Microwave-promoted and Lewis acid catalysed synthesis of steroidal A- and D-ring fused 4,6-diarylpyridines

Article abstract of DOI:10.1016/j.steroids.2013.01.006

The preparation of novel steroidal heterocycles containing 4,6-diaryl substituted pyridine moiety fused to the 2,3- and 16,17-positions of the steroid nucleus is described. The Michael reaction of steroidal ketones (1a, 1b and 1c) with in situ generated chalcones provided the intermediates 3,5-diaryl-1,5-dicarbonyl steroidal derivatives (4a-s). Subsequently, the intermediates 4a-s were converted to the pyridine derivatives (5a-s) by solid phase reaction with urea in presence of BF₃.OEt₂ as the catalyst under microwave irradiation. All the synthesized heterosteroids are new compounds and are currently being evaluated for their biological activities.

Full text of DOI:10.1016/j.steroids.2013.01.006

Steroids 78 (2013) 387–395
Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Microwave-promoted and Lewis acid catalysed synthesis of steroidal A- and
D-ring fused 4,6-diarylpyridines
⇑
⇑
Mandakini Dutta, Pallabi Saikia, Sanjib Gogoi , Romesh C. Boruah
Medicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat, Assam 785006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of novel steroidal heterocycles containing 4,6-diaryl substituted pyridine moiety fused to
the 2,3- and 16,17-positions of the steroid nucleus is described. The Michael reaction of steroidal ketones
(1a, 1b and 1c) with in situ generated chalcones provided the intermediates 3,5-diaryl-1,5-dicarbonyl
steroidal derivatives (4a–s). Subsequently, the intermediates 4a–s were converted to the pyridine deriv-
atives (5a–s) by solid phase reaction with urea in presence of BF3.OEt2 as the catalyst under microwave
irradiation. All the synthesized heterosteroids are new compounds and are currently being evaluated for
their biological activities.
Received 5 November 2012
Received in revised form 30 December 2012
Accepted 18 January 2013
Available online 30 January 2013
Keywords:
Heterosteroid
Steroidal pyridine
Microwave
Ó 2013 Published by Elsevier Inc.
Multicomponent reaction
1. Introduction
strategy for A- and D-ring annelated heterosteroids [13], herein we
describe a microwave-promoted and Lewis acid catalysed synthe-
The pyridine substructure is one of the most prevalent hetero-
cycle due to its widespread distribution in natural products, phar-
maceuticals and synthetic biologically active compounds [1].
Consequently, the development of methods for the preparation of
substituted pyridine derivatives is of importance to medicinal
chemistry and represents a worthwhile goal of organic synthesis
[2]. During the last decades, steroids bearing heterocycles fused
to the A- or D-ring of the steroid skeleton continue to attract much
pharmaceutical interest as many of these heterosteroids possess
widespread biological activities [3–7]. Due to the remarkable
importance from the pharmacological and synthetic viewpoints,
great efforts are being made to annelate steroidal moiety with pyr-
azole, isoxazole, pyridine, pyran, pyrrole or pyrimidine rings using
various synthetic strategies [8–10]. Some of the biologically active
heterosteroids are shown in Fig. 1.
Among these annelated heterosteroids, the synthesis of A-and
D-ring fused pyridines draw particular interest because of the
inherent biological activities of these heterosteroids [7–8,10–11].
Over the last decade, microwave assisted organic synthesis (MAOS)
has emerged as a new field in organic synthesis, which is recog-
nized as a ‘‘green’’ technology has been applied as a very efficient
way to accelerate the course of many organic reactions, producing.
high yields, higher selectivity, and lower quantities of side prod-
ucts [12]. In view of the therapeutic importance of heterosteroids
and in continuation of our interest towards development of newer
sis of new steroidal 4,6-diarylpyridines from steroidal 1,5-dicar-
bonyl compounds. The intermediate, steroidal 1,5-dicarbonyl
compounds were synthesized via a base catalyzed multicompo-
nent reaction of ketosteroids, aromatic aldehydes and aryl ketones
at room temperature.
2. Experimental
2.1. General remarks
Melting points were measured with a Buchi B-540 melting point
apparatus and are uncorrected. IR spectra were recorded on Perkin-
Elmer FT-IR-2000 spectrometer using KBr pellets or on a thin film
using chloroform. NMR spectra were recorded on Avance DPX
300 MHz FT-NMR spectrometer using tetramethylsilane (TMS) as
an internal standard. Mass spectra were recorded on Trace DSQ
GCMS instrument. All the commercially available regents were
used as received. All experiments were monitored by thin layer
chromatography (TLC). TLC was performed on pre-coated silica
gel plates (Merck). Column chromatography was performed on sil-
ica gel (60–120 mesh, Merck Chemicals). All MW reactions were
carried out in a Synthos 3000 (Anton Paar) microwave reactor.
2.2. Chemical synthesis
2.2.1. General procedure for synthesis of steroidal 1,5-dicarbonyl
compounds
⇑
To a stirring solution of steroidal ketone (1.0 mmol), aromatic
aldehyde (1.0 mmol) and aryl ketone (1.0 mmol) in toluene
Corresponding authors. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail addresses: skgogoi1@gmail.com, rc_boruah@yahoo.co.in (R.C. Boruah).
0039-128X/$ - see front matter Ó 2013 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.steroids.2013.01.006

388
M. Dutta et al. / Steroids 78 (2013) 387–395
O
O
O
S
OH
HO
NC
NH
N
H
N
H
HO
H
F
I
Cortivazol ( )
Ref7
II
(Antiinflammatory)
(Antiinflammatory)Ref4
O
NC
N
N
N
O
H
H
HO
O
Cl
Ref7
Ref8
III
(Anticancer)
IV
(Antiinflammatory)
Fig. 1. Examples of biologically active heterosteroids (I-IV).
(5.0 mL), KOH (2.0 mmol) was added at room temperature. The
reaction mixture was stirred for 6 h and after completion of the
reaction, as indicated by TLC, solvent was removed under vacuum.
The residue obtained was washed with water, extracted with DCM
and dried over Na2SO4. The crude product obtained after removal
of the solvent was purified by silica gel column chromatography
using ethyl acetate/hexane as the eluent to get pure steroidal
1,5-dicarbonyl compounds.
2.41-0.62 (m, 44H); 13C NMR (CDCl3, 75 MHz) d 211.5, 196.9,
140.8, 136.4, 134.7, 132.3, 129.9, 128.8, 117.3, 56.3, 55.9, 53.7,
51.01, 49.2, 42.5, 40.6, 39.5, 36.4, 36.1, 35.7, 35.2, 31.0, 28.2,
27.9, 24.2, 23.8, 22.8, 22.6, 18.4, 12.6, 12.2; IR (CHCl3, cmꢀ1
)
2933, 2868, 1707, 1688, 1448, 1224, 771; MS (EI, m/z) 624.4[M]+,
505.4[M+-PhCOCH2]. Anal. calcd. for C43H60O3: C, 82.64; H, 9.68;
Found: C, 82.69; H, 9.86.
All the crude hydroxy 1,5-dicarbonyl compounds 4k, 4m and 4o
were treated with acetic anhydride (1.0 mL) and pyridine (1.0 mL)
at room temperature for 6 hours. The crude product obtained after
removal of the solvent and unreacted reagent was purified by silica
gel column chromatography using ethyl acetate/hexane as the elu-
ent to get pure acetate derivatives 4l, 4n and 4p.
2.2.1.4.
2-[10-(p-Flurophenyl)-30-phenyl-propyl-30-one]-5
a-chole-
stan-3-one (4d). White solid; m.p. 180-183 °C; 1H NMR (CDCl3,
300 MHz) d 7.94-6.89 (m, 9H), 3.64-3.59 (m, 2H), 3.22-3.17 (m,
1H), 2.82-2.68 (m, 1H), 2.42-0.66 (m, 44H); 13C NMR (CDCl3,
75 MHz) d 212.4, 198.9, 162.9, 137.9, 136.9, 132.9, 130.4, 129.7,
128.7, 115.3, 56.2, 56.1, 53.7, 51.0, 49.2, 42.5, 40.6, 39.5, 36.5,
36.1, 35.7, 35.2, 30.9, 28.2, 28.0, 24.1, 23.8, 22.8, 22.6, 18.6, 12.6,
12.0; IR (CHCl3, cmꢀ1) 2932, 2867, 1707, 1687, 1448, 1224, 759;
MS (EI, m/z) 612.4 [M]+. Anal. calcd. for C42H57FO2: C, 82.31; H,
9.37; Found: C, 82.63; H, 9.56.
2.2.1.1. 2-(10,30-Diphenyl-propyl-30-one)-5
a-cholestan-3-one (4a).
White solid; m.p. 194–196 °C; 1H NMR (CDCl3, 300 MHz) d 7.88-
7.03 (m, 10H), 3.58-3.50 (m, 2H), 3.18-3.02 (m, 1H), 2.80-2.70
(m, 1H), 2.36-0.52 (m, 44H); 13C NMR (CDCl3, 75 MHz) d 212.7,
199.1, 142.2, 137.1, 132.8, 128.5, 128.4, 128.3, 128.2, 126.5, 56.2,
56.1, 53.7, 51.0, 49.3, 42.5, 41.4, 39.5, 36.5, 36.1, 35.8, 35.2, 28.2,
28.0, 24.2, 23.8, 22.83, 22.6, 21.3, 18.6, 12.6, 12.0; IR (CHCl3, cm-
1) 2931, 2867, 1708, 1686, 1448, 1236, 756; MS (EI, m/z) 594
[M]+. Anal. calcd. for C42H58O2: C, 84.79; H, 9.83; Found: C,
84.98; H, 9.63.
2.2.1.5.
2-[30-(p-Chlorophenyl)-10-phenyl-propyl-30-one]-5
a-chole-
stan-3-one (4e). White solid; m.p. 185-187 °C; 1H NMR (CDCl3,
300 MHz) d 7.86-6.71 (m, 9H), 3.66-3.56 (m, 2H), 3.22-3.19 (m,
1H), 2.89-2.69 (m, 1H), 2.41-0.59 (m, 44H); 13C NMR (CDCl3,
75 MHz) d 211.5, 196.9, 143.7, 138.4, 134.6, 129.4, 128.3, 126.6,
56.2, 56.0, 53.7, 51.0, 49.2, 42.6, 41.1, 39.5, 36.4, 36.0, 35.7, 35.1,
29.7, 28.2, 27.9, 23.2, 23.0, 22.5, 22.1, 18.4, 12.6, 12.0; IR (CHCl3,
cmꢀ1) 2932, 2868, 1706, 1687, 1447, 1221, 761; MS (EI, m/z)
628.4 [M]+, 630.4 [M++2]. Anal. calcd. for C42H57ClO2: C, 80.15; H,
9.13; Found: C, 80.26; H, 9.40.
2.2.1.2. 2-[10-(p-Methylphenyl)-30-phenyl-propyl-30-one]-5
a-chole-
stan-3-one (4b). White solid; m.p. 160-162 °C; 1H NMR (CDCl3,
300 MHz) d 7.88 (d, J = 9 Hz, 2H), 7.47-6.80 (m, 7H), 3.56-3.50 (m,
2H), 3.14-3.09 (m, 1H), 2.85-2.68 (m, 1H), 2.35-0.53 (m, 47H);
13C NMR (CDCl3, 75 MHz) d 212.8, 199.3, 138.9, 137.1, 135.8,
132.7, 129.1, 128.4, 128.3, 128.2, 56.2, 56.1, 53.8, 51.1, 49.3, 42.6,
41.0, 39.5, 36.5, 36.1, 35.8, 35.2, 31.7, 28.2, 28.0, 23.8, 22.8, 22.6,
21.1, 18.6, 12.7, 12.0; IR (CHCl3, cmꢀ1) 2933, 2867, 1709, 1687,
1447, 1235, 757; MS (EI, m/z) 608 [M]+, 489 [M+-PhCOCH2]. Anal.
calcd. for C43H60O2: C, 84.81; H, 9.93; Found: C, 84.93; H, 9.74.
2.2.1.6. 2-[30-(p-Chlorophenyl)-10-(p-methylphenyl)-propyl-30-one]-
5a-cholestan-3-one (4f). White solid; m.p. 172-175 °C; 1H NMR
(CDCl3, 300 MHz) d 7.89-6.78 (m, 8H), 3.64-3.56 (m, 2H), 3.18-
3.17 (m, 1H), 2.76-2.66 (m, 1H), 2.44-0.60 (m, 47H); 13C NMR
(CDCl3, 75 MHz) d 212.3, 198.5, 138.4, 137.7, 134.6, 130.0, 129.4,
128.5, 127.1, 126.6, 56.2, 56.0, 53.7, 51.0, 49.2, 42.6, 40.6, 39.5,
36.4, 36.1, 35.7, 35.2, 28.6, 28.2, 28.0, 23.9, 23.0, 22.6, 21.7, 18.6,
12.7, 12.0; IR (CHCl3, cmꢀ1) 2938, 2867.4, 1709, 1682, 1444,
1221, 772; MS (EI, m/z) 642.4 [M]+, 644.4 [M++2]. Anal. calcd. for
2.2.1.3. 2-[10-(p-Methoxyphenyl)-30-phenyl-propyl-30-one]-5
a-chole-
stan-3-one (4c). White solid; m.p. 162–163 °C; 1H NMR (CDCl3,
300 MHz) d 7.88 (d, J = 8.8 Hz, 2H), 7.50-6.81 (m, 7H), 3.82 (s,
3H), 3.69-3.56 (m, 2H), 3.28-3.17 (m, 1H), 2.79-2.69 (m, 1H),
C43H59ClO2: C, 80.27; H, 9.24; Found: C, 80.35; H, 9.45.

M. Dutta et al. / Steroids 78 (2013) 387–395
389
2.2.1.7. 2-[30-(p-Chlorophenyl)-10-(p-flurophenyl)-propyl-30-one]-5
a-
2.2.1.14.
3b-Acetoxy-16-[10-(p-methylphenyl)-30-phenyl-propyl-30-
cholestan-3-one (4g). White solid; m.p. 182-184 °C; 1H NMR
(CDCl3, 300 MHz) d 7.91-7.06 (m, 8H), 3.72-3.56 (m, 2H), 3.20-
3.14 (m, 1H), 2.78-2.66 (m, 1H), 2.42-0.61 (m, 44H); 13C NMR
(CDCl3, 75 MHz) d 211.6, 197.6, 160.7, 137.1, 136.9, 134.1, 131.5,
129.2, 128.0, 115.3, 55.9, 55.0, 53.3, 51.2, 49.4, 42.5, 40.6, 38.2,
36.4, 36.1, 35.4, 34.9, 29.2, 28.1, 27.1, 24.2, 23.5, 22.8, 21.3, 19.0,
12.4, 12.0; IR (CHCl3, cm-1) 2932, 2867, 1709, 1682, 1446, 1220,
771; MS (EI, m/z) 646.2 [M]+. Anal. calcd. for C42H56ClFO2: C,
77.93; H, 8.72; Found: C, 77.76; H, 8.75.
one]-5-en-androst-17-one (4n). Gum; 1H NMR (CDCl3, 300 MHz) d
7.64-7.00 (m, 9H), 5.42-5.34 (m, 1H), 4.60-4.51 (m, 1H), 2.85-
2.68 (m, 1H), 2.44 (s, 3H), 2.04 (s, 3H), 1.09 (s, 3H), 0.89 (s, 3H),
2.45-0.88 (m, 20H); 13C NMR (CDCl3, 75 MHz) d 209.8, 207.0,
170.5, 140.0, 139.9, 139.6, 134.9, 133.2, 132.8, 130.4, 129.5,
129.0, 128.6, 128.2, 121.8, 73.7, 50.2, 50.1, 49.8, 47.3, 38.1, 36.9,
36.8, 31.5, 31.46, 31.4, 31.1, 30.9, 29.4, 27.7, 21.5, 21.4, 20.4,
19.4, 14.3, 13.5; IR (CHCl3, cmꢀ1) 2946, 1729, 1713, 1628, 1255,
1032, 755; MS (EI, m/z) 492 [M-60]+.
2.2.1.15.
3b-Hydroxy-16-[10-(p-chlorophenyl)-30-phenyl-propyl-30-
2.2.1.8. 2-[30-(p-Methylphenyl)-10-phenyl-propyl-30-one)-5
a-chole-
one]-5-en-androst-17-one (4o). Gum; 1H NMR (CDCl3, 300 MHz) d
7.85-7.17 (m, 9H), 5.42-5.34 (m, 1H), 3.62-3.45 (m, 1H), 1.07 (s,
3H), 0.96 (s, 3H), 2.80-0.87 (m, 21H); IR (CHCl3, cmꢀ1) 3432,
2948, 1726, 1715, 1626, 1259, 1036; MS (EI, m/z) 512 [M-18]+.
stan-3-one (4h). White solid; m.p. 165-167 °C; 1H NMR (CDCl3,
300 MHz) d 7.88 (d, J = 8.8 Hz, 2H), 7.76-6.74 (m, 7H), 3.64-3.56
(m, 2H), 3.20-3.18 (m, 1H), 2.86-2.72 (m, 1H), 2.42-0.60 (m,
47H); 13C NMR (CDCl3, 75 MHz) d 212.6, 198.8, 143.4, 142.3,
134.7, 129.2, 128.4, 128.3, 126.4, 56.2, 56.1, 53.8, 51.0, 49.3, 42.6,
41.4, 39.5, 36.6, 36.1, 35.6, 35.2, 28.2, 27.9, 23.8, 22.8, 22.6, 21.6,
21.3, 18.6, 12.6, 12.0; IR (CHCl3, cm-1) 2931.9, 2867.5, 1709.2,
1681.4, 1445.0, 1224.5, 758.4; MS (EI, m/z) 608.4[M]+. Anal. calcd.
for C43H60O2: C, 84.81; H, 9.93; Found: C, 84.70; H, 9.78.
2.2.1.16.
3b-Acetoxy-16-[10-(p-chlorophenyl)-30-phenyl-propyl-30-
one]-5-en-androst-17-one (4p). Gum; 1H NMR (CDCl3, 300 MHz) d
7.63-7.05 (m, 9H), 5.42-5.34 (m, 1H), 4.62-4.53 (m, 1H), 2.84-
2.68 (m, 1H), 2.03 (s, 3H), 1.08 (s, 3H), 0.91 (s, 3H), 2.43-0.87 (m,
20H); 13C NMR (CDCl3, 75 MHz) d 209.5, 207.2, 170.4, 140.1,
139.7, 139.6, 134.7, 133.1, 132.8, 130.4, 129.5, 129.0, 128.6,
128.2, 121.8, 73.5, 50.2, 50.1, 49.8, 47.2, 38.1, 36.9, 36.8, 31.5,
31.46, 31.4, 31.2, 30.9, 29.4, 27.5, 21.4, 20.4, 19.4, 14.4, 13.3; IR
(CHCl3, cmꢀ1) 2948, 1726, 1715, 1626, 1259, 1036; MS (EI, m/z)
512 [M-60]+, 514 [(M+2)-60]+.
2.2.1.9. 2-[10,30-bis(p-Methylphenyl)-propyl-30-one]-5
a-cholestan-3-
one (4i). White solid; m.p. 169-172 °C; 1H NMR (CDCl3, 300 MHz)
d 7.45-6.79 (m, 8H), 3.66-3.54 (m, 2H), 3.20-3.16 (m, 1H), 2.79-2.68
(m, 1H), 2.44-0.60 (m, 50H); 13C NMR (CDCl3, 75 MHz) d 212.3,
198.7, 142.4, 139.1, 134.6, 132.1, 128.5, 128.4, 56.3, 56.1, 53.2,
51.4, 48.3, 42.5, 40.6, 38.5, 36.5, 36.1, 35.7, 35.1, 28.7, 28.1, 27.8,
23.9, 23.2, 22.6, 21.9, 18.6, 12.7, 11.9; IR (CHCl3, cmꢀ1) 2932,
2868, 1709, 1681, 1445, 1225, 758; MS (EI, m/z) 622.5 [M]+. Anal.
calcd. for C44H62O2: C, 84.83; H, 10.03; Found: C, 84.77; H, 9.98.
2.2.1.17.
2,16-Bis[10-phenyl-30-phenyl-propyl-30-one]-5
a-androst-
3,17-dione (4q). Gum; 1H NMR (CDCl3, 300 MHz) d 7.89-7.17 (m,
20H), 3.75-2.80 (m, 6H), 1.08 (s, 3H), 0.90 (s, 3H), 2.49-0.87 (m,
20H); 13C NMR (CDCl3, 75 MHz) d 220.6, 212.2, 198.8, 198.6,
139.4, 139.2, 137.2, 133.1, 132.7, 132.9, 130.5, 129.5, 129.2,
128.9, 128.5, 128.4, 128.3, 128.1, 128.0, 125.5, 124.8, 53.0, 51.2,
47.8, 47.4, 44.1, 42.0, 40.9, 37.1, 36.6, 35.7, 35.2, 35.0, 31.6, 29.5,
26.3, 24.6, 22.6, 21.7, 21.4, 21.0, 13.9; IR (CHCl3, cmꢀ1) 2924,
1709, 1686, 1448, 756; MS (ESI, m/z) 705.4 [M+1]+.
2.2.1.10. 2-[10-(p-Flurophenyl)-30-(p-methylphenyl)-propyl-30-one]-
5a-cholestan-3-one (4j). White solid; m.p. 175 °C; 1H NMR (CDCl3,
300 MHz) d 7.97-6.88 (m, 8H), 3.64-3.55 (m, 2H), 3.17-3.15 (m,
1H), 2.85-2.68 (m, 1H), 2.42-0.61 (m, 47H); 13C NMR (CDCl3,
75 MHz) d 212.5, 198.6, 163.0, 143.6, 137.9, 134.5, 129.8, 129.2,
128.3, 115.3, 56.2, 56.1, 53.8, 51.1, 49.2, 42.6, 40.7, 39.5, 36.5,
36.1, 35.8, 35.2, 28.7, 28.2, 28.0, 23.8, 22.8, 22.6, 21.6, 18.6, 12.6,
12.0; IR (CHCl3, cmꢀ1) 2932, 2867, 1709, 1682, 1446, 1219, 771;
MS (EI, m/z) 626.4[M]+. Anal. calcd. for C43H59FO2: C, 82.38; H,
9.49; Found: C, 82.64; H, 9.50.
2.2.1.18. 2,16-Bis[10-(p-methylphenyl)-30-phenyl-propyl-30-one]-5
a-
antrost-3,17-dione (4r). Gum; 1H NMR (CDCl3, 300 MHz) d 7.89-
7.17 (m, 18H), 3.75-2.80 (m, 6H), 2.18 (s, 6H), 1.07 (s, 3H), 0.91
(s, 3H), 2.46-0.87 (m, 20H); 13C NMR (CDCl3, 75 MHz) d 220.9,
213.0, 199.1, 198.5, 139.6, 139.1, 137.0, 133.0, 132.9, 132.7,
130.9, 129.5, 129.0, 128.9, 128.5, 128.4, 128.3, 128.1, 128.0,
125.3, 53.8, 51.3, 47.8, 47.7, 44.1, 42.2, 40.9, 37.1, 36.9, 35.7,
35.1, 35.0, 31.6, 29.7, 26.3, 24.7, 22.6, 21.7, 21.5, 21.0, 13.8; IR
(CHCl3, cmꢀ1) 2948, 1727, 1715, 1625, 1260, 1036; MS (ESI, m/z)
733.4 [M + 1]+, 755.9 [M + 23]+.
2.2.1.11.
3b-Hydroxy-16-(10,30-diphenyl-propyl-30-one)-5-en-and-
rost-17-one (4k). Gum, 1H NMR (CDCl3, 300 MHz) d 7.87-7.17 (m,
10H), 5.41-5.36 (m, 1H), 3.60-3.48 (m, 1H), 1.08 (s, 3H), 0.96 (s,
3H), 2.88-0.89 (m, 21H); IR (CHCl3, cmꢀ1) 3411, 2935, 1719,
1715, 1629, 1254, 1034; MS (EI, m/z) 478 [M-18]+.
2.2.1.19. 2,16-Bis[10-(p-chlorophenyl)-30-phenyl-propyl-30-one]-5
a-
2.2.1.12. 3b-Acetoxy-16-(10,30-diphenyl-propyl-30-one)-5-en-androst-
17-one (4l). Gum; 1H NMR (CDCl3, 300 MHz) d 7.67-7.03 (m, 10H),
5.44-5.33 (m, 1H), 4.65-4.50 (m, 1H), 2.84-2.68 (m, 1H), 1.07 (s,
3H), 0.90 (s, 3H), 2.47-0.87 (m, 23H); 13C NMR (CDCl3, 75 MHz) d
209.6, 207.5, 170.2, 140.2, 139.5, 139.1, 134.0, 133.2, 132.4,
130.2, 129.5, 129.1, 128.5, 128.1, 121.7, 73.8, 50.4, 50.0, 49.7,
47.4, 38.0, 36.8, 36.6, 31.5, 31.3, 31.0, 30.9, 29.5, 27.6, 21.3, 20.3,
19.4, 14.3, 13.3; IR (CHCl3, cmꢀ1) 2947, 1729, 1715, 1629, 1256,
1030; MS (EI, m/z) 478 [M-60]+.
antrost-3,17-dione (4s). Gum; 1H NMR (CDCl3, 300 MHz) d 7.90-
7.18 (m, 18H), 3.73-2.79 (m, 6H), 1.09 (s, 3H), 0.88 (s, 3H), 2.46-
0.87 (m, 20H); 13C NMR (CDCl3, 75 MHz) d 220.5, 213.1, 198.6,
198.2, 139.4, 139.0, 137.1, 132.7, 132.6, 132.6, 130.7, 129.3,
128.7, 128.5, 128.2, 128.1, 128.0, 127.8, 127.77, 127.5, 125.0,
53.8, 51.1, 47.8, 47.4, 44.1, 42.0, 40.9, 37.1, 36.9, 35.7, 35.0, 31.6,
29.8, 26.3, 24.7, 22.7, 21.7, 21.5, 21.1, 13.5; IR (CHCl3, cmꢀ1
)
2950, 1729, 1713, 1624, 1260, 1036; MS (ESI, m/z) 773.3 [M + 1]+.
2.2.2. General procedure for synthesis of steroidal 40,60-diphenyl-
pyridines
Steroidal 1,5-dicarbonyl compound (0.75 mmol) and ammo-
nium acetate (1.5 mmol) were irradiated in a closed vessel in pres-
ence of 10 mol% of boron trifluoride etherate in a Synthos 3000
microwave reactor at 720 Watt (130 °C and 21 bar) for 6 min.
The reaction mixture was treated with water (30 mL), extracted
2.2.1.13. 3b-Hydroxy-16-[10-(p-methylphenyl)-30-phenyl-propyl-30-
one]-5-en-androst-17-one (4m). Gum; 1H NMR (CDCl3, 300 MHz)
d 7.83-7.15 (m, 9H), 5.40-5.36 (m, 1H), 3.60-3.46 (m, 1H), 2.37 (s,
3H), 1.07 (s, 3H), 0.96 (s, 3H), 2.82-0.89 (m, 21H); IR (CHCl3, cm-
1) 3428, 2946, 1729, 1713, 1628, 1255, 1032; MS (EI, m/z) 492
[M-18]+.

390
M. Dutta et al. / Steroids 78 (2013) 387–395
with dichloromethane. The organic portion was washed with
water, dried over anhydrous sodium sulfate and the solvent was
removed to obtain a crude product which on silica gel column
chromatographic purification using EtOAc/hexane as eluent affor-
ded the pyridine derivative.
21.3, 21.3, 18.7, 11.9, 11.7; IR (CHCl3, cmꢀ1) 2928, 2867, 1588,
1542, 1444, 1218, 775; MS (EI, m/z) 607.4 [M]+. Anal. calcd. for C42-
H54ClN: C, 82.92; H, 8.95; N, 2.30; Found: C, 82.73; H, 8.94; N, 2.18.
2.2.2.6.
60-(p-Chlorophenyl)-40-(p-methylphenyl)-5
a-chloest[3,2-
All the crude hydroxy pyridine derivatives 5k, 5m and 5o were
treated with acetic anhydride (1.0 mL) and pyridine (1.0 mL) at
room temperature for 6 h. The crude product obtained after re-
moval of the solvent and unreacted reagent was purified by silica
gel column chromatography using ethyl acetate/hexane as the elu-
ent to get pure acetate derivative 5l, 5n and 5p.
b]pyridine (5f). White solid; m.p. 176-177 °C; 1H NMR (CDCl3,
300 MHz) d 7.99-7.22 (m, 9H), 3.07-2.99 (m, 1H), 2.66-2.63 (m,
2H), 2.35 (s, 3H), 2.24-0.71 (m, 35H), 0.70 (s, 3H), 0.63 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 156.9, 153.7, 151.2, 139.4, 136.9,
133.0, 129.3, 129.0, 128.6, 127.6, 127.1, 126.7, 119.9, 56.5, 56.4,
53.8, 42.5, 41.9, 40.0, 39.7, 36.6, 35.7, 35.4, 35.2, 28.3, 28.1, 23.2,
22.7, 22.2, 21.3, 21.3, 18.6, 12.0, 11.7; IR (CHCl3, cmꢀ1) 2929,
2867, 1589, 1542, 1444, 1223, 774; MS (EI, m/z) 621.4 [M]+. Anal.
calcd. for C43H56ClN: C, 82.98; H, 9.07; N, 2.25; Found: C, 82.74;
H, 9.07; N, 2.21.
2.2.2.1. 40,60-Diphenyl-5
a-cholest[3,2-b]pyridine (5a). White solid;
m.p. 196 °C; 1H NMR (CDCl3, 300 MHz) d 7.89 (d, J = 7.1 Hz, 2H),
7.42-7.03 (m, 9H), 3.01-2.94 (m, 1H), 2.71-2.56 (m, 2H), 2.26 (d,
J = 15 Hz, 1H), 2.01-0.82 (m, 34H), 0.72 (s, 3H), 0.64 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 156.8, 154.2, 150.8, 139.8, 139.7, 128.6,
128.56, 128.5, 128.3, 127.7, 127.4, 126.9, 119.3, 56.5, 56.4, 53.7,
42.5, 41.9, 39.9, 39.5, 36.2, 35.8, 35.6, 35.2, 31.7, 28.7, 28.3, 24.3,
23.9, 22.9, 22.6, 21.2, 18.7, 12.0, 11.7; IR (CHCl3, cmꢀ1) 2929,
2867, 1588, 1541, 1445, 1218, 774; MS (EI, m/z) 573.4 [M]+. Anal.
calcd. for C42H55N: C, 87.90; H, 9.66; N, 2.44; Found: C, 87.82; H,
9.64; N, 2.27.
2.2.2.7. 60-(p-Chlorophenyl)-40-(p-flurophenyl)-5
a-chloest[3,2-b]pyri-
dine (5g). White solid; m.p. 185-186 °C; 1H NMR (CDCl3, 300 MHz)
d 7.94-7.26 (m, 9H), 3.04-2.87 (m, 1H), 2.67-2.60 (m, 2H), 2.20-0.70
(m, 35H), 0.72 (s, 3H), 0.62 (s, 3H),; 13C NMR (CDCl3, 75 MHz) d
167.0, 156.8, 154.3, 150.1, 138.2, 135.0, 132.1, 130.0, 129.7,
128.3, 127.7, 127.1, 115.5, 56.4, 56.4, 53.8, 42.4, 41.9, 39.6, 36.2,
35.9, 35.5, 35.2, 28.7, 28.2, 27.1, 24.0, 23.8, 22.9, 22.6, 21.3, 18.7,
12.0, 11.7; IR (CHCl3, cmꢀ1) 2929, 2867, 1600, 1542, 1443, 1223,
774; MS (EI, m/z) 625.4 [M]+. Anal. calcd. for C42H53ClFN: C,
80.54; H, 8.53; N, 2.24; Found: C, 80.47; H, 8.81; N, 2.45.
2.2.2.2.
40-(p-Methylphenyl)-60-phenyl-5
a-chloest[3,2-b]pyridine
(5b). White solid; m.p. 174-176 °C; 1H NMR (CDCl3, 300 MHz) d
7.87 (d, J = 7.1 Hz, 2H), 7.49-6.90 (m, 8H), 3.07-3.01 (m, 1H),
2.73-2.67 (m, 2H), 2.37 (s, 3H), 2.41-0.80 (m, 35H), 0.72 (s, 3H),
0.64 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 156.4, 154.2, 150.7,
139.8, 137.5, 136.8, 129.1, 128.6, 128.5, 128.3, 127.5, 126.9,
119.4, 56.4, 56.3, 53.7, 42.4, 39.5, 36.2, 35.8, 35.6, 35.2, 31.0,
29.8, 28.3, 28.0, 24.3, 23.9, 22.9, 22.6, 21.3, 18.7, 12.0, 11.6; IR
(CHCl3, cmꢀ1) 2926, 2866, 1592, 1542, 1444, 1219, 773; MS (EI,
m/z) 587.4 [M]+. Anal. calcd. for C43H57N: C, 87.85; H, 9.77; N,
2.38; Found: C, 87.85; H, 9.79; N, 2.28.
2.2.2.8.
60-(p-Methylphenyl)-40-phenyl-5
a-chloest[3,2-b]pyridine
(5h). White solid; m.p. 169 °C; 1H NMR (CDCl3, 300 MHz) d 7.89-
7.22 (m, 10H), 3.06-2.99 (m, 1H), 2.69-2.63 (m, 2H), 2.38 (s, 3H),
2.21-0.71 (m, 35H), 0.70 (s, 3H), 0.61 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 156.7, 154.2, 150.7, 139.9, 138.3, 136.9, 129.4, 128.6,
128.3, 127.7, 127.1, 126.7, 119.0, 56.4, 56.3, 53.7, 42.4, 41.9, 40.0,
39.5, 36.2, 35.8, 35.6, 35.2, 28.3, 28.1, 23.9, 22.9, 22.6, 21.3, 21.2,
18.7, 12.0, 11.7; IR (CHCl3, cmꢀ1) 2929, 2867, 1588, 1542, 1445,
1218, 774; MS (EI, m/z) 587.5 [M]+. Anal. calcd. for C43H57N: C,
87.85; H, 9.77; N, 2.38; Found: C, 87.48; H, 9.79; N, 2.16.
2.2.2.3. 40-(p-Flurophenyl)-60-phenyl-5
a-chloest[3,2-b]pyridine (5c).
White solid; m.p. 185–186 °C; 1H NMR (CDCl3, 300 MHz) d 7.86 (d,
J = 7.0 Hz, 2H), 7.52-7.10 (m, 8H), 3.02-2.96 (m, 1H), 2.60-2.52 (m,
2H), 2.30-0.73 (m, 35H), 0.71 (s, 3H), 0.63 (s, 3H),; 13C NMR (CDCl3,
75 MHz) d 157.0, 153.3, 151.5, 139.0, 136.2, 132.2, 130.0, 128.6,
128.2, 127.6, 127.1, 126.8, 119.8, 56.4, 56.3, 53.8, 42.4, 41.9, 39.9,
39.6, 36.2, 35.9, 35.5, 35.2, 31.6, 28.3, 28.2, 24.2, 23.6, 22.9, 22.6,
18.7, 11.9, 11.6; IR (CHCl3, cmꢀ1) 2927, 2866, 1597, 1540, 1444,
1219, 774; MS (EI, m/z) 591.4 [M]+. Anal. calcd. for C42H54FN: C,
85.23; H, 9.20; N, 2.37; Found: C, 85.44; H, 9.10; N, 2.49.
2.2.2.9.
40,60-bis(p-Methylphenyl)-5
a-chloest[3,2-b]pyridine (5i).
White solid; m.p. 189-192 °C; 1H NMR (CDCl3, 300 MHz) d 7.97-
7.25 (m, 9H), 3.08-2.99 (m, 1H), 2.71-2.65 (m, 2H), 2.38 (s, 3H),
2.36 (s, 3H), 2.24-0.74 (m, 35H), 0.70 (s, 3H), 0.62 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 157.0, 153.2, 150.9, 138.3, 136.4, 131.0,
129.4, 129.0, 128.4, 127.5, 127.2, 119.6, 56.5, 56.4, 54.0, 42.5,
41.9, 40.0, 39.7, 36.5, 35.3, 35.2, 35.1, 28.1, 28.0, 23.2, 22.9, 22.3,
21.5, 21.2, 18.3, 11.9, 11.1; IR (CHCl3, cmꢀ1) 2929, 2867, 1590,
1542, 1444, 1223, 774; MS (EI, m/z) 601.5 [M]+. Anal. calcd. for
2.2.2.4.
40-(p-Methoxyphenyl)-60-phenyl-5
a-chloest[3,2-b]pyridine
C44H59N: C, 87.79; H, 9.88; N, 2.33; Found: C, 87.86; H, 9.74; N,
(5d). White solid; m.p. 183 °C; 1H NMR (CDCl3, 300 MHz) d 7.85
(d, J = 7.2 Hz, 2H), 7.50-7.03 (m, 8H), 3.84 (s, 3H), 3.01-2.94 (m,
1H), 2.63-2.56 (m, 2H), 2.24-0.74 (m, 35H), 0.70 (s, 3H), 0.62 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 157.1, 153.2, 151.6, 139.8,
134.7, 131.0, 129.2, 128.6, 128.0, 127.6, 127.4, 126.9, 119.6, 56.4,
56.2, 53.8, 42.4, 41.9, 39.9, 39.5, 36.2, 35.8, 35.6, 35.2, 31.7, 28.7,
2.45.
2.2.2.10.
40-(p-Flurophenyl)-60-(p-methylphenyl)-5
a-chloest[3,2-
b]pyridine (5j). White solid; m.p. 173-174 °C; 1H NMR (CDCl3,
300 MHz) d 7.95-6.96 (m, 9H), 3.04-2.96 (m, 1H), 2.73-2.58 (m,
2H), 2.39 (s, 3H), 2.22-0.70 (m, 35H), 0.72 (s, 3H), 0.60 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 160.7, 156.8, 154.2, 149.7, 138.4,
136.8, 130.3, 129.9, 128.8, 128.6, 127.1, 126.7, 115.2, 56.4, 56.3,
53.7, 42.4, 41.9, 39.5, 36.2, 35.8, 35.6, 35.2, 28.6, 28.3, 28.2, 24.3,
23.9, 22.9, 22.6, 21.3, 18.7, 11.9, 11.7; IR (CHCl3, cmꢀ1) 2929,
2867, 1589, 1542, 1444, 1223, 775; MS (EI, m/z) 605.4 [M]+. Anal.
calcd. for C43H56FN: C, 85.24; H, 9.32; N, 2.31; Found: C, 85.36;
H, 9.57; N, 2.40.
28.3, 24.2, 23.9, 22.8, 22.6, 21.2, 18.7, 11.9, 11.7; IR (CHCl3, cmꢀ1
)
2929, 2867, 1589, 1543, 1445, 1218, 774; MS (EI, m/z) 603.4
[M]+. Anal. calcd. for C43H57NO: C, 85.52; H, 9.51; N, 2.32; Found:
C, 85.57; H, 9.48; N, 2.58.
2.2.2.5. 60-(p-Chlorophenyl)-40-phenyl-5
a-chloest[3,2-b]pyridine (5e).
White solid; m.p. 189 °C; 1H NMR (CDCl3, 300 MHz) d 7.89 (d,
J = 7.1 Hz, 2H), 7.47-7.03 (m, 8H), 3.06-2.98 (m, 1H), 2.68-2.64
(m, 2H), 2.20-0.74 (m, 35H), 0.68 (s, 3H), 0.62 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 157.0, 153.9, 151.1, 139.4, 136.9, 133.0, 129.3,
128.9, 128.7, 127.7, 127.1, 126.7, 119.1, 56.4, 56.2, 53.7, 42.5,
41.9, 40.0, 39.6, 36.3, 35.8, 35.6, 35.2, 28.3, 28.0, 23.0, 22.7, 22.2,
2.2.2.11. 3b-Hydroxy-5-en-androst[17,16-b][40-phenyl-60-phenyl]pyr-
idine (5k). Gum; 1H NMR (CDCl3, 300 MHz) d 8.00 (d, J = 6.4 Hz,
2H), 7.57-7.19 (m, 9H), 5.45-5.37 (m, 1H), 3.60-3.48 (m, 1H), 1.03

M. Dutta et al. / Steroids 78 (2013) 387–395
391
R
R
R
R1
N
R1
O
H
H
H
R1
R2
R2
R2
O
O
O
H
H
H
5
A
4
1
Scheme 1. Reterosynthetic analysis of steroidal pyridine derivatives.
CHO
O
KOH,toluene
rt,6h,94%
H
H
+
+
O
O
O
H
H
1a
2a
3a
4a
Scheme 2. Synthesis of steroidal 1,5-dicarbonyl compound 4a.
Table 1
Synthesis of steroidal 1, 5-dicarbonyl compounds 4a-o.
Entry
R1
R2
Producta
Yield (%)b
1
2
3
4
5
6
7
8
9
10
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
92
93
94
88
89
90
90
92
90
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
C6H5
4-Me-C6H4
4-F-C6H4
C6H5
4-Me-C6H4
4-F-C6H4
4j
a
All the reactions were stirred at rt for 6 hours.
Referring to the amount of product isolated by chromatography.
b
(s, 3H), 0.91 (s, 3H), 2.84-0.89 (m, 17H); IR (CHCl3, cmꢀ1) 3414,
2933, 1255, 1031; MS (EI, m/z) 457 [M-18]+.
2.2.2.13. 3b-Hydroxy-5-en-androst[17,16-b][40-(p-methylphenyl)-60-
phenyl]pyridine (5m). Gum; 1H NMR (CDCl3, 300 MHz) d 8.03 (d,
J = 6.6 Hz, 2H), 7.59-7.16 (m, 8H), 5.44-5.34 (m, 1H), 3.62-3.48
(m, 1H), 2.42 (s, 3H), 1.01 (s, 3H), 0.89 (s, 3H), 2.82-0.91 (m,
17H); IR (CHCl3, cmꢀ1) 3412, 2933, 1255, 1033; MS (EI, m/z)
471.3 [M-18]+.
2.2.2.12. 3b-Acetoxy-5-en-androst[17,16-b][40-phenyl-60-phenyl]pyri-
dine (5l). White solid; m.p. 174 °C; 1H NMR (CDCl3, 300 MHz) d
8.02 (d, J = 6.2 Hz, 2H), 7.56-7.19 (m, 9H), 5.42-5.35 (m, 1H),
4.63-4.49 (m, 1H), 2.04 (s, 3H), 1.06 (s, 3H), 0.93 (s, 3H), 2.84-
0.89 (m, 17H); 13C NMR (CDCl3, 75 MHz) d 170.5, 154.8, 145.7,
140.2, 140.0, 138.0, 135.6, 132.1, 128.9, 128.1, 127.4, 127.1,
122.4, 117.3, 73.2, 56.7, 45.2, 38.1, 36.5, 33.8, 31.4, 30.6, 30.4,
27.6, 21.5, 21.3, 20.6, 19.2, 17.2; IR (CHCl3, cmꢀ1) 2934, 1733,
1371, 1245; IR (CHCl3, cmꢀ1) 2924, 1736, 1245, 772; MS (ESI, m/
z) 518.3 [M + 1]+. Anal. calcd. for C36H39NO2: C, 83.52; H, 7.59; N,
2.71; Found: C, 83.56; H, 7.47; N, 2.59.
2.2.2.14. 3b-Acetoxy-5-en-androst[17,16-b][40-(p-methylphenyl)-60-
phenyl]pyridine (5n). White solid; m.p. 177-179 °C; 1H NMR
(CDCl3, 300 MHz) d 8.01 (d, J = 6.9 Hz, 2H), 7.57-7.21 (m, 8H),
5.42-5.37 (m, 1H), 4.63-4.50 (m, 1H), 2.84-2.69 (m, 1H), 2.43 (s,
3H), 2.04 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H), 2.44-0.87 (m, 16H);
13C NMR (CDCl3, 75 MHz) d 170.6, 155.9, 145.9, 140.3, 140.1,
138.2, 136.1, 132.2, 129.4, 128.6, 128.3, 128.2, 127.1, 122.1,

392
M. Dutta et al. / Steroids 78 (2013) 387–395
Table 2
Optimization of reaction condition for the synthesis of 5a.
Entry
Solvent
Methoda
Catalyst
Time
T (oC)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
i-PrOH
CH3CN
DMF
Neat
Neat
Neat
Neat
Neat
Neat
Neat
TH
TH
TH
TH
MW
MW
MW
MW
MW
MW
–
–
–
–
8 h
8 h
8 h
8 h
8 min
8 min
8 min
8 min
8 min
8 min
100
90
0
0
155
140
140
140
140
140
140
140
21
49
62
66
53
90
59
64
–
AlCl3
TiCl4
BF3.OEt2
ZnCl2
InCl3
a
TH: thermal heating, MW: microwave irradiation.
Yield of the isolated product.
b
Table 3
Synthesis of 40,60-diaryl-chloest[3,2-b]pyridine derivatives 5.
Entry
R1
R2
Producta
Yield (%)b
1
2
3
4
5
6
7
8
9
10
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
92
93
81
86
84
82
85
82
88
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
C6H5
4-Me-C6H4
4-F-C6H4
C6H5
4-Me-C6H4
4-F-C6H4
5j
a
Time taken 6 min.
Referring to the amount of product isolated by chromatography.
b
117.8, 73.9, 56.2, 50.7, 45.8, 38.2, 36.9, 33.8, 31.4, 30.9, 30.4, 27.8,
21.5, 21.3, 20.6, 19.4, 17.4; IR (CHCl3, cmꢀ1) 2934, 1733, 1371,
1245; MS (ESI, m/z) 532.7 [M+1]+. Anal. calcd. for C37H41NO2: C,
83.58; H, 7.77; N, 2.63; Found: C, 83.66; H, 7.64; N, 2.79.
2.2.2.16. 3b-Acetoxy-5-en-androst[17,16-b][40-(p-chlorophenyl)-60-
phenyl]pyridine (5p). White solid; m.p. 185 °C; 1H NMR (CDCl3,
300 MHz) d 7.95 (d, J = 7.5 Hz, 2H), 7.57-7.11 (m, 8H), 5.41-5.37
(m, 1H), 4.60-4.50 (m, 1H), 2.80-2.65 (m, 1H), 2.04 (s, 3H), 1.18
(s, 3H), 1.12 (s, 3H), 2.34-0.86 (m, 16H); 13C NMR (CDCl3,
75 MHz) d 170.9, 156.5, 146.3, 140.8, 140.4, 138.6, 136.4, 132.4,
129.1, 128.7, 128.4, 128.3, 127.6, 122.2, 118.5, 73.7, 56.3, 50.9,
45.8, 38.2, 36.8, 33.8, 31.2, 30.9, 30.4, 27.9, 21.8, 21.3, 20.6, 19.8,
17.6; IR (CHCl3, cmꢀ1) 2930, 1733, 1246, 772; MS (ESI, m/z) 552.3
[M+1]+. Anal. calcd. for C36H38ClNO2: C, 78.31; H, 6.94; N, 2.54;
Found: C, 78.60; H, 6.68; N, 2.62.
2.2.2.15. 3b-Hydroxy-5-en-androst[17,16-b][40-(p-chlorophenyl)-60-
phenyl]pyridine (5o). Gum; 1H NMR (CDCl3, 300 MHz) d 8.01 (d,
J = 6.6 Hz, 2H), 7.56-7.16 (m, 8H), 5.42-5.34 (m, 1H), 3.61-3.46
(m, 1H), 1.03 (s, 3H), 0.90 (s, 3H), 2.80-0.90 (m, 17H); IR (CHCl3,
cmꢀ1) 3409, 2936, 1254, 1033; MS (EI, m/z) 491.2 [M-18]+.

M. Dutta et al. / Steroids 78 (2013) 387–395
393
Table 4
Synthesis of steroid fused pyridine derivatives 5k–s.
Entry
1
Ketone (1b–c), R1CHO & R2COCH3
1,5-Diketones (Yield)a,b
Pyridine derivatives (Yield)a,c
2
1b, p-Me-PhCHO & PhCOCH3
3
1b, p-Cl-PhCHO & PhCOCH3
4
5
6
1c, p-Me-PhCHO & PhCOCH3
1c, p-Cl-PhCHO & PhCOCH3
a
b
c
Yield of the isolated product.
Time taken = 12 h.
Time taken = 6 min.
2.2.2.17.
5
a
-Androst[3,2-b][17,16-b][bis-(40-phenyl-60-phenyl)]pyri-
2.2.2.18.
5a
-Androst[3,2-b][17,16-b][bis-{40-(p-methylphenyl)-60-
dine (5q). Gum; 1H NMR (CDCl3, 300 MHz) d 8.08-7.19 (m, 22H),
3.00-2.67 (m, 6H), 2.39-0.80 (m, 18H); 13C NMR (CDCl3, 75 MHz)
d 173.3, 155.7, 146.2, 141.0, 140.2, 140.1, 138.6, 137.4, 135.4,
132.3, 129.8, 128.7, 128.5, 128.2, 127.4, 126.7, 122.6, 117.7, 74.0,
56.4, 51.7, 46.4, 39.3, 36.6, 33.8, 31.4, 30.7, 30.4, 27.4, 21.3, 21.2,
21.1, 20.7, 19.3, 17.2, 13.3; IR (CHCl3, cmꢀ1) 2924, 1598, 1546,
775; MS (ESI, m/z) 662.4 [M + 1]+.
phenyl}]pyridine (5r). White solid; m.p. 187-188 °C; 1H NMR
(CDCl3, 300 MHz) d 7.99-7.17 (m, 20H), 3.02-2.65 (m, 6H), 2.38
(s, 3H), 2.37 (s, 3H), 2.36-0.81 (m, 18H); 13C NMR (CDCl3,
75 MHz) d 174.6, 156.9, 145.4, 140.6, 140.1, 140.0, 138.8, 137.6,
135.4, 132.3, 129.8, 128.9, 128.8, 128.5, 127.6, 126.6, 122.4,
117.4, 73.8, 56.4, 51.7, 46.6, 39.5, 36.7, 33.8, 31.4, 30.5, 30.4,
27.4, 21.3, 21.1, 20.7, 19.2, 17.2, 13.5; IR (CHCl3, cmꢀ1) 2924,

394
M. Dutta et al. / Steroids 78 (2013) 387–395
1597, 1547, 775; MS (ESI, m/z) 691.3 [M+1]+. Anal. calcd. for
51H50N2: C, 88.65; H, 7.29; N, 4.05; Found: C, 88.57; H, 7.35; N,
4.21.
amounts of 5a-cholestan-3-one (1a), benzaldehyde (2a) and aceto-
C
phenone (3a) in presence of two equivalent of potassium hydrox-
ide as base (Scheme 2) using acetonitrile as the solvent at room
temperature, which afforded compound 4a in only 24% yield. It
was found that outcome of the reaction was dependent on the nat-
ure of the solvent used. The reaction was unsuccessful in most of
the protic solvents such as methanol, ethanol, water and with
some aprotic organic solvents such as DMF, 1,4-dioxane it gave
very less yield of the products (19–21%) even after 12 h of heating.
Surprisingly, when the reactants were stirred in toluene at room
temperature for six hours, compound 4a was obtained as the only
product in 94% yield.
2.2.2.19.
5a
-Androst[3,2-b][17,16-b][bis–{40-(p-chlorophenyl)-60-
phenyl}]pyridine (5s). Gum; 1H NMR (CDCl3, 300 MHz) d 8.04-
7.15 (m, 20H), 3.02-2.69 (m, 6H), 2.35-0.82 (m, 18H); 13C NMR
(CDCl3, 75 MHz) d 173.5, 156.6, 146.8, 141.3, 140.8, 140.5, 138.9,
137.8, 135.5, 132.3, 129.7, 128.6, 128.5, 128.2, 127.4, 126.8,
122.6, 117.7, 74.2, 56.4, 51.7, 46.6, 39.3, 36.6, 33.9, 31.4, 31.1,
30.6, 27.4, 21.3, 21.1, 20.9, 19.4, 17.2, 13.4; IR (CHCl3, cmꢀ1
)
2926, 1598, 1547, 775; MS (ESI, m/z) 731.3 [M+1]+.
The scope of the reaction was then investigated by the reaction
of steroidal ketones1a, 1b, 1c with a variety of aromatic aldehydes
(2) and arylketones (3) including both electron-deficient and elec-
tron-rich groups (Tables 1–4). Gratifyingly, the 1,5-dicarbonyl
compounds were obtained in excellent yield in all cases and no
undesired side reactions were observed. For the steroidal ketones
1b and 1c the reaction took longer time for completion of the reac-
tion. The products obtained were characterized by various spectro-
scopic means such as NMR, IR and mass spectrometric analysis.
In the next step, reaction of the 1,5-dicarbonyl compound 4a
with urea was explored. An extensive reaction optimization of
the cyclization reaction was performed in order to find out the best
condition to synthesize the pyridine fused steroid 5a (Table 2). Ini-
tially, the synthesis of 5a was evaluated using two different meth-
odologies: conventional thermal heating (TH) and microwave
irradiation (MW). When the reaction of 4a with urea was carried
in isopropanol and acetonitrile under thermal condition, the reac-
tion could not afford product 5a after 8 hours of refluxing (entry 1–
2, Table 2). However, we observed that the use of DMF as the sol-
vent, afforded 21% yield of 5a (entry 3, Table 2). Performing the
reaction in solid phase under TH and MW conditions increased
the yield of the product 5a up to 49% and 62% respectively (entry
4-5, Table 2). To further improve the product yield in the solid
phase reaction, we screened several Lewis acids as the catalyst,
employing microwave as a source of energy (entry 6–10, Table
2). The best result was obtained by conducting the reaction under
MW irradiation and using BF3.OEt2 as the catalyst (entry 8, Table
2). With the optimized reaction conditions in hand, we then ap-
plied the protocol for the cyclization reaction of different steroidal
diketones (4b–s), to afford steroidal pyridines (5b–s) in excellent
yields (Table 3 and 4). All the new compounds were characterized
by 1H, 13C NMR and mass spectra.
3. Results and discussion
The first synthesis of steroidal heterocycles containing a pyri-
dine ring was described by Miller T. C. using high temperature
and multistep reaction strategy [14]. Chelucci and co-workers re-
ported the synthesis of linear cholestanopyridine through
a
three-step pyridoannelation of its N,N-dimethylhydrazones with
bromoethyl-1,3-dioxolane [15]. Another method to synthesize ste-
roidal pyridines from corresponding carbonyl compounds was re-
ported by Abbiati and co-workers using Gold (III) salts as a
catalyst [11]. In a recent report, Yan and co-workers developed a
method for the synthesis of steroidal [3,4] b pyridines from 3-keto
steroids and propargylamine using Cu (II) salt as the catalyst with
very low yield (6–51%) and limited substrate scope [10]. We also
reported synthesis of steroidal A ring fused chloropyridines by
refluxing a mixture of steroidal enamides with Vilsmeier reagent
in DMF [16]. To the best of our knowledge, there is no report focus-
ing on the synthesis of steroidal 4,6-diarylpyridines in the
literature.
Scheme 1 illustrates our retrosynthetic analysis of steroidal pyr-
idine derivatives 5. The synthetic strategy was centered on cycliza-
tion of diketo compound 4, to produce target pyridine derivative 5,
which contains not only the pyridine framework but also different
substituents in the pyridine ring. A Michael reaction of chalcone
with steroidal ketone would furnish diketo compound 4. We envi-
sioned that synthesis of compound 4 would be much more advan-
tageous if the ketosteroid 1 could be reacted with an in-situ
generated chalcone (from a suitable ketone and an aldehyde) in-
stead of reacting it directly with chalcone, which requires another
synthetic step.
A proposed mechanism for the formation of pyridine ring fused
to steroid backbone is shown in Scheme 3. Under the influence of
base, steroidal ketone 1 undergoes Michael addition reaction to
Our initial effort was directed towards developing a suitable
method for the synthesis of steroidal 1,5-dicarbonyl compound 4.
We began our study by investigating the reaction of equimolar
R2
R2
MW
OH-
O
Urea NH3
BF3.OEt2
R1
+
R1
Michael
reaction
R1
R2
O
O
O
N
O
H
A
1
4
B
R2
R2
R2
H
H
R
-BF3.OEt2
-H2O
Aromatization
N
H
1 O
R1
N
H
R1
N
BF3.OEt2
5
C
D
Scheme 3. Proposed mechanism for the formation of steroidal pyrinine 5.

M. Dutta et al. / Steroids 78 (2013) 387–395
395
(b) Kase K, Goswami A, Ohtaki K, Tanable E, Saino N, Okamoto S. On demand
generation of an efficient catalyst for pyridine formation from unactivated
in situ generated chalcone A to afford the steroidal 1,5-dicarbonyl
intermediate 4. It is believed that ammonia released by urea under
microwave condition forms an imine intermediate B with the non
conjugated carbonyl group of steroidal 1,5-dicarbonyl compound
4. Activation of conjugated carbonyl group in intermediate B by
BF3.OEt2 followed by the nucleophilic attack of the NH-group of
imine on the activated carbonyl functionality facilitated the aza
cyclization reaction with consequent loss of a water molecule to af-
ford intermediate D. The oxidation of 1,4-dihydropyrinine inter-
mediate D under aerial condition led to stable product 5 due to
aromatization [17].
In summary, we have developed a solvent less one pot reaction
of steroidal 1,5-diketo compound with urea by employing BF3.OEt2
as the catalyst, for the synthesis of steroidal A- and D-ring fused
4,6-diarylpyridines under microwave irradiation. The intermediate
steroidal 1,5-diketo compounds were synthesized by Michael addi-
tion reaction of steroidal ketones with in situ generated chalcones
from aromatic ketones and aldehydes.
nitriles and
a, x-diynes using CoCl2-6H2O, dppe, and Zn. Org Lett
2007;9:931–4.
[3] Ackerman JH, Potts GO, Beyler AL, Clinton RO. Steroidal heterocycles X1
steroidal [3,2-d] pyrimidines and related compounds.
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[4] Hirschmann R, Buchschacher P, Steinberg NG, Fried JH, Ellis R, Kent GJ, et al.
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Acknowledgements
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amination/annulation/aromatization reaction of carbonyl compounds and
propargylamine: a new one-pot approach to functionalized pyridines. J Org
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We thank the Department of Science & Technology, New Delhi
for financial support. One of us (Mandakani Dutta), thanks CSIR,
New Delhi for the award of Senior research fellowship (CSIR-
SRF). We are grateful to Director, CSIR-NEIST for his keen interests.
(b)
Anastas
PT,
Warner
JC.
Green
chemistry:
theory
and
practice. Oxford: Oxford University Press; 1998.
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