A microwave promoted and Lewis acid catalysed solventless approach to 4-azasteroids

Article abstract of DOI:10.1016/j.steroids.2008.01.022

The preparation of 3-oxo-4-azasteroid from A-nor-3,5-secosteroid-3-oic acid is described in a solventless condition catalysed by Lewis acid under microwave irradiation. We utilized urea as an environmentally benign source for the generation of ammonia for the aza cyclization reaction.

Full text of DOI:10.1016/j.steroids.2008.01.022

steroids 7 3 ( 2 0 0 8 ) 637–641
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
A microwave promoted and Lewis acid catalysed solventless
approach to 4-azasteroids
Moyurima Borthakur, Romesh C. Boruah∗
Medicinal Chemistry Division, 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:
The preparation of 3-oxo-4-azasteroid from A-nor-3,5-secosteroid-3-oic acid is described in a
solventless condition catalysed by Lewis acid under microwave irradiation. We utilized urea
as an environmentally benign source for the generation of ammonia for the aza cyclization
reaction.
Received 6 December 2007
Received in revised form
13 January 2008
Accepted 26 January 2008
Published on line 8 February 2008
© 2008 Elsevier Inc. All rights reserved.
Keywords:
4-Azasteroids
Urea
Lewis acid
Microwave
1.
Introduction
secoandrostan-3-oic acid. However, the reported reaction
conditions are often stringent as these employed either
The replacement of one or more carbon atoms in a steroidal
molecule by a nitrogen atom affects the chemical properties
of the steroid and changes its biological activity [1]. The aza-
steroids thus accomplished received much attention during
last few decades [2,3]. Among the large group of azasteroids are
4-aza lactams which exhibited 5␣-reductase inhibitory prop-
erty for the conversion of major circulating androgen testos-
terone to more active metabolite 5␣-dihydrotestosterone.
The most potent 5␣-reductase inhibitor N-t-butyl-3-oxo-4-
aza-5␣-androst-1-ene-17␤-carboxamide (finasteride) is used
for treatment of benign prostatic hyperplasia, baldness and
prostate cancer [4,5].
The preparation of finasteride has been reported mostly
from 3␤-hydroxy-5-pregnen-20-one (pregnenolone) or 4-
androsten-3,17-dione in multi-step synthesis [6,7]. One
of the key steps in the total synthesis of finasteride,
is the construction of 3-oxo-4-azasteroid from A-nor-3,5-
toxic reagents or harsh reaction conditions [8]. Conse-
quently, the aza-cyclization reaction necessitates further
attention for a safe and environmentally benign synthetic
method.
The microwave promoted and solid-phase heterogeneous
reaction is well-known as environmentally benign reac-
tion methodology that usually provides improved selectivity,
enhanced reaction rates, cleaner products and manipulative
simplicity. We recently reported our efforts for the fast and
facile reaction strategies that involve microwave energy as
an unconventional energy source for three-component reac-
tion [9]. We also succeeded in utilizing urea as a safe source
of ammonia in the preparation of pyrimidines from ␤-formyl
enamides under microwave irradiation [10].
Herein, we describe a convenient solid phase high yield-
ing approach for the conversion of A-nor-3,5-secosteroid-3-oic
acid to 3-oxo-4-azasteroid using urea as a facile source of
∗
Corresponding author. Tel.: +91 3762370012; fax: +91 3762370011.
E-mail address: rc boruah@yahoo.co.in (R.C. Boruah).
0039-128X/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2008.01.022

638
steroids 7 3 ( 2 0 0 8 ) 637–641
ammonia catalysed by a Lewis acid under microwave irradia-
tion.
24.23, 23.25 (2C), 22.98, 21.31, 19.10, 12.35; MS (ESI): m/z 386
(M++1).
This procedure was followed for the synthesis of all prod-
ucts listed in Table 1.
2.
Experimental
2.2.2. 4-Aza-3-oxo-24-ethyl-cholest-5,22-dien (8)
All reactions were carried in a solventless condition and mon-
itored on Merck aluminium thin layer chromatography (TLC,
UV254 nm) plates. Column chromatography was carried out
on silica gel (60–120 mesh, Merck Chemicals). Melting points
were determined in open capillary tubes on Buchi B-540 appa-
ratus and are uncorrected. IR spectra were recorded on a
PerkinElmer FT-IR spectrometer using KBr pellets or on a thin
film using chloroform. All the 1H and 13C NMR spectra were
recorded on Brucker Avance DPX 300 MHz spectrometer using
tetramethylsilane (TMS) as internal standard. Chemical shifts
values were given as ı ppm values. ESI mass spectra were
recorded on a Brucker Daltonic Data Analysis 2.0 spectrometer.
Yield (880 mg 93%); mp 205–208 ◦C; IR (cm−1): 3200, 2950, 1680,
1665, 1460, 1385, 1225; 1H NMR (CDCl3, 300 MHz) ı: 8.08 (1H, bs,
–NH), 5.12–5.04 (2H, m, 22-H and 23-H), 4.94 (1H, s, 6-H), 1.01
(3H, s, 19-CH3), 0.73 (3H, s, 18-CH3), 2.65–0.61 (35H, m, alkane
protons); 13C NMR (CDCl3, 300 MHz) ı: 170.00, 149.30, 147.72,
138.90, 126.29, 66.10, 65.36, 60.76, 57.47, 51.82, 50.04, 48.85,
43.61, 41.41, 41.12, 40.95, 39.24, 38.43, 34.95, 33.78, 30.66, 28.52
(2C), 28.24, 21.82, 21.66, 10.58 (2C); MS (ESI): m/z 412 (M++1).
2.2.3. 17ˇ-Hydroxy-4-aza-3-oxo-androst-5-ene (9)
Yield (880 mg 84%); mp 289–291 ◦C; IR (cm−1): 3345, 2949, 1675,
1655, 1456, 1387, 1220; 1H NMR (CDCl3, 300 MHz) ı: 8.07 (1H,
bs, –NH), 4.85 (1H, s, 6-H), 3.63 (1H, m, 17-H), 1.07 (3H, s, 19-
CH3), 0.75 (3H, s, 18-CH3), 2.45–0.70 (18H, m, alkane protons);
13C NMR (CDCl3, 300 MHz) ı: 170.31, 140.33, 103.93, 82.06, 51.49,
48.47, 43.29 (2C), 36.68, 34.64, 32.11, 31.91, 30.79, 29.73, 28.82,
23.77, 19.20, 11.53; MS (ESI): m/z 290 (M++1).
2.1.
The typical oxidation procedure
2.1.1. Synthesis of 5-oxo-A-nor-3,5-secocholestan-3-oic
acid (1)
To a solution of 4-cholesten-3-one (3 g, 7.8 mmol) in iso-
propanol (40 ml) was added a solution of Na2CO3 (1.2 g,
11.8 mmol) in water (6 ml). The mixture was brought to reflux
and a solution of NaIO4 (12 g, 56 mmol) and KMnO4 (90 mg,
0.5 mmol) in warm water (75 ◦C) was added gradually (1 h)
while reflux temperature was maintained. The reaction was
cooled to 30 ◦C, and after 15 min the solids were removed by
filtration. The solid was washed with water and the combined
filtrates were concentrated under reduced pressure to remove
most of the isopropanol. The aqueous residue was cooled and
acidified (pH 3) with concentrated HCl solution. The product
was extracted with CH2Cl2, washed with water and dried over
anhydrous Na2SO4. Removal of the solvent afforded 1 (2.8 g,
89%) as a white solid.
2.2.4. 17ˇ-O-Acetoxy-4-aza-3-oxo-androst-5-ene (10)
Yield (850 mg 90%); mp 276–277.8 ◦C; IR (cm−1): 3209, 2937,
1731, 1694, 1677, 1449, 1389, 1247; 1H NMR (CDCl3, 300 MHz)
ı: 8.80 (1H, bs, –NH), 4.95 (1H, s, 6-H), 4.62 (1H, m, 17-H), 2.06
(3H, s, 17-OCOCH3), 1.10 (3H, s, 19-CH3), 0.83 (3H, s, 18-CH3),
2.48–0.80 (17H, m, alkane protons); 13C NMR (CDCl3, 300 MHz)
ı: 176.06, 174.97, 144.63, 108.37, 87.32, 55.56, 52.62, 47.24 (2C),
41.18, 38.84, 36.18, 34.04, 33.10, 32.21, 28.23, 25.98, 25.17, 23.51,
16.80; MS (ESI): m/z 332 (M++1).
2.2.5. 4-Aza-3-oxo-pregn-5-ene (11)
Yield (863 mg 92%); mp 274–276 ◦C; IR (cm−1): 3061, 2927, 1702,
1682, 1663, 1446, 1398, 1220; 1H NMR (CDCl3, 300 MHz) ı: 8.80
(1H, bs, –NH), 4.94 (1H, s, 6-H), 2.14 (3H, s, 20-CH3), 1.09 (3H,
s, 19-CH3), 0.66 (3H, s, 18-CH3), 2.82–0.62 (18H, m, alkane
protons); 13C NMR (CDCl3, 300 MHz) ı: 209.98, 170.60, 140.10,
104.03, 63.90, 56.98, 45.92, 44.42, 38.85, 34.37, 33.31, 31.98, 31.86,
29.98, 28.74, 24.77, 23.18, 21.07, 19.12, 13.73; MS (ESI): m/z 316
(M++1).
2.2.
The typical azacyclization procedure
2.2.1. Synthesis of 4-aza-3-oxo-cholest-5-en (7)
A mixture of 1 (1 g, 2.47 mmol) and urea (446 mg, 7.43 mmol)
and BF3·Et2O (0.4 ml, 3.2 mmol) was mixed intimately in a mor-
tar and irradiated in an open reaction vessel of a Synthwave
402 Prolabo focused microwave reactor (manufactured by M/S
Prolabo, 54 rue Roger Salengro, Cedex, France) after setting
the reaction temperature at 140 ◦C and power 80% (maximum
output 300 W). On completion of reaction after 3 min (vide
TLC), the reaction mixture was cooled and poured into water
(50 ml) and extracted with CH2Cl2 (3× 30 ml). The organic por-
tion was washed with water, dried over anhydrous Na2SO4
and the solvent was removed to obtain a crude product. Col-
umn chromatography separation using EtOAc:Hexane (15:85)
as eluant over silica gel afforded the title compound 7 (900 mg
95%); mp 232–35 ◦C; IR (cm−1): 3193, 3050, 2950, 1683, 1670,
1467, 1384, 1225; 1H NMR (CDCl3, 300 MHz) ı: 8.59 (1H, bs,
–NH), 4.92 (1H, s, 6-H), 1.08 (3H, s, 19-CH3), 0.87 (3H, s, 18-CH3),
2.46–0.70 (35H, m, alkane protons); 13C NMR (CDCl3, 300 MHz)
ı: 170.59, 140.22, 104.36, 56.87, 56.46, 48.33, 42.81, 39.89, 36.54,
36.18, 34.46, 32.00, 31.85, 30.12, 28.77, 28.59, 28.42 (2C), 24.57,
2.2.6. 4-Aza-androstan-5-en-3,17-dione (12)
Yield (840 mg 90%); mp >300 ◦C; IR (cm−1): 3189, 3066, 2944,
1737, 1677, 1663, 1451, 1389, 1212; 1H NMR (CDCl3, 300 MHz) ı:
8.70 (1H, bs, –NH), 4.97 (1H, s, 6-H), 1.12 (3H, s, 19-CH3), 0.92
(3H, s, 18-CH3), 2.50–1.06 (17H, m, alkane protons); 13C NMR
(CDCl3, 300 MHz) ı: 221.18, 170.41, 140.45, 103.41, 51.87, 48.44,
48.03, 36.19, 34.60, 31.82, 31.64, 31.52, 29.03, 28.74, 22.20, 20.64,
19.17, 14.04; MS (ESI): m/z 288 (M++1).
3.
Results and discussion
We applied this method of using urea as a source ammonia [11]
on 5-oxo-A-nor-3,5-secosteroid-3-oic acids (1–6) and obtained
the corresponding 4-azasteroidal products (7–12) in excellent
yields. As the experiments show, these azacyclization reac-

steroids 7 3 ( 2 0 0 8 ) 637–641
639
Table 1 – Synthesis of 3-oxo-4-azasteroids using urea and BF3·Et2O under microwave irradiation
Substrates
Products
Yield (%)
95
93
84
90
92
90
tions are carried in a solventless condition under microwave
irradiation and catalysed by BF3·Et2O.
tion medium instead of tert-BuOH as reported in the literature
[12].
The 5-oxo-A-nor-3,5-secosteroid-3-oic acids (1–6) could
be derived from 4-cholesten-3-one, 24-ethyl-4-cholesten-5,22-
dien-3-one, testosterone, testosterone acetate, progesterone
and 4-androsten-3,17-dione via oxidation method using NaIO4
and KMnO4 in presence of Na2CO3 in excellent yields
(80–86%). We employed isopropanol successfully as the reac-
In our approach, finely ground mixture of 5-oxo-A-nor-
3,5-secocholestan-3-oic acid (1) was irradiated in microwave
with urea in presence of BF3·Et2O for 3 min after setting
the reaction temperature at 140 ◦C and power 80% (maxi-
mum output 300 W). On completion of reaction (vide TLC),
the reaction mixture was cooled and poured into water and
Fig. 1 – Synthesis of 4-azasteroids using urea as a source of ammonia under microwave irradiation.

640
steroids 7 3 ( 2 0 0 8 ) 637–641
Fig. 2 – The suggested mechanism for Lewis acid catalysed azacyclization.
extracted with CH2Cl2. The organic portion was washed with
water, dried over anhydrous Na2SO4 and the solvent was
removed to obtain a crude product 7 in 95% yield. The prod-
uct was characterized by spectral and analytical analysis. The
1H NMR of 7 showed a broad singlet signal at ı 8.59 due
to amide –NH proton and C-6 olefinic proton at ı 4.92. The
13C NMR spectrum of 7 exhibited characteristic signal for C-
3 amide carbonyl carbon at ı 170.59, C-4 and C-5 olefinic
carbons at ı 140.22 and 104.36, respectively. The ESI mass
spectrum showed molecular ion peak at m/z 386 (M++1). Sim-
ilarly, 5-oxo-A-nor-24-ethyl-3,5-seco-22-cholesten-3-oic acid
(2), 5-oxo-A-nor-3,5-seco-17␤-hydroxy-androstan-3-oic acid
(3), 5-oxo-A-nor-3,5-seco-17␤-acetoxy-androstan-3-oic acid
(4), 5-oxo-A-nor-3,5-seco-pregnan-3-oic acid (5), 5-oxo-A-nor-
3,5-seco-androst-17-one-3-oic acid (6) and reacted with urea
under identical condition to afford 4-azasteroids (8–12) in
84–93% yields (Fig. 1). However, the reaction of 5-oxo-A-nor-
3,5-secosteroid-3-oic acids (1–6) with urea and BF3·Et2O under
conventional heating method (refluxing toluene) for 3–4 h
failed to afford the desired 3-oxo-4-azasteroids (7–12).
various Lewis acids under microwave irradiation; however,
BF3·Et2O gave the best result. We successfully demonstrated
that urea can be used as an environmentally benign and safe
source of ammonia avoiding liquid ammonia or toxic solvent
[4]. In addition, the application of urea as a source of ammonia
will become a feasible synthetic strategy and we believe that
the expansion of this method will offer great benefit in organic
synthesis.
Acknowledgements
We thank the Department of Science and Technology, New
Delhi for financial support and CSIR, New Delhi for the award
of a fellowship to one of us (MB). We also thank Director of this
Institute for his keen interests.
r e f e r e n c e s
In order to study the influence of the Lewis acid on the
azacyclization reaction, we carried the solid-phase reaction of
1 independently with SmCl3, ZrCl4, TiCl4, InCl3 and AlCl3 and
obtained 2 in 60–80% yield. However, the reactions were found
to be sluggish in absence of Lewis acid and the products were
obtained in very poor yields (<15%).
A proposed mechanism for the formation of 3-oxo-4-
azasteroid 7 from 1 is shown in Fig. 2. Under microwave
heating urea released ammonia which reacted with 1 to afford
imine intermediate (A). Tautomerization of intermediate (A)
led to enamine intermediate (B) under the reaction condition.
Activation of the carboxyl group by BF3·Et2O led to the nucle-
ophilic attack of the amino group to electron deficient carbonyl
function facilitating aza cyclization with loss of water to afford
7. The catalytic role of Lewis acid in aza cyclization is evi-
dent from the fact that the reaction was sluggish in absence
of Lewis acid with poor yield of the product.
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from solvent-less one-pot reaction of 5-oxo-A-nor-3,5-
secocholestan-3-oic acid. The reaction was catalysed by
a novel and effi-
a

steroids 7 3 ( 2 0 0 8 ) 637–641
641
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