Chirally n-substituted indole-2-carbaldehydes. Preparation and use in asymmetric synthesis

Article abstract of DOI:10.1007/s10593-005-0315-0

A simple method is proposed for the synthesis of optically active indole-2-carbaldehydes via alkylation of 2-cyanoindole by optically active secondary alcohols and subsequent reduction of the cyano group to an aldehyde. Reaction of the aldehydes obtained

Full text of DOI:10.1007/s10593-005-0315-0

Chemistry of Heterocyclic Compounds, Vol. 41, No. 10, 2005
CHIRALLY N-SUBSTITUTED INDOLE-
2-CARBALDEHYDES. PREPARATION
AND USE IN ASYMMETRIC SYNTHESIS
N. E. Golantsov1, A. V. Karchava1, Z. A. Starikova2, F. M. Dolgushin2, and M. A. Yurovskaya1
A simple method is proposed for the synthesis of optically active indole-2-carbaldehydes via alkylation
of 2-cyanoindole by optically active secondary alcohols and subsequent reduction of the cyano group to
an aldehyde. Reaction of the aldehydes obtained with aromatic amines gave imines whose reaction with
the Danishefsky diene was studied. The structure of the major diastereomer of (2R')-1-phenyl-2-[1-
((1R')-1-phenylethyl)indol-2-yl]-1,2,3,4-tetrahydropyridine-4-one and minor diastereomer (2S)-2-[1-
((1S)-2-methoxy-1-phenylethyl)indol-2-yl]-1-phenyl-1,2,3,4-tetrahydropyridine-4-one respectively were
established by X-ray analysis.
Keywords: N-substituted indoles, chiral aldehydes, 2-cyanoindole, aza Diels–Alder reaction,
asymmetric synthesis, Mitsunobu reaction.
The preparation of optically active indole derivatives remains an important problem for synthetic
chemists [1]. At this time a large number of examples of the asymmetric synthesis involving chiral indole
derivatives have been reported [1-3] but instances of the use in asymmetric synthesis of indole derivatives
containing a chiral substituent on the nitrogen atom are rare [4, 5]. We propose a simple method for preparing
chiral N-substituted indole-2-carbaldehydes (1a,b) and have studied their potential use in asymmetric synthesis
in the case of the aza Diels–Alder reaction.
OH
R1
LiAlH(OEt)3
or DIBAL-H
Ph
CHO
CN
CN
N
THF
N
N
DIAD, PPh3, THF
H
Ph
R1
1a,b
Ph
2
R1
3a,b
1, 3 a R1 = Me, b R1 = CH2OMe
The starting compound was 2-cyanoindole (2). We have previously shown the possibility of alkylating
the nitrile 2 with ethyl (S)-2-hydroxypropionate under Mitsunobu reaction conditions in the presence of the
classical oxidative-reductive system PPh3-azodicarboxylate [7]. The Mitsunobu reaction occurs in mild
__________________________________________________________________________________________
1
M. V. Lomonosov State University, Moscow 119234, Russia; e-mail: yumar@org.chem.msu.ru.
2 A. N. Nesmeyanov Institute of Organoelement Compounds, Moscow 119991, Russia. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1540-1550, October, 2005. Original article submitted June
14, 2005.
1290
0009-3122/05/4110-1290©2005 Springer Science+Business Media, Inc.

conditions with complete inversion of configuration [7]. For this work racemic 1-phenylethanol and optically
25
active (R)-2-methoxy-1-phenylethanol ([α]D -32.1° (c 1.4, CH2Cl2), enantiomeric excess 63%) [8, 9]) were
used for alkylating 2-cyanoindole in the presence of PPh3 and diisopropyl azodicarboxylate (DIAD). The
alkylation products 3a,b were obtained in high yields. For compound 3b it was particularly important to carry
out the Mitsunobu reaction at 0-5°C because a concurrent elimination takes place even at room temperature and
the yield of the alkylation product does not exceed 50%.
LiAlH(OEt)3 [10] was used for reduction of the cyano group of compound 3a to an aldehyde but for
nitrile 3b the given reduction surprisingly proved ineffective and variation of the reaction conditions did not lead
to a positive result. Diisobutyl aluminum hydride (DIBAL-H) [11] was used to reduce 3b and the aldehyde 1b
was obtained in high yield.
The aldehydes 1a,b were converted to the imines 4a-d by reaction with aromatic amines. The aza Diels–
Alder reaction involving imines is widely used in the asymmetric synthesis of nitrogen-containing heterocyclic
systems [12]. Electron-excessive siloxidenes [13, 14] are often used as dienes. The reaction of the imines with
such dienes can occur together or in stages including a tandem sequence of Mannich and Michael reactions [12,
14, 15]. The Danishefsky diene (1-methoxy-3-trimethylsiloxybuta-1,3-diene) has proved particularly efficient
[13] and leads to substituted 1,2,3,4-tetrahydropyridin-4-ones. An indole fragment containing a piperidine
substituent in position 2 occurs in the composition of a whole series of alkaloids and biologically active
materials and the synthesis of such compounds is of significant interest [2, 3].
We have studied the reaction of the prepared imines 4a-d with the Danishefsky diene. The imines 4a and
4b were tried out under different reaction conditions and catalysts. Diastereomer products of cycloaddition 5a,b
and 6a,b were observed in different ratios and with yields from low to high. The results of the investigation are
summarized in Table 1.
The best results were obtained using anhydrous ZnCl2 (1.1 equivalents) as catalyst and methylene
chloride as solvent. The yield of the major isomer for imine 4b with the reaction carried out at -60°C was 70%.
A significant difference in the ratio of diastereomers for imines 4a and 4b was not observed.
SiMe3
O
R2
OMe
R2NH2
N
1a,b
TsOH, PhH
N
Ph
R1
4a–d
R2
R2
Ph
N
N
+
N
N
O
O
Ph
R1
R1
6a–d
5a–d
4-6 a R1 = Me, b-d R1 = MeOCH2; a, b R2 = Ph, c R2 = o-MeOC6H4,
d R2 = o-FC6H4
Increase in the amount of catalyst for the imine 4b led to a small decrease in the yield and the
diastereoselectivity. When the reaction was carried out in LiClO4 solution in ether (0.5 molar) [16] the yield was
close to quantitative but the diastereoselectivity was markedly lower. The use of a proton acid in aqueous-
organic medium as catalyst [17] did not proved effective.
1291

TABLE 1. Reaction of Imines 4a-d with the Danishefsky Diene under
Varying Conditions
Reaction conditions
No Imine
Catalyst
Yield 5+6, %
5 : 6
Solvent
T, °С
1
4а
4а
4а
4b
4b
4b
4b
4b
4c
4d
ZnCl2, 1.1 eq.
ZnCl2, 1.1 eq.
ZnCl2, 1.1 eq.
ZnCl2, 1.1 eq.
ZnCl2, 2.1 eq.
TFA, 0.1 eq.
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN–H2O
Et2O
-60
-20
-60
-60
-60
-50
20
25
68
72
90
85
30
95
53
79
23
35 : 65
34 : 66
25 : 75
22 : 78
25 : 75
23 : 77
37 : 63
24 : 76
16 : 84
19 : 81
2
3
4
5
6
7
0.5 mol/l LiClO4
0.5 mol/l LiClO4
ZnCl2, 1.1 eq.
ZnCl2, 1.1 eq.
8
THF
-60
-60
-60
9
10
CH2Cl2,
CH2Cl2,
The cycloaddition products with good diastereoselectivity were obtained in the reaction of the
Danishefsky diene with the imines 4c and 4d using methylene chloride at -60°C in the presence of anhydrous
ZnCl2. The yield for the imine 4d prepared from o-fluoroaniline was moderate.
Attempts to carry out the aza Diels–Alder reaction with imines obtained from the aldehydes 1a,b and
2-aminopyridine under similar conditions did not give the corresponding cycloaddition products but the
Mannich reaction products 7a and 7b were produced in high yield as a mixture of diastereomers. The ratio of
diastereomers was 1:2 in both cases which is significantly lower that in the case of the cycloaddition.
NH2
N
1.
2.
N
NH
OMe
1a,b
N
SiMe3
O
O
Ph
R1
OMe
7a,b
7 a R1 = Me; b R1 = MeOCH2
The diastereomers 5 and 6 have a marked difference in Rf when chromatographed on silica gel and can
be separated quite readily in the pure state by preparative column chromatography.
The structure of the major diastereomer 6a and the minor isomer 5b were determined by X-ray analysis
of their single crystals (Figs. 1 and 2). The structure of 6a contains two crystallographically independent
molecules, differing in the rotation about the Ph-rings.
The molecules have similar structures with the exception of the orientation of the phenyl ring C(22)-
C(27). The indole ring, atoms C(9) and C(20) form a planar fragment (plane 1), relative to which the
1,2,3,4-tetrahydropyridin-4-one ring is positioned orthogonally, the dihedral angle between plane 1 and the mean
square plane of the 1,2,3,4-tetrahydropyridin-4-one ring (plane 2) being 79.7° (5b) and 88.7° and 90.2° (in the
individual molecules of 6a). The ring has a twist conformation, atoms C(9) and C(10) deviating from the plane
of atoms C(11), C(12), C(13), and N(2) to different sides. In both molecules of 6a they are symmetrical with an
average of 0.32 Å whereas in 5b they are 0.18 and 0.43 Å. The phenyl ring C(14)-C(19) is twisted relative to
plane 2 by about the same in all of the molecules (the corresponding dihedral angle being 31.5° (5b)
1292

Fig. 1. Structure of molecule 6a.
and 35.4 and 41.0° (6a)). The orientations of the Ph-ring C(22)-C(27) relative to the 1,2,3,4-tetrahydropyridin-4-
one ring in molecules 6a and 5b are different, the torsional angles C(8)–N(1)–C(20)–C(21) and C(8)–N(1)–
C(20)–C(22) being 106.0, 114.6 and -115.7, -125.3° respectively in 6a and 130.6, -101.5° in 5b.
Fig. 2. Structure of molecule 5b.
1293

TABLE 2. Some Bond Lengths (d) in the Molecule 5b and the Two
Independent Molecules of 6a
d, Å
Bond
5b
6а
1.389(2)
1.390(2)
1.511(2)
1.535(2)
1.519(2)
1.223(2)
1.435(2)
1.356(2)
1.361(2)
1.473(2)
1.423(2)
1.378(6)
1.393(5)
1.500(6)
1.533(6)
1.513(7)
1.232(6)
1.417(8)
1.347(7)
1.348(6)
1.477(6)
1.417(6)
1.386(5)
1.380(5)
1.507(5)
1.523(6)
1.517(7)
1.222(5)
1.417(7)
1.338(7)
1.359(6)
1.477(6)
1.411(6)
N(1)−C(8)
N(1)−C(1)
C(8)−C(9)
C(9)−C(10)
C(10)−C(11)
C(11)−O(1)
C(11)−C(12)
C(12)−C(13)
C(13)−N(2)
N(2)−C(9)
N(2)−C(14)
The geometric parameters for the molecules are identical. Several bond lengths are given in Table 2.
On the basis of the X-ray data it can be deduced that the diastereomers of 6a and 5b have the (R',R')-
configuration, i.e. the major diastereomer of 6a is (2R')-1-phenyl-2-[(1-((1R')-1-phenylethyl)indol-2-yl]-1,2,3,4-
tetrahydropyridin-4-one and the major diastereomer of 6b obtained from optically active (R)-2-methoxy-1-
phenylethanol is (2R)-2-[1-((1S)-2-methoxy-1-phenylethyl)indol-2-yl)]-1-phenyl-1,2,3,4-tetrahydropyridin-4-
one.
Hence we have shown that the aza Diels–Alder reaction of the Danishefsky diene with enamines
prepared from indole-2-carbaldehydes containing a chiral substituent on the nitrogen atom occurs with good
diastereoselectivity and with yields from moderate to high.
EXPERIMENTAL
X-ray Structural Investigation of 6a and 5b. Crystals of 6a were prepared by crystallization from a
1:1 mixture of ethyl acetate and petroleum ether and crystals of 5b from a 1:2 mixture of methylene chloride and
petroleum ether. The crystallographic parameters, experimental details, and structural refinement data are given
in Table 3.
The structures were solved by a direct method in which all of the non hydrogen atoms were localized in
electron density difference synthesis with F2hkl refinement in the anisotropic approximation. All of the hydrogen
atoms were placed in the geometrically calculated positions and refined using the "riding" model with
U(H) = 1.2 U(C) where U(C) is the equivalent temperature factor for the carbon atom with which the
corresponding H atom is bonded. Treatment of the experimental data, calculations, and illustrations were
performed using the programs [18-22]. Atomic coordinates and temperature factors have been deposited in the
Cambridge structural data bank.
IR spectra were obtained on a UR-20 instrument for suspensions in vaseline oil or for the pure
1
compounds. The specific rotation was measured on a Jasco DIP-360 polarimeter (589 nm). H NMR and
13C NMR spectra were recorded on a Bruker Avance-400 instrument (400 and 100 MHz respectively) for
solutions in DMSO-d6 (unless another solvent is quoted) and the internal standard was TMS. UPT experiments
were carried out for compounds 5a,b and 6a-d.
1294

TABLE 3. Crystallographic Data and Refinement Parameters for
Compounds 6a and 5b
Parameter
Empirical formula
6a
5b
C27H24N2O
392.48
Cc, 8
C28H26N2О2
422.51
Mol. weight
Space group, Z
P21/n, 4
100(2)
Temperature, K
293(2)
Crystal lattice parameters, Å
a
21.68(2)
10.462(6)
8.7334(4)
17.2868(8)
b
c
18.51(1)
14.4271(7)
β, deg
99.52(5)
90.272(1)
Unit cell volume, V, Å3
4140(14)
2178.1(2)
Dcalc, g·cm-3
1.340
1.288
Color and crystal form
Colorless needle
0.40 × 0.35 × 0.25
CAD4 Enraf-Nonius
Light yellow prism
0.40 × 0.30 × 0.08
Bruker SMART
Size, mm
Diffractometer
Irradiation
MoKα (λ = 0.71073 Å)
µ, cm-1
0.77
θ −5/3θ
0.81
φ/ω
Scanning mode
2θmax, deg
46.0
58.74
Total reflections
3118
23332
Number of independent reflections (Rint)
2947 (0.0314)
0.0406 (2654 refl.)
0.1041
6007 (0.0389)
0.0583 (4796 refl.)
0.1331
R1 (from F for reflections with I > 2σ(I))
wR2 (from F2 for all reflections)
Number of refinement parameters
541
289
w-1 = σ2(Fo ) + (aP)2 + bP, where P =1/3(Fo +2Fc2)
2
2
Weighting scheme
A
0.0653
2.5501
1.003
1664
0.0609
0.7565
1.075
896
B
GOOF
F(000)
Assignment of the signals in the 1H NMR spectra for compounds 7a,b were made on the basis of double
resonance experiments. Melting points were measured in open capillaries and values given are not corrected.
Monitoring of the reaction course and the purity of the compounds obtained was carried out by TLC on Silufol
UV-254 and Merck Silica gel 60 F254 plates. Solvents were dehydrated by standard methods [23].
Mitsunobu Reaction (General Method). The alcohol (26 mmol) and then dropwise a solution of
diisopropyl azodicarboxylate (5.1 ml, 26 mmol) in THF (10 ml) were added to a solution of 2-cyanoindole
(2.5 g, 17.5 mmol) and triphenylphosphine (6.8 g, 26 mmol) in THF (50 ml) at 0-5°C. The mixture was stirred at
this temperature for 1 h and left for 24 h. Solvent was removed in vacuo and the residue was chromatographed
on silica gel with elution using a mixture of petroleum ether and ethyl acetate.
2-Cyano-1-(2-phenylethyl)indole (3a). Yield 95%. Viscous liquid. IR spectrum, ν, cm-1: 710 (C6H5),
1
750, 760, 2235 (CN). H NMR spectrum, δ, ppm (J, Hz): 2.02 (3H, d, J = 7.1, CH3); 6.15 (1H, q, J = 7.1,
CHCH3); 7.16-7.23 (3H, m, Н arom.); 7.27-7.39 (4H, m, Н arom.); 7.52 (1H, s, C(3)H); [7.60 (1H, d, J = 8.5);
7.71 (1H, d, J = 7.9); H-4 and H-7]. Mass spectrum, m/z (I, %): 246 [M]+ (22), 142 (35), 105 (100), 77 (17).
Found, %: C 82.62; H 5.70; N 11.18. C17H14N2. Calculated, %: C 82.90; H 5.73; N 11.37.
(S)-2-Cyano-1-(2-methoxy-1-phenylethyl)indole (3b). Yield 91%; mp 76-78°C (ethyl acetate–hexane).
25
1
[α]D 34.8 (c 5.3, CH2Cl2). IR spectrum, ν, cm-1: 705 (C6H5); 720, 755, 770, 2230 (CN). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 3.43 (3H, s, OCH3); 4.34 (1H, dd, J = 10.1, J = 5.6, CHaHb); 4.42 (1H, t, J = 10.1,
CHaHb); 6.03 (1H, dd, J = 10.1, J = 5.6, CHC6H5); 7.30-7.85 (9H, m, Н arom.); 7.69 (1H, d, J = 8.0, Н arom.).
Found, %: C 77.99; H 5.76; N 10.22. C18H16N2O. Calculated, %: C 78.24; H 5.84; N 10.14.
1295

2-Formyl-1-(1-phenylethyl)indole (1a). A mixture of ethyl acetate (1.2 ml, 12 mmol) and THF (1 ml)
was added to a suspension of lithium aluminum hydride (0.3 g, 8 mmol) in THF (2.5 ml) at 0-10°C under an
argon atmosphere. The mixture was cooled to 0°C, stirred at this temperature for 30 min, and a solution of
compound 3a (1 g, 4 mmol) in THF (1.5 ml) was added. The reaction mixture was stirred for 1 h at 0-5°C,
H2SO4 (5N, 20 ml) was added, the product was stirred for 5 min, and extracted with ether (3 × 30 ml). The
extract was washed with saturated NaCl solution and dried over anhydrous sodium sulfate. Solvent was
evaporated off in vacuo and the residue was chromatographed on silica gel eluting with a mixture of petroleum
ether and ethyl acetate (100:6) to give 0.76 g (76%) of compound 1a; mp 48-49°C (ethyl acetate–hexane).
1
IR spectrum, ν, cm-1: 720 (C6H5), 750, 765, 780, 1680 (C=O). H NMR spectrum, δ, ppm (J, Hz): 1.92 (3H, d,
J = 7.1, CH3); 6.92 (1H, q, J = 7.1, CHCH3); 7.10 (1H, dd, J = 8.1, J = 6.1, H arom.); 7.16-7.39 (7H, m,
Н arom.); 7.57 (1H, s, С(3)H); 7.60 (1H, d, J = 8.1, Н arom.); 9.94 (1H, s, СHО). Found, %: C 82.20; H 6.16;
N 5.47. C17H15NO. Calculated, %: C 81.90; H 6.06; N 5.62.
(S)-2-Formyl-1-(2-methoxy-1-phenylethyl)indole (1b). A solution of DIBAL-H (1 molar, 6.6 ml) in
hexane (~ 6.6 mmol) was added to a solution of compound 3b (0.9 g) in a mixture of hexane (15 ml) and THF
(15 ml) at -70°C under an argon atmosphere. The reaction mixture was stirred at the same temperature for 1 h
letting the mixture warm to room temperature and stirred for a further 1 h. A saturated solution of NH4Cl (50 ml)
was added and the product was stirred for 20 min, dilute H2SO4 (1:5, 15 ml) was added followed by extraction
with ethyl acetate (3 × 30 ml). The extract was washed with a saturated solution of NaHCO3, saturated NaCl
solution, and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo and the residue was
chromatographed on silica gel eluting with a mixture of petroleum ether and ethyl acetate (100:6). Yield 0.78 g
25
(85%). Viscous liquid. [α]D 28.2 (c 5.3, CH2Cl2). IR spectrum, ν , cm-1: 710 (C6H5), 750, 770, 1675 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 3.24 (3H, s, CH3); 4.27-4.37 (2H, m, СН2); 6.96 (1H, t, J = 6.6, CHC6H5);
7.12 (1H, dd, J = 7.9, J = 6.9, Н arom.); 7.20-7.35 (7H, m, Н arom.); 7.58 (1H, s, H-3); 7.79 (1H, d, J = 8.0, Н
arom.); 9.91 (1H, s, СHО). Found, %: C 77.56; H 5.95; N 5.30. C18H17NO2. Calculated, %: C 77.40; H 6.13; N
5.01.
Synthesis of Imines. (General Method). A catalytic amount of p-toluenesulfonic acid was added to a
solution of the aldehyde (6.8 mmol) and the amine (7.1 mmol) in benzene (7 ml) and the product was refluxed
for 2 h in a Dean and Stark apparatus filled with molecular sieve (4 Å). The course of the reaction was monitored
by TLC. The solvent was evaporated in vacuo and the product was used without further purification.
Aza Diels–Alder Reaction of Imines with the Danishefsky Diene. (General Method). Anhydrous
ZnCl2 (0.1 g, 7.5 mmol) was added to a solution of the imine (6.8 mmol) in CH2Cl2 (7 ml) at -60°C. The product
was stirred for 10 min, the Danishefsky diene [24] (0.2 ml, 10.2 mmol) was added, and stirring was continued at
the same temperature for 6 h. Decomposition was brought about by the addition of HCl (1 molar, 10 ml) to the
reaction mixture. Product was let to heat to room temperature. The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3 × 10 ml). The extract was washed with a saturated solution of NaHCO3 and then
saturated NaCl solution and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo and the
residue was chromatographed on silica gel eluting with a mixture of petroleum ether and ethyl acetate.
Compounds 5a and 6a were prepared from 2-formyl-1-(1-phenylethyl)indole (1a) and aniline.
(2R')-1-Phenyl-2-[1-((1S')-1-phenylethyl)indol-2-yl]-1,2,3,4-tetrahydropyridin-4-one (5a) (minor
diastereomer). Yield 18%; mp 228-229°C (ethyl acetate–hexane). IR spectrum, ν, cm-1: 710 (C6H5), 780, 1650
(C=O). 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 1.93 (3H, d, J = 7.1, CH3); 2.85 (1H, dd, J = 16.4, J = 2.9,
CHaHb); 3.31 (1H, dd, J = 16.4, J = 7.1, CHaHb); 5.38 (1H, d, J = 7.8, NCH=CHCO); 5.53 (1H, dd, J = 7.1,
J = 2.9, CHCHaHb); 5.67 (1H, q, J = 7.1, CHCH3); 6.64 (1H, s, C(3)H); 6.86 (1H, d, J = 8.4, Н arom.); 6.98 (1H,
t, J = 7.6, Н arom.); [7.03-7.10 (3H, m), 7.13-7.23 (3H, m), 7.26-7.40 (5H, m), 7.55 (1H, d, J = 7.8), 7.66 (1H, d,
J = 8.0), Н arom. and NCH=CHCO]. 13C NMR spectrum, δ, ppm: 19.35 (CH3); 42.55 (CH2); 52.77 (CH); 54.80
(CH); 101.26 (CH); 101.52 (CH); 113.02 (CH); 118.89 (2CH); 119.81 (CH); 120.90 (CH); 121.35 (CH); 124.40
(CH); 126.39 (2CH); 127.70 (CH); 128.45 (C); 129.17 (2CH); 129.93 (2CH); 135.97 (C); 136.95
1296

(C); 141.18 (C); 144.53 (C); 149.38 (CH); 189.45 (C=O). Found, %: C 82.47; H 6.08; N 7.18. C27H24N2O.
Calculated, %: C 82.62; H 6.16; N 7.14.
(2R')-1-Phenyl-2-[1-((1R')-1-phenylethyl)indol-2-yl]-1,2,3,4-tetrahydropyridin-4-one (6a) (major
diastereomer). Yield 54%; mp 219-220°C (ethyl acetate–hexane). IR spectrum, ν, cm-1: 710 (C6H5), 770, 1660
(C=O). 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 1.96 (3H, d, J = 7.1, CH3); 2.69 (1H, dd, J = 16.4, J = 4.0,
CHaHb); 3.20 (1H, dd, J = 16.4, J = 7.1, CHaHb); 5.36 (1H, d, J = 7.6, NCH=CHCO); 5.51 (1H, dd, J = 7.1,
J = 4.0, CHCHaCHb); 5.64 (1H, q, J = 7.1, CHCH3); 6.63 (1H, s, C(3)H); [6.97-7.13 (8H, m), 7.20-7.34 (5H, m),
13
7.51 (1H, d, J = 8.0), 7.63 (1H, d, J = 7.8), Н arom. and NCH=CHCO]. C NMR spectrum (CDCl3), δ, ppm:
19.44 (CH3); 42.16 (CH2); 53.48 (CH); 56.25 (CH); 102.04 (CH); 102.65 (CH); 112.61 (CH); 119.84 (3CH);
120.92 (CH); 121.60 (CH); 125.07 (CH); 126.09 (2CH); 127.56 (CH); 128.31 (C); 128.86 (2CH); 129.53 (2CH);
135.60 (C); 136.14 (C); 140.72 (C); 144.63 (C); 149.60 (CH); 189.62 (C=O). Found, %: C 82.50; H 6.10; N
7.25. C27H24N2O. Calculated, %: C 82.62; H 6.16; N 7.14.
Compounds 5b and 6b were prepared similarly from (S)-2-formyl-1-(2-methoxy-1-phenylethyl)indole
(1b) and aniline.
(2S)-2-[1-((1S)-2-Methoxy-1-phenylethyl)indol-2-yl]-1-phenyl-1,2,3,4-tetrahydropyridin-4-one (5b)
25
(minor diastereomer). Yield 20%; mp 181-182°C (ethyl acetate–hexane). [α]D 24.0 (c 2.0, CH2Cl2).
1
IR spectrum, ν, cm-1: 710 (C6H5), 770, 1650 (C=O). H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 2.77 (1H, d,
J = 16.3, CHaHbC=O); 3.32 (1H, dd, J = 16.3, J = 7.1, CHaHbC=O); 3.38 (3H, s, OCH3); 4.26 (1H, t, J = 9.3,
CHaHbOCH3); 4.41 (1H, dd, J = 9. 3, J = 3.9, CHaHbOCH3); 5.38 (1H, d, J = 7.9, NCH=CHCO); 5.67 (1H, dd,
J = 9.3, J = 3.9, CHCHaHbOCH3); 5.78 (1H, d, J = 7.1, CHCHaHbC=O); 6.50 (1H, s, C(3)H); [6.72 (1H, d,
J = 8.4); 6.93 (1H, t, J = 7.8); 7.04 (1H, t, J = 7.4); 7.14 (1H, t, J = 6.8); 7.22-7.44 (9H, m), 7.52 (1H, d, J = 7.6),
7.79 (1H, d, J = 8.0), Н arom. and NCH=CHCO]. 13C NMR spectrum, δ, ppm: 42.40 (CH2); [55.31, 57.28,
59.16, 2CH + CH3]; 71.59 (CH2); 100.98 (CH); 101.82 (CH); 112.85 (CH); 117.89 (2CH); 119.81 (CH); 120.86
(CH); 121.19 (CH); 123.90 (CH); 126.48 (2CH); 128.12 (CH); 128.46 (C); 129.32 (2CH); 129.68 (2CH); 136.12
(C); 137.52 (C); 137.90 (C); 144.41 (C); 148.93 (CH); 189.56 (C=O). Found, %: C 79.74; H 6.14; N 6.26.
C28H26N2O2. Calculated, %: C 79.59; H 6.20; N 6.63.
(2R)-2-[1-((1S)-2-Methoxy-1-phenylethyl)indol-2-yl]-1-phenyl-1,2,3,4-tetrahydropyridin-4-one (6b)
25
(major diastereomer). Yield 70%. Glassy material. [α]D -94.1 (c 4.8, CH2Cl2). IR spectrum, ν, cm-1: 705
(C6H5), 745, 760, 1645 (C=O). 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 2.97 (1H, d, J = 16.3, CHaHbC=O);
3.25 (1H, dd, J = 16.3, J = 7.1, CHaHbC=O); 3.34 (3H, s, OCH3); 4.10 (1H, dd, J = 9.6, J = 7.1, CHaHbOCH3);
4.40 (1H, dd, J = 9.6, J = 5.9, CHaHbOCH3); 5.37 (1H, d, J = 8.1, NCH=CHCO); 5.54 (1H, dd, J = 7.1, J = 5.9,
CHCHaHbOCH3); 5.65 (1H, t, J = 7.1, CHCHaHbC=O); 6.72 (1H, s, C(3)H); [6.94-7.12 (8H, m), 7.21 (2H, t,
13
J = 8.0), 7.27-7.34 (3H, m), 7.54 (1H, d, J = 7.8), 7.62 (1H, d, J = 7.8), Н arom. and NCH=CHCO]. C NMR
spectrum, δ, ppm: 42.04 (CH2); [54.68, 57.69, 59.00, 2CH + CH3]; 72.24 (CH2); 101.08 (CH); 101.25 (CH);
112.97 (CH); 119.51 (2CH); 119.87 (CH); 120.79 (CH); 121.49 (CH); 124.51 (CH); 127.10 (2CH); 127.99
(CH); 128.30 (C); 128.95 (2CH); 129.71 (2CH); 136.09 (C); 138.31 (C); 138.37 (C); 144.55 (C); 149.59 (CH);
189.70 (C=O). Found, %: C 82.50; H 6.10; N 7.25. C27H24N2O. Calculated, %: C 82.62; H 6.16; N 7.14.
(2R)-1-(2-Methoxyphenyl)-2-[(1-((1S)-2-methoxy-1-phenylethyl)indol-2-yl]-1,2,3,4-tetrahydro-pyridin-
4-one (6c) (major diastereomer) was prepared from compound 1b and o-methoxyaniline. Yield 66%.
1
[α]D25 -93.3 (c 2.4, CH2Cl2). Glassy material. IR spectrum, ν, cm-1: 715 (C6H5), 770, 1645 (C=O). H NMR
spectrum, (CDCl3), δ, ppm (J, Hz): 2.85 (1H, d, J = 16.7, CHaHbC=O); 3.12 (1H, dd, J = 16.7, J = 6.2,
CHaHbC=O); 3.22 (3H, s, OCH3); 3.69 (3H, s, OCH3); 3.85 (1H, t, J = 9.1, CHaHbOCH3); 4.25 (1H, dd, J = 9.1,
J = 5.5, CHaHbOCH3); 5.29 (1H, d, J = 7.8, NCH=CHCO); 5.59-5.69 (2H, m, CHCHaHbC=O +
CHCHaHbOCH3); 6.68-6.81 (5H, m, Н arom.); 6.85 (1H, s, C(3)H); 6.91 (1H, t, J = 7.6); [7.02 (1H, t, J = 7.5),
7.07 (1H, dd, J = 7.7, J = 1.4), 7.11-7.27 (5H, m), 7.56 (1H, d, J = 7.8), Н arom. and NCH=CHCO]. 13C NMR
spectrum, δ, ppm: 42.58 (CH2); [54.86, 56.27, 56.87, 58.94, 2CH + 2CH3]; 71.82 (CH2); 99.21 (CH); 100.92
(CH); 112.49 (CH); 113.16 (CH); 119.78 (CH); 120.79 (CH); 121.25 (CH); 121.30 (CH); 126.94 (2CH); 127.33
1297

(CH); 127.88 (CH); 128.26 (C); 128.52 (CH); 128.82 (2CH); 133.23 (C); 135.30 (C); 138.04 (C); 139.49 (C);
153.84 (C); 153.94 (CH); 189.36 (C=O). Found, %: C 76.69; H 6.18; N 6.00. C29H28N2O3. Calculated, %:
C 76.97; H 6.24; N 6.19.
(2R)-1-(2-Fluorophenyl)-2-[1-((1S)-2-methoxy-1-phenylethyl)indol-2-yl]-1,2,3,4-tetrahydropyridin-4-
one (6d) (major diastereomer) was prepared from (S)- 2-formyl-1-(2-methoxy-1-phenylethyl)-indole (1b) and o-
25
fluoroaniline. Yield 19%. Glassy material. [α]D -133.7(c 2.1, CH2Cl2). IR spectrum, ν, cm-1: 710 (C6H5), 770,
1
800, 1505, 1590, 1660 (C=O). H NMR spectrum, (CDCl3) δ, ppm (J, Hz): 2.87 (1H, d, J = 16.0, CHaHbC=O);
3.18 (1H, dd, J = 16.0, J = 6.9, CHaHbC=O); 3.24 (3H, s, OCH3); 3.93 (1H, t, J = 9.6, CHaHbOCH3); 4.29 (1H,
dd, J = 9.6, J = 5.5, CHaHbOCH3); 5.36 (1H, d, J = 8.0, NCH=CHCO); 5.54-5.66 (2H, m, CHCHaHbC=O +
CHCHaHbOCH3); 6.75-6.90 (4H, m, Н arom.); [6.91-7.07 (4H, m), 7.10-7.17 (2H, m), 7.19-7.27 (3H, m), 7.31
(1H, dd, J = 7.9, J = 1.2); 7.57 (1H, d, J = 7.8), Н arom. and NCH=CHCO]. 13C NMR spectrum, δ, ppm: 42.72
(CH2); 55.79 (d, J = 2.0, CH); [57.56, 59.18, CH + CH3]; 72.97 (CH2); 101.55 (CH); 102.26 (CH); 112.27 (CH);
116.96 (d, J = 20.0, CH); 119.86 (CH); 121.03 (CH); 121.51 (CH); 125.00 (d, J = 4.0, CH); 126.34 (2CH);
127.11 (CH); 127.67 (CH); 128.28 (C); 128.36 (CH); 128.68 (2CH); 132.40 (d, J = 11.0, C); 135.46 (C); 137.34
(C); 138.29 (C); 151.93 (CH); 156.84 (d, J = 249.0, C); 190.79 (C=O). Found, %: C 76.03; H 5.70; N 6.26.
C28H25FN2O2. Calculated, %: C 76.34; H 5.72; N 6.36.
2-[5-Methoxy-3-oxo-2-(2-pyridylamino)pent-4-enyl]-1-(1-phenylethyl)indole (7a). Anhydrous ZnCl2
(0.18 g, 13.2 mmol) was added to a solution of the imine prepared from compound 1a (0.15 g, 0.6 mmol) and
2-aminopyridine (62 mg, 0.66 mmol) in CH2Cl2 (7 ml) at -60°C. The product was stirred for 10 min, the
Danishefsky diene (0.18 ml, 9 mmol) was added, and stirring was continued for 6 h at the same temperature.
Decomposition was brought about by the addition of HCl (1 molar, 20 ml), the product was let to heat to room
temperature. A solution of concentrated ammonia solution was added to pH ~ 12, the organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 15 ml). The extract was washed with water and
then saturated NaCl solution and dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the
residue was chromatographed on silica gel eluting with a mixture of petroleum ether and ethyl acetate (1:2).
Yield 0.19 g (81%) as a white crystalline material. IR spectrum, ν, cm-1; 710, 750, 760, 785, 1470, 1600, 1645,
1680, 3350 (br, NH). 1H NMR spectrum, (CDCl3), (1:2 mixture of diastereomers), δ, ppm (J, Hz): 1.89 and 1.99
(3H, 2d, J = 7.0 and J = 7.1, respectively, CHCH3); 3.13-3.37 (2H, m, СH2); 3.69 and 3.71 (3H, 2с, OCH3); 4.89
and 4.97 (1Н, 2d, J = 8.4 each, NH); 5.64 and 5.67 (1H, 2d, J = 12.5 and J = 12.6, respectively, СH=CHOCH3);
5.88-6.04 (2H, m, CHNH+CHCH3); 6.29 and 6.39 (1Н, 2d, J = 8.4 and J = 8.2, respectively, Н arom.); 6.51-6.65
(2Н, m, Н arom.); 6.89-7.07 (3Н, m, Н arom.); 7.18-7.43 (6Н, m, Н arom.); 7.57 (1Н, d, J = 7.6, Н arom.); 7.70
and 7.71 (1Н, 2d, J = 12.5 and J = 12.6, respectively, СH=CHOCH3); 8.07 and 8.11 (1Н, 2d, J = 3.9 each, Н
arom.). Found, %: C 75.81; H 6.34; N 9.31. C27H27N3O2. Calculated, %: C 76.21; H 6.40; N 9.87.
2-[5-Methoxy-3-oxo-2-(2-pyridylamino)pent-4-enyl]-1-(2-methoxy-1-phenylethyl)indole (7b) was
prepared similarly to compound 7a. Yield 83%. White crystalline material. IR spectrum, ν, cm-1: 710, 750, 790,
1
1475, 1505, 1600, 1645, 1680, 3330 (br, NH). H NMR spectrum, (CDCl3) (1: 2 mixture of isomers), δ, ppm
(J, Hz): [3.10-3.55 (m), 3.28 (с), 3.36 (с), 5Н overall, CH3OCH2+CH2C=O]; 3.68 and 3.69 (3H, 2с, CHOCH3);
4.18-4.31 (1H, m, СHaHbOCH3); 4.38-4.52 (1H, m, СHaHbOCH3); 5.31 (1Н, d, J = 8.1, NH); 5.64 and 5.66 (1H,
2d, J = 12.7 and J = 12.5, respectively, СH=CHOCH3); [5.76-5.84 (m), 5.86-5.96 (m), 6.04 (t, J = 6.7), 2H
overall, CHNH+CHC6H5]; 6.33 and 6.40 (1Н, 2d, J = 8.4 and J = 7.8, respectively, Н arom.); 6.50-6.64 (2Н, m,
Н arom.); 6.90-7.08 (3Н, m, Н arom.); 7.20-7.42 (6Н, m, Н arom.); 7.55 and 7.57 (1Н, 2d, J = 7.9 each,
Н arom.); 7.74 and 7.75 (1Н, 2d, J = 12.7 and J = 12.5, respectively, СH=CHOCH3); 8.06 and 8.13 (1Н, 2d,
J = 3.9 each, Н arom.). Found, %: C 73.45; H 6.30; N 9.01. C28H29N3O3. Calculated, %: C 73.82; H 6.42;
N 9.22.
1298

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