Michael addition of N-sulfinyl metalloenamines to β-trifluoromethyl- α,β-unsaturated ester: An efficient access to chiral 4-trifluoromethyl-2-piperidones

Article abstract of DOI:10.1016/j.tet.2010.06.047

Michael addition of N-sulfinyl metalloenamines to β-trifluoromethyl- α,β-unsaturated ester was investigated. High diastereoselectivities and excellent yields were obtained. The conversion of addition products into 4-trifluoromethyl-2-piperidones asymmetrically, which involved a DIBAL-H reduction and the following cyclization, was illustrated. The absolute configuration of Michael addition products and 4-trifluoromethyl-2-piperidones were determined by X-ray crystallographic analysis and NOESY experiment, respectively. This method affords an efficient and asymmetric approach to a variety of chiral 4-trifluoromethyl-2-piperidones.

Full text of DOI:10.1016/j.tet.2010.06.047

Tetrahedron 66 (2010) 6864e6868
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Michael addition of N-sulfinyl metalloenamines to b-trifluoromethyl-a,b-
unsaturated ester: an efficient access to chiral 4-trifluoromethyl-2-piperidones
*
Fan Zhang, Zhen-Jiang Liu, Jin-Tao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2010
Received in revised form 14 June 2010
Accepted 21 June 2010
Available online 25 June 2010
Michael addition of N-sulfinyl metalloenamines to
b-trifluoromethyl-a,b-unsaturated ester was in-
vestigated. High diastereoselectivities and excellent yields were obtained. The conversion of addition
products into 4-trifluoromethyl-2-piperidones asymmetrically, which involved a DIBAL-H reduction
and the following cyclization, was illustrated. The absolute configuration of Michael addition products
and 4-trifluoromethyl-2-piperidones were determined by X-ray crystallographic analysis and NOESY
experiment, respectively. This method affords an efficient and asymmetric approach to a variety of chiral
4-trifluoromethyl-2-piperidones.
Keywords:
Michael addition
N-Sulfinyl metalloenamine
Ó 2010 Elsevier Ltd. All rights reserved.
b-Trifluoromethyl-a,b-unsaturated ester
Asymmetric
4-Trifluoromethyl-2-piperidone
1. Introduction
yields were obtained when LDA (lithium diisopropylamide) was
used as base and ZnBr2 was utilized as additive to improve the re-
Piperidones are of particular value due to their unique bio-
chemical properties.1 They also serve as precursors to the corre-
sponding piperidine ring, which is a ubiquitous moiety in many
alkaloid natural products and drug candidates.2,3a In this frame,
considerable efforts have been devoted to the synthesis of novel
substituted piperidones.3 Owing to the special properties of fluo-
rine, the introduction of trifluoromethyl group into piperidone ring
may modify the chemical and biological properties of the target
molecule.4 Despite approaches to non-fluoro substituted piper-
idones have been well developed, methodologies to introduce tri-
fluoromethyl group into piperidone rings were less explored
relatively.5
sults. Nevertheless, the substrates were largely limited due to the
competitive deprotonation of the Michael acceptor.
b
-Trifluoromethyl-a,b-unsaturated esters are easily available
fluorine-containing compounds and have been used in the synthesis
of many fluorine-containing compounds. Due to the electron with-
drawing effect of trifluoromethyl group, the C]C bond is greatly
activated and easy to undergo conjugate addition. On the other
hand, deprotonation under base conditions could be avoided due to
the trifluoromethyl substituent. Therefore, we envisioned that the
conjugate addition reaction of N-tert-butanesulfinyl metalloen-
amine could be improved when b-trifluoromethyl-a,b-unsaturated
esters are employed as acceptors. Herein we report a practical
As one of the most powerful chiral auxiliaries, N-tert-butane-
sulfinyl amine has been widely used in organic synthesis. Different
from N-tert-butanesulfinyl aldimine, except for being a good elec-
trophilic reagent, N-tert-butanesulfinyl ketimine can be deproto-
nated to form N-tert-sulfinyl metalloenamine and further react with
electrophilic reagents. For example, N-tert-butanesulfinyl metallo-
enamine has been employed in the addition to aldehydes,6a,b
trifluoromethyl ketones,6c and imines.6def
asymmetric carbonecarbon bond formation reaction of chiral N-
((R)-tert-butanesulfinyl) ketimines and
b-trifluoromethyl-a,b-un-
saturated ester, whose adducts could be easily converted into
4-trifluoromethyl-2-piperidones asymmetrically in excellent yields.
2. Results and discussion
We embarked on our investigation by examining the reaction
In 2005, Ellman et al. reported the conjugate addition of N-tert-
of N-((R)-tert-butanesulfinyl) ketimine 1a and
b-trifluoromethyl-a,
butanesulfinyl metalloenamines tounsaturated ketones.6g Moderate
b-unsaturated ester 2 (as shown in Table 1). When potassium tert-
butoxide and sodium ethoxide were used as bases, Michael adducts
were obtained in moderate yields but low diastereoseletivities
(entries 1 and 2). However, the use of LHMDS (Lithium bis(trime-
thylsilyl)amide) and LDA greatly improved both yields and
* Corresponding author. Tel.: þ86 21 54925188; fax: þ86 21 64166128; e-mail
address: jtliu@mail.sioc.ac.cn (J.-T. Liu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.047

F. Zhang et al. / Tetrahedron 66 (2010) 6864e6868
6865
Table 1
A possible stereochemical model was proposed to explain the ste-
reochemistry of the products. As shown in Figure 1, the reaction may
proceed via four possible pathways: A and D, which provide the
major diastereoisomer 3, and B and C, which provide the minor di-
astereoisomer 30. Model A apparently is most favored due to lest
stereohindrances, whilemodel B, C andD aredisfavoredowingtothe
repulsion between R and CF3, or the hindrance between the bulky
tert-butanesulfinyl group and the ester group. When R is isopropyl
(1g), the stereo repulsion between R and CF3 in model B could be
greatly diminished. Therefore, 1g may approach 2 via model A and B
at the same time. Accordingly, 3g and 3g0 could be obtained in
a similar ratio, just as Table 2, entry 7 shown.
Screening of reaction conditions
S
O
S
S
O
N
O
N
CF3
O
O
N
CF3 O
+
+
OEt
F3C
Ph
Ph
OEt
Ph
OEt
1a
3a
2
3a'
Entry Solvent Base (equiv) Temperature (ꢁC) Time (h) Yielda (%) 3a:3a0
b
1
2
3
4
5
6
7
CH3CN tBuOK (0.5) ꢀ30
1
3
1
1
1
1
1
72
63
80
93
91
89
90
70:30
Ndc
CH3CN EtONa (1.0) ꢀ30
THF
THF
THF
Et2O
LHMDS (1.2) ꢀ78
93:7
95:5
92:8
92:8
91:9
LDA (1.2)
LDA (1.2)
LDA (1.2)
ꢀ78
0
0
Toluene LDA (1.2)
0
a
b
c
Combined isolated yields of 3a and 3a0.
dr values were determined by 19F NMR.
Not determined.
S
O
EtO
S
O
OEt
S
R
N
N
O
N
CF3 O
O
O
R
H
R
H
CF3
OEt
H
H
F3C
H
3
H
diastereoselectivities (entries 3 and 4). Scrutinizing reaction tem-
perature and solvent (entries 5e7) found that excellent yield (93%)
and diastereoselectivity (95:5) were obtained at ꢀ78 ꢁC in THF
while LDA was employed (entry 4). Even though it was reported
that additives could improve the results through affecting the
reaction intermediates in related reactions,6 since excellent yields
have been achieved, we did not try to add any additives to the
reaction system but chose entry 4 as the model reaction condition.
Having established the optimized conditions of the reaction, we
turned to investigate its generality by probing an array of structurally
diverse N-(tert-butanesulfinyl) ketimines 1. As outlined in Table 2,
D
A
S
O
EtO
N
S
O
OEt
S
O
O
N
CF3 O
N
R
H
O
R
OEt
R
H
CF3
H
F3C
H
H
H
3'
B
C
Figure 1.
under similar conditions,
a range of aryl and heterocyclic
The absolute configuration of 3f was assigned to be (Rs,S) by
X-ray crystallographic analysis (Fig. 2),7 and the absolute configu-
rations of 3aee, 3g, 3h were deduced to be (Rs,S) accordingly.
N-((R)-tert-butanesulfinyl) ketimines, including tolyl, methoxy-
phenyl, chlorophenyl, nitrophenyl, and morphlino substituted sul-
finylketimines, were alluniformlytransferredintothecorresponding
Michael adducts in high to quantitative yields with high dr values
(entries1e6). Additionally, thisnew protocolwasalsoapplied toalkyl
substituted sulfinyl ketimines. The addition of the metalloenamine
derived from 1h exhibited excellent diastereoselectivityand afforded
the desired products in good yield (entry 8). However, even in good
yield, the addition of 1g and 2 gave the corresponding adduct with
low and converse diastereoselectivity (entry 7).
Thestericrepulsions betweensulfinylketimine1andunsaturated
ester 2 might play an important role in the diastereoselectivity.
Table 2
Michael addition of N-((R)-tert-butanesulfinyl) ketimines to 3-trifluoromethyl
acrylic ester
O
S
O
S
R
S
R
N
O
N
CF3
O
O
N
CF3 O
F3C
OEt
LDA
THF, -78oC
+
+
R
OEt
OEt
2
3
3'
1
b
Entry
R
Time (h)
Product
Yielda (%)
3aeg:3a0eg0
1
2
3
4
5
Ph (1a)
1
1
3
1
1
3aþ3a0
3bþ3b0
3cþ3c0
3dþ3d0
3eþ3e0
93
96
90
96
95
95:5
96:4
>95:5
96:4
>95:5
4-CH3C6H4 (1b)
4-CH3OC6H4 (1c)
4-ClC6H4 (1d)
4-NO2C6H4 (1e)
Figure 2. X-ray crystal structure of 3f.
6
1
3fþ3f0
96
95:5
N
O
The above Michael adducts are versatile multifunctional fluo-
rine containing building blocks. To demonstrate their synthetic
applications, we next performed the transformation of 3a to 4-
trifluoromethyl-2-piperidone 5a (Scheme 1). Reduction of 3a with
DIBAL-H at ꢀ78 ꢁC gave 4a in 90% yield with a dr value of >95:5.
7
8
iPr (1g)
1
1
3gþ3g0
3hþ3h0
91
90
43:57c
>95:5
tBu (1h)
a
Combined isolated yields of 3aeg and 3a0eg0.
b
c
Determined by 19F NMR.
Determined by 1H NMR.

6866
F. Zhang et al. / Tetrahedron 66 (2010) 6864e6868
Melting points were taken on a Melt-Temp apparatus and un-
O
corrected. IR spectra were obtained with a Nicolet AV-360 spec-
trophotometer. 1H NMR spectra were recorded in CDCl3 on a Bruker
AM-300 spectrometer (300 MHz) with TMS as an internal standard.
19F NMR spectra were taken on a Bruker AM-300 (282 MHz)
spectrometer using CFCl3 as an external standard. 13C NMR spectra
were recorded on Bruker DPX-400 (100.7 MHz) spectrometer. Mass
spectra were obtained on a Shimadzu LCMS-2010EV spectrometer.
High-resolution mass data were obtained on Bruker Daltonics, Inc.
APEXIII 7.0 TESLA FTMS spectrometer. Elemental analyses were
performed by this institute.
2
S
S
(1) HCl / Et2O
DIBAL-H
THF,-78oC
HN
O
O
N
CF3
O
HN
Ph
H
CF3
COOEt
4
(2) DABCO
95%
Ph
Ph
OEt
6
CF3
90%
3a
4a
5a
Scheme 1. Synthesis of 4-trifluoromethyl-2-piperidone 5a.
Then 4a was hydrolyzed in the presence of hydrochloride ether
solution at room temperature to remove tert-butanesulfinyl group.
Without further purification, the crude hydrolysis product un-
derwent cyclization easily under 1.0 equiv DABCO (1,4-diazabicyclo
[2.2.2]octane) to give 5a in satisfactory results (95% yield and >95:5
dr value).
The stereochemistry of 5a was determined by NOESY experi-
ment (Fig. 3). While compound (4S,5S,6S)-5-nitro-6-phenyl-4-
trifluoromethyl-piperidin-2-one (I) showed strong correlation
between Ha and Hb in NOESY experiment,5a no correlation be-
tween the corresponding hydrogens in 5a (Hc and Hd) was
detected, revealing that Hc and Hd were in the trans configuration.
Since the absolute configuration of C4 in 5a is S based on the
previously established configuration in the Michael addition step,
the absolute configuration of C6 in 5a was assigned to be R ac-
cordingly. As far as 4a was concerned, its absolute configuration
was determined to be (3S,5R) according to 5a.
4.2. Typical procedure
4.2.1. Typical procedure for the Michael addition of N-sulfinyl met-
alloenamine. Into a dried 20 mL Schlenk flask containing a mixture
of N-(tert-butanesulfinyl) ketimine (R)-1a (92 mg, 0.4 mmol) and 2
(33 mg, 0.2 mmol) in THF (5 mL) was added LDA (0.5 mmol, 0.5 mL,
1.0 M in THF) at ꢀ78 ꢁC under N2 atmosphere. After stirring for 1 h
at this temperature, the reaction was quenched with saturated
aqueous ammonium chloride (2.5 mL). After warming up to room
temperature, the resulting mixture was extracted with dichloro-
methane (30 mLꢂ3) and washed with saturated aqueous NaCl so-
lution (20 mLꢂ2). The combined organic layer was dried over
anhydrous sodium sulfate. Filtration and evaporation of the volatile
solvents under vacuum afforded the crude product, which was
purified by flash column chromatography on silica gel (pet. ether/
EtOAc¼9/1) to give 3.
NO2
CF3
CF3
4
4
H
4.2.1.1. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-phenyl-3-(tri-
H
N
H
N
6
6
Hd
Ph
fluoromethyl)pentanoate (3a). Yellowish solid, yield 93%; mp
20
48e49 ꢁC; [
a
]
ꢀ23.4 (c 1.01, CHCl3); FTIR (KBr, cmꢀ1):
n 2984,
Hc
Ha
D
O
1739, 1693, 1606, 1574, 1449, 1159, 1117, 1072, 1026; 1H NMR
O
Hb
Ph
(CDCl3):
d
7.83e7.81 (m, 2H), 7.48e7.45 (m, 3H), 4.12 (q, J¼6.9 Hz,
2H), 3.85e3.83 (m, 1H), 3.47e3.44 (m, 1H), 3.18e3.15 (m, 1H),
2.74e2.56 (m, 2H), 1.32 (s, 9H), 1.23 (t, J¼6.9 Hz, 3H); 19F NMR
I
(CDCl3):
d
ꢀ71.85 (d, J¼5.4 Hz, 3F); ESI MS (m/z): 392 (Mþþ1).
( ) (4S,5S,6S)-5-nitro-6-
phenyl-4-trifluoromethyl-
piperidin-2-one
5a
Anal. Calcd for C18H24F3NO3S: C, 55.23; H, 6.18; N, 3.58. Found: C,
55.29; H, 6.18; N, 3.49.
Figure 3. Absolute configuration assignment of 5a.
4.2.1.2. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-p-tolyl-3-(tri-
20
fluoromethyl)pentanoate (3b). Yellowish viscous oil, yield 96%; [a]
D
ꢀ15.8 (c 1.18, CHCl3); FTIR (KBr, cmꢀ1):
n
2983,1740,1596,1566,1449,
7.73e7.71 (m, 2H),
3. Conclusion
1269, 1158, 1116, 1074, 1017; 1H NMR (CDCl3):
d
7.27e7.24(m, 2H),4.11(q,J¼6.9 Hz, 2H),3.80e3. 78(m,1H), 3.41e3.40
In conclusion, we have developed a practical asymmetric car-
bonecarbon bond formation method, which provides an efficient
stereoseletive approach to the synthesis of 4-trifluoromethyl-2-
piperidones. In the presence of LDA, chiral N-((R)-tert-butane-
(m,1H), 3.20e3.18 (m,1H), 2.73e2.55 (m, 2H), 2.40 (s, 3H),1.31 (s, 9H),
1.23 (t, J¼6.9 Hz, 3H); 19F NMR (CDCl3):
ꢀ71.20 (d, J¼5.9 Hz, 3F); ESI
d
MS (m/z):406(Mþþ1). Anal. CalcdforC19H26F3NO3S:C, 56.25;H, 6.46;
N, 3.45. Found: C, 56.56; H, 6.60; N, 3.36.
sulfinyl) ketimines reacted with b-trifluoromethyl-a,b-unsaturated
ester readily to give the corresponding Michael addition adducts in
excellent yields with high diastereoselectivites. Further
transformation of the Michael adducts, which involves a DIBAL-H
4.2.1.3. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-(4-methoxy-
phenyl)-3-(trifluoromethyl)pentanoate (3c). Yellowish viscous oil,
yield 90%; [
a
]
20 ꢀ15.9 (c 0.88, CHCl3); FTIR (KBr, cmꢀ1):
n
2987, 2237,
reduction and
a base promoted cyclization, provides 4-tri-
D
1740, 1613, 1438, 1372, 1248, 1141; 1H NMR (CDCl3):
d 7.83e7.81 (m,
fluoromethyl-2-piperidone asymmetrically in excellent yield.
2H), 6.97e6.94 (m, 2H), 4.11 (q, J¼6.9 Hz, 2H), 3.86 (s, 3H), 3. 87e3.75
(m, 1H), 3.39e3.21 (m, 2H), 2.72e2.56 (m, 2H), 1.31 (s, 9H), 1.23 (t,
4. Experimental
4.1. General
J¼6.9 Hz, 3H); 19F NMR (CDCl3):
d
ꢀ71.88 (d, J¼5.9 Hz, 3F); ESI MS
(m/z): 422 (Mþþ1). Anal. Calcd for C19H26F3NO4S: C, 54.14; H, 6.22;
N, 3.32. Found: C, 54.39; H, 6.16; N, 3.21.
All manipulations were performed under a nitrogen atmosphere
using standard Schlenk techniques. Solvents were freshly distilled
using general method to remove water. Column chromatography
was performed on silica gel employing petroleum ethereethyl ac-
etate mixture as eluant. Compounds 1aeh, and 2 were prepared
following literature procedures.8
4.2.1.4. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-(4-chloroph-
enyl)-3-(trifluoromethyl)pentanoate (3d). Yellowish viscous oil,
yield 96%; [
a]
20 ꢀ3.7 (c 1.00, CHCl3); FTIR (KBr, cmꢀ1):
n 2984, 1737,
D
1607, 1589, 1491, 1423, 1399, 1369, 1268, 1159, 1118, 1095, 1012; 1H
NMR (CDCl3):
d 7.80e7.77 (m, 2H), 7.45e7.41 (m, 2H), 4.13 (q,
J¼6.9 Hz, 2H), 3.90e3.82 (m, 1H), 3.40e3.34 (m, 1H), 3.12e3.10 (m,

F. Zhang et al. / Tetrahedron 66 (2010) 6864e6868
6867
1H), 2.75e2.55 (m, 2H), 1.31 (s, 9H), 1.25 (t, J¼6.9 Hz, 3H); 13C NMR
(q, J¼6.9 Hz, 2H), 3.78e3.75 (m, 1H), 2.83e2.81 (m, 1H), 2.67e2.60
(m, 1H), 2.43e2.35 (m, 1H), 2.16e2.07 (m, 1H), 2.01e1.94 (m, 1H),
(CDCl3): d 174.4, 170.6, 137.9, 135.8, 129.0, 125.6, 61.2, 58.3, 38.8 (m),
32.9, 30.2, 22.7, 14.0; 19F NMR (CDCl3):
d
ꢀ71.09 (d, J¼5.3 Hz, 3F);
1.29e1.23 (m, 12H); 13C NMR (CDCl3):
d 170.8, 141.5, 129.0, 128.3,
ESI MS (m/z): 426 (Mþþ1); HRMS calcd for C18H23ClF3NNaO3S
[MþNaþ]: 448.0932; Found: 448.0937.
126.9, 61.2, 56.9, 56.2, 36.4 (m), 33.4, 22.6, 14.1; 19F NMR (CDCl3):
d
ꢀ71.70 (d, J¼8.7 Hz, 3F); ESI MS (m/z): 394 (Mþþ1); HRMS calcd
for C18H27F3NO3S [Mþþ1]: 394.1658; Found: 394.1671.
4.2.1.5. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-(4-nitrophen-
yl)-3-(trifluoromethyl)pentanoate (3e). Yellowish viscous oil, yield
4.2.3. Synthesis of 5a. Into a solution of 4a (30 mg, 0.08 mmol) in
CH3OH (2 mL) was added saturated HCl/Et2O solution (2 mL) slowly
at room temperature. After stirring for 0.5 h at room temperature,
CH2Cl2 (30 mL) was added. The mixture was washed with aqueous
sodium hydroxide (10 mLꢂ3, 1 N). Concentrating the combined
organic layer under vacuum afforded crude hydrolysis product.
Without further purification, this crude product was dissolved into
Et2O (2 mL). DABCO (1,4-diazabicyclo[2.2.2]octane, 8.5 mg,
0.08 mmol) was added at room temperature. After stirring at this
temperature for 1 h, the reaction mixture was concentrating under
vacuum. Pure 5a was obtained via flash column chromatography on
silica gel (pet. ether/EtOAc¼2/1) in the yield of 95%.
20
95%; [
a
]
þ28.9 (c 0.88, CHCl3); FTIR (KBr, cmꢀ1):
n 2983, 2930,
D
1737, 1599, 1526, 1349, 1268, 1160, 1118; 1H NMR (CDCl3):
d
8.33e8.30 (m, 2H), 8.03e8.00 (m, 2H), 4.16 (q, J¼6.6 Hz, 2H),
4.02e4.00 (m, 1H), 3.47e3.40 (m, 1H), 3.04e3.01 (m, 1H), 2.78e2.57
(m, 2H), 1.33 (s, 9H), 1.25 (t, J¼6.6 Hz, 3H); 13C NMR (CDCl3):
d 173.5,
170.7, 149.4, 142.8, 128.5, 123.9, 61.4, 58.9, 38.7 (m), 32.8, 30.3, 22.8,
14.3; 19F NMR (CDCl3):
d
ꢀ70.90 (d, J¼5.3 Hz, 3F); ESI MS (m/z): 437
(Mþþ1); HRMS calcd for C18H23F3N2NaO5S [MþNaþ]: 459.1170.
Found: 459.1180.
4.2.1.6. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-5-morpholino-
3-(trifluoromethyl)pentanoate (3f). Colorless crystal, yield 96%; mp
20
82e83 ꢁC; [
a]
ꢀ117.3 (c 0.95, CHCl3); FTIR (KBr, cmꢀ1):
n
2982,
4.2.3.1. (4S,6R)-6-Phenyl-4-(trifluoromethyl)piperidin-2-one
D
1737, 1540, 1481, 1359, 1301, 1256, 1207, 1113, 1057; 1H NMR
(5a). Colorless solid, yield 95%; mp 153e154 ꢁC; [ 20 64.1 (c 0.23,
a]
D
(CDCl3):
d
4.13 (q, J¼7.5 Hz, 2H), 3.77e3.68 (m, 5H), 3.57e3.39 (m,
CHCl3); FTIR (KBr, cmꢀ1):
1113, 1060; 1H NMR (CDCl3):
4.56e4.51 (m, 1H), 2.76e2.71 (m, 2H), 2.54e2.43 (m, 1H),
n
3214, 2926, 1625, 1474, 1402, 1270, 1175,
7.41e7.26 (m, 5H), 5.96 (br, 1H),
3H), 3.18e3.16 (m, 1H), 2.90e2.83 (m, 1H), 2.70e2.62 (m, 1H),
1.43e1.33 (m, 1H), 1.26 (t, J¼7.5 Hz, 3H), 1.19 (s, 9H); 19F NMR
d
(CDCl3):
d
ꢀ72.03 (d, J¼9.3 Hz, 3F); ESI MS (m/z): 401 (Mþþ1). Anal.
2.34e2.29 (m,1H),1.78e1.64 (m, 1H); 19F NMR (CDCl3):
d
ꢀ74.04 (d,
Calcd for C16H27F3N2O4S: C, 47.99; H, 6.80; N, 7.00. Found: C, 47.96;
H, 6.67; N, 6.95.
J¼8.7 Hz, 3F); ESI MS (m/z): 244 (Mþþ1). Anal. Calcd for
C12H12F3NO: C, 59.26; H, 4.97; N, 5.76. Found: C, 59.21; H, 5.17; N,
5.65.
4.2.1.7. Ethyl 5-((R)-tert-butylsulfinylimino)-6-methyl-3-(trifluoro-
methyl)heptanoate (3g and 3g0). Yellow liquid, yield 91%; FTIR (KBr,
Acknowledgements
cmꢀ1): 2976,1741,1625,1365,1265,1165,1115,1077;1HNMR(CDCl3):
n
d
4.15 (q, J¼7.2 Hz, 1.14H), 3.86e3.65 (m, 0.57H), 3.47 (q, J¼7.2 Hz,
We thank the National Natural Science Foundation of China for
financial support (No. 20872166).
.86H), 3.35e3.09 (m, 0.57H), 3.03e2.87 (m, 0.43H), 2. 83e2.45 (m,
3.43H),1.29e1.13 (m,19H); 19FNMR(CDCl3):
d
ꢀ71.4 (s,1.29F), ꢀ71.6(s,
1.71F); ESI MS (m/z): 358 (Mþþ1). Anal. Calcd for C15H26F3NO3S: C,
Supplementary data
50.40; H, 7.33; N, 3.92. Found: C, 50.48; H, 7.35; N, 3.98.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.06.047.
4.2.1.8. (S)-Ethyl 5-((R)-tert-butanesulfinylimino)-6,6-dimethyl-
20
3-trifluoromethyl)heptanoate (3h). Yellow liquid, yield 90%; [a]
D
ꢀ100.1 (c 0.85, CHCl3); FTIR (KBr, cmꢀ1):
n 2966, 2872, 1738, 1611,
1478, 1393, 1367, 1299, 1267, 1220, 1164, 1111, 1073, 1029; 1H NMR
References and notes
(CDCl3):
1H), 2.97e2.85 (m, 1H), 2.70e2.49 (m, 2H), 1.35e1.14 (m, 21H); 13C
NMR (CDCl3):
187.1, 170.7, 127.1 (q, J¼280.1 Hz), 61.1, 57.7, 44.0,
d
4.15 (q, J¼6.9 Hz, 2H), 3.67e3.46 (m, 1H), 3.27e3.21 (m,
1. For example, see: (a) Kaiser, A.; Ulmer, D.; Goebel, T.; Holzgrabe, U.; Saeftel, M.;
Hoerauf, A. Mini-Rev. Med. Chem. 2006, 6, 1231e1241; (b) Lopez, O.; Bols, M.
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Med. Chem. 2003, 46, 2467e2473 and references therein.
d
38.1 (q, 26.9 Hz), 33.0, 29.6, 28.5, 22.5, 14.0; 19F NMR (CDCl3):
d
ꢀ71.72 (d, J¼8.2 Hz, 3F); ESI MS (m/z): 372 (Mþþ1); HRMS calcd
for C16H28F3NO3S [MþHþ]: 372.1815. Found: 372.1810.
4.2.2. Reduction of 3a. DIBAL-H (0.7 mL,1.0 M in THF) was added to
a solution of 3a (90 mg, 0.23 mmol) in THF at ꢀ78 ꢁC under N2
atmosphere. After stirring for 1 h at this temperature, the reaction
was quenched with saturated aqueous ammonium chloride
(2.5 mL). The resulting mixture was then allowed to return to room
temperature and aqueous hydrochloric acid (2.5 mL, 1.0 M) was
added dropwise. The mixture was extracted with dichloromethane
(30 mLꢂ3) and washed with saturated aqueous NaCl solution
(20 mLꢂ2). The combined organic layer was dried over anhydrous
sodium sulfate. Filtration and evaporation of the solvents afforded
the crude product, which was purified by flash column chroma-
tography on silica gel (pet. ether/EtOAc¼3/1) to give 4a.
2. (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701e1729; (b) Rodriguez, J. Stud. Nat.
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Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679e3681; (f) Davis, F.; Fang, T.; Chao, B.;
Burns, D. M. Synthesis 2000, 2106e2112.
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NY, 1994; (d) Organofluorine Compounds in Medicinal Chemistry and Bio-
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Amsterdam, 1993.
5. (a) Ruano, J. L. G.; Haro, T.; Singh, R.; Cid, M. B. J. Org. Chem. 2008, 73, 1150e1153;
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G. A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593e594; (e)
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4.2.2.1. (3S,5R)-Ethyl 5-((R)-tert-sulfinylamido)-5-phenyl-3-(trifl-
uoromethyl)pentanoate (4a). Yellowish viscous oil, yield 90%; FTIR
(KBr, cmꢀ1):
1029; 1H NMR (CDCl3):
n
3191, 2982, 1740, 1655, 1456, 1366, 1269, 1158, 1118,
7.35e7.26 (m, 5H), 4.50e4.45 (m, 1H), 4.17
d

6868
F. Zhang et al. / Tetrahedron 66 (2010) 6864e6868
6. (a) Kochi, T.;Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,124, 6518e6519; (b) Kochi,
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7. Crystal data: C16H27F3N2O4S; M¼400.46; Tetragonal, P4(1); a¼13.5525(11) Å,
data for the structures of 3f reported in this paper, have been deposited with the
Cambridge Crystallographic Data Centre (CCDC 756866). Copies of the data can
be obtained, free of charge, on application to the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, United Kingdom (Fax: 44 1223 336033 or email: deposit@
ccdc.cam.uk).
8. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem.
1999, 64, 1278e1284; (b) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126,
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980e982.
b¼13.5525(11) Å, c¼11.1134(13) Å;
a
¼90.00,
b¼90.00,
g
¼90.00, V¼2041.2(3) Å3;
Z¼4; 4545 reflections; Rint¼0.0887; R1¼0.0511 and wR2¼0.1047. Crystallographic