Synthesis of 1-alkyl-2-(trifluoromethyl)azetidines and their regiospecific ring opening toward diverse α-(trifluoromethyl)amines via intermediate azetidinium salts

Article abstract of DOI:10.1021/jo300694y

A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl) azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF₃-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.

Full text of DOI:10.1021/jo300694y

Article
pubs.acs.org/joc
Synthesis of 1-Alkyl-2-(trifluoromethyl)azetidines and Their
Regiospecific Ring Opening toward Diverse α-
(Trifluoromethyl)Amines via Intermediate Azetidinium Salts
Sara Kenis,† Matthias D’hooghe,*,† Guido Verniest,§,† Tuyet Anh Dang Thi,‡ Chinh Pham The,‡
Tuyen Van Nguyen,*,‡ and Norbert De Kimpe*,†
†Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
‡Institute of Chemistry, Vietnam Academy of Sciences & Technology, 18 Hoang Quoc Viet, Cau giay, Hanoi, Vietnam
S
* Supporting Information
ABSTRACT: A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained
azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and
base-induced ring closure. Furthermore, the reactivity profile of these 2-CF3-azetidines was assessed by means of quaternization
and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and
halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-
withdrawing groups at C2.
Azetidines are an important class of four-membered
azaheterocycles with a high ring strain energy (25.2 kcal/
mol),8 making them suitable precursors for a variety of
functionalized amine derivatives.9 Nevertheless, the chemistry
of azetidines has not been explored as intensively as that of
their lower homologues, aziridines, which already demonstrated
their broad applicability as versatile building blocks through a
variety of ring-opening and ring-transformation reactions.10
A potentially interesting subclass of these four-membered
azaheterocycles involves the group of 2-(trifluoromethyl)-
azetidines. The chemistry of 2-CF3-azetidines comprises an
unexplored field of research, both in terms of their synthesis
and their reactivity. No reports regarding nonactivated 2-
(trifluoromethyl)azetidines, i.e., 2-CF3-azetidines bearing an
electron-donating substituent at nitrogen, are available in the
literature, and only one approach toward activated 4-
trifluoromethyl-2-alkyl- and -2,3-dialkylazetidines has been
described, involving Wittig reaction of a 4-CF3-β-lactam
followed by alkylation and hydrogenation.11 Two other
INTRODUCTION
■
Because of the unique chemical and physical properties of
fluorine,1 the interest in fluorinated compounds in organic and
pharmaceutical chemistry has increased considerably over the
years.2 In that respect, particular attention has been paid to the
introduction of a trifluoromethyl group, leading to numerous
CF3-containing drugs and drug-candidates2c such as fluoxetine
(antidepressant),3 celecoxib (anti-inflammatory activity),4 and
efavirenz (antiviral activity).4 In general, fluorine-substituted
amines are of high importance for the design of new drugs with
a broad spectrum of biological activities.5 The selective
introduction of fluorine, for example, as a CF3 group, can
strongly alter the biological and pharmacological properties
such as pKa, lipophilicity, acute toxicity, and metabolic stability
of bioactive compounds.6 The synthesis of CF3-containing
structures can be accomplished by either the selective
introduction of a CF3 group using trifluoromethylating reagents
or by the use of CF3-containing building blocks. Trifluor-
omethylation in a late stage of the synthesis, however, often
appears to be problematic,7 and a building block approach can
provide an efficient alternative.
Received: April 5, 2012
© XXXX American Chemical Society
A
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Scheme 1
approaches toward (rather elusive) activated 2-CF3-azetidines
are based on either a cycloaddition reaction of a perfluorinated
imine and an alkene to give 2,2-bis-(trifluoromethyl)-
azetidines12 or a cycloaddition reaction of a CF3-imine and
an alkene to furnish polysubstituted azetidines,13 but both
strategies do not provide selective and efficient entries into the
class of 2-(trifluoromethyl)azetidines, as these compounds were
obtained as side products or even only speculatively
characterized by mass spectrometry. Moreover, no reports of
monosubstituted 2-(trifluoromethyl)azetidines are available to
date, except for two structures accommodating a 2-CF3-
azetidine unit as part of a large framework claimed in the
patent literature.14 In addition to the challenge to develop a
convenient synthetic approach toward 2-(trifluoromethyl)-
azetidines, the study of the unexplored reactivity of these
synthons might provide new insights and opportunities from
both a fundamental and an applied viewpoint. Therefore, in this
paper, a straightforward synthetic method toward novel 1-alkyl-
2-(trifluoromethyl)azetidines is evaluated starting from com-
mercially available ethyl 4,4,4-trifluoroacetoacetate. Further-
more, important information concerning the reactivity of these
novel small-ring azaheterocycles toward a variety of nucleo-
philes is acquired after initial quaternization of the azetidine
moiety to the corresponding azetidinium intermediates,
demonstrating a regiospecific C4 ring opening of 2-CF3-
azetidines as opposed to the behavior of azetidines bearing
other types of electron-withdrawing groups at C2.
In the next part, the reactivity of these novel azetidines 5 was
investigated toward ring-opening reactions with different
nucleophiles in order to assess the influence of the strong
electron-withdrawing trifluoromethyl group on the aptitude and
selectivity of these transformations. Because of the presence of
an electron-donating substituent at nitrogen, activation of the
azetidine moiety to the corresponding azetidinium ion by
means of protonation, alkylation, or acylation was required
prior to ring opening. In a first approach, 2-CF3-azetidines 5b,e
were dissolved in hydrochloric acid (37% solution in water) or
hydrobromic acid (48% solution in water), which, after heating
at 100 °C for 2−3 days, yielded 4-chloro-N-(4-methylbenzyl)-
1,1,1-trifluorobutan-2-amine 4b and 4-bromo-N-phenylethyl-
1,1,1-trifluorobutan-2-amine 7e, respectively (Scheme 2). The
Scheme 2
reaction occurred regiospecifically by nucleophilic attack of the
halide (Cl−, Br−) at the less-hindered position of the
intermediate azetidinium ions 6. This observation was in
accordance with previously reported results on the acid-induced
ring opening of their smaller counterparts, 2-CF3-aziridines.16
A regiospecific ring opening of 2-CF3-azetidines 5b,e was
also accomplished using 1.5 equiv of acetyl chloride in dry
CH2Cl2 at reflux for 4 h, resulting in the corresponding N-alkyl-
N-[3-chloro-2-(trifluoromethyl)propyl]acetamides 9b,e (68−
85%, Scheme 3). Furthermore, in analogy with the ring
opening of 1-alkyl-2-cyano- and 2-acyl-1-alkylazetidines with
chloroformates,17 2-CF3-substituted azetidines 5a,b,e were
treated with 3 equiv of methyl chloroformate in dry acetonitrile
under reflux for 5 h, yielding methyl N-alkyl-N-[3-chloro-1-
(trifluoromethyl)propyl]carbamates 10a,b,e (63−70%, Scheme
3). It is noteworthy that the ring opening of the azetidinium
ions 8 by chloride proceeds regiospecifically at the C4 position,
whereas the ring opening of the azetidinium ions of 1-
phenylethyl-2-acylazetidines by chloride is known to occur at
the more electrophilic C2 position.17 This difference could be
explained by the steric hindrance and the electronic effect
exerted by the trifluoromethyl group, rendering the less-
electrophilic C4 position more accessible toward nucleophilic
RESULTS AND DISCUSSION
■
At first, enamines 2a−g (77−99%) were prepared through
condensation of ethyl 4,4,4-trifluoroacetoacetate 1 upon
treatment with a primary amine in the presence of acetic
acid.15 Reduction of these enamines 2a−g using sodium
borohydride (3 equiv) in EtOH (10 equiv) and THF as the
solvent afforded the corresponding 3-alkylamino-4,4,4-trifluor-
obutan-1-ols 3a−g in 50−79% yield (Scheme 1), and treatment
of these γ-amino alcohols 3a−g with thionyl chloride in
dichloromethane under reflux for 5 h resulted in novel N-alkyl-
4-chloro-1,1,1-trifluorobutan-2-amines 4a−g (50−83%, Scheme
1). γ-Chloroamines 4a−g were treated with two times 1.1 equiv
of LiHMDS in THF under reflux for 4 h, affording 1-alkyl-2-
(trifluoromethyl)azetidines 5a−g in good to excellent yields
(59−90%, Scheme 1).16 The use of this strong base was
required because of the reduced nucleophilicity of the nitrogen
atom, caused by the strong electron-withdrawing effect of the
trifluoromethyl substituent in α-position. It should be noted
that the above-described method comprises a new and efficient
approach for the construction of the α-CF3-azetidine frame-
work as a suitable template for further elaboration.
B
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Scheme 3
attack. The corresponding methyl carbamates 10 showed to be
valuable precursors for the synthesis of interesting CF3-
substituted 1,3-oxazinan-2-ones 11a,b. When the latter methyl
carbamates 10a,b were heated in DMF under reflux, full
conversion toward the corresponding 1,3-oxazinan-2-ones
11a,b was achieved upon prolonged heating (>6 days).
However, this drawback was easily overcome by the use of
microwave irradiation, resulting in the corresponding 3-alkyl-4-
trifluoromethyl-1,3-oxazinan-2-ones 11a,b after heating of
methyl carbamates 10a,b at 140 °C (200 W) for 30 min
(Scheme 3). Many drugs contain the 1,3-oxazinan-2-one
substructure, and their derivatives exhibit important biological
activities such as antibacterial,18 anti-inflammatory,19 and
antitumor activities.20
In the next part, activation of the azetidine moiety was
effected by alkylation of the nitrogen atom to produce
quaternary ammonium salts. Treatment of 2-CF3-azetidines
5b,c with 1 equiv of benzyl iodide at 100 °C for 1 day in a
pressure vial resulted in the corresponding γ-iodoamines 13b,c
in 72−77% yield through regioselective ring opening of
azetidinium intermediates 12 at the C4 position (Scheme 4).
In analogy with the corresponding nonactivated 2-CF3-
aziridines, the ring opening of azetidines 5 by benzyl iodide
affords primary iodides as the final products, pointing to a
kinetically controlled reaction pathway.16
Alkylation of 2-CF3-azetidines 5 was also performed utilizing
1.5 equiv of Me3OBF4 in dry CH2Cl2 at room temperature for 2
h, affording stable azetidinium salts 14a−d in a quantitative way
(Scheme 5). Afterward, these salts 14 were subjected to ring
opening in a regiospecific way by using oxygen, nitrogen,
carbon, and sulfur nucleophiles, thus providing a convenient
entry into a variety of α-(trifluoromethyl)amines 15−18. In a
first experiment, azetidinium ions 14b,c were treated with 2
equiv of sodium cyanide in CH3CN under reflux for 3 h,
resulting in 4-(N-alkyl-N-methyl)amino-5,5,5-trifluoropentane-
nitriles 15b,c (74−78%, Scheme 5). In analogy, treatment of
intermediates 14a−d with thiophenol and benzylamine resulted
in the corresponding 4-phenylthio-1,1,1-trifluorobutan-2-
amines 17b,c (63−64%, Scheme 5) and 4,4,4-trifluorobutan-
1,3-diamines 18a,d (52−56%, Scheme 5), respectively. In
addition, 3-aminobutan-1-ols 16b,d were obtained in good
yields (72−88%, Scheme 5) by heating azetidinium salts 14b,d
in aq CH3CN (1/1) for 24 h.
On the basis of all of the above-described transformations, it
can be concluded that the ring opening of nonactivated 2-CF3-
azetidines proceeds regiospecifically at C4, independent of the
type of activation and the nature of the nucleophile involved.
Thus, a clear difference in reactivity between α-CF3-azetidines
and azetidines bearing other types of electron-withdrawing
groups at C2 toward ring-opening reactions can be noted. For
example, the Lewis acid-mediated ring opening of activated 2-
aryl-1-tosylazetidines occurs regiospecifically at the more
electrophilic C2 position,9a,21 whereas nucleophilic ring open-
ing of the azetidinium salts derived from nonactivated 2-acyl- or
2-cyano-1-alkylazetidines generally occurs regioselectively at the
Scheme 4
Scheme 5
C
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Scheme 6
C4 position with formation of the C2 ring-opening products as
minor constituents (2−25%, sometimes up to 63%),9a,22 except
for the ring opening with methyl chloroformate, which
exclusively occurs at the C2 position. On the other hand, the
ring opening of 2-CF3-azetidines 5a−e proved to be
regiospecific in all cases, providing new insights into the
chemistry of azetidines. In that respect, it is also fair to state
that 2-CF3-azetidines 5 are suitable substrates for efficient
syntheses of a variety of novel acyclic α-trifluoromethylated
amines (52−88%).
Scheme 7
A final objective of this study comprised the assessment of
the reactivity of 1-alkyl-2-(trifluoromethyl)azetidines 5 relative
to that of their nonfluorinated analogues, i.e., 1-alkyl-2-
methylazetidines, as very little information concerning the
latter 2-methylazetidines is available in the literature.23 In
particular, nothing is known regarding their behavior toward
alkyl halides, hence an effort was made in that respect in the
present study.
In order to evaluate the reactivity of 1-alkyl-2-methylazeti-
dines toward alkyl halides, 1-benzyl-2-methylazetidine 23 was
chosen as a reference compound and was prepared in a four-
step approach adapted from the literature starting from methyl
2-butenoate 19 (Scheme 6). In the first step, methyl 2-
butenoate 19 was treated with benzylamine in methanol at
reflux temperature to afford methyl 2-(benzylamino)butanoate
20 in excellent yield.24 The use of microwave irradiation
according to a literature protocol25 afforded amino ester 20
after 3 h at 150 °C, albeit in a lower yield (86%). In the next
step, methyl 2-(benzylamino)butanoate 20 was reduced by
using LiAlH4 in THF under reflux, resulting in the
corresponding butan-1-ol 21.26 Treatment of this γ-amino
alcohol 21 with thionyl chloride in dichloromethane under
reflux resulted in N-benzyl-4-chlorobutan-2-amine 22,27 which
was ring closed toward the desired 1-benzyl-2-methylazetidine
2328 by using 1.5 equiv of n-BuLi in THF at room temperature
for 2 h.
literature reports on the thermodynamically controlled ring
opening of nonactivated 2-alkylaziridines by alkyl halides to
produce secondary halides through ring opening at C2.29
It is clear that replacement of a methyl group by a
trifluoromethyl group at the 2-position results in a complete
switch of the reactivity of 1-alkylazetidines with respect to alkyl
halides, providing secondary halides using the former and
affording primary halides using the latter azetidines after ring
opening. This profound difference in reactivity can be
attributed to the strong electron-withdrawing property of the
CF3-substituent and is in line with the established reactivity of
nonactivated 2-CF3-aziridines.16
In conclusion, a straightforward four-step approach toward
novel α-trifluoromethyl-substituted azetidines was developed
starting from ethyl 4,4,4-trifluoroacetoacetate. Furthermore,
activation of these 1-alkyl-2-(trifluoromethyl)azetidines via
protonation, alkylation, or acylation and subsequent regiospe-
cific ring opening of the intermediate azetidinium ions was
achieved at the C4 azetidine carbon atom by means of oxygen,
nitrogen, carbon, sulfur, and halogen nucleophiles, providing an
entry into a broad variety of acyclic α-CF3-amines. In addition,
novel 4-CF3-1,3-oxazinan-2-ones were obtained via cyclization
of the corresponding methyl N-alkyl-N-[3-chloro-1-
(trifluoromethyl)propyl]carbamates upon microwave irradia-
tion.
In the next phase, 2-methylazetidine 23 was treated with 1
equiv of benzyl bromide in acetonitrile under reflux for 3 h to
evaluate its behavior with respect to alkyl halides. As expected,
this reaction resulted in the sole formation of the secondary
bromide 25 (Scheme 7), which can be explained by ring
opening of the intermediate azetidinium salt 24 at the
substituted azetidine carbon atom under thermodynamic
control. This result is in perfect agreement with different
EXPERIMENTAL SECTION
■
Synthesis of Ethyl 3-Alkylamino-4,4,4-trifluorobut-2-
enoates 2. As a representative example, the synthesis of ethyl 3-
benzylamino-4,4,4-trifluorobut-2-enoate 2a is described here. A
solution of benzylamine (55.0 mmol) and CH3COOH (55.0 mmol)
in CHCl3 (80 mL) was stirred at room temperature for 5 min, after
which a solution of ethyl 4,4,4-trifluoroacetoacetate (50 mmol) in
D
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CHCl3 (100 mL) was added. After stirring for 5 h under reflux, the
solvent was evaporated under reduced pressure, and the residue was
filtered through a short silica column using hexane to afford the
desired ethyl 3-benzylamino-4,4,4-trifluorobut-2-enoate 2a. The
spectral data of enamines 2a and 2f were in full accordance with
those available in the literature.30
Synthesis of 3-Alkylamino-4,4,4-trifluorobutan-1-ols 3. As a
representative example, the synthesis of 3-benzylamino-4,4,4-trifluor-
obutan-1-ol 3a is described. To a solution of ethyl 3-benzylamino-
4,4,4-trifluorobut-2-enoate 2a (54 mmol) and EtOH (540 mmol) in
THF (130 mL) at 0 °C was added NaBH4 (54 mmol) in small
portions while stirring. Subsequently, the reaction mixture was heated
under reflux for 16 h, and every 5 h an extra equivalent of NaBH4 was
added (3 equiv in total). Afterward, the reaction mixture was quenched
by a saturated solution of NH4Cl (65 mL). Extraction with CH2Cl2 (3
× 40 mL), washing with brine (3 × 40 mL), drying (MgSO4), filtration
of the drying agent, and evaporation of the solvent afforded 3-
benzylamino-4,4,4-trifluorobutan-1-ol 3a, which was purified by means
of column chromatography on silica gel (petroleum ether/EtOAc 7/3)
in order to obtain an analytically pure sample.
3-Benzylamino-4,4,4-trifluorobutan-1-ol 3a. Pale yellow oil: Rf
0.29 (petroleum ether/EtOAc 7/3); yield 79% (9.9 g); 1H NMR (300
MHz, CDCl3) δ 1.62−1.75 and 1.81−1.90 (2H, 2 × m), 2.76 (2H, s
(broad)), 3.22−3.34 (1H, m), 3.71−3.79 (2H, m), 3.84 and 4.06 (2H,
2 × d, J = 12.7 Hz), 7.27−7.34 (5H, m); 13C NMR (75 MHz, CDCl3)
δ 30.5 (CH2), 51.7 (CH2), 58.1 (q, J = 27.7 Hz, CH), 60.8 (CH2),
126.5 (q, J = 280.0 Hz, C), 127.6 (CH), 128.5 (CH), 128.7 (CH),
139.0 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −74.58 (d, J =
6.6 Hz); IR (cm−1) νNH, OH = 3337; νmax = 1496, 1454, 1265, 1123,
1060, 1028, 740, 698; MS (70 eV) m/z (%) 234 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C11H14F3NO 234.1106 [M + H]+, found
234.1104.
Ethyl 3-(4-Methylbenzyl)amino-4,4,4-trifluorobut-2-enoate 2b.
1
Transparent oil: yield 92% (13.2 g); H NMR (300 MHz, CDCl3) δ
1.25 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 4.41
(2H, d, J = 6.1 Hz), 5.15 (1H, s), 7.13−7.22 (4H, m), 8.40 (1H, s
(broad)); 13C NMR (75 MHz, ref = CDCl3) δ 14.3 (CH3), 21.0
(CH3), 48.0 (∼d, J = 2.3 Hz, CH2), 59.7 (CH2), 85.2 (q, J = 5.8 Hz,
CH), 120.6 (q, J = 277.3 Hz, C), 127.4 (CH), 129.6 (CH), 134.9 (C),
137.6 (C) 148.2 (q, J = 31.2 Hz, C), 169.9 (C); 19F NMR (282 MHz,
CDCl3, ref = CFCl3) δ −67.09 (s); IR (cm−1) νNH = 3228; νCO
=
1670; νCC = 1629; νmax = 1150, 1286, 1214, 1200, 1130, 1035, 797,
759, 698, 662; MS (70 eV) m/z (%) 288 (M+ + 1, 10), 224 (100);
HRMS (ES-TOF) calcd for C14H17F3NO2 288.1211 [M + H]+, found
288.1193.
Ethyl 3-(4-Chlorobenzyl)amino-4,4,4-trifluorobut-2-enoate 2c.
1
Pale yellow oil: yield 99% (15.2 g); H NMR (300 MHz, CDCl3) δ
1.25 (3H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.41 (2H, d, J = 6.1
Hz), 5.18 (1H, s), 7.20 and 7.30 (4H, 2 × d, J = 8.8 Hz), 8.46 (1H, s
(broad)); 13C NMR (75 MHz, CDCl3) δ 14.3 (CH3), 47.5 (∼d, J =
3.2 Hz, CH2), 59.94 (CH2), 86.0 (q, J = 5.8 Hz, CH), 120.4 (q, J =
276.9 Hz, C), 128.7 (CH), 129.1 (CH), 133.8 (C), 136.5 (C), 148.1
(q, J = 31.2 Hz, C), 169.7 (C); 19F NMR (282 MHz, CDCl3) δ
3-(4-Methylbenzyl)amino-4,4,4-trifluorobutan-1-ol 3b. Yellow
1
oil: Rf 0.22 (petroleum ether/EtOAc 8/2); yield 77% (10.3 g); H
−66.53 (s); IR (cm−1) νNH = 3281; νCO = 1670, νCC = 1631; νmax
=
NMR (300 MHz, CDCl3) δ 1.59−1.72 and 1.78−1.87 (2H, 2 × m),
2.32 (3H, s), 3.19−3.29 (1H, m), 3.65−3.78 (2H, m), 3.78 and 3.99
(2H, 2 × d, J = 12.7 Hz), 7.13 and 7.19 (4H, d, J = 7.7, 8.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 21.1 (CH3), 30.7 (CH2), 51.6 (CH2), 57.7
(q, J = 27.7 Hz, CH), 60.4 (CH2), 127.0 (q, J = 285.4 Hz, C), 128.5
(CH), 129.4 (CH), 136.3 (C), 137.3 (C); 19F NMR (282 MHz,
1670, 1631, 1291, 1186, 1132, 1084, 797; MS (70 eV) m/z (%) 308/
310 (M+ + 1, 25), 264/6 (100); HRMS (ES-TOF) calcd for
C13H14ClF3NO2 308.0665 [M + H]+, found 308.0663.
Ethyl 3-(2-Chlorobenzyl)amino-4,4,4-trifluorobut-2-enoate 2d.
Transparent oil: Rf 0.55 (petroleum ether/EtOAc 95/5); yield 64%
(9.8 g); 1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J = 7.2 Hz), 4.14
(2H, q, J = 7.2 Hz), 4.55 (2H, d, J = 6.6 Hz), 5.19 (1H, s), 7.18−7.26
and 7.29−7.38 (4H, m), 8.57 (1H, s (broad)); 13C NMR (75 MHz,
CDCl3) δ 14.4 (CH3), 45.9 (∼d, J = 3.4 Hz, CH2), 59.9 (CH2), 85.9
(q, J = 5.8 Hz, CH), 120.4 (q, J = 276.9 Hz, C), 127.2 (CH), 128.9
(CH), 129.2 (CH), 129.8 (CH), 133.4 (C), 135.6 (C), 148.2 (q, J =
31.2 Hz, C), 169.9 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ
CDCl3, ref = CFCl3) δ −74.63 (d, J = 6.6 Hz); IR (cm−1) νNH, OH
=
3338; νmax = 1515, 1266, 1123, 1060, 1022, 806, 698; MS (70 eV) m/z
(%) 248 (M+ + 1, 72), 226 (100); HRMS (ES-TOF) calcd for
C12H16F3NO 248.1262 [M + H]+, found 248.1261.
3-(4-Chlorobenzyl)amino-4,4,4-trifluorobutan-1-ol 3c. Yellow oil:
1
Rf 0.08 (petroleum ether/EtOAc 9/1); yield 57% (8.2 g); H NMR
(300 MHz, CDCl3) δ 1.60−1.72 and 1.81−1.91 (2H, 2 × m), 2.13
(1H, s (broad)), 3.19−3.31 (1H, m), 3.70−3.80 (2H, m), 3.80 and
4.00 (2H, 2 × d, J = 13.2 Hz), 7.22−7.30 (4H, m); 13C NMR (75
MHz, CDCl3) δ 30.8 (CH2), 51.1 (CH2), 57.8 (q, J = 27.7 Hz, CH),
60.3 (CH2), 126.8 (q, J = 285.0 Hz, C), 128.8 (CH), 129.8 (CH),
133.2 (C), 137.8 (C); 19F NMR (282 MHz, CDCl3) δ −74.61 (d, J =
7.8 Hz); IR (cm−1) νNH, OH = 3344; νmax = 1492, 1265, 1123, 1090,
1060, 1015, 808; MS (70 eV) m/z (%) 268/70 (M+ + 1, 100); HRMS
(ES-TOF) calcd for C11H13ClF3NO 268.0716 [M + H]+, found
268.0711.
−66.90 (s); IR (cm−1) νNH = 3283; νCO = 1670; νCC = 1631; νmax
=
1446, 1305, 1288, 1184, 1131, 1037, 797, 750, 670; MS (70 eV) m/z
(%) 308/310 (M+ + 1, 100); HRMS (ES-TOF) calcd for
C13H14ClF3NO2 308.0665 [M + H]+, found 308.0670.
Ethyl 3-(Phenylethyl)amino-4,4,4-trifluorobut-2-enoate 2e. Yel-
low oil: yield 78% (11.2 g); 1H NMR (300 MHz, CDCl3) δ 1.25 (3H,
t, J = 7.2 Hz), 2.86 (2H, t, J = 7.43), 3.51 (2H, q, J = 6.6 Hz), 4.13
(2H, q, J = 7.2 Hz), 5.09 (1H, s), 7.18−7.25 and 7.28−7.33 (5H, 2 ×
m), 8.24 (1H, s (broad)); 13C NMR (75 MHz, ref = CDCl3) δ 14.4
(CH3), 37.3 (CH2), 45.7 (d, J = 2.3 Hz, CH2), 59.7 (CH2), 84.9 (q, J
= 5.8 Hz, CH), 120.4 (q, J = 276.9 Hz, C), 126.9 (CH), 128.8 (CH),
128.9 (CH), 138.1 (C), 148.4 (q, J = 30.8 Hz, C), 169.9 (C) 19F NMR
(282 MHz, CDCl3, ref = CFCl3) δ −67.27 (s); IR (cm−1) νNH = 3282;
νCO = 1670; νCC = 1630; νmax = 1473, 1455, 1287, 1181, 1131, 1090,
1039, 796, 698; MS (70 eV) m/z (%) 288 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C14H17F3NO2 288.1211 [M + H]+, found 288.1217.
Ethyl 3-(3-Methoxybenzyl)amino-4,4,4-trifluorobut-2-enoate 2g.
3-(2-Chlorobenzyl)amino-4,4,4-trifluorobutan-1-ol 3d. Yellow oil:
1
Rf 0.36 (petroleum ether/EtOAc 9/1); yield 60% (8.7 g); H NMR
(300 MHz, CDCl3) δ 1.62−1.74 and 1.84−1.93 (2H, 2 × m), 3.26−
3.36 (1H, m), 3.37 (1H, s (broad)), 3.67−3.80 (2H, m), 3.90 and 4.16
(2H, 2 × d, J = 13.2 Hz), 7.18−7.27 and 7.33−7.39 (4H, 2 × m); 13C
NMR (75 MHz, CDCl3) δ 30.7 (CH2), 49.7 (CH2), 58.3 (q, J = 27.7
Hz, CH), 60.3 (CH2), 126.7 (q, J = 285.0 Hz, C), 127.1 (CH), 129.0
(CH), 129.8 (CH), 130.5 (CH), 134.0 (C), 136.8 (C); 19F NMR (282
MHz, CDCl3) δ −74.90 (d, J = 7.8 Hz); IR (cm−1) νNH, OH = 3342;
νmax = 1574, 1444, 1265, 1121, 1055, 1038, 752, 698; MS (70 eV) m/z
(%) 268/70 (M+ + 1, 72), 300/2 (100); HRMS (ES-TOF) calcd for
C11H13ClF3NO 268.0716 [M + H]+, found 268.0716.
3-(Phenylethyl)amino-4,4,4-trifluorobutan-1-ol 3e. Transparent
oil: Rf 0.21 (petroleum ether/EtOAc 7/3); yield 71% (9.5 g); 1H
NMR (300 MHz, CDCl3) δ 1.39 (1H, s (broad)), 1.57−1.74 and
1.78−1.85 (2H, 2 × m), 2.78 (2H, t, J = 6.9 Hz), 2.92−2.98 (1H, m),
3.23−3.31 (2H, m), 3.74−3.78 (2H, m), 7.19−7.26 and 7.29−7.34
(5H, 2 × m); 13C NMR (75 MHz, CDCl3) δ 30.1 (CH2), 37.0 (CH2),
48.8 (CH2), 59.8 (q, J = 25.4 Hz, CH), 61.2 (CH2), 126.4 (q, J = 286.1
Hz, C), 126.5 (CH), 128.7 (CH), 139.1 (C); 19F NMR (282 MHz,
1
Yellow oil: Rf 0.74 (hexane/EtOAc 85/15); yield 94% (14.2 g); H
NMR (300 MHz, CDCl3) δ 1.27 (3H, t, J = 7.1 Hz), 3.81 (3H, s), 4.14
(2H, q, J = 7.1 Hz), 4.45 (2H, d, J = 6.3 Hz), 5.17 (1H, s), 6.84 (2H, d,
J = 6.2 Hz), 6.89 (1H, d, J = 7.5 Hz), 7.26−7.29 (1H, m), 8.44 (1H, s
(broad)); 13C NMR (75 MHz, ref = CDCl3) δ 14.3 (CH3), 48.0 (d, J
= 2.7 Hz, CH2), 55.2 (CH3), 59.7 (CH2), 85.4 (q, J = 5.8 Hz, CH),
112.9 (CH), 113.2 (CH), 119.4 (CH), 120.3 (q, J = 277.0 Hz, C),
129.9 (CH), 139.3 (C), 148.1 (q, J = 31.0 Hz, C), 160.0 (C), 169.8
(C); IR (cm−1) νNH = 3416; νCO = 1671; νCC = 1633; νmax = 1298,
1206, 1137, 1042, 613, 542; MS (70 eV) m/z (%)304 (M+ + 1, 20),
282 (100); HRMS (ES-TOF) calcd for C14H17F3NO3 304.1161 [M +
H]+, found 304.1137.
E
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CDCl3) δ −74.92 (d, J = 7.9 Hz); IR (cm−1) νNH, OH = 3332; νmax
=
(CH), 133.1 (C), 138.4 (C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −74.82 (d, J = 6.6 Hz); IR (cm−1) νNH = 3358; νmax = 1492,
1260, 1147, 1178, 1090, 810, 663; MS (70 eV) m/z (%) 286/88/90
(M+ + 1, 100); HRMS (ES-TOF) calcd for C11H12Cl2F3N 286.0377
[M + H]+, found 286.0365.
1454, 1264, 1125, 1099, 1060, 1030, 749, 698; MS (70 eV) m/z (%)
248 (M+ + 1, 100); HRMS (ES-TOF) calcd for C12H16F3NO
248.1262 [M + H]+, found 248.1259.
3-(4-Methoxybenzyl)amino-4,4,4-trifluorobutan-1-ol 3f. Yellow
1
oil: Rf 0.18 (hexane/EtOAc 9/1); yield 60% (8.6 g); H NMR (300
4-Chloro-N-(2-chlorobenzyl)-1,1,1-trifluorobutan-2-amine 4d.
MHz, CDCl3) δ 1.71−1.77 and 1.84−1.89 (2H, 2 × m), 2.31 (2H, s
(broad)), 3.29−3.33 (1H, m), 3.71−3.76 (2H, m), 3.80 (3H, s), 3.81
and 4.03 (2H, 2 × d, J = 13.7 Hz), 6.88 and 7.25 (2H, d, J = 8.6, 7.1
Hz); 13C NMR (75 MHz, ref = CDCl3) δ 30.3 (CH2), 51.0 (CH2),
55.3 (CH3), 57.9 (q, J = 27.1 Hz, CH), 60.9 (CH2), 114.1 (CH), 125.9
(q, J = 284.0 Hz, C), 129.8 (CH), 130.4 (C) and 159.2 (C); IR (cm−1)
νNH, OH = 3351; νmax = 1607, 1514, 1250, 1129, 1033, 834, 466; MS
(70 eV) m/z (%) 264 (M+ + 1, 100); HRMS (ES-TOF) calcd for
C12H16F3NO2 264.1211 [M + H]+, found 264.1229.
Orange oil: Rf 0.36 (petroleum ether/EtOAc 99/1); yield 83% (7.3
g); H NMR (300 MHz, CDCl3) δ 1.44 (1H, s (broad)), 1.78−1.89
1
and 2.04−2.18 (2H, 2 × m), 3.31−3.43 (1H, m), 3.60−3.75 (2H, m),
3.88 and 4.16 (2H, 2 × d, J = 13.2 Hz), 7.18−7.27 and 7.32−7.42 (4H,
2 × m); 13C NMR (75 MHz, CDCl3) δ 32.2 (CH2), 40.9 (CH2), 49.6
(CH2), 56.1 (q, J = 27.7 Hz, CH), 127.0 (q, J = 285.0 Hz, C), 127.0
(CH), 128.8 (CH), 129.7 (CH), 130.4 (CH), 134.0 (C), 137.1 (C);
19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −75.11 (d, J = 7.9 Hz);
IR (cm−1) νNH = 3363; νmax = 1574, 1444, 1261, 1153, 1116, 1051,
752, 682; MS (70 eV) m/z (%) 286/88/90 (M+ + 1, 42), 248 (100);
HRMS (ES-TOF) calcd for C11H12Cl2F3N 286.0377 [M + H]+, found
286.0373.
3-(3-Methoxybenzyl)amino-4,4,4-trifluorobutan-1-ol 3g. Yellow
1
oil: Rf 0.20 (hexane/EtOAc 8/2); yield 50% (7.1 g); H NMR (300
MHz, CDCl3) δ 1.86−1.90 and 1.99−2.04 (2H, 2 × m), 2.74 (2H, s
(broad)), 3.42−3.48 (1H, m), 3.87−3.99 (2H, m), 3.95 (3H, s), 3.98
and 4.20 (2H, 2 × d, J = 12.9 Hz), 6.96−6.98, 7.03−7.06 and 7.38−
7.41 (4H, 3 × m); 13C NMR (75 MHz, ref = CDCl3) δ 30.5 (CH2),
51.6 (CH2), 55.2 (CH3), 57.9 (q, J = 27.4 Hz, CH), 60.8 (CH2), 113.2
(CH), 113.9 (CH), 120.7 (CH), 129.7 (CH), 126.6 (q, J = 285.9 Hz,
C), 140.3 (C), 159.9 (C); IR (cm−1) νNH, OH = 3360; νmax = 1602,
1492, 1267, 1134, 1055, 700; MS (70 eV) m/z (%) 264 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C12H16F3NO2 264.1211 [M + H]+, found
264.1250.
Synthesis of N-Alkyl-4-chloro-1,1,1-trifluorobutan-2-amines
4. As a representative example, the synthesis of N-benzyl-4-chloro-
1,1,1-trifluorobutan-2-amine 4a is described. To an ice-cooled solution
of 3-benzylamino-4,4,4-trifluorobutan-1-ol 3a (31.0 mmol) in dry
CH2Cl2 (100 mL), SOCl2 (34.1 mmol) was added dropwise. After
heating under reflux for 5 h, the reaction mixture was neutralized by a
saturated solution of NaHCO3 (50 mL). Extraction with CH2Cl2 (3 ×
30 mL), washing with brine (3 × 30 mL), drying (MgSO4), filtration
of the drying agent, and evaporation of the solvent afforded N-benzyl-
4-chloro-1,1,1,-trifluorobutan-2-amine 4a, which was purified by means
of column chromatography on silica gel (petroleum ether/EtOAc 98/
2) in order to obtain an analytically pure sample.
4-Chloro-N-(phenylethyl)-1,1,1-trifluorobutan-2-amine 4e. Pale
yellow oil: Rf 0.15 (petroleum ether/EtOAc 98/2); yield 73% (6.0 g);
1H NMR (300 MHz, CDCl3) δ 1.02 (1H, s (broad)), 1.71−1.82 and
1.99−2.11 (2H, 2 × m), 2.73−2.82 (2H, m), 2.89−2.97 and 3.14−3.23
(2H, m), 3.26−3.36 (1H, m), 3.59−3.63 (1H, m), 7.20−7.33 (5H, 2 ×
m); 13C NMR (75 MHz, CDCl3) δ 32.0 (CH2), 37.0 (CH2), 41.0
(CH2), 49.0 (CH2), 57.0 (q, J = 27.3 Hz, CH), 127.0 (q, J = 285.0 Hz,
C), 126.3 (CH), 128.5 (CH), 128.7 (CH), 139.57 (C); 19F NMR (282
MHz, CDCl3, ref = CFCl3) δ −75.21 (d, J = 7.9 Hz); IR (cm−1) νNH
=
3367; νmax = 1603, 1454, 1261, 1142, 1117, 748, 698; MS (70 eV) m/z
(%) 266/8 (M+ + 1, 100); HRMS (ES-TOF) calcd for C12H15ClF3N
266.0923 [M + H]+, found 266.0919.
4-Chloro-N-(4-methoxybenzyl)-1,1,1-trifluorobutan-2-amine 4f.
Dark orange oil: Rf 0.50 (hexane/EtOAc 8/2); yield 50% (4.4 g);
1H NMR (300 MHz, CDCl3) δ 1.55 (1H, s (broad)), 1.83−1.89 and
2.07−2.14 (2H, 2 × m), 3.33−3.37 (1H, m), 3.66−3.70 and 3.72−3.78
(2H, 2 × m), 3.81 (3H, s (broad)), 3.80 and 4.00 (2H, 2 × d, J = 12.3
Hz), 6.86−6.89 and 7.26−7.28 (4H, 2 × m); 13C NMR (75 MHz, ref
= CDCl3) δ 32.2 (CH2), 41.0 (CH2), 51.2 (CH2), 55.3 (CH3), 55.7
(q, J = 27.4 Hz, CH), 113.9 (CH), 127.1 (q, J = 285.8 Hz, C), 129.5
(CH), 139.6 (C), 159.0 (C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −74.79 (s (broad)); IR (cm−1) νNH = 3356; νmax = 1610,
1519, 1253, 1122, 1039, 828; MS (70 eV) m/z (%) 282/4 (M+ + 1,
13), 278 (100).
N-Benzyl-4-chloro-1,1,1-trifluorobutan-2-amine 4a. Orange oil:
1
Rf 0.16 (petroleum ether/EtOAc 98/2); yield 70% (5.4 g); H NMR
(300 MHz, CDCl3) δ 1.43 (1H, s (broad)), 1.79−1.91 and 2.05−2.16
(2H, 2 × m), 3.30−3.42 (1H, m), 3.65−3.81 (2H, m), 3.85 and 4.07
(2H, 2 × d, J = 12.9 Hz), 7.34−7.39 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 32.2 (CH2), 41.0 (CH2), 51.8 (CH2), 55.9 (q, J = 27.7 Hz,
CH), 127.1 (q, J = 285.8 Hz, C), 127.4 (CH), 128.3 (CH), 128.5
(CH), 139.6 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −74.83
(d, J = 6.6 Hz); IR (cm−1) νNH = 3354; νmax = 1454, 1261, 1145, 1117,
870, 741, 698, 663; MS (70 eV) m/z (%) 252/4 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C11H13ClF3N 252.0767 [M + H]+, found
252.0762.
4-Chloro-N-(3-methoxybenzyl)-1,1,1-trifluorobutan-2-amine 4g.
1
Dark orange oil: Rf 0.56 (hexane/EtOAc 8/2); yield 50% (4.4 g); H
NMR (300 MHz, CDCl3) δ 1.72 (1H, s (broad)), 1.97−2.04 and
2.22−2.29 (2H, 2 × m), 3.48−3.54 (1H, m), 3.81−3.85 and 3.89−3.94
(2H, 2 × m), 3.96 (3H, s (broad)), 3.98 and 4.19 (2H, 2 × d, J = 13.2
Hz), 6.95−6.97, 7.07−7.08 and 7.38−7.41 (4H, 3 × m); 13C NMR
(75 MHz, ref = CDCl3) δ 32.2 (CH2), 40.9 (CH2), 51.7 (CH2), 55.2
(CH3), 55.9 (q, J = 27.5 Hz, CH), 112.9 (CH), 113.8 (CH), 120.5
(CH), 129.5 (CH), 127.0 (q, J = 285.7 Hz, C), 141.1 (C), 159.8 (C);
19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −74.84 (d, J = 6.6 Hz);
IR (cm−1) νNH = 3355; νmax = 1597, 1487, 1265, 1124, 1047, 875; MS
(70 eV) m/z (%) 282/4 (M+ + 1, 100); HRMS (ES-TOF) calcd for
C12H15ClF3NO 282.0873 [M + H]+, found 282.0903.
Synthesis of 1-Alkyl-2-(trifluoromethyl)azetidines 5. As a
representative example, the synthesis of 1-benzyl-2-(trifluoromethyl)-
azetidine 5a is described. In a flame-dried flask under N2 atmosphere,
N-benzyl-4-chloro-1,1,1-trifluorobutan-2-amine 4a (17.0 mmol) was
dissolved in dry THF (50 mL). The resulting mixture was then cooled
to 0 °C, and LiHMDS (18.7 mmol) was added dropwise via a syringe.
After stirring at reflux temperature for 2 h, the reaction was again
cooled to 0 °C, and an additional 1.1 equiv of LiHMDS (18.7 mmol)
was added. The reaction mixture was stirred for another 2 h at reflux
temperature. Afterward, the reaction mixture was quenched with a
saturated solution of NH4Cl (25 mL), extracted with EtOAc (3 × 15
mL), and washed with brine (3 × 15 mL). Drying (MgSO4), filtration
of the drying agent, and evaporation of the solvent yielded 1-benzyl-2-
(trifluoromethyl)azetidine 5a, which was purified by means of column
4-Chloro-N-(4-methylbenzyl)-1,1,1-trifluorobutan-2-amine 4b.
1
Orange oil: yield 88% (7.2 g); H NMR (300 MHz, CDCl3) δ 1.29
(1H, s (broad)), 1.75−1.87 and 2.02−2.13 (2H, 2 × m), 2.33 (3H, s),
3.27−3.36 (1H, m), 3.61−3.73 (2H, m), 3.78 and 4.00 (2H, 2 × d, J =
12.7 Hz), 7.11−7.14 and 7.18−7.30 (4H, 2 × m); 13C NMR (75 MHz,
ref = CDCl3) δ 21.2 (CH3), 32.3 (CH2), 41.1 (CH2), 51.6 (CH2), 56.0
(q, J = 27.7 Hz, CH), 127.3 (q, J = 285.4 Hz, C), 128.4 (CH), 129.3
(CH), 136.8 (C), 137.1 (C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −74.82 (d, J = 6.6 Hz); IR (cm−1) νNH = 3347; νmax = 1515,
1261, 1152, 1117, 871, 806, 663; MS (70 eV) m/z (%) 266/8 (M+ + 1,
15), 226 (100); HRMS (ES-TOF) calcd for C12H15ClF3N 266.0923
[M + H]+, found 266.0918.
4-Chloro-N-(4-chlorobenzyl)-1,1,1-trifluorobutan-2-amine 4c.
Yellow oil: Rf 0.31 (petroleum ether/EtOAc 9/1); yield 50% (4.4
1
g); H NMR (300 MHz, CDCl3) δ 1.31 (1H, s (broad)), 1.73−1.84
and 2.00−2.12 (2H, 2 × m), 3.28−3.33 (1H, m), 3.59−3.72 (2H, m),
3.77 and 3.98 (2H, 2 × d, J = 13.2 Hz), 7.24 (4H, s (broad)); 13C
NMR (75 MHz, CDCl3) δ 32.2 (CH2), 41.0 (CH2), 51.1 (CH2), 56.0
(q, J = 27.7 Hz, CH), 127.2 (q, J = 285.4 Hz, C), 128.7 (CH), 129.7
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chromatography on silica gel (petroleum ether/EtOAc 95/5) to obtain
an analytically pure sample.
ref = CFCl3) δ −77.56 (d, J = 6.6 Hz); IR (cm−1) νmax = 1613, 1512,
1283, 1247, 1158, 1135, 1125, 1090, 1035, 984, 824, 814, 694; MS (70
eV) m/z (%) 246 (M+ + 1, 100); HRMS (ES-TOF) calcd for
C12H15F3NO 246.1106 [M + H]+, found 246.1103.
1-Benzyl-2-(trifluoromethyl)azetidine 5a. Transparent oil: Rf 0.25
1
(petroleum ether/EtOAc 95/5); yield 80% (2.9 g); H NMR (300
MHz, CDCl3) δ 2.05−2.17 and 2.25−2.37 (2H, 2 × m), 2.93 (1H, ∼q,
J = 8.1 Hz), 3.27−3.33 (1H, m), 3.52 and 3.91 (2H, 2 × d, J = 12.7
Hz), 3.59−3.71 (1H, m), 7.23−7.35 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 17.4 (∼d, J = 3.5 Hz, CH2), 50.3 (CH2), 61.9 (CH2), 63.4
(q, J = 33.5 Hz, CH), 125.5 (q, J = 278.1 Hz, C), 127.5 (CH), 128.5
(CH), 128.9 (CH), 137.2 (C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −77.66 (d, J = 6.6 Hz); IR (cm−1) νmax = 1397, 1283, 1159,
1125, 1092, 984, 701; MS (70 eV) m/z (%) 216 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C11H12F3N 216.1000 [M + H]+, found
216.1000.
1-(3-Methoxybenzyl)-2-(trifluoromethyl)azetidine 5g. Orange oil:
yield 72% (3.0 g); H NMR (300 MHz, CDCl3) δ 2.06−2.20 and
1
2.25−2.37 (2H, 2 × m), 2.94 (1H, ∼q, J = 8.1 Hz), 3.29−3.34 (1H,
m), 3.49 and 3.88 (2H, 2 × d, J = 13.2 Hz), 3.59−3.71 (1H, m), 3.81
(3H, s), 6.79−6.87 and 7.20−7.32 (4H, 2 × m); 13C NMR (75 MHz,
CDCl3) δ 17.4 (∼d, J = 2.3 Hz, CH2), 50.2 (CH2), 55.2 (CH3), 61.7
(CH2), 63.2 (q, J = 32.3 Hz, CH), 112.8 (CH), 114.3 (CH), 121.1
(CH), 125.2 (q, J = 278.1 Hz, C), 129.4 (CH), 138.5 (C), 158.9 (C);
19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −77.64 (d, J = 6.6 Hz);
IR (cm−1) νmax = 1601, 1586, 1489, 1283, 1265, 1146, 1136, 1125,
1091, 1044, 777, 707, 691; MS (70 eV) m/z (%) 246 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C12H15F3NO 246.1106 [M + H]+, found
246.1108.
1-(4-Methylbenzyl)-2-(trifluoromethyl)azetidine 5b. Yellow oil: Rf
1
0.26 (petroleum ether/EtOAc 95/5); yield 77% (3.0 g); H NMR
(300 MHz, CDCl3) δ 2.03−2.13 and 2.23−2.35 (2H, 2 × m), 2.33
(3H, s), 2.92 (1H, ∼q, J = 8.1 Hz), 3.24−3.30 (1H, m), 3.47 and 3.87
(2H, 2 × d, J = 12.7 Hz), 3.57−3.69 (1H, m), 7.11−7.18 (4H, m); 13C
NMR (75 MHz, CDCl3) δ 17.4 (∼d, J = 2.3 Hz, CH2), 21.1 (CH3),
49.9 (CH2), 61.3 (CH2), 63.1 (q, J = 32.3 Hz, CH), 125.2 (q, J = 278.1
Hz, C), 128.8 (CH), 129.1 (CH), 133.8 (C), 136.9 (C); 19F NMR
(282 MHz, CDCl3, ref = CFCl3) δ −77.57 (d, J = 6.6 Hz); IR (cm−1)
νmax = 1515, 1397, 1283, 1159, 1136, 1125, 1091, 984, 810, 693; MS
(70 eV) m/z (%) 230 (M+ + 1, 100); HRMS (ES-TOF) calcd for
C12H15F3N 230.1157 [M + H]+, found 230.1160.
Synthesis of 4-Chloro-N-(4-methylbenzyl)-1,1,1-trifluorobu-
tan-2-amine 4b. In a 10 mL pressure vial, 1-(4-methylbenzyl)-2-
(trifluoromethyl)azetidine 5b (0.44 mmol) was dissolved in a 37%
solution of HCl in water (2 mL). The reaction mixture was stirred at
100 °C for 3 days. Afterward the reaction mixture was neutralized by
using a saturated solution of NaHCO3 and extracted with CH2Cl2 (3 ×
5 mL). Drying (MgSO4), filtration of the drying agent, and
evaporation of the solvent afforded 4-chloro-N-(4-methylbenzyl)-
1,1,1-trifluorobutan-2-amine 4b. The spectral data were in accordance
with those described above.
1-(4-Chlorobenzyl)-2-(trifluoromethyl)azetidine 5c. Yellow oil: Rf
1
0.31 (petroleum ether/EtOAc 95/5); yield 90% (3.8 g); H NMR
Synthesis of 4-Bromo-N-phenylethyl-1,1,1-trifluorobutan-2-
(300 MHz, CDCl3) δ 2.03−2.13 and 2.22−2.34 (2H, 2 × m), 2.86
(1H, ∼q, J = 8.1 Hz), 3.23−3.29 (1H, m), 3.44 and 3.83 (2H, 2 × d, J
= 13.2 Hz), 3.55−3.67 (1H, m), 7.18−7.28 (4H, m); 13C NMR (75
MHz, CDCl3) δ 17.4 (∼d, J = 2.3 Hz, CH2), 50.4 (CH2), 61.2 (CH2),
63.5 (q, J = 32.3 Hz, CH), 125.2 (q, J = 278.1 Hz, C), 128.6 (CH),
130.1 (CH), 133.1 (C), 135.8 (C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −77.71 (d, J = 6.6 Hz); IR (cm−1) νmax = 1491, 1282, 1159,
1137, 1098, 814, 692; MS (70 eV) m/z (%) 250/2 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C11H12ClF3N 250.0610 [M + H]+, found
250.0610.
amine 7e. In
a 10 mL pressure vial, 1-phenylethyl-2-
(trifluoromethyl)azetidine 5e (0.44 mmol) was dissolved in a 48%
solution of HBr in water (2 mL). The reaction mixture was stirred at
100 °C for 2 days. Afterward, the reaction mixture was neutralized by
using a saturated solution of NaHCO3 (10 mL) and extracted with
CH2Cl2 (3 × 5 mL). Drying (MgSO4), filtration of the drying agent,
and evaporation of the solvent afforded 4-bromo-N-phenylethyl-1,1,1-
trifluorobutan-2-amine 7e.
4-Bromo-N-phenylethyl-1,1,1-trifluorobutan-2-amine 7e. Yellow
oil: yield 66% (89.7 mg); 1H NMR (300 MHz, CDCl3) δ 1.03 (1H, s
(broad)), 1.79−1.91 and 2.05−2.16 (2H, 2 × m), 2.72−2.79 (2H, m),
2.89−2.97 and 3.14−3.23 (2H, 2 × m), 3.25−3.34 (1H, m), 3.43−3.47
(2H, m), 7.19−7.23 and 7.27−7.35 (5H, 2 × m); 13C NMR (75 MHz,
CDCl3) δ 29.4 (CH2), 32.0 (CH2), 36.9 (CH2), 48.8 (CH2), 57.7 (q, J
= 27.7 Hz, CH), 126.9 (q, J = 285.4 Hz, C), 126.3 (CH), 128.5 (CH),
128.7 (CH), 139.5 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ
−75.09 (d, J = 7.9 Hz); IR (cm−1) νNH = 3352; νmax = 1603, 1454,
1257, 1148, 1114, 1088, 873, 749, 698; MS (70 eV) m/z (%) 310/312
(M+ + 1, 100); HRMS (ES-TOF) calcd for C12H16BrF3N 310.0418
[M + H]+, found 310.0419.
1-(2-Chlorobenzyl)-2-(trifluoromethyl)azetidine 5d. Yellow oil: Rf
1
0.36 (petroleum ether/EtOAc 99/1); yield 59% (2.5 g); H NMR
(300 MHz, CDCl3) δ 2.08−2.18 and 2.26−2.38 (2H, 2 × m), 2.96
(1H, ∼q, J = 8.1 Hz), 3.36−3.42 (1H, m), 3.72 and 3.94 (2H, 2 × d, J
= 14.3 Hz), 3.68−3.80 (1H, m), 7.13−7.24, 7.31−7.34 and 7.39−7.42
(4H, 3 × m); 13C NMR (75 MHz, CDCl3) δ 17.5 (∼d, J = 3.5 Hz,
CH2), 51.1 (CH2), 58.7 (CH2), 63.6 (q, J = 32.7 Hz, CH), 125.2 (q, J
= 278.1 Hz, C), 126.9 (CH), 128.5 (CH), 129.5 (CH), 130.2 (CH),
133.8 (C), 135.1 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ
−77.90 (d, J = 6.6 Hz); IR (cm−1) νmax = 1574, 1444, 1398, 1283,
1161, 1131, 1091, 751, 693; MS (70 eV) m/z (%) 250/2 (M+ + 1,
100); HRMS (ES-TOF) calcd for C11H12ClF3N 250.0610 [M + H]+,
found 250.0607.
Synthesis of N-Alkyl-N-[3-chloro-1-(trifluoromethyl)propyl]-
acetamides 9. As a representative example, the synthesis of N-[3-
chloro-1-(trifluoromethyl)propyl]-N-(4-methylbenzyl)acetamide 9b is
described. In a flame-dried flask under N2 atmosphere, 1-(4-
methylbenzyl)-2-(trifluoromethyl)azetidine 5b (0.44 mmol) was
dissolved in dry CH2Cl2 (3 mL). Acetyl chloride (0.66 mmol) was
added via a syringe, and the resulting mixture was stirring under reflux
for 4 h. Afterward, the reaction mixture was quenched with a saturated
solution of NaHCO3 (10 mL) and extracted with EtOAc (3 × 5 mL).
Drying (MgSO4), filtration of the drying agent, and evaporation of the
solvent yielded N-[3-chloro-1-(trifluoromethyl)propyl]-N-(4-
methylbenzyl)acetamide 9b, which was purified by means of
preparative TLC (petroleum ether/EtOAc 95/5) to obtain an
1-(2-Phenylethyl)-2-(trifluoromethyl)azetidine 5e. Yellow oil: Rf
1
0.33 (petroleum ether/EtOAc 99/1); yield 81% (3.2 g); H NMR
(300 MHz, CDCl3) δ 2.00−2.13 and 2.22−2.34 (2H, 2 × m), 2.54−
2.75 (3H, m), 2.83−2.96 (2H, m), 3.40−3.59 (2H, m), 7.15−7.18 and
7.23−7.28 (5H, m); 13C NMR (75 MHz, CDCl3) δ 17.3 (∼d, J = 3.5
Hz, CH2), 34.0 (CH2), 51.0 (CH2), 60.2 (CH2), 64.3 (q, J = 32.3 Hz,
CH), 125.2 (q, J = 277.7 Hz, C), 126.2 (CH), 128.5 (CH), 128.7
(CH), 139.8 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −77.66
(d, J = 6.6 Hz); IR (cm−1) νmax = 1604, 1397, 1283, 1158, 1135, 1125,
1094, 748, 696; MS (70 eV) m/z (%) 230 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C12H15F3N 230.1157 [M + H]+, found 230.1151.
1-(4-Methoxybenzyl)-2-(trifluoromethyl)azetidine 5f. Orange oil:
1
analytically pure sample. In H and 13C NMR, two rotamers were
observed because of hindered rotation.
1
yield 85% (3.5 g); H NMR (300 MHz, CDCl3) δ 2.03−2.13 and
N-[3-Chloro-1-(trifluoromethyl)propyl]-N-(4-methylbenzyl)-
acetamide 9b. Pale yellow oil: Rf 0.06 (petroleum ether/EtOAc 99/
2.23−2.36 (2H, 2 × m), 2.92 (1H, ∼q, J = 8.1 Hz), 3.23−3.29 (1H,
m), 3.45 and 3.84 (2H, 2 × d, J = 13.2 Hz), 3.56−3.68 (1H, m), 3.80
(3H, s), 6.83−6.88 and 7.17−7.22 (4H, 2 × m); 13C NMR (75 MHz,
CDCl3) δ 17.4 (∼d, J = 3.5 Hz, CH2), 49.8 (CH2), 55.2 (CH3), 61.0
(CH2), 63.0 (q, J = 32.3 Hz, CH), 113.8 (CH), 125.2 (q, J = 278.1 Hz,
C), 128.9 (C), 130.1 (CH), 158.9 (C); 19F NMR (282 MHz, CDCl3,
1
1); yield 68% (91.9 mg); H NMR (300 MHz, CDCl3) δ 2.09−2.17
(4H, m), 2.29 and 2.32 (12H, 2 × s (broad)), 3.01−3.09 and 3.30−
3.34 (2H, 2 × m), 3.43−3.45 (2H, m), 4.05 and 5.14 (2H, 2 × d, J =
15.4 Hz), 4.51 and 4.63 (2H, 2 × d, J = 18.2 Hz), 4.66 (1H, s
(broad)), 5.60 (1H, s (broad)) 7.09−7.15 (8H, m); 13C NMR (75
G
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MHz, CDCl3) δ 21.0 (2 × CH3), 22.1 (CH3), 22.4 (CH3), 29.2
(CH2), 29.4 (CH2), 40.0 (CH2), 40.4 (CH2), 45.3 (2 × CH2), 57.1 (q,
J = 30.0 Hz, 2 × CH), 125.3 (q, J = 283.4 Hz, 2 × C), 125.8 (2 × CH),
127.6 (2 × CH), 129.4 (2 × CH), 129.7 (2 × CH), 133.7 (C), 135.2
(C), 137.1 (C), 137.5 (C), 172.6 (C), 173.3 (C); 19F NMR (282
28.8 Hz, 2 × CH), 125.3 (q, J = 283.4 Hz, 2 × C), 126.7 (2 × CH),
128.7 (2 × CH), 128.8 (2 × CH), 128.9 (2 × CH), 138.65 (C),
138.89 (C), 156.47 (C), 157.49 (C); 19F NMR (282 MHz, CDCl3, ref
= CFCl3) δ −72.98 (s, minor), −72.71 (s, major); IR (cm−1) νCO
=
1708; νmax = 1454, 1275, 1229, 1168, 1127, 1113, 1031, 774, 748, 700;
MS (70 eV) m/z (%) 324/6 (M+ + 1, 100).
MHz, CDCl3, ref = CFCl3) δ −71.89 (d, J = 7.9 Hz); IR (cm−1) νCO
=
Synthesis of 3-Alkyl-4-trifluoromethyl-1,3-oxazinan-2-ones
11. As a representative example, the synthesis of 3-benzyl-4-
trifluoromethyl-1,3-oxazinan-2-one 11a is described. In a 10 mL
thick-walled Pyrex reaction vessel, methyl N-benzyl-N-[(3-chloro-1-
(trifluoromethyl)propyl]carbamate 10a (0.49 mmol) was dissolved in
DMF (4 mL). The mixture was heated to 140 °C for 30 min under
microwave irradiation (200 W). Afterward, the reaction mixture was
dissolved in Et2O (4 mL) and washed with brine (4 × 2 mL). Drying
(MgSO4), filtration of the drying agent, and evaporation of the solvent
afforded 3-benzyl-4-trifluoromethyl-1,3-oxazinan-2-one 11a, which was
purified by means of column chromatography on silica gel (petroleum
ether/EtOAc 8/2).
1665; νmax = 1516, 1407, 1273, 1230, 1166, 1153, 1121, 1048, 1020,
796, 735; MS (70 eV) m/z (%) 308/10 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C14H18ClF3NO 308.1029 [M + H]+, found 308.1033.
N-[3-Chloro-2-(trifluoromethyl)propyl]-N-(2-phenylethyl)-
acetamide 9e. Pale yellow oil: Rf 0.14 (petroleum ether/EtOAc 95/
1
5); yield 61% (82.4 mg); H NMR (300 MHz, CDCl3) δ 2.11−2.29
(4H, m), 2.27 (6H, 2 × s), 2.72−2.81 (1H, m), 2.84−2.96 (2H, m),
2.99−3.11 (1H, m), 3.20−3.31 (3H, m), 3.35−3.63 (5H, m), 4.49−
4.64 (1H, m), 5.50 (1H, s (broad)), 7.17−7.36 (10H, m); 13C NMR
(75 MHz, CDCl3) δ 21.6 (CH3), 22.2 (CH3), 28.9 (CH2), 29.1
(CH2), 34.0 (CH2), 36.2 (CH2), 39.8 (CH2), 40.1 (CH2), 44.8 (2 ×
CH2), 56.3 (q, J = 30.0 Hz, 2 × CH), 125.2 (q, J = 283.8 Hz, 2 × C),
126.6 (CH), 127.1 (CH), 128.6 (2 × CH), 128.7 (2 × CH), 128.9 (2
× CH), 129.0 (2 × CH), 137.7 (C), 139.2 (C), 171.9 (C), 172.2 (C);
19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −72.72 (d, J = 7.9 Hz);
3-Benzyl-4-trifluoromethyl-1,3-oxazinan-2-one 11a. White crys-
tals: mp 73−75 °C: yield 59% (74.9 mg); 1H NMR (300 MHz,
CDCl3) δ 2.00−2.13 and 2.15−2.21 (2H, 2 × m), 3.72−3.81 (1H, m),
4.06 and 5.53 (2H, 2 × d, J = 15.5 Hz), 4.29−4.34 and 4.42−4.50 (2H,
2 × m), 7.27−7.40 (5H, m); 13C NMR (75 MHz, CDCl3) δ 21.9
(CH2), 51.5 (CH2), 53.2 (q, J = 30.0 Hz, CH), 63.6 (CH2), 125.3 (q, J
= 285.0 Hz, C), 128.3 (CH), 128.4 (CH), 129.1 (CH), 135.6 (C),
152.9 (C); 19F NMR (282 MHz, CDCl3) δ −71.46 (d, J = 6.5 Hz); IR
(cm−1) νCO = 1679; νmax = 1456, 1264, 1232, 1163, 1156, 1148, 1128,
1049, 704, 694; MS (70 eV) m/z (%) 260 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C12H13F3NO2 260.0898 [M + H]+, found 260.0903.
3-(4-Methylbenzyl)-4-trifluoromethyl-1,3-oxazinan-2-one 11b.
Pale yellow oil: Rf 0.17 (petroleum ether/EtOAc 9/1); yield 54%
IR (cm−1) νCO = 1662; νmax = 1413, 1271, 1227, 1167, 1149, 1122,
741, 700; MS (70 eV) m/z (%) 308/310 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C14H18ClF3NO 308.1029 [M + H]+, found 308.1032.
Synthesis of Methyl N-Alkyl-N-[3-chloro-1-(trifluoromethyl)-
propyl]carbamates 10. As a representative example, the synthesis of
methyl N-benzyl-N-[3-chloro-1-(trifluoromethyl)propyl]carbamate
10a is described. In a flame-dried flask under N2 atmosphere, 1-
benzyl-2-(trifluoromethyl)azetidine 5a (2.3 mmol) was dissolved in
dry CH3CN (10 mL). Methyl chloroformate (6.9 mmol) was added
via a syringe, and the resulting mixture was stirred under reflux for 5 h.
Afterward, the reaction mixture was quenched with a saturated
solution of NaHCO3 (5 mL), extracted with EtOAc (3 × 5 mL), and
washed with brine (3 × 5 mL). Drying (MgSO4), filtration of the
drying agent, and evaporation of the solvent afforded pure methyl N-
benzyl-N-[3-chloro-1-(trifluoromethyl)propyl]carbamates 10a. In 1H
and 13C, two rotamers were observed because of hindered rotation.
Methyl N-Benzyl-N-[3-chloro-1-(trifluoromethyl)propyl]-
1
(72.3 mg); H NMR (300 MHz, CDCl3) δ 1.97−2.12 and 2.14−2.21
(2H, 2 × m), 2.35 (3H, s), 3.74−3.79 (1H, m), 4.00 and 5.52 (2H, 2 ×
d, J = 14.9 Hz), 4.27−4.36 and 4.42−4.51 (2H, 2 × m), 7.11−7.23
(4H, m); 13C NMR (75 MHz, CDCl3) δ 21.1 (CH3), 21.7 (CH2),
51.1 (CH2), 52.8 (q, J = 30.0 Hz, CH), 63.5 (CH2), 125.2 (q, J = 285.0
Hz, C), 128.4 (CH), 129.7 (CH), 132.4 (C), 137.3 (C), 152.9 (C);
19F NMR (282 MHz, CDCl3) δ −72.39 (d, J = 6.6 Hz); IR (cm−1) νCO
1
carbamate 10a. Orange oil: yield 64% (455.0 mg); H NMR (300
= 1678; νmax = 1457, 1262, 1129, 1218, 1162, 1148, 1127, 1049, 762,
642; MS (70 eV) m/z (%) 274 (M+ + 1, 100); HRMS (ES-TOF)
calcd for C13H15F3NO2 274.1055 [M + H]+, found 274.1055.
Synthesis of N-Alkyl-N-benzyl-4-iodo-1,1,1-trifluorobutan-2-
amines 13. As a representative example, the synthesis of N-benzyl-N-
(4-methylbenzyl)-4-iodo-1,1,1-trifluorobutan-2-amine 13b is de-
scribed. In a 10 mL pressure vial, 1-(4-methylbenzyl)-2-
(trifluoromethyl)azetidine (1.31 mmol) and benzyl iodide (1.31
mmol) was heated at 100 °C under neat conditions for 1 day,
affording N-benzyl-N-(4-methylbenzyl)-4-iodo-1,1,1-trifluorobutan-2-
amine 13b, which was purified by means of column chromatography
on silica gel (hexane) to obtain an analytically pure sample.
MHz, CDCl3) δ 2.14−2.17 (4H, m), 3.16 (2H, m), 3.31 (2H, m), 3.80
(6H, s (broad)), 4.37 and 4.67 (4H, 2 × d, J = 16.0 Hz), 4.87 (1H, m),
5.02 (1H, m), 7.31−7.36 (10H, m); 13C NMR (75 MHz, CDCl3) δ
29.4 (2 × CH2), 40.1 (2 × CH2), 48.0 (2 × CH2), 53.6 (2 × CH3),
55.4 (q, J = 27.7 Hz, 2 × CH), 125.4 (q, J = 284.6 Hz, 2 × C), 127.6
(2 × CH), 128.7 (8 × CH), 137.8 (2 × C), 157.5 (2 × C); 19F NMR
(282 MHz, CDCl3, ref = CFCl3) δ −72.07 (s (broad)); IR (cm−1) νCO
= 1708; νmax = 1451, 1335, 1268, 1233, 1167, 1126, 1115, 733, 699;
MS (70 eV) m/z (%) 310/2 (M+ + 1, 100); HRMS (ES-TOF) calcd
for C13H16ClF3NO2 310.0822 [M + H]+, found 310.0812.
Methyl N-[3-Chloro-1-(trifluoromethyl)]propyl-N-(4-
methylbenzyl)carbamate 10b. Pale orange oil: Rf 0.17 (petroleum
N-Benzyl-N-(4-methylbenzyl)-4-iodo-1,1,1-trifluorobutan-2-
amine 13b. Transparent oil: Rf 0.35 (hexane); yield 75% (439.2 mg);
1H NMR (300 MHz, CDCl3) δ 1.99−2.12 and 2.17−2.31 (2H, 2 ×
1
ether/EtOAc 99/1); yield 63% (468.2 mg); H NMR (300 MHz, 50
°C, CDCl3) δ 2.09−2.14 and 2.20−2.25 (4H, 2 × m), 2.31 (6H, s),
3.18−3.26 and 3.28−3.36 (4H, 2 × m), 3.78 (6H, s), 4.31 and 4.67
(4H, 2 × d, J = 14.6 Hz), 4.92 (2H, m), 7.10−7.16 (8H, m); 13C NMR
(75 MHz, CDCl3) δ 21.1 (2 × CH3), 29.4 (2 × CH2), 40.1 (2 ×
CH2), 47.8 (2 × CH2N), 53.5 (2 × CH3), 55.3 (q, J = 28.8 Hz, 2 ×
CH), 125.3 (q, J = 283.8 Hz, 2 × C), 129.4 (8 × CH), 134.7 (2 × C),
137.3 (2 × C), 157.5 (2 × C); 19F NMR (282 MHz, CDCl3, ref =
CFCl3) δ −72.10 (s (broad)); IR (cm−1) νCO = 1710; νmax = 1451,
1330, 1268, 1232, 1167, 1117, 1025, 774; MS (70 eV) m/z (%) 324/6
(M+ + 1, 100); HRMS (ES-TOF) calcd for C14H18ClF3NO2 324.0978
[M + H]+, found 324.0969.
m), 2.34 (3H, s), 2.96−3.05 (1H, m), 3.20−3.33 (2H, m), 3.61−3.69
(2H, m), 3.89 and 3.93 (2H, 2 × d, J = 12.4 Hz), 7.10−7.22 and 7.23−
7.37 (9H, 2 × m); 13C NMR (75 MHz, CDCl3) δ 1.3 (CH2), 21.2
(CH3), 31.2 (CH2), 53.9 (CH2), 54.1 (CH2), 59.0 (q, J = 25.4 Hz,
CH), 127.4 (q, J = 291.9 Hz, C), 127.4 (CH), 128.6 (CH), 129.0
(CH), 129.1 (CH), 129.3 (CH), 135.4 (C), 137.1 (C), 138.6 (C); 19F
NMR (282 MHz, CDCl3, ref = CFCl3) δ −69.96 (d, J = 9.2 Hz); IR
(cm−1) νmax = 1514, 1495, 1454, 1249, 1142, 1111, 1091, 801, 735,
698; MS (70 eV) m/z (%) 448 (M+ + 1, 80), 320 (100); HRMS (ES-
TOF) calcd for C19H22F3IN 448.0749 [M + H]+, found 448.0740.
N-Benzyl-N-(4-chlorobenzyl)-4-iodo-1,1,1-trifluorobutan-2-
amine 13c. Pale yellow oil: Rf 0.33 (hexane); yield 75% (458.8 mg);
1H NMR (300 MHz, CDCl3) δ 2.00−2.12 and 2.16−2.28 (2H, 2 ×
Methyl N-[3-Chloro-1-(trifluoromethyl)]propyl-N-(phenylethyl)-
1
carbamate 10e. Yellow oil: yield 70% (520.2 mg); H NMR (300
MHz, CDCl3) δ 2.14−2.21 (4H, m), 2.80−2.94 (3H, m), 2.96−3.09
(1H, m), 3.21−3.34 (2H, m), 3.37−3.53 (2H, m), 3.79 (3H, s), 3.82
(3H, s), 5.00 (2H, m), 7.17−7.24 and 7.28−7.33 (10H, 2 × m); 13C
NMR (75 MHz, CDCl3) δ 29.1 (2 × CH2), 34.6 (CH2), 35.6 (CH2),
39.9 (2 × CH2), 45.9 (2 × CH2), 53.3 (CH3), 53.5 (CH3), 54.8 (q, J =
m), 2.33 (3H, s), 3.03 (1H, ∼q, J = 8.3 Hz), 3.20−3.33 (2H, m), 3.66
and 3.86 (2H, 2 × d, J = 13.8 Hz), 3.66 and 3.89 (2H, 2 × d, J = 13.2
Hz), 7.20−7.36 (9H, m); 13C NMR (75 MHz, CDCl3) δ 1.1 (CH2),
31.0 (CH2), 53.7 (CH2), 54.3 (CH2), 59.3 (q, J = 25.0 Hz, CH), 127.3
H
dx.doi.org/10.1021/jo300694y | J. Org. Chem. XXXX, XXX, XXX−XXX

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(q, J = 291.5 Hz, C), 127.6 (CH), 128.7 (CH), 128.8 (CH), 129.0
(CH), 130.4 (CH), 133.26 (C), 137.03 (C), 138.28 (C); 19F NMR
(282 MHz, CDCl3) δ −67.38 (d, J = 7.9 Hz); IR (cm−1) νmax = 1491,
1454, 1248, 1142, 1112, 1089, 1073, 802, 736, 698; MS (70 eV) m/z
(%) 468 (M+ + 1, 91), 415 (100); HRMS (ES-TOF) calcd for
C18H19ClF3IN 468.0203 [M + H]+, found 468.0205.
azetidinium tetrafluoroborate 14b (0.80 mmol) was dissolved in 4
mL of H2O/CH3CN (1/1). After stirring for 24 h under reflux, the
reaction mixture was poured out in a saturated solution of NaHCO3
(10 mL), extracted with CH2Cl2 (3 × 5 mL), and washed with brine
(3 × 5 mL). Drying (MgSO4), filtration of the drying agent, and
evaporation of the solvent yielded 3-[N-methyl-N-(4-methylbenzyl)-
amino]-4,4,4-trifluorobutan-1-ol 16b, which was purified by means of
column chromatography on silica gel (petroleum ether/EtOAc 98/2)
to obtain an analytically pure sample.
Synthesis of 1-Alkyl-1-methyl-2-(trifluoromethyl)-
azetidinium Tetrafluoroborates 14. As a representative example,
the synthesis of 1-methyl-1-(4-methylbenzyl)-2-(trifluoromethyl)-
azetidinium tetrafluoroborate 14b is described. In a flame-dried flask
under N2 atmosphere, Me3OBF4 (1.95 mmol) was added to an ice-
cooled solution of 1-(4-methylbenzyl)-2-(trifluoromethyl)azetidine 5b
(1.30 mmol) in dry CH2Cl2 (4 mL). After stirring for 2 h at room
temperature, the solvent was evaporated, affording 1-methyl-1-(4-
methylbenzyl)-2-(trifluoromethyl)azetidinium tetrafluoroborate 14b,
which was used as such in the following step without prior purification.
In order to confirm the structure, the spectral data are reported below.
1-Methyl-1-(4-methylbenzyl)-2-(trifluoromethyl)azetidinium Tet-
3-[N-Methyl-N-(4-methylbenzyl)]amino-4,4,4-trifluorobutan-1-ol
16b. Pale yellow oil: Rf 0.37 (petroleum ether/EtOAc 8/2); yield 72%
(150.4 mg); 1H NMR (300 MHz, CDCl3) δ 1.63−1.72 and 1.95−2.08
(2H, 2 × m), 2.34 (3H, s), 2.42 (3H, q, J = 2.0 Hz), 3.29−3.42 (1H,
m), 3.66−3.82 (2H, m), 3.77 and 3.88 (2H, 2 × d, J = 13.2 Hz), 7.14−
7.23 (4H, m); 13C NMR (75 MHz, CDCl3) δ 21.2 (CH3), 27.5
(CH2), 36.3 (CH3), 59.7 (CH2), 61.2 (CH2), 62.1 (q, J = 25.4 Hz,
CH), 127.1 (q, J = 291.9 Hz, C), 129.0 (CH), 129.4 (CH), 135.0 (C),
137.4 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −68.47 (d, J =
7.9 Hz); IR (cm−1) νOH = 3362; νmax = 1514, 1456, 1262, 1161, 1107,
1052, 805, 701; MS (70 eV) m/z (%) 262 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C13H19F3NO 262.1419 [M + H]+, found 262.1420.
3-[N-(2-Chlorobenzyl)-N-methylamino]-4,4,4-trifluorobutan-1-ol
16d. Yellow oil: Rf 0.23 (petroleum ether/EtOAc 8/2); yield 88%
(197.9 mg); 1H NMR (300 MHz, CDCl3) δ 1.68−1.77 and 1.91−2.05
(2H, 2 × m), 2.42 (3H, s), 3.05−3.06 and 3.66−3.75 (2H, 2 × m),
3.37−3.50 (1H, m), 3.93 and 4.00 (2H, 2 × d, J = 13.8 Hz), 7.20−
7.27, 7.32−7.37 and 7.38−7.41 (4H, 3 × m); 13C NMR (75 MHz, ref
= CDCl3) δ 28.0 (CH2), 35.6 (CH3), 58.0 (CH2), 60.7 (CH2), 62.7
(q, J = 25.4 Hz, CH), 126.9 (CH), 129.1 (CH), 127.3 (q, J = 291.9
Hz, C), 130.0 (CH), 131.3 (CH), 134.7 (C), 135.8 (C); 19F NMR
(282 MHz, CDCl3, ref = CFCl3) δ −68.47 (d, J = 7.9 Hz); IR (cm−1)
νOH = 3366; νmax = 1444, 1260, 1149, 1164, 1091, 1107, 1054, 751,
702, 683; MS (70 eV) m/z (%) 282/284 (M+ + 1, 100); HRMS (ES-
TOF) calcd for C12H16ClF3NO 282.0873 [M + H]+, found 282.0875.
Synthesis of N-Alkyl-N-methyl-4-phenylthio-1,1,1-trifluoro-
butan-2-amines 17. As a representative example, the synthesis of N-
methyl-N-(4-methylbenyl)-4-phenylthio-1,1,1-trifluorobutan-2-amine
17b is described. To a solution of 1-methyl-1-(4-methylbenzyl)-2-
(trifluoromethyl)azetidinium tetrafluoroborate 14b (1 mmol) in
CH3CN (5 mL) was added thiophenol (2 mmol). After stirring for
3 h under reflux, the reaction mixture was poured out in a saturated
solution of NaHCO3 (10 mL), extracted with CH2Cl2 (3 × 5 mL), and
washed with brine (3 × 5 mL). Drying (MgSO4), filtration of the
drying agent, and evaporation of the solvent yielded N-methyl-N-(4-
methylbenyl)-4-phenylthio-1,1,1-trifluorobutan-2-amine 17b, which
was purified by means of column chromatography on silica gel
(hexane) to obtain an analytically pure sample.
N-Methyl-N-(4-methylbenyl)-4-phenylthio-1,1,1-trifluorobutan-
2-amine 17b. Pale orange oil: Rf 0.17 (hexane); yield 64% (226.0
mg); 1H NMR (300 MHz, CDCl3) δ 1.76−1.88 and 1.94−2.06 (2H, 2
× m), 2.31 (3H, ∼q, J = 1.8 Hz), 2.34 (3H, s), 2.91−3.01 and 3.12−
3.20 (2H, 2 × m), 3.34−3.49 (1H, m), 3.72 and 3.84 (2H, 2 × d, J =
13.5 Hz), 7.10−7.23 and 7.25−7.37 (9H, 2 × m); 13C NMR (75 MHz,
CDCl3) δ 21.1 (CH3), 25.7 (CH2), 30.3 (CH2), 36.1 (CH3), 59.2
(CH2), 62.0 (q, J = 25.0 Hz, CH), 127.6 (q, J = 291.9 Hz, C), 126.3
(CH), 128.6 (CH), 129.0 (CH), 129.1 (CH), 129.7 (CH), 135.8 (C),
136.0 (C), 136.8 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ
−68.57 (d, J = 9.2 Hz); IR (cm−1) νmax = 1584, 1480, 1256, 1154,
1105, 1079, 803, 737, 690; MS (70 eV) m/z (%) 354 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C19H23F3NS 354.1503 [M + H]+, found
354.1509.
N-(4-Chlorobenyl)-N-methyl-4-phenylthio-1,1,1-trifluorobutan-2-
amine 17c. Pale orange oil: Rf 0.19 (hexane); yield 63% (235.0 mg);
1H NMR (300 MHz, CDCl3) δ 1.78−1.90 and 1.94−2.06 (2H, 2 ×
m), 2.28 (3H, d, J = 1.7 Hz), 2.92−3.02 and 3.11−3.19 (2H, 2 × m),
3.36−3.51 (1H, m), 3.73 and 3.84 (2H, 2 × d, J = 13.8 Hz), 7.18−7.37
(9H, m); 13C NMR (75 MHz, CDCl3) δ 25.6 (CH2),30.4 (CH2), 35.9
(CH3), 58.8 (CH2), 62.2 (q, J = 25.4 Hz, CH), 127.5 (q, J = 291.9
Hz,), 126.4 (CH), 128.5 (CH), 129.1 (CH), 129.8 (CH), 132.9 (C),
135.6 (C), 137.6 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ
1
rafluoroborate 14b. Orange oil: yield 100% (430.5 mg); H NMR
(300 MHz, CDCl3) δ 2.37 (3H, s), 2.90 (2H, ∼q, J = 8.4 Hz), 3.21
(3H, s), 4.03−4.11 (1H, m), 4.67 and 4.72 (2H, 2 × d, J = 13.8 Hz),
4.87 (1H, q, J = 9.9 Hz), 5.33−5.47 (1H, m), 7.18−7.30 and 7.34−
7.42 (4H, 2 × m); 13C NMR (75 MHz, CDCl3) δ 16.0 (CH2), 21.2
(CH3), 44.2 (CH3), 63.3 (CH2), 68.2 (q, J = 35.8 Hz, CH), 69.5
(CH2), 121.3 (q, J = 279.2 Hz, C), 123.6 (C), 130.3 (CH), 132.0
(CH), 141.6 (C); 19F NMR (282 MHz, CDCl3, ref = CFCl3) δ −69.96
(d, J = 6.6 Hz), −150.19 (s); IR (cm−1) νmax = 1708, 1473, 1379, 1280,
1184, 1052, 1037, 1017, 815, 691.
Synthesis of 4-(N-Alkyl-N-methylamino)-5,5,5-trifluoropen-
tanenitriles 15. As a representative example, the synthesis of 4-[N-
methyl-N-(4-methylbenzyl)amino]-5,5,5-trifluoropentanenitrile 15b is
described. To a solution of 1-methyl-1-(4-methylbenzyl)-2-
(trifluoromethyl)azetidinium tetrafluoroborate 14b (0.90 mmol) in
CH3CN (8 mL) was added NaCN (1.80 mmol). After stirring for 3 h
under reflux, the reaction mixture was poured out in a saturated
solution of NaHCO3 (10 mL), extracted with CH2Cl2 (3 × 5 mL), and
washed with brine (3 × 5 mL). Drying (MgSO4), filtration of the
drying agent, and evaporation of the solvent yielded 4-[N-methyl-N-
(4-methylbenzyl)amino]-5,5,5-trifluoropentanenitrile 15b, which was
purified by means of column chromatography on silica gel (petroleum
ether/EtOAc 98/2) to obtain an analytically pure sample.
4-[N-Methyl-N-(4-methylbenzyl)amino]-5,5,5-trifluoropentaneni-
trile 15b. Transparent oil: Rf 0.16 (petroleum ether/EtOAc 98/2);
yield 74% (179.9 mg); 1H NMR (300 MHz, CDCl3) δ 1.86−2.06 (2H,
m), 2.34 (6H, s), 2.37−2.57 (2H, m), 3.18−3.31 (1H, m), 3.76 and
3.85 (2H, 2 × d, J = 13.2 Hz), 7.11−7.22 (4H, m); 13C NMR (75
MHz, ref = CDCl3) δ 14.1 (CH2), 21.2 (CH3), 22.4 (CH2), 35.8
(CH3), 59.4 (CH2), 61.9 (q, J = 25.4 Hz, CH), 119.1 (C), 127.2 (q, J
= 292.3 Hz, C), 128.8 (CH), 129.4 (CH), 135.4 (C), 137.3 (C); 19F
NMR (282 MHz, CDCl3, ref = CFCl3) δ −68.47 (d, J = 7.9 Hz); IR
(cm−1) νmax = 2859, 1514, 1457, 1258, 1166, 1144, 1085, 1110, 1046,
805, 700; MS (70 eV) m/z (%) 271 (M+ + 1, 100); HRMS (ES-TOF)
calcd for C14H18F3N2 271.1422 [M + H]+, found 271.1453.
4-[N-(4-Chlorobenzyl)-N-methylamino]-5,5,5-trifluoropentaneni-
trile 15c. Transparent oil: Rf 0.10 (petroleum ether/EtOAc 98/2);
yield 78% (203.6 mg); 1H NMR (300 MHz, CDCl3) δ 1.90−2.08 (2H,
m), 2.32 (3H, d, J = 1.7 Hz), 2.42−2.59 (2H, m), 3.22−3.35 (1H, m),
3.79 and 3.87 (2H, 2 × d, J = 13.8 Hz), 7.22−7.24 and 7.30−7.33 (4H,
2 × m); 13C NMR (75 MHz, CDCl3) δ 14.1 (CH2), 22.3 (CH2), 35.5
(CH3), 59.1 (CH2), 62.5 (q, J = 25.4 Hz, CH), 119.1 (C), 127.2 (q, J
= 292.3 Hz, C), 128.8 (CH), 130.2 (CH), 133.1 (C), 137.3 (C); 19F
NMR (282 MHz, CDCl3, ref = CFCl3) δ −68.56 (d, J = 7.9 Hz); IR
(cm−1) νmax = 1598, 1579, 1491, 1258, 1166, 1110, 1088, 1045, 1015,
851, 824, 803, 700; MS (70 eV) m/z (%) 291/3 (M+ + 1, 100);
HRMS (ES-TOF) calcd for C13H15ClF3N2 291.0876 [M + H]+, found
291.0881.
Synthesis of 3-(N-Alkyl-N-methylamino)-4,4,4-trifluorobu-
tan-1-ols 16. As a representative example, the synthesis of 3-[N-
methyl-N-(4-methylbenzyl)amino]-4,4,4-trifluorobutan-1-ol 16b is
described. 1-Methyl-1-(4-methylbenzyl)-2-(trifluoromethyl)-
I
dx.doi.org/10.1021/jo300694y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−68.66 (d, J = 7.9 Hz); IR (cm−1) νmax = 1490, 1256, 1154, 1107,
1088, 844, 802, 738, 690; MS (70 eV) m/z (%) 374/6 (M+ + 1, 30),
230 (100); HRMS (ES-TOF) calcd for C18H20ClF3NS 374.0957 [M +
H]+, found 374.0959.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: matthias.dhooghe@UGent.be; ngvtuyen@hotmail.
com; norbert.dekimpe@UGent.be.
Synthesis of N3-Alkyl-N1-benzyl-N3-methyl-4,4,4-trifluorobu-
tan-1,3-diamines 18. As a representative example, the synthesis of
N1,N3-dibenzyl-N3-methyl-4,4,4-trifluorobutan-1,3-diamine 18a is de-
scribed. To a solution of 1-benzyl-1-methyl-2-(trifluoromethyl)-
azetidinium tetrafluoroborate 14a (0.65 mmol) in CH3CN (4 mL)
was added benzylamine (1.30 mmol). After stirring for 2 h at room
temperature, the reaction mixture was poured out in a saturated
solution of NaHCO3 (4 mL), extracted with CH2Cl2 (3 × 2 mL) and
washed with brine (3 × 2 mL). Drying (MgSO4), filtration of the
drying agent, and evaporation of the solvent yielded N1,N3-dibenzyl-
N3-methyl-4,4,4-trifluorobutan-1,3-diamine 18a, which was purified by
means of column chromatography on silica gel (petroleum ether/
EtOAc 8/2) to obtain an analytically pure sample.
Present Address
§Vrije Universiteit Brussel, Faculty of Science and Bioengineer-
ing Sciences, Department of Chemistry, Pleinlaan 2, B-1050
Brussels, Belgium
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are indebted to Ghent University, the Research
Foundation-Flanders (FWO-Vlaanderen), the Vietnamese Na-
tional Foundation for Science and Technology Development
(NAFOSTED) and Janssen Research and Development, a
Division of Janssen Pharmaceutica NV for financial support.
N1,N3-Dibenzyl-N3-methyl-4,4,4-trifluorobutan-1,3-diamine 18a.
Yellow oil: Rf 0.11 (petroleum ether/EtOAc 8/2); yield 56% (122.4
mg); 1H NMR (300 MHz, CDCl3) δ 1.49 (1H, s (broad)), 1.69−1.80
and 1.84−1.96 (2H, 2 × m), 2.34 (3H, ∼d, J = 1.7 Hz), 2.73−2.86
(2H, 2 × m), 3.26−3.39 (1H, m), 3.76 and 3.81 (2H, 2 × d, J = 13.2
REFERENCES
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ASSOCIATED CONTENT
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S
* Supporting Information
Spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J
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