Synthesis of novel D-ring fused 7′-aryl-androstano[17,16-d][1,2,4] triazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.steroids.2011.12.012

The preparation of novel steroidal heterocycles containing the 7-aryl-substituted 1,2,4-triazolo[1,5-a]pyrimidine moiety fused to the 16,17-positions of the steroid nucleus is described. The Aldol reaction of 4-aza-androst-3,17-dione (1a) and dehydroepiandrosterone (DHEA, 1b) with aromatic aldehydes was catalyzed by KF/Al₂O₃ to give the corresponding 3-oxo-4-aza-5α- and 3β-hydroxy-5-en-16-arylidene-17- ketosteroids (2a-r). Subsequently, the intermediates 2a-r reacted with dinucleophilic 3-amino-1,2,4-triazole in presence of t-BuOK to afford the title compounds (3a-r). All the synthesized heterosteroids are new and are currently being evaluated for their biological activities.

Full text of DOI:10.1016/j.steroids.2011.12.012

Steroids 77 (2012) 367–374
Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of novel D-ring fused 70-aryl-androstano[17,16-d][1,2,4]
triazolo[1,5-a]pyrimidines
Li-Hua Huang a,b, Yong-Fei Zheng a, Chuan-Jun Song b, Yan-Guang Wang a, Zhi-Yu Xie a, Yao-Wen Lai a,
Yong-Zheng Lu b, Hong-Min Liu a,b,c,
⇑
a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
b Department of Chemistry, Zhengzhou University, Zhengzhou 450001, China
c New Drug Research and Development Center, Zhengzhou University, Zhengzhou 450001, China
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 the 7-aryl-substituted 1,2,4-triazolo
[1,5-a]pyrimidine moiety fused to the 16,17-positions of the steroid nucleus is described. The Aldol reac-
tion of 4-aza-androst-3,17-dione (1a) and dehydroepiandrosterone (DHEA, 1b) with aromatic aldehydes
Received 24 September 2011
Received in revised form 27 November 2011
Accepted 2 December 2011
Available online 13 December 2011
was catalyzed by KF/Al2O3 to give the corresponding 3-oxo-4-aza-5a- and 3b-hydroxy-5-en-16-arylid-
ene-17-ketosteroids (2a–r). Subsequently, the intermediates 2a–r reacted with dinucleophilic 3-
amino-1,2,4-triazole in presence of t-BuOK to afford the title compounds (3a–r). All the synthesized
heterosteroids are new and are currently being evaluated for their biological activities.
Ó 2011 Elsevier Inc. All rights reserved.
Keywords:
Heterosteroids
Steroidal[17,16-d]triazolopyrimidines
3-Amino-1,2,4-triazole
16-Arylidene-17-ketosteroids
1,2,4-Triazolo[1,5-a]pyrimidine
1. Introduction
On the other hand, 1,2,4-triazolo[1,5-a]pyrimidines (TPs),
which are analogues of purine bases widely investigated (Fig. 1
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 (Fig. 1, I–III) [1–8].
For example, Cortivazol (I) and similar arylpyrazolo steroids
exhibited powerful glucocorticoids and have been extensively
investigated as anti-inflammatory agents [2]. Steroidal[17,16-
d]thiopyridone derivative (II) also showed significant anti-
inflammatory activity and was found to be more potent but less
toxic than Prednisolone [7]. In addition, Potter et al. reported
that N-substituted 1,3,5(10)-estratrien[17,16-c]pyrazole (III)
was a potent inhibitors of 17b-hydroxysteroid dehydrogenases
(17b-HSD) with an IC50 of 530 nM in T47-D human breast cancer
cells [8]. Considering the remarkable importance from the phar-
macological and synthetic viewpoints, great efforts are being
made to annelate steroidal moiety with pyrazole, isoxazole, pyr-
idine, pyran, pyrrole or pyrimidine rings using various synthetic
strategies [9–13].
IV and V) [14], have been identified to possess multifaceted
pharmacological properties, including antihypertensive, cardiac
stimulant, antimalarial, antifungal, anti-HBV, antimicrobial, anti-
cancer and herbicidal activities [15–22]. The most widely known
derivative is the simple molecule of Trapidil (IV), a clinically
used vasodilator, which acts as a platelet-derived growth factor
(PDGF) antagonist and as a phosphodiesterase inhibitor [15b].
Recently, a new antibiotic substance named Essramycin (V),
the first isolated 1,2,4-triazolo[1,5-a]pyrimidine natural product,
was reported to exhibit broad-spectrum antibacterial properties
[20b].
In view of the therapeutic importance of heterosteroids and
in continuation of our previous work in developing new biolog-
ically active modified steroids [23], we are interested in the
design, synthesis and biological evaluation of novel heteroster-
oids. According to the literatures [24], 16-arylidene-17-ketoste-
roids reacted with dinucleophilic urea or hydrazines to afford
the corresponding steroidal pyrimidines or pyrazoles. Further-
more, the condensation of aromatic
a,b-unsaturated ketones
with dinucleophilic 3-amino-1,2,4-triazole (3-AT) was a facile
approach to prepare TPs [19,21b,25]. Herein, we report the syn-
thesis of a novel class of heterosteroids containing the 7-aryl-
substituted 1,2,4-triazolo[1,5-a]pyrimidine moiety fused with
⇑
Corresponding author at: School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China. Tel./fax: +86 371 67767200.
E-mail addresses: liuhm@zzu.edu.cn, liuhm@public2.zz.ha.cn (H.-M. Liu).
0039-128X/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2011.12.012

368
L.-H. Huang et al. / Steroids 77 (2012) 367–374
2.2.3. 4-Aza-5a-16-(3-nitrobenzylidene)-androst-3,17-dione (2c)
Yellow solid, yield 94%. 1H NMR (400 MHz, CDCl3): d 8.37 (d,
J = 1.6 Hz, 1H, ArH), 8.21 (d, J = 8.0 Hz, 1H, ArH), 7.82 (d,
J = 7.6 Hz, 1H, ArH), 7.61 (t, J = 8.0 Hz, 1H, ArH), 7.46 (s, 1H, Ar–
CH@), 6.31 (brs, 1H, 4-NH), 3.10 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H,
O
O
S
O
NC
HO
OH
NH
N
N
5
a
-H), 0.99 (d, J = 9.2 Hz, 6H, 18-CH3 and 19-CH3). HRMS (ESI):
HO
N
m/z calcd for C25H31N2O4 (M+H)+, 423.2284; found, 423.2286.
F
Cortivazol (I)
(II)
2.2.4. 4-Aza-5a-16-(3,4,5-trimethyoxybenzylidene)-androst-3,17-
N
N
O
O
dione (2d)
O
N
N
White solid, yield 92%. 1H NMR (400 MHz, CDCl3): d 7.37 (s, 1H,
Ar–CH@), 6.77(s, 2H, ArH), 5.73 (brs, 1H, 4-NH), 3.89 (d, J = 0.8 Hz,
N
N
N
N
N
H
N
HO
9H, Ar-(OCH3)3), 3.10 (dd, J1 = 12.4 Hz, J2 = 4.0 Hz, 1H, 5
(d, J = 5.6 Hz, 6H, 18-CH3 and 19-CH3). HRMS (ESI): m/z calcd for
28H38NO5 (M+H)+, 468.2750; found, 468.2751.
a-H), 0.98
IV
III
(
)
V
Essramycin ( )
(
)
Trapidil
C
Fig. 1. Structures of heterosteroids I–III and 1,2,4-triazolo[1,5-a]pyrimidines IV, V.
2.2.5. 4-Aza-5a-16-(4-bromobenzylidene)-androst-3,17-dione (2e)
D-ring via the condensation of 3-AT with readily available 16-
arylidene-17-ketosteroids.
White solid, yield 95%. 1H NMR (400 MHz, CDCl3): d 7.54 (d,
J = 8.4 Hz, 2H, ArH), 7.40–7.37 (m, 3H, ArH and Ar–CH@), 5.86
(brs, 1H, 4-NH), 3.10 (dd, J1 = 12.4 Hz, J2 = 4.0 Hz, 1H, 5a-H), 0.97
2. Experimental
(s, 6H, 18-CH3 and 19-CH3). HRMS (ESI): m/z calcd for C25H31BrNO2
(M+H)+, 456.1538; found, 456.1540.
2.1. General remarks
2.2.6. 4-Aza-5a-16-(4-fluorobenzylidene)-androst-3,17-dione (2f)
All reagents and solvents used were of analytical grade pur-
chased from commercial sources. Thin-layer chromatography
(TLC) was carried out on glass plates coated with silica gel (Qing-
dao Haiyang Chemical Co., G60F-254) and visualized by UV light
(254 nm). The products were purified by column chromatography
over silica gel (Qingdao Haiyang Chemical Co., 200–300 mesh).
Melting points were determined on a Beijing Keyi XT4A apparatus
and are uncorrected. All NMR spectra were recorded with a Bruker
DPX 400 MHz spectrometer, with TMS as internal standard in
CDCl3. Chemical shifts are given as d ppm values relative to TMS.
Mass spectra (MS) were recorded on Esquire3000 mass spectrom-
eter by electrospray ionization (ESI).
White solid, yield 93%. 1H NMR (400 MHz, CDCl3): d 7.52 (m, 2H,
ArH), 7.40 (d, J = 2.0 Hz, 1H, Ar–CH@), 7.14–7.08 (m, 2H, ArH), 5.93
(brs, 1H, 4-NH), 3.10 (dd, J1 = 12.0 Hz, J2 = 4.0 Hz, 1H, 5a-H), 0.97 (s,
6H, 18-CH3 and 19-CH3). HRMS (ESI): m/z calcd for C25H31FNO2
(M+H)+, 396.2339; found, 396.2340.
2.2.7. 4-Aza-5a-16-(4-methoxybenzylidene)-androst-3,17-dione (2g)
White solid, yield 90%. 1H NMR (400 MHz, CDCl3): d 7.51 (d,
J = 8.8 Hz, 2H, ArH), 7.41 (s, 1H, Ar–CH@), 6.96 (d, J = 8.7 Hz, 2H,
ArH), 6.40 (s, 1H, 4-NH), 3.86 (s, 3H, Ar-OCH3), 3.10 (dd, J = 12.2,
3.8 Hz, 1H, 5a-H), 0.97 (d, J = 1.8 Hz, 6H, 18-CH3 and 19-CH3).
HRMS (ESI): m/z calcd for C26H34NO3 (M+H)+, 408.2539; found,
408.2536.
2.2. General procedure for the synthesis of 16-arylidene-17-
ketosteroids 2a–r
2.2.8. 4-Aza-5a-16-(4-dimethylaminobenzylidene)-androst-3,17-
dione (2h)
A mixture of 4-aza-androst-3,17-dione (1a) [26] or dehydroepi-
androsterone (DHEA, 1b) (2.0 mmol), aromatic aldehydes
(2.1 mmol) and KF/Al2O3 (1.6 mmol) [27] in EtOH (20 mL) was
heated to reflux for about 1 h. After completion of the reaction as
evident from TLC, the slurry was filtered and the residue was
washed thoroughly with CH2Cl2. The filtrate was condensed under
reduced pressure, and the solid obtained was crystallized from
EtOH or MeOH to yield the corresponding 16-arylidene-17-keto-
steroids 2a–r (Table 1).
Yellow solid, yield 92%. 1H NMR (400 MHz, CDCl3): d 7.47 (d,
J = 8.8 Hz, 2H, ArH), 7.40 (s, 1H, Ar–CH@), 6.73 (d, J = 8.9 Hz, 2H,
ArH), 6.29 (s, 1H, 4-NH), 3.10 (dd, J = 12.2, 3.8 Hz, 1H, 5a-H), 3.04
(s, 6H, Ar-N(CH3)2), 0.97 (d, J = 4.8 Hz, 6H, 18-CH3 and 19-CH3).
HRMS (ESI): m/z calcd for C27H37N3O3 (M+H)+, 421.2855; found,
421.2854.
2.2.9. 4-Aza-5a-16-(4-isopropylbenzylidene)-androst-3,17-dione (2i)
White solid, yield 91%. 1H NMR (400 MHz, CDCl3): d 7.49 (d,
J = 8.1 Hz, 2H, ArH), 7.44 (s, 1H, Ar–CH@), 7.30 (d, J = 9.2 Hz, 2H,
2.2.1. 4-Aza-5a-16-benzylidene-androst-3,17-dione (2a)
ArH), 6.37 (s, 1H, 4-NH), 3.10 (dd, J = 12.2, 3.7 Hz, 1H, 5a-H), 1.28
White solid, yield 92%. 1H NMR (400 MHz, CDCl3): d 7.54 (d,
J = 6.8 Hz, 2H, ArH), 7.44–7.35 (m, 4H, ArH and Ar–CH@), 6.49 (s,
(d, J = 6.9 Hz, 6H, ArCH(CH3)2), 0.97 (d, J = 8.6 Hz, 6H, 18-CH3 and
19-CH3). HRMS (ESI): m/z calcd for C26H38NO2 (M+H)+, 420.2903;
found, 420.2903.
1H, 4-NH), 3.09 (dd, J1 = 12.0 Hz, J2 = 4.0 Hz, 1H, 5
J = 3.2 Hz, 6H, 18-CH3 and 19-CH3). HRMS (ESI): m/z calcd for
25H32NO2 (M+H)+, 378.2433; found, 378.2334.
a-H), 0.97 (d,
C
2.2.10. 4-Aza-5a-16-(4-morpholinylbenzylidene)-androst-3,17-dione
(2j)
2.2.2. 4-Aza-5
a
-16-(4-chlorobenzylidene)-androst-3,17-dione (2b)
Yellow solid, yield 90%. 1H NMR (400 MHz, CDCl3): d 7.48 (d,
J = 8.7 Hz, 2H, ArH), 7.39 (s, 1H, Ar–CH@), 6.92 (d, J = 8.7 Hz, 2H,
ArH), 6.25 (s, 1H, 4-NH), 3.93–3.81 (m, 4H, protons of morpholine),
3.33–3.20 (m, 4H, protons of morpholine), 3.10 (dd, J = 12.2, 3.6 Hz,
White solid, yield 92%. 1H NMR (400 MHz, CDCl3): d 7.46 (d,
J = 8.8 Hz, 2H, ArH), 7.40–7.38 (m, 3H, ArH and Ar–CH@), 6.53
(brs, 1H, 4-NH), 3.09 (dd, J1 = 12.4 Hz, J2 = 4.0 Hz, 1H, 5a-H), 0.97
(s, 6H, 18-CH3 and 19-CH3). HRMS (ESI): m/z calcd for C25H31ClNO2
1H, 5
a-H), 0.97 (d, J = 3.2 Hz, 6H, 18-CH3 and 19-CH3). HRMS (ESI):
(M+H)+, 412.2043; found, 412.2044.
m/z calcd for C29H39N2O3 (M+H)+, 463.2961; found, 463.2958.

L.-H. Huang et al. / Steroids 77 (2012) 367–374
369
Table 1
Synthesis of steroidal[17,16-d]triazolopyrimidines (3a–r).
Entry
1
1
ArCHO
2/Yiedsa (%)
2a/92
Productb
Yieldsc (%)
1a
58
N
N
N
OHC
N
O
O
N
H
H
3a
3b
2
1a
2b/92
67
N
N
N
OHC
OHC
Cl
N
N
Cl
H
H
N
N
N
3
4
1a
1a
2c/94
2d/92
64
52
NO
2
N
N
O
O
N
H
H
O N
2
N
N
H
3c
N
O
N
OHC
OHC
O
O
N
H
O
O
3d
O
5
6
1a
1a
2e/95
2f/93
65
68
N
N
N
Br
N
O
O
N
Br
H
H
3e
3f
H
N
N
N
N
OHC
OHC
F
N
N
N
H
F
N
N
N
7
1a
2g/90
54
O
O
O
O
N
H
O
H
3g
3h
3i
8
9
1a
1a
2h/92
2i/96
55
60
N
N
N
N
OHC
OHC
N
N
N
N
H
N
H
H
N
N
N
H
N
10
1a
2j/90
51
N
OHC
N
O
N
N
N
O
N
H
N
H
O
3j
11
12
1b
1b
2k/94
2l/91
67
63
N
N
N
OHC
OHC
N
3k
HO
N
N
N
O
N
HO
HO
O
3l
13
14
1b
1b
2m/93
2n/90
65
61
N
N
OHC
OHC
N
Cl
N
N
Cl 3m
N
N
N
N
HO
N
3n
(continued on next page)

370
L.-H. Huang et al. / Steroids 77 (2012) 367–374
Table 1 (continued)
Entry
15
1
ArCHO
2/Yiedsa (%)
2o/92
Productb
Yieldsc (%)
71
1b
N
N
O
N
N
OHC
HO
O
3o
3p
16
17
1b
1b
2p/93
66
63
N
N
N
OHC
OHC
N
HO
HO
2q/88
N
N
O
N
N
N
N
O
3q
3r
18
1b
2r/90
70
N
N
O O
S
N
N
OHC
O
O
HO
S
a
Reaction conditions: 1a or 1b (2.0 mmol), aromatic aldehydes (2.1 mmol), KF/Al2O3 (1.6 mmol) EtOH (20 mL), reflux, 1 h.
Reaction conditions: 2 (1.0 mmol), 3-AT (2.0 mmol), t-BuOK (2.0 mmol), n-BuOH (10 mL), reflux, 30 h.
Isolated yields.
b
c
2.2.11. 3b-Hydroxy-16-benzylidene-5-androsten-17-one (2k)
(m, 5H), 0.97 (s, 3H, 18-CH3). HRMS (ESI): m/z calcd for C32H37O3
White solid, yield 94%. 1H NMR (400 MHz, CDCl3): d 7.56 (d,
J = 7.4 Hz, 2H, ArH), 7.49–7.34 (m, 4H, ArH and Ar–CH@),
(M+H)+, 469.2743; found, 469.2745.
5.45–5.37 (m, 1H, 6-H), 3.63–3.49 (m, 1H, 3a-H), 1.18–1.04 (m,
2.2.16. 3b-Hydroxy-16-(4-isopropylbenzylidene)-5-androsten-17-one
(2p)
5H), 1.00 (s, 3H, 18-CH3). HRMS (ESI): m/z calcd for C26H33O2
(M+H)+, 377.2481; found, 377.2479.
White solid, yield 93%. 1H NMR (400 MHz, CDCl3): d 7.56–7.40
(m, 3H, ArH and Ar–CH@), 7.36–7.23 (m, 2H, ArH), 5.41 (d,
J = 6.6 Hz, 1H, 6-H), 3.55 (m, 1H,
3a-H), 1.92–1.68 (m, 6H,
2.2.12. 3b-Hydroxy-16-(4-methoxybenzylidene)-5-androsten-17-one
(2l)
Ar-CH(CH3)2), 1.09 (m, 5H), 0.99 (d, J = 12.7 Hz, 3H, 18-CH3). HRMS
(ESI): m/z calcd for C29H39O2 (M+H)+, 419.2950; found, 419.2953.
White solid, yield 91%. 1H NMR (400 MHz, CDCl3): d 7.52 (d,
J = 8.7 Hz, 2H, ArH), 7.42 (s, 1H, Ar–CH@), 6.96 (d, J = 8.7 Hz, 2H,
ArH), 5.46–5.38 (m, 1H, 6-H), 3.85 (d, J = 8.8 Hz, 3H, Ar-OCH3),
2.2.17. 3b-Hydroxy-16-(4-morpholinylbenzylidene)-5-androsten-17-
one (2q)
3.56 (m, 1H, 3a-H), 1.18–1.03 (m, 5H), 0.99 (s, 3H, 18-CH3). HRMS
Yellow solid, yield 87%. 1H NMR (400 MHz, CDCl3): d 7.50 (d,
J = 3.7 Hz, 2H, ArH), 7.40 (s, 1H, Ar–CH@), 6.93 (d, J = 3.7 Hz, 2H,
ArH), 5.41 (s, 1H, 6-H), 3.88 (d, J = 4.2 Hz, 4H, protons of morpho-
(ESI): m/z calcd for C27H35O3 (M+H)+, 407.2586; found, 407.2584.
2.2.13. 3b-Hydroxy-16-(4-chlorobenzylidene)-5-androsten-17-one
(2m)
line), 3.55 (d, J = 4.5 Hz, 1H, 3a-H), 3.26 (d, J = 4.2 Hz, 4H, protons
of morpholine), 1.11 (m, 5H), 0.98 (d, J = 4.5 Hz, 3H, 18-CH3). HRMS
White solid, yield 93%. 1H NMR (400 MHz, CDCl3): d 7.49 (d,
J = 8.4 Hz, 2H, ArH), 7.40 (d, J = 8.1 Hz, 3H, ArH and Ar–CH@),
(ESI): m/z calcd for C30H40NO3 (M+H)+, 462.3008; found, 462.3004.
5.42 (d, J = 4.8 Hz, 1H, 6-H), 3.63–3.49 (m, 1H, 3a-H), 1.19–1.04
2.2.18. 3b-Hydroxy-16-(4-methylsulfonylbenzylidene)-5-androsten-
17-one (2r)
(m, 5H), 1.00 (s, 3H, 18-CH3). HRMS (ESI): m/z calcd for C26H32ClO2
(M+H)+, 411.2091; found, 411.2092.
White solid, yield 93%. 1H NMR (400 MHz, CDCl3): d 7.99 (d,
J = 8.3 Hz, 2H, ArH), 7.71 (d, J = 8.4 Hz, 2H, ArH), 7.46 (s, 1H,
2.2.14. 3b-Hydroxy-16-(4-dimethylaminobenzylidene)-5-androsten-
17-one (2n)
Ar–CH@), 5.45–5.36 (m, 1H, 6-H), 3.60–3.50 (m, 1H, 3a-H), 3.09
(s, 3H, Ar-SO2CH3), 1.19–1.04 (m, 5H), 1.01 (s, 3H, 18-CH3). HRMS
(ESI): m/z calcd for C27H34O4SNa (M+Na)+, 477.2075; found,
477.2075.
Yellow solid, yield 90%. 1H NMR (400 MHz, CDCl3): d 7.49 (d,
J = 8.8 Hz, 2H, ArH), 7.41 (s, 1H, Ar–CH@), 6.73 (d, J = 8.8 Hz, 2H,
ArH), 5.42 (d, J = 5.1 Hz, 1H, 6-H), 3.55 (d, J = 3.7 Hz, 1H, 3a-H),
3.04 (s, 6H, Ar-N(CH3)2), 1.18–1.02 (m, 5H), 0.98 (s, 3H, 18-CH3).
HRMS (ESI): m/z calcd for C28H38NO2 (M+H)+, 420.2903; found,
420.2900.
2.3. General procedure for the synthesis of steroidal[17,16-d]triazo-
lopyrimidines 3a–r
The condensation products 2a–r (1.0 mmol) was dissolved in
n-BuOH (10 mL). To the solution was added 3-AT (2.0 mmol) and
t-BuOK (2.0 mmol). The resulting mixture was refluxed for 30 h.
The solvent was removed and CH2Cl2 was added. The insoluble
t-BuOK was filtered and washed thoroughly with CH2Cl2. After
removal of the solvent, the residue was purified by silica gel
chromatography with ethyl acetate/petroleum ether/acetone
2.2.15. 3b-Hydroxy-16-(3-phenoxybenzylidene)-5-androsten-17-one
(2o)
White solid, yield 92%. 1H NMR (400 MHz, CDCl3): d 7.38 (dd,
J = 11.9, 4.0 Hz, 4H, ArH), 7.27 (d, J = 7.8 Hz, 1H, Ar–CH@),
7.22–7.12 (m, 2H, ArH), 7.05 (ddd, J = 12.8, 8.4, 1.6 Hz, 3H, ArH),
5.42 (d, J = 5.0 Hz, 1H, 6-H), 3.63–3.49 (m, 1H, 3a-H), 1.20–1.02

L.-H. Huang et al. / Steroids 77 (2012) 367–374
371
(4:2:1) and petroleum ether/ethyl acetate (3:2) to give the corre-
sponding steroidal[17,16-d]triazolopyrimidines 3a–j and 3k–r,
respectively (Table 1).
d 180.4, 172.4, 155.9, 154.7, 143.0, 131.1, 129.6, 129.1, 128.7,
122.4, 60.6, 55.3, 51.5, 46.7, 36.0, 34.3, 33.2, 32.8, 29.0, 29.0,
28.5, 27.0, 20.7, 17.4, 11.4. HRMS (ESI): m/z calcd for C27H31FN5O
(M+H)+, 460.2513; found, 460.2518.
2.3.1. 3-Oxo-4-aza-70-phenyl-5
a-androstano[17,16-d][1,2,4]triazolo-
[1,5-a]pyrimidine (3a)
2.3.7. 3-Oxo-4-aza-70-(4-methoxyphenyl)-5
a-androstano[17,16-d][1,
White solid, yield 58%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.38 (s, 1H, 20-H), 7.81 (dd, J = 6.7, 3.0 Hz, 2H, Ar–H), 7.64–7.56
(m, 3H, Ar–H), 6.40 (s, 1H, 4-NH), 3.10 (dd, J = 12.2, 3.8 Hz, 1H,
2,4]triazolo[1,5-a] pyrimidine (3g)
White solid, yield 54%, mp 268–270 °C. 1H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H, 20-H), 7.81 (d, J = 8.8 Hz, 2H, Ar–H), 7.10 (d,
J = 8.8 Hz, 2H, Ar–H), 6.36 (s, 1H, 4-NH), 3.92 (s, 3H, Ar-OCH3),
5a
-H), 1.20 (s, 3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR (100 MHz,
CDCl3): d 180.4, 172.4, 155.8, 154.7, 143.0, 131.1, 129.6, 129.1,
128.7, 122.4, 60.6, 55.3, 51.4, 46.7, 36.0, 34.2, 33.2, 32.8, 29.0,
29.0, 28.5, 27.0, 20.7, 17.4, 11.4. HRMS (ESI): m/z calcd for
3.10 (dd, J = 12.1, 3.7 Hz, 1H, 5a-H), 1.19 (s, 3H, 18-H), 1.00 (s,
3H, 19-H). 13C NMR (100 MHz, CDCl3): d 180.2, 172.3, 161.6,
156.0, 154.6, 142.9, 131.4, 121.6, 121.2, 114.1, 60.6, 55.5, 55.4,
51.5, 46.7, 36.0, 34.3, 33.2, 32.8, 29.3, 29.0, 28.6, 27.0, 20.7, 17.4,
11.4. HRMS (ESI): m/z calcd for C28H34N5O (M+H)+, 472.2713;
found, 472.2702.
C
27H32N5O (M+H)+, 442.2607; found, 442.2610.
2.3.2. 3-Oxo-4-aza-70-(4-chlorophenyl)-5
a-androstano[17,16-
d][1,2,4]triazolo[1,5-a] pyrimidine (3b)
White solid, yield 67%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.37 (s, 1H, 20-H), 7.78 (d, J = 8.2 Hz, 2H, Ar–H), 7.57 (d, J = 8.2 Hz,
2.3.8. 3-Oxo-4-aza-70-(4-dimethylaminophenyl)-5
a-androstano[17,
16-d][1,2,4]triazolo[1,5-a] pyrimidine (3h)
2H, Ar–H), 6.56 (s, 1H, 4-NH), 3.09 (d, J = 9.5 Hz, 1H, 5a-H), 1.19 (s,
Yellow solid, yield 55%, mp 257–259 °C. 1H NMR (400 MHz,
CDCl3): d 8.35 (s, 1H, 20-H), 7.79 (d, J = 8.9 Hz, 2H, Ar–H), 6.83 (d,
3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR (100 MHz, CDCl3): d 180.4,
172.3, 155.9, 154.8, 141.7, 137.3, 131.0, 129.1, 127.5, 122.4, 60.6,
55.3, 51.5, 46.8, 35.9, 34.3, 33.2, 32.8, 29.0, 29.0, 28.6, 27.0, 20.7,
J = 8.9 Hz, 2H, Ar–H), 6.52 (s, 1H, 4-NH), 3.09 (s, 7H, 5a-H and
Ar–N(CH3)2), 1.18 (s, 3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR
(100 MHz, CDCl3): d 179.9, 172.4, 156.1, 154.4, 151.8, 143.7,
131.2, 125.0, 120.6, 115.6, 111.1, 60.6, 55.5, 51.5, 46.6, 40.1, 35.9,
34.3, 33.2, 32.9, 29.7, 29.1, 28.6, 27.0, 20.7, 17.3, 11.4. HRMS
(ESI): m/z calcd for C29H37N6O (M+H)+, 485.3029; found, 485.3033.
17.4, 11.4. HRMS (ESI): m/z calcd for
476.2217; found, 476.2223.
C
27H31ClN5O (M+H)+,
2.3.3. 3-Oxo-4-aza-70-(3-nitrophenyl)-5
a-androstano[17,16-d][1,2,
4]triazolo[1,5-a]pyrimidine (3c)
White solid, yield 64%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.68 (t, J = 1.7 Hz, 1H, Ar-H), 8.44 (dd, J = 8.3, 1.3 Hz, 1H, Ar–H),
8.38 (s, 1H, 20–H), 8.21 (d, J = 7.8 Hz, 1H, Ar–H), 7.82 (t, J = 8.0 Hz,
2.3.9. 3-Oxo-4-aza-70-(4-isopropylphenyl)-5
a-androstano[17,16-d][1,
2,4]triazolo[1,5-a] pyrimidine (3i)
White solid, yield 60%, mp 234–236 °C. 1H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H, 20-H), 7.75 (d, J = 8.0 Hz, 2H, Ar–H), 7.45 (d,
J = 8.0 Hz, 2H, Ar–H), 6.33 (s, 1H, 4-NH), 3.10 (dd, J = 12.0, 3.4 Hz,
1H, Ar–H), 6.49 (s, 1H, 4-NH), 3.09 (dd, J = 12.2, 3.7 Hz, 1H, 5a-
H), 1.21 (s, 3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR (100 MHz,
CDCl3): d 180.7, 172.3, 155.8, 155.0, 148.3, 140.1, 135.5, 130.7,
129.9, 125.7, 124.8, 123.0, 60.5, 55.3, 51.5, 46.9, 36.0, 34.3, 33.2,
32.8, 29.0, 28.8, 28.5, 26.9, 20.6, 17.5, 11.4. HRMS (ESI): m/z calcd
for C27H31N6O3 (M+H)+, 487.2458; found, 487.2459.
1H, 5a-H), 3.08–2.97 (m, 1H, Ar-CH(CH3)2), 1.33 (d, J = 6.8 Hz, 6H,
Ar-CH(CH3)2), 1.19 (s, 3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR
(100 MHz, CDCl3): d 180.3, 172.2, 156.0, 154.7, 152.3, 143.1,
129.6, 126.8, 126.5, 122.0, 60.6, 55.4, 51.5, 46.7, 36.0, 34.3, 34.2,
33.3, 32.9, 29.1, 29.1, 28.6, 27.0, 23.7, 23.7, 20.7, 17.4, 11.4. HRMS
(ESI): m/z calcd for C30H37N5ONa (M+Na)+, 506.2896; found,
506.2897.
2.3.4. 3-Oxo-4-aza-70-(3,4,5-trimethoxyphenyl)-5
a-androstano[17,
16-d][1,2,4]triazolo[1,5-a] pyrimidine (3d)
White solid, yield 52%, mp 197–199 °C. 1H NMR (400 MHz,
CDCl3): d 8.36 (s, 1H, 20-H), 7.01 (s, 2H, Ar–H), 6.58 (s, 1H, 4-NH),
3.92 (d, J = 17.1 Hz, 9H, Ar-(OCH3)3), 3.08 (dd, J = 12.1, 3.3 Hz, 1H,
2.3.10. 3-Oxo-4-aza-70-(4-morpholinylphenyl)-5
a-androstano[17,16-
5a
-H), 1.18 (s, 3H, 18-H), 0.98 (s, 3H, 19-H). 13C NMR (100 MHz,
d][1,2,4]triazolo[1,5-a] pyrimidine (3j)
CDCl3): d 180.3, 172.3, 156.0, 154.8, 153.3, 142.9, 140.4, 124.0,
122.2, 107.3, 61.0, 60.6, 56.4, 55.3, 51.5, 46.7, 35.9, 34.2, 33.2,
32.8, 29.2, 29.1, 28.5, 26.9, 20.7, 17.4, 11.4. HRMS (ESI): m/z calcd
for C30H38N5O4 (M+H)+, 532.2924; found, 532.2921.
Yellow solid, yield 51%, mp 298–300 °C. 1H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H, 20-H), 7.81 (d, J = 8.7 Hz, 2H, Ar–H), 7.04 (d,
J = 8.7 Hz, 2H, Ar–H), 6.20 (s, 1H, 4-NH), 3.98–3.82 (m, 4H, protons
of morpholine), 3.43–3.27 (m, 4H, protons of morpholine), 3.10
(dd, J = 12.0, 3.7 Hz, 1H, 5a-H), 1.19 (s, 3H, 18-H), 1.01 (s, 3H, 19-
2.3.5. 3-Oxo-4-aza-70-(4-bromophenyl)-5
a-androstano[17,16-d][1,2,
H). 13C NMR (100 MHz, CDCl3): d 180.0, 172.2, 156.1, 154.6,
152.7, 143.1, 131.2, 121.1, 119.1, 114.0, 66.6, 60.6, 55.5, 51.5,
47.9, 46.6, 36.0, 34.3, 33.3, 32.9, 29.4, 29.1, 28.6, 27.1, 20.7, 17.3,
4]triazolo[1,5-a]pyrimidine (3e)
White solid, yield 65%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.39 (s, 1H, 20-H), 7.73 (q, J = 8.6 Hz, 4H, Ar–H), 5.98 (s, 1H, 4-NH),
11.4. HRMS (ESI): m/z calcd for
C
31H38N6O2Na (M+Na)+,
3.12 (dd, J = 11.9, 3.6 Hz, 1H, 5a-H), 1.20 (s, 3H, 18-H), 1.02 (s, 3H,
549.2954; found, 549.2949.
19-H). 13C NMR (100 MHz, CDCl3): d 180.4, 172.2, 155.9, 154.8,
141.8, 132.0, 131.2, 127.9, 125.8, 122.3, 60.6, 55.3, 51.5, 46.8,
36.0, 34.3, 33.2, 32.8, 29.7, 29.0, 28.5, 27.1, 20.7, 17.4, 11.4. HRMS
2.3.11. 3b-Hydroxy-5-en-70-phenyl-androstano[17,16-d][1,2,4]tria-
zolo[1,5-a]pyrimidine (3k)
(ESI): m/z calcd for
C
27H31BrN5O (M+H)+, 520.1712; found,
520.1710.
White solid, yield 67%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.38 (s, 1H, 20-H), 7.82 (m, 2H, Ar–H), 7.64–7.57 (m, 3H, Ar–H),
2.3.6. 3-Oxo-4-aza-70-(4-fluorophenyl)-5
a-androstano[17,16-d][1,2,
5.37 (d, J = 5.0 Hz, 1H, 6-H), 3.63–3.46 (m, 1H, 3a-H), 1.21 (s, 3H,
4]triazolo[1,5-a] pyrimidine (3f)
18-H), 1.19–1.08 (m, 5H). 13C NMR (100 MHz, CDCl3): d 180.7,
156.0, 154.7, 142.8, 141.4, 131.0, 129.6, 129.2, 128.7, 122.6,
120.6, 71.5, 56.0, 50.3, 46.4, 42.2, 37.1, 36.8, 33.0, 31.6, 31.2,
31.1, 29.2, 20.5, 19.5, 17.1. HRMS (ESI): m/z calcd for C28H32N4ONa
(M+Na)+, 463.2474; found, 463.2478.
White solid, yield 68%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.38 (s, 1H, 20-H), 7.84 (dd, J = 8.5, 5.3 Hz, 2H, Ar–H), 7.29 (t,
J = 8.5 Hz, 2H, Ar–H), 6.34 (s, 1H, 4-NH), 3.14–3.06 (m, 1H, 5
a-H),
1.19 (s, 3H, 18-H), 1.00 (s, 3H, 19-H). 13C NMR (100 MHz, CDCl3):

372
L.-H. Huang et al. / Steroids 77 (2012) 367–374
O
O
3'
N
2'
1'
3a'
7'
4'
5'
6'
O
O
N
H
N
N
H
N
i
ii
8'
1a
1b
R
R
2a-r
3a-r
HO
Scheme 1. Protocol for the synthesis of 70-aryl-androstano[17,16-d][1,2,4]triazolo[1,5-a] pyrimidines (3a–r). Reagents and conditions: (i) ArCHO, KF/Al2O3, EtOH, reflux; (ii)
3-amino-1,2,4-triazole, t-BuOK, n-BuOH, reflux.
2.3.12. 3b-Hydroxy-5-en-70-(4-methoxyphenyl)-androstano[17,16-
Table 2
d][1,2,4]triazolo[1,5-a] pyrimidine (3l)
Optimization of reaction conditions for preparation of 3a.
White solid, yield 63%, mp 275–277 °C. 1H NMR (400 MHz,
Yieldsa (%)
CDCl3): d 8.37 (s, 1H, 20-H), 7.83 (d, J = 8.7 Hz, 2H, Ar–H), 7.10 (d,
J = 8.6 Hz, 2H, Ar–H), 5.37 (d, J = 4.5 Hz, 1H, 6-H), 3.92 (s, 3H, Ar-
Entry
Catalyst
Solvent
1
2
3
4
5
6
7
8
Lewis acids
NaOH
DBU
NaOCH3
NaOCH3
t-BuOK
t-BuOK
t-BuOK
EtOH
EtOH
CH3CN
MeOH
EtOH
EtOH
t-BuOH
n-BuOH
0b
15b
OCH3), 3.61–3.48 (m, 1H, 3a-H), 1.20 (s, 3H, 18-H), 1.18–1.08 (m,
24b
5H). 13C NMR (100 MHz, CDCl3): d 180.6, 161.6, 156.0, 154.5,
142.8, 141.4, 131.5, 122.0, 121.3, 120.6, 114.8, 71.5, 56.1, 55.5,
50.3, 46.4, 42.2, 37.1, 36.8, 33.0, 31.6, 31.2, 31.1, 29.4, 20.5, 19.5,
28b
31b
36b 41c
38b 44c
47b 58c
17.1. HRMS (ESI): m/z calcd for
C
29H34N4O2Na (M+Na)+,
493.2579; found, 493.2581.
a
b
c
Isolated yields.
2.3.13. 3b-Hydroxy-5-en-70-(4-chlorophenyl)-androstano[17,16-d][1,
2,4]triazolo[1,5-a]pyrimidine (3m)
2a (1 mmol), 3-AT (2 mmol), catalyst (1 mmol), solvent (10 mL), reflux, 30 h.
Under the same other conditions except that the amount of catalyst was
increased to 2 mmol.
White solid, yield 65%, mp 291–293 °C. 1H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H, 20-H), 7.79 (d, J = 8.4 Hz, 2H, Ar–H), 7.58 (d,
J = 8.4 Hz, 2H, Ar–H), 5.38 (d, J = 4.8 Hz, 1H, 6-H), 3.61–3.48 (m,
1H, 3a
-H), 1.21 (s, 3H, 18-H), 1.19–1.08 (m, 5H). 13C NMR
J = 8.1 Hz, 2H, Ar–H), 5.37 (d, J = 4.2 Hz, 1H, 6-H), 3.62–3.49 (m,
1H, 3a-H), 3.08–2.98 (m, 1H, Ar-CH(CH3)2), 1.34 (d, J = 6.8, 3H,
(100 MHz, CDCl3) d 180.8, 155.9, 154.7, 141.6, 141.4, 137.3, 131.1,
129.0, 127.6, 122.7, 120.5, 71.5, 56.0, 50.3, 46.5, 42.2, 37.1, 36.8,
33.0, 31.6, 31.2, 31.1, 29.2, 20.5, 19.5, 17.1. HRMS (ESI): m/z calcd
for C28H32ClN4O (M+H)+, 475.2265; found, 475.2260.
Ar-CH(CH3)2), 1.33 (d, J = 6.8, 3H, Ar-CH(CH3)2), 1.21 (s, 3H, 18-
H), 1.19–1.08 (m, 5H). 13C NMR (100 MHz, CDCl3): d 180.7, 156.0,
154.6, 152.2, 143.0, 141.4, 129.7, 126.8, 126.6, 122.4, 120.6, 71.5,
56.1, 50.3, 46.4, 42.2, 37.1, 36.8, 34.3, 33.0, 31.6, 31.2, 31.1, 29.3,
23.8, 23.7, 20.5, 19.5, 17.1. HRMS (ESI): m/z calcd for C31H39N4O
(M+H)+, 483.3124; found, 483.3122.
2.3.14. 3b-Hydroxy-5-en-70-(4-dimethylaminophenyl)-
androstano[17,16-d][1,2,4]triazolo [1,5-a]pyrimidine (3n)
Yellow solid, yield 61%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.36 (s, 1H, 20-H), 7.81 (d, J = 8.8 Hz, 2H, Ar–H), 6.84 (d, J = 8.8 Hz,
2.3.17. 3b-Hydroxy-5-en-70-(4-morpholinylphenyl)-
2H, Ar–H), 5.37 (d, J = 4.1 Hz, 1H, 6-H), 3.60–3.49 (m, 1H, 3a-H),
3.09 (s, 6H, Ar–N(CH3)2), 1.20 (s, 3H, 18-H), 1.14 (m, 5H). 13C
NMR (100 MHz, CDCl3): d 180.3, 154.3, 151.8, 143.6, 141.4, 131.2,
125.0, 120.9, 120.7, 115.8, 111.1, 71.5, 56.2, 50.4, 46.3, 42.2, 40.1,
37.1, 36.8, 33.1, 31.6, 31.2, 31.1, 29.8, 20.5, 19.5, 17.1. HRMS
(ESI): m/z calcd for C30H38N5O (M+H)+, 484.3076; found, 484.3079.
androstano[17,16-d][1,2,4]triazolo[1,5-a] pyrimidine (3q)
Yellow solid, yield 63%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.37 (s, 1H, 20-H), 7.82 (d, J = 8.9 Hz, 2H, Ar–H), 7.05 (d, J = 8.9 Hz,
2H, Ar–H), 5.38 (d, J = 4.9 Hz, 1H, 6-H), 3.97–3.83 (m, 4H, protons of
morpholine), 3.61–3.49 (m, 1H, 3a-H), 3.42–3.26 (m, 4H, protons
of morpholine), 1.21 (s, 3H, 18-H), 1.19–1.07 (m, 5H). 13C NMR
(100 MHz, CDCl3): d 180.4, 156.1, 154.5, 152.6, 143.0, 141.4,
131.2, 121.5, 120.6, 119.2, 114.0, 76.7, 71.6, 66.7, 56.2, 50.3, 47.9,
46.3, 42.2, 37.1, 36.8, 33.0, 31.6, 31.2, 31.1, 29.6, 20.5, 19.5, 17.1.
HRMS (ESI): m/z calcd for C32H40N5O2 (M+H)+, 526.3182; found,
526.3185.
2.3.15. 3b-Hydroxy-5-en-70-(3-phenoxyphenyl)-androstano[17,16-d]-
[1,2,4]triazolo[1,5-a] pyrimidine (3o)
White solid, yield 71%, mp 167–169 °C. 1H NMR (400 MHz,
CDCl3): d 8.37 (s, 1H, 20-H), 7.65–7.51 (m, 2H, Ar–H), 7.48–7.35
(m, 3H, Ar–H), 7.26–7.15 (m, 2H, Ar–H), 7.12 (d, J = 7.7 Hz, 2H,
Ar–H), 5.39 (d, J = 4.9 Hz, 1H, 6-H), 3.60–3.52 (m, 1H, 3a-H), 1.18
(s, 3H, 18-H), 1.17–1.05 (m, 5H). 13C NMR (100 MHz, CDCl3): d
180.7, 157.7, 156.4, 155.9, 154.7, 142.1, 141.5, 130.7, 130.1,
130.0, 124.2, 124.1, 122.7, 120.8, 120.5, 119.7, 119.4, 71.5, 55.9,
50.3, 46.4, 42.2, 37.1, 36.8, 33.0, 31.6, 31.2, 31.1, 29.1, 20.5, 19.5,
17.1. HRMS (ESI): m/z calcd for C34H37N4O2 (M+H)+, 533.2917;
found, 533.2915.
2.3.18. 3b-Hydroxy-5-en-70-(4-methylsulfonylphenyl)-
androstano[17,16-d][1,2,4]triazolo [1,5-a]pyrimidine (3r)
White solid, yield 70%, mp > 300 °C. 1H NMR (400 MHz, CDCl3):
d 8.39 (s, 1H, 20-H), 8.18 (d, J = 8.4 Hz, 2H, Ar–H), 8.04 (d, J = 8.4 Hz,
2H, Ar–H), 5.38 (d, J = 4.9 Hz, 1H, 6-H), 3.62–3.48 (m, 1H, 3a-H),
3.16 (s, 3H, Ar–SO2CH3), 1.22 (s, 3H, 18-H), 1.20–1.07 (m, 5H).
13C NMR (100 MHz, CDCl3): d 181.1, 155.8, 154.9, 142.6, 141.4,
140.5, 134.5, 130.7, 127.8, 123.5, 120.4, 71.5, 56.0, 50.3, 46.6,
44.4, 42.2, 37.1, 36.8, 33.0, 31.6, 31.2, 31.1, 29.0, 20.5, 19.5, 17.1.
HRMS (ESI): m/z calcd for C29H35N4O3S (M+H)+, 519.2430; found,
519.2429.
2.3.16. 3b-Hydroxy-5-en-70-(4-isopropylphenylphenyl)-
androstano[17,16-d][1,2,4]triazolo [1,5-a]pyrimidine (3p)
White solid, yield 66%, mp 248–250 °C. 1H NMR (400 MHz,
CDCl3): d 8.38 (s, 1H, 20-H), 7.77 (d, J = 8.0 Hz, 2H, Ar–H), 7.46 (d,

L.-H. Huang et al. / Steroids 77 (2012) 367–374
373
BuO H
H2N
H2N
N
N
N
H2N
OH
O
N
N
O
N
N
- N
N
O
O
O
N
H
N
H
O
N
H
2a
A
H
N
N
N
N
N
N
N
HO
N
HN
N
N
N
- H2O
- 2H
N
H
O
N
O
N
H
H
C
3a
B
Scheme 2. Proposed mechanism for the formation of steroidal triazolopyrimidine 3a.
conditions in hand, we then applied the protocol to the condensa-
tion reaction of different 16-arylidene-17-ketosteroids (2b–r) with
3-AT, affording the desired steroidal[17,16-d][1,2,4]triazolo
[1,5-a]pyrimidines (3b–r) in moderate to good yields (Table 1).
All the new compounds were characterized by 1H, 13C NMR and
mass spectra.
3. Results and discussion
The protocol for the synthesis of 70-aryl-androstano
[17,16-d][1,2,4]triazolo[1,5-a]pyrimidines (3a–r) is very simple
and straightforward involving condensation reaction of 16-arylid-
ene-17-ketosteroids (2a–r) with 3-AT (Scheme 1). The intermedi-
A proposed mechanism for the ring formation of these novel
heterosteroids is shown in Scheme 2. Under basic conditions, ami-
notriazole exists as the anion and attacks the double bond of aro-
ates 2a–r containing the aromatic a,b-unsaturated ketone moiety
were prepared in excellent yields via Aldol condensation of
4-aza-androstane-3,17-dione (1a) or DHEA (1b) with aromatic
aldehydes in ethanol catalyzed by KF/Al2O3 [28]. The results was
shown in Table 1.
Initially, the reaction for the synthesis of target compounds was
carried out using 16-arylidene-17-ketosteroid (2a) and 3-AT as
model substrates with a molar ratio of 1:2 in presence of Lewis
acids in ethanol. Unfortunately, the desired product was not
observed. Presumably, the presence of a acid was not conducive
to nucleophilic attack of aminotriazole, although it could activate
matic
a,b-unsaturated ketone (2a) through aza-Michael addition
reaction to afford the intermediate A. Subsequently, the amino
group attacks the 17-ketone to form the heterocycle B via an intra-
molecular cyclisation reaction followed by elimination of H2O to
give the dihydrotriazolopyrimidine C. Finally, the 70-phenyl-substi-
tuted steroidal[17,16-d][1,2,4]triazolo[1,5-a]pyrimidine (3a) is
formed by automatic aromatization of intermediate C under the
reaction conditions.
In conclusion, we have developed a facile approach for the
synthesis of novel 70-aryl-androstano[17,16-d][1,2,4]triazolo
[1,5-a]pyrimidines (3a–r) starting from readily available 4-aza-
androstane-3,17-dione (1a) or DHEA (1b). This provides a facile
strategy to annelate steroid nucleus with widespread bioactive
1,2,4-triazolo[1,5-a]pyrimidine moiety, extending the categories of
heterosteroids. The strategy can be applied to diverse 3- or 17-keto-
steroids and the steroidal triazolopyrimidines may also allow fur-
ther modifications on the steroid skeleton. Biological evaluation of
these new compounds is in progress and will be reported elsewhere.
the aromatic
tion to Lewis bases to promote the reaction. To our delight, the
desired product 3-oxo-4-aza-70-phenyl-5
-androstano[17,16-
d][1,2,4]triazolo[1,5-a]pyrimidine (3a) could be isolated after
refluxing a mixture of 2a and 3-AT in ethanol in the presence of
NaOH for 30 h, although the yield was low (15%, Table 2).
Structural elucidation of 3a was determined from 1D and 2D
NMR spectra. Compared to 2a, the 1H NMR spectra of 3a exhibited
the characteristic 20-H signal (N–CH@N) as a sharp singlet at
8.38 ppm and absence of the olefinic proton (>C@CH–C6H5). In
addition, the other five characteristic aromatic protons, 4-NH and
a,b-unsaturated ketone. Thus, we turned our atten-
a
5a-H protons appeared at 7.56–7.81, 6.40 and 3.10 ppm, respec-
tively. The 13C, 2D NMR and mass spectra of 3a were also in accor-
dance with its proposed structure. Based on the DEPT-135 and 2D
NMR spectra, the characteristic signal at 154.71 ppm was assigned
to 20-C. There were five quaternary carbon signals at 180.4, 172.3,
155.8, 142.9, and 122.3 ppm, respectively belonging to 3a0-C, 3-C,
70-C, 50-C and 60-C. The 13C NMR spectrum of 3a also exhibited four
signals at 131.1, 129.6 (2C), 129.1 and 128.7 (2C) ppm for six aro-
matic carbons and absence of the 17-C carbonyl carbon compared
with 2a.
Acknowledgements
This work was supported by the National Natural Sciences
Foundation of China (No. 81172937).
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