PRACTICAL SYNTHETIC PROCEDURES
Synthesis of trans-2-(Trifluoromethyl)cyclopropylamine
1153
1H NMR (500 MHz, CDCl3): d = 3.28 (s, 3 H, CH3N), 3.74 (s, 3 H,
CH3O), 6.82 (m, 1 H, CHCF3), 7.06 (d, J = 16 Hz, 1 H, CHCO).
latter was reacted with dimethylsufoxonium iodide under 13C NMR (125 MHz, CDCl3): d = 32.3 (s, CH3N), 62.1 (s, CH3O),
fluorobut-2-enoic acid (2)6b (Scheme 1) prepared from its
ethyl ester was converted into Weinreb-type amide 3. The
122.6 (q, J = 270 Hz, CF3), 126.4 (m, CHCO), 130.1 (q, J = 36 Hz,
CHCF3), 163.48 (s, C=O).
19F NMR (376 MHz, CDCl3): d = 65.75 (dd, 3JF,H = 8 Hz, 4JF,H = 3.8
Hz, CF3).
Corey–Chaykovsky conditions to give cyclopropane de-
rivative 4 in nearly quantitative yield.
As shown in Scheme 1, the hydrolysis of amide 4 afforded
2-trifluoroethylcarboxylic acid 5. The reaction of the lat-
ter with diphenyl phosphorazidate with Curtius rearrange-
MS: m/z = 183.
ment and the reaction of the cyclopropane isocyanate
N-Methoxy-N-methyl-2-(trifluoromethyl)cyclopropanecarbox-
amide (4)
A degassed solution of trimethylsulfoxonium iodide (288 g, 1.31
intermediate with tert-butyl alcohol were carried out in
1
one pot affording Boc-protected amine 6. H and 13C
NMR spectra of 6 were identical with those formerly re-
ported by us for the Boc-protected trans-2-(trifluorometh-
yl)cyclopropylamine in which the trans-configuration
was unambiguously proven by single crystal X-ray analy-
sis.1 Finally, the Boc group was removed from 6 with hy-
drochloric acid to yield the title compound in the form of
its hydrochloride. The overall amount of 1·HCl obtained
in the five synthetic steps illustrated in Scheme 1 was ca.
13 grams.
mol) in DMSO (750 mL) was allowed to reach r.t. NaH (60% in
mineral oil, 53 g, 1.31 mol) was added to the solution in small por-
tions over 20 minutes. The suspension was stirred for 1 h. A solution
of alkene 3 (120 g, 0.65 mol) in DMSO (250 mL) was added to the
stirred suspension and the reaction mixture was stirred for 16 h. The
mixture was poured into sat. aq NH4Cl (1500 mL) and extracted
with CH2Cl2 (3 × 350 mL). The combined organic layers were
washed with brine (500 mL), dried (Na2SO4), filtered, and concen-
trated in vacuum. The concentrated residue was distilled under vac-
uum to afford 4 (121 g, 0.61 mol, 94%) as a yellow oil; bp 72–
82 °C/15 mmHg.
To conclude, we have developed a reliable five-step pro-
cedure for the multigram-scale preparation of trans-2-(tri-
fluoromethyl)cyclopropylamine (1). All synthetic steps
are high yielding and fully reproducible. The key step of
the synthesis is the Corey–Chaykovsky cyclopropanation
reaction of the Winereb-type amide of 4,4,4-trifluorobut-
2-enoic acid, which proceeded in nearly quantitative
yield. Unlike our formerly reported synthesis of the title
compound, the present procedure does not involve the use
of highly toxic sulfur tetrafluoride and, therefore, is of
much wider applicability.
1H NMR (500 MHz, CDCl3): d = 1.20 (m, 1 H, CH2), 1.32 (m, 1 H,
CH2), 2.08 (br s, 1 H, CH2CHCF3), 2.5 (br s, 1 H, CH2CHCO), 3.19
(s, 3 H, CH3N), 3.73 (s, 3 H, CH3O).
13C NMR (125 MHz, CDCl3): d = 9.6 (s, CH2), 13.7 (s, CHCO),
2
21.6 (q, JC,F = 38 Hz, CHCF3), 32.2 (s, CH3N), 61.5 (s, CH3O),
124.2 (q, 1JC,F = 270 Hz, CF3), 170.4 (s, C=O).
19F NMR (376 MHz, CDCl3): d = 65.75 (d, 3JF,H = 7 Hz, CF3).
MS: m/z = 197.
2-(Trifluoromethyl)cyclopropanecarboxylic Acid (5)
To a solution of amide 4 (115 g, 0.58 mol) in THF (650 mL) was
added t-BuOK (325 g, 2.90 mol). H2O (21 mL, 1.2 mol) was added
to the reaction mixture and the mixture was stirred at r.t. under ar-
gon atmosphere for 18 h. Ice was added to the reaction mixture until
it became homogeneous. The aqueous layer was acidified with aq 1
N HCl to adjust the pH value to 4. The aqueous layer was extracted
with EtOAc (4 × 350 mL). The combined organic layers were
washed successively with H2O (500 mL) and brine (500 mL), dried
(Na2SO4), and evaporated under reduced pressure to provide com-
pound 5 (70.5 g, 0.46 mol, 70%) as a colorless oil. The spectral
characteristics of the obtained material were identical with those re-
ported previously.8
Solvents were purified according to standard procedures. All other
materials were purchased from commercial sources (mainly from
Aldrich and Enamine). Diphenyl phosphorazidate was purchased
from Nanjing Chemlin Chemical Industry Co., Ltd. 4,4,4-trifluo-
robut-2-enoic acid (2) was prepared from commercial ethyl 4,4,4-
trifluorocrotonate according to a literature procedure.6b Melting
points are uncorrected. Analytical TLC was performed using Poly-
chrom SI F254 plates. 1H, 13C and 19F NMR spectra were recorded on
a Bruker Avance 500 spectrometer at 499.9 MHz, 124.9 MHz, and
376 MHz, respectively. Chemical shifts are reported in ppm down-
field from TMS (1H, 13C) and CFCl3 (19F) as internal standards.
Mass spectra were recorded on an Agilent 1100 LCMSD SL instru-
ment with chemical ionization (APCI) mode.
tert-Butyl [2-(Trifluoromethyl)cyclopropyl]carbamate (6)
A solution of acid 5 (45 g, 0.29 mol) and anhyd Et3N (29.5 g, 0.29
mol) in anhyd t-BuOH (250 mL) was stirred at r.t. over 4 Å molec-
ular sieves. Diphenyl phosphorazidate (80.3 g, 0.29 mol) was added
dropwise to the solution. The reaction mixture was heated at reflux
for 18 h under N2 and then concentrated under vacuum. The residue
was triturated with Et2O (400 mL) and filtered to give a biphasic so-
lution. The Et2O layer was isolated and the remaining oily liquid
was extracted with Et2O (4 × 100 mL). The combined Et2O layers
were washed with 10% aq citric acid (450 mL), sat. aq NaHCO3
(2 × 250 mL), and brine (250 mL) and then dried (Na2SO4). Evapo-
ration of the solvent under reduced pressure afforded compound 6
(46.0 g, 0.20 mol, 72%) as a white solid, which was used in the next
synthetic step without additional purification.
4,4,4-Trifluoro-N-methoxy-N-methylbut-2-enamide (3)
A solution of N,O-dimethylhydroxylamine was prepared by slow
addition of DIPEA (209 g, 1.60 mol) to the N,O-dimethylhydroxyl-
amine hydrochloride (118 g, 1.27 mol) suspended in CH2Cl2 (300
mL). This mixture was added to a solution of acid 2 (142 g, 1.01
mol) in CH2Cl2 (500 mL) at –15 °C. EDC (186 g, 1.20 mol) was
added and the reaction mixture was stirred at 0 °C for 16 h. The or-
ganic phase was washed with brine (700 mL), dried (Na2SO4), and
evaporated under reduced pressure to provide product 3 (150 g, 0.82
mol, 82%) as a colorless oil. The compound was used in the next
synthetic step without additional purification. The analytical sample
was prepared by distillation of the crude product under vacuum;
bp 40–44 °C/1 mmHg.
An analytical sample was prepared by recrystallization of the crude
product from hexane; mp 64–65 °C (Lit.1 mp 64 °C). The spectral
characteristics of the obtained material were identical with those re-
ported previously.1
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1152–1154