Multigram synthesis of trans -2-(trifluoromethyl)cyclopropanamine

Article abstract of DOI:10.1055/s-0030-1258323

2-(Trifluoromethyl)cyclopropanamine was synthesized. The key step of the synthesis is a transformation of the carboxy group into the trifluoromethyl group by using sulfur tetrafluoride. Twenty gram of the target product was conveniently prepared in a single batch. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258323

PAPER
119
Multigram Synthesis of trans-2-(Trifluoromethyl)cyclopropanamine
M
ultigra
m
Synthes
n
is of trans-2
d
-(Trifluorom
r
ethyl)cy
i
cloprop
i
anamine V. Bezdudny,a,b Denis Klukovsky,a,b Natalia Simurova,b Pavel K. Mykhailiuk,*a,c Oleg V. Shishkin,d
Yurii M. Pustovita,b
a
Enamine Ltd., Oleksandra Matrosova Street 23, 01103 Kyiv, Ukraine
Fax +380(44)2351273; E-mail: Pavel.Mykhailiuk@gmail.com
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, 02660 Kyiv-94, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kyiv, Ukraine
STC, Institute for Single Crystals, National Academy of Science of Ukraine, 60 Lenina Avenue, 61001 Kharkiv, Ukraine
b
c
d
Received 24 September 2010; revised 5 October 2010
12 h), otherwise the yield of product 4 decreases signifi-
cantly. Next, the ester group in 4 was hydrolyzed with an
aqueous mixture of hydrochloric and acetic acids to
smoothly provide the corresponding acid 5 in 87% yield.10
The crucial step of the synthesis, namely the transforma-
tion of the carboxy group into the trifluoromethyl group,
was successfully performed with the use of sulfur tetra-
fluoride.11 Treating acid 5 with 2.5 equivalents of sulfur
tetrafluoride in the presence of a catalytic amount of water
(to generate HF) at 90 °C for two hours afforded the tri-
fluoromethyl-substituted cyclopropane 6 in 91% yield af-
ter distillation. Importantly, several experiments on the
fluorination of compound 5 were performed, and each
time reproducible results were obtained. Finally, reduc-
tion of the nitro group in 6 by the use of aqueous hydro-
chloric acid with zinc powder completed the synthesis of
2-(trifluoromethyl)cyclopropanamine hydrochloride (2·HCl)
in 67% yield.
Abstract: 2-(Trifluoromethyl)cyclopropanamine was synthesized.
The key step of the synthesis is a transformation of the carboxy
group into the trifluoromethyl group by using sulfur tetrafluoride.
Twenty gram of the target product was conveniently prepared in a
single batch.
Key words: fluorine, trifluoromethyl group, amines, cyclopropyl
group, sulfur tetrafluoride
The introduction of small, privileged motifs into com-
pounds with biological activity is a well-known strategy
used in medicinal chemistry.1 The cyclopropyl group,
which often has beneficial effects upon biological activity
and metabolic stability, is one such privileged motif, the
use of which has become increasingly popular in drug de-
sign.2,3 Cyclopropanamine is a small building block,
which is often used to provide the pharmacologically rel-
evant compound of interest with the cyclopropyl group.4
Worth noting is that the cyclopropanamine motif also fre-
quently occurs in drugs (Figure 1).
O
NH
F
CO2H
N
O
The trifluoromethyl group is another privileged substruc-
ture within medicinal chemistry.3,5 With this group, the
beneficial effect of fluorine substitution is utilized to im-
prove numerous characteristics important to drug mole-
cules. Surprisingly, despite the great potential of
cyclopropanamine, to date little is known about the corre-
sponding trifluoromethyl-substituted analogues. For ex-
ample, 1-(trifluoromethyl)cyclopropanamine (1) has
received significant attention only in recent years
(Figure 2).6 However, to the best of our knowledge, the
synthesis of the isomeric compound 2-(trifluorometh-
yl)cyclopropanamine (2) has remained unknown so far.7
In this context, herein we report a concise multigram prep-
aration of amine 2.
HN
N
N
N
HN
ciprofloxacin
nevirapine
HO
NH2
N
N
HN
N
N
abocavir
O
The synthesis of amine 2 commenced from dibromide 3 as
a starting material (Scheme 1).8 Slow addition of ni-
tromethane to a stirred suspension of potassium carbonate
and dibromide 3 in dimethyl sulfoxide gave cyclopropane
4 in 54% yield.9 It is important that the time used for ni-
tromethane addition should be as long as possible (up to
O
N
O
O
N
HN
cyclazodone
encyprate
Figure 1 Some marketed drugs possessing the cyclopropanamine
moiety: ciprofloxacin (antibiotic, FDA-approved), nevirapine (for
treatment of HIV-1 infection, FDA-approved), abocavir (for treat-
ment of HIV-1 infection, FDA-approved), cyclazodone (CNS stimu-
lant), encyprate (antidepressant)
SYNTHESIS 2011, No. 1, pp 0119–0122
Advanced online publication: 12.11.2010
DOI: 10.1055/s-0030-1258323; Art ID: Z23910SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

120
A. V. Bezdudny et al.
PAPER
NH2
believe compound 2 would find wide application within
drug design as a novel fluorine-containing building block.
NH2
NH2
F3C
F3C
Dibromide 3 was synthesized as reported previously.8 1H, 13C, and
19F NMR spectra were recorded on a Bruker Avance 500 spectrom-
eter at 499.9 MHz, 124.9 MHz, and 470.3 MHz, respectively.
Chemical shifts are reported relative to TMS (1H, 13C) or CFCl3
(19F) as internal standard. Mass spectra (CI) were recorded on an
Agilent 1100 LCMSD SL instrument.
1
2
Figure 2 The structures of cyclopropanamine and its trifluoro-
methyl-substituted analogues 1 and 2
NO2
NO2
MeNO2
DMSO
Br
Br
HCl
AcOH
K2CO3
54%
87%
EtO2C
Ethyl rel-(1S,2S)-2-Nitrocyclopropanecarboxylate (4)
EtO2C
HO2C
MeNO2 (42.2 g, 692 mmol) was added over a period of 12 h to a
stirred suspension of dibromide 3 (166.8 g, 642 mmol) and K2CO3
(255.4 g, 1.85 mol) in DMSO (310 mL). After the addition had been
completed, the reaction mixture was stirred for an additional 16 h at
r.t. Thereafter, it was poured into H2O (3.2 L). The aqueous soln
was extracted with Et2O (3 × 400 mL), and the combined organic
extracts were washed with H2O (2 × 400 mL) and dried (MgSO4).
Evaporation of the solvent under reduced pressure provided the
crude product 4 as a brown oil. The product (~90% purity) was used
in the next step without additional purification.
3
4
5
NO2
NH2
⋅HCl
SF4
Zn/HCl
67%
91%
F3C
F3C
6
2⋅HCl
Scheme 1 Synthesis of amine 2·HCl
Yield: 55.2 g (348 mmol; 54%); brown oil.
1H NMR (500 MHz, CDCl3): d = 4.57 (m, 1 H, CHNO2), 4.17 (q,
J = 7.0 Hz, 2 H, OCH2CH3), 2.69 (m, 1 H, CHCO2Et), 2.03 (m, 1 H,
CHH), 1.70 (q, J = 7.0 Hz, 1 H, CHH), 1.26 (t, J = 7.0 Hz, 3 H,
OCH2CH3).
Importantly, the synthesis of 2·HCl was easily scaled up,
so that 20 grams of the product was conveniently prepared
in a single batch from dibromide 3.
To determine the stereoconfiguration of the synthesized
compounds, amine 2 was converted into the correspond-
ing Boc-protected derivative 7 (Scheme 2). The trans
configuration of compound 7 was proven by an X-ray
crystallographic analysis (Figure 3).
rel-(1S,2S)-2-Nitrocyclopropanecarboxylic Acid (5)
A suspension of ester 4 (53.2 g, 335 mmol) in AcOH (46 mL) and
12 N aq HCl (46 mL) was stirred at 90 °C for 2 h. The solvent was
evaporated under vacuum. The residue was recrystallized from
AcOH to provide acid 5.
Yield: 38.1 g (291 mmol; 87%); white solid.
Analytical data are identical to those previously described.9
NH2
Boc2O
Et3N
NHBoc
CH2Cl2
84%
rel-(1S,2S)-1-Nitro-2-(trifluoromethyl)cyclopropane (6)
A mixture of acid 5 (34.0 g, 0.26 mol), H2O (1 mL), and SF4 (70.0
g, 0.64 mol) was kept in a stainless steel autoclave at 90 °C for 2 h.
Then the gaseous products were removed (under a good fumehood),
and the content was poured into ice (1000 g). The mixture was neu-
tralized with 10% aq NH3. The organic layer was separated, dried
(MgSO4), and purified by distillation (68–70 °C/50 Torr); this gave
pure product 6.
F3C
F3C
7
2⋅HCl
Scheme 2 Synthesis of compound 7
Yield: 36.6 g (236 mmol, 91%); colorless liquid.
1H NMR (500 MHz, CDCl3): d = 4.52 (m, 1 H, CHNO2), 2.76 (m,
1 H, CHCF3), 2.03 (m, 1 H, CHH), 1.62 (q, J = 7.5 Hz, 1 H, CHH).
13C NMR (125 MHz, CDCl3): d = 123.25 (q, 1JCF = 270.0 Hz, CF3),
2
54.93 (s, CHNO2), 24.35 (q, JCF = 38.8 Hz, CHCF3), 12.78 (q,
3JCF = 2.5 Hz, CH2).
19F NMR (470 MHz, DMSO-d6): d = –67.54 (d, 3JFH = 9.5 Hz, CF3).
MS (CI): m/z = 155 [M+].
Figure 3 The molecular structure of compound 7 obtained by an
X-ray diffraction study
rel-(1S,2S)-2-(Trifluoromethyl)cyclopropanamine Hydrochlo-
ride (2·HCl)
In summary, we have developed a practical synthesis of
trans-2-(trifluoromethyl)cyclopropanamine (2). The key
step of the synthesis is a transformation of the carboxy
group in cyclopropane 5 into a trifluoromethyl group by
using sulfur tetrafluoride. As much as 20 grams of the tar-
get amine 2 was conveniently prepared in one synthetic
run. Because of its rapid access and scalable synthesis, we
Cooled by ice water, compound 6 (36.0 g, 232 mmol) was dissolved
in i-PrOH (200 mL) and treated with 6 N aq HCl (1000 mL). Zn dust
(102.8 g, 1.58 mmol, 7 equiv) was added slowly, so that the temper-
ature of the reaction mixture did not exceed 40 °C. The reaction
mixture was thereafter stirred at r.t. for 12 h. The suspension was
collected by filtration. The filtrate was quenched by an addition of
sat. aq NaHCO3 (1200 mL). The aqueous phase was extracted with
Et2O (3 × 300 mL). The combined organic extracts were dried
(MgSO4) and filtered. An excess of gaseous anhyd HCl was bub-
Synthesis 2011, No. 1, 119–122 © Thieme Stuttgart · New York

PAPER
Multigram Synthesis of trans-2-(Trifluoromethyl)cyclopropanamine
121
bled through the organic layer. The precipitate (2·HCl) was collect-
ed by filtration and dried under vacuum.
sities of 5557 reflections (2502 independent, Rint = 0.014) were
measured on the ‘Xcalibur-3’ diffractometer (graphite monochro-
mated Mo Ka radiation, CCD detector, w-scaning, 2Qmax = 60°).
The structure was solved by direct methods using the SHELXTL
package.12 Positions of the hydrogen atoms were located from elec-
tron density difference maps and refined by using isotropic approx-
imation. Full-matrix least-squares refinement against F2 in
anisotropic approximation for non-hydrogen atoms using 2484 re-
flections was converged to wR2 = 0.062 [R1 = 0.024 for 2314 reflec-
tions with F > 4s(F), S = 1.011]. CCDC 791009 contains the
supplementary crystallographic data for 7. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Yield 25.6 g (159 mmol, 67%); white solid; mp 193 °C (dec).
1H NMR (500 MHz, DMSO-d6): d = 9.91 (br s, 3 H, NH3 ), 2.96 (br
+
+
s, 1 H, CHNH3 ), 2.45 (m, 1 H, CHCF3), 1.42 (m, J = 7.5 Hz, 1 H,
CHH), 1.23 (dd, J = 8.0, 1 H, 6.5 Hz, CHH).
1
13C NMR (125 MHz, DMSO-d6): d = 125.55 (q, JCF = 268.8 Hz,
3
+
2
CF3), 25.12 (d, JCF = 3.8 Hz, CHNH3 ), 18.05 (q, JCF = 37.5 Hz,
CHCF3), 7.55 (s, CH2).
19F NMR (377 MHz, DMSO-d6): d = –60.72 (d, 3JFH = 7.5 Hz, CF3).
tert-Butyl rel-(1S,2S)-N-[2-(Trifluoromethyl)cyclopropyl]car-
bamate (7)
Boc2O (1.66 g, 7.6 mmol) was added to a suspension of amine
2·HCl (1.23 g, 7.6 mmol) and Et3N (1.62 g, 16.0 mmol) in CH2Cl2
(5 mL) at 0 °C. The mixture was stirred at r.t. for 12 h. H2O (5 mL)
and CH2Cl2 (5 mL) were added to the reaction mixture. The organic
phase was separated, washed with H2O (5 mL) and dried (Na2SO4).
Evaporation of the solvent provided the residue, which was recrys-
tallized (benzene–hexane) to afford pure product 7.
References
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Yield: 1.44 g (6.4 mmol, 84%); white solid; mp 64 °C.
The crystals suitable for an X-ray diffractional study were obtained
by a slow evaporation of a diluted soln of 7 in cyclohexane.
Main Atropisomer of 7
1H NMR (500 MHz, CDCl3): d = 4.93 (br s, 1 H, NH), 2.87 (br s, 1
H, CHNH), 1.68 (br s, 1 H, CHCF3), 1.17 (d, J = 6.0 Hz, 1 H, CHH),
1.05 (br s, 1 H, CHH).
13C NMR (125 MHz, CDCl3): d = 155.95 (s, NC=O), 125.21 (q,
1JCF = 270.0 Hz, CF3), 80.34 [br s, OC(CH3)3], 28.26 [s, OC(CH3)3],
26.35 (br s, CH, c-Pr), 21.95 (br s, CH, c-Pr), 10.31 (br s, CH2, c-Pr).
19F NMR (470 MHz, CDCl3): d = –66.77 (d, 3JFH = 3.8 Hz, CF3).
MS (CI): m/z = 225 [M+].
X-ray Diffraction Study of 7
The molecule of compound 7 contains two chiral centers (at the C1
and C3 atoms), which have identical configurations (S,S or R,R, ac-
cordingly). Compound 7 crystallizes in a noncentrosymmetric
space group; however, the absence of heavy atoms does not allow
the unambiguous determination of the configuration of the chiral
centers. The substituents at the C1 and C3 atoms occupy trans po-
sitions relative to the plane of the propane ring [the C4–C1–C3–N1
torsion angle is 138.2(1)°]. The trifluoromethyl group is turned in
such a way that the C4–F1 bond is orthogonal to the propane ring
[the C2–C1–C4–F1 torsion angle is 87.3(1)°], which leads to the ap-
pearance of an H3···F2 intramolecular shortened contact (the dis-
tance between the atoms is 2.49 Å; cf. van der Waals radii sum 2.57
Å). The planar carbamide fragment of the substituent at the C3 atom
is turned relatively to the C2–C3 bond of the ring [the C5–N1–C3–
C2 torsion angle is 100.3(1)°]. The tert-butyl group has an ap con-
formation with respect to the N1–C5 bond and is turned in such way
that the C6–C9 bond is antiperiplanar to the C5–O2 bond [the C6–
O2–C5–N1 and C5–O2–C6–C9 torsion angles are 175.9(1)° and
179.8(1)°, respectively].
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In the crystal phase, the molecules 7 form infinite chains along the
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H···O1¢ (1 + x, y, z) intermolecular hydrogen bond (H···O 2.08 Å, N–
H···O 163°). A C2–H···F2¢ (x, –y, –0.5 + z) intermolecular hydrogen
bond (H···F 2.49 Å, C–H···F 156°) is observed in the crystal phase.
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a = 5.1064(2), b = 20.0360(7), c = 10.4797(4) Å, b = 98.768(3)°,
V = 1059.67(7) Å3, Mr = 225.21, Z = 4, space group Cc,
dcalc = 1.412 g·cm–3, m(Mo Ka) = 0.133 mm–1, F(000) = 472. Inten-
Synthesis 2011, No. 1, 119–122 © Thieme Stuttgart · New York

122
A. V. Bezdudny et al.
PAPER
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Synthesis 2011, No. 1, 119–122 © Thieme Stuttgart · New York