Preparation of indole-phosphine oxazoline (IndPHOX) ligands and their application in allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2010.08.008

Two classes of indole-phosphine oxazoline ligands have been prepared from readily available starting materials in good overall yields. These modular ligands include an indole skeleton with either a phosphine moiety or an oxazoline ring at the 2- or 3-position, respectively. The utility of these ligands was demonstrated in a catalytic asymmetric reaction: the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate was performed with enantioselectivities as high as 98%.

Full text of DOI:10.1016/j.tetasy.2010.08.008

Tetrahedron: Asymmetry 21 (2010) 2376–2384
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of indole-phosphine oxazoline (IndPHOX) ligands
and their application in allylic alkylation
⇑
Yu Wang, Antti Hämäläinen, Jan Tois, Robert Franzén
Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Two classes of indole-phosphine oxazoline ligands have been prepared from readily available starting
materials in good overall yields. These modular ligands include an indole skeleton with either a phos-
phine moiety or an oxazoline ring at the 2- or 3-position, respectively. The utility of these ligands was
demonstrated in a catalytic asymmetric reaction: the palladium-catalyzed allylic alkylation of 1,3-diphe-
nyl-2-propenyl acetate with dimethyl malonate was performed with enantioselectivities as high as 98%.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 July 2010
Accepted 12 August 2010
Available online 9 September 2010
1. Introduction
1a: R=i-Pr
1b: R=t-Bu
O
Asymmetric synthesis is a vital and challenging field due to the
need for enantiomerically pure compounds in pharmaceuticals,
biochemical research, and agrochemicals. Asymmetric induction
via metal catalysts and chiral ligands is one of the most elegant
and effective methods. Among the diverse chiral ligands reported
to date, the oxazoline ring-containing ligands are one of the most
versatile and widely used classes.1 The large majority of these
are synthesized from readily available chiral amino alcohols, and
the stereogenic carbon atom is located next to the nitrogen atom
coordinating with metals, thus having a direct influence on the
stereochemistry.1
A classic representative of oxazoline ligands is phosphino-oxaz-
oline (PHOX) ligand (Fig. 1), pioneered by Pfaltz,2a Helmchen,2b
and Williams.2c These outstanding and tunable class of chiral
P,N-ligands have been utilized in several metal-catalyzed transfor-
mations, such as Heck reactions,3 allylic substitutions,4,5 and hydro-
genations.6,7 Due to the success of the PHOX ligands, a variety of
derivatives have been prepared and used extensively in catalytic
applications(Fig. 2).8 A successful strategyhas been the replacement
of the phenyl ring with a heterocycle bearing an oxazoline moiety.
Several highly effective hetero PHOX (Het-PHOX) ligands have been
prepared (Fig. 3), and utilized in asymmetric allylic alkylations,9a,9b
Heck reactions,9c hydrogenations,9d,9e and hydrosilylations.9f
Although the indole core has been investigated for over a cen-
tury, it has gained attention as a ligand only very recently. Excel-
lent results for the utility of achiral indolylphosphine ligands in
Pd-catalyzed reactions, such as Suzuki-Miyaura couplings,10 Hiy-
ama cross-couplings,11 cross-couplings utilizing organotitanium
nucleophiles,12 and aminations13 have been reported. Moreover,
1c: R=Bn
1d: R=Ph
N
PPh2
R
Figure 1. Phosphinooxazoline (PHOX) ligands.
R
O
O
R1
O
PPh2
Ph2P
N
N
PPh2
N
O
R
OR2
28a
38b
48c
Figure 2. Some PHOX ligand derivatives.
only a few chiral indole ligands have been prepared,14–16 and only
three of them have been utilized in catalytic asymmetric reactions
until now (Fig. 4).15,16a,17 In comparison with other benzofused
heterocycles, the selective modification methods for indole are
much more diverse and thus offer more possibilities for tuning
the electronic and steric properties. Due to the accessible diversity,
tunability, and potential activity in asymmetric reactions, we envi-
sioned that indole-phosphine oxazoline (IndPHOX) ligands18 could
be valuable additions to PHOX and Het-PHOX derivatives. Herein,
we report the synthesis and application of eight novel IndPHOX
ligands (Fig. 5), which were conveniently prepared from commer-
cially available starting materials in good overall yields.
⇑
Corresponding author.
E-mail address: robert.franzen@tut.fi (R. Franzén).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.008

Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
2377
PPh2
PPh2
PPh2
O
N
O
O
N
O
N
PPh2
R
O
N
S
S
N
R
R
O
R
69a
59a-d
79a
89e, 9f
O
N
O
N
N
N
N
N
R
PPh2
PPh2
PPh2
99e, 9f
119b
109e
Figure 3. Examples of Het-PHOX ligands.
PPh2
N
P
O
O
PPh2
N
O
N
N
N
H
R
Ph2P
IndOX14
INDOLPHOS15
N-Me-2-BINPO16a
PPh2
N
PPh2
N
N
N
R
PPh2
Me
PPh2
BISCAP16b
axially chiral indole phosphine ligand17
Figure 4. Indole based ligands with chirality.
ium exchange of 27, and treatment with ClPCy2, ligands 15 and 16
were obtained (Route C).
2. Results and discussion
Recently a new synthetic approach for PHOX ligands was re-
ported by Tani et al.20 The P–C bond was formed by an Ullman-
type coupling developed by Buchwald.21 With compound 28a in
hand, we investigated this method preliminarily for IndPHOX li-
gand 13 (Route D). Although the yield was poor (14%), our opinion
is that this methodology could offer a wide range of possibilities in
the future. A similar synthetic strategy was utilized for ligand class
II (Scheme 2). Indole-3-carboxylic acid 29 was prepared from in-
dole in good yield.22 The ‘acid chloride-approach’ was found
Indole-2-carboxylic acid was converted into the corresponding
acid chloride using oxalyl chloride with a catalytic amount of
DMF, and the subsequent amidation with L-valinol provided 22.
Oxazoline formation was accomplished by treatment of MsCl in
the presence of DMAP under basic conditions to yield 23.14 Follow-
ing N-functionalization with methyl or MOM group, the corre-
sponding compounds were treated with sec-BuLi and TMEDA,
followed by electrophilic quenching by ClPPh2 or ClPCy2, respec-
tively. The desired products 13 and 14 were not formed, indicating
that direct lithiation at the 3-postion was unsuccessful (Route A,
Scheme 1). A literature survey revealed that the 3-position could
be modified by a more powerful P-electrophile.19 Thus we treated
the lithiated 24a and 24b with diphenylphosphinic chloride, and
25a and 25b were obtained in good yields. Reduction of 25a and
25b by trichlorosilane in the presence of Et3N afforded ligands 13
and 14 in moderate yields (Route B).
unsuitable for the preparation of 30, and L-valinol was coupled to
indole-3-carboxylic acid by EDC-activation, and 30 was obtained
in 75% yield. Oxazoline formation at the 3-position was not accom-
plished in CH2Cl2, probably due to poor solubility, so the addition
of DMF was found necessary. After optimization, 31 was obtained
in 77% yield. After N-functionalization, direct lithiation at the
2-position and ClPR2 treatment, ligands 17–20 were obtained.
Synthesized ligands 13–20 were investigated for the asymmet-
ric allylic alkylation of 1,3-diphenyl-2-propenyl acetate 33 with
dimethyl malonate [a standard model reaction for evaluation of
In order to attempt the preparation of 15 and 16 by halogen–
lithium exchange, compound 23 was brominated with NBS in
CHCl3 in 82% yield. After the N-functionalization, the bromine–lith-

2378
Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
PCy2
PCy2
PPh2
PPh2
O
N
O
N
O
N
O
N
N
N
N
N
O
O
16
14
15
13
Class I
O
O
O
O
N
N
N
N
PPh2
PCy2
PPh2
PCy2
N
N
N
N
O
O
20
18
19
17
Class II
Figure 5. Indole-phosphine oxazoline ligands synthesized.
novel chiral ligands (Scheme 3)], and the results are summarized in
Table 1.
4. Experimental
4.1. General
For class I-type ligands, 13 and 14 with a diphenylphosphine-
group greatly increased the reaction rate compared to ligands 15
and 16 with dicyclohexylphosphine. All of the ligands provided
excellent enantiomeric excess. In contrast, the different phospho-
rus substituents of class II have a bigger influence on the results
than class I. Although ligands 17 and 18 resulted in good ee%, the
yields were poor, while ligands 19 and 20 increased the yield, reac-
tion rate, and enantioselectivity. The opposite configured ligand
Solvent THF was distilled over sodium and benzophenone ketyl
before use. Other solvents and reagents were used as received. TLC
was performed on precoated (Silica Gel 60 F254) aluminum plates
and visualization was performed by UV-light. Silica Gel 60, particle
size 0.040–0.063 nm was used for column chromatography. 1H, 13
C
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 tetramethylsilane. Melt-
ing points were not corrected.
(R)-20 was synthesized utilizing the developed route from D-valin-
ol. When (R)-20 was subjected to the alkylation reaction, 34 was
obtained with an (R)-configuration (Table 1). Recrystallization of
product 34 with n-hexane/diethyl ether further improved the
enantiomeric excesses from 97% to 99%.
4.2. Preparation of ligands 13–16
Compared to other Het-PHOX ligands utilized in the asymmet-
ric allylic alkylation, most IndPHOX ligands provided similar yields
and higher ee% at room temperature. The requirement for lower
temperature, needed for ligands 5a–7a, was found unnecessary. Li-
gands 13, 14, and 20 also greatly increased the reaction rate in
comparison with other Het-PHOX ligands. In addition, compared
to PHOX ligand 1a, the IndPHOX ligands with diphenylphosphine
achieved equally excellent ee values (Table 1).
4.2.1. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-1H-indole-2-
carboxamide 22
To
a suspension of indole-2-carboxylic acid 21 (1.61 g,
10.0 mmol) in CH2Cl2 (10 ml), oxalyl chloride (10 ml 2 mol/L,
20.0 mmol), and DMF (0.15 ml, 2.0 mmol) were added dropwise
at 0 °C and further stirred 2.5 h at rt. The solvent was removed in
vacuo. The crude acid chloride was dissolved in CH2Cl2 (15 ml),
and added dropwise to a solution of L-valinol (1.08 g, 10.5 mmol)
and Et3N (2.8 ml, 20.0 mmol) in CH2Cl2 (15 ml) at 0 °C. After stir-
ring for 3 h at rt, 1 M HCl was added. The aqueous phase was ex-
tracted with CH2Cl2 and the combined organic layers were
washed with brine and dried over MgSO4. The solvent was re-
moved and the crude product was triturated with cold CH2Cl2 to
afford a light yellow solid (1.54 g). An additional amount of prod-
uct (0.40 g) was obtained from the filtrate after silica chromatogra-
phy (n-hexane/ethyl acetate = 2:1 to 1:1). Combined yield 79%. Mp
3. Conclusion
In conclusion, we have designed and prepared two classes of
novel chiral indole-phosphine oxazoline ligands. Ligands could con-
veniently be synthesized from commercially available starting
materials in good overall yields. The ligands were utilized in the
Pd-catalyzed allylic alkylation of 1,3-dipheny-2-propenyl acetate
with dimethyl malonate resulting in high enantioselectivities of
up to 98%. IndPHOX ligands are in our opinion superior to the pres-
ent related Het-PHOX ligands available for the Pd-catalyzed allylic
alkylation. Our best results, when taking reaction time, yield, and
enantiomeric purity into account, were achieved when the indole
core was combined with a diphenylphosphine functionality. Further
modification of the IndPHOX ligands and their applications in other
asymmetric reactions are currently underway in our laboratory.
158–159 °C; ½a 2D0
ꢀ
¼ ꢁ46:3 (c 1.0, MeOH); 1H NMR (300 MHz,
DMSO-d6): d = 0.89–0.94 (2 ꢂ d, J = 6.9 Hz, 6H), 1.91–1.98 (m,
1H), 3.52–3.56 (m, 2H), 3.84–3.87 (m, 1H), 4.65 (t, J = 5.5 Hz, 1H),
7.00–7.05 (m, 1H), 7.14–7.20 (m, 1H), 7.21–7.22 (m, 1H), 7.43
(dd, J = 8.2, 0.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 9.0 Hz,
1H), 11.5 (br, 1H); 13C NMR (75 MHz, DMSO-d6): 19.6, 20.7, 29.6,
57.1, 62.3, 103.7, 113.2, 120.6, 122.4, 124.1, 128.0, 133.0, 137.3,

Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
2379
1.(COCl)2, DMF
MsCl
DMAP, Et3N
O
DCM
OH
COOH
N
H
N
H
HN
2.L-valinol, NEt3
79%
DCM, 82%
21
22
s-BuLi, TMEDA
ClPOPh2, THF
CH3I or MOMCl
NaH, THF
O
N
O
N
N
R
N
H
25a: 83%
25b: 81%
24a: 94%
24b: 78%
24a: R=CH3
24b: R=MOM
23
Route B
NBS
Route A
s-BuLi, TMEDA
ClPPh2, THF
82%
CHCl3
POPh2
Br
PR'2
HSiCl3, NEt3
m-xylene
O
O
N
O
N
N
N
N
H
13: 50%
14: 71%
N
R
R
26
25a: R=CH3
25b: R=MOM
13: R=CH3, R'=Ph
14: R=MOM, R'=Ph
15: R=CH3, R'=Cy
16: R=MOM, R'=Cy
27a: 94%
27b: 97%
CH3I or MOMCl
NaH, DMF
n-BuLi, ClPCy2
THF
15: 70%
16: 66%
Br
O
N
N
R
Route C
27a: R=CH3
27b: R=MOM
Scheme 1. Synthesis of ligands 13–16 of class I.
162.0. HRMS-ESI (m/z) for C14H18N2O2Na, (M+Na)+ found 269.1276,
calcd 269.1266.
4.2.3. (S)-2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1-methyl-1H-
indole 24a
Compound 23 (1.10 g, 4.8 mmol) in THF (10 ml) was added to a
suspension of NaH (0.29 g, 7.2 mmol) in THF (10 ml) at 0 °C. After
stirring for 1 h at rt, the solution was recooled to 0 °C, and CH3I
(0.36 ml, 5.8 mmol) was added. After 2 h at rt, the reaction was
quenched with water, and extracted with Et2O. The organic layer
was washed with brine and dried over MgSO4. After concentration
in vacuo, the crude product was filtered through a pad of silica
using Et2O as eluent. The product was obtained as a light yellow
4.2.2. (S)-2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1H-indole 23
At first, MsCl (0.42 ml, 5.4 mmol) was added to a cooled mixture
(0 °C) of 22 (1.21 g, 4.9 mmol), Et3N (5.4 ml, 39.2 mmol) and DMAP
(0.12 g, 0.98 mmol) in CH2Cl2 (20 ml). After 2 h at rt, the starting
material was consumed according to TLC. The reaction was
quenched with water 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 column chromatography
(n-hexane/ethyl acetate = 5:1) to afford 23 as a light yellow solid
solid after concentration (1.09 g, 94%). Mp 91–92 °C;
½
a 2D0
ꢀ
¼
ꢁ55:8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.95 (d,
J = 6.7 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 1.83–1.89 (m, 1H), 4.04–
4.18 (m, 5H), 4.35 (td, J = 8.0, 1.4 Hz, 1H), 7.07 (d, J = 0.6 Hz, 1H),
7.12 (ddd, J = 6.8, 5.6, 1.2 Hz, 1H), 7.28–7.38 (m, 2H), 7.64 (dt,
J = 8.0, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): 19.2, 19.3, 32.1,
33.3, 69.2, 73.6, 107.4, 110.2, 120.4, 122.2, 124.1, 126.8, 127.2,
(0.92 g, 82%). Mp 81–82 °C; ½a D20
ꢀ
¼ þ52:0 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.95 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.7 Hz,
3H), 1.83–1.89 (m, 1H), 4.29–4.35 (m, 2H), 4.55–4.59 (m, 1H), 7.10
(d, J = 1.0 Hz, 1H), 7.16 (td, J = 8.0, 1.0 Hz, 1H), 7.30 (td, J = 8.2,
1.0 Hz, 1H), 7.38 (d, J = 7.9, 1H), 7.72 (d, J = 8.0 Hz, 1H), 11.5 (br,
1H); 13C NMR (75 MHz, CDCl3): 18.5, 33.4, 71.0, 72.0, 106.4, 111.9,
120.3, 122.1, 124.4, 125.7, 127.9, 137.9, 159.8.
139.7, 158.2. HRMS-ESI (m/z) for
C
15H19N2O, (M+H)+ found
243.1483, calcd 243.1473.

2380
Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
OH
H
N
O
EDC HCl
COOH
1. (CF3CO)2O, DMF
2. 20% NaOH aq.
Et3N, DCM
N
H
75%
N
H
N
77%
H
30
29
28
O
Et3N, DMAP, MsCl
DCM/DMF=4/1
N
O
CH3I or MOMCl
N
NaH, THF
77%
32a: 99%
32b: 76%
N
N
R
H
32a: R=CH3
32b: R=MOM
31
t-BuLi, TMEDA
ClPPh2, THF
t-BuLi, TMEDA
ClPCy2, THF
17: 61%
18: 70%
O
19: 60%
20: 57%
N
PPh2
O
N
N
R
19: R=CH3
20: R=MOM
PCy2
N
R
17: R=CH3
18: R=MOM
Scheme 2. Synthesis of ligands 17–20 of class II.
4.0 mol% [Pd(allyl)Cl]2
12 mol% ligand
MeO2C
Ph
CO2Me
OAc
Ph
∗
10 mol% KOAc
Ph
Ph
BSA (3.0 equiv)
dimethyl malonate (3.0 equiv)
in THF, RT
33
34
Scheme 3. Enantioselective allylic alkylation.
4.2.4. (S)-2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1-
(methoxymethyl)-1H-indole 24b
56.10, 69.5, 73.7, 75.0, 109.4, 111.3, 121.3, 122.2, 124.8, 127.1,
127.2, 139.7, 157.8. HRMS-ESI (m/z) for C16H20N2O2Na, (M+Na)+
found 295.1419, calcd 295.1422.
Compound 23 (0.68 g, 3.0 mmol) in THF (5 ml) was added to a
suspension of NaH (0.18 g, 4.5 mmol) in THF (10 ml) at 0 °C. After
stirring for 1 h at rt, the solution was recooled to 0 °C, and MOMCl
(0.27 ml, 3.6 mmol) was added. After 2 h at rt, the reaction was
quenched with water and extracted with Et2O. The organic layer
was washed with brine and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (n-hexane/ethyl acetate = 5:1) to afford 24b as a light
4.2.5. (S)-3-(Diphenylphosphoryl)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-methyl-1H-indole 25a
Compound 24a (1.00 g, 4.1 mmol) was dissolved in THF (10 ml)
with TMEDA (0.80 ml, 5.3 mmol) and treated with s-BuLi (4.1 ml
1.4 mol/L, 5.7 mmol) at ꢁ78 °C. After 0.5 h under the same temper-
ature, diphenylphosphinic chloride (1.1 ml, 5.7 mmol) was added.
The cooling bath was removed after 0.5 h, and the reaction was al-
lowed to warm to 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-hexane/ethyl acetate = 2:1
to 1:2) to afford a light yellow solid (1.50 g, 83%). Mp 172–174 °C;
yellow oil (0.64 g, 78%). ½a D20
ꢀ
¼ ꢁ37:3 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.97 (d, J = 6.7 Hz, 3H), 1.06 (d, J = 6.7 Hz,
3H), 1.82–1.88 (m, 1H), 3.29 (s, 3H), 4.04–4.17 (m, 2H), 4.34–
4.39 (m, 1H), 6.13 (A, JAB = 10.6 Hz, 1H), 6.19 (B, JAB = 10.6 Hz,
1H), 7.12 (d, J = 0.8 Hz, 1H), 7.17 (ddd, J = 7.1, 7.0, 1.0 Hz, 1H),
7.33 (ddd, J = 7.1, 7.0, 1.2 Hz, 1H), 7.54–7.57 (m, 1H), 7.66 (dt,
J = 7.9, 1.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): 19.0, 19.3, 33.4,

Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
2381
Table 1
was added dropwise at 0 °C. The mixture was heated to 90 °C for
3 h. The mixture was cooled on ice-bath, and the pH was adjusted
to 10 by the addition of 2 M NaOH. The solution was extracted with
ethyl acetate, and the organic layers 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-
Asymmetric allylic alkylation with various ligandsa
Entry
Ligand
Time(h)
Isolated yield (%)
eeb (%)
Configuration
1
2
3
4
5
6
7
8
13
14
15
16
17
18
19
20
(R)-20
1a
5a
6a
7a
2
2
77c
79c
42
63
17
17
55
95c
77c
98
83
86
89
97
97
93
90
72
86
97
98
98
98
75
88
86
(S)d
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)e
(S)
(S)
(S)
(S)
24
24
24
24
24
0.5
0.5
1
tate = 5:1) to afford a light yellow oil (0.43 g, 50%). ½a D20
¼ ꢁ59:4 (c
ꢀ
1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.94 (d, J = 6.7 Hz, 3H),
1.04 (d, J = 6.7 Hz, 3H), 1.79–1.84 (m, 1H), 4.00 (s, 3H), 4.04–4.08
(m, 2H), 4.21–4.28 (m, 1H), 6.82–6.87 (m, 2H), 7.17–7.49 (m,
12H); 13C NMR (75 MHz, CDCl3): 18.9, 19.3, 32.0, 33.2, 70.2, 73.4,
110.5, 120.6, 122.92 (d, JCP = 2.2 Hz), 123.8, 128.1 (d, JCP = 12.4 Hz),
128.4–128.5 (4 lines), 129.4 (d, JCP = 2.0 Hz), 132.7, 133.0 (d,
JCP = 1.8 Hz), 133.2, 134.0, 134.5, 138.1 (d, JCP = 9.8 Hz), 138.1 (d,
JCP = 9.8 Hz), 139.5 (d, JCP = 2.6 Hz), 158.0 (d, JCP = 1.0 Hz); 31P
NMR (121 MHz, CDCl3): ꢁ25.2. HRMS-ESI (m/z) for C27H28N2OP,
(M+H)+ found 427.1946, calcd 427.1939.
9
10f
11g
12g
13g
14
14
14
a
b
c
See the Experimental for details concerning the reaction conditions.
Determined by chiral HPLC.
The conversion was 100%.
a 2D0
ꢀ
¼ ꢁ17:8 (c 1.0, DCM).
¼ þ22:1 (c 1.05, DCM).
d
½
½
a 2D0
ꢀ
e
f
4.2.8. (S)-3-(Diphenylphosphino)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxymethyl)-1H-indole 14
See Ref. 4h.
g
Reaction at ꢁ10 °C. See Ref. 9a.
To a mixture of 25b (0.71 g, 1.5 mmol) and Et3N (0.83 ml,
6.0 mmol) in m-xylene (20 ml), trichlorosilane (0.61 ml, 6.0 mmol)
was added dropwise at 0 °C. The mixture was heated to 90 °C for
3 h. The mixture was cooled on ice-bath, and the pH was adjusted
to 10 by the addition of 2 M NaOH. The solution was extracted with
ethyl acetate, and the organic layers 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-
½
a 2D0
ꢀ
¼ ꢁ88:9 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.82 (d,
J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 1.54–1.59 (m, 1H), 3.38–3.45
(m, 1H), 3.48–3.58 (m, 2H), 3.98 (s, 3H), 7.03 (ddd, J = 7.0, 5.9,
1.1 Hz, 1H), 7.26–7.51 (m, 9H), 7.81–7.88 (m, 4H); 13C NMR
(75 MHz, CDCl3): 19.0, 19.2, 31.8, 32.8, 69.9, 73.3, 105.8, 107.4,
110.3 (d, JCP = 1.0 Hz), 121.7 (d, JCP = 0.7 Hz), 122.8 (d, JCP = 1.1 Hz),
124.2, 128.3 (2d, JCP = 2.4, 3.3 Hz), 129.2 (d, JCP = 8.5 Hz), 131.3–
131.8 (7 lines), 132.8 (d, JCP = 16.17 Hz), 134.0 (d, JCP = 1.1 Hz),
135.5 (d, JCP = 1.1 Hz), 138.4 (d, JCP = 10.8 Hz), 156.4 (d,
JCP = 1.1 Hz); 31P NMR (121 MHz, CDCl3): 20.7. HRMS-ESI (m/z)
for C27H27N2O2PNa, (M+Na)+ found 465.1716, calcd 465.1708.
tate = 5:1) to provide light yellow oil (0.49 g, 71%). ½a D20
¼ ꢁ53:1 (c
ꢀ
1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.7 Hz, 3H),
1.04 (d, J = 6.7 Hz, 3H), 1.76–1.80 (m,1H), 3.24 (s, 3H), 3.96–4.04
(m, 2H), 4.20–4.23 (m, 1H), 5.83 (A, JAB = 10.8 Hz, 1H), 5.90 (B,
JAB = 10.8 Hz, 1H), 6.83–6.89 (m, 2H), 7.15–7.54 (m, 12H); 13C
NMR (75 MHz, CDCl3): 19.0, 19.3, 33.2, 56.2, 70.3, 73.4, 75.3,
111.3, 112.6 (d, JCP = 16.6 Hz), 121.3, 123.0 (d, JCP = 2.0 Hz), 124.3,
128.2 (d, JCP = 11.0 Hz), 128.4–128.5 (4 lines), 129.8 (d,
JCP = 2.0 Hz), 132.7, 133.0 (d, JCP = 1.4 Hz), 133.2, 133.6, 134.1,
137.7 (d, JCP = 10.0 Hz), 137.9 (d, JCP = 10.0 Hz), 139.2 (d,
JCP = 2.4 Hz), 157.7 (d, JCP = 1.0 Hz); 31P NMR (121 MHz, CDCl3):
ꢁ24.9. HRMS-ESI (m/z) for C28H30N2O2P, (M+H)+ found 457.2051,
calcd 457.2045.
4.2.6. (S)-3-(Diphenylphosphoryl)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxymethyl)-1H-indole 25b
Compound 24b (1.00 g, 3.7 mmol) was dissolved in THF (10 ml)
with TMEDA (0.72 ml, 4.8 mmol) and treated with s-BuLi (3.7 ml
1.4 mol/L, 5.1 mmol) at ꢁ78 °C. After 0.5 h at the same tempera-
ture, diphenylphosphinic chloride (1.0 ml, 5.1 mmol) was added.
The cooling bath was removed after 0.5 h, and the reaction was al-
lowed to warm to 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-hexane/ethyl acetate = 2:1
to 1:2) to afford a light yellow solid (1.40 g, 81%). Mp 123–124 °C;
4.2.9. (S)-3-Bromo-2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-1H-
indole 26
Compound 23 (1.70 g, 7.4 mmol) was dissolved in chloroform
(30 ml), and NBS (1.32 g, 7.4 mmol) was added at 0 °C. The mixture
was stirred further at the same temperature for 2 h. After concentra-
tion, water was added, followed by Et2O extraction. The organic lay-
ers were washed with brine and dried over MgSO4. The solvent was
removed in vacuo and the residue was triturated with n-hexane/
ethyl acetate (5:1) to afford a light yellow solid (1.46 g). An addi-
tional amountof product(0.40 g) was obtained from the filtrateafter
silica chromatography (n-hexane/ethyl acetate = 20:1 to 5:1). Com-
½
a 2D0
ꢀ
¼ ꢁ79:5 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.80 (d,
J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 1.50–1.54 (m, 1H), 3.23 (s,
3H), 3.40–3.48 (m, 3H), 5.78 (A, JAB = 10.9 Hz, 1H), 5.86 (B,
JAB = 10.9 Hz, 1H), 7.06 (ddd, J = 7.2, 7.1, 1.0 Hz, 1H), 7.30 (ddd,
J = 7.2, 7.1, 1.0 Hz, 1H), 7.40–7.50 (m, 7H), 7.55–7.58 (m, 1H),
7.80–7.89 (m, 4H); 13C NMR (75 MHz, CDCl3): 18.9, 19.3, 32.8,
56.2, 70.1, 73.3, 75.2, 107.8, 109.4, 111.1 (d, JCP = 1.0 Hz), 122.2
(d, JCP = 0.7 Hz), 122.9 (d, JCP = 1.1 Hz), 124.7, 128.3 (2d, JCP = 12.4,
2.8 Hz), 129.4 (d, JCP = 8.5 Hz), 131.5–131.9 (8 lines), 132.5 (d,
JCP = 16.3 Hz), 133.6 (d, JCP = 3.8 Hz), 135.0 (d, JCP = 3.9 Hz), 137.9
(d, JCP = 10.6 Hz), 156.2 (d, JCP = 1.2 Hz); 31P NMR (121 MHz, CDCl3):
21.2. HRMS-ESI (m/z) for C28H29N2O3PNa, (M+Na)+ found 495.1822,
calcd 465.1814.
bined yield 82%. Mp 122–124 °C; ½a D20
ꢀ
¼ þ60:4 (c 1.0, DCM); 1H NMR
(300 MHz, DMSO-d6): d = 0.87 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz,
3H), 1.75–1.79 (m, 1H), 4.05–4.19 (m, 2H), 4.42–4.48 (m, 1H), 7.15
(ddd, J = 7.0, 6.9, 0.9 Hz, 1H), 7.27 (ddd, J = 7.2, 7.0, 1.1 Hz, 1H),
7.44–7.46 (m, 1H), 7.47–7.48 (m, 1H), 12.03 (br, 1H); 13C NMR
(75 MHz, DMSO-d6): 19.1, 19.6, 33.2, 70.9, 72.6, 93.7, 113.6, 120.4,
121.7, 123.7, 125.8, 128.0, 136.8, 157.3. HRMS-ESI (m/z) for
C
14H15N2OBrNa, (M+Na)+ found 329.0251, calcd 329.0265.
4.2.7. (S)-3-(Diphenylphosphino)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-methyl-1H-indole 13
4.2.10. (S)-3-Bromo-2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-1-
methyl-1H-indole 27a
To a mixture of 25a (0.88 g, 2.0 mmol) and Et3N (1.1 ml,
8.0 mmol) in m-xylene (25 ml), trichlorosilane (0.81 ml, 8.0 mmol)
Compound 26 (0.86 g, 2.8 mmol) in DMF (10 ml) was added to
suspension of NaH (0.17 g, 4.2 mmol) in DMF (5 ml) at 0 °C. After

2382
Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
stirring for 1 h at rt, the solution was recooled to 0 °C, and CH3I
(0.21 ml, 3.4 mmol) was added. After 2 h at rt, the reaction was
quenched with water, and the precipitate was filtered and tritu-
rated with water. Compound 27a was obtained as a white solid
MgSO4. The solvent was removed in vacuo and the residue was
purified by silica chromatography (n-hexane/ethyl acetate = 10:1
to 5:1) to afford a colorless oil (0.47 g, 66%). ½a D20
¼ ꢁ33:8 (c 1.0,
ꢀ
DCM); 1H NMR (300 MHz, CDCl3): d = 1.00–2.00 (m, 27H), 2.29–
2.34 (m, 2H), 3.17 (s, 3H), 4.12–4.20 (m, 2H), 4.47–4.51 (m, 1H),
5.71 (A, JAB = 10.9 Hz, 1H), 5.76 (B, JAB = 10.9 Hz, 1H), 7.18 (ddd,
J = 7.2, 7.0, 1.0 Hz, 1H), 7.30 (ddd, J = 7.1, 7.1, 1.1 Hz 1H), 7.53 (d,
J = 8.2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):
19.1, 19.6, 26.6 (d, JCP = 1.5 Hz), 27.3–27.5 (5 lines), 30.4, 30.6 (d,
JCP = 1.6 Hz), 30.7, 32.1 (d, JCP = 4.9 Hz), 32.4 (d, JCP = 7.8 Hz), 33.3,
34.2, 34.4 (d, JCP = 2.9 Hz), 34.5, 56.1, 70.4, 73.6, 75.2, 111.3,
112.0 (d, JCP = 23.5 Hz), 121.2, 122.9 (d, JCP = 2.8 Hz), 124.0, 138.7
(d, JCP = 2.0 Hz), 158.5; 31P NMR (121 MHz, CDCl3): ꢁ15.4.
HRMS-ESI (m/z) for C28H42N2O2P, (M+H)+ found 469.2980, calcd
469.2984.
(0.85 g, 94%). Mp 72–73 °C; ½a D20
ꢀ
¼ ꢁ59:9 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.95 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz,
3H), 1.80–1.86 (m, 1H), 3.97 (s, 3H), 4.10–4.14 (m, 2H), 4.34–4.42
(m, 1H), 7.16 (ddd, J = 5.9, 5.8, 2.1 Hz, 1H), 7.26–7.31 (m, 2H),
7.60 (dt, J = 8.4, 1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): 18.7, 19.2,
32.8, 33.2, 70.0, 73.0, 95.7, 110.4, 120.9, 121.1, 124.9, 125.2,
127.2, 138.2, 157.3. HRMS-ESI (m/z) for C15H17N2OBrNa, (M+Na)+
found 343.0406, calcd 343.0422.
4.2.11. (S)-3-Bromo-2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-1-
(methoxymethyl)-1H-indole 27b
Compound 26 (0.61 g, 2 mmol) in DMF (10 ml) was added to
suspension of NaH (0.12 g, 3.0 mmol) in DMF (5 ml), at 0 °C. After
stirring for 1 h at rt, the solution was recooled to 0 °C, and MOMCl
(0.18 ml, 2.4 mmol) was added. After 2 h at rt, the reaction was
quenched with water, and the precipitate was filtered and tritu-
rated with water. Compound 27b was obtained as a white solid
4.3. Preparation of ligands 17–20
4.3.1. Indole-3-carboxylic acid 29
At first, indole (2.34 g, 20 mmol) was dissolved in DMF (10 ml)
and trifluoroacetic anhydride (4.2 ml, 30 mmol) was added drop-
wise at 0 °C. After stirring for 3 h at rt, water was added and the
pink solid was filtered. The collected solid was treated with 20%
NaOH (40 ml, 0.2 mol) at 50 °C overnight. After cooling to rt, the
solution was extracted with Et2O. The aqueous phase was acidified
with concd HCl and the product was filtered. Compound 29 was
obtained as a light yellow solid (2.47 g, 77%). Mp 194–196 °C
(decomposed); 1H NMR (300 MHz, CDCl3): d = 7.14–7.33 (m, 2H),
7.46–7.50 (m, 1H), 8.00–8.06 (m, 2H), 11.85–11.97 (m, 2H); 13C
NMR (75 MHz, CDCl3): 108.4, 113.2, 121.6, 122.0, 123.2, 127.0,
133.3, 137.5, 167.0.
(0.68 g, 97%). Mp 55–57 °C; ½a D20
ꢀ
¼ ꢁ46:0 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.99 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz,
3H), 1.86–1.90 (m, 1H), 3.23 (s, 3H), 4.14–4.20 (m, 2H), 4.41–4.50
(m, 1H), 5.96 (A, JAB = 10.7 Hz, 1H), 6.03 (B, JAB = 10.8 Hz, 1H),
7.25 (ddd, J = 7.0, 6.9, 0.9 Hz 1H), 7.37 (ddd, J = 7.1, 7.0, 1.2 Hz
1H), 7.45 (d, J = 8.0, 1H), 7.65(d, J = 6.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): 18.8, 19.2, 33.3, 56.3, 70.1, 73.0, 75.7, 98.6,
111.3, 121.1, 122.0, 125.9, 127.7, 129.6, 138.1, 157.1. HRMS-ESI
(m/z) for
C
16H19N2O2BrNa, (M+Na)+ found 373.0517, calcd
373.0528.
4.3.2. (S)-N-(1-Hydroxy-3-methylbutan-2-yl)-1H-indole-3-
carboxamide 30
The EDC hydrochloride (2.30 g, 12 mmol) was added to a mix-
ture of 29 (1.61 g, 10 mmol) and Et3N (2.8 ml, 20 mmol) in CH2Cl2
4.2.12. (S)-3-(Dicyclohexylphosphino)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-methyl-1H-indole 15
A cooled solution (ꢁ78 °C) of 27a (0.64 g, 2.0 mmol) in THF
(10 ml) was treated with n-BuLi (0.96 ml, 2.5 mol/L, 2.4 mmol).
After 0.5 h under the same temperature, chlorodicyclohexylphos-
phine (0.55 ml, 2.4 mmol) was added. The temperature was al-
lowed to gradually 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 silica chromatography (n-hexane/ethyl ace-
(30 ml), and stirred for 0.5 h under rt. Next, L-valinol (1.24 g,
12 mmol) in CH2Cl2 (5 ml) was added dropwise and the mixture
was stirred overnight at rt. The precipitate formed was filtered
and triturated with 1 M HCl and CH2Cl2. Compound 30 was ob-
tained as a white solid (1.85 g, 75%). Mp 193–195 °C (decom-
posed); ½a 2D0
ꢀ
¼ ꢁ37:8 (c 1.0, MeOH); 1H NMR (300 MHz, DMSO-
d6): d = 0.89–0.93 (2 ꢂ d, J = 6.7 Hz, 6H), 1.90–1.97 (m, 1H), 3.50–
3.54 (m, 2H), 3.80–3.82 (m, 1H), 4.60 (t, J = 5.5 Hz, 1H), 7.06–7.16
(2 ꢂ td, J = 7.1, 1.4 Hz, 2H), 7.35 (d, J = 8.9 Hz, 1H), 7.41 (dd,
J = 7.0, 1.6 Hz, 1H), 8.11–8.13 (m, 2H), 11.5 (br, 1H); 13C NMR
(75 MHz, DMSO-d6): 19.6, 20.7, 29.5, 56.3, 62.6, 111.8, 112.7,
121.1, 122.0, 122.7, 127.2, 128.6, 137.0, 165.5. HRMS-ESI (m/z)
for C14H18N2O2Na, (M+Na)+ found 269.1254, calcd 269.1266.
tate = 10:1 to 5:1) to afford
a colorless oil (0.61 g, 70%).
½
a 2D0
ꢀ
¼ ꢁ36:5 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 1.00–
1.96 (m, 27H), 2.20–2.36 (m, 2H), 3.86 (s, 3H), 4.15–4.18 (m, 2H),
4.44–4.53 (m, 1H), 7.14 (ddd, J = 6.8, 6.8, 1.3 Hz, 1H), 7.28 (td,
J = 6.7, 1.0 Hz 1H), 7.34 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): 19.0, 19.5, 26.6 (d, JCP = 1.3 Hz), 27.4–27.6 (8
lines), 30.4, 30.6 (d, JCP = 2.6 Hz), 30.7, 31.8, 32.0 (d, JCP = 7.5 Hz),
32.3 (d, JCP = 7.5 Hz), 33.3, 34.2, 34.3 (d, JCP = 4.1 Hz), 34.5, 70.3,
73.5, 109.8 (d, JCP = 21.8 Hz), 110.4, 120.4, 122.9 (d, JCP = 3.0 Hz),
123.4, 139.0 (d, JCP = 2.2 Hz), 158.8; 31P NMR (121 MHz, CDCl3):
ꢁ15.1. HRMS-ESI (m/z) for C27H40N2OP, (M+H)+ found 439.2875,
calcd 439.2878.
4.3.3. (S)-3-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1H-indole 31
At first, MsCl (2.3 ml, 29.2 mmol) was added to a cooled mixture
(0 °C) of 30 (2.88 g, 11.7 mmol), Et3N (13.0 ml, 93.6 mmol), and
DMAP (0.28 g, 2.3 mmol) in CH2Cl2/DMF (40 ml:10 ml). After 3 h
at rt, the starting material was consumed. The reaction was
quenched with water and extracted with CH2Cl2. The extracts were
washed with brine and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (n-hexane/ethyl acetate = 3:1 to 2:1) to afford 31 as a
4.2.13. (S)-3-(Dicyclohexylphosphino)-2-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxy-methyl)-1H-indole 16
white solid (2.05 g, 77%). Mp 139–140 °C; ½a D20
¼ ꢁ29:7 (c 1.0,
ꢀ
A cooled solution (ꢁ78 °C) of 27b (0.53 g, 1.5 mmol) in THF
(5 ml) was treated with n-BuLi (0.72 ml, 2.5 mol/L, 1.8 mmol). After
0.5 h under the same temperature, chlorodicyclohexylphosphine
(0.41 ml, 1.8 mmol) was added. The temperature was allowed to
gradually 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
DCM); 1H NMR (300 MHz, CDCl3): d = 0.97 (d, J = 6.8 Hz, 3H), 1.11
(d, J = 6.8 Hz, 3H), 1.86–1.92 (m, 1H), 4.13–4.20 (m, 2H), 4.37–
4.41 (m, 1H), 7.19–7.31 (m, 3H), 7.62 (d, J = 2.7 Hz, 1H), 8.24 (dd,
J = 6.2, 2.7 Hz, 1H), 10.44 (br, 1H); 13C NMR (75 MHz, CDCl3):
18.4, 19.2, 33.3, 69.6, 72.1, 104.8, 112.0, 121.4, 121.6, 123.0,
126.0, 128.6, 136.6, 162.0.

Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
2383
4.3.4. (S)-3-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1-methyl-1H-
indole 32a
dicyclohexylphosphine (0.12 ml, 0.42 mmol) was added. The tem-
perature was allowed to reach rt with stirring overnight. The
reaction was quenched with saturated solution of NH4Cl and ex-
tracted 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-hexane/
Compound 31 (0.57 g, 2.5 mmol) in THF (5 ml) was added to a
suspension of NaH (0.12 g, 3.0 mmol) in THF (5 ml) at 0 °C. After
stirring for 1 h at rt, the solution was recooled to 0 °C, and CH3I
(0.17 ml, 2.8 mmol) was added. After 2 h at rt, the reaction was
quenched with water and extracted with Et2O. The organic layer
was washed with brine and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (n-hexane/ethyl acetate = 5:1 to 2:1) to afford 32a as a
ethyl acetate = 20:1) to afford
a colorless oil (0.13 g, 70%).
½
a 2D0
ꢀ
¼ ꢁ20:1 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3): d = 0.85–
2.00 (m, 27H), 2.63–2.80 (m, 2H), 3.28 (s, 3H), 4.07–4.15 (m, 2H),
4.39–4.42 (m, 1H), 5.94 (app d, J = 3.7 Hz, 2H), 7.20–7.28 (2 ꢂ td,
J = 7.0, 1.5 Hz, 2H), 7.51 (dd, J = 7.0, 1.7 Hz, 1H), 8.20 (dd, J = 7.0,
1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): 19.1, 19.5, 26.5 (d,
JCP = 1.6 Hz), 27.1–27.4 (5 lines), 30.8, 31.0 (d, JCP = 1.4 Hz), 32.5,
32.8 (d, JCP = 4.1 Hz), 33.1, 33.6, 34.8, 34.9, 35.0, 55.8, 69.6, 73.1,
74.6 (d, JCP = 24.1 Hz), 110.6 (d, JCP = 1.7 Hz), 121.9 (d, JCP = 2.8 Hz),
123.4, 128.2, 138.6 (d, JCP = 2.5 Hz), 140.0 (d, JCP = 24.1 Hz), 161.1;
31P NMR (121 MHz, CDCl3): ꢁ17.1. HRMS-ESI (m/z) for
light yellow oil (0.60 g, 99%). ½a D20
ꢀ
¼ ꢁ35:0 (c 0.8, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.95 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz,
3H), 1.84–1.88 (m, 1H), 3.80 (s, 3H), 4.04–4.11 (m, 2H), 4.32–4.38
(m, 1H), 7.22–7.34 (m, 3H), 7.60 (s, 1H), 8.21–8.25 (m, 1H); 13C
NMR (75 MHz, CDCl3): 18.5, 19.3, 33.4, 33.5, 69.3, 72.8, 104.2,
109.7, 121.4, 122.1, 122.8, 126.7, 132.1, 137.4, 160.6. HRMS-ESI
(m/z) for C15H19N2O, (M+H)+ found 243.1486, calcd 243.1497.
C
28H42N2O2P (M+H)+ found 469.2989, calcd 469.2984.
4.3.5. (S)-3-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-1-
(methoxymethyl)-1H-indole 32b
4.3.8. (S)-2-(Diphenylphosphino)-3-(4-isopropyl-4,5-
Compound 31 (0.91 g, 4 mmol) in THF (10 ml) was added to a
suspension of NaH (0.24 g, 6 mmol) in THF (10 ml) at 0 °C. After
stirring for 1 h at rt, the solution was recooled to 0 °C, and MOMCl
(0.36 ml, 4.8 mmol) was added. After 2 h at rt, the reaction was
quenched with water and extracted with Et2O. The organic layers
were washed with brine and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography (n-hexane/ethyl acetate = 3:1) to provide 32b as a light
dihydrooxazol-2-yl)-1-methyl-1H-indole 19
A cooled solution (ꢁ78 °C) of 32a (0.34 g, 1.4 mmol) and TMEDA
(0.25 ml, 1.7 mmol) in degassed THF (5 ml) was treated with t-BuLi
(1.0 ml, 1.7 mol/L, 1.7 mmol). After 0.5 h at the same temperature,
chlorodiphenylphosphine (0.32 ml, 1.8 mmol) was added. The
temperature was allowed to reach rt with stirring overnight. The
reaction was quenched with saturated solution of NH4Cl and ex-
tracted 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-hexane/
ethyl acetate = 10:1) to afford a white solid (0.36 g, 60%). Mp 52–
yellow oil (0.83 g, 76%). ½a D20
ꢀ
¼ ꢁ31:2 (c 1.0, DCM); 1H NMR
(300 MHz, CDCl3): d = 0.96 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz,
3H), 1.85–1.89 (m, 1H), 3.23 (s, 3H), 4.05–4.15 (m, 2H), 4.33–
4.36 (m, 1H), 5.42 (A, JAB = 11.0 Hz, 1H), 5.44 (B, JAB = 11.0 Hz,
1H), 7.27–7.32 (m, 2H), 7.47–7.50 (m, 1H), 7.70 (s, 1H), 8.25–8.29
(m, 1H); 13C NMR (75 MHz, CDCl3): 18.6, 19.3, 33.4, 56.3, 69.4,
72.9, 78.1, 105.7, 110.5, 122.1, 122.3, 123.4, 127.2, 131.2, 136.8,
160.3. HRMS-ESI (m/z) for C16H21N2O2, (M+H)+ found 273.1592,
calcd 273.1603.
53 °C; ½a 2D0
ꢀ
¼ ꢁ75:6 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3):
d = 0.89 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H), 1.68–1.73 (m,
1H), 3.49 (s, 3H), 3.52–3.82 (m, 3H), 7.21–8.15 (m, 13H), 8.17 (d,
J = 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): 18.9, 19.4, 32.6 (d,
JCP = 11.2 Hz), 33.4, 69.5, 72.7, 109.6 (d, JCP = 1.0 Hz), 121.4, 121.9
(d, JCP = 0.9 Hz), 123.9, 127.7 (d, JCP = 4.9 Hz), 128.4, 128.8 (d,
JCP = 6.7 Hz), 128.9, 132.2–133.2 (4 lines), 135.1 (d, JCP = 10.0 Hz),
135.4 (d, JCP = 10.0 Hz), 139.7 (d, JCP = 1.7 Hz), 160.6; 31P NMR
(121 MHz, CDCl3): ꢁ24.1. HRMS-ESI (m/z) for C27H28N2OP (M+H)+
found 427.1941, calcd 427.1939.
4.3.6. (S)-2-(Dicyclohexylphosphino)-3-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-methyl-1H-indole 17
A cooled solution (ꢁ78 °C) of 32a (0.48 g, 2 mmol) and TMEDA
(0.36 ml, 2.4 mmol) in THF (8 ml) was treated with t-BuLi (1.4 ml,
2.4 mmol). After 0.5 h under the same temperature, chloro-
dicyclohexylphosphine (0.59 ml, 2.6 mmol) was added. The tem-
perature was allowed to reach rt with stirring overnight. The
reaction was quenched with saturated solution of NH4Cl and ex-
tracted 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-hexane/
ethyl acetate = 20:1) to afford a white solid (0.54 g, 61%). Mp 90–
4.3.9. (S)-2-(Diphenylphosphino)-3-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxymethyl)-1H-indole 20
A cooled solution (ꢁ78 °C) of 32b (0.46 g, 1.7 mmol) and TME-
DA (0.38 ml, 2.5 mmol) in degassed THF (5 ml) was treated with
t-BuLi (1.5 ml, 1.7 mol/L, 2.5 mmol). After 0.5 h at the same tem-
perature, chlorodiphenylphosphine (0.47 ml, 2.5 mmol) was
added. The temperature was allowed to reach rt with stirring over-
night. 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 va-
cuo and the residue was purified by column chromatography (n-
hexane/ethyl acetate = 10:1) to afford a white solid (0.44 g, 57%).
91 °C; ½a 2D0
ꢀ
¼ ꢁ21:0 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3):
d = 0.88–1.98 (m, 27H), 2.68–2.77 (m, 2H), 4.00 (s, 3H), 4.04–4.13
(m, 2H), 4.36–4.44 (m, 1H), 7.15–7.28 (m, 2H), 7.31–7.34 (m,
1H), 8.20–8.23 (m, 1H); 13C NMR (75 MHz, CDCl3): 19.1, 19.6,
26.5 (d, JCP = 1.7 Hz), 27.0–27.3 (6 lines), 30.9, 31.0 (d, JCP = 1.2 Hz),
32.2, 32.5 (d, JCP = 5.0 Hz), 32.8 (d, JCP = 4.7 Hz), 33.1, 33.6, 34.4,
34.5 (d, JCP = 1.8 Hz), 34.7, 69.5, 73.1, 109.9 (d, JCP = 1.2 Hz), 121.2,
121.9, 122.8, 127.9 (d, JCP = 1.0 Hz), 138.7 (d, JCP = 2.8 Hz), 161.3;
31P NMR (121 MHz, CDCl3): ꢁ16.2. HRMS-ESI (m/z) for C27H40N2OP
(M +H)+ found 439.2871, calcd 439.2878.
Mp 89–90 °C; ½a 2D0
ꢀ
¼ ꢁ77:6 (c 1.0, DCM); 1H NMR (300 MHz,
CDCl3): d = 0.84 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 1.58–
1.63 (m, 1H), 2.91 (s, 3H), 3.42–3.46 (m, 2H), 3.53–3.57 (m, 1H),
5.68 (app d, J = 2.6 Hz, 2H), 7.21–7.32 (m, 9H), 7.38–7.55 (m, 4H),
8.07–8.10 (m, 1H); 13C NMR (75 MHz, CDCl3): 19.3, 19.4, 33.2,
55.5 (d, JCP = 1.3 Hz), 69.3, 72.5, 75.4 (d, JCP = 17.0 Hz), 110.6 (d,
JCP = 1.6 Hz), 114.0 (d, JCP = 2.2 Hz), 121.6, 122.0, 124.3, 128.0–
128.9 (8 lines), 132.6 (d, JCP = 20.6 Hz), 133.7 (d, JCP = 20.4 Hz),
134.3 (d, JCP = 6.4 Hz), 135.0 (d, JCP = 6.2 Hz), 136.6 (d,
JCP = 19.3 Hz), 139.2 (d, JCP = 2.5 Hz), 160.1; 31P NMR (121 MHz,
CDCl3): ꢁ23.1. HRMS-ESI (m/z) for C28H30N2O2P (M+H)+ found
457.2035, calcd 457.2045.
4.3.7. (S)-2-(Dicyclohexylphosphino)-3-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxy-methyl)-1H-indole 18
A cooled solution (ꢁ78 °C) of 32b (0.11 g, 0.4 mmol) and TME-
DA (0.07 ml, 0.48 mmol) in THF (2.5 ml) was treated with t-BuLi
(0.28 ml, 0.48 mmol). After 0.5 h at the same temperature, chloro-

2384
Y. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2376–2384
Jonathan, W. M. J.; Michael, L. S. Chem. Commun. 1999, 77, 913–914; (d) Reiser,
O. Angew. Chem., Int. Ed. Engl. 1993, 32, 547–549; (e) Pretot, R.; Lloyd-Jones, G.
C.; Pfaltz, A. Pure Appl. Chem. 1998, 70, 1035–1040; (f) Helmchen, G.; Kudis, S.;
Sennhenn, P.; Steinhagen, H. Pure Appl. Chem. 1997, 69, 513–518; (g) Williams,
J. M. J. Synlett 1996, 8, 705–710; (h) Sprinz, J.; Kiefer, M.; Heimchen, G.
Tetrahedron Lett. 1994, 35, 1523–1526. See also Ref. 2.
4.3.10. (R)-2-(Diphenylphosphino)-3-(4-isopropyl-4,5-
dihydrooxazol-2-yl)-1-(methoxymethyl)-1H-indole (R)-20
Mp 89–90 °C; ½a 2D0
ꢀ
¼ þ79:5 (c 1.0, DCM); 1H NMR (300 MHz,
CDCl3): d = 0.83 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 1.58–
1.61 (m, 1H), 2.90 (s, 3H), 3.42–3.46 (m, 2H), 3.56–3.59 (m, 1H),
5.68 (app d, J = 2.6 Hz, 2H), 7.20–7.56 (m, 13H), 8.08–8.11 (m,
1H); 13C NMR (75 MHz, CDCl3): 18.9, 19.3, 33.1, 55.5 (d,
JCP = 1.3 Hz), 69.3, 72.5, 75.2 (d, JCP = 17.0 Hz), 110.6 (d,
JCP = 1.6 Hz), 114.0 (d, JCP = 2.2 Hz), 121.5, 122.0, 124.3, 128.0–
128.8 (8 lines), 132.6 (d, JCP = 19.1 Hz), 133.7 (d, JCP = 20.3 Hz),
5. For allylic amination see: (a) von Matt, P.; Loiseleur, O.; Koch, G.; Pfaltz, A.
Tetrahedron: Asymmetry 1994, 5, 573–584; (b) Constantine, R. N.; Kim, N.; Bunt,
R. C. Org. Lett. 2003, 5, 2279–2282; (c) Jumnah, R.; Williams, A. C.; Williams, J.
M. J. Synlett 1995, 8, 821–822; (d) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen,
G. Chem. Commun. 2004, 7, 896–897.
6. For Ru-catalyzed hydrogenation, see: (a) Langer, T.; Helmchen, G. Tetrahedron
Lett. 1996, 37, 1381–1384; (b) Sammakia, T.; Stangeland, E. L. J. Org. Chem.
1997, 62, 6104–6105; (c) Naud, F.; Malan, C.; Spindler, F.; Ruggeberg, C.;
Schmidt, A. T.; Blaser, H. U. Adv. Synth. Catal. 2006, 348, 47–50; (d)
Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999, 18,
2291–2293; (e) Arikawa, Y.; Ueoku, M.; Matoba, K.; Nishibayashi, Y.; Hidai, M.;
Uemura, S. J. Organomet. Chem. 1999, 572, 163–168.
7. For Ir-catalyzed hydrogenation see: (a) Schnider, P.; Koch, G.; Pretot, R.; Wang,
G.; Bohnen, F. M.; Kruger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887–892; (b) Kainz,
S.; Brikmann, A.; Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999, 121, 6421–6429;
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2899.
134.2 (d, JCP = 6.4 Hz), 134.9 (d, JCP = 6.3 Hz), 136.5 (d, JCP
=
19.4 Hz), 139.1 (d, JCP = 2.5 Hz), 160.0; 31P NMR (121 MHz, CDCl3):
ꢁ23.2. HRMS-ESI (m/z) for C28H30N2O2P (M+H)+ found 457.2039,
calcd 457.2045.
4.4. General procedure for allylic alkylation
IndPHOX ligand (4.8 mmol %), [Pd(allyl)Cl]2 (1.6 mmol %), KOAc
(4 mmol %), and 2 mL of THF were added into the flask, and stirred
for 0.5 h at rt. Then 33 (0.10 g, 0.4 mmol) in 2 mL of THF, BSA
(0.30 ml, 1.2 mmol), and dimethyl malonate (0.14 ml, 1.2 mmol)
were added separately. After stirring at rt for 1–24 h, the solvent
was removed in vacuo and the residue was purified by column
chromatography (n-hexane/ethyl acetate = 20:1) to afford 34 as a
colorless oil. 1H NMR (300 MHz, CDCl3): d = 3.51 (s, 3H), 3.70 (s,
3H), 3.96 (d, J = 10.9 Hz, 1H), 4.27 (dd, J = 8.5, 10.9 Hz, 1H), 6.33
(dd, J = 15.8, 8.5 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 7.19–7.34 (m,
10H); 13C NMR (75 MHz, CDCl3): 49.5, 52.8, 52.9, 57.9, 126.7,
127.5, 127.9, 128.2, 128.8, 129.0, 129.4, 132.1, 137.1, 140.4,
168.1, 168.5. The enantiomeric excess was determined by HPLC
using a Chiralpak IA column: i-PrOH/hexane: 5:95; flow rate:
1 mL/min; UV at 254 nm; tR1 = 18.6 min, tR2 = 23.6 min.
8. (a) Zhang, W.; Xie, F.; Yoshinage, H.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Synlett
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Acknowledgment
The financial support of this work was provided by National
Technology Agency of Finland (TEKES).
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