Trifluoroacetaldehyde: A useful industrial bulk material for the synthesis of trifluoromethylated amino compounds

Article abstract of DOI:10.1016/j.jfluchem.2009.12.023

The synthesis of various trifluoromethylated amino compounds was studied using trifluoroacetaldehyde, an industrial bulk material, as a starting compound. One general application of trifluoroacetaldehyde is the preparation of trifluoroethylamino derivatives via reductive amination reaction. This synthesis includes the formation of the corresponding N,O-acetal intermediates followed by their reduction using NaBH₄ or 2-picoline borane complex, affording the target trifluoroethylamino compounds in moderate to good yields (47-87%). Another general application of trifluoroacetaldehyde is the synthesis of chiral α-substituted trifluoroethylamino compounds. In this synthesis, trifluoroacetaldehyde was first converted into the chiral trifluoromethyl tert-butyl sulfinimine, which was subjected to 1,2-nucleophilic addition reactions across its C{double bond, long}N double bond. The addition of phenyllithium afforded α-(phenyl)trifluoroethylamino derivative in 83% yield and with 96% de. Allylation and Reformatsky reactions produced the corresponding α-substituted trifluoroethylamino derivatives in 82 and 58% yields and with 90 and 91% de, respectively.

Full text of DOI:10.1016/j.jfluchem.2009.12.023

Journal of Fluorine Chemistry 131 (2010) 477–486
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Trifluoroacetaldehyde: A useful industrial bulk material for the synthesis of
trifluoromethylated amino compounds
a
b
b
b
Hideyuki Mimura a, , Kosuke Kawada , Tetsuya Yamashita , Takeshi Sakamoto , Yasuo Kikugawa
*
a Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
b Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of various trifluoromethylated amino compounds was studied using trifluoroacetalde-
hyde, an industrial bulk material, as a starting compound. One general application of trifluoroace-
taldehyde is the preparation of trifluoroethylamino derivatives via reductive amination reaction. This
synthesis includes the formation of the corresponding N,O-acetal intermediates followed by their
reduction using NaBH4 or 2-picoline borane complex, affording the target trifluoroethylamino
compounds in moderate to good yields (47–87%).
Received 30 September 2009
Received in revised form 24 December 2009
Accepted 28 December 2009
Available online 7 January 2010
Keywords:
Another general application of trifluoroacetaldehyde is the synthesis of chiral
a-substituted
Trifluoroacetaldehyde
Reductive amination
N,O-Acetal
trifluoroethylamino compounds. In this synthesis, trifluoroacetaldehyde was first converted into the
chiral trifluoromethyl tert-butyl sulfinimine, which was subjected to 1,2-nucleophilic addition reactions
across its C55N double bond. The addition of phenyllithium afforded
derivative in 83% yield and with 96% de. Allylation and Reformatsky reactions produced the
corresponding -substituted trifluoroethylamino derivatives in 82 and 58% yields and with 90 and
91% de, respectively.
a-(phenyl)trifluoroethylamino
Trifluoroacetaldimine
1,2-Addition
Trifluoromethyl tert-butyl sulfinimine
Asymmetric synthesis
a
ß 2010 Elsevier B.V. All rights reserved.
1. Introduction
bound to the stereogenic carbon have recently been shown to
undergo a self-disproportionation of enantiomers (SDE) [7] under
achiral chromatography [8] and sublimation conditions [9].
Trifluoroacetaldehyde has long been known as one of the most
versatile CF3-containing building blocks. The aldehyde is a highly
reactive gaseous material with a boiling point of ꢀ18 8C; it
polymerizes easily, and therefore is stored as a hydrate or a
hemiacetal. Nevertheless, as reported in numerous publications,
hydrate and hemiacetal forms can be directly used for many
synthetic purposes without generating the free aldehyde [1], thus
facilitating the synthetic use of trifluoroacetaldehyde.
In a previous study, we developed a catalytic process for the
large-scale production of trifluoroacetaldehyde on the basis of
vapor-phase oxidation of 2,2,2-trifluoroethanol [2]. This catalytic
process had been proved quite durable for industrial manufactur-
ing, making trifluoroacetaldehyde readily accessible and inexpen-
sive.
However, almost all these studies have been conducted on
hydroxycarboxylic acid derivatives. We expect that general
methods for the preparation of -substituted trifluoroethylamines
a-
a
will make these compounds readily available for SDE and
pharmacological studies.
Several methods have been reported for the synthesis of
trifluoroethylamino compounds, including the trifluoroethylation
of amines using trifluoroethyl triflate [10], the substitution of
trifluoroethylamine [11], and reductive amination using trifluor-
oacetaldehyde [12]. However, these methods often faced problems
related to reagent toxicity (trifluoroethyl triflate) and poor
reactivity (trifluoroethylamine). From this viewpoint, reductive
amination is suitable for the preparation of trifluoroethylamino
compounds.
One practical application of trifluoroacetaldehyde is in the
preparation of trifluoromethylated amino compounds.
a
-Unsub-
a-Substituted trifluoroethylamino compounds have been
stituted [3] and chiral -substituted trifluoroethylamino com-
a
synthesized through 1,2-nucleophilic addition reactions of tri-
fluoroacetaldimines and related N,O-acetals [13], trifluoromethy-
lation of imines [14], and reduction or isomerization of
trifluoromethyl ketimines [15]. The 1,2-nucleophilic addition
reactions, in which the starting material trifluoroacetaldimine
was directly prepared by the reaction of trifluoroacetaldehyde
hydrate or hemiacetal with an amine, have been well developed:
various racemic and asymmetric reactions, including alkylation
pounds [4–6] have been extensively used in the design of new
pharmaceuticals and agrochemicals (Fig. 1). Furthermore, chiral
organic derivatives containing a trifluoromethyl group directly
* Corresponding author. Tel.: +81 834 62 1300; fax: +81 834 62 1303.
E-mail address: hideyuki-mimura@f-techinc.co.jp (H. Mimura).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.12.023

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H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
Fig. 1. Examples of viologically active trifluoromethylated amino compounds.
[16], allylation [17], Mannich reaction [18], and Reformatsky
reactions [19], have been achieved successfully.
To overcome this obstacle, we examined a method that uses
N,O-acetal or hemiaminal as a starting material instead of
trifluoroacetaldimine. Thus, we prepared N,O-acetal 5a [21] and
hemiaminal 6a [22] from p-anisidine and reduced them with
NaBH4. Reduction of N,O-acetal 5a produced trifluoroethylamino
derivative 4a in 71% yield, while reduction of hemiaminal 6a
produced 2,2,2-trifluoroethanol almost quantitatively (Scheme 2).
The following mechanism is proposed to explain the observed
difference in reactivity of the N,O-acetal and hemiaminal. The N,O-
acetal was in equilibrium with trifluoroacetaldimine, which was
reduced to the target trifluoroethylamino derivative by NaBH4,
thereby continuously shifting the equilibrium to the aldimine. On
the other hand, the hemiaminal was in equilibrium with
trifluoroacetaldehyde and trifluoroacetaldimine. The reduction
of trifluoroacetaldehyde was faster under these conditions, leading
to the formation of the corresponding 2,2,2-trifluoroethanol.
Several aniline derivatives possessing various substituents
were examined to evaluate the scope of the reaction (Table 1). The
N,O-acetal derivatives 5 without substituent and with an electron-
donating substituent at the para- or meta-position were reduced
by NaBH4 in methanol (method A), affording the corresponding
trifluoroethylamino derivatives 4 in yields ranging from 71 to 90%.
This method was also applied to the N,O-acetal derivative with
electron-donating substituent at ortho-position or with electron-
withdrawing substituents and produced target trifluoroethyla-
mino derivatives 4 in similar 58–80% yields. This reduction was
performed using 2-picoline borane in acetic acid (method B)
because the reaction did not proceed under the condition of
method A (Table 1, Entry 4) and the acidic condition enables the
equilibrium to shift to the trifluoroacetaldimine.
In this report, we discuss preparative aspects for the generalized
synthesis of various trifluoromethylated amino compounds starting
from trifluoroacetaldehyde. We also discuss the reactivity and
physico-chemical properties of trifluoroacetaldehyde and related
derivatives in detail to produce trifluoromethylated amino com-
pounds in a reproducible and economical manner on a large scale.
2. Results and discussion
2.1. Synthesis of trifluoroethylamino compounds
Reductive amination is a well-established method for the
preparation of alkylamines. However, its adaptation to trifluor-
oacetaldehyde has received little attention. First, we attempted to
prepare trifluoroethylamino derivatives via reduction of trifluor-
oacetaldimine 3, which was synthesized according to the
conventional method [20]. Trifluoroacetaldimine 3a, derived from
p-anisidine 2a, was easily reduced by catalytic hydrogenation
using Pd–C catalyst to produce trifluoroethylamine 4a in 90% yield
(Scheme 1). However, the corresponding trifluoroacetaldimine 3b–
c was not obtained when this method was applied to anilines
containing electron-withdrawing substituents. This dramatic
difference in reactivity may be because the dehydration of the
hemiaminal intermediate becomes less favorable in the presence
of the strongly electron-withdrawing CF3 group and the amine
substituent. In addition, the resulting aldimine was expected to be
extremely electrophilic and therefore unstable, producing various
undesirable by-products.
Scheme 1.
Scheme 2. A plausible mechanism for the different results of hydride reduction.

H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
479
Table 1
Reductive amination reaction of trifluoroacetaldehyde hemiacetal with primary aminesa.
Entry
Amine
#
Yield, %b of 5
Method
Yield, %b of 4
Conditions
R
1
2
3
4
5
6
7
8
2d
2a
2e
2f
H
91
94
68
80
80
88
84
81
A
A
A
A
B
B
B
B
71 (65)
90 (85)
87 (59)
0c
Reflux, 0.25 h
Reflux, 1 h
Reflux, 1 h
Reflux, 0.5 h
rt, 1 h
p-OMe
m-OMe
o-OMe
o-OMe
p-Cl
2f
66 (53)
79 (70)
80 (67)
58 (47)
2g
2b
2c
rt, 0.5 h
p-CO2Et
p-CN
Reflux, 0.5 h
Reflux, 0.5 h
a
Preparation of N,O-acetals were carried out in MeOH in the presence of p-TsOH under reflux condition for 2 h.
Isolated yield after chromatography. The values in parentheses are overall yields based on 2.
The starting material 5f was recovered in 83% yield.
b
c
Next, the reductive amination reaction of secondary amines
starting materials were recovered almost intact (Table 2, Entry 1).
On the other hand, when the reaction mixture was heated in
toluene, aromatic and aliphatic secondary amines 2h–l led to the
expected N,O-acetals 5h–l, which were isolated in good yields
was examined (Table 2). When the mixture of a secondary amine
and hemiacetal 1b was heated in methanol in the presence of acid
catalyst, the formation of N,O-acetal 5 was extremely slow and the
Table 2
Reductive amination reaction of trifluoroacetaldehyde hemiacetal with secondary aminesa.
Entry
1c
Amine
Yield, %b of 5
Yield, %b of 4
Conditions
–
2h
Trace
–
2d
2h
2h
2i
68
68
75
0e
Reflux, 2 h
rt, 1 h
3
72 (49)
92 (69)
4
Reflux, 0.5 h
5
6
2j
68
96
83
79 (54)
91 (87)
96 (80)
rt, 0.5 h
2k
2l
rt, 1 h
7
Reflux, 0.5 h
a
Preparation of N,O-acetals were carried out in toluene in the presence of p-TsOH under reflux condition for 3 h.
Isolated yield after chromatography. The values in parentheses are overall yields based on 2.
Preparation of N,O-acetal was performed in MeOH in the presence of p-TsOH under reflux condition for 1 h.
Reduction was performed using NaBH4 in MeOH (method A).
b
c
d
e
The starting material 5h was recovered in 86% yield.

480
H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
Scheme 3.
Scheme 4.
(68–96%). The obtained N,O-acetals 5h–l were reduced using 2-
picoline borane in acetic acid (method B) though the reduction did
not occur under the condition of method A (Table 2, Entry 2). The
corresponding trifluoroethylamino derivatives 4h–l were isolated
in yields ranging from 72 to 96%.
The synthesis of N,O-acetals from secondary amines had been
reported previously but the electrochemical procedures developed
by Fuchigami and Ichikawa were inconvenient [23]. The method
described in this study offers substantially simpler and more
operationally convenient [24] procedures for the generalized
preparation of these N,O-acetals.
below 60 8C and that its stereochemical integrity was not affected
below 100 8C (Table 3).
With these data in hand, we studied the addition reactions of
(S)-3d with phenyllithium (Scheme 4). The desired product 8a was
isolated in 83% yield (96% de). This yield was greater compared to
the 64% yield (96% de) obtained using (S)-3d prepared according to
the literature procedure. This result demonstrates the advantage of
using our procedure to purify (S)-3d.
Next, we studied Zn-mediated allylation reactions using (S)-3d
as a starting compound to demonstrate its applicability to
generalized preparations of chiral
a-substituted trifluoroethyla-
mino compounds (Table 4). The reaction conducted in DMF gave
target allylated product 8b in 82% yield with high diastereoselec-
tivity (90% de), while the reaction conducted in THF gave 8b with
substantially lower diastereoselectivity (43% de). Deprotection
under acidic conditions followed by neutralization, afforded the
allylated free amine in good yield. Following Mosher’s method
[27], we found that the major enantiomer had a S configuration
from the 1H NMR spectra of the corresponding (R)- and (S)-MTPA
amides. This result suggests that this addition reaction may
proceed through a non-chelated transition state (Scheme 5). The
stereochemical outcome of Zn-mediated allylation reactions has
been reported to be reversed depending on solvent choice for non-
fluorinated chiral tert-butyl sulfinimines [28]. In contrast, the
coordination ability of the nitrogen atom is substantially
weakened in (S)-3d due to the electron-withdrawing CF3 group.
Therefore, the non-chelated transition state is preferred regardless
of the solvent used.
2.2. Synthesis of chiral
a-substituted trifluoroethylamino compounds
Chiral -substituted trifluoroethylamino compounds are of
a
particular interest for the design and development of new
pharmaceuticals. Therefore, the asymmetric synthesis of these
derivatives is of great importance. These compounds are
accessible from nucleophilic reactions using trifluoroacetaldi-
mine starting materials that bear a chiral auxiliary at the amine
site. In particular, Truong et al. have recently reported an
effective asymmetric induction and an easy deprotection of the
chiral auxiliary for trifluoromethyl tert-butyl sulfinimine 3d
[25,26]. Using the described literature method [25], we reacted
trifluoroacetaldehyde hydrate 1c with chiral tert-butane sulfi-
namide (S)-7 in the presence of molecular sieves (MS4A) at 40 8C
(Scheme 3). We monitored the condensation process by 19F NMR
analysis and noted the formation of by-products that were not
mentioned previously. Therefore, we needed to modify the
literature procedure to make it more reliable for large-scale
synthesis.
Consequently, we conducted a series of experiments and found
that compound 3d was efficiently purified by vacuum distillation
at a low temperature (40 8C, 0.6 kPa). This procedure allowed the
preparation of highly chemically and enantiomerically pure (S)-3d
in 76% overall yield.
Taking advantage of this highly chemically and enantiomeri-
cally pure sample, we examined the thermal stability of (S)-3d. We
found that compound (S)-3d was relatively chemically stable
Table 3
Thermal stability of (S)-3da.
Entry
Temperature, 8C
Chemical purity, %b
Optical purity, % eec
1
2
3
4
Before heat
>99
>99
99
>99
>99
>99
>99
60
80
100
86
a
(S)-3d (0.50 g) was placed in 20 ml Schlenk flask and heated for 6 h under N2
atmosphere.
b
Determined by 19F NMR.
c
Determined by chiral GC analysis.

H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
481
Table 4
Zn-mediated addition reaction of (S)-3d with various nucleophiles.
Entry
1
Substrate
Solvent
DMF
Product
Yield, %a
82
de, %b
90
Free amine
Yield, %a
67 (55)
Configuration
Sc
2
3
a
THF
86
65
43
91
–
–
S
DMF
89 (58)
Sd
Isolated yield. The values in parentheses are overall yields based on (S)-3d.
Determined by GC analysis.
Speculated by 1H NMR analysis using Mosher’s method.
Speculated by optical rotation.
b
c
d
Scheme 5. A plausible mechanism for stereocontrol.
In the Reformatsky reaction of (S)-3d with ethyl bromoacetate,
the use of DMF as a solvent also produced the desired derivative 8c
with high diastereoselectivity (91% de). The optical rotation of the
mino derivatives to be prepared in good yields from a wide range of
amine derivatives, including primary and secondary amines
substituted with electron-withdrawing and donating groups.
corresponding free amine 9c ([
literature data for the (S)-enantiomer ([
indicating that this reaction also proceeded through similar
mechanism that involves the non-chelated transition state.
a
]
25 = ꢀ19.48) agreed with
In regard to the synthesis of chiral a-substituted trifluoroethy-
D
a]
25 = ꢀ21.18 [29]),
lamino compounds, trifluoromethyl tert-butyl sulfinimine was
demonstrated to possess excellent properties as a precursor. Its
1,2-addition reactions with various nucleophiles were highly
diastereoselective.
D
In general,
a-trifluoromethyl amino derivatives of high
enantiomeric purity have been made available by methods
developed by Bravo, Sorochinsky, and Soloshonok [30,31].
However, our developed procedures are more operationally
convenient and can be reliably reproduced on a large scale. In
addition, starting materials used in our approach are substantially
more inexpensive; thus, they are attractive.
4. Experimental
Trifluoroacetaldehyde ethyl hemiacetal, trifluoroacetaldehyde
methyl hemiacetal and trifluoroacetaldehyde hydrate used in this
study were commercial products of Tosoh F-tech. 2-Picoline
borane complex was obtained from Mitsui Chemical Company.
All other chemicals and solvents were purchased commercially
and used without further purification.
3. Conclusion
The method using an N,O-acetal intermediate followed by
hydride reduction was proven to be general and efficient for
synthesizing trifluoroethylamino compounds starting from tri-
fluoroacetaldehyde. This method allows various trifluoroethyla-
The 1H and 19F NMR spectra were recorded on JEOL JNM-EX270
spectrometer or BRUCHER AVANCE 400 spectrometer. 1H NMR
spectra were obtained using chloroform-d or acetone-d6 as the
solvent with tetramethylsilane as the internal standard. 19F NMR

482
H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
spectra were recorded in chloroform-d or acetone-d6 using CFCl3
as the internal standard unless otherwise noted.
IR spectra were obtained on JASCO IR 810 spectrophotometer.
Mass spectra (EIMS and HRMS) were obtained with a JEOL JMX-
DX 300 spectrometer with a direct inlet system at 70 eV. Mass
spectra (ESI) were obtained with a Micromass LCT.
hemiacetal (16 mmol) and p-toluene sulfonic acid monohydrate
(0.3 mmol) and then heated under reflux for 1 h. After cooled to
room temperature, 10% aqueous NaHCO3 (30 ml) was added. The
mixture was extracted with ethyl acetate twice (30 ml), dried over
Na2SO4. The solvent was removed in vacuo and the residue was
chromatographed on SiO2 column. Elution with a mixture of
hexane and ethyl acetate afforded N,O-acetal 5a–g.
4.1. Preparation of N-(4-methoxyphenyl)trifluoroacetaldimine (3a)
[20]
4.5.1. N-(2,2,2-Trifluoro-1-methoxyethyl)-4-methoxyaniline (5a)
Oil. IR (neat): 3390, 2850, 1600, 1520, 1380, 1280, 1240, 1180,
A round bottom flask equipped with a magnetic stirrer bar and a
Dean-Stark trap was charged with 120 ml of toluene, p-anisidine
(83 mmol), trifluoroacetaldehyde ethyl hemiacetal (94 mmol) and
p-toluene sulfonic acid monohydrate (0.3 mmol) and then heated
under reflux for 2 h. After cooled to room temperature, the reaction
mixture was filtered and the solvent was removed in vacuo. The
residue was distilled under a pressure of 0.4 kPa. Then 3a
(56 mmol, 68%) was obtained as colorless oil.
1140, 900, 820, 780, 720, 650 cmꢀ1 1H NMR (270 MHz, CDCl3)
; d
3.47 (s, 3H), 3.76 (s, 3H), 4.02 (brs, 1H), 4.83–4.92 (m, 1H), 6.72–
6.84 (m, 4H); 19F NMR (376 MHz, CDCl3)
d
ꢀ80.41 (d, J = 4.6 Hz);
EIMS m/z 235 [M]+ (93), 204 (48), 203 (19), 166 (100), 151 (28), 134
(34), 122 (25), 108 (15), 63 (10); HRMS (EI) Calcd for C10H12F3NO2:
235.0820. Found: 235.0823.
4.5.2. Ethyl 4-[(2,2,2-trifluoro-1-methoxyethyl)amino]benzoate (5b)
Solid, mp 101 8C. IR (KBr): 3325, 1710, 1610, 1600, 1540, 1320,
1300, 1260, 1180, 1150, 1130, 1090, 770 cmꢀ1; 1H NMR (270 MHz,
1H NMR (400 MHz, CDCl3)
7.27 (d, J = 9.0 Hz, 2H), 7.81 (q, J = 3.7 Hz, 1H); 19F NMR (376 MHz,
CDCl3)
ꢀ71.13 (d, J = 3.5 Hz).
d 3.83 (s, 3H), 6.93 (d, J = 9.0 Hz, 2H),
d
CDCl3)
4.63 (brd, J = 10.1, 1H), 5.04–5.13 (m, 1H), 6.78 (d, J = 8.7 Hz, 2H),
7.95 (d, J = 8.7 Hz, 2H); 19F NMR (376 MHz, CDCl3)
d 1.37 (t, J = 7.1 Hz, 3H), 3.49 (s, 3H), 4.34 (q, J = 7.1 Hz, 2H),
4.2. Catalytic hydrogenation of trifluoroacetaldimine 3a
d
ꢀ80.44 (d,
J = 4.3 Hz); EIMS m/z 277 [M]+ (30), 245 (47), 208 (94), 200 (100),
176 (40); Anal. Calcd for C12H14F3NO3: C, 51.99; H, 5.09; N, 5.05.
Found: C, 52.07, H, 5.10, N, 5.14.
A stainless steel vessel equipped with a magnetic stirrer bar was
charged with 20 g of toluene, 3a (9.6 mmol) and 5% palladium on
charcoal (96 mg). After sealed, a pressure of 0.2 MPa of hydrogen
was applied and kept until its absorption ended. The reaction
mixture was filtered and the solvent was removed in vacuo. The
residue was distilled under a pressure of 0.3 kPa. Then 4a
(8.7 mmol, 90%) was obtained as colorless oil.
4.5.3. 4-[(2,2,2-Trifluoro-1-methoxyethyl)amino]benzonitrile (5c)
Solid, mp 100–101 8C. IR (KBr): 3360, 3340, 2230, 1620, 1540,
1340, 1280, 1260, 1180, 1140, 1080, 980, 830 cmꢀ1 1H NMR
;
(270 MHz, CDCl3)
d 3.50 (s, 3H), 4.70 (brd, 1H), 4.99–5.08 (m, 1H),
1H NMR (400 MHz, CDCl3)
(brs, 1H), 3.73 (s, 3H), 6.63 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 9.2 Hz,
2H); 19F NMR (376 MHz, CDCl3)
ꢀ72.83 (d, J = 8.9 Hz).
d
3.67 (q, J = 9.1 Hz, 2H), 3.64–3.70
6.80 (d, J = 8.7 Hz, 2H), 7.53, d, J = 8.7 Hz, 2H); 19F NMR (376 MHz,
CDCl3)
d
ꢀ80.31 (d, J = 4.3 Hz); EIMS m/z 230 [M]+ (34), 199 (39),
d
161 (100), 129 (68), 102 (35); Anal. Calcd for C10H9F3N2O: C, 52.18;
H, 3.94; N, 12.17. Found: C, 52.52, H, 4.01, N, 12.33.
4.3. Preparation of 2,2,2-trifluoro-1-(4-methoxypheylamino)ethanol
(6a) [22]
4.5.4. N-(2,2,2-Trifluoro-1-Methoxyethyl)aniline (5d)
Oil. IR (neat): 3400, 2950, 1610, 1520, 1505, 1380, 1280, 1260,
1190, 1150, 900, 850, 760, 720, 700 cmꢀ1; 1H NMR (270 MHz, CDCl3)
A round bottom flask equipped with a magnetic stirrer bar was
charged with 10 ml of diethyl ether, p-anisidine (18 mmol),
trifluoroacetaldehyde ethyl hemiacetal (18 mmol) and molecular
sieves 4 A (6.0 g). After stirred at room temperature for 3 h, the
reaction mixture was filtered and the solvent was removed in vacuo.
The crude hemiaminal was used without further purification.
d
3.48 (s, 3H), 4.23–4.26 (brs, 1H), 4.97–5.06 (m, 1H), 6.75–7.29 (m,
5H); 19F NMR (376 MHz, CDCl3)
d
ꢀ80.49 (d, J = 4.6 Hz); EIMS m/z
205 [M]+ (39), 174 (39), 136 (100), 104 (42), 93 (23), 77 (31), 51 (10);
HRMS (EI) Calcd for C9H10F3NO: 205.0714. Found: 205.0719.
19F NMR (376 MHz, CDCl3, internal standard C6F6)
d
80.06 (d,
4.5.5. N-(2,2,2-Trifluoro-1-methoxyethyl)-3-methoxyaniline (5e)
Oil. IR (neat): 3370, 3000, 2950, 2850, 1720, 1620, 1530, 1500,
1470, 1380, 1310, 1280, 1260, 970, 880, 840, 770, 710, 690 cmꢀ1
;
J = 4.7 Hz). EIMS m/z 203 [MꢀH2O]+ (59), 134 (100), 107 (34), 92
(26), 77 (43), 64 (24).
1H NMR (270 MHz, CDCl3)
(brs, 1H), 4.96–5.05 (m, 1H), 6.31–6.46 (m, 3H), 7.12–7.18 (m, 1H);
19F NMR (376 MHz, CDCl3)
[M]+ (61), 204 (51), 203 (19), 166 (100), 134 (29), 123 (13), 107
(20), 92 (13), 77 (12); HRMS (EI) Calcd for C10H12F3NO2: 235.0820.
Found: 235.0822.
d 3.48 (s, 3H), 3.79 (s, 3H), 4.25–4.29
4.4. Reduction of hemiaminal 6a
d
ꢀ80.50 (d, J = 4.5 Hz); EIMS m/z 235
A round bottom flask equipped with a magnetic stirrer bar was
charged with 8 ml of methanol and 5a (2.0 mmol). NaBH4
(4 mmol) was added to the solution at room temperature and
the mixture was stirred for 1 h. After the quench with 6N-HCl
(4 ml), 19F NMR analysis (internal standard method) and GC–MS
analysis of the crude reaction mixture indicated the production of
2,2,2-trifluoroethanol (1.85 mmol, 93%).
4.5.6. N-(2,2,2-Trifluoro-1-methoxyethyl)-2-methoxyaniline (5f)
Oil. IR (neat): 3420, 3000, 2950, 2850, 1740, 1610, 1520, 1460,
1380, 1330, 1280, 1260, 1230, 1180, 1140, 1090, 980, 900, 780, 740,
19F NMR (376 MHz, CDCl3)
d
ꢀ77.65 (d, J = 9.0 Hz); EIMS m/z 81
720 cmꢀ1
;
1H NMR (270 MHz, CDCl3)
d
3.45 (d, 3H), 3.87 (s, 3H),
[MꢀF]+ (3), 69 (9), 61 (20), 51 (15), 33 (26), 31 (100).
4.90–5.08 (m, 2H), 6.77–6.93 (m, 4H); 19F NMR (376 MHz, CDCl3)
d
ꢀ80.38 (d, J = 4.3 Hz); EI-MS m/z 235 [M]+ (81), 204 (49), 203 (27),
166 (68), 134 (100), 121 (28), 120 (23), 92 (14), 77 (20); HRMS (EI)
Calcd for C10H12F3NO2: 235.0820. Found: 235.0810.
4.5. General procedure for the preparation of N,O-acetal from primary
amines 5a–g [21]
A round bottom flask equipped with a magnetic stirrer bar and a
condenser connected to a nitrogen source was charged with 10 ml
of methanol, amine (4.1 mmol), trifluoroacetaldehyde methyl
4.5.7. 4-Chloro-N-(2,2,2-trifluoro-1-methoxyethyl)aniline (5g)
Oil. IR (neat): 3400, 2950, 1605, 1510, 1500, 1280, 1255, 1190,
1150, 110 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d 3.48 (s, 3H), 4.26 (brd,

H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
483
1H), 4.93 (m, 1H), 6.72 (d, J = 8.9, 2H), 7.21 (d, J = 8.7 Hz, 2H); 19F
(25); HRMS (EI) Calcd for
274.1298.
C
13H17F3N2O: 274.1293. Found:
NMR (376 MHz, CDCl3)
d
ꢀ80.40 (d, J = 4.4 Hz); EIMS m/z 239 [M]+
(31), 208 (34), 170 (100), 155 (12), 138 (66), 127 (25), 111 (39), 107
(10), 75 (34), 63 (25); HRMS (EI) Calcd for C9H9ClF3NO: 239.0352.
Found: 239.0337.
4.7. General procedure for the reduction method A
A round bottom flask equipped with a magnetic stirrer bar and
a condenser connected to a nitrogen source was charged with 3 ml
of methanol and N,O-acetal 5 (1.0 mmol). NaBH4 (2.0 mmol) was
added and the mixture was heated under reflux for 1 h. After that
MeOH was removed under reduced pressure. The residue was
quenched with water (10 ml), extracted with ethyl acetate twice
(20 ml). The organic layer was washed with brine and dried over
Na2SO4. The solvent was removed in vacuo and the residue was
chromatographed on SiO2 column. Elution with a mixture of
hexane and ethyl acetate afforded trifluoroethylamino com-
pounds 4.
4.6. General procedure for the preparation of N,O-acetal from
secondary amines 5h–l
A round bottom flask equipped with a magnetic stirrer bar and a
condenser connected to a nitrogen source was charged with 25 ml
of toluene, amine (4.1 mmol), trifluoroacetaldehyde methyl
hemiacetal (16 mmol) and p-toluene sulfonic acid monohydrate
(0.15 mmol) and then heated under reflux for 2 h. After cooled to
room temperature, 10% aqueous NaHCO3 (30 ml) was added and
extracted with ethyl acetate twice (30 ml). The organic layer was
washed with brine and dried over Na2SO4. The solvent was
removed in vacuo and the residue was chromatographed on SiO2
column. Elution with a mixture of hexane and ethyl acetate
afforded N,O-acetal 5h–l.
4.7.1. N-(2,2,2-Trifluoroethyl)-4-methoxyaniline (4a)
Oil. IR (neat): 3400, 1520, 1470, 1440, 1390, 1330, 1280,
1240, 1160, 1120, 1040, 950, 820, 730, 670, 640 cmꢀ1 1H NMR
;
(270 MHz, CDCl3)
d 3.66–3.75 (m, 2H), 3.66–3.75 (brs, 1H), 3.75
4.6.1. N-(2,2,2-Trifluoro-1-methoxyethyl)-N-methylaniline (5h)
Oil. IR (neat): 3000, 2950, 2830, 1610, 1510, 1460, 1410,
1350, 1320, 1300, 1280, 1220, 1180, 1150, 1120, 1080, 1040,
(s, 3H), 6.64–6.68 (m, 2H), 6.79–6.83 (m, 2H); 19F NMR
(376 MHz, CDCl3)
d
ꢀ72.83 (d, J = 8.9 Hz); EIMS m/z 205 [M]+
(98), 190 (100), 170 (12), 162 (13), 136 (74), 121 (16), 120 (15),
92 (10); HRMS (EI) Calcd for C9H10F3NO: 205.0714. Found:
205.0708.
1010, 950, 870, 810, 760, 720, 700, 640 cmꢀ1
(270 MHz, CDCl3)
1H), 6.87–7.33 (m, 5H); 19F NMR (376 MHz, CDCl3)
J = 4.9 Hz); EIMS m/z 219 [M]+ (27), 188 (40), 150 (100), 106
(13), 77 (20); HRMS (EI) Calcd for C10H12F3NO: 219.0871. Found:
219.0873.
;
1H NMR
d
2.92 (s, 3H), 3.34 (s, 3H), 5.08–5.14 (q,
d
ꢀ76.99 (d,
4.7.2. N-(2,2,2-Trifluoroethyl)aniline (4d)
Oil. IR (neat): 3420, 1610, 1520, 1450, 1400, 1340, 1280, 1260,
1160, 830, 760, 700, 670, 620 cmꢀ1 1H NMR (270 MHz, CDCl3)
; d
3.71–3.81 (m, 2H), 3.91 (brs, 1H), 6.67–7.27 (m, 5H); 19F NMR
4.6.2. N-(2,2,2-Trifluoro-1-methoxyethyl)-1,2,3,4-
tetrahydroquinoline (5i)
Oil. IR (neat): 2950, 2930, 1610, 1510, 1310, 1270, 1150,
750 cmꢀ1 1H NMR (270 MHz, CDCl3)
; d 1.81–2.04 (m, 2H), 2.75–
(376 MHz, CDCl3)
106 (100), 104 (15), 77 (34), 51 (11); HRMS (EI) Calcd for C8H8F3N:
175.0609. Found: 175.0601.
d
ꢀ72.87 (d, J = 8.8 Hz); EIMS m/z 175 [M]+ (46),
2.89 (m, 2H), 3.17–3.26 (m, 1H), 3.40 (s, 3H), 3.44–3.53 (m, 1H),
4.7.3. N-(2,2,2-Trifluoroethyl)-3-methoxyaniline (4e)
5.22 (q, J = 5.2, 1H), 6.71–6.78 (m, 2H), 7.02–7.11 (m, 2H); 19F NMR
Oil. IR (neat): 3440, 2950, 1620, 1610, 1520, 1505, 1265, 1220,
(376 MHz, CDCl3)
214 (22), 176 (100); HRMS (EI) Calcd for C12H14F3NO: 245.1027.
Found: 245.1044.
d
ꢀ76.77 (d, J = 5.2 Hz); EIMS m/z 245 [M]+ (36),
1170 cmꢀ1
;
1H NMR (270 MHz, CDCl3)
d
3.70–3.90 (m, J = 9.0 Hz,
2H), 3.78 (s, 3H), 3.95 (brs, 1H), 6.23–6.46 (m, 3H) 7.12 (t, J = 8.3 Hz,
1H); 19F NMR (376 MHz, CDCl3)
d
ꢀ72.80 (d, J = 8.9 Hz); EIMS m/z
205 [M]+ (60), 136 (100), 108 (11); HRMS (EI) Calcd for C9H10F3NO:
205.0714. Found: 205.0729.
4.6.3. N-(2,2,2-Trifluoro-1-methoxyethyl)-N-methylbenzylamine (5j)
Oil. IR (neat): 2970–2850, 1505, 1460, 1290, 1180–1120,
1060 cmꢀ1
;
1H NMR (270 MHz, CDCl3)
d
2.41 (s, 3H), 3.51 (s,
4.8. General procedure for the reduction method B
3H), 3.85 (d, J = 13.9, 1H), 3.85 (d, J = 14.0, 1H), 4.20 (q, J = 5.6, 1H),
7.24–7.38 (m, 5H); 19F NMR (376 MHz, CDCl3)
d
ꢀ74.95 (d,
A round bottom flask equipped with a magnetic stirrer bar and a
condenser connected to a nitrogen source was charged with 2.5 ml
of acetic acid and N,O-acetal 5 (1.0 mmol). 2-Picoline borane
complex (1.2 mmol) was added at room temperature and the
mixture was stirred for 0.5 h. After the quench with 6N-HCl (10 ml)
and the neutralization with NaHCO3, the mixture was extracted
with ethyl acetate twice (20 ml). The organic layer was washed
with brine and dried over Na2SO4. The solvent was removed in
vacuo and the residue was chromatographed on SiO2 column.
Elution with a mixture of hexane and ethyl acetate afforded
trifluoroethylamino compounds 4.
J = 5.0 Hz); EIMS m/z 233 [M]+ (1), 164 (56), 91 (100); HRMS (EI)
Calcd for C11H14F3NO: 233.1027. Found: 233.1021.
4.6.4. N-(2,2,2-Trifluoro-1-methoxyethyl)-1,2,3,4-
tetrahydroisoquinoline (5k)
Oil. IR (neat): 2950, 2850, 1280, 1170, 1150, 1110 cmꢀ1
;
1H
NMR (270 MHz, CDCl3)
d 2.86 (t, J = 5.8, 2H), 2.98–3.07 (m, 1H),
3.14–3.22 (m, 1H), 3.47 (s, 3H), 3.83 (d, J = 15.0 Hz, 1H), 4.03 (d,
J = 15.0 Hz, 1H), 4.25 (q, J = 5.6 Hz, 1H), 7.00–7.15 (m, 4H); 19F NMR
(376 MHz, CDCl3)
244 (22), 214 (23), 176 (100); HRMS (EI) Calcd for C12H14F3NO:
245.1027. Found: 245.1011.
d
ꢀ74.78 (d, J = 5.4 Hz); EIMS m/z 245 [M]+ (27),
4.8.1. Ethyl 4-[(2,2,2-trifluoroethyl)amino]benzoate (4b)
Solid, mp 94–95 8C. IR (KBr): 3380, 1695, 1605, 1540, 1520,
4.6.5. N-(2,2,2-Trifluoro-1-methoxyethyl)-N0-phenylpiperazine (5l)
Oil. IR (neat): 2950, 2900, 2830, 1605, 1505, 1460, 1280, 1240,
1180, 1160, 1140, 1020, 760, 690 cmꢀ1; 1H NMR (270 MHz, CDCl3)
1275, 1250, 1180, 1150, 770 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d
1.37 (t, J = 7.1), 3.79–389 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H),
4.37 (brs, 1H), 6.67 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H); 19
NMR (376 MHz, CDCl3)
ꢀ72.72 (d, J = 8.8 Hz); EIMS m/z 247
[M]+ (53), 202 (100), 178 (22), 150 (26); Anal. Calcd for
11H12F3NO2: C, 53.44; H, 4.89; N, 5.67. Found: C, 53.54, H, 4.94,
N, 5.75.
F
d
2.90–2.97 (m, 2H), 3.03–3.12 (m, 2H), 3.15–3.20 (m, 4H), 3.51 (s,
3H), 4.12 (q, J = 5.5 Hz, 1H), 6.85–7.00 (m, 3H), 7.24–7.31 (m, 2H);
19F NMR (376 MHz, CDCl3)
ꢀ74.96 (d, J = 5.3 Hz); EIMS m/z 274
[M]+ (100), 259 (23), 243 (31), 205 (69), 132 (27), 105 (43), 104
d
d
C

484
H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
4.8.2. 4-[(2,2,2-Trifluoroethyl)amino]benzonitrile (4c)
4.9. Preparation of trifluoromethy (S)-tert-butyl sulfinimine ((S)-3d)
Solid, mp 116–118 8C. IR (KBr): 3360, 3165–2955, 2215, 1605,
1530, 1350, 1295, 1275, 1260, 1155, 1125, 950, 825, 670,
[25]
545 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
3.82 (qd, J = 8.8, 6.8 Hz,
A round bottom flask equipped with a magnetic stirrer bar and a
condenser connected to a nitrogen source was charged with
1800 ml of dichloromethane, (S)-tert-butane sulfinamide (S)-7
(0.83 mol), trifluoroacetaldehyde hydrate 1c (0.91 mol) and MgSO4
(0.60 mol) and heated at 40 8C for 4 h. After cooled to room
temperature, MgSO4 was removed by filtration. To the filtrate,
molecular sieves 4 A (500 g) was added and heated again for 8 h.
After that, molecular sieves were removed by filtration and washed
with dichloromethane (600 ml). The solvent was removed in vacuo.
The residue was distilled under a pressure of 0.6 kPa. Then (S)-3d
(0.63 mol, 76%) was obtained as colorless oil. The chemical purity
of (S)-3d was determined by 19F NMR analysis with benzotri-
fluoride as internal standard. The optical purity was determined by
chiral GC (Inertcap CHIRAMIX) analysis after (S)-3d (0.25 mmol)
was mixed with excess amount (11 mmol) of MeOH to be
converted into the N,O-acetal form.
2H), 4.78 (brt, J = 6.2 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 7.46 (d,
J = 8.8 Hz, 2H); 19F NMR (376 MHz, CDCl3)
d
ꢀ72.56 (d, J = 8.8 Hz);
EIMS m/z 200 [M]+ (26), 131 (100), 102 (24), 75 (16), 69 (23), 64
(14), 51 (16).
4.8.3. N-(2,2,2-Trifluoroethyl)-2-methoxyaniline (4f)
Oil. IR (neat): 3440, 2950, 2850, 1610, 1605, 1520, 1500, 1400,
1280–1260, 1220, 1165, 1060, 960, 830, 770, 695 cmꢀ1 1H NMR
;
(270 MHz, CDCl3)
d 3.72–3.79 (m, 2H), 3.78 (s, 3H), 3.94 (brs, 1H),
6.23–6.43 (m, 3H), 7.09–7.18 (m, 1H); 19F NMR (376 MHz, CDCl3)
d
ꢀ72.72 (d, J = 9.0 Hz); EIMS m/z 205 [M]+ (100), 190 (54), 162 (33),
136 (87), 121 (51), 120 (67), 115 (9), 93 (16), 77 (21), 65 (23), 52
(21).
4.8.4. 4-Chloro-N-(2,2,2-trifluoroethyl)aniline (4g)
Oil. IR (neat): 3430, 1605, 1505, 1330, 1290, 1270, 1250,
Oil. IR (neat): 2985, 2970, 2930, 1480, 1460, 1370, 1335, 1285,
1180, 1165, 1120, 1090, 950, 820, 675, 505 cmꢀ1
;
1H NMR
1170, 1155, 1100, 870, 735, 515, 455 cmꢀ1 1H NMR (400 MHz,
;
(270 MHz, CDCl3)
d
3.68–3.80 (m, 2H), 3.94 (brs, 1H), 6.62 (d,
CDCl3)
CDCl3)
d
1.27 (s, 9H), 7.99 (q, J = 3.6 Hz, 1H); 19F NMR (376 MHz,
d
J = ꢀ8.9 Hz, 2H,), 7.17 (d, J = 9.1, 2H); 19F NMR (376 MHz, CDCl3)
ꢀ70.60 (d, J = 3.5 Hz); EIMS m/z 145 [MꢀC4H8]+ (1), 144
d
ꢀ72.79 (d, J = 8.8 Hz); EIMS m/z 211 (9), 209 [M]+ (28), 142
(2), 69 (7), 57 (100), 41 (83).
(31), 140 (100), 111 (16), 105 (16), 77 (22), 75 (27), 69 (14), 63
(14), 50 (18).
4.10. General procedure for the reaction of (S)-3d with phenyllithium
4.8.5. N-(2,2,2-Trifluoroethyl)-N-methylaniline (4h)
A flame-dried Schlenk flask equipped with a magnetic stirrer
bar was charged with 3 ml of THF and bromobenzen (5.0 mmol)
and then cooled to ꢀ78 8C. After 1.65 M n-butyllithium hexane
solution (2.5 ml, 4.1 mmol) was added, the solution was stirred at
ꢀ78 8C for 1 h. Then a cooled (ꢀ78 8C) solution of (S)-3d (3.8 mmol)
in THF was transferred to the mixture via cannula. The resulting
mixture was aged at ꢀ78 8C for 5 min and transferred to a cooled
(0 8C) saturated aqueous NH4Cl. The aqueous layer was extracted
three times with ethyl acetate. The organic extracts were
combined, dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on SiO2 column. Elution with a
mixture of hexane and ethyl acetate (3:1) afforded 8a as colorless
oil.
Oil. IR (neat): 1610, 1510, 1380, 1170, 1150, 1100, 1000, 980,
830, 760, 700, 670 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d 3.05 (s, 3H),
3.86 (q, J = 8.1, 2H), 6.79–6.83 (m, 3H), 7.24–7.29 (m, 2H); 19F NMR
(376 MHz, CDCl3)
120 (100), 105 (13), 104 (12), 77 (17).
d
ꢀ70.91 (d, J = 9.0 Hz); EIMS m/z 189 [M]+ (47),
4.8.6. N-(2,2,2-Trifluoroethyl)-1,2,3,4-tetrahydroquinoline (4i)
Oil. IR (neat): 2935, 2850, 1605, 1500, 1460, 1350, 1265, 1205,
1140, 1110, 1065, 1020, 800, 750, 660 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d 1.98–1.92 (m, 2H), 2.76 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 5.6,
2H), 3.78 (q, J = 9.1 Hz, 2H), 6.67 (t, J = 8.0, 2H), 6.96 (dd, J = 7.6,
1.4 Hz, 1H), 7.06 (td, J = 7.8, 1.6, 1H); 19F NMR (376 MHz, CDCl3)
ꢀ70.70 (d, J = 9.1 Hz); EIMS m/z 215 [M]+ (59), 146 (100).
d
4.10.1. (S)-2-Methyl-N-[(1S)-2,2,2-trifluoro-1-phenyl]propane-2-
sulfinamide (8a)
4.8.7. N-(2,2,2-Trifluoroethyl)-N-methylbenzylamine (4j)
Oil. IR (neat): 2800, 1500, 1460, 1410, 1320, 1270, 1150, 1130,
1100, 1050, 750, 700 cmꢀ1 1H NMR (270 MHz, CDCl3)
2.43 (s,
Oil. IR (neat): 3200, 2965–2870, 1460, 1365, 1265, 1170, 1125,
;
d
1070, 905, 760, 700, 635, 585; 1H NMR (400 MHz, acetone-d6)
d
3H), 3.04 (q, J = 9.6 Hz, 2H), 3.72 (s, 2H), 7.24–7.34 (m, 5H); 19F
1.15 (s, 9H), 5.02–5.10 (m, J = 8.0 Hz, 1H), 5.40 (d, J = 8.0, 1H), 7.41–
NMR (376 MHz, CDCl3)
d
ꢀ69.29 (t, J = 9.5 Hz); EIMS m/z 203 [M]+
7.46 (m, 3H), 7.59–7.61 (m, 2H); 19F NMR (376 MHz, acetone-d6)
d
(30), 134 (41), 126 (23), 91 (100); HRMS (EI) Calcd for C10H12F3N:
203.0922. Found: 203.0932.
ꢀ73.20 (d, J = 7.9 Hz); EIMS m/z 223 [MꢀC4H8]+ (10), 159 (20), 140
(12), 109 (21), 57 (100), 41 (41).
Deprotection of 8a was performed according to the literature
procedure [25]. The optical rotation of corresponding amine salt
4.8.8. N-(2,2,2-Trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline (4k)
Oil. IR (neat): 3070, 2960, 2800, 1430, 1270, 1140, 1125, 1100,
([a]
23: +15.68; c 1.0, MeOH) agreed with literature data, indicating
D
1055, 1030, 945, 845, 800, 745, 720, 700, 515 cmꢀ1
;
1H NMR
S configuration of 8a.
(400 MHz, CDCl3)
d 2.89 (t, J = 5.6, 2H), 2.96 (t, J = 5.6, 2H), 3.13 (q,
J = 9.5, 2H), 3.86 (s, 2H), 6.98–7.00 (m, 1H), 7.07–7.13 (m, 3H); 19
F
4.11. General procedure for the allylation reaction of (S)-3d
NMR (376 MHz, CDCl3)
(74), 214 (100), 146 (37), 104 (87).
d
ꢀ69.70 (d, J = 9.5 Hz); EIMS m/z 215 [M]+
A Schlenk flask equipped with a magnetic stirrer bar was
charged with 2 ml of solvent, (S)-3d (0.91 mmol), allyl bromide
(1.2 mmol) and zinc powder (1.2 mmol) and then cooled to 0 8C.
After a drop of trimethylsilyl chrolide was added, resulting mixture
was aged at 0 8C for 3 h and transferred to a cooled (0 8C) saturated
aqueous NH4Cl. The aqueous layer was extracted three times with
ethyl acetate. The organic extracts were combined, dried over
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed on SiO2 column. Elution with a mixture of hexane and
ethyl acetate (1:4) afforded 8b.
4.8.9. N-(2,2,2-Trifluoroethyl)-N0-phenylpiperazine (4l)
Solid. IR (KBr): 2850, 2830, 1610, 1515, 1460, 1320, 1270, 1170,
1150, 1105, 760, 690 cmꢀ1 1H NMR (270 MHz, CDCl3)
2.83 (t,
4H), 3.03 (q, J = 9.6 Hz, 2H), 3.21 (t, 4H), 6.84–6.94 (m, 3H), 7.23–
7.30 (m, 2H); 19F NMR (376 MHz, CDCl3)
;
d
d
ꢀ69.41 (d, J = 9.6 Hz);
EIMS m/z 244 [M]+ (100), 132 (19), 106 (24), 105 (65); Anal. Calcd
for C12H15F3N2: C, 59.01; H, 6.19; N, 11.47. Found: C, 59.04, H, 6.23,
N, 11.72.

H. Mimura et al. / Journal of Fluorine Chemistry 131 (2010) 477–486
485
4.11.1. (S)-2-Methyl-N-[(1S)-2,2,2-trifluoro-1-(propen-2-
yl)ethyl]propane-2-sulfinamide (8b)
Solid. IR (KBr): 3175, 3165, 2985–2870, 1645, 1475, 1435, 1365,
1275, 1230, 1170, 1115, 1065, 990, 920, 855, 700, 600; 1H NMR
diisopropylethylamine (0.36 mmol),
a
-methoxy-
a
-(trifluoro-
methyl)phenylacetyl chloride (0.29 mmol). The mixture was
stirred at room temperature for 1 h. After cooled in an ice bath,
aqueous 1 M NH4Cl (2 ml) was added. The organic layer was dried
over MgSO4 and condensed in vacuo. The residue was chromato-
graphed on SiO2 column. Elution with a mixture of hexane and
ethyl acetate (8:2) afforded MTPA amide.
(400 MHz, acetone-d6)
d 1.19 (s, 9H), 2.49–2.59 (m, 2H), 3.83–3.91
(m, 1H), 5.04 (d, J = 9.2 Hz, 1H), 5.12–5.25 (m, 2H), 5.87–5.97 (m,
1H); 19F NMR (376 MHz, CDCl3)
d
ꢀ75.25 (d, J = 6.4 Hz); EIMS m/z
187 [MꢀC4H8]+ (2), 57 (100), 41 (43); HRMS (ESI) Calcd for
C9H17F3NOS [M+H]+: 244.0983. Found: 244.0966.
4.14.1. N-[(1S)-2,2,2-Trifluoro-1-(propen-2-yl)ethyl]-(S)-
methoxy- -(trifluoromethyl)phenylacetamide
Yield 74%. Oil. 1H NMR (400 MHz, CDCl3)
d 2.28–2.34 (m, 1H),
a-
a
4.12. Reformatsky reaction of (S)-3d
2.52–2.58 (m, 1H), 3.47 (q, J = 1.6, 3H), 4.66–4.77 (m, 1H), 4.99 (dq,
J = 17.2, 1.3 Hz, 1H), 5.05 (dq, J = 10.4, 1.2 Hz, 1H), 5.56–5.66 (m,
A Schlenk flask equipped with a magnetic stirrer bar was charged
with 20 ml of DMF, (S)-3d (10 mmol), ethyl bromoacetate
(13 mmol) and zinc powder (13 mmol) and then cooled to 0 8C.
After two drops of trimethylsilyl chrolide in DMF were added,
resulting mixture was aged at 0 8C for 5 h and transferred to a cooled
(0 8C) saturated aqueous NH4Cl (50 ml). The aqueous layer was
extracted three times with ethyl acetate. The organic extracts were
combined, dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on SiO2 column. Elution with a
mixture of hexane and ethyl acetate (3:2) afforded8c as colorless oil.
1H), 6.70 (d, J = 9.6, 1H), 7.37–7.42 (m, 3H), 7.50–7.53 (m, 2H); 19
F
NMR (376 MHz, CDCl3)
d
ꢀ75.98 (d, J = 7.4 Hz, 3F), ꢀ69.62 (s, 3F);
EIMS m/z 355 [M]+ (1), 189 (100), 175 (45), 170 (42), 119 (32), 105
(92), 91 (39), 77 (54); HRMS (ESI) Calcd for C15H15F6 N O2 [M+H]+:
356.1085. Found: 356.1119.
4.14.2. N-[(1S)-2,2,2-Trifluoro-1-(propen-2-yl)ethyl]-(R)-
methoxy- -(trifluoromethyl)phenylacetamide
Yield 74%. Solid. 1H NMR (400 MHz, CDCl3)
a-
a
d
2.35–2.43 (m, 1H),
2.58–2.64 (m, 1H), 3.36 (q, J = 1.3, 3H), 4.68–4.80 (m, 1H), 5.19 (dq,
J = 5.6, 1.5 Hz, 1H), 5.22 (bs, 1H), 5.69–5.79 (m, 1H), 6.97 (d, J = 9.6,
1H), 7.40–7.42 (m, 3H), 7.48–7.50 (m, 2H); 19F NMR (376 MHz,
4.12.1. (S)-2-Methyl-N-[(1S)-2,2,2-trifluoro-1-
(ethoxycarbonylmethyl)ethyl]propane-2-sulfinamide (8c)
Oil. IR (neat): 3205, 2985–2875, 1740, 1475, 1370, 1345, 1275,
1230, 1195, 1170, 1125, 1070, 1025, 940, 885, 660; 1H NMR
CDCl3)
d
ꢀ75.82 (d, J = 7.4 Hz, 3F), ꢀ69.59 (s, 3F); EIMS m/z 355
[M]+ (1), 189 (100), 175 (48), 170 (45), 119 (34), 105 (97), 91 (42),
77 (57); HRMS (ESI) Calcd for C15H15F6 N O2 [M+H]+: 356.1085.
Found: 356.1085.
(400 MHz, acetone-d6)
d 1.16 (s, 9H), 1.24 (t, J = 7.0, 3H), 2.77 (dd,
J = 16.0, 9.4 Hz, 1H), 2.85 (dd, J = 16.0, 4.2 Hz, 1H), 4.11–4.20 (m,
2H), 4.23–4.34 (m, 1H), 5.27 (d, J = 10.0 Hz, 1H); 19F NMR
The negative dS dR value for the allyl protons on 1H NMR
–
(376 MHz, acetone-d6)
d
ꢀ74.83 (d, J = 7.8 Hz); EIMS m/z 233
indicates S configuration of 1-(trifluoromethyl)but-3-enylamino
moiety.
[MꢀC4H8]+ (5), 57 (100), 41 (52); HRMS (ESI) Calcd for
C
10H19F3NO3S [M+H]+: 290.1038. Found: 290.1039.
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ꢀ79.40
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