An efficient route for annulation of pyrimidines to steroids and non-steroids via a base catalyzed one-pot three component reaction

Article abstract of DOI:10.1016/j.steroids.2014.06.015

A facile strategy for the synthesis of steroidal A- and D-ring fused pyrimidines has been accomplished in high yields via a one-pot reaction of steroidal ketones, aromatic aldehydes and amidine derivatives in presence of potassium tert-butoxide in refluxi

Full text of DOI:10.1016/j.steroids.2014.06.015

Steroids 88 (2014) 1–6
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
An efficient route for annulation of pyrimidines to steroids
and non-steroids via a base catalyzed one-pot three component reaction
⇑
⇑
Pallabi Saikia, Shyamalee Gogoi, Sanjib Gogoi , Romesh C. Boruah
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile strategy for the synthesis of steroidal A- and D-ring fused pyrimidines has been accomplished in
high yields via a one-pot reaction of steroidal ketones, aromatic aldehydes and amidine derivatives in
presence of potassium tert-butoxide in refluxing ethanol. The generality of the reaction was also
extended to non-steroidal ketones.
Received 26 February 2014
Received in revised form 5 June 2014
Accepted 17 June 2014
Available online 25 June 2014
Ó 2014 Elsevier Inc. All rights reserved.
Keywords:
Pyrimidine
Heterosteroid
Potassium tert-butoxide
Amidine
Multicomponent reaction
1. Introduction
significant molecules. For instance, in Fig. 1 the pyrimidino andro-
stane derivatives I have showed promising antibacterial activity [8]
Pyrimidines represent a very important class of aza heterocyclic
compounds. They occur as main subunit in a variety of natural
products including vitamins, coenzymes, nucleic acids and in sev-
eral therapeutically important synthetic molecules [1]. Pharmaco-
phores based upon the pyrimidine structure finds immense
importance in modern day medicinal chemistry as they possess
numerous biological activities, such as antiinflammatory, antima-
larial, anti-hypertensive, antibacterial, antiasthmatic, antiprotozo-
an, antituberculosis, anti HIV and anticancer activities [2–4]. On
the other hand, heterosteroids, particularly the azasteroids have
also emerged as pharmaceutically important molecules due to
their inherent biological properties [5–7] and hence considerable
attention has been paid by medicinal chemists to annelate steroid
moiety with isoxazole, pyrazole, pyridine and pyrrole rings using
various synthetic methods. However, methods to annelate pyrimi-
dines to steroidal moiety are still scarce [6,7]. This prompted us to
design new reaction strategies to fuse pyrimidine nucleus at the 2,
3- and 16, 17-positions of the steroid core.
whereas compound II has showed potent antineuroinflammatory
activity [9].
In the present scenario of organic synthesis, multicomponent
reactions (MCRs) are tremendously gaining popularity due to their
features like one-pot method, atom economy, high product yields,
manipulative simplicity and targeted synthesis in a much shorter
time [10]. Keeping the above facts in mind, recently our research
group has reported some novel microwave-assisted routes for
the synthesis of steroidal pyrimidines utilizing steroidal b-formyl
enamides [7], 2-hydroxymethylidene-3-ketosteroid [11] and
b-halo-a,b-unsaturated aldehydes [12] as versatile synthons. To
the best of our knowledge, there is no report focusing on the syn-
thesis of steroidal 2,4-diarylpyrimidines in the literature. In contin-
uation of our ongoing research interests in designing novel
methodologies for the synthesis of azasteroids [13], herein, we
report a yet another efficient synthesis of A- and D-ring fused ste-
roidal disubstituted pyrimidines by a base catalyzed, one-pot,
three component reaction of ketosteroids, aldehydes and amidine
derivatives under thermal conditions (Scheme 1).
Fig. 1 depicts some therapeutically important compounds bear-
ing pyrimidine subunit such as the antibacterial Bacimethrin,
dopamine receptor stimulant Pirebidil and the COX-2 inhibitor
Epirizole. Apart from non steroidal pyrimidines, some steroidal
pyrimidine derivatives have also come up recently as biologically
2. Experimental
2.1. General remarks
⇑
Corresponding authors. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail addresses: skgogoi1@gmail.com (S. Gogoi), rc_boruah@yahoo.co.in
Melting points were measured with a Buchi B-540 melting
point apparatus and are uncorrected. IR spectra were recorded on
(R.C. Boruah).
http://dx.doi.org/10.1016/j.steroids.2014.06.015
0039-128X/Ó 2014 Elsevier Inc. All rights reserved.

2
P. Saikia et al. / Steroids 88 (2014) 1–6
2H). 13C NMR (CDCl3, 75 MHz): 14.1, 17.0, 19.5, 20.6, 22.7, 29.0,
NH2
N
N
29.2, 29.4, 30.8, 31.0, 31.4, 31.6, 31.9, 33.2, 36.8, 37.2, 42.3, 45.9,
50.7, 55.4, 55.8, 71.6, 113.9, 121.0, 127.3, 128.3, 128.7, 130.1,
130.3, 130.5, 138.4, 141.3, 161.1. MS (ESI, m/z) = 507 [M+1]+. Anal.
calcd. for C34H38N2O2: C, 80.60; H, 7.56; N, 5.53; Found: C, 80.68; H,
7.71; N, 5.50.
N
N
O
O
HO
N
N
O
N
N
N
N
O
Epirizole
(COX-2 inhibitor)
Pirebidil
Bacimethrin
(Antibacterial)
(Dopamine receptor stimulant)
X
2.2.1.2. 3b-Hydroxy-20-amino-40-(p-methoxyphenyl)-androst-[16,17-
e]pyrimidine (4b). Yellow solid; m.p. 155–158 °C; Rf: 0.4
(EtOAc/Hexane = 3:7); [a]
N
NH
N
HN
NH
S
D = ꢁ87 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1):
O
3384, 2933, 1602, 1512, 1377, 1254, 1033, 755. 1H NMR (CDCl3,
300 MHz): d 0.98 (s, 3H), 1.08 (s, 3H), 0.85–2.95 (m, 17H), 3.45–
3.58 (m, 1H), 3.85 (s, 3H), 5.35–5.45 (m, 1H), 6.94 (d, J = 8.7 Hz,
2H), 7.41 (s, 2H), 7.51 (d, J = 8.7 Hz, 2H). 13C NMR (CDCl3,
75 MHz): 14.3, 16.8, 19.4, 20.5, 30.1, 30.7, 30.9, 31.1, 31.2, 31.6,
32.8, 36.7, 37.1, 42.2, 46.0, 47.3, 50.5, 55.4, 55.5, 71.5,
114.1,114.2, 120.8, 128.2, 130.2, 132.9, 141.3, 161.4. MS (ESI, m/
z) = 446 [M+1]+. Anal. calcd. for C28H35N3O2: C, 75.47; H, 7.92; N,
9.43; Found: C, 75.26; H, 7.72; N, 9.56.
Ph
HO
HO
H
X = O, S
H
II
I
(Antineuroinflammatory agent)
(Antibacterial)
Fig. 1. Some therapeutically important molecules having pyrimidine subunit.
Elmer FT-IR-2000 spectrometer on a thin film using chloroform.
NMR spectra were recorded on Bruker Avance DPX 300 MHz FT-
NMR spectrometer or Bruker Avance III 500 MHz FT-NMR spec-
trometer using tetramethylsilane (TMS) as an internal standard.
Mass spectra were recorded on Trace DSQ GCMS instrument or
Bruker ESQUIRE 3000 LCMS instrument. All the commercially
available reagents were used as received. All experiments were
monitored by thin layer chromatography (TLC) using pre-coated
silica gel plates (Merck). Column chromatography was performed
on silica gel (100–200 mesh, Merck Chemicals). Elemental analysis
‘Found values’ for carbon, hydrogen and nitrogen are within 0.4% of
the ‘Calcd values’ for the proposed formula.
2.2.1.3. 3b-Hydroxy-20-(phenyl)-40-(m-bromophenyl)-androst-[16,17-
e]pyrimidine (4c). Yellow solid; m.p. 127–129 °C, Rf: 0.7
(EtOAc/Hexane = 3:7);
[
a
]
D = ꢁ109 (c 0.1, CHCl3); IR (CHCl3,
cmꢁ1): 3392, 2927, 1547, 1376, 1053, 771. 1H NMR (CDCl3,
300 MHz): d 1.13 (s, 3H), 1.15 (s, 3H), 0.85–2.90 (m, 17H), 3.45–
3.58 (m, 1H), 5.32–5.42 (m, 1H), 7.48 (m, 3H), 7.92 (d, J = 7.7 Hz,
2H), 8.04 (d, J = 6.5 Hz, 2H), 8.20 (s, 1H), 8.56 (d, J = 9.01 Hz, 1H).
13C NMR (CDCl3, 75 MHz): 17.0, 19.5, 20.5, 29.7, 30.6, 30.9, 31.4,
31.6, 33.2, 36.8, 37.2, 42.3, 45.9, 50.7, 55.8, 71.6, 120.9, 122.8,
128.3, 128.4, 128.5, 128.8, 129.9, 130.3, 131.7, 138.2, 140.1,
141.3, 163.0. MS (ESI, m/z) = 555 [M+1]+. Anal. calcd. for C33H35-
BrN2O: C, 71.34; H, 6.35; N, 5.04; Found: C, 71.61; H, 6.31; N, 5.19.
2.2. Chemical synthesis
2.2.1. General procedure for the synthesis of steroidal and non-
steroidal pyrimidines
2.2.1.4. 3b-Hydroxy-20-amino-40-(m-bromophenyl)-androst-[16,17-
e]pyrimidine (4d). Yellow solid; m.p. 127–130 °C; Rf: 0.4
A solution of ketone (1, 1.0 mmol) and aldehyde (2, 1.0 mmol)
in ethanol (10 mL) was refluxed for half an hour in presence of
potassium tertiary butoxide (2.0 mmol) as base. After 30 min, ami-
dine hydrochloride (3, 1.0 mmol) was added slowly to the reaction
mixture and then the reaction mixture was allowed to reflux for
another 5 h. On completion of the reaction (vide TLC), the solvent
was removed from the reaction mixture, treated with water
(50 mL) and extracted with dichloromethane (30 mL ꢀ 3). The
organic portion was washed with water, dried over anhydrous
sodium sulfate and the solvent was removed in vacuo to obtain
the crude product. Finally, column chromatographic purification
of the crude mixture using EtOAc/hexane (2:3) as the eluant over
silica gel afforded the purified product 4.
(EtOAc/Hexane = 3:7); [
a
]
D = ꢁ80 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1):
3333, 2932, 1561, 1453, 1376, 1041, 755. 1H NMR (CDCl3,
300 MHz): d 1.10 (s, 3H), 1.12 (s, 3H), 0.85–2.80 (m, 17H), 3.50–
3.60 (m, 1H), 5.35–5.45 (m, 1H), 7.36 (s, 2H), 7.40 (m, 1H), 7.62
(d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.9 (s, 1H). 13C NMR
(CDCl3, 75 MHz): 16.8, 19.4, 20.4, 29.6, 30.7, 30.9, 32.8, 36.7,
37.1, 39.8, 40.0, 40.3, 40.6, 42.2, 45.9, 50.4, 55.5, 71.2, 120.5,
122.7, 127.1, 130.1, 131.4, 133.1, 141.5, 161.0. MS (ESI, m/
z) = 495 [M+1]+. Anal. calcd. For C27H32BrN3O: C, 65.58; H, 6.52;
N, 8.50; Found: C, 65.74; H, 6.50; N, 8.36.
2.2.1.5. 3b-Hydroxy-20-phenyl-40-tolyl-androst-[16,17-e]pyrimidine
(4e). Yellow solid; m.p. 127–130 °C; Rf: 0.6 (EtOAc/Hexane = 3:7);
2.2.1.1.
3b-Hydroxy-20-(phenyl)-40-(p-methoxyphenyl)-androst-
[
a
]
D = ꢁ69 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1): 3397, 2926, 1547,
[16,17-e]pyrimidine (4a). Yellow solid; m.p. 151–153 °C; Rf: 0.6
1375, 755. 1H NMR (CDCl3, 300 MHz): d 1.13 (s, 3H), 1.15 (s, 3H),
0.80–2.95 (m, 20H), 3.48–3.60 (m, 1H), 5.35–5.45 (m, 1H), 7.07–
7.49 (m, 5H), 7.94 (d, J = 7.9 Hz, 2H), 8.57 (d, J = 7.4 Hz, 2H). 13C
NMR (CDCl3, 75 MHz): 14.1, 14.3, 17.0, 19.5, 20.6, 21.5, 29.4,
29.7, 30.9, 31.2, 31.9, 36.7, 42.2, 45.9, 47.3, 49.9, 50.7, 55.9, 71.6,
121.0, 128.3, 128.7, 129.5, 130.4, 132.8, 133.2, 134.9, 139.6,
(EtOAc/Hexane = 3:7); [
a
]
D = ꢁ84 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1):
3383, 2924, 1585, 1509, 1376, 1251, 1038, 770. 1H NMR (CDCl3,
300 MHz): d 1.13 (s, 3H), 1.15 (s, 3H), 0.80–2.95 (m, 17H), 3.45–
3.60 (m, 1H), 3.90 (s, 3H), 5.35–5.42 (m, 1H), 7.05 (d, J = 8.7 Hz,
2H), 7.46–7.50 (m, 3H), 8.05 (d, J = 8.7 Hz, 2H), 8.57 (d, J = 7.9 Hz,
O
N
N
CHO
NH
NH2.HCl
i
+
+
HO
HO
OMe
2a
OMe
4a
1a
3a
Scheme 1. Reagents and conditions: (i) KOtBu, EtOH, reflux, 5.5 h.

P. Saikia et al. / Steroids 88 (2014) 1–6
3
141.1, 161.3. MS (ESI, m/z) = 491 [M+1]+. Anal. calcd. For
34H38N2O: C, 83.22; H, 7.81; N, 5.71; Found: C, 83.37; H, 7.68;
N, 5.85.
75 MHz): 17.4, 26.2, 27.5, 29.6, 30.4, 33.2, 37.6, 44.4, 46.4, 54.8,
55.2, 111.6, 113.9, 122.9, 126.2, 127.3, 128.6, 129.7, 130.1, 131.7,
132.2, 132.8, 136.4, 136.7, 137.7, 139.9, 157.6, 162.1. MS (ESI,
m/z) = 585 [M + 1]+. Anal. calcd. For C33H30BrClN2O: C, 67.64; H,
5.16; N, 4.78; Found C, 67.74; H, 5.19; N, 4.91.
C
2.2.1.6. 3b-Hydroxy-20-phenyl-40-(p-chlorophenyl)-androst-[16,17-e]-
pyrimidine (4f). White solid; m.p. 126–129 °C; Rf: 0.5 (EtOAc/Hex-
D = ꢁ80 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1): 3387, 2929,
2.2.1.11. 20,40-Diphenyl-5
solid; m.p. 189 °C; Rf: 0.8 (EtOAc/Hexane = 3:7); [
a
-cholest[2,3-e]pyrimidine (4k). Yellow
D = +30 (c 0.1,
ane = 3:7); [
a
]
1548, 1491, 1376, 1043, 771. 1H NMR (CDCl3, 300 MHz): d 0.85–
2.87 (m, 25H), 3.50–3.54 (m, 1H), 5.35–5.45 (m, 1H), 7.12 (d,
J = 7.5 Hz, 1H), 7.46–7.53 (m, 2H), 7.99 (d, J = 8.7 Hz, 2H), 8.54–
8.57 (d, J = 7.7 Hz, 2H). 13C NMR (CDCl3, 75 MHz): 17.0, 19.4,
20.6, 22.7, 29.3, 29.7, 30.9, 31.5, 31.9, 32.5, 36.8, 37.1, 42.2, 45.9,
49.8, 50.3, 55.5, 71.7, 120.8, 121.3, 128.3, 128.5, 128.7, 129.7,
130.1, 130.2, 130.4, 131.3, 140.6, 140.8, 140.3, 146.7, 161.0. MS
(ESI, m/z) = 511 [M + 1]+. Anal. calcd. For C33H35ClN2O: C, 77.55;
H, 6.90; N, 5.48; Found: C, 77.82; H, 6.95; N, 5.52.
a]
CHCl3); IR (CHCl3, cmꢁ1): 2929, 1740, 1544, 1445, 1397, 1242,
1027, 909. 1H NMR (CDCl3, 300 MHz): d 0.64 (s, 3H), 0.72 (s, 3H),
0.60–2.80 (m, 38H), 7.10–7.49 (m, 6H), 7.66 (d, J = 5.1 Hz, 2H),
8.46 (d, J = 4.8 Hz, 2H). 13C NMR (CDCl3, 75 MHz): 11.4, 11.8,
18.5, 21.2, 22.6, 22.7, 23.7, 24.1, 27.9, 28.1, 28.2, 29.6, 31.4, 35.1,
35.2, 35.3, 35.6, 35.9, 39.2, 39.4, 42.2, 42.3, 42.5, 53.5, 56.2,
124.2, 125.5, 127.7, 128.0, 128.2, 128.8, 128.9, 129.0, 129.2,
129.8, 138.0, 138.6, 161.1, 165.4, 165.9. MS (ESI, m/z) = 575
[M + 1]+. Anal. calcd. For C41H54N2: C, 85.66; H, 9.47; N, 4.87; Found
C, 85.74; H, 9.40; N, 4.69.
2.2.1.7. 3b-Hydroxy-20-(p-chlorophenyl)-40-(tolyl)-androst-[16,17-e]-
pyrimidine (4g). Yellow solid; m.p. 74–76 °C; Rf: 0.6 (EtOAc/Hex-
ane = 3:7); [a]
D = -91 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1): 3397, 2926,
2.2.1.12. 20-Phenyl-40-(p-chlorophenyl)-5
(4l). Yellow solid; m.p. 209 °C; Rf: 0.8 (EtOAc/Hexane = 3:7);
D = +67 (c 0.1, CHCl3); IR (CHCl3, cmꢁ1): 2928, 1538, 1445,
a-cholest[2,3-e]pyrimidine
1621, 1375, 1019, 772. 1H NMR (CDCl3, 300 MHz): d 1.07 (s, 3H),
1.15 (s, 3H), 0.85–2.95 (m, 20H), 3.45–3.55 (m, 1H), 5.35–5.45
(m, 1H), 7.2 (d, J = 7.9 Hz, 1H) 7.34 (d, J = 7.9 Hz, 1H), 7.45 (d,
J = 8.2 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 8.53 (d, J = 7.4 Hz, 2H). 13C
NMR (CDCl3, 75 MHz): 14.3, 19.5, 20.4, 21.5, 29.4, 29.7, 30.8,
30.9, 31.2, 31.6, 36.7, 37.1, 42.2, 47.3, 49.9, 50.4, 71.6, 120.8,
128.6, 128.8, 129.4, 129.5, 129.9, 130.4, 139.6, 140.6, 141.2,
141.3, 157.7, 161.9. MS (ESI, m/z) = 525 [M + 1]+. Anal. calcd. For
[a]
1395, 1090, 910. 1H NMR (CDCl3, 300 MHz): d 0.64 (s, 3H), 0.72
(s, 3H), 0.60–2.80 (m, 38H), 7.40–7.51 (m, 5H), 7.64 (d, J = 4.5 Hz,
2H), 8.43 (d, J = 4.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz): 11.4, 11.8,
18.6, 21.2, 22.5, 22.6, 22.7, 23.7, 24.1, 27.9, 28.1, 28.4, 29.6, 31.4,
35.2, 35.4, 35.7, 36.0, 36.6, 39.4, 39.8, 40.6, 41.1, 42.3, 53.5, 56.2,
124.7, 128.1, 128.3, 128.5, 128.6, 129.0, 129.1, 129.4, 136.2,
138.3, 160.0, 165.9. MS (ESI, m/z) = 609 [M + 1]+. Anal. calcd. For
C34H37ClN2O: C, 77.77; H, 7.10; N, 5.33; Found C, 77.54; H, 7.27;
N, 5.60.
C41H53ClN2: C, 80.82; H, 8.77; N, 4.60; Found C, 80.91; H, 8.73; N,
4.67.
2.2.1.8.
3-Methoxy-20-phenyl-40-(p-chlorophenyl)-estra-1,3,5-tri-
ene(10)-[16,17-e]pyrimidine (4h). Yellow solid; m.p. 79–82 °C; Rf:
0.8 (EtOAc/Hexane = 3:7); [ D = +75 (c 0.1, CHCl3); IR (CHCl3,
2.2.1.13.
8-Methoxy-4-phenyl-5,6-dihydro-benzo[h]quinazolin-2-
a]
amine (4m). Brown solid; m.p. 73–75 °C; Rf: 0.4 (EtOAc/Hex-
ane = 3:7); IR (CHCl3, cmꢁ1): 3312, 3189, 2936, 1606, 1546, 1250,
773. 1H NMR (CDCl3, 300 MHz): d 2.80–2.88 (m, 4H), 3.87 (s, 3H),
5.35–5.45 (m, 2H), 6.75 (s, 1H), 6.90 (d, J = 6.2 Hz, 1H), 7.40–7.60
(m, 2H), 7.56 (d, J = 4.8 Hz, 2H), 8.24 (d, J = 8.6 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): 24.1, 28.7, 55.4, 112.7, 112.9, 115.2, 125.9,
127.6, 128.3, 128.6, 129.0, 138.1, 141.7, 161.2, 161.8, 164.7. MS
(EI, m/z) = 303 [M]+. Anal. calcd. For C19H17N3O: C, 75.23; H, 5.65;
N, 13.85; Found C, 75.47; H, 5.47; N, 13.97.
cmꢁ1): 2929, 1549, 1498, 1377, 1255, 1047, 733. 1H NMR (CDCl3,
300 MHz): d 1.17 (s, 3H), 0.85–3.00 (m, 13H), 3.80 (s, 3H), 6.67
(s, 1H), 6.74 (d, J = 8.7 Hz, 2H), 7.48–7.52 (m, J = 7.2 Hz, 5H), 8.05
(d, J = 6.4 Hz, 2H), 8.60 (d, J = 6.0 Hz, 2H). 13C NMR (CDCl3,
75 MHz): 17.4, 26.2, 27.5, 29.7, 30.5, 33.3, 37.7, 44.4, 46.4, 54.9,
55.2, 111.6, 113.9, 126.2, 128.3, 128.5, 128.8, 130.1, 132.4, 137.4,
137.7, 137.9, 138.1, 138.5, 157.6, 159.2, 162.9. MS (ESI,
m/z) = 507 [M + 1]+. Anal. calcd. For C33H31ClN2O: C, 78.17; H,
6.16; N, 5.52; Found C, 78.03; H, 6.14; N, 5.70.
2.2.1.14.
4-(p-Methoxyphenyl)-5H-chromeno[3,4-e]pyrimidin-2-
2.2.1.9. 3-Methoxy-20-phenyl-40-(3’’,4’’-dichlorophenyl)-estra-1,3,5-
amine (4n). Yellow solid; m.p. 76–79 °C; Rf: 0.3 (EtOAc/Hex-
ane = 3:7); IR (CHCl3, cmꢁ1): 3395, 2945, 1665, 1602, 1567, 1509,
1453, 1369, 1247, 771. 1H NMR (CDCl3, 300 MHz): d 3.80 (s, 3H),
3.99 (s, 2H), 5.60 (s, 2H), 6.85 (d, J = 8.3 Hz, 2H), 7.02 (d,
J = 8.9 Hz, 2H), 7.22–7.35 (m, 2H), 8.18 (d, J = 8.7 Hz, 2H). 13C
NMR (CDCl3, 75 MHz): 35.1, 55.3, 114.3, 118.1, 119.0, 120.8,
129.5, 129.9, 131.5, 132.2, 158.3, 159.1, 162.7, 164.2. MS (EI,
m/z) = 305 [M]+. Anal. calcd. For C18H15N3O2: C, 70.81; H, 4.95; N,
13.76; Found C, 70.66; H, 4.78; N, 13.90.
triene(10)-[16,17-e] pyrimidine (4i). Yellow solid; m.p. 86–89 °C;
Rf: 0.8 (EtOAc/Hexane = 3:7); [a]D = + 72 (c 0.1, CHCl3); IR (CHCl3,
cmꢁ1): 2928, 1549, 1453, 1377, 1055, 758. 1H NMR (CDCl3,
300 MHz): d 1.14 (s, 3H), 0.85–2.95 (m, 11H), 3.80 (s, 3H), 6.67
(d, J = 2.2 Hz, 2H), 6.75 (d, J = 6.1 Hz, 2H), 7.20–7.30 (m, 1H), 7.50
(d, J = 6.8 Hz, 1H), 7.60 (d, J = 5.94 Hz, 1H), 7.88 (d, J = 6.6 Hz, 2H),
8.17 (s, 2H), 8.56 (d, J = 2.4 Hz, 2H). 13C NMR (CDCl3, 75 MHz):
19.1, 19.2, 23.4, 24.2, 24.6, 24.7, 28.4, 29.7, 33.4, 36.6, 36.8, 37.3,
44.4, 54.8, 55.2, 61.4, 61.6, 90.2, 92.1, 100.8, 111.6, 113.9, 126.2,
128.1, 128.3, 128.4, 132.2, 132.9, 137.6, 138.0, 157.6. MS (ESI,
m/z) = 541 [M + 1]+. Anal. calcd. For C33H30Cl2N2O: C, 73.19; H,
5.58; N, 5.17; Found C, 73.31; H, 5.29; N, 5.12.
3. Results and discussions
Initially, we selected ketone 1a, aldehyde 2a and amidine 3a as
model substrates for the base induced multicomponent reaction
for the synthesis of pyrimidine derivative 4a (Scheme 1). Refluxing
a mixture of ketone 1a and aldehyde 2a in ethanol in presence of
base potassium tertiary butoxide for half an hour followed by addi-
tion of amidine 3a to the reaction mixture and refluxing the reac-
tion mixture for another five hours furnished pyrimidine derivative
4a in 75% yield. The product 4a was identified and characterized by
1H NMR, 13C NMR and mass spectral data. The 1H NMR of com-
2.2.1.10. 3-Methoxy-20-(p-chlorophenyl)-40-(m-bromophenyl)-estra-
1,3,5-triene(10)-[16,17-e]pyrimidine (4j). Yellow solid; m.p. 78–
81 °C; Rf: 0.8 (EtOAc/Hexane = 3:7); [a]D = + 65 (c 0.1, CHCl3); IR
(CHCl3, cmꢁ1): 2928, 1546, 1499, 1376, 1219, 1014, 772. 1H NMR
(CDCl3, 300 MHz): d 1.14 (s, 3H), 0.85–2.95 (m, 13H), 3.77 (s,
3H), 6.66 (s, 1H), 6.74 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 4.6 Hz, 1H),
7.45 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 7.7 Hz,
1H), 8.18 (s, 1H), 8.54 (d, J = 8.4 Hz, 2H). 13C NMR (CDCl3,

4
P. Saikia et al. / Steroids 88 (2014) 1–6
pound 4a exhibited three characteristic aromatic doublet signals at
d 7.05 (J = 8.7 Hz, 2H), 8.05 (J = 8.7 Hz, 2H), 8.57 (J = 7.9 Hz, 2H) and
a multiplet at d 7.46–7.50 (3H). The 1H NMR also showed a singlet
signal at d 3.90 (s, 3H) for the methoxy protons. The 13C NMR spec-
trum of 4a showed eleven signals in the aromatic region at d 113.9,
120.9, 127.3, 128.3, 128.7, 130.1, 130.3, 130.5, 138.4, 141.3 and
161.1. The ESI mass spectra showed a sharp [M+1]+ molecular
ion peak at m/z = 507 which finally confirmed the formation of
compound 4a.
pyrimidines 4c, 4e–f in 70–74% yields (entries 5–6, Table 1). We
observed that this reaction was also effective with other amidine
derivative and amidine analog. For example, the reaction of ketone
1a, aldehyde 2c and 4-chlorobenzamidine hydrochloride (3c) pro-
vided 70% yield of steroidal pyrimidine derivative 4g (entry 7,
Table 1), whereas ketone 1a, aldehyde 2a and guanidine hydro-
chloride (3b) provided 74% yield of pyrimidine derivative 4b (entry
2, Table 1). Furthermore, we performed the reaction of 3-methyl
ether derivative of estrone (1b) with aldehydes 2b, 2d–e and ami-
dine derivatives 3a–c under the above reaction conditions to
obtain steroidal pyrimidines 4h–j in 71–75% yields (entries 8–10,
Table 1). Similarly, reaction of steroidal A-ring ketone cholestanone
(1c), on reaction with aldehydes 2d, 2f and benzamidine hydro-
chloride (3a) afforded pyrimidines fused in A-ring of steroid (4k–
l, 68–70%, entries 11–12, Table 1). To extend the scope of the reac-
tion, we further employed our reaction strategy to nonsteroidal
ketone 1d, which on reaction with aldehyde 2f and guanidine
hydrochloride (3b) provided nonsteroidal pyrimidine 4m in 80%
Comparative study on different based such as KOtBu, NaOMe,
NaH and KOH showed that KOtBu was the best base to perform this
multicomponent reaction to afford the pyrimidine derivative 4a.
When we used NaOMe, NaH and KOH in place of KOtBu, we
obtained 35%, 41% and 27% yield of 4a, respectively, for the above
multicomponent reaction. With the optimized reaction conditions
in hand, we then explored the feasibility of this synthetic route by
carrying out the reactions of ketone 1a, amidine 3a and different
electron rich/poor aldehydes (2b–d) which afforded steroidal
Table 1
Steroidal and non steroidal pyrimidines.
Entry
1
Ketone
Aldehyde
Amidine
NH
NH2.HCl
Product
Yielda (%)
75
O
CHO
H
N
H
N
3a
OMe
2a
HO
H
H
1a
H
H
HO
HO
4a
OMe
2
3
1a
2a
74
72
NH
NH2.HCl
3b
NH2
N
N
H2N
4b
OMe
1a
3a
CHO
N
Br
N
2b
H
H
Br
H
H
HO
HO
4c
4
5
1a
1a
2b
3b
3a
72
70
NH2
N
N
Br
4d
CHO
N
N
Me
2c
H
H
HO
4e
Me
6
1a
3a
73
CHO
N
N
Cl
2d
H
H
HO
4f
Cl

P. Saikia et al. / Steroids 88 (2014) 1–6
5
Table 1 (continued)
Entry
7
Ketone
Aldehyde
Amidine
Product
Yielda (%)
70
1a
2c
NH
Cl
NH2
.HCl
Cl
3c
N
N
H
H
HO
4g
Me
8
2d
3a
75
71
71
O
H
N
H
N
MeO
H
1b
H
MeO
4h
Cl
CHO
9
1b
3a
Cl
Cl
2e
N
N
H
Cl
H
MeO
4i
Cl
10
1b
2b
3c
Cl
N
N
H
Br
H
MeO
4j
11
12
3a
3a
70
68
CHO
H
H
H
H
2f
N
H
H
N
O
H
H
4k
1c
1c
2d
Cl
H
H
N
H
N
H
4l
13
14
a
2f
3b
3b
80
82
O
NH2
N
N
MeO
1d
MeO
4m
2a
O
NH2
N
N
O
O
1e
OMe
4n
Yield of the isolated product.
yield (entry 13, Table 1). Similar reaction of nonsteroidal ketone 1e
with aldehyde 2a and guanidine hydrochloride (3b) provided non-
steroidal pyrimidine 4n in 82% yield (entry 14, Table 1).
A probable mechanism for the formation of aryl substituted
pyrimidine derivative 4a is shown in Scheme 2. Initially, ketone
1a undergoes base catalyzed condensation with aldehyde 2a to
give intermediate 16-benzylidene ketone 5a. The intermediate 5a
then reacts with benzamidine 3a to produce the imine intermedi-
ate 5b. Deprotonation of the imine under basic reaction conditions
followed by intramolecular aza-Michael addition and aromatiza-
tion of the Michael adduct afforded the desired product 4a. To
see the validity of the mechanism we isolated the intermediate

6
P. Saikia et al. / Steroids 88 (2014) 1–6
CHO
O
O
N
NH
NH2.HCl
3a
NH
H
H
Ph
H
OMe
2a
H
H
H
KOtBu
HO
HO
HO
5a
1a
5b
OMe
OMe
H
N
N
N
N
H
H
H
KOtBu
Aromatization
H
HO
HO
4a
OMe
5c
OMe
Scheme 2. Proposed mechanism for the formation of steroidal pyrimidine 4a.
5a by refluxing a mixture of ketone 1a, aldehyde 2a and KOtBu
for half an hour. This intermediate 5a on reaction with amidine
hydrochloride 3a under reflux condition for four hours provided
the same steroidal pyrimidine 4a.
In conclusion, we have developed a new route towards a series
of substituted pyrimidines via a one pot multi component strategy
employing various steroidal and non-steroidal ketones as starting
molecules. Our methodology is simple, efficient and high yielding,
thereby making a new entry into the field of pyrimidine chemistry.
Further work on biological screening of these pyrimido products
are in progress with an expectation to find a unique place in the
field of medicinal chemistry in the near future.
[4] Botta M, Occhionero F, Nicoletti R, Mastromarino P, Conti C, Magrini M, et al.
Synthesis and biological evaluation of 2-methoxy- and 2-methylthio-6-[(2b-
alkylamino)ethyl]-4(3H)-pyrimidinones with anti-rubella virus activity.
Bioorg Med Chem 1999;7:1925–31.
[5] (a) Clinton RO, Manson AJ, Stonner FW, Beyler AL, Potts GO, Arnold A.
Steroidal[3,2-c]pyrazoles. J Am Chem Soc 1959;81:1513–4;
(b) Tapolcsanyi P, Woelfling J, Falkay G, Marki A, Minorics R, Schneider G.
Synthesis and receptor-binding examination of 16-hydroxymethyl-3,17-
estradiol. Steroids 2002;67:371–7;
(c) Hirschmann R, Steinberg NG, Buschacher P, Fried JH, Kent GJ, Tishler M.
Synthesis and structure of steroidal 4-pregeno[3,2-c]pyrazoles. A novel class of
potent anti-inflammatory steroids. J Am Chem Soc 1963;85:120–2;
(d) Abdelhalim MM, Kamel EM, Rabie ST, Mohamed NR. Synthesis and
biological evaluation of some nitrogen containing steroidal heterocycles.
Steroids 2011;76:78–84.
[6] (a) Matsumoto T, Watanabe M, Mataka S, Thiemann T. Estrano[17,16-
e]pyrimidine-peptide conjugates. Steroids 2003;68:751–7;
(b) Ackerman JH, Potts GO, Beyler AL, Clinton RO. Steroidal heterocycles X1.
Acknowledgements
Steroidal [3,2-d]pyrimidines and related compounds.
1964;7:238–40;
J
Med Chem
We acknowledge CSIR, New Delhi, for financially supporting us
with CSIR-OSDD (HCP-0001), CSIR-ACT (CSC-0301) and CSIR-ORI-
GIN (CSC-0108) projects. One of us (P.S.) thanks, UGC, New Delhi,
for the award of Junior Research Fellowship. We are grateful to
the Director, CSIR-NEIST, for his keen interests and for providing
us with necessary laboratory facilities.
(c) Forgo P, Vincze I. Syntheses and advanced NMR structure determination of
androsteno-[17,16-d]-pyrimidine derivatives. Steroids 2002;67:749–56;
(d) Laitonjam WS, Rajkumar TS, Chingakham BS. Synthesis of some A and D-
ring fused steroidal pyrazoles, isoxazoles and pyrimidines. Steroids
2002;67:203–9.
[7] Barthakur MG, Borthakur M, Devi P, Saikia CJ, Saikia A, Boruah RC. A novel and
efficient Lewis acid catalysed preparation of pyrimidines: microwave
promoted reaction of urea and b-formyl enamides. Synlett 2007:223–6.
[8] Abdelhalim MM, El-Saidi MMT, Rabie ST, Elmegeeda GA. Synthesis of novel
steroidal heterocyclic derivatives as antibacterial agents. Steroids
2007;72:459–65.
Appendix A. Supplementary data
[9] Mohamed NR, Abdelhalim MM, Khadrawy YA, Elmegeed GA, Abdel-Salam
OME. One-pot three-component synthesis of novel heterocyclic steroids as a
central antioxidant and antiinflammatory agents. Steroids 2012;77:1469–76.
[10] Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angew Chem
Int Ed 2000;39:3168–210.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.steroids.
2014.06.015.
[11] Barthakur MG, Gogoi S, Dutta M, Boruah RC. A facile three-component solid
phase synthesis of steroidal A-ring fused pyrimidines under microwave
irradiation. Steroids 2009;74:730–4.
Reference
[12] Gogoi J, Gogoi P, Bezbaruah P, Boruah RC. Microwave-assisted Pd-catalyzed
[1] (a) Brown DJ. In: Katritzky AR, Rees CW, editors. Comprehensive heterocyclic
chemistry, vol. 3. Pergamon Press Ltd; 1984. p. 142–55.(b) Undheim K,
Benneche T. In: Katritzky AR, Rees CW, Scriven EFV, editors. Comprehensive
heterocyclic chemistry II, vol. 6. Elsevier Science Ltd.; 1996. p. 221–5.
[2] Jain KS, Chitra TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS. Biological
and medicinal significance of pyrimidines. Curr Sci 2006;90:793–803.
[3] Botta M, Corelli F, Maga G, Manetti F, Renzulli M, Spadari S. Research on anti-
HIV-1 agents. Part 2. Solid-phase synthesis, biological evaluation and
molecular modeling studies of 2,5,6-trisubstituted-4(3H)-pyrimidones
targeting HIV-1 reverse transcriptase. Tetrahedron 2001;57:8357–67.
synthesis of fused steroidal and non-steroidal pyrimidines from b-halo-a, b-
unsaturated aldehydes. Tetrahedron Lett 2013;54:7136–9.
[13] (a) Gogoi S, Shekarrao K, Duarah A, Bora TC, Gogai 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;
(b) Shekarrao K, Nath D, Kaishap PP, Gogoi S, Boruah RC. Palladium-catalyzed
multi-component synthesis of steroidal A- and D-ring fused 5,6-disubstituted
pyridines under microwave irradiation. Steroids 2013;78:1126–33.