Regioselective synthesis of optically active trifluoromethyl group substituted allylic amines by palladium-catalyzed allylic amination

Article abstract of DOI:10.1055/s-0030-1259039

We succeeded in the regioselective synthesis of chiral trifluoromethyl group substituted allylic amines from chiral allyl acetate using two types of palladium catalysts. Furthermore, we found that the kinetic resolution had occurred during the isomerizati

Full text of DOI:10.1055/s-0030-1259039

LETTER
2887
Regioselective Synthesis of Optically Active Trifluoromethyl Group
Substituted Allylic Amines by Palladium-Catalyzed Allylic Amination
O
ptically Activ
a
e
T
rifluorom
k
ethyl-Subst
u
ituted Allyli
y
c
A
mines a Hirakawa, Kazunori Ikeda, Hiroshi Ogasa, Motoi Kawatsura,* Toshiyuki Itoh*
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Fax +81(857)315179; E-mail: kawatsur@chem.tottori-u.ac.jp; E-mail: titoh@chem.tottori-u.ac.jp
Received 15 September 2010
tate (S)-1 (99% ee) with morpholine (2a) by the
Abstract: We succeeded in the regioselective synthesis of chiral
Pd(OAc)2/DPPE catalyst at 60 °C gave the g-produt 4a in
trifluoromethyl group substituted allylic amines from chiral allyl
acetate using two types of palladium catalysts. Furthermore, we
found that the kinetic resolution had occurred during the isomeriza-
an 99% yield with 81% ee (Scheme 2, Table 1, entry 1).8
Furthermore,
the
a-selective
reaction
by
tion step from the g-type product to the a-type product by the [Pd(C3H5)(cod)]BF4/DPPF at 100 °C resulted in a 85%
yield with a 0% ee (entry 3).8 We then initiated a study to
[Pd(C3H5)(cod)]BF4/(S)-BINAP catalyst.
find the reaction conditions to retain the chirality of the
starting allyl substrate, which produces optically active
trifluoromethyl-substituted aminated products. As we
mentioned above, we recognized that the allylic amination
of (S)-1 by the Pd(OAc)2/DPPE catalyst at 60 °C de-
creased the enantiopurity, but fortunately, a reinvestiga-
tion of the reaction conditions revealed that the reaction
proceeded at 25 °C with retention of the enantiomeric ex-
cess, and gave the optically active trifluoromethyl-substi-
tuted g-type product (R)-4a in 98% ee (entry 2). We next
attempted the formation of the chiral a-product 3a using
the [Pd(C3H5)(cod)]BF4/ligand catalyst. Again, we rein-
vestigated the reaction conditions, but soon realized that a
reduced reaction temperature was not effective for retain-
ing the chirality. For example, the reaction at 60 °C gave
the almost racemic a-product 3a with a low regioselectiv-
ity (entry 4). However, after the screening of several types
of phosphine ligands, we succeeded in obtaining the chiral
a-product (S)-3a with complete chirality transfer using
the chiral BINAP ligand. When (S)-BINAP was used as
Key words: palladium catalyst, allylic amination, trifluoromethyl
group, chiral allylic amine, kinetic resolution
The transition-metal-catalyzed allylic substitution reac-
tion is a useful process to construct the carbon–carbon and
carbon–heteroatom bonds in organic synthesis.1 Especial-
ly, the transition-metal-catalyzed allylic amination reac-
tion of allylic esters is a versatile method to produce
allylic amines, and several transition-metal catalysts have
realized these reactions.2,3 However, most of them were
the reactions of nonfluorinated substrates, and there is
only a limited example for the reaction of the a-trifluo-
romethylated allyl substrates (Scheme 1).4 In 2002,
Konno et al. reported the first example of palladium-
catalyzed regioselective (g-selective) allylic amination of
the a-trifluoromethylated allyl substrates.5 Recently, our
group reported both the a-selective and g-selective allylic
aminations of a-trifluoromethylated allyl acetate using
two types of palladium catalysts.6 However, in the report,
we used only the racemic allyl acetates for both regiose-
lective reactions, which resulted in the formation of race-
mic products. On the other hand, the net retention (double
inversion) mechanism is a very popular stereochemical
phenomenon for palladium-catalyzed allylic substitu-
tions, and the reaction of optically active allyl substrates
generally forms optically active substitution products
without losing any enantiomeric excess.7 According to
this mechanism, we examined the a- and g-selective allyl-
ic aminations of chiral allyl acetate using two types of pal-
ladium catalysts, then succeeded in obtaining chiral a- and
g-allylic amines.
NR2R3
α
R1
CF3
α-product
X
cat. [Pd]
HNR2R3
+
and/or
NR2R3
γ
R1
CF3
X = leaving group
R1
CF3
γ-product
Scheme 1
Initially, we expected that both the chiral a- and g-allyl
amines were easily obtained by the net retention mecha-
nism. However, we soon recognized that the chirality of
the allyl acetate was lost under our reported catalytic con-
ditions.7 For example, the reaction of the chiral allyl ace-
OAc
O
O
Ph
CF3
(S)-1 (99% ee)
cat. [Pd]
N
N
+
+
α
γ
Ph
CF3
Ph
CF3
HN
O
(S)-3a: α-product
(R)-4a: γ-product
SYNLETT 2010, No. 19, pp 2887–2890
Advanced online publication: 10.11.2010
x
x
.x
x
.2
0
1
0
2a
DOI: 10.1055/s-0030-1259039; Art ID: U08210ST
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

2888
T. Hirakawa et al.
LETTER
Table 1 Palladium-Catalyzed Allylic Amination of Chiral (S)-1 with Morpholine (2a)
Entry [Pd/L]a Temp (°C) Yield (%)b of 3a + 4a Ratioc of 3a/4a ee (%)d of (S)-3a ee (%)d of (R)-4a
1
2
3
4
5
6
7e
8
Pd(OAc)2/DPPE
60
25
99
77
85
94
95
95
98
80
2:>98
2:>98
n.d.
n.d.
0
81
Pd(OAc)2/DPPE
98
[Pd(C3H5)(cod)]BF4/DPPF
[Pd(C3H5)(cod)]BF4/DPPF
[Pd(C3H5)(cod)]BF4/(S)-BINAP
[Pd(C3H5)(cod)]BF4/(S)-BINAP
[Pd(C3H5)(cod)]BF4/(S)-BINAP
[Pd(C3H5)(cod)]BF4/(R)-BINAP
100
60
95:5
n.d.
n.d.
n.d.
n.d.
n.d.
91
82:18
93:7
4
100
40
33
99
99
13f
93:7
40
97:3
40
13:87
a Reaction conditions: (S)-1 (0.21 mmol), 2a (0.31 mmol), [Pd] (0.021 mmol), ligand (0.021 mmol), and solvent (1.0 mL; THF for entries 1 and
2, dioxane for entries 3–8), 12 h.
b The yields were determined by 1H NMR using an internal standard (trioxane).
c The ratio was determined by 400 MHz 1H NMR spectral analysis of the crude materials.
d Values of ee were determined by chiral HPLC: Daicel CHIRALPAK AD-H (hexane–2-PrOH = 99:1) for 3a. Daicel CHIRALCEL OD-H
(hexane–2-PrOH = 99:1) for 4a.
e Reaction was conducted using 5 mol% [Pd] and ligand for 24 h.
f (R)-3a was obtained as a major enantiomer.
the ligand for the reaction of (S)-1 with morpholine (2a) (S)-1 with 2a. As shown in Table 1, the reaction by (S)-
at 100 °C, the a-product was produced as the major regio- BINAP gave a chiral a-product (S)-3a with 99% ee
isomer with 33% ee (entry 5). The racemization was pre- (Table 1, entries 6 and 7). However, when the (R)-BINAP
vented at 40 °C, then the enantiomerically pure a-product was used for the same reaction, the g-product (R)-4a was
(S)-3a was obtained in good yield even with 5 mol% obtained as a major regioisomer with a high enantiomeric
[Pd(C3H5)(cod)]BF4/(S)-BINAP (entries 6 and 7).9–11 We excess (91% ee; entry 8). These results indicate that the
also examined this regioselective synthesis of the optical- kinetic resolution might have occurred during the isomer-
ly active allylic amines with other amines using two types ization step from the g-product to a-product. To clarify the
of palladium catalysts (Scheme 3). As we intended, the re- kinetic resolution, we next demonstrated the isomeriza-
action with 1-phenylpiperazine (2b) and N-methylbenzyl- tion reaction of the chiral allyl amine (R)-4a using chiral
amine (2c) gave both the chiral a- and g-products with a palladium/BINAP catalysts (Scheme 4).
high enantiomeric excess.
The isomerization reaction of (R)-4a (97% ee) smoothly
Furthermore, we realized that (S)-BINAP and (R)-BINAP occurred when (S)-BINAP was used and the chiral a-
exhibited different results regarding both the regiochem- product (S)-3a was obtained in 91% yield without any loss
istry and enantiomeric excess for the allylic amination of of enantiomeric excess (97% ee). On the other hand, the
isomerization of (R)-4a was very slow when (R)-BINAP
OAc
was used, and 92% of the g-product was recovered. These
two results strongly suggest that the (S)-BINAP ligand is
Ph
CF3
a matching enantiomer for the stereospecific isomeriza-
tion of the chiral allyl amine (R)-4a to (S)-3a. To the best
of our knowledge, there are several reports about the ki-
netic resolution of the palladium-catalyzed allylic substi-
tutions,12,13 but there are no examples of the kinetic
resolution for the palladium-catalyzed isomerization of
1,3-disubstituted unsymmetrical allyl amines. We then
demonstrated the kinetic resolution of the racemic allyl
amine rac-4a by [Pd(C3H5)(cod)]BF4/(S)-BINAP-cata-
lyzed isomerization (Scheme 5). As we intended, the se-
lective kinetic resolution took place at 40 °C for 12 hours
and produced a 58% chiral g-product [46% ee (S)] and
42% chiral a-product [85% ee (S)] (S value = 19).14,15
NR1R2
CF3
NR1R2
(S)-1 (99% ee)
conditions
A or B
+
+
Ph
Ph
CF3
1-phenylpiperazine (2b)
or
3b,c: α-product
4b,c: γ-product
N-methylbenzylamine (2c)
(1.5 equiv)
Conditions
Major product
Amine
A
(S)-3b: 91% yield, 97% ee
(R)-4b: 94% yield, 97% ee
(S)-3c: 83% yield, 96% ee
(R)-4c: 87% yield, 96% ee
2b
B (40 °C)
A
2c
B (25 °C)
A: 10 mol% Pd(OAc)2, 10 mol% DPPE, THF, 25 °C
B: 10 mol% [Pd(C3H5)(cod)]BF4, 10 mol% (S)-BINAP,
dioxane, 25 or 40 °C
In conclusion, we demonstrated the regioselective synthe-
sis of the chiral trifluoromethyl-substituted allylic amines
from chiral allyl acetate using two types of palladium cat-
Scheme 3
Synlett 2010, No. 19, 2887–2890 © Thieme Stuttgart · New York

LETTER
Optically Active Trifluoromethyl-Substituted Allylic Amines
2889
O
N
O
N
O
N
10 mol%
[Pd(C3H5)(cod)]BF4/L
dioxane
40 °C, 12 h
Ph
CF3
Ph
CF3
Ph
CF3
(R)-4a (97% ee)
(S)-3a: α-product
(R)-4a: γ-product
+
8% yield
L = (S)-BINAP:
L = (R)-BINAP:
91% yield
(97% ee)
morpholine (2a)
(1.5 equiv)
7% yield
92% yield
(96% ee)
Scheme 4
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
O
O
N
O
(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. Eur.
J. 2006, 12, 3596. (h) Weihofen, R.; Tverskoy, O.;
Helmchen, G. Angew. Chem. Int. Ed. 2006, 45, 5546; and
references therein . For [Rh]: (i) Evans, P. A.; Robinson, J.
E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.
(j) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem.
Soc. 1999, 121, 12214. For [Ru]: (k) Morisaki, Y.; Kondo,
T.; Mitsudo, T. Organometallics 1999, 18, 4742.
10 mol%
[Pd(C3H5)(cod)]BF4/
(S)-BINAP
N
N
dioxane
Ph
CF3
Ph
CF3
Ph
CF3
40 °C, 12 h
rac-4a
(S)-3a: α-product
42% yield
(S)-4a: γ-product
58% yield
+
85% ee
46% ee
morpholine (2a)
(1.5 equiv)
S value: 19
(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.
Scheme 5
Organometallics 2004, 23, 3763. (n) Kawatsura, M.; Ata,
F.; Hirakawa, T.; Hayase, S.; Itoh, T. Tetrahedron Lett.
2008, 49, 4873; and references cited therein.
alysts. We also found that the kinetic resolution had oc-
curred during the isomerization step using the chiral
[Pd(C3H5)(cod)]BF4/BINAP catalyst. The studies of the
reactions by other types of amines and the details of the
isomerization step including the kinetic resolution are
now in progress in our laboratory.
(4) 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.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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.
References and Notes
(1) (a) Tsuji, J. Palladium Reagents and Catalysts: New
Perspectives for the 21st Century; John Wiley and Sons:
Chichester, 2004. (b) Tsuji, J. Transition Metal Reagents
and Catalysts: Innovations in Organic Synthesis; Wiley and
Sons: Chichester, 2000. (c) Trost, B. M.; Lee, C. B. In
Catalytic Asymmetric Synthesis II; Ojima, I., Ed.; Wiley-
VCH: Weinheim, 2000. (d) Pfaltz, A.; Lautens, M. In
Comprehensive Asymmetric Catalysis I–III; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
(e) Hayashi, T. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley-VCH: Weinheim, 1993.
(2) (a) Jørgensen, K. A. In Modern Amination Methods; Ricci,
A., Ed.; Wiley-VCH: Weinheim, 2000, Chap. 1, 1.
(b) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98,
1689.
(3) Selected examples of transition-metal-catalyzed allylic
aminations of allylic esters: for [Pd] (a) 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. For [Ir]:
(d) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga,
N. J. Am. Chem. Soc. 2001, 123, 9525. (e) Ohmura, T.;
(5) Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org.
Chem. 2002, 67, 1768.
(6) Kawatsura, M.; Hirakawa, T.; Tanaka, T.; Ikeda, D.; Hayase,
S.; Itoh, T. Tetrahedron Lett. 2008, 49, 2450.
(7) Examples of net retention mechanism in the palladium-
catalyzed allylic substitutions: (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.
(8) We observed the racemization of allylic amines took place
by palladium catalysts. For example, the ee of (R)-4a
decreased from 88% to 80% by Pd(OAc)2/DPPE at 60 °C for
12 h, and the ee of (S)-3a also decreased from 98% to 13%
by [Pd(C3H5)(cod)]BF4/(S)-BINAP at 100 °C for 12 h.
(9) We also confirmed the reaction with 10 mol% of
[Pd(C3H5)(cod)]BF4/BIPHEP [2,2¢-bis(diphenyl-
phosphino)-1,1¢-biphenyl] gave an a-product with 96%
regioselectivity at 60 °C, but the ee decreased to 66%.
Synlett 2010, No. 19, 2887–2890 © Thieme Stuttgart · New York

2890
T. Hirakawa et al.
LETTER
analysis of the products from the reaction of (S)-4-(4-
(10) Typical Procedure for the [Pd(C3H5)(cod)]BF4/(S)-
BINAP-Catalyzed Allylic Amination of (S)-1 with 2a
To a solution of [Pd(C3H5)(cod)]BF4 (7.0 mg, 0.021 mmol),
(S)-BINAP (12.8 mg, 0.021 mmol), (S)-1,1,1-trifluoro-4-
phenylbut-3-en-2-yl acetate [(S)-1, 50 mg, 0.21 mmol] in
dioxane (1.0 mL) was added morpholine (2a) and stirred at
r.t. for 5 min and 40 °C for 12 h. The reaction mixture was
quenched with brine and H2O (1 mL), then extracted with
EtOAc (3 × 2 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The NMR yield
(95%, trioxane as an internal standard) and ratio of 3a and 4a
was determined by 1H NMR of the crude materials.
Analytical Data of 3a
chlorophenyl)-1,1,1-trifluorobut-3-en-2-yl acetate with 1-
phenylpiperazine. See details in the Supporting Information.
(12) 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) Cook, G. R.; Sankaranarayanan, S. Org. Lett. 2001,
3, 3531. (g) Lüssem, B. J.; Gais, H.-J. J. Org. Chem. 2004,
69, 4041. (h) Castillo, A. B.; Favier, I.; Teuma, E.; Castillón,
S.; Godard, C.; Aghmiz, A.; Claver, C.; Gómez, M. Chem.
Commun. 2008, 6197. (i) Hou, X. L.; Zheng, B. H. Org.
Lett. 2009, 11, 1789; and references cited therein.
(13) 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. Tetrahedron Lett. 2004, 45, 7613.
(14) Calculated by eeP and eeS. S = ln[(1 – c)(1 + eeP)]/ln[(1 – c)
(1 – eeP)]. c = eeS/(eeS + eeP).
(15) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
[a]D26 +69.2 [c 1.37, CHCl3; 99% ee (S)]. The enantiomeric
purity was determined to be 99% ee by HPLC analysis with
a Daicel CHIRALPAK AD-H [hexane–2-PrOH (99:1),
flow: 1.0 mL/min, 254 nm, 35 °C, tmajor = 11.2 min,
tminor = 13.0 min]. 1H NMR (500 MHz, CDCl3): d = 2.71–
2.80 (m, 4 H), 3.60 (quin, J = 8.2 Hz, 1 H), 3.72 (t, J = 4.6
Hz, 4 H), 6.18 (dd, J = 8.2, 16.0 Hz, 1 H), 6.72 (d, J = 16.0
Hz, 1 H), 7.28–7.42 (m, 5 H). 13C NMR (125 MHz, CDCl3):
d = 50.4, 67.2, 68.6 (q, JCF = 27.5 Hz), 118.5, 125.7 (q,
JCF = 285.0 Hz), 126.7, 128.5, 128.7, 135.7, 137.5. 19F NMR
(470 MHz, CDCl3): d = 92.0 (d, J = 8.2 Hz). HRMS (EI):
m/z calcd for C14H16F3NO: 271.1184; found: 271.1195.
(11) The absolute configuration of (S)-3a and (R)-4a were
determined by the comparison of the X-ray crystallographic
Synlett 2010, No. 19, 2887–2890 © Thieme Stuttgart · New York