Synthesis of novel 16-spiro steroids: 7-(Aryl)tetrahydro-1H-pyrrolo[1,2-c] [1,3]thiazolo estrone hybrid heterocycles

Article abstract of DOI:10.1016/j.steroids.2014.01.003

The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatins or acenaphthylene-1,2-dione and 1,3-thiazolane-4- carboxylic acid to various exocyclic dipolarophiles synthesized from estrone afforded a library of novel C-

Full text of DOI:10.1016/j.steroids.2014.01.003

Steroids 82 (2014) 29–37
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of novel 16-spiro steroids: 7-(Aryl)tetrahydro-1H-pyrrolo
[1,2-c][1,3]thiazolo estrone hybrid heterocycles
⇑
Veerappan Jeyachandran, Sundaravel Vivek Kumar, Raju Ranjith Kumar
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2013
Received in revised form 16 December 2013
Accepted 6 January 2014
Available online 21 January 2014
The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of isatins or
acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles
synthesized from estrone afforded a library of novel C-16 spiro oxindole or acenaphthylene-1-one –
7-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole – estrone hybrid heterocycles. These reactions occur
regio- and stereo-selectively affording a single isomer of the spiro estrones in excellent yields with the
formation of two C–C and one C–N bonds along with the generation of four new contiguous stereo-cen-
ters in a single step.
Keywords:
Estrone
16-Spiro steroids
1,3-Dipolar cycloaddition
Azomethine ylide
Pyrrolothiazole
Ó 2014 Elsevier Inc. All rights reserved.
1. Introduction
hybrid heterocycles [10] via 1,3-dipolar cycloaddition. In view of
our continuous interest in synthesizing hybrid C-16 spiro steroids,
Steroids form a group of structurally related compounds widely
distributed in nature and posses a broad spectrum of biological
activities. Synthetic derivatives of steroids have also attracted a
good deal of attention for the purpose of developing lead com-
pounds to treat several diseases. In particular, the syntheses of ste-
roids comprising heterocycles have received much attention of the
chemists since many of such compounds have been shown to dis-
play important pharmacological properties [1].
Spiro steroids are ubiquitous in nature, for instance spirostanes,
which include a spiro-acetal moiety in the structure have been
shown to posses significant biological properties [2]. Further, it is
noteworthy that investigations pertaining to the synthesis of
steroids comprising a spiro heterocycle at C-17 [3] have gained
much importance whereas the reports on the synthesis of C-16
spiro heterocyclic steroids are scarce [4]. The known C-16 spiro
steroids are the cycloalkano derivatives [5], dioxaphosphorinanes
[6], pyrazolines [7] and pyrrolidines [8]. In general, 1,3-dipolar cyc-
loadditions offer a facile route towards the construction of spiro
heterocycles and in particular, the cycloaddition of azomethine
ylides to exocyclic olefins are among the best employed protocol
for the construction of spiro-pyrrolidines, pyrrolizines, pyrrolo-
thiazoles and octahydroindolizines [9]. Recently, we reported the
synthesis of novel C-16 spiro steroids comprising trans-androster-
one/dehydroandrosterone–tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole
we herein report for the first time the synthesis of novel C-16 spiro
pyrrolo[1,2-c][1,3]thiazole containing estrone hybrid heterocycles.
Incidentally, estrone is a very vital steroid that has key role in
many biological processes. Numerous methods for the synthesis
of modified estrone derivatives have been reported in view of their
wide range of biological applications. For instance, estrone deriva-
tives are used as potent inhibitors of 17b-hydroxysteroid dehydro-
genase type1 [11], steroid sulfatase inhibitors [12] and also
exhibits antiproliferative [13], anticancer [14], antimicrobial and
antifungal activities [15]. Many of the drugs for menopausal estro-
gen therapy contain estrone core [16].
2. Experimental
The melting points were measured in open capillary tubes and
are uncorrected. The 1H, 13C and the 2D NMR spectra were re-
corded on a Bruker (Avance) 300 MHz NMR instrument using
TMS as internal standard and CDCl3 as solvent. Standard Bruker
software was used throughout. Chemical shifts are given in parts
per million (d-scale) and the coupling constants are given in Hertz.
Elemental analyses were performed on a Perkin Elmer 2400 Series
II Elemental CHNS analyzer. The single crystal X-ray data of 2b
were collected on Enraf–Nonius (CAD4) diffractometer with Mo
Ka (k = 0.71073 Å) radiation. Scan range was 2.02° 6 h 6 24.97°.
SHELXTL software was used for structure solution and refinement.
Silica gel-G plates (Merck) were used for tlc analysis with a mix-
ture of petroleum ether (60–80 °C) and ethyl acetate as eluent.
⇑
Corresponding author. Tel.: +91 9655591445.
E-mail address: raju.ranjithkumar@gmail.com (R. Ranjith Kumar).
http://dx.doi.org/10.1016/j.steroids.2014.01.003
0039-128X/Ó 2014 Elsevier Inc. All rights reserved.

30
V. Jeyachandran et al. / Steroids 82 (2014) 29–37
All the chemicals were purchased from Aldrich and used without
any further purification.
2.2.3. Spiro[50.300]oxindole-spiro[60.16]-70-(4-fluorophenyl)tetrahydro-
1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3c)
Isolated as white solid; yield 81%; mp 190–191 °C; Anal. Calcd.
for C36H35FN2O3S: C, 72.70; H, 5.93; N, 4.71. Found: C, 72.67; H,
5.90; N, 4.68. 1H NMR 0.33 (s, 3H), 0.49–0.59 (m, 1H), 0.95–1.05
(m, 1H), 1.10–1.20 (m, 2H), 1.23–1.28 (m, 1H), 1.60–1.61 (m,
2H), 1.62–1.66 (m, 2H), 1.80–1.82 (m, 1H), 2.00–2.04 (m, 1H),
2.48–2.51 (m, 1H), 2.64–2.67 (m, 2H), 2.80–2.93 (m, 2H), 3.61
(m, 2H), 3.70 (d, J = 9.6 Hz, 1H), 4.71 (dt, J = 7.6, 6.6 Hz, 1H), 5.06
(s, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.4, 2.7 Hz, 1H), 6.77
(d, J = 7.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 7.00–7.25 (m, 6H), 7.43
(d, J = 7.5 Hz, 1H), 7.85 (s, 1H). 13C NMR 14.6, 26.4, 28.8, 31.1,
31.3, 33.2, 34.4, 36.7, 40.3, 43.8, 47.2, 54.2, 72.1, 72.5, 74.3,
109.6, 112.6, 115.2, 115.5, 121.3, 122.3, 125.5, 125.8, 129.3,
129.7, 131.4, 132.8, 136.4, 137.5, 140.5, 153.3, 178.9 and 219.4.
2.1. General procedure for the synthesis of 16-(E)-arylidene-estrones 2
A mixture of estrone 1 (1 mmol) and aromatic aldehyde
(1 mmol) were dissolved in ethanol (5 mL) to which an alcoholic
solution of potassium hydroxide (20%) was added. The mixture
was refluxed on an oil bath with continuous stirring for 5 h and
the progress of the reaction was monitored by TLC intermittently.
After completion of the reaction, the mixture was allowed to cool.
The precipitated solid was filtered, washed with water (100 mL)
and dried under vacuum to afford the product 2 as yellow solid.
The yields of the 16-(E)-arylidene-estrones 2 were almost quanti-
tative except for the loss during work-up.
2.2.4. Spiro[50.300]oxindole-spiro[60.16]-70-(4-bromophenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3d)
2.2. General procedure for the synthesis of spiro[50.300]oxindole/
acenaphthylene-100-one-spiro[60.16]-70-(aryl)tetrahydro-1H-
pyrrolo[10,20-c][10,30]thiazolo estrones 3–5
Isolated as white solid; yield 80%; mp 290–291 °C; Anal. Calcd.
for C36H35BrN2O3S: C, 65.95; H, 5.38; N, 4.27. Found: C, 65.87; H,
5.49; N, 4.12. 1H NMR 0.39 (s, 3H), 0.48–0.57 (m, 1H), 0.96–1.01
(m, 1H), 1.08–1.15 (m, 2H), 1.21–1.29 (m, 1H), 1.60–1.61 (m,
2H), 1.63–1.67 (m, 2H), 1.80–1.83 (m, 1H), 2.00–2.04 (m, 1H),
2.41–2.48 (m, 1H), 2.55–2.73 (m, 2H), 2.82–2.87 (m, 2H), 3.56 (d,
J = 6.0 Hz, 1H), 3.61 (d, J = 6 Hz, 1H), 3.67 (m, 1H), 4.72 (dt, J = 7.6,
6.6, 1H), 4.96 (s, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.4,
2.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.03–
7.26 (m, 5H), 7.37 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.67
(s, 1H). 13C NMR 14.7, 25.2, 26.5, 28.9, 31.1, 31.3, 33.0, 34.3, 36.8,
44.0, 47.1, 54.3, 72.1, 72.6, 74.5 109.5, 112.7, 115.2, 115.4, 121.5,
122.6, 125.8, 126.0, 129.3, 129.8, 131.5, 131.8, 136.6, 137.7,
140.7, 153.4, 178.3 and 219.7.
A mixture of 2 (1 mmol), isatin/5-chloro-isatin/acenaphthyl-
ene-1,2-dione (1.1 mmol) and 1,3-thiazolane-4-carboxylic acid
(1.2 mmol) were taken in isopropanol (10 mL) and boiled to reflux
for 3 h. The progress of the reaction was monitored by TLC. After
completion of the reaction as evident from TLC, the reaction mix-
ture was poured into ice water (50 mL). The resultant precipitate
was filtered, dried and purified by flash filtration column on silica
gel employing petroleum ether/ethyl acetate (90:10) as eluting sol-
vent to get the products 3, 4 or 5.
2.2.1. Spiro[50.300]oxindole-spiro[60.16]-70-(phenyl)tetrahydro-1H-
pyrrolo[10,20-c][10,30]thiazolo estrone (3a)
2.2.5. Spiro[50.300]oxindole-spiro[60.16]-70-(4-methylphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3e)
Isolated as pure white solid; yield 82%; mp 185–186 °C; Anal.
Calcd. for C36H36N2O3S: C, 74.97; H, 6.29; N, 4.86. Found: C,
74.89; H, 6.38; N, 4.80. 1H NMR 0.32 (s, 3H), 0.50–0.60 (m, 1H),
0.95–0.97 (m, 1H), 1.04–1.18 (m, 2H), 1.23–1.33 (m, 1H), 1.60–
1.61 (m, 2H), 1.62–1.68 (m, 2H), 1.80–1.84 (m, 1H), 2.01–2.05
(m, 1H), 2.50–2.51 (m, 1H), 2.54–2.69 (m, 2H), 2.82–2.95 (m,
2H), 3.63 (d, J = 6.6 Hz, 1H), 3.64 (d, J = 6.6 Hz, 1H), 3.73 (d,
J = 9.6 Hz, 1H), 4.74–4.81 (m, 2H), 6.48 (d, J = 2.4 Hz, 1H), 6.54
(dd, J = 8.1, 2.4 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.4 Hz,
1H), 7.04–7.34 (m, 7H), 7.47 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H). 13C
NMR 14.3, 25.2, 26.5, 29.0, 31.3, 31.4, 33.5, 36.9, 44.0, 47.2, 48.4,
55.1, 72.2, 72.7, 74.6, 109.7, 112.7, 115.3, 115.6, 122.3, 125.7,
126.0, 127.5, 128.5, 129.5, 129.8, 131.6, 137.1, 137.7, 140.6,
153.4, 179.1 and 219.5.
Isolated as white solid; yield 85%; mp 199–200 °C; Anal. Calcd.
for C37H38N2O3S: C, 75.22; H, 6.48; N, 4.74. Found: C, 75.34; H,
6.57; N, 4.79. 1H NMR 0.33 (s, 3H), 0.52–0.59 (m, 1H), 0.95–0.97
(m, 1H), 1.00–1.18 (m, 2H), 1.23–1.33 (m, 1H), 1.59–1.74 (m,
4H), 1.81–1.84 (m, 1H), 1.99–2.04 (m, 1H), 2.33 (s, 3H), 2.51–
2.56 (m, 1H), 2.64–2.67 (m, 2H), 2.80–2.95 (m, 2H), 3.61 (d,
J = 6.6 Hz, 1H), 3.64 (d, J = 6.6 Hz, 1H), 3.70 (d, J = 9.6 Hz, 1H),
4.74 (dt, J = 6.6, 9.3 Hz, 1H), 5.03 (s, 1H), 6.55 (dd, J = 8.4, 2.7 Hz,
1H), 6.77 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.1, 1H), 7.48 (d,
J = 7.5 Hz, 1H), 7.03–7.26 (m, 7H), 7.80 (s, 1H). 13C NMR 14.3,
25.3, 26.5, 30.0, 31.3, 31.5, 33.7, 34.6, 44.0, 47.3, 47.4, 54.3, 55.0,
72.4, 72.8, 74.6, 109.8, 112.7, 113.4, 115.4, 122.3, 125.7, 126.0,
129.3, 129.5, 129.8, 131.6, 133.8, 137.2, 137.6, 140.6, 153.4, 179.5
and 220.0.
2.2.6. Spiro[50.300]oxindole-spiro[60.16]-70-(4-methoxyphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3f)
2.2.2. Spiro[50.300]oxindole-spiro[60.16]-70-(4-chlorophenyl)tetrahydro-
1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3b)
Isolated as white solid; yield 86%; mp 214–215 °C; Anal. Calcd.
for C37H38N2O4S: C, 73.24; H, 6.31; N, 4.62. Found: C, 73.12; H,
6.23; N, 4.69. 1H NMR 0.29 (s, 3H), 0.52–0.60 (m, 1H), 0.95–1.00
(m, 1H), 1.03–1.18 (m, 2H), 1.23–1.30 (m, 1H), 1.60–1.61 (m,
2H), 1.62–1.70 (m, 2H), 1.80–1.83 (m, 1H), 1.99–2.04 (m, 1H),
2.52–2.57 (m, 1H), 2.63–2.65 (m, 2H), 2.80–2.96 (m, 2H), 3.61 (d,
J = 6.9 Hz, 1H), 3.65 (d, J = 6.9, 1H), 3.69 (d, J = 9.6 Hz, 1H), 3.78 (s,
3H), 4.71 (dt, J = 6.0, 9.9 Hz, 1H), 5.34 (s, 1H), 6.46 (d, J = 2.4 Hz,
1H), 6.55 (dd, J = 8.4, 2.7 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.93 (d,
J = 8.4 Hz, 1H), 7.03–7.25 (m, 6H), 7.50 (d, J = 7.8 Hz, 1H), 8.03 (s,
1H). 13C NMR 14.2, 25.0, 26.3, 28.8, 30.9, 31.2, 32.7, 36.6, 43.7,
46.5, 47.0, 54.7, 71.8, 72.5, 72.9, 73.7, 109.3, 112.5, 113.5, 115.0,
121.3, 125.4, 125.4, 128.4, 129.2, 130.0, 130.5, 134.0, 137.0,
141.8, 154.5, 158.4, 178.1 and 219.7.
Isolated as white solid; yield 84%; mp 200–201 °C; Anal. Calcd.
for C36H35ClN2O3S: C, 70.74; H, 5.77; N, 4.58. Found: C, 70.71; H,
5.73; N, 4.54. 1H NMR 0.39 (s, 3H), 0.49–0.56 (m, 1H), 0.73–0.75
(m, 1H), 0.98–1.06 (m, 2H), 1.15–1.20 (m, 2H), 1.26–1.42 (m,
1H), 1.60–1.67 (m, 2H), 1.79–1.82 (m, 1H), 2.02–2.06 (m, 1H),
2.43 (d, J = 9.3 Hz, 1H), 2.71 (m, 2H), 2.79–2.91 (m, 2H), 3.59 (dd,
J = 12.9, 6.0 Hz, 2H), 4.68–4.74 (m, 2H), 6.49 (d, J = 2.4 Hz, 1H),
6.55 (dd, J = 8.4, 2.7 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.93 (d,
J = 9.6 Hz, 1H) 7.06 (t, J = 7.5 Hz, 1H), 7.21–7.39 (m, 6H), 7.57 (s,
1H). 13C NMR 14.7, 25.3, 26.6, 29.1, 31.2, 33.1, 36.9, 44.1, 47.1,
47.2, 54.3, 72.2, 72.7, 74.3, 109.6, 112.8, 115.3, 122.6, 125.8,
126.1, 128.9, 129.4, 129.9, 131.3, 133.4, 136.1, 137.7, 140.7,
153.5, 178.5 and 219.7.

V. Jeyachandran et al. / Steroids 82 (2014) 29–37
31
2.2.7. Spiro[50.300]oxindole-spiro[60.16]-70-(4-N,N-dimethylphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3g)
47.2, 55.0, 72.0, 72.8, 74.6, 109.1, 110.1, 112.6, 115.1, 120.7,
122.5, 125.9, 126.5, 126.7, 127.9, 129.5, 130.4, 131.7, 137.7,
141.1, 153.3, 177.9 and 219.6.
Isolated as white solid; yield 83%; mp 199–201 °C; Anal. Calcd.
for C38H41N3O3S: C, 73.64; H, 6.67; N, 6.78. Found: C, 73.62; H,
6.78; N, 6.67. 1H NMR 0.39 (s, 3H), 0.50–0.60 (m, 1H), 0.91–0.98
(m, 3H), 1.04–1, 13 (m, 2H), 1.13–1.30 (m, 1H), 1.55–1.72 (m,
2H), 1.60–1.62 (m, 2H), 1.79–1.82 (m, 1H), 2.05–2.10 (m, 1H),
2.49–2.53 (m, 1H), 2.63–2.67 (m, 2H), 2.81–2.95 (m, 2H), 3.03 (s,
6H), 3.60–3.69 (m, 3H), 4.68–4.73 (m, 1H), 5.09 (s, 1H), 6.54 (d,
J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 9 Hz, 1H), 6.77
(d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H),
7.20–7.23 (m, 4H), 7.43 (s, 1H), 7.49 (d, J = 9 Hz, 1H). 13C NMR
14.7, 26.1, 26.8, 29.2, 29.5, 31.9, 32.6, 38.1, 40.1, 44.2, 46.2, 47.6,
49.0, 72.7, 73.3, 74.1, 111.1, 112.9, 115.3, 123.6, 124.2, 125.4,
126.4, 127.2, 128.3, 129.7, 131.0, 132.2, 132.4, 134.1, 138.0,
151.0, 153.6 and 210.0.
2.2.11. Spiro[50.300]oxindole-spiro[60.16]-70-(2-fluorophenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3k)
Isolated as white solid; yield 81%; mp 192–194 °C; Anal. Calcd.
for C36H35FN2O3S: C, 72.70; H, 5.93; N, 4.71. Found: C, 72.60; H,
5.98; N, 4.62. 1H NMR 0.47 (s, 3H), 0.51–0.55 (m, 2H), 0.90–1.00
(m, 2H), 1.02–1.15 (m, 2H), 1.21–1.34 (m, 1H), 1.58–1.68 (m,
3H), 2.86–2.88 (m, 2H), 2.34–2.39 (m, 1H), 1.96–2.04 (m, 2H),
1.62–1.71 (m, 2H), 1.22–1.30 (m, 2H), 1.98–2.05 (m, 1H), 2.26–
2.29 (m, 2H), 2.52–2.68 (m, 2H), 3.52 (d, J = 5.4 Hz, 1H), 3.62 (d,
J = 5.4 Hz, 1H), 4.15–4.20 (m, 1H), 4.80 (s, 1H), 6.54 (dd, J = 8.4,
2.7 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H),7.03–
7.07 (m, 2H), 7.20–7.26 (m, 5H), 7.47–7.48 (m, 1H), 7.84 (s, 1H).
13C NMR 14.9, 25.2, 26.5, 26.9, 28.9, 30.4, 31.2, 31.5, 33.2, 36.8,
44.0, 46.6, 47.3, 72.4, 74.8, 109.5, 112.7, 115.2, 115.7, 122.7,
124.4, 126.0, 127.3, 128.6, 129.4, 129.8, 131.5, 137.0, 137.6,
140.7, 153.4, 179.0 and 219.8.
2.2.8. Spiro[50.300]oxindole-spiro[60.16]-70-(2-chlorophenyl)tetrahydro-
1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3h)
Isolated as white solid; yield 82%; mp 198–200 °C; Anal. Calcd.
for C36H35ClN2O3S: C, 70.74; H, 5.77; N, 4.58. Found: C, 70.63; H,
5.70; N, 4.66. 1H NMR 0.38 (s, 3H), 0.54–0.66 (m, 1H), 0.90–0.97
(m, 1H), 1.01–1.17 (m, 2H), 1.22–1.33 (m, 1H), 1.53–1.69 (m,
2H), 1.60–1.61 (m, 2H), 1.99–2.03 (m, 2H), 2.26–2.29 (m, 1H)
2.68–2.73 (m, 2H), 2.80–2.94 (m, 2H), 3.48 (d, J = 5.1 Hz, 1H),
3.62 (d, J = 5.1 Hz, 1H), 4.46 (d, J = 8.7 Hz, 1H), 4.70–4.74 (m, 2H),
6.48 (d, J = 2.7 Hz, 1H), 6.55 (dd, J = 8.4, 2.7 Hz, 1H), 6.76 (d,
J = 7.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.03–7.07 (m, 1H), 7.17–
7.23 (m, 2H), 7.33–7.37 (m, 3H), 7.53 (s, 1H), 7.91 (d, J = 7.5 Hz,
1H). 13C NMR 15.4, 25.0, 26.5, 28.9, 30.8, 32.3, 33.0, 36.7, 43.9,
46.5, 47.4, 49.0, 72.1, 72.5, 73.4, 109.5, 112.7, 115.1, 122.7, 125.9,
127.0, 128.1, 129.1, 129.3, 131.2, 131.5, 135.0, 135.9, 137.4,
141.1, 153.4, 178.4 and 219.5.
2.2.12. Spiro[50.300]oxindole-spiro[60.16]-70-(3-fluorophenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3l)
Isolated as white solid; yield 82%; mp 192–194 °C; Anal. Calcd.
for C36H35FN2O3S: C, 72.70; H, 5.93; N, 4.71. Found: C, 72.65; H,
5.90; N, 4.75. 1H NMR 0.40 (s, 3H), 0.53–0.56 (m, 1H), 0.95–0.97
(m, 1H), 1.02–1.15 (m, 2H), 1.17–1.30 (m, 1H), 1.57–1.69 (m,
4H), 1.82–1.84 (m, 1H), 2.01–2.05 (m, 1H), 2.49 (d, J = 9.3 Hz,
1H), 2.60–2.69 (m, 2H), 2.81–2.94 (m, 2H), 3.58–3.62 (m, 2H),
3.71 (d, J = 9.6 Hz, 1H), 4.69–4.75 (m, 1H), 4.88 (s, 1H), 6.48 (d,
J = 2.7 Hz, 1H), 6.55 (dd, J = 11.1, 2.7 Hz, 1H), 6.78 (d, J = 7.8 Hz,
1H), 6.95 (d, J = 9.0 Hz, 1H), 7.00–7.02 (m, 1H), 7.03–7.09 (m,
1H), 7.21–7.24 (m, 2H), 7.29–7.35 (m, 2H), 7.40 (d, J = 7.5 Hz,
1H), 7.74 (s, 1H). 13C NMR 14.6, 25.3, 26.6, 29.0, 31.2, 31.4, 33.2,
36.9, 44.0, 47.2, 47.7, 54.6, 72.0, 72.6, 74.5, 109.7, 112.7, 114.4,
114.7, 115.3, 122.6, 125.7, 126.0, 129.4, 129.9, 131.6, 133.4,
137.7, 140.8, 141.3, 153.4, 178.8 and 219.8.
2.2.9. Spiro[50.300]oxindole-spiro[60.16]-70-(2-methylphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3i)
Isolated as white solid; yield 83%; mp 199–200 °C; Anal. Calcd.
for C37H38N2O3S: C, 75.22; H, 6.48; N, 4.74. Found: C, 73.34; H,
6.32; N, 4.63. 1H NMR 0.43 (s, 3H), 0.55–0.62 (m, 1H), 0.95–0.99
(m, 1H), 1.03–1.19 (m, 2H), 1.23–1.32 (m, 1H), 1.60–1.61 (m,
2H), 1.62–1.67 (m, 2H), 1.80–1.81 (m, 1H), 1.90–2.04 (m, 2H),
2.24 (s, 3H), 2.63–2.69 (m, 2H), 2.80–2.86 (m, 2H), 3.53 (d,
J = 5.7 Hz, 1H), 3,64 (d, J = 5.7 Hz, 1H), 4.15 (d, J = 9.3 Hz, 1H),
4.75–4.77 (m, 1H), 4.80 (s, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.55 (dd,
J = 8.4, 2.4 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H),
7.03–7.08 (m, 1H), 7.13–7.15 (m, 2H), 7.18–7.21 (m, 2H), 7.33 (d,
J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H). 13C NMR 14.7,
19.9, 25.2, 26.6, 29.0, 31.0, 32.7, 36.8, 44.0, 46.5, 46.8, 47.3, 49.2,
72.8, 73.5, 73.9, 109.5, 112.6, 115.2 122.6, 126.0, 126.2, 126.8,
129.3, 129.7, 130.4, 131.5, 135.9, 137.2, 137.6, 141.0, 153.4, 178.4
and 220.2.
2.2.13. Spiro[50.300]oxindole-spiro[60.16]-70-(2,4-dichlorophenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3m)
Isolated as white solid; yield 83%; mp 195–197 °C; Anal. Calcd.
for C36H34Cl2N2O3S: C, 66.97; H, 5.31; N, 4.34. Found: C, 66.91; H,
5.39; N, 4.30. 1H NMR 0.38–0.46 (m, 1H), 0.60 (s, 3H), 0.92–0.97
(m, 2H), 1.11–1.16 (m, 2H), 1.25–1.31 (m, 1H), 1.59–1.74 (m,
4H), 1.99–2.04 (m, 1H), 2.25 (d, J = 9.3 Hz, 1H), 2.67–2.70 (m,
2H), 2.79–2.93 (m, 2H), 3.46 (d, J = 5.1 Hz, 1H), 3.61 (d, J = 5.1 Hz,
1H), 4.40 (d, J = 8.4 Hz, 1H), 4.62–4.69 (m, 1H), 4.97 (s, 1H), 6.49–
6.51 (m, 1H), 6.55–6.58 (m, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.95 (d,
J = 8.7 Hz, 1H), 7.02–7.08 (m, 1H), 7.21–7.23 (m, 2H), 7.30–7.38
(m, 1H), 7.74 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H). 13C NMR 15.7, 25.2,
26.9, 29.1, 31.0, 32.4, 33.3, 36.8, 44.1, 45.5, 46.7, 48.7, 71.0, 72.5,
73.5, 109.6, 112.8, 115.3, 123.0, 126.0, 127.7, 129.1, 130.0, 131.5,
132.7, 133.4, 135.0, 135.7, 137.6, 141.2, 153.5, 178.3 and 219.0.
2.2.10. Spiro[50.300]oxindole-spiro[60.16]-70-(2-methoxyphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3j)
Isolated as white solid; yield 84%; mp 212–214 °C; Anal. Calcd.
for C37H38N2O4S: C, 73.24; H, 6.31; N, 4.62. Found: C, 73.10; H,
6.39; N, 4.67. 1H NMR 0.31–0.43 (m, 1H), 0.45 (s, 3H), 0.90–0.97
(m, 1H), 1.00–1.14 (m, 2H), 1.20–1.32 (m, 1H), 1.58–1.68 (m,
4H), 1.85–1.91 (m, 2H), 1.97–2.02 (m, 1H), 2.23–2.26 (m, 2H),
2.59–2.63 (m, 2H), 3.51 (d, J = 5.4 Hz, 1H), 3.62 (d, J = 6.0 Hz, 1H),
3.69 (s, 3H), 4.35 (d, J = 9.9 Hz, 1H), 4.77–4.85 (m, 1H), 5.10 (s,
1H), 6.46 (d, J = 2.4 Hz, 1H), 6.56 (dd, J = 8.4, 2.7 Hz, 1H), 6.76 (d,
J = 7.8 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H),
7.02 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 7.17–7.24 (m, 2H),
7.30 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H). 13C
NMR 14.9, 25.2, 26.6, 28.9, 31.1, 32.4, 32.6, 36.9, 44.1, 44.7, 46.8,
2.2.14. Spiro[50.300]oxindole-spiro[60.16]-70-(3,4-dimethoxyphenyl)
tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (3n)
Isolated as white solid; yield 85%; mp 213–215 °C; Anal. Calcd.
for C38H40N2O5S: C, 71.67; H, 6.33; N, 4.40. Found: C, 71.61; H,
6.26; N, 4.45. 1H NMR 0.35 (s, 3H), 0.54–0.57 (m, 1H), 0.90–1.00
(m, 2H), 1.15–1.26 (m, 2H), 1.57–1.65 (m, 4H), 1.74–1.77 (m,
2H), 1.99–2.04 (m, 2H), 2.46–2.49 (m, 1H), 2.62–2.64 (m, 2H),
2.84–2.93 (m, 2H), 3.62–3.67 (m, 2H), 3.87 (s, 6H), 4.71–4.75 (m,
1H), 6.47 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H),
6.92 (d, J = 7.8 Hz, 1H), 7.03–7.08 (m, 3H), 7.21–7.26 (m, 3H),
7.39–7.42 (m, 1H), 8.14 (s, 1H). 13C NMR 14.5, 25.3, 26.5, 26.8,
28.9, 31.3, 33.4, 34.6, 36.9, 44.0, 47.1, 47.3, 54.8, 55.7, 72.2, 72.7,

32
V. Jeyachandran et al. / Steroids 82 (2014) 29–37
74.5, 109.6, 109.8, 111.1, 112.7, 115.3, 122.3, 125.9, 129.3, 129.9,
131.3, 137.6, 140.8, 148.2, 148.3, 148.9, 153.6, 179.0 and 220.2.
125.9, 127.3, 128.0, 128.9, 129.7, 131.5, 137.7, 139.2, 153.4,
156.5, 164.2, 172.6 and 218.7.
2.2.15. Spiro[50.300]oxindole-spiro[60.16]-70-(naphthyl)-tetrahydro-1H-
pyrrolo[10,20-c][10,30]thiazolo estrone (3o)
2.2.19. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(4-bromoph-
enyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4d)
Isolated as white solid; yield 82%; mp 223–225 °C; Anal. Calcd.
for C36H34BrClN2O3S: C, 62.66; H, 4.97; N, 4.06. Found: C, 62.61; H,
4.99; N, 4.03. 1H NMR 0.33 (s, 3H), 0.53–0.64 (m, 2H), 0.98–1.05
(m, 2H), 1.05–1.26 (m, 3H), 1.60–1.74 (m, 3H), 2.06–2.10 (m, 2H),
2.52 (d, J = 11.1 Hz, 1H), 2.63–2.68 (m, 2H), 2.82–2.92 (m, 2H),
3.58–3.68 (m, 2H), 4.61–4.72 (m, 1H), 5.299 (s, 1H), 6.42–6.58
(m, 2H), 6.60 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.96 (d,
J = 8.4 Hz, 1H), 7.24–7.27 (m, 2H), 7.43–7.50 (m, 3H). 13C NMR
14.6, 21.3, 25.3, 26.6, 28.9, 30.8, 31.2, 33.0, 36.9, 44.2, 47.3, 47.5,
54.4, 72.1, 72.7, 74.2, 110.3, 112.7, 115.3, 126.0, 128.2, 129.4,
129.7, 131.5, 131.8, 136.3, 137.6, 139.1, 153.4, 155.6, 164.4, 177.8
and 219.3.
Isolated as white solid; yield 81%; mp 192–194 °C; Anal. Calcd.
for C40H38N2O3S: C, 76.65; H, 6.11; N, 4.47. Found: C, 76.71; H,
6.18; N, 4.42. 1H NMR 0.18 (s, 3H), 0.37–0.41 (m, 1H), 0.90–0.99
(m, 1H), 1.01–1.19 (m, 2H), 1.20–1.25 (m, 1H), 1.60–1.61 (m,
2H), 1.62–1.70 (m, 2H), 1.94–1.98 (m, 2H), 2.36–2.41 (m, 1H),
2.56–2.62 (m, 2H), 2.81–2.84 (m, 2H), 3.57 (d, J = 5.4 Hz, 1H),
3.68 (d, J = 5.4 Hz, 1H), 4.70 (d, J = 4.7 Hz, 1H), 4.79 (s, 1H), 4.99–
5.05 (m, 1H), 6.52 (dd, J = 8.4, 2.7 Hz, 1H), 6.64 (m, 1H), 6.74 (m,
1H), 6.78 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H),
7.07–7.12 (m, 1H), 7.37–7.60 (m, 4H), 7.77–7.96 (m, 4H). 13C
NMR 15.5, 25.2, 26.6, 26.9, 28.9, 31.0, 32.6, 36.8, 40.6, 44.1, 46.4,
47.4, 73.2, 73.5, 74.0, 109.8, 112.8, 115.3, 122.8, 123.5, 125.6,
126.0, 126.4, 127.3, 128.8, 129.3, 129.9, 131.5, 132.8, 133.8,
134.1, 137.6, 141.2, 153.4, 178.6 and 220.1.
2.2.20. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(4-
methylphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone
(4e)
2.2.16. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-
(phenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4a)
Isolated as white solid; yield 83%; mp 206–208 °C; Anal. Calcd.
for C36H35ClN2O3S: C, 70.74; H, 5.77; N, 4.58. Found: C, 70.65; H,
5.72; N, 4.61. 1H NMR 0.20 (s, 3H), 0.54–0.59 (m, 2H), 0.95–1.28
(m, 3H), 1.60–1.62 (m, 2H), 1.64–1.68 (m, 2H), 1.82 (s, 1H), 2.01–
2.16 (m, 2H), 2.56–2.63 (m, 2H), 2.85 (dd, J = 10.2, 5.7 Hz, 1H),
2.96 (dd, J = 10.2, 5.7 Hz, 1H), 3.57 (d, J = 7.5 Hz, 1H), 3.65–3.75
(m, 2H), 4.70–474 (m, 1H), 5.76 (s, 1H), 6.45 (d, J = 2.7 Hz, 1H),
6.56 (dd, J = 8.4, 5.7 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.01–7.07 (m,
2H), 7.24–7.32 (m, 5H),7.63 (d, J = 2.1 Hz, 1H). 13C NMR 14.0,
21.0, 25.2, 26.8, 31.3, 34.5, 36.9, 44.1, 47.0, 48.2, 55.2, 60.4, 72.6,
74.8, 76.5, 110.3, 110.4, 112.7, 115.2, 120.5, 125.9, 127.4, 127.9,
128.6, 129.5, 129.8, 131.4, 137.7, 139.3, 153.5, 155.6, 175.4 and
129.8.
Isolated as white solid; yield 83%; mp 199–201 °C; Anal. Calcd.
for C37H37ClN2O3S: C, 71.08; H, 5.96; N, 4.48. Found: C, 71.20; H,
5.91; N, 4.55. 1H NMR 0.41 (s, 3H), 0.47–0.56 (m, 2H), 1.10–1.34
(m,6H), 1.61–1.82 (m,5H), 2.04–2.07 (d, J = 7.6 Hz, 1H), 2.46–2.52
(m, 2H), 2.77–2.89 (m, 3H), 3.61–3.66 (m, 2H), 4.14 (d, J = 9.6 Hz,
1H), 4.68–4.75 (m, 1H), 5.06 (s, 1H), 6.47 (d, J = 1.8 Hz, 1H), 6.55–
6.58 (m 2H), 6.74 (d, J = 8.1 Hz, 1H) 6.96 (d, J = 8.7 Hz, 1H) 7.14–
7.15 (m, 2H), 7.22–7.25 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.62 (d,
J = 8.1 Hz, 1H). 13C NMR 14.2, 21.0, 25.3, 26.5, 28.9, 29.7, 31.4,
33.6, 36.9, 44.1, 47.3, 47.7, 55.0, 71.8, 72.4, 76.5, 110.3, 112.7,
115.2, 126.0, 127.6, 127.9, 129.3, 129.6, 129.9, 131.7, 133.6,
137.3, 137.7, 138.9, 153.4, 178.4 and 218.6.
2.2.21. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(4-
methyoxyphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone
(4f)
2.2.17. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(4-chloroph-
enyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4b)
Isolated as white solid; yield 86%; mp 118–220 °C; Anal. Calcd.
for C36H34Cl2N2O3S: C, 66.97; H, 5.31; N, 4.34. Found: C, 67.09; H,
5.37; N, 4.31. 1H NMR 0.33 (s, 3H), 0.56–0.62 (m, 2H), 0.97–1.04
(m, 2H), 1.08–1.30 (m, 2H), 1.60–1.73 (m, 3H), 2.05–2.10 (m, 2H),
2.48–2.53 (m, 1H), 2.79–2.85 (m, 2H), 2.88–2.94 (m, 2H), 3.56–
3.68 (m, 2H), 4.65–4.68 (m, 2H), 5.09 (s, 1H), 6.47–6.48 (m, 1H),
6.53–6.57 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H),
7.22–7.27 (m, 2H), 7.31–7.35 (m, 1H), 7.48–7.50 (m, 1H), 8.11 (s,
1H). 13C NMR 19.4, 31.2, 33.7, 35.7, 36.0, 37.4, 41.6, 41.6, 48.8,
51,4, 51.7, 52.0, 58.7, 76.9, 77.6, 78.3, 110.8, 115.6, 117.6, 120.0,
130.4, 131.7, 132.2, 134.4, 134.6, 137.9, 138.9, 141.0, 141.9,
145.8, 159.6, 182.5 and 219.8.
Isolated as white solid; yield 83%; mp 226–228 °C; Anal. Calcd.
for C37H37ClN2O4S: C, 69.30; H, 5.82; N, 4.37. Found: C, 69.36; H,
5.90; N, 4.40. 1H NMR 0.52 (s, 3H), 0.85–0.89 (m, 1H), 0.90–1.09
(m, 1H), 1.05–1.17 (m, 2H), 1.25–1.27 (m, 2H), 1.39–1.46 (m,
1H), 1.62–1.68 (m, 2H), 1.69–1.73 (m,1H), 1.82–1.86 (m, 1H),
2.04–2.09 (m, 2H), 2.17–2.67 (m, 1H), 2.51–2.56 (m, 2H), 2.83–
2.91 (m, 2H), 3.48 (d, J = 6.8 Hz, 1H), 3.58 (d, J = 6.8 Hz, 1H), 3.69
(s, 3H), 4.73–4.81 (m, 1H), 4.95 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H),
6.55 (m, 2H), 6.71 (d, J = 6.9 Hz, 1H) 6.82 (d, J = 7.2 Hz, 1H), 6.91–
7.05 (m, 2H), 7.15–7.26 (m, 2H), 7.52 (d, J = 6.9 Hz, 1H), 7.69 (d,
J = 7.2 Hz, 1H). 13C NMR 7.86, 14.6, 22.3, 25.4, 26.8, 29.1, 29.3,
32.2, 33.6, 37.0, 44.4, 47.4, 53.4, 55.2, 71.2, 71.8, 72.7, 110.1,
111.0, 112.8, 115.4, 120.9, 125.2, 126.2, 126.5, 128.4, 129.6,
129.9, 130.1, 130.6, 131.8, 132.5, 156.2, 172.1, 218.9.
2.2.18. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(4-fluoroph-
enyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4c)
2.2.22. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(2-
Isolated as white solid; yield 83%; mp 213–215 °C; Anal. Calcd.
for C36H34ClFN2O3S: C, 68.72; H, 5.45; N, 4.45. Found: C, 68.67; H,
5.51; N, 4.40. 1H NMR 0.31 (s, 3H), 0.60–0.67 (m, 1H), 0.96–1.00
(m, 1H), 1.06–1.25 (m, 3H), 1.38–1.43 (m, 2H), 1.60–167 (m, 2H),
1.82–1.86 (m, 1H), 2.11–2.06 (m, 2H), 2.51–2.69 (m, 3H), 2.81–
2.95 (m, 1H), 3.56 (d, J = 6.9 Hz, 1H), 3.64–3.70 (m, 2H), 4.63–
4.70 (m, 1H), 4.89 (s, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.4,
2.4 Hz, 1H), 6.72 (dd, J = 8.4, 2.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H),
6.96 (d, J = 8.4 Hz, 1H), 7.01–7.07 (m, 1H), 7.23–7.25 (m, 2H),
7.52 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 6.2 Hz, 1H), 7.79 (d, J = 7.2 Hz,
1H). 13C NMR 14.4, 21.6, 25.3, 26.5, 26.8, 28.9, 33.2, 36.9, 44.1,
47.3, 47.6, 54.4, 63.4, 72.2, 72.7, 73.6, 110.2, 112.7, 115.3, 121.1,
chlorophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone
(4h)
Isolated as white solid; yield 83%; mp 213–215 °C; Anal. Calcd.
for C36H34Cl2N2O3S: C, 66.97; H, 5.31; N, 4.34. Found: C, 66.90; H,
5.40; N, 4.38. 1H NMR 0.60 (s, 3H), 0.94–0.99 (m, 2H), 1.09–1.19
(m, 2H), 1.25–1.46 (m, 3H), 1.59–1.80 (m, 3H), 2.05–2.16 (m,
2H), 2.27 (dd, J = 12.9, 3.6 Hz, 1H), 2.61–2.67 (m, 2H), 2.74–2.89
(m, 1H), 3.47 (d, J = 5.4 Hz, 1H), 3.59 (d, J = 5.1 Hz, 1H), 4.57 (d,
J = 8.7 Hz, 1H), 4.68–4.70 (m, 1H), 4.85 (s, 1H), 6.48 (d, J = 2.4 Hz,
1H), 6.55–6.59 (m, 1H) 6.73 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.7 Hz,
1H), 7.12–7.37 (m, 4H), 7.85–7.88 (m, 2H). 13C NMR 15.5, 25.2,
26.7, 29.0, 32.3, 32.9, 36.8, 44.2, 45.4, 47.1, 47.6, 49.0, 72.8, 73.2,

V. Jeyachandran et al. / Steroids 82 (2014) 29–37
33
73.5, 110.4, 112.8, 115.2, 126.1, 127.1, 128.0, 128.4, 128.6, 129.5,
129.8, 131.4, 131.6, 135.4, 137.5, 139.6, 153.4, 177.7 and 219.4.
2.2.27. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-
(phenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5a)
Isolated as white solid; yield 81%; mp 178–181 °C; Anal. Calcd.
for C40H37NO3S: C, 78.53; H, 6.10; N, 2.29. Found: C, 78.45; H, 6.17;
N, 2.37. 1H NMR 0.30 (s, 3H), 0.65–0.70 (m, 1H), 1.03–1.19 (m, 2H),
1.24–1.28 (m, 2H), 1.41–1.46 (m, 1H), 1.60–1.62 (m, 2H), 1.65–1.88
(m, 2H), 2.50–2.66 (m, 1H), 2.06–2.68 (m, 3H), 2.92–3.13 (m, 2H),
3.67 (d, J = 8.1 Hz, 1H), 3.83 (d, J = 8.1 Hz, 1H), 3.90 (d, J = 9.9 Hz,
1H), 4.76–4.82 (m, 2H), 6.46–6.53 (m, 2H), 6.86 (d, J = 8.4 Hz,
1H), 7.27–7.33 (m, 4H), 7.66–7.76 (m, 2H), 7.47 (d, J = 7.8 Hz,
1H), 7.60 (m, 2H), 8.10 (d, J = 7.2 Hz, 1H), 7.907.47 (d, J = 7.2 Hz,
1H). 13C NMR 13.9, 25.0, 26.2, 28.8, 28.9, 31.4, 34.6, 36.8, 43.9,
47.2, 48.2, 50.1, 56.1, 71.9, 72.7, 80.0, 112.5, 115.2, 120.7, 125.4,
125.8, 126.1, 127.5, 127.7, 128.3, 128.5, 129.9, 130.5, 131.6,
131.7, 132.1, 132.7, 233.4, 134.7, 136.9, 137.8, 141.2, 153.4, 205.9
and 218.7.
2.2.23. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(2-methylphe-
nyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4i)
Isolated as white solid; yield 83%; mp 202–204 °C; Anal. Calcd.
for C37H37ClN2O3S: C, 71.08; H, 5.96; N, 4.48. Found: C, 71.01; H,
6.08; N, 4.37. 1H NMR 0.41 (s, 3H), 0.47–0.55 (m, 2H), 0.90–1.02
(m, 2H), 1.10–1.34 (m, 2H), 1.61–1.81 (m, 4H), 2.05–2.09 (m,
2H), 2.24 (s, 3H), 2.46–2,52 (m, 1H), 2.77–2.83 (m, 2H), 2.85–
2.88 (m, 1H), 3.55 (d, J = 5.7 Hz, 1H), 3.60 (d, J = 5.7 Hz, 1H),
4.67–4.75 (m, 2H), 5.15 (s, 1H), 6.46–6.47 (m, 1H), 6.56 (d,
J = 8.7 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.94–6.97 (m, 1H), 7.14–
7.15 (m, 2H), 7.22–7.25 (m, 2H), 7.40 (s, 1H), 7.62 (d, J = 7.5 Hz,
1H). 13C NMR 14.5, 19.9, 25.2, 26.6, 28.9, 31.8, 32.8, 36.9, 44.1,
47.0, 47.4, 49.3, 72.7, 73.5, 74.3, 110.6, 112.8, 115.3, 126.1, 126.2,
127.0, 128.0, 128.2, 129.7, 129.9, 130.6, 131.5, 135.4, 137.4,
137.6, 139.4, 153.4, 178.4 and 219.2.
2.2.28. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(4-chloro-
phenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5b)
Isolated as white solid; yield 82%; mp 199–200 °C; Anal. Calcd.
for C40H36ClNO3S: C, 74.34; H, 5.61; N, 2.17. Found: C, 74.44; H,
5.52; N, 2.25. 1H NMR 0.16 (s, 3H), 0.51–0.60 (m, 1H), 0.95–1.37
(m, 3H), 1.60–1.62 (m, 2H), 1.64–1.68 (m, 2H), 1.84–1.89 (m,
1H), 2.45–2.52 (m, 1H), 2.63–2.66 (m, 2H), 2.88–3.08 (m, 2H),
3.76 (d, J = 7.5 Hz, 1H), 3.75 (d, J = 7.5 Hz, 1H), 3.84 (d, J = 9.9 Hz,
1H), 3.67 (m, 1H), 4.77–4.84 (m, 1H), 4.53 (s, 1H), 6.46–6.51 (m,
2H), 6.86 (d, J = 8.1 Hz, 1H), 7.27–7.33 (m, 6H), 7.68–7.74 (m,
4H), 8.10 (d, J = 8.4 Hz, 1H). 13C NMR 14.2, 24.9, 26.0, 28.8, 29.3,
31.2, 34.1, 36.6, 43.8, 47.0, 49.2, 50.4, 55.1, 72.1, 72.7, 79.2,
112.4, 115.1, 120.7, 125.4, 125.7, 125.9, 126.1, 127.7, 128.2,
128.7, 130.4, 131.1, 131.3, 131.6, 132.1, 133.3, 134.6, 135.7,
137.6, 141.3, 153.4, 206.0 and 219.3.
2.2.24. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(2-fluorophen-
yl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4k)
Isolated as white solid; yield 81%; mp 221–223 °C; Anal. Calcd.
for C36H34ClFN2O3S: C, 68.72; H, 5.45; N, 4.45. Found: C, 68.58; H,
5.41; N, 4.43. 1H NMR 0.54 (s, 3H), 0.60–0.67 (m, 1H), 0.95–1.12
(m, 2H), 1.25–1.30 (m, 2H), 1.38–1.43 (m, 2H), 1.6–1.62 (m, 1H),
1.71–1.98 (m, 2H), 2.01–2.16 (m, 2H), 2.23–2.31 (m, 1H), 2.62–
2.66 (m, 2H), 2.84–2.90 (m, 1H), 3.56 (d, J = 6.9 Hz, 2H), 4.41–
4.49 (m, 2H), 4.73 (s, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.41–6.58 (m,
2H), 6.73 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.95–7.00 (m,
2H), 7.03–7.15 (m, 2H), 7.22–7.33 (m, 1H). 13C NMR 15.2, 25.2,
26.6, 26.8, 28.9, 31.8, 36.9, 44.2, 47.4, 52.1, 52.9, 58.3, 77.1, 77.6,
77.9, 110.2, 112.7, 115,7, 120.3, 124.5, 126.0, 128.1, 129.7, 131,5,
153.4, 153.4, 153.4, 177.3, 197.2 and 220.3.
2.2.25. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(3-fluorophe-
nyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4l)
2.2.29. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(4-brom-
ophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5d)
Isolated as white solid; yield 79%; mp 176–178 °C; Anal. Calcd.
for C40H36BrNO3S: C, 69.56; H, 5.25; N, 2.03. Found: C, 69.50; H,
5.15; N, 2.09. 1H NMR 0.37 (s, 3H), 0.48–0.59 (m, 1H), 0.96–1.18
(m, 2H), 1.21–1.88 (m, 3H), 1.60–167 (m, 4H), 2.04–2.66 (m, 4H),
2.88–3.07 (m, 2H), 3.65–3.84 (m, 4H), 4.57 (s, 1H), 6.45–6.52 (m,
2H), 6.86 (d, J = 8.4 Hz, 1H), 7.47–7.50 (m, 2H), 7.60–7.74 (m,
2H), 7.81–7.93 (m, 4H), 8.10 (d, J = 7.8 Hz, 1H), 8.32–8.35 (m,
1H), 8.63–8.66 (m, 1H). 13C NMR 13.9, 22.5, 25.0, 26.1, 28.8, 31.5,
34.1, 36.7, 43.8, 47.1, 47.9, 49.2, 55.3, 72.2, 72.7, 79.1, 112.5,
115.1, 120.8, 121.5, 125.4, 125.8, 126.0, 127.4, 127.9, 128.3,
131.4, 131.7, 132.2, 133.3, 234.5, 135.1, 137.7, 141.3, 153.9,
158.5, 208.2 and 219.8.
Isolated as white solid; yield 81%; mp 209–212 °C; Anal. Calcd.
for C36H34ClFN2O3S: C, 68.72; H, 5.45; N, 4.45. Found: C, 68.64; H,
5.52; N, 4.42. 1H NMR 0.34 (s, 3H), 0.62–0.68 (m, 1H), 0.95–1.00
(m, 2H), 1.09–1.17 (m, 2H), 1.20–1.33 (m, 1H), 1.38–1.43 (m,
1H), 1.59–1.79 (m, 3H), 2.01–2.06 (m, 2H), 2.54–2.61 (m, 2H),
2.81–2.97 (m, 2H), 3.56 (d, J = 6.4 Hz, 1H), 3.63–3.72 (m, 2H),
4.66–4.69 (m, 1H), 4.94 (s, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.54 (dd,
J = 8.2, 2.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.92–7.33 (m, 6H),
7.51 (d, J = 1.8 Hz, 1H). 13C NMR 1 4.0, 24.6, 25.9, 28.4, 30.4, 30.6,
32.1, 36.3, 43.4, 46.3, 46.6, 53.7, 71.5, 72.2, 73.0, 110.3, 112.3,
114.6, 115.6, 125.1, 126.2, 126.9, 128.0, 128.9, 129.1, 136.5,
138.8, 139.2, 154.3, 177.1 and 219.4.
2.2.26. Spiro[50.300]-500-chloro-oxindole-spiro[60.16]-70-(2,4-dichloro-
phenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (4m)
Isolated as white solid; yield 84%; mp 228–230 °C; Anal. Calcd.
for C36H33Cl3N2O3S: C, 63.58; H, 4.89; N, 4.12. Found: C, 63.50; H,
4.83; N, 4.18. 1H NMR 0.62 (s, 3H), 0.94–1.04 (m, 1H), 1.01–1.18
(m, 2H), 1.24–1.29 (m, 1H), 1.42–1.45 (m, 1H), 1.61–1.67 (m,
2H), 1.61–1.70 (m, 3H), 2.02–2.09 (m, 2H), 2.20–2.27 (m, 1H),
2.70–2.78 (m, 2H), 2.80–2.91 (m, 2H), 3.44 (d, J = 1.8 Hz, 1H),
3.57 (d, J = 5.1 Hz, 1H), 4.58–4.68 (m, 1H), 5.21 (s, 1H), 6.48 (d,
J = 2.4 Hz, 1H), 6.56 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H) 6.84 (d,
J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.21–7.26 (m, 1H), 7.31–
7.35 (m, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.84
(d, J = 8.4 Hz, 1H). 13C NMR 15.6, 22.5, 25.2, 26.7, 28.9, 29.6, 30.9,
32.1, 33.1, 36.8, 44.2, 47.5, 48.6, 72.8, 73.6, 110.4, 112.8, 115.2,
126.1, 127.6, 127.9, 128.6, 129.2, 129.5, 129.8, 131.4, 132.6,
133.5, 135.7, 137.5, 139.6, 153.5, 177.5 and 218.7.
2.2.30. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(4-meth-
ylphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5e)
Isolated as white solid; yield 81%; mp 177–179 °C; Anal. Calcd.
for C41H39NO3S: C, 78.69; H, 6.28; N, 2.24. Found: C, 78.61; H, 6.20;
N, 2.16. 1H NMR 0.06 (s, 3H), 0.47–0.71 (m, 1H), 1.00–1.19 (m, 2H),
1.21–1.28 (m, 1H), 1.40–1.47 (m, 2H), 1.60–1.69 (m, 4H), 2.33–2.39
(m, 4H), 2.56–2.65 (m, 2H), 2.91–3.12 (m, 2H), 3.67 (d, J = 8.1 Hz,
1H), 3.77–3.88 (m, 1H), 4.73–4.86 (m, 2H), 6.46 (m, 2H), 6.87 (d,
J = 8.4, 1H), 7.13–7.25 (m, 5H), 7.66–7.76 (m, 2H), 7.87–7.92 (m,
2H), 8.00–8.11 (m, 2H). 13C NMR 13.9, 21.0, 25.1, 26.2, 28.5, 28.9,
31.4, 34.7, 36.8, 43.9, 47.1, 48.2, 50.6, 55.7, 71.9, 72.5, 80.3,
112.5, 115.2, 120.8, 125.4, 125.7, 125.2, 122.9, 126.1, 127.7,
128.3, 129.2, 130.4, 131.5, 131.9, 132.7, 132.2, 133.6, 134.6,
137.2, 137.8, 141.1, 153.5, 206.1 and 218.9.

34
V. Jeyachandran et al. / Steroids 82 (2014) 29–37
2.2.31. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(4-met-
hoxyphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5f)
Isolated as white solid; yield 83%; mp 180–183 °C; Anal. Calcd.
for C41H39NO4S: C, 76.73; H, 6.12; N, 2.18. Found: C, 76.82; H, 6.19;
N, 2.28. 1H NMR 0.07 (s, 3H), 0.60–0.66 (m, 1H), 1.03–1.21 (m, 2H),
1.23–1.30 (m, 1H), 1.44–1.48 (m, 1H), 1.23–1.70 (m, 3H), 1.80–2.04
(m, 2H), 2.56–2.67 (m, 2H), 2.97–3.13 (m, 2H), 3.66 (d, J = 8.1, 1H),
3.79–3.86 (m, 2H), 3.79 (s, 3H), 4.70–4.73 (m, 1H), 5.21 (s, 1H),
6.47–6.53 (m, 2H), 6.86–6.89 (m, 2H), 7.02–7.10 (m, 1H), 7.66–
7.76 (m, 3H), 7.88–7.92 (m, 3H), 8.04–8.12 (m, 3H). 13C NMR
13.8, 26.2, 28.4, 28.9, 31.4, 34.7, 36.8, 43.9, 47.2, 48.3, 50.6, 55.2,
55.4, 71.9, 72.4, 80.3, 112.5, 113.9, 115.2, 120.8, 123.4, 125.4,
125.8, 126.1, 127.2, 127.8, 128.3, 128.7, 130.4, 131.0, 131.4,
132.2, 133.5, 134.5, 137.8, 141.1, 153.5, 158.9, 206.1 and 219.2.
2.2.35. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(2-
methoxyphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone
(5j)
Isolated as white solid; yield 82%; mp 191–193 °C; Anal. Calcd.
for C41H39NO4S: C, 76.73; H, 6.12; N, 2.18. Found: C, 76.79; H, 6.16;
N, 2.23. 1H NMR 0.61–0.71 (m, 1H), 0.80 (s, 3H), 0.96–0.99 (m, 1H),
1.10–1.16 (m, 2H), 1.29–1.71 (m, 3H), 1.88–1.97 (m, 2H), 1.99–2.69
(m, 2H), 2.91–3.16 (m, 3H), 3.64 (d, J = 8.1, 1H), 3.77–3.86 (m, 2H),
3.77 (s, 3H), 4.71–4.82 (m, 2H), 5.30 (s, 1H), 6.47–6.53 (m, 2H), 6.87
(d, J = 8.4, 3H), 7.26–7.33 (m, 1H), 7.66–7.76 (m, 3H), 7.9 (t, J = 6.3,
2H), 8.03–8.11 (m, 3H). 13C NMR 13.9, 25.1, 26.2, 28.6, 28.9, 31.3,
34.6, 36.8, 43.9, 47.2, 48.3, 50.3, 55.1, 55.4, 72.1, 72.6, 80.1,
112.5, 113.9, 115.2, 120.7, 125.3, 125.8, 126.1, 126.1, 127.7,
128.2, 128.8, 130.5, 130.9, 131.5, 131.9, 132.1, 134.7, 135.4,
137.8, 141.6, 153.4, 158.9, 205.9 and 218.8.
2.2.36. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(2-fluor-
ophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5k)
Isolated as white solid; yield 79%; mp 178–180 °C; Anal. Calcd.
for C40H36FNO3S: C, 76.28; H, 5.76; N, 2.22. Found: C, 76.21; H,
5.70; N, 2.17. 1H NMR 0.47 (s, 3H), 0.51–0.55 (m, 2H), 0.90–1.00
(m, 2H), 1.02–1.15 (m, 2H), 1.60–1.67 (m, 4H), 1.86–2.88 (m,
4H), 1.34–2.39 (m, 1H), 1.96–2.04 (m, 2H), 1.62–1.71 (m, 2H),
1.22–1.30 (m, 2H), 2.02–2.68 (m, 2H), 2.91–3.12 (m, 3H), 3.52 (d,
J = 5.4 Hz, 1H), 3.62 (d, J = 5.4 Hz, 1H), 4.15–4.20 (m, 1H), 4.80 (s,
1H), 6.47–6.53 (m, 2H), 6.87 (d, J = 8.1, 1H), 7.27–7.34 (m, 1H),
7.66–7.75 (m, 3H), 7.81–7.93 (m, 3H), 8.06–8.12 (m, 2H), 8.33 (d,
J = 7.2, 1H), 8.65 (d, J = 7.2, 1H). 13C NMR 14.0, 14.7, 22.5, 25.1,
26.2, 28.9, 31.3, 34.5, 36.7, 43.9, 47.2, 48.1, 50.1, 51.1, 72.2, 79.8,
112.6, 114.4, 115.2, 115.7, 120.9, 125.5, 125.8, 126.1, 127.4,
127.9, 128.3, 130.5, 131.2, 131.6, 132.3, 133.4, 134.5, 135.3,
137.7, 141.2, 153.6, 160.5, 206.2 and 218.2.
2.2.32. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(4-N,N
dimethylaminophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo
estrone (5g)
Isolated as white solid; yield 82%; mp 178–180 °C; Anal. Calcd.
for C42H42N2O3S: C, 77.03; H, 6.46; N, 4.28. Found: C, 77.11; H,
6.54; N, 4.20. 1H NMR 0.06 (s, 3H), 0.46–0.63 (m, 1H), 0.93–1.13
(m, 4H), 1.14–1.82 (m, 5H), 2.04–2.54 (m, 2H), 2.68–2.84 (m,
4H), 2.96 (s, 6H), 3.64–3.88 (m, 3H), 4.76–4.79 (m, 2H), 6.48–
6.52 (m, 2H), 6.67–6.71 (m, 2H), 6.88 (d, J = 8.4, 1H), 7.16–7.19
(m, 1H), 7.65–7.91 (m, 6H), 8.07–8.12 (m, 2H), 8.33 (d, J = 8.4,
1H), 8.65 (d, J = 8.4, 1H). 13C NMR 13.8, 13.9, 22.5, 25.2, 26.2,
28.4, 31.4, 34.8, 36.9, 37.9, 40.3, 43.9, 47.2, 48.4, 50.6, 71.9, 72.6,
80.4, 112.3, 112.5, 118.8, 120.6, 124.2, 125.2, 127.7, 126.2, 127.3,
127.6, 128.2, 130.5, 131.6, 131.8, 132.0, 133.3, 134.8, 135.1,
137.8, 141.0, 149.8, 153.4, 205.9 and 218.8.
2.2.37. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(3-
2.2.33. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(2-chloro-
phenyl)tetrahydro-1H-pyrrolo[1020-c][10,30]thiazolo estrone (5h)
Isolated as white solid; yield 85%; mp 192–194 °C; Anal. Calcd.
for C40H36ClNO3S: C, 74.34; H, 5.61; N, 2.17. Found: C, 74.30; H,
5.53; N, 2.14. 1H NMR 0.17–0.38 (m, 1H), 0.51 (s, 3H), 1.07–1.60
(m, 3H), 1.56–1.67 (m, 4H), 1.81–1.81 (m, 2H), 2.01–2.17 (m, 2H)
2.41–2.51 (m, 3H), 2.90–3.04 (m, 2H), 3.54 (d, J = 6.0 Hz, 1H),
3.70 (d, J = 6.0 Hz, 1H), 4.57 (d, J = 8.4 Hz, 1H), 4.79–4.87 (m, 1H),
6.40–6.41 (m, 1H), 6.50 (dd, J = 8.4, 2.7 Hz, 1H), 6.82 (d, J = 8.7 Hz,
1H), 7.20–7.25 (m, 2H), 7.36–7.48 (m, 2H), 7.62–7.73 (m, 4H),
7.86–8.01 (m, 3H), 8.10 (d, J = 7.8 Hz, 1H). 13C NMR 15.4, 24.9,
26.1, 28.7, 29.2, 29.5, 31.2, 32.4, 32.9, 36.5, 43.8, 46.5, 47.3, 47.4,
50.0, 73.2, 74.3, 77.3, 112.6, 115.1, 120.7, 125.4, 125.8, 126.2,
127.2, 127.9, 128.2, 128.5, 129.4, 130.4, 130.9, 131.3, 131.9,
132.3, 135.2, 135.5, 136.5, 137.5, 142.4, 153.5, 207.0 and 220.1.
fluorophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5l)
Isolated as white solid; yield 80%; mp 176–178 °C; Anal. Calcd.
for C40H36FNO3S: C, 76.28; H, 5.76; N, 2.22. Found: C, 76.25; H,
5.72; N, 2.29. 1H NMR 0.14 (s, 3H), 0.35–00.96 (m, 3H), 1.05–1.69
(m, 3H), 1.60–151 (m, 2H), 1.84–2.05 (m, 2H), 2.52–2.67 (m, 4H),
2.91–3.11 (m, 2H), 3.66 (d, J = 9.9 Hz, 1H), 3.79 (d, J = 7.8 Hz, 1H),
3.85 (d, J = 7.8 Hz, 1H), 4.77–4.87 (m, 2H), 6.47–6.54 (m, 2H),
6.86 (d, J = 8.4 Hz, 1H), 6.96–7.02 (m, 1H), 7.10–7.12 (m, 1H),
7.30–7.35 (m, 1H), 7.67–7.75 (m, 2H), 7.81–7.98 (m, 3H), 8.10 (d,
J = 8.1 Hz, 1H), 8.32–8.35 (m, 1H), 8.63–8.66 (m, 1H). 13C NMR
14.2, 25.1, 28.9, 29.2, 31.4, 34.3, 36.8, 43.9, 47.2, 48.1, 49.6, 50.3,
55.6, 72.0, 72.7, 79.6, 112.6, 114.4, 114.6, 115.2, 116.6, 11 6.9,
120.8, 125.5, 125.7, 126.0, 127.4, 127.9, 128.3, 129.9, 130.1,
130.5, 131.3, 131.7, 132.3, 133.3, 134.6, 135.2, 137.7, 139.8,
141.3, 153.6, 161.2, 206.0 and 219.8.
2.2.38. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(2,4-dich-
lorophenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5m)
Isolated as white solid; yield 80%; mp 168–171 °C; Anal. Calcd.
for C40H35Cl2NO3S: C, 70.58; H, 5.18; N, 2.06. Found: C, 70.53; H,
5.14; N, 2.02. 1H NMR 0.26–0.32 (m, 1H), 0.54 (s, 3H), 0.92–0.97
(m, 1H), 1.11–1.32 (m, 3H), 1.60–1.68 (m, 4H), 1.83–1.86 (m,
1H), 2.06–2.11 (m, 2H), 2.51–2.56 (m, 2H), 2.89–3.03 (m, 2H),
3.52 (d, J = 5.7 Hz, 1H), 3.69 (d, J = 5.7 Hz, 1H), 4.50 (d, J = 8.1 Hz,
1H), 4.64 (s, 1H), 4.72–4.78 (m, 1H), 6.40–6.51 (m, 2H), 6.8 (d,
J = 8.4 Hz, 1H), 7.39–7.42 (m, 2H), 7.59 (d, J = 6.9 Hz, 1H), 7.66–
7.74 (m, 2H), 7.81–7.99 (m, 3H), 8.10 (d, J = 8.4 Hz, 1H), 8.34 (d,
J = 8.4 Hz, 1H), 8.65 (d, J = 7.5 Hz, 1H). 13C NMR 14.0, 15.6, 24.9,
26.1, 26.8, 28.8, 31.1, 32.5, 32.8, 36.4, 43.7, 46.2, 47.1, 49.4, 73.1,
74.3, 112.6, 115.3, 120.1, 121.6, 125.9, 125.5, 126.5, 127.1, 127.7,
128.6, 131.3, 131.6, 132.4, 133.2, 234.7, 135.4, 137.5, 141.3,
153.9, 158.3, 208.4 and 219.7.
2.2.34. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(2-methy-
lphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5i)
Isolated as white solid; yield 80%; mp 179–181 °C; Anal. Calcd.
for C41H39NO3S: C, 78.69; H, 6.28; N, 2.24. Found: C, 78.65; H, 6.23;
N, 2.20. 1H NMR 0.33 (s, 3H), 0.51–0.66 (m, 1H), 0.95–1.35 (m, 4H),
1.59–1.84 (m, 3H), 1.83–1.86 (m, 1H), 2.28 (s, 3H), 2.34–2.46 (m,
1H), 2.56–2.61 (m, 2H), 2.86–3.01 (m, 4H), 3.65 (d, J = 6.6 Hz,
1H), 3.72 (d, J = 6.6 Hz, 1H), 4.29 (d, J = 9.3 Hz, 1H), 4.69 (s, 1H),
6.42–6.51 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.13–7.19 (m, 2H),
7.29–7.35 (m, 2H), 7.68–7.73 (m, 3H), 7.80–7.95 (m, 3H),8.10 (d,
J = 7.8 Hz, 1H). 13C NMR 14.3, 19.9, 25.0, 26.1, 28.8, 31.1, 31.5,
33.6, 36.6, 43.8, 47.2, 47.5, 48.1, 50.2, 73.0, 74.0, 78.5, 112.5,
113.7, 115.1, 120.8, 125.4, 125.8, 126.0, 126.2, 127.9, 128.4,
130.1, 130.4, 130.5, 131.3, 131.8, 132.3, 135.4, 135.8, 137.5,
137.7, 141.8, 153.5, 206.6 and 220.0.

V. Jeyachandran et al. / Steroids 82 (2014) 29–37
35
2.2.39. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(3,4-dim-
ethoxyphenyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone
(5n)
Isolated as white solid; yield 80%; mp 188–190 °C; Anal. Calcd.
for C42H41NO5S: C, 75.08; H, 6.15; N, 2.08. Found: C, 75.01; H, 6.10;
N, 2.03. 1H NMR 0.35 (s, 3H), 0.54–0.57 (m, 1H), 0.90–1.00 (m, 2H),
1.15–1.26 (m, 2H), 1.60–1.64 (m, 4H), 1.74–1.77 (m, 1H), 1.99–2.04
(m, 2H), 2.46–2.49 (m, 2H), 2.62–2.64 (m, 2H), 2.84–2.93 (m, 2H),
3.62–3.67 (m, 2H), 3.87 (s, 6H), 4.71–4.75 (m, 1H), 6.60–6.80 (m,
2H), 6.91 (d, J = 8.1, 1H), 7.15–7.21 (m, 3H), 7.40–7.43 (m, 1H),
7.80–7.86 (m, 3H), 8.31–8.35 (m, 2H), 8.62–8.65 (m, 2H). 13C
NMR 14.5, 25.9, 26.7, 28.9, 29.4, 31.6, 34.3, 37.9, 44.0, 47.6, 48.7,
50.1, 55.9, 72.1, 72.5, 80.6, 112.8, 113.3, 115.3, 118.8, 123.9,
126.3, 127.3, 127.4, 128.6, 130.2, 131.7, 131.9, 133.3, 133.4,
133.8, 135.1, 135.3, 137.7, 148.9, 150.3, 153.7, 160.4, 209.6 and
220.4.
Entry Comp
Ar
C6H5
4-ClC6H4
4-FC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
4-(CH3)2NC6H4
2-ClC6H4
2-CH3C6H4
2-CH3OC6H4
2-FC6H4
Yielda (%)
1
2
3
4
5
2a
2b
2c
2d
2e
2f
93
95
92
97
95
98
94
96
97
93
94
98
94
91
95
6
7
8
9
2g
2h
2i
10
11
12
13
14
15
2j
2k
2l
2.2.40. Spiro[50.200]acenaphthylene-100-one-spiro[16.60]-70-(1-nap-
hthyl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo estrone (5o)
Isolated as white solid; yield 82%; mp 180–182 °C; Anal. Calcd.
for C44H39NO3S: C, 79.85; H, 5.94; N, 2.12. Found: C, 79.80; H, 5.89;
N, 2.20. 1H NMR 0.17 (s, 3H), 0.39–0.46 (m, 1H), 0.53–0.54 (m, 2H),
0.93–1.03 (m, 1H), 1.01–1.19 (m, 1H), 1.27–2.04 (m, 2H), 1.60–1.67
(m, 3H), 2.02–2.42 (m, 2H), 2.48–2.62 (m, 2H), 2.84–2.98 (m, 2H),
3.67 (d, J = 6.3 Hz, 1H), 3.77 (d, J = 6.3 Hz, 1H), 4.82–4.86 (m, 3H),
6.38–6.48 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 7.43–8.17 (m, 11H),
8.33 (d, J = 8.4 Hz, 1H), 8.63–8.66 (m, 1H). 13C NMR 18.7, 24.9,
25.2, 28.8, 29.3, 31.4, 33.5, 34.6, 36.4, 43.8, 47.4, 48.3, 48.7, 73.7,
78.1, 112.5, 115.1, 120.8, 123.6, 125.5, 125.7, 125.8, 126.0, 126.3,
127.4, 127.5, 127.6, 128.0, 128.5, 128.7, 130.4, 131.2, 132.3,
133.4, 134.1, 135.3, 135.6, 137.6, 142.0, 153.5, 160.5, 206.7 and
220.4.
3-FC6H4
2m
2n
2o
2,4-Cl2C6H3
3,4-(CH3O)2C6H3
Naphthyl
aYields were quantitative except for the loss during workup
Scheme 1. Synthesis of (E)-16-arylmethylidene-estrones 2.
thiazolo estrones 3a–o and spiro[50.300]-500-chloro-oxindole-
spiro[60.16]-70-(aryl)tetrahydro-1H-pyrrolo[10,20-c][10,30]thiazolo
estrones 4a–o, respectively. The significances of this reaction in-
clude a facile one-pot three-component process, excellent yields
(81–86%) with generation of four new contiguous stereo-centers
and formation of two C–C and one C–N bonds in a single step. Fur-
ther, this reaction assumes importance in the viewpoint of its high
atom economy since the only by-products are water and carbon
dioxide. A total of 26 new C-16 spiro estrone hybrid heterocycles
3 and 4 have been synthesized employing this cycloaddition. It is
pertinent to note that the reaction proceeded smoothly with dipol-
arophiles 2 comprising electron-withdrawing or electron-donating
group in the aryl ring affording the spiro estrones 3 and 4 in excel-
lent yields. Further, the presence of sterically hindered groups and
bulky 1-naphthyl in the aryl too had no adverse effects in the yield
of the product 3. However, the reaction failed to occur in the cases
of 4g, 4j, 4n and 4o. Three cases viz. 4j, 4n and 4o may presumably
be attributed to the steric hindrance and/or other electronic effects
but in the case of 4g the reason is unclear.
The structure of all the C-16 spiro estrone hybrid heterocycles
3a–o and 4a–o were elucidated with the help of elemental analy-
sis, 1H, 13C and 2D NMR spectroscopic techniques. As a representa-
tive case the selected H,H-COSY and HMBC correlations of 3b are
shown in Fig. 2 whereas the complete assignment of 1H and 13C
chemical shifts of 3b are shown in Fig. 3.
The spiro estrones 3 and 4 are formed by the addition of elec-
tron rich carbon of the 1,3-dipole to the b-carbon of the dipolaro-
philes 2. This regioselectivity can be attributed to the polarization
3. Results and discussion
In the present work, the C-16 exocyclic dipolarophiles viz. (E)-
16-arylidene estrones 2 were synthesized from the reaction of es-
trone 1 with various aromatic aldehydes (Scheme 1). An equivalent
mixture of estrone and the appropriate aldehyde were dissolved in
ethanol followed by the addition of alcoholic potassium hydroxide.
The mixture was boiled to reflux for 5 h and the completion of the
reaction was realized when the (E)-16-arylidene estrones 2 precip-
itated out of the reaction mixture as yellow solid, which was fil-
tered and washed with water. A total of fifteen (E)-16-arylidene
estrones 2a–o were synthesized in almost quantitative yields
(>91%, Scheme 1). However, the reaction failed to occur with ali-
phatic aldehydes.
The structure of these dipolarophiles 2 was elucidated with the
help of NMR spectroscopy and is in complete agreement with the
literature reports [8]. Moreover, the NMR spectra of (E)-16-arylid-
ene estrones 2 and estrone 1 were similar except for the presence
of new signals in the 1H and 13C NMR spectra of 2 due to the aro-
matic ring and benzylidene protons and carbons. Further, the
DEPT-135 spectrum of 2 reveals the absence of one ‘CH2’ carbon
and appearance of new signals due to aromatic ‘C’ and ‘CH’ car-
bons. The structure of 2 assigned from NMR spectroscopy was fur-
ther confirmed from single crystal X-ray studies. The ORTEP
diagram of 2b reveals (E)-configuration for the D-ring C-16 exocy-
clic alkene (Fig. 1) [17].
of the C@C bond of the
a,b-unsaturated moiety with a more
To begin with, the 1,3-dipolar cycloaddition of azomethine
ylides generated in situ from the reaction of 1,3-thiazolane-4-car-
boxylic acid and isatin or 5-chloroisatin to (E)-16-arylidene estro-
nes 2a–o was investigated (Scheme 2). The reaction proceeded
stereoselectively affording a single isomer of novel spiro[50.300]
oxindole-spiro[60.16]-70-(aryl)-tetrahydro-1H-pyrrolo[10,20-c][10,30]
Fig. 1. ORTEP diagram of 2b [17].

36
V. Jeyachandran et al. / Steroids 82 (2014) 29–37
219.2
72.7
74.0
178.1
47.1
131.5
137.6
Fig. 3. 1H and 13C chemical shifts of 3b.
Scheme 2. Synthesis of C-16 spiro estrones 3 and 4.
electron-deficient b-carbon which could preferentially react with
the electron-rich site of the approaching 1,3-dipole.
The above reaction proceeds stereoselectively since a single iso-
mer of the product was obtained in both the cases (3 and 4) even
though four new chiral centers are generated during the cycloaddi-
tion (C-16, C-50, C-70 and C-7a0). As the crystallization of either 3 or
4 failed to afford suitable crystals for the single crystal X-ray stud-
ies, the determination of absolute configuration of the newly
formed chiral centers of 3 and 4 were done on the basis of our ear-
lier report [10] (ORTEP diagrams of androsterone analogs are pro-
vided in Supporting information) and were tentatively assigned as
16-R, 50-R, 70-S and 7a0-S.
Further, the facial selectivity involved in the cycloaddition lead-
ing to the formation of 3 and 4 is apparent from the fact that the
azomethine ylides add to the dipolarophile 2 preferentially from
the less hindered bottom side of the exocyclic C@C bond of 2.
The angular methyl group at 13th position of 2 presumably hinders
the approach of the dipole from the top side (Fig. 4).
With a view to vary the 1,3-dipole, we further investigated the
cycloaddition of azomethine ylide generated in situ from the
reaction of acenaphthylene-1,2-dione and 1,3-thiazolane-4-car-
boxylic acid to the dipolarophiles 2. The reaction afforded novel
spiro[50.200]acenaphthylene-100-one-spiro[16.60]-(70-aryl)-tetrahydro-
1H-pyrrolo[1,2-c][1,3]thiazolo estrone hybrid heterocycles 5 in
Scheme 3. Synthesis of C-16 spiro estrones 5.
excellent yields (Scheme 3). A total of fourteen C-16 spiro estrone
hybrid heterocycles 5a–o were synthesized with varying substitu-
tions in the aryl ring of 2. It is pertinent to note that the reaction
Fig. 2. Selected H,H-COSY and the HMBC correlations of 3b.

V. Jeyachandran et al. / Steroids 82 (2014) 29–37
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Acknowledgements
R.R.K., V.J. and S.V.K. would like to thank the University Grants
Commission, New Delhi for funds through Major Research Project
F. No. 42-242/2013 (S.R.) and Department of Science and Technol-
ogy, New Delhi for funds under (i) DST-SERC Fast Track scheme No.
SR/FT/CS-073/2009 and (ii) IRHPA program for the high resolution
NMR facility in the Department. V.J. thanks the University Grants
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