Chlorotrimethylsilane-promoted one-pot synthesis of steroidal[17,16-d] pyrimidines

Article abstract of DOI:10.1016/j.steroids.2010.06.007

A novel and practical procedure was developed for the preparation of steroidal[17,16-d]pyrimidines by chlorotrimethylsilane (TMSCl)-promoted one-pot multicomponent Biginelli-like condensations of steroid-17-ones, urea and aromatic aldehydes. First, treatment of the steroid-17-ones with urea and aromatic aldehydes in dimethylformamide (DMF)/acetonitrile (ACN) gives the corresponding Biginelli products, following the aromatising reaction of the Biginelli products at the same time under air to yield the desired steroidal[17,16-d]pyrimidines (78-88%). Since steroidal[17,16-d]pyrimidines with hydroxyl group can be subsequently converted into steroidal[17,16-d]pyrimidine derivatives, this general method provides a highly efficient route to these biologically important compounds.

Full text of DOI:10.1016/j.steroids.2010.06.007

Steroids 75 (2010) 1033–1038
Contents lists available at ScienceDirect
Steroids
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Rapid communication
Chlorotrimethylsilane-promoted one-pot synthesis of
steroidal[17,16-d]pyrimidines
Cunde Wang∗, Hangxian Xu, Zengyang Xie, Xingbin Wang, Zonglei Zhang, Qian Sun
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, Jiangsu, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical procedure was developed for the preparation of steroidal[17,16-d]pyrimidines
by chlorotrimethylsilane (TMSCl)-promoted one-pot multicomponent Biginelli-like condensations of
steroid-17-ones, urea and aromatic aldehydes. First, treatment of the steroid-17-ones with urea and
aromatic aldehydes in dimethylformamide (DMF)/acetonitrile (ACN) gives the corresponding Biginelli
products, following the aromatising reaction of the Biginelli products at the same time under air to yield
the desired steroidal[17,16-d]pyrimidines (78–88%). Since steroidal[17,16-d]pyrimidines with hydroxyl
group can be subsequently converted into steroidal[17,16-d]pyrimidine derivatives, this general method
provides a highly efficient route to these biologically important compounds.
Received 6 March 2010
Received in revised form 3 June 2010
Accepted 17 June 2010
Available online 25 June 2010
Keywords:
Steroidal[17,16-d]pyrimidines
Biginelli-type reaction
Steroid-17-ones
Pyrimidine
© 2010 Elsevier Inc. All rights reserved.
TMSCl
1. Introduction
have high significant antibacterial activity against the used strains
of Gram-positive and Gram-negative bacteria [12c]. Pyrimidines
Pentacyclic steroids and their derivatives are a very impor-
tant class of steroids. There are many examples of pentacyclic
steroidal derivatives of pharmacological and biological importance
[1–5]. For many years, the preparation of pentacyclic steroids
has attracted considerable attention from medicinal and synthetic
organic chemists. Further, it is proved that a number of biologi-
cally important properties of modified steroids are dependent upon
structural features of the steroid D-ring [6]. Chemical modifica-
tion of the steroid D-ring provides a way to alter the functional
groups, sizes and stereochemistry of the D-ring, and numerous
structure–activity relationships have been established by such syn-
thetic alterations.
It is known that substituted pyrimidines are an impor-
tant class of heterocyclic compounds. A number of synthetic
pharmacophores based upon the pyrimidyl structure exhibit bio-
logical activities, which were used widely as anti-inflammatory
agents, antimalarial, anti-hypertensive, antibacterial, antiasth-
matic, antiprotozoan, anti-rubella virus, antituberculosis, tyrosine
kinase-inhibiting agents, anti-HIV and anticancer activity [7–9].
On the other hand, steroids’ fused heterocyclic rings are pharma-
ceutically important compounds due to their inherent biological
properties [10–13]. For example, the in vitro antibacterial evalu-
ation of the pyrimidinoandrostane derivatives showed that they
of the estratriene series are agents for the treatment of hyperc-
holesterolaemia [10l]. Considerable attention is being paid to the
annelate steroidal moiety with isoxazole, pyrazole, pyridine and
pyrrole rings using various synthetic methods. Nevertheless, the
effort made towards the development of newer preparation for
annelated steroidal pyrimidines is still limited [10l,11–13].
Realising that the structure–activity relationship of the pen-
tacyclic steroids indicates that the fusion of the carbocyclic or
heterocyclic ring plays an important role of biological activity, we
synthesised steroidal D-ring fused pyrimidines as new pentacyclic
steroid skeletons for promising potential drug candidates.
In view of the remarkable importance from the pharmacologi-
cal and synthetic viewpoints, the development of new pentacyclic
steroids promising biological activity by new synthetic approaches
using mild reaction conditions remains an active research area.
Many previous studies proved that chlorotrimethylsilane (TMSCl)
has been used as a mild and efficient promoter for various
organic transformations [14,15]. It has also been reported as a
mild useful and inexpensive Lewis acid catalyst or promoter for
biguanide formation with benzylamine and dicyandiamide, [16]
‘direct’ cross aldol additions and the related Claisen condensa-
tion using TiCl4/Bu3N [17]. In our previous work [18], TMSCl was
employed to carry out several unusual cyclo-condensations includ-
ing one-pot synthesis of substituted quinolines and pyrroles. The
search for novel steroid libraries with potential biological activi-
ties is a major focus for chemical biology and medicinal chemistry.
Therefore, efficient methodologies to access new steroid skele-
∗
Corresponding author. Tel.: +86 514 8797 5568; fax: +86 514 8797 5244.
E-mail address: wangcd@yzu.edu.cn (C. Wang).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.06.007

1034
C. Wang et al. / Steroids 75 (2010) 1033–1038
2.3. (2aS,4S,6aS,6bS,8aS,13aS,13bR)-10-Hydroxy-6a,8a-
dimethyl-12-phenyl-2,2a,3,4,5,6,6a,
6b,7,8,8a,13,13a,13b-tetradecahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl acetate
(3aa)
Following the general procedure, the title compound 3aa (85%)
was obtained as a white solid. Mp 320 ◦C (dec); IR (KBr) ꢀ 3413,
2939, 1733, 1648, 1578, 1464, 1378, 1245, 1025 cm−1 1H NMR
;
Fig. 1. Structure and numbering of the steroidal[17,16-d]pyrimidine ring systems.
(300 MHz, CDCl3, ppm): 7.77–7.73 (m, 2H, aromatic H), 7.28–7.51
(m, 3H, aromatic H), 4.69–4.67 (m, 1H, C3-H), 2.63–2.48 (m, 2H,
C15-H), 2.19 (s, 1H, C14-H), 2.02 (s, 3H, CH3CO2), 1.08 (s, 3H, C18-
H), 0.89 (s, 3H, C19-H); 13C NMR (75 MHz, CDCl3, ppm): 171.8 (C17),
170.4 (CH3CO2), 160.5 (pyimidinyl C2-OH), 150.5 (pyimidinyl C6-
Ar), 131.6 (Ar), 130.7 (Ar), 128.9 (2C, Ar), 128.3 (2C, Ar), 114.6 (C16),
73.4 (C3), 54.8 (C14), 54.3 (C9), 46.7 (C13), 44.6 (C10), 36.4 (C5), 35.6
(C8), 34.3 (C12), 33.8 (C4), 32.5 (C1), 31.3 (C2), 28.7 (C15), 28.2 (C7),
27.3 (C6), 21.3 (C11), 20.6 (CH3CO2), 16.6 (C18), 12.1 (C19). Anal.
Calcd for C29H36N2O3: C, 75.62; H, 7.88; N, 6.08. Found: C, 75.48;
H, 7.64; N, 6.23.
tons of privileged structures are of special interest. Some studies
observed that pentacyclic steroids obtained by fusion of a carbo-
cyclic ring, such as benzene or cyclohexane or cyclopentane, to
the steroid nucleus or pentacyclic steroids derived from the fusion
of a carbocyclic ring to a heterosteroid skeleton was a convenient
procedure [4].
However, none of the synthetic procedures provides a general
route for one-pot synthesis of the steroids’ D-ring of fused pyrim-
idines promoted by TMSCl described here. Thus, as part of our
ongoing research on the development of new synthetic methods,
we report a TMSCl-promoted one-pot synthesis of steroidal[17,16-
d]pyrimidines (Fig. 1) from steroid-17-ones, urea and aromatic
aldehydes (Scheme 1 and Table 1).
2.4. (2aS,4S,6aS,6bS,8aS,13aS,13bR)-12-(4-Fluorophenyl)-10-
hydroxy-6a,8a-dimethyl-2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-
tetradecahydro-1H-naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-
yl acetate
(3ab)
2. Experimental section
Following the general procedure, the title compound 3ab (88%)
was obtained as a white solid. Mp 310–312 ◦C (methanol); IR (KBr)
ꢀ 3415, 2939, 1734, 1647, 1605, 1583, 1510, 1453, 1376, 1244,
2.1. General remarks
1026 cm−1 1H NMR (CDCl3, ppm): 7.84 (m, 2H, aromatic H), 7.27
;
All melting points (mps) were determined on a Yanaco melt-
ing point apparatus and are uncorrected. Infrared (IR) spectra were
recorded on a Nicolet FT-IR 5DX spectrometer as KBr pellets. The
1H nuclear magnetic resonance (NMR) and 13C NMR spectra were
recorded on a Bruker ACF-300 spectrometer with TMS as internal
reference. The J values are given in hertz. The elemental analyses
were performed on a Perkin–Elmer 240C instrument.
(m, 2H, aromatic H), 4.73 (m, 1H, C3-H), 2.63–2.53 (m, 2H, C15-
H), 2.28 (s, 1H, C14-H), 2.07 (s, 3H, CH3CO), 1.14 (s, 3H, C18-H),
0.95 (s, 3H, C19-H); 13C NMR (CDCl3, ppm): 170.3 (CH3CO2), 165.7
(C17), 162.3 (d, 1JCF = 246 Hz, Ar-F), 160.5 (pyimidinyl C2-OH), 150.5
(pyimidinyl C6-Ar), 130.6 (Ar), 130.5 (Ar), 128.0 (Ar), 115.9 (d,
2JCF = 21.6 Hz, (2C)Ar), 114.5 (C16), 73.2 (C3), 54.7 (C14), 54.2 (C9),
46.6 (C13), 44.5 (C10), 36.3 (C5), 35.5 (C8), 34.2 (C12), 33.7 (C4),
32.3 (C1), 31.2 (C2), 28.7 (C15), 28.0 (C7), 27.2 (C6), 21.2 (C11), 20.4
(CH3CO2), 16.5 (C18), 12.0 (C19). Anal. Calcd for C29H35FN2O3: C,
72.78; H, 7.37; N, 5.85. Found: C, 72.74; H, 7.32; N, 5.76.
2.2. Organic synthesis
General procedures for the synthesis of steroidal[17,16-
d]pyrimidines: To a mixture of steroid-17-one (1 mmol), urea
(120 mg, 2 mmol) and aromatic aldehyde (1.5 mmol) in dimethyl-
formamide (DMF)/CH3CN (6/12 ml) were added TMSCl (0.26 ml,
2 mmol) at room temperature. The resultant mixture was heated at
90 ◦C for 12 h. After the mixture was cooled to room temperature,
water (20 ml) was added to the reaction mixture and the resulting
mixture was extracted with CH2Cl2 (2× 15 ml), the organic phase
was washed with water and brine, and dried over Na2SO4. After
removal of solvent, the residue was purified by column chro-
matography (silica gel, EtOAc/CH2Cl2/MeOH, 1:1:0.05) to give the
desired product (3aa–cc; Table 1).
2.5. (2aS,4S,6aS,6bS,8aS,13aS,13bR)-10-Hydroxy-12-(4-
methoxyphenyl)-6a,8a-dimethyl-
2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl acetate
(3ac)
Following the general procedure, the title compound 3ac (88%)
was obtained as a white solid. Mp 265–267 ◦C (methanol); IR (KBr)
ꢀ 3415, 2939, 1732, 1640, 1606, 1563, 1512, 1443, 1378, 1251,
1026 cm−1 1H NMR (CDCl3, ppm): 7.73 (d, J = 6.9 Hz, 2H, aromatic
;
H), 7.04 (d, J = 6.9 Hz, 2H, aromatic H), 4.67 (m, 1H, C3-H), 3.87
(s, 3H, OCH3), 2.61–2.51 (m, 2H, C15-H), 2.18 (s, 1H, C14-H), 2.02
Scheme 1. Novel preparation of some steroidal[17,16-d]pyrimidines promoted by TMSCl.

C. Wang et al. / Steroids 75 (2010) 1033–1038
1035
(s, 3H, CH3CO), 1.07 (s, 3H, C18-H), 0.89 (s, 3H, C19-H); 13C NMR
(CDCl3, ppm): 171.8 (C17), 170.5 (CH3CO2), 161.7 ((Ar)COCH3),
160.6 (pyimidinyl C2-OH), 150.6 (pyimidinyl C6-Ar), 130.0 (2C, Ar),
123.8 (Ar), 114.4 (2C, Ar), 113.9 (C16), 73.4 (C3), 55.3 ((Ar)COCH3),
54.9 (C14), 54.4 (C9), 46.6 (C13), 44.6 (C10), 36.5 (C5), 35.7 (C8),
34.3 (C12), 33.9 (C4), 32.5 (C1), 31.4 (C2), 29.0 (C15), 28.2 (C7), 27.3
(C6), 21.3 (C11), 20.6 (CH3CO2), 16.6 (C18), 12.1 (C19). Anal. Calcd
for C30H38N2O4: C, 73.44; H, 7.81; N, 5.71. found: C, 73.28; H, 7.72;
N, 5.76.
3H, CH3CO), 1.17 (s, 3H, C18-H), 1.09 (s, 3H, C19-H); 13C NMR
(CDCl3, ppm): 171.7 (C17), 170.2 (CH3CO2), 160.5 (pyimidinyl C2-
OH), 150.5 (pyimidinyl C6-Ar), 140.0 (C CH), 131.6 (Ar), 130.5 (Ar),
129.0 (2C, Ar), 128.3 (2C, Ar), 121.6 (C CH), 114.5 (C16), 73.5 (C3),
55.0 (C14), 50.1 (C9), 46.4 (C13), 38.0 (C4), 36.7 (2C, C10 and C12),
32.4 (C8), 31.1 (C1), 30.7 (C2), 28.8 (C7), 27.6 (C15), 21.2 (C11), 20.2
(CH3CO2), 19.2 (C19), 16.3 (C18). Anal. Calcd for C29H34N2O3: C,
75.95; H, 7.47; N, 6.11. Found: C, 75.80; H, 7.38; N, 6.32.
2.9. (4S,6aR,6bS,8aS,13aS,13bR)-12-(4-Fluorophenyl)-10-
hydroxy-6a,8a-dimethyl-3,4,5,6,6a,6b,7,8,8a,13,13a,13b-
2.6. (2aS,4S,6aS,6bS,8aS,13aS,13bR)-10-Hydroxy-6a,8a-
dimethyl-12-(2-nitrophenyl)-
dodecahydro-1H-naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl
2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl acetate
(3ad)
acetate (3bb)
Following the general procedure, the title compound 3bb (83%)
was obtained as a white solid. Mp 230–232 ◦C (methanol); IR
(KBr) ꢀ 3445, 2943, 1734, 1646, 1558, 1499, 1439, 1377, 1246,
Following the general procedure, the title compound 3ad (78%)
was obtained as a white solid. Mp 216–218 ◦C (methanol); IR
(KBr) ꢀ 3425, 2939, 1732, 1646, 1564, 1529, 1452, 1348, 1247,
1033 cm−1 1H NMR (CDCl3, ppm): 7.79 (d, J = 8.1 Hz, 2H, aromatic
;
H), 7.23 (d, J = 8.1 Hz, 2H, aromatic H), 5.39 (s, 1H, C CH), 4.60 (m,
1H, C3-H), 2.63–2.57 (m, 2H, C15-H), 2.34 (m, 3H, C-CH), 2.04
(s, 3H, CH3CO), 1.13 (s, 3H, C18-H), 1.10 (s, 3H, C19-H); 13C NMR
(CDCl3, ppm): 171.3 (C17), 170.2 (CH3CO2), 162.4 (d, 1JCF = 246 Hz,
Ar-F), 160.5 (pyimidinyl C2-OH), 150.5 (pyimidinyl C6-Ar), 140.0
(C CH), 131.6 (Ar), 130.7 (Ar), 129.0 (Ar), 121.5 (C CH), 116.0 (d,
2JCF = 21.6 Hz, (2C)Ar), 114.5 (C16), 73.5 (C3), 55.0 (C14), 50.1 (C9),
46.4 (C13), 37.9 (C4), 36.7 (2C, C10 and C12), 32.3 (C8), 31.0 (C1),
30.6 (C2), 28.8 (C7), 27.5 (C15), 21.2 (C11), 20.2 (CH3CO2), 19.1
(C19), 16.3 (C18). Anal. Calcd for C29H33FN2O3: C, 73.09; H, 6.98; N,
5.88. Found: C, 73.02; H, 6.88; N, 5.72.
1026 cm−1 1H NMR (CDCl3, ppm): 8.13 (d, J = 7.8 Hz, 1H, aromatic
;
H), 7.76 (t, J = 7.2 Hz, 1H, aromatic H), 7.67–7.53 (m, 2H, aromatic
H), 4.67 (m, 1H, C3-H), 2.40–2.08 (m, 3H, C15-H and C14-H), 2.02
(s, 3H, CH3CO), 1.05 (s, 3H, C18-H), 0.85 (s, 3H, C19-H); 13C NMR
(CDCl3, ppm): 171.8 (C17), 170.5 (CH3CO2), 160.1 (pyimidinyl C2-
OH), 150.2 (pyimidinyl C6-Ar), 147.3 ((Ar)CNO2), 133.9 (Ar), 131.1
(Ar), 131.0 (Ar), 130.8 (Ar), 124.9 (Ar), 116.5 (C16), 73.1 (C3), 54.6
(C14), 54.3 (C9), 46.9 (C13), 44.6 (C10), 36.4 (C5), 35.6 (C8), 34.0
(C12), 33.8 (C4), 32.2 (C1), 31.2 (C2), 28.0 (C15), 27.3 (C7), 26.9
(C6), 21.3 (C11), 20.4 (CH3CO2), 16.6 (C18), 12.0 (C19). Anal. Calcd
for C29H35N3O5: C, 68.89; H, 6.98; N, 8.31. found: C, 68.82; H, 7.06;
N, 8.22.
2.10. (4S,6aR,6bS,8aS,13aS,13bR)-10-Hydroxy-12-(4-
methoxyphenyl)-6a,8a-dimethyl-3,4,5,6,6a,6b,7,8,8a,13,13a,13b-
dodecahydro-1H-naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl
acetate (3bc)
2.7. (2aS,4S,6aS,6bS,8aS,13aS,13bR)-10-Hydroxy-6a,8a-
dimethyl-12-(3-nitrophenyl)-
2,2a,3,4,5,6,6a,6b,7,8,8a,13,13a,13b-tetradecahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl acetate
(3ae)
Following the general procedure, the title compound 3bc (87%)
was obtained as a white solid. Mp 242–244 ◦C (ethanol); 1H NMR
(CDCl3, ppm): 7.75 (d, J = 6.6 Hz, 2H, aromatic H), 7.05 (d, J = 8.1 Hz,
2H, aromatic H), 5.39 (s, 1H, C CH), 4.60 (m, 1H, C3-H), 3.87 (s,
3H, CH3OAr), 2.62–2.56 (m, 2H, C15-H), 2.35–2.12 (m, 3H, C-CH),
2.03 (s, 3H, CH3CO), 1.23 (s, 2 × 3H, C18-H and C19-H); 13C NMR
(CDCl3, ppm): 171.0 (C17), 170.2 (CH3CO2), 161.6 ((Ar)COCH3),
160.6 (pyimidinyl C2-OH), 150.0 (pyimidinyl C6-Ar), 140.0 (C CH),
130.0 (2C, Ar), 123.7 (Ar), 121.6 (C CH), 114.4 (2C, Ar), 113.7 (C16),
73.5 (C3), 55.2 ((Ar)COCH3), 54.9 (C14), 50.1 (C9), 46.3 (C13), 37.9
(C4), 36.6 (2C, C10 and C12), 32.3 (C8), 31.0 (C1), 30.6 (C2), 29.0
(C7), 27.5 (C15), 21.2 (C11), 20.2 (CH3CO2), 19.2 (C19), 16.3 (C18).
Anal. Calcd for C30H36N2O4: C, 73.74; H, 7.43; N, 5.73. Found: C,
73.68; H, 7.22; N, 5.68.
Following the general procedure, the title compound 3ae (81%)
was obtained as a white solid. Mp 210–212 ◦C (methanol); IR (KBr)
ꢀ 3425, 3330, 2939, 1732, 1640, 1576, 1531, 1452, 1349, 1247,
1026 cm−1 1H NMR (CDCl3, ppm): 8.58 (s, 1H, aromatic C2-H),
;
8.37 (d, J = 8.1 Hz, 1H, aromatic C4-H), 8.23 (d, J = 7.8 Hz, 1H, aro-
matic C6-H), 7.77 (t, J = 8.1 Hz, 1H, aromatic C5-H), 4.68 (m, 1H,
C3-H), 2.65 (d, J = 6.3 Hz, 2H, C15-H), 2.34 (s, 1H, C14-H), 2.03 (s,
3H, CH3CO), 1.15 (s, 3H, C18-H), 0.91 (s, 3H, C19-H); 13C NMR
(CDCl3, ppm): 170.9 (C17), 170.2 (CH3CO2), 160.1 (pyimidinyl C2-
OH), 150.3 (pyimidinyl C6-Ar), 148.0 ((Ar)CNO2), 134.1 (Ar), 131.5
(Ar), 130.0 (Ar), 125.0 (Ar), 123.3 (Ar), 115.4 (C16), 73.1 (C3), 54.9
(C14), 54.1 (C9), 46.5 (C13), 44.4 (C10), 36.2 (C5), 35.4 (C8), 34.0
(C12), 33.6 (C4), 32.1 (C1), 31.1 (C2), 28.6 (C15), 27.9 (C7), 27.1
(C6), 21.1 (C11), 20.3 (CH3CO2), 16.6 (C18), 11.9 (C19). Anal. Calcd
for C29H35N3O5: C, 68.89; H, 6.98; N, 8.31. Found: C, 68.78; H, 7.00;
N, 8.34.
2.11. (6bS,8aS,13aS,13bR)-4-Methoxy-8a-methyl-12-phenyl-
2,6b,7,8,8a,13,13a,13b-octahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-10-ol
(3ca)
2.8. (4S,6aR,6bS,8aS,13aS,13bR)-10-Hydroxy-6a,8a-dimethyl-
12-phenyl-3,4,5,6,6a,6b,7,8,8a,13,13a,13b-dodecahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-4-yl acetate
(3ba)
Following the general procedure, the title compound 3ca (84%)
was obtained as a white solid. Mp 282–284 ◦C (methanol); IR (KBr)
ꢀ 3411, 2932, 1638, 1559, 1498, 1462, 1378, 1253, 1075 cm−1 1H
;
NMR (CDCl3, ppm): 7.78 (d, J = 6.0 Hz, 2H, aromatic H), 7.53 (m, 3H,
aromatic H), 7.22 (d, J = 8.4 Hz, 1H, aromatic C1-H), 6.74 (d, J = 8.4 Hz,
1H, aromatic C2-H), 6.64 (s, 1H, aromatic C4-H), 3.78 (s, 3H, C3-
OCH3), 2.89 (m, 2H, C6-H and C9-H), 2.71 (m, 2H, C15-H), 2.46 (d,
J = 12.9 Hz, 1H, C6-H), 2.33 (m, 2H, C11-H and C12-H), 1.96 (m, 1H,
C14-H), 1.76 (m, 4H, C7-H, C11–2 and C12-H), 1.44 (m, 1H, C7-
H), 1.13 (s, 3H, C18-H); 13C NMR (CDCl3, ppm): 171.7 (C17), 160.6
(pyimidinyl C2-OH), 157.5 (C3), 150.2 (pyimidinyl C6-Ar), 137.4
Following the general procedure, the title compound 3ba (83%)
was obtained as a white solid. Mp 292–294 ◦C (methanol); IR
(KBr) ꢀ 3445, 2943, 1734, 1646, 1558, 1499, 1439, 1377, 1246,
1033 cm−1 1H NMR (CDCl3, ppm): 7.53 (m, 3H, aromatic H), 7.42
;
(d, J = 6.9 Hz, 2H, aromatic H), 5.30 (s, 1H, C CH), 4.60 (m, 1H,
C3-H), 2.61–2.51 (m, 2H, C15-H), 2.35 (m, 3H, C-CH), 2.04 (s,

1036
C. Wang et al. / Steroids 75 (2010) 1033–1038
Table 1
Preparation of steroidal[17,16-d]pyrimidines (3aa–cc) promoted by TMSCl.
Entry
1
R1
R2
R3
2(ArCHO)
R
3(product)
Yield (%)
1
2
3
4
5
6
7
8
9
a
a
a
a
a
b
b
b
c
␤-OAc
␤-OAc
␤-OAc
␤-OAc
␤-OAc
␤-OAc
␤-OAc
␤-OAc
OCH3
␣-H
␣-H
␣-H
␣-H
␣-H
ꢁ5(6)
ꢁ5(6)
ꢁ5(6)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
a
b
c
d
e
a
b
c
H
4-F
4-OCH3
2-NO2
3-NO2
H
4-F
4-OCH3
H
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3ca
3cc
85
88
88
78
81
83
83
87
84
87
ꢁ
ꢁ
1,3,5(10)-Triene
1,3,5(10)-Triene
a
c
10
c
OCH3
4-OCH3
(C5), 132.0 (C10), 131.8 (Ar), 130.8 (Ar), 128.9 (2C, Ar), 128.3 (2C,
Ar), 126.0 (C1), 114.6 (C16), 113.8 (C4), 111.4 (C2), 55.1 (Ar)COCH3),
54.0 (C14), 46.9 (C13), 43.9 (C9), 37.5 (C8), 32.5 (C12), 29.4 (C6), 28.6
(C15), 27.2 (C7), 26.0 (C11), 16.7 (C18). Anal. Calcd for C27H28N2O2:
C, 78.61; H, 6.84; N, 6.79. Found: C, 78.70; H, 6.72; N, 6.78.
ter choice as a promoter for this reaction. Next, solvent, time and
the amount of TMSCl were varied. First, the solvent in the prepara-
tion of steroidal[17,16-d]pyrimidines (3aa) was varied. Among the
solvents tested (Table 2, entries 6–9), the mixed solvent DMF/ACN
gave the best result. The result showed that DMF/ACN gave the
product 3aa in 73%. In the second set of experiments, the model
reaction in DMF/ACN was carried out by varied reaction temper-
ature. After some experimentation, it was found that the model
reaction using a reaction temperature of about 90 ◦C produced the
corresponding compound 3aa in excellent yield. Furthermore, the
reaction time and the catalyst concentration could be reduced to
12 h and two equivalents, respectively (Table 2, entry 1, 85%).
Thus, with these results in hand, the optimised procedure
includes the application of one equivalent of the steroid-17-
one (1a–c) with one-and-a-half equivalents of aromatic aldehyde
(2a–e) and a twofold excess of urea in DMF/ACN in the presence of
two equivalents of TMSCl under air and requires the reaction mix-
ture to be initially maintained at room temperature, and then at
90 ◦C for 12 h. The desired steroidal[17,16-d]pyrimidines(3aa–cc)
were obtained in good yields (Scheme 1). Evidently, a sequence
of reactions involving Biginelli-like condensation took place dur-
ing formation of the product. This may be concluded from the
fact that when condensation of steroid-17-one and benzaldehyde
was carried out, 16-benzylidene-steroid-17-one was isolated as
the product, thereby indicating that a condensation reaction is the
first step in this three-component process. The proposed mecha-
nism of this novel ring formation is depicted in Scheme 2. The silyl
enol ether A is initially generated by TMSCl. A ␤-siloxy ketone B is
preformed by nucleophilic addition reaction of the aldehyde with
the silyl enol ether A; expectedly, the siloxy substituent plays the
role of the leaving group, followed by subsequent elimination of
trimethylsilyl alcohol to give the ketone C and Michael addition
reaction with urea promoted by TMSCl to yield the new silyl enol
ether D. Next, the silyl enol ether D isomerises ketone E quickly.
2.12. (6bS,8aS,13aS,13bR)-4-Methoxy-12-(4-methoxyphenyl)-
8a-methyl-2,6b,7,8,8a,13,13a,13b-octahydro-1H-
naphtho[2ꢀ,1ꢀ:4,5]indeno[1,2-d]pyrimidin-10-ol
(3cc)
Following the general procedure, the title compound 3cc (87%)
was obtained as a white solid. Mp 240–242 ◦C (methanol); IR
(KBr) ꢀ 3413, 2933, 1632, 1608, 1563, 1513, 1461, 1376, 1256,
1181 cm−1; 1H NMR (dimethyl sulphoxide (DMSO)-d6, ppm): 11.44
(brs, 1H, pyimidinyl C2-OH), 7.57 (d, J = 8.4 Hz, 2H, aromatic H), 7.07
(d, J = 8.7 Hz, 1H, aromatic C2-H), 7.97 (d, J = 8.4 Hz, 2H, aromatic H),
6.58 (d, J = 8.7 Hz, 1H, aromatic C1-H), 6.52 (s, 1H, aromatic C4-H),
3.73 (s, 3H, CH3OAr), 3.58 (s, 3H, C3-OCH3), 0.92 (s, 3H, C18-H);
13C NMR (DMSO-d6, ppm):172.8 (C17), 161.6 ((Ar)COCH3), 161.2
(pyimidinyl C2-OH), 159.2 (pyimidinyl C6-Ar), 157.2 (C3), 137.4
(C5), 132.2 (C10), 131.9 (Ar), 130.2 (2C, Ar), 128.0 (C1), 126.1 (Ar),
114.1 (2C, C16 and Ar), 113.7 (C4), 111.6 (C2), 55.5 ((Ar)COCH3),
55.0 ((Ar)COCH3), 53.4 (C14), 46.3 (C13), 43.6 (C9), 37.3 (C8), 32.5
(C12), 29.1 (C6), 28.1 (C15), 26.8 (C7), 25.8 (C11), 16.8 (C18). Anal.
Calcd for C28H30N2O3: C, 75.99; H, 6.83; N, 6.33. Found: C, 75.82;
H, 6.73; N, 6.36
3. Results and discussion
The reaction was initially studied with (3␤,5␣)-3-
acetyloxyandrosterone, urea and benzaldehyde, which were
selected as suitable substrates for reaction development in var-
ious promoters or catalysts and various solvents. At the outset,
various promoters or catalysts (HCl, FeCl3, ZnCl2, ZnO, p-toluene
sulphonic acid (PTSA) and TMSCl) and solvents (DMF, DMSO,
ACN, and DMF + ACN) were screened. To our delight, we observed
the formation of the desired product, 3aa (Table 2), when the
reaction was carried out using steroid (1.0 mmol), benzaldehyde
(1.5 mmol), urea (2.0 mmol) and DMF (10 ml) in the presence of
various promoters or catalysts (0.10 mmol or 2.0 mmol) under
90 ◦C for 12 h.
A comparison of the methods using TMSCl as a promoters
(Table 2, entry 6, 71% in yield), with selected other promoters
such as HCl, PTSA and other Lewis acids (FeCl3 and ZnCl2) or ZnO
(Table 2, entry 1, 68% in yield; entry 2, 36% in yield; entry 3, 65%
in yield; entry 4, 57% in yield; entry 5, 10% in yield, respectively)
that were examined is assembled in Table 2 to demonstrate that
the method using TMSCl as a promoter is indeed superior to sev-
eral of the other protocols. When the catalytic amount of HCl or
PTSA or FeCl3 or TMSCl was used in the reaction, a low yield of
product 3aa was obtained. Thus, TMSCl was found to be the bet-
Table 2
Various promoter/catalysts and solvents effect on reaction.a,b
.
Entry
Promoter/catalyst
Solvent
Yieldsc (%)
1
2
3
4
5
6
7
8
9
HCl
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
ACN
DMF/ACN
DMF/ACN
62a 68b
28a 36b
52a 65b
57b
PTSA
FeCl3
ZnCl2
ZnO
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
10b
47a 71b
66b
48b
73b
10
85d
a
Steroid (1 mmol), urea (2.0 mmol), benzaldehyde (1.5 mmol), catalyst
(0.10 mmol), solvent (10 ml); reflux for ACN, 90 ◦C for DMSO, DMF and DMF/ACN
(6/12 ml); 12 h.
b
Besides the amount of promoter/catalysts was changed to 1 mmol, other reac-
tion conditions were the same as above conditions.
c
Isolated yields.
Two equivalents of TMSCl were used in the reaction.
d

C. Wang et al. / Steroids 75 (2010) 1033–1038
1037
Scheme 2. Proposed mechanism of pyrimidine formation.
Then, as the key step, the nitrogen of urea within the 17-ketone
moiety of steroidal skeleton forms the six-membered heteroring
F in an intramolecular cyclisation reaction. Subsequently, water
is eliminated from compound F, giving the dihydropyrimidine
compound G. Finally, aromatisation occurs under air that leads
to the steroidal[17,16-d]pyrimidines (3aa–cc) [19]. The air oxy-
gen apparently acts as an effective oxidant for the aromatisation
of the dihydropyrimidine [19]. In general, unsaturated pyrimidi-
nol compounds are difficult to oxidise. Here, the aromatisation of
dihydropyridinones with aromatic groups was promoted by “HCl”
generated from TMSCl. However, the aromatisation took a long
time.
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Acknowledgements
We are grateful to the Natural Science Foundation of Jiangsu
Education Ministry of China (Grant 07KJB150135) and the NSF of
Jiangsu Province (Grant BK2008216) for financial support.
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