Convenient synthesis of monomeric steroids from steroidal oxalate dimers using flash vacuum pyrolysis (FVP)

Article abstract of DOI:10.3906/kim-0907-111

Flash vacuum pyrolysis (FVP) or thermolysis (FVT), an environmentally friendly method for studying organic reaction mechanisms as well as synthesis, was applied to a series of oxalate dimers (1, 3, 5, 7, 9, 11, 13, and 15) to synthesise monomeric enes, dienes, and a triene (2, 4, 6, 8, 10, 12, 14, and 16). All steroidal monomers were identified by spectroscopic means. TUBITAK.

Full text of DOI:10.3906/kim-0907-111

Turk J Chem
34 (2010) , 359 – 366.
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˙
c
ꢀ TUBITAK
doi:10.3906/kim-0907-111
Convenient synthesis of monomeric steroids from
steroidal oxalate dimers using flash vacuum pyrolysis
(FVP)
Lutfun NAHAR1,∗, Alan B. TURNER2 and Satyajit D. SARKER3
1Drug Discovery and Design Research Division, Department of Pharmacy, School of Applied Sciences,
University of Wolverhampton, MA Building, Wulfruna Street,
Wolverhampton WV1 1LY, England, UK
e-mail: L.Nahar@wlv.ac.uk
2Japp Laboratory, Department of Chemistry, University of Aberdeen,
Aberdeen AB24 3UE, Scotland, UK
3Department of Pharmacy, School of Applied Sciences, University of Wolverhampton,
MM Building, Molineux Street, Wolverhampton WV1 1SB, England, UK
Received 10.07.2009
Flash vacuum pyrolysis (FVP) or thermolysis (FVT), an environmentally friendly method for studying
organic reaction mechanisms as well as synthesis, was applied to a series of oxalate dimers (1, 3, 5, 7, 9,
11, 13, and 15) to synthesise monomeric enes, dienes, and a triene (2, 4, 6, 8, 10, 12, 14, and 16). All
steroidal monomers were identified by spectroscopic means.
Key Words: Steroid, oxalate dimers, steroidal alkene, diene, triene, FVP.
Introduction
Flash vacuum pyrolysis (FVP) or thermolysis (FVT) is an environmentally friendly method for studying organic
reaction mechanisms as well as synthesis. It generates unimolecular radical reactions that are not generally
observed in conventional solution reactions.1 The FVP of symmetrical oxalate of alcohols and phenols has
attracted sporadic attention over the years.2−9 The Trahanovsky group observed that the bibenzyl oxalates
∗Corresponding author
359

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
readily gave bibenzyls,2 whereas substrates containing β-hydrogens suffered elimination,3,4 as did dialkyl
oxalates in the liquid phase.5,6 McNab7 studied the mechanism of thermolysis of a fluorene oxalate, and
smoking compositions containing oxalate ester flavorant-release additives were patented.8 Pyrolysis has also
been utilised as an analytical technique for sterol esters.9
Alkenes containing one or more double bonds are an important group of compounds, as they serve as
feedstocks for the petrochemical industry. They are conveniently used to synthesise a wide range of compounds
via simple addition reactions. The FVP techniques have been widely applied for synthesis of olefinic compounds.
As part of our ongoing studies on synthesis and reactions of steroidal dimers, we report here the FVP studies
on a series of steroidal oxalate dimers.10−12
Experimental
The starting materials, oxalate dimers, [bis (androst-4-en-3-on)-17β-yl oxalate (1), bis (5α-androstan-3-
on)-17β-yl oxalate (3), bis (androst-5-en-17-on)-3β-yl oxalate (5), bis (pregn-5-en-20-on)-3β-yl-oxalate (7),
bis-(5β-Cholan-24-oic acid methyl ester)-3α-yl oxalate (9), bis (cholest-5-en)-3β-yl oxalate (11), bis (5α-
cholestan)-3β-yl oxalate (13), and bis (stigmasta-5,22t-dien)-3β-yl oxalate (15)] were synthesised and iden-
tified previously in our lab.10−12 Melting points of the products were determined on a Gallenkamp melting
point apparatus. Infrared spectra (wave numbers in cm−1) were recorded on an ATI Mattson Genesis FTIR
spectrophotometer as KBr pellets. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian
Unity INOVA 400 MHz NMR spectrometer. Mass spectroscopic analyses were performed at the EPSRC Mass
Spectrometry Service at Swansea.
General procedure for the flash vacuum pyrolysis (FVP) of oxalate dimers. The furnace was
heated to 600 ◦ C. A small quantity of oxalate dimer (20 mg) in a small round bottom flask was placed in the
head of the apparatus and the system was evacuated to 10−2 mbar. The cold trap was cooled with liquid N2
and the head was heated to 300 ◦ C. Over a period of 1 h all the oxalate had sublimed. The liquid N2 bath was
removed and the system was opened to the atmosphere. The crude pyrolysate was washed out of the trap with
the use of a small amount of CHCl3 or DCM and EtOH. The solvent was evaporated to obtain the product
and the crude residue was purified by preparative thin layer chromatography (PTLC) using 15%-20% EtOAc
in a pet-ether (40-60 ◦ C) solvent system.
Androsta-4,16-dien-3-one (2). The title compound (2, 5 mg, 29%) was obtained as a white solid,
mp: 128-129 ◦ C (lit. mp13 127-129.5 ◦ C; IR13 ; MS14 and 1 H-NMR13). 13 C-NMR (62.5 MHz, CDCl3): δ
35.8 (C-1), 33.9 (C-2), 199.5 (C-3), 124.2 (C-4), 170.5 (C-5), 32.8 (C-6), 31.5 (C-7), 35.4 (C-8), 53.8 (C-9), 38.6
(C-10), 20.7 (C-11), 36.6 (C-12), 42.7 (C-13), 50.3 (C-14), 28.6 (C-15), 129.3 (C-16), 143.8 (C-17), 17.1 (C-18),
11.6 (C-19). ESIMS m/z: 271 [M+H]+
.
5α-Androst-16-en-3-one (4). The title compound (4, 5.5 mg, 32%) was obtained as a colourless solid,
mp: 141-142 ◦ C (lit. mp13 : 140-141 ◦ C; MS15 ;1 H- and 13 C-NMR16). IR (CHCl3): νmax cm−1 2964s (C-H),
2913s (C-H), 2854s (C-H), 1710s (ketonic C=O), 1628w (C=C), 1450m, 1414m, 1261m, 1068s, 1033s and 800m.
ESIMS m/z: 273 [M+H]+ .
Androsta-3,5-dien-17-one (6). The crude product was subjected to PTLC (20% EtOAc in pet-ether)
to obtain the title compound 6 (5 mg, 39%) as a white solid, mp: 88-89 ◦ C (lit. mp17 : 87-88 ◦ C; MS18 ; UV17
;
360

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
1 H- and 13 C-NMR17). IR (CHCl3): νmax cm−1 2965s (C-H), 2926s (C-H), 2852s (C-H), 1732s (ketonic C=O),
1637w (C=C), 1627w (C=C), 1444m, 1338m, 1311s, 1260s, 1188s, 1088s, 1020s and 809s. ESIMS m/z: 271
[M+H]+ .
Pregna-3,5-dien-20-one (8). The crude product was purified by PTLC (20% EtOAc in pet-ether) and
the title compound 8 (5.5 mg, 32%) was obtained as a colourless solid, mp: 137-138 ◦ C (lit. mp19 : 138-141
;
◦ C; UV19 ; MS20 1 H- and 13 C-NMR20). IR (CHCl3): νmax cm−1 2962s (C-H), 2858s (C-H), 1703s (ketonic
C=O), 1651w (C=C), 1637w (C=C), 1628w (C=C), 1497m, 1399m, 1260s, 1091s, 1018s and 799s. ESIMS m/z:
299 [M+H]+ .
5β-Cholan-3-en-24-oic acid methyl ester (10). PTLC (20% EtOAc in pet-ether) of the crude
product yielded the title compound 10 (5.3 mg, 30%) as a white solid, mp: 72-73 ◦ C (lit. mp21 : 74.5-75
◦ C and 1 H-NMR22). IR (CHCl3): νmax cm−1 2954s (C-H), 2936s (C-H), 2873s (C-H), 1735s (ester C=O),
1637w (C=C), 1560w (C=C), 1497m, 1399m, 1260s, 1091s, 1018s and 799s. 13 C-NMR (62.5 MHz, CDCl3): δ
35.9 (C-1), 35.3 (C-2), 127.6 (C-3), 125.0 (C-4), 43.5 (C-5), 27.7 (C-6), 26.3 (C-7), 35.9 (C-8), 40.3 (C-9), 34.1
(C-10), 21.5 (C-11), 40.1 (C-12), 42.7 (C-13), 56.6 (C-14), 24.2 (C-15), 28.2 (C-16), 56.0 (C-17), 12.0 (C-18),
23.3 (C-19), 35.4 (C-20), 18.3 (C-21), 31.1 (C-22), 31.0 (C-23), 174.8 (C-24), 51.5 (24-OMe). ESIMS m/z: 373
[M+H]+ .
Cholesta-3,5-diene (12). The crude product was subjected to PTLC (15% EtOAc in pet-ether) to
obtain the title compound 12 (5.9 mg, 33%) as a colourless solid, mp: 77-78 ◦ C (lit. mp23 : 77-78.5 ◦ C; UV
and MS24
(C=C), 1638w (C=C), 1467m, 1378m, 1261s, 1090s, 1035s and 800s. ESIMS m/z: 369 [M+H]+ .
5α-Cholest-2-ene (14). PTLC (15% EtOAc in pet-ether) of the crude product yielded the title
compound 14 (5.5 mg, 31%) as a white solid, mp: 68-69 ◦ C (lit.25 mp: 65-68 ◦ C and IR; UV25 ; MS26 1 H-
and 13 C-NMR26). ESIMS m/z: 371 [M+H]+
;
1 H- and 13 C-NMR16). IR (CHCl3): νmax cm−1 2964s (C-H), 2934s (C-H), 2852s (C-H), 1655w
;
.
Stigmasta-3,5,22t-triene (16). The crude was purified by PTLC (15% EtOAc in pet-ether) and the
title compound 16 (5.8 mg, 32%) was obtained as a colourless solid, mp: 109-110 ◦ C, white solid (lit.27 mp:
111-112 ◦ C). IR (CHCl3): νmax cm−1 2962s (C-H), 2922s (C-H), 2858m (C-H), 1655w (C=C), 1637w (C=C),
1458w, 1261s and 799s; UV27 1 H- and 13 C-NMR (Table). ESIMS m/z: 395 [M+H]+
; .
Results and discussion
All steroidal oxalate dimers (1, 3, 5, 7, 9, 11, 13 and 15) were pyrolysed over 1 h at 600 ◦ C and 10−2 mbar
pressure (Schemes 1-8). All monomeric steroid enes, dienes, and triene (2, 4, 6, 8, 10, 12 and 14), except 16,
were identified by comparison of their mp, IR, and NMR data with respective literature data. Compound 16
was identified by independent spectral analysis.
The FVP on dimers offered a good synthetic procedure for the generation of double bonds in all cases.
These types of pyrolytic conversion take place via elimination of the CO2 from the oxalate functionality and
form a diradical intermediate, which then convert to form new double bonds. The possible reaction mechanism
for the formation of a double bond via radical is shown in Scheme 9. In the intermediate step, the oxalate linkage
was broken homolytically and radicals were formed. Then the alkyl radicals were formed via decarboxylation.
361

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
Generation of another new radical and extrusion of the hydrogen gas led to the formation of the double bond
at Δ3 .
Table. 1 H- (coupling constant J in Hz in parentheses)a and 13 C-NMRb data of compound 16.
Chemical shifts (δ) in ppm
Chemical shifts (δ) in ppm
No.
No
1H
13C
35.5
23.3
129.3
125.3
141.8
123.4
32.0
32.2
51.5
34.1
21.2
40.0
42.7
57.4
24.5
1H
13C
29.2
56.3
12.5
21.4
40.8
21.5
138.6
129.6
48.7
32.1
19.3
21.1
25.7
12.5
t
1
2
0.95-2.30c
0.95-2.30c
5.60 br dt
5.92 br d
t
16
17
18
19
20
21
0.95-2.30c
0.95-2.30c
0.72 s
3
4
0.95 s
0.95-2.30c
5
6
5.37 br t
0.95-2.30c
0.95-2.30c
0.95-2.30c
t
0.95-2.30c
0.95-2.30c
t
1.00 d (6.1)
7
22 5.12 dd (8.5, 5.1)
23 4.98 dd (8.5, 5.1)
8
9
24
25
26
27
28
29
t
0.95-2.30c
0.95-2.30c
0.80 d (5.5)
0.80 d (5.5)
0.95-2.30c
0.83 t (5.5)
t
10
11
12
13
14 0.95 – 2.30c
15 0.95 – 2.30c
a Spectrum obtained in CDCl3 , 400 MHz; b Spectrum obtained in CDCl3 , 100 MHz; c Overlapped peaks within the
region of δ 0.90 to 3.00 ppm
O
O
FVP
O
O
O
O
2
O
1
Scheme 1. The FVP of testosterone oxalate dimer (1).
FVP of the testosterone oxalate dimer (1) afforded steroid diene, androsta-4,16-dien-3-one (2)13,14
(Scheme 1). 5α-Androst-16-en-3-one (4)13,15,16 was obtained from 5α-testosterone oxalate dimer (3) by
pyrolysis (Scheme 2), and pyrolysis of dehydroandrostane (DHEA) oxalate dimer (5) produced monomeric
steroid diene, androsta-3,5-dien-17-one (6)17,18 (Scheme 3). Similar treatment of pregnenolone oxalate dimer
(7) yielded pregna-3,5-dien-20-one (8) (Scheme 4).
362

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
H
O
O
O
FVP
O
O
O
H
3
4
O
H
Scheme 2. The FVP of 5α-testosterone oxalate dimer (3).
O
O
O
FVP
O
O
O
6
5
O
Scheme 3. The FVP of dehydroandrostane (DHEA) oxalate dimer (5).
O
O
FVP
O
O
O
O
8
7
O
Scheme 4. The FVP of pregnenolone oxalate dimer (7).
O
O
OMe
OMe
FVP
O
H
O
O
H
O
H
9
10
MeO
O
Scheme 5. The FVP of methyl lithocholate oxalate dimer (9).
363

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
FVP
O
O
O
O
12
11
Scheme 6. The FVP of cholesterol oxalate dimer (11).
FVP
O
H
O
O
H
O
H
14
13
Scheme 7. The FVP of cholestane oxalate dimer (13).
FVP
O
O
O
O
16
15
Scheme 8. The FVP of stigmasterol oxalate dimer (15).
The FVP of methyl lithocholate oxalate dimer (9) and cholesterol oxalate dimer (11) resulted in the
synthesis of, respectively, 5β-chol-3-en-24-oic acid methyl ester (10)21,22 (Scheme 5) and cholesta-3,5-diene
(12)16,23,24 (Scheme 6). 5α-Cholest-2-ene (14)25,26 was obtained from the pyrolysis of the cholestane oxalate
dimer (13) (Scheme 7). Interestingly, it was found that, in the case of dimer 9, solely 5β-cholan-3-en-24-oic
acid methyl ester (10) was formed, whereas, in the case of dimer 13, 90% 5α-cholest-2-ene (14) and also a
small amount of 5α-cholest-3-ene were produced.
364

Convenient synthesis of monomeric steroids from steroidal oxalate..., L. NAHAR, et al.,
O
o
-2
600 C, 10 mbar
.
O
O
.
O
o
O
Hotplate 300 C, 2h
O
O
O
O
H2
2 x CO2
2 x
.
.
2 x
2 x
O
+
.
2 x
.
.
H
H.
Scheme 9. Possible reaction mechanism for the formation of a double bond via radical.
The FVP of the stigmasterol oxalate dimer (15) yielded the monomer stigmasta-3,5,22t-triene (16)
(Scheme 8). Compound 16 was identified primarily by comparing its mp and UV data with literature values.27
The ESIMS spectrum of 16 displayed the pseudomolecular ion [M+H]+ at m/z395. The IR spectrum showed
absorption bands at 1655 and 1637 cm−1 , providing evidence for the presence of the double bonds in the
molecule. The 1 H-NMR spectrum of compound 16 (Table) was similar to that of stigmasterol16 with the
exception that, instead of the signal for the C-3 oxymethine proton (as in stigmasterol), signals (δ 5.60 and
5.92) for an extra pair of olefinic protons (H-3 and H-4) were observed. The 13 C-NMR spectrum (Table)
confirmed further the presence of the extra double bond between C-3 and C-4.
The FVP studies on oxalate dimers (1, 3, 5, 7, 9, 11, 13 and 15) established a convenient and environ-
mentally friendly (as no reaction reagents were involved) one-step synthetic route for the synthesis of steroidal
enes, dienes, and triene (2, 4, 6, 8, 10, 12, 14, and 16) for the first time.
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366

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