A facile process for the asymmetric synthesis of β-trifluoromethylated β-amino ketones via addition of ketone enolates to sulfinylimine

Article abstract of DOI:10.1039/c0ob00586j

An efficient method for the asymmetric synthesis of β- trifluoromethylated β-amino ketones via addition of ketone-derivative enolates to trifluoromethylated sulfinylimine has been developed, with good chemical yields and excellent diastereoselectivities.

Full text of DOI:10.1039/c0ob00586j

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PAPER
A facile process for the asymmetric synthesis of b-trifluoromethylated
b-amino ketones via addition of ketone enolates to sulfinylimine†‡
Haibo Mei,a Yiwen Xiong,a Jianlin Han*a and Yi Pan*a,b
Received 16th August 2010, Accepted 11th November 2010
DOI: 10.1039/c0ob00586j
An efficient method for the asymmetric synthesis of b-trifluoromethylated b-amino ketones via addition
of ketone-derivative enolates to trifluoromethylated sulfinylimine has been developed, with good
chemical yields and excellent diastereoselectivities. This practical method was also proved to be suitable
for large-scale preparation.
N-tert-butylsulfinylimine with good yields and excellent diastere-
oselectivities (Scheme 1).
Introduction
b-Amino ketones represent an important class of compounds in
modern organic and medicinal chemistry because of their diverse
biological properties.1 They are also useful building blocks for
the synthesis of various pharmaceuticals and biologically active
natural products.2 They can be converted into the corresponding
Scheme 1 Addition of ketone-derivative enolates to sulfinylimine.
g-amino alcohols that are also biologically important molecules
and can serve as chiral ligands for asymmetric synthesis.3 The
fluorinated molecules often show some significant changes in
their chemical, physical and biological properties.4 Consequently,
fluorinated b-amino carbonyl compounds, especially the b-
trifluoromethylated b-amino ketones have been attracting many
attentions in the field of biochemistry and pharmacology.5,6
However, there were only a few methods reported for the synthesis
of chiral b-trifluoromethylated b-amino ketones until now,7–9
which were focused on the organocatalytic asymmetric synthesis.8
So the development of efficient and facile methods for synthesis
of chiral b-trifluoromethylated b-amino ketones becomes great
challenges now.
Mannich-type reaction of imines or their precursors have
been the most widespread synthetic routes to b-amino car-
bonyl compounds.10 Besides, N-tert-butanesulfinamides have been
proved to be highly efficient chiral auxiliaries in the synthesis
of various active chiral amines by the virtue of their excellent
diastereocontrol and easy cleavage.11 Herein, we reported, for the
first time, an auxiliary-based process for the asymmetric synthesis
of chiral b-trifluoromethylated b-amino ketones, which proceeds
through the addition of ketone enolates to trifluoromethylated
Results and discussion
Base on the previous studies on the synthesis of b-amino ketones,10
and the reported examples with N-tert-butylsulfinylimine as
starting material,6b,6c,12 the initial reaction condition was focused
on the using of sulfinylimine 1 with 1.5 equiv of acetophenone in
the presence of LDA with THF as solvent at -78 ◦C. The reaction
proceeded smoothly, affording the desired b-trifluoromethyl-b-
amino ketone 3a in 72% yield with 96 : 4 dr after 1 h (entry 1,
Table 1). Further optimizing the reaction conditions was then
carried out to improve both the yields and the diastereoselectivities
of the reaction. The screening of the reaction time demonstrated
that this transformation could complete in 2 h (entry 2), and
extending reaction time resulted in a decrease in both yield and
diastereoselectivity (entry 3). Temperature was founded to be
crucial for this reaction. Elevating reaction temperature brought
an obvious increase in the yields (up to 90%), but caused dramatic
decrease in diastereoselectivities (entries 4–6). The investigation of
various solvents was shown in entries 7–10, and THF was found
to be the best choice. Notably, the best diastereoselectivity (>99 : 1
dr) was obtained with CH2Cl2 as solvent, but along with really
lower yield (43%, entry 8). Furthermore, the loading amount of
acetophenone enolate 2a was examined and it was found that
the use of 1.7 equiv of 2a gave the highest yield and excellent
diastereoselectivity (84% yield and 99 : 1 dr, entry 12).
aSchool of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, China. E-mail: hanjl@nju.edu.cn; Fax: +86-25-83592846;
Tel: +86-25-83593153
bState of Key Laboratory of Coordination, Nanjing University, Nanjing,
210093, China. E-mail: yipan@nju.edu.cn
† This publication is part of the web themed issue on fluorine chemistry.
‡ Electronic supplementary information (ESI) available: General experi-
After obtaining the optimized reaction conditions, varieties of
ketones were used as substrates to investigate the scope of the
current system (Table 2). As shown in Table 2, almost all of
the tested substrates worked well in this reaction. Generally, the
1
mental procedures, spectral data and copies of H NMR and 13C NMR
spectra. CCDC reference number 787957. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ob00586j
1402 | Org. Biomol. Chem., 2011, 9, 1402–1406
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Table 1 Optimization of reaction conditionsa
Good yield (74%) and excellent diastereoselectivity (95 : 5 dr)
were obtained, even the loading amount of sulfinylimine 1 was
increased from 0.10 g to 1.01 g in the reaction (Scheme 2). To our
delight, only slight decrease in the yield and diastereoselectivity
were detected, comparing to the 0.10 g scale reaction. This result
allows the large scale preparation of chiral b-trifluoromethylated
b-amino ketones.14
Entry 2a (equiv) Solvent T/◦C Time (h) Yield (%)b drc
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.1
1.7
THF
THF
THF
THF
THF
THF
Toluene -78
CH2Cl2 -78
Hexane -78
Et2O
THF
THF
-78
-78
-78
-41
-22
0
1
2
3
2
2
2
2
2
2
2
2
2
72
79
74
76
90
83
74
43
57
70
67
84
96 : 4
95 : 5
91 : 9
83 : 17
89 : 11
83 : 17
83 : 17
>99 : 1
84 : 16
92 : 8
Scheme 2 Large scale application of the reaction.
9
10
11
12
-78
-78
-78
98 : 2
99 : 1
The structure of these b-trifluoromethylated b-amino ketones
has been confirmed by the X-ray diffraction analysis of 3a
(Fig. 1). As shown in Fig. 1, the absolute configuration of the
newly generated chiral center in this process is S. The absolute
configurations of other corresponding products were assigned by
analogy.
a Reaction conditions: sulfinylimine (0.5 mmol), LDA (1.1 equiv of ketone),
solvent (5 mL). b Isolated yields. c Determined by 1H NMR analysis.
Table 2 Scope of ketones for the asymmetric additiona
Entry
R
Product
Yield (%)b
drc
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
84
81
84
74
70
66
73
68
87
76
42
61
99 : 1
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-PhC6H4
4-EtC6H4
4-EtOC6H4
2-Naphthyl
2-Furyl
>99 : 1
>99 : 1
>99 : 1
86 : 14
74 : 26
97 : 3
97 : 3
9
>99 : 1
88 : 12
>99 : 1
93 : 7
10
11
12
3j
3k
3l
t-Bu
a Reaction conditions: sulfinylimine (0.5 mmol), ketone (0.85 mmol), LDA
(0.94 mmol), solvent (5 mL). b Isolated yields. c Determined by 1H NMR
analysis.
Fig. 1 ORTEP diagram showing of compound 3a.
Based on the absolute configuration detected by X-ray diffrac-
tion analysis, the asymmetric addition of ketone enolates was
suggested to proceed via a non-chelated transition state model.15
In this model, enolates preferably added to the imine from the less
hindered face to afford (Ss,S)-3a as major diastereomer (Fig. 2).
ketones with electron-donating substituent on the aromatic ring
could participate better in the reaction, resulting in the desired
products with higher yields (81%–87%) and diastereoselectivities
(>99 : 1 dr) (entries 2, 3 and 9). However, the substrates with
electron-withdrawing substituent on the aromatic ring usually
gave slightly lower yields and diastereoselectivities (entries 5–7),
except for the case of p-fluoro acetophenone enolate 2d (entry 4).
Notably, 2-naphthyl ketone enolate 2j was also well tolerated in
this reaction with good yield (76%) and good diastereoselectivity
(88 : 12) (entry 10). More significantly, the reaction from the
substrate with heteroaromatic ring also proceeded well, affording
the desired product with high diastereoselectivity (>99 : 1) (entry
11). It was found that the aliphatic ketone also worked well as
substrate in the current system (entry 12),13 and the reaction from
pinacolone gave 61% chemical yield and good diastereoselectivity.
The current system was found to tolerate broad scope of
the ketone substrates. Furthermore, it has also been proved to
be efficient on large scale preparation (gram-scale or greater).
Fig. 2 Proposed mechanism for the asymmetric addition.
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The N-tert-butylsulfinyl group can serve as not only an efficient
chiral auxiliary for the asymmetric synthesis of b-amino ketones,
but also an amine protecting group.11 It can be readily cleaved by
treatment with aqueous HCl in methanol under mild condition
(Scheme 3).12a,16 Free b-trifluoromethylated b-amino ketone 4 was
obtained in high isolated yield of 90%. The resulting chirality of
the b-carbon center was proved again to be S by comparison of
the optical rotation with the literature value.7
(d, J = 8.7 Hz, 1 H), 3.75 (dd, J = 9.6, 17.7 Hz, 1 H), 3.31 (dd,
J = 3.3, 17.7 Hz, 1 H), 1.15 (s, 9 H). 13C NMR (CDCl3, 75 MHz):
d = 194.9, 136.2, 133.8, 128.8, 128.2, 123.5 (q, J = 280.0 Hz),
56.9, 53.8 (q, J = 30.2 Hz), 38.0, 22.3. 19F NMR (CDCl3, 376
MHz): d = -74.5. IR (KBr): n = 3277, 2966, 2925, 1685, 1292,
1269, 1168, 1121, 1060, 690, 753 cm-1. HRMS [M+Na+]: calcd for
C14H18O2SNF3Na: 344.0903, found: 344.0893.
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-oxo-4-p-tolylbutan-2-
yl)propane-2-sulfinamide (3b)
◦
Colorless solid, yield 81%, mp 148–150 C, [a]2D5 +36.1 (c 0.17,
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.87 (d, J = 6.9 Hz,
2 H), 7.30 (d, J = 5.7 Hz, 2 H), 4.51–4.60 (m, 1 H), 4.07 (d, J =
26.7 Hz, 1 H), 3.71 (dd, J = 9.3, 17.4 Hz, 1 H), 3.29 (dd, J = 2.7,
17.7 Hz, 1 H), 2.43 (d, J = 1.2 Hz, 3 H), 1.16 (d, J = 2.4 Hz, 9 H).
13C NMR (CDCl3, 75 MHz): d = 194.4, 144.8, 133.8, 129.5, 128.3,
123.5 (q, J = 280.0 Hz), 56.9, 53.9 (q, J = 30.8 Hz), 37.9, 22.3, 21.7.
19F NMR (CDCl3, 376 MHz): d = -74.5. IR (KBr): n = 3265, 2962,
2924, 1683, 1610, 1345, 1292, 1270, 1167, 1118, 1060, 804 cm-1.
HRMS [M+Na+]: calcd for C15H20O2SNF3Na: 358.1059, found:
358.1048.
Scheme 3 Conversion of 3a to free b-trifluoromethylated b-amino ketone.
Experimental section
General information
All imine addition reactions were performed in oven-dried vials
under N2 atmosphere. Solvent THF was dried and distilled prior
to use. Sulfinylimine 1 was obtained from TOSOH F-TECH,
INC. LDA (2 M in THF) was from Aldrich. These and other
chemicals were used as obtained from commercial sources without
further purification. Flash chromatography was performed using
silica gel 60 (200–300 mesh). Thin layer chromatography was
carried out on silica gel 60 F-254 TLC plates of 20 cm ¥
20 cm. Melting points are uncorrected. IR spectra were collected
on Bruker Vector 22 in KBr pellets. Values of optical rotation
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-(4-methoxyphenyl)-4-
oxobutan-2-yl)propane-2-sulfinamide (3c)
White solid, yield 84%, mp 99–100 ◦C, [a]D25 +87.5 (c 0.17, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.92–7.97 (m, 2 H), 6.94–6.98
(m, 2 H), 4.50–4.60 (m, 1 H), 4.12 (d, J = 6.3 Hz, 1 H), 3.88 (s, 3
H), 3.69 (dd, J = 9.6, 17.4 Hz, 1 H), 3.26 (dd, J = 3.3, 17.4 Hz, 1 H),
1.16 (s, 9 H). 13C NMR (CDCl3, 75 MHz): d = 193.3, 164.1, 130.5,
129.3, 123.5 (q, J = 279.6 Hz), 114.0, 56.9, 55.5, 54.0 (q, J = 30.9
Hz), 37.6, 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.5. IR (KBr):
n = 3265, 2963, 2927, 1678, 1603, 1369, 1291, 1267, 1168, 1121,
1058, 820 cm-1. HRMS [M+Na+]: calcd for C15H20O3SNF3Na:
374.1008, found: 374.1004.
1
were measured on Rudolph Automatic Polarimeter A21101. H
and 13C NMR (TMS used as internal standard) spectra were
recorded with a Bruker ARX 300 spectrometer and a Bruker
ARX 500 spectrometer.19F NMR spectra (referenced to external
CF3COOH) were recorded wirh a Bruker ARX 400 spectrometer.
High resolution mass spectra for all the new compounds were done
by Micromass Q-Tof instrument (ESI‡).
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-
oxobutan-2-yl)propane-2-sulfinamide (3d)
Typical procedure for asymmetric addition of sulfinylimine
◦
Colorless solid, yield 74%, mp 149–151 C, [a]2D5 +99.0 (c 0.19,
Into an oven-dried reaction vial flushed with N2 were taken ketone
(0.85 mmol) and anhydrous THF (3.0 mL). The reaction vial was
cooled to -78 ◦C and LDA (2 M in THF, 0.47 mL) was added
dropwise with stirring. After 40 min at -78 ◦C, sulfinylimine 1 (0.5
mmol) dissolved in anhydrous THF (2.0 mL) was added dropwise.
Stirring was continued at -78 ◦C for 2 h, then the reaction was
quenched with saturated NH4Cl (3.0 mL), followed by H2O (5.0
mL) and the mixture was brought to room temperature. The
organic layer was taken and the aqueous layer was extracted with
EtOAc (2 ¥ 20 mL). The combined organic layers were dried with
anhydrous Na2SO4, filtered and the solvent was removed to give
the crude product, which was purified by TLC plate (hexane–
EtOAc, 2 : 1).
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.96–8.03 (m, 2 H),
7.11–7.19 (m, 2 H), 4.49–4.59 (m, 1 H), 4.15 (d, J = 7.5 Hz, 1 H),
3.76 (dd, J = 9.3, 17.7 Hz, 1 H), 3.29 (dd, J = 3.3, 17.7 Hz, 1 H),
1.16 (s, 9 H). 13C NMR (CDCl3, 75 MHz): d = 193.3, 167.8, 164.5,
131.0 (d, J = 9.5 Hz), 123.4 (q, J = 280.1 Hz), 116.1 (d, J = 21.9
Hz), 56.9, 53.6 (q, J = 30.5 Hz), 37.9, 22.3. 19F NMR (CDCl3, 376
MHz): d = -74.4, -103.8. IR (KBr): n = 3271, 2966, 2926, 2871,
1687, 1599, 1293, 1271, 1233, 1169, 1121, 1061, 821 cm-1. HRMS
[M+Na+]: calcd for C14H17O2SNF4Na: 362.0808, found: 362.0810.
(S)-N-((S)-4-(4-Chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-
methylpropane-2-sulfinamide (3e)
◦
Colorless solid, yield 70%, mp 147–148 C, [a]2D5 +95.8 (c 0.14,
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-oxo-4-phenylbutan-2-
yl)propane-2-sulfinamide (3a)
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.89–7.93 (m, 2 H),
7.44–7.49 (m, 2 H), 4.49–4.59 (m, 1 H), 4.06 (d, J = 8.4 Hz, 1 H),
3.77 (dd, J = 9.9, 17.7 Hz, 1 H), 3.30 (dd, J = 3.0, 18 Hz, 1 H),
1.17 (s, 9 H). 13C NMR (CDCl3, 75 MHz): d = 193.7, 140.4, 134.5,
129.6, 129.2, 123.4 (q, J = 279.0 Hz), 56.9, 53.5 (q, J = 30.8 Hz),
◦
Colorless solid, yield 84%, mp 146–148 C, [a]2D5 +47.2 (c 0.46,
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.93–7.97 (m, 2 H),
7.56–7.62 (m, 1 H), 7.45–7.50 (m, 2 H), 4.49–4.63 (m, 1 H), 4.25
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38.0, 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.3. IR (KBr):
n = 3267, 2964, 2923, 1686, 1592, 1290, 1270, 1176, 1120, 1095,
1060, 813 cm-1. HRMS [M+Na+]: calcd for C14H17O2SNF3ClNa:
378.0513, found: 378.0498.
HRMS [M+Na+]: calcd for C16H22O3SNF3Na: 388.1165, found:
388.1169.
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-(naphthalen-2-yl)-4-
oxobutan-2-yl)propane-2-sulfinamide (3j)
(S)-N-((S)-4-(4-Bromophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-
methylpropane-2-sulfinamide (3f)
◦
Colorless solid, yield 76%, mp 140–143 C, [a]2D5 +34.2 (c 0.08,
CHCl3). 1H NMR (CDCl3, 300 MHz): d = 8.49 (s, 1 H), 7.98–8.05
(m, 2 H), 7.94 (t, J = 8.7 Hz, 2 H), 7.56–7.67 (m, 2 H), 4.56–4.72
(m, 1 H), 4.01 (s, 1 H), 3.92 (dd, J = 9.6, 17.7 Hz, 1 H), 3.48 (dd,
J = 3.3, 17.7 Hz, 1 H), 1.18 (s, 9 H). 13C NMR (CDCl3, 75 MHz):
d = 194.7, 135.9, 133.6, 132.5, 130.1, 129.7, 128.9, 128.8, 127.8,
127.0, 123.6, 123.5 (d, J = 280.7 Hz), 56.9, 53.9 (q, J = 31.5 Hz),
38.2, 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.3. IR (KBr): n =
3260, 2970, 2936, 1674, 1286, 1171, 1119, 1058, 1046, 822 cm-1.
HRMS [M+Na+]: calcd for C18H20O2SNF3Na: 394.1059, found:
394.1050.
White solid, yield 66%, mp 142–144 ◦C, [a]D25 +61.1 (c 0.55, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.84 (d, J = 8.7 Hz, 2 H), 7.65
(d, J = 8.7 Hz, 2 H), 4.49–4.59 (m, 1 H), 4.06 (d, J = 8.1 Hz, 1 H),
3.77 (dd, J = 9.6, 17.4 Hz, 1 H), 3.29 (dd, J = 3.3, 17.7 Hz, 1 H),
1.17 (s, 9 H). 13C NMR (CDCl3, 75 MHz): d = 193.9, 134.9, 132.2,
129.7, 129.2, 123.3 (q, J = 280.2 Hz), 56.9, 53.5 (q, J = 30.5 Hz),
38.0, 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.3. IR (KBr):
n = 3202, 2964, 2923, 1688, 1586, 1397, 1348, 1287, 1175, 1112,
1056, 835 cm-1. HRMS [M+Na+]: calcd for C14H17O2SNF3BrNa:
423.9988, found: 424.0010.
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-(furan-2-yl)-4-oxobutan-2-
yl)propane-2-sulfinamide (3k)
(S)-N-((S)-4-(Biphenyl-4-yl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-
methylpropane-2-sulfinamide (3g)
◦
Colorless solid, yield 42%, mp 110–111 C, [a]2D5 +48.8 (c 0.08,
White solid, yield 73%, mp 147–148 ◦C, [a]D25 +91.2 (c 0.19, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 8.06 (d, J = 7.8 Hz, 2 H), 7.70–
7.73 (m, 2 H), 7.62–7.65 (m, 2 H), 7.40–7.52 (m, 3 H), 4.54–4.68
(m, 1 H), 4.29 (d, J = 2.1 Hz, 1 H), 3.83 (dd, J = 9.6, 17.4 Hz, 1 H),
3.37 (dd, J = 2.7, 17.4 Hz, 1 H), 1.19 (s, 9 H). 13C NMR (CDCl3,
75 MHz): d = 194.5, 146.5, 139.6, 135.0, 129.0, 128.8, 128.4, 127.5,
127.3, 123.5 (d, J = 278.4 Hz), 56.9, 53.8 (q, J = 31.3 Hz), 38.1,
22.4. 19F NMR (CDCl3, 376 MHz): d = -74.4. IR (KBr): n = 3163,
2960, 2922, 1685, 1604, 1273, 1158, 1122, 1061, 765 cm-1. HRMS
[M+Na+]: calcd for C20H22O2SNF3Na: 420.1216, found: 420.1199.
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.64 (dd, J = 0.6,
1.5 Hz, 1 H), 7.31 (dd, J = 0.6, 3.3 Hz, 1 H), 6.61 (q, J = 1.8 Hz,
1 H), 4.45–4.55 (m, 1 H), 3.88 (d, J = 9.0 Hz, 1 H), 3.59 (dd, J =
9.9, 17.4 Hz, 1 H), 3.21 (dd, J = 3.3, 17.1 Hz, 1 H), 1.17 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 183.8, 152.2, 147.1, 123.2 (q, J =
280.3 Hz), 118.1, 112.8, 57.0, 53.8 (q, J = 31.1 Hz), 37.9 (d, J = 1.3
Hz), 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.7. IR (KBr): n =
3283, 3129, 3091, 2967, 1666, 1468, 1304, 1267, 1172, 1125, 1075,
767 cm-1. HRMS [M+Na+]: calcd for C12H16O3SNF3Na: 334.0695,
found: 334.0699.
(S)-N-((S)-4-(4-Ethylphenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-
methylpropane-2-sulfinamide (3h)
(S)-2-Methyl-N-((S)-1,1,1-trifluoro-5,5-dimethyl-4-oxohexan-2-
yl)propane-2-sulfinamide (3l)
◦
Colorless solid, yield 68%, mp 97–98 C, [a]2D5 +100.0 (c 0.07,
◦
Colorless solid, yield 61%, mp 85–86 C, [a]2D5 +32.3 (c 0.76,
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.88–7.91 (m, 2 H),
1
CHCl3). H NMR (CDCl3, 500 MHz): d = 4.33–4.39 (m, 1 H),
7.28–7.33 (m, 2 H), 4.51–4.61 (m, 1 H), 3.95 (d, J = 8.4 Hz, 1 H),
3.73 (dd, J = 9.6, 17.4 Hz, 1 H), 3.31 (dd, J = 3.0, 17.4 Hz, 1 H),
2.76 (q, J = 7.2 Hz, 2 H), 1.30 (t, J = 7.8 Hz, 3 H), 1.17 (s, 9 H).
13C NMR (CDCl3, 75 MHz): d = 194.4, 151.0, 134.0, 128.4, 128.3,
123.5 (q, J = 279.8 Hz), 56.9, 53.9 (q, J = 30.5 Hz), 37.9, 29.0, 22.3,
15.1. 19F NMR (CDCl3, 376 MHz): d = -74.4. IR (KBr): n = 3262,
2975, 2875, 1685, 1609, 1293, 1269, 1169, 1117, 1060, 819 cm-1.
HRMS [M+Na+]: calcd for C16H22O2SNF3Na: 372.1216, found:
372.1206.
3.83 (d, J = 8.5 Hz, 1 H), 3.25 (dd, J = 9.5, 18.5 Hz, 1 H), 2.88
(dd, J = 3.5, 18.5 Hz, 1 H), 1.20 (s, 18 H).13C NMR (CDCl3, 125
MHz): d = 210.5, 124.2 (d, J = 279.9 Hz), 56.8, 53.5 (q, J = 30.8 Hz),
44.2, 36.3, 26.3, 22.3. 19F NMR (CDCl3, 376 MHz): d = -74.2. IR
(KBr): n = 3244, 2967, 2928, 1712, 1473, 1365, 1281, 1222, 1168,
1125, 1061 cm-1. HRMS [M+Na+]: calcd for C12H22O2SNF3Na:
324.1216, found: 324.1209.
Reaction of large scale application study
(S)-N-((S)-4-(4-Ethoxyphenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-
methylpropane-2-sulfinamide (3i)
Into an oven-dried round-bottom flask flushed with N2 were taken
acetophenone (8.5 mmol) and anhydrous THF (20.0 mL). The
White solid, yield 87%, mp 114–115 ◦C, [a]D25 +78.8 (c 0.21, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.90–7.95 (m, 2 H), 6.90–6.96
(m, 2 H), 4.50–4.56 (m, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.03 (d, J =
8.7 Hz, 1 H), 3.68 (dd, J = 9.3, 17.4 Hz, 1 H), 3.26 (dd, J = 3.0,
17.4 Hz, 1 H), 1.47 (t, J = 6.9 Hz, 3 H), 1.16 (s, 9 H). 13C NMR
(CDCl3, 75 MHz): d = 193.2, 163.5, 130.5, 129.1, 123.5 (q, J =
279.8 Hz), 114.4, 63.9, 56.9, 54.0 (q, J = 29.7 Hz), 37.6, 22.3, 14.6.
19F NMR (CDCl3, 376 MHz): d = -74.5. IR (KBr): n = 3167, 2980,
1682, 1602, 1366, 1287, 1261, 1231, 1171, 1117, 1061, 833 cm-1.
reaction flask was cooled to -78 C and LDA (2 M in THF, 4.7
◦
mL) was added dropwise with stirring. After 45 min at -78 ◦C,
sulfinylimine 1 (5 mmol) dissolved in anhydrous THF (10.0 mL)
◦
was added dropwise. Stirring was continued at -78 C for 2.5 h,
then the reaction was quenched with saturated NH4Cl (10.0 mL),
followed by H2O (15.0 mL) and the mixture was brought to room
temperature. The organic layer was taken and the aqueous layer
was extracted with EtOAc (3 ¥ 50 mL). The combined organic
layers were dried with anhydrous Na2SO4, filtered and the solvent
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was removed to give the crude product, which was purified by
column chromatography (hexane–EtOAc, 4 : 1).
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Conversion of 3a affording free b-amino ketone 4
3a (0.5 mmol) and MeOH (5 mL) were placed in a 25 mL round-
bottom flask and aq HCl (36%, 1 mL) was added. The reaction was
stirred at rt for 8 h, during which the cleavage was monitored by
TLC. Volatiles were removed under reduced pressure. The residue
was dissolved in CH2Cl2 (10 mL) and Et3N (15 mmol) was added.
The mixture was stirred at rt for 1 h, then H2O (10 mL) was added.
The organic layer was taken, washed with H2O (2 ¥ 10 mL), dried
with anhydrous Na2SO4, filtered and the solvent was removed to
give the crude product, which was purified by TLC plate (hexane–
EtOAc, 2 : 1).
(S)-3-Amino-4,4,4-trifluoro-1-phenylbutan-1-one (4)
White solid, yield 90%, mp 31–32 ◦C, [a]D25 -57.2 (c 0.25, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.97–8.00 (m, 2 H), 7.60–7.66
(m, 1 H), 7.49–7.54 (m, 2 H), 3.98–4.10 (m, 1 H), 3.38 (dd, J =
2.7, 17.7 Hz, 1 H), 3.25 (dd, J = 9.6, 17.1 Hz, 1 H), 1.66 (s, 2
H). 13C NMR (CDCl3, 75 MHz): d = 196.2, 136.3, 133.8, 128.8,
128.1, 124.6 (q, J = 278.8 Hz), 50.0 (q, J = 29.6 Hz), 39.3 (q,
J = 1.4 Hz). 19F NMR (CDCl3, 376 MHz): d = -78.3. IR (KBr):
n = 3391, 3332, 2937, 1684, 1596, 1333, 1257, 1221, 1177, 1106,
754, 687 cm-1. HRMS [M+H+]: calcd for C10H11ONF3: 218.0787,
found: 218.0796.
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Conclusions
8 For the organocatalytic asymmetric synthesis of b-trifluoromethylated
b-amino ketone, see: K. Funabiki, M. Nagamori, S. Goushi and M.
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3436.
In summary, we have developed the first auxiliary-based process
for the asymmetric synthesis of b-trifluoromethylated b-amino
ketones via addition of ketone-derivative enolates to sulfinylimine.
This facile and efficient system gives good yields and excellent
diastereoselectivities, even on the large scale preparation. Further
study on synthesis of a-branched b-trifluoromethylated b-amino
ketones is presently under progress.
10 For selected examples, see (a) S. Kobayashi and H. Ishitani, Chem.
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3600–3740.
Acknowledgements
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685; (b) Z. J. Liu and J. T. Liu, Chem. Commun., 2008, 5233–5235.
13 The reaction with other aliphatic ketones, including acetone and
trifluoroacetone, did not result in any major products.
14 For examples of large-scale preparation in asymmetric synthesis, see:
(a) T. M. Gøgsig, A. T. Lindhardt, M. Dekhane, J. Grouleff and T.
Skrydstrup, Chem.–Eur. J., 2009, 15, 5950–5955; (b) S. Mizuta, N.
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310; (b) W. Jiang, C. Chen, D. Marinkovic, J. A. Tran, C. W. Chen,
L. M. Arellano, N. S. White and F. C. Tucci, J. Org. Chem., 2005, 70,
8924–8931.
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (No. 20772056 and
20932004). The Jiangsu 333 program (for Pan) and the set-up fund
of Nanjing University (for Han) are also acknowledged.
Notes and references
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1406 | Org. Biomol. Chem., 2011, 9, 1402–1406
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©