N1-functionalized indole-phosphane oxazoline (IndPHOX) ligands in asymmetric allylic substitution reactions

Article abstract of DOI:10.1002/ejoc.201101540

N-Functionalized IndPHOX ligands bearing various groups have been synthesized and the effects of the N¹-substituent on the reaction rate, yield, and asymmetric induction in a palladium-catalyzed allylic substitution reaction are reported. The p

Full text of DOI:10.1002/ejoc.201101540

FULL PAPER
DOI: 10.1002/ejoc.201101540
N1-Functionalized Indole-Phosphane Oxazoline (IndPHOX) Ligands in
Asymmetric Allylic Substitution Reactions
Yu Wang,[a] Matti J. P. Vaismaa,[a] Kari Rissanen,[b] and Robert Franzén*[a]
Keywords: Nitrogen heterocycles / Allylic compounds / Enantioselectivity / Amination / Alkylation / Palladium
N-Functionalized IndPHOX ligands bearing various groups
have been synthesized and the effects of the N1-substituent
on the reaction rate, yield, and asymmetric induction in a
palladium-catalyzed allylic substitution reaction are re-
ported. The presence of an oxygen atom in the ligands,
namely an N-MOM or N-THP group, led to enhancement
of the enantioselectivity in the allylic amination reaction. In
addition, a ligand with a chiral oxazoline ring at C-1 and a
phosphane substituent at C-2 provided high enantio-
selectivity in good yield in an asymmetric allylic alkylation
reaction.
Suzuki–Miyaura coupling reactions.[6] Herein we report the
synthesis of two types of N1-functionalized IndPHOX li-
gands (Figure 1) and their use in allylic amination and
alkylation reactions, respectively.
Introduction
Metal-catalyzed asymmetric allylic substitution using
chiral ligands has become a powerful method for the forma-
tion of carbon–carbon and carbon–heteroatom bonds.[1]
Therefore the design and synthesis of efficient chiral ligands
for use in catalytic enantioselective transformations is of
high importance. The size of the metal-binding site of the
ligand, the chirality, and the bulkiness of the side group are
all known to affect these reactions. Recently we reported the
preparation of novel IndPHOX ligands, the use of which led
to high yields and excellent enantioselectivities in catalyzed
asymmetric allylic alkylation[2a] and amination[2b] reactions.
We noticed that the indole scaffold was advantageous as it
provided a platform for a systematic investigation of how
minor changes in the ligand structure could affect the asym-
metric induction.
The N1 position is one of the main reactive sites of in-
doles.[3] Modifications at N1 can allow the tuning of the
electronic and steric properties of the indole core. Pro-
cedures for N1-substitution usually involve base-catalyzed
nucleophilic substitution or conjugate addition. Moreover,
functionalization at the indole nitrogen can be achieved by
a catalytic cross-coupling reaction.[4,5] Recently, Kwong and
co-workers described the synthesis of indolylphosphane li-
gands with various groups at N1 and their application in
Figure 1. Structures of the N1-functionalized IndPHOX ligands.
Results and Discussion
The ligand 1 with a phosphane moiety at C-2 and an
oxazoline ring at C-3 was chosen for further investigation
due to its high efficiency in allylic substitution reactions.[2]
3-Oxazolylindole 4, readily prepared from indole (3),[2a] was
first deprotonated with NaH and then treated with alkyl,
benzyl, or carbamic halides to afford N-substituted indol-
yloxazolines 5a–5d. Compound 5e was synthesized by a Cu-
catalyzed cross-coupling reaction with phenyl bromide.[4b]
Ligands 1 bearing various groups at the N1 position were
obtained after direct lithiation at C-2 followed by treatment
with ClPPh2 (Scheme 1).
With the ligands 1a–e in hand, we investigated the asym-
metric allylic amination reaction between 1,3-diphenyl-2-
propenyl acetate (6) and benzylamine (Table 1). Good-to-
excellent enantioselectivities and high yields were achieved.
The reactions with the N-methyl and N-MOM ligands 1a
and 1b proceeded well, both yielding amine 7 in excellent
yields (97 and 96%) and with good (77%) and excellent
(96%) enantioselectivities, respectively (entries 1 and 2).
[a] Department of Chemistry and Bioengineering, Tampere
University of Technology,
Korkeakoulunkatu 8, 33101 Tampere, Finland
Fax: +358-331152108
E-mail: robert.franzen@tut.fi
[b] Department of Chemistry, Nanoscience Center, University of
Jyväskylä,
P. O. Box 35, 40014 Jyväskylä, Finland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101540.
Eur. J. Org. Chem. 20112, 1569–1576
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Y. Wang, M. J. P. Vaismaa, K. Rissanen, R. Franzén
FULL PAPER
Scheme 1. Synthesis of IndPHOX ligands 1.
However, despite the fact that the introduction of a bulkier similar steric bulkiness to the N-MOM ligand 1b, by using
group at the N1 position gave better asymmetric induction, the same synthetic method as before (see Scheme 1). The
it was achieved at the cost of the isolated yields (entries 3– new ligand 1f was used in the asymmetric allylic amination
5).
reaction, providing good ee (87%) and high yield (90%)
(Table 1, entry 6). Compared with the N-methyl ligand 1a,
the increased steric effect of 1f led to enhancement of the
enantioselectivity at the expense of the yield. On the other
hand, the N-MOM ligand 1b, with a similar steric demand
to ligand 1f, still exhibited better enantiodiscriminating
power. A possible explanation for this would be that the
oxygen atom in the MOM group stabilizes the catalytic in-
termediate and therefore increases conformational restric-
tion, thus achieving high enantioselectivity.
Encouraged by the results above, we investigated the in-
fluence of other ligands with an oxygen atom in the N1
substituent. Thus, we prepared an IndPHOX ligand with a
N-THP substituent, which provides a new stereocenter next
to the nitrogen atom and thus two ligand diastereomers.
Assuming the existence of the oxygen effect, the ligands
could be expected to demonstrate altered enantiodiscrimin-
ating powers due to different stabilizing abilities caused by
different spatial positions of the oxygen atom in the cataly-
Table 1. Asymmetric allylic amination of 6 with benzylamine.[a]
Entry
Ligand
Time [h] Isolated yield [%]
ee [%][b]
1
2
3
4
5
6
1a[c]
1b[e]
1c
18[d]
18[d]
24
97
96
93
72
84
90
77
96
98
97
97
87
1d
24
24
1e
1f
18
[a] See Exp. Sect. for details. Conc. of 6: 0.2 mol/L. [b] Determined
by chiral HPLC. [c] 31P NMR (121 MHz, CDCl3): δ = –25.2 ppm.
[d] 100% conversion based on TLC. [e] 31P NMR (121 MHz,
CDCl3): δ = –24.9 ppm.
sis.
There is a significant difference in the enantioselectivities
N-Functionalization with a THP group was achieved by
yielded by ligands 1a and 1b having a CH3 and MOM using 3-oxazolylindole 4 as a starting material in the reac-
group at the N1 position, respectively (entries 1 and 2).[7] tion with 2-chlorotetrahydro-2H-pyran (9), which was
Considering their similar electronic properties (similar P freshly prepared from DHP (8).[10] The reaction yielded 5g
NMR shifts),[8] the higher ee achieved by ligand 1b might as a mixture of two diastereomers. This mixture was lithi-
derive from the increased bulkiness of the catalytic interme- ated at C-2 and treated with ClPPh2 to afford diastereomers
diate. However, the similar yields obtained with ligands 1a 1g and 1h, which were separated by column chromatog-
and 1b suggests that there is no obvious difference in steric raphy (Scheme 2). The absolute configuration of 1g was de-
properties that would lead to such differences in the termined to be (S,S) by X-ray crystallographic analysis[11]
enantioselectivities. Furthermore, the positive effect of the of its corresponding phosphane oxide 10 (Figure 2), which
oxygen atom in the ligand structures in enhancing the was prepared from 1g by oxidation with H2O2 and recrys-
enantioselectivity has previously been reported.[9] Therefore tallized from ethanol. The X-ray crystallographic analysis
we assume that in addition to steric factors, the presence of of 10 showed the sterically bulky diphenylphosphane oxide
the oxygen atom in the MOM group of ligand 1b might group, THP, and the oxazoline group are oriented nearly
influence the catalytic transition as well.
perpendicularly (82.8 and 71.9°, respectively) to the indole
To determine the existence of the oxygen effect, we syn- moiety. The absolute configuration of the other dia-
thesized ligand 1f with an N-propyl substituent, which has stereomer 1h was therefore assigned (S,R) stereochemistry.
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Asymmetric Allylic Substitution Reactions
Scheme 2. Synthesis of IndPHOX ligands 1g and 1h.
ing 4-methoxybenzylamine or electron-withdrawing 4-
chlorobenzylamine as nucleophiles with slightly decreased
yields (89 and 91%, respectively, entries 1 and 2). The reac-
tion with bulky potassium phthalimide proceeded well to
afford 7d with excellent ee (97%) and high yield (entry 3).
The poor nucleophile aniline was also investigated; 7e was
obtained with high enantioselectivity in moderate yield (en-
try 4).
Table 3. Asymmetric allylic amination of 6 using different N-nu-
cleophiles.[a]
Entry Nucleophiles
Time Product Isolated yield ee[b]
[h]
[%]
[%]
Figure 2. Crystal structure of compound 10 with thermal ellipsoids
drawn at the 40% propability level and labeling of the P, O, and N
atoms.
1
2
4-methoxybenzylamine
18
18
24
24
7b
7c
7d
7e
89
91
73
50
96
96
97
89
4-chlorobenzylamine
potassium phthalimide
aniline
3
4[c]
The ligands 1g and 1h were investigated in the allylic
amination of 6 with benzylamine (Table 2). They provided
the same yield (81%) but different enantioselectivities (97
and 80% ee, respectively), which further indicates that the
oxygen atom plays a positive role in enhancing the enantio-
selectivity.
[a] See the Exp. Sect. for details. Conc. of 6: 0.2 mol/L. [b] Deter-
mined by chiral HPLC. [c] 4.0 mol-% catalyst and 12.0 mol-% li-
gand were used. Conc. of 6: 0.1 mol/L.
Previously we have prepared IndPHOX ligands with a
chiral oxazoline moiety at either the 2- or C-3. As a result
of the different catalytic abilities arising from the different
ligand structures,[2b] we envisioned that an indole with an
oxazoline ring at the C-1 and a phosphane group at C-2
(2) would be a valuable addition to the series of IndPHOX
ligands.
Table 2. Asymmetric allylic amination using ligand 1g and 1h.[a]
Entry
Ligand
Time [h] Isolated yield [%]
ee [%][b]
1
2
1g
1h
24
24
81
81
97
80
[a] See the Exp. Sect. for details. Conc. of 6: 0.2 mol/L. [b] Deter-
mined by chiral HPLC.
The same synthetic strategy as reported previously for
IndPHOX ligands was used in the synthesis of ligand 2
We studied the reaction with various N-nucleophiles by (Scheme 3).[2a] Indole-1-carboxylic acid (11)[12] with the
using ligand 1b, which was chosen on the basis of the yield EDC coupling reagent gave the indole-1-carboxylic acid an-
and enantiomeric purity obtained in the initial experiments hydride. Subsequent condensation with l-valinol provided
(Table 3). Compared with benzylamine, the enantio- compound 12 in good yield. Oxazoline ring formation was
selectivities were excellent (96%) with either electron-donat- accomplished by treatment with MsCl in the presence of
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Y. Wang, M. J. P. Vaismaa, K. Rissanen, R. Franzén
FULL PAPER
DMAP under basic conditions yielding 13 after heating at
reflux for 24 h. Finally, ligand 2 was obtained after direct
lithiation at C-2 and treatment with ClPPh2 (Scheme 3).
Experimental Section
General: Dry THF was obtained by distillation over metallic so-
dium and by using benzophenone ketyl as indicator. Other solvents
and reagents were used as received. TLC was performed on pre-
coated (silica gel 60 F254) aluminium plates and visualized by UV
light. Silica gel 60, particle size 0.040–0.063 nm, was used for col-
umn chromatography. 1H, 13C, and 31P NMR spectra were re-
corded at 300, 75, and 121 MHz, respectively, using CDCl3 or
[D6]DMSO as solvent. Chemical shifts are reported in δ values
(ppm) relative to tetramethylsilane (internal standard) or H3PO4
(external standard).
Synthesis of IndPHOX Ligand 1
(S)-2-(1-Benzyl-1H-indol-3-yl)-4-isopropyl-4,5-dihydrooxazole (5c):
Compound 4 (0.68 g, 3.0 mmol) in DMF (5 mL) was added to a
suspension of NaH (0.156 g, 3.9 mmol) in DMF (5 mL) at 0 °C.
After stirring for 1 h at room temp., the solution was recooled to
0 °C and benzyl bromide (0.56 mL, 3.3 mmol) was added. After 2 h
at room temp., the reaction was quenched with water and extracted
with ethyl acetate. The organic layer was washed with brine and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due was purified by column chromatography (n-hexane/ethyl acet-
ate, 5:1) to afford 5c as a colorless oil (0.88 g, 92%). [α]2D0 = –50.0
Scheme 3. Synthesis of IndPHOX ligand 2.
Ligand 2 was used in the asymmetric allylic alkylation of
1,3-diphenyl-2-propenyl acetate (6) with dimethyl malonate
(Table 4). A good yield and enantioselectivity were obtained
with 4 mol-% catalyst loading and 12 mol-% of the ligand
(entry 1). Furthermore, the enantioselectivity increased to
92% with a catalyst/ligand ratio of 1:2 (entry 2). The full
conversion of 6 was achieved with high enantioselectivity
by using a small amount of catalyst and ligand after a pro-
longed reaction time (entry 3).
1
(c = 0.51, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ = 8.30–
8.26 (m, 1 H, Ar-H), 7.63 (s, 1 H, Ar-H), 7.30–7.06 (m, 8 H, Ar-
H), 5.21 (s, 2 H, CH2Ph), 4.32–4.28 (m, 1 H, OCH2), 4.08–4.00 (m,
2 H, OCH2, C=NCH), 1.86–1.82 (m, 1 H, CHMe2), 1.06 (d, J =
6.8 Hz, 3 H, CH3), 0.93 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 20 °C): δ = 160.6, 136.9, 136.6, 131.4, 129.1,
128.6, 128.1, 127.2, 127.1, 126.8, 123.0, 122.2, 121.6, 110.2, 104.8,
72.7, 69.3, 50.6, 33.4, 19.4, 18.5 ppm. HRMS (ESI): calcd. for
C21H23N2O [M + H]+ 319.1810; found 319.1802.
Table 4. Asymmetric allylic alkylation using ligand 2.[a]
(S)-N,N-Diisopropyl-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-1H-
indole-1-carboxamide (5d): Compound 4 (0.50 g, 2.2 mmol) in THF
(3 mL) was added to a suspension of NaH (0.11 g, 2.9 mmol) in
THF (3 mL) at 0 °C. After stirring for 1 h at room temp., the solu-
tion was recooled to 0 °C and diisopropylcarbamyl chloride (0.43 g,
2.6 mmol) in THF (2 mL) was added. After 2 h at room temp., the
reaction was quenched with water and extracted with Et2O. The
organic layer was washed with brine, dried with MgSO4, and
passed through a pad of silica gel, diluted with diethyl ether. The
solvent was removed in vacuo to afford 5d as a white solid (0.70 g,
Entry
Catalyst
[mol-%]
Ligand
[mol-%]
Time
[h]
Isolated yield
[%]
ee[b]
[%]
1
2
3
4
4
3
12
8
6
2
2
24
77[c]
71
85
92
92
76[c]
[a] See the Exp. Sect. for details. Conc. of 6: 0.2 mol/L. [b] Deter-
mined by chiral HPLC. [c] 100% conversion based on TLC.
90%); m.p. 98–100 °C. [α]2D0 = –46.0 (c = 0.50, CHCl3); H NMR
1
(300 MHz, CDCl3, 20 °C): δ = 8.30–8.25 (m, 1 H, Ar-H), 7.68 (s,
1 H, Ar-H), 7.61 (dd, J = 6.4, 2.4 Hz, 1 H, Ar-H), 7.34–7.25 (m, 2
H, Ar-H), 4.40–4.30 (m, 1 H, OCH2), 4.13–4.04 (m, 2 H, OCH2,
C=NCH), 3.78–3.69 (m, 2 H, 2ϫ CHNC=O), 1.91–1.80 (m, 1 H,
CHMe2), 1.38 (d, J = 6.7 Hz, 12 H, 4ϫ CH3), 1.07 (d, J = 6.8 Hz,
3 H, CH3), 0.95 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 20 °C): δ = 159.8, 151.8, 136.4, 128.0, 126.6,
124.3, 122.8, 122.2, 112.7, 107.6, 73.0, 69.5, 49.1, 33.4, 21.3, 21.2,
19.3, 18.6 ppm. HRMS (ESI): calcd. for C21H30N3O2 [M + H]+
356.2338; found 356.2335.
Conclusions
We have synthesized a series of IndPHOX ligands 1a–1h
with different substituents at the N1 position. With these
ligands we obtained good-to-excellent enantioselectivities
and high yields in Pd-catalyzed asymmetric allylic amin-
ation reactions. By introducing an N-alkoxymethyl group,
namely a MOM (1b) or (S)-THP group (1g), we improved
the enantioselectivity of the catalytic reaction. Further-
more, good-to-excellent enantioselectivities were achieved
with various N-nucleophiles by using ligand 1b. Finally, a
new type of IndPHOX ligand 2 with an oxazoline ring at
C-1 and a phosphane substituent at the C-2 was prepared
and used in the asymmetric allylic alkylation reaction, re-
sulting in good yield and high enantioselectivity.
(S)-4-Isopropyl-2-(1-phenyl-1H-indol-3-yl)-4,5-dihydrooxazole (5e):
Bromobenzene (0.06 mL, 0.6 mmol) was added to a mixture of 4
(011 g, 0.5 mmol), K3PO4 (0.22 g, 1.05 mmol), CuI (19 mg,
0.1 mmol), and DMEDA (0.02 mL, 0.15 mmol) in toluene (1 mL).
The reaction was stirred at 100 °C for 48 h under argon. The reac-
tion mixture was cooled to ambient temperature, diluted with n-
hexane/ethyl acetate (2:1), and filtered through a pad of silica gel,
eluting with additional n-hexane/ethyl acetate (2:1). The filtrate was
concentrated to afford a light-yellow oil (0.15 g, 98%). [α]2D0 = –51.6
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Asymmetric Allylic Substitution Reactions
1
(c = 0.50, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ = 8.36 extracts were washed with brine and dried with MgSO4. The sol-
(dd, J = 8.4, 1.5 Hz, 1 H, Ar-H), 7.85 (s, 1 H, Ar-H), 7.50–7.44 vent was removed in vacuo and the residue purified by column
(m, 5 H, Ar-H), 7.36–7.22 (m, 3 H, Ar-H), 4.38–4.31 (m, 1 H,
OCH2), 4.14–4.04 (m, 2 H, OCH2, C=NCH), 1.89–1.81 (m, 1 H, lid (0.56 g, 62%); m.p. 137–138 °C. [α]2D0 = –74.4 (c = 0.50, CHCl3).
CHMe2), 1.07 (d, J = 6.7 Hz, 3 H, CH3), 0.95 (d, J = 6.7 Hz, 3 H,
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.10–8.08 (m, 1 H, Ar-
CH3) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 160.3, 139.0, H), 7.70–7.20 (m, 13 H, Ar-H), 3.55–3.48 (m, 3 H, OCH2,
chromatography (n-hexane/ethyl acetate, 10:1) to afford a white so-
136.6, 131.0, 129.9, 127.5, 127.1, 124.7, 123.5, 122.3, 122.1, 110.9,
106.5, 72.8, 69.3, 33.3, 19.2, 18.5 ppm. HRMS (ESI): calcd. for
C20H21N2O [M + H]+ 305.1654; found 305.1642.
C=NCH), 1.71–0.81 (m, 21 H, 6ϫ CH3, 3ϫ CHMe2) ppm. 13C
NMR (75 MHz, CDCl3, 20 °C): δ = 160.0, 150.9, 136.9, 128.6–
128.4 (4 lines), 128.1, 124.6 (d, JCP = 0.9 Hz), 122.4, 121.9, 110.6
(d, JCP = 1.9 Hz), 72.6, 69.5, 33.3 (d, JCP = 1.0 Hz), 31.9, 23.0,
21.0, 19.1, 14.4 ppm. 31P NMR (121 MHz, CDCl3, 20 °C): δ =
–18.3 ppm. HRMS (ESI): calcd. for C33H39N3O2P [M + H]+
540.2780; found 540.2786.
(S)-4-Isopropyl-2-(1-propyl-1H-indol-3-yl)-4,5-dihydrooxazole (5f):
Compound 4 (0.41 g, 1.8 mmol) in DMF (2 mL) was added to a
suspension of NaH (0.14 g, 3.6 mmol) in DMF (2 mL) at 0 °C.
After stirring for 1 h at room temp., the solution was recooled to
0 °C, and 1-bromopropane (0.21 mL, 2.3 mmol) was added. After
2 h at room temp., the reaction was quenched with water and ex-
tracted with Et2O. The organic layer was washed with brine, dried
with MgSO4, and passed through a pad of silica gel, diluted with
diethyl ether. The solvent was removed in vacuo to afford 5f as a
(S)-2-[2-(Diphenylphosphanyl)-1-phenyl-1H-indol-3-yl]-4-isopropyl-
4,5-dihydrooxazole (1e): A cooled solution (–78 °C) of 5e (0.15 g,
0.5 mmol) and TMEDA (0.09 mL, 0.6 mmol) in degassed THF
(2 mL) was treated with nBuLi (0.24 mL, 2.5 mol/L, 0.6 mmol). Af-
ter 0.5 h at the same temperature, chlorodiphenylphosphane
(0.11 mL, 0.6 mmol) in THF (0.5 mL) was added. The temperature
was allowed to reach room temp. with stirring overnight. The reac-
tion was quenched with a saturated solution of NH4Cl and ex-
tracted with ethyl acetate. The extracts were washed with brine and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due purified by column chromatography (n-hexane/ethyl acetate =
1
light-yellow oil (0.46 g, 95%). [α]2D0 = –51.8 (c = 0.50, CHCl3). H
NMR (300 MHz, CDCl3, 20 °C): δ = 8.26–8.23 (m, 1 H, Ar-H),
7.64 (s, 1 H, Ar-H), 7.34–7.21 (m, 3 H, Ar-H), 4.36–4.30 (m, 1 H,
OCH2), 4.11–4.04 (m, 4 H, OCH2, C=NCH, NCH2), 1.90–1.83 (m,
3 H, CHMe2, CH2), 1.06 (d, J = 6.7 Hz, 3 H, CH3), 0.94 (d, J =
6.7 Hz, 3 H, CH3), 0.92 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 20 °C): δ = 160.8, 136.8, 131.2, 126.8, 122.7,
122.2, 121.3, 110.0, 104.2, 72.8, 69.4, 48.7, 33.4, 23.6, 19.4, 18.6,
11.7 ppm. HRMS (ESI): calcd. for C17H23N2O [M + H]+ 271.1810;
found 271.1827.
10:1) to afford a white solid (95 mg, 39%); m.p. 54–56 °C. [α]2D0
=
1
–104.3 (c = 0.3, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ =
8.13 (dd, J = 7.0, 1.2 Hz, 1 H, Ar-H), 7.49–7.43 (m, 2 H, Ar-H),
7.35–6.94 (m, 16 H, Ar-H), 3.58–3.55 (m, 1 H, C=NCH), 3.48–
3.36 (m, 2 H, OCH2), 1.64–1.56 (m, 1 H, CHMe2), 0.98 (d, J =
6.7 Hz, 3 H, CH3), 0.84 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3, 20 °C): δ = 160.3 (d, JCP = 1.0 Hz), 140.5 (d, JCP
= 2.7 Hz), 138.4, 138.1 (d, JCP = 3.4 Hz), 135.7 (d, JCP = 7.6 Hz),
(S)-2-[1-Benzyl-2-(diphenylphosphanyl)-1H-indol-3-yl]-4-isopropyl-
4,5-dihydrooxazole (1c): A cooled solution (–78 °C) of 5c (0.40 g,
1.3 mmol) and TMEDA (0.23 mL, 1.5 mmol) in degassed THF
(4 mL) was treated with tBuLi (0.89 mL, 1.7 mol/L, 1.5 mmol). Af-
ter 0.5 h at the same temperature, chlorodiphenylphosphane
(0.28 mL, 1.5 mmol) in THF (1.5 mL) was added. The temperature
was allowed to reach room temp. with stirring overnight. The reac-
tion was quenched with a saturated solution of NH4Cl and ex-
tracted with ethyl acetate. The extracts were washed with brine and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due purified by column chromatography (n-hexane/ethyl acetate,
135.2 (d, JCP = 7.5 Hz), 133.9 (d, JCP = 20.9 Hz), 133.0 (d, JCP
=
19.7 Hz), 129.3, 128.7–128.2 (7 lines), 127.9 (d, JCP = 1.6 Hz),
124.1, 121.8, 121.4, 113.2 (d, JCP = 1.3 Hz), 110.9 (d, JCP = 1.8 Hz),
72.6, 69.4, 33.2, 19.4, 18.9 ppm. 31P NMR (121 MHz, CDCl3,
20 °C): δ = –18.4 ppm. HRMS (ESI): calcd. for C32H30N2OP [M
+ H]+ 489.2096; found 489.2092.
(S)-2-[2-(Diphenylphosphanyl)-1-propyl-1H-indol-3-yl]-4-isopropyl-
4,5-dihydrooxazole (1f): A cooled solution (–78 °C) of 5f (0.40 g,
1.5 mmol) and TMEDA (0.27 mL, 1.8 mmol) in degassed THF
(4 mL) was treated with tBuLi (1.10 mL, 1.7 mol/L, 1.95 mmol).
After 0.5 h at the same temperature, chlorodiphenylphosphane
(0.34 mL, 1.85 mmol) in THF (2.0 mL) was added. The tempera-
ture was allowed to reach room temp. 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 with MgSO4. The solvent was removed in vacuo and the
residue purified by column chromatography (n-hexane/ethyl acet-
ate, 10:1) to afford a colorless oil (0.46 g, 68%). [α]2D0 = –118.0 (c
10:1) to afford a white solid (0.33 g, 52%); m.p. 51–53 °C. [α]2D0
=
1
–107.8 (c = 0.51, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ
= 8.16–8.12 (m, 1 H, Ar-H), 7.48–7.00 (m, 16 H, Ar-H), 6.76–6.73
(m, 2 H, Ar-H), 5.58 (s, 2 H, CH2Ph), 3.61–3.58 (m, 1 H, C=NCH),
3.47–3.44 (m, 2 H, OCH2), 1.66–1.58 (m, 1 H, CHMe2), 0.99 (d, J
= 6.7 Hz, 3 H, CH3), 0.84 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3, 20 °C): δ = 138.9 (d, JCP = 2.5 Hz), 137.1,
136.5 (d, JCP = 17.3 Hz), 134.7 (d, JCP = 6.3 Hz), 134.0 (d, JCP
=
6.5 Hz), 133.6 (d, JCP = 20.3 Hz), 132.5 (d, JCP = 19.0 Hz), 128.7–
128.2 (9 lines), 127.2, 126.3 (d, JCP = 0.2 Hz), 124.0, 121.5 (d, JCP
= 6.5 Hz), 112.8 (d, JCP = 2.6 Hz), 110.5 (d, JCP = 1.9 Hz), 72.5,
69.3, 48.7 (d, JCP = 18.2 Hz), 33.2, 19.4, 18.9 ppm. 31P NMR
(121 MHz, CDCl3, 20 °C): δ = –23.4 ppm. HRMS (ESI): calcd. for
C33H32N2OP [M + H]+ 503.2252; found 503.2263.
1
= 0.50, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ = 8.13 (d,
J = 7.8 Hz, 1 H, Ar-H), 8.11–7.17 (m, 13 H, Ar-H), 4.27–4.22 (m,
2 H, OCH2, C=NCH), 3.62–3.56 (m, 1 H, OCH2), 3.46 (app. d, J
(S)-2-(Diphenylphosphanyl)-N,N-diisopropyl-3-(4-isopropyl-4,5-di- = 8.9 Hz, 2 H, NCH2), 1.61–1.57 (m, 1 H, CHMe2), 0.97 (d, J =
hydrooxazol-2-yl)-1H-indole-1-carboxamide (1d): A cooled solution 6.7 Hz, 3 H, CH3), 0.83 (d, J = 6.7 Hz, 3 H, CH3), 0.71 (t, J =
(–78 °C) of 5d (0.59 g, 1.7 mmol) and TMEDA (0.30 mL, 7.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ =
2.0 mmol) in degassed THF (5 mL) was treated with tBuLi
(1.20 mL, 1.7 mol/L, 2.0 mmol). After 0.5 h at the same tempera-
ture, chlorodiphenylphosphane (0.37 mL, 2.0 mmol) in THF
(1.5 mL) was added. The temperature was allowed to reach room
temp. with stirring overnight. The reaction was quenched with a
saturated solution of NH4Cl and extracted with ethyl acetate. The
160.4, 138.6 (d, JCP = 2.6 Hz), 135.7 (d, JCP = 17.6 Hz), 135.2 (d,
JCP = 7.0 Hz), 134.5 (d, JCP = 7.3 Hz), 133.5 (d, JCP = 20.2 Hz),
132.4 (d, JCP = 19.0 Hz), 128.7–128.2 (6 lines), 128.1 (d, JCP
2.9 Hz), 123.6, 121.7, 121.2, 112.5 (d, JCP = 4.4 Hz), 110.0 (d, JCP
= 3.0 Hz), 72.5, 69.2, 47.0 (d, JCP = 16.0 Hz), 33.2, 23.4 (d, JCP
2.0 Hz), 19.3, 18.9, 11.4 ppm. 31P NMR (121 MHz, CDCl3, 20 °C):
=
=
Eur. J. Org. Chem. 20112, 1569–1576
© 20112 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1573

Y. Wang, M. J. P. Vaismaa, K. Rissanen, R. Franzén
FULL PAPER
δ = –23.8 (d, J = 0.9 Hz) ppm. HRMS (ESI): calcd. for
[α]2D0 = –26.0 (c = 0.50, CHCl3). 1H NMR (300 MHz, CDCl3,
20 °C): δ = 8.16–8.13 (m, 1 H, Ar-H), 7.76 (d, J = 7.9 Hz, 1 H, Ar-
H), 7.57 (td, J = 7.7, 1.7 Hz, 2 H, Ar-H), 7.44–7.16 (m, 10 H, Ar-
H), 5.55 (ddd, J = 10.9, 4.3, 2.4 Hz, 1 H, NCHO), 4.07–4.01 (m, 1
H, C=NCH), 3.93–3.88 (m, 3 H, THP-H, OCH2), 3.14 (td, J =
11.9, 2.2 Hz, 1 H, THP-H), 2.07–1.34 (m, 6 H, THP-H, CHMe2),
1.04 (d, J = 6.8 Hz, 3 H, THP-H), 0.94 (d, J = 6.8 Hz, 3 H, CH3),
0.60–0.54 (m, 1 H, THP-H) ppm. 13C NMR (75 MHz, CDCl3,
C29H32N2OP [M + H]+ 455.2252; found 455.2243.
(4S)-4-Isopropyl-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-indol-3-yl]-
4,5-dihydrooxazole (5g): HCl solution in diethyl ether (18.8 mL,
1 mol/L) was added to a solution of DHP (8; 1.14 mL, 12.5 mmol)
in diethyl ether (5 mL) at 0 °C and the reaction was stirred for 3 h
at the same temperature. The solvent was removed in vacuo to af-
ford 9 as a yellow oil. Compound 4 (1.14 g, 5.0 mmol) in THF
(10 mL) was added to a suspension of NaH (0.40 g, 10.0 mmol) in
THF (5 mL) at 0 °C. After stirring for 1 h at room temp., the solu-
tion was recooled to 0 °C and 9 in THF (5 mL) was added. After
3 h at room temp. the reaction was quenched with water and ex-
tracted with Et2O. The organic layer was washed with brine and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due was purified by column chromatography (n-hexane/ethyl acet-
20 °C): δ = 160.6, 137.6, 136.7 (d, JCP = 13.3 Hz), 133.6 (d, JCP
9.6 Hz), 133.3 (d, JCP = 19.3 Hz), 131.6 (d, JCP = 18.3 Hz), 128.9–
128.6 (6 lines), 128.2 (d, JCP = 0.9 Hz), 124.1, 121.9 (d, JCP
=
=
1.0 Hz), 121.5, 113.9, 86.4 (d, JCP = 9.8 Hz), 72.8, 69.5, 69.3, 33.3,
29.4, 25.3, 23.5, 19.3, 18.7 ppm. 31P NMR (121 MHz, CDCl3,
20 °C): δ = –26.1 ppm. HRMS (ESI): calcd. for C31H34N2O2P [M
+ H]+ 497.2358; found 497.2360.
ate, 3:1) to afford 5g as a light-yellow oil (1.00 g, 64%). [α]2D0
–43.0 (c = 0.50, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ = pyran-2-yl]-1H-indol-2-yl}diphenylphosphane Oxide (10): Com-
8.25–8.21 (m, 1 H, Ar-H), 7.86 (d, J = 5.6 Hz, 1 H, Ar-H), 7.47– pound 10 was obtained by oxidation of compound 1g with hydro-
=
{3-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-yl]-1-[(S)-tetrahydro-2H-
1
7.44 (m, 1 H, Ar-H), 7.30–7.21 (m, 2 H, Ar-H), 5.48 (dd, J = 9.5,
2.6 Hz, 1 H, NCHO), 4.36–4.30 (m, 1 H, CH2O), 4.12–4.04 (m, 3 NMR (300 MHz, CDCl3, 20 °C): δ = 7.91–7.82 (m, 6 H, Ar-H),
H, THP-H, C=NCH, CH2O), 3.77–3.68 (m, 1 H, THP-H), 2.10– 7.56–7.42 (m, 6 H, Ar-H), 7.30 (t, J = 7.2 Hz, 1 H, Ar-H), 7.19 (t,
2.01 (m, 3 H, THP-H), 1.87–1.59 (m, 4 H, CHMe2, THP-H), 1.05 J = 7.7 Hz, 1 H, Ar-H), 6.34 (dd, J = 9.9, 0.5 Hz, 1 H, NCHO),
(d, J = 6.8 Hz, 3 H, CH3), 0.94 (dd, J = 6.8, 1.0 Hz, 3 H, 4.05–4.01 (m, 1 H, C=NCH), 3.39–3.27 (m, 4 H, 2ϫ CH2O), 2.28–
CH3) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 160.7, 160.6, 2.15 (m, 1 H, THP-H), 1.88–1.84 (m, 1 H, CHMe2), 1.71–1.47 (m,
gen peroxide. M.p. 195–196 °C. [α]2D0 = –94.0 (c = 0.50, CHCl3). 1H
136.5 (2 peaks), 127.9 (2 peaks), 127.0, 126.9, 123.1 (2 peaks), 122.2
(2 peaks), 121.9 (2 peaks), 110.7, 110.6, 105.6, 105.5, 83.9, 83.8,
5 H, THP-H), 0.94 (d, J = 6.7 Hz, 3 H, CH3), 0.79 (d, J = 6.7 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 160.6 (d,
72.8, 72.7, 69.4, 69.3, 68.3, 68.2, 33.4, 33.3, 30.9 (2 peaks), 25.4, JCP = 1.0 Hz), 137.7 (d, JCP = 7.6 Hz), 133.9, 133.4, 132.4, 132.3–
23.3, 23.2, 19.3 (2 peaks), 18.5 (2 peaks) ppm. HRMS (ESI): calcd.
132.1 (5 lines), 132.0 (d, JCP = 2.9 Hz), 131.9 (d, JCP = 1.8 Hz),
129.7, 128.7–128.4 (4 lines), 128.3 (d, JCP = 1.0 Hz), 128.2 (d, JCP
= 1.0 Hz), 127.9 (d, JCP = 10.2 Hz), 125.1, 121.9 (d, JCP = 1.8 Hz),
for C19H25N2O2 [M + H]+ 313.1916; found 313.1907.
(S)-2-{2-(Diphenylphosphanyl)-1-[(SR)-tetrahydro-2H-pyran-2-yl]-
1H-indol-3-yl}-4-isopropyl-4,5-dihydrooxazole (1g and 1h): A cooled
solution (–78 °C) of 5g (0.78 g, 2.5 mmol) and TMEDA (0.45 mL,
3.0 mmol) in degassed THF (5 mL) was treated with tBuLi
(1.80 mL, 1.7 mol/L, 3.0 mmol). After 0.5 h at the same tempera-
ture, chlorodiphenylphosphane (0.55 mL, 3.0 mmol) in THF
(2.0 mL) was added. The temperature was allowed to reach room
temp. 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 with MgSO4. The sol-
vent was removed in vacuo and the residue was purified by column
chromatography (n-hexane/ethyl acetate, 15:1) to afford 1g (0.29 g,
23%) and 1h (0.36 g, 29%) as white solids.
121.8 (d, JCP = 1.1 Hz), 115.1 (d, JCP = 1.4 Hz), 114.5 (d, JCP
=
12.3 Hz), 87.1 (d, JCP = 2.3 Hz), 73.0, 69.6, 69.3, 33.0, 30.4, 25.4,
23.4, 19.3, 18.9 ppm. 31P NMR (121 MHz, CDCl3, 20 °C): δ =
22.9 ppm. HRMS (ESI): calcd. for C31H34N2O3P [M + H]+
513.2307; found 513.2326.
Synthesis of Ligand 2
(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-1H-indole-1-carboxamide
(12): EDC hydrochloride (1.78 g, 9.3 mmol) was added to a solu-
tion of indole-1-carboxylic acid (11; 2.50 g, 15.5 mmol) in CH2Cl2
(20 mL) and stirred for 0.5 h at room temp. l-Valinol (0.96 g,
9.3 mmol) was added and the mixture was stirred for 1 h at room
temp. The reaction was quenched with H2O and extracted with
CH2Cl2. The extracts were washed with brine and dried with
MgSO4. The solvent was removed in vacuo and the residue was
purified by column chromatography (n-hexane/ethyl acetate, 2:1, to
(S)-2-{2-(Diphenylphosphanyl)-1-[(S)-tetrahydro-2H-pyran-2-yl]-
1H-indol-3-yl}-4-isopropyl-4,5-dihydrooxazole (1g): M.p. 65–67 °C.
[α]2D0 = –149.6 (c = 0.50, CHCl3). 1H NMR (300 MHz, CDCl3,
20 °C): δ = 8.12 (d, J = 7.9 Hz, 1 H, Ar-H), 7.75 (d, J = 8.0 Hz, 1 ethyl acetate) to afford 12 (1.66 g, 87%) as a white solid; m.p. 109–
H, Ar-H), 7.55 (td, J = 7.9, 1.5 Hz, 2 H, Ar-H), 7.50–7.20 (m, 10
H, Ar-H), 5.44 (ddd, J = 11.1, 2.8, 2.7 Hz, 1 H, NCHO), 4.17 (dd,
111 °C. [α]2D0 = –44.2 (c = 0.60, CHCl3). 1H NMR (300 MHz,
CDCl3, 20 °C): δ = 8.03 (dd, J = 8.2, 0.7 Hz, 1 H, Ar-H), 7.56 (dt,
J = 8.1, 7.6 Hz, 1 H, C=NCH), 4.12–3.88 (m, 3 H, THP-H, OCH2), J = 7.6, 1.2 Hz, 1 H, Ar-H), 7.44 (d, J = 3.7 Hz, 1 H, Ar-H), 7.28
3.14–3.05 (m, 1 H, THP-H), 2.10–1.97 (m, 1 H, THP-H), 1.85–1.74 (td, J = 7.3, 1.3 Hz, 1 H, Ar-H), 7.19 (td, J = 7.7, 1.1 Hz, 1 H, Ar-
(m, 1 H, CHMe2), 1.61–1.52 (m, 2 H, THP-H), 1.37–1.26 (m, 2 H, H), 6.54 (dd, J = 3.6, 0.6 Hz, 1 H, Ar-H), 6.01 (d, J = 8.3 Hz, 1
THP-H), 1.05 (d, J = 6.7 Hz, 3 H, CH3), 0.93 (d, J = 6.7 Hz, 3 H, H, NH), 3.84–3.76 (m, 3 H, NCHCH2O), 2.95 (br. s, 1 H, OH),
CH3), 0.47–0.52 (m, 1 H, THP-H) ppm. 13C NMR (75 MHz, 2.04–1.93 (m, 1 H, CHMe2), 1.01 (d, J = 1.2 Hz, 3 H, CH3), 0.99
CDCl3, 20 °C): δ = 160.6, 137.7, 136.9 (d, JCP = 14.1 Hz), 133.7
(d, JCP = 10.3 Hz), 132.9 (d, JCP = 18.7 Hz), 131.8 (d, JCP
(d, J = 1.2 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
20 °C): δ = 153.0, 135.3, 130.6, 124.6, 124.5, 122.6, 121.6, 114.2,
107.3, 63.4, 58.4, 29.6, 19.8, 19.4 ppm. HRMS (ESI): calcd. for
C14H18N2O2Na [M + Na]+ 269.1266; found 269.1247.
=
18.7 Hz), 128.9–128.5 (7 lines), 128.3 (d, JCP = 2.0 Hz), 124.1, 122.0
(d, JCP = 1.6 Hz), 121.4, 114.0, 86.4 (d, JCP = 7.2 Hz), 72.9, 69.7,
69.2, 33.4, 29.0, 25.3, 23.5, 19.3 (d, JCP = 0.9 Hz), 18.8 ppm. 31P
NMR (121 MHz, CDCl3, 20 °C): δ = –27.0 ppm. HRMS (ESI):
calcd. for C31H34N2O2P [M + H]+ 497.2358; found 497.2348.
(S)-2-(1H-Indol-1-yl)-4-isopropyl-4,5-dihydrooxazole (13): MsCl
(0.88 mL, 11.4 mmol) was added to a cooled mixture (0 °C) of 12
(1.66 g, 6.7 mmol), Et3N (5.6 mL,40.2 mmol), and DMAP (0.12 g,
1.0 mmol) in CH2Cl2 (20 mL). After heating at reflux for 24 h, the
starting material had been consumed according to TLC. The reac-
(S)-2-{2-(Diphenylphosphanyl)-1-[(R)-tetrahydro-2H-pyran-2-yl]-
1H-indol-3-yl}-4-isopropyl-4,5-dihydrooxazole (1h): M.p. 68–70 °C.
1574
www.eurjoc.org
© 20112 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 20112, 1569–1576

Asymmetric Allylic Substitution Reactions
tion was quenched with water and extracted with CH2Cl2. The ex-
tracts were washed with brine and dried with MgSO4. The solvent
was removed in vacuo and the residue purified by column
chromatography (n-hexane/ethyl acetate, 20:1) to afford 13 as a col-
PhCH=C), 6.29 (dd, J = 15.8, 7.4 Hz, 1 H, C=CH-C), 4.36 (d, J
= 7.4 Hz, 1 H, C=C-CH), 3.75 (s, 3 H, OMe), 3.69–3.70 (m, 2 H,
PhCH2), 1.78 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 155.9, 143.2, 137.2, 133.0, 132.8, 130.6, 129.6, 128.9, 128.8,
127.7, 127.6, 127.5, 126.7, 114.1, 64.7, 55.5, 51.0 ppm. The enantio-
meric excess was determined by HPLC using a Chiralpak IA col-
umn (n-hexane/iPrOH/DEA, 97:3:0.1, flow rate: 0.4 mL/min, wave-
orless oil (1.39 g, 91%). [α]2D0 = –32.0 (c = 0.55, CHCl3). H NMR
1
(300 MHz, CDCl3, 20 °C): δ = 8.35–8.31 (m, 1 H, Ar-H), 7.60–7.57
(m, 1 H, Ar-H), 7.54 (d, J = 3.6 Hz, 1 H, Ar-H), 7.32 (td, J = 7.3,
1.3 Hz, 1 H, Ar-H), 7.25–7.19 (m, 1 H, Ar-H), 6.59 (dd, J = 3.6, length 254 nm, tR1 = 35.23 min, tR2 = 37.99 min).
0.8 Hz, 1 H, Ar-H), 4.52 (dd, J = 9.1, 8.0 Hz, 1 H, OCH2), 4.24
(E)-N-(4-Chlorobenzyl)-1,3-diphenylprop-2-en-1-amine (7c): Color-
(dd, J = 8.0, 7.4 Hz, 1 H, OCH2), 4.18–4.05 (m, 1 H, C=NCH),
less oil. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.19 (m, 14 H, Ar-
1.90–1.79 (m, 1 H, CHMe2), 1.07 (d, J = 6.7 Hz, 3 H, CH3), 0.97
H), 6.55 (d, J = 15.9 Hz, 1 H, PhCH=C), 6.28 (dd, J = 15.8, 7.4 Hz,
(d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3,
1 H, C=CH-C), 4.34 (d, J = 7.4 Hz, 1 H, C=C-CH), 3.77–3.67 (m,
20 °C): δ = 154.0, 135.4, 130.2, 125.6, 124.0, 122.4, 121.0, 115.1,
2 H, PhCH2), 1.69 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz,
106.6, 71.4, 71.2, 33.4, 18.9, 18.5 ppm. HRMS (ESI): calcd. for
CDCl3): δ = 143.0, 139.2, 137.1, 132.9, 132.7, 130.8, 129.8, 129.0,
C14H17N2O [M + H]+ .229.1341; found 229.1324.
128.9, 128.8, 127.8, 127.7, 127.6, 126.7, 64.8, 50.9 ppm. HRMS
(ESI): calcd. for C22H21NCl [M + H]+ 334.1363; found 334.1375.
(S)-2-[2-(Diphenylphosphanyl)-1H-indol-1-yl]-4-isopropyl-4,5-
The enantiomeric excess was determined by HPLC using a Chi-
ralpak IA column (n-hexane/iPrOH, 99.5:0.5, flow rate: 0.7 mL/
min, wavelength 254 nm, tR1 = 29.47 min, tR2 = 32.63 min).
dihydrooxazole (2): A cooled solution (–78 °C) of 13 (0.46 g,
2.0 mmol) and TMEDA (0.36 mL, 2.4 mmol) in degassed THF
(2 mL) was treated with nBuLi (0.96 mL, 2.5 mol/L, 2.4 mmol). Af-
ter 0.5 h at the same temperature, chlorodiphenylphosphane
(0.44 mL, 2.4 mmol) in THF (1.5 mL) was added. The temperature
was allowed to reach room temp. with stirring overnight. The reac-
tion was quenched with a saturated solution of NH4Cl and ex-
tracted with ethyl acetate. The extracts were washed with brine and
dried with MgSO4. The solvent was removed in vacuo and the resi-
due purified by column chromatography (n-hexane/ethyl acetate,
30:1) to afford a white solid (0.32 g, 39%); m.p. 139–141 °C. [α]2D0
(E)-2-(1,3-Diphenylallyl)isoindoline-1,3-dione (7d): White solid; m.p.
107–108 °C. 1H NMR (300 MHz, CDCl3): δ = 7.26–7.84 (m, 14 H,
Ar-H), 7.07 (dd, J = 15.9, 8.6 Hz, 1 H, C=CH-C), 6.71 (d, J =
15.9 Hz, 1 H, PhCH=C), 6.13 (d, J = 8.6 Hz, 1 H, C=C–CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.2, 136.5, 134.7, 134.3, 132.3,
128.9, 128.8, 128.4, 127.7, 127.0, 125.6, 123.6, 56.8 ppm. The enan-
tiomeric excess was determined by HPLC using a Chiralpak IA
column (n-hexane/iPrOH, 95:5, flow rate: 0.5 mL/min, wavelength
254 nm, tR1 = 32.94 min, tR2 = 38.35 min).
1
= –22.0 (c = 0.45, CHCl3). H NMR (300 MHz, CDCl3, 20 °C): δ
= 8.20–8.17 (m, 1 H, Ar-H), 7.24–7.23 (m, 12 H, Ar-H), 7.15 (td,
J = 7.3, 1.0 Hz, 1 H, Ar-H), 5.99 (s, 1 H, Ar-H), 4.21 (dd, J = 8.3,
7.4 Hz, 1 H, OCH2), 3.96–3.84 (m, 2 H, OCH2, C=NCH), 1.58–
1.51 (m, 1 H, CHMe2), 0.83 (d, J = 6.7 Hz, 3 H, CH3), 0.74 (d, J
= 6.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ
(E)-N-(1,3-Diphenylallyl)aniline (7e): Colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.11–7.44 (m, 12 H, Ar-H), 6.59–6.65 (m,
4 H, Ar-H), 6.38 (dd, J = 15.9, 6.2 Hz, 1 H, C=CH-C), 5.08 (d, J
= 6.0 Hz, 1 H, C=C-CH), 4.06 (br. s, 1 H, NH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 147.6, 142.4, 137.0, 131.4, 131.1, 129.5,
129.2, 128.9, 128.0, 127.9, 127.6, 126.8, 118.0, 113.9, 61.0 ppm. The
enantiomeric excess was determined by HPLC using a Chiralpak
IA column (n-hexane/iPrOH, 99:1, flow rate: 0.55 mL/min, wave-
length 254 nm, tR1 = 26.44 min, tR2 = 31.78 min).
= 154.5 (d, JCP = 3.0 Hz), 139.0 (d, JCP = 1.4 Hz), 138.6 (d, JCP
19.8 Hz), 137.6 (d, JCP = 0.7 Hz), 137.4 (d, JCP = 3.5 Hz), 137.3,
134.3–133.6 (4 lines), 129.4 (d, JCP = 0.8 Hz), 129.0 (d, JCP
=
=
9.2 Hz), 128.6 (d, JCP = 1.8 Hz), 128.5 (d, JCP = 1.9 Hz), 124.2,
122.4, 120.5 (d, JCP = 0.6 Hz), 117.4 (d, JCP = 1.8 Hz), 114.9, 71.2,
70.8, 33.0, 18.7, 18.5 ppm. 31P NMR (121 MHz, CDCl3, 20 °C): δ General Procedure for the Allylic Alkylation Reaction. Synthesis of
= –17.5 ppm. HRMS (ESI): calcd. for C26H26N2OP [M + H]+
413.1783; found 413.1777.
Dimethyl 2-(1,3-Diphenylallyl)malonate (14): The IndPHOX ligand,
[Pd(allyl)Cl]2, KOAc (4 mg, 0.04 mmol) and THF (1 mL) were
added to the flask and the mixture was stirred for 0.5 h at room
temp. Then 6 (0.10 g, 0.40 mmol) in THF (1 mL), BSA (0.30 mL,
1.20 mmol), and dimethyl malonate (0.14 mL, 1.20 mmol) were
added separately. After stirring at room temp. for 2 or 24 h, the
solvent was removed in vacuo and the residue purified by column
chromatography (n-hexane/ethyl acetate, 20:1) to afford 14 as a col-
orless oil. 1H NMR (300 MHz, CDCl3): δ = 7.34–7.19 (m, 10 H,
Ar-H), 6.48 (d, J = 15.8 Hz, 1 H, PhCH=C), 6.33 (dd, J = 15.8,
8.5 Hz, 1 H, C=CH-C), 4.27 (dd, J = 8.5, 10.9 Hz, 1 H, C=C-CH),
3.96 [d, J = 10.9 Hz, 1 H, CH(CO2Me)2], 3.70 (s, 3 H, CH3), 3.51
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.5, 168.1,
140.4, 137.1, 132.1, 129.4, 129.0, 128.8, 128.2, 127.9, 127.5, 126.7,
57.9, 52.9, 52.8, 49.5 ppm. The enantiomeric excess was determined
by HPLC using a Chiralpak IA column (n-hexane/iPrOH, 95:5,
General Procedure for the Allylic Amination Reaction: The Ind-
PHOX ligand (0.024 mmol) and [Pd(allyl)Cl]2 (0.012 mmol) were
dissolved in anhydrous THF (1 mL) and stirred for 0.5 h at room
temp. Compound 6 (0.10 g, 0.40 mmol) in THF (1 mL) and the N-
nucleophile (1.20 mmol) were then added. After stirring at room
temp. for the reported time, the solvent was removed in vacuo and
the residue purified by column chromatography (n-hexane/ethyl
acetate, 20:1) to afford compounds 7a–e.
1
(E)-N-Benzyl-1,3-diphenylprop-2-en-1-amine (7a): Colorless oil. H
NMR (300 MHz, CDCl3): δ = 7.44–7.18 (m, 15 H, Ar-H), 6.57 (d,
J = 15.9 Hz, 1 H, PhCH=C), 6.31 (dd, J = 15.8, 7.4 Hz, 1 H,
C=CH-C), 4.39 (d, J = 7.4 Hz, 1 H, C=C-CH), 3.82–3.72 (m, 2 H,
PhCH2), 1.89 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 143.2, 140.7, 137.2, 132.9, 130.7, 128.9, 128.8, 128.7, 128.5,
127.8, 127.7, 127.6, 127.2, 126.7, 64.8, 51.6 ppm. The enantiomeric
excess was determined by HPLC using a Chiralpak IA column (n-
hexane/iPrOH, 99.5:0.5, flow rate: 1.0 mL/min, wavelength 254 nm,
tR1 = 23.74 min, tR2 = 26.80 min).
flow rate: 1 mL/min, wavelength 254 nm, tR1 = 18.6 min, tR2
=
23.6 min).
X-ray Crystallography: Colorless crystals of 10 were obtained by
the slow recrystallization of 10 from ethanol solution at room tem-
perature. The crystal analysis was performed by using a Bruker
Kappa Apex II diffractometer with graphite-monochromatized Cu-
Kα (λ = 1.54183 Å) radiation. The COLLECT software[13] was used
for data measurement and DENZO-SMN[14] for the processing.
(E)-N-(4-Methoxybenzyl)-1,3-diphenylprop-2-en-1-amine (7b): Col-
orless oil. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.16 (m, 12 H,
Ar-H), 6.86–6.83 (m, 2 H, Ar-H), 6.55 (d, J = 15.9 Hz, 1 H,
Eur. J. Org. Chem. 20112, 1569–1576
© 20112 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1575

Y. Wang, M. J. P. Vaismaa, K. Rissanen, R. Franzén
FULL PAPER
[4] For some examples of N-arylation, see: a) D. W. Old, M. C.
Harris, S. L. Buchwald, Org. Lett. 2000, 2, 1403–1406; b) J. C.
Antilla, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2002,
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Chem. 2007, 119, 952; Angew. Chem. Int. Ed. 2007, 46, 934–
936; d) A. Correa, C. Bolm, Angew. Chem. 2007, 119, 9018;
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4254–4259; g) M. S. Kabir, M. Lorenz, O. A. Namjoshi, J. M.
Cook, Org. Lett. 2010, 12, 464–467.
[5] For some examples of N-vinylation, see: a) A. Y. Lebedev, V. V.
Izmer, D. N. Kazyul’kin, I. P. Beletskaya, A. Z. Voskoboynikov,
Org. Lett. 2002, 4, 623–626; b) M. Taillefer, A. Ouali, B. Re-
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The structure was solved by the charge-flipping method using
SUPERFLIP[15] and refined by full-matrix least-squares methods
using the WinGX software,[16] which uses the SHELXL-97
module.[17] Multi-scan absorption correction was performed by
using the SADABS software.[18] All C–H hydrogen positions were
calculated by using a riding atom model with UH = 1.2UC. All non-
hydrogen atoms were refined anisotropically. The absolute configu-
ration of 10 was determined by refining the Flack parameter.[19]
Crystal data for 10:
M
=
512.56, colorless blocks,
0.40ϫ0.40ϫ0.40 mm3, orthorhombic, space group P212121, a =
11.1551(3), b = 15.0790(4), c = 15.7866(4) Å, V = 2655.4(1) Å3, Z
= 4, Dc = 1.282 g/cm3, F(000) = 1088, μ = 1.197 mm–1, T =
173(2) K, 2θmax = 126.92°, 4275 reflections, 4082 with Io Ͼ 2σ(Io),
Rint = 0.0424, 336 parameters, 0 restraints, GoF = 1.059, R =
0.0344 [Io Ͼ 2σ(Io)], wR = 0.0857 (all reflections), 0.170Ͻ ΔρϽ
–0.255 e/Å3.
[7] Ligands 1a and 1b provided the same ee value (94%) in more
diluted solutions (conc. of 6: 0.1 mol/L, using 4 mol-% catalyst
and 12 mol-% ligand) with 72 and 85% isolated yields, respec-
CCDC-830168 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
tively; see ref.[2b]
.
[8] O. Kühl, Phosphorus-31 NMR Spectroscopy, Springer, Berlin,
Heidelberg, 2008, chapter 2, pp. 9–15.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra.
[9] A. Frölander, C. Moberg, Org. Lett. 2007, 9, 1371–1374.
[10] T. D. Lee, M. V. Pickering, G. D. Daves, J. Org. Chem. 1974,
39, 1106–1109.
[11] M = 512.56, colourless blocks, 0.40ϫ0.40ϫ0.45 mm3, ortho-
rhombic, space group P212121, a = 11.1551(3), b = 15.0790(4),
c = 15.7866(4) Å, V = 2655.1(1) Å3, Z = 4, Dc = 1.282 g/cm3,
T = 173(2) K, 336 parameters, R = 0.0344 [Io Ͼ2σ(Io)], wR =
0.0857 (all reflections).
Acknowledgments
The National Technology Agency of Finland (TEKES) and The
Academy of Finland (project numbers 212588 and 218325) are
greatly acknowledged for their financial support.
[12] D. L. Boger, M. Patel, J. Org. Chem. 1987, 52, 3934–3936.
[13] R. W. Hooft, COLLECT, Nonius BV, Delft, 1998.
[14] Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307–
326.
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[16] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837.
[17] G. M. Sheldrick, SHELXL-97 – A program for the Refinement
of Crystal Structures, release 97-2, University of Göttingen,
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[18] G. M. Sheldrick, SADABS, version 2008/2, University
Göttingen, Germany, 2008.
[19] A. L. Spek, PLATON, A Multipurpose Crystallographic Tool,
Utrecht University, The Netherlands, 2008.
Received: October 21, 2011
[2] a) Y. Wang, A. Hämäläinen, J. Tois, R. Franzén, Tetrahedron:
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Published Online: January 25, 2012
1576
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© 20112 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 20112, 1569–1576