Zinc-mediated enantioselective addition of terminal 1,3-diynes to N-arylimines of trifluoropyruvates

Article abstract of DOI:10.1016/j.tet.2012.05.086

A facile and effective enantioselective addition of terminal 1,3-diynes to acyclic α-CF₃ ketimine esters has been developed by using zinc/Binol complexes. The reaction works well with a variety of aromatic-, aliphatic- and silyl-substituted diynes, providing the desired products in up to 97% yield and 97% enantiomeric excess.

Full text of DOI:10.1016/j.tet.2012.05.086

Tetrahedron 68 (2012) 7663e7669
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Zinc-mediated enantioselective addition of terminal 1,3-diynes to N-arylimines
of trifluoropyruvates
*
Fa-Guang Zhang, Hai Ma, Yan Zheng, Jun-An Ma
Department of Chemistry, Tianjin University, Tianjin 300072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and effective enantioselective addition of terminal 1,3-diynes to acyclic a-CF3 ketimine esters has
Received 28 February 2012
Received in revised form 30 April 2012
Accepted 22 May 2012
been developed by using zinc/Binol complexes. The reaction works well with a variety of aromatic-,
aliphatic- and silyl-substituted diynes, providing the desired products in up to 97% yield and 97% en-
antiomeric excess.
Available online 29 May 2012
Ó 2012 Published by Elsevier Ltd.
Keywords:
Diynylation
Propargylamines
Addition
Enantioselectivity
Ketimines
1. Introduction
Conjugated diynes are potentially intriguing building blocks for
advanced materials and fascinating bioactive natural products.9
As optically active propargylamines are synthetically versatile
intermediates for many natural products and compounds of bi-
ological and pharmaceutical significance, asymmetric nucleophilic
addition of alkynylmetallic reagents to imines, providing
a straightforward access to chiral propargylamines, has attracted
more and more attention in the past decade.1 The early studies
focused on using Li and Cu salts in combination with nitrogen-
containing ligands to catalyze the enantioselective alkynylation of
N-aryl aldimines.2 Subsequently, several methods without the use
of Cu complexes have also been developed, such as Hoveyda’s
Zr(OiPr)4epeptide system,3 Bolm and Jiang’s Zneamino alcohol
complexes,4 Rueping and Arndtsen’s combination catalysis of
Brønsted acids and metal salts,5 as well as Chong and Soderquist’s
chiral alkynylborane system.6 Recently, Pedro and co-workers de-
scribed an alternative alkynylation reaction of N-sulfonylaldimines
by using a zinc/Binol complex.7 Most of the above metal-catalyzed
or -mediated asymmetric alkynylation reactions produced enan-
tioenriched secondary propargylamines. In sharp contrast, reports
about the catalytic enantioselective alkynylation of ketimines are
very limited.8 Therefore, the development of new asymmetric
catalytic reactions for the synthesis of chiral tertiary propargyl-
amines is still needed.
Metal-triggered asymmetric addition of diyne nucleophiles to
prochiral carbonyl and imine substrates represents the most con-
vergent and efficient approach to the synthesis of enantioenriched
diyne derivatives, but only a few methods to prepare such in-
teresting compounds have been developed. Carreira and co-
workers provided the first example of asymmetric addition of
1,3-diynes to aldehydes in the presence of excess Zn(OTf)2, Et3N,
and N-methyl ephedrine,10 whereas Trost,11a Pu,11b and Tyk-
winski11c demonstrated asymmetric diynylation reactions of
a range of aldehydes by using zinc-complexes. Recently, our group
disclosed Cu-catalyzed and Zn-mediated enantioselective addition
of 1,3-dynes to aromatic ketones and cyclic trifluoromethyl N-
acylketimines.12 Encouraged by these results and as a part of our
continued interests in the enantioselective synthesis of organo-
fluorine compounds,13 we envisioned that trifluoromethylated
tertiary chiral
a-amino acids could be constructed by a Zn-
mediated enantioselective diynylation of N-arylimines of tri-
fluoropyruvates. Herein, we wish to report the successful imple-
mentation of this process to provide diynylated
derivatives.
a-amino acid
2. Results and discussion
1,3-Diynes were easily prepared according to Scheme 1a. Re-
action of simple alkynes with readily available 2-methyl-3-butyn-
2-ol in the presence of CuCl produced the coupling products, which
* Corresponding author. Tel.: þ86 022 2740 2903; fax: þ86 22 2740 3475; e-mail
address: majun_an68@tju.edu.cn (J.-A. Ma).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.05.086

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F.-G. Zhang et al. / Tetrahedron 68 (2012) 7663e7669
the 3,30-positions of the binaphthyl backbone, the adduct 3a was
obtained in high yield with 20e65% ee (entries 2e5). Subsequently,
ligands L6e10 having heteroatom substituents at the 3,30-positions
of the binaphthyl backbone were tested (entries 6e10). The enan-
tioselectivity can be significantly improved from 64% ee (L3) to 83%
ee (L7) and 84% ee (L8, entries 7 and 8). However, the introduction
of bulky substituents and strong-withdrawing groups led to de-
creased activity and/or enantioselectivity (entries 9 and 10). Fur-
ther optimization of the enantioselectivity was achieved with
ligand L8 by screening different solvents, lowering the reaction
temperature, and the amount of ligand (entries 11e16). Thus, the
addition reaction of 1,3-terminal alkyne 2a to ketimine ester 1a
could be efficiently performed in toluene at 0 ꢀC providing the
trifluoromethylated product 3a in 93% yield 88% ee.
Scheme 1. Synthesis of 1,3-diynes.
were converted into 1,3-diynes by treatment with potassium hy-
droxide in refluxing toluene.14a For the bulky ethynylanthracene,
however, the yield of this sequence is poor. Therefore, an alterna-
tive mild two-step synthesis of 9-(buta-1,3-diynyl)anthracene was
employed as shown in Scheme 1b. Reaction of ethynylanthracene
with cis-1,2-dichloroethylene in the presence of butylamine and
CuI gave the corresponding coupling product, which was converted
to the resulting bis-ethynylanthracene by treatment with tetrabu-
tylammonium fluoride in tetrahydrofuran.14b Due to their intrinsic
instability, some of the resulting terminal diynes were dissolved
into the solvent for the utility of subsequent asymmetric addition.
In our initial screening study, we chose the a-CF3 ketimine ester
1a and simple phenyl diyne 2a as model substrates. First, a 1.2 M
dimethylzinc solution in toluene (2 equiv) was added dropwise to
the terminal 1,3-diyne (2 equiv) under nitrogen at rt. After stirring
for 1 h, the appropriate chiral ligand was added to the mixture and
stirred for 3 h. Finally, the ketimine ester was injected slowly to
complete the reaction. Preliminarily, we found that the desired
product 3a was obtained in 90% yield and 26% ee when using Binol
as chiral ligand L1 (Table 1, entry 1). This result encouraged us to
investigate this reaction systematically. A series of Binol-derived
ligands, which incorporated different substituents at the 3,30-po-
sitions of the binaphthyl backbone, were evaluated in this model
reaction (Scheme 2). The results revealed that the steric and elec-
tronic effects of the substituents influence the reaction activity and
enantioselectivity. When the aromatic substituents were placed in
Scheme 2. Enantioselective diynylation of acyclic a-CF3 ketimine ester.
Table 2
Catalytic enantioselective addition of terminal 1,3-diynes 2 to
a-CF3 ketimine esters
1 to afford the adducts 3a
Table 1
Optimization studies for the enantioselective addition of terminal 1,3-diynes 2a to
a
Entry
Product 3 (R1, R2, R)
3a (2-OMe, Et, Ph)
Yieldb (%)
eec (%)
-CF3 ketimine ester 1aa
1
2
3
4
5
6
7
8
93
95
90
94
85
97
91
88
90
87
92
85
92
76
90
90
92
90
88
88
87
87
86
93
92
92
90
89
92
87
92
89
90
86
97
94
Entry
Ligand
Solvent
T (ꢀC)
Yieldb (%)
eec (%)
3b (2-OMe, Et, 4-FC6H4)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L8
L8
L8
L8
L8
L8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
Xylene
Toluene
Toluene
Toluene
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
90
90
93
92
92
93
95
95
80
90
93
85
70
93
80
90
26
46
64
60
20
65
83
84
6
50
81
82
70
88
85
75
3c (2-OMe, Et, 4-ClC6H4)
3d (2-OMe, Et, 4-BrC6H4)
3e (2-OMe, Et, 2-ClC6H4)
3f (2-OMe, Et, 4-OMeC6H4)
3g (2-OMe, Et, 4-MeC6H4)
3h (2-OMe, Et, 2-OMeC6H4)
3i (2-OMe, Et, 3-OMeC6H4)
3j (2-OMe, Et, 1-naphthyl)
3k (2-OMe, Et, 1-cyclohexenyl)
3l (2-OMe, Et, triisopropylsilyl)
3m (2-OMe, Et, PhCH2CH2)
3n (2-OMe, Et, cyclopropyl)
3o (2-OMe, Me, Ph)
9
10
11
12d
13
14d
15
16
17
18
9
10
11
12
13
14
15
16d
3p (4-OMe, Et, Ph)
3q (2,4-Br2e6-OMe, Et, 1-naphthyl)
3r (2,4-Br2e6-OMe, Et, 9-anthryl)
ꢁ10
0
a
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), 1.2 M ZnMe2 in toluene
Reaction conditions (unless otherwise specified): 1 (0.1 mmol), 2 (0.2 mmol),
(0.2 mmol), ligand (10 mol %) at rt for 24 h (or 0 ꢀC for 48 h/ꢁ10 ꢀC for 96 h).
1.2 M ZnMe2 in toluene (0.2 mmol), L8 (10 mol %) at 0 ꢀC for 48 h.
b
b
Isolated yield.
Isolated yield.
c
c
Enantiomeric excess was determined by chiral HPLC analysis.
Ligand (5 mol %).
Enantiomeric excess was determined by chiral HPLC analysis.
3 equiv of 2 was used.
d
d

F.-G. Zhang et al. / Tetrahedron 68 (2012) 7663e7669
7665
With the optimized reaction conditions in hand, we then set
out to investigate the scope of this addition reaction. Represen-
tative results are summarized in Table 2. A variety of terminal
1,3-diynes, including aryl-, alkyl-, and silyl-substituted terminal
diynes are all tolerated in the reaction and provided good to high
yields (76e97%) with ee values ranging from 86% to 97%. It was
found that the electronic nature of the substituent groups has
some influences on the enantioselectivity. Aromatic terminal
1,3-diynes with an electron-withdrawing group on the phenyl ring
gave slightly lower ee values (products 3be3e, entries 2e5). On
the other hand, several terminal diynes having electron-donating
groups on the aromatic rings gave higher enantioselectivity (ad-
ducts 3fe3i, entries 6e9). It should be noted that when the sub-
stituent is in the ortho position of the aromatic rings, reduced
investigation, and extending substrate classes are undertaken in
our laboratory.
3. Experimental section
3.1. General information
1H, 13C, and 19F NMR spectra were recorded on a Bruker AV
400 MHz spectrometer at 400 MHz (1H NMR), 100 MHz (13C NMR),
as well as 376 MHz (19F NMR). Chemical shifts were reported in
parts per million (ppm) from the solvent resonance as the internal
standard (CDCl3: 7.26 ppm). MS was recorded on a VG-7070E or HP
5988A spectrometer using the ESI method. Melting points were
measured on a WRS-1A digital melting point apparatus and are
uncorrected. Optical rotations were determined using an Autopol
IV-T. IR spectra were recorded on an AVATAR 360 FT-IR spectrom-
eter. HPLC analyses were carried out on a Hewlett Packard Model
HP 1200 instrument. Tetrahydrofuran (THF), diethyl ether, and
toluene were distilled from sodium/benzophenone prior to use;
CH2Cl2 was distilled from CaH2. Analytical thin layer chromatog-
raphy was performed on 0.20 mm Qingdao Haiyang silica gel
plates. Silica gel (200e300 mesh) (from Qingdao Haiyang Chem.
Company, Ltd.) was used for flash chromatography. Dimethylzinc,
1.2 M solution in toluene was purchased from ACROS. Most of the
terminal diynes were prepared in pure form and used directly in
the asymmetric addition reaction. The diyne 2h was too unstable to
handle it in its pure form and should be dissolved into dry toluene
before use. The Binol ligands L2eL7,15a L8 and L9,15b and L1015c were
prepared according to the literatures. Trifluoromethylated ketimine
esters were synthesized according to the literature.8 Standard re-
agents and solvents were purified according to known procedures.
yields were observed (entries
5
and 8). 10-Naphthyl- and
10-cyclohexenyl-1,3-diyne also gave the diynylation adducts 3j and
3k in high yields with 89% ee and 92% ee, respectively (entries 10
and 11). Triisopropylsilyl-substituted 1,3-diyne is also a feasible
substrate, affording the desired product 3l in 85% yield with 87% ee
(entry 12), which could be a potential building block for further
transformation. Gratifyingly, aliphatic-substituted terminal
1,3-diynes were found to be suitable for this asymmetric trans-
formation, providing the diynylation adducts 3m and 3n in high
enantioselectivity (entries 13 and 14). In addition, other acyclic
a
-CF3 ketimine esters were also probed, and the desired adducts
3oe3r were obtained in high yields and enantioselectivities (en-
tries 15e18).
Adducts 3 are versatile synthetic intermediates and can be
readily transformed into highly functionalized a-amino acid and
amino alcohol derivatives that are otherwise difficult to access. For
example, we performed the diynylation addition on a large scale
(2 mmol of substrate 1a) under this zinc/Binol catalysis system. The
trifluoromethylated adduct 3a was obtained in 92% yield with 88%
ee (Scheme 3). Then, direct hydrogenation of 3a in the presence of
3.2. General procedures for the diynylation of
ester 1
a-CF3 ketimine
Pd/C, followed by deprotection, afforded trifluoromethylated
a-
amino acid 4 in 72% total yield without any loss of enantiose-
lectivity. In addition, reduction of 3a in the presence of LiAlH4 in
THF delivered the highly functionalized amino alcohol 5 in 71%
isolated yield with 89% ee.
A 1.2 M solution of Me2Zn in toluene (0.2 mmol) was added
dropwise to a solution of terminal 1,3-diyne 2 (0.2 mmol) in tolu-
ene (0.5 mL) at rt under nitrogen in about 5 min. After stirring for
1 h, the Binol ligand (0.02 mmol) was added as a solid in one por-
tion. The reaction mixture was stirred for 3 h at the same temper-
ature, after which the ketimine ester (0.1 mmol) in toluene (0.5 mL)
was added slowly (10 min) at 0 ꢀC. The solution was stirred at 0 ꢀC
until the reaction was complete (detected by TLC). The reaction
mixture was quenched with saturated NH4Cl (10 mL), extracted
with EtOAc (10 mLꢂ3), dried over MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography on silica gel
(petroleum ether/ethyl acetate¼100:1) afforded the product 3.
3.2.1. Ethyl 2-(2-methoxyphenylamino)-6-phenyl-2-(trifluoromethyl)
hexa-3,5-diynoate (3a). 37 mg, light yellow solid, mp 60e62 ꢀC, 93%
yield, 88% ee, HPLC (DAICEL Chiralpak IA, hexane/iPrOH (IPA)¼
98.7:1.3, 0.8 mL/min, 254 nm) tR (major)¼8.3 min, tR (minor)¼
7.6 min, ½a 2D0
ꢃ
ꢁ34.8 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.53
(d, J¼7.1 Hz, 2H), 7.42 (t, J¼7.3 Hz, 1H), 7.35 (t, J¼7.4 Hz, 2H), 7.16 (d,
J¼7.4 Hz, 1H), 6.96e6.86 (m, 3H), 5.77 (s, 1H), 4.50e4.39 (m, 2H),
3.92 (s, 3H), 1.39 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
Scheme 3. Scaled-up version of the addition reaction and further synthetic
transformations.
d
ꢁ73.76 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.5, 148.4, 132.8,
1
132.6, 129.8, 128.5, 122.8 (q, JFeC¼287.2 Hz), 120.7, 120.6, 120.3,
2
In conclusion, we have developed a facile and efficient catalytic
115.4, 110.0, 80.0, 74.1, 72.7, 71.6, 64.6, 63.8 (q, JFeC¼32.1 Hz), 55.7,
13.8; MS (ESI): 402.3(MþH)þ; HRMS (ESI) found: m/z 424.1158
enantioselective addition of terminal 1,3-diynes to acyclic
a-CF3
[MþNa]þ; calcd for C22H18F3NO3þNa 424.1239; IR (KBr):
n 3371,
ketimine esters. In the presence of a zinc/Binol complex, a series of
trifluoromethylated tertiary amino acid esters were obtained in
76e97% yields with 86e97% ee. The products can be conveniently
converted into the corresponding optically active functionalized
amino acid and alcohol derivatives. Further studies including the
determination of the products’ absolute configuration, mechanistic
2967, 2937, 2231, 1749, 1513, 1262, 1027, 753, 457 cmꢁ1
.
3.2.2. Ethyl 6-(4-fluorophenyl)-2-(2-methoxyphenyl amino)-2-(tri-
fluoromethyl)hexa-3,5-diynoate (3b). 40 mg, light yellow oil, 95%
yield, 88% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.5:1.5,

7666
F.-G. Zhang et al. / Tetrahedron 68 (2012) 7663e7669
0.8 mL/min, 254 nm) tR (major)¼7.6 min, tR (minor)¼7.2 min, ½a D20
ꢃ
3H), 1.37 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.81 (s,
ꢁ28.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.51 (dd, J¼8.6,
3F); 13C NMR (100 MHz, CDCl3)
d 164.6, 160.8, 148.4, 134.5, 132.6,
5.4 Hz, 2H), 7.13 (d, J¼8.3 Hz, 1H), 7.05 (t, J¼8.6 Hz, 2H), 6.93e6.85
122.9 (q, 1JFeC¼287.1 Hz),120.6,120.2,115.4,114.2,112.5,109.9, 80.3,
2
(m, 3H), 5.74 (s, 1H), 4.49e4.38 (m, 2H), 3.91 (s, 3H), 1.37 (t,
74.5, 71.7, 71.1, 64.5, 63.7 (q, JFeC¼31.9 Hz), 55.7, 55.3, 13.8; MS
J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.79 (s, 3F), ꢁ107.36
(ESI): 453.6 (MþNa)þ; HRMS (ESI) found: m/z 454.1240 [MþNa]þ;
to ꢁ107.43 (m, 1F); 13C NMR (100 MHz, CDCl3)
d
164.4, 163.4 (d,
calcd for C23H20F3NO4þNa 454.1344; IR (KBr):
n
3374, 2957, 2925,
.
3
1JFeC¼251.4 Hz), 148.4, 134.9 (d, JFeC¼8.7 Hz), 132.5, 122.8 (q,
2234, 1756, 1512, 1257, 1178, 1029, 743, 536 cmꢁ1
1JFeC¼287.2 Hz), 120.7, 120.5, 120.3, 116.0 (d, JFeC¼22.3 Hz), 115.4,
2
110.0, 78.9, 73.9, 72.5, 71.7, 64.6, 63.8 (q, 2JFeC¼32.4 Hz), 55.7, 13.8;
MS (ESI): 442.1 (MþNa)þ; HRMS (ESI) found: m/z 442.1044
3.2.7. Ethyl 2-(2-methoxyphenylamino)-6-p-tolyl-2-(trifluoromethyl)
hexa-3,5-diynoate (3g). 37 mg, yellow solid, mp 48e50 ꢀC, 91% yield,
92% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.8:1.2, 0.8 mL/
[MþNa]þ; calcd for C22H17F4NO3þNa 442.1145; IR (KBr):
n 3375,
2957, 2924, 2238, 1757, 1511, 1261, 1028, 743, 532 cmꢁ1
.
min, 254 nm) tR (major)¼7.9 min, tR (minor)¼7.6 min, ½a D20
ꢁ18.8 (c
ꢃ
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.42 (d, J¼7.9 Hz, 2H), 7.16
3.2.3. Ethyl 6-(4-chlorophenyl)-2-(2-methoxyphenyl amino)-2-(tri-
fluoromethyl)hexa-3,5-diynoate (3c). 39 mg, light yellow oil, 90%
yield, 87% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3,
(d, J¼7.7 Hz, 3H), 6.95e6.84 (m, 3H), 5.76 (s, 1H), 4.49e4.39 (m, 2H),
3.91 (s, 3H), 2.38 (s, 3H), 1.38 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz,
CDCl3)
d
ꢁ73.39 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.5, 148.4,
0.8 mL/min, 254 nm) tR (major)¼8.6 min, tR (minor)¼8.0 min, ½a D20
ꢃ
140.4, 132.7, 129.3, 122.8 (q, 1JFeC¼287.1 Hz),120.6,120.2,120.0,117.6,
ꢁ25.8 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.45 (d, J¼8.4 Hz,
115.4, 110.0, 80.3, 74.3, 72.2, 71.3, 64.5, 63.7 (q, JFeC¼31.9 Hz), 55.7,
2
2H), 7.33 (d, J¼8.4 Hz, 2H), 7.13 (d, J¼7.9 Hz, 1H), 6.91 (dd, J¼10.4,
6.3 Hz, 3H), 5.75 (s, 1H), 4.49e4.39 (m, 2H), 3.91 (s, 3H), 1.38 (t,
21.6, 13.8; MS (ESI): 429.9 (MþNa)þ; HRMS (ESI) found: m/z
438.1306 [MþNa]þ; calcd for C23H20F3NO3þNa 438.1395; IR (KBr):
n
J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.75 (s, 3F); 13C NMR
3372, 2957, 2925, 2236, 1757, 1513, 1260, 1027, 817, 743, 530,
(100 MHz, CDCl3)
d
164.4, 148.4, 136.1, 133.9, 132.5, 128.9, 122.8 (q,
452 cmꢁ1
.
1JFeC¼286.9 Hz), 120.5, 120.3, 119.2, 115.4, 110.0, 78.7, 73.8, 73.6,
2
72.2, 64.6, 63.8 (q, JFeC¼31.9 Hz), 55.7, 13.8; MS (ESI): 457.6
3.2.8. Ethyl 6-(2-methoxyphenyl)-2-(2-methoxy phenylamino)-2-
(trifluoromethyl)hexa-3,5-diynoate (3h). 38 mg, slight yellow solid,
mp 68e70 ꢀC, 88% yield, 92% ee, HPLC (DAICEL Chiralpak IB, hex-
ane/IPA¼98.7:1.3, 0.8 mL/min, 254 nm) tR (major)¼11.2 min, tR
(MþNa)þ; HRMS (ESI) found: m/z 458.0733 [MþNa]þ; calcd for
C22H17ClF3NO3þNa 458.0849; IR (KBr):
n
3380, 3003, 2948, 2233,
.
1753, 1513, 1263, 1183, 1013, 750, 451 cmꢁ1
(minor)¼11.5 min, ½a D20
ꢃ
ꢁ18.8 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
3.2.4. Ethyl 6-(4-bromophenyl)-2-(2-methoxy phenylamino)-2-(tri-
fluoromethyl)hexa-3,5-diynoate (3d). 45 mg, light yellow solid, mp
66e67 ꢀC, 94% yield, 87% ee, HPLC (DAICEL Chiralpak IA, hexane/
IPA¼98.7:1.3, 0.8 mL/min, 254 nm) tR (major)¼9.9 min, tR (minor)¼
CDCl3)
d
7.47 (d, J¼7.6 Hz, 1H), 7.37 (t, J¼7.9 Hz, 1H), 7.14 (d,
J¼7.2 Hz, 1H), 6.95e6.86 (m, 5H), 5.75 (s, 1H), 4.48e4.37 (m, 2H),
3.91 (s, 3H), 3.90 (s, 3H), 1.37 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz,
CDCl3)
d
ꢁ73.70 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.5, 161.7,
8.9 min, ½a 2D0
ꢃ
ꢁ25.6 (c 2.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.49
148.3, 134.8, 132.6, 131.3, 122.8 (q, JFeC¼287.0 Hz), 120.6, 120.1,
115.4, 110.7, 110.0, 109.9, 76.6, 76.4, 74.4, 72.1, 64.5, 63.7 (q,
2JFeC¼32.0 Hz), 55.8, 55.7, 13.8; MS (ESI): 453.6 (MþNa)þ; HRMS
(ESI) found: m/z 454.1243 [MþNa]þ; calcd for C23H20F3NO4þNa
1
(d, J¼8.4 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.12 (d, J¼6.5 Hz, 1H),
6.92e6.86 (m, 3H), 5.75 (s, 1H), 4.49e4.39 (m, 2H), 3.91 (s, 3H), 1.38
(t, J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.75 (s, 3F); 13C
NMR (100 MHz, CDCl3)
d
164.3,148.4,134.1,132.6,131.9,124.4,122.7
454.1344; IR (KBr):
n 3362, 2957, 2925, 2235, 1756, 1513, 1462, 1257,
.
(q, 1JFeC¼287.1 Hz), 120.6, 120.3, 119.7, 115.4, 110.0, 78.9, 73.9, 73.8,
1025, 748, 455 cmꢁ1
2
72.3, 64.6, 63.8 (q, JFeC¼32.3 Hz), 55.7, 13.8; MS (ESI): 501.4
(MþNa)þ; HRMS (ESI) found: m/z 504.0196 [MþNa]þ; calcd for
3.2.9. Ethyl 6-(3-methoxyphenyl)-2-(2-methoxy phenylamino)-2-
(trifluoromethyl)hexa-3,5-diynoate (3i). 39 mg, yellow oil, 90%
yield, 90% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3,
C22H17BrF3NO3þNa 504.0323; IR (KBr):
n 3382, 2960, 2233, 1757,
1509, 1263, 1013, 749, 458 cmꢁ1
.
0.8 mL/min, 254 nm) tR (major)¼8.0 min, tR (minor)¼7.6 min, ½a D20
ꢃ
3.2.5. Ethyl 6-(2-chlorophenyl)-2-(2-methoxyphenyl amino)-2-(tri-
fluoromethyl)hexa-3,5-diynoate (3e). 37 mg, light yellow solid, mp
50e52 ꢀC, 85% yield, 86% ee, HPLC (DAICEL Chiralpak IA, hexane/
IPA¼99.0:1.0, 0.8 mL/min, 254 nm) tR (major)¼9.6 min, tR (minor)¼
ꢁ25.6 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.26 (dd, J¼13.1,
5.1 Hz, 1H), 7.13 (t, J¼7.6 Hz, 2H), 7.04 (s, 1H), 7.00e6.83 (m, 4H),
5.76 (s, 1H), 4.53e4.36 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 1.38 (t,
J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.77 (s, 3F); 13C NMR
9.0 min, ½a 2D0
ꢃ
ꢁ37.4 (c 2.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.55
(100 MHz, CDCl3) d 164.4, 159.3, 148.4, 132.5, 129.6, 125.3, 122.8 (q,
(d, J¼7.5 Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H), 7.33 (t, J¼7.7 Hz, 1H), 7.24 (t,
J¼7.5 Hz, 1H), 7.14 (d, J¼8.0 Hz, 1H), 6.92e6.88 (m, 3H), 5.76 (s, 1H),
4.50e4.39 (m, 2H), 3.91 (s, 3H), 1.38 (t, J¼7.1 Hz, 3H); 19F NMR
1JFeC¼287.1 Hz), 121.6, 120.6, 120.3, 117.3, 116.7, 115.4, 110.0, 79.9,
2
74.1, 72.5, 71.6, 64.6, 63.8 (q, JFeC¼32.0 Hz), 55.7, 55.3, 13.8; MS
(ESI): 453.7 (MþNa)þ; HRMS (ESI) found: m/z 454.1236 [MþNa]þ;
(376 MHz, CDCl3)
d
ꢁ73.67 (s, 3F); 13C NMR (100 MHz, CDCl3)
calcd for C23H20F3NO4þNa 454.1344; IR (KBr):
n
3363, 2958, 2924,
.
d
164.3, 148.4, 137.2, 134.7, 132.5, 130.7, 129.5, 126.6, 122.8 (q,
2231, 1754, 1513, 1462, 1261, 1025, 748, 451 cmꢁ1
1JFeC¼287.0 Hz), 121.0, 120.6, 120.4, 115.5, 110.0, 77.3, 76.3, 73.8,
2
73.2, 64.6, 63.8 (q, JFeC¼32.1 Hz), 55.7, 13.8; MS (ESI): 457.5
3.2.10. Ethyl
2-(2-methoxyphenylamino)-6-(naphthalen-1-yl)-2-
(MþNa)þ; HRMS (ESI) found: m/z 458.0742 [MþNa]þ; calcd for
(trifluoromethyl)hexa-3,5-diynoate (3j). 39 mg, slight yellow solid,
mp 92e94 ꢀC, 87% yield, 89% ee, HPLC (DAICEL Chiralpak IA, hex-
ane/IPA¼98.7:1.3, 0.8 mL/min, 254 nm) tR (major)¼7.9 min, tR
C22H17ClF3NO3þNa 458.0849; IR (KBr):
n
3380, 3003, 2948, 2233,
.
1753, 1513, 1263, 1183, 1013, 750, 451 cmꢁ1
(minor)¼7.6 min, ½a D20
ꢃ
ꢁ27.0 (c 1.0, CH2Cl2); 1H NMR (400 MHz,
3.2.6. Ethyl 6-(4-methoxyphenyl)-2-(2-methoxy phenylamino)-2-
(trifluoromethyl)hexa-3,5-diynoate (3f). 42 mg, yellow oil, 97%
yield, 93% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3,
0.8 mL/min, 254 nm) tR (major)¼10.6 min, tR (minor)¼9.7 min,
CDCl3)
d
8.30 (d, J¼8.2 Hz, 1H), 7.93e7.86 (m, 2H), 7.79 (d, J¼7.2 Hz,
1H), 7.65e7.59 (m, 1H), 7.56 (t, J¼7.4 Hz, 1H), 7.44 (t, J¼7.7 Hz, 1H),
7.21 (d, J¼7.6 Hz, 1H), 6.97e6.86 (m, 3H), 5.80 (s, 1H), 4.52e4.42 (m,
2H), 3.93 (s, 3H), 1.40 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
½
a 2D0
ꢃ
ꢁ29.6 (c 2.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.46 (d,
d
ꢁ73.68 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.5, 148.4, 133.9,
J¼8.8 Hz, 2H), 7.15 (d, J¼7.3 Hz, 1H), 6.94e6.88 (m, 2H), 6.86 (d,
J¼8.9 Hz, 3H), 5.75 (s, 1H), 4.49e4.38 (m, 2H), 3.91 (s, 3H), 3.83 (s,
133.0, 132.7, 132.6, 130.4, 128.5, 127.4, 126.8, 125.9, 125.1, 122.9 (q,
1JFeC¼286.8 Hz), 120.6, 120.3, 118.4, 115.5, 110.0, 78.5, 77.2, 74.3,

F.-G. Zhang et al. / Tetrahedron 68 (2012) 7663e7669
7667
2
72.7, 64.6, 63.9 (q, JFeC¼31.9 Hz), 55.7, 13.9; MS (ESI): 452.2
yield, 90% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3,
(MþH)þ; HRMS (ESI) found: m/z 474.1282 [MþNa]þ; calcd for
0.8 mL/min, 254 nm) tR (major)¼8.4 min, tR (minor)¼8.0 min, ½a D20
ꢃ
C26H20F3NO3þNa 474.1395; IR (KBr):
n
3369, 3005, 2948, 2230,
ꢁ13.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.52 (d, J¼7.1 Hz,
1752, 1513, 1289, 1032, 744, 448 cmꢁ1
.
2H), 7.41 (d, J¼7.3 Hz, 1H), 7.35 (t, J¼7.4 Hz, 2H), 7.12 (d, J¼8.6 Hz, 1H),
6.91 (dd, J¼10.6, 6.7 Hz, 3H), 5.70 (s, 1H), 3.98 (s, 3H), 3.91 (s, 3H); 19F
3.2.11. Ethyl 6-cyclohexenyl-2-(2-methoxyphenyl amino)-2-(tri-
fluoromethyl)hexa-3,5-diynoate (3k). 37 mg, yellow oil, 92% yield,
92% ee, HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3, 0.8 mL/min,
NMR (376 MHz, CDCl3)
d
ꢁ73.90 (s, 3F); 13C NMR (100 MHz, CDCl3)
1
d
165.1, 148.4, 132.8, 132.4, 129.9, 128.5, 122.7 (q, JFeC¼286.8 Hz),
120.7, 120.6, 120.4, 115.4, 110.0, 80.1, 74.2, 72.6, 71.4, 63.7 (q,
2JFeC¼32.0 Hz), 55.7, 54.9; MS (ESI): 387.2 (M)þ; HRMS (ESI) found:
m/z 410.0976 [MþNa]þ; calcd for C21H16F3NO3þNa 410.1082; IR (KBr):
254 nm) tR (major)¼7.0 min, tR (minor)¼6.5 min, ½a D20
ꢁ14.0 (c 1.0,
ꢃ
CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.11 (d, J¼8.2 Hz,1H), 6.86e6.90
(m, 3H), 6.36 (s, 1H), 5.72 (s, 1H), 4.46e4.36 (m, 2H), 3.90 (s, 3H), 2.13
(s, 4H), 1.65e1.58 (m, 4H), 1.35 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz,
n .
3365, 2962, 2928, 2232, 1761, 1511, 1293, 1028, 746, 454 cmꢁ1
CDCl3)
d
ꢁ73.88 (s, 3F); 13C NMR (100 MHz, CDCl3)
d
164.6, 148.3,
3.2.16. Ethyl 2-(4-methoxyphenylamino)-6-phenyl-2-(trifluoromethyl)
hexa-3,5-diynoate (3p). 36 mg, light yellow oil, 90% yield, 86% ee,
HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.7:1.3, 0.8 mL/min,
140.6, 132.6, 122.8 (q, 1JFeC¼286.7 Hz),120.5, 120.1, 119.1, 115.4,109.9,
2
82.0, 74.5, 70.5, 70.3, 64.5, 63.7 (q, JFeC¼32.1 Hz), 55.7, 28.3, 25.9,
21.9, 21.2, 13.8; MS (ESI): 406.4 (MþH)þ; HRMS (ESI) found: m/z
254 nm) tR (major)¼12.3 min, tR (minor)¼13.3 min, ½a D20
ꢁ31.6 (c
ꢃ
428.1441 [MþNa]þ; calcd for C22H22F3NO3þNa 428.1552; IR (KBr):
n
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.53 (d, J¼7.3 Hz, 2H),
3370, 2927, 2856, 2237, 1757, 1513, 1257, 1030, 743, 454 cmꢁ1
.
7.42 (t, J¼7.3 Hz, 1H), 7.35 (t, J¼7.4 Hz, 2H), 7.04 (d, J¼8.8 Hz, 2H),
6.85 (d, J¼8.8 Hz, 2H), 4.64 (s, 1H), 4.47e4.36 (m, 2H), 3.80 (s, 3H),
3.2.12. Ethyl 2-(2-methoxyphenylamino)-2-(trifluoromethyl)-6-(trii-
sopropylsilyl)hexa-3,5-diynoate (3l). 41 mg, slight yellow solid, mp
84e86 ꢀC, 85% yield, 87% ee, HPLC (DAICEL Chiralpak OJ-H, hexane/
IPA¼98.9:1.1, 0.7 mL/min, 220 nm) tR (major)¼5.7 min, tR (minor)¼
1.38 (t, J¼7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ74.23 (s, 3F);
13C NMR (100 MHz, CDCl3)
d 165.0, 155.5, 135.9, 132.8, 129.8, 128.5,
122.6 (q, 1JFeC¼286.2 Hz), 122.2, 120.7, 114.1, 79.9, 74.7, 72.6, 71.5,
65.6 (q, JFeC¼30.7 Hz), 64.5, 55.5, 13.9; MS (ESI): 402.3 (MþH)þ;
2
6.4 min, ½a 2D0
ꢃ
ꢁ16.2 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.11
HRMS (ESI) found: m/z 424.1133 [MþNa]þ; calcd for
(d, J¼4.2 Hz, 1H), 6.92e6.82 (m, 3H), 5.71 (s, 1H), 4.49e4.37 (m, 2H),
C22H18F3NO3þNa 424.1239; IR (KBr):
n 2957, 2924, 2240, 1753,
3.90 (s, 3H), 1.36 (t, J¼7.1 Hz, 3H), 1.11 (s, 21H); 19F NMR (376 MHz,
1513, 1244, 1034, 757, 530 cmꢁ1
.
CDCl3)
d
ꢁ73.76 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.35, 148.37,
1
132.48, 122.75 (q, JFeC¼287.0 Hz), 120.49, 120.26, 115.46, 109.89,
3.2.17. Ethyl 2-(2,4-dibromo-6-methoxyphenyl amino)-6-(naph-
thalen-1-yl)-2-(trifluoro methyl)hexa-3,5-diynoate (3q). 49 mg,
slight yellow solid, mp 94e96 ꢀC, 92% yield, 97% ee, HPLC (DAICEL
Chiralpak IA, hexane/IPA¼98.7:1.3, 0.8 mL/min, 254 nm) tR
2
88.02, 87.29, 74.58, 65.74, 64.51, 63.57 (q, JFeC¼31.8 Hz), 55.66,
18.46, 13.76, 11.18; MS (ESI): 481.9 (M)þ; HRMS (ESI) found: m/z
504.2163 [MþNa]þ; calcd for C25H34F3NO3SiþNa 504.2260; IR (KBr):
n
3356, 2948, 2868, 2230, 1759, 1512, 1263, 1018, 743, 455 cmꢁ1
.
(major)¼14.2 min, tR (minor)¼15.1 min, ½a D20
þ29.0 (c 1.0, CH2Cl2);
ꢃ
1H NMR (400 MHz, CDCl3)
d
8.22 (d, J¼8.3 Hz, 1H), 7.88 (t,
3.2.13. Ethyl 2-(2-methoxyphenylamino)-8-phenyl-2-(trifluoromethyl)
octa-3,5-diynoate (3m). 40 mg, colorless oil, 92% yield, 92% ee,
HPLC (DAICEL Chiralpak IA, hexane/IPA¼98.0:1.0, 0.8 mL/min,
J¼8.5 Hz, 2H), 7.76 (d, J¼6.8 Hz, 1H), 7.63 (t, J¼7.4 Hz, 1H), 7.55 (t,
J¼7.2 Hz, 1H), 7.42 (dd, J¼13.6, 4.8 Hz, 2H), 7.01 (d, J¼1.5 Hz, 1H),
4.73 (s, 1H), 4.51e4.40 (m, 2H), 3.83 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H);
254 nm) tR (major)¼12.9 min, tR (minor)¼11.9 min, ½a D20
ꢃ
ꢁ11.0 (c
19F NMR (376 MHz, CDCl3)
d
ꢁ74.56 (s, 3F); 13C NMR (100 MHz,
1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.33 (t, J¼7.3 Hz, 2H), 7.27
CDCl3) d 165.3, 154.7, 133.9, 133.0, 132.6, 130.4, 130.1, 128.5, 127.5,
1
(d, J¼6.6 Hz, 1H), 7.23 (t, J¼7.4 Hz, 2H), 7.15e7.09 (m, 1H),
6.85e6.92 (m, 3H), 5.73 (s, 1H), 4.47e4.36 (m, 2H), 3.91 (s, 3H),
2.88 (t, J¼7.5 Hz, 2H), 2.60 (t, J¼7.5 Hz, 2H), 1.36 (t, J¼7.1 Hz, 3H);
127.2, 126.8, 125.8, 125.1, 122.5 (q, JFeC¼286.5 Hz), 120.9, 118.3,
2
117.4, 114.4, 78.3, 73.5, 72.3, 66.2 (q, JFeC¼30.3 Hz), 65.6, 63.9,
55.9, 14.0; MS (ESI): 632.2 (MþNa)þ; HRMS (ESI) found: m/z
19F NMR (376 MHz, CDCl3)
d
ꢁ73.91 (s, 3F); 13C NMR (100 MHz,
631.9487 [MþNa]þ; calcd for C26H18Br2F3NO3þNa 631.9585; IR
CDCl3)
d
164.6, 148.4, 139.8, 132.6, 128.5, 128.4, 126.6, 122.8 (q,
(KBr):
n 3317, 2958, 2926, 2233, 1753, 1496, 1257, 1190, 1038, 773,
1JFeC¼286.8 Hz), 120.5, 120.2, 115.5, 109.9, 82.5, 74.5, 65.1, 64.7,
64.5, 63.8 (q, 2JFeC¼32.0 Hz), 55.7, 34.2, 21.5, 13.8; MS (ESI): 429.3
(M)þ; HRMS (ESI) found: m/z 452.1438 [MþNa]þ; calcd for
565 cmꢁ1
.
3.2.18. Ethyl 6-(anthracen-1-yl)-2-(2,4-dibromo-6-methoxyphen-
ylamino)-2-(trifluoromethyl)hexa-3,5-diynoate (3r). 52 mg, yellow
solid, mp 116e118 ꢀC, 90% yield, 94% ee, HPLC (DAICEL Chiralpak
AD-H, hexane/IPA¼98.9:1.1, 0.8 mL/min, 254 nm) tR (major)¼
C24H22F3NO3þNa 452.1552; IR (KBr):
n 3372, 2957, 2925, 2259,
1755, 1514, 1254, 1224, 1033, 744, 454 cmꢁ1
.
3.2.14. Ethyl 6-cyclopropyl-2-(2-methoxyphenyl
amino)-2-(tri-
12.9 min, tR (minor)¼15.1 min, ½a D20
ꢃ
þ34.6 (c 1.0, CH2Cl2); 1H NMR
fluoromethyl)hexa-3,5-diynoate (3n). 28 mg, slight yellow solid, mp
82e84 ꢀC, 76% yield, 89% ee, HPLC (DAICEL Chiralpak IA, hexane/
IPA¼98.7:1.3, 0.8 mL/min, 254 nm) tR (major)¼5.5 min, tR
(400 MHz, CDCl3)
d
8.44 (s, 1H), 8.39 (d, J¼8.6 Hz, 2H), 8.00 (d,
J¼8.3 Hz, 2H), 7.64 (t, J¼7.5 Hz, 2H), 7.53 (dd, J¼14.8, 7.4 Hz, 3H),
7.44 (s, 1H), 7.04 (s, 1H), 4.75 (s, 1H), 4.54e4.42 (m, 2H), 3.86 (s,
(minor)¼5.2 min, ½a D20
ꢃ
ꢁ13.2 (c 0.5, CH2Cl2); 1H NMR (400 MHz,
3H), 1.46 (t, J¼7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3)
d
ꢁ74.44 (s,
CDCl3)
d
7.09 (d, J¼8.2 Hz, 1H), 6.87 (dd, J¼9.4, 5.3 Hz, 3H), 5.69 (s,
3F); 13C NMR (100 MHz, CDCl3)
d 165.4, 155.0, 134.3, 130.9, 130.2,
1H), 4.48e4.32 (m, 2H), 3.89 (s, 3H), 1.34 (t, J¼7.1 Hz, 3H),
129.6, 128.9, 128.9, 127.6, 127.2, 126.2, 125.9, 122.6 (q,
1JFeC¼286.3 Hz), 121.2, 117.6, 114.3, 83.1, 77.3, 74.1, 73.9, 66.4 (q,
2JFeC¼30.3 Hz), 65.6, 56.0, 14.0; MS (ESI): 682.3 (MþNa)þ; HRMS
(ESI) found: m/z 681.9845 [MþNa]þ; calcd for C30H20Br2F3NO3þNa
1.31e1.21 (m, 1H), 0.91e0.80 (m, 4H); 19F NMR (376 MHz, CDCl3)
d
ꢁ73.96 (s, 3F); 13C NMR (100 MHz, CDCl3)
d 164.6, 148.3, 132.6,
122.8 (q, 1JFeC¼286.7 Hz), 120.5, 120.0, 115.4, 109.9, 86.3, 77.2, 74.8,
2
64.4, 63.4 (q, JFeC¼32.0 Hz), 59.4, 55.7, 13.8, 8.9, 0.0; MS (ESI):
681.9742; IR (KBr):
n 3335, 2959, 2925, 2237, 1756, 1496, 1257,
365.2 (M)þ; HRMS (ESI) found: m/z 388.1136 [MþNa]þ; calcd for
1186, 1037, 773, 547 cmꢁ1
.
C19H18F3NO3þNa 388.1239; IR (KBr):
n 2957, 2924, 2252, 1756,
1514, 1254, 1222, 1029, 743, 573 cmꢁ1
.
3.3. Further transformations of the adducts
3.2.15. Methyl
2-(2-methoxyphenylamino)-6-phenyl-2-(trifluorom-
3.3.1. Ethyl 2-(2-methoxyphenylamino)-6-phenyl-2-(trifluoromethyl)
hexanoate. To a solution of 3a (80 mg, 0.2 mmol) in MeOH (15 mL)
ethyl)hexa-3,5-diynoate (3o). 35 mg, white solid, mp 70e72 ꢀC, 90%

7668
F.-G. Zhang et al. / Tetrahedron 68 (2012) 7663e7669
was added Pd/C 10% (20 mg). The reaction mixture was stirred
under H2 (1 atm) overnight at rt. The reaction mixture was filtered
through a silica gel pad, washed with CH2Cl2, and filtrate was
concentrated. The residue was purified using chromatography on
silica gel (petroleum ether/ethyl acetate¼100:1) to give the hy-
drogenated product (78 mg, 96% yield, 88% ee) as a slight yellow
122.7, 120.6, 119.4, 116.5, 116.5, 110.0, 92.8, 86.5, 65.3 (q,
2JFeC¼28.1 Hz), 64.6, 55.7; HPLC (DAICEL Chiralpak IC, hexane/
IPA¼95:5, 0.8 mL/min, 254 nm) tR (major)¼8.1 min, tR (minor)¼
7.1 min, ½a 2D0
ꢃ
ꢁ10.6 (c 1.0, CH2Cl2); MS (ESI): 362.4 (MþH)þ; HRMS
(ESI) found: m/z 384.1181 [MþNa]þ; calcd for C20H18F3NO2þNa
384.1290; IR (KBr): n 3401, 2957, 2929, 1613, 1517, 1252, 1151, 1029,
oil. 1H NMR (400 MHz, CDCl3)
d
7.27 (dd, J¼9.6, 5.0 Hz, 2H), 7.19 (t,
747, 528 cmꢁ1
.
J¼7.3 Hz, 1H), 7.09 (d, J¼7.3 Hz, 2H), 6.84 (s, 4H), 5.59 (s, 1H),
4.38e4.29 (m, 2H), 3.89 (s, 3H), 2.59e2.39 (m, 3H), 2.30e2.17 (m,
1H), 1.55 (dd, J¼14.6, 7.5 Hz, 2H), 1.29 (t, J¼7.1 Hz, 3H), 1.23e1.14
Acknowledgements
(m, 2H); 19F NMR (376 MHz, CDCl3)
d
ꢁ72.57 (s, 3F); 13C NMR
This work was supported financially by NSFC (20902067 and
20972110) and the Ministry of Education of China.
(100 MHz, CDCl3)
d 168.5, 148.4, 142.0, 133.5, 128.3, 125.0 (q,
1JFeC¼286.3 Hz), 125.7, 120.7, 119.3, 115.0, 110.1, 67.7 (q,
2JFeC¼27.2 Hz), 63.0, 55.8, 35.2, 30.9, 29.4, 22.32, 13.9; HPLC
(DAICEL Chiralpak IA, hexane/IPA¼99.0:1.0, 0.8 mL/min, 254 nm)
tR (major)¼7.7 min, tR (minor)¼8.6 min; MS (ESI): 409.4 (M)þ;
HRMS (ESI) found: m/z 432.1779 [MþNa]þ; calcd for
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.086.
C22H26F3NO3þNa 432.1865; IR (KBr):
n
3367, 2958, 2926, 1747,
.
1518, 1261, 1175, 1027, 803, 743, 700 cmꢁ1
References and notes
3.3.2. Ethyl 2-amino-6-phenyl-2-(trifluoromethyl) hexanoate (4). To
a solution of Cerium (IV) Ammonium Nitrate (CAN, 5.0 equiv) in
MeCN/H2O (4 mL, 1:1) at 0 ꢀC was added a solution of the above
hydrogenated product (41 mg, 0.1 mmol, 1 equiv, 88% ee) in MeCN
(2 mL). The reaction mixture was stirred at 0 ꢀC for 1 h and
quenched with saturated aqueous NaHSO3 (1 mL). The reaction
mixture was extracted with EtOAc. The combined organic extract
was washed with brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo. The residue was purified using chromatogra-
phy on Al2O3 (100% CH2Cl2) to give the desired product 4 (21 mg,
75% yield, 88% ee) as a brown oil. 1H NMR (400 MHz, CDCl3)
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d
7.32e7.28 (m, 2H), 7.22e7.17 (m, 3H), 4.27 (q, J¼6.9 Hz, 2H), 2.64
(t, J¼7.6 Hz, 3H), 2.12 (td, J¼12.9, 4.4 Hz, 1H), 1.82 (br, 2H),
1.73e1.65 (m, 3H), 1.29 (t, J¼7.1 Hz, 4H); 19F NMR (376 MHz, CDCl3)
d
ꢁ77.79 (s, 3F); 13C NMR (100 MHz, CDCl3)
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€
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127.9 (q, 1JFeC¼283.6 Hz), 125.8, 64.7 (q, 2JFeC¼26.4 Hz), 62.5, 35.5,
32.6, 31.3, 22.7, 14.0; HPLC (DAICEL Chiralpak IC, hexane/IPA¼95:5,
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½
a 2D0
ꢃ
ꢁ9.6 (c 0.5, CH2Cl2); MS (ESI): 304.1 (MþH)þ; HRMS (ESI)
found: m/z 304.1503 [MþH]þ; calcd for C15H20F3NO2þH 304.1446;
IR (KBr):
n 3421, 3343, 2962, 2927, 1746, 1460, 1261, 1023, 802, 700,
396 cmꢁ1
.
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a brown oil. 1H NMR (400 MHz, CDCl3)
d 7.50e7.43 (m, 2H), 7.35 (d,
J¼2.2 Hz, 3H), 6.91 (s, 1H), 6.84 (d, J¼5.6 Hz, 3H), 6.33 (d,
J¼16.2 Hz, 1H), 6.20 (d, J¼16.2 Hz, 1H), 5.24 (s, 1H), 4.11 (d,
J¼12.0 Hz, 1H), 3.91 (s, 3H), 3.81 (d, J¼11.9 Hz, 1H), 2.90 (s, 1H); 19F
NMR (376 MHz, CDCl3)
d
d
ꢁ71.98 (s, 3F); 13C NMR (100 MHz, CDCl3)
148.3, 134.2, 132.9, 131.6, 128.7, 128.4, 126.1 (q, 1JFeC¼288.4 Hz),

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