Asymmetric synthesis of β-aryl-β-trifluoromethyl-β- aminoarones via Mannich-type reactions of ketone enolates with chiral aryl CF3-substituted N-tert-butanesulfinyl ketimines

Article abstract of DOI:10.1016/j.tet.2012.04.070

A method for the preparation of chiral β-aryl-β-trifluoromethyl- β-aminoarones has been developed involving the Mannich-type reactions of ketone-derivative enolates with chiral aryl CF₃-substituted N-tert-butanesulfinyl ketimines. This method tolerates a wide of aromatic ketones, giving the products in moderate to excellent yields (up to 91%) with good diastereoselectiveties (up to 93:7 dr). Acidic cleavage of the tert-butanesulfinyl group gave optically pure β-aryl-β- trifluoromethyl-β-aminoarones in excellent yields (up to 98%), which can be further transformed into CF₃-substituted aziridine derivatives.

Full text of DOI:10.1016/j.tet.2012.04.070

Tetrahedron 68 (2012) 4955e4961
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of b-aryl-b-trifluoromethyl-b-aminoarones via
Mannich-type reactions of ketone enolates with chiral aryl CF3-substituted
N-tert-butanesulfinyl ketimines
,
a,b
Yingle Liu a, Yangen Huang a , Feng-Ling Qing
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China
b 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:
A method for the preparation of chiral
b-aryl-b-trifluoromethyl-b-aminoarones has been developed
Received 7 December 2011
Received in revised form 6 April 2012
Accepted 18 April 2012
involving the Mannich-type reactions of ketone-derivative enolates with chiral aryl CF3-substituted
N-tert-butanesulfinyl ketimines. This method tolerates a wide of aromatic ketones, giving the products in
moderate to excellent yields (up to 91%) with good diastereoselectiveties (up to 93:7 dr). Acidic cleavage
Available online 26 April 2012
of the tert-butanesulfinyl group gave optically pure b-aryl-b-trifluoromethyl-b-aminoarones in excellent
yields (up to 98%), which can be further transformed into CF3-substituted aziridine derivatives.
Keywords:
Mannich addition
Aminoarone
Ó 2012 Elsevier Ltd. All rights reserved.
N-tert-Butanesulfinyl ketimine
Trifluoromethyl
Asymmetric
1. Introduction
and auxiliary-based asymmetric synthesis, but the yields of the
target products are usually moderate.6 For instance, Vovk’s group
b
-Amino ketones derivatives have received considerable atten-
succeeded in applying
-trifluoromethyl- -aminoketone derivatives via asymmetric
Mannich reaction between aryl trifluoromethyl ketimines and ac-
etone.7 However, the synthesis of
-aryl- -trifluoromethyl-b-
L-proline as organocatalyst to obtain b-aryl-
tion because they are valuable building blocks for the synthesis of
various pharmaceuticals and biologically active compounds.1 Spe-
cifically, these aminoketones can be readily prepared and easily
b
b
b
b
transformed into the corresponding
g
-amino alcohols,
b
-amino
amino ketones by auxiliary-based asymmetric nucleophilic addi-
tion of ketimines are rare due to the low electrophilicity and in-
creased steric hindrance to nucleophilic attack on the C]N bond.
Chiral N-tert-butanesulfinamides developed by Ellman et al. are
versatile reagents for the asymmetric synthesis of various classes of
substituted amines, amino acids, amino alcohols, and diamines.8 In
recent years, N-tert-butanesulfinamide as a chiral auxiliary has
been applied in the asymmetric synthesis of fluorine-containing
esters and 1,3-diamines.2 In the last two decades, a big challenge
has also arisen from the progressively higher requirements on the
enantiomeric purity of chiral ligands and therapeutic agents.3
Consequently, the asymmetric synthesis of optically pure
noketone derivatives become a crucial issue. Most recently, a Rh-
catalyzed asymmetric hydrogenation of -keto enamides as an ef-
ficient way to prepare enantiomerically pure -amino ketones and
their derivatives,
-aryl amines was reported by Zhang’s group.4
b-ami-
b
b
g
amines.9 For instance, Hu reported the asymmetric synthesis of
a-
Fluorine-containing compounds are considered the particularly
promising drug candidates because the introduction of fluorine-
containing group often critically improves pharmacological prop-
erties of biologically active molecules (e.g., membrane permeability,
hydrophobic binding stability against metabolic oxidation, etc.).5
difluoromethyl amines and chiral monofluoromethyl amines via the
nucleophilic addition of difluoromethyl phenyl sulfone and fluo-
romethyl phenyl sulfone anion to N-tert-butanesulfinyl aldimines.10
Our group reported the synthesis of enantio-pure
-propargyl sulfinamides by the addition of lithium acetylides to
chiral CF3-substituted (S)-N-tert-butanesulfinyl ketimines.11 Re-
cently, Pan reported the synthesis of -trifluoromethylated -amino
a-trifluoromethyl
a
Thereinto, a lot of enantiomerically pure fluorine-containing
b-
aminocarbonyl compounds can be obtained via the organocatalytic
b
b
ketones via addition of ketone-derivative enolates to tri-
fluoromethylated N-tert-butanesulfinylimine with good chemical
yields and excellent diastereoselectivities.12 Considering that
asymmetric construction of CF3-substituted quaternary carbon
* Corresponding author. Tel.: þ86 21 67792612; fax: þ86 21 67792608; e-mail
addresses: hyg@dhu.edu.cn, yangenhuang@gmail.com (Y. Huang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.070

4956
Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
center is still a challenge and inspired by Pan’s methodology, we
here reported the synthesis of -aryl- -trifluoromethyl- -amino-
arones with good yields and high diastereoselectivities via nucle-
ophilic additions of aromatic ketone enolates to chiral aryl CF3-
substituted N-tert-butanesulfinyl ketimines.
time (2 h), the yield of the reaction was lowered to 69%, and no
significant improvement for the diastereoselectivity (78:22 dr) was
observed (entry 2). The reaction would not proceed or gave lower
yield when dichloromethane (entry 4) or toluene (entry 3) was used
as solvent. Further optimization of the reaction condition was car-
ried out by changing the feeding order of starting materials. When
LDA was slowly added into a solution of aryl CF3-substituted (S)-N-
tert-butanesulfinyl ketimines 1a and acetophenone 2a (entry 5) in
THF, the desired products 3 were isolated in a moderate yield (60%)
but in a higher diastereoselectivity (91:9 dr). The highest yield (90%)
and a remaining diastereoselectivity (91%, 81:19 dr, entry 6) were
achieved when 5.0 equiv of 2a was used. It was noteworthy that the
two adducts as diastereoisomers could be easily separated from
each other by silica gel flash chromatography (entry 6).
b
b
b
2. Result and discussion
The aryl CF3-substituted (S)-N-tert-butanesulfinyl ketimines 1
were generated and isolated quickly prior to use (not fully charac-
terized because of their low hydrostability).13 Then the reaction of
chiral ketimines and acetophenone 2a in the presence of LDA was
investigated. Firstly, the 1,2-addition reaction of ketimine 1a with
lithium acetophenone enolate, which prepared in advance from
acetophenone 2a and slightly excess of LDA at ꢀ78 ꢁC was con-
ducted in THF. The desired products 3a and 3a0 were obtained in
a good combined yield (81%) but in a moderate diastereoselectivity
(73:27 dr) after 8 h (Table 1, entry 1). With the reduction of reaction
Under the optimized condition, the reactions were then in-
vestigated between various aromatic ketones with chiral aryl CF3-
substituted N-tert-butanesulfinyl ketimines. As shown in Table 2,
the yields of the reaction were decreased by substituent on the
Table 1
Optimization of reaction conditionsa
O
S
O
S
O
S
O
N
NH
CF3
3a
O
NH
O
1) LDA,THF, -78oC
2) aq NH4Cl
CH3
CF3
CF3
3a'
1a
2a
Entry
2a (equiv)
Solvent
Time (h)
Yieldb (%)
drc
1
2
3
4
5
6
1.7
1.7
1.7
1.7
1.7
5
THF
THF
Toluene
CH2Cl2
THF
8
2
8
8
8
4
81
64
73:27
78:22
77:23
dd
41
dd
60e
90e
91:9
81:19
THF
a
All reactions were conducted with N-tert-butanesulfinyl ketimine 1a (1 mmol), LDA (1.87 mmol), solvent (5 mL) unless stated otherwise.
b
c
Isolated yield.
Diastereomeric ratios were determined by 19F NMR analysis of the crude reaction mixture.
No reaction.
d
e
LDA was slowly added into the mixture of sulfinyl ketimine 1a and acetophenone 2a.
Table 2
Asymmetric nucleophilic addition of ketones to chiral ketiminesa
O
S
O
S
O
S
1) LDA,THF,
-78oC
CH3
2) aq NH4Cl
O
NH
O
NH
O
N
R2
R1
R2
R1
R2
R1
CF3
CF3
CF3
3
3'
1
2
Entry
R1
R2
Product
Yieldb (%)
drc,d
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-ClC6H4 (1c)
Ph (2a)
3aþ3a0
3bþ3b0
3cþ3c0
3dþ3d0
3eþ3e0
3fþ3f0
3gþ3g0
3hþ3h0
3iþ3i0
3jþ3j0
df
91
55
69
47
72
56
62
63
29
60
df
81:19
89:11
85:15
93:7e
80:20
71:29
70:30
72:28
84:16
55:45
df
4-MeC6H4 (2b)
4-ClC6H4 (2c)
4-MeOC6H4 (2d)
2-MeC6H4 (2e)
Ph (2a)
4-MeC6H4 (2b)
4-ClC6H4 (2c)
4-MeOC6H4 (2d)
2-MeC6H4 (2e)
Ph (2a)
9
10
11
a
N-tert-Butanesulfinyl ketimine (1 mmol), arone (5 mmol), LDA (1.87 mmol), solvent (5 mL).
b
c
d
e
f
Isolated yields.
Diastereomeric ratios were determined by 19F NMR analysis.
Configurations were determined by X-ray crystallographic analysis.
Only 3d was collected.
No reaction.

Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
4957
aromatic ring of ketones 2 (<80%) (Table 2, entries 1e5). Better
diastereoselectivities were observed when the unsubstituted keti-
mines 1a was reacted with arones (>80:20 dr, entries 1e5).
Electron-rich arones gave higher diastereoselectivities but lower
yields than those of electron-deficient arones (entries 3e4, 8e9).
Starting from more hindered o-substituted arones 2e, the adducts
3e, 3e0, 3j and 3j0 were also obtained under the optimized condition
(entries 5, 10). However, all attempts to carry out the reaction be-
tween p-chlorophenyl ketimine 1c and arone 2a were failed to give
any desired product under the optimized or other reaction condi-
tions (entry 11).
yield of 94% with retention of configuration. Subsequently, we tried
to construct an oxazine ring from 5a by using phosphorus penta-
chloride as dehydrant because oxazine is a versatile synthon in
heterocyclic chemistry and a skeleton found frequently in manifold
biologically active compounds.18 However, only aziridine derivative
7a was obtained in 73% of yield when 2.5 equiv of phosphorus
pentachloride (PCl5) was used as shown in Scheme 2. A proposed
mechanism for the formation of aziridine 7a was shown in Scheme
3 where one molecule of hydrogen chloride was eliminated firstly
to form the chloroimino intermediate A,19 which then transferred
to aziridine 7a by intramolecular cyclization.
The absolute configuration of the addition product 3e was de-
termined by X-ray crystallographic analysis. The newly formed
stereocenter is a (S)-configuration (Fig. 1).14 The stereocenters of
other corresponding major products were assigned by analogy, and
(Ss,S)-3a was obtained as major diastereomer. Based on the out-
come of configuration, the mechanism of asymmetric addition was
suggested to proceed via a chelated transition state model in which
the CF3 and bulky tert-butanesulfinyl groups were stated in e
3. Conclusions
In summary, nucleophilic additions of ketone-derivative eno-
lates to aryl CF3-substituted N-tert-butanesulfinyl ketimines pro-
vided a general and efficient method for the asymmetric synthesis
of b-aryl-b-trifluoromethyl-b-aminoarones. The product obtained
could be further applied in the synthesis of valuable CF3-
substituted aziridine derivative in good yield.
bond.13 Consequently, a
pep interaction may also exist between
the two axial aromatic groups (Fig. 2). It is different from the ad-
dition of ketone enolates to sulfinylimine, which was proceeded via
a non-chelated transition state model.12,15
4. Experimental section
4.1. General experiment methods
Unless otherwise noted, all reactions were carried out under
nitrogen atmosphere and all reagents were obtained from com-
mercial suppliers and used without further purification. THF and
hexane were distilled from sodium/benzophenone ketyl and tolu-
ene was distilled from sodium immediately before use. Standard
column chromatography was performed on 300e400 mesh silica
gel using flash column chromatography techniques. IR spectra of
liquids were recorded as thin film on KBr plates. Melting points
were determined on a Melt-Temp apparatus and are uncorrected.
1H NMR spectra were recorded on Bruker AM-400 spectrometer
with TMS as an internal standard. 19F NMR spectra were recorded
on Bruker AM-400 spectrometer with CFCl3 as an external stan-
dard. 13C NMR spectra were recorded on a Bruker 400 (101 MHz)
spectrometer. High Resolution MS spectra were taken on Bruker
Daltonics, Inc. APEXIII 7.0 TESLA FTMS. Optical rotations were de-
termined on a Rudolph Autopol III, automatic polarimeter using
CHCl3 as solvent.
4.2. Typical experimental procedure for addition reactions of
Fig. 1. X-ray crystal structure of (Ss,S)-3e.
ketone-derivative enolates to N-tert-butanesulfinyl ketimines
As representative examples, the optically pure
b-aryl-b-tri-
Into a flame-dried 25 mL Schlenk flask containing a solution of
N-tert-butanesulfinyl ketimine (S)-1a (1.0 mmol) and ketone
(5 mmol) in THF (5 mL) was slowly added a solution of LDA
fluoromethy- -aminoarones 4a and 4h could be readily accessed
b
with retention of configuration by cleaving the N-tert-butane-
sulfinyl group under mild acidic condition (4 M HCl in dioxane). As
(0.94 mL, 1.87 mmol,
2 M solution in THF/heptane/ethyl-
enebenzene) at ꢀ78 ꢁC under N2 atmosphere. After stirring at
ꢀ78 ꢁC for 4 h, saturated aqueous NH4Cl solution (8 mL) and H2O
(10 mL) were added to quench the reaction, and the mixture was
brought to room temperature. The resulting mixture was extracted
with EtOAc (15 mLꢂ3). The combined organic solution was dried
over anhydrous Na2SO4. After removal of volatile solvents under
shown in Scheme 1, free b-phenyl-b-trifluoromethyl-b-aminoarone
4a was obtained in high isolated yield (98%), and the substituted
aminoarone 4h was also obtained in good yield (88%).
Although the nucleophilicity of amino group was reduced by the
geminal trifluoromethyl group, acylation of optically pure 4a with
benzoyl chloride could be smoothly underwent16,17 to afford 5a in
O
S
O
S
R1
R2
O
S
R2
OLi
Li
N
NH
O
F3C
N
O
R1
R2
F3C
R1
CF3
Fig. 2. Proposed mechanism for the asymmetric addition.

4958
Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
O
S
NH2
CF3
O
1) 4 M HCl in dioxane, CH3OH, rt
2) 1 M NaOH
NH
O
R1
R2
R1
R2
CF3
(Ss,S)-3a: R1=Ph, R2=Ph
(Ss,S)-3h: R1=4-MeOC6H4 ,
R2=4-ClC6H4
(S)-4a: R1=Ph, R2=Ph
(S)-4h: R1=4-MeOC6H4
R2=4-ClC6H4
Scheme 1. Preparation of
b-aryl-b-trifluoromethyl-b-aminoarones.
Ph
O
Ph
NH2
O
BzNH O
N
PhCOCl
toluene
PCl5, toluene
120 oC, 36 h
N
O
F3C
Ph
+
Ph
Ph
Ph
Ph
Ph
CF3
CF3
F3C
Ph
120 oC, 5 h
Ph
O
6a
yield 0 %
5a
yield 94%
4a
7a
yield 73%
Scheme 2. Preparation of oxazine with 4a.
O
O
Cl
O
PCl5
PCl3,
NH
O
N
O
HCl
N
HCl
CF3
CF
3 H
F3C
O
5a
7a
A
Scheme 3. Proposed mechanism for the formation of aziridine 7a.
reduced pressure, the crude product was purified by silica gel col-
umn chromatography (petroleum ether/EtOAc, 6:1).
134.7, 134.5, 129.4, 129.1, 128.4, 128.3, 128.2, 125.4 (q, J¼287.9 Hz),
66.1 (q, J¼27.3 Hz), 56.9, 30.8, 22.7, 21.6; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.1; IR (KBr, cmꢀ1): 3233, 3056, 2965, 2913, 2872, 1679, 1606,
4.2.1. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-oxo-2,4-diphenylbutan-
1355, 1224,1169,1074, 799; HRMS[MþHþ]: calcd for C21H25F3NO2S:
2-yl)propane-2-sulfinamide(3a). Yellow oil, yield 74%, ½a D35
ꢃ
þ312.7
412.1553, found: 412.1564.
(c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.94 (d, J¼7.8 Hz, 2H), 7.69
(d, J¼7.4 Hz, 2H), 7.56 (t, J¼7.2 Hz, 1H), 7.42 (dt, J¼15.2, 7.6 Hz, 5H),
4.2.4. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-4-oxo-2-phenyl-4-p-tol-
ylbutan-2-yl)propane-2-sulfinamide (3b0). Colorless oil, yield 6%,
6.52 (s, 1H), 4.05 (AB, J¼17.1 Hz, 1H), 3.94 (AB, J¼17.1 Hz, 1H), 1.31 (s,
9H); 13C NMR (101 MHz, CDCl3)
d
196.1, 136.0, 133.6, 132.7, 128.2,
½
a 3D3
ꢃ
ꢀ82.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.84 (d,
127.8, 127.5, 127.4, 127.1, 124.4 (q, J¼287.9 Hz), 65.0 (q, J¼27.3 Hz),
J¼8.2 Hz, 2H), 7.48 (dd, J¼6.4, 2.6 Hz, 2H), 7.36 (m, 1H), 7.34 (d,
J¼2.8 Hz, 2H), 7.25 (d, J¼3.2 Hz, 2H), 5.27 (s,1H), 4.29 (AB, J¼18.4 Hz,
1H), 4.21 (AB, J¼18.4 Hz, 1H), 2.40 (s, 3H), 1.32 (s, 9H); 13C NMR
55.9, 40.5, 21.8; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.5; IR (KBr, cmꢀ1):
3227, 3056, 2953, 2917, 2872,1686,1598,1356,1251,1167,1073, 836;
HRMS[MþHþ]: calcd for C20H23F3NO2S: 398.1396, found: 398.1402.
(101 MHz, CDCl3) d 195.2, 144.6, 137.2, 134.3, 129.4, 128.8, 128.5,
128.2,126.8,125.0 (q, J¼286.8 Hz), 65.1 (q, J¼26.3 Hz), 57.1, 29.7, 22.5,
4.2.2. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-4-oxo-2,4-diphenylbutan-
2-yl)propane-2-sulfinamide(3a0). Pale yellow oil, yield 17%,
21.7; 19F NMR (376 MHz, CDCl3)
d
ꢀ72.8. IR (KBr, cmꢀ1): 3289, 3064,
2967, 2925, 2857, 1681, 1605, 1353, 1251, 1166, 1074, 799; HRMS
½
a 3D4
ꢃ
ꢀ330.8 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.89e8.04
[MþNaþ]: calcd for C21H24F3NO2SNa: 434.1372, found: 434.1379.
(m, 2H), 7.57 (dd, J¼10.6, 4.2 Hz, 1H), 7.49e7.54 (m, 2H), 7.46 (t,
J¼7.7 Hz, 2H), 7.32e7.40 (m, 3H), 5.22 (s, 1H), 4.36 (AB, J¼18.5 Hz,
1H), 4.26 (AB, J¼18.5 Hz, 1H), 1.35 (s, 9H); 13C NMR (101 MHz,
4.2.5. (S)-N-((S)-4-(4-Chlorophenyl)-1,1,1-trifluoro-4-oxo-2-
phenylbutan-2-yl)-2-methylpropane-2-sulfinamide (3c). Yellow oil,
CDCl3)
d
194.4, 136.1, 135.7, 132.7, 127.8, 127.7, 127.6, 127.0, 125.7,
yield 59%, ½a 3D4
ꢃ
þ232.8 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3)
124.3 (q, J¼286.8 Hz), 63.9 (q, J¼26.4 Hz), 56.1, 39.5, 21.4; 19F NMR
d
8.24 (d, J¼8.4 Hz, 2H), 8.01 (d, J¼6.2 Hz, 2H), 7.78 (dd, J¼7.2,
(376 MHz, CDCl3)
d
ꢀ72.9; IR (KBr, cmꢀ1): 3289, 3072, 2967, 2919,
4.7 Hz, 5H), 6.76 (s,1H), 4.37 (AB, J¼17.1 Hz,1H), 4.26 (AB, J¼17.2 Hz,
2869, 1685, 1585, 1352, 1251, 1163, 1074, 821; HRMS[MþHþ]: calcd
1H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3)
d
195.8, 140.2, 135.3,
for C20H23F3NO2S: 398.1396, found: 398.1412.
134.3, 129.5, 129.2, 129.0, 128.4, 128.4, 125.2 (q, J¼287.9 Hz), 65.7 (q,
J¼27.3 Hz), 57.0, 41.3, 22.7; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.5; IR
4.2.3. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-oxo-2-phenyl-4-p-tol-
ylbutan-2-yl)propane-2-sulfinamide (3b). Pale yellow oil, yield 49%,
(KBr, cmꢀ1): 3248, 3056, 2967, 2908, 2960, 1686, 1580, 1352, 1221,
1167, 1076, 833; HRMS[MþHþ]: calcd for C20H22ClF3NO2S:
432.1006, found: 432.1017.
½
a 3D3
ꢃ
þ86.0 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.79e7.88 (m,
2H), 7.69 (d, J¼6.5 Hz, 2H), 7.41 (d, J¼5.4 Hz, 3H), 7.25 (d, J¼7.1 Hz,
2H), 6.57 (s, 1H), 4.00 (AB, J¼16.9 Hz, 1H), 3.86 (AB, J¼17.0 Hz, 1H),
4.2.6. (S)-N-((R)-4-(4-Chlorophenyl)-1,1,1-trifluoro-4-oxo-2-
phenylbutan-2-yl)-2-methylpropane-2-sulfinamide (3c0). Colorless
2.39 (s, 3H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3)
d 196.7, 144.8,

Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
4959
oil, yield 10%, ½a D33
ꢃ
ꢀ242.6 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3)
7.59 (d, J¼8.6 Hz, 2H), 7.07 (d, J¼8.8 Hz, 2H), 5.36 (s, 1H), 4.51 (AB,
d
7.88 (d, J¼2.4 Hz, 2H), 7.46e7.51 (m, 2H), 7.43 (d, J¼1.6 Hz, 2H),
J¼18.5 Hz, 1H), 4.39 (AB, J¼18.5 Hz,1H), 3.99 (s, 3H), 1.51 (s, 9H); 13
C
7.37 (d, J¼1.2 Hz, 2H), 7.27 (d, J¼9.5 Hz, 1H), 5.10 (s, 1H), 4.32 (AB,
NMR (101 MHz, CDCl3) d 195.5, 159.7, 136.8, 133.7,128.7,128.0,125.5
J¼18.5 Hz, 1H), 4.20 (AB, J¼18.5 Hz, 1H), 1.32 (s, 9H); 13C NMR
(q, J¼285.8 Hz), 113.9, 64.6 (q, J¼26.3 Hz), 57.1, 55.2, 40.3, 22.5; 19F
(101 MHz, CDCl3)
d
194.2, 140.2, 136.9, 135.0, 129.5, 129.1, 129.0,
NMR (376 MHz, CDCl3)
d
ꢀ73.0; IR (KBr, cmꢀ1): 3276, 3061, 2964,
128.7, 126.7, 124.9 (q, J¼286.8 Hz), 64.8 (q, J¼27.3 Hz), 57.2, 40.4,
2919, 2845, 1685, 1604, 1344, 1253, 1160, 1075, 828; HRMS[MþHþ]:
22.4; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.1; IR (KBr, cmꢀ1): 3282,
calcd for C21H25F3NO3S: 428.1502, found: 428.1514.
3065, 2968, 2919, 2869, 1687, 1580, 1344, 1251, 1165, 1077, 824;
HRMS[MþNaþ]: calcd for C20H21ClF3NO2SNa: 454.0826, found:
454.0832.
4.2.12. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-p-tolylbutan-2-yl)propane-2-sulfinamide (3g). White solid,
yield 43%, mp 134e136 ꢁC,½a D34
ꢃ
þ91.0 (c 1.0, CHCl3); 1H NMR
4.2.7. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-(4-methoxyphenyl)-4-
oxo-2-phenylbutan-2-yl)propane-2-sulfinamide (3d). Yellow oil,
(300 MHz, CDCl3)
d
8.04 (d, J¼8.1 Hz, 2H), 7.79 (d, J¼8.6 Hz, 2H),
7.45e7.48 (m, 2H), 7.13 (d, J¼8.9 Hz, 2H), 6.81 (s, 1H), 4.19 (AB,
J¼16.8 Hz,1H), 4.02 (s, 3H), 3.95 (s, J¼16.8 Hz,1H), 2.61 (s, 3H),1.50 (s,
yield 31%, ½a 2D4
ꢃ
þ192.5 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.83e7.87 (m, 2H), 7.59e7.64 (m, 2H), 7.32e7.37 (m, 3H),
9H); 13C NMR (101 MHz, CDCl3)
d 197.1, 160.0, 144.8, 134.7, 130.1, 130.0,
6.84e6.88 (m, 2H), 6.57 (s, 1H), 3.89 (AB, J¼16.7 Hz, 1H), 3.80 (s,
129.5, 128.3, 125.6 (q, J¼287.9 Hz),113.7, 65.7 (q, J¼27.3 Hz), 56.9, 55.3,
3H), 3.74 (AB, J¼16.7 Hz, 1H), 1.22 (s, 9H); 13C NMR (100 MHz,
41.3, 22.8, 21.7; 19F NMR (282 MHz, CDCl3)
d
ꢀ73.3; IR (KBr, cmꢀ1):
CDCl3)
d
195.6, 164.1, 130.8, 130.6, 130.0, 129.1, 128.5, 128.4, 125.4 (q,
3223, 3047, 2958, 2917, 2848, 1675, 1601, 1356, 1253, 1165, 1073, 821;
J¼285.0 Hz),113.9, 66.3 (q, J¼27.3 Hz), 57.1, 55.5, 25.0, 22.7; 19F NMR
HRMS[MþHþ]: calcd for C22H27F3NO3S: 442.1658, found: 442.1677.
(376 MHz, CDCl3)
d
ꢀ73.2; IR (KBr, cmꢀ1): 3215, 3068, 2964, 2926,
2856, 1671, 1598, 1368, 1253, 1171, 1026, 809; HRMS[MþHþ]: calcd
4.2.13. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-p-tolylbutan-2-yl)propane-2-sulfinamide (3g0). Colorless oil,
for C21H25F3NO3S: 428.1502, found: 428.1520.
yield 19%, ½a 3D5
ꢃ
ꢀ108.4 (c 0.1, CHCl3); NMR (400 MHz, CDCl3)
d 7.76 (d,
4.2.8. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-4-oxo-2-phenyl-4-o-tol-
ylbutan-2-yl)propane-2-sulfinamide (3e). White solid, yield 58%,
J¼8.3 Hz, 2H), 7.31 (d, J¼8.8 Hz, 2H), 7.04e7.19 (m, 2H), 6.68e6.92
(m, 2H), 5.17 (s,1H), 4.17 (AB, J¼18.3 Hz,1H), 4.09 (AB, J¼18.3 Hz,1H),
3.69 (s, 3H), 2.32 (s, 3H), 1.23 (s, 9H); 13C NMR (101 MHz, CDCl3)
mp 111e113 ꢁC, ½a D35
ꢃ
þ147.8 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
7.56e7.60 (m, 2H), 7.52 (d, J¼7.8 Hz,1H), 7.35e7.36 (m,1H),
d 194.2, 158.7, 143.6, 133.3, 128.4, 128.0, 127.1, 127.1, 124.1 (q,
7.35 (d, J¼1.7 Hz, 1H), 7.29e7.32 (m, 1H), 7.19 (d, J¼8.9 Hz, 3H), 6.52
J¼284.7 Hz), 112.9, 63.70 (q, J¼26.6 Hz), 56.0, 54.2, 39.1, 21.5, 20.6;
(s, 1H), 3.85 (s, 2H), 2.37 (s, 3H), 1.27 (s, 9H); 13C NMR (101 MHz,
19F NMR (282 MHz, CDCl3)
d
ꢀ72.9; IR (KBr, cmꢀ1): 3276, 3064, 2962,
CDCl3)
d
201.4, 138.4, 137.8, 134.5, 131.9, 131.6, 129.3, 128.6, 128.4,
2917, 2840, 1682, 1608, 1351, 1252, 1156, 1075, 829; HRMS[MþNaþ]:
127.8, 126.8, 125.8, 125.4 (q, J¼287.9 Hz), 65.9 (q, J¼28.3 Hz), 57.0,
calcd for C22H26F3NO3SNa: 464.1478, found: 464.1487.
44.6, 22.8, 20.7; 19F NMR (376 MHz, CDCl3)
3232, 3060, 2962, 2923, 2851, 1687, 1595, 1393, 1214, 1167, 1073,
909, 738; HRMS[MþHþ]: calcd for C21H25F3NO2S: 412.1553, found:
412.1571.
d
ꢀ73.8; IR (KBr, cmꢀ1):
4.2.14. (S)-N-((S)-4-(4-Chlorophenyl)-1,1,1-trifluoro-2-(4-
methoxyphenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide
(3h). White solid, yield 45%, mp 129e131 ꢁC, ½a D34
ꢀ367.0 (c 0.2,
ꢃ
CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.85e7.95 (m, 2H), 7.57 (d,
4.2.9. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-4-oxo-2-phenyl-4-o-tol-
ylbutan-2-yl)propane-2-sulfinamide (3e0). Pale yellow oil, yield 14%,
J¼8.8 Hz, 2H), 7.40e7.50 (m, 2H), 6.86e7.03 (m, 2H), 6.45 (s, 1H),
3.99 (AB, J¼17.0 Hz,1H), 3.84 (AB, J¼17.0 Hz,1H), 3.83 (s, 3H),1.31 (s,
½
a 3D4
ꢃ
ꢀ249.2 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.70 (d,
9H); 13C NMR (100 MHz, CDCl3)
d 196.1, 160.1, 140.3, 135.5, 129.9,
J¼7.7 Hz, 1H), 7.41e7.51 (m, 2H), 7.32 (dt, J¼5.6, 3.6 Hz, 4H), 7.23 (t,
J¼7.6 Hz, 1H), 7.12 (dd, J¼33.6, 5.3 Hz, 1H), 5.15 (s, 1H), 4.25 (AB,
J¼18.6 Hz,1H), 4.09 (AB, J¼18.6 Hz,1H), 2.30 (s, 3H),1.28 (s, 9H); 13C
129.6, 129.1, 125.4 (q, J¼282.8 Hz), 126.0, 113.7, 65.4 (q, J¼27.3 Hz),
56.9, 55.3, 29.7, 22.8; 19F NMR (376 MHz, CDCl3)
d
ꢀ74.1; IR (KBr,
cmꢀ1): 3346, 2917, 2870, 1658, 1378, 1262, 1098, 1025, 800; HRMS
NMR (101 MHz, CDCl3)
d
199.4, 138.4, 137.5, 137.2, 132.1, 131.8, 128.8,
[MþNaþ]: calcd for C21H23ClF3NO3SNa: 484.0932, found: 484.0952.
128.5, 128.2, 126.8, 125.8, 124.9 (q, J¼286.8 Hz), 65.0 (q, J¼26.3 Hz),
57.1, 53.1, 43.1, 22.5, 21.0; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.0; IR
4.2.15. (S)-N-((R)-4-(4-Chlorophenyl)-1,1,1-trifluoro-2-(4-
methoxyphenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide
(KBr, cmꢀ1): 3289, 3060, 2982, 2917, 2876, 1690, 1601, 1343, 1251,
1167, 1074, 910, 741; HRMS[MþHþ]: calcd for C21H25F3NO2S:
412.1553, found: 412.1563.
(3h0). Pale yellow oil, yield 17%, ½a 3D2
ꢃ
ꢀ350.0 (c 0.4, CHCl3); 1H NMR
(400 MHz, CDCl3)
d 7.86e7.93 (m, 2H), 7.41e7.50 (m, 2H), 7.38 (d,
J¼8.8 Hz, 2H), 6.84e6.92 (m, 2H), 5.05 (s, 1H), 4.29 (AB, J¼18.5 Hz,
4.2.10. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-phenylbutan-2-yl)propane-2-sulfinamide (3f). White solid,
1H), 4.16 (AB, J¼18.5 Hz, 1H), 3.80 (s, 3H), 1.31 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 194.2, 159.8, 140.2, 135.0, 129.4, 129.0, 128.7,
yield 40%, mp 145e146 ꢁC,½a D35
ꢃ
þ346.9 (c 0.7, CHCl3); 1H NMR
128.0,126.1 (q, J¼286.8 Hz),114.0, 64.5 (q, J¼26.3 Hz), 57.1, 55.2, 30.9,
(300 MHz, CDCl3)
d
8.39 (d, J¼4.9 Hz, 2H), 8.04 (d, J¼6.0 Hz, 2H), 7.94
22.4; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.4; IR (KBr, cmꢀ1): 3289, 3065,
(d, J¼4.5 Hz, 2H), 7.71 (d, J¼2.9 Hz,1H), 7.39 (d, J¼5.8 Hz, 2H), 7.00 (s,
1H), 4.48 (AB, J¼17.1 Hz, 1H), 4.33 (AB, J¼17.1 Hz, 1H), 4.28 (s,
2962, 2917, 2835, 1688, 1592, 1354, 1253, 1163, 1079, 826; HRMS
[MþHþ]: calcd for C21H24ClF3NO3S: 462.1112, found: 462.1130.
J¼2.7 Hz, 3H), 1.76 (s, 9H); 13C NMR (101 MHz, CDCl3)
d 197.5, 160.0,
137.2, 133.7, 130.1, 130.0, 128.8, 128.7, 125.5 (q, J¼285.8 Hz), 113.7,
4. 2.16. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-2, 4-bis(4-
methoxyphenyl)-4-oxobutan-2-yl)propane-2-sulfinamide
65.3 (q, J¼26.8 Hz), 56.9, 55.3, 41.5, 22.8; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.5; IR (KBr, cmꢀ1): 3227, 3060, 2962, 2916, 2848, 1687, 1609,
(3i). Yellow solid, yield 24%, mp 87e88 ꢁC, ½a D35
þ228.0 (c 0.5,
ꢃ
1356,1256,1164,1072, 833; HRMS[MþHþ]: calcd for C21H25F3NO3S:
CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.89e7.98 (m, 2H), 7.59 (d,
428.1502, found: 428.1518.
J¼8.6 Hz, 2H), 6.95 (s, 2H), 6.92 (d, J¼1.1 Hz, 2H), 6.68 (s, 1H), 3.94
(AB, J¼16.6 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73 (AB, J¼16.5 Hz,
4.2.11. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-phenylbutan-2-yl)propane-2-sulfinamide(3f0). Pale yellow oil,
1H), 1.29 (s, 9H); 13C NMR (101 MHz, CDCl3)
d 196.0, 164.1, 159.9,
130.6, 130.1, 130.0, 129.9, 125.6 (q, J¼284.8 Hz), 113.9, 113.7, 65.9 (q,
yield 16%, ½a 3D5
ꢃ
ꢀ357.5 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3)
J¼26.3 Hz), 56.9, 55.6, 55.2, 41.1, 22.8; 19F NMR (376 MHz, CDCl3)
d
8.15 (d, J¼7.6 Hz, 2H), 7.76 (d, J¼7.3 Hz, 1H), 7.66 (t, J¼7.6 Hz, 2H),
d
ꢀ73.5; IR (KBr, cmꢀ1): 3211, 3072, 2958, 2916, 2843, 1666, 1601,

4960
Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
1360, 1252, 1167, 1072, 833; HRMS[MþHþ]: calcd for C22H27F3NO4S:
1686, 1590, 1319, 1276, 1154, 747, 695; HRMS[MþHþ]: calcd for
458.1607, found: 458.1621.
C16H15F3NO: 294.1100, found: 294.1103.
4. 2.17. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-2, 4-bis(4-
m e t h o x y p h e n y l ) - 4 - o x o b u t a n - 2 - y l ) p r o p a n e - 2 -
4.3.2. (S)-3-Amino-1-(4-chlorophenyl)-4,4,4-trifluoro-3-(4-
methoxyphenyl)butan-1-one(4h). Yellow oil, yield 88%, ½a D34
ꢀ192.0
ꢃ
sulfinamide(3i0). Yellow oil, yield 5%, ½a 3D4
ꢃ
þ243.2 (c 0.3, CHCl3); 1H
(c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.81 (d, J¼5.4 Hz, 2H), 7.47
NMR (400 MHz, CDCl3)
d
7.93 (d, J¼9.0 Hz, 2H), 7.39 (d, J¼8.6 Hz,
(d, J¼8.8Hz, 2H), 7.41(d, J¼8.5Hz, 2H),6.86(d, J¼8.8Hz, 2H), 4.05(AB,
2H), 6.93 (d, J¼8.9 Hz, 2H), 6.86 (d, J¼9.0 Hz, 2H), 5.30 (s, 1H), 4.22
J¼17.3 Hz, 1H), 3.49 (AB, J¼17.3 Hz, 1H), 3.77 (s, 3H), 2.46 (s, 2H); 13C
(AB, J¼18.2 Hz, 1H), 4.14 (AB, J¼18.2 Hz, 1H), 3.87 (s, 3H), 3.79 (s,
NMR (101 MHz, CDCl3) d 195.3, 159.4, 140.1, 135.4, 129.7, 129.4, 129.0,
3H), 1.30 (s, 9H); 13C NMR (101 MHz, CDCl3)
d
194.1, 164.0, 159.7,
127.8, 126.2 (q, J¼285.8 Hz), 113.8, 60.9 (q, J¼26.3 Hz), 55.2, 42.7; 19F
130.4, 129.9, 129.1, 128.1, 125.1 (q, J¼286.8 Hz), 113.9, 113.9, 64.8 (q,
MNR (376 MHz, CDCl3)
d
ꢀ79.1; IR (KBr, cmꢀ1): IR (KBr, cmꢀ1): 3398,
J¼27.3 Hz), 57.1, 55.5, 55.2, 40.0, 22.5; 19F NMR (376 MHz, CDCl3)
3333, 3061, 2938, 2841,1687, 1592,1407, 1258,1099, 734, 639; HRMS
d
ꢀ73.0; IR (KBr, cmꢀ1): 3260, 3068, 2970, 2931, 2847, 1670, 1602,
[MþHþ]: calcd for C17H16ClF3NO2: 358.0816, found: 358.0826.
1356,1254,1167,1075, 820; HRMS[MþHþ]: calcd for C22H27F3NO4S:
458.1607, found: 458.1626.
4.3.3. Preparation of (S)-N-(1,1,1-trifluoro-4-oxo-2,4-diphenylbutan-
2-yl)benzamide (5a). To a solution of (S)-3-amino-4,4,4-trifluoro-
1,3-diphenylbutan-1-one 4a (150 mg, 0.51 mmol) in dry toluene
(2 mL), benzoyl chloride (144 mg, 1.02 mmol) was added. The re-
action mixture was boiled for 5 h, followed 15 mL of H2O was added
to quench the reaction. The organic layer was removed and the
aqueous layer was extracted with EtOAc (10 mLꢂ2). The organic
layers were combined and dried over anhydrous Na2SO4, filtered,
concentrated, and the residue was purified by chromatography
(silica gel, petroleum ether/EtOAc, 3:1).
4.2.18. (S)-2-Methyl-N-((S)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-o-tolylbutan-2-yl)propane-2-sulfinamide (3j). White solid,
yield 33%, mp 109e111 ꢁC, ½a D35
ꢃ
ꢀ96.3 (c 0.4, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
7.54e7.58 (m, 3H), 7.37 (d, J¼7.5 Hz, 1H),
7.24e7.28 (m, 2H), 6.93 (d, J¼9.2 Hz, 2H), 6.65 (s, 1H), 3.87e3.92
(m, 2H), 3.83 (s 3H), 2.45 (s, 3H), 1.33 (s, 9H); 13C NMR (101 MHz,
CDCl3)
d 201.7, 160.1, 138.6, 137.8, 131.9, 131.5, 130.0, 127.8, 126.2,
125.8, 125.5 (q, J¼288.9 Hz), 113.7, 65.4 (q, J¼27.3 Hz), 56.8, 55.3,
44.6, 22.8, 20.7; 19F NMR (376 MHz, CDCl3)
3242, 3068, 2965, 2921, 2851, 1679, 1613, 1348, 1256, 1165, 1072,
830; HRMS[MþHþ]: calcd for C22H27F3NO3S: 442.1658, found:
442.1672.
d
ꢀ74.1; IR (KBr, cmꢀ1):
4.3.4. (S)-N-(1,1,1-Trifluoro-4-oxo-2,4-diphenylbutan-2-yl)benza-
mide (5a). Yellow oil, yield 94%, ½a D23
ꢃ
ꢀ209.5 (c 0.2, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
7.97 (m, 2H), 7.95 (d, J¼1.5 Hz, 2H), 7.93 (d,
J¼1.3 Hz, 1H), 7.55e7.62 (m, 4H), 7.39e7.53 (m, 7H), 4.44 (AB,
4.2.19. (S)-2-Methyl-N-((R)-1,1,1-trifluoro-2-(4-methoxyphenyl)-4-
oxo-4-o-tolylbutan-2-yl)propane-2-sulfinamide (3j0). Pale yellow
J¼16.4 Hz, 1H), 3.87 (AB, J¼16.4 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d
196.7, 166.6, 136.7, 136.12, 134.3, 133.7, 131.8, 128.7, 128.6, 128.6,
oil, yield 27%, ½a D31
ꢃ
ꢀ81.0 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
128.5, 128.2, 127.1, 125.8, 125.4 (q, J¼286.0 Hz), 64.2 (q, J¼28.1 Hz),
d
7.74 (dd, J¼7.7, 1.1 Hz, 1H), 7.41 (d, J¼8.8 Hz, 2H), 7.35 (dd, J¼7.5,
39.9; 19F NMR (376 MHz, CDCl3)
d
ꢀ71.3; IR (KBr, cmꢀ1): 3341, 3063,
1.3 Hz, 1H), 7.27 (d, J¼7.6 Hz, 1H), 7.21 (d, J¼7.6 Hz, 1H), 6.87e6.91
(d, J¼8.0 Hz, 2H), 5.20 (s, 1H), 4.26 (AB, J¼18.6 Hz, 1H), 4.09 (AB,
J¼18.6 Hz, 1H), 3.78 (s, 3H), 2.37 (s, 3H), 1.32 (s, 9H); 13C NMR
2921, 1689, 1521, 1167, 908, 733; HRMS[MþHþ]: calcd for
C23H19F3NO2: 398.1362, found: 398.1373.
(101 MHz, CDCl3)
d
199.6, 159.8, 138.4, 137.6, 132.1, 131.8, 129.0,
4.4. Procedure for (S)-2,4,6-triphenyl-4-(trifluoromethyl)-4H-
128.2, 128.1, 125.8, 125.0 (q, J¼285.8 Hz), 113.9, 64.7 (q, J¼27.3 Hz),
1,3-oxazine (7a)
57.1, 55.2, 42.9, 22.5, 21.1; 19F NMR (376 MHz, CDCl3)
d
ꢀ73.2; IR
(KBr, cmꢀ1): 3283, 3060, 2967, 2922, 2848, 1690, 1610, 1350, 1253,
1162, 1074, 829; HRMS[MþHþ]: calcd for C22H27F3NO3S: 442.1658,
found: 442.1678.
To a solution of amide 5a (292 mg, 0.73 mmol) in dry toluene
(10 mL), phosphorus pentachloride (380 mg, 1.83 mmol) was added
and the reaction mixture was boiled for 48 h. Then 20 mL of H2O
was added to quench the reaction, the organic layer was removed
and the aqueous layer was extracted with EtOAc (15 mLꢂ2). The
combined organic layer was dried over anhydrous Na2SO4, filtered,
concentrated, and the residue was purified by chromatography
(silica gel, petroleum ether/EtOAc, 20:1).
4.3. Typical experimental procedure for acidic cleavage of
tert-butanesulfinyl group
To a solution of sulfinamide (0.4 mmol) in methanol (0.5 M)
was added HCl (0.25 mL, 4.0 M in 1,4-dioxane). The reaction
mixture was stirred at room temperature for 2 h and diluted with
EtOAc (10 mL) after which a NaOH aqueous solution (1 M) was
carefully added dropwise to adjust the pH of the mixture to 8. The
organic layer was removed and the aqueous layer was extracted
with EtOAc (15 mLꢂ2). The organic layers were combined and
dried over anhydrous Na2SO4, filtered, concentrated, and the
residue was purified by chromatography (silica gel, petroleum
ether/EtOAc, 10:1).
4.4.1. (S)-2,4,6-Triphenyl-4-(trifluoromethyl)-4H-1,3-oxazine
(7a). Yellow oil, yield 73%, ½a D34
ꢃ
þ140.0 (c 0.1, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
8.19 (d, J¼7.1 Hz, 2H), 7.96 (d, J¼7.2 Hz, 2H), 7.81
(d, J¼7.2 Hz, 2H), 7.64 (dd, J¼15.4, 7.6 Hz, 2H), 7.42e7.56 (m, 7H),
5.96 (s, 1H); 13C NMR (101 MHz, CDCl3)
d
194.4, 166.2, 138.2, 136.0,
133.7, 132.7, 129.1, 129.0, 129.0, 128.7, 128.6, 128.5, 127.4, 125.9, 124.1
(q, J¼283.1 Hz), 88.3, 84.2 (q, J¼27.2 Hz); 19F NMR (377 MHz, CDCl3)
d
ꢀ69.7; IR (KBr, cmꢀ1): 3064, 2913, 2843, 1696, 1654, 1447, 1252,
1169, 1070, 1025, 691; HRMS calcd for C23H17F3NO2 [MþHþ]:
396.1206, found: 396.1209.
4.3.1. (S)-3-Amino-4,4,4-trifluoro-1,3-diphenylbutan-1-one
(4a). Colorless oil, yield 98%, ½a D34
ꢃ
þ161.0 (c 0.8, CHCl3); 1H NMR
Acknowledgements
(400 MHz, CDCl3)
d
7.69e7.82 (m, 2H), 7.46 (d, J¼7.6 Hz, 2H), 7.41 (t,
J¼7.4 Hz, 1H), 7.28 (t, J¼7.8 Hz, 2H), 7.13e7.23 (m, 3H), 4.02 (AB,
The National Natural Science Foundation of China (21072028),
the Fundamental Research Funds for the Central Universities and
the Scientific Research Foundation for the Returned Overseas Chi-
nese Scholars, State Education Ministry are greatly acknowledged
for funding this work.
J¼17.5 Hz, 1H), 3.43 (AB, J¼17.5 Hz, 1H), 2.43 (s, 2H); 13C NMR
(101 MHz, CDCl3)
d 196.4, 138.0, 137.0, 133.7, 128.8, 128.4, 128.2,
127.9, 126.6, 1256.2 (q, J¼284.8 Hz), 61.3 (q, J¼26.3 Hz), 42.8; 19F
NMR (376 MHz, CDCl3)
d
ꢀ78.9; IR (KBr, cmꢀ1): 3395, 3330, 2925,

Y. Liu et al. / Tetrahedron 68 (2012) 4955e4961
4961
7. Sukach, V. A.; Golovach, N. M.; Pirozhenko, V. V.; Rusanov, E. B.; Vovk, M. V.
Tetrahedron: Asymmetry 2008, 19, 761.
References and notes
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