Regioselective synthesis of trifluoromethyl group substituted allylic amines via palladium-catalyzed allylic amination

Article abstract of DOI:10.1016/j.tetlet.2008.02.034

The palladium-catalyzed regioselective allylic amination of α-trifluoromethylated allyl acetate occurred using Pd(OAc)₂/DPPE and [Pd(π-allyl)(cod)]BF₄/DPPF. The selective formation of the γ-product was attained by Pd(OAc)₂

Full text of DOI:10.1016/j.tetlet.2008.02.034

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2450–2453
Regioselective synthesis of trifluoromethyl group substituted
allylic amines via palladium-catalyzed allylic amination
Motoi Kawatsura *, Takuya Hirakawa, Tomoko Tanaka, Daiji Ikeda,
Shuichi Hayase, Toshiyuki Itoh *
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 14 January 2008; revised 5 February 2008; accepted 7 February 2008
Available online 10 February 2008
Abstract
The palladium-catalyzed regioselective allylic amination of a-trifluoromethylated allyl acetate occurred using Pd(OAc)2/DPPE and
[Pd(p-allyl)(cod)]BF4/DPPF. The selective formation of the c-product was attained by Pd(OAc)2/DPPE, while the a-product was
obtained using [Pd(p-allyl)(cod)]BF4/DPPF.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Palladium; Allylic amination; Regioselectivity; Fluorine
The transition metal-catalyzed allylic substitution of
allyl esters is one of the most efficient means for realizing
carbon–carbon and carbon–heteroatom bond formation
reactions in organic synthesis.1 Especially, there are several
excellent stereoselective allylic substitutions, including
allylic amination,2,3 that have been reported using palla-
dium catalysts.4 Although there have been numerous exam-
ples of reactions of non-fluorinated substrates, only a few
reports about the palladium-catalyzed allylic substitution
reaction using fluorinated substrates have been reported.5
To the best of our knowledge, there is only one example
of the transition metal-catalyzed allylic amination of the
a-trifluoromethylated allyl substrate, which was reported
by Konno et al. in 2002.5e They demonstrated the palla-
dium-catalyzed allylic amination of a-trifluoromethylated
allyl mesylate, and found that the reaction produced the
c-product as a single regioisomer. With this result in mind,
we started to investigate other palladium catalyst systems,
which would give the other regioisomer (a-product). We
now report both the a-selective and c-selective allylic amin-
ations of a-trifluoromethylated allyl acetate using two
types of palladium catalysts.
We examined the allylic amination of the a-trifluoro-
methylated allyl acetate 1 with diethylamine (2a) using
several palladium/phosphine catalysts (Scheme 1). Based
on the initial screening, we confirmed that some palladium
catalysts, which were generated from Pd2(dba)3 or [Pd(p-
allyl)Cl]2 with several phosphine ligands,6 did not catalyze
the desired amination reaction nor resulted in the low con-
version of substrate 1 (<20%). On the other hand, we found
that the Pd(OAc)2 and [Pd(p-allyl)(cod)]BF4 exhibited a
catalyst activity for this intended reaction. The results
obtained for the palladium-catalyzed allylic amination of
1 with diethylamine (2a) are summarized in Table 1.7 We
first conducted the reaction using Pd(OAc)2 with PPh3
(4 equiv to Pd), but the reaction rate was low (entry 1).
OAc
NEt2
NEt2
CF3
4a: α-product
γ
α
cat.[Pd/L]
Ph
CF3
+
Ph
1
Ph
CF3
+
HNEt2
3a: γ-product
*
Corresponding authors. Tel./fax: +81 857 31 5179 (M.K.).
2a
E-mail addresses: kawatsur@chem.tottori-u.ac.jp (M. Kawatsura),
Scheme 1.
titoh@chem.tottori-u.ac.jp (T. Itoh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.034

M. Kawatsura et al. / Tetrahedron Letters 49 (2008) 2450–2453
2451
Table 1
Palladium-catalyzed allylic amination of 1 with diethylamine 2aa
Entry
[Pd/L]
Solvent
Temp (°C)/time (h)
Yieldb of 3a + 4a (%)
3a:4ac
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PPh3
Pd(OAc)2/DPPE
Pd(OAc)2/DPPF
Pd(OAc)2/DPPE
[Pd(p-allyl)(cod)]BF4/PPh3
[Pd(p-allyl)(cod)]BF4/DPPE
[Pd(p-allyl)(cod)]BF4/DPPF
[Pd(p-allyl)(cod)]BF4/DPPF
[Pd(p-allyl)(cod)]BF4/DPPF
[Pd(p-allyl)(cod)]BF4/DPPF
[Pd(p-allyl)(cod)]BF4/DPPF
THF
THF
THF
Dioxane
THF
THF
THF
Dioxane
Dioxane
Dioxane
Dioxane
60/12
60/12
60/12
100/12
60/12
60/12
60/12
60/12
100/9
100/12
100/0.5
20
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
68:32
69:31
2:>98
73:27
61:39
86 (80)d
64 (58)d
68
12
17
56
78
95 (87)d
66
10e
11
a
68
All reactions were carried out with 1 (0.20 mmol), 2a (0.31 mmol), palladium (0.020 mmol), and ligand (0.021 mmol for DPPE and DPPF, 0.084 mmol
for PPh3) in solvent (1.0 mL) under nitrogen unless otherwise noted.
b
The yields were determined by 1H NMR.
c
The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude materials.
d
Isolated yield by silica gel column chromatography in parentheses.
[Pd(p-allyl)(cod)]BF4 (0.010 mmol) and DPPF (0.010 mmol) were used.
e
Fortunately, we found that DPPE [1,2-bis(diphenylphos-
phino)ethane] (1 equiv to Pd) is an effective ligand for the
allylic amination of 1, and the c-trifluoromethyl group
substituted allyl amine 3a (c-product) was obtained as a
single regioisomer in 80% isolated yield (entry 2). We also
examined the reaction with DPPF, but the yield was lower
(entry 3). A further investigation revealed that [Pd(p-
allyl)(cod)]BF4 also catalyzed the allylic amination of 1.
Again, the c-selective amination was observed in the reac-
tion using PPh3 and DPPE ligated palladium catalyst, but
the yield was very low (entries 5 and 6). Interestingly, the
palladium catalyst, which coordinated with DPPF, exhib-
ited a higher reactivity and gave a mixture of two diastereo-
isomers 3a and 4a (a-product) in the ratio of 68:32 (entry
7). This a-selectivity was improved by elevating the reac-
tion temperature to 100 °C in dioxane, and 4a was obtained
as a single regioisomer in 87% isolated yield (entry 9). It
was found that several other reaction conditions, such as
a lower temperature (60 °C) (entry 8), reduced the catalyst
amount (5 mol % of Pd and DPPF) (entry 10) or shorter
reaction times (30 min) (entry 11), decreased this a-selectiv-
ity and produced the c-product as the major product.
We applied these two catalyst systems to the reaction
with other amines (Scheme 2), and the results are summa-
rized in Table 2. The reaction with aliphatic secondary
amines, such as morpholine (2b) and dibutylamine (2c),
proceeded with the same regioselective trend as the reaction
with 2a. For example, the Pd(OAc)2/DPPE catalyzed reac-
tion of 1 with 2b or 2c formed the c-product (3b or 3c) as a
single regioisomer (entries 1 and 3). On the other hand, the
[Pd(p-allyl)(cod)]BF4/DPPF catalyst exhibited an another
regioselectivity and produced the a-products 4b and 4c as
the major regioisomers (entries 2 and 4). Unfortunately,
these palladium-catalyzed allylic aminations with both
Pd(OAc)2/DPPE and [Pd(p-allyl)(cod)]BF4/DPPF are very
sensitive to the steric factor of the amines. As shown in
entries 5 and 6, the reaction with N-ethylisopropylamine
using Pd(OAc)2/DPPE proceeded with a >98% c-selectivity,
Table 2
Palladium-catalyzed allylic amination of 1 with amines 2b–ha
Entry
2
Conditionb
Yieldc of 3 + 4 (%)
3:4d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
2b
A
B
A
B
A
B
A
B
A
B
A
B
A
B
92 (99)e
75 (79)e
64 (72)e
80
97:3
7:93
2c
2d
2e
2f
>98:2
2:>98
>98:2
75:25
—
(12)e
(15)e
0
0
—
54 (56)e
61 (66)e
66 (68)e
79 (80)e
(22)e
>98:2
2:>98
>98:2
2:>98
>98:2
2:>98
OAc
NRR'
NRR'
cat.[Pd/L]
2g
2h
+
Ph
CF3
γ
α
Ph
CF3
Ph
CF3
1
+
3b-h
58 (60)e
4b-h
2b-h
All reactions were carried out with 1 (0.20 mmol) and 2 (0.31 mmol) in
2b: morpholine
2c: dibutylamine
solvent (1.0 mL) for 12 h under nitrogen unless otherwise noted.
b
Condition A: 10 mol % Pd(OAc)2 and 10 mol % DPPE in THF at
2d: N-ethylisopropylamine
60 °C. Condition B: 10 mol % [Pd(p-allyl)(cod)]BF4 and 10 mol % DPPF
in dioxane at 100 °C.
2e: diisopropylamine
-butylamine
2f:
n
c
Isolated yield by silica gel column chromatography.
The ratio was determined by 400 MHz 1H NMR spectral analysis of
2g: benzylamine
2h: aniline
d
the crude materials.
e
Scheme 2.
The NMR yield in parentheses.

2452
M. Kawatsura et al. / Tetrahedron Letters 49 (2008) 2450–2453
Table 3
but the yield was very low (12% NMR yield), and the
reaction using [Pd(p-allyl)(cod)]BF4/DPPF gave a mixture
of two diastereoisomers, 3d and 4d, in the ratio of 75:25.
The reaction with diisopropylamine (2e) resulted in no
reaction (entries 7 and 8). We also demonstrated the reac-
tion with the primary amines 2f and 2g, and obtained the
expected results. We observed the perfect c-selectivity in
the reaction of 2f using Pd(OAc)2/DPPE, though the yield
was low (entry 9). On the other hand, the reaction with
[Pd(p-allyl)(cod)]BF4/DPPF produced the a-product in
moderate yield (61% isolated yield) as a single regioisomer
(entry 10). Similar results were obtained for the reaction
with benzylamine (2g) (entries 11 and 12). This trend in
regioselectivity was again observed in the reaction with
an aromatic amine 2h; the Pd(OAc)2 catalyst exhibited
the perfect c-selectivity (entry 13), and the [Pd(p-allyl)-
(cod)]BF4 catalyst again selectively produced the a-product
(entry 14).
The reaction of c-product 3a using the palladium catalysta
Entry [Pd/L]
Et2NH
Conversionb Yieldb of
of 3a (%)
4a (%)
1
2
[Pd(p-allyl)(cod)]BF4
[Pd(p-allyl)(cod)]BF4/
DPPF
—
—
>80
>99
Trace
52
3
4
[Pd(p-allyl)(cod)]BF4/
DPPF
Pd(OAc)2/DPPE
1.5 equiv >99
1.5 equiv
73
0
0
a
All reactions were carried out with 3a (0.20 mmol), palladium
(0.020 mmol), and ligand (0.021 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.
and Table 3). On the other hand, we also confirmed that
the Pd(OAc)2/DPPE did not catalyze the isomerization of
3a to 4a under the same conditions. These results strongly
support the idea that the c-product was selectively formed
at first, then it was isomerized to the a-product by the
[Pd(p-allyl)(cod)]BF4/DPPF catalyst.
In conclusion, we have demonstrated the regioselective
formation of both the a- and c-trifluoromethyl group-
substituted allyl amines via the palladium-catalyzed allylic
amination of a-trifluoromethylated allyl acetate. The con-
ventional c-product was obtained using the Pd(OAc)2/
DPPE catalyst, and the unusual a-product was obtained
using the [Pd(p-allyl)(cod)]BF4/DPPF catalyst. We also
revealed that the c-product was easily isomerized to the
a-product under the [Pd(p-allyl)(cod)]BF4/DPPF catalyzed
reaction conditions, then concluded that the a-product was
formed by the isomerization of the c-product.
We next studied the reaction mechanism and/or path-
way for the regioselective substitution especially for the
unusual selective formation of the a-product. Generally,
the palladium catalyst forms the p-allylpalladium interme-
diate and nucleophiles attack the p-allyl terminus. Accord-
ing to the report about the allylic substitution of
a-trifluoroalkylated allyl mesylates by Konno et al.,5d the
allyl substrate easily formed the p-allylpalladium complex,
and nucleophiles selectively attacked the less sterically hin-
dered p-allyl terminus to form the c-product.8 We believe
that the same mechanism is applicable to the reaction of
1 with 2 by Pd(OAc)2/DPPE. In contrast, it is unclear
whether or not the selective substitution occurred during
the reaction of the [Pd(p-allyl)(cod)]BF4/DPPF catalyst
because, as we previously mentioned, the c-product was
obtained as the major product under several different con-
ditions (Table 1, entries 8, 10, and 11). Based on these
results, we assumed that [Pd(p-allyl)(cod)]BF4/DPPF had
also selectively formed c-product, thus causing isomeriza-
tion to provide the a-product under the given reaction con-
ditions.3f,g,9 To prove these hypotheses, the c-product 3a
Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
1
was treated with the palladium catalyst and the H NMR
References and notes
spectrum measured. When the reaction was carried out
with 10 mol % [Pd(p-allyl)(cod)]BF4 (without DPPF) in
dioxane at 100 °C for 12 h, we confirmed the >80% conver-
sion of 3a, but a complex mixture was produced. However,
the reaction with 10 mol % of [Pd(p-allyl)(cod)]BF4 and
10 mol % of DPPF indicated the formation of a-product
4a (52% NMR yield), which suggested that 3a was isomer-
ized to 4a by [Pd(p-allyl)(cod)]BF4/DPPF.10 Furthermore,
the addition of excess Et2NH (1.5 equiv to 3a) increased
the formation of 4a up to a 73% NMR yield (Scheme 3
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CF3
Ph
4a
3a
Scheme 3.

M. Kawatsura et al. / Tetrahedron Letters 49 (2008) 2450–2453
2453
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9 h. The reaction mixture was quenched with water, and extracted
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over anhydrous MgSO4, and evaporated. The NMR yield (95%,
trioxane as a internal standard) and diastereomeric ratio were
determined by 400 MHz 1H NMR for crude material. The residue
was purified by silica gel column chromatography (hexane/EtOAc/
Et3N = 97:2:1) to give 46 mg (87%) of 4a (a-product) as a colorless
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d 1.08 (t,
J = 7.1 Hz, 6H), 2.79 (dq, J = 6.4, 7.1 Hz, 2H), 2.64 (dq, J = 6.4,
7.1 Hz, 2H), 3.77–3.86 (m, 1H), 6.22 (dd, J = 8.1, 15.7 Hz, 1H), 6.68
(d, J = 16.1 Hz, 1H), 7.23–7.41 (m, 5H). 13C NMR (125 MHz,
CDCl3): d 14.0, 44.8, 63.8 (q, JCF = 27.5 Hz), 120.1, 126.3 (q,
JCF = 285.3 Hz), 126.6, 128.2, 128.6, 136.2, 136.4. 19F NMR
(470 MHz, CDCl3): d À70.7 (d, J = 11.5 Hz). Anal. Calcd for
C14H18F3N: C, 65.35; H, 7.05; N, 5.44. Found: C, 65.24; H, 7.14;
N, 5.40. Regioisomer 3a (c-product): 1H NMR (500 MHz, CDCl3): d
0.99 (t, J = 6.9 Hz, 6H), 2.53 (q, J = 7.0 Hz, 4H), 4.27 (d, J = 8.2 Hz,
1H), 5.77–5.84 (m, 1H), 6.50–6.56 (m, 1H), 7.26–7.36 (m, 5H). 13C
NMR (125 MHz, CDCl3): d 11.8, 43.1, 66.6, 119.3 (q, JCF = 33.6 Hz),
122.9 (q, JCF = 269.3 Hz), 127.6, 128.1, 128.6, 140.3, 141.4 (q,
JCF = 6.1 Hz). 19F NMR (470 MHz, CDCl3): d À63.7. Anal. Calcd
for C14H18F3N: C, 65.35; H, 7.05; N, 5.44. Found: C, 65.26; H, 7.17;
N, 5.31.
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´
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˚
´
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typical procedure is given for the reaction of 1 with 2a (Table 1, entry
9). To a solution of [Pd(p-allyl)(cod)]BF4 (7.0 mg, 0.020 mmol) and
DPPF (11.4 mg, 0.021 mmol) in dioxane (1.0 mL) were added allyl
acetate 1 (50 mg, 0.20 mmol) and amine 2a (23 mg, 0.31 mmol) at
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