Regioselective synthesis of trifluoromethyl group containing allylic amines by palladium-catalyzed allylic amination and sequential isomerization

Article abstract of DOI:10.1016/j.tet.2011.08.093

The palladium-catalyzed regioselective allylic amination of the α-trifluoromethyl group-substituted allyl acetate has been accomplished using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF as catalysts. The selective formation of the γ-product was attained in the presence of Pd(OAc)₂/DPPE, while the α-product was obtained using [Pd(π-allyl)(cod)]BF₄/DPPF. We also succeeded in the regioselective synthesis of the enantiomerically enriched aminated product from chiral allyl acetate using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)] BF₄/(S)-BINAP. Furthermore, we found that kinetic resolution had occurred during the isomerization step from the γ-type product to the α-type product by the [Pd(π-allyl)(cod)]BF₄/(S)-BINAP catalyst.

Full text of DOI:10.1016/j.tet.2011.08.093

Tetrahedron 67 (2011) 8238e8247
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Regioselective synthesis of trifluoromethyl group containing allylic amines by
palladium-catalyzed allylic amination and sequential isomerization
*
Takuya Hirakawa, Kazunori Ikeda, Daiji Ikeda, Tomoko Tanaka, Hiroshi Ogasa, Motoi Kawatsura ,
*
Toshiyuki Itoh
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2011
Received in revised form 30 August 2011
Accepted 31 August 2011
Available online 7 September 2011
The palladium-catalyzed regioselective allylic amination of the
a
p
-trifluoromethyl group-substituted allyl
-allyl)(cod)]BF4/DPPF as catalysts. The
-product was attained in the presence of Pd(OAc)2/DPPE, while the -product
-allyl)(cod)]BF4/DPPF. We also succeeded in the regioselective synthesis of the
enantiomerically enriched aminated product from chiral allyl acetate using Pd(OAc)2/DPPE and [Pd(
allyl)(cod)]BF4/(S)-BINAP. Furthermore, we found that kinetic resolution had occurred during the
acetate has been accomplished using Pd(OAc)2/DPPE and [Pd(
selective formation of the
was obtained using [Pd(
g
a
p
p-
isomerization step from the
catalyst.
g
-type product to the
a
-type product by the [Pd(
p-allyl)(cod)]BF4/(S)-BINAP
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
enantiomerically enriched a- and g-allylic amines, although appli-
cable combinations of the allylic esters and amines were limited. In
this paper, we report the results of detailed study of our palladium-
catalyzed regioselective allylic amination of a-trifluoromethylated
allylic esters with several amines, including synthesis of the tri-
fluoromethyl group containing optically active allylic amines.
Recently, fluorine substituted organic compounds have attracted
much interest in the field of medicinal chemistry and material sci-
ence because of their unique properties due to the influence of
fluorine. For example, the replacement of hydrogen atoms by fluo-
rine atoms in organic molecules causes a relatively small steric
change, but leads to major changes in the electron character of the
molecules. Also, some fluorine-contained compounds sometimes
exhibit an unusual stereoselectivity under standard organic reaction
conditions. Therefore, the development of new transformation
methods of fluorinated compounds should be one of the important
subjects in organic chemistry. The transition metal-catalyzed allylic
amination reaction of allylic esters is a versatile method to produce
allylic amines, and several transition metal catalysts have realized
these reactions.1,2 However, most of them were the reactions in-
volving non-fluorinated substrates, and there is only a limited ex-
2. Results and discussion
2.1. Regioselective allylic amination
We examined the allylic amination of the a-trifluoromethylated
allyl acetate 1a with diethylamine (2a) using several palladium/
phosphine catalysts (Table 1). We found that the Pd(OAc)2 and
[Pd(p-allyl)(cod)]BF4 exhibited a catalytic activity for this intended
reaction. On the contrary, palladium catalysts, which were gener-
ated from Pd2(dba)3 or [Pd(p-allyl)Cl]2 with several phosphine li-
ample of the reaction of the
In 2002, Konno and co-workers demonstrated the first example of
the palladium-catalyzed regioselective ( -selective) allylic amina-
tion of -trifluoromethylated allyl mesylate, and found that the re-
actionproduced the
-product as a single regioisomer.4 On the other
hand, we recently reported on both the -selective and -selective
a
-trifluoromethylated allyl substrates.3
gands,6 showed no catalytic activity toward the desired amination
reaction or resulted in a low conversion of the substrate 1a (<20%).
The results obtained for the palladium-catalyzed allylic amination
of 1a with diethylamine (2a) are summarized in Table 1.
g
a
g
We first conducted the reaction using Pd(OAc)2 with PPh3
(4 equiv vs Pd). Although the desired product 3aa was obtained,
while poor reaction rate was recorded (Table 1, entry 1). Fortu-
nately, we found that DPPE [1,2-bis(diphenylphosphino)ethane]
(1 equiv to Pd) is an effective ligand for the allylic amination of 1a,
a
g
allylic aminations of a-trifluoromethylated allyl acetate using two
types of palladium catalysts.5 We further succeeded in obtaining the
and the
-product) was obtained as a single regioisomer in 80% isolated
yield (entry 2). We also examined the reaction with DPPF, but the
g-trifluoromethyl group with substituted allyl amine 3aa
(g
* Corresponding authors. E-mail addresses: kawatsur@chem.tottori-u.ac.jp
(M. Kawatsura), titoh@chem.tottori-u.ac.jp (T. Itoh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.093

T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
8239
Table 2
Palladium-catalyzed allylic amination of 1a,b with amines 2bema
Table 1
Palladium-catalyzed allylic amination of 1a with diethylamine 2aa
N
Entry
[Pd/L]
Solvent
Temp
(ꢀC)
Yieldb (%) of
3aa/4aac
3aaþ4aa
1
2
3
4
5
Pd(OAc)2/PPh3
Pd(OAc)2/DPPE
Pd(OAc)2/DPPF
Pd(OAc)2/DPPE
THF
THF
THF
Dioxane
THF
60
60
60
100
60
20
>98:2
>98:2
>98:2
>98:2
>98:2
86 (80)d
64 (58)d
68
[Pd(
PPh3
p
-allyl)(cod)]BF4/
-allyl)(cod)]BF4/
-allyl)(cod)]BF4/
-allyl)(cod)]BF4/
-allyl)(cod)]BF4/
-allyl)(cod)]BF4/
12
Entry
1
2
Yieldb,c (%) of
3 and 4
3/4d
97:3
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
d
6
[Pd(p
THF
60
60
17
>98:2
68:32
60:40
15:85
2:>98
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1b
1a
1b
1a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2j
2k
2k
2l
92 (99)
88 (96)
73 (76)
91 (95)
64 (72)
68 (82)
(12)
DPPE
7
[Pd(p
THF
56
DPPF
8
[Pd(p
Dioxane
Dioxane
Dioxane
100
100
100
43
DPPE
9
[Pd(
DPPB
[Pd(
DPPF
p
53
10e
p
95 (87)d
0
9
54 (56)
60 (80)
60 (76)
74 (85)
66 (68)
84 (84)
(22)
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
10
11
12
13
14
15
a
All reactions were carried out with 1a (0.20 mmol), 2a (0.31 mmol), palladium
(0.020 mmol), and ligand (0.020 mmol for DPPE, DPPB, and DPPF, 0.084 mmol for
PPh3) in solvent (1.0 ml) for 12 h under nitrogen.
b
The yields were determined by 1H NMR.
2l
2m
c
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude
materials.
a
d
All reactions were carried out with 1 (0.20 mmol), 2 (0.31 mmol), Pd(OAc)2
Isolated yield by silica gel column chromatography in parentheses.
The reaction was carried out 9 h.
(10 mol %), and DPPE (10 mol %) in THF (1.0 ml) at 60 ꢀC for 12 h under nitrogen.
e
b
Isolated yield by silica gel column chromatography.
c
The NMR yield in parentheses.
d
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude
yield was not a satisfactory one (entry 3). A further investigation
revealed that [Pd(
materials.
p-allyl)(cod)]BF4 also catalyzed the allylic ami-
nation of 1a (entries 5e10). Again, the
g-selective amination was
observed for the reaction using PPh3 and DPPE ligated the palla-
dium catalyst, but the yield was very low (entries 5 and 6). In-
terestingly, the palladium catalyst, which coordinated with DPPF,
The results of the [Pd(
lective allylic amination are summarized in Table 3. As we expected,
the -products were obtained as the major regioisomers with high
regioselectivity in the reaction using amines 2beg (Table 3, entries
1e6), while the [Pd( -allyl)(cod)]BF4/DPPF catalyst system was
sensitive to the steric factor of the amines (entries 7 and 8) and no
desired product was obtained when diisopropylamine (2i) was
employed as substrate (entry 8). Changing the leaving group from
acetate to tert-butyl carbonate effectively increased the yield of the
p-allyl)(cod)]BF4/DPPF-catalyzed a-se-
a
exhibited
regioisomers, 3aa and 4aa (
7). This
a
higher reactivity and gave
a mixture of two
a
-product) in the ratio of 68:32 (entry
p
a
-selectivity was improved by raising the reaction tem-
perature to 100 ꢀC in dioxane (entries 8e10), and 4aa was obtained
as a single regioisomer in 87% isolated yield (entry 10).
We demonstrated the regioselective allylic amination of 1 with
several amines using these two types of palladium catalysts. The
desired
2jel (entries 9e14). We further established that perfect
reaction was accomplished when an aromatic primary amine 2m
a
-product for the reaction of the aliphatic primary amines
results of the Pd(OAc)2/DPPE-catalyzed
g-selective allylic amination
a
-selective
are summarized in Table 2. The reaction with aliphatic secondary
amines, such as morpholine (2b), piperazine analogues (2c and 2d),
4-phenylpiperidine (2e), and dibutyl- or dipropylamine (2f and 2g),
was used in the presence of [Pd(
(entry 15).
p-allyl)(cod)]BF4/DPPF as catalyst
proceeded with a high regioselectivityand gave
g
-products 3 in good
We also examined the reaction of some 1,1,1-trifluoro-4-arylbut-
3-en-2-yl acetates (1aee)7 with piperidine (2n) using the two types
of palladium catalysts. As shown in Table 4, the reaction of 1a with
yields (Table 2, entries 1e6). Unfortunately, it was found that the
Pd(OAc)2/DPPE-catalyzed allylic aminations were very sensitive to
the steric factor of the amines; the reaction with N-ethylisopropyl-
2n by Pd(OAc)2/DPPE exhibited perfect
hand, as mentioned, the reaction by the [Pd(
catalyst produced an -product as a single regioisomer (Table 4,
g
-selectivity. On the other
amine (2h) proceeded with a >98%
g-selectivity, but the yield was
p-allyl)(cod)]BF4/DPPF
very low (12% NMR yield) (entry 7). In addition, the reaction with
diisopropylamine (2i) resulted in no reaction (entry 8). We also
demonstrated the reaction of 1a with the aliphatic primary amines
a
entries 1 and 2). The reactions of 1,1,1-trifluoro-4-arylbut-3-en-2-yl
acetates 1c and 1d, which have an electron-donating or electron-
withdrawing group at the para-position on the aromatic ring, did
not show any significant difference in regioselectivity (entries 3e6).
It should be noted that an increased yield was obtained for the
2jel, and obtained the expected g-products in moderate yields with
>98% regioselectivities (entries 9, 11, and 13). In these reactions, ally
alcohols were produced by the deacylation of 1a with amines. For-
tunately, however, we succeeded inpreventing the formation of such
an undesired reaction and increasing the yields of the desired
products by changing the leaving group of allyl substrate from allyl
acetate 1a to allyl tert-butyl carbonate 1b (entries 10, 12, and 14).
g
-selective condition (entry 3), while a decreased yield was ob-
served for the -selective condition (entry 4).
We next studied the reaction pathway for the regioselective
substitution, especially for the unusual selective formation of the
a
a
-

8240
T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
Table 3
attacked the less sterically hindered p-allyl terminus to form the g-
Palladium-catalyzed allylic amination of 1a,b with amines 2bema
product.8 We believe the same mechanism might be involved in the
reaction of 1a with 2a by Pd(OAc)2/DPPE. In contrast, it is unclear
whether or not a direct substitution occurred during the reaction of
the [Pd(
mentioned, the
several different conditions (Table 1, entries 7 and 8). Based on
these results, we assumed that [Pd( -allyl)(cod)]BF4/DPPF had se-
lectively formed the -product, thus causing isomerization to
provide the
-product under the given reaction conditions.9 To
prove this hypothesis, the -product 3aa was treated with the
palladium catalyst, and the 1H NMR spectrum was measured. When
p
-allyl)(cod)]BF4/DPPF catalyst because, as we previously
g-product was obtained as the major product under
p
g
a
Entry
1
2
Yieldb,c (%) of
3 and 4
3/4d
7:93
3:97
2:98
4:96
2:>98
2:98
g
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1b
1a
1b
1a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2j
2k
2k
2l
75 (79)
73 (73)
68 (69)
77 (78)
80
70 (70)
(15)
0
61 (66)
82 (82)
57 (57)
73 (73)
79 (80)
83 (83)
58 (60)
the reaction was carried out using 10 mol % [Pd(p-allyl)(cod)]BF4
(without DPPF) in dioxane at 100 ꢀC for 12 h, almost all 3aa was
consumed (>80% conversion), a complex mixture was produced
and no desired product was produced (Table 5, entry 1). However,
the reaction with 10 mol % of [Pd(
DPPF showed formation of the
(entry 2), which suggested that 3aa was isomerized to 4aa by the
[Pd(
-allyl)(cod)]BF4/DPPF catalyst system.10 Furthermore, the ad-
p-allyl)(cod)]BF4 and 10 mol % of
75:25
d
a-product 4aa (52% NMR yield)
9
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
p
10
11
12
13
14
15
dition of excess Et2NH (1.5 equiv to 3aa) increased the formation of
4aa up to a 73% NMR yield (entry 3). We also confirmed that the
Pd(OAc)2/DPPE did not catalyze the isomerization of 3aa to 4aa
under the same conditions (entry 4). These results strongly support
2l
2m
the idea that the g-product was first selectively formed, and then
a
All reactions were carried out with
1 (0.20 mmol), 2 (0.31 mmol), [Pd(p-
was isomerized to the
catalyst.
a-product by the [Pd(p-allyl)(cod)]BF4/DPPF
allyl)(cod)]BF4 (10 mol %), and DPPF (10 mol %) in dioxane (1.0 ml) at 100 ꢀC for 12 h
under nitrogen.
b
Isolated yield by silica gel column chromatography.
c
Table 5
The NMR yield in parentheses.
The reaction of g
-product 3aa using the palladium catalysta
d
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude
materials.
Table 4
Palladium-catalyzed allylic amination of several allylic acetates 1aee with piperi-
dine (2n)a
Entry
[Pd/L]
Et2NH
Conversionb (%)
Yieldb (%)
of 3aa
of 4aa
1
2
[Pd(
p
-allyl)(cod)]BF4
-allyl)(cod)]BF4/
d
d
>80
>99
Trace
52
[Pd(p
DPPF
3
[Pd(
DPPF
Pd(OAc)2/DPPE
p
-allyl)(cod)]BF4/
1.5 equiv
1.5 equiv
>99
73
0
4
0
a
All reactions were carried out with 3aa (0.20 mmol), palladium (0.020 mmol),
and ligand (0.020 mmol) in dioxane (1 ml) at 100 ꢀC for 12 h under nitrogen.
b
Determined by 400 MHz 1H NMR spectral analysis of the crude materials.
Entry
1
Conditionb
Yieldc,d (%) of
3/4e
3 and 4 (%)
1
2
3
4
5
6
7
8
1a
1c
1d
1e
A
B
A
B
A
B
A
B
60 (74) (3an)
64 (70) (4an)
78 (89) (3cn)
52 (59) (4cn)
64 (84) (3dn)
60 (62) (4dn)
63 (84) (3en)
73 (75) (4en)
>98:2
2:>98
>98:2
2:>98
>98:2
2:>98
>98:2
2:>98
2.2. Synthesis of enantiomerically enriched CF3-group
containing allylic amines
The net retention (double inversion) mechanism is a very popular
stereochemical phenomenon for palladium-catalyzed allylic sub-
stitutions; the reaction of the optically active allyl substrates
generally forms optically active substitution products without loss
of any enantiomeric excess.11 Based on this mechanism, we next
a
All reactions were carried out with 1 (0.20 mmol) and 2n (0.31 mmol) in solvent
(1.0 ml) for 12 h under nitrogen.
b
Condition A: 10 mol % Pd(OAc)2 and 10 mol % DPPE in THF at 60 ꢀC for 12 h.
examined the
merically enriched allyl acetate using two types of palladium cat-
alysts to obtain optically active - and -allylic amines. We
expected that both the chiral - and -allyl amines would be easily
a- and g-selective allylic aminations of enantio-
Condition B: 10 mol % [Pd(p C
-allyl)(cod)]BF4 and 10 mol % DPPF in dioxane at 100 ꢀ
for 12 h.
c
a
g
Isolated yield by silica gel column chromatography.
The NMR yield in parentheses.
d
e
a
g
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude
obtained by the net retention mechanism. However, we soon
recognized that the enantiomeric excess of the allyl acetate was
lost under the reaction conditions. For example, the reaction of the
enantiomerically enriched allyl acetate (S)-1a (99% ee) with mor-
materials.
product. Generally, the palladium catalyst forms the
p
-allylpalla-
-allyl terminus.
report on the allylic substitution of -tri-
fluoroalkylated allyl mesylates by Konno,3d the allyl substrate
formed the -allylpalladium complex, and nucleophiles selectively
dium intermediate and nucleophiles attack the
According to
p
pholine (2b) by the Pd(OAc)2/DPPE catalyst at 60 ꢀC gave the
g-
a
a
product 3ab in 99% yield with 81% ee (Table 6, entry 1). Further-
more, the -selective reaction by [Pd( -allyl)(cod)]BF4/DPPF at
100 ꢀC provided 4ab in an 85% yield with a 0% ee (entry 3). We
a
p
p

T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
8241
Table 6
Table 7
Palladium-catalyzed allylic amination of chiral (S)-1a with morpholine (2b)a
Palladium-catalyzed allylic amination of chiral allylic acetates (S)-1aef with several
amines 2ceoa
S
R
S
Entry [Pd/L]
Temp Yieldb,c
(ꢀC) (%) of 3ab
and 4ab
3ab/4abd eee (%) of eee (%) of
(R)-3ab (S)-4ab
1
2
3
Pd(OAc)2/DPPE
Pd(OAc)2/DPPE
60
25
99
77 (66)
85
>98:2
>98:2
5:95
81
98
n.d.
n.d.
n.d.
0
[Pd(
DPPF
p
-allyl)(cod)]BF4/ 100
-allyl)(cod)]BF4/ 60
-allyl)(cod)]BF4/ 100
4
5
6
7f
8
[Pd(p
94
18:82
7:93
n.d.
n.d.
n.d.
n.d.
91
4
DPPF
Entry
1
2
Conditionb
Time
Yieldc,d
(%) of 3
and 4
3/4e
eef (%) of
major product
[Pd(
(S)-BINAP
[Pd( -allyl)(cod)]BF4/ 40
(S)-BINAP
[Pd( -allyl)(cod)]BF4/ 40
(S)-BINAP
[Pd( -allyl)(cod)]BF4/ 40
(R)-BINAP
p
95
33
99
99
13g
p
95
7:93
1
2
3
4
5
6
7
8
9
1a
1a
1a
1c
1f
2c
2d
2o
2c
2c
A
9 h
12 h
12 h
5 days
12 h
25 h
12 h
5 days
12 h
5 days
82 (91)
81 (99)
80 (89)
87 (93)
69 (83)
61 (99)
84 (86)
81 (97)
71 (71)
65 (82)
>98:2
6:94
>98:2
6:94
>98:2
13:87
>98:2
8:92
>98:2
8:92
97 (3ac)
97 (4ac)
95 (3ad)
98 (4ad)
96 (3ao)
96 (4ao)
94 (3cc)
98 (4cc)
83 (3fc)
95 (4fc)
B (40 ꢀC)
p
98 (74)
80
3:97
A
B (40 ꢀC)
A
p
87:13
B (25 ꢀC)
A
a
All reactions were carried out with (S)-1a (0.20 mmol), 2b (0.31 mmol), palla-
B (25 ꢀC)
A
dium (0.020 mmol), and ligand (0.020 mmol) in solvent (1.0 ml) for 12 h under
nitrogen.
B (25 ꢀC)
b
The yield were determined by 1H NMR.
10
c
Isolated yield by silica gel column chromatography in parentheses.
a
All reactions were carried out with 1 (0.20 mmol) and 2 (0.31 mmol) in solvent
d
The ratio was determined by 400 MHz 1HMR spectral analysis of the crude
(1.0 ml) for 12 h under nitrogen unless otherwise noted.
materials.
b
Condition A: 10 mol % Pd(OAc)2 and 10 mol % DPPE in THF at 25 ꢀC. Condition B:
e
Values of ee were determined by chiral HPLC analysis.
Reaction was conducted using 5 mol % [Pd] and ligand for 24 h.
10 mol % [Pd(p
-allyl)(cod)]BF4 and 10 mol % (S)-BINAP in dioxane at 40 or 25 ꢀC
f
unless otherwise noted.
g
(R)-4ab was obtained as a major enantiomer.
c
Isolated yield by silica gel column chromatography.
d
The NMR yield in parentheses.
e
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude
materials.
then attempted to optimize the reaction conditions to retain the
enantiomeric excess of the starting allyl substrate, which produces
optically active trifluoromethyl group substituted aminated prod-
ucts. As mentioned, the allylic amination of (S)-1a by the Pd(OAc)2/
DPPE catalyst at 60 ꢀC decreased the enantiopurity. Fortunately,
reinvestigation of the reaction conditions revealed that the re-
action proceeded at 25 ꢀC with retention of the enantiomeric ex-
cess, and gave the optically active trifluoromethyl group
f
Values of ee were determined by chiral HPLC analysis.
and 9). On the other hand, as we expected, the [Pd(
BF4/(S)-BINAP catalyst produced the enantiomerically enriched
product with a high regioselectivity and enantiomeric excess. Al-
though we observed a slow reaction rate and/or decreased regio-
selectivity,13 a lower reaction temperature (25 ꢀC)14 and/or longer
p-allyl)(cod)]
a
-
substituted
g-type product (R)-3ab in 98% ee (entry 2). We next
reaction time (5 days) gave the intended optically active a-product
attempted formation of the chiral
a
-product 4ab using the [Pd(
p-
in a moderate to good yield with high regioselectivity (entries 2, 4,
6, 8, 10). Unfortunately, all reactions in Tables 6 and 7 were done by
aliphatic secondary amines, because reactions by primary amines
exhibited a decreased yield (<30%) owing to the deacylation of 1a.
We further established that (S)-BINAP and (R)-BINAP exhibited
different results of both the regiochemistry and enantiomeric ex-
cess for the allylic amination of (S)-1a with 2b. As shown in Table 6,
allyl)(cod)]BF4/ligand catalyst, but soon found that a reduced re-
action temperature was not effective for retaining the enantio-
meric excess. For example, the reaction at 60 ꢀC gave primarily
a-
product 4ab with low regioselectivity (entry 4). However, after the
screening of several types of phosphine ligands, we succeeded in
obtaining the enantiomerically enriched
a-product (S)-4ab with
complete chirality transfer using the chiral BINAP ligand. When
(S)-BINAP was used as the ligand for the reaction of (S)-1a with
the reaction by (S)-BINAP gave the chiral
99% ee (Table 6, entries 6 and 7). However, when the (R)-BINAP was
used for the same reaction, the -product (R)-3ab was obtained as
the major regioisomer with a high enantiomeric excess (91% ee)
(entry 8). These results indicated that kinetic resolution might take
a-product (S)-4ab with
morpholine (2b) at 100 ꢀC, the
a
-product was produced as the
major regioisomer with a 33% ee (entry 5). The racemization was
prevented at 40 ꢀC, then the enantiomerically pure
-product (S)-
-allyl)(-
g
a
4ab was obtained in good yield even with 5 mol % [Pd(
p
place during the isomerization step from the
g-product to a-
cod)]BF4/(S)-BINAP (entries 6 and 7).12
product. To clarify this, we next demonstrated the isomerization
reaction of the chiral allyl amine (R)-3ab using chiral palladium/
BINAP catalysts (Scheme 1). The isomerization reaction of (R)-3ab
(97% ee) smoothly occurred when (S)-BINAP was used and the
We demonstrated the Pd(OAc)2/DPPE or [Pd(p-allyl)(cod)]BF4/
(S)-BINAP catalyzed reactions of other optically active allyl acetates
and amines (Table 7). The reaction by Pd(OAc)2/DPPE exhibited
a perfect regioselectivity, and produced the enantiomerically
chiral a-product (S)-4ab was obtained in 91% yield without any loss
enriched
2c, 2d or 2o, we succeeded in obtaining the enantiomerically
enriched -product 3 with over a 95% ee (entries 1, 3, 5), although
the enantiomeric excess of the -product from the reaction of 1c
and 1f was slightly reduced during the reaction with 2c (entries 7
g-products (entries 1, 3, 5, 7, 9). For the reaction of 1a with
of enantiomeric excess (97% ee). On the other hand, the isomeri-
zation of (R)-3ab proceeded very slowly when (R)-BINAP was used,
and 92% of the g-product was recovered. These two results strongly
suggest that the (S)-BINAP ligand is a matching enantiomer for the
stereospecific isomerization of the chiral allyl amine (R)-3ab to (S)-
g
g

8242
T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
4ab. To the best of our knowledge, this is the first example of the
palladium-catalyzed isomerization of 1,3-disubstituted un-
symmetrical allyl amines, though several examples have been re-
ported of the kinetic resolution of the palladium-catalyzed allylic
substitutions.15,16
allyl acetate using two types of palladium catalysts. We also found
that kinetic resolution had occurred during the isomerization step
using the chiral [Pd(p-allyl)(cod)]BF4/BINAP catalyst.
3. Experimental section
3.1. General information
All manipulations were carried out under a nitrogen atmo-
sphere. Nitrogen gas was dried by passage through P2O5. NMR
spectra were recorded on a JEOL JNM-LA400 (400 MHz for 1H), JEOL
JNM-ECP500 (500 MHz for 1H, 125 MHz for 13C, and 470 MHz for
19F) or Bruker Biospin AVACNE II 600 (600 MHz for 1H, 150 MHz for
13C, and 564 MHz for 19F). Chemical shifts are reported in
d
parts per
million referenced to an internal SiMe4 standard for 1H NMR and an
internal C6F6 standard for 19F NMR. Residual chloroform (
77.0 for
d
13C) was used as internal reference for 13C NMR. Data are reported
as follows: chemical shift, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, quin¼quintet, sep¼septet, m¼multiplet, br
s¼broad signal), coupling constant (Hz), and integration. Pd(OAc)2,
DPPE, DPPF, BINAP, and other reagents and solvents were pur-
chased from common commercial sources and were used without
Scheme 1.
We thus demonstrated the kinetic resolution of the racemic allyl
amine rac-3ab by the [Pd(p-allyl)(cod)]BF4/(S)-BINAP catalyzed
isomerization (Eq. 1 in Scheme 2). As we intended, the selective
kinetic resolution took place at 40 ꢀC in 12 h and produced a 58%
further purification. [Pd(p
-allyl)(cod)]BF4,19 racemic allyl acetates 1
optically active g-product 3ab (46% ee (S)) and 42% chiral a-product
and chiral allyl acetates (S)-120,21 were prepared according to the
literatures.
4ab (85% ee (S)) (S value¼19).17,18 When the racemic allyl amine
rac-3ao was treated with [Pd(p-allyl)(cod)]BF4/(S)-BINAP, we ob-
served that the resulting S value was 15 (Eq. 2 in Scheme 2).
3.2. General procedure for the allylic amination of 1,1,1-
trifluoro-4-phenylbut-3-en-2-yl acetate (1a) with
diethylamine (2a)
A typical procedure is given for the reaction of 1a with 2a (Table
1, entry 10). To
a solution of [Pd(p-allyl)(cod)]BF4 (7.0 mg,
0.020 mmol) and DPPF (11.4 mg, 0.020 mmol) in dioxane (1.0 ml)
was added allyl acetate 1a (50 mg, 0.20 mmol) and amine 2a
(23 mg, 0.31 mmol) at room temperature. The resultant mixture
was stirred at 100 ꢀC for 9 h. The reaction mixture was quenched
with water, and extracted with ethyl acetate. The organic phase was
washed with brine, dried over anhydrous MgSO4, and evaporated.
The NMR yield (95%, trioxane as an internal standard) and regioi-
someric ratio were determined by 400 MHz 1H NMR for crude
material. The residue was purified by silica gel column chroma-
tography (hexane/EtOAc/Et3N¼97/2/1) to give 46 mg (87%) of 4aa
(a-product) as a colorless oil.
3.2.1. 1,1,1-Trifluoro-4-phenylbut-3-en-2-yl acetate (1a)5b,21. Yellow
oil. 1H NMR (500 MHz, CDCl3)
2.18 (s, 3H), 5.80e5.85 (m, 1H), 6.11
(dd, J¼7.8, 16.0 Hz, 1H), 6.86 (d, J¼16.0 Hz, 1H), 7.30e7.42 (m, 5H).
d
13C NMR (125 MHz, CDCl3)
d
20.6, 71.1 (q, JCF¼33.6 Hz), 117.3, 123.2
(q, JCF¼280.5 Hz), 127.0, 128.7, 129.0, 135.0, 138.8, 168.8. 19F NMR
(470 MHz, CDCl3)
d
85.3 (d, J¼6.8 Hz). IR (neat) 3034, 2971, 1760,
Scheme 2.
1657, 1370, 1277, 1223 cmꢁ1
.
3.2.2. tert-Butyl 1,1,1-trifluoro-4-phenylbut-3-en-2-yl carbonate
(1b). Colorless solid. Mp 53e55 ꢀC. 1H NMR (500 MHz, CDCl3)
1.51
d
In conclusion, we have demonstrated the regioselective forma-
(s, 9H), 5.59 (dquin, J¼1.1, 6.6 Hz, 1H), 6.14 (dd, J¼7.7, 16.0 Hz, 1H),
6.88 (d, J¼16.0 Hz,1H), 7.28e7.46 (m, 5H). 13C NMR (125 MHz, CDCl3)
tion of both the
amines via the palladium-catalyzed allylic amination of
fluoromethylated allyl acetate. The conventional -product was
obtained using the Pd(OAc)2/DPPE catalyst, while the unusual
product was obtained when the reaction was conducted in the
presence of [Pd( -allyl)(cod)]BF4/DPPF as catalyst. We further
revealed that the -product was easily isomerized to the -product
under the [Pd( -allyl)(cod)]BF4/DPPF catalyzed reaction condi-
tions; the -product was formed by isomerization of the -product.
a- and
g
-trifluoromethyl group-substituted allyl
a-tri-
d
27.6, 73.9 (q, JCF¼34.0 Hz), 83.9, 117.1, 123.1 (q, JCF¼280.7 Hz), 127.0,
128.7, 129.0, 135.0, 138.7, 151.7. 19F NMR (470 MHz, CDCl3)
d 85.2 (d,
g
a
-
J¼6.5 Hz). IR (KBr) 2985, 1755, 1657, 1581, 1375, 1250, 1178,
1138 cmꢁ1. Anal. Calcd for C15H17F3O3: C, 59.60; H, 5.67. Found (%): C,
59.67; H, 5.67.
p
g
a
p
3.2.3. 1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-yl acetate (1c).
White solid. Mp 51e52 ꢀC. 1H NMR (500 MHz, CDCl3)
d 2.17 (s, 3H),
a
g
Furthermore, we demonstrated the regioselective synthesis of the
chiral trifluoromethyl group substituted allylic amines from chiral
3.82 (s, 3H), 5.76e5.82 (m, 1H), 5.97 (dd, J¼8.0, 16.0 Hz, 1H), 6.80
(d, J¼16.0 Hz, 1H), 6.87 (d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 2H). 13C

T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
8243
NMR (125 MHz, CDCl3)
d
20.6, 55.3, 71.3 (q, JCF¼33.2 Hz), 114.1,
1679, 1455, 1344, 1277, 1125, 1008 cmꢁ1. HRMS (ESI) m/z calcd for
[MþH]þ: C15H20F3N2 285.1579, found 285.1569.
114.8, 123.2 (q, JCF¼280.3 Hz), 127.7, 128.4, 138.4, 160.3, 168.9. 19F
NMR (470 MHz, CDCl3)
d
85.2 (d, J¼7.2 Hz). IR (KBr) 2963,
2936, 2842, 1760, 1608, 1514, 1379, 1353, 1192, 1031 cmꢁ1. HRMS
(DART) m/z calcd for [MþH]þ: C13H14F3O3 275.0895, found
275.0895.
3.2.10. 1-(4,4,4-Trifluoro-1-phenylbut-2-enyl)-4-phenylpiperidine
(3ae). Yellow solid. Mp 59e65 ꢀC. 1H NMR (600 MHz, CDCl3)
d
1.70e1.84 (m, 4H), 1.91 (dt, J¼3.4, 11.0 Hz, 1H), 2.12 (dt, J¼3.4,
11.0 Hz, 1H), 2.43e2.48 (m, 1H), 2.82 (d, J¼11.3 Hz, 1H), 3.11 (d,
J¼11.3 Hz, 1H), 3.88 (d, J¼7.9 Hz, 1H), 5.85 (dq, J¼6.4, 15.4 Hz, 1H),
6.55 (ddq, J¼2.3, 7.9, 15.4 Hz, 1H), 7.17e7.21 (m, 3H), 7.27e7.36 (m,
3.2.4. 1,1,1-Trifluoro-4-(4-fluorophenyl)but-3-en-2-yl acetate (1d).
Yellow oil. 1H NMR (500 MHz, CDCl3)
d
2.18 (s, 3H), 5.77e5.83 (m,
1H), 6.03 (dd, J¼7.7, 16.0 Hz, 1H), 6.82 (d, J¼16.0 Hz, 1H), 7.02e7.06
(m, 2H), 7.38e7.42 (m, 2H). 13C NMR (125 MHz, CDCl3)
20.3, 71.0
7H). 13C NMR (150 MHz, CDCl3)
d 33.6, 33.7, 42.7, 51.7, 52.6, 72.1,
d
119.4 (q, JCF¼33.6 Hz), 123.0 (q, JCF¼269.7 Hz), 126.2, 126.9, 127.9,
(q, JCF¼33.6 Hz), 115.6 (d, JCF¼21.6 Hz), 117.0, 123.2 (q,
128.3, 128.5, 128.8, 139.5, 141.8 (q, JCF¼6.3 Hz), 146.3. 19F NMR
JCF¼280.3 Hz), 128.7 (d, JCF¼8.4 Hz), 131.2 (d, JCF¼2.4 Hz), 137.4,
(564 MHz, CDCl3)
d
97.9 (d, J¼6.1 Hz). IR (KBr) 3034, 2935, 2802,
163.1 (d, JCF¼249.5 Hz), 168.7. 19F NMR (470 MHz, CDCl3)
d
49.8 (tt,
2752, 1679, 1599, 1493, 1453, 1286, 1123 cmꢁ1. HRMS (ESI) m/z calcd
for [MþH]þ: C21H23F3N 346.1783, found 346.1781.
J¼5.3, 8.5 Hz, 1F), 85.3 (d, J¼6.7 Hz, 3F). IR (neat) 3052, 2927, 1764,
1661, 1514, 1375, 1218, 1035, 972 cmꢁ1. HRMS (ESI) m/z calcd for
[MþNa]þ: C12H10F4NaO2 285.0515, found 285.0514.
3.2.11. N,N-Dibutyl-4,4,4-trifluoro-1-phenylbut-2-en-1-amine
(3af). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
0.86 (t, J¼7.3 Hz,
3.2.5. 1,1,1-Trifluoro-4-o-tolylbut-3-en-2-yl acetate (1e). Yellow oil.
6H),1.21e1.29 (m, 4H),1.37e1.43 (m, 4H), 2.41 (t, J¼7.6 Hz, 4H), 4.30
(d, J¼8.2 Hz, 1H), 5.79 (dq, J¼6.4, 16.0 Hz, 1H), 6.54 (ddq, J¼1.8, 8.2,
1H NMR (500 MHz, CDCl3)
d
2.19 (s, 3H), 2.36 (s, 3H), 5.80e5.86 (m,
1H), 5.99 (dd, J¼8.0, 16.0 Hz, 1H), 7.10 (d, J¼16.0 Hz, 1H), 7.16e7.24
(m, 3H), 7.43e7.45 (m, 1H). 13C NMR (125 MHz, CDCl3)
19.6, 20.7,
16.0 Hz, 1H), 7.25e7.35 (m, 5H). 13C NMR (125 MHz, CDCl3)
d 14.0,
d
20.4, 29.5, 49.8, 66.3, 119.9 (q, JCF¼33.6 Hz), 122.9 (q, JCF¼269.7 Hz),
71.3 (q, JCF¼33.2 Hz), 118.7, 123.2 (q, JCF¼279.5 Hz), 126.0, 126.2,
127.5, 128.1, 128.4, 140.2, 140.8 (q, J¼5.8 Hz). 19F NMR (564 MHz,
128.8, 130.5, 134.2, 136.1, 136.8, 168.8. 19F NMR (470 MHz, CDCl3)
CDCl3)
d
98.0 (d, J¼6.3 Hz). IR (neat) 2958, 2869, 2819, 1679, 1455,
d
85.2 (d, J¼6.8 Hz). IR (neat) 3065, 3025, 2963, 1764, 1652, 1603,
1281, 1125, 981 cmꢁ1. HRMS (ESI) m/z calcd for [MþH]þ: C18H27F3N
1487, 1375, 1272, 1223, 1138, 1035 cmꢁ1. HRMS (ESI) m/z calcd for
314.2096, found 314.2092.
[MþH]þ: C13H14F3O2 259.0946, found 259.0945.
3.2.12. 4,4,4-Trifluoro-1-phenyl-N,N-dipropylbut-2-en-1-amine
3.2.6. N,N-Diethyl-4,4,4-trifluoro-1-phenylbut-2-en-1-amine
(3ag). Colorless oil. 1H NMR (600 MHz, CDCl3)
6H), 1.41e1.47 (m, 4H), 2.34e2.42 (m, 4H), 4.30 (d, J¼8.3 Hz, 1H),
5.79 (dq, J¼6.4, 15.8 Hz, 1H), 6.54 (ddq, J¼2.3, 8.3, 15.8 Hz, 1H),
7.25e7.28 (m, 1H), 7.31e7.35 (m, 4H). 13C NMR (150 MHz, CDCl3)
d
0.83 (t, J¼7.5 Hz,
(3aa)5a. Colorless oil. 1H NMR (500 MHz, CDCl3)
d
0.99 (t, J¼6.9 Hz,
6H), 2.53 (q, J¼6.9 Hz, 4H), 4.27 (d, J¼8.2 Hz, 1H), 5.81 (dq, J¼6.4,
16.0 Hz,1H), 6.53 (ddq, J¼1.8, 8.2,16.0 Hz,1H), 7.26e7.36 (m, 5H).13C
NMR (125 MHz, CDCl3)
d
11.8, 43.1, 66.6,119.3 (q, JCF¼33.6 Hz),122.9
d
11.7, 20.5, 52.2, 66.3, 120.0 (q, JCF¼33.8 Hz), 123.0 (q,
(q, JCF¼269.7 Hz), 127.6, 128.0, 128.6, 140.3, 141.4 (q, JCF¼6.1 Hz). 19
F
JCF¼269.6 Hz), 127.5, 128.2, 128.4, 140.2, 140.8 (q, JCF¼5.9 Hz). 19F
NMR (470 MHz, CDCl3)
d
98.0 (d, J¼6.3 Hz). IR (neat) 2976, 2819,
NMR (564 MHz, CDCl3)
d
98.1 (d, J¼5.6 Hz). IR (neat) 2963, 2873,
1679, 1491, 1455, 1281, 1125 cmꢁ1. Anal. Calcd for C14H18F3N: C,
65.35; H, 7.05; N, 5.44. Found: C, 65.26; H, 7.17; N, 5.31.
2819, 1675, 1496, 1455, 1281, 1125, 981 cmꢁ1. HRMS (ESI) m/z calcd
for [MþH]þ: C16H23F3N 286.1783, found 286.1774.
3.2.7. 4-(4,4,4-Trifluoro-1-phenylbut-2-enyl)morpholine
3.2.13. N-Ethyl-4,4,4-trifluoro-N-isopropyl-1-phenylbut-2-en-1-
(3ab)5b. Colorless oil. 1H NMR (500 MHz, CDCl3)
d
2.33e2.41 (m,
amine (3ah). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 0.92e1.00
4H), 3.69 (t, J¼4.8 Hz, 4H), 3.77 (d, J¼8.2 Hz, 1H), 5.85 (dq, J¼6.4,
(m, 9H), 2.53 (ddd, J¼1.8, 6.9, 14.2 Hz, 2H), 2.95e3.03 (m, 1H), 4.38
15.6 Hz, 1H), 6.47 (ddq, J¼2.1, 8.7, 15.6 Hz, 1H), 7.28e7.36 (m, 5H).
(d, J¼8.2 Hz, 1H), 5.78 (dq, J¼6.4, 15.6 Hz, 1H), 6.57 (ddq, J¼2.1, 8.2,
13C NMR (125 MHz, CDCl3)
d
51.8, 67.0, 72.4, 119.7 (q, JCF¼33.9 Hz),
15.6 Hz, 1H), 7.24e7.36 (m, 5H). 13C NMR (125 MHz, CDCl3)
d 16.3,
122.7 (q, JCF¼269.7 Hz), 128.1, 128.2, 128.9, 138.8, 141.2 (q,
19.3, 19.9, 39.3, 48.6, 65.8, 118.8 (q, JCF¼33.6 Hz), 123.0 (q,
JCF¼6.1 Hz). 19F NMR (564 MHz, CDCl3)
97.8 (d, J¼7.3 Hz). IR (neat)
d
JCF¼269.7 Hz), 127.4, 128.0, 128.5, 141.4, 142.2 (q, JCF¼6.1 Hz). 19F
2961, 2857, 2812, 1682, 1492, 1451, 1282, 1117 cmꢁ1. HRMS (EI) m/z
NMR (564 MHz, CDCl3)
d
98.0 (d, J¼6.2 Hz). IR (neat) 2971, 2931,
calcd for [M]: C14H16F3NO 271.1184, found 271.1195.
2873, 1675, 1286, 1125, 981 cmꢁ1. HRMS (EI) m/z calcd for [M]:
C15H20F3N 271.1548, found 271.1542.
3.2.8. 1-(4,4,4-Trifluoro-1-phenylbut-2-enyl)-4-phenylpiperazine
(3ac)5b. Colorless oil. 1H NMR (500 MHz, CDCl3)
d
2.48e2.63 (m,
3.2.14. N-Butyl-4,4,4-trifluoro-1-phenylbut-2-en-1-amine
4H), 3.17 (t, J¼5.2 Hz, 4H), 3.84 (d, J¼8.6 Hz, 1H), 5.87 (dq, J¼6.3,
15.5 Hz, 1H), 6.53 (ddq, J¼2.0, 8.6, 15.5 Hz, 1H), 6.85 (t, J¼7.4 Hz,
1H), 6.89 (d, J¼8.0 Hz, 2H), 7.22e7.39 (m, 7H). 13C NMR (125 MHz,
(3aj). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
0.89 (t, J¼7.3 Hz,
3H), 1.30e1.51 (m, 5H), 2.48e2.59 (m, 2H), 4.27e4.28 (m, 1H), 5.87
(ddq, J¼1.4, 6.4, 15.6 Hz, 1H), 6.43e6.49 (m, 1H), 7.27e7.37 (m, 5H).
CDCl3)
d
49.1, 51.1, 71.8, 115.9, 119.5 (q, JCF¼33.6 Hz), 119.6, 122.8 (q,
13C NMR (125 MHz, CDCl3)
d 13.9, 20.4, 32.3, 47.4, 63.6, 118.1 (q,
JCF¼269.3 Hz), 127.9, 128.1, 128.8, 129.0, 139.1, 141.3 (q, JCF¼6.0 Hz),
151.1. 19F NMR (470 MHz, CDCl3)
97.9 (d, J¼6.3 Hz). IR (neat) 3061,
3030, 2958, 2824, 1679, 1603, 1500, 1451, 1339, 1290, 1124 cmꢁ1
JCF¼34.2 Hz), 123.2 (q, JCF¼270.6 Hz), 127.3, 127.9, 128.8, 140.9, 142.4
d
(q, JCF¼6.4 Hz). 19F NMR (564 MHz, CDCl3)
d
97.9 (d, J¼6.4 Hz). IR
.
(neat) 3329, 2961, 2932, 2874, 1678, 1603, 1493, 1455, 1287,
1120 cmꢁ1. HRMS (EI) m/z calcd for [M]: C14H18F3N 257.1391, found
257.1393.
HRMS (EI) m/z calcd for [M]: C20H21F3N2 346.1657, found 346.1663.
3.2.9. 1-(4,4,4-Trifluoro-1-phenylbut-2-enyl)-4-methylpiperazine
(3ad). Colorless oil. 1H NMR (600 MHz, CDCl3)
d
2.27 (s, 3H),
3.2.15. 4,4,4-Trifluoro-N-isopropyl-1-phenylbut-2-en-1-amine
2.10e2.80 (m, 8H), 3.80 (d, J¼8.7 Hz, 1H), 5.84 (dq, J¼6.4, 15.8 Hz,
(3ak). Colorless oil. 1H NMR (600 MHz, CDCl3)
d
1.04 (d, J¼6.0 Hz,
1H), 6.49 (ddq, J¼2.0, 8.7, 15.8 Hz, 1H), 7.27e7.35 (m, 5H). 13C NMR
3H), 1.07 (d, J¼6.4 Hz, 3H), 1.27 (br s, 1H), 2.70e2.77 (m, 1H),
4.41e4.42 (m, 1H), 5.84 (ddq, J¼1.5, 6.4, 15.8 Hz, 1H), 6.45e6.50 (m,
(150 MHz, CDCl3)
d
45.9, 51.1, 55.2, 71.9, 119.5 (q, JCF¼33.8 Hz), 122.8
(q, JCF¼269.6 Hz), 127.9, 128.2, 128.8, 139.3, 141.5 (q, JCF¼6.4 Hz). 19
F
1H), 7.27e7.37 (m, 5H). 13C NMR (150 MHz, CDCl3)
d 22.8, 23.4, 45.8,
NMR (564 MHz, CDCl3)
d
97.8 (d, J¼6.0 Hz). IR (neat) 2945, 2802,
60.5, 118.1 (q, JCF¼33.4 Hz), 123.3 (q, JCF¼269.6 Hz), 127.3, 127.8,

8244
T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
128.9, 141.1, 142.8 (q, JCF¼5.9 Hz). 19F NMR (564 MHz, CDCl3)
d
98.0
1376, 1268, 1163, 1109, 1012 cmꢁ1. HRMS (DART) m/z calcd for
[MþH]þ: C15H20F3N2 285.1579, found 285.1576.
(d, J¼6.7 Hz). IR (neat) 3325, 3030, 2967, 1679, 1491, 1455, 1290,
1125, 977 cmꢁ1. HRMS (ESI) m/z calcd for [MþH]þ: C13H17F3N
244.1313, found 244.1304.
3.2.22. 1-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-4-phenylpiperidine
(4ae). Yellow solid. Mp 85e90 ꢀC. 1H NMR (600 MHz, CDCl3)
3.2.16. N-Benzyl-4,4,4-trifluoro-1-phenylbut-2-en-1-amine
d
1.77e1.85 (m, 4H), 2.46e2.51 (m, 1H), 2.61 (dt, J¼3.0, 11.1 Hz, 1H),
(3al). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
3.72 (s, 2H),
4.32e4.34 (m, 1H), 5.90 (ddq, J¼1.4, 6.4, 15.6 Hz, 1H), 6.46e6.51 (m,
1H), 7.24e7.39 (m, 10H). 13C NMR (125 MHz, CDCl3)
51.3, 62.3,
2.69 (dt, J¼2.9, 11.1 Hz, 1H), 3.03e3.05 (m, 1H), 3.14e3.17 (m, 1H),
3.69e3.74 (m, 1H), 6.25 (dd, J¼7.9, 15.8 Hz, 1H), 6.74 (d, J¼15.8 Hz,
1H), 7.18e7.23 (m, 3H), 7.28e7.31 (m, 3H), 7.34e7.37 (m, 2H),
d
118.4 (q, JCF¼33.9 Hz), 123.2 (q, JCF¼269.7 Hz), 127.2, 127.4, 128.0,
7.43e7.45 (m, 2H). 13C NMR (150 MHz, CDCl3)
d 33.9, 34.0, 42.5,
128.1, 128.5, 128.9, 139.7, 140.4, 142.1 (q, JCF¼6.1 Hz). 19F NMR
50.7, 51.3, 68.5 (q, JCF¼27.4 Hz), 119.4, 126.1 (q, JCF¼286.5 Hz), 126.2,
(564 MHz, CDCl3)
d
97.9 (d, J¼6.0 Hz). IR (neat) 3325, 3061, 3030,
126.7, 126.9, 128.3, 128.5, 128.7, 136.0, 136.8, 146.2. 19F NMR
2842, 1679, 1603, 1491, 1455, 1290, 1120, 1026, 977 cmꢁ1. HRMS (EI)
(564 MHz, CDCl3)
d
92.3 (d, J¼8.3 Hz). IR (KBr) 3025, 2940, 2810,
m/z calcd for [M]: C17H16F3N 291.1235, found 291.1233.
1652, 1599, 1496, 1451, 1397, 1272, 1098 cmꢁ1. HRMS (DART) m/z
calcd for [MþH]þ: C21H23F3N 346.1783, found 346.1780.
3.2.17. N-(4,4,4-Trifluoro-1-phenylbut-2-enyl)benzenamine
(3am). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
3.97 (d, J¼4.1 Hz,
3.2.23. N,N-Dibutyl-1,1,1-trifluoro-4-phenylbut-3-en-2-amine
1H), 5.01e5.04 (m,1H), 5.94 (ddq, J¼1.8, 6.4,15.6 Hz,1H), 6.57e6.62
(4af). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
0.92 (t, J¼7.3 Hz,
(m, 3H), 6.76 (tt, J¼1.1, 7.6 Hz, 1H), 7.16e7.20 (m, 2H), 7.32e7.41 (m,
6H), 1.25e1.51 (m, 8H), 2.50e2.55 (m, 2H), 2.64e2.70 (m, 2H),
3.72e3.79 (m, 1H), 6.21 (dd, J¼7.8, 16.0 Hz, 1H), 6.66 (d, J¼16.0 Hz,
5H). 13C NMR (125 MHz, CDCl3)
d 59.1, 113.5, 118.4, 119.5 (q,
JCF¼33.9 Hz), 123.2 (q, JCF¼270.6 Hz), 127.4, 128.4, 129.2, 129.3,
1H), 7.25e7.41 (m, 5H). 13C NMR (125 MHz, CDCl3)
d 14.0, 20.2, 31.0,
139.6, 140.2 (q, JCF¼5.8 Hz), 146.5. 19F NMR (564 MHz, CDCl3)
d
98.1
51.0, 64.1 (q, JCF¼27.5 Hz), 120.0, 126.3 (q, JCF¼285.7 Hz), 126.6,
(d, J¼5.8 Hz). IR (neat) 3410, 3056, 3030, 1684, 1603, 1500, 1455,
1429, 1290, 1120, 972 cmꢁ1. HRMS (EI) m/z calcd for [M]: C16H14F3N
277.1078, found 277.1078.
128.1, 128.6, 136.2, 136.4. 19F NMR (564 MHz, CDCl3)
d
91.1 (d,
J¼8.9 Hz). IR (neat) 2960, 2933, 2874, 1686, 1497, 1468, 1379, 1268,
1173, 1111 cmꢁ1. Anal. Calcd for C18H26F3N: C, 68.93; H, 8.36; N, 4.47.
Found: C, 68.98; H, 8.55; N, 4.33.
3.2.18. N,N-Diethyl-1,1,1-trifluoro-4-phenylbut-3-en-2-amine
(4aa)5a. Colorless oil. 1H NMR (500 MHz, CDCl3)
d
1.09 (t, J¼7.1 Hz,
3.2.24. 1,1,1-Trifluoro-4-phenyl-N,N-dipropylbut-3-en-2-amine
6H), 2.59e2.66 (m, 2H), 2.75e2.82 (m, 2H), 3.78e3.85 (m, 1H), 6.22
(dd, J¼7.8, 16.0 Hz, 1H), 6.68 (d, J¼16.0 Hz, 1H), 7.25e7.41 (m, 5H).
(4ag). Colorless oil. 1H NMR (600 MHz, CDCl3)
d
0.90 (t, J¼7.3 Hz,
6H), 1.45e1.51 (m, 4H), 2.50e2.54 (m, 2H), 2.60e2.64 (m, 2H),
3.72e3.78 (m, 1H), 6.22 (dd, J¼7.9, 15.8 Hz, 1H), 6.67 (d, J¼15.8 Hz,
1H), 7.27e7.29 (m, 1H), 7.33e7.36 (m, 2H), 7.41e7.42 (m, 2H). 13C
13C NMR (125 MHz, CDCl3)
d
14.0, 44.8, 63.8 (q, JCF¼27.5 Hz), 120.1,
126.2 (q, JCF¼285.0 Hz), 126.6, 128.2, 128.6, 136.2, 136.4. 19F NMR
(564 MHz, CDCl3)
d
90.9 (d, J¼8.1 Hz). IR (neat) 2976, 2833, 1451,
NMR (150 MHz, CDCl3)
d
11.5, 21.9, 53.2, 64.2 (q, JCF¼27.5 Hz), 120.0,
1388, 1268, 1107, 968 cmꢁ1. Anal. Calcd for C14H18F3N: C, 65.35; H,
7.05; N, 5.44. Found: C, 65.24; H, 7.14; N, 5.40.
126.3 (q, JCF¼285.3 Hz), 126.6, 128.2, 128.7, 136.2, 136.4. 19F NMR
(564 MHz, CDCl3)
d
91.0 (d, J¼8.4 Hz). IR (neat) 2964, 2935, 2875,
1469, 1380, 1267, 1177, 1155, 1110, 968 cmꢁ1. HRMS (ESI) m/z calcd
3.2.19. 4-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)morpholine
for [MþH]þ: C16H23F3N 286.1783, found 286.1780.
(4ab)5b. Colorless oil. 1H NMR (500 MHz, CDCl3)
d 2.72e2.80 (m,
4H), 3.57e3.64 (m, 1H), 3.73 (t, J¼4.6 Hz, 4H), 6.18 (dd, J¼8.2,
3.2.25. N-Ethyl-1,1,1-trifluoro-N-isopropyl-4-phenylbut-3-en-2-
16.0 Hz, 1H), 6.72 (d, J¼16.0 Hz, 1H), 7.25e7.42 (m, 5H). 13C NMR
amine (4ah). Colorless oil. 1H NMR (600 MHz, CDCl3)
d 1.01 (d,
(125 MHz, CDCl3)
d
50.4, 67.2, 68.6 (q, JCF¼27.5 Hz), 118.5, 125.7 (q,
J¼6.4 Hz, 3H),1.07 (t, J¼6.9 Hz, 3H),1.10 (d, J¼6.4 Hz, 3H), 2.61e2.68
(m, 1H), 2.78e2.85 (m, 1H), 3.17e3.25 (m, 1H), 3.81e3.88 (m, 1H),
6.26 (dd, J¼7.8, 16.0 Hz, 1H), 6.66 (d, J¼16.0 Hz, 1H), 7.25e7.41 (m,
JCF¼285.0 Hz), 126.7, 128.5, 128.7, 135.7, 137.5. 19F NMR (470 MHz,
CDCl3)
d
92.0 (d, J¼8.2 Hz). IR (neat) 2963, 2857, 1453, 1362, 1264,
1108, 1012 cmꢁ1. HRMS (EI) m/z calcd for [M]: C14H16F3NO 271.1184,
5H). 13C NMR (150 MHz, CDCl3)
d 15.4, 19.5, 21.7, 40.3, 49.5, 61.3 (q,
found 271.1195.
JCF¼28.6 Hz),121.8,126.2 (q, JCF¼284.0 Hz),126.5,128.1,128.7,135.9,
136.4. 19F NMR (564 MHz, CDCl3)
d
89.2 (d, J¼8.9 Hz). IR (neat) 2971,
3.2.20. 1-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-4-phenylpiperazine
(4ac)5b. White solid. Mp 135e137 ꢀC. 1H NMR (500 MHz, CDCl3)
2936, 2873, 1455, 1384, 1268, 1111, 972 cmꢁ1. HRMS (EI) m/z calcd
for [M]: C15H20F3N 271.1548, found 271.1544.
d
2.87e2.97 (m, 4H), 3.21 (t, J¼4.9 Hz, 4H), 3.71 (quin, J¼8.0 Hz,
1H), 6.22 (dd, J¼8.0, 16.0 Hz, 1H), 6.74 (d, J¼16.0 Hz, 1H), 6.86 (t,
3.2.26. N-Butyl-1,1,1-trifluoro-4-phenylbut-3-en-2-amine
J¼7.4 Hz, 1H), 6.91 (d, J¼7.4 Hz, 2H), 7.21e7.47 (m, 7H). 13C NMR
(4aj). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
0.91 (t, J¼7.3 Hz,
(125 MHz, CDCl3)
d
49.7, 49.9, 68.1 (q, JCF¼27.6 Hz), 116.2, 118.7,
3H), 1.30e1.55 (m, 4H), 2.62e2.76 (m, 2H), 3.68e3.74 (m, 1H), 6.04
(dd, J¼8.2, 15.6 Hz, 1H), 6.70 (d, J¼15.6 Hz, 1H), 7.27e7.42 (m, 5H).
119.9, 125.8 (q, JCF¼285.5 Hz), 126.7, 128.4, 128.6, 129.0, 135.8,
137.4, 151.3. 19F NMR (470 MHz, CDCl3)
d
92.1 (d, J¼8.5 Hz). IR
13C NMR (125 MHz, CDCl3)
d 13.9, 20.2, 32.1, 47.1, 62.8 (q,
(KBr) 2806, 1652, 1603, 1581, 1500, 1388, 1303, 1268, 1236,
1187 cmꢁ1. HRMS (EI) m/z calcd for [M]: C20H21F3N2 346.1657,
found 346.1661.
JCF¼28.8 Hz), 122.1, 125.5 (q, J¼286.0 Hz), 126.7, 128.3, 128.7, 135.8,
136.0. 19F NMR (470 MHz, CDCl3)
d
87.0 (d, J¼7.2 Hz). IR (neat) 3347,
2961, 2932, 2874, 1468, 1336, 1258, 1155, 1114, 968 cmꢁ1. HRMS
(DART) m/z calcd for [MþH]þ: C14H19F3N 258.1470, found 258.1466.
3.2.21. 1-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-4-methylpiperazine
(4ad). Yellow oil. 1H NMR (600 MHz, CDCl3)
d
2.28 (s, 3H),
3.2.27. 1,1,1-Trifluoro-N-isopropyl-4-phenylbut-3-en-2-amine
2.20e2.60 (m, 4H), 2.76e2.84 (m, 4H), 3.62e3.68 (m, 1H), 6.18 (dd,
J¼8.0, 16.0 Hz, 1H), 6.70 (d, J¼16.0 Hz, 1H), 7.27e7.29 (m, 1H), 7.33
(t, J¼7.4 Hz, 2H), 7.39e7.41 (m, 2H). 13C NMR (150 MHz, CDCl3)
(4ak). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
1.07 (d, J¼6.3 Hz,
3H), 1.10 (d, J¼6.3 Hz, 3H), 1.16 (br s, 1H), 2.96 (sep, J¼6.3 Hz, 1H),
3.78 (quin, J¼7.4 Hz, 1H), 6.02 (dd, J¼8.2, 16.0 Hz, 1H), 6.67 (d,
d
46.0, 49.8, 55.4, 68.1 (q, JCF¼13.8 Hz), 118.9, 125.8 (q,
J¼16.0 Hz,1H), 7.24e7.43 (m, 5H). 13C NMR (125 MHz, CDCl3)
d 22.2,
JCF¼285.4 Hz), 126.7, 128.4, 128.7, 135.9, 137.3. 19F NMR (564 MHz,
23.6, 45.8, 60.2 (q, JCF¼29.2 Hz), 122.4, 125.6 (q, JCF¼280.7 Hz),
CDCl3)
d
92.0 (d, J¼8.2 Hz). IR (neat) 2939, 2844, 2799, 1679, 1457,
126.7, 128.3, 128.6, 135.6, 135.8. 19F NMR (470 MHz, CDCl3)
d 86.7 (d,

T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
8245
J¼7.4 Hz). IR (neat) 3329, 3030, 2967, 2873, 1719, 1447, 1379, 1263,
NMR (470 MHz, CDCl3)
d
92.3 (d, J¼8.8 Hz). IR (neat) 2940, 2837,
1183, 1156, 1116, 963 cmꢁ1. HRMS (DART) m/z calcd for [MþH]þ:
1608, 1514, 1460, 1254, 1160, 1107, 1035 cmꢁ1. Anal. Calcd for
C16H20F3NO: C, 64.20; H, 6.73; N, 4.68. Found: C, 64.32; H, 7.00; N,
4.47.
C13H17F3N 244.1313, found 244.1314.
3.2.28. N-Benzyl-1,1,1-trifluoro-4-phenylbut-3-en-2-amine
(4al). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
3.70e3.76 (m, 1H),
3.2.34. 1-(4,4,4-Trifluoro-1-(4-fluorophenyl)but-2-en-1-yl)piperidine
3.84 (d, J¼13.3 Hz, 1H), 3.96 (d, J¼13.3 Hz, 1H), 6.06 (dd, J¼8.2,
(3dn). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.41 (quin,
16.0 Hz, 1H), 6.66 (d, J¼16.0 Hz, 1H), 7.26e7.42 (m, 10H). 13C NMR
J¼5.7 Hz, 2H), 1.55 (quin, J¼5.7 Hz, 4H), 2.24e2.39 (m, 4H), 3.80 (d,
J¼8.2 Hz, 1H), 5.80 (dq, J¼6.4, 15.6 Hz, 1H), 6.46 (ddq, J¼2.0, 8.2,
15.6 Hz, 1H), 7.00e7.06 (m, 2H), 7.22e7.28 (m, 2H). 13C NMR
(125 MHz, CDCl3)
d
50.7, 61.4 (q, JCF¼28.8 Hz), 121.6, 125.6 (q,
JCF¼283.1 Hz), 126.7, 127.3, 128.1, 128.4, 128.6, 128.7, 135.7, 136.4,
139.1. 19F NMR (470 MHz, CDCl3)
d
87.1 (d, J¼7.2 Hz). IR (neat) 3347,
(125 MHz, CDCl3)
d
24.4, 26.1, 52.2, 71.5, 115.5 (d, JCF¼21.1 Hz), 119.3
3030, 2927, 2855, 1657, 1603, 1500, 1455, 1259, 1174, 1125,
1031 cmꢁ1. HRMS (EI) m/z calcd for [M]: C17H16F3N 291.1235, found
291.1225.
(q, JCF¼33.9 Hz),122.8 (q, JCF¼269.3 Hz), 129.6 (d, JCF¼8.6 Hz),135.4,
141.6 (q, JCF¼6.1 Hz), 162.2 (d, JCF¼245.7 Hz). 19F NMR (470 MHz,
CDCl3)
d
47.0e47.1 (m, 1F), 97.9 (d, J¼6.3 Hz, 3F). IR (neat) 2940,
2855, 2802, 2757, 1679, 1608, 1509, 1227, 1125, 977 cmꢁ1. Anal.
Calcd for C15H17F4N: C, 62.71; H, 5.96; N, 4.88. Found: C, 62.80; H,
6.19; N, 4.84.
3.2.29. N-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)benzenamine
(4am). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
3.91 (d, J¼8.7 Hz,
1H), 4.58e4.66 (m, 1H), 6.20 (dd, J¼6.2, 15.8 Hz, 1H), 6.73 (d,
J¼8.2 Hz, 2H), 6.79e6.83 (m, 2H), 7.20e7.39 (m, 7H). 13C NMR
3.2.35. 1-(1,1,1-Trifluoro-4-(4-fluorophenyl)but-3-en-2-yl)piperidine
(125 MHz, CDCl3)
d
58.2 (q, JCF¼30.1 Hz),113.8,119.3,120.8,125.2 (q,
(4dn). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.44 (quin,
JCF¼283.1 Hz), 126.8, 128.5, 128.7, 129.5, 135.5, 135.6, 145.7. 19F NMR
J¼5.6 Hz, 2H), 1.59 (quin, J¼5.6 Hz, 4H), 2.70 (t, J¼5.2 Hz, 4H), 3.61
(quin, J¼8.3 Hz, 1H), 6.12 (dd, J¼7.7, 15.8 Hz, 1H), 6.66 (d, J¼15.8 Hz,
1H), 7.03 (t, J¼8.6 Hz, 2H), 7.38 (dd, J¼5.4, 8.6 Hz, 2H). 13C NMR
(564 MHz, CDCl3)
d
86.5 (t, J¼5.6 Hz). IR (neat) 3410, 3056, 3030,
1603, 1509, 1250, 1125, 968 cmꢁ1. HRMS (EI) m/z calcd for [M]:
C16H14F3N 277.1078, found 277.1086.
(125 MHz, CDCl3)
d
24.2, 26.5, 51.2, 68.7 (q, JCF¼27.2 Hz), 115.6 (d,
JCF¼21.1 Hz), 119.4, 126.1 (q, JCF¼286.9 Hz), 128.3 (d, JCF¼7.7 Hz),
3.2.30. 1-(4,4,4-Trifluoro-1-phenylbut-2-en-1-yl)piperidine
132.3 (d, JCF¼3.8 Hz), 135.2, 162.65 (d, JCF¼247.6 Hz). 19F NMR
(3an). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
1.36e1.47 (m, 2H),
(470 MHz, CDCl3)
d
48.2e48.3 (m, 1F), 92.4 (d, J¼8.5 Hz, 3F). IR
1.55 (quin, J¼5.7 Hz, 4H), 2.21e2.43 (m, 4H), 3.81 (d, J¼8.3 Hz, 1H),
(neat) 2940, 2855, 2819, 1603, 1509, 1227, 1160, 1111, 972 cmꢁ1
.
5.81 (dq, J¼6.3, 15.6 Hz, 1H), 6.51 (ddq, J¼1.9, 8.3, 15.6 Hz, 1H),
Anal. Calcd for C15H17F4N: C, 62.71; H, 5.96; N, 4.88. Found: C, 62.79;
H, 4.94; N, 6.19.
7.25e7.37 (m, 5H). 13C NMR (125 MHz, CDCl3)
d 24.4, 26.1, 52.3, 72.3,
119.1 (q, JCF¼33.6 Hz), 122.9 (q, JCF¼269.3 Hz), 127.7, 128.2, 128.6,
139.6, 141.9 (q, JCF¼5.8 Hz). 19F NMR (470 MHz, CDCl3)
d
98.0 (d,
3.2.36. 1-(4,4,4-Trifluoro-1-(o-tolyl)but-2-en-1-yl)piperidine
J¼6.6 Hz). IR (neat) 3034, 2936, 2797, 1679, 1455, 1281, 1125 cmꢁ1
.
(3en). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.43 (quin,
Anal. Calcd for C15H18F3N: C, 66.90; H, 6.74; N, 5.20. Found: C, 66.56;
H, 6.75; N, 5.11.
J¼5.6 Hz, 2H), 1.48e1.61 (m, 4H), 2.26e2.33 (m, 4H), 2.35 (s, 3H),
3.96 (d, J¼8.9 Hz, 1H), 5.77 (dq, J¼6.4, 15.8 Hz, 1H), 6.44 (ddq, J¼2.0,
8.9, 15.8 Hz, 1H), 7.11e7.23 (m, 3H), 7.43 (d, J¼7.4 Hz, 1H). 13C NMR
3.2.31. 1-(1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)piperidine
(125 MHz, CDCl3)
d
19.6, 24.6, 26.1, 52.6, 68.5, 118.4 (q, JCF¼33.9 Hz),
(4an). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
1.43 (quin,
122.8 (q, JCF¼269.7 Hz), 126.4, 127.2, 127.9, 130.7, 136.3, 138.1, 141.6
J¼5.7 Hz, 2H), 1.59 (quin, J¼5.7 Hz, 4H), 2.65e2.74 (m, 4H), 3.62
(q, JCF¼5.8 Hz). 19F NMR (470 MHz, CDCl3)
d
98.0 (d, J¼6.3 Hz). IR
(quin, J¼8.3 Hz, 1H), 6.21 (dd, J¼7.7, 15.8 Hz, 1H), 6.70 (d, J¼15.8 Hz,
(neat) 2936, 2855, 2797, 2757, 1675, 1451, 1290, 1125, 977 cmꢁ1
.
1H), 7.25e7.44 (m, 5H). 13C NMR (125 MHz, CDCl3)
d
24.3, 26.5, 51.2,
Anal. Calcd for C16H20F3N: C, 67.83; H, 7.11; N, 4.94. Found: C, 67.80;
H, 7.10; N, 5.00.
68.8 (q, JCF¼27.2 Hz), 119.6, 126.1 (q, JCF¼286.6 Hz), 126.7, 128.2,
128.6, 136.1, 136.5. 19F NMR (470 MHz, CDCl3)
d
92.4 (d, J¼8.5 Hz). IR
(neat) 3025, 2936, 2851, 2815, 1455, 1263, 1156, 1107 cmꢁ1. Anal.
Calcd for C15H18F3N: C, 66.90; H, 6.74; N, 5.20. Found: C, 67.02; H,
7.02; N, 5.15.
3.2.37. 1-(1,1,1-Trifluoro-4-(o-tolyl)but-3-en-2-yl)piperidine
(4en). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.44 (quin,
J¼5.6 Hz, 2H), 1.60 (quin, J¼5.6 Hz, 4H), 2.36 (s, 3H), 2.71 (t,
J¼5.0 Hz, 4H), 3.65 (quin, J¼8.4 Hz, 1H), 6.06 (dd, J¼7.7, 15.8 Hz,
1H), 6.93 (d, J¼15.6 Hz, 1H), 7.13e7.22 (m, 3H), 7.42e7.48 (m, 1H).
3.2.32. 1-(4,4,4-Trifluoro-1-(4-methoxyphenyl)but-2-en-1-yl)piperi-
dine (3cn). Colorless oil. 1H NMR (500 MHz, CDCl3)
d
1.41 (quin,
13C NMR (125 MHz, CDCl3)
d 19.8, 24.3, 26.6, 51.3, 68.9 (q,
J¼5.5 Hz, 2H), 1.55 (quin, J¼5.5 Hz, 4H), 2.25e2.31 (m, 4H), 3.76 (d,
J¼7.8 Hz, 1H), 3.80 (s, 3H), 5.78 (dq, J¼6.4, 15.6 Hz, 1H), 6.49 (ddq,
J¼2.1, 7.8, 15.6 Hz, 1H), 6.87 (d, J¼8.8 Hz, 2H), 7.19 (d, J¼8.8 Hz, 2H).
JCF¼27.2 Hz), 121.0, 125.0, 125.9, 126.1 (q, JCF¼286.6 Hz), 128.0,
130.3, 134.4, 135.5, 135.6. 19F NMR (470 MHz, CDCl3)
d
92.3 (d,
J¼8.8 Hz). IR (neat) 2940, 2851, 2819, 1460, 1254, 1165, 1107,
968 cmꢁ1. Anal. Calcd for C16H20F3N: C, 67.83; H, 7.11; N, 4.94.
Found: C, 67.80; H, 7.18; N, 4.98.
13C NMR (125 MHz, CDCl3)
d 24.5, 26.1, 52.3, 55.2, 71.6, 114.0, 118.8
(q, JCF¼33.6 Hz), 123.0 (q, JCF¼269.7 Hz), 129.3, 131.6, 142.1 (q,
JCF¼6.1 Hz), 159.1. 19F NMR (470 MHz, CDCl3)
98.0 (d, J¼6.3 Hz). IR
d
(neat) 2940, 2851, 2797, 1679, 1612, 1514, 1250, 1120, 1040,
977 cmꢁ1. Anal. Calcd for C16H20F3NO: C, 64.20; H, 6.73; N, 4.68.
Found: C, 64.05; H, 6.72; N, 4.66.
3.3. General procedure for the allylic amination of (S)-1,1,1-
trifluoro-4-phenylbut-3-en-2-yl acetate ((S)-1a) with
morpholine (2b)
3.2.33. 1-(1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-yl)piperi-
A typical procedure is given for the reaction of (S)-1,1,1-trifluoro-
4-phenylbut-3-en-2-yl acetate ((S)-1a) with morpholine (2b)
(Table 6, Entry 2). To a solution of Pd(OAc)2 (4.5 mg, 0.020 mmol),
DPPE (8.0 mg, 0.020 mmol), (S)-1,1,1-trifluoro-4-phenylbut-3-en-2-
yl acetate ((S)-1a) (50 mg, 0.20 mmol) in THF (1.0 ml) was added
morpholine (2b) and stirred at 25 ꢀC for 12 h. The reaction mixture
was quenched with brine and H2O (1 ml), then extracted with ethyl
dine (4cn). Colorless oil. 1H NMR (500 MHz, CDCl3)
d 1.42 (quin,
J¼5.7 Hz, 2H), 1.59 (quin, J¼5.7 Hz, 4H), 2.63e2.73 (m, 4H), 3.58
(quin, J¼8.4 Hz, 1H), 3.81 (s, 3H), 6.06 (dd, J¼8.0, 16.0 Hz, 1H), 6.62
(d, J¼16.0 Hz, 1H), 6.87 (d, J¼8.8 Hz, 2H), 7.35 (d, J¼8.8 Hz, 2H). 13C
NMR (125 MHz, CDCl3)
d
24.3, 26.5, 51.2, 55.3, 68.9 (q, JCF¼27.2 Hz),
114.0, 117.1, 126.2 (q, JCF¼279.9 Hz), 127.9, 128.9, 136.0, 159.7. 19F

8246
T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
acetate. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The NMR yield (77%, trioxane as an internal
standard) and ratio of 3ab and 4ab was determined by 1H NMR of
the crude materials. The residue was purified by silica gel pre-
parative thin-layer chromatography (hexane/EtOAc/Et3N¼10/1/0.1)
to give 37 mg (66%) of (R)-3ab (98% ee) as a colorless oil.
0.1, flow: 1.0 ml/min, 254 nm, 35 ꢀC, tR 5.8 min (minor); tR 10.1 min
(major)).
3.3.10. (R)-N-Benzyl-4,4,4-trifluoro-N-methyl-1-phenylbut-2-en-1-
amine ((R)-3ao)5b. Colorless oil. 1H NMR (500 MHz, CDCl3)
d 2.11 (s,
3H), 3.42 (d, J¼13.5 Hz, 1H), 3.53 (d, J¼13.5 Hz, 1H), 4.07 (d,
J¼7.8 Hz, 1H), 5.87 (dq, J¼6.4, 15.6 Hz, 1H), 6.59 (ddq, J¼2.0, 7.8,
3.3.1. (S)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl acetate ((S)-1a)5b,20
.
15.6 Hz, 1H), 7.20e7.40 (m, 10H). 13C NMR (125 MHz, CDCl3)
d 39.1,
Yellow oil. ½a 2D6
ꢂ
þ143.14 (c 0.89, CHCl3) (99% ee). Enantiomeric
58.9, 69.9, 119.9 (q, JCF¼33.6 Hz), 122.9 (q, JCF¼269.3 Hz), 127.0,
purity was determined by HPLC using a Daicel CHIRALPAK AD-H
(hexane/2-propanol¼99/1, flow: 1.0 ml/min, 254 nm, 35 ꢀC, tR
4.4 min (major); tR 5.6 min (minor)).
127.8, 128.2, 128.3, 128.6, 128.7, 139.1, 139.5, 141.0 (q, JCF¼6.4 Hz). 19
F
NMR (470 MHz, CDCl3) d 97.9e98.1 (m). IR (neat) 3065, 2846, 2797,
1684, 1496, 1455, 1286, 1125, 981 cmꢁ1. HRMS (MALDI-TOF) m/z
calcd for [MþH]þ: C18H19F3N 306.1470, found 306.1470 (matrix:
3.3.2. (S)-1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-yl acetate
SA). ½a 2D6
ꢁ26.8 (c 1.38, CHCl3) (96% ee). Enantiomeric purity was
ꢂ
((S)-1c). White solid. Mp 71e75 ꢀC. ½a D26
ꢂ
þ170.5 (c 1.09, CHCl3) (99%
determined by HPLC using a Daicel CHIRALPAK AD-H (hexane/2-
propanol¼199/1, flow: 1.0 ml/min, 254 nm, 35 ꢀC, tR 3.8 min (ma-
jor); tR 4.6 min (minor)).
ee). Enantiomeric purity was determined by HPLC using a Daicel
CHIRALPAK AD-H (hexane/2-propanol¼99/1, flow: 1.0 ml/min,
254 nm, 35 ꢀC, tR 7.5 min (major); tR 9.2 min (minor)).
3.3.11. (S)-N-Benzyl-1,1,1-trifluoro-N-methyl-4-phenylbut-3-en-2-
3.3.3. (S)-4-(4-Chlorophenyl)-1,1,1-trifluorobut-3-en-2-yl
acetate
amine ((S)-4ao)5b. Colorless oil. 1H NMR (500 MHz, CDCl3)
d 2.40 (s,
((S)-1f)5b. Yellow solid. Mp 77e79 ꢀC. 1H NMR (500 MHz, CDCl3)
3H), 3.67 (d, J¼13.2 Hz, 1H), 3.75 (quin, J¼8.0 Hz, 1H), 3.81 (d,
d
2.19 (s, 3H), 5.78e5.84 (m, 1H), 6.09 (dd, J¼7.4, 16.0 Hz, 1H), 6.81
J¼13.2 Hz, 1H), 6.24 (dd, J¼8.0, 16.0 Hz, 1H), 6.67 (d, J¼16.0 Hz, 1H),
(d, J¼16.0 Hz, 1H), 7.31e7.36 (m, 4H). 13C NMR (125 MHz, CDCl3)
7.18e7.45 (m, 10H). 13C NMR (125 MHz, CDCl3)
d 38.2, 59.1, 65.5 (q,
d
20.6, 70.9 (q, JCF¼33.6 Hz), 118.0, 123.1 (q, JCF¼280.3 Hz), 128.2,
JCF¼28.0 Hz), 118.8, 126.3 (q, JCF¼286.3 Hz), 126.7, 127.3, 128.3,
128.9, 133.5, 134.9, 137.4, 168.8. 19F NMR (470 MHz, CDCl3)
J¼6.8 Hz). IR (KBr) 2958, 2931, 1760, 1491, 1375, 1272, 1223, 1187,
1031 cmꢁ1
a 2D6
d
85.3 (d,
128.4, 128.6, 128.7, 136.0, 137.2, 138.7. 19F NMR (470 MHz, CDCl3)
d
92.1 (d, J¼8.2 Hz). IR (neat) 2956, 2808, 1496, 1453, 1370, 1269,
½
ꢂ
þ118.3 (c 0.81, CHCl3) (99% ee). Enantiomeric purity
1168, 1107, 1025 cmꢁ1. HRMS (MALDI-TOF) m/z calcd for [MþH]þ:
was determined by HPLC using a Daicel CHIRALCEL OD-H (hexane/
2-propanol¼99/1, flow: 0.5 ml/min, 254 nm, 35 ꢀC, tR 11.3 min
(major); tR 12.3 min (minor)).
C18H19F3N 306.1470, found 306.1458 (matrix: SA). ½a D27
þ150.3 (c
ꢂ
0.74, CHCl3) (96% ee). Enantiomeric purity was determined by HPLC
using a Daicel CHIRALCEL OJ-H (hexane/2-propanol¼99/1, flow:
1.0 ml/min, 254 nm, 35 ꢀC, tR 8.4 min (major); tR 9.4 min (minor)).
3.3.4. 4-((R)-4,4,4-Trifluoro-1-phenylbut-2-enyl)morpholine
((R)-
3ab)5b. Colorless oil. ½a 2D6
ꢂ
ꢁ40.3 (c 0.73, CHCl3) (96% ee). Enantio-
3.3.12. 1-((R)-4,4,4-Trifluoro-1-(4-methoxyphenyl)but-2-enyl)-4-
phenylpiperazine ((R)-3cc). Yellow oil. 1H NMR (500 MHz, CDCl3)
meric purity was determined by HPLC using a Daicel CHIRALCEL
OD-H (hexane/2-propanol¼99/1, flow: 1.0 ml/min, 254 nm, 35 ꢀC,
tR 5.9 min (major); tR 6.9 min (minor)).
d
2.50e2.60 (m, 4H), 3.17 (t, J¼5.2 Hz, 4H), 3.79e3.81 (m, 1H), 3.81
(s, 3H), 5.85 (dq, J¼6.3, 16.0 Hz, 1H), 6.51 (ddq, J¼2.3, 8.6, 16.0 Hz,
1H), 6.84 (t, J¼7.4 Hz, 1H), 6.89 (d, J¼8.6 Hz, 4H), 7.23e7.26 (m, 4H).
3.3.5. 4-((S)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)morpholine ((S)-
13C NMR (125 MHz, CDCl3)
d 49.1, 51.1, 55.2, 71.2, 114.2, 115.9, 119.2
4ab)5b. Colorless oil. ½a 2D6
ꢂ
þ69.2 (c 1.37, CHCl3) (99% ee). Enantio-
(q, JCF¼33.6 Hz), 119.7, 122.8 (q, JCF¼268.7 Hz), 129.1, 129.2, 131.0,
meric purity was determined by HPLC using a Daicel CHIRALPAK
AD-H (hexane/2-propanol¼99/1, flow: 1.0 ml/min, 254 nm, 35 ꢀC,
tR 11.2 min (major); tR 13.0 min (minor)).
141.6 (q, JCF¼6.0 Hz), 151.2, 159.3. 19F NMR (564 MHz, CDCl3)
d 97.9
(d, J¼6.2 Hz). IR (neat) 2958, 2819, 1679, 1603, 1509, 1455, 1384,
1344, 1250, 1116 cmꢁ1
.
HRMS (ESI) m/z calcd for [MþH]þ:
C21H24F3N2O 377.1841, found 377.1833. ½a D25
ꢁ22.1 (c 2.82, CHCl3)
ꢂ
3.3.6. 1-((R)-4,4,4-Trifluoro-1-phenylbut-2-enyl)-4-phenylpiperazine
(94% ee). Enantiomeric purity was determined by HPLC using
a Daicel CHIRALCEL OD-H (hexane/2-propanol¼99/1, flow: 1.0 ml/
min, 254 nm, 35 ꢀC, tR 14.7 min (minor); tR 16.9 min (major)).
((R)-3ac)5b. Colorless oil. ½a 2D6
ꢁ22.2 (c 0.18, CHCl3) (97% ee). En-
ꢂ
antiomeric purity was determined by HPLC using a Daicel CHIR-
ALCEL OD-H (hexane/2-propanol¼99/1, flow: 1.0 ml/min, 254 nm,
35 ꢀC, tR 11.1 min (minor); tR 12.6 min (major)).
3.3.13. 1-((S)-1,1,1-Trifluoro-4-(4-methoxyphenyl)but-3-en-2-yl)-4-
phenylpiperazine ((S)-4cc). White solid. Mp 176e184 ꢀC. 1H NMR
3.3.7. 1-((S)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-4-
(600 MHz, CDCl3) d 2.87e2.95 (m, 4H), 3.18e3.23 (m, 4H),
phenylpiperazine ((S)-4ac)5b. White solid. Mp 135e137 ꢀC. ½a 2D6
ꢂ
3.65e3.71 (m, 1H), 3.81 (s, 3H), 6.07 (dd, J¼8.3, 15.8 Hz, 1H), 6.67 (d,
þ61.1 (c 0.36, CHCl3) (99% ee). Enantiomeric purity was determined
by HPLC using a Daicel CHIRALPAK AD-H (hexane/2-propanol¼9/1,
flow: 1.0 ml/min, 254 nm, 35 ꢀC, tR 6.2 min (major); tR 9.2 min
(minor)).
J¼15.8 Hz, 1H), 6.84e6.88 (m, 3H), 6.90e6.92 (m, 2H), 7.23e7.27
(m, 2H), 7.34e7.36 (m, 2H). 13C NMR (150 MHz, CDCl3)
d 49.8, 50.0,
55.4, 68.4 (q, JCF¼27.6 Hz), 114.1, 116.2, 116.3, 120.0, 126.0 (q,
JCF¼285.1 Hz), 128.1, 128.6, 129.2, 137.0, 151.4, 159.9. 19F NMR
(564 MHz, CDCl3)
d
91.9 (d, J¼8.2 Hz). IR (KBr) 3003, 2909, 2842,
3.3.8. 1-((R)-4,4,4-Trifluoro-1-phenylbut-2-enyl)-4-methylpiperazine
1652, 1608, 1581, 1514, 1308, 1250, 1183, 1142, 1102 cmꢁ1. HRMS
((R)-3ad). Colorless oil. ½a D24
ꢂ
ꢁ45.7 (c 1.88, CHCl3) (95% ee). Enan-
(DART) m/z calcd for [MþH]þ: C21H24F3N2O 377.1841, found
tiomeric purity was determined by HPLC using a Daicel CHIRALPAK
AD-H (hexane/2-propanol/diethylamine¼99/1/0.1, flow: 1.0 ml/
min, 254 nm, 35 ꢀC, tR 5.9 min (major); tR 6.5 min (minor)).
377.1838. ½a 2D5
þ86.7 (c 1.17, CHCl3) (98% ee). Enantiomeric purity
ꢂ
was determined by HPLC using a Daicel CHIRALPAK AD-H (hexane/
2-propanol¼9/1, flow: 1.0 ml/min, 254 nm, 35 ꢀC, tR 9.4 min (ma-
jor); tR 12.5 min (minor)).
3.3.9. 1-((S)-1,1,1-Trifluoro-4-phenylbut-3-en-2-yl)-4-
methylpiperazine ((S)-4ad). Colorless oil. ½a D25
ꢂ
þ63.4 (c 2.03, CHCl3)
3.3.14. 1-((R)-1-(4-Chlorophenyl)-4,4,4-trifluorobut-2-enyl)-4-
phenylpiperazine ((R)-3fc)5b. Yellow oil. 1H NMR (500 MHz, CDCl3)
(98% ee). Enantiomeric purity was determined by HPLC using
a Daicel CHIRALCEL OJ-H (hexane/2-propanol/diethylamine¼99/1/
d
2.49e2.60 (m, 4H), 3.17 (t, J¼5.0 Hz, 4H), 3.83 (d, J¼8.6 Hz, 1H),

T. Hirakawa et al. / Tetrahedron 67 (2011) 8238e8247
8247
Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 12214; (k) For [Ru] Mor-
isaki, Y.; Kondo, T.; Mitsudo, T. Organometallics 1999,18, 4742; (l) Matsushima, Y.;
Onitsuka, K.; Kondo, T.; Mitsudo, T.; Takahashi, S. J. Am. Chem. Soc. 2001, 123,
10405; (m) Matsushima, Y.; Onitsuka, K.; Takahashi, S. Organometallics 2004, 23,
3763; (n) Kawatsura, M.; Ata, F.; Hirakawa, T.; Hayase, S.; Itoh, T. Tetrahedron Lett.
2008, 49, 4873 and references therein.
3. Examples of allylic substitutions of fluorinated allyl substrates: (a) Hanzawa, Y.;
Ishizawa, S.; Kobayashi, Y. Chem. Pharm. Bull. 1988, 36, 4209; (b) Hanzawa, Y.;
Ishizawa, S.; Ito, H.; Kobayashi, Y.; Taguchi, T. J. Chem. Soc., Chem. Commun. 1990,
394; (c) Fish, P. V.; Reddy, S. P.; Lee, C. H.; Johnson, W. S. Tetrahedron Lett. 1992,
33, 8001; (d) Konno, T.; Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 2000, 41,
8467; (e) Okano, T.; Matsubara, H.; Kusukawa, T.; Fujita, M. J. Organomet. Chem.
2003, 676, 43; (f) Konno, T.; Takehana, T.; Ishihara, T.; Yamanaka, H. Org. Biomol.
Chem. 2004, 2, 93; (g) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org.
Chem. 2006, 71, 3545; (h) Kawatsura, M.; Wada, S.; Hayase, S.; Itoh, T. Synlett
2006, 2483.
4. Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002, 67, 1768.
5. (a) Kawatsura, M.; Hirakawa, T.; Tanaka, T.; Ikeda, D.; Hayase, S.; Itoh, T. Tet-
rahedron Lett. 2008, 49, 2450; (b) Hirakawa, T.; Ikeda, K.; Ogasa, H.; Kawatsura,
M.; Itoh, T. Synlett 2010, 2887.
6. We examined PPh3, DPPE, and DPPF as a phosphine ligand.
7. The reaction of alkyl group substituted acetates, such as 1,1,1-trifluorohept-3-
en-2-yl acetate, didn’t provide any aminated products.
5.87 (dq, J¼6.3, 15.8 Hz, 1H), 6.47 (ddq, J¼2.0, 8.6, 15.8 Hz, 1H), 6.86
(t, J¼7.2 Hz, 1H), 6.90 (d, J¼8.6 Hz, 2H), 7.24e7.35 (m, 6H). 13C NMR
(125 MHz, CDCl3)
d 49.2, 51.1, 71.2, 116.0, 119.9, 120.0 (q,
JCF¼34.0 Hz), 122.6 (q, JCF¼269.9 Hz), 129.2, 129.2, 129.4, 133.8,
137.8, 140.8 (q, JCF¼6.4 Hz), 151.1. 19F NMR (470 MHz, CDCl3)
d 97.7
(d, J¼6.1 Hz). IR (neat) 2958, 2825, 1681, 1600, 1490, 1453, 1344,
1286, 1123, 1006 cmꢁ1. HRMS (MALDI-TOF) m/z calcd for [MþH]þ:
C20H21ClF3N2 381.1345, found 381.1348 (matrix: SA). ½a D25
ꢁ22.3 (c
ꢂ
2.39, CHCl3) (83% ee). Enantiomeric purity was determined by HPLC
using a Daicel CHIRALCEL OJ-H (hexane/2-propanol¼9/1, flow:
1.0 ml/min, 254 nm, 35 ꢀC, tR 14.8 min (major); tR 19.8 min (mi-
nor)). Recrystallization of isolated product from hexane gave an
enantiomerically pure (R)-3fc (>99% ee).
3.3.15. 1-((S)-4-(4-Chlorophenyl)-1,1,1-trifluorobut-3-en-2-yl)-4-
phenylpiperazine ((S)-4fc)5b. White solid. Mp 151e153 ꢀC. 1H NMR
(500 MHz, CDCl3)
d
2.89e2.96 (m, 4H), 3.21 (t, J¼4.9 Hz, 4H), 3.72
(quin, J¼8.0 Hz, 1H), 6.19 (dd, J¼8.0, 16.0 Hz, 1H), 6.71 (d, J¼16.0 Hz,
8. The electronic effect of trifluoromethyl group is also important for this
regioselectivity.
1H), 6.87 (t, J¼7.4 Hz, 1H), 6.92 (d, J¼8.0 Hz, 2H), 7.24e7.36 (m, 6H).
13C NMR (125 MHz, CDCl3)
d
49.8, 49.9, 68.1 (q, JCF¼28.0 Hz), 116.3,
ꢀ
ꢀ
9. (a) Akermark, B.; Akermark, G.; Hegedus, L. S.; Zetterberg, K. J. Am. Chem. Soc.
ꢁ
1981, 103, 3037; (b) Amatore, C.; Genin, E.; Jutand, A.; Mensah, L. Organome-
119.5, 120.0, 125.7 (q, JCF¼285.5 Hz), 127.9, 128.9, 129.1, 134.1, 134.3,
tallics 2007, 26, 1875; (c) Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2005, 127,
17516; (d) Watson, I. D. G.; Styler, S. A.; Yudin, A. K. J. Am. Chem. Soc. 2004, 126,
5086.
136.0, 151.3. 19F NMR (470 MHz, CDCl3)
d
92.1 (d, J¼8.9 Hz). IR (KBr)
2884, 2823, 1602, 1492, 1455, 1388, 1268, 1245, 1150, 1105, 1013,
976 cmꢁ1. HRMS (MALDI-TOF) m/z calcd for [MþH]þ: C20H21ClF3N2
10. The examples of Pd-catalyzed allylic substitution of allyl amines, see: (a)
Murahashi, S.-I.; Imada, Y.; Nishimura, K. J. Chem. Soc., Chem. Commun. 1988,
1578; (b) Miyazawa, M.; Wang, S.-Z.; Takeda, H.; Yamamoto, K. Synlett 1992,
323; (c) Miyazawa, M.; Yamamoto, K. Chem. Lett. 1994, 491; (d) Doi, T.; Yana-
gisawa, A.; Miyazawa, M.; Yamamoto, K. Tetrahedron: Asymmetry 1995, 6, 389.
11. Examples of net retention mechanism in the palladium-catalyzed allylic sub-
stitutions: (a) Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc.
1983, 105, 7767; (b) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986,
51, 723; (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
12. The absolute configuration of (R)-3ab and (S)-4ab were determined by the
comparison of the X-ray crystallographic analysis of (R)-3fc and (S)-4fc. Crys-
tallographic data for compounds (R)-3fc and (S)-4fc have been deposited with
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 792223 (for (R)-3fc) and CCDC 792751 (for (S)-4fc). Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: þ44(1223)336033 or e-mail: data_request@ccdc.cam.
ac.uk].
381.1345, found 381.1340 (matrix: SA). ½a D25
þ71.4 (c 0.95, CHCl3)
ꢂ
(95% ee). Enantiomeric purity was determined by HPLC using
a Daicel CHIRALPAK AD-H (hexane/2-propanol¼9/1, flow: 1.0 ml/
min, 254 nm, 35 ꢀC, tR 7.1 min (major); tR 10.2 min (minor)). Re-
crystallization of isolated product from hexane gave an enantio-
merically pure (S)-4fc (>99% ee).
Acknowledgements
This study was financially supported in part by Grant-in-Aid for
Scientific Research (C) (No. 23550123) from the Japan Society for
the Promotion of Science.
13. We confirmed that the
a-selectivity in the [Pd(p-allyl)(cod)]BF4/(S)-BINAP
catalyst system is inferior to the [Pd(p-allyl)(cod)]BF4/DPPF catalyst system.
14. The reaction of 1a (99% ee) with 2o at 40 ꢀC under the condition B gave 4ao
(94% ee) with 93% regioselectivity.
Supplementary data
15. Selected examples of kinetic resolution in the palladium-catalyzed allylic
substitutions of disubstituted symmetrical or monosubstituted allylic esters:
(a) Cook, G. R. Curr. Org. Chem. 2000, 4, 869; (b) Robinson, D. E. J. E.; Bull, S. D.
Tetrahedron: Asymmetry 2003, 14, 1407; (c) Longmire, J. M.; Wang, B.; Zhang, X.
Tetrahedron Lett. 2000, 41, 5435; (d) Reetz, M. T.; Sostmann, S. J. Organomet.
Chem. 2000, 603, 105; (e) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237; (f)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.093.
References and notes
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ꢁ
Castillon, S.; Godard, C.; Aghmiz, A.; Claver, C.; Gomez, M. Chem. Commun. 2008,
6197; (i) Hou, X. L.; Zheng, B. H. Org. Lett. 2009, 11, 1789 and references therein.
16. Examples of kinetic resolution in the palladium-catalyzed allylic substitutions
of 1,3-disubstituted unsymmetrical allylic esters: (a) Hayashi, T.; Yamamoto, A.;
Ito, Y. J. Chem. Soc., Chem. Commun. 1986, 1090; (b) Faller, J. W.; Wilt, J. C. Tet-
rahedron Lett. 2004, 45, 7613.
2. Selected examples of transition metal-catalyzed allylic aminations of allylic es-
ters: (a) For [Pd] Dubovyk, I.; Watson, I. D. G.; Yudin, A. K. J. Am. Chem. Soc. 2007,
129, 14172; (b) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46,
7259; (c) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633 and references therein; (d)
For [Ir] Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc.
2001,123, 9525; (e) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002,124,15164; (f)
Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005,127,15506;
(g) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.
dEur. J. 2006, 12, 3596; (h) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew.
Chem., Int. Ed. 2006, 45, 5546 and references therein; (i) For [Rh] Evans, P. A.;
Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761; (j) Evans, P. A.;
17. Calculated by eeP and eeS. S¼ln[(1ꢁc)(1þeeP)]/ln[(1ꢁc)(1ꢁeeP)]. c¼eeS/
(eeSþeeP).
18. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
19. White, D. A.; Doyle, J. R.; Lewis, H. Inorg. Synth. 1972, 13, 55.
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