Preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonyl aziridine

Article abstract of DOI:10.1021/jo201554g

The preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonylaziridine is described. Optically pure aziridine was prepared with a 60% yield via three steps from optically pure 2,3-epoxy-1,1,1-trifluoro

Full text of DOI:10.1021/jo201554g

Article
pubs.acs.org/joc
Preparation of Optically Pure α-Trifluoromethyl-α-amino Acids from
N-Tosyl-2-trifluoromethyl-2-alkyloxycarbonyl Aziridine
Toshimasa Katagiri,* Yousuke Katayama, Mayuko Taeda, Takanori Ohshima, Naomi Iguchi,
and Kenji Uneyama
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1 Kita-ku, Okayama, 700-8530,
Japan
S
* Supporting Information
ABSTRACT: The preparation of optically pure α-trifluoromethyl-α-amino
acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonylaziridine is described.
Optically pure aziridine was prepared with a 60% yield via three steps from
optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). Ring-opening
reactions of the aziridine with a variety of nucleophiles and subsequent
deprotection of the N-tosyl moieties gave the optically pure β-substituted-α-
trifluoromethyl-α-amino acids in moderate to good yields (up to 85%) without racemization at the quaternary stereogenic center
of the amino acid.
We hypothesized that our optically pure N-tosyl-2-trifluor-
omethyl-2-alkyloxycarbonylaziridine (2), which was prepared
from optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO,
1),6,7 could be a common precursor of optically pure α-
trifluoromethyl-α-amino acids (4) (Scheme 1).8
INTRODUCTION
■
The importance of the preparative method for fluorinated
amino acids need not be repeated here.1 Among fluorinated
amino acids, α-trifluoromethylated amino acids have altered
properties of the functional groups.1i,2 and fix the conforma-
tions of the peptides in which they are incorporated;1l,q,s thus,
these amino acids have been the synthetic targets of recent
stereoselective organic syntheses.1a,r,2 Despite the remarkable
developments in the syntheses of α-trifluoromethylated amino
acids, there have been few reports on the bioactivities of
peptides incorporating α-trifluoromethyl-α-amino acids.2,3 The
poor knowledge of the chemistry and biological activities of α-
trifluoromethyl-α-amino acids is due to the difficulty in
preparing α-trifluoromethyl-α-amino acids that are optically
pure. Automatic syntheses of peptides are demanding an
optimization-free preparation for the optically pure α-
trifluoromethyl-α-amino acids.
Scheme 1. A Strategy for the Preparation of Optically Pure
α-Trifluoromethyl-α-amino Acids8
Our syntheses of α-trifluoromethyl-α-amino acid 4 from
optically pure aziridine 2 involve nucleophilic addition without
modification of the stereogenic center. Thus, the product
requires no further optical purification, which is the advantage
of our strategy. However, we experienced a few problems to
overcome before the implementation of this strategy. (1) The
preparation of the aziridine from the optically pure epoxide (4
steps, 27%, see Scheme 2) should be condensed. (2) Aziridine
2 has two electrophilic centers: the aziridine ring and the ester
moiety. Thus, the nucleophilic attack should be chemoselective
(Scheme 1). (3) Although the tosyl group on the aziridine N-
atom is essential for the nucleophilic ring-opening reaction of
the aziridine, it should be removed at the last stage. Therefore, a
method for the facile detosylation from the nitrogen of the ring-
opening products should be developed.
To date, many racemic2,a,4 and optically active1d,5 α-
trifluoromethyl-α-amino acids have been prepared, independ-
ently. Many of these compounds have been prepared by the
addition of nucleophiles to imino-carbons, for example, the
addition of an alkyl moiety to trifluoromethyl imino-
esters,3a,f,g,j−z,ab,ad,b−j,l−o,t,v the nucleophilic addition of CF3 to
imino-esters,4h,ac and the Strecker-type addition of cyanide to
alkyl trifluoromethyl imines followed by hydrolysis of the cyano
group.4af,m,q,u,w Some of these amino acids have been prepared
by the addition of electrophiles to an enamine form of
trifluoroalanine. These strategies construct the stereogenic
quaternary C-atoms via the addition of a variety of nucleophiles
or electrophiles. Therefore, these strategies require the
optimization of the asymmetric reaction or optical resolution
of the products. These conventional strategies are not suitable
for the general synthesis of a series of optically pure α-
trifluoromethyl-α-amino acids.
Received: July 27, 2011
Published: September 27, 2011
© 2011 American Chemical Society
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Scheme 2. Our Conventional Method for Preparation of the
Aziridine 2 (See Ref 6)
Scheme 4. Nucleophilic Additions to the Aziridine 2 and
Subsequent Detosylation
Herein, we report an improved method for the preparation
of N-tosyl-2-trifluoromethyl-2-alkyloxycarbonyl aziridine 2
(Scheme 3), including the scope of the relevant nucleophilic
Scheme 3. Improved Preparation of Aziridine 2
ring-opening reactions and the detosylation of the aziridine N-
atom (Scheme 4), for the preparation of optically pure α-
trifluoromethyl-α-amino acids.
RESULTS AND DISCUSSION
■
An Improved Preparation of Aziridine 2. As illustrated
in Scheme 2, the total yield of the conventional synthesis of
aziridine 2 from epoxide 1 was 27%.8b The low yield was the
result of the low yield of the ring-opening reaction of 1 and of
the following tosylation of the amino alcohol. Thus, a reduction
of these processes would give a better total yield of aziridine 2.
Therefore, the direct ring-opening reaction of epoxide 1 with p-
toluenesulfonamide (TsNH2) was investigated.
Ring-Opening Reactions of Aziridine 2 and Subse-
quent Detosylation. Aziridine 2 has two nucleophile-
reactive sites: the aziridine ring and the ester moiety. Therefore,
there would be two competing reactions with the nucleophile.
However, except for some nucleophiles, the nucleophilic
additions were regioselective with the nucleophiles attacking
the aziridine ring to give ring-opening products 7 in good to
moderate yields (Scheme 4). This regioselectivity could be due
to the high hindrance of the nucleophilic attack on the carbonyl
carbon, which is shielded by the bulky and negatively charged
trifluoromethyl group (Figure 1).6d,11
In our experiments, the hydride (NaBH4) and the stabilized
carbanion of acetonitrile reacted with the ester group of 2
(Scheme 5). This means that the sterically small nucleophiles
reacted with the highly hindered ester moiety.
Although the cyanide ion is also a small nucleophile, its
addition led selectively to the ring-opening product 7a. Among
these three small nucleophiles, only the cyanide ion could be a
leaving group from an initially formed ester addition product.
The direct ring-opening reaction of epoxide 1 with TsNH2
and Lewis acid catalysis (Ti(OiPr)4)/Et3N9 gave amide alcohol
5 with a 67% yield. Here, the yield is based on the amount of
epoxide 1 used. Therefore, the yield of the product was
essentially quantitative based on the amount of TsNH2. To
avoid the problematic separation of tosylated amide alcohol 5
from the remaining TsNH2, an excess amount (1.5 equiv.) of
epoxide 1 was used to ensure complete consumption of the
TsNH2 present.
The amino alcohol derivative 5 was converted into aziridine
6 by an intramolecular Mitsunobu reaction10 with a 91% yield.
This improvement of the process for the synthesis of aziridine 2
resulted in a better total yield (60%). Further reduction of
technical losses of the volatile epoxide 1 in the first step could
increase the total yield up to 90%.
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trifluoromethyl-α-amino acids 8 without the need to optimize a
stereoselective processes.
EXPERIMENTAL SECTION
■
(S)-N-(3,3,3-Trifluoro-2-hydroxypropyl)toluenesulfonamide
(5). To a solution of TsNH2 (17.144 g, 100.1 mmol) in CHCl3 (180
mL), Ti(OiPr)4 (29.3 mL, 100 mmol), 2,3-epoxy-1,1,1-trifluoropro-
pane 1 (10.3 mL, 150 mmol), and Et3N (13.9 mL, 100 mmol) were
added. The reaction mixture was stirred at room temperature for 12 h.
After removal of the solvent under reduced pressure, reaction mixture
was dissolved in AcOEt and 10% HCl(aq). After extraction with
AcOEt, the combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude mixture
of the product was washed with hexane to give product 5 as a white
solid in <99% yield from TsNH2 (in 67% yield from epoxide 1).
Optical purity was >99% ee confirmed by comparison of the HPLC
Figure 1. Steric hindrance around the carbonyl C-atom.
Scheme 5. Reaction of Aziridine 2 with the Hydride and the
Carbanion of Acetonitrile
1
results (see Supporting Information). H NMR (CDCl3): δ (ppm)
7.76 (m, 2H), 7.35 (m, 2H), 4.93 (dd, J = 9, 5 Hz, 1H), 4.14 (m, 1H),
3.36 (ddd, J = 14, 9, 3 Hz, 1H), 3.13 (d, J = 5 Hz, 1H), 3.07 (ddd, J =
14, 9, 5 Hz, 1H), 2.45 (s, 3H). 19F NMR (CDCl3): δ (ppm) 83.2 (d, 7
Hz, 3F). 13C NMR (CDCl3): δ (ppm) 144.3, 135.9, 130.0, 127.1,
123.9, 69.3, 42.5, 21.5. IR (KBr): 3500, 3280, 1320, 1140 cm−1. GC/
MS m/z (%): 184 (41), 155 (50), 91 (100). Anal. calcd for
C10H12F3NO3S: C, 42.40; H, 4.27; N, 4.94. Found: C, 42.46; H, 4.05;
N, 5.07. [α]D = −30.6° (c = 1.64, AcOEt).
25
(R)-1-Tosyl-2-trifluoromethylaziridine (6).8 To a solution of 5
(0.283 g, 1.0 mmol) and PPh3 (0.286 g, 1.09 mmol) in dry THF (4
mL) was added dropwise 40% DEAD (0.45 mL, 1.0 mmol) in toluene
at room temperature under an Ar atmosphere. After stirring for 30 min
at room temperature, water was added. The reaction mixture was
extracted with Et2O, and the combined organic layer was washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude mixture of the product was purified by
short column chromatography on silica gel (eluent hexane/Et2O = 1/
That is, the cyanide ion could react with ester group reversibly,
while the ring-opening reaction is irreversible.
To prepare the α-trifluoromethyl glutamic acid precursor, we
allowed the aziridine 2 to react with the carbanion of dimethyl
malonate to give compound 7c via 7b. Detosylation proceeded
smoothly to give 7c.
It is noteworthy that the ring-opening reaction of aziridine 2
i
with PrMgBr gave, in addition to the product 7d (16%),
1
1) to give product 6 as white solid in 91% yield. Mp: 87.8 °C. H
difluoroolefin 9 (68%) via cleavage of the N(1)−C(2) bond of
2, followed by defluorination, along with recovered aziridine 2
(Scheme 6).
NMR (CDCl3): δ (ppm) 7.85 (d, J = 8 Hz, 2H), 7.38 (d, J = 9 Hz,
2H), 3.27 (m, 1H), 2.82 (d, J = 7 Hz,1H), 2.53 (d, J = 7 Hz, 1H), 2.47
(s, 3H). 19F NMR (CDCl3): δ (ppm) 90.8 (s, 3F). IR(KBr): 1340,
1130 cm−1. GC-MS m/z (rel. int): 265 (7, M+), 155 (50), 110 (15),
91 (100), 69 (6), 65 (35). Anal. Calcd. for C10H10F3NO2S: C, 45.28;
H, 3.80; N, 5.28. Found: C, 45.36; H, 3.91; N, 5.28. [α]D25= −16.3° (c
= 1.37, THF).
i
Scheme 6. Reaction of the Aziridine 2 with PrMgBr
(S)-Ethyl 1-Tosyl-2-(trifluoromethyl)aziridine-2-carboxylate
(2).8 n-BuLi (1.1 equiv., 2.66 M in hexane) was added dropwise to
a solution of 6 (5 mmol) in THF (25 mL) at −102 °C, and the
solution was stirred at this temperature for 20 min to generate
aziridinyl anion. Then, ClCOOEt (10 mmol, 2.0 equiv) was added
dropwise to the solution at this temperature. After the reaction mixture
was allowed to warm to −40 °C for 3 h, Et2O (5 mL) was added. The
solution was warmed to room temperature followed by addition of sat.
NH4Cl (8 mL). The combined organic layer was separated; then the
aqueous layer was extracted with Et2O. The combined organic layer
was washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture of the
product was purified by column chromatography on silica gel (eluent
hexane/Et2O = 5/1) to give products 2 as a white solid in 95% yield.
1H NMR (CDCl3): δ (ppm) 7.85 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 9
The reaction would be initiated by electron transfer(s)12a
from the Grignard reagent12b,c to the aziridine 2, followed by
defluorination.12d The product olefin could be a precursor of
β,β-difluoro-β-amino acids via nucleophilic addition to the
difluoromethylene carbon.13
Detosylation of 7 was attained by reaction with concentrated
sulfuric acid, with 62−86% yields.14 Fortunately, the stereo-
genic centers of amino acids 7 and 8 were quarternary; thus, the
reactions proceeded without racemization. Popular reductive
detosylations, such as the Birch-type reduction,15 resulted in the
defluorination or decomposition of the products, and no amino
acid 8 was obtained.
Hz, 2H), 4.39 (q, J = 7 Hz, 2H), 3.52 (br, 1H), 2.77 (s, 1H), 2.45 (s,
3H), 1.38 (t, J = 7 Hz, 3H) {lit.8 7.84 (d, J = 8 Hz, 2H), 7.36 (d, J = 8
Hz, 2H), 4.38 (q, J = 7 Hz, 2H), 3.52 (br, 1H), 2.77 (s, 1H), 2.45 (s,
3H), 1.37 (t, J = 7 Hz, 3H)}. 19F NMR (CDCl3): δ (ppm) 90.8 (s,
3F); {lit.8 89.8 (s, 3F)}.
(S)-Ethyl 3-Cyano-2-trifluoromethyl-2-tosylaminopropa-
noate (7a). A solution of aziridine 2 (1.349 g, 4 mmol) and
NaCN (0.217 g, 4.4 mmol) in H2O (16 mL) and CF3CH2OH (16
mL) was stirred for 12 h. Then, sat. NH4Cl was added, the mixture
was extracted with AcOEt, and the combined organic layer was washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude mixture of the product was purified
CONCLUSION
■
In conclusion, we have developed a method of preparation of
α-trifluoromethyl-α-amino acids from optically pure epoxide 1
via optically pure aziridine 2. This process retains the
configuration of the stereogenic center; the use of optically
pure epoxide 1 resulted in preparation of optically pure α-
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by column chromatography on silica gel (eluent hexane/Et2O = 5/1)
to give product 7a in 80% yield as colorless oil. Mp: 50 °C. H NMR
was made alkaline by addition of NaOH(aq) and was then extracted
with Et2O. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude
mixture of the product was purified by column chromatography on
silica gel (eluent hexane/AcOEt = 5/1) to give product 8c in 92% as
white solid. Mp: 78.2−79.0 °C. 1H NMR (CDCl3): δ (ppm) 6.36 (br,
1H), 4.33 (q, J = 7 Hz, 2H), 2.5 (m, 4H), 1.33 (t, J = 7 Hz, 3H). 19F
NMR (CDCl3): δ (ppm) 83.9 (s, 3F). GC/MS m/z (%): 225 (<1),
152 (100), 132 (11), 104 (9), 54 (16). IR(KBr): 3200, 1760, 1710
cm−1. Anal. calcd for C8H10F3NO3: C, 42.67; H, 4.48; N, 6.22. Found:
C, 42.66; H, 4.51; N, 6.19.
1
(CDCl3): δ (ppm) 7.81 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 6.03
(s, 1H), 4.38 (dq, J = 11, 7 Hz, 1H), 4.29 (dq, J = 11, 7 Hz, 1H), 3.67
(d, J = 17 Hz, 1H), 3.31 (d, J = 17 Hz, 1H), 2.43 (s, 3H), 1.32 (t, J = 7
Hz, 3H). 19F NMR (CDCl3): δ (ppm) 87.9 (s, 3F). 13C NMR
(CDCl3): δ (ppm) 163.3, 144.4, 137.2, 129.5, 126.9, 121.9, 113.9, 65.0,
65.0, 21.4, 20.9, 13.5. IR(KBr): 3290, 1740 cm−1. GC/MS m/z (%):
364 (tr M+), 155(48), 91 (100), 65 (31). Anal. calcd for
C14H15F3N2O4S: C, 46.15; H, 4.15; N, 7.69. Found: C, 46.13; H,
4.30; N, 7.53. [α]D = −25.9° (c = 1.27, Et2O).
25
(S)-3-Amino-3-(ethoxycarbonyl)-4,4,4-trifluorobutanoic
Acid (8a). Compound 7a (1.0 mmol) was dissolved in 98% H2SO4 (1
mL), and the resulting solution was kept at room temperature for 18 h.
The solution was cooled to 0 °C and then added dropwise into Et2O
with stirring, and ice−water was added to the solution. The aqueous
layer was made alkaline by addition of NaOH(aq) and was then
extracted with Et2O. The combined organic layer was dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The crude mixture of the product was purified by column
chromatography on silica gel to give product 8a in 72% yield as a
colorless oil. 1H NMR (CDCl3): δ (ppm) 4.11 (q, J = 7 Hz, 2H), 3.11
(d, J = 19 Hz, 1H), 2.74 (d, J = 19 Hz, 1H), 1.25 (t, J = 7 Hz, 1H)
{lit.5n (D2O) δ (ppm) 4.16 (q, J = 7.1 Hz, 2H), 2.78 (q, J = 16.7 Hz,
2H), 1.14 (t, J = 7.1 Hz, 3H)}. 19F NMR (CDCl3): δ (ppm) 82.3 (s,
3F) {lit.5n (D2O) δ (ppm) 87.2 (s)}. GC/MS m/z (%): 156 (5), 154
(S)-Ethyl 3,3,3-Trifluoro-2-(2-methylpropyl)-2-tosylamino-
propanoate (7d) and Ethyl 3,3-Difluoro-2-tosylamino-2-pro-
penoate (9). To Cu(OTf)2 (0.037 g, 0.1 mmol) in a flame-dried
flask under Ar, THF (1.5 mL) and HMPA (0.3 mL, 1.7 mmol) were
added at −40 °C. Then, isopropyl magnesium chloride (iPrMgCl) (2.1
mL, 4.0 mmol) was added dropwise. The mixture was stirred for 2 h at
−30 °C. The reaction was quenched by NH4Cl(aq) and extracted with
Et2O. The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The crude mixture of the
product was purified by column chromatography on silica gel (eluent
hexane/Et2O = 5/1) to give product 7d in 16% yield as colorless oil.
The main product was difluoroolefin 9 (68%).
(S)-Ethyl 3,3,3-Trifluoro-2-(2-methylpropyl)-2-tosylaminopropa-
noate (7d). 1H NMR (CDCl3): δ (ppm) 7.73 (d, J = 8 Hz, 2H),
7.27 (d, J = 8 Hz, 2H), 5.95 (s,1H), 4.38 (dq, J = 11, 7 Hz, 1H), 4.27
(dq, J = 11, 7 Hz, 1H), 2.57 (dd, J = 14, 4 Hz, 1H), 2.41 (s, 3H), 2.10
(m, 1H), 1.94 (dd, J = 14, 4 Hz, 1H), 1.33 (t, J = 7 Hz, 3H), 1.05 (d, J
= 7 Hz, 3H), 0.83 (d, J = 7 Hz, 3H). 19F NMR (CDCl3): δ (ppm)
88.8 (s, 3F). GC/MS m/z (%): 308 (6), 170 (11), 155 (66), 91 (100).
IR(neat): 2970, 1750 cm−1. Anal. calcd for C16H22F3NO4S: C, 50.38;
H, 5.81; N, 3.67. Found: C, 50.42; H, 5.68; N, 3.57. [α]D20 = +36.0° (c
= 0.005, Et2O).
(100) 69 (4), 59 (5). IR(neat): 1730, 1190 cm−1
.
(S)-Ethyl 4,4-Bis(methoxycarbonyl)-2-tosylamino-2-trifluor-
omethylbutanoate (7b). To NaOH (0.1219 g, 3.0 mmol) powder
in DMSO (3 mL) in a flame-dried flask under Ar, a mixture of
aziridine 2 (0.3303 g, 0.98 mmol) and CH2(CO2Me)2 (0.24 mL, 2.1
mmol) in DMSO (3 mL) was added; the suspension was stirred for 2
h at room temperature. Then, 10% HCl(aq) was added, the mixture
was extracted with AcOEt, and the combined organic layer was washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude mixture of the product was purified
by column chromatography on silica gel (eluent hexane/AcOEt = 3/1)
gave product 7b in 67% yield as a white solid. Further purification was
attained by recrystallization in 18% yield. Mp: 137−138 °C. 1H NMR
(CDCl3): δ (ppm) 7.73 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 5.85
(s, 1H), 4.34 (dq, J = 11, 7 Hz, 1H), 4.23 (dq, J = 11, 7 Hz, 1H), 3.94
(dd, J = 8, 5 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.01 (dd, J = 15, 5
Hz, 1H), 2.78 (dd, J = 15, 8 Hz), 2.42 (s, 3H), 1.31 (t, J = 7 Hz, 3H).
19F NMR (CDCl3): δ (ppm) 88.6 (s, 3F). GC/MS m/z (%): 396 (9),
Ethyl 3,3-Difluoro-2-tosylamino-2-propenoate (9). Mp: 65.5−
1
66.0 °C. H NMR (CDCl3): δ 7.76 (d, J = 8 Hz, 2H), 7.32 (d, J =
8 Hz, 2H), 5.86 (s, 1H), 4.16(q, J = 7 Hz, 2H), 3.14 (t, J = 3 Hz, 2H),
2.44 (s, 3H), 1.26 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ 73.7(d, J =
32 Hz, 1F), 68.3 (d, J = 32 Hz, 1F). IR(KBr): 3200, 1770, 1740 cm−1
.
GC/MS m/z (%): 274 (tr), 246 (1), 178(5), 155 (22), 136 (24), 91
(100). Anal. calcd for C13H15F2NO4S: C, 48.90; H, 4.73; N, 4.39.
Found: C, 48.95; H, 4.75; N, 4.41.
(S)-Ethyl 2-Amino-4-methyl-2-trifluoromethylpentanoate
(8d). Compound 7d (1.0 mmol) was dissolved in 98% H2SO4 (1
mL), and the resulting solution was kept at room temperature for 1 h.
Then the solution was added dropwise into Et2O with stirring, and
ice−water was added to the solution. The aqueous layer was made
alkaline by addition of NaOH(aq) and was then extracted with Et2O.
The combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude mixture
of the product was purified by column chromatography on silica gel
(eluent hexane/Et2O = 5/1) to give product 8d in 57% as colorless oil.
1H NMR (CDCl3): δ 4.27 (m, 2H), 2.03 (dd, J = 14, 8 Hz, 1H), 1.7
224 (68), 155 (53), 91 (100). IR(KBr): 3280, 1770 cm−1. Anal. calcd
for C18H22F3NO8S: C, 46.05; H, 4.72; N, 2.98. Found: C, 45.96; H,
4.62; N, 2.99. [α]D = +29.6° (c = 0.04, Et2O).
20
(S)-Ethyl 5-Oxo-2-(trifluoromethyl)-N-tosylpyrrolidine-2-car-
boxylate (7c). To 7b (0.56 mmol), 1 M NaOH(aq) was added at
room temperature. After the solution was stirred for 4 h, 10% HCl(aq)
was added at 0 °C, the mixture was extracted with Et2O, and the
combined organic layer was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. After the
crude mixture of the product was heated at 150 °C for 4 h, it was
purified by column chromatography on silica gel (eluent hexane/
AcOEt = 5/1) to give product 7c in 32% as a white solid. Mp: 113.2−
113.8 °C. 1H NMR (CDCl3): δ (ppm) 8.01 (d, J = 9 Hz, 2H), 7.34 (d,
J = 8 Hz, 2H), 4.44 (dq, J = 7, 1 Hz, 2H), 2.5 (m, 4H), 2.44 (s, 3H),
(m, 1H), 1.65 (dd, J = 14, 5 Hz, 1H), 1.32 (t, J = 7 Hz, 3H), 0.99 (d, J
= 7 Hz, 3H), 0.86 (d, J = 7 Hz, 3H). 19F NMR (CDCl3): δ 83.2 (s,
3F). IR(neat): 1750 cm−1. GC/MS m/z (%): 154 (97), 112 (100).
Anal. calcd for C9H16F3NO2: C, 47.57; H, 7.10; N, 6.16. Found: C,
47.54; H, 7.11; N, 6.26. [α]D = −30.0° (c = 0.002, Et2O).
20
(S)-Ethyl 2-Benzyl-3,3,3-trifluoro-2-tosylaminopropanoate
(7e). CuBr (0.0137 g, 0.095 mmol) was added to the solution of
PhMgBr (5.3 mL, 2 mmol); then the solution was cooled to 0 °C. To
the solution of Grignard reagent, a solution of aziridine 2 (0.331 g,
0.99 mmol) in dry THF (5 mL) was added dropwise. The suspension
was stirred at room temperature for 27 h; then sat. NH4Cl was added
to quench, and the mixture was extracted with Et2O. The combined
organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture of the
product was purified by column chromatography on silica gel (hexane/
Et2O = 5/1) to give product 7e in 59% yield as a colorless oil. Optical
purity was confirmed by comparison of the HPLC results (see
Supporting Information). The product was submitted to the
1.42 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ (ppm) 89.4 (s, 3F). 13
C
NMR (CDCl3): δ (ppm) 172.6, 165.9, 145.8, 134.6, 129.6, 129.3,
123.8 (q, J = 284 Hz), 70.5(q, J = 20 Hz), 63.6, 29.1, 27.1, 21.7, 12.8.
GC/MS m/z (%): 315 (17), 242 (100), 155 (20), 91 (65). IR(KBr):
1750 cm−1. Anal. calcd for C15H16F3NO5S: C, 47.49; H, 4.25; N, 3.69.
Found: C, 47.35; H, 4.21; N, 3.66. [α]D = +34.3° (c = 0.014,
20
AcOEt).
(S)-Ethyl 5-Oxo-2-(trifluoromethyl)pyrrolidine-2-carboxate
(8c). Compound 7c (0.22 g, 0.58 mmol) was dissolved in 98%
H2SO4 (0.5 mL), and the resulting solution was kept at 50 °C for 3 h.
The solution was cooled to 0 °C, then added dropwise into Et2O with
stirring, and ice−water was added to the solution. The aqueous layer
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detosylation without further purification. Mp: 85.0−85.7 °C. 1H NMR
(CDCl3): δ (ppm) 7.73 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.30 (m,
5H), 5.83 (s, 1H), 4.26 (dq, J = 11, 7 Hz, 1H), 4.17 (dq, J = 11, 7 Hz,
1H), 3.97 (d, J = 14 Hz, 1H), 3.35 (d, J = 14 Hz, 1H), 2.41 (s, 3H),
7.34 (m, 2H), 7.27 (m, 5H), 4.29 (dq, J = 7, 14 Hz, 1H), 3.84 (d, J =
14 Hz, 1H), 3.76 (d, J = 14 Hz, 1H), 3.49 (d, J = 13 Hz, 1H), 3.14 (d,
J = 13 Hz, 1H), 2.40 (s, 3H), 1.27 (t, J = 7 Hz, 3H). 19F NMR
(CDCl3): δ (ppm) 89.7(s, 3F). 13C NMR (CDCl3): δ (ppm) 166.0,
143.4, 139.1, 138.4, 129.3, 128.4, 127.9, 127.2, 126.4, 122.8, 67.6, 63.6,
53.7, 47.9, 21.5, 13.8. IR(neat): 3290, 1750, 1600 cm−1. GC/MS m/z
(%): 301 (19), 274 (4), 155 (7), 91 (100). Anal. calcd for
C20H23F3N2O4S: C, 54.05; H, 5.22; N, 6.30. Found: C, 54.12; H,
1.24 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ (ppm) 90.4 (s, 3F). 13
C
NMR (CDCl3): δ (ppm) 165.4, 143.2, 138.9, 132.6, 130.5, 129.2,
128.4, 127.7, 126.6, 122.9, 68.9, 63.9, 36.1, 21.4, 13.6. IR(KBr): 3280,
1750, 1160 cm−1. GC/MS m/z (%): 342 (tr), 244 (19), 155 (28), 91
(100). [α]D = +31.6° (c = 1.28, AcOEt).
5.21; N, 6.24. [α]D = +5.0° (c = 3.21, AcOEt).
(S)-Ethyl252-Amino-2-benzyl-3,3,3-trifluoropropanoate (8e).
Compound 7e (1.0 mmol) was dissolved in 98% H2SO4 (1 mL), and
the resulting solution was kept at room temperature for 1 h. Then the
solution was added dropwise into Et2O with stirring, and ice−water
was added to the solution. The aqueous layer was made alkaline by
addition of NaOH(aq) and was then extracted with Et2O. The
combined organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture of the
product was purified by column chromatography on silica gel (hexane/
(S)-Ethyl-2-amino-3-benzylamino-2-trifluoromethylpropa-
noate (8g). Compound 7g (1.0 mmol) was dissolved in 98% H2SO4
(1 mL), and the resulting solution was kept at 100 °C for 2 h. The
solution was cooled to 0 °C, then added dropwise into Et2O with
stirring, and ice−water was added to the solution. The aqueous layer
was made alkaline by addition of NaOH(aq) and was then extracted
with Et2O. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude
mixture of the product was purified by column chromatography on
25
1
1
silica gel to give product 8g in 82% yield as colorless oil. H NMR
Et2O = 5/1) to give product 8e in 73% yield as a colorless oil. H
(CDCl3): δ (ppm) 7.30 (m, 5H), 4.23 (m, 2H), 3.81 (d, J = 2 Hz,
2H), 3.26 (d, J = 12 Hz, 1H), 2.84 (d, J = 12 Hz, 1H), 1.29 (t, J = 7
Hz, 3H). 19F NMR (CDCl3): δ (ppm) 85.2(s, 3F). IR(neat): 1750
cm−1. GC/MS m/z (%): 291 (tr M+), 217 (1), 120 (21), 91 (100).
Anal. calcd for C13H17F3N2O2: C, 53.79; H, 5.90; N, 9.65. Found: C,
NMR (CDCl3): δ (ppm) 7.23 (m, 5H), 4.27 (dq, J = 11, 7 Hz, 1H).
4.22 (dq, J = 11, 7 Hz, 1H), 3.47 (d, J = 14 Hz, 1H), 2.98 (d, J = 14
Hz, 1H), 1.85 (br, 2H), 1.30 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ
(ppm) 84.9 (s, 3F). IR(neat): 1750 cm−1. GC/MS m/z (%): 188 (43),
91(100). Anal. calcd for C12H14F3NO2: C, 55.17; H, 5.40; N, 5.36.
Found: C, 55.24; H, 5.42; N, 5.40.
54.03; H, 6.07; N, 9.70. [α]D = −13.56° (c = 0.05, AcOEt).
25
(S)-Ethyl 3-Phenylthio-2-tosylamino-2-trifluoromethylpro-
panoate (7h). To a solution of aziridine 2 (2.704 g, 8.02 mmol)
and DABCO (0.050 g, 0.44 mmol) in CH3CN (64 mL), PhSH (0.99
mL, 9.6 mmol) was added dropwise. After stirring at room
temperature for 19 h, the reaction mixture was concentrated under
reduced pressure. The crude mixture of the product was purified by
column chromatography on silica gel (eluent hexane/AcOEt = 5/1) to
give product 7h in 99% yield as a colorless oil. Optical purity was
confirmed by comparison of the HPLC results (see Supporting
(S)-Ethyl 3-Methoxy-2-tosylamino-2-trifluoromethylpropa-
noate (7f). To an ice-cooled solution of aziridine 2 (3.376 g, 10
mmol) in MeOH (50 mL), BF3·OEt2 (47%) (5.1 mL, 20 mmol) was
added dropwise. After the mixture was refluxed (54 h), water was
added. The reaction mixture was exacted with Et2O, and the combined
organic layer was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude mixture
of the product was purified by column chromatography on silica gel
(eluent hexane/Et2O = 3/1) to give product 7f in 82% yield as a white
solid. Optical purity was confirmed by comparison of the HPLC
results (see Supporting Information). The product was submitted to
1
Information). H NMR (CDCl3): δ (ppm) 7.77 (d, J = 8 Hz, 2H),
7.44 (d, J = 7 Hz, 2H), 7.30 (m, 5H), 6.08 (s, 1H), 4.22 (d, J = 14 Hz,
1H), 4.08 (dq, J = 10, 7 Hz, 1H), 3.61 (d, J = 14 Hz, 1H), 3.67 (dq, J =
10, 7 Hz, 1H), 2.42 (s, 3H), 1.03 (t, J = 7 Hz, 3H). 19F NMR
(CDCl3): δ (ppm) 89.5 (s, 3F). 13C NMR (CDCl3): δ (ppm) 164.6,
143.5, 138.7, 134.5, 131.8, 129.1, 128.9, 127.4, 126.7, 122.1, 68.4, 64.1,
36.4, 21.4, 13.3. IR(neat): 3300, 1750, 1060 cm−1. GC/MS m/z (%):
447 (2: M+), 276 (16), 123 (100), 91 (37). Anal. calcd for
C19H20F3NO4S2: C, 51.00; H, 4.50; N, 3.13. Found: C, 51.02; H, 4.41;
1
the detosylation without further purification. Mp: 69.0−70.5 °C. H
NMR (CDCl3): δ (ppm) 7.76 (d, J = 8 Hz, 2H), 7.27 (d, J = 8 Hz,
2H), 5.84 (s, 1H), 4.31 (q, J = 7 Hz, 2H), 4.23 (d, J = 10 Hz, 1H),
3.91 (d, J = 10 Hz, 1H), 3.18 (s, 3H), 2.41 (s, 3H), 1.28 (t, d = 7 Hz,
3H). 19F NMR (CDCl3): δ (ppm) 89.5 (s, 3F). 13C NMR (CDCl3): δ
(ppm) 164.7, 143.2, 139.0, 129.1, 126.6, 122.3, 68.3, 68.0, 63.9, 59.0,
21.5, 13.8. IR(KBr): 3300, 1760 cm−1. GC/MS m/z (%): 369 (tr M+),
214 (9), 155 (9), 91 (32), 45 (100). [α]D25 = −12.3° (c = 1.02, Et2O).
(S)-Ethyl 2-Amino-3-methoxy-2-trifluoromethylpropanoate
(8f). Compound 7f (1.0 mmol) was dissolved in 98% H2SO4 (1
mL), and the resulting solution was kept at 0 °C for 2 h. The solution
was added dropwise into Et2O with stirring, and ice−water was added
to the solution. The aqueous layer was made alkaline by addition of
NaOH(aq) and was then extracted with Et2O. The combined organic
layer was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude mixture of the product was purified
by column chromatography on silica gel to give product 8f in 77% as a
colorless oil. Optical purity was confirmed by comparison of the
N, 3.12. [α]D = +43.1° (c = 1.08, AcOEt).
25
(S)-Ethyl 2-Amino-3-phenylthio-2-trifluoromethylpropa-
noate (8h). Compound 7h (1.0 mmol) was dissolved in 98%
H2SO4 (1 mL), and the resulting solution was kept at 0 °C for 2 h.
Then the solution was added dropwise into Et2O with stirring, and
ice−water was added to the solution. The aqueous layer was made
alkaline by addition of NaOH(aq) and was then extracted with Et2O.
The combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude mixture
of the product was purified by column chromatography on silica gel to
1
give product 8h in 86% as colorless oil. H NMR (CDCl3): δ (ppm)
1
7.43 (m, 2H), 7.32 (m, 3H), 4.13 (dq, J = 11, 7 Hz, 1H), 3.90 (dq, J =
11, 7 Hz, 1H), 3.68 (d, J = 14 Hz, 1H), 3.26 (d, J = 14 Hz, 1H), 2.09
(br, 2H), 1.16 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ (ppm) 84.8 (s,
3F). IR(neat): 1750 cm−1. GC/MS m/z (%): 293 (6, M), 220 (2), 123
(100), 109(25), 69 (3). Anal. calcd for C12H14F3NO2S: C, 49.14; H,
4.81; N, 4.78. Found: C, 49.20; H, 4.77; N, 4.90. [α]D25 = +26.8° (c =
1.37, Et2O).
HPLC results (see Supporting Information). H NMR (CDCl3): δ
(ppm) 4.29 (q, J = 7 Hz, 2H), 3.86 (d, J = 9 Hz, 1H), 3.63 (d, J = 9
Hz, 1H), 3.39 (s, 3H), 2.04 (br, 2H), 1.31 (t, J = 7 Hz, 3H). 19F NMR
(CDCl3) δ (ppm) 86.0 (s, 3F). IR(neat): 1750 cm−1. GC/MS m/z
(%): 142 (63), 69 (2), 45 (100). Anal. calcd for C7H12F3NO3: C,
39.07; H, 5.62; N, 6.51. Found: C, 38.81; H, 5.90; N, 6.52. [α]D
−6.6° (c = 1.67, Et2O).
=
25
(S)-Ethyl 3-Benzylamino-2-tosylamino-2-trifluoromethyl
propionate (7g). To a solution of aziridine 2 (2.703 g, 8.02
mmol) in THF (80 mL), BnNH2 (1.31 mL, 12.0 mmol) was added
dropwise. After 2 h refluxing, the reaction mixture was concentrated
under reduced pressure. The crude mixture of the product was purified
by column chromatography on silica gel (eluent hexane/Et2O = 3/1)
to give product 7g in 99% yield as colorless oil. Optical purity was
confirmed by comparison of the HPLC results (see Supporting
(S)-Ethyl 3-Bromo-2-tosylamino-2-trifluoromethylpropa-
noate (7i). To a mixture of aziridine 2 (0.7557 g, 2.23 mmol) and
MgBr2·Et2O (1.0386 g, 4.02 mmol) placed in an oven-dried round-
bottom flask under Ar, Et2O (20 mL) was added. After refluxing for 24
h, 10% HCl(aq) (2 mmol) was added at 0 °C. The reaction mixture
was exacted with Et2O, and the combined organic phase was washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude mixture of the product was purified
by column chromatography on silica gel (eluent hexane/Et2O = 5/1)
1
Information). H NMR (CDCl3): δ (ppm) 7.76 (d, J = 8 Hz, 2H),
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to give product 7i in 99% yield as colorless crystal. Mp: 104.5−105.5
°C. 1H NMR (CDCl3): δ (ppm) 7.79 (d, J = 8 Hz, 2H), 7.30 (d, J = 8
Hz, 2H), 5.97 (s, 1H), 4.52 (d, J = 11 Hz, 1H), 4.39 (m, 2H), 3.97 (d,
J = 11 Hz, 1H), 2.42 (s, 3H), 1.34 (t, 3H). 19F NMR (CDCl3): δ
(ppm) 90.4 (s, 3F). IR(KBr): 3270, 1770 cm−1. GC/MS m/z (%): 346
(5), 344 (5), 155 (84), 91 (100). Anal. calcd for C13H15BrF3NO4S: C,
yield as a yellowish white crystal. 1H NMR (CDCl3): δ (ppm) 7.82 (d,
J = 8 Hz, 2H), 7.40 (d, J = 8 Hz, 2H), 4.24 (d, J = 20 Hz, 1H), 3.98 (d,
J = 20 Hz, 1H), 3.48 (d, J = 1 Hz, 1H), 2.80 (s, 1H), 2.48 (s, 3H). 19
F
NMR (CDCl3): δ (ppm) 92.0 (s. 3F). GC/MS m/z (%): 332(6),
155(50), 91(100). IR(KBr): 1750 cm−1. Anal. calcd for
C13H11F3N2O3S: C, 46.99; H, 3.34; N, 8.43. Found: C, 46.99; H,
3.38; N, 8.39. [α]D = 19.3° (c =0.01, Et2O).
37.33; H, 3.62; N, 3.35. Found: C, 37.39; H, 3.45; N, 3.32. [α]D
−8.23° (c = 7.20, Et2O).
=
20
20
(S)-Ethyl 2-Tosylamino-2-trifluoromethylpropanoate (7j).
ASSOCIATED CONTENT
■
To a mixture of compound 7i (0.9868 g, 2.4 mmol) and Zn
(0.7480 g, 11.4 mmol), AcOH (3 mL) was added. After the solution
was stirred at 130 °C for 16 h, AcOH (3 mL) was added. After
completion (6 h) of the reaction, AcOH was removed under reduced
pressure. The reaction mixture was dissolved in Et2O and 10%
HCl(aq) and then extracted with Et2O. The combined organic layer
was dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude mixture of the product was purified by
column chromatography on silica gel (eluent hexane/dichloroethane
=3/1) to give product 7j in 88% yield as a white solid. Mp: 115.5−
116.0 °C. 1H NMR (CDCl3): δ (ppm) 7.76 (d, J = 8 Hz, 2H), 7.31 (d,
J = 8 Hz, 2H), 5.65 (s, 1H), 4.23 (q, J = 7 Hz, 2H), 2.43 (s, 3H), 1.65
(s, 3H), 1.28 (t, J = 7 Hz, 3H). 19F NMR (CDCl3): δ (ppm) 83.9 (s,
3F). GC/MS m/z (%): 266 (15), 155 (76), 139 (4), 112 (6), 91
(100), 65 (30). IR(KBr): 3280, 1600 cm−1. Anal. calcd for
C13H16F3NO4S: C, 46.01; H, 4.75; N, 4.13. Found: C, 46.23; H,
S
* Supporting Information
Spectroscopic data (1H NMR, 19F NMR, 13C NMR, and chiral
LC charts). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tkata@cc.okayama-u.ac.jp.
■
ACKNOWLEDGMENTS
■
We thank SC-NMR laboratory of Okayama University for 19F
NMR analysis.
REFERENCES
5.00; N, 4.11. [α]D = 0.0° (c = 1.37, Et2O).
■
20
α-CF3-Ala (8j).5o Compound 7j (0.1005 g 0.30 mmol) was
dissolved in 98% H2SO4 (0.5 mL), and the resulting solution was kept
at 50 °C for 10 min. The solution was cooled to 0 °C, and ice−water
was added to the solution. The combined organic phase was extracted
with Et2O and washed with 10% HCl(aq). The aqueous layer was
made alkaline by addition of NaOH(aq) and was then extracted with
Et2O. After being concentrated under reduced pressure, the crude
mixture of the product was added to KOH(aq). After the mixture was
stirred for 3 h, HCl(aq) was added until the aqueous layer was made
acidic. After being concentrated under reduced pressure, the crude
mixture of the product was purified by column chromatography on
ion-exchange regins (DOWEX 50W-X8) to give product α-CF3-Ala
(1) Books and recent reviews see: (a) Welch, J. T.; Eswarakrishnan,
S. Fluorine in Bioorganic Chemistry; Wiley: New York, 1991; Chapter 2,
p 7. (b) Fluorine-containing Amino Acids, Synthesis and Properties;
Kuhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, U.K., 1995.
(c) Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J.
R., Welch, J. T., Eds.; ACS Symposium Series 639; American Chemical
Society: Washington DC, 1996; Chapters 9−11, 13, and 14.
(d) Uneyama, K. In Enantiocontrolled Synthesis of Fluoro-organic
Compounds, Stereochemical Challenges and Biomedicinal Targets;
Soloshonok, V. A., Eds.; Wiley: Chichester, U.K., 1999; Chapter 13,
pp 391−418. (e) Hiyama, T. Organofluorine Compounds, Chemistry and
Applications; Springer: Berlin, 2000; Chapter 5.3, pp 144−148.
(f) Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; ACS
Symposium Series 911; American Chemical Society: Washington,
DC, 2005; Chapters 31−35, pp 544−635. (g) Haufe, G.; Kroger, S.
Amino Acids 1996, 11, 409−424. (h) Tolmann, V. Amino Acids 1996,
11, 15−36. (i) Schlosser, M. Angew. Chem., Int. Ed. 1998, 37, 1496−
1513. (j) Uneyama, K. J. Fluorine Chem. 1999, 97, 11−25.
(k) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17, 621−631.
(l) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335−341.
(m) Katagiri, T.; Uneyama, K. Chirality 2003, 15, 4−9. (n) Dave, R.;
Badet, B.; Meffre, P. Amino Acids 2003, 24, 245−261. (o) Otaka, A.;
Mitsuyama, E.; Watanabe, J.; Watanabe, H.; Fujii, N. Biopolymers 2004,
76, 140−149. (p) Fustero, S.; Sanz-Cervera, J. F.; Piera, J.; Sanchez-
Rosello, M.; Chiva, G.; Simon-Fuentes, A. J. Fluorine Chem. 2004, 125,
621−627. (q) Jackel, C.; Seufert, W.; Thust, S.; Koksch, B.
ChemBioChem 2004, 5, 717−720. (r) Qiu, X.-L.; Meng, W.-D.;
Qing, F.-L. Tetrahedron 2004, 60, 6711−6745. (s) Jackel, C.; Koksch,
B. Eur. J. Org. Chem. 2005, 4483−4503. (t) Begue, J.-P.; Bonnet-
Delpon, D. J. Fluorine Chem. 2006, 127, 992−1012. (u) Ojima, I.
Fluorine in Medicinal Chemistry and Chemical Biology; Blackwell
Publishing, Ltd.: Chichester, U.K., 2009; Chapter 9, pp 213−256.
(v) Kukhar, V. P.; Sorochinsky, A. E.; Soloshonok, V. A. Future Med.
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1
(8j) as a yellowish white powder. H NMR (D2O): δ (ppm) 1.57 (s,
3H) {lit.5o (D2O) δ (ppm) 1.55 (s, 3H)}.19F NMR (CDCl3): δ (ppm)
86.3 (s, 3F) {lit.5o (D2O) δ (ppm) 87.1 (s, 3F)}.GC/MS m/z (%):
112 (100).
(R)-2-Hydroxymethyl-2-trifluoromethyl-N-tosylaziridine
(10). To a mixture of compound 2 (0.3362 g, 1.0 mmol) and NaBH4
(0.0593 g, 1.6 mmol), EtOH (3 mL) was added. After the solution was
stirred for 2 h, NH4Cl(aq) was added, and the solution was extracted
with Et2O. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude
mixture of the product was purified by column chromatography on
silica gel (hexane/AcOEt = 5/1) to give product 10 in 51% yield as a
white solid. 1H NMR (CDCl3): δ (ppm) 7.86 (d, J = 8 Hz, 2H), 7.38
(d, J = 8 Hz, 2H), 4.56 (d, J = 14 Hz, 1H), 4.21 (d, J = 14 Hz, 2H),
3.13 (br, 1H), 2.98 (s, 1H), 2.63 (s, 1H), 2.47 (s, 3H). 19F NMR
(CDCl3): δ (ppm) 88.9 (s. 3F). GC/MS m/z (%): 295 (<1), 155
(29), 140 (20), 91 (100). IR(KBr): 3540, 1600 cm−1. Anal. calcd for
C11H12F3NO3S: C, 44.74; H, 4.10; N, 4.74. Found: C, 44.75; H, 4.06;
N, 4.81.
2-Cyanomethylcarbonyl-2-trifluoromethyl-N-tosylaziridine
(11). The reaction was influenced by the possible existence of a small
amount of water. Under a highly dried condition, aziridine 6 with
cyanoacetate was the main product.
To acetonitrile (0.035 mL, 0.6 mmol) in THF (0.5 mL) at −78 °C,
n-BuLi (0.19 mL, 0.5 mmol) was added. After the mixture was stirred
for 20 min, a solution of 2 (0.1684 g, 0.5 mmol) in THF (1.0 mL) was
added dropwise. After the mixture was stirred for 10 min, NH4Cl(aq)
was added, and the solution was extracted with Et2O. The combined
organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture of the
product was purified by column chromatography on silica gel (eluent
hexane/AcOEt = 3/1) and recrystallization to give product 11 in 44%
(2) (a) Kobzev, S. V.; Soloshonok, V. A.; Galushko, S. V.;
Yagupolskii, Y. L.; Kukhar, V. P. Zh. Obshch. Khim. 1989, 59, 909−
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K. J. Fluorine Chem. 1993, 61, 163−170. (c) Soloshonok, V. A. Curr.
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Containing Synthons; Soloshonok, V. A., Ed.; ACS Symposium Series
911; American Chemical Society: Washington DC, 2005; Chapter 35,
pp 611−635.
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(3) (a) Sewald, N.; Hollweck, W.; Mutze, K.; Schierlinger, C.;
Seymour, L. C.; Gaa, K.; Burger, K.; Koksch, B.; Jakubke, H. D. Amino
Acids 1995, 8, 187−194. (b) Koksch, B.; Ullmann, D.; Jakubke, H.-D.;
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Radics, G.; Vocks, A.; Arnold, K.; Arnhold, J.; Sieler, J.; Burger, K. J.
Pept. Sci. 2004, 10, 67−81. (d) Wehner, V.; Stilz, H.-U.; Osipov, S. N.;
Golubev, A. S.; Sieler, J.; Burger, K. Tetrahedron 2004, 60, 4295−4302.
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