Synthesis of cholestan-3-one derivatives possessing a C-2 spiro-oxindole substituent

Article abstract of DOI:10.3184/174751918X15161933697781

A series of C-2 cholestan-3-one spiro-oxindole derivatives were prepared by the 1:3 dipolar cycloaddition reaction between the cholestan- 3-one substituted by a C-2 arylidene and the azomethine ylid derived from isatin and sarcosine. The dipolarophiles we

Full text of DOI:10.3184/174751918X15161933697781

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 JANUARY, 15–19
RESEARCH PAPER 15
Synthesis of cholestan-3-one derivatives possessing a C-2 spiro-oxindole
substituent
Hongwen Tao*, Yinan Yuan, Jian Chen, Xianyong Yu and Pinggui Yi
Key Laboratory of Theoretical Organic Chemistry and Functional Molecules, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan, Hunan 411201, P.R. China
A series of C-2 cholestan-3-one spiro-oxindole derivatives were prepared by the 1:3 dipolar cycloaddition reaction between the cholestan-
3-one substituted by a C-2 arylidene and the azomethine ylid derived from isatin and sarcosine. The dipolarophiles were efficiently
obtained by a Claisen-Schmidt reaction of cholestan-3-one and aromatic aldehydes. The structures of the products were established by a
combination of NMR, high-resolution mass spectrometry (HRMS) and X-ray data analysis.
Keywords: 1:3 dipolar cycloaddition, azomethine ylid, cholestan-3-one, steroidal spiro-oxindole
Chemical modification of the steroidal nucleus and side
chain often gives products with increased structural diversity
and biological activity.1 In particular, the introduction of a
heterocycle onto the steroid skeleton has been a focus for
pharmaceutical chemists.2
Among the nitrogen heterocycles, spiro-oxindoles have
attracted wide attention because of their unique structure and
significant bioactivity.3 The introduction of a spiro-oxindole
moiety onto the steroid core has been attempted previously and
has led to novel structures with potential activities (Fig. 1).4–6
Yu Bin et al. obtained two groups of anti-proliferative steroidal
derivatives by creating a spiro-oxindole structure on ring D and
the C-17 side chain (II and III in Fig. 1).
an aromatic aldehyde.7 The 1:3 dipolar cycloaddition reaction
of the dipolarophile 1 to the azomethine ylid generated in
situ from isatin and sarcosine yielded steroidal spiro-oxindole
derivative 2.
The structures of 1a–g were established by examination of
their NMR and HRMS data. The positive ESI-HRMS of 1a
gave a quasi-molecular ion peak at m/z 505.4039 ([M+H]+),
which indicated the addition of 4-methoxyphenyl methylene to
cholestan-3-one. The characteristic arylidene proton was found
as a singlet at δ 7.54 in the 1H NMR. The protons of the aromatic
ring and the 4-methoxyl group were clearly identified as two
doublets at δ 7.38, 6.92 and a singlet at δ 3.84, respectively.
The related structures of 2a–g were established by a
combination of HRMS and 1D and 2D NMR data. The
positive ESI-HRMS of 2a exhibited a quasi-molecular ion
peak at m/z 679.4836 ([M+H]+), implying a molecular formula
All of these achievements stimulate our interest in
constructing more novel steroidal heterocyclic structures, and
in this paper we report the synthesis of steroidal spiro-oxindole
derivatives obtained by modifying the A-ring of cholestan-3-
one (Scheme 1).
1
of C45H62N2O3. The H NMR spectrum of 2a showed seven
methyl proton signals at δ 3.83 (–OCH3), 2.13 (–NCH3), 0.86
(CH3-21), 0.85 × 2 (CH3-26 and CH3-27), 0.49 (CH3-18) and
–0.06 (CH3-19). The upfield shift of CH3-19 protons probably
arose because of the anisotropic effect of the aromatic ring in
the spiro-heterocycle moiety. The –NH proton of the oxindole
Results and discussion
The arylidene-substituted cholestan-3-one (1) was efficiently
obtained by a Claisen–Schmidt reaction of cholestan-3-one and
Ar
O
Ar
O
HN
O
O
N
H
N
N
O
NH
O
NH
H
r
A
H
H
O
H
O
H
R
H
O
II
I
III
Fig. 1 Steroidal spiro-oxindole derivatives.
R
NH
O
H
N
H
H
ii
i
H
H
H
H
H
H
O
H
O
O
H
H
R
1a 1g
-
cholestan-3-one
Reaction conditions: i; R
2a 2g
-
CHO, NaOH-H2O methanol, r.t., 24h. ii; isatin, sarcosine, methanol, reflux, 6 h.
R: a, 4-OCH3; b, 4-SCH3; c, 4-CH3; d, 4-H; e, 4-F; f, 4-Cl; g, 4-Br
Scheme 1 Synthesis of cholestan-3-one spiro-oxindole derivatives.
* Correspondent. E-mail: hongwtao@hnust.edu.cn

16 JOURNAL OF CHEMICAL RESEARCH 2018
21
18
''
1
NH
26
''
O
2
'
17
N'
1
2
1
27
9
'
4
7
O
5
3
O
Fig. 2 Partial HMBC correlations of 2a.
Fig. 3 ORTEP diagram of 2d (H atoms omitted for clarity).
moiety appeared as a singlet at δ 8.38. The benzylic proton H4’
occurred as a triplet at δ 4.71 (J = 8.6 Hz), which confirmed
the regiochemistry of the cycloaddition reaction. Otherwise,
of the product 2 was supported by X-ray data analysis. No
reaction in this paper involved C-10 and C-13 in the starting
steroidal skeleton. Since the angular methyl groups, CH3-18 and
CH3-19, in cholestan-3-one were both initially β-oriented, the
absolute configuration of 2 was further established as 2R, 5S,
8R, 9S, 10S, 13R, 14S, 17R, 20R, 2’R and 4’R, which is shown in
Scheme 1 and Figs. 2 and 3.
1
it would have appeared as a singlet in the H NMR spectrum.
The H5’ protons of the pyrrolidine moiety were identified as
two triplets at δ 3.44 (J = 8.6 Hz) and δ 3.78 (J = 8.5 Hz). The
carbonyl vicinal protons were identified as a doublet at δ 2.34
(J = 14.6 Hz, H4a) and an overlapping signal at δ 1.83 (m, H4b),
and the H5 proton was located at δ 2.00 (m).
Conclusion
The 13C NMR spectrum showed two spiro carbons at δ 64.33
(C2)andδ80.14(C2’),andtheamideandcyclohexanonecarbonyl
carbons at δ 179.95 (C2”) and δ 212.93 (C3), respectively. The
signals at δ 35.19, 41.60 and 53.67 correspond to the carbons
of C1, C5 and C9, respectively, in the cyclohexanone ring. The
signal at δ 59.95 was assigned to the carbon of CH2 (C5’) in the
pyrrolidine ring based on the heteronuclear multiple quantum
coherence (HMQC) spectrum. In the heteronuclear multiple
bond coherence (HMBC) spectrum, the correlations between
the protons of CH3-19 (δ −0.06) to C1, C5 and C9 were readily
observed. The HMBC spectrum showed correlations between
the characteristic –NCH3 proton (δ 2.13) and C2’ and C5’ in the
pyrrolidine ring. The protons of CH2 (C5’) correlated with the
spiro carbons C2 and C2’. The H4a proton (δ 2.34) exhibited
a correlation with the spiro carbon C2. The H4’ (δ 4.71) and
H5 (δ 2.00) protons correlated with the cyclohexanone carbonyl
carbon C3. All of the HMBC correlations confirm the spiro
pyrrolidine heterocycle structure of 2a (Fig. 2). In addition, a
suitable crystal of 2d was obtained, and the relative structure
An efficient synthesis of ring A steroidal spiro-oxindoles
from the starting material cholestan-3-one was established
by a 1:3 dipolar cycloaddition reaction in a catalyst-free, one-
pot procedure. The dipolarophile, cholestan-3-one containing
substituent arylidenes, was obtained by an efficient Claisen-
Schmidt reaction of cholestan-3-one and an aromatic aldehyde.
The dipole, azomethine ylid, was generated in situ from
isatin and sarcosine. The regioselectivity of this reaction was
established by single-crystal X-ray diffraction. This work
provides a facile strategy for transforming 3-ketosteroids and
allows for further modifications to other steroidal skeleta.
Experimental
All chemical reagents were obtained from commercial suppliers and
were used without further purification. All solvents were dried and
redistilled before use. TLC analysis was performed with silica gel
GF254 plates. Column chromatography was carried out using silica
gel (200–300 mesh). All NMR spectra were recorded on a Bruker
1
AV-II 500 MHz NMR spectrometer, operating at 500 MHz for H

JOURNAL OF CHEMICAL RESEARCH 2018 17
ESI-HRMS: Calcd for [C35H52SONa]+ ([M+Na]+): 543.3631; found:
543.3631.
Table 1 Crystallographic data for 2d
Empirical formula
C44H60N2O2
2-(4-Methylbenzylidene)cholestan-3-one (1c): White solid; yield
Mr
648.46
293(2) K
Monoclinic
C2
1
90%; m.p. 165–167 °C; H NMR (500 MHz, CDCl3): δ 7.54 (s, 1H),
Temperature
Crystal system
Space group
7.30 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 7.5 Hz, 2H), 3.10 (d, J = 15.8 Hz,
1H), 2.44 (dd, J = 18.5, 4.6 Hz, 1H), 2.37 (s, 3H), 2.27–2.15 (m, 2H), 2.01
(d, J = 12.2 Hz, 1H), 1.88–1.68 (m, 3H), 1.62–1.43 (m, 5H), 1.38–1.29
(m, 5H), 1.28–1.19 (m, 3H), 1.10 (m, 4H), 1.06–0.96 (m, 3H), 0.91 (d,
J = 6.1 Hz, 3H), 0.87 (d, J = 5.4 Hz, 6H), 0.78 (s, 3H), 0.65 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 201.62, 138.75, 137.30, 134.61, 132.89,
130.47 × 2, 129.13 × 2, 56.38, 56.33, 53.66, 42.80, 42.49, 42.32, 41.99,
39.95, 39.51, 36.16, 35.88, 35.78, 35.43, 31.53, 28.70, 28.24, 28.02, 24.25,
23.85, 22.83, 22.57, 21.45, 21.40, 18.68, 11.98, 11.87; ESI-HRMS: Calcd
for [C35H52ONa]+ ([M+Na]+): 511.3910; found: 511.3906.
a = 23.1003(18) Å, α = 90°
b = 9.8731(16) Å, β = 103.2250(10)°
c = 17.7064(2) Å, γ = 90°
Unit cell dimensions
Volume
Z
3931.2(5) Å3
4
Calculated density
Absorption coefficient μ
F(000)
1.096 g m−3
0.066 mm−1
1416
2-Benzylidenecholestan-3-one (1d): White solid; yield 94%; m.p.
1
125–126 °C; H NMR (500 MHz, CDCl3): δ 7.55 (s, 1H), 7.39 (d,
6016 reflections, 5351 with I > 2σ(I) for 439
Reflections collected
Goodness-of-fit on F2
parameters
J = 3.3 Hz, 4H), 7.33 (d, J = 3.9 Hz, 1H), 3.11 (d, J = 15.7 Hz, 1H),
2.45 (dd, J = 18.6, 4.7 Hz, 1H), 2.21 (m, 2H), 2.01 (d, J = 12.3 Hz, 1H),
1.91–1.70 (m, 4H), 1.61–1.44 (m, 5H), 1.32 (m, 5H), 1.27–1.20 (m, 3H),
1.12 (m, 4H), 0.99 (m, 3H), 0.90 (d, J = 6.1 Hz, 3H), 0.87 (d, J = 5.3 Hz,
6H), 0.79 (s, 3H), 0.65 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 201.71,
137.12, 135.73, 135.46, 130.33 × 2, 128.36× 2, 128.12, 56.37, 56.33,
53.63, 42.87, 42.49, 42.41, 41.86, 39.93, 39.51, 36.16, 35.94, 35.78,
35.44, 31.52, 28.69, 28.24, 28.02, 24.24, 23.85, 22.82, 22.57, 21.43,
18.68, 11.97, 11.86; ESI-HRMS: Calcd for [C34H50ONa]+ ([M+Na]+):
497.3754; found: 497.3752.
1.057
Final R indices
[I > 2sigma(I)]
R indices (all data)
R1 = 0. 0422, wR2 = 0.1110
R1 = 0.0487, wR2 = 0.1156
and 125 MHz for 13C. Tetramethylsilane (TMS) was used as internal
1
reference for H and 13C chemical shifts and CDCl3 was used as the
solvent. All mass spectra were obtained using a Waters ACQUITY
UPLC XEVO Q-TOF mass spectrometer. Melting points were
measured with a Yanaco MP500 melting point apparatus and are
uncorrected. X-ray analysis was performed on a Bruker Apex-II CCD
diffractometer.
The crystallographic data for compound 2d are summarised
in Table 1.
2-(4-Fluorobenzylidene)cholestan-3-one (1e): White solid; yield
1
92%; m.p. 123–125 °C; H NMR (500 MHz, CDCl3): δ 7.51 (s, 1H),
7.40–7.34 (m, 2H), 7.08 (t, J = 8.5 Hz, 2H), 3.04 (d, J = 15.7 Hz, 1H),
2.45 (dd, J = 18.6, 5.0 Hz, 1H), 2.23 (m, 1H), 2.16 (m, 1H), 2.02 (d,
J = 12.6 Hz, 1H), 1.79 (m, 3H), 1.63–1.44 (m, 5H), 1.39–1.29 (m, 5H),
1.28–1.22 (m, 2H), 1.18–1.06 (m, 5H), 0.99 (m, 3H), 0.91 (d, J = 6.3 Hz,
3H), 0.87 (d, J = 5.1 Hz, 6H), 0.79 (s, 3H), 0.65 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 201.47, 162.58, 135.96, 135.23, 132.17 × 2,
131.84, 115.49 × 2, 56.35, 56.32, 53.62, 42.80, 42.48, 42.35, 41.83,
39.91, 39.51, 36.15, 35.93, 35.77, 35.43, 31.50, 28.67, 28.23, 28.01, 24.23,
23.84, 22.82, 22.56, 21.45, 18.67, 11.97, 11.88; ESI-HRMS: Calcd for
[C34H49FONa]+ ([M+Na]+): 515.3660; found: 515.3658.
Synthesis of arylidene substituted cholestan-3-one dipolarophiles
(1a–g); general procedure
A
mixture of cholestan-3-one (200 mg, 0.52 mmol) and
p-methoxybenzaldehyde (77.5 mg, 0.57 mmol) was dissolved in
EtOH (10 mL) and aqueous KOH solution (KOH, 290 mg, 5.2 mmol,
2 mL) was added. The mixture was stirred at room temperature for
24 h. The reaction mixture was then filtered and washed with 50%
aqueous EtOH solution. The residue was dried and identified as pure
1a (234 mg, 92%) by TLC analysis eluted with petroleum ether–ethyl
acetate (4:1, v/v). The other arylidene-substituted cholestan-3-one
dipolarophiles (1b–g) were similarly prepared from the corresponding
aromatic aldehydes with yields of 90–95%.
2-(4-Chlorobenzylidene)cholestan-3-one (1f): White solid; yield
1
95%; m.p. 146–148 °C; H NMR (500 MHz, CDCl3): δ 7.48 (s, 1H),
7.36 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 3.03 (d, J = 15.6 Hz,
1H), 2.45 (dd, J = 18.6, 4.3 Hz, 1H), 2.28–2.19 (m, 2H), 2.15 (d,
J = 15.5 Hz, 1H), 2.02 (d, J = 12.3 Hz, 1H), 1.87–1.68 (m, 4H), 1.51
(m, 5H), 1.34 (m, 5H), 1.25 (m, 2H), 1.15–1.07 (m, 4H), 0.99 (m, 3H),
0.91 (d, J = 5.9 Hz, 3H), 0.87 (d, J = 5.1 Hz, 6H), 0.78 (s, 3H), 0.65
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 201.42, 136.04, 135.68, 134.44,
134.16, 131.48 × 2, 128.64 × 2, 56.34, 56.32, 53.59, 42.83, 42.48, 42.40,
41.84, 39.89, 39.51, 36.15, 35.98, 35.77, 35.42, 31.49, 28.67, 28.23, 28.01,
24.23, 23.84, 22.82, 22.57, 21.45, 18.67, 11.97, 11.87; ESI-HRMS:
Calcd for [C34H49ClONa]+ ([M+Na]+): 531.3364; found: 531.3359.
2-(4-Bromobenzylidene)cholestan-3-one (1g): Light-yellow solid;
yield 90%; m.p. 113–115 °C; 1H NMR (500 MHz, CDCl3): δ 7.51
(d, J = 8.1 Hz, 2H), 7.45 (s, 1H), 7.23 (d, J = 8.1 Hz, 2H), 3.02 (d,
J = 15.7 Hz, 1H), 2.45 (dd, J = 18.6, 4.8 Hz, 1H), 2.23 (dd, J = 18.4, 13.4
Hz, 1H), 2.14 (d, J = 15.5 Hz, 1H), 2.02 (d, J = 12.5 Hz, 1H), 1.88–1.68
(m, 3H), 1.62–1.44 (m, 5H), 1.33 (m, 5H), 1.29–1.21 (m, 3H), 1.13 (m,
5H), 1.05–0.94 (m, 3H), 0.90 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 5.5 Hz,
6H), 0.78 (s, 3H), 0.65 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 201.43,
136.17, 135.69, 134.60, 131.71, 131.60, 122.75, 56.34, 56.31, 53.58,
42.84, 42.48, 42.42, 41.84, 39.89, 39.51, 36.16, 35.99, 35.77, 35.42,
31.49, 28.67, 28.23, 28.01, 24.23, 23.84, 22.83, 22.57, 21.45, 18.67,
11.97, 11.87; ESI-HRMS: Calcd for [C34H49BrONa]+ ([M+Na]+):
575.2859; found: 575.2863.
2-(4-Methoxybenzylidene)cholestan-3-one (1a): White solid; yield
1
92%; m.p. 157–159 °C; H NMR (500 MHz, CDCl3): δ 7.54 (s, 1H),
7.38 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 3.08
(d, J = 15.7 Hz, 1H), 2.43 (dd, J = 18.7, 5.1 Hz, 1H), 2.21 (dd, J = 18.1,
13.9 Hz, 2H), 2.03 (d, J = 12.4 Hz, 1H), 1.79 (m, 3H), 1.60–1.44 (m,
5H), 1.36 (m, 5H), 1.28–1.20 (m, 2H), 1.10 (m, 4H), 1.05–0.95 (m,
3H), 0.91 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 5.6 Hz, 6H), 0.78 (s, 3H),
0.65 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 201.44, 159.92, 137.22,
133.29, 132.30 × 2, 128.36, 113.91 × 2, 56.38, 56.34, 55.31, 53.72, 42.68,
42.50, 42.15, 42.11, 39.98, 39.51, 36.16, 35.79, 35.78, 35.44, 31.53, 28.70,
28.24, 28.02, 24.25, 23.85, 22.83, 22.57, 21.47, 18.69, 11.98, 11.92; ESI-
HRMS: Calcd for [C35H53O2]+ ([M+H]+): 505.4040; found: 505.4039.
2-[4-Methylthiobenzylidene]cholestan-3-one (1b): Light-yellow
1
solid; yield 93%; m.p. 159–161 °C; H NMR (500 MHz, CDCl3): δ
7.51 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.25 (t, J = 6.7 Hz, 2H), 3.07 (d,
J = 15.8 Hz, 1H), 2.50 (s, 3H), 2.44 (dd, J = 18.7, 5.0 Hz, 1H), 2.27–2.15
(m, 2H), 2.02 (d, J = 12.5 Hz, 1H), 1.88–1.68 (m, 3H), 1.53 (m, 5H),
1.40–1.31 (m, 5H), 1.29–1.18 (m, 3H), 1.10 (m, 4H), 1.04–0.95 (m, 3H),
0.91 (d, J = 6.3 Hz, 3H), 0.87 (d, J = 5.4 Hz, 6H), 0.78 (s, 3H), 0.65
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 201.41, 139.85, 136.74, 134.76,
132.24, 130.89 × 2, 125.70 × 2, 56.37, 56.33, 53.67, 42.74, 42.49, 42.26,
42.09, 39.95, 39.51, 36.16, 35.88, 35.78, 35.43, 31.51, 28.69, 28.24,
28.02, 24.24, 23.85, 22.83, 22.57, 21.47, 18.68, 15.23, 11.98, 11.91;
Synthesis of cholestan-3-one spiro-oxindole derivatives (2a–g);
general procedure
A solution of 1a (100 mg, 0.2 mmol) in methanol (4 mL) was treated
with isatin (44 mg, 0.3 mmol) and sarcosine (27 mg, 0.3 mmol). The

18 JOURNAL OF CHEMICAL RESEARCH 2018
solution was refluxed (approx. 6 h) to afford the cycloadduct. After
completion of the reaction, as monitored by TLC analysis eluted with
petroleum ether–ethyl acetate (3:1, v/v), the solvent was evaporated
under reduced pressure. The residue was subJected to silica gel (50 g)
column chromatography and eluted with petroleum ether–ethyl acetate
(3:1, v/v) to afford the product 2a (103 mg) in 77 % yield. Using a
similar procedure, the other steroidal spiro-oxindoles derivatives
(2b–g) were prepared from the corresponding steroidal dipolarophiles
(1b–g) with yields in the range 67–82%.
1.75 (m, 2H), 1.55–1.38 (m, 4H), 1.36–1.25 (m, 4H), 1.20–1.07 (m,
7H), 1.03–0.89 (m, 6H), 0.86 (d, J = 6.3 Hz, 9H), 0.78–0.70 (m, 1H),
0.69–0.60 (m, 1H), 0.52 (m, 1H), 0.49 (s, 3H), −0.06 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 212.83, 178.21, 141.11, 135.27, 133.24 × 2, 129.76,
127.66, 125.35, 122.94, 114.76 × 2, 109.89, 79.97, 63.99, 59.87, 56.33,
56.27, 56.22, 53.44, 49.76, 44.23, 42.39, 41.61, 40.27, 39.81, 39.50,
36.16, 35.76, 35.33, 35.10, 35.05, 30.99, 28.35, 28.16, 28.00, 24.06,
23.87, 22.81, 22.56, 20.78, 18.60, 11.92, 11.70; ESI-HRMS: Calcd for
[C44H61N2O2]+ ([M+H]+): 649.4728; found: 649.4730.
[2′.2]-1′-Methyl-2′- (indolin-2-one)-4′- (4′′-methoxyphenyl)-
tetrahydro-1H-pyrrolo-cholestan-3-one (2a): White solid; yield 77%;
m.p. 189–191 °C; 1H NMR (500 MHz, CDCl3): δ 8.38 (s, 1H), 7.47 (d,
J = 7.8 Hz, 2H), 7.28 (t, J = 8.8 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.06
(t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H),
4.71 (t, J = 8.6 Hz, 1H), 3.83 (s, 3H), 3.78 (t, J = 8.5 Hz, 1H), 3.44 (t,
J = 8.6 Hz, 1H), 2.34 (d, J = 14.6 Hz, 1H), 2.13 (s, 3H), 2.00 (m, 1H),
1.83 (m, 3H), 1.50 (m, 1H), 1.44 (m, 2H), 1.29 (m, 3H), 1.24–1.04 (m,
7H), 1.02–0.90 (m, 4H), 0.86 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.4 Hz,
6H), 0.79–0.69 (m, 1H), 0.68–0.59 (m, 1H), 0.54 (m, 1H), 0.50 (s, 3H),
−0.06 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 212.93, 179.95, 158.66,
141.15, 132.77 × 2, 129.75, 127.84, 125.77, 125.14, 122.97, 113.48 × 2,
110.02, 80.14, 64.33, 59.69, 56.46, 56.40, 55.48, 53.67, 49.68, 44.33,
42.53, 41.60, 40.05, 39.99, 39.63, 36.28, 35.89, 35.59, 35.25, 35.19,
31.15, 28.55, 28.29, 28.13, 24.19, 24.00, 22.95, 22.69, 20.95, 18.75,
12.09, 11.81; ESI-HRMS: Calcd for [C45H63N2O3]+ ([M+H]+):
679.4833; found: 679.4836.
[2′.2]-1′-Methyl-2′- (indolin-2-one) -4′- (4′′-fluorophenyl) -
tetrahydro-1H-pyrrolo-cholestan-3-one (2e): White solid; yield
70%; m.p. 194–197 °C; 1H NMR (500 MHz, CDCl3): δ 7.90 (brs,
1H), 7.52 (dd, J = 7.2, 6.0 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.16 (d,
J = 6.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 8.5 Hz, 2H), 6.87
(d, J = 7.5 Hz, 1H), 4.70 (t, J = 9.0 Hz, 1H), 3.77 (t, J = 9.1 Hz, 1H),
3.48 (t, J = 8.8 Hz, 1H), 2.27 (d, J = 14.8 Hz, 1H), 2.12 (s, 3H), 2.00
(m, 1H), 1.84 (m, 2H), 1.74 (m, 2H), 1.63 (m, 1H), 1.55–1.47 (m, 1H),
1.43 (m, 2H), 1.29 (m, 3H), 1.20–1.05 (m, 7H), 1.02–0.89 (m, 6H),
0.85 (d, J = 6.5 Hz, 9H), 0.76–0.59 (m, 2H), 0.53 (m, 1H), 0.49 (s, 3H),
−0.06 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 212.86, 178.58, 162.05,
141.28, 135.38, 133.34 × 2, 129.88, 127.76, 125.51, 123.05, 114.87 × 2,
110.12, 80.13, 64.16, 59.89, 56.47, 56.38, 53.60, 49.78, 44.33, 42.51,
41.69, 40.27, 39.96, 39.63, 36.29, 35.88, 35.48, 35.21, 35.17, 31.23, 28.49,
28.28, 28.13, 24.16, 23.99, 22.94, 22.69, 20.92, 18.74, 12.04, 11.84;
ESI-HRMS: Calcd for [C44H60FN2O2]+ ([M+H]+): 667.4633; found:
667.4634.
[2′.2]-1′-Methyl-2′- (indolin-2-one) -4′- (4′′-chlorophenyl) -
tetrahydro-1H-pyrrolo-cholestan-3-one (2f): White solid; yield 82%;
m.p. 172–174 °C; 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 7.50 (d,
J = 7.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.28 (t, J = 6.8 Hz, 1H), 7.16
(d, J = 6.4 Hz, 1H), 7.07 (t, J = 6.8 Hz, 1H), 6.89 (d, J = 6.7 Hz, 1H),
4.70 (t, J = 8.3 Hz, 1H), 3.77 (t, J = 8.2 Hz, 1H), 3.46 (t, J = 9.0 Hz, 1H),
2.25 (d, J = 14.7 Hz, 1H), 2.12 (s, 3H), 2.01 (m, 1H), 1.89–1.78 (m, 3H),
1.73 (s, 1H), 1.59–1.37 (m, 4H), 1.33–1.25 (m, 4H), 1.23–1.07 (m, 8H),
1.03–0.92 (m, 5H), 0.86 (d, J = 5.3 Hz, 9H), 0.74 (m, 1H), 0.63 (m, 1H),
0.54 (m, 1H), 0.50 (s, 3H), −0.06 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 212.89, 178.41, 141.18, 138.17, 133.16 × 2, 132.90, 129.94, 128.21 × 2,
127.73, 125.33, 123.08, 110.09, 80.05, 64.02, 59.76, 56.39, 56.38, 53.54,
49.93, 44.28, 42.46, 41.62, 40.25, 39.89, 39.59, 36.23, 35.85, 35.47,
35.15, 35.14, 31.07, 28.46, 28.26, 28.12, 24.14, 23.95, 22.95, 22.69,
20.88, 18.71, 12.05, 11.90; ESI-HRMS: Calcd for [C44H60ClN2O2]+
([M+H]+): 683.4338; found: 683.4340.
[2′.2]-1′-Methyl-2′-(indolin-2-one)-4′-(4′′-methylthiophenyl)-
tetrahydro-1H-pyrrolo-cholestan-3-one (2b): Light-yellow solid; yield
1
72%; m.p. 195–197 °C; H NMR (500 MHz, CDCl3): δ 7.91 (s, 1H),
7.46 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H),7.23 (d, J = 8.1 Hz, 2H),
7.17 (d, J = 6.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.2 Hz,
1H), 4.71 (t, J = 8.8 Hz, 1H), 3.78 (t, J = 8.6 Hz, 1H), 3.43 (t, J = 8.4 Hz,
1H), 2.48 (s, 3H), 2.27 (d, J = 14.7 Hz, 1H), 2.12 (s, 3H), 1.98 (m, 1H),
1.91–1.75 (m, 3H), 1.77–1.69 (m, 1H), 1.63 (s, 1H), 1.53–1.36 (m, 4H),
1.35–1.23 (m, 3H), 1.23–1.04 (m, 7H), 1.02–0.90 (m, 5H), 0.86 (d,
J = 6.4 Hz, 6H), 0.85 (d, J = 6.4 Hz, 3H), 0.80 – 0.72 (m, 1H), 0.65
(m, 1H), 0.54 (m, 1H), 0.51 (s, 3H), –0.06 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 212.61, 178.09, 157.04, 140.99, 136.81, 132.09 × 2, 131.08,
129.67, 127.70, 126.54 × 2, 122.87, 109.90, 79.91, 64.30, 59.39, 56.33,
56.25, 53.48, 49.76, 44.16, 42.41, 41.41, 39.96, 39.83, 39.50, 36.15,
35.76, 35.45, 35.13, 35.06, 31.02, 28.41, 28.17, 28.00, 24.07, 23.87,
22.82, 22.57, 20.83, 18.63, 16.28, 11.97, 11.81; ESI-HRMS: Calcd for
[C45H63N2SO2]+ ([M+H]+): 695.4605; found: 695.4608.
[2′.2]-1′-Methyl-2′- (indolin-2-one) -4′- (4′′-bromophenyl) -
tetrahydro-1H-pyrrolo-cholestan-3-one (2g): Light-yellow solid;
yield 78%; m.p. 153–155 °C; 1H NMR (500 MHz, CDCl3): δ7.94
(s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.29 (t,
J = 7.4 Hz, 1H), 7.16 (d, J = 6.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.88
(d, J = 7.3 Hz, 1H), 4.69 (t, J = 8.8 Hz, 1H), 3.75 (t, J = 8.9 Hz, 1H),
3.46 (d, J = 8.5 Hz, 1H), 2.22 (d, J = 14.8 Hz, 1H), 2.12 (s, 3H), 1.99 (m,
1H), 1.83 (m, 3H), 1.78–1.69 (m, 1H), 1.57–1.38 (m, 4H), 1.37–1.24 (m,
4H), 1.23–1.08 (m, 8H), 1.03–0.92 (m, 5H), 0.87 (d, J = 6.5 Hz, 3H),
0.85 (d, J = 6.6 Hz, 6H), 0.81–0.71 (m, 1H), 0.65 (m, 1H), 0.54 (m, 1H),
0.51 (s, 3H), −0.05 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 212.70,
178.20, 141.17, 138.74, 133.54 × 2, 131.21 × 2, 129.94, 127.81, 125.48,
123.09, 121.18, 110.03, 80.01, 64.17, 59.69, 56.47, 56.42 , 53.62, 49.96,
44.29, 42.54, 41.60, 40.35, 39.95, 39.64, 36.29, 35.89, 35.49, 35.25,
35.19, 31.15, 28.52, 28.29, 28.13, 24.20, 24.00, 22.95, 22.70, 20.94,
18.76, 12.10, 11.98; ESI-HRMS: Calcd for [C44H60BrN2O2]+ ([M+H]+):
727.3833; found: 727.3837.
[2′.2]-1′-Methyl-2′- (indolin-2-one) -4′- (4′′-methylphenyl) -
tetrahydro-1H-pyrrolo-cholestan-3-one (2c): White solid; yield 67%;
m.p. 204–205 °C; 1H NMR (500 MHz, CDCl3): δ 7.80 (s, 1H), 7.39 (d,
J = 7.3 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.12 (d,
J = 7.3 Hz, 2H), 7.05 (t, J = 7.1 Hz, 1H), 6.86 (d, J = 6.6 Hz, 1H), 4.73
(t, J = 8.2 Hz, 1H), 4.73 (t, J = 8.2 Hz, 1H), 3.81 (t, J = 8.4 Hz, 1H), 3.81
(t, J = 8.4 Hz, 1H), 3.42 (t, J = 8.6 Hz, 1H), 3.42 (t, J = 8.6 Hz, 1H), 2.35
(s, 3H), 2.30 (d, J = 15.1 Hz, 1H), 2.12 (s, 3H), 1.96 (m, 1H), 1.90–1.78
(m, 3H), 1.73 (s, 1H), 1.61 (s, 1H), 1.55–1.37 (m, 4H), 1.29 (m, 3H),
1.15 (m, 5H), 0.98 (m, 5H), 0.86 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.4 Hz,
6H), 0.78–0.70 (m, 1H), 0.66 (m, 1H), 0.56 (m, 1H), 0.49 (s, 3H), −0.09
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 212.57, 178.30, 156.93, 140.91,
136.48, 131.45 × 2, 130.48, 129.58, 128.66 × 2, 127.76, 122.81, 109.82,
79.92, 64.40, 59.33, 56.31, 56.24, 53.52, 49.71, 44.15, 42.41, 41.36,
39.87, 39.81, 39.51, 36.15, 35.78, 35.50, 35.15, 35.01, 31.04, 28.43, 28.17,
28.00, 24.07, 23.88, 22.82, 22.57, 21.14, 20.77, 18.64, 11.96, 11.70;
ESI-HRMS: Calcd for [C45H63N2O2]+ ([M+H]+): 663.4884; found:
663.4887.
Acknowledgements
[2′.2]-1′-Methyl-2′-(indolin-2-one)-4′-(4′′-phenyl)-tetrahydro-
1H-pyrrolo-cholestan-3-one (2d): White solid; yield 75%; m.p.
215–217 °C; 1H NMR (500 MHz, CDCl3): δ 7.95 (s, 1H), 7.52 (t,
J = 7.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.06
(t, J = 7.5 Hz, 1H), 7.02 (t, J = 8.4 Hz, 2H), 6.88 (d, J = 7.5 Hz, 1H),
4.70 (t, J = 9.0 Hz, 1H), 3.77 (t, J = 9.1 Hz, 1H), 3.48 (t, J = 8.9 Hz,
1H), 2.27 (d, J = 14.8 Hz, 1H), 2.13 (s, 3H), 2.00 (m, 1H), 1.84 (m, 2H),
We are grateful to the National Natural Science Foundation of
China (No. 21172066), the Scientific Research Fund of Hunan
Provincial Education Department (No. 15C0560) and the Open
Project Programme of the Key Laboratory of Theoretical
Chemistry and Molecular Simulation of the Ministry of
Education (No. E21203) for financial support.

JOURNAL OF CHEMICAL RESEARCH 2018 19
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