Polystyrene-supported cu(II)-R-Box as recyclable catalyst in asymmetric Friedel–Crafts reaction

Article abstract of DOI:10.1134/S1070428016120010

The complex of copper(II) trifluoromethanesulfonate with chiral isopropyl bis(oxazoline) ligand (i-Pr-Box) was immobilized on accessible and inexpensive Merrifield resin according to a “click” procedure. The resulting catalyst showed high efficiency and r

Full text of DOI:10.1134/S1070428016120010

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 12, pp. 1717–1727. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.G. Desyatkin, M.V. Anokhin, V.O. Rodionov, I.P. Beletskaya, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 12, pp. 1727–1737.
Polystyrene-Supported Cu(II)-R-Box as Recyclable Catalyst
in Asymmetric Friedel–Crafts Reaction
V. G. Desyatkina, M. V. Anokhina, V. O. Rodionovb, and I. P. Beletskayaa*
a Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
*e-mail: beletska@org.chem.msu.ru
b King Abdullah University of Science and Technology, Thuwal, 23955-6900 Saudi Arabia
Received August 3, 2016
Abstract—The complex of copper(II) trifluoromethanesulfonate with chiral isopropyl bis(oxazoline) ligand
(i-Pr-Box) was immobilized on accessible and inexpensive Merrifield resin according to a “click” procedure.
The resulting catalyst showed high efficiency and recyclability in the asymmetric Friedel–Crafts alkylation of
indole and its derivatives. The catalyst can be recycled five times without appreciable loss in activity and
enantioselectivity.
DOI: 10.1134/S1070428016120010
Asymmetric catalysis [1] (i.e., catalysis by transi-
tion metal complexes with chiral ligands [2], catalysis
by chiral Lewis [3] or Brønsted acids [4], and organo-
catalysis [5]) is one of the brightest research lines in
modern organic chemistry. However, large-scale ap-
plication of chiral catalysts is limited by the high cost
of chiral reagents, whereas metal complex catalysis
involves a problem related to separation of the target
products from micro impurities of heavy metals, as
well as from phosphine ligands and their oxidation
products [6]. The use of recyclable catalysts im-
mobilized on soft or hard supports [7–9] makes it
possible to partially solve the above problems; how-
ever, obvious advantages of such catalytic systems are
often counterpoised by lowering of the reaction rate in
going from homogeneous to heterogeneous conditions
and by reduction of the yield and enantioselectivity.
phenylamine-linked bis(oxazoline) ligand immobilized
onto Fréchet-type dendrimers. High yields and repro-
ducible enantioselectivities were achieved in four
catalytic cycles. Silicon dioxide- and MCM-41-sup-
ported Cu(II)-Ph-Box catalyzed the reaction of 1,3-di-
methoxybenzene with methyl 3,3,3-trifluoropyruvate;
however the enantioselectivity considerably decreased
after reuse [32]. Aza(bisoxazoline) immobilized on
a soluble poly(ethylene glycol) [22, 33] was reported
to catalyze asymmetric reaction of indole with
benzylidenemalonate in the presence of Cu(OTf)2;
however, the possibility of recycling the catalyst was
not noted [34].
Jørgensen et al. [35–37] studied asymmetric
Friedel–Crafts alkylation of indole with (arylmeth-
ylidene)malonates and (arylmethylidene)pyruvates in
the presence of Cu(OTf)2 complex with chiral
t-Bu-Box ligand. Such reactions are of great practical
importance; however, no examples of asymmetric
Friedel–Crafts alkylation with the use of analogous
complexes under heterogeneous conditions have been
reported so far.
Chiral bis(oxazoline) ligands (Box, aza-Box, Py-
Box) are widely used in asymmetric organic synthesis
[10–13], and their immobilization on soluble and in-
soluble polymers and inorganic supports makes it pos-
sible to successfully accomplish various asymmetric
transformations [14, 15]. For instance, supported cop-
per-containing bis(oxazoline) complexes were used to
catalyze cyclopropanations [16–19], aziridinations
[20, 21], ene reactions [22], Mukaiyama aldol con-
densations [23–26], and Henry and Mannich reactions
[27–30]. Liu and Du [31] studied reactions of indole
with nitroalkenes catalyzed by zinc complex with di-
Supported catalysts can be obtained according to
two approaches: (1) immobilization of a ligand, fol-
lowed by complexation with a metal salt and (2) im-
mobilization of a preliminarily prepared complex.
Taking into account inactivity of polymeric supports
toward metal salts, we selected the first approach im-
plying ligand binding to polymeric support via copper-
1717

DESYATKIN et al.
1718
Scheme 1.
N
N
N
N
Ph
Ph
N
N
Me
Me
N
i
Cu(OTf)2
O
O
O
O
N
N
N
Cu
TfO OTf
Cu(OTf)2·L2a, Cu(OTf)2·L2b
HC
R
R
R
R
Me
N
O
O
L2a, L2b
N
N
N
N
N
R
R
N
N
Cu(OTf)2
DMF–THF (1:1)
L1a, L1b
Me
N
Me
N
ii
O
N
O
O
O
N
Cu
TfO OTf
Cu(OTf)2·L3
i-Pr
Pr-i
i-Pr
Pr-i
L3
stands for Merrifield resin
R = Ph (a), i-Pr (b); reagents and conditions: i: Cu(OAc)2, NaAsc, TTTA, PhCH2N3, THF–H2O, 5:1, 20°C, 20 h;
ii: polystyrene-N3, CuI/TTTA, DMF–THF, 1:1, 60°C, 30 h.
catalyzed 1,3-dipolar cycloaddition of azides to
alkynes [38]. “Click” chemistry provides well studied,
simple, and efficient methods for covalent binding of
catalysts, including Cu-Box [15] and Cu-azaBox com-
plexes [39, 40], to various supports.
The reaction catalyzed by Cu(OTf)2 · L2a
(10 mol %) containing phenyl groups gave the corre-
sponding 3-substituted indole with lower enantioselec-
tivity (Scheme 2; Table 1, run nos. 1, 2) than in the
presence of Cu(OTf)2 · L2b containing isopropyl
groups (run nos. 3, 4). When Cu(OTf)2·L2a was used
as catalyst, lowering the temperature to 0°C resulted in
more significant reduction of the yield than in the reac-
tion catalyzed by Cu(OTf)2·L2b, but the enantioselec-
tivity increased. Therefore, the ligand containing iso-
propyl groups is preferred from the viewpoint of
enantioselectivity. The reactions of indole (1a) with di-
methyl and diethyl benzylidenemalonates were charac-
terized by almost similar yields and enantioselectivities
(run nos. 4, 5), whereas replacement of ethanol as
solvent by isobutyl alcohol led to a slight reduction in
both yield and enantioselectivity (run no. 6).
Initially, we have synthesized in high yields (85–
87%) triazoles L2a and L2b by reacting alkynyl-sub-
stituted Box-ligands L1a and L1b [41] with benzyl
azide in the presence of Cu(OAc)2/NaAsc/TTTA as
catalytic system {TTTA is tris[(1-tert-butyl-1H-1,2,3-
triazol-4-yl)methyl]amine [42]} (Scheme 1). The use
of TTTA made it possible to avoid copper(II) coordina-
tion to the Box ligand. The reactions of L2a and L2b
with Cu(OTf)2 afforded complexes Cu(OTf)2·L2a and
Cu(OTf)2·L2b which were used without isolation to
optimize the conditions of the Friedel–Crafts reaction
of indole with benzylidenemalonate (Table 1). The re-
actions were carried out in ethanol or isobutyl alcohol
at 20 and 0°C.
Thus, the complex Cu(OTf)2 ·L2b showed high
efficiency in the catalytic alkylation of indole. The ob-
Scheme 2.
COOR
COOR
Ph
*
COOR
Catalyst, ∆, AlkOH
Ph
+
N
N
COOR
2a, 2b
H
H
1a
3a, 3b
R = Et (a), Me (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

POLYSTYRENE-SUPPORTED Cu(II)-R-Box AS RECYCLABLE CATALYST
1719
Table 1. Reaction of indole with benzylidenemalonates catalyzed by copper(II) complexesa
Run no. Compound no.
Catalyst
Solvent, temperature Reaction time, h
Product
Yield, %
ee, %
1
2
3
4
5
6
2a
2a
2a
2a
2b
2b
Cu(OTf)2·L2a
Cu(OTf)2·L2a
Cu(OTf)2·L2b
Cu(OTf)2·L2b
Cu(OTf)2·L2b
Cu(OTf)2·L2b
EtOH, 20°C
EtOH, 0°C
EtOH, 20°C
EtOH, 0°C
EtOH, 0°C
i-BuOH, 0°C
24
48
20
24
24
24
3a
3a
3a
3a
3b
3b
85
68
92
88
89
83
53
54
83
89
86
83
a
Reaction conditions: indole 1a, 1.2 mmol; benzylidenemalonate 2, 1 mmol; catalyst, 10 mol %; ethanol, 4 mL.
tained ee values indicated that the triazole substituent
in L2b does not compete for coordination to the metal
and hence does not hamper the reaction. In view of the
aforesaid, in the second stage of our study ligand L1b
was immobilized onto polystyrene (Merrifield resin).
mixture (run no. 2–4). High enantioselectivity (82–
93% ee) was reached at –30°C in all the examined
solvents except for toluene; in particular, the ee value
of the alkylation product after recrystallization was
99% when the reaction was carried out in EtOH–THF
(1:1) (run no. 3). It is quite probable that only highly
accessible catalytic sites are active at low temperature,
whereas those located more deeply inside a randomly
packed cross-linked polymer are merely inaccessible.
Nevertheless, prolonged reaction without stirring
afforded a high yield and enantioselectivity. The poly-
styrene resin used in nonpolar solvents remained
swollen even at such low temperatures.
Unlike “click” reactions of ligands L1a and L1b
with benzyl azide, the reaction with azidomethylpoly-
styrene required more severe conditions (DMF–THF,
1:1; 60°C, 30 h; Scheme 1). The progress of the reac-
tion was monitored by IR spectroscopy, following the
disappearance of the N3 stretching band at 2094 cm–1
and appearance of the C=N band at 1658 cm–1. The
subsequent treatment of polymer-supported i-Pr-Box
(L3) with copper(II) trifluoromethanesulfonate af-
forded the target catalyst Cu(OTf)2·L3. The concentra-
tion of copper therein (~0.5 mmol/g) was determined
by inductively coupled plasma mass spectrometry
(ICP-MS).
Unlike the homogeneous reaction catalyzed by
Cu(OTf)2–i-Pr-Box [43, 44], the steric configuration of
the product did not change in going from ethanol to
Table 2. Optimization of the conditions for the synthesis of
diethyl (S)-2-[(1H-indol-3-yl)(phenyl)methyl]malonate (3a)
from indole (1a) and diethyl benzylidenemalonate (2a) in
the presence of Cu(OTf)2·L3a
In the reaction of indole with diethyl benzylidene-
malonate in the presence of 10 mol % of Cu(OTf)2·L3
in ethanol, the yield of the alkylation product was 74%
(ee 87%) (Table 2, run no. 1), which is comparable
with the result obtained with Cu(OTf)2·L2b as catalyst
(Table 1, run no. 4). The reaction catalyzed by
Cu(OTf)2·L3 (Table 2, run no. 1) under the same con-
ditions was expectedly much slower than under homo-
geneous conditions using Cu(OTf)2 ·L2b (Table 1,
run no. 4), and seven days against one was necessary
to attain a comparable yield in the case of heterogene-
ous catalyst. The observed reduction of the reaction
rate is a common drawback of all heterogeneous
reactions since localization of reaction sites on a poly-
meric support considerably diminishes their acces-
sibility for reagents residing in solution.
Run
no.
Solvent,
temperature
Reaction
time, day
Yield, % ee, %
1
2
EtOH, 0°C
07
07
74
76
87
87
EtOH–THF (1:1),
0°C
3
EtOH–THF (1:1),
–30°C
21
83
92
>99b0
4
5
6
7
8
CH2Cl2, –30°C
Acetone, –30°C
EtOAc, –30°C
PhMe, –30°C
MeCN, –30°C
21
21
21
21
21
91
87
93
82
64
87
66 (93)c
31 (68)c
25 (71)c
25 (83)c
a
The catalytic efficiency of Cu(OTf)2 ·L3 in asym-
metric Friedel–Crafts alkylation in different solvents
was studied (Table 2). The best yields were obtained
in methylene chloride and 1:1 ethanol–tetrahydrofuran
Reaction conditions: 1a, 1.2–2 mmol (1.2–2 equiv); 2a, 1 mmol;
catalyst, 10 mol %; solvent, 4 mL.
b
c
After recrystallization from ethanol.
Calculated on the reacted 2a.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESYATKIN et al.
1720
Table 3. Recycling of the catalyst Cu(OTf)2·L3 in the reac-
tion of indole (1a) with diethyl benzylidenemalonate (2a)a
almost constant activity and enantioselectivity in at
least five cycles.
The nature of substituents in the initial indole
molecule (both in the benzene ring and on the nitrogen
atom), as well as in the aromatic ring of the olefinic
component, strongly affects the asymmetric alkylation
reaction under homogeneous catalysis [45–50]. We
have studied how the substituents in the 5-position of
indole and in the para position of the phenyl group of
benzylidenemalonate, as well as the N-methyl group
in indole, affect the results of Cu(OTf)2·L3-catalyzed
asymmetric alkylation of indole (Scheme 3, Table 4).
Cycle no.
1
2
3
4
5
Yield, %
83
92 (>99b)
71
91
72
92
74
92
73
92
ee, %
a
Reaction conditions: 1a, 2 mmol; 2a, 1 mmol; catalyst,
10 mol %; THF–EtOH (1:1), 4 mL; –30°C, 21 days.
After recrystallization from ethanol.
b
methylene chloride. In all solvents indicated in
Table 2, the configuration of the target product ob-
tained in the presence of Cu(OTf)2·L3 was the same.
We have found that the reaction catalyzed by
Cu(OTf)2 ·L3 shows the same trends with respect
to the substituent effects as those observed in the
homogeneous catalytic reactions in the presence of
Cu(OTf)2·R-Box [45–51]. Introduction of a methoxy
group into the indole molecule decreased the yield but
did not change the ee value (run no. 2). The reduced
yield in the reaction with 5-methoxyindole (1b) may
be related to its instability in the presence of Lewis
acids (the reaction was accompanied by tarring, and
the catalyst turned brown). The presence of a bromine
atom or methyl group in the 5-position of indole (1d
and 1c, respectively), increased both ee (94 and 97%,
respectively, and yield (run nos. 4 and 5).
Similar enantioselectivities in different solvents
suggest stability and uniformity of catalytic sites,
which is very important for recycling. The hetero-
geneous catalyst Cu(OTf)2·L3 can be readily separated
by filtration. After washing with THF and drying, it
was reused five times in the reaction of indole with
diethyl benzylidenemalonate (Table 3). Reduction of
the yield was observed only in the second cycle, which
may be due to washout of weakly bound active cata-
lytic sites, and the catalyst then becomes stable to
repeated filtrations, washings, and dryings and shows
Table 4. Reaction of indoles 1a–1f with arylmethylidene-
malonates 2a–2da
The lowest yield and enantioselectivity (run nos. 6,
11) were obtained in the alkylation of N-methylindole.
This may be rationalized assuming a contribution of
hydrogen bonding to fixation of the reactants in the
metal coordination sphere. There were no appreciable
variations in the yield and enantioselectivity of the
alkylation of indole and its derivatives upon intro-
duction of a bromine atom into the para position
of the phenyl group of benzylidenemalonate (run
nos. 7–10, 12).
Run
no.
Initial
Tempera-
ture, °C
Yield,
%
Product
ee, %
reactants
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
1a + 2b
1b + 2a
1b + 2a
1c + 2a
1d + 2a
1f + 2a
1a + 2c
1b + 2c
1c + 2c
1d + 2c
1f + 2c
1e + 2c
1a + 2d
1b + 2d
1e + 2d
–30
–30
–00
–30
–30
–30
–30
–30
–30
–30
–30
–00
–00
–00
–00
3b
3c
3c
3d
3e
3f
58
73
79
91
84
51
80
86
82
78
46
76
99
69
81
38
94
73
97
94
66
89
89
91
86
61
87
86
78
73
The reactions with diethyl 4-nitrobenzylidene-
malonate 2d were carried out at 0°C because of its
poor solubility at –30°C; nevertheless, these reactions
were characterized by high yields (excluding alkyla-
tion of 5-methoxyindole) and fairly high enantioselec-
tivities (run nos. 13–15).
3g
3h
3i
3j
3k
3l
The catalyst Cu(OTf)2 ·L3 was also tried in the
reaction of indoles with a β-keto ester, namely methyl
(E)-2-oxo-4-phenylbut-3-enoate [52, 53]. Analogous
reactions under homogeneous catalysis were described
in [51, 54–56]. We reacted 1 equiv of indole 1a–1f
with 2 equiv of methyl (E)-2-oxo-4-phenylbut-3-eno-
ate (4) at –30 and –78°C in a 1:1 mixture of methanol
and THF (Scheme 4, Table 5). Unfortunately, hetero-
3m
3n
3o
a
Reaction conditions: 1, 2 mmol; 2, 1 mmol; Cu(OTf)2 · L3,
10 mol %; THF–EtOH (1:1), 4 mL; 21 days.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

POLYSTYRENE-SUPPORTED Cu(II)-R-Box AS RECYCLABLE CATALYST
1721
Scheme 3.
R1
COOR2
COOR2
R3
R1
Cu(OTf)2·L3
EtOH–THF (1:1), –30°C
*
COOR2
R3
+
N
R4
COOR2
N
R4
1a–1f
2a–2d
3b–3o
1, R4 = H, R3 = H (a), MeO (b), Me (c), Br (d), I (e); R3 = H, R4 = Me (f); 2, R1 = H, R2 = Et (a), Me (b); R2 = Et, R1 = Br (c),
O2N (d); 3, R1 = R3 = R4 = H, R2 = Me (b); R1 = R4 = H, R2 = Et, R3 = MeO (c), Me (d), Br (e); R1 = R3 = H, R2 = Et, R4 = Me (f);
R1 = Br, R2 = Et, R3 = R4 =H (g); R1 = Br, R2 = Et, R4 = H, R3 = MeO (h), Me (i), Br (j); R1 = Br, R2 = Et, R3 = H, R4 = Me (k);
R1 = Br, R2 = Et, R3 = I, R4 =H (l); R1 = O2N, R2 = Et, R4 = H (m), MeO (n), I (o).
Scheme 4.
O
O
R1
Cu(OTf)2·L3
EtOH–THF (1:1), –30 or 78°C
*
OMe
R1
+
OMe
O
N
R2
O
N
R2
1a–1f
4
5a–5f
R2 = H, R1 = H (a), MeO (b), Me (c), Br (d), I (e); R1 = H, R2 = Me (f).
geneous catalysis turned out to be much less efficient
than homogeneous catalysis, primarily with respect to
enantioselectivity which considerably decreased. Low-
ering the temperature to –78°C did not improve the
results. Electron-donating methoxy and methyl groups
in the initial indole (run nos. 3–6) insignificantly in-
crease enantiomeric excess as compared to unsubstitut-
ed indole (run nos. 1, 2). 5-Bromo substitution in
indole (run nos. 7, 8) favors enantioselectivity but
reduces the yield. The reaction of methyl (E)-2-oxo-4-
phenylbut-3-enoate (4) with N-methylindole (1f) was
characterized by considerably lower enantioselectivity
(30% ee, run no. 9).
geneous catalysis. The target products were obtained
in up to 99% yield with up to 97% ee. The catalyst
ensured high yield and enantioselectivity after recy-
cling five times.
Table 5. Reaction of indoles 1a–1f with methyl 2-oxo-4-
phenylbut-3-enoate (4) catalyzed by Cu(OTf)2·L3a
Run
no.
Temperature,
°C
Yield,
%
Indole
Product
ee, %
01
02
03
04
05
06
07
08
09
10
11
1a
1a
1b
1b
1c
1c
1d
1d
1e
1f
–30
–78
–30
–78
–30
–78
–30
–78
–78
–30
–78
5a
5a
5b
5b
5c
5c
5d
5d
5e
5f
82
77
68
94
73
75
79
43
22
66
68
34
37
39
36
39
41
49
45
30
06
37
Unexpectedly sharp increase of the yield (94%) at
–78°C for methoxyindole 1b should be noted (run
no. 4), which may be related to inhibition of side
processes; however, the enantioselectivity remained
fairly low. Considerable increase of the enantioselec-
tivity (from 6 to 37% ee) was observed in the reaction
with N-methylindole on lowering the temperature to
–78°C (run nos. 9, 10).
1f
5f
In summary, we were the first to accomplish
asymmetric Friedel–Crafts alkylation of indoles with
benzylidenemalonates under conditions of hetero-
a
Reaction conditions: 1, 1 mmol; 4, 2 mmol; Cu(OTf)2 · L3,
10 mol %; THF–MeOH (1:1), 4 mL; 27 days.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESYATKIN et al.
40 mol %) of sodium ascorbate in 0.25 mL of water,
1722
EXPERIMENTAL
a solution of 10 mg (0.05 mmol) of copper(II) acetate
monohydrate in 0.25 mL of water, and 67 mg
(0.5 mmol) of benzyl azide were added under argon.
The mixture was stirred for 20 h at room temperature
until the reaction was complete (TLC; petroleum
ether–EtOAc, 3:2), and 20 mL of methylene chloride
and 20 mL of aqueous ammonium chloride were
added. The organic phase was separated, the aqueous
phase was extracted with methylene chloride (3×
10 mL), and the extracts were combined with the
organic phase, dried over Na2SO4, and evaporated. The
product was isolated by column chromatography
(gradient elution with CH2Cl2–MeOH, 50:1 to 20:1).
The H and 13C NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400 and
100.6 MHz, respectively, using the residual proton and
carbon signals of the deuterated solvents as reference
(CHCl3, δ 7.26 ppm; CDCl3, δC 77.16 ppm; DMSO-d5,
δ 2.5 ppm; DMSO-d6, δC 39.52 ppm). The MALDI-
TOF mass spectra (positive ion detection) were ob-
tained on a Bruker Daltonics Ultraflex instrument
using 1,8,9-trihydroxyanthracene as matrix and poly-
(ethylene glycols) PEG-300, PEG-400, and PEG-600
as internal standards. The IR spectra were recorded on
a UR-20 spectrometer. The elemental compositions
were obtained with a Vario MICRO Cube Elementar
analyzer. The ee values were determined by chiral
HPLC on a Hitachi LaChrome Elite-2000 chromato-
graph using a Daicel column (0.46×25 cm); the chro-
matograms were processed by means of MultiKhrom
program. The copper content of the catalyst was
determined with a Varian 720-ES ICP-OES instrument.
The melting points were measured in open capillaries
using an Electrothermal 9100 melting point indicator;
uncorrected values are given. The purity of the isolated
compounds was checked, and the progress of reactions
was monitored, by TLC on Silica gel 60 F254 plates
(Merck, Germany). The products were isolated by
column chromatography on Macherey-Nagel 60 silica
gel (0.040–0.063 mm) using 2.5×25-cm columns.
1
(4S,4′S)-2,2′-[1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-
propane-2,2-diyl]bis(4-phenyl-4,5-dihydro-1,3-ox-
azole) (L2a). Yield 208 mg (85%), yellow oily mate-
1
rial. H NMR spectrum, δ, ppm: 1.66 s (3H, CCH3),
3.57–3.45 m (2H, CCH2), 4.15–4.10 m (2H, CH2O),
3
4.67–4.57 m (2H, CH2O), 5.11–5.20 t (1H, NCH, J =
8.4 Hz), 5.46–5.36 m (2H, CH2Ph), 7.32–7.15 m (16H,
H
arom). 13C NMR spectrum, δC, ppm: 21.84 (CCH3),
30.91 [CH(CH3)2], 33.16 [C(CH3)CH2], 53.74
(CH2Ph), 53.99 (CCH3), 55.99 and 56.09 (CH2O),
123.13 (NCH=C); 126.47, 126.58, 127.59, 127.72,
127.75, 128.32, 128.40, 128.43, 128.73 (CHarom);
134.49, 139.45, 142.96 (Carom); 145.96 (NCH=C),
172.46 and 172.87 (NCO). Found: m/z 514.2234
[M + Na]+. C30H29N5O2. Calculated: M + Na 514.2219.
4,4-Bis[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-
yl]pent-1-yne (L2a) and (4S,4′S)-2,2′-(pent-4-yne-2,2-
diyl)bis(4-isopropyl-4,5-dihydro-1,3-oxazole) (L2b)
were prepared according to the procedure described in
[41]; their physicochemical constants coincided with
published data.
(4S,4′S)-2,2′-[4-(1-Benzyl-1H-1,2,3-triazol-4-yl)-
propan-2,2-diyl]bis(4-isopropyl-4,5-dihydro-1,3-ox-
azole) (L2b). Yield 452 mg (87%), yellow oily mate-
1
rial. H NMR spectrum, δ, ppm: 0.77, 0.78 d [6H,
3
3
CH(CH3)2, J = 6.8 Hz], 0.84 d [6H, CH(CH3)2, J =
6.8 Hz], 1.46 s (3H, CCH3), 1.59–1.70 m [2H,
CH(CH3)2], 3.28–3.43 m (2H, CCH2), 3.78–3.93 m
(4H, CH2O, NCH), 4.08–4.10 d (1H, CH2O, J =
8.4 Hz), 4.15–4.17 d (1H, CH2O, J = 7.1 Hz), 5.40–
5.50 m (2H, CH2Ph), 7.17–7.38 m (6H, Harom).
13C NMR spectrum, δC, ppm: 17.61 and 17.79
[CH(CH3)2], 18.54 and 18.83 [CH(CH3)2], 22.86
(CCH3), 28.83 [CH(CH3)2], 33.16 [C(CH3)CH2], 53.93
(CCH3), 54.04 (CH2Ph), 57.28 and 57.49 (CH2O),
62.66 and 63.33 (NCH), 123.56 (NCH=C), 127.92
(2C, CHarom), 128.59 (CHarom), 128.96 (2C, CHarom),
134.44 (Carom), 143.74 (NCH=C), 172.95 and 173.62
(NCO). Found: m/z 446.5548 [M + Na]+. C24H33N5O2.
Calculated: M + Na 446.5508.
Azidomethylpolystyrene. Chloromethyl polysty-
rene (f = 1.6 mmol/g), 6 g, was added to a solution of
8 g (123 mmol) of sodium azide in 40 mL of DMF, and
the mixture was heated for 24 h at 60°C. After cooling,
the mixture was filtered, and the precipitate was
washed with water (400 mL), THF (200 mL), THF–
MeOH (1 :1; 200 mL), MeOH (200 mL), and THF
(200 mL), and dried under reduced pressure at 60°C.
Yield 5.74 g (96%), white powder (f = 1.62 mmol/g).
IR spectrum (KBr): ν 2089 cm–1 (N3). Found, %:
C 85.51; H 7.67; N 6.82. C45H49N3. Calculated, %:
C 85.58; H 7.77; N 6.66.
“Click” reactions with benzyl azides (general
procedure). Bis(oxazoline) L1a or L1b, 0.5 mmol, was
dissolved in 2.5 mL of THF, and 21 mg (0.05 mmol,
10 mol %) of TTTA, a solution of 40 mg (0.2 mmol,
4-[(4S,4′S)-2,2′-Bis(4-isopropyl-4,5-dihydro-
1,3-oxazol-2-yl)propyl]-1H-1,2,3-triazol-1-ylmethyl
polystyrene (L3). A 100-mL flask was charged with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

POLYSTYRENE-SUPPORTED Cu(II)-R-Box AS RECYCLABLE CATALYST
1723
1.12 g (3.84 mmol) of (4S,4′S)-2,2′-(pent-4-yn-2,2-
diyl)bis(4-isopropyl-4,5-dihydro-1,3-oxazole), 2 g of
azido polystyrene (f = 1.62 mmol/g), 20 mL of DMF–
THF (1:1), 61 mg (0.32 mmol) of copper(I) iodide,
137 mg (0.32 mmol) of TTTA, and 0.827 g (1.11 mL,
6.4 mmol) of N,N-diisopropylethylamine (DIPEA).
The mixture was stirred for 30 h at 60°C and filtered,
and the precipitate was washed with DMF (400 mL),
DMF–THF (1:1, 400 mL), and THF (400 mL) and
dried under reduced pressure. Yield 2.82 g (96%),
yellow powder, f = 1.06 mmol/g. IR spectrum (KBr),
ν: 1657 cm–1 (C=N); no band assignable to azido group
was observed. Found, %: C 80.35; H 7.91; N 7.45.
C62H75N5O2. Calculated, %: C 80.78; H 8.14; N 7.60.
mp 147–149°C; published data [57]: mp 150–151°C;
[α]D20 = +27.9° (c = 1.00, CH2Cl2), 37.9% ee [Daicel
Chiralcel OD-H; hexane–propan-2-ol, 85:15, flow rate
1 mL/min; 25°C, λ 254 nm; retention time 13.5 min
(major isomer), 11.0 min (minor isomer)]. The
1H and 13C NMR spectra were consistent with those
reported in [43].
Diethyl (S)-2-[(5-methoxy-1H-indol-3-yl)-
(phenyl)methyl]malonate (3c). Yield 289 mg (73%),
white powder, mp 118–120°C; published data [58]:
mp 143–145°C, [α]D20 = +14.0° (c = 1.00, CH2Cl2),
94.2% ee [Daicel Chiralcel OD-H; hexane–propan-
2-ol, 85:15, flow rate 1 mL/min; 25°C, λ 254 nm;
retention time 11.9 min (major isomer), 9.5 min (minor
isomer)]. The 1H and 13C NMR spectra were consistent
with those reported in [43].
Copper(II) trifluoromethanesulfonate complex
with 4-[(4S,4′S)-2,2′-bis(4-isopropyl-4,5-dihydro-
1,3-oxazol-2-yl)propyl]-1H-1,2,3-triazol-1-ylmethyl
polystyrene [Cu(OTf)2 ·L3]. A 100-mL flask was
charged with 1.79 g of L3 (f = 1.06 mmol/g), 50 mL of
THF–DMF (1:1), and 687.3 mg (1.90 mmol) of
Cu(OTf)2. The mixture was stirred for 24 h, and the
resulting resin was filtered off, washed with THF–
DMF (1:1, 2×100 mL) and THF (2×100 mL), and
dried under reduced pressure at 70°C. Yield 2.32 g
(94%), green powder, f = 0.52 mmol/g. Found, %:
C 69.07; H 6.84; N 6.30; S 5.54. C62H75N5O2·Cu(OTf)2.
Calculated, %: C 69.44; H 6.78; N 6.33; S 5.69.
Diethyl (S)-2-[(5-methyl-1H-indol-3-yl)(phenyl)-
methyl]malonate (3d). Yield 346 mg (91%), white
powder, mp 174.5–176°C; published data [58]:
mp 176.5–178°C, [α]D20 = +39.5° (c = 1.00, CH2Cl2),
91.2% ee [Daicel Chiralcel OD-H; hexane–propan-2-
ol, 85 : 15, flow rate 1 mL/min; 25°C, λ 254 nm;
retention time 6.9 min (major isomer), 8.3 min (minor
isomer)]. The 1H and 13C NMR spectra were consistent
with those reported in [43].
Diethyl (S)-2-[(5-bromo-1H-indol-3-yl)(phenyl)-
methyl]malonate (3e). Yield 374 mg (84%), white
powder, mp 146–147°C, [α]D20 = –12.9° (c = 1.00,
CH2Cl2), 87.2% ee [Daicel Chiralcel OD-H; hexane–
propan-2-ol, 85 : 15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 8.9 min (major isomer),
7.3 min (minor isomer)]. The 1H and 13C NMR spectra
were consistent with those reported in [59].
Reaction of indoles with benzylidenemalonates
(general procedure). A solution of 1 mmol of benzyli-
denemalonate 2a–2d and 2 mmol of indole 1a–1f in
4 mL of THF–EtOH (1 : 1) was cooled to –30°C,
200 mg (10 mol %) of Cu(OTf)2·L3 was added, and
the mixture was stirred for 21 days at –30°C. When the
reaction was complete (TLC, CH2Cl2–petroleum ether,
1:1), the catalyst was filtered off and washed with
THF (5×10 mL) and methylene chloride (2×10 mL).
The filtrate was evaporated, and the product was
isolated by column chromatography using methylene
chloride–petroleum ether (1:3 to 1:1) and then pure
methylene chloride as eluents.
Diethyl (S)-2-[(1-methyl-1H-indol-3-yl)(phenyl)-
methyl]malonate (3f). Yield 195 mg (51%), white
powder, mp 84.5–85.5°C; published data [60]: mp 87–
88°C; [α]D20 = +50.4° (c = 1.00, CH2Cl2), 66.2% ee
[Daicel Chiralcel AD-H; hexane–propan-2-ol, 90:10,
flow rate 1 mL/min; 25°C, λ 254 nm; retention time
20.9 min (major isomer), 26.0 min (minor isomer)].
Diethyl (S)-2-[(1H-indol-3-yl)(phenyl)methyl]-
malonate (3a). Yield 294 mg (81%), white powder,
mp 178–179°C; published data [50]: mp 178–180°C;
[α]D20 = +73.0° (c = 1.00, CH2Cl2), 92.4% ee [Daicel
Chiralcel OD-H; hexane–propan-2-ol, 85:15, flow rate
1 mL/min; 25°C, λ 254 nm; retention time 9.2 min
(major isomer), 7.7 min (minor isomer)]. The
1H and 13C NMR spectra were consistent with those
reported in [35].
1
The H and 13C NMR spectra were consistent with
those reported in [46].
Diethyl (S)-2-[(4-bromophenyl)(1H-indol-3-yl)-
methyl]malonate (3g). Yield 355 mg (80%), white
powder, mp 146–147°C; published data [61]: mp 148–
150°C; [α]D20 = +25.5° (c = 1.00, CH2Cl2), 88.8% ee
[Daicel Chiralcel OD-H; hexane–propan-2-ol, 85:15,
flow rate 1 mL/min; 25°C, λ 254 nm; retention time
8.7 min (major isomer), 8.1 min (minor isomer)]. The
Dimethyl (S)-2-[(1H-indol-3-yl)(phenyl)methyl]-
malonate (3b). Yield 197 mg (58%), white powder,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESYATKIN et al.
1724
1H and 13C NMR spectra were consistent with those
reported in [35].
CH2Cl2), 85.7% ee [Daicel Chiralcel OD-H; hexane–
propan-2-ol, 85 : 15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 8.5 min (major isomer),
Diethyl (S)-2-[(4-bromophenyl)(5-methoxy-1H-
indol-3-yl)methyl]malonate (3h). Yield 409 mg
(86%), white powder, mp 141–142°C, [α]D20 = –23.5°
(c = 1.00, CH2Cl2), 89.4% ee [Daicel Chiralcel OD-H;
hexane–propan-2-ol, 90:10, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 15.7 min (major isomer),
1
7.8 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
1.01 t and 1.07 t (3H, CH3, J = 7.2 Hz), 3.93–4.10 m
3
(4H, OCH2), 4.20 d [1H, CH(COOEt)2, J = 11.6 Hz],
3
4.97 d (1H, 3-CH, J = 11.6 Hz), 7.21–7.24 m (3H,
Harom), 7.15–7.18 m (2H, Harom), 7.30–7.43 m (2H,
4
1
H
arom), 7.63 d (1H, Harom, J = 1.8 Hz), 8.14 s (1H,
14.8 min (minor isomer)]. H NMR spectrum, δ, ppm:
NH). 13C NMR spectrum, δC, ppm: 13.89 and 13.97
(OCH2CH3), 43.06 (3-CH), 58.23 [CH(COOEt)2],
61.81 (OCH2CH3), 112.74 (CHarom), 113.19 (Carom),
116.26 (Carom), 120.97 (Carom), 121.82 (CHarom), 122.38
(CHarom), 125.55 (CHarom), 128.33 (Carom), 129.95 (2C,
CHarom), 131.73 (2C, CHarom), 134.91 (Carom), 140.25
(Carom), 167. 59 and 167. 76 (C=O). Found:
m/z 543.9687 [M + Na]+. C22H21Br2NO4. Calculated:
M + Na 543.9735.
3
1.01 t and 1.06 t (3H, OCH2CH3, J = 7.1 Hz), 3.78 s
3
(3H, OCH3), 4.01 t and 4.02 t (OCH2CH3, J =
3
4
7.1 Hz), 4.21 d.d [1H, CH(COOEt)2, J = 11.6, J =
1.4 Hz], 4.99 d (1H, 3-CH, 3J = 11.6 Hz), 6.80 d.d (1H,
arom, J = 8.8, J = 2.4 Hz), 6.90 d (1H, Harom, J =
2.3 Hz), 7.10–7.15 m (1H, Harom), 7.15–7.21 m (1H,
arom), 7.21–7.26 m (2H, Harom), 7.33–7.39 m (2H,
3
4
H
H
Harom), 7.98 s (1H, NH). 13C NMR spectrum, δC, ppm:
13.90 and 13.96 (OCH2CH3), 42.34 (3-CH), 55.96
(OCH3), 58.20 [CH(COOEt)2], 61.72 (OCH2CH3),
101.22 (CHarom), 111.90 (CHarom), 112.67 (CHarom),
116.25 (Carom), 120.73 (Carom), 121.73 (CHarom), 127.07
(Carom), 129.58 (Carom), 130.08 (2C, CHarom), 131.57
(2C, CHarom), 140.64 (Carom), 154.15 (C5), 167.66 and
167. 93 (C=O). Found: m/z 473. 0760 [M]+.
C23H24BrNO5. Calculated: M 473.0838.
Diethyl (S)-2-[(4-bromophenyl)(1-methyl-1H-in-
dol-3-yl)methyl]malonate (3k). Yield 210 mg (46%),
white powder, mp 116–117°C, [α]D20 = +13.7° (c = 1.00,
CH2Cl2), 85.7% ee [Daicel Chiralcel AD-H; hexane–
propan-2-ol, 90 : 10, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 26.9 min (major isomer),
1
35.7 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
1.00 t and 1.06 t (3H, OCH2CH3, J = 7.1 Hz), 3.74 s
Diethyl (S)-2-[(4-bromophenyl)(5-methyl-1H-
indol-3-yl)methyl]malonate (3i). Yield 375 mg
(82%), white powder, mp 170–171°C, [α]D20 = –2.2°
(c = 1.00, CH2Cl2), 90.9% ee [Daicel Chiralcel OD-H;
hexane–propan-2-ol, 85:15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 8.2 min (major isomer),
(3H, NCH3), 3.92–4.06 m (4H, OCH2CH3), 4.22 d
3
[1H, CH(COOEt)2, J = 11.6 Hz], 5.03 d (1H, 3-CH,
3J = 11.6 Hz), 6.96–7.08 m (2H, Harom), 7.10–7.28 m
(4H, Harom), 7.29–7.40 m (2H, Harom), 7.49 d (1H,
Harom, J = 7.8 Hz). 13C NMR spectrum, δC, ppm: 13.86
and 13.95 (OCH2CH3), 32.92 (NCH3), 42.33 (3-CH),
58.23 [CH(COOEt)2], 61.64 (OCH2CH3), 109.29
(CHarom), 114.93 (Carom), 119.26 (CHarom), 119.42
(CHarom), 120.62 (Carom), 122.07 (CHarom), 125.81
(CHarom), 127.05 (Carom), 130.04 (2C, CHarom), 131.54
(2C, CHarom), 137.13 (Carom), 140.97 (Carom), 167.77
and 167.87 (C=O). Found: m/z 457.0940 [M]+.
C23H24BrNO4. Calculated: M 457.0888.
1
7.3 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
1.00 t and 1.06 t (3H, OCH2CH3, J = 7.1 Hz), 2.39 s
(3H, 5-CH3), 3.98–4.04 m (4H, OCH2CH3), 4.23 d
3
[1H, CH(COOEt)2, J = 11.7 Hz], 5.02 d (1H, 3-CH,
3
3J = 11.6 Hz), 6.97 d (1H, Harom, J = 8.3 Hz), 7.08–
3
7.15 m (1H, Harom), 7.18 d (1H, Harom, J = 8.3 Hz),
7.22–7.31 m (3H, Harom), 7.32–7.41 m (2H, Harom).
13C NMR spectrum, δC, ppm: 13.87 and 13.96
(OCH2CH3), 21.65 (5-CH3), 42.32 (3-CH), 58.31
[CH(COOEt)2], 61.68 (OCH2CH3), 110.87 (CHarom),
116.03 (Carom), 118.87 (CHarom), 120.68 (Carom), 121.11
(CHarom), 124.22 (CHarom), 126.86 (CHarom), 129.01
(Carom), 130.10 (2C, CHarom), 131.55 (2C, CHarom),
134.68 (Carom), 140.80 (Carom), 167.83 and 167.89
(C=O). Found: m/z 457.0750 [M]+. C23H24BrNO5. Cal-
culated: M 457.0888.
Diethyl (S)-2-[(4-bromophenyl)(5-iodo-1H-indol-
3-yl)methyl]malonate (3l). Yield 433 mg (76%),
white powder, mp 183–184°C, [α]D20 = –67.2° (c = 1.00,
CH2Cl2), 86.4% ee [Daicel Chiralcel OD-H; hexane–
propan-2-ol, 85 : 15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 8.5 min (major isomer),
1
7.7 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
1.01 t and 1.07 t (3H, OCH2CH3, J = 7.1 Hz), 3.94–
Diethyl (S)-2-[(5-bromo-1H-indol-3-yl)(4-bromo-
phenyl)methyl]malonate (3j). Yield 408 mg (78%),
white powder, mp 157–158°C, [α]D20 = –53.2° (c = 1.00,
4.08 m (4H, OCH2CH3), 4.19 d [1H, CH(COOEt)2,
3
3J = 11.6 Hz], 4.97 d (1H, 3-CH, J = 11.6 Hz), 7.05–
7.15 m (2H, Harom), 7.17–7.25 m (2H, Harom), 7.33–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

POLYSTYRENE-SUPPORTED Cu(II)-R-Box AS RECYCLABLE CATALYST
1725
7.45 m (3H, Harom), 7.84 s (1H, CHarom), 8.12 s (1H,
NH). 13C NMR spectrum, δC, ppm: 13.92 and 13.98
(OCH2CH3), 42.00 (3-CH), 58.30 [CH(COOEt)2],
61.81 (OCH2CH3), 83.42 (C5), 113.23 (CHarom), 116.01
(Carom), 120.97 (Carom), 121.99 (CHarom), 128.10
(CHarom), 129.16 (Carom), 129.95 (2C, CHarom), 131.03
(CHarom), 131.74 (2C, CHarom), 135.34 (Carom), 140.28
(Carom), 167. 59 and 167. 74 (C=O). Found:
m/z 568.9640 [M]+. C22H21BrINO4. Calculated:
M 568.9698.
3J = 11.5 Hz], 5.12 d (1H, 3-CH, 3J = 11.5 Hz), 7.10 d
3
4
(1H, Harom, J = 8.5 Hz), 7.17 d (1H, Harom, J =
2.2 Hz), 7.41 q (2H, Harom, J = 8.6, 1.1 Hz), 7.52 d
(2H, Harom, 3J = 8.6 Hz), 7.83 s (1H, Harom), 8.12 d (1H,
3
H
arom, J = 8.7 Hz), 8.23 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 13.91 and 14.01 (OCH2CH3), 42.18
(3-CH), 57.88 [CH(COOEt)2], 62.02 (OCH2CH3),
83.62 (C5), 113.40 (CHarom), 114.92 (Carom), 122.32
(CHarom), 123.94 (2C, CHarom), 127.80 (CHarom), 128.93
(Carom), 129.14 (2C, CHarom), 131.26 (CHarom), 135.33
(Carom), 146.99 (Carom), 148.88 (Carom), 167.33 and
167.40 (C=O). Found: m/z 559.0320 [M + Na]+.
C22H21IN2O6. Calculated: M + Na 559.0342.
Diethyl (S)-2-[(1H-indol-3-yl)(4-nitrophenyl)-
methyl]malonate (3m). Yield 410 mg (99%), yellow
powder, mp 108–110°C; published data [61]: mp 105–
107°C; [α]D20 = +9.1° (c = 1.00, CH2Cl2), 85.5% ee
[Daicel Chiralcel AS-H; hexane–propan-2-ol, 85:15,
flow rate 1 mL/min; 25°C, λ 254 nm; retention time
21.1 min (major isomer), 34.5 min (minor isomer)].
Addition of indoles to (E)-2-oxo-4-phenylbut-
3-enoate (general procedure). A solution of 380 mg
(2 mmol) of (E)-2-oxo-4-phenylbut-3-enoate (4) and
1 mmol of indole 1a–1f in 4 mL of THF–MeOH (1:1)
was cooled to –30°C, 200 mg (10 mol %) of
Cu(OTf)2·L3 was added, and the mixture was kept for
27 days at –30°C. When the reaction was complete
(TLC, Et2O–petroleum ether, 1:1), the catalyst was
filtered off and washed with THF (5×10 mL) and
methylene chloride (2×10 mL). The filtrate was evap-
orated, and the product was isolated by column chro-
matography (gradient elution with Et2O–petroleum
ether, 1:3 to 1:1).
1
The H and 13C NMR spectra were consistent with
those given in [43].
Diethyl (S)-2-[(5-methoxy-1H-indol-3-yl)-
(4-nitrophenyl)methyl]malonate (3n). Yield 305 mg
(69%), yellow powder, mp 157–158°C, [α]D20 = –49.8°
(c = 1.00, CH2Cl2), 78.0% ee [Daicel Chiralcel AS-H;
hexane–propan-2-ol, 85:15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 27.0 min (major isomer),
1
33.8 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
Methyl (S)-4-(1H-indol-3-yl)-2-oxo-4-phenyl-
butanoate (5a). Yield 253 mg (82%), white powder,
mp 137–138°C; published data [62]: mp 99–102°C,
[α]D20 = –22.7° (c = 1.00, CH2Cl2), –12.0 (c = 1.00,
CHCl3), 30.9% ee [Daicel Chiralcel D-H; hexane–
propan-2-ol, 80 : 20, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 18.4 min (major isomer),
1.02 t and 1.07 t (3H, OCH2CH3, J = 7.1 Hz), 3.79 s
(3H, OCH3), 3.98–4.08 m (4H, OCH2CH3), 4.28 d
3
[1H, CH(COOEt)2, J = 11.5 Hz], 5.14 d (1H, 3-CH,
3
4
3J = 11.5 Hz), 6.82 d.d (1H, Harom, J = 8.8, J =
4
2.3 Hz), 6.89 d (1H, Harom, J = 2.2 Hz), 7.16–7.23 m
(2H, Harom), 7.54 d (2H, Harom, 3J = 8.7 Hz), 8.03 s (1H,
NH), 8.11 d (2H, Harom, J = 8.7 Hz). 13C NMR spec-
3
1
16.8 min (minor isomer)]. The H and 13C NMR
trum, δC, ppm: 13.90 and 14.01 (OCH2CH3), 42.52
(3-CH), 56.00 (5-OCH3), 57.80 [CH(COOEt)2], 61.93
(OCH2CH3), 100.99 (CHarom), 112.08 (CHarom), 112.85
(CHarom), 115.26 (Carom), 122.03 (CHarom), 123.80 (2C,
CHarom), 126.89 (Carom), 129.23 (2C, CHarom), 131.46
(Carom), 149.33 (Carom), 154.35 (C5), 167.56 (C=O).
Found: m/z 463.1463 [M + Na]+. C23H24N2O7. Calcu-
lated: M + Na 463.1481.
spectra were consistent with those given in [36].
Methyl (S)-4-(5-methoxy-1H-indol-3-yl)-2-oxo-4-
phenylbutanoate (5b). Yield 229 mg (68%), orange
powder, mp 134–136°C; published data [63]: mp 135–
136°C, [α]D20 = +10.1° (c = 1, CH2Cl2), 32.6% ee [Daicel
Chiralcel OD-H; hexane–propan-2-ol, 80:20, flow rate
1 mL/min; 25°C, λ 254 nm; retention time 19.5 min
(major isomer), 21.4 min (minor isomer)]. The
1H and 13C NMR spectra were consistent with those
given in [36].
Diethyl (S)-2-[(5-iodo-1H-indol-3-yl)(4-nitro-
phenyl)methyl]malonate (3o). Yield 436 mg (81%),
white powder, mp 181–182°C, [α]D20 = –98.6° (c = 1.00,
CH2Cl2), 78.0% ee [Daicel Chiralcel AS-H; hexane–
propan-2-ol, 85 : 15, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 21.5 min (major isomer),
Methyl (S)-4-(5-methyl-1H-indol-3-yl)-2-oxo-4-
phenylbutanoate (5c). Yield 233 mg (73%), orange
powder, mp 137–139°C; published data [62]: mp 125–
126°C; [α]D20 = +6.8° (c = 0.99, CH2Cl2), 36.6% ee
[Daicel Chiralcel OD-H; hexane–propan-2-ol, 85:15,
flow rate 1 mL/min; 25°C, λ 254 nm; retention time
1
28.9 min (minor isomer)]. H NMR spectrum, δ, ppm:
3
1.03 t and 1.07 t (3H, OCH2CH3, J = 7.1 Hz), 3.96–
4.09 m (4H, OCH2CH3), 4.27 d [1H, CH(COOEt)2,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 12 2016

DESYATKIN et al.
1726
2. Bates, R., Organic Synthesis Using Transition Metals,
New York: Wiley, 2012.
20.3 min (major isomer), 21.3 min (minor isomer)].
1
The H and 13C NMR spectra were consistent with
3. Lewis Acids in Organic Synthesis, Yamamoto, H., Ed.,
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those given in [51].
Methyl (S)-4-(5-bromo-1H-indol-3-yl)-2-oxo-4-
phenylbutanoate (5d). Yield 304 mg (79%), orange
powder, mp 160–161°C, [α]D20 = +9.9° (c = 0.51,
CH2Cl2), 53.8% ee [Daicel Chiralcel OD-H; hexane–
propan-2-ol, 90 : 10, flow rate 1 mL/min; 25°C,
λ 254 nm; retention time 46.5 min (major isomer),
50.6 min (minor isomer)]. The H and 13C NMR spec-
1
tra were consistent with those given in [54].
Methyl (S)-4-(5-iodo-1H-indol-3-yl)-2-oxo-4-
phenylbutanoate (5e). Yield 272 mg (66%), white
powder, mp 152.5–153.5°C, [α]D20 = +16.0° (c = 1.02,
CH2Cl2), 83.1% ee [Daicel Chiralcel OD-H; hexane–
propan-2-ol, 80:20, flow rate 0.5 mL/min; 25°C,
λ 254 nm; retention time 46.0 min (major isomer),
1
49.9 min (minor isomer)]. H NMR spectrum, δ, ppm:
3.58 d.d (1H, CH2CO, 2J = 17.6, 3J = 7.6 Hz), 3.62 d.d
2
3
(1H, CH2CO, J = 17.0, J = 7.2 Hz), 3.76 s (3H,
3
OCH3), 4.85 t (1H, 3-CH, J = 7.6 Hz), 6.99 d (1H,
3
3
2-H, J = 2.4 Hz), 7.09 d (1H, Harom, J = 8.8 Hz),
7.18–7.22 m (1H, Harom), 7.28–7.32 m (4H, Harom),
7.36 d.d (1H, Harom, 3J = 8.8, 4J = 1.8 Hz), 7.70–7.74 m
(1H, Harom), 8.07 s (1H, NH). 13C NMR spectrum, δC,
ppm: 37.40 (3-CH), 45.64 (CH2CO), 53.00 (OCH3),
83.07 (C5), 113.11 (CHarom), 117.71 (Carom), 122.27
(CHarom), 127.60 (CHarom), 126.78 (CHarom), 128.12
(2C, CHarom), 128.64 (2C, CHarom), 128.95 (Carom),
130.68 (CHarom), 135.53 (Carom), 142.66 (Carom), 161.18
(COOCH3), 192.33 (CH2CO). Found, m/z: 456.0051
[M + Na]+, 432.0086 [M]–. C19H16INO3. Calculated:
M + Na 456.0073, M 432.0102.
Methyl (S)-4-(1-methyl-1H-indol-3-yl)-2-oxo-
4-phenylbutanoate (5f). Yield 213 mg (66%), orange
powder, mp 118–119°C; published data [36]:
mp 100°C, [α]D20 = –14.1° (c = 0.64, CHCl3), 5.9% ee
[Daicel Chiralcel OD-H; hexane–propan-2-ol, 80:20,
flow rate 1 mL/min; 25°C, λ 254 nm; retention time
18.9 min (major isomer), 16.1 min (minor isomer)].
18. Clarke, R.J. and Shannon, I.J., Chem. Commun., 2001,
p. 1936.
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́
́
́
Verdugo, E., Herrerıas, C.I., Luis, S.V., Mayoral, J.A.,
́
Sánchez-Verdú, P., and Tolosa, J., Tetrahedron: Asym-
metry, 2003, vol. 14, p. 773.
1
The H and 13C NMR spectra were consistent with
20. Langham, C., Piaggio, P., McMorn, P., Willock, D.J.,
Hutchings, G.J., Bethell, D., Lee, D.F., Bulman
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those given in [36].
This study was performed under financial support
by the Russian Science Foundation (project no. 14-23-
00186).
21. Sakthivel, A., Hijazi, A.K., Hanzlik, M., Chiang, A.S.T.,
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