (c)
Glennon, R. A.; Yousif, M. Y.; Ismaiel, A. M.; El-
Ashmawy, M. B.; Herndon, J. L.; Fischer, J. B.; Server, A.
C.; Burke Howie, K. J. J. Med. Chem. 1991, 34, 3360.
6. (a) Kumar, K.; Michalik, D.; Garcia Castro, I.; Tillack,
A.; Zapf, A.; Arlt, M.; Heinrich, T.; Bo¨ttcher, H.; Beller,
M. Chem. Eur. J. 2004, 10, 746; (b) Beller, M.; Breindl, C.;
Riermeier, T. H.; Eichberger, M.; Trauthwein, H. Angew.
Chem. 1998, 110, 3571; Angew. Chem., Int. Ed. 1998, 38,
3389; (c) Beller, M.; Breindl, C. Tetrahedron 1998, 54,
6359; (d) For amination of styrenes in the presence of
(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-1-iodooct-1-enyl)benzene
(1) (1.0g, 1.82mmol) in THF was added dropwise. The
reaction mixture was allowed to stir at 70°C for 12h. After
cooling to room temperature, the mixture was diluted with
ethyl acetate, washed twice with water, dried over sodium
sulfate, and concentrated in vacuo to give the crude
product, which was purified by column chromatography
1
(ethyl acetate/heptane 20:80) to yield 0.455g (50%) 5. H
=
3
NMR (250MHz, CDCl3): d [ppm] = 2.77 (t, JHH
3
4.6Hz, 4H, 2 morpholine N–CH2), 3.53 (t, JHH = 4.6Hz,
4H, 2 morpholine O–CH2), 6.5 (s, 1H, Ph–CH), 7.26 (m,
5H, aromatic CH). 13C{1H} NMR (126MHz, CDCl3): d
[ppm] = 51.4(2 morpholine N– C2), 66.9 (2 morpholine O–
3
C2), 126.7 (t, JCF = 6.5Hz, Ph–CH), 128.2 (2 aromatic
CH), 128.2 (1 aromatic CH), 129.1 (2 aromatic CH), 134.3
(1 aromatic C), 136.4(t, 2JCF = 21.9Hz, C(NC4H8O)–
´
stoichiometric amounts of base, see: Seijas, J. A.; Vazquez-
´
´
Tato, M. P.; Entenza, C.; Martınez, M. M.; Onega, M. G.;
Veiga, S. Tetrahedron Lett. 1998, 39, 5073.
CF2).
19F{1H}
NMR
(235MHz,
CDCl3):
d
7. Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M.
Tetrahedron 2000, 56, 5157.
[ppm] = À125.9 (m, CF2), À122.4(m, C F2), À121.5 (m,
3
CF2), À120.5 (m, CF2), À108.8 (t, JFF = 14.5Hz,
8. (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (b)
¨
3
C(NC4H8O)–CF2), À80.6 (t, JFF = 10Hz, CF3). MS (EI,
For a personal account on hydroamination, see: Beller, M.;
Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.;
Thiel, O.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579.
9. (a) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93; (b)
70eV): m/z (%) 507 (M+, 85), 188 (100).
19. A representative procedure is given for (2-amino-
3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-yl)benzene (16):
A mixture of (Z)-[2-(N,N-dibenzylamino)-3,3,4,4,5,5,6,6,
7,7,8,8,8-tridecafluorooct-1-en-1-yl]benzene (6) (0.50g,
0.81mmol) and 10mol% Pd (86mg, 10% Pd/C) in THF
(10mL) was stirred under an atmosphere of hydrogen
(1bar) at room temperature for 48h. The mixture was then
filtered through a bed of Celite. The filtrate was concen-
trated in vacuo to get the crude product which was further
purified by column chromatography (ethyl acetate/heptane
30:70) to yield 16 as a white amorphous solid (0.32g, 90%).
Hamprecht, G.; Wurzer, B.; Witschel, M. Chimia 2004, 58,
¨
117; (c) Heinrich, T.; Bo¨ttcher, H.; Bartoszyk, G. D.;
Schwartz, H.; Anzali, S.; Ma¨rz, J.; Greiner, H. E.;
Seyfried, C. A. Chimia 2004, 58, 143; (d) Biomedical
Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y.,
Eds.; Kodansha and Elsevier: Amsterdam, 1983.
10. Biomedical Frontiers of Fluorine ChemistryACS Sympo-
sium Series; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.;
American Chemical Society: Washington, DC, 1996; Vol.
639.
11. (a) Pandey, S. K.; Gryshuk, A. L.; Graham, A.; Ohkubo,
K.; Fukuzumi, S.; Dobhal, M. P.; Zheng, G.; Ou, Z.;
Zhan, R.; Kadish, K. M.; Oseroff, A.; Ramaprasad, S.;
Pandey, R. K. Tetrahedron 2003, 59, 10059; (b) Martino,
1H NMR (250MHz, CDCl3):
d [ppm] = 2.50 (dd,
3
2JHH = 13.9Hz, JHH = 10.8Hz, 1H, Ph–CHa), 3.10 (d,
2JHH = 14.0Hz, 1H, Ph–CHb), 3.45–3.59 (m, 1H, CH–
NH2), 7.18–7.28 (m, 5H, 5 aromatic H). 13C{1H} NMR
(126MHz, CDCl3): d [ppm] = 35.8 (Ph–C2), 54.5 (t,

A. Tewari et al. / Tetrahedron Letters 45 (2004) 7703–7707
7707
2JCF = 23.3Hz, CH–NH2), 127.0 (1 aromatic CH), 128.7 (2
aromatic CH), 129.2 (2 aromatic CH), 136.7 (1 aromatic
C). 19F{1H} NMR (235MHz, CDCl3): d [ppm] = À125.9
(m, CF2), À121.7 (m, CF2), À120.0 (m, CF2), À119.4
2
3
(dm, JFF = 290Hz, CH–CFb), À80.5 (t, JFF = 10Hz,
CF3). MS (EI, 70eV): m/z (%) 439 (M+, 2.7), 348 (100).
HRMS calcd for C14H10NF13 439.06097, found 439.06058.
2
(m, CF2), À123.1 (dm, JFF = 290Hz, CH–CFa), À122.5