Utilization of IndPHOX-ligands in palladium-catalysed asymmetric allylic aminations

Article abstract of DOI:10.1016/j.tetasy.2011.03.004

IndPHOX (indole phosphine oxazoline) ligands were utilized in palladium-catalysed asymmetric allylic amination with different N-nucleophiles. The reactions proceeded well and excellent enantioselectivities of up to 99% were achieved.

Full text of DOI:10.1016/j.tetasy.2011.03.004

Tetrahedron: Asymmetry 22 (2011) 524–529
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Utilization of IndPHOX-ligands in palladium-catalysed asymmetric allylic
aminations
⇑
Yu Wang, Matti J. P. Vaismaa, Antti M. Hämäläinen, Jan E. Tois, Robert Franzén
Department of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33101 Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2011
Accepted 10 March 2011
IndPHOX (indole phosphine oxazoline) ligands were utilized in palladium-catalysed asymmetric allylic
amination with different N-nucleophiles. The reactions proceeded well and excellent enantioselectivities
of up to 99% were achieved.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
temperature. The results were clearly better than when using the
2-dicyclohexylphosphine substituted ligands 3a and 3b (entries
The transition metal catalysed asymmetric allylic substitution is
a powerful and well-established synthetic method for carbon–
heteroatom bond formation.1 In particular, catalytic asymmetric
allylic amination is an important reaction to synthesize the allyla-
mine moiety, which is encountered in natural products, and is of-
ten converted into compounds possessing biological activity, such
as amino acids,2 carbohydrate derivatives3 and various alkaloids.4
Allylic amination is utilizing palladium complexes containing chi-
ral P,N-ligands5–7 have become valuable tools for the synthesis of
chiral allylamines. In order to make catalytic transformations more
efficient, ligand design has a key role. By developing new ligands, a
better understanding of the catalytic cycle and asymmetric induc-
tion can be obtained.8 Recently, we described the preparation of
novel IndPHOX ligands (Fig. 1), resulting in high yields and excel-
lent enantioselectivities in asymmetric allylic alkylations.9 Herein
we report on the utilization of these ligands in Pd-catalysed asym-
metric allylic amination.
9–14). When the reaction was performed at 40 °C, the yields were
improved at the expense of enantioselectivity. It is also noteworthy
that a N-MOM group (instead of a N-methyl group) in the ligands
tended to improve the enantioselectivities.
Generally, the use of PHOX-ligands10 with a tert-butyl group at
C-4 in the oxazoline ring affords the highest enantioselectivities in
various asymmetric catalyses.11 Recently Bélanger et al.12 demon-
strated that an effective substitute for t-Bu-PHOX-ligands can be
obtained by modifying i-Pr-PHOX-ligands with two methyl sub-
stituents at C-5. Encouraged by this idea, ligand 4d and the
tert-butyl variant 4c were synthesized based on the results
obtained with the IndPHOX ligand 4b (Scheme 1).
Ligands 4c and 4d were investigated in the asymmetric allylic
amination of 5 with benzylamine (Table 2). As expected, the ee val-
ues were further improved to 99% and 96%, respectively (entries 2
and 3). In addition, with ligand 4c, the reaction rate and yield in-
creased remarkably, without a loss in enantioselectivity when
the reaction was performed at a higher concentration. A yield of
94% and an ee of 98% were achieved in 1 h (entry 4). In conclusion,
all ligands 4a–4d resulted in better enantioselectivities than when
using the t-Bu-PHOX ligand (entry 5) or any Het-PHOX ligand pre-
viously reported.13
After optimization of the oxazoline moiety, we turned our
attention towards various N-nucleophiles. Our selection of nucleo-
philes was based on the following aspects: (i) different cleavage
possibilities (PMB and phthalimide);14,15 (ii) highly nucleophilic
and hard to control secondary amine (morpholine); and (iii) rarely
utilized, poor N-nucleophile (aniline). The best ligand 4c was cho-
sen for this investigation (see Table 3).
2. Results and discussion
We initiated our investigation by utilizing recently synthesized
IndPHOX ligands 1a–4b9a for the asymmetric allylic amination of
1,3-diphenyl-2-propenyl acetate 5 with benzylamine (Table 1).
The preparation of 6a was performed with 3-diphenylphosphine li-
gands 1a and 1b in yields of 52% and 21% with moderate to good
enantioselectivities (52% and 89%, respectively); ligands 2a and
2b containing a dicyclohexylphosphine group afforded higher
yields (71% and 84%), but the enantioselectivities remained moder-
ate (62% and 65%). In contrast, with ligands 4a and 4b adorned
with a 2-diphenylphosphine substituent, high yields (72% and
85%) and excellent ee values (both 94%) were achieved at room
4-Methoxybenzylamine reacted similarly to benzylamine to
afford amine 6b in excellent yield (91%) and enantioselectivity
(98%) (entry 1). Morpholine, as a more reactive nucleophile,
required a low temperature (0 °C) to obtain excellent enantioselec-
tivity (99%) (entry 2).
⇑
Corresponding author.
E-mail address: robert.franzen@tut.fi (R. Franzén).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.004

Y. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 524–529
525
O
O
PPh2
PCy2
N
N
O
N
O
N
PPh2
PCy2
N
R
N
R
N
N
R
R
1a: R=CH3
2a: R=CH3
4a: R=CH3
3a: R=CH3
3b: R=MOM
1b: R=MOM
2b: R=MOM
4b: R=MOM
Figure 1. IndPHOX ligands.
particular allylic amination procedure. In our opinion, there are
possibilities to improve both yield and ee% in the future.
Table 1
Pd-catalysed asymmetric allylic amination of 5 with IndPHOX ligandsa
4.0 mol% [Pd(allyl)Cl]2
12 mol% ligand
OAc
Ph
HN
Ph
3. Conclusion
benzylamine (3.0 equiv.)
∗
Ph
Ph
Ph
THF
We have reported examples of Pd-catalysed asymmetric allylic
aminations usingIndPHOX ligands. When taking reactiontime, yield
and enantiomeric excess into account, the IndPHOX ligands 4a–4d,
with a diphenylphosphine group at the 2-position and an oxazoline
moiety at the 3-position of the indole-moiety, provided the best
results. Good to excellent enantioselectivities were achieved with
different nucleophiles at room temperature using ligands 4b and
4c. A low temperature (0 °C) was required with morpholine to afford
an excellent ee of 99%. We have thus demonstrated that IndPHOX
ligands are good alternatives to previously reported PHOX and
Het-PHOX ligands for Pd-catalysed asymmetric allylic aminations.
Furthermore, we have reported the first Pd-catalysed asymmetric
allylic amination procedure of the allylic alcohol 15 with aniline.
5
6a
Entry
Ligand
Temp (°C)
Time (h)
Isolated yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1b
1b
2a
2a
2b
2b
3a
3b
4a
4a
4b
4b
rt
40
rt
40
rt
40
rt
40
rt
rt
rt
40
rt
48
24
48
24
24
24
24
24
24
48
24
2
52
63
21
38
71
88
84
88
29
21
72
98
85
87
52
45
89
88
62
37
65
53
23
39
94
66
94
88
24
2
4. Experimental
4.1. General
40
a
See Section 4 for details.
Determined by chiral HPLC.
b
Dry THF was obtained by distillation over metallic sodium using
benzophenone ketyl as an indicator. Other solvents and reagents
were used as received. TLC was performed on precoated (Silica
Gel 60 F254) aluminium plates and visualized by UV-light. Silica
Gel 60, particle size 0.040–0.063 nm, was used for column chroma-
tography. 1H, 13C and 31P NMR spectra were measured at 300, 75
and 121 MHz, respectively, using CDCl3 or DMSO-d6 as solvents.
Chemical shifts are reported in d values (ppm) relative to tetra-
methylsilane (internal standard) or H3PO4 (external standard).
Melting points are uncorrected.
The reactions using bulky potassium phthalimide and aniline as
nucleophiles did not proceed as expected (entries 3 and 4). These
results might be rationalized in terms of steric hindrance of the
catalytic center caused by the t-butyl group in the oxazoline ring.
Thus we decided to investigate ligand 4b in these reactions (Ta-
ble 3, entries 5–9).
As expected, ligand 4b decreased both the yield and ee with
PMB (entry 5). Morpholine derivative 6c was formed in excellent
yield with increased reaction rate, but at the cost of enantioselec-
tivity (entry 6). In the case of potassium phthalimide (entries 7 and
8) and aniline (entry 9), the yields and enantioselectivities were
both improved.
There are only a few examples concerning the use of aniline and
its derivatives as nucleophiles in Pd-catalysed allylic amination
from carbonate or acetate to afford an enantiomerically pure prod-
uct,18 presumably due to the low nucleophilicity of the substrate.5a
The catalytic allylic amination of allylic alcohols with aniline deriv-
atives has been reported,19 but to the best of our knowledge, data
on the enantioselectivity has only been reported once.20 Therefore,
we attempted to prepare a chiral product directly from an allylic
alcohol by using our IndPHOX ligands.
4.2. Synthesis of ligands 4c and 4d
4.2.1. (S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)-1H-indole-3-
carboxamide 8
At first, EDC hydrochloride (1.43 g, 7.4 mmol) was added to a
mixture of 7 (1.00 g, 6.2 mmol) and Et3N (1.9 ml, 13.7 mmol) in
CH2Cl2 (20 ml), and stirred for 0.5 h ar rt. Next, (S)-tert-leucinol
(0.73 g, 6.2 mmol) was added in portions and the mixture was stir-
red overnight at rt. The reaction mixture was concentrated to half
of its original volume and 20 ml of 1 M HCl was added. The white/
blue precipitate formed was triturated with 1 M HCl, 1 M NaOH
and CH2Cl2. Compound 8 was obtained as a white solid (1.13 g,
a 2D0
ꢀ
¼ ꢁ4:0 (c 0.6, MeOH); 1H NMR
Yang et al.19e reported the achiral allylation of an aniline with
allylic alcohol using a Pd-catalyst, triphenylphosphine and a car-
boxylic acid. Initially we investigated this approach with ligand
4b (Scheme 2). Compound 6e was obtained with good enantiose-
lectivity (85%) in 11% yield. To the best of our knowledge, this is
the first example of the enantioselective synthesis of 6e via this
70%). Mp 177–178 °C;
½
(300 MHz, DMSO-d6): d ppm 0.94 (s, 9H), 3.48 (dd, J = 11.1,
8.2 Hz, 1H), 3.66 (dd, J = 11.1, 3.7 Hz, 1H), 3.92 (td, J = 8.2, 3.7 Hz,
1H), 4.45 (br, s, 1H), 7.01–7.16 (m, 2H), 7.26 (d, J = 9.4 Hz, 1H),
7.42 (d, J = 7.6 Hz, 1H), 8.03–8.24 (m, 2H), 11.26 (br, s, 1H); 13C
NMR (75 MHz, DMSO-d6): 26.5 (3C), 33.5, 57.4, 60.1, 110.3,

526
Y. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 524–529
OH
O
H
N
O
COOH
N
EDC·HCl, Et3N
(S)-tert-Leucinol
MsCl, DMAP, Et3N
N
N
CH2Cl2/DMF
67 %
H
CH2Cl2
70 %
N
H
H
7
8
9
5
4
O
O
t-BuLi, TMEDA,
N
N
ClPPh2
NaH, MOMCl
PPh2
THF
THF
N
N
60 %
63 %
MOM
MOM
4c
10
OH
O
H
N
O
COOH
N
EDC·HCl, Et3N
compound 11
MsOH, DMAP, Et3N
N
H
N
H
CH2Cl2
65 %
CH2Cl2
85 %
N
H
7
12
13
5
O
4
O
N
N
t-BuLi, TMEDA,
NaH, MOMCl
ClPPh2
OH
HCl H2N
PPh2
THF
THF
N
N
60 %
MOM
MOM
69 %
1112
4d
14
Scheme 1. Synthesis of t-Bu-IndPHOX 4c and dimethyl-i-Pr-IndPHOX 4d.
chromatography (n-hexane/ethyl acetate 3/2) to yield 9 as a white
Table 2
Asymmetric allylic amination of 5 with benzylaminea
solid (0.62 g, 67%). Mp 144–146 °C; ½a D20
ꢀ
¼ ꢁ61:7 (c 0.3, CHCl3); 1H
NMR (300 MHz, CDCl3): d ppm 0.98 (s, 9H), 4.08 (dd, J = 9.9, 7.0 Hz,
1H), 4.21 (dd, J = 8.4, 7.0 Hz, 1H), 4.30 (dd, J = 9.9, 8.4 Hz, 1H), 7.16–
7.30 (m, 2H), 7.33–7.43 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 8.19–8.34
(m, 1H), 8.89 (br, s, 1H); 13C NMR (75 MHz, CDCl3): 25.9 (3 C), 34.1,
67.7, 75.9, 105.5, 111.3, 121.3, 121.7, 122.9, 125.8, 127.5, 136.1,
160.5; HRMS-ESI+ (m/z) for C15H19N2O, (M+H)+ calcd 243.1497,
found 243.1500.
Entry
Ligand
Time (h)
Isolated yield (%)
eeb (%)
1
4b
4c
4d
4c
24
24
24
1
85
78
91
94
87
94
99d
96
98
89
2c
3
4e
5f
t-Bu-PHOX
96
a
b
c
d
e
f
See Section 4 for details. The reactions were performed at room temperature.
Determined by chiral HPLC.
Concn of 5: 0.1 mol/L.
4.2.3. (S)-4-(tert-Butyl)-2-(1-(methoxymethyl)-1H-indol-3-yl)-
4,5-dihydrooxazole 10
½ ꢀ ¼ ꢁ27:5 (c 0.85, CHCl3).
a 2D0
Concn of 5: 0.2 mol/L.
Compound 9 (0.6 g, 2.5 mmol) in THF (5 ml) was added to a sus-
pension of NaH (60% in mineral oil, 0.20 g, 5.0 mmol) in THF (5 ml)
at 0 °C. After stirring for 1 h at rt, the solution was recooled to 0 °C,
and MOMCl (0.28 ml, 3.75 mmol) was added. After 30 min, the
reaction was quenched with H2O and extracted with Et2O. The
combined extracts were washed with brine and dried over MgSO4.
The solvents were removed in vacuo and the residue was purified
by column chromatography (n-hexane/ethyl acetate 3/1) to pro-
Ref. 7g.
111.1, 119.5, 120.4, 121.0, 125.6, 127.1, 135.5, 164.3; HRMS-ESI+
(m/z) for C15H20N2O2Na, (M+Na)+ calcd 283.1422, found 283.1415.
4.2.2. (S)-4-(tert-Butyl)-2-(1H-indol-3-yl)-4,5-dihydrooxazole 9
At first, MsCl (0.75 ml, 9.6 mmol) was added to a cooled mixture
(0 °C) of 8 (1.00 g, 3.8 mmol), Et3N (4.3 ml, 30.7 mmol) and DMAP
(0.094 g, 0.77 mmol) in CH2Cl2/DMF (12 ml/3 ml). After 3 h at rt,
the starting material was consumed. The reaction was quenched
with water and extracted with EtOAc. The combined extracts were
washed with 1 M HCl, brine and dried over MgSO4. The solvent was
removed in vacuo, and the residue was purified by column
vide 10 as a light yellow oil (0.45 g, 63%). ½a D20
¼ ꢁ60:5 (c 0.6,
ꢀ
CHCl3); 1H NMR (300 MHz, CDCl3): d ppm 0.98 (s, 9H), 3.25 (s,
3H), 4.07 (dd, J = 9.9, 7.2 Hz, 1H), 4.19 (dd, J = 8.3, 7.2 Hz, 1H),
4.29 (dd, J = 9.9, 8.3 Hz, 1H), 5.44 (A, JAB = 11 Hz, 1H), 5.46 (B,
JAB = 11 Hz, 1H), 7.23–7.35 (m, 2H), 7.46–7.53 (m, 1H), 7.70 (s,
1H), 8.24–8.33 (m, 1H); 13C NMR (75 MHz, CDCl3): 25.9 (3C),
34.1, 56.1, 67.6, 76.1, 77.9, 105.5, 110.2, 121.8, 122.1, 123.2,

Y. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 524–529
527
Table 3
Asymmetric allylic amination of 5 with different N-nucleophilesa
4.0 mol% [Pd(allyl)Cl]2
12 mol% ligand
Nu
OAc
Ph
∗
Nucleophile (3.0 equiv.)
Ph
Ph
Ph
rt, THF
5
6b-e
Entry
Ligand
Nucleophile
Time(h)
Product
Isolated yield (%)
eeb (%)
Configurationc
1
2e
3
4c
4c
4c
4c
4b
4b
4b
4b
4b
4-Methoxybenzylamine
Morpholine
Potassium phthalimide
Aniline
4-Methoxybenzylamine
Morpholine
Potassium phthalimide
Potassium phthalimide
Aniline
24
24
48
24
24
1
48
48
24
6b
6c
6d
6e
6b
6c
6d
6d
6e
91
73
21
24
81
94
50
84
51
98d
9917
84
42
87
(R)
(R)
(R)
—
(R)
(R)
(R)
(R)
—
4
5
6e
7
75
97f
90
8g
9
89h
a
b
c
See Section 4 for details.
Determined by chiral HPLC.
The configuration was determined by comparing the specific rotation with reported values.16
½
a 2D0
ꢀ
¼ ꢁ30:5 (c 0.82, CHCl3).
The reaction was performed at 0 °C.
¼ ꢁ18:2 (c 0.87, CHCl3).
The reaction was performed at 45 °C.
¼ ꢁ48:0 (c 0.30, CHCl3).
d
e
f
½ ꢀ
a 2D0
g
h
½ ꢀ
a 2D0
30 min, 11 (1.0 g, 6.0 mmol), Et3N (0.8 ml, 6 mmol) and CH2Cl2
(5 ml) were added. The milky blue mixture was stirred 24 h at rt.
The reaction mixture was concentrated to half of its original vol-
ume, then quenched with 1 M HCl and extracted with CH2Cl2.
The extracts were washed with brine and dried over MgSO4. The
solvent was removed in vacuo and the residue was purified by col-
umn chromatography (ethyl acetate) to afford 12 as a white solid
4.0 mol% [Pd(allyl)Cl]2
12 mol% ligand 4b
12.5 mol% PhCO2H
aniline (1.25 equiv.)
NHPh
OH
Ph
∗
Ph
Ph
Ph
rt, THF, 24h
15
6e
Scheme 2. Enantioselective allylic amination of allylic alcohol 15.
(1.06 g, 65%). Mp 178–179 °C; ½a D20
ꢀ
¼ ꢁ12:3 (c 0.3, MeOH); 1H
NMR (300 MHz, DMSO-d6): d ppm 0.91 (d, J = 6.7 Hz, 3H), 0.97 (d,
J = 6.7 Hz, 3H), 1.12 (s, 3H), 1.20 (s, 3H), 2.16 (dquin, J = 10.1,
6.7 Hz, 1H), 3.86 (dd, J = 10.1, 3.2 Hz, 1H), 4.40 (s, 1H), 6.91 (d,
J = 10.1 Hz, 1H), 7.13 (2 ꢂ td, J = 7.0, 1.3 Hz, 2H), 7.44 (dd, J = 7.2,
1.3 Hz, 1H), 8.05 (dd, J = 7.0, 1.3 Hz, 1H), 8.11 (d, J = 2.9 Hz, 1H),
11.59 (br, s, 1H); 13C NMR (75 MHz, DMSO-d6): 18.8, 23.4, 28.6,
28.7, 28.9, 59.9, 72.9, 111.5, 112.6, 121.0, 121.3, 122.5, 126.5,
128.6, 136.9, 165.3; HRMS-ESI+ (m/z) for C16H22N2O2Na, (M+Na)+
calcd 297.1579, found 297.1588.
127.0, 130.9, 136.6, 159.9. HRMS-ESI+ (m/z) for C17H23N2O2, MH+
calcd 287.1760, found 287.1757.
4.2.4. (S)-4-(tert-Butyl)-2-(2-(diphenylphosphino)-1-
(methoxymethyl)-1H-indol-3-yl)-4,5-dihydro-oxazole 4c
A cooled solution (ꢁ78 °C) of 10 (0.21 g, 0.73 mmol) and TMEDA
(0.14 ml, 0.91 mmol) in degassed THF (3 ml) was treated with t-
BuLi (0.54 ml, 1.7 mol/L, 0.91 mmol). After stirring for 0.5 h at
ꢁ78 °C, chlorodiphenylphosphine (0.17 ml, 0.91 mmol) was added.
The temperature was allowed to reach rt with stirring overnight.
The reaction was quenched with a saturated solution of NH4Cl
and extracted with ethyl acetate. The extracts were washed with
brine and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by column chromatography (n-hex-
ane/ethyl acetate 10/1) to afford a white solid (0.205 g, 60%). Mp
4.2.6. (S)-2-(1H-Indol-3-yl)-4-isopropyl-5,5-dimethyl-4,5-
dihydrooxazole 13
Methanesulfonic acid (1.3 ml, 19.8 mmol) was added to a
cooled mixture (0 °C) of 12 (0.92 g, 3.7 mmol) in CH2Cl2 (20 ml).
The reaction mixture was refluxed for 5 days. The reaction was
cooled, quenched with saturated solution of NaHCO3, and ex-
tracted with CH2Cl2. The extracts were washed with brine and
dried over MgSO4. The solvent was removed in vacuo and the res-
idue was purified by column chromatography (n-hexane/ethyl ace-
tate 2/3) to afford 13 as a white solid (0.73 g, 85%). Mp 166–167 °C;
111–113 °C; ½a 2D0
ꢀ
¼ ꢁ156:3 (c 0.6, CHCl3); 1H NMR (300 MHz,
CDCl3): d ppm 0.88 (s, 9H), 2.90 (s, 3H), 3.25 (dd, J = 18.3, 8.2 Hz,
1H), 3.52 (dd, J = 17.6, 7.6 Hz, 1H), 3.69 (t, 7.9 Hz, 1H), 5.68 (app.
dd, J = 3.1, 0.6 Hz, 2H), 7.23–7.58 (m, 13H), 8.11–8.14 (m, 1H);
13C NMR (75 MHz, CDCl3): 26.2, 33.9, 55.5, 67.5, 75.2, 75.4, 76.9,
110.6 (d, JCP = 1.5 Hz), 114.0 (d, JCP = 2.0 Hz), 121.6, 122.0, 124.3,
128.1–129.0 (8 lines), 132.2 (d, JCP = 18.7 Hz), 133.8, 134.0 (d,
JCP = 6.4 Hz), 134.1, 135.2 (d, JCP = 6.3 Hz), 136.6 (d, JCP = 19.6 Hz),
139.2 (d, JCP = 2.5 Hz), 160.1; 31P NMR (121 MHz, CDCl3): ꢁ23.2.
HRMS-ESI+ (m/z) for C29H32N2O2P, (M+H)+ calcd 471.2201, found
471.2207.
½
a 2D0
ꢀ
¼ ꢁ51:7 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3): d ppm 1.06
(d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 1.41 (s, 3H), 1.55 (s, 3H),
1.90 (dquin, J = 8.2, 6.4 Hz, 1H), 3.48 (d, J = 8.2 Hz, 1H), 7.14–7.30
(m, 2H), 7.31–7.44 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 8.20–8.34 (m,
1H), 8.62 (br, s, 1H); 13C NMR (75 MHz, CDCl3): 20.6, 21.2, 21.4,
29.2, 29.4, 79.7, 85.3, 105.6, 111.5, 121.1, 121.5, 122.6, 125.8,
127.9, 136.2, 160.1. HRMS-ESI+ (m/z) for C16H21N2O, (M+H)+ calcd
257.1654, found 257.1644.
4.2.5. (S)-N-(2-Hydroxy-2,4-dimethylpentan-3-yl)-1H-indole-3-
carboxamide 12
At first, EDC hydrochloride (1.37 g, 7.2 mmol) was added to a
mixture of 7 (9.60 g, 6.0 mmol) and Et3N (1.8 ml, 13 mmol) in
CH2Cl2 (15 ml) at room temperature. After stirring at rt. for
4.2.7. (S)-4-Isopropyl-2-(1-(methoxymethyl)-1H-indol-3-yl)-5,5-
dimethyl-4,5-dihydrooxazole 14
Compound 13 (0.5 g, 2.0 mmol) in THF (5 ml) was added to a
suspension of NaH (60% in mineral oil, 0.18 g, 2.9 mmol) in THF

528
Y. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 524–529
(5 ml) at ꢁ10 °C. After stirring for 1 h at rt, the solution was re-
cooled to ꢁ10 °C, and MOMCl (0.18 ml, 2.3 mmol) was added over
10 min. Reaction was completed in 20 min based on TLC, quenched
with water, and extracted with CH2Cl2. The extracts were washed
with brine and dried over MgSO4. The solvent was removed in va-
cuo and the residue was purified by column chromatography (n-
hexane/ethyl acetate 4/5) to afford 14 as a yellow solid (0.35 g,
4.3.2. N-(4-Methoxybenzyl)-1,3-diphenylprop-2-en-1-amine 6b
The IndPHOX ligand (0.048 mmol) and [Pd(allyl)Cl]2 (0.016
mmol) were dissolved in 1 ml of anhydrous THF, and stirred for
0.5 h at rt, followed by the addition of 5 (0.10 g, 0.4 mmol) in THF
(1 ml) and 4-methoxybenzylamine (0.16 ml, 1.2 mmol). After stir-
ring at rt for 24 h, the solvent was removed in vacuo and the residue
was purified by column chromatography (n-hexane/ethyl acetate
15/1) to afford 6b as a while solid. Mp 46–47 °C; 1H NMR
(300 MHz, CDCl3): d = 1.78 (s, 1H), 3.69–3.70 (m, 2H), 3.75 (s, 3H),
4.36 (d, J = 7.4 Hz, 1H), 6.29 (dd, J = 15.8, 7.4 Hz, 1H), 6.55 (d,
J = 15.8 Hz, 1H), 7.16–7.42 (m, 15H); 13C NMR (75 MHz, CDCl3):
51.0, 55.5, 64.7, 114.1, 126.7, 127.5, 127.6, 127.7, 128.8, 128.9,
129.6, 130.6, 132.8, 133.0, 137.2, 143.2, 1558.9. The enantiomeric
excess was determined by HPLC using a Chiralpak IA column: n-hex-
ane/i-PrOH: DEA = 97/3/0.1; flow rate: 0.4 ml/min; wave length at
254 nm; tR1 = 32.64 min, tR2 = 34.19 min.
60%). Mp 83–84 °C;
(300 MHz, CDCl3):
½
a 2D0
ꢀ
¼ ꢁ51:0 (c 0.3, CHCl3); 1H NMR
d
ppm 1.05 (d, J = 6.6 Hz, 3H), 1.20 (d,
J = 6.6 Hz, 3H), 1.40 (s, 3H), 1.55 (s, 3H), 1.90 (dquin, J = 8.4,
6.6 Hz, 1H), 3.25 (s, 3H), 3.47 (d, J = 8.4 Hz, 1H), 5.45 (s, 2H),
7.23–7.34 (m, 1H), 7.44–7.54 (m, 1H), 7.68 (s, 1H), 8.24–8.32 (m,
1H); 13C NMR (75 MHz, CDCl3): 20.8, 21.7, 21.3, 29.1, 29.4, 56.1,
77.8, 80.2, 85.2, 106.2, 110.1, 121.8, 122.1, 123.1, 127.0, 130.7,
136.6, 158.8. HRMS-ESI+ (m/z) for C18H25N2O2, (M+H)+ calcd
301.1916, found 301.1925.
4.3.3. 4-(1,3-Diphenylallyl)morpholine 6c
4.2.8. (S)-2-(2-(Diphenylphosphino)-1-(methoxymethyl)-1H-
indol-3-yl)-4-isopropyl-5,5-dimethyl-4,5-dihydrooxazole 4d
A cooled solution (ꢁ78 °C) of 14 (60 mg, 0.2 mmol) and TMEDA
(0.04 ml, 0.24 mmol) in degassed THF (2 ml) was treated with
t-BuLi (0.14 ml, 1.7 mol/l, 0.24 mmol). After 0.5 h at the same tem-
perature, chlorodiphenylphosphine (0.05 ml, 0.26 mmol) in THF
(0.5 ml) was added. The reaction mixture was allowed to warm
to rt. overnight with stirring. The reaction was quenched with a
saturated solution of NH4Cl and extracted with ethyl acetate. The
extracts were washed with brine and dried over MgSO4. The sol-
vent was removed in vacuo and the residue was purified by col-
umn chromatography (n-hexane/ethyl acetate 5/1) to afford a
The IndPHOX ligand (0.024 mmol) and [Pd(allyl)Cl]2
(0.008 mmol) were dissolved in 1 ml of anhydrous THF, and stirred
for 0.5 h at rt, followed by the addition of 5 (50 mg, 0.2 mmol) in
THF (1 ml) and morpholine (0.10 ml, 0.6 mmol). After stirring at
0 °C for 1 or 24 h, the reaction was quenched with H2O and ex-
tracted with ethyl ether. The extracts were washed with brine
and dried over MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography (n-hexane/
ethyl acetate 15/1) to afford 6c as a colourless oil. 1H NMR
(300 MHz, CDCl3): d = 2.36–2.41 (m, 2H), 2.51–2.55 (m, 2H), 3.70
(2 ꢂ d, J = 4.7 Hz, 4H), 3.77 (d, J = 8.9 Hz, 1H), 6.27 (dd, J = 8.9,
15.8 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 7.18–7.41 (m, 10H); 13C
NMR (75 MHz, CDCl3): 52.5, 67.4, 75.1, 126.7, 127.6, 127.9, 128.3,
128.8, 129.0, 131.7, 131.8, 137.0, 141.8. The enantiomeric excess
was determined by HPLC using a Chiralpak IA column: n-hexane/
i-PrOH: 99.5/0.5; flow rate: 0.8 ml/min; wave length at 254 nm;
tR1 = 22.21 min, tR2 = 24.37 min.
colourless oil (67 mg, 69%). ½a D20
ꢀ
¼ ꢁ48:6 (c 0.63, CHCl3); 1H NMR
(300 MHz, CDCl3):
d ppm 0.85 (d, J = 6.6 Hz, 3H), 1.03 (d,
J = 6.6 Hz, 3H), 1.18 (s, 3H), 1.20 (s, 3H), 1.65–1.71 (m, 1H), 2.66
(d, J = 9.7 Hz, 1H), 2.91 (s, 3H), 5.73 (app. dd, J = 2.9, 1.4 Hz, 2H),
7.18–7.43 (m, 10H), 7.50 (dt, J = 8.2,0.9 Hz, 1H), 7.68–7.80 (m,
2H), 8.04 (m, 1H); 13C NMR (75 MHz, CDCl3): 20.7, 21.1, 21.5,
28.5, 28.8, 55.2 (d, JCP = 1.1 Hz), 75.1 (d JCP = 17.4 Hz), 79.9, 85.7,
110.4 (d, JCP = 1.1 Hz), 114.4 (d, JCP = 2.8 Hz), 121.4 (d, JCP = 10.5 Hz),
123.9 127.7–128.7 (8 lines), 132.3 (d, JCP = 19.1 Hz), 133.8 (d,
JCP = 21.0 Hz), 134.1 (d, JCP = 6.4 Hz), 135.3 (d, JCP = 6.1 Hz), 136.8
(d, JCP = 21.0 Hz), 138.8 (d, JCP = 2.5 Hz), 157.8; 31P NMR
(121 MHz, CDCl3): ꢁ23.9. HRMS-ESI+ (m/z) for C30H34N2O2P,
(M+H)+ calcd 485.2358, found 485.2363.
4.3.4. 2-(1,3-Diphenylallyl)isoindoline-1,3-dione 6d
The IndPHOX ligand (0.024 mmol) and [Pd(allyl)Cl]2
(0.008 mmol) were dissolved in 1 ml of anhydrous THF, and stirred
for 0.5 h at rt, followed by the addition of 5 (50 mg, 0.2 mmol) in
THF (1 ml) and potassium phthalimide (0.11 g, 0.6 mmol). After
stirring at rt or 45 °C for 48 h, the reaction was quenched with
H2O and extracted with ethyl ether. The extracts were washed with
brine and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified by column chromatography (n-hex-
ane/ethyl acetate 15/1) to afford 6d as a white solid. Mp 107–
108 °C; 1H NMR (300 MHz, CDCl3): d = 6.13 (d, J = 8.6 Hz, 1H),
6.71 (d, J = 15.9 Hz, 1H), 7.07 (dd, J = 8.6, 15.9 Hz, 1H), 7.26–7.84
(m, 14H); 13C NMR (75 MHz, CDCl3): 56.8, 123.6, 125.6, 127.0,
127.7, 128.1, 128.4, 128.8, 128.9, 132.3, 134.3, 134.7, 136.5,
139.2. The enantiomeric excess was determined by HPLC using a
Chiralpak IA column: n-hexane/i-PrOH: 95/5; flow rate: 0.5 ml/
min; wave length at 254 nm; tR1 = 38.96 min, tR2 = 47.01 min.
4.3. General procedure for allylic amination
4.3.1. N-Benzyl-1,3-diphenylprop-2-en-1-amine 6a
The IndPHOX ligand (0.048 mmol) and [Pd(allyl)Cl]2
(0.016 mmol) were dissolved in 2 ml of anhydrous THF, and stirred
for 0.5 h at rt, followed by the addition of 5 (0.10 g, 0.4 mmol) in
THF (2 ml) and benzylamine (0.13 ml, 1.2 mmol). After stirring at
rt according to the reported time, the solvent was removed in va-
cuo and the residue was purified by column chromatography (n-
hexane/ethyl acetate = 20/1) to afford 6a as a colourless oil.
Rf = 0.18 (n-hexane/ethyl acetate = 10/1); 1H NMR (300 MHz,
CDCl3): d = 1.89 (s, 1H), 3.72–3.82 (m, 2H), 4.39 (d, J = 7.4 Hz,
1H), 6.31 (dd, J = 15.8, 7.4 Hz, 1H), 6.57 (d, J = 15.9 Hz, 1H), 7.18–
7.44 (m, 15H); 13C NMR (75 MHz, CDCl3): 51.6, 64.8, 126.7,
127.2, 127.6, 127.7, 127.8, 128.5, 128.7, 128.8, 128.9, 130.7,
132.9, 137.2, 140.7, 143.2. The enantiomeric excess was deter-
mined by HPLC using a Chiralpak IA column: hexane/i-PrOH:
99.5/0.5; flow rate: 1.0 ml/min; wave length at 254 nm;
tR1 = 23.74 min, tR2 = 26.80 min. The configuration was determined
to be (R) by comparing the sign of the specific rotation value to the
reported one.
4.3.5. N-(1,3-Diphenylallyl)aniline 6e (from acetate 5)
The IndPHOX ligand (0.024 mmol) and [Pd(allyl)Cl]2
(0.008 mmol) were dissolved in 1 ml of anhydrous THF, and stirred
for 0.5 h at rt, followed by the addition of 5 (50 mg, 0.2 mmol) in
THF (1 ml) and aniline (0.05 ml, 0.6 mmol). After stirring at rt for
24 h, the solvent was removed in vacuo and the residue was puri-
fied by column chromatography (n-hexane/ethyl acetate 30/1) to
afford 6e as a colourless oil. 1H NMR (300 MHz, CDCl3): d = 4.06
(br, s, 1H), 5.08 (d, J = 6.0 Hz, 1H), 6.38 (dd, J = 6.2, 15.9 Hz, 1H),
6.59–6.65 (m, 4H), 7.11–7.44 (m, 11H); 13C NMR (75 MHz, CDCl3):
61.0, 113.9, 118.0, 126.8, 127.6, 127.9, 128.0, 128.9, 129.2, 129.5,
131.1, 131.4, 137.0, 142.4, 147.6. The enantiomeric excess was

Y. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 524–529
529
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345; (e) Constantieux, T.;
Brunel, J.-M.; Labande, A.; Buono, G. Synlett 1998, 49–50; (f) Jumnah, R.;
Williams, A. C.; Williams, J. M. J. Synlett 1995, 821–822; (g) von Matt, P.;
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9. (a) Wang, Y.; Hämäläinen, A.; Tois, J.; Franzén, R. Tetrahedron: Asymmetry 2010,
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4.3.6. N-(1,3-Diphenylallyl)aniline 6e (from alcohol 15)
Compound 15 (100.0 mg, 0.47 mmol), ligand 4b (26.0 mg,
0.056 mmol), [Pd(allyl)Cl]2 (7.0 mg, 0.019 mmol) and benzoic acid
(7.2 mg, 0.059 mmol) were dissolved in 3.0 ml of anhydrous THF,
and stirred for 10 min, followed by the addition of aniline
(0.05 ml, 0.59 mmol). After stirring at rt for 24 h, the solvent was
removed in vacuo and the residue was purified by column chroma-
tography (n-hexane/ethyl acetate 30/1) to afford 6e as a colourless
oil (15.0 mg, 11%).
Acknowledgement
The National Technology Agency of Finland (TEKES) is greatly
acknowledged for the financial support.
12. Bélanger, É.; Pouliot, M.-F.; Paquin, J.-F. Org. Lett. 2009, 11, 2201–2204.
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ꢀ
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