Palladium-catalyzed multi-component synthesis of steroidal A- and D-ring fused 5,6-disubstituted pyridines under microwave irradiation

Article abstract of DOI:10.1016/j.steroids.2013.08.002

The preparation of steroidal A-, D-ring fused 5,6-disubstituted pyridines and nonsteroidal substituted pyridines is described form Pd(OAc)₂ catalyzed multi-component reaction of steroidal/nonsteroidal β-halovinyl aldehyde, alkyne and benzylamin

Full text of DOI:10.1016/j.steroids.2013.08.002

Steroids 78 (2013) 1126–1133
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Palladium-catalyzed multi-component synthesis of steroidal A- and
D-ring fused 5,6-disubstituted pyridines under microwave irradiation
⇑
⇑
Kommuri Shekarrao, Dipankar Nath, Partha Pratim Kaishap, Sanjib Gogoi , Romesh C. Boruah
Medicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat, Assam 785 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 30 July 2013
Accepted 1 August 2013
Available online 14 August 2013
The preparation of steroidal A-, D-ring fused 5,6-disubstituted pyridines and nonsteroidal substituted
pyridines is described form Pd(OAc)2 catalyzed multi-component reaction of steroidal/nonsteroidal b-
halovinyl aldehyde, alkyne and benzylamine in solvent-free condition under microwave irradiation.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Steroid pyridine
Microwave
Multicomponent reaction
b-Bromovinyl aldehyde
Benzyl amine
1. Introduction
aldehyde, alkyne and benzylamine under microwave irradiation
for the synthesis of steroidal and nonsteroidal pyridines [Scheme 1].
The development of methods for substituted pyridine deriva-
tives is of importance to medicinal chemistry because of its wide-
spread distribution in natural products, pharmaceuticals and
synthetic biologically active compounds [1]. Due to the remarkable
biological activities of steroids bearing heterocycles, enormous ef-
forts are being made to annelate steroidal moiety with heterocy-
cles such as pyrazole, isoxazole, pyridine, pyran, pyrrole or
pyrimidine rings using various synthetic strategies [2–7]. Some
of the biologically active steroids fused with heterocycles are
shown in Fig. 1. Among annelated heterosteroids, the synthesis
of A- and D-ring fused pyridines is drawing particular interest in
last decade because of their inherent biological activities [4,6,8–9].
Microwave assisted organic synthesis (MAOS) which has been
applied over the last decade as a very efficient tool to accelerate
the course of many organic reactions, producing high yields, higher
selectivity and lower quantities of side products is recognized as a
‘‘green’’ technology in the field of organic synthesis [10]. In view
of the therapeutic importance of heterosteroids and in continuation
of our interests in development of newer strategy for A- and D-ring
annelated heterosteroids [11], herein we wish to report a solvent-
free Pd(OAc)2 catalyzed three component reaction of b-halovinyl
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 on a thin film using chloro-
form. 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 instru-
ment. All the commercially available regents were used as re-
ceived. 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 the synthesis of steroidal and non-
steroidal pyridines from b-bromovinyl aldehydes
Steroidal/nonsteroidal bromo vinyl aldehyde (0.5 mmol), al-
kyne (0.5 mmol), benzyl amine (0.5 mmol), Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), Na2CO3 (1.5 mmol) and neutral alumina
(200 mg) were mixed intimately and the mixture was irradiated
⇑
Corresponding authors. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail addresses: skgogoi1@gmail.com (S. Gogoi), rc_boruah@yahoo.co.in (R.C.
Boruah).
0039-128X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.08.002

K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
1127
O
O
O
OH
HO
NH
N
N
H
N
H
AcO
H
I
Cortivazol ( )
Ref 2
(Anti inflammatory)Ref 5
II
(Cytotoxic agent)
O
N
NC
N
N
N
N
H
O
H
O
O
N
H
Cl
H
Ref 3
Ref 6
III
(Cytotoxic agent)
IV
(Anti inflammatory)
Fig. 1. Examples of biological active heterosteroids (I–IV).
COOMe
N
MeOOC
Br
NH2
COOMe
CHO
i
+
+
AcO
AcO
COOMe
2a
3a (81%)
1a
Scheme 1. Reagents and condition (i) Pd(OA)2, PPh3, Na2CO3, neutral alumina, 10 min, MW.
in a closed vessel in a Synthos 3000 microwave reactor at 600 Watt
(140 °C and 12 bar) for 10 min. After 10 min ethylacetate (30 mL)
was added to the reaction mixture and it was filtered through
whatman filter paper. The residue obtained after removal of
ethylacetate layer was purified by silica gel column chromatogra-
phy using EtOAc/hexane as the eluent to afford the pyridine deriv-
ative. The alumina on the filter paper was then dried in vacuo and
can be used again for another two times in place of Pd(OAc)2 with-
out substantial loss of the yield of the product.
2.2.1.3.
3b-Acetoxy-50-carbethoxy-60-phenyl-5-en-androst[16,17-
c]pyridine (3c). Yellow gum; 1H NMR (CDCl3, 300 MHz): d 8.46 (s,
1H), 7.54–7.28 (m, 5H), 5.38–5.34 (m, 1H), 4.57–4.52 (m, 1H),
4.10–4.00 (m, 2H), 1.97 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.93 (t,
J = 7.1 Hz, 3H), 2.79–0.85 (m, 17H). 13C NMR (CDCl3, 75 MHz): d
170.4, 168.9, 160.4, 156.6, 146.18, 140.2, 139.6, 138.1, 128.8,
128.5, 128.3, 124.0, 121.9, 73.7, 57.5, 56.2, 54.7, 52.2, 49.8, 49.7,
46.8, 40.8, 40.4, 36.7, 33.2, 31.4, 30.9, 30.8, 30.6, 21.5, 19.2, 17.2.
IR (CHCl3, cmꢀ1): 2924, 1732, 1650, 1048, 997, 769. MS (EI, m/z):
453.3 [M-60]. Anal. calcd. for C33H39NO4: C, 77.16; H, 7.65; N,
2.73; Found: C, 77.21; H, 7.69; N, 2.86.
2.2.1.1. 3b-Acetoxy-50,60-dicarbmethoxy-5-en-androst[16,17-c]pyridine
(3a). Yellow gum; 1H NMR (CDCl3, 300 MHz): d 8.51 (s, 1H), 5.36–
5.32 (m, 1H), 4.56–4.50 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 1.97 (s,
3H), 1.10 (s, 3H), 1.01 (s, 3H), 2.84–0.84 (m, 17H). 13C NMR (CDCl3,
75 MHz): d 170.5, 167.8, 166.8, 165.2, 164.1, 160.2, 146.2, 140.1,
127.1, 121.7, 73.7, 57.1, 53.4, 53.2, 52.7, 49.9, 46.9, 38.1, 36.8,
33.2, 31.4, 30.6, 29.9, 27.7, 21.4, 20.6, 19.3, 17.1. IR (CHCl3,
cmꢀ1): 2952, 1733, 1438, 1375, 1251, 755. MS (EI, m/z): 481.2,
421.2 [M+–60]. Anal. calcd. for C28H35NO6: C, 69.83; H, 7.33; N,
2.91; Found: C, 69.92; H, 7.42; N, 2.83.
2.2.1.4. 3b-Acetoxy-50-trimethylsilyl-60-phenyl-5-en-androst[16,17-
c]pyridine (3d). Yellow solid; m.p. 250–251 °C; 1H NMR (CDCl3,
300 MHz): d 8.39 (s, 1H), 7.50–7.28 (m, 5H), 5.40–5.31 (m, 1H),
4.60–4.52 (m, 1H), 2.00 (s, 3H), 1.11 (s, 3H), 1.00 (s, 3H), 2.82–
0.83 (m, 17H), 0.03 (s, 9H). 13C NMR (CDCl3, 75 MHz): d 170.5,
165.2, 145.1, 139.9, 138.0, 129.5, 127.8, 127.0, 122.2, 73.8, 57.8,
49.7, 48.5, 38.1, 36.9, 36.7, 36.0, 31.5, 31.0, 29.7, 29.4, 27.8, 22.7,
21.4, 21.0, 19.3, 15.9, 14.1, 4.2; IR (CHCl3, cmꢀ1) 2923, 1730,
1649, 1049, 996, 768. MS (EI, m/z): 453.3 [M-60]. Anal. calcd. for
2.2.1.2. 3b-Acetoxy-50-carbmethoxy-60-phenyl-5-en-androst[16,17-c]
pyridine (3b). Yellow gum; 1H NMR (CDCl3, 300 MHz): d 8.61 (s,
1H), 7.71–7.28 (m, 5H), 5.42–5.39 (m, 1H), 4.47–4.42 (m, 1H),
3.65 (s, 3H), 1.99 (s, 3H), 1.09 (s, 3H), 1.00 (s, 3H), 2.80–0.85 (m,
17H). 13C NMR (CDCl3, 75 MHz): d 170.2, 168.8, 160.1, 156.6,
146.2, 140.1, 139.6, 138.0, 128.7, 128.5, 128.3, 124.0, 121.9, 73.6,
57.4, 56.1, 54.7, 52.4, 49.8, 46.8, 40.7, 40.4, 36.7, 36.66, 33.1,
31.4, 30.9, 30.85, 30.6, 21.3, 19.2, 17.0. IR (CHCl3, cmꢀ1): 2923,
1731, 1649, 1048, 1026, 997, 768. MS (EI, m/z): 439.2 [M-60]. Anal.
calcd. for C32H37NO4: C, 76.92; H, 7.46; N, 2.80; Found: C, 76.80; H,
7.32; N, 2.87.
C
33H43NO2Si: C, 77.14; H, 8.44; N, 2.73; Found: C, 77.31; H, 8.50;
N, 2.89.
2.2.1.5. 3b-Acetoxy-50-methyl-60-phenyl-5-en-androst[16,17-c]pyri-
dine (3e). Yellow solid; m.p. 190–191 °C; 1H NMR (CDCl3,
300 MHz): d 8.36 (s, 1H), 7.47–7.31 (m, 5H), 5.46–5.39 (m, 1H),
4.65–4.56 (m, 1H), 2.29 (s, 3H), 2.05 (s, 3H), 1.11 (s, 3H), 1.08 (s,
3H), 3.01–0.87 (m, 17H). 13C NMR (CDCl3, 75 MHz) d 170.6,
160.8, 157.8, 143.2, 141.1, 140.0, 137.0, 129.3 128.0, 127.5, 126.0,
122.1, 73.8, 57.1, 50.9, 49.9, 47.4, 38.1, 36.9, 35.6, 31.5, 30.8,
29.7, 29.4, 27.7, 21.5, 20.9, 19.3, 15.9. IR (CHCl3, cmꢀ1): 2938,

1128
K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
1731, 1373, 1245, 1033, 772. MS (EI, m/z) 395.2 [M-60]+. Anal.
calcd. for C31H37NO2: C, 81.72; H, 8.19; N, 3.07; Found: C, 81.92;
H, 8.33; N, 3.27.
3H), 2.05 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H), 2.82–0.87 (m, 17H).
13C NMR (CDCl3, 75 MHz): d 170.6, 164.0, 158.0, 155.9, 145.6,
140.0, 137.0, 135.3, 134.7, 130.1, 129.0, 127.1, 125.9, 125.4,
122.1, 119.1, 113.5, 105.6, 73.8, 57.2, 55.3, 50.5, 45.6, 38.1, 36.9,
34.2, 31.7, 30.8, 30.2, 29.8, 21.7, 21.4, 20.7, 19.4, 18.7. IR (CHCl3,
cmꢀ1): 2958, 2927, 1731, 1242, 1033, 772. MS (EI, m/z): 461.2
[M-60]+. Anal. calcd. for C35H39NO3: C, 80.58; H, 7.54; N, 2.68;
Found: C, 80.62; H, 7.55; N, 2.70.
2.2.1.6.
3b-Acetoxy-50,60-diphenyl-5-en-androst[16,17-c]pyridine
(3f). Yellow solid; m.p. 225–226 °C; 1H NMR (CDCl3, 300 MHz): d
8.55 (s, 1H), 7.29–6.99 (m, 10H), 5.42–5.36 (m, 1H), 4.63–4.55
(m, 1H), 2.03 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 2.82–0.83 (m,
17H). 13C NMR (CDCl3, 75 MHz): d 170.5, 160.7, 156.3, 144.8,
140.7, 140.0, 137.7, 137.2, 132.1, 131.0, 130.4, 129.8, 127.5,
127.4, 127.0, 126.9, 122.0, 73.8, 57.5, 49.8, 48.0, 47.3, 41.3, 36.6,
32.0, 31.6, 30.8, 29.7, 27.7, 21.4, 20.4, 19.2, 18.2, 14.3, 11.4. IR
(CHCl3, cmꢀ1): 2941, 1731, 1374, 1245, 1033, 904, 758, 700. MS
(EI, m/z): 517.3 [M+]. Anal. calcd. for C36H39NO2: C, 83.52; H,
7.59; N, 2.71; Found: C, 83.55; H, 7.67; N, 2.91.
2.2.1.12. 50-Carbmethoxy-60-phenyl-cholest[2,3-c]pyridine (3l). Yel-
low gum; 1H NMR (CDCl3, 300 MHz): d 8.42 (s, 1H), 7.64–7.27
(m, 5H), 3.64 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz,
6H), 2.89–0.86 (m, 29H), 0.77 (s, 3H), 0.69 (s, 3H). 13C NMR (CDCl3,
75 MHz) d 169.5, 153.3, 151.2, 143.4, 139.9, 132.2, 131.0, 128.4,
128.1, 127.6, 56.4, 56.3, 53.6, 52.3, 42.5, 41.2, 39.9, 39.5, 36.2,
35.8, 35.5, 34.7, 29.7, 29.4, 28.2, 28.0, 23.9, 22.9, 22.6, 18.7, 12.0,
11.7. IR (CHCl3, cmꢀ1): 1730, 1457, 1219, 772. MS (EI, m/z): 555.3
[M+]. Anal. calcd. for C38H53NO2: C, 82.11; H, 9.61; N, 2.52; Found:
C, 82.22; H, 9.63; N, 2.43.
2.2.1.7.
3b-Acetoxy-50,60-n-dipropyl-5-en-androst[16,17-c]pyridine
(3g). Red solid; m.p. 154–155 °C; 1H NMR (CDCl3, 300 MHz): d
8.28 (s, 1H), 5.44–5.41 (m, 1H), 4.67–4.55 (m, 1H), 2.05 (s, 3H),
1.12 (s, 3H), 1.01 (s, 3H), 2.83–0.85 (m, 31H). 13C NMR (CDCl3,
75 MHz): d 170.6, 156.9, 139.9, 139.0, 138.1, 133.3, 123.0, 73.7,
56.7, 49.6, 48.3, 38.0, 36.8, 36.7, 36.0, 34.5, 31.4, 30.8, 30.5, 27.7,
25.1, 23.8, 21.5, 21.2, 19.3, 17.2, 14.8, 14.3. IR (CHCl3, cmꢀ1):
2958, 2931, 1732, 1244, 1033, 772. MS (EI, m/z): 449.3 [M+]. Anal.
calcd. for C30H43NO2: C, 80.13; H, 9.64; N, 3.11; Found: C, 80.35; H,
9.74; N, 2.85.
2.2.1.13. 50-Methyl-60-phenyl-cholest[2,3-c]pyridine (3m). Yellow
gum; 1H NMR (CDCl3, 300 MHz): d 8.22 (s, 1H), 7.75–7.19 (m,
5H), 2.17 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 6H),
2.86–0.82 (m, 29H), 0.75 (s, 3H), 0.70 (s, 3H). 13C NMR (CDCl3,
75 MHz): d 155.7, 147.6, 144.6, 141.2, 130.6, 129.3, 128.6, 128.3,
128.2, 128.0, 127.4, 56.4, 56.3, 53.7, 42.5, 41.7, 39.5, 36.2, 35.8,
35.6, 34.5, 31.9, 28.3, 28.0, 24.3, 23.9, 22.9, 22.6, 21.2, 18.7, 15.8,
12.0, 11.6. IR (CHCl3, cmꢀ1): 2930, 1676, 1465, 1382, 1261, 1025,
770. MS (EI, m/z): 510.4 [M+]. Anal. calcd. for C37H53N: C, 86.83;
H, 10.44; N, 2.74; Found: C, 86.92; H, 10.57; N, 2.81.
2.2.1.8. 3b-Acetoxy-60-(400-trifluoromethylphenyl)-5-en-androst[16,17-c]
pyridine (3h). Red gum; 1H NMR (CDCl3, 300 MHz): d 10.0 (s, 1H),
8.10–7.18 (m, 5H), 5.43–5.38 (m, 1H), 4.66–4.56 (m, 1H), 2.04 (s,
3H), 1.12 (s, 3H), 1.00 (s, 3H), 2.83–0.85 (m, 17H). 13C NMR (CDCl3,
75 MHz): d 189.2, 170.5, 153.2, 147.8, 140.0, 134.4, 131.6, 129.2,
126.1, 126.0, 122.0, 120.3, 73.7, 54.8, 51.0, 50.3, 38.1, 36.8, 33.5,
31.3, 30.7, 29.4, 29.2, 21.4, 20.6, 19.2, 15.9, 14.1. IR (CHCl3,
cmꢀ1): 2959, 1730, 1030, 774. MS (EI, m/z): 509.3 [M+]. Anal. calcd.
for C31H34F3NO2: C, 73.06; H, 6.72; N, 2.75; Found: C, 73.31; H,
6.62; N, 2.85.
2.2.1.14. 50,60-Diphenyl-cholest[2,3-c]pyridine (3n). Yellow gum; 1H
NMR (CDCl3, 300 MHz): d 8.33 (s, 1H), 7.45–6.90 (m, 10H), 0.93
(d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 6H), 2.88–0.85 (m, 29H),
0.77 (s, 3H), 0.69 (s, 3H). 13C NMR (CDCl3, 75 MHz) d 155.9,
147.8, 144.5, 141.2, 141.0, 130.6, 129.4, 128.7, 128.3, 128.2,
127.4, 56.6, 56.3, 53.7, 42.6, 41.7, 39.5, 36.2, 35.8, 35.8, 34.5,
31.9, 28.3, 24.3, 23.8, 22.9, 22.6, 21.2, 18.7, 15.9, 12.0, 11.7. IR
(CHCl3, cmꢀ1): 2931, 1677, 1465, 1383, 1263, 1025, 770. MS (EI,
m/z): 572.4 [M+]. Anal. calcd. for C42H55N: C, 87.90; H, 9.66; N,
2.44; Found: C, 87.81; H, 9.50; N, 2.73.
2.2.1.9. 3b-Acetoxy-60-(thiophen-2-yl)-5-en-androst[16,17-c]pyridine
(3i). Red solid; m.p. 215–216 °C; 1H NMR (CDCl3, 300 MHz): d 8.36
(s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 5.0 Hz, 1H), 7.32–7.28 (m,
2H), 5.38–5.34 (m, 1H), 4.61–4.48 (m, 1H), 2.05 (s, 3H), 1.12 (s, 3H),
1.01 (s, 3H), 2.83–0.85 (m, 17H). 13C NMR (CDCl3, 75 MHz): d 170.6,
163.9, 151.9, 145.5, 142.8, 140.0, 136.9, 126.4, 126.0, 122.8, 122.1,
113.3, 73.8, 57.1, 50.4, 45.5, 38.1, 36.9, 36.87, 34.2, 31.6, 30.8, 29.8,
27.7, 21.5, 20.6, 19.4, 18.6. IR (CHCl3, cmꢀ1): 2961, 1731, 772. MS
(EI, m/z): 447.2 [M+]. Anal. calcd. for C28H33NO2S: C, 75.13; H,
7.43; N, 3.13; Found: C, 75.40; H, 7.52; N, 3.04.
2.2.1.15. 50,60-Di-n-propyl-cholest[2,3-c]pyridine (3o). Yellow gum;
1H NMR (CDCl3, 300 MHz): d 8.05 (s, 1H), 0.93 (d, J = 6.4 Hz, 3H),
0.87 (d, J = 6.4 Hz, 6H), 2.87–0.85 (m, 43H), 0.77 (s, 3H), 0.68 (s,
3H). 13C NMR (CDCl3, 75 MHz): d 156.0, 146.2, 146.1, 133.8,
130.6, 57.0, 56.3, 53.6, 42.5, 41.6, 39.5, 36.2, 35.8, 34.4, 29.7,
28.9, 28.2, 28.0, 23.8, 23.5, 22.9, 22.6, 18.7, 14.8, 14.4, 12.0, 11.5.
IR (CHCl3, cmꢀ1): 2932, 1677, 1463, 1263, 1025, 768. MS (EI, m/
z): 505.4 [M+]. Anal. calcd. for C36H59N: C, 85.48; H, 11.76; N,
2.77; Found: C, 85.54; H, 11.89; N, 2.90.
2.2.1.10. 3b-Acetoxy-60-(30,50-difluorophenyl)-5-en-androst[16,17-c]pyr-
idine (3j). Red solid; m.p. 193–194 °C; 1H NMR (CDCl3, 300 MHz): d
8.50 (s, 1H), 7.55–7.47 (m, 2H), 7.42 (s, 1H), 6.86–6.77 (m, 1H),
5.45–5.41 (m, 1H), 4.65–4.57 (m, 1H), 2.05 (s, 3H), 1.12 (s, 3H),
1.00 (s, 3H), 2.82–0.87 (m, 17H). 13C NMR (CDCl3, 75 MHz):
170.6, 165.2, 164.3, 161.8, 153.3, 145.8, 143.4, 140.0, 138.5,
122.0, 113.5, 109.9, 109.5, 103.7, 73.8, 57.2, 50.4, 45.6, 38.1, 36.9,
34.1, 31.6, 30.8, 29.8, 27.7, 21.4, 20.6, 19.3, 18.6, 14.1. IR (CHCl3,
cmꢀ1): 2957, 2929, 1731, 1243, 1033, 771. MS (EI, m/z): 417.2
[M-60]+. Anal. calcd. for C30H33F2NO2: C, 75.45; H, 6.96; N, 2.93;
Found: C, 75.69; H, 6.75; N, 2.78.
2.2.1.16. 50,60-Dicarbmethoxy-cholest[2,3-c]pyridine (3p). Yellow
gum; 1H NMR (CDCl3, 300 MHz): d 8.35 (s, 1H), 3.74 (s, 3H), 3.59
(s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 6H), 2.89–0.82
(m, 29H), 0.77 (s, 3H), 0.69 (s, 3H). 13C NMR (CDCl3, 75 MHz) d
168.7, 168.1, 165.3, 164.6, 151.9, 151.0, 140.1, 56.2, 53.7, 52.8,
52.7, 51.9, 51.1, 42.4, 40.9, 39.5, 35.8, 34.6, 31.4, 30.4, 30.3, 29.7,
28.0, 23.8, 22.8, 22.5, 18.7, 12.0, 11.7. IR (CHCl3, cmꢀ1): 2952,
1740, 1594, 1435, 1259, 1049. MS (EI, m/z): 537.3 [M+]. Anal. calcd.
for C34H51NO4: C, 75.94; H, 9.56; N, 2.60; Found: C, 76.12; H, 9.52;
N, 2.73.
2.2.1.11. 3b-Acetoxy-60-(600-methoxynaphthalen-2-yl)-5-en-androst[16,
17-c]pyridine (3k). Yellow solid; m.p. 234–235 °C; 1H NMR (CDCl3,
300 MHz): d 8.55 (s, 1H), 8.37 (s, 1H), 8.09 (dd,J = 8.6 Hz & 1.7 Hz,
1H), 7.85 (d, J = 6.3 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.59 (s, 1H),
7.13–7.19 (m, 2H), 5.45–5.41 (m, 1H), 4.65–4.57 (m, 1H), 3.95 (s,
2.2.1.17. 60-Carbethoxy-cholest[2,3-c]pyridine (3q). Red gum; 1H
NMR (CDCl3, 300 MHz): d 8.54 (s, 1H), 7.75 (s, 1H), 4.38 (q,
J = 7.14 Hz, 2H), 0.96 (t, J = 7.0 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H),

K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
1129
Table 1
Synthesis of steroidal D-ring fused substituted pyridines.
R1
N
R2
Br
NH2
R2
Pd(OAc)2, PPh3, Na2CO3,
CHO
+
+
neutral alumina,
MW (600 W), 10 min
R1
AcO
AcO
3b-k
1a
2b-k
Entry
1
b-Bromovinyl aldehyde (1a)
Alkyne (2b-k)
Pyridine derivatives (% Yield)a
Br
COOMe
MeOOC
N
CHO
AcO
1a
2b
3b (79%)
AcO
AcO
AcO
AcO
2
3
4
5
1a
COOEt
EtOOC
N
2c
3c (75%)
1a
1a
1a
Si
Si
N
2d
3d (76%)
Me
Me
N
2e
3e (72%)
N
3f (68%)
AcO
AcO
2f
6
7
1a
1a
N
3g (75%)
CF3
CF3
2h
N
3h
(71%)
AcO
(continued on next page)

1130
K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
Table 1 (continued)
Entry
8
b-Bromovinyl aldehyde (1a)
Alkyne (2b-k)
Pyridine derivatives (% Yield)a
1a
S
S
N
2i
3i
(76%)
F
AcO
9
1a
F
F
F
N
2j
3j
(74%)
AcO
10
1a
OMe
N
OMe
2k
3k
(74%)
AcO
a
Yield of the isolated product.
0.88 (d, J = 6.4 Hz, 6H), 2.90–0.86 (m, 29H), 0.78 (s, 3H), 0.70 (s,
3H). 13C NMR (CDCl3, 75 MHz) d 165.8, 151.0, 146.2, 136.7, 128.4,
125.0, 61.7, 56.3, 56.2, 53.6, 42.4, 39.5, 36.2, 35.8, 35.5, 35.0,
30.0, 28.2, 28.0, 23.8, 22.8, 22.6, 21.2, 18.7, 14.4, 14.1, 12.0, 11.6.
IR (CHCl3, cmꢀ1): 2928, 2869, 1725, 1255, 772. MS (EI, m/z):
493.3 [M+]. Anal. calcd. for C33H51NO2: C, 80.27; H, 10.41; N,
2.84; Found: C, 80.28; H, 10.48; N, 2.97.
kynes, long reaction time, and low yield of the annulated products
with terminal mono-substituted acetylenes [13].
Miller described the first synthesis of steroidal heterocycles con-
taining a pyridine ring using high temperature and multistep reac-
tion strategy [14] which was followed by three-steps synthesis by
Chelucci and co-workers through pyridoannelation of N,N-dim-
ethylhydrazones with bromoethyl-1,3-dioxolane [15]. Moreover,
Abbiati et al., developed one method to synthesize steroidal pyri-
dines from corresponding carbonyl compounds by using Gold(III)
salts as a catalyst [8]. Recently, Yan et al., reported Cu(II) salt-med-
iated 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 [4]. We also reported synthesis
of steroidal A ring fused chloropyridines by refluxing a mixture of
steroidal enamides with Vilsmeier reagent in DMF [16] as well as Le-
wis acid catalyzed synthesis of steroidal 4,6-diarylpyridines from
steroidal 1,5-dicarbonyl compounds under microwave-irradiation
[11]. However these existing syntheses led to steroidal pyridines
with no diversity at 5,6-position of the pyridine ring. To the best
of our knowledge, there is no report focusing on the synthesis of ste-
roidal 5,6-disubstituted pyridines in the literature.
2.2.1.18.
(3r). Red liquid; 1H NMR (CDCl3, 300 MHz): d 8.51 (s, 1H), 7.30–
6.95 (m, 11H), 6.63 (dd, J = 8.3 Hz 2.9 Hz, 1H), 6.22 (d,
8-Methoxy-1,2-diphenyl-5,6-dihydrobenzo[f]isoquinoline
&
J = 2.7 Hz, 1H), 3.07 (s, 3H), 2.82–2.77 (m, 4H). 13C NMR (CDCl3,
75 MHz) d 157.6, 157.2, 147.1, 141.8, 140.5, 139.1, 133.1, 132.5,
132.4, 131.2, 129.7, 128.6, 127.6, 127.1, 116.1, 113.7, 54.7, 29.7,
27.2. MS (EI, m/z): 363.1 [M+]. IR (CHCl3, cmꢀ1): 2933, 1670,
1462, 1262, 768. Anal. calcd. for C26H21NO: C, 85.92; H, 5.82; N,
3.85; Found: C, 86.07; H, 5.90; N, 3.96.
2.2.1.19. 2,3,4-Triphenylpyridine (3s). Red solid; m.p. 188–190 °C;
1H NMR (CDCl3, 300 MHz): d 8.70 (s, 1H), 7.33 (d, J = 5.0 Hz, 1H),
7.45–6.79 (m, 15H). 13C NMR (CDCl3, 75 MHz) d 158.4, 149.9,
148.2, 140.7, 139.3, 137.7, 134.4, 131.4, 129.9, 129.7, 129.3,
128.4, 128.2, 127.9, 127.7, 127.6, 127.4, 126.7, 123.7. IR (CHCl3,
cmꢀ1): 2959, 1576, 1491, 1074. Anal. calcd. for C23H17N: C,
89.87; H, 5.57; N, 4.56; Found: C, 89.98; H, 5.41; N, 4.40.
The starting material steroidal b-bromovinyl aldehyde 1a was
synthesized from commercially available 3-acetoxy-androst-5-
en-17-one by treatment with Vilsmeier reagent prepared from
PBr3 and DMF [17]. Another steroidal b-bromovinyl aldehyde 1b
was synthesized starting from commercially available 5a-chole-
stan-3-one by reacting with Vilsmeier reagent under refluxing
chloroform [17]. Similarly, other nonsteroidal b-bromovinyl alde-
hydes 1c-d were synthesized by using the same procedure. Then,
a mixture of steroidal b-bromovinyl aldehyde 1a (1.0 equivalent),
benzylamine (1.1 equivalent), dimethylacetylene dicarboxylate
(1.0 equivalent), palladium acetate (5 mol%), triphenylphosphine
(1.0 equivalent), Na2CO3 (3.0 equivalent) and neutral alumina
(200 mg) was irradiated in a closed vessel in a Synthos 3000 micro-
wave reactor at 600 Watt (140 °C and 12 bar) for 10 min which
3. Results and discussion
The palladium and nickel catalyzed annulation processes which
found a range of applications in organic synthesis were used to
synthesize many nitrogen heterocycles including substituted pyri-
dines [12]. Although these methods are highly useful, they have
some disadvantages such as stepwise synthesis of tert-butylimines
followed by coupling reactions of imine intermediates with al-

K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
1131
afforded compound 3b-acetoxy-50,60-dicarbmethoxy-5-en-and-
rost[16,17-c]pyridine (3a, Scheme 1) in excellent yield (81%). It
was observed that the alumina used in this reaction, where the
Pd catalyst was trapped can be reused for another two times with-
out losing the yield of 3a to a great extent (1st recycle, yield of
3a = 73%, 2nd recycle, yield of 3a = 56%). Instead of benzyl amine
Table 2
Synthesis of steroidal A-ring fused substituted pyridines and nonsteroidal pyridines.
R2
NH2
R2
R1
R1
Pd(OAc)2, PPh3, Na2CO3,
Br
+
+
N
neutral alumina,
MW (600 Watt),
10 min
CHO
3l-t
1b-d
2a-b, 2e-f, 2g, 2l
Entry
1
b-Bromovinyl aldehyde (1b-d)
Alkyne
Pyridine derivatives (% Yield)a
COOMe
OHC
N
Br
1b
2b
COOMe
3l
(76%)
2
3
1b
Me
N
N
2e
Me
3m (70%)
1b
2f
3n (66%)
4
1b
N
2g
3o (74%)
5
1b
1b
COOMe
COOMe
N
2a
MeOOC
COOMe
3p (77%)
3q (70%)
6
7
COOMe
2l
N
EtOOC
Br
CHO
MeO
N
1c
MeO
3r (73%)
2f
(continued on next page)

1132
K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
Table 2 (continued)
Entry
8
b-Bromovinyl aldehyde (1b-d)
Alkyne
Pyridine derivatives (% Yield)a
Br
CHO
1d
N
2f
3s (77%)
a
Yield of the isolated product.
R1
X
R2
Pd(0)
Pd(II)
CHO
N
NH2
1
X
R1
R2
4d
PdX
N
Pd
N
X
R1
4a
R1
R2
X
R1
R2
+
N
R2
4c
3
Pd
X
N
4b
Scheme 2. Plausible mechanism of Pd-mediated formation of compound 3.
when we tried some other (Table 1) amine such as tert-butylamine
to perform the reaction of 1a with dimethylacetylene dicarboxyl-
ate we obtained decreased yield (48%) of compound 3a which
could be due the lower boiling point of tert-buylamine. We also ob-
served that reducing the quantity of Pd(OAc)2 from 5 mol% to
2.5 mol% decreased the yield of 3a to 65% while increase of catalyst
loading to 10 mol% did not affect the yield of 3a at all. Although there
is the possibility of formation of product 3a in the three component
reaction in absence of Pd catalyst also, via a Diels Alder reaction be-
tween the benzylimine of b-bromovinyl aldehyde (1a) with alkyne
2a, followed by elimination of benzyl group as benzyl bromide, our
efforts to obtain 3a in absence of the Pd catalyst met with failure (Ta-
ble 2). After having the product 3a in hand it was identified from
spectroscopic and analytical data. The 1H NMR of compound 3a
exhibited a characteristic aromatic singlet signal at d 8.51 and two
singlet signals at d 3.90 and d 3.88 for two ester methyl groups.
The 13C NMR spectrum of 3a showed signals for five aromatic car-
bons of pyridine, two steroidal B-ring olefinic carbons and three es-
ter carbonyls at d 170.5, 167.8, 166.8, 165.2, 164.1, 160.2, 146.2,
140.1, 127.1 and 121.7. The EI mass spectra of compound 3a exhib-
ited molecular ion peaks at m/z 481.2 and 421.2 [M+–60].
Similarly, microwave reactions of steroidal b-bromovinyl alde-
hyde 1a with alkynes 2b-k and steroidal b-bromovinyl aldehyde
1b with alkynes 2a-b, 2e-f, 2g, 2l afforded steroidal D-ring fused
substituted pyridines 3b-k and steroidal A-ring fused substituted
pyridines 3l-q respectively in high yields (Tables 1 and 2). In addi-
tion, the reaction of non-steroidal b-bromovinyl aldehydes 1c and
1d with alkyne 2f yielded non-steroidal pyridine derivatives 3r
(73%) and 3s (77%) under the same reaction condition. It was note-
worthy to observe that in all the reactions of b-bromovinyl alde-
hydes with substituted alkynes and benzylamine under the
above reaction condition afforded only one regioisomer of the pyr-
idine derivative as shown in Tables 1 and 2.
Based on our findings and literature information, we propose a
mechanism for this palladium-catalyzed iminoannulation chemis-
try which is shown in Scheme 2 [18,19]. Oxidative addition of the
vinylic halide group of 1 to Pd(0) and reaction of aldehyde group of
1 with benzylamine produces an organopalladium imine interme-
diate 4a. Literature on similar alkyne annulations chemistry shows
that Pd of 4a adds to the more hindered end of the alkyne to pro-
vide vinylic palladium intermediate 4b which accounts for the reg-
ioselectivity of the final pyridine derivatives [19]. Intramolecular
reaction of vinylic palladium with the benzyl imine of intermediate
4b produces a seven-membered palladacyclic ammonium salt 4c
which on subsequent reductive elimination produces a benzylpy-
ridinium salt 4d and regenerates Pd(0). The fragmentation of the
benzyl group of 4d to relieve the strain resulting from interaction
of benzyl group with the substituent present in the ortho-position
of the pyridine ring leads to the formation of compound 3 as well
as benzyl halide.
In conclusion, a solvent free multi-component reaction condition
for the synthesis steroidal A-, D-ring fused 5,6-disubstituted pyri-
dines and nonsteroidal substituted pyridines was developed using
Pd(OAc)2 as the catalyst under microwave irradiation. A wide vari-
ety of alkyl-, aryl- and ester-substituted alkynes undergo this highly
regioselective reaction to give good yields of pyridine derivatives.
K.S. thanks CSIR, New Delhi for the award of Senior research fel-
lowship (CSIR-SRF). We are grateful to Director, CSIR-NEIST for his
keen interests. This work was financially supported by CSIR-OSDD
(HCP-0001) and CSIR-ORIGIN (CSC 0108) projects.
References
[1] (a) Bull AJ, Mousseau JJ, Pelletier G, Charectte BA. Synthesis of pyridine and
dihydropyridine derivatives by regio- and stereoselective addition to N-
activated pyridines. Chem Rev 2012;112:2642–713;
(b) Wang Q, Wan C, Gu Y, Zhang J, Gao L, Wang Z. A metal-free decarboxylative

K. Shekarrao et al. / Steroids 78 (2013) 1126–1133
1133
cyclization from natural
Chem 2011;13:578–81.
[2] Abdelhalim MM, Kamel EM, Rabie ST, Mohamed NR. Synthesis and biological
evaluation of some nitrogen containing steroidal heterocycles. Steroids
2011;76:78–84.
a
-amino acids to construct pyridine derivatives. Green
(b) Sharma A, Appukkuttanab P, Eycken EV. Microwave-assisted synthesis of
medium-sized heterocycles. Chem Commun 2012;48:1623–37.
[11] Dutta M, Saikia P, Gogoi S, Boruah RC. Microwave-promoted and Lewis acid
catalyzed synthesis of steroidal A- and D-ring fused 4,6-diarylpyridines.
Steroids 2013;78:387–95. and references cited therein.
[3] Huang L-H, Zheng Y-F, Lu Y-Z, Song C-J, Wang C-G, Yu B, Liu H-M. Synthesis
and biological evaluation of novel steroidal[1,2,4][17,16-d]triazolo [1,5-
a]pyrimidines. Steroids 2012;77:710–5.
[4] Yan J-Z, Li J, Rao G-W. One-pot synthesis of new A-ring fused steroidal
heterocycles. Steroids 2007;72:736–9.
[12] (a) For review, see Larock RC. Palladium-catalyzed annulation. J Organomet
Chem 1999;576:111–24.;
(b) Korivi RP, Cheng C-H. Highly efficient synthesis of isoquinolines via nickel-
catalyzed annulation of 2-iodobenzaldimines with alkynes: evidence for dual
pathways of alkyne insertion. Org Lett 2005;23:5179–82.
[5] Hirschmann R, Buchschacher P, Steinberg NG, Fried JH, Ellis R, Kent GJ, et al.
Synthesis and structure of steroidal pregn-4-eno- and 5-pregnano[3,2-
c]pyrazoles. A novel class of potent anti-inflammatory steroids. J Am Chem
Soc 1964;86:1520–7.
[13] Roesch KR, Larock RC. Synthesis of isoquinolines and pyridines by the
palladium- and copper-catalyzed coupling and cyclization of terminal
acetylenes. Org Lett 1999;1:553–6.
[14] Miller TC.
5a-Androstano[3,2-b]pyridines, 5a-androstano[17,16-b]pyridines
[6] Amr AE, Abdalla MM. Anti-inflammatory profile of some synthesized
heterocyclic pyridine and pyridine derivatives fused with steroidal structure.
Bioorg Med Chem 2006;14:4341–52.
and androst-4 and 5-eno[17,16-b]pyridines.
1966;3:338–42.
[15] Chelucci G, Gladiali S, Marchetti MA. Three-step pyridoannelation of carbonyl
compounds. J Heterocyclo Chem 1988;25:1761–5.
J
Heterocyclo Chem
[7] Mohareb
RM,
Al-Omran
F.
Reaction
of
pregnenolone
with
cyanoacetylhydrazine: novel synthesis of hydrazide–hydrazone, pyrazole,
pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations.
Steroids 2012;77:1551–9.
[16] Barthakur MG, Borthakur M, Boruah RC. Convenient preparation of A-ring
fused pyridines from steroidal enamides. Steroids 2008;73:1137–42.
[17] Gogoi S, Shekarrao K, Duarah A, Bora TC, Gogoi S, Boruah RC. A microwave
promoted solvent-free approach to steroidal quinolines and their in vitro
evaluation for antimicrobial activities. Steroids 2012;77:1438–45.
[8] Abbiati G, Arcadi A, Bianchi G, Di Giuseppe S, Marinelli F, Rossi E. Sequential
amination/annulation/aromatization reaction of carbonyl compounds and
propargylamine: a new one-pot approach to functionalized pyridines. J Org
Chem 2003;68:6959–66.
[9] Fischer DS, Allan GM, Bubert C, Vicker N, Smith A, Tutill HJ, et al. E-Ring
modified steroids as novel potent inhibitors of 17b-hydroxy steroid
dehydrogenase type 1. J Med Chem 2005;48:5749–70.
[18] Zhang H, Larock RC. Synthesis of annulated c-carbolines and heteropolycycles
by the Palladium-catalyzed intramolecular annulation of alkynes. J Org Chem
2003;68:5132–8.
[19] Roesch KR, Zhang H, Larock RC. Synthesis of isoquinolines and pyridines by the
Palladium-catalyzed iminoannulation of internal alkynes.
2001;66:8042–51. and references cited therein.
J Org Chem
[10] (a) For general references on green chemistry, see: Anastas PT, Warner JC.
Green chemistry: theory and practice; Oxford University Press: Oxford, 1998.;