Straightforward synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone

Article abstract of DOI:10.1039/c1ob05813d

An efficient and straightforward approach towards the synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone via imination, α-chlorination, hydride reduction and ring closure was developed. In addition, novel primary β-iodo amines were obtained by regioselective ring opening of these 2-(trifluoromethyl)aziridines using alkyl iodides, and their synthetic potential was demonstrated by converting them into novel α-CF₃-β-phenylethylamines upon treatment with lithium diphenylcuprate.

Full text of DOI:10.1039/c1ob05813d

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PAPER
Straightforward synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting
from 1,1,1-trifluoroacetone
Sara Kenis,a Matthias D’hooghe,*a Guido Verniest,†a Vinh Duc Nguyen,b Tuyet Anh Dang Thi,b
Tuyen Van Nguyenb and Norbert De Kimpe*a
Received 24th May 2011, Accepted 17th June 2011
DOI: 10.1039/c1ob05813d
An efficient and straightforward approach towards the synthesis of 1-alkyl-2-(trifluoromethyl)aziridines
starting from 1,1,1-trifluoroacetone via imination, a-chlorination, hydride reduction and ring closure
was developed. In addition, novel primary b-iodo amines were obtained by regioselective ring opening
of these 2-(trifluoromethyl)aziridines using alkyl iodides, and their synthetic potential was
demonstrated by converting them into novel a-CF3-b-phenylethylamines upon treatment with lithium
diphenylcuprate.
ing of (S)-3,3,3-trifluoropropylene oxide by the corresponding
Introduction
alkylamines. A drawback of this procedure involves the high
In the past decade, organofluorine compounds have gained a lot of
cost of the optically pure starting material, and the prepa-
interest in organic and medicinal chemistry.1 This is due to the fact
ration of racemic 3,3,3-trifluoropropylene oxide elongates this
synthetic procedure substantially.8 In a second approach, 1-
alkyl-2-(trifluoromethyl)aziridines have been prepared by the
reaction of (b-trifluoromethyl)vinyl diphenyl sulfonium triflate
with different alkylamines.6j This (b-trifluoromethyl)vinyl diphenyl
sulfonium triflate was synthesized starting from 3,3,3-trifluoro-2-
bromopropene, which was converted by an addition–elimination
reaction with thiophenol into phenyl (b-trifluoromethyl)vinyl
sulfide.9 Treatment of this sulfide with the expensive diphenyliodo-
nium triflate results in (b-trifluoromethyl)vinyl diphenyl sul-
fonium triflate. The relatively high cost of diphenyliodonium
triflate, however, represents an important drawback if large-scale
preparations are desired. In a third approach, dimethylsulfo-
nium methylide has been used to synthesize 1-(2-methoxy-1-
phenylethyl)-2-(trifluoromethyl)aziridine.6k Despite the synthetic
value of the above-described procedures, their application for
large-scale approaches is less attractive from an economical point
of view, hence the interest in short and straightforward alternatives.
Therefore, a new and convenient approach towards 1-alkyl-2-
(trifluoromethyl)aziridines is disclosed in this paper starting from
the commercially available and inexpensive 1,1,1-trifluoroacetone,
known as a useful building block for fluorinated compounds.10
In addition, ring-opening reactions of these 1-alkyl-2-
(trifluoromethyl)aziridines were evaluated in order to provide a
new and selective approach towards CF3-substituted nitrogen-
containing target compounds. A number of ring-opening reactions
of non-activated 2-(trifluoromethyl)aziridines has previously been
studied,11 involving proton-catalyzed ring-opening reactions and
aziridinium ion formation through N-alkylation followed by ring
opening. Complementary to these results, the regioselective ring
opening by acetic acid and alkyl iodides was studied in this work,
leading in the case of alkyl iodides to interesting novel primary
that the incorporation of one or more fluorine atoms, for example
as a trifluoromethyl group, often results in an improvement of the
biological properties of bioactive compounds.2 For this reason,
fluorinated and trifluoromethylated compounds are increasingly
used in the pharmaceutical and agrochemical industry.3 The direct
introduction of a fluorine atom or a trifluoromethyl group on hete-
rocyclic compounds, however, is often problematic,4 and therefore
a building block approach can provide a useful alternative in some
cases.
Aziridines are known to be excellent building blocks for the
preparation of a large variety of nitrogen-containing compounds,
and numerous synthetic approaches towards the preparation of
aziridines have been described.5 An interesting subclass of these
three-membered rings is the class of 2-(trifluoromethyl)aziridines,
and their preparation has been relatively well studied.6 However,
although the reactivity of non-activated aziridines is known to
be different and often complementary to that of their acti-
vated counterparts,7 only a few approaches towards the syn-
thesis of non-activated 2-(trifluoromethyl)aziridines have been
reported in the literature.6h–k In a first approach, 1-alkyl-2-
(trifluoromethyl)aziridines have been obtained by ring closure of
N-alkylamino alcohols using dichlorotriphenylphosphorane.6h,6i
These N-alkylamino alcohols were synthesized through ring open-
aDepartment of Sustainable Organic Chemistry and Technology, Fac-
ulty of Bioscience Engineering, Ghent University, Coupure Links 653,
B-9000, Ghent, Belgium. E-mail: norbert.dekimpe@UGent.be, matthias.
dhooghe@UGent.be
bInstitute of Chemistry, Vietnam Academy of Science & Technology, 18
Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
† Present address: Vrije Universiteit Brussel, Faculty of Sciences and
Bio-engineering Sciences, Department of Chemistry, Pleinlaan 2, B-1050
Brussel, Belgium.
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Table 1 Synthesis of N-alkyl-3-chloro-1,1,1-trifluoropropan-2-amines
4a–e and 1-alkyl-2-(trifluoromethyl)aziridines 5a–e
b-iodo amines which can be used as precursors for the synthesis
of a variety of compounds. As an example, new trifluorinated am-
phetamine derivatives were prepared through further elaboration
of these b-iodo amines. Amphetamines are of pharmacological
interest due to their stimulating or inhibiting effect on the
central nervous system, their anti-inflammatory activity and their
ability to inhibit several enzymes.12 Although a few methods
for the preparation of a-CF3-b-phenylethylamines are known
in the literature, i.e. through reductive amination of 3-phenyl-
1,1,1-trifluoropropan-2-one,13 the addition of Grignard reagents
to fluoral hemiacetal14 and trifluoromethylation of enamines,15 this
particular methodology represents a new approach in that respect.
Compound
R1
Yielda
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
Bn
56%
54%
58%
65%
63%
92%
78%
80%
83%
81%
4-ClC6H4CH2
4-MeOC6H4CH2
n-Octyl
(CH2)2C6H5
Bn
4-ClC6H4CH2
4-MeOC6H4CH2
n-Octyl
(CH2)2C6H5
a Yield after column chromatography (SiO2).
Results and discussion
N-(1-Methyl-2,2,2-trifluoroethylidene)alkylamines 2 were pre-
pared through condensation of 1,1,1-trifluoroacetone 1 with
3 equiv. of the corresponding alkylamines in diethyl ether in the
presence of 0.5 equiv. of titanium(IV) chloride.16 Subsequently,
imines 2 were a-chlorinated using 1 equiv. of N-chlorosuccinimide
(NCS) in cyclohexane upon reflux for 3 h. Traditionally, carcino-
genic carbon tetrachloride is used as a solvent for this type of
transformations,17 but could be replaced by cyclohexane in this
case without altering the rate or yield of the reaction. Next to N-
(1-chloromethyl-2,2,2-trifluoroethylidene)alkylamines 3, the pres-
ence of the corresponding enamines18 was observed as well (ratio:
9/1). Due to their hydrolytic instability, no attempts were made to
obtain analytically pure samples of a,a,a-trifluoromethyl imines 2
and 3 through silica gel purification. However, these imines 2 and
3 were obtained in a purity of at least 90%. In the following step,
N-(1-chloromethyl-2,2,2-trifluoroethylidene)alkylamines 3 were
reduced by using 4 equiv. of sodium borohydride in methanol
under reflux, yielding the corresponding b-chloro amines 4 in good
overall yields (Scheme 1, Table 1). The spectral data obtained
for compound 4a were in full accordance with those reported
in the literature.11a Attempted reductive cyclization of a-chloro
imines 3 towards the desired 2-(trifluoromethyl)aziridines 5 using
different reducing agents (e.g. 1 equiv. of LiAlH4 in THF at 0 ◦C or
1 equiv. of LiBH4 in THF under reflux) did not lead to the desired
conversion due to the reduced nucleophilicity of the nitrogen atom
in amines 4, caused by the strong electron-withdrawing effect of
the trifluoromethyl substituent in a-position. Therefore, a strong
base, such as lithium bis(trimethylsilyl)amide (LiHMDS), was
shown to be necessary to affect ring closure of b-chloro amines
4. In this way, several new 1-alkyl-2-(trifluoromethyl)aziridines
5 were obtained in high yields by treatment of a-CF3-b-chloro
amines 4 with 1.1 equiv. of LiHMDS in THF for 4 h at room
temperature (Scheme 1, Table 1). The spectral data obtained
for compounds 5a and 5e were in full accordance with those
reported in the literature,9,11a whereas aziridines 5b–d have not
been described before. Compared to known procedures for the
preparation of 1-alkyl-2-(trifluoromethyl)aziridines, which either
need expensive reagents or consist of multiple reaction steps, this
short and efficient approach is based on the use of commercially
available and relatively inexpensive resources and is therefore a
suitable alternative for large-scale applications.
With this novel and straightforward approach towards 2-
(trifluoromethyl)aziridines 5 in hand, additional studies on
the reactivity of these interesting building blocks were per-
formed. As mentioned in the introduction, Katagiri and Ka-
rimova had already explored the reactivity of non-activated 2-
(trifluoromethyl)aziridines towards a number of electrophiles and
nucleophiles.11 Complementary to these studies, ring-opening
reactions with acetic acid and alkyl iodides were investigated in this
work. The ring opening of 1-benzyl-2-(trifluoromethyl)aziridine5a
to 2-benzylamino-3,3,3-trifluoropropyl acetate 6 using 5 equiv. of
acetic acid in CH2Cl2 proceeded very sluggishly, as heating for 7
days at 60 ◦C in a pressure vial was required to drive the reaction
to completion, affording acetate 6 in 52% yield. Performing the
reaction in acetic acid as a solvent appeared to be less successful, as
Scheme 1
7218 | Org. Biomol. Chem., 2011, 9, 7217–7223
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Scheme 2
Table 2 Synthesis of 2-benzylamino-3,3,3-trifluoropropyl acetate 6 and
N,N-dialkyl-1,1,1-trifluoro-3-iodopropan-2-amines 7
it led to more formation of impurities. The ring opening with acetic
acid had already briefly been explored in the literature, resulting
in the conclusion that the acidity of acetic acid is too weak to
induce ring opening of 1-alky◦l-2-(trifluoromethyl)aziridines, even
after prolonged storage at 20 C.11b The rather drastic conditions
required for the acetic acid-induced ring opening of aziridine 5a to
acetate 6 (Scheme 2) corroborate the previously described finding
that the trifluoromethyl-substituted aziridine ring is quite inert
towards electrophiles due to the strong electron-withdrawing effect
of the CF3-group,11 but refute the conclusion that acetic acid is too
weak to affect a ring-opening reaction.
Entry R1
R2
Reaction conditionsa Product (yield)
1
2
3
4
5
Bn
Bn
Bn
A
A
A
B
B
7a (74%)
7b (88%)
7c (81%)
7d (87%)
7e (72%)
4-ClC6H4CH2
4-MeOC6H4CH2 Bn
Bn
Me
Me
4-ClC6H4CH2
a A = 1 equiv. BnI, neat, 100 ◦C, 24h; B = 1 equiv. MeI, CH3CN, 100 ◦C, 3
d, pressure vial.
In a second part, ring opening of 1-alkyl-2-(trifluoromethyl)-
aziridines 5a–c with alkyl iodides towards b-iodo amines was
investigated, as this approach has not been studied before (only
chloride- and bromide-induced ring openings have been studied).
At first, ring opening using 1 equiv. of benzyl bromide in acetoni-
trile was evaluated, which did not lead to complete conversion,
even after 13 days of heating at reflux temperature. Attempts to
accelerate the reaction, for example by replacing acetonitrile with
a high-boiling solvent such as dimethylformamide and performing
the reaction in acetonitrile under microwave irradiation, only
resulted in complex mixtures. Finally, complete conversion was
attained by treatment of 2-(trifl◦uoromethyl)aziridines 5a–c with
1 equiv. of benzyl iodide19 at 100 C under neat conditions, afford-
ing 1,1,1-trifluoro-3-iodopropan-2-amines 7a–c (Scheme 2, Table
2, Entries 1–3) in good yields. Detailed spectroscopic analysis
ruled out the formation of the other regioisomers.11a,20 It should be
noted that the ring opening of non-activated aziridines by benzyl
bromide in acetonitrile constitutes a highly efficient regio- and
stereoselective approach towards the preparation of secondary b-
bromo amines.21 The observations made here once again confirm
the reduced reactivity of CF3-substituted 1-alkylaziridines with
respect to electrophiles. In addition to benzyl iodide, ring opening
of 2-(trifluoromethyl)aziridines 5a–b by methyl iodide towards
1,1,1-trifluoro-3-iodopropan-2-amines 7d–e (Scheme 2, Table 2,
Entries 4–5) was attained in good yields by using 1 equiv. of methyl
iodide in acetonitrile at 100 ◦C for 3 days in a pressure vial (Scheme
2 Table 2). In an effort to improve the reaction rate, the amount
of methyl iodide was increased to 5 equiv., which unfortunately
resulted in the formation of benzyltrimethylammonium iodide as
a side-product. It should be mentioned that b-iodo amines 7a–e
represent a novel class of compounds with unexplored synthetic
potential.
As know from different literature reports, the ring opening of
non-activated 2-alkylaziridines by alkyl iodides usually produces
secondary b-iodo amines through ring opening of intermediate
aziridinium salts at the substituted aziridine carbon atom under
thermodynamic control.22 In this case, however, ring opening
of the aziridinium salts 10 by iodide proceeded regiospecifically
towards primary b-iodo amines 7, pointing to the conclusion that
this transformation probably occurs under kinetic control. This
change in regioselectivity can again be attributed to the strong
electron-withdrawing property of the CF3-substituent, which
prevents thermodynamic equilibration through recyclization of
primary b-iodo amines 7 towards intermediate aziridinium salts
10.
In order to demonstrate the synthetic potential of these novel
1,1,1-trifluoro-3-iodopropan-2-amines 7, their coupling with ben-
zene towards novel b-phenylethylamines, an interesting class of
amphetamine derivatives, was evaluated. In a first approach, b-
iodo amines 7a–b were treated with phenylmagnesium chloride
under various reaction conditions (2 equiv. of PhMgCl in THF
or CH2Cl2 at -78 ◦C, 0 ◦C, room temperature or under reflux).
Unfortunately, no desired b-phenylethylamines were formed, and
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even at low temperatures (-78 ◦C) elimination products were
observed. Another attempt involved a Negishi cross-coupling
of b-iodo amines 7a–b with iodobenzene. In accordance to
literature procedures,23 b-iodo amines 7a–b were converted into
the corresponding organozinc reagents using zinc, activated with
catalytic iodine, in DMF. Subsequent Pd-catalyzed cross-coupling
of the zinc reagents with iodobenzene using 2.5 mol % of Pd2(dba)3
and 10 mol % of a precatalyst such as P(o-tol)3 or SPhos,
only resulted in complex mixtures. Finally, a successful synthesis
of a-trifluoromethyl-b-phenylethylamines 8a–b was accomplished
by using a Gilman reagent such as lithium diphenylcuprate.24
Thus, b-iodo amines 7a–b were treated◦with 3 equiv. of lithium
diphenylcuprate in diethyl ether at -78 C, and stirring at room
temperature for 5 h eventually afforded the desired 1,1,1-trifluoro-
3-phenylpropan-2-amines 8a–b (Scheme 2), which were purified
by means of column chromatography on silica gel. In this way,
1,1,1-trifluoro-3-iodopropan-2-amines 7a–b were applied for the
formation of new trifluorinated amphetamine derivatives 8a–
b, demonstrating their synthetic potential. From a medicinal
point of view, the introduction of an electron-withdrawing CF3
group onto a b-phenylethylamino moiety can have a pronounced
influence on the basicity of the nitrogen atom and hence on
the pharmacological properties of these compounds. It should
be mentioned that attempted direct conversion of aziridines 5
into the corresponding b-phenylethylamines upon treatment with
1.5 equiv. of PhLi in THF or with 2 equiv. of Ph2CuLi in
Et2O was unsuccessful, resulting in full recovery of the starting
material.
In conclusion, a novel and convenient method for the prepa-
ration of 1-alkyl-2-(trifluoromethyl)aziridines was developed us-
ing easily accessible and inexpensive resources, making it an
economical approach for large-scale synthesis. Furthermore,
additional information concerning the reactivity of these 2-
(trifluoromethyl)aziridines was acquired by treatment of the latter
with acetic acid and alkyl iodides. In the case of alkyl iodides,
novel primary b-iodo amines were obtained through regioselective
ring opening of intermediate aziridinium salts, which proved to be
valuable precursors for the synthesis of novel a-trifluoromethyl-
b-phenylethylamines, an interesting class of trifluorinated am-
phetamines derivatives.
points of crystalline compounds were measured with a Bu¨chi 540
apparatus.
Synthesis of N-alkyl-3-chloro-1,1,1-trifluoropropan-2-amines 4 via
N-(1-chloromethyl-2,2,2-trifluoroethylidene)alkylamines 3
General procedure. To an ice-cooled solution of 1,1,1-
trifluoroacetone (0.09 mol, 1 equiv.) and the alkylamine (0.27 mol,
3 equiv.) in dry Et2O (250 mL) was added dropwise a solution
of TiCl4 (0.05 mol, 0.5 equiv.) in dry petroleum ether (80 mL).
After stirring for 3 h under reflux, the reaction mixture was
R
filtered over a pad of Celiteꢀ and washed with Et2O (2 ¥ 50 mL).
Evaporation of the solvent under reduced pressure afforded N-(1-
methyl-2,2,2-trifluoroethylidene)alkylamine 2 (purity >95% based
on NMR). Subsequently, a solution of imine 2 (0.065 mol)
and N-chlorosuccinimide (0.065 mol, 1 equiv.) in cyclohexane
(200 mL) was heated under reflux for 3 h. Afterwards, the
resulting succinimide was filtered off and washed with cyclohexane
(2 ¥ 20 mL). Evaporation of the solvent in vacuo afforded the
desired N-(1-chloromethyl-2,2,2-trifluoroethylidene)alkylamine 3
which occurs in equilibrium with a minor amount of N-alkyl-
2-amino-1-chloro-3,3,3-trifluoropropene (ratio: 9/1). To an ice-
cooled solution of the crude mixture of imine 3 (0.06 mol, 1 equiv.)
in MeOH (150 mL) was added NaBH4 (0.06 mol, 1 equiv.) in
small portions whilst stirring. Subsequently, the reaction mixture
was heated under reflux for 4 h, and every hour an extra equiv. of
NaBH4 (3 equiv. in total) was added in small portions. Afterwards,
the reaction mixture was quenched by a saturated solution of
NH4Cl (75 mL), extracted with EtOAc (3 ¥ 50 mL) and washed
with brine (3 ¥ 50 mL). Drying (MgSO4), filtration of the drying
agent and evaporation of the solvent afforded N-alkyl-3-chloro-
1,1,1-trifluoropropan-2-amine 4, which was purified by means of
column chromatography on silicagel (hexane/EtOAc) in order to
obtain an analytically pure sample.
N -(1-Chloromethyl-2,2,2-trifluoroethylidene)alkylamines 3
were obtained in high purity (>90% based on NMR, CDCl3) and
were used as such in the following step without prior purification.
However, in order to confirm their structure, the spectral data of
three derivatives are reported below. Despite several attempts, no
conclusive mass spectra were obtained for these compounds due
to their instability.
N-(1-Chloromethyl-2,2,2-trifluoroethylidene)benzylamine 3a
Experimental part
Brown oil. 1H NMR (300 MHz, CDCl3): d 4.18 (2H, s), 4.88 (2H,
d, J = 1.7 Hz), 7.30–7.40 (5H, m). 13C NMR (75 MHz, ref =
CDCl3): d 30.54, 55.47, 119.32 (q, J = 278.8 Hz), 127.57, 127.74,
128.76, 137.05, 153.96 (q, J = 34.2 Hz). 19F NMR (282 MHz,
CDCl3): d -72.32 (3F, s). IR (ATR, cm-1): nCN = 1686; nmax = 1454,
1339, 1194, 1116, 751, 699.
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent and tetramethylsilane as internal standard.
19F NMR spectra were recorded at 282 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent and CFCl3 as internal standard. Electron
spray (ES) mass spectra were obtained with an Agilent 1100
Series MS (ES, 4000V) mass spectrometer. Electron impact (EI)
mass spectra were recorded by using a HP 6890 GC coupled
to a HP 5973 MSD (mass selective detector). IR spectra were
measured with a Spectrum One FT-IR spectrophotometer. High
resolution electron spray (ES) mass spectra were obtained with
an Agilent Technologies 6210 Series Time-of-Flight. Diethyl ether
and tetrahydrofuran were dried over sodium benzophenone ketyl.
Other solvents were used as received from the supplier. Melting
N-(1-Chloromethyl-2,2,2-trifluoroethylidene)-(4-
chlorobenzyl)amine 3b
1
Orange oil. H NMR (300 MHz, CDCl3): d 4.18 (2H, s), 4.83
(2H, d, J = 1.7 Hz), 7.24–7.36 (4H, m). 13C NMR (75 MHz, ref =
CDCl3): d 30.48, 54.54, 119.32 (q, J = 280.9 Hz), 128.74, 128.96,
133.23, 135.52, 154.14 (q, J = 34.2 Hz). 19F NMR (282 MHz,
CDCl3): d -72.40 (3F, s). IR (ATR, cm-1): nCN = 1636; nmax = 1492,
1345, 1200, 1167, 1129, 1088, 1015, 833, 804.
7220 | Org. Biomol. Chem., 2011, 9, 7217–7223
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N-(1-Chloromethyl-2,2,2-trifluoroethylidene)-(4-
Synthesis of 1-alkyl-2-(trifluoromethyl)aziridines 5
methoxybenzyl)amine 3c
General procedure: In a flame-dried flask, N-alkyl-3-chloro-1,1,1-
trifluoropropan-2-amine 4 (0.05 mol, 1 equiv.) was dissolved in dry
THF (100 mL) under nitrogen atmosphere. The resulting mixture
was then cooled to 0 ◦C and LiHMDS (1.1 equiv., 1 M in THF) was
added dropwise via a syringe. After stirring at room temperature
for 4 h, the reaction mixture was quenched with a saturated
solution of NH4Cl (50 mL), extracted with EtOAc (3 ¥ 25 mL)
and washed with brine (3 ¥ 25 mL). Drying (MgSO4), filtration
of the drying agent and evaporation of the solvent afforded 1-
alkyl-2-(trifluoromethyl)aziridine 5, which was purified by means
of column chromatography on silicagel (Petroleum ether/EtOAc)
to obtain an analytically pure sample.
Orange oil. 1H NMR (300 MHz, CDCl3): d 3.81 (3H, s), 4.17 (2H,
s), 4.81 (2H, d, J = 1.1 Hz), 6.87–6.92 and 7.30–7.40 (4H, 2 ¥ m).
13C NMR (75 MHz, ref = CDCl3): d 30.39, 54.95, 55.17, 114.06,
119.23 (q, J = 280.4 Hz), 128.90, 128.99, 153.47 (q, J = 33.5 Hz),
158.99. 19F NMR (282 MHz, CDCl3): d -72.33 (3F, s). IR (ATR,
cm-1): nCN = 1613; nmax = 1513, 1247, 1168, 1130, 1087, 1033, 819.
N-Alkyl-3-chloro-1,1,1-trifluoropropan-2-amines 4
3-Chloro-N-(4-chlorobenzyl)-1,1,1-trifluoropropan-2-amine 4b.
Yellow oil. Rf 0.28 (Petroleum ether/EtOAc 95/5). Yield 54%. 1H
NMR (300 MHz, CDCl3): d 1.91 (1H, bs), 3.31–3.40 (1H, m), 3.63
(1H, d ¥ d, J = 11.8, 6.6 Hz), 3.79 (1H, d ¥ d, J = 11.8, 3.3 Hz), 3.90
and 3.97 (2H, 2 ¥ (d ¥ d), J = 13.5, 5.5, 5.0 Hz), 7.31–7.33 (4H, m).
13C NMR (75 MHz, ref = CDCl3): d 41.43 (d, J = 2.3 Hz), 50.82,
59.17 (q, J = 27.7 Hz), 125.23 (q, J = 284.6 Hz), 128.58, 129.51,
133.11, 137.33. 19F NMR (282 MHz, CDCl3): d -72.88 (3F, d, J =
6.6 Hz). IR (ATR, cm-1): nNH = 3362; nmax = 1492, 1274, 1162,
1090, 1015, 798, 688. MS (70 eV): m/z (%): 272/4 (M++1, 100).
HRMS (ES) calcd for C10H11Cl2F3N: 272.0221 [M+H]+; Found:
272.0216.
1-(4-Chlorobenzyl)-2-(trifluoromethyl)aziridine 5b. Yellow oil.
Rf 0.28 (Petroleum ether/EtOAc 95/5). Yield 83%. 1H NMR
(300 MHz, CDCl3): d 1.65 (1H, d, J = 6.1 Hz), 2.09–2.17 (2H,
m), 3.46 and 3.53 (2H, 2 ¥ d, J = 13.8 Hz), 7.25–7.32 (4H, m). 13
C
NMR (75 MHz, ref = CDCl3): d 30.04, 37.40 (q, J = 39.2 Hz),
62.65, 123.98 (q, J = 272.3 Hz), 128.59, 129.24, 133.27, 135.92.
19F NMR (282 MHz, CDCl3, ref = CFCl3): d -70.93 (3F, d, J =
5.3 Hz). IR (ATR, cm-1): nmax = 1492, 1284, 1138, 1088, 1016, 803.
MS (70 eV): m/z (%): 236/8 (M++1, 100). HRMS (ES) calcd for
C10H10ClF3N: 236.0454 [M+H]+; Found: 236.0451.
3-Chloro-1,1,1-trifluoro-N-(4-methoxybenzyl)propan-2-amine
4c. Yellow oil. Rf 0.22 (Petroleum ether/EtOAc 95/5). Yield
1-(4-Methoxybenzyl)-2-(trifluoromethyl)aziridine 5c. Yellow
oil. Rf 0.25 (Petroleum ether/EtOAc 95/5). Yield 80%. 1H NMR
(300 MHz, CDCl3): d 1.63 (1H, d, J = 5.5 Hz), 2.07–2.15 (2H,
m), 3.44 and 3.50 (2H, 2 ¥ d, J = 13.8 Hz), 3.78 (3H, s), 6.85–
6.89 and 7.21–7.26 (4H, 2 ¥ m). 13C NMR (75 MHz, CDCl3): d
29.83, 37.19 (q, J = 29.2 Hz), 55.24, 62.83, 113.93, 124.24 (q, J =
272.3 Hz), 129.32, 129.46, 159.16. 19F NMR (282 MHz, CDCl3,
1
58%. H NMR (300 MHz, CDCl3): d 1.88 (1H, bs), 3.34–3.40
(1H, m), 3.63 (1H, d ¥ d, J = 11.6, 6.6 Hz), 3.77 (1H, d ¥ d, J =
11.6, 3.9 Hz), 3.81 (3H, s), 3.86 and 3.94 (2H, 2 ¥ d, J = 13.2 Hz),
6.86–6.91 and 7.23–7.35 (4H, 2 ¥ m). 13C NMR (75 MHz, ref =
CDCl3): d 41.34 (CH2Cl, d, J = 2.3 Hz), 50.88, 54.97, 58.83 (q,
J = 27.7 Hz), 113.75, 125.30 (q, J = 283.8 Hz), 129.37, 130.75,
158.92. 19F NMR (282 MHz, CDCl3): d -72.84 (3F, d, J = 6.6 Hz).
IR (ATR, cm-1): nNH = 3358; nmax = 2838, 1513, 1247, 1165, 1121,
1033, 830. GC-MS (EI): m/z (%): 267 (M+, 15), 266 (19), 236 (7),
136 (7), 121 (100).
ref = CFCl3): d -71.52 (3F, d, J = 4.0 Hz). IR (ATR, cm-1): nmax
=
1613, 1513, 1284, 1243, 1135, 1032, 811. MS (70 eV): m/z (%):
232 (M+ +1, 100). HRMS (ES) calcd for C11H13F3NO: 232.0949
[M+H]+; Found: 232.0953.
1-Octyl-2-(trifluoromethyl)aziridine 5d. Light-yellow oil. Rf
0.29 (Petroleum ether/EtOAc 98/2). Yield 78%. 1H NMR
(300 MHz, CDCl3): d 0.85–0.90 (2H, m), 0.88 (3H, t, J = 6.3 Hz),
1.23–1.39 (8H, m), 1.50 (1H, d, J = 6.6 Hz), 1.54–1.61 (2H, m),
1.91–1.99 (1H, m), 2.07 (1H, d, J = 3.3 Hz), 2.16–2.25 and 2.38–
2.47 (2H, 2 ¥ m). 13C NMR (75 MHz, ref = CDCl3): d 14.05, 22.62,
27.06, 29.15, 29.33, 29.44, 30.04 (d, J = 2.3 Hz), 31.78, 37.32 (q,
J = 39.2 Hz), 60.59, 124.21 (q, J = 272.3 Hz).19F NMR (282 MHz,
N-(3-Chloro-1,1,1-trifluoropropan-2-yl)octan-1-amine 4d. Yel-
low oil. Rf 0.26 (Petroleum ether/EtOAc 99/1). Yield 65%. H
1
NMR (300 MHz, CDCl3): d 0.86–0.90 (2H, m), 0.88 (3H, t, J =
6.8 Hz), 1.23–1.35 (8H, m), 1.45–1.56 (2H, m), 2.67–2.81 (2H, m),
3.27–3.38 (1H, m), 3.61 (1H, d ¥ d, J = 11.6, 6.6 Hz), 3.79 (1H, d ¥
d, J = 11.6, 3.3 Hz). 13C NMR (75 MHz, ref = CDCl3): d 13.96,
22.62, 26.94, 29.21, 29.36, 30.16, 31.79, 41.42 (d, J = 3.5 Hz),
48.21, 60.73 (q, J = 27.7 Hz), 125.26 (q, J = 284.4 Hz). 19F NMR
(282 MHz, CDCl3): d -73.34 (3F, d, J = 6.6 Hz). IR (ATR, cm-1):
nNH = 3320; nmax = 1467, 1270, 1148, 1120, 688. GC-MS (EI): m/z
(%): 259 (M+, 1), 160 (100).
CDCl3): d –71.16 (3F, d, J = 5.3 Hz). IR (ATR, cm-1): nmax
=
1405, 1286, 1155, 1089, 700, 658. GC-MS (EI): m/z (%): 223 (M+,
0.54); (M+-CH2CH3, 8); (M+-(CH2)2CH3, 26); (M+-(CH2)4CH3,
34); (M+-(CH2)6CH3, 100). HRMS (ES) calcd for C11H21F3N:
224.1626 [M+H]+; Found: 224.1626.
3-Chloro-1,1,1-trifluoro-N-(2-phenylethyl)propan-2-amine 4e.
Yellow oil. Rf 0.36 (Petroleum ether/EtOAc 95/5). Yield 63%.
1H NMR (300 MHz, CDCl3): d 2.75–2.88 (2H, m), 2.95–3.07
and 3.17–3.24 (2H, 2 ¥ m), 3.33–3.41 (1H, m), 3.57 (1H, d ¥ d,
J = 11.6, 7.2 Hz), 3.76 (1H, d ¥ d, J = 11.6, 3.9 Hz). 7.19–7.33
(5H, m). 13C NMR (75 MHz, ref = CDCl3): d 36.46, 41.26 (d, J =
2.3 Hz), 49.24, 60.62 (q, J = 27.7 Hz), 125.14 (q, J = 283.8 Hz),
126.25, 128.41, 128.58, 139.06. 19F NMR (282 MHz, CDCl3): d
Synthesis of 2-benzylamino-3,3,3-trifluoropropyl acetate 6
In a 20 mL pressure vial, 1-alkyl-2-(trifluoromethyl)aziridine 5a
(0.5 mmol, 1 equiv.) and CH3COOH (2.5 mmol, 5 equiv.) were
dissolved in CH2Cl2 (3 mL), after which the reaction mixture was
stirred for 7 days at 60 ◦C. Afterwards, the reaction mixture was
neutralised by means of a saturated solution of NaHCO3, poured
into water (4 mL) and extracted with CH2Cl2 (3 ¥ 2 mL). The
combined organic layers were dried over anhydrous magnesium
-73.30 (3F, d, J = 6.6 Hz). IR (ATR, cm-1): nNH = 3350; nmax
=
1454, 1266, 1123, 1087, 749, 698. GC-MS (EI): m/z (%): 251 (M+,
0.1), 216 (1), 160 (100).
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sulfate. Filtration of the drying agent and evaporation of the
solvent afforded 2-benzylamino-3,3,3-trifluoropropyl acetate 6,
which was purified by means of column chromatography on
silicagel (Petroleum ether/EtOAc) to obtain an analytically pure
sample (25% yield, 33 mg).
(ATR, cm-1): nmax = 1511, 1241, 1164, 1143, 1105, 1036, 738, 698.
MS (70 eV): m/z (%): 450 (M++1, 100). HRMS (ES) calcd for
C18H20F3INO: 450.0542 [M+H]+; Found: 450.0539.
Synthesis of N-alkyl-1,1,1-trifluoro-3-iodo-N-methylpropan-2-
Light-yellow oil. Rf 0.21 (Petroleum ether/EtOAc 90/10). Yield
25%. 1H NMR (300 MHz, CDCl3): d 1.71 (1H, bs), 2.06 (3H, s),
3.29–3.39 (1H, m), 3.90 and 4.01 (4H, 2 ¥ d, J = 13.2 Hz), 4.22 (1H,
d ¥ d, J = 12.1 Hz, 4.4 Hz), 4.29 (1H, d ¥ d, J = 12.1 Hz, 5.5 Hz),
7.26–7.35 (5H, m). 13C NMR (75 MHz, CDCl3): d 20.70, 51.66,
57.27 (q, J = 27.7 Hz), 61.12, 125.70 (q, J = 283.8 Hz), 127.47,
128.20, 128.55, 139.06, 170.57. 19F NMR (282 MHz, CDCl3): d
amines 7d–e
General procedure: In
a 20 mL pressure vial, 1-alkyl-2-
(trifluoromethyl)aziridine 5 (2 mmol, 1 equiv.) and MeI (2 mmol,
1 equiv.) were dissolved in acetonitrile (6 mL). After stirring for
3 days at 100 ◦C, the solvent was removed in vacuo, affording
N-alkyl-1,1,1-trifluoro-3-iodo-N-methylpropan-2-amine 7, which
was purified by means of column chromatography on silicagel
(hexane) to obtain an analytically pure sample.
-73.00 (3F, d, J = 6.6 Hz). IR (ATR, cm-1): nNH = 3359; nCO
=
1745; nmax = 1226, 1133, 1047, 739, 698. MS (70 eV): m/z (%):
262 (M++1, 100). HRMS (ES) calcd for C12H15F3NO2: 262.1055
[M+H]+; Found: 262.1047.
N-Benzyl-1,1,1-trifluoro-3-iodo-N-methylpropan-2-amine 7d.
Light-yellow oil. Rf 0.34 (Hexane). Yield 12%. 1H NMR
(300 MHz, CDCl3): d 2.35 (3H, s), 3.28–3.48 (3H, m), 3.85 and
3.96 (2H, 2 ¥ d, J = 13.8 Hz), 7.24–7.46 (5H, m). 13C NMR
(75 MHz, CDCl3): d -1.72, 35.78, 59.37, 66.29 (q, J = 25.4 Hz),
125.26 (q, J = 295.4 Hz), 127.41, 128.42, 128.86, 138.66. 19F NMR
(282 MHz, CDCl3): d -68.55 (3F, d, J = 7.9 Hz). IR (ATR, cm-1):
nmax = 1712, 1454, 1251, 1163, 1105, 1075, 734, 698. MS (70 eV):
m/z (%): 344 (M++1, 20). HRMS (ES) calcd for C11H14F3IN:
344.0123 [M+H]+; Found: 344.0106.
Synthesis of N-alkyl-N-benzyl-1,1,1-trifluoro-3-iodopropan-2-
amines 7a–c
General procedure: A mixture of 1-alkyl-2-(trifluoromethyl)-
aziridine 5 (6 mmol, 1 equiv.) and benzyl iodide19 (6 mmol, 1 equiv.)
was heated at 100 ◦C under neat conditions for 24 h, affording
b-iodo amine 7 in 72–88% yield. This compound was purified
by recrystallisation from absolute EtOH or by means of column
chromatography on silicagel (Petroleum ether/EtOAc) to obtain
an analytically pure sample.
N-(4-Chlorobenzyl)-1,1,1-trifluoro-3-iodo-N-methylpropan-2-
amine 7e. Yellow oil. Rf 0.34 (Hexane). Yield 10%. H NMR
1
(300 MHz, CDCl3): d 2.32 (3H, s), 3.26–3.44 (3H, m), 3.81 and
3.92 (2H, 2 ¥ d, J = 13.8 Hz), 7.30 and 7.39 (4H, 2 ¥ d, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d -1.80, 35.58, 58.63, 66.25 (q, J =
25.8 Hz), 125.15 (q, J = 293.1 Hz), 128.51, 130.04, 133.01, 137.09.
19F NMR (282 MHz, CDCl3): d -68.01 (3F, d, J = 6.6 Hz). IR
(ATR, cm-1): nmax = 1490, 1321, 1252, 1163, 1104, 1076, 1014, 837,
804. MS (70 eV): m/z (%): 378/80 (M++1, 45). HRMS (ES) calcd
for C11H13ClF3IN: 377.9733 [M+H]+; Found: 377.9724.
N,N-Dibenzyl-1,1,1-trifluoro-3-iodopropan-2-amine 7a. Whi-
te crystals. Recrystallisation from absolute EtOH; Mp = 94.8 ◦C.
Yield 32%. H NMR (300 MHz, CDCl3): d 3.30–3.46 (3H, m),
3.72 and 3.99 (4H, 2 ¥ d, J = 13.2 Hz), 7.25–7.37 and 7.44–7.47
(10H, m). 13C NMR (75 MHz, CDCl3): d -2.92, 53.96, 60.43 (q, J =
25.4 Hz), 125.56 (q, J = 294.2 Hz), 127.52, 128.36, 129.45, 137.79.
19F NMR (282 MHz, CDCl3): d -67.14 (3F, d, J = 7.9 Hz). IR
(ATR, cm-1): nmax = 1238, 1144, 1109, 1090, 748, 697. MS (70 eV):
m/z (%): 420 (M++1, 100). HRMS (ES) calcd for C17H18F3IN:
420.0436 [M+H]+; Found: 420.0414.
1
Synthesis of N,N-dialkyl-1,1,1-trifluoro-3-phenylpropan-2-amines
8
N -Benzyl-N -(4-chlorobenzyl)-1,1,1-trifluoro-3-iodopropan-2-
amine 7b. White crystals. Recrystallisation from absolute EtOH;
Mp = 70.3 ◦C. Yield 50%. 1H NMR (300 MHz, CDCl3): d 3.26–
3.45 (3H, m), 3.70 and 3.95 (2H, 2 ¥ d, J = 13.2 Hz), 3.70 and
3.97 (2H, 2 ¥ d, J = 13.8 Hz), 7-27–7.44 and 7.44–7.47 (9H, m).
13C NMR (75 MHz, CDCl3): d -3.00, 53.35, 54.02, 60.58 (q, J =
25.4 Hz), 125.44 (q, J = 293.1 Hz), 127.64, 128.42, 128.53, 129.46,
130.76, 133.28, 136.34, 137.55. 19F NMR (282 MHz, CDCl3, ref =
CFCl3): d -67.88 (3F, d, J = 7.9 Hz). IR (ATR, cm-1): nmax = 2852,
1490, 1260, 1235, 1164, 1144, 1088, 1100, 1074, 695. MS (70 eV):
m/z (%): 454/6 (M++1, 100). HRMS (ES) calcd for C17H17ClF3IN:
454.0046 [M+H]+; Found: 454.0055.
A suspension of CuI (3 mmol, 3 equiv.) in dry Et2O was cooled
to -78 ◦C and PhLi (6 equiv., 1.8 M in dibutyl ether) was slowly
added to the solution under nitrogen atmosphere via a syringe.
After stirring for 30 min at -78 ◦C, a solution of N-benzyl-1,1,1-
trifluoro-3-iodopropan-2-amine 7 (1 mmol) in dry Et2O was added
at -78 ◦C, and the resulting suspension was further stirred for 5 h at
room temperature. Afterwards, the reaction mixture was quenched
with a saturated solution of NH4Cl (10 mL), filtered through a
R
pad of Celiteꢀ and washed with Et2O (2 ¥ 10 mL). The filtrate was
poured into H2O (15 mL), extracted with Et2O (3 ¥ 10 mL), and
the combined organic layers were washed with a saturated solution
of NH4Cl (15 mL) and brine (15 mL). Drying (MgSO4), filtration
of the drying agent and evaporation of the solvent under reduced
pressure afforded N,N-dialkyl-1,1,1-trifluoro-3-phenylpropan-2-
amine 9, which was purified by means of column chromatography
on silica gel (hexane) in order to obtain an analytically pure
sample.
N -Benzyl-1,1,1-trifluoro-3-iodo-N -(4-methoxybenzyl)propan-
2-amine 7c. Light-yellow oil. Rf 0.29 (Petroleum ether/EtOAc
98/2). Yield 34%. 1H NMR (300 MHz, CDCl3): d 3.30–3.45 (3H,
m), 3.81 (3H, s), 3.65 and 3.98 (2H, 2 ¥ d, J = 13.2 Hz), 3.69 and
3.92 (2H, 2 ¥ d, J = 13.8 Hz), 6.86–6.89, 7-25–7.36 and 7.44–7.47
(9H, 3 ¥ m). 13C NMR (75 MHz, CDCl3): d -2.72, 53.38, 53.67,
55.22, 60.28 (q, J = 25.4 Hz), 113.70, 125.56 (q, J = 293.1 Hz),
127.46, 128.36, 129.38, 129.67, 130.69, 138.02, 159.02. 19F NMR
(282 MHz, CDCl3, ref = CFCl3): d -67.76 (3F, d, J = 7.9 Hz). IR
N,N-Dibenzyl-1,1,1-trifluoro-3-phenylpropan-2-amine
8a.
Colourless oil. Rf 0.30 (Hexane). Yield: 48%. 1H NMR (300 MHz,
CDCl3): d 2.96–2.99 (2H, m), 3.42–3.56 (1H, m), 3.73 and 3.88
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(4H, 2 ¥ d, J = 13.8 Hz), 6.59–6.63 (2H, m), 6.96–7.48 (13H, m).
13C NMR (75 MHz, ref = CDCl3): d 32.52, 53.85, 59.86 (q, J =
24.6 Hz), 126.55, 127.06, 127.38, 127.61 (q, J = 281.9 Hz), 128.22,
128.74, 129.51, 138.55, 140.91. 19F NMR (282 MHz, CDCl3, ref =
CFCl3): d -68.52 (3F, d, J = 7.9 Hz). IR (ATR, cm-1): nmax = 1454,
1247, 1165, 1140, 1101, 744, 697. MS (70 eV): m/z (%): 370 (M+
+1, 100). HRMS (ES) calcd for C23H23F3N: 370.1783 [M+H]+;
Found: 370.1779.
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N-Benzyl-N-(4-chlorobenzyl)-1,1,1-trifluoro-3-phenylpropan-
1
2-amine 8b. Colourless oil. Rf 0.25 (Hexane). Yield: 50%. H
NMR (300 MHz, CDCl3): d 2.90–3.01 (2H, m), 3.39–3.52 (1H,
m), 3.68 and 3.81 (2H, 2 ¥ d, J = 13.8 Hz), 3.71 and 3.87 (2H, 2 ¥
d, J = 13.8 Hz), 6.93–7.41 (14H, m). 13C NMR (75 MHz, CDCl3):
d 32.52, 53.25, 53.83, 59.99 (q, J = 24.6 Hz), 127.24, 127.58 (q, J =
291.1 Hz), 127.84, 128.31, 128.37, 128.77, 129.49, 130.02, 130.59,
137.09, 137.34, 138.31. 19F NMR (282 MHz, CDCl3, ref = CFCl3):
d -68.62 (3F, d, J = 7.9 Hz). IR (ATR, cm-1): nmax = 1491, 1455,
1247, 1141, 1097, 747, 698. MS (70 eV): m/z (%): 404/6 (M+
+1, 100). HRMS (ES) calcd for C23H22ClF3N: 404.1393 [M+H]+;
Found: 404.1389.
Acknowledgements
The authors are indebted to Ghent University (GOA), the
Research Foundation-Flanders (FWO-Vlaanderen) and the Viet-
namese National Foundation for Science and Technology Devel-
opment (NAFOSTED) for financial support.
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