A chronicle review: Regioselective synthesis of trifluoromethyl group containing allylic amines using palladium-catalyzed allylic amination pathway

Journal of Fluorine Chemistry 152 (2013) 62–69

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A chronicle review: Regioselective synthesis of trifluoromethyl group containing allylic amines using palladium-catalyzed allylic amination pathway Takuya Hirakawa a, Motoi Kawatsura b, Toshiyuki Itoh a,* a b

Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan Department of Chemistry, College of Humanities and Sciences, Nihon University, 3-25-40 Sakurajosui, Setagaya, Tokyo 156-8550, Japan

A R T I C L E I N F O

A B S T R A C T

Article history: Received 10 January 2013 Received in revised form 4 March 2013 Accepted 5 March 2013 Available online 6 April 2013

Palladium-catalyzed regioselective allylic amination of the a-trifluoromethyl group-substituted allyl acetate has been accomplished using Pd(OAc)2/DPPE and [Pd(p-allyl)(cod)]BF4/DPPF as catalysts. The selective formation of the g-product was attained by the use of Pd(OAc)2/DPPE, while the a-product was obtained in the presence of [Pd(p-allyl)(cod)]BF4/DPPF. We also succeeded in synthesizing optically active allylic amines using Pd(OAc)2/DPPE and [Pd(p-allyl)(cod)]BF4/BINAP began from optically active trifluoromethyl-substituted allyl acetate. Furthermore, we established that kinetic resolution of two types of allylic amines was possible using enantioselective isomerization by the [Pd(p-allyl)(cod)]BF4/ (S)-BINAP catalyst. ß 2013 Elsevier B.V. All rights reserved.

Keywords: Trifluoromethyl Pd-catalyzed allylic amination Regioselective Kinetic resolution Synthesis

1. Introduction

a-trifluoromethyl-substituted allyl substrates when we launched

Fluorine substituted organic compounds have attracted strong interest in the field of medicinal chemistry and material sciences because of their unique properties due to the strong electron withdrawing nature of fluorine, while the atomic size of fluorine is believed to be similar to that of hydrogen. For example, the replacement of hydrogen atoms by fluorine atoms in organic molecules causes a relatively small steric change, but leads to major changes in the electron character of the molecules. Also, some compounds containing fluorines sometimes exhibit an unusual stereoselectivity under standard organic reaction conditions [1]. Therefore, the development of efficient means of preparing fluorinated compounds is one of the important subjects in organic chemistry [1]. The transition metal-catalyzed allylic amination reaction of allyl esters is a versatile method of producing allylic amines, and several transition metal catalysts have been employed to realize these reactions [2,3]. However, most of them were reactions involving non-fluorinated substrates, and there had been reported only limited examples of the palladium-catalyzed reaction of

the present project [4]. Konno et al. demonstrated the first example of the palladium-catalyzed regioselective (g-selective) allylic amination of a-trifluoromethyl-substituted allyl mesylate, and in 2002 established that the reaction produced the g-product as a single regioisomer [5]. Okano and co-workers demonstrated regioselective palladium-catalyzed allylic substitution reaction with a malonate in 2003, though the authors demonstrated no allylic amination [6] (Fig. 1). We have been investigating the possibility of palladiumcatalyzed allylic amination and established several reactions in this field: regiocontrol of allylic amination, isomerization of the amino group of the allylic position, kinetic resolution of allylic amines via chiral palladium complex, and finally, accomplishment of enantioselective allylic amination [7–9]. In this chronicle, we report studies on the palladium-catalyzed regioselective allylic amination of atrifluoromethyl-substituted allyl esters with amines, including the synthesis of the trifluoromethyl group containing optically active allylic amines. We also report the achievement of enantioselective Pd-catalyzed a-amination of a-trifluoromethyl-substituted allyl ester with various types of amines. 2. Regiostereocontrol of allylic amination

* Corresponding author. E-mail addresses: [email protected] (M. Kawatsura), [email protected] (T. Itoh). 0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jfluchem.2013.03.008

We examined the allylic amination of (E)-1,1,1-trifluoro-4phenylbut-3-en-2-yl acetate (1a) with diethylamine using several

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

R1 X OAc Ar

cat. [Pd/L]

* CF3 1

R1

Pd(II)

R2 Ar

Solvent

* CF3

63

N

R2

Ar * CF3 2 -product

NH

+

Base

R1 Ar

cf. Previous

3

examples EtO2C

N

R2

* CF3 -product

CO2Et

NRR' CF3 n-C6H13

CF3

Pd(PPh3)4/Et3N, THF, 0°C Konno (2002)

[Pd( -allyl)Cl]2/ NaOtBu THF, 50°C Okano (2003)

Fig. 1. Regioselective Pd-catalyzed allylic substitution reaction of 1,1,1-trifluoro-4-arylbut-3-en-2-yl acetate.

palladium/phosphine catalysts (Fig. 2) and we found that Pd(OAc)2 and [Pd(p-allyl)(cod)]BF4 exhibited a catalytic activity for this intended reaction [7,8]. On the contrary, palladium catalysts, which were generated from Pd2(dba)3 or [Pd(p-allyl)Cl]2 with several phosphine ligands, showed no catalytic activity toward the desired amination reaction or resulted in a low conversion of the substrate 1a (<20%). Furthermore, it was established that the regioselectivity significantly depended on the ligand system. Initially, we conducted the reaction using Pd(OAc)2 with PPh3 (4 equiv. versus Pd), and a poor reaction rate was recorded. After evaluation of six types of phosphine ligands: which included 1,1bis(diphenylphosphino)methane (DPPM), 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), and (diphenylphosphino)ferrocene (DPPF), we succeeded in controlling regioselectivity of the reaction. The results obtained for the palladiumcatalyzed allylic amination of 1a with diethylamine (2a) are summarized in Table 1.

10 mol% Pd(OAc)2 or [Pd( -allyl)cod]BF4 OAc CF3

10 mol% Lignad Et2NH (1.5 eq.)

NEt2 CF3 2a -product

Solvent

1a

NEt2 CF3 3a -product

Ligand: Ph2P

PPh2 Ph2P

DPPM

Ph2P

PPh2

DPPB

PPh2 Ph2P PPh2 DPPP DPPE

Fe

PPh2 PPh2

DPPF

It was found that DPPE [1,2-bis(diphenylphosphino)ethane] (1 equiv. to Pd) worked as an effective ligand for the allylic amination of 1a, and allyl amine 2a (g-product) was obtained as a single regioisomer in 86% isolated yield when the reaction was carried out in THF at 60 8C (entry 1). [Pd(p-allyl)(cod)]BF4 [10] also catalyzed the allylic amination of 1a using dioxane as solvent but in different modes (entries 3–6). The g-selective aminated product 2a was obtained for the reaction using DPPE ligated palladium catalyst with very poor yield (entry 2). The regioselectivity depended on the ligand, and a-selectivity was improved by increased distance between two diphenylphosphino groups. DPPB ligated Pd-catalyst gave a-product 3a preferentially (entry5), and 3a was obtained as a sole product (>98%) in 95% yield when the reaction was carried out in the presence of DPPF ligand at 100 8C using dioxane as solvent (entry 6). We thus established regioselective allylic amination of 1 with several amines using these two types of palladium catalyst systems (Condition A and B) (Fig. 3). The results of Pd-catalyzed regioselective allylic amination are summarized in Table 2, where we described our control of the regioselectivity of allylic amination of 1 using two types of Pd-catalyst systems: Pd(OAc)2/DPPE mediated reactions exhibited perfect g-selectivity and trifluoromethyl-substituted allyl amine 2 was produced as a sole product (Table 2). Reactions of 1a with various amines, such as morpholine, N,N-dibutylamine, N-butylamine, or benzylamine were conducted under condition A, to give g-products 2b, 2c, 2d, 2e, and 2g with perfect selectivity in high to acceptable yields (entries, 1, 3, 5, 7, 9, and 11). However, the reaction with aniline gave 2f poor yield while excellent regisoelectivity was still obtained (entry 9). On the Table 1 Regioselective amination of 1,1,1-trifluoro-4-phenylbut-3-en-2-yl acetate. Entry

Pd cat.a

Ligand

Solvent

Temp (8C)

Yield

1 2 3 4 5 6

A B B B B B

DPPE DPPM DPPE DPPP DPPB DPPF

THF dioxane dioxane dioxane dioxane dioxane

60 100 100 100 100 100

86 11 43 67 53 95

a

Fig. 2. Regioselective allylic amination of 1,1,1-trifluoro-4-phenylbut-3-en-2-yl acetate using various Pd-catalyst systems.

b c

b

(%)

Pd cat. A: 10 mol% Pd(OAc)2, B: 10 mol% [Pd(p-allyl)cod][BF4]. Isolated yield. The ratio of diastereoisomers are determined by 1H NMR analysis.

g:ac >98:<2 >98:<2 60:40 69:31 15:85 <2:>98

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

64

Table 2 Regioselective amination of (E)-1,1,1-trifluoro-4-arylbut-3-en-2-yl acetate. R

Entry

Amine

Condition

a

Major product

Yield

b

(g: a)c

1

H

A

2b

99% (>98:<2)

2

H

B

3b

79% (<2:>98)

3 4 5 6 7 8 9

H H H H H H H

A B A B A B A

2c 3c 2d 3d 2e 3e 2f

72% 80% 56% 66% 68% 80% 22%

10

H

B

3f

60% (<2:>98)

11

H

A

2g

68% (>98:<2)

12

H

B

3g

74% (<2:>98)

13

2-Me

A

2h

82% (>98:<2)

14

2-Me

B

3h

74% (<2:>98)

15

4-MeO

A

2i

89% (>98:<2)

16

4-MeO

B

3i

62% (<2:>98)

17

4-F

A

2j

82% (>98:<2)

18

4-F

B

3j

64% (<2:>98)

a b c

nBu2NH nBu2NH nBuNH2 nBuNH2 BnNH2 BnNH2

(>98:<2) (<2:98) (>98:<2) (<2:>98) (>98:<2) (<2:>98) (>98:<2)

Condition A: 10 mol% Pd(OAc)2, 10 mol% DPPE, THF, 60 8C. Condition B: 10 mol% [Pd(p-allyl)cod]BF4, 10 mol% DPPF, dioxane, 100 8C. Isolated yield. The ratio was determined by 1H NMR analysis.

other hand, reactions of 1 with amines were carried out under condition B, and a-products 3 were obtained with perfect regioselectivity for all reactions (entries 2, 4, 6, 8, 10, and 12). An electron-withdrawing or electron-donating group at the paraposition on the aromatic ring of substrate 1, did not show any significant difference in the regioselectivity (entries 13–18), but, introduction of a substituent at the para or ortho position influenced chemical yield and an increased yield for the gselective product 2 (entries 13, 15, and 17) was obtained. On the contrary, a slightly lower yield was observed for the a-selective reactions (entries 14, 16, and 18).

During performance of these reactions, we found an interesting palladium-catalyzed isomerization reaction (Fig. 4) [9]. As previously mentioned, reported examples of Pd-catalyzed allylic substitution reaction of a-trifluoromethyl-substituted allyl substrates gave only g-products [7,8]. It is well known that the palladium catalyst forms the p-allylpalladium intermediate and nucleophiles attack the p-allyl terminus. According to Konno’s report of the allylic substitution of a-trifluoroalkyl-substituted allyl mesylates [5], the allyl substrate formed the p-allylpalladium complex, and nucleophiles selectively attacked the less sterically hindered p-allyl terminus to furnish the g-product. Therefore, it is

Condition A or B R1 Pd catalyst OAc

R1R2NH

(1.5 eq.)

R

CF3 R

1

N

N

R2 CF3

Condition A: 10 mol% Pd(OAc)2, 10 mol% DPPE, THF, 60°C

R

3 -product

Condition B: 10 mol% [Pd( -allyl)cod]BF4, 10 mol% DPPF, Dioxane, 100°C Fig. 3. Pd-catalyzed regioselective allylic amination.

Et2NH (1.5 eq.)

CF3

CF3 2 -product R1

Solvent

OAc

R2

(±)-1a

Solvent

Condition A: Pd(OAc)2, DPPE, THF, 60ºC

Condition A

Condition B: [Pd( -allyl)cod][BF4], DPPF, dioxane, 100°C

NEt2 (±)-2a -product

CF3

Condition B NEt2 CF3 (±)-3a -product

Fig. 4. Pd-catalyzed allylic amination of (E)-1,1,1-trifluoro-4-phenylbut-3-en-2-yl acetate.

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

65

Table 3 Preparation of chiral trifluoromethyl-substituted amines 2 and 3 via Pd-catalyzed amination began from optically active trifluoromethyl-substituted allyl acetate. R

Entry

Amine

Condition

a

Product: yield

b

(g: a)

1

H

A

2b

77%, 98% ee (>99:<1)

2

H

C

3b

95%, 99% ee (3:97)

3

H

A

2k

91%, 97% ee (>99:<1)

4

H

C

3k

99%, 97% ee (3:97)

5

H

A

2e

83%, 96% ee (>99:<1)

6

H

C

3e

99%, 96% ee (6:94)

7

H

A

2l

91%, 97% ee (>99:<1)

8

H

C

3l

99%, 97% ee (3:97)

9

4-MeO

A

2m

86%, 94% ee (>99:<1)

10

4-MeO

C

3m

97%, 98% ee (4:96)

11

4-Cl

A

2n

71%, 83% ee (>99:<1)

12

4-Cl

C

3n

82%, 95% ee (4:96)

a b c

c

Condition A: 10 mol% Pd(OAc)2, 10 mol% DPPE, THF, 60 8C. Condition C: 10 mol% [Pd(p-allyl)cod]BF4, 10 mol% (S)-BINAP, dioxane, 100 8C. Isolated yield. The ratio was determined by 1H NMR analysis.

believed that the same mechanism is applicable for the reaction of 1 with amines by Pd(OAc)2/DPPE. As described in Table 2, the catalyst [Pd(p-allyl)(cod)]BF4/DPPF provides a-products selectively, while g-product was the major product obtained when Pd(p-allyl)(cod)]BF4 [10] was used as catalyst under different conditions [11]. Inspired by these results, we hypothesized that gproduct might be produced selectively at the initial stage even

O Condition A OAc

morpholine (1.5 eq.)

CF3 (S)-1a

N CF3 (R)-2b Y= 79% (98% ee)

Solvent

O

99% ee

Condition A: Pd(OAc)2, DPPE, THF, 60°C

N

Condition B

CF3 3b Y= 85% (0% ee)

Condition C

Y= 93% (99%ee(S))

Condition B: [Pd( -allyl)cod][BF4], DPPF, dioxane, 100°C

Condition C: [Pd( -allyl)cod][BF4], (S)-BINAP, dioxane, 40°C Fig. 5. Different results in the chirality transfer of Pd-catalyzed regioselective allylic amination.

when [Pd(p-allyl)(cod)]BF4/DPPF was used as a catalyst, but the catalyst may cause isomerization of g-product 2 and provide the aproduct 3 under given reaction conditions. To prove this hypothesis, the g-product 2a was treated with the palladium catalyst and the isomerization reaction was examined using 1H NMR experiments. When the reaction was carried out in the presence of 10 mol% [Pd(p-allyl)(cod)]BF4 (without DPPF) in dioxane at 100 8C for 12 h, it was confirmed that isomerization indeed occurred with >80% conversion of 2a, but a complex mixture was produced. On the other hand, the reaction with 10 mol% of [Pd(p-allyl)(cod)]BF4 and 10 mol% of DPPF indicated the formation of the a-product 3a (52% NMR yield), which clearly suggested that 2a was isomerized to 3a by [Pd(p-allyl)(cod)]BF4/ DPPF. Finally, we found that addition of excess Et2NH (1.5 equiv. to 2a) increased the formation of 3a up to a 73% NMR yield. We also confirmed that the Pd(OAc)2/DPPE did not catalyze the isomerization of 2a to 3a under the same conditions (Fig. 4). These results strongly support the idea that the g-product is initially selectively formed, and then is isomerized to the a-product by the [Pd(pallyl)(cod)]BF4/DPPF catalyst [12,13]. 3. Synthesis of optically active CF3-group containing allylic amines The net retention (double inversion) mechanism is widely accepted for the palladium-catalyzed allylic substitutions [13], and the reaction of the optically active allylic substrates generally forms optically active substitution products without any loss of their optical purity. Therefore, we next examined the a- and gselective allylic amination of optically active allylic acetate using two types of palladium catalysts to prepare optically active a- and g-allylic amines (Fig. 5) [9]. Initially, we expected that both the chiral a- and g-allylic amines would be easily obtained by the net retention mechanism. However, we soon recognized that the enantiomeric excess of

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

66

R1

N

R2 CF3

R

OAc Condition A or C R1R2NH (1.5 eq.) CF3 Solvent (S)-1

R

(R)-2

R1

99% ee

R

N

R2

CF3 (S)-3

Fig. 6. Preparation of chiral amines via Pd-catalyzed allylic amination began from optically active trifluoromethyl-substituted allyl acetate.

products was dependent on the catalyst systems. 98% ee of (R)-2b was obtained in 79% yield when 99% ee of (S)-1a reacted with morpholine in the presence of Pd(OAc)2/DPPE in THF at 25 8C (Condition A) (Fig. 5), though the enantiomeric excess of 2b was dependent on the reaction temperature. As we earlier established, a-product 3b might be obtained selectively when the reaction was conducted using [Pd(p-allyl)(cod)]BF4/DPPF (Condition B). In fact, we found that 3b was produced in 85% yield, although it was obtained in a racemic state (Fig. 5). We reinvestigated the reaction conditions, but a reduced reaction temperature was not effective in retaining the enantiomeric excess. To our delight, we finally succeeded in obtaining the enantiomerically enriched a-product (S)-3b by complete chirality transfer using the chiral BINAP ligand after screening of several types of phosphine ligands. When (S)-BINAP was used as the ligand for the reaction of (S)-1a with morpholine at 40 8C, aproduct (S)-3b was obtained in excellent yield (93%) with 99% ee (Fig. 5). Since preferable reaction systems were established (Conditions A and C), we demonstrated the preparation of chiral allyllic amines 2 and 3 began from optically active trifluoromethyl-substituted allyl acetate (S)-1 as substrates with various types of amines as reactants (Fig. 6); the results are summarized in Table 3. The reaction using Pd(OAc)2/DPPE exhibited a perfect regioselectivity, and produced enantiomerically enriched gproducts 2 (entries 1, 3, 5, 7, 9). For the reaction of (S)-1 with morpholine, 1-phenylpiperazine, or N-benzyl,N-methylamine using catalyst system A, we obtained enantiomerically enriched g-product (R)-2 with over 95% ee (entries 1, 3, and 5), though the enantiomeric excess of g-product (R)-2 was slightly reduced for the reaction of (S)-1b (R = 4-MeO) and (S)1c (R = 4-Cl) (entries 9 and 11). As we expected, the [Pd(pallyl)(cod)]BF4/(S)-BINAP catalyst produced enantiomerically enriched a-products (S)-3 with excellent regioselectivity (entries 2, 4, 6, 8, 10, and 12) [9]. The stereochemistry of gand a -products was determined by X-ray crystallographic analyses of (R)-2n and (S)-3n (Fig. 7) [14]. We next found an interesting phenomenon of a-selective amination during performance of these reactions when the

O 10 mol% [Pd( -allyl)cod][BF4] 10 mol% BINAP OAc

morpholine (1.5 eq.) CF3 dioxane, 40°C, 12 h (S)-1a 99% ee

N CF3 (S)-2b (S)-BINAP, 40°C, 24 h Y= 7% (R)-BINAP, 40°C, 12 h Y= 69%, 91% ee (S)

O N CF3 (S)-3b (S)-BINAP, 40°C, 24h Y= 93%, 99% ee (S) (R)-BINAP, 40°C, 12 h Y=11%, 13% ee (S)

Fig. 7. ORTEP view of (R)-2n and (S)-3n.

Fig. 8. Different results in the chirality transfer of chiral Pd-complex-mediated regioselective allylic amination.

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

[Pd( -allyl)(cod)]BF4 (S)-BINAP

O

HN

N H CF3 (R)-2b 97%ee

O

O O

CF3 (S)-3b

THF

N

10 mol% [Pd( -allyl)cod][BF4]

H N

O

CF3 (S)-2b Y= 58%, 46% ee

10 mol% (S)-BINAP morpholine (1.5 eq.)

N

Y= 91% (97% ee)

CF3

[Pd( -allyl)(cod)]BF4 (R)-BINAP HN

67

N

S value = 19

(±)-2b

(1)

O

dioxane, 40°C, 12 h

CF3 (S)-3b

O

(S)-3b

Y= 42%, 85% ee

Fig. 9. BINAP-Pd complex-mediated isomerization of (R,E)-4-(4,4,4-trifluoro-1phenylbut-2-en-1-yl)morpholine.

Me

Me

N

Ph

Me N

Ph

(±)-2k

(S)-2k Y= 49%, 66% ee

S value = 15

Fig. 10. Kinetic resolution of (E)-4-(4,4,4-trifluoro-1-phenylbut-2-en-1yl)morpholine and (E)-N-benzyl-4,4,4-trifluoro-N-methyl-1-phenylbut-2-en-1amine using chiral Pd-complex.

(R)-2b may be unfavorable. This means that kinetic resolution of allylic amine 2b may be possible during the isomerization step from the g-product to a-product [9]. To prove this hypothesis, we attempted to demonstrate the isomerization reaction of the chiral allylic amine (R)-2b using chiral palladium/BINAP catalysts (Fig. 9). The isomerization reaction of (R)-2b (97% ee) smoothly occurred when (S)-BINAP was used and the chiral a-product (S)-3b was

(S)-BINAP O

O N H CF3 (R)-2b

O (S)

CF3 (S)-3b Y= 42% (85% ee) Product

N +

H CF3 (S)-2b

Y= 58% (46% ee) Unreacted substrate

Ph P P Ph Ph Pd0 Ph

fast

(S)

O

NH

O

Ph P P Ph Ph Pd Ph BF4

NH

CF3 Good matching complex

(S)

(S)-2b (S)

Ph P P Ph Ph Pd0 Ph

HN slow

(2)

(S)-3k Y= 51%, 77% ee

[Pd( -allyl)(cod)]BF4

H N

Ph CF3

CF3

CF3

[Pd(p-allyl)(cod)]BF4 catalyst was used in the presence of (S)BINAP or (R)-BINAP: (S)-BINAP and (R)-BINAP exhibited different results on both the regiochemistry and enantiomeric excess for the allylic amination of (S)-1a with morpholine (Fig. 8). The reaction using [Pd(p-allyl)(cod)]BF4/(S)-BINAP gave the chiral aproduct (S)-3b with 99% ee in 93%yield (Fig. 8). On the contrary, g-product (R)-2b was obtained as the major product with high enantiomeric excess (91% ee) in 69% yield when (R)-BINAP was used for the reaction for 12 h at 40 8C (Fig. 8). Since the same product (R)-3b was produced for the reactions (Fig. 8), it was anticipated that reactivity of (S)-2b or (R)-2b with BINAP-Pd-complex might be different. Hence we hypothesized that (S)-2b reacts with (S)-BINAP-Pd complex to afford the corresponding Pd-complex which reacts with morpholine and gives (S)-3b. On the contrary, the matching of (S)-BINAP-Pd and

N

O Ph P P Ph Ph Pd Ph

BF4

(R)-3b

F3C

Poor matching complex derived from (S)-2b Fig. 11. Working hypothesis on (S)-BINAP-Pd complex-mediated kinetic resolution of (E)-4-(4,4,4-trifluoro-1-phenylbut-2-en-1-yl)morpholine.

T. Hirakawa et al. / Journal of Fluorine Chemistry 152 (2013) 62–69

68

5 mol% [Pd( -allyl)Cl]2 10 mol% (S)-BINAP Me

N

Ph CF3

(±)-2k

HN

N Ph

dioxane, r.t. 3 days

a-product 3 was formed by isomerization of the g-product 2 with a certain enantioselectivity. Using the isomerization reaction, we prepared chiral trifluoromethyl-substituted allylic amines via kinetic resolution of racemic allylic amines using [Pd(p-allyl)(cod)]BF4/BINAP catalyst complex.

Ph N N CF3 (±)-2l Y= 82% (racemic)

Fig. 12. Preparation of (S,E)-1-phenyl-4-(1,1,1-trifluoro-4-phenylbut-3-en-2yl)piperazine by the cross amination.

obtained in 91% yield without any loss of enantiomeric excess (97% ee). The isomerization of (R)-2b, however, was very slow when (R)BINAP was used, and 92% of the g-product (R)-2b was recovered. These two results clearly indicate that the (S)-BINAP ligand is a matching enantiomer for the stereospecific isomerization of the chiral allylic amine (R)-2b to (S)-3b. We then demonstrated the kinetic resolution of the racemic allylic amine ()-2b via [Pd(pallyl)(cod)]BF4/(S)-BINAP catalyzed isomerization (Fig. 10). As we intended, the selective kinetic resolution took place at 40 8C in 12 h and produced optically active 42% of chiral a-product 3b with 85% ee and (S)-2b in 58% yield with 46% ee. The S value [15] was calculated as 19 (Fig. 10, eq. 1). We further achieved kinetic resolution of (E)-Nbenzyl-4,4,4-trifluoro-N-methyl-1-phenylbut-2-en-1-amine using the same catalyst system, though a slightly reduced S-value was recorded for this substrate (Fig. 10, eq. 2). Although several examples of the kinetic resolution of palladium-catalyzed allylic substitution reactions have been reported [16,17], this is the first kinetic resolution of allylic amines using a palladium catalyzed reaction [9]. Our working hypothesis on (S)-BINAP-Pd complex-mediated kinetic resolution of (E)-4-(4,4,4-trifluoro-1-phenylbut-2-en-1-yl)morpholine (2b) is illustrated in Fig. 11. Since p-allyl palladium complex was formed during the isomerization process, we hypothesized that cross-amination reaction might be possible using the present palladium catalyst system. Hence, we attempted cross-amination reaction of aallylic amine using palladium catalyst-mediated reaction. After optimization of the catalyst system, we found the desired crossamination reaction indeed occurred when racemic (E)-N-benzyl4,4,4-trifluoro-N-methyl-1-phenylbut-2-en-1-amine (()-2k) was treated with [Pd(p-allyl)Cl]2/(S)-BINAP in dioxane as solvent at rt for 3 days in the presence of 1.5 equivalent of 1-phenylpiperazine. The desired product (E)-1-phenyl-4-(4,4,4-trifluoro-1-phenylbut-2-en-1-yl)piperazine (()-2l) was obtained in 82% yield (Fig. 12). Thus it had been confirmed that cross-amination reaction of g-allyl amine through a common p-allyl palladium complex, and this step was assumed to be the rate limiting step; therefore, substitution reaction with 1-phenylpiperazine might take place very smoothly. 4. Conclusion We have successfully demonstrated regioselective preparation of trifluoromethyl group-substituted g- and a-allyl amines via the palladium catalyzed allylic amination of a-trifluoromethylated allyl acetate. Conventional g-products were 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 further found that the g-product was easily isomerized to the a-product under the [Pd(p-allyl)(cod)]BF4/ DPPF catalyzed reaction conditions, then concluded that the

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