Highly enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones with simple Cu(II)-oxazoline-imidazoline catalysts

Article abstract of DOI:10.1016/j.tet.2013.04.063

A series of novel chiral ligands L1-L4 with an imidazoline-oxazoline framework have been developed as new type of non-symmetric N,N-bidentate ligands. All the chiral ligands were prepared from 2,2-diethylmalonic acid and enantiomerically pure (S)-2-amino-

Full text of DOI:10.1016/j.tet.2013.04.063

Tetrahedron 69 (2013) 5185e5192
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Highly enantioselective FriedeleCrafts alkylation of indoles with
a,
b-unsaturated ketones with simple Cu(II)eoxazolineeimidazoline
catalysts
*
Assem Barakat, Mohammad Shahidul Islam , Abdullah M.A. Al Majid,
Zeid Abdullah Al-Othman
Department of Chemistry, Faculty of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel chiral ligands L1eL4 with an imidazolineeoxazoline framework have been developed as
new type of non-symmetric N,N-bidentate ligands. All the chiral ligands were prepared from 2,2-
diethylmalonic acid and enantiomerically pure (S)-2-amino-3-methyl-1-butanol in four steps with ex-
cellent optical purity. These newly developed ligands efficiently affect the copper-catalyzed enantiose-
Received 11 January 2013
Received in revised form 27 March 2013
Accepted 15 April 2013
Available online 18 April 2013
lective addition of indole to a,b-unsaturated ketones, yielding the corresponding adducts in good yield
and high enantiomeric excess. The fine-tuning capability of these ligands plays a significant role in
achieving high enantioselectivity in the asymmetric alkylation (up to 99% ee). The higher enantiose-
lectivity of the reaction could be due to the activation and asymmetric induction of chiral Lewis acid
metal complex coordinated by enones through a concerted mechanism of 1,4-metal bonding model.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Oxazolineeimidazoline ligands
FriedeleCrafts alkylation
Indoles
1. Introduction
phosphonates,8 and acyl heterocyclic compounds9,10 remains of
interest. Although, a large variety of chiral bisoxazolines have been
Asymmetric catalysis catalyzed by Lewis acid metal complexes
of chiral ligands, has attracted synthetic chemists, owing to its ef-
ficacy in producing enantiopure compounds.1 The development of
various chiral ligands has become a vast expanding research area in
this field. Recently the preparation and application of C2-symmetric
bisoxazoline ligands that have two oxazoline rings separated by
a single carbon atom with two identical substituents, have been
reported by several authors.2 Moreover the box type chiral bisox-
azolines provide an advantageous combination of structural di-
versity and outstanding enantioselectivity for a wide variety of
reactions. These types of ligands have shown excellent potential for
the construction of new stereogenic CeC bonds through Lewis acid
catalyzed FriedeleCrafts alkylation reaction.3 Throughout the lit-
erature, enantioselective FriedeleCrafts alkylation reaction of in-
reported from malonate,11 tartrate,5 ferrocene12 or cyclo-
hexane,6b,13 biphenyl or binaphthyl,14 pyridine,15 cyclopropane
framework,16 and other derivatives. However, very little research
work has been reported in the recent literature for the synthesis
and application of non-symmetric imidazolineeoxazoline box li-
gands. This new class of imidazolineeoxazoline chiral ligands could
be useful for the asymmetric allylic substitutions,17 enantiose-
lective addition of diethylzinc to acyclic enones,18 asymmetric
cyclopropanation,19 DielseAlder reactions,20 asymmetric Henry
reactions.21 To the best of our knowledge, only one example has
been reported in the recent literature for the synthesis and appli-
cation of non-symmetric imidazolineeoxazoline ligand.22 There-
fore, designing, syntheses, and the evaluation of non-symmetric
box type novel imidazolineeoxazoline ligands remains a tremen-
dous challenge.23 Moreover the Lewis acid-catalyzed enantiose-
dole with
a
,b
-unsaturated-R-ketoesters (R¼alkyl, aryl),4 R-hydroxy
enones (R¼alkyl, aryl),5 nitroalkenes,6 alkylidene malonates,7 acyl
lective FriedeleCrafts reaction of prochiral a,b-unsaturated enones
building blocks is one of the most important and straightforward
strategies to access structurally elaborated and optically pure
molecules. Herein, as part of our ongoing interest toward the de-
velopment of enantioselective catalysis, we report a series of
diethylmalonate-derived oxazolineeimidazoline ligands L1eL4
with isopropyl stereogenic center on both imidazoline and
* Corresponding author. Tel.: þ966 532417633; fax: þ966 1 4675992; e-mail
addresses: ambarakat@ksu.edu.sa (A. Barakat), mislam@ksu.edu.sa, shahid.10a-
mui@gmail.com (M.S. Islam), amajid@ksu.edu.sa (A.M.A. Al Majid), zaothman@
ksu.edu.sa (Z.A. Al-Othman).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.063

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A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
oxazoline ring and their Cu(II) complexes in the highly enantiose-
2.2. Catalytic asymmetric FriedeleCrafts alkylation of indole
lective FriedeleCrafts alkylation of indole with enones.
with a variety of enones
Initial findings of FriedeleCrafts alkylation reaction between
(E)-chalcone 6a and indole 5 as the model substrates in the
presence of chiral oxazolineeimidazoline ligand L1. L/Cu (OTf)2
ratio (10:11 mol %) were used, aiming at screening the optimal
conditions, and the results of these experiments are summarized
in Table 1. By screening different solvents, such as toluene, ben-
zene, tetrahydrofuran (THF), ethanol, dichloromethane (CH2Cl2),
acetonitrile, and mixture of THF/iPrOH (1:1), we found that CH3CN
was the best solvent for this asymmetric FriedeleCrafts alkylation,
affording the corresponding product 7a with 49e58% chemical
yield and in 93%, 89%, and 92% ee at room temperature within
24 h, 36 h, and 40 h, respectively (Table 1, entries 7, 10, 11). Upon
lowering the reaction temperature to 0 ꢀC, a remarkable lowering
of yield (13%) could be observed after 24 h, with only 3% in-
crement in enantioselectivity (96%) (Table 1, entry 8). On the other
hand, upon raising the reaction temperature to 45 ꢀC, the chemical
yield increased dramatically to 87% and only 7% enantioexcess
were obtained. But in case of other solvents like toluene, benzene,
dichloromethane only trace amount of product formation was
observed (Table 1, entries 1, 2, 6), while using polar solvent, such
2. Result and discussion
2.1. Synthesis of chiral imidazolineeoxazoline ligands
A set of four non-symmetric oxazolineeimidazoline type li-
gands L1eL4 with sp2 hybridized two coordinating N atoms were
synthesized from commercially available and cheap material 2,2-
diethylmalonic acid 1 and (S)-valinol by following the procedure
reported by Xin-Qi Hao et al. as illustrated in Scheme 1.22 The
chemistry for synthesizing bisoxazoline compounds starting from
dicarboxylic acid is well known, but to synthesize one imidazoline
ring and another oxazoline ring selectively was a challenging task.
At the outset, 2,2-diethylmalonic acid 1 was converted into dicar-
bonyl chloride, via oxalyl chloride in the presence of catalytic
amount of dimethylformamide (DMF), followed by subsequent
reaction with (S)-valinol in the presence of excess diisopropylamine
(DIPA) produced 2,2-diethyl-N1,N3-bis((S)-1-hydroxy-3-methyl-
butan-2-yl)malonamide 2 with overall 92% yield. The compound
bis-amidoalcohol 2 (2 mmol) was then refluxed with thionyl-
chloride to obtain bis-amidochloride, which was then treated with
different aromatic amines (3 mmol) (p-chloroaniline, p-methox-
yaniline, 3-quinolin, and p-toluidine) in presence of triethylamine
leading to the formation of corresponding products 3aed. Then the
intermediates 3aed resulted in imidazoline ring closure by using
10% aqueous solution of sodium hydroxide to afford crude product
4aed, mainly containing imidazolineeamidochloride with some
expected imidazolineeoxazoline product (intermediates 4aed,
Scheme 1).
i
as THF, ethanol, and PrOH, 11e21% yield and 29e43% ee were
obtained (Table 1, entries 2e5).
To elucidate the catalytic activity of imidazolineeoxazoline li-
gands at different L/Cu(OTf)2 mole ratio, ligands L1eL4 were
screened for the asymmetric FriedeleCrafts alkylation of indole 5
with (E)-chalcone 6a, affording the corresponding adduct 7a and
the results are depicted in Table 1. All the ligands L1eL4 showed
outstanding catalytic activity in producing chiral compounds 7a
R
N
O
O
O
O
i. SOCl2 (3.5 ml/mmol)
refluxed, 2h
O
10% NaOH aq.
6h, RT
NH HN
NH HN
NH Cl
N
HN
Cl
ii. TEA (6 equiv.)
RNH2 (1.5 equuiv),
Et2O, 4h, RT
OH HO
R
2
Intermediate 4a-d
3a-d
i. MeOH:THF(1:4)
ii. NaOH (2 equiv.),
reflux 12h
i. (COCl)2 (3 equiv.), DCM
Cat. DMF, 2h, RT.
ii. DIPA (6 equiv.), DCM
(S)-valinol (2.1 equiv.)
R = p-Chlorophenyl (L1)
p-Methoxyphenyl (L2)
3-Quinolinyl (L3)
p-tolyl (L4)
R
N
O
N
N
O
O
OH OH
1
L1- L4
Scheme 1. Synthesis of chiral oxazolineeimidazoline ligands L1eL4.
The isolation of these intermediates 4aed was very difficult by
column chromatography because of their high polarity. To cir-
cumvent this obstacle, crude intermediates were taken into next
step without further purification for the oxazoline ring closer re-
action. Thus, the ligands L1eL4 were obtained by refluxing the
crude intermediates 4aed with NaOH (4 mmol) in THF/MeOH
mixture (4:1) for 12 h. The overall isolated yield of the ligands in
four steps was obtained in the range of 45e59%. The bis-
amidoalcohol and the ligands L1eL4 were fully characterized by
1H NMR, 13C NMR, and mass spectroscopy techniques.
with high enantioexcess 95e99.9% ee and moderate to good
chemical yields 67e86%, by simply using 5e10 mol % ligands and
10e30 mol % Cu(OTf)2. Although ligand L1 and L2 gave the best
result for enantioselectivity (Table 1, entries 12e16) as compared to
L3 and L4 (Table 1, entries 17 and 18). Best result was achieved with
86% yield and 99.9% ee by using 10:20 mol % of L2/Cu(OTf)2 (Table 1,
entry 15). No significant changes were observed in enantiose-
lectivity by increasing the percentage of ligands from 5 to 10% and
Cu(OTf)2 from 15 to 30 mol %, but the chemical yields increased
from 39% to 86% (Table 1, entries 12e15).

A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
5187
Table 1
Screening of conditions for the FriedeleCrafts alkylation reaction of model substrate 6I
#
L:Cu(OTf)2 (mol %)
Ligands (L)
T [ꢀC]
Solvent
t [h]
Yielda [%]
ee [%]b
1
2
3
4
5
6
7
8
10:11
10:11
10:11
10:11
10:11
10:11
10:11
10:11
10:11
10:11
10:11
5:10
10:15
10:15
10:20
10:30
10:20
10:20
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L1
L2
L2
L2
L3
L4
rt
rt
rt
rt
rt
rt
rt
0
45
rt
rt
rt
rt
rt
rt
rt
rt
rt
Toluene
Benzene
THF
36
36
30
30
40
40
24
24
24
36
40
36
24
24
24
24
32
32
d
d
d
d
11
23
21
d
29
43
37
d
Ethanol
THF/iPrOH
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
49
13
87
58
55
39
67
73
86
83
81
84
93
96
7
89
9
10
11
12
13
14
15
16
17
18
92
99.8
99.9
99.9
99.9
98.6
96.7
94.9
Bold represents highest enantiomeric excess (ee 99.92) achieved in this set of condition for reaction optimization process.
a
The reactions were performed on a 0.425 mmol scale and the isolated yield after column purification.
Determined by chiral HPLC analysis.
b
To illustrate the generality of this asymmetric FriedeleCrafts
alkylation of indole 5, with various substrates (6bel), eleven ex-
amples were carried out with ligand L2 10 mol % and 20 mol % of
Cu(OTf)2 in CH3CN at room temperature and the results are shown
in Table 2.
strong þI effect on the benzene ring, gave the corresponding
products 7d, 7e, and 7f in very low yields 40%, 22%, and 27%, re-
spectively, which could be attributed to the poor solubility of the
substrate but high selectivity was observed 93e97% ee values,
suggesting that the electron donating group on the benzene ring,
Table 2
Highly enantioselective FriedeleCrafts reactions of indole with a,b-unsaturated enones (6aek) catalyzed by ligand L2 (10 mol %)eCu(OTf)2 (20 mol %) in acetonitrile at room
temperature
#
6
R1
R2
Time (h)
Yieldd (%)
ee (%)e
1
2
6a
6b
6c
6d
6e
6f
6g
6h
6i
p-ClPh
p-ClPh
2,4,6-(CH3)3Ph
2,4,6-(CH3)3Ph
Tolyl
Ph
Napthyl
Ph
Napthyl
Ph
Napthyl
Ph
Napthyl
Napthyl
Ph
24
24
36
36
24
30
24
24
24
24
48
84
81
40
22
73
27
89
66
47
65
8
93.8(S)
95.6(S)
96.0(S)
97.8(S)
95.7(S)
93.4(S)
96.4(S)
90.8(S)
95.5(S)
89.7(R)
87.7(R)
3a
4b
5
6
7
8
9
Tolyl
p-MeOPh
p-MeOPh
Ph
Thiophene
Ferrocene
10
6j
6k
11c
Ph
a
15 mol % of L2 and 30 mol % of Cu(OTf)2 has been used in this run.
20 mol % of L2 and 30 mol % of Cu(OTf)2 has been used in this run.
b
c
Temperature raised up to 40 ꢀC and 20 mol % of L2 and 30 mol % of Cu(OTf)2 has been used in this run.
Isolated yield after column purification.
d
e
Determined by chiral HPLC analysis and the configuration was assigned by comparison of the optical rotation sign of all compounds with literature data.23
As can be seen, by using substrate 6b, 6c, 6f, 6h, 6i, and 6k, the
does not have a significant impact on the enantioselectivity (Table
2, entries 3, 4, and 6). However the L/Cu(OTf)2 ratio (15:30 mol %
and 20:30 mol %) has been applied in case of 6d, 6e accordingly, in
order to increase the yield, unfortunately no improvement in
chemical yield were observed. Moreover, the lowest yield was
corresponding FriedeleCrafts alkylation products 7b, 7c, 7f, 7h, 7i,
and 7k were obtained in moderate to good chemical yields 65e89%
and excellent enantioselectivity 89e97% ee (Table 2, entries 1, 2, 5,
7, 8, and 10). At the same time, using substrate 6d, 6e, and 6f with

5188
A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
ꢀ
noticed in case of substrate 6l affording only 8% of product 7l with
87% ee value under the most harsh conditions, again the reason for
this low yield could be attributed to the poor solubility of com-
pound 6l (Table 2, entry 11).
4 A molecular sieves. Diethyl ether, tetrahydrofuran, benzene,
toluene were distilled from sodium benzophenone ketyl. Aceto-
nitrile and dimethylformamide were dried by distillation over
calcium hydride. Triethylamine and diisopropylamine were dried
over sodium hydroxide. (S)-(þ)-2-Amino-3-methyl-1-butanol, ar-
omatic amines, oxalyl chloride, and indole were commercially
obtained and used as purchased without further purification.
Enones 6ael were prepared according to procedures reported in
the literature.24
The absolute configuration of the stereogenic center (S) in
compound 7a was determined by comparison of its optical rotation
with those reported in the literature.23 The configurations of the
rest of the products (7bej) and (7kel) were assigned as (S) and (R),
respectively, on the assumption of a uniform mechanistic path-
way23 (Fig. 1).
R
N
+
2
addition
O
H
i
N
r
P
i
r
P
2 TfO
N
N
N
H
( )
II
Cu
O
R
N
+
2
O
R1
R2
i
2 Tf
decomplexation
R1
O
r
P
i
r
P
N
N
( )
Cu II
R1
O
R2
O
R2
N
H
R
Friedel–Crafts adduct
complexation
O
O
N
i
i
r
P
r
P
N
N
Cu
R1
R2
TfO
OTf
Fig. 1. Activation mechanism and stereo chemical model.
3. Conclusion
4.1.2. Instrumentation. NMR spectra were recorded with a Jeol
spectrometer at 400 MHz (1H NMR) and 100 MHz (13C NMR). The
chemical shifts ( in parts per million) were reported down field
from tetramethylsilane (TMS, scale) with the deuterated solvent
In summary, we have developed a Cu(II) oxazolineeimidazo-
line catalyst, which enables the enantioselective FriedeleCrafts
alkylation of indole with enones. The non C2-symmetric oxazoli-
neeimidazoline ligands L1eL4 were prepared from enantiopure
(S)-valinol with overall satisfactory yield and excellent optical
purity. These ligands were proven to be highly potent in inducing
chirality in the FriedeleCrafts alkylation reactions. With
10:20 mol % of the Cu(II) oxazolineeimidazoline catalyst in ace-
tonitrile at ambient temperature, up to 99% ee could be achieved
for a variety of substrates. The application of this new catalyst to
other reactions, such as asymmetric allylic substitutions and
d
d
resonance referenced as internal standard. Specific optical rotations
€
were measured on a highly sensitive automatic ‘A. KRUSS OPTRO-
NOCS’ polarimeter using sodium light (D line 589 nm). Elemental
analyses were performed on a Perkin Elmer 2400 Elemental Ana-
lyzer. Chiral HPLC analyses were performed in an ultra-flow liquid
chromatography (UFLC) SHIMADZU instrument equipped with
a PDA detector using chiral stationary Chiralcel OD-H column,
hexane/isopropanol (80:20). IR spectra were obtained using Perkin
Elmer FTIR-800 Model. Mass spectrometric analysis was conducted
by using ESI mode on AGILENT Technologies 6410-triple quad LC/
MS instrument.
Henry reactions, involving olefin and alkyne
currently being investigated.
p-bond activation is
4. Experimental
4.2. Synthesis of ligands
4.1. General remarks
4.2.1. Synthesis of 2,2-diethyl-N1,N3-bis((S)-1-hydroxy-3-methyl-
butan-2-yl)malonamide (2). In a 100 mL round bottom flask
compound 1 (5.00 g, 31.3 mmol) was suspended in dry CH2Cl2
(75 mL) and a catalytic amount of DMF (three drops) was added.
Then oxalyl chloride (11.9 g, 93.8 mmol) was added dropwise to
the reaction mixture at room temperature. The reaction mixture
was stirred at ambient temperature for 1.5 h and gave a light
yellow solution of acid chloride. Then the solvent was removed
under reduced pressure to afford the crude acid chloride (6.15 g,
w100%) (crude). IR (cmꢁ1): 1802 cmꢁ1 (C]O str.), (absence of OH
str. frequency at 3451 cmꢁ1). Then the solution of acid chloride
(6.15 g, 31.3 mmol) in CH2Cl2 (60 mL), was added slowly to
Glassware was oven-dried overnight at 120 ꢀC before use. Re-
actions were performed under an inert atmosphere using an argon
filled glove box and standard Schlenk-line techniques. All the re-
actions were monitored by TLC analysis using Merck Silica Gel 60
F254 thin layer plates. Column chromatography was performed on
silica gel 100e200 mesh.
4.1.1. Materials. Petroleum ether (PE), hexane, and ethyl acetate
for column chromatography were distilled prior to use. CH2Cl2,
EtOH were distilled from P2O5 and Mg, respectively, and stored on

A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
5189
a solution of amine (6.77 g, 65.6 mmol, 2.1 equiv) and diisopro-
pylamine (19.0, 26.5 mL, 187 mmol, 6 equiv) at 0e5 ꢀC. Then the
reaction mixture was allowed to stir at ambient temperature for
4 h. TLC analyses (10% MeOH/CH2Cl2) showed complete con-
sumption of the starting material. The reaction mixture was then
quenched with a saturated aqueous solution of ammonium chlo-
ride (50 mL) and extracted with chloroform (5ꢂ100 mL). The
combined organic layers were washed with brine (100 mL) and
dried over anhydrous magnesium sulfate. The solvent was re-
moved under reduced pressure to afford the crude product, which
was washed with diethyl ether to afford pure amide 2 (9.5 g, 92%)
163.00 (NCN), 167.01 (OCN); LC/MS (ESI): Mþ, 403.25,
C23H34ClN3O requires 403.24.
4.2.4. (S)-4-Isopropyl-2-(3-((S)-4-isopropyl-1-(4-methoxyphenyl)-
4,5-dihydro-1H-imidazol-2-yl)pentan-3-yl)-4,5-dihydrooxazole
(L2). The ligand L2 was prepared from bis-amidoalcohol 2 (660 mg,
2.00 mmol) and p-anisidine (369 mg, 3.00 mmol) according to GP1
as described above. Light yellow colored oily product L2 (470 mg,
58.9%, over three steps) was isolated after purification by silica gel
chromatography (EtOAc/Pet. Ether/Et3N¼1:1:0.02, Rf¼0.25). ½a D25
ꢃ
þ121.3 (c 0.5, CHCl3); [Anal. Calcd for C24H37N3O2: C, 72.14; H, 9.33;
as a white solid; mp 76e78 ꢀC; ½a D25
ꢃ
þ19.9 (c 0.45, CHCl3); [Anal.
N, 10.52; found C, 71.93; H, 9.11; N, 10.45]; IR (KBr): 2959, 2875,
Calcd for C17H34N2O4: C, 61.79; H, 10.37; N, 8.48; found C, 61.39; H,
10.63; N, 8.43]; IR (KBr): 3319 (br s, OH str.), 2963, 1637, 1071,
1658, 1607, 1511, 1485, 1241, 1037, 984, 836 cmꢁ1 1H NMR (CDCl3,
;
400 MHz)
d 0.71e0.99 (m, 18H, CH3CH2 & (CH3)2CH), 1.59e1.72 (m,
1545 cmꢁ1
;
1H NMR (DMSO-d6, 400 MHz)
d
0.70 (t, 6H, J¼3.6 Hz,
1H, (CH3)2CH, imidazole), 1.73e1.85 (m, 1H, (CH3)2CH, oxazole),
1.85e2.10 (m, 4H, CH3CH2), 3.38e3.50 (m, 2H, NCH2CH, imidazole),
3.58e3.72 (m, 1H, OCH2(a)CH, oxazole), 3.72e3.77 (m, 1H,
OCH2(b)CH, oxazole), 3.79 (s, 3H, ArOCH3), 3.87e3.96 (m, 1H,
OCH2CH(CH3)2, oxazole), 4.06e4.19 (m, 1H, NCH2CH(CH3)2, imid-
azole), 6.80 (d, 2H, J¼8.8 Hz, ArH), 7.06 (d, 2H, J¼8.8 Hz, ArH); 13C
CH3CH2), 0.81e0.87 (m, 12H, (CH3)2CH), 1.74e1.87 (m, 6H, CH3CH2,
& (CH3)2CH), 3.35e3.39 (m, 4H, CHCH2OH), 3.65e3.67 (m, 2H,
CH2OH), 4.55e4.65 (m, 2H, NHCH(CH2OH)), 8.26 (d, 2H, J¼8.8 Hz,
CONH); 13C NMR (DMSO-d6, 100 MHz):
d 8.9 (CH3CH2), 19.0
((CH3)2CH), 19.8 ((CH3)2CH), 27.3 ((CH3)2CH), 29.0 (CH3CH2), 57.3
(NHCH), 58.6 ((CO)CCH2), 63.8 (CH2OH), 173.9 (CONH); LC/MS
(ESI): Mþ, found 330.23, C17H34N2O4 requires 330.25.
NMR (CDCl3, 100 MHz):
d 7.9 (CH3CH2), 8.0 (CH3CH2), 17.9
((CH3)2CH, imidazole), 18.2 ((CH3)2CH, oxazole), 19.4 (CH3CH2), 19.6
(CH3CH2), 32.4 ((CH3)2CH, imidazole), 32.8 ((CH3)2CH, oxazole),
46.4 (C(CH2CH3)2), 55.5 (NCH2, imidazole), 59.0 (ArOCH3), 69.2
(OCH2, oxazole), 72.0 ((NCH2CH(CH3)2, imidazole)), 72.4
(OCH2CH(CH3)2, oxazole), 114.2 (ArC2), 129.9 (ArC3), 135.3
(ArC4OMe), 158.4 (ArC1N), 163.4 (NCN), 167.2 (OCN); LC/MS (ESI):
Mþ, found 399.30, C24H37N3O2 requires 399.29.
4.2.2. General procedure for the synthesis of chiral oxazolinee
imidazoline ligands L1eL4 (GP1). Bis-amidoalcohol 2 (2 mmol) was
treated with thionylchloride (6 mL) at reflux for 2 h. Excess thio-
nylchloride was removed under reduced pressure and the residue
was dissolved in diethyl ether (20 mL). To this solution triethyl-
amine (1.6 mL, 12 mmol) and RNH2 (3 mmol) were added. The
reaction mixture was then stirred for 4 h at room temperature. 10%
aqueous NaOH solution (8.3 mL) was then added and the reaction
mixture was stirred for further 6 h. Then the aqueous layer was
extracted with CH2Cl2 (2ꢂ20 mL) and the combined organic phases
were washed with brine (25 mL) and dried over anhydrous mag-
nesium sulfate. Then the organic part was concentrated under re-
duced pressure to afford the crude product mainly containing
imidazolineeamidochloride with some expected oxazoline-
eimidazoline product (Intermediate 4aed, Scheme 1). The imida-
zolineeamidochloride was cyclized to oxazoline by treating with
10% NaOH (160 mg, 4 mmol) in MeOH/THF (3 mL/12 mL) at reflux
for 12 h. The solvent was then removed and ligands were isolated
by column chromatography using 100e200 mesh silica gel.
4.2.5. (S)-4-Isopropyl-2-(3-((S)-4-isopropyl-1-(quinolin-3-yl)-4,5-
dihydro-1H-imidazol-2-yl)pentan-3-yl)-4,5-dihydrooxazole
(L3).
The ligand L3 was prepared from bis-amidoalcohol 2 (660 mg,
2.00 mmol) and quinolin-3-amine (432 mg, 3.00 mmol) according
to GP1 as described above. Light yellow colored oily product L3
(410 mg, 48.8%, over three steps) was isolated after purification by
silica gel chromatography (EtOAc/Pet. Ether/Et3N¼1:1:0.02,
Rf¼0.3). ½a 2D5
þ76.5 (c 0.5, CHCl3); [Anal. Calcd for C26H36N4O: C,
ꢃ
74.25; H, 8.63; N, 13.32; found C, 74.41; H, 8.38; N, 12.97]; IR (KBr):
2960, 2874, 1660, 1601, 1516, 1489, 1418, 1382, 1238, 1114, 787,
753 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
0.58e0.79 (m, 6H, CH3CH2),
0.79e1.06 (m, 12H, (CH3)2CH), 1.52e1.71 (m, 2H, (CH3)2CH, oxazole
imidazole), 1.72e2.11 (m, 4H, CH3CH2), 3.11e3.16 (m, 1H,
&
NCH2(a)CH, imidazole), 3.16e3.34 (m, 1H, NCH2(b)CH, imidazole),
3.57e3.67 (m, 1H, OCH2(a)CH, oxazole), 3.67e3.71 (m, 1H,
OCH2(b)CH, oxazole), 3.72e3.83 (m, 1H, OCH2CH, oxazole),
4.03e4.12 (m, 1H, NCH2CH, imidazole), 7.25 (s, 1H, ArH), 7.54e8.05
(m, 4H, ArH),7.50e7.59 (m, 1H, ArH), 7.64e7.79 (m, 2H, ArH), 8.06
(d, J¼7.4 Hz, 1H, ArH), 8.70 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz):
4.2.3. (S)-2-(3-((S)-1-(4-Chlorophenyl)-4-isopropyl-4,5-dihydro-1H-
imidazol-2-yl)pentan-3-yl)-4-isopropyl-4,5-dihydrooxazole
(L1).
This ligand was prepared from bis-amidoalcohol 2 (660 mg,
2.0 mmol) and p-chloroaniline (381 mg, 3.0 mmol) according to
GP1 as described above. Light yellow colored oily product L1
(392 mg, 48.6%, over three steps) was isolated after purification
by silica gel chromatography (EtOAc/Pet. Ether/Et3N¼1:1:0.02,
d
7.9 (CH3CH2), 8.0 (CH3CH2), 18.1 ((CH3)2CH, imidazole), 19.4
((CH3)2CH, oxazole), 25.3 (CH3CH2), 25.9 (CH3CH2), 32.3 (CH3)2CH,
imidazole), 32.9 (CH3)2CH, oxazole), 46.7 ((NCH2, imidazole), 59.1
(OCH2, oxazole), 69.9 (NCH2CH, imidazole), 72.1 ((OCH2CH, oxa-
zole), 127.2 (ArC), 127.7 (ArC), 128.1 (ArC), 129.2 (ArC), 129.7 (ArC),
134.4 (ArC), 136.2 (ArC), 146.7 (ArC), 151.6 (ArC), 162.7 (NCN), 166.8
(OCN); LC/MS (ESI): Mþ, found 420.27, C26H36N4O requires 420.29.
Rf¼0.2). ½a 2D5
þ93.7 (c 0.5, CHCl3); [Anal. Calcd for C23H34ClN3O: C,
ꢃ
68.38; H, 8.48; N, 10.40; found C, 68.47; H, 8.67; N, 10.23]; IR
(KBr): 2960, 1660, 1606, 1491, 1381, 1231, 1092, 983, 836 cmꢁ1
;
1H
NMR (CDCl3, 400 MHz) 0.54e1.03 (m, 18H, CH3CH2 & (CH3)2CH),
d
1.48e1.63 (m, 1H, (CH3)2CH, imidazole), 1.63e1.82 (m, 1H,
(CH3)2CH, oxazole), 1.82e2.10 (m, 4H, CH3CH2), 3.30e3.42 (m, 1H,
NCH2(a)CH, imidazole), 3.42e3.51 (m, 1H, NCH2(b)CH, imidazole),
3.61e3.71 (m, 1H, OCH2(a)CH, oxazole), 3.71e3.80 (m, 1H,
OCH2(b)CH, oxazole), 3.62e3.98 (m, 1H, OCH2CH(CH3)2, oxazole),
4.01e4.13 (m, 1H, NCH2CH(CH3)2, imidazole), 7.08 (d, 2H,
J¼8.8 Hz, ArH), 7.26 (d, 2H, J¼8.8 Hz, ArH); 13C NMR (CDCl3,
4.2.6. (S)-4-Isopropyl-2-(3-((S)-4-isopropyl-1-(p-tolyl)-4,5-dihydro-
1H-imidazol-2-yl)pentan-3-yl)-4,5-dihydrooxazole (L4). The ligand
L4 was prepared from bis-amidoalcohol 2 (660 mg, 2.00 mmol) and
p-toluidine (321 mg, 3.00 mmol) according to the described pro-
cedure GP1. Light yellow colored oily product L4 (345 mg, 45%, over
three steps) was isolated after purification by silica gel chroma-
100 MHz):
d 7.94 (CH3CH2), 17.97 ((CH3)2CH), 18.33 ((CH3)2CH),
19.35 (CH3CH2), 19.54 (CH3CH2), 28.01 ((CH3)2CH), 32.52
(C(CH2CH3)2), 46.55 (NCH2, imidazole), 58.88 (NCH2CH(CH3)2,
imidazole), 69.57 (OCH2, oxazole), 72.40 (OCH2CH(CH3)2, oxazole),
129.22 (ArC2), 129.83 (ArC3), 135.94 (ArC4Cl), 141.88 (ArC1N),
tography (EtOAc/Pet. Ether/Et3N¼1:1:0.02, Rf¼0.25). ½a D25
ꢃ
111.7 (c
0.5, CHCl3); [Anal. Calcd for C24H37N3O: C, 75.15; H, 9.72; N, 10.95;
found C, 75.27; H, 9.53; N, 11.12]; IR (KBr): 2959, 2874, 1660, 1596,
1515, 1466, 1382, 1236, 1110, 1035, 985, 824, 751 cmꢁ1 1H NMR
;

5190
A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
(CDCl3, 400 MHz)
d
0.65e0.10 (m, 18H, CH3CH2 & (CH3)2CH),
7.99 (s, NH of Indole); 13C NMR (CDCl3, 100 MHz):
d 29.8, 45.0, 113.3,
1.69e2.07 (m, 6H, CH3CH2, & (CH3)2CH), 2.30 (s, 3H, ArCH3),
3.32e3.43 (m, 1H, NCH2(a)CH, imidazole), 3.43e3.53 (m, 1H,
NCH2(b)CH, imidazole), 3.62e3.71 (m, 1H, OCH2(a)CH, oxazole),
3.71e3.79 (m, 1H, OCH2(b)CH, oxazole), 3.79e3.98 (m, 1H,
OCH2CH(CH3)2, oxazole), 4.01e4.15 (m, 1H, NCH2CH(CH3)2, imid-
azole), 7.03 (d, 2H, J¼8.0 Hz, ArH), 7.09 (d, 2H, J¼8.0 Hz, ArH); 13C
119.0, 119.9, 121.2, 123.3, 126.5, 128.1, 128.2, 128.6, 128.7, 132.0,
133.8, 136.7, 137.0, 140.0, 142.8, 198.3; LC/MS (ESI): Mþ, found
359.10, C23H18ClNO requires 359.11.
4.3.4. (S)-3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-(naphthalen-2-yl)
propan-1-one (7c). Oxazolineeimidazoline ligand L2 (17 mg,
0.042 mmol, 10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %),
indole 5 (50 mg, 0.425 mmol), and enone 6c (124 mg, 0.425 mmol)
in CH3CN (3 mL) were reacted according to GP2. Purification by
chromatography on silica (EtOAc/hexane 1:9) yielded 7c as a light
yellow solid (141 mg, 81%). Enantiomeric excess was determined by
chiral HPLC (Chiracel OD-H column), hexane/i-PrOH 80:20, 0.4 mL/
NMR (CDCl3, 100 MHz):
d 7.9 (CH3CH2), 17.9 ((CH3)2CH, imidazole),
18.3 ((CH3)2CH, oxazole), 19.4 (CH3CH2), 21.7 (ArCH3), 32.3
((CH3)2CH, imidazole), 32.8 ((CH3)2CH, oxazole), 46.5 (C(CH2CH3)2),
58.9 (NCH2, imidazole), 69.1 (OCH2, oxazole), 69.3 ((NCH2CH(CH3)2,
imidazole)), 72.4 (OCH2CH(CH3)2, oxazole), 128.4 (ArC2), 129.7
(ArC3), 136.9 (ArC4Me), 140.0 (ArC1N), 163.3 (NCN), 167.2 (OCN); LC/
MS (ESI): Mþ, found 383.29, C24H37N3O requires 383.29.
min,
l
¼220 nm, tR (minor)¼8.80 min, tR (major)¼9.73 min, to be
95.6%; mp 237e241 ꢀC, ½a D25
þ19.1 (c 0.45, CHCl3); [Anal. Calcd for
ꢃ
4.3. Asymmetric FriedeleCraft’s alkylation
C27H20ClNO: C, 79.11; H, 4.92; N, 3.42; found C, 79.35; H, 5.02; N,
3.59]; IR (KBr): 3409, 2923, 1677, 815, 744, 476 cmꢁ1
;
1H NMR
4.3.1. General procedure for enantioselective addition of conjugated
enones with indole (GP2). A solution of Cu(OTf)2 (15 mg,
0.042 mmol, 20 mol %) and chiral ligand L2 (17 mg, 0.042 mmol,
10 mol%)indry CH3CN(2mL)wasstirredfor1hatroom temperature
under the argon atmosphere. To this resulting blue-green solution,
a solution of indole 5 (50 mg, 0.425 mmol) and conjugated ketones
(6ael) (0.425 mmol) in dry CH3CN (1 mL) was added via syringe. The
reaction was then stirred at ambient temperature for 24e48 h. The
reaction mixture was monitored by TLC until the starting material
was completely consumed, then the solvent was removed under
vacuum. Water (10 mL) was added and the mixture was extracted
with EtOAc (2ꢂ25 mL), washed with brine (10 mL), and dried over
MgSO4. The product was purified by column chromatography.
(CDCl3, 400 MHz) 3.75e3.86 (m, 1H, COCH2(a)), 3.86e3.98 (m, 1H,
d
COCH2(b)), 5.09 (t, 1H, J¼7.3 Hz, ArCHCH2), 7.01e7.07 (m, 2H, ArH),
7.14e7.38 (m, 7H, ArH), 7.38e7.46 (m, 1H, ArH), 7.48e7.66 (m, 2H,
ArH), 7.83e7.91 (m, 2H, ArH), 7.91e7.99 (m, 2H, ArH), 8.42 (s,1H, NH
of Indole); 13C NMR (CDCl3,100 MHz):
d 28.5, 45.0,111.1,119.0,119.5,
121.1, 122.0, 123.9, 124.6, 126.5, 128.1, 128.2, 128.6, 128.7, 129.3,
132.0, 133.8, 134.1, 135.2, 136.7, 137.0, 139.8, 142.7, 199.9; LC/MS
(ESI): Mþ, found 409.09, C27H20ClNO requires 409.12.
4.3.5. (S)-3-(1H-Indol-3-yl)-3-mesityl-1-phenylpropan-1-one (7d).
Oxazolineeimidazoline ligand L2 (25 mg, 15 mol %), Cu(OTf)2
(22 mg, 30 mol %), indole 5 (50 mg, 0.425 mmol), and enone 6d
(107 mg, 0.425 mmol) in CH3CN (3 mL) were reacted according to
GP2. Purification by chromatography on silica (EtOAc/hexane 1:9)
yielded 7d as a light yellow solid (63 mg, 40%). Enantiomeric excess
was determined by chiral HPLC (Chiracel OD-H), hexane/i-PrOH
4.3.2. (S)-3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (7a). Oxazo-
lineeimidazoline ligand L2 (17 mg, 0.042 mmol, 10 mol %), Cu(OTf)2
(15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg, 0.425 mmol), and
chalcone 6a (89 mg, 0.425 mmol) in CH3CN (3 mL) were reacted
according to GP2. Purification by chromatography on silica (EtOAc/
hexane 1:9) yielded 7a as a white solid (119 mg, 86%). This is
a known compound.23a Enantiomeric excess was determined by
chiral HPLC (Chiracel OD-H column), hexane/i-PrOH 80:20, 0.4 mL/
80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼18.9 min, tR (major)¼
23.0 min, to be 96%; mp 169e171 ꢀC, ½a D25
þ11.5 (c 0.45, CHCl3);
ꢃ
[Anal. Calcd for C26H25NO: C, 84.98; H, 6.86; N, 3.81; found C, 85.11;
H, 6.73; N, 3.75]; IR (KBr): 3409, 2921, 1677, 1451, 744, 690 cmꢁ1; 1H
NMR (CDCl3, 400 MHz)
d 2.27 (s, 9H, ArCH3), 3.57e3.63 (m, 1H,
COCH2(a)), 4.05e4.12 (m, 1H, COCH2(a)), 5.49 (t, 1H, J¼6.6 Hz,
ArCHCH2), 6.81 (s, 2H, Me3PhH), 6.85e6.94 (m, 1H, ArH), 6.94e7.02
(m, 1H, ArH), 7.02e7.15 (m, 1H, ArH), 7.20e7.36 (m, 2H,
ArH),7.41e7.50 (m, 2H, ArH), 7.50e7.59 (m, 1H, ArH), 7.90 (s, 1H, NH
of Indole), 7.98 (d, J¼7.3 Hz, 2H, ArH(orthoproton)); 13C NMR (CDCl3,
min,
l
¼220 nm, tR (minor)¼8.73 min, tR (major)¼9.68 min, to be
99.92%; mp 147e149 ꢀC, ½a D25
ꢃ
þ29.6 (c 0.45, CHCl3) [lit.23a mp
148e152 ꢀC, ½a 2D5
þ25.3 (c 0.3, CHCl3)]; [Anal. Calcd for C23H19NO: C,
ꢃ
84.89; H, 5.89; N, 4.30; found C, 85.17; H, 5.63; N, 4.42]; IR (cmꢁ1):
3413, 1679, 1597, 1451, 745, 698; 1H NMR (CDCl3, 400 MHz)
100 MHz):
d 20.9, 21.4, 29.8, 33.2, 43.0, 111.09, 117.8, 118.7, 119.1,
d
3.73e3.80 (m, 2H, COCH2), 5.07 (t, 1H, J¼6.6 Hz, ArCHCH2), 6.99 (s,
119.9,121.7,122.1,127.0,128.2,128.3,128.8,130.0, 138.8,136.8,137.2,
137.3, 199.24; LC/MS (ESI): Mþ, found 367.17, C26H25NO requires
367.19.
1H, CHNH), 7.25e7.44 (m, 11H, ArH), 7.92 (d, J¼7.3 Hz, 1H of 4H-
indole & 2H of COPhHortho), 7.96 (s, 1H, NH of Indole); 13C NMR
(CDCl3, 100 MHz):
d 38.29, 45.28, 111.18, 119.4, 119.5, 119.6, 121.5,
122.2, 126.4, 126.5, 127.9, 128.2, 128.5, 128.7, 133.1, 136.6, 137.1, 144.3,
4.3.6. (S)-3-(1H-Indol-3-yl)-3-mesityl-1-(naphthalen-2-yl)propan-
1-one (7e). Oxazolineeimidazoline ligand L2 (34 mg, 20 mol %),
Cu(OTf)2 (22 mg, 30 mol %), indole 5 (50 mg, 0.425 mmol), and
enone 6e (129 mg, 0.425 mmol) in CH3CN (3 mL) were reacted
according to GP2. Purification by chromatography on silica (EtOAc/
hexane 1:9) yielded 7e as a yellow solid (39 mg, 22%). Enantiomeric
excess was determined by chiral HPLC (Chiracel OD-H), hexane/i-
198.62; LC/MS (ESI): Mþ, found 325.15, C23H19NO requires 325.15.
4.3.3. (S)-3-(4-Chlorophenyl)-3-(1H-indol-3-yl)-1-phenylpropan-1-
one (7b). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6b (103 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9, Rf¼0.75) yielded 7b as a light yellow solid
(128.5 mg, 84%). Enantiomeric excess was determined by chiral
HPLC (Chiracel OD-H column), hexane/i-PrOH 80:20, 0.4 mL/min,
PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼18.8 min, tR
(major)¼22.9 min, to be 97.8%; mp 227e229 ꢀC, ½a D25
þ17.3 (c 0.45,
ꢃ
CHCl3); [Anal. Calcd for C30H27NO: C, 86.30; H, 6.52; N, 3.35; found
C, 86.19; H, 6.61; N, 3.49]; IR (KBr): 3410, 3319, 2652, 1653, 1619,
l
¼220 nm, tR (minor)¼8.84 min, tR (major)¼9.74 min, to be 93.85%;
1590, 1457, 744 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 2.27 (s, 9H,
mp 189e192 ꢀC, ½a D25
ꢃ
þ23.7 (c 0.45, CHCl3); [Anal. Calcd for
ArCH3), 3.68e3.78 (m, 1H, COCH2(a)), 4.17e4.23 (m, 1H, COCH2(b)),
5.54 (t, 1H, J¼6.6 Hz, ArCHCH2), 6.79e6.92 (m, 3H, ArH), 7.92e7.20
(m, 2H, ArH), 7.20e7.38 (m, 3H, ArH), 7.50e7.68 (m, 2H, ArH),
7.84e7.98 (m, 3H, ArH), 8.05e8.08 (m, 1H, ArH), 8.47 (s, 1H, NH of
C23H18ClNO: C, 76.77; H, 5.04; N, 3.89; found C, 76.92; H, 5.12; N,
3.71]; IR (cmꢁ1): 3369, 1677, 745, 582, 502; 1H NMR (CDCl3,
400 MHz)
d
3.64e3.38 (m, 2H, COCH2), 5.04 (t, 1H, J¼7.3 Hz,
ArCHCH2), 6.93e7.11 (m, 2H, ArH & 1H of NCH of Indole), 7.12e7.63
(m, 8H, ArH), 7.92 (d, J¼7.3 Hz, 1H of 4H-indole & 2H of COPhHortho),
Indole); 13C NMR (CDCl3, 100 MHz):
d
21.4, 21.5, 29.8, 33.4, 43.0,
111.0, 115.8, 116.2, 117.6, 119.1, 119.3, 120.0, 121.5, 122.0, 123.2, 124.1,

A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
5191
125.5,127.1,128.0,128.5,129.6,131.0,132.8,134.6,135.9,137.0,137.3,
199.1; LC/MS (ESI): Mþ, found 417.22, C30H27NO requires 417.21.
indole 5 (50 mg, 0.425 mmol), and enone 6i (123 mg, 0.425 mmol)
in CH3CN (3 mL) were reacted according to GP2. Purification by
chromatography on silica (EtOAc/hexane 1:9) yielded 7i as an off
white solid (112 mg, 66%). Enantiomeric excess was determined by
chiral HPLC (Chiracel OD-H), hexane/i-PrOH 80:20, 0.4 mL/min,
4.3.7. (S)-3-(1H-Indol-3-yl)-1-phenyl-3-(p-tolyl)propan-1-one (7f).
Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol, 10 mol %),
Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6f (95 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7f as a yellow solid (105 mg, 73%).
Enantiomeric excess was determined by chiral HPLC (Chiracel OD-
l
¼220 nm, tR (major)¼39.4 min, tR (minor)¼49.1 min, to be 90.8%;
mp 159e162 ꢀC, ½a D25
þ17.5 (c 0.45, CHCl3); [Anal. Calcd for
ꢃ
C28H23NO2: C, 82.94; H, 5.72; N, 3.45; found C, 83.22; H, 5.61; N,
3.73]; IR (KBr): 3413, 3007, 2930, 1679, 1610, 1509, 1246, 1177, 1032,
745, 544 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
3.65e3.82 (m, 2Hþ3H,
H), hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼
COCH2 & ArOCH3), 5.01 (t, 1H, J¼7.3 Hz, ArCHCH2), 6.75e6.83 (m,
2H, ArH), 6.97e7.07 (m, 2H, ArH), 7.11e7.20 (m, 1H, ArH), 7.21e7.48
(m, 8H, ArH), 7.49e7.56 (m, 1H, ArH), 7.91 (s, 1H, NH of Indole), 7.93
27.3 min, tR (major)¼31.2 min, to be 95.8%; mp 153e155 ꢀC, ½a D25
ꢃ
þ14.6 (c 0.45, CHCl3); [Anal. Calcd for C24H21NO: C, 84.92; H, 6.24;
N, 4.13; found C, 84.66; H, 6.15; N, 3.97]; IR (KBr): 3413, 1680, 1452,
(s, 2H. ArH); 13C NMR (CDCl3, 100 MHz):
d 37.5, 45.5, 55.3, 111.4,
743, 689 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
2.26 (s, 3H, ArCH3),
113.8, 116.2, 118.1, 119.7, 119.9, 121.6, 122.1, 123.4, 126.7, 127.0, 128.3,
128.9, 130.1, 130.4, 131.9, 133.3, 135.2, 136.4, 136.7, 137.2, 158.0,
198.8; LC/MS (ESI): Mþ, found 405.18, C28H23NO2 requires 405.17.
3.65e3.78 (m, 1H, COCH2(a)), 3.78e3.89 (m, 1H, COCH2(b)), 5.02 (t,
1H, J¼7.4 Hz, ArCHCH2), 6.98e7.61 (m, 12H, ArH), 7.89 (s, 1H, NH of
Indole), 7.93 (d, J¼7.3 Hz, 2H of COPhHortho); 13C NMR (CDCl3,
100 MHz):
d
21.1 (ArCH3), 37.9 (ArCHCH2), 45.4 (ArCHCH2), 111.2,
4.3.11. (S)-3-(1H-Indol-3-yl)-1-(naphthalen-2-yl)-3-phenylpropan-
1-one (7j). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6j (110 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7j as a white solid (75 mg, 47%).
Enantiomeric excess was determined by chiral HPLC (Chiracel OD-
119.4, 119.5, 119.6, 121.6, 122.2, 126.9, 127.8, 128.2, 128.7, 129.4,
133.3, 135.8, 136.7, 137.1, 141.3, 198.71; LC/MS (ESI): Mþ, found
339.19, C24H21NO requires 339.16.
4.3.8. (S)-3-(1H-Indol-3-yl)-1-(naphthalen-2-yl)-3-(p-tolyl)propan-
1-one (7g). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6g (116 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7g as a yellowish solid (45 mg,
27%). Enantiomeric excess was determined by chiral HPLC (Chiracel
H), hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼
12.0 min, tR (major)¼14.9 min, to be 95.5%; mp 166e169 ꢀC, ½a D25
ꢃ
þ24.2 (c 0.45, CHCl3); [Anal. Calcd for C27H21NO: C, 86.37; H, 5.64; N,
3.73; found C, 85.98; H, 5.87; N, 3.93]; IR (KBr): 3415, 1677, 1597,
1456, 746, 476 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 3.83e3.91 (m, 1H,
OD-H), hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼
COCH2(a)), 3.91e3.95 (m, 1H, COCH2(b)), 5.13 (t, 1H, J¼7.3 Hz,
ArCHCH2), 7.00e7.11 (m, 3H, ArH), 7.11e7.23 (m, 2H, ArH), 7.23e7.50
(m, 6H, ArH), 7.50e7.63 (m, 2H, ArH), 7.95e8.19 (m, 4H, ArH), 8.43 (s,
7.6 min, tR (major)¼9.7 min, to be 93.4%; mp 174e177 ꢀC, ½a D25
þ9.1
ꢃ
(c 0.45, CHCl3); [Anal. Calcd for C28H23NO: C, 86.34; H, 5.95; N, 3.60;
found C, 86.24; H, 6.09; N, 3.37]; IR (KBr): 3413, 2923, 2854, 1676,
1H, NH of Indole); 13C NMR (CDCl3, 100 MHz):
d 38.3, 45.3, 111.2,
1625, 1461, 816, 748, 476 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
2.27 (s,
116.0, 119.4, 119.5, 119.6, 121.5, 122.2, 123.3, 125.1, 126.4, 126.6, 127.9,
128.2, 128.5,128.7,129.4,131.0,133.0,136.5, 137.1,141.1,144.3,198.6;
LC/MS (ESI): Mþ, found 375.15, C27H21NO requires 375.16.
3H, ArCH3), 3.76e3.88 (m, 1H, COCH2(a)), 3.89e3.98 (m, 1H,
COCH2(b)), 5.08 (t, 1H, J¼7.3 Hz, ArCHCH2), 6.87e7.45 (m, 7H, ArH),
7.55e7.71 (m, 3H, ArH), 7.83e8.02 (m, 6H, ArH), 8.42 (s, 1H, NH of
Indole); 13C NMR (CDCl3, 100 MHz):
d
21.1, 38.1, 45.4, 111.2, 116.1,
4.3.12. (R)-3-(1H-Indol-3-yl)-1-phenyl-3-(thiophen-2-yl)propan-1-
one (7k). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6k (91 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7k as a white solid (91 mg, 65%).
Enantiomeric excess was determined by chiral HPLC (Chiracel OD-
118.0, 119.5, 122.2, 123.8, 124.2, 125.8, 126.7, 127.8, 128.4, 129.2,
129.8, 132.2, 134.1, 135.9, 136.8, 138.2, 139, 8, 141.1, 197.8; LC/MS
(ESI): Mþ, found 389.18, C28H23NO requires 389.18.
4.3.9. (S)-3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-phenylpropan-
1-one (7h). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6h (101 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7h as a yellow solid (134 mg, 89%).
Enantiomeric excess was determined by HPLC (Chiracel OD-H),
H), hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼
3.1 min, tR (major)¼8.6 min, to be 89.8%; mp 112e115 ꢀC, ½a D25
þ6.3
ꢃ
(c 0.45, CHCl3); [Anal. Calcd for C21H17NOS: C, 76.10; H, 5.17; N, 4.23;
found C, 75.89; H, 5.31; N, 4.43]; IR (KBr): 3419,1676,1594,1456, 741,
576 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
3.84 (t, J¼6.6 Hz, 2H, COCH2),
hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (minor)¼
5.37 (t, 1H, J¼6.6 Hz, ArCHCH2), 6.85e6.98 (m, 2H, ArH), 7.02e8.65,
20.1 min, tR (major)¼24.0 min, to be 96.4%; mp 134e136 ꢀC, ½a D25
ꢃ
(m, 9H, ArH), 7.92e7.94 (m, 2H, ArH), 7.99 (s, NH of Indole); 13C NMR
þ21.4 (c 0.45, CHCl3); [Anal. Calcd for C24H21NO2: C, 81.10; H, 5.96; N,
(CDCl3, 100 MHz): d 33.6, 46.2, 111.3, 116.1, 119.5, 119.6, 121.9, 122.3,
3.94; found C, 80.79; H, 5.86; N, 4.07]; IR (KBr): 3412, 2923, 1674,
123.5, 124.3, 126.6, 128.2, 128.7, 133.2, 136.0, 136.4, 143.9, 148.8,
1509,1245,1177, 746, 476 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 3.73 (s,
198.1; LC/MS (ESI): Mþ, found 331.11, C21H17NOS requires 331.10.
3H, ArOCH3), 3.77e3.85 (m, 1H, COCH2(a)), 3.85e3.98 (m, 1H,
COCH2(b)), 5.06 (t, 1H, J¼7.4 Hz, ArCHCH2), 6.78e7.83 (m, 2H, ArH),
6.97e7.05 (m, 2H, ArH), 7.11e7.19 (m, 1H, ArH), 7.22e7.62 (m, 6H,
ArH), 7.84e8.01 (m, 3H, ArH), 8.42 (s, 1H, NH of Indole); 13C NMR
4.3.13. (R)-3-(1H-Indol-3-yl)-1-phenyl-3-(ferrocene-2-yl)-propan-1-
one (7l). Oxazolineeimidazoline ligand L2 (17 mg, 0.042 mmol,
10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %), indole 5 (50 mg,
0.425 mmol), and enone 6l (91 mg, 0.425 mmol) in CH3CN (3 mL)
were reacted according to GP2. Purification by chromatography on
silica (EtOAc/hexane 1:9) yielded 7l as a white solid (15 mg, 8%).
Enantiomeric excess was determined by chiral HPLC (Chiracel OD-
(CDCl3, 100 MHz):
d 37.8, 45.5, 55.3, 111.3, 113.9, 119.7, 121.5, 122.0,
124.0,126.8,127.8,128.5,128.8,129.6,132.4,134.9,135.8,136.7,158.1,
198.8; LC/MS (ESI): Mþ, found 355.19, C24H21NO2 requires 355.16.
4.3.10. (S)-3-(1H-Indol-3-yl)-3-(4-methoxyphenyl)-1-(naphthalen-
2-yl)propan-1-one (7i). Oxazolineeimidazoline ligand L2 (17 mg,
0.042 mmol, 10 mol %), Cu(OTf)2 (15 mg, 0.042 mmol, 20 mol %),
H), hexane/i-PrOH 80:20, 0.4 mL/min,
l
¼220 nm, tR (major)¼
16.5 min, tR (minor)¼22.6 min, to be 89.8%; mp 273e275 ꢀC, ½a D25
ꢃ
þ8.1 (c 0.45, CHCl3); [Anal. Calcd for C27H23FeNO2: C, 74.83; H, 5.31;

5192
A. Barakat et al. / Tetrahedron 69 (2013) 5185e5192
(e) Yamazaki, S.; Kashima, S.; Kuriyama, T.; Iwata, Y.; Morimoto, T.; Kakiuchi, K.
Tetrahedron: Asymmetry 2009, 20, 1224.
N, 3.23; found C, 74.61; H, 5.17; N, 3.51]; IR (KBr): 3409, 3011, 2934,
1678, 1615, 1503, 1247, 1179, 1031, 743, 541 cmꢁ1 1H NMR (CDCl3,
400 MHz) 3.61e3.73 (m, 1H, COCH2(a)), 3.73e3.85 (m, 1H,
;
8. (a) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756; (b) Evans, D. A.; Mac-
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Corey, E. J.; Imai, N.; Zhang, H. Y. J. Am. Chem. Soc. 1991, 113, 728; (c) Evans, D. A.;
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Huang, H.; Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604; (e) Jautze, S.; Peters, R.
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d
COCH2(b)), 4.06 (s, 5H, protons of Cp), 4.09-4.31 (m, 4H, protons of
Cp), 4.90 (t, 1H, J¼7.36 Hz, CpCHCH2), 7.04e7.09 (m, 1H, ArH),
7.10e7.16 (m, 1H, ArH), 7.23e7.30 (m, 2H, ArH), 7.35e7.44 (m, 2H,
ArH), 7.48e7.53 (m, 1H, ArH), 7.61e7.68 (m, 1H, ArH), 7.87e7.98 (m,
2H of ArH & 1H of Indole); 13C NMR (CDCl3, 100 MHz):
d 29.8, 45.8,
67.1, 67.3, 68.7, 111.2, 115.9, 119.3, 119.9, 121.8, 126.4, 128.2, 128.5,
131.3, 133.0, 137.1, 137.4, 199.1; LC/MS (ESI): Mþ, found 433.22,
C27H23FeNO2 requires 433.23.
Acknowledgements
The authors extend their appreciation to the Deanship of Sci-
entific Research at King Saud University for funding the work
through the research group project Number RGP-VPP-044.
13. (a) Kato, K.; Tanaka, M.; Yamamura, S.; Yamamoto, Y.; Akita, H. Tetrahedron Lett.
2003, 44, 3089; (b) Kim, S. G.; Cho, C. W.; Ahn, K. H. Tetrahedron 1999, 55,
10079.
Supplementary data
14. (a) Uozumi, Y.; Kyota, H.; Kitayama, K.; Hayashi, T. Tetrahedron: Asymmetry
1996, 7, 1603; (b) Imai, Y.; Zhang, W. B.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetra-
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.063.
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