Substituent effects in selenoxide elimination chemistry

Article abstract of DOI:10.1016/j.tet.2008.01.044

2α-(Arylseleno)cholestan-3-ones (3), 2α-(arylseleno)cholest-4-en-3-ones (4), and 4β-(arylseleno)-24-nor-5β-cholan-3-ones (5) were prepared and their stabilities toward oxidative elimination assessed. Simple competitive experiments demonstrate that electro

Full text of DOI:10.1016/j.tet.2008.01.044

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2824e2831
www.elsevier.com/locate/tet
Substituent effects in selenoxide elimination chemistry
Phoebe E. Macdougall a,b, Naomi A. Smith a,b, Carl H. Schiesser a,b,
*
a School of Chemistry, The University of Melbourne, Victoria 3010, Australia
b Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
Received 1 October 2007; received in revised form 17 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
2a-(Arylseleno)cholestan-3-ones (3), 2a-(arylseleno)cholest-4-en-3-ones (4), and 4b-(arylseleno)-24-nor-5b-cholan-3-ones (5) were pre-
pared and their stabilities toward oxidative elimination assessed. Simple competitive experiments demonstrate that electron-withdrawing sub-
stituents stabilize arylselenides toward oxidation, while electron-donating groups accelerate the oxidation process. In addition, ab initio and
density functional calculations on model systems reveal that selenoxides are relatively insensitive to the nature of substituents on selenium
toward elimination, suggesting that the oxidation step is rate-determining during oxidative elimination of selenides. Some results for sulfur
and tellurium are also presented.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
transition state (2), and there are computational studies that
support this hypothesis.3,4
The elimination of selenoxides to form unsaturated link-
ages is firmly entrenched in the synthetic chemists’ toolbox
and there are many examples of the use of these transforma-
tions in the literature.1 In the example given in Scheme 1,
Thomas and co-workers used this chemistry to prepare a key
intermediate (1) during work toward the synthesis of the anti-
parasitic compound, milbemycin G.2
ArSe
O
ArSe
O
H
4
3a: Ar = Ph
b: Ar = 4-CF3-Ph
c: Ar = 4-MePh
d: Ar = 4-MeOPh
CO2Et
CO2Et
O
Ph
Se
OH
OH
O
O
O
O
H
TMS
TMS
ArSe
H
BnO
BnO
SePh
5
O
O
1
2
As part of ongoing studies into selenium-containing thera-
peutic agents,5e7 we need to prepare arylseleno derivatives
(3e5) of 3-cholestanone, cholest-4-en-3-one, and 24-nor-5b-
cholan-3-one that were reasonably stable to elimination under
aerobic conditions. In principle, this outcome could be
achieved by either slowing down the rate of oxidation of aryl-
selenides (3e5) through judicious choice of aryl substituent,
or by decreasing the rate of the elimination step itself (or
both). We reasoned that electron-withdrawing substituents on
the aryl group (e.g., CF3) should decrease the rate of oxidation
Scheme 1. Reagents and conditions: 30% aq H2O2, CH2Cl2 (50%).
It is generally agreed that the mechanism of this transfor-
mation most likely involves oxidation of the selenide to the
corresponding oxide followed by rapid elimination via a cyclic
* Corresponding author. Tel.: þ61 3 8344 2432; fax: þ61 3 9347 8189.
E-mail address: carlhs@unimelb.edu.au (C.H. Schiesser).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.044

P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
2825
by reducing the electron density on selenium, while donating
groups (e.g., MeO) should have the opposite effect (Scheme
2). However, it was less clear to us what effect, if any, these
same groups would have on the elimination step itself.
When 24-nor-5b-cholan-3-one,10 prepared by the PCC
oxidation of 24-nor-5b-cholan-3a-ol,11 was reacted with
phenylselenenyl chloride in ethyl acetate, 4b-(phenylseleno)-
24-nor-5b-cholan-3-one (5a) was isolated in 49% yield after
chromatographic separation from minor amounts of the 2b-
isomer (8) and products (9e11) of elimination (Scheme 3).
The use of 4-(trifluoromethyl)phenylselenenyl chloride af-
forded the required compounds (3be5b) in similar yields after
chromatographic separation from the same sets of byproducts
as was observed with phenylselenenyl chloride (Scheme 3).
When these reactions were repeated using (4-methoxyphe-
nyl)selenenyl chloride, the only products observed were those
(6, 7, 9e11) of elimination,12 while 4-tolylselenenyl chloride
led to mixtures in which the required products (3ce5c)
Se
O
Se
O
CF3
MeO
H
H
Scheme 2.
We now report the results of both laboratory and computa-
tional studies into the effects of substituents in selenoxide
elimination chemistry. Simple competitive studies allow us
to conclude that, in line with expectation, donating groups ac-
celerate the oxidation step, while withdrawing groups stabilize
these arylselenides toward oxidation. In addition, the effect of
electron-withdrawing and donating groups on the ability of
selenoxides to undergo concerted elimination was examined
using computational techniques that also provide a comparison
with the analogous processes involving sulfur and tellurium.
1
appeared to be minor constituents as evidenced by H NMR
spectroscopy and were unable to be adequately purified by
chromatography.
Based on these observations, one can tentatively conclude
that the compounds bearing the more electron-rich arylseleno
substituents (3c,de5c,d) are more susceptible to aerobic oxida-
tion and subsequent elimination than the ‘parent’ or electron-
deficient selenides (3a,be5a,b). This conclusion is further
supported by simple competition studies involving 3a,b and
5a,b. For example, after an NMR solution containing an equi-
molar amount of 3a and 3b in CDCl3 was allowed to sit in con-
tact with 10 mol % hydrogen peroxide (as a 30% aqueous
2. Results and discussion
2.1. Competitive oxidation studies
1
solution) for 72 h, H NMR spectroscopy revealed signals at
d 5.84 and 7.14 characteristic of cholest-1-ene-3-one (6).13 Im-
portantly, the ratio of the signals at d 4.26 and 4.16 correspond-
ing to H-2 in 3b and 3a, respectively, was observed to be 1.7,
indicating that the trifluoromethyl substituted system (3b) is
less susceptible to oxidation and subsequent elimination than
the ‘parent’ steriod (3a). This ratio increased to 2.4 after 96 h.
Similar results were observed for competition studies involving
4a/4b.14 We conclude that electron-withdrawing groups on the
arylseleno substituent offer some protection against aerobic
oxidation and elimination, at least for the systems in this study.
We began this work by preparing phenylseleno-substituted
steroids (3ae5a). 2a-(Phenylseleno)cholestan-3-one (3a) was
prepared from 3-cholestanone and isolated in 57% yield by
treatment with phenylselenenyl chloride in ethyl acetate and
could be separated from varying amounts of cholest-1-ene-3-
one (6), the product of elimination, by flash chromatography
(Scheme 3). Prepared in this manner, 3a was identical to
that reported previously.8 In similar fashion, 4a was isolated
in 20% yield from cholest-4-ene-3-one, and after separation
from cholesta-1,4-dien-3-one (7), proved to be identical to
that prepared previously.9
2.2. Computational studies
3a or 3b
+
O
O
O
In order to determine the effect, if any, that groups of vary-
ing electron demand have on the elimination step itself, we
chose to use ab initio and density functional (DFT) techniques,
initially on simple systems (12) derived from 3-(methylsele-
no)butanone (Scheme 4). This system would also afford us
the opportunity to benchmark various computational methods.
H
H
6
4a or 4b
+
O
7
ArSe
O
O
+
+
O
O
O
O
Se
Me
Se
O
O
H
H
ΔE2‡
ΔE1‡
SeMe
ox
9
8
Me
O
+
5a or 5b
+
H
O
MeSeOH
H
12
13
Scheme 4.
O
11
10
It should be noted that oxidation of racemic 3-(methyl-
seleno)butanone will lead to a pair of erythro (R,S:S,R) and
Scheme 3. Reagents and conditions: PhSeCl or 4-(CF3)PhSeCl, EtOAc.

2826
P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
Table 1
Calculated energy barriers ðDEz1; DE2zÞ for the forward and reverse elimination
reactions involving 12t and imaginary frequency (n) associated with transition
state 13t (Scheme 4)
z
DEz1
DE1 þ ZPEa DEz2
DEz2 þ ZPEa nb
a
a
Level
RHF/6-31G*
RHF/6-311G**
171.1 156.2
157.3 142.5
187.1 180.3
229.5 222.5
1897i
1850i
d
RHF/cc-pVDZ
RHF/aug-cc-pVDZ
MP2/6-311G**
QCISD/6-311G**c
CCSD(T)/6-311G**d
B3LYP/6-311G**
B3LYP/cc-pVDZ
B3LYP/aug-cc-pVDZ
149.2
163.3
71.7
99.6
85.5
64.8
55.5
66.0
d
d
227.3
224.7
63.3
d
d
d
57.6
59.2
798i
d
d
d
113.5
93.1
90.8
d
d
d
Figure 1. B3LYP/6-311G** optimized structures of transition states 13t, 13e
involved in the oxidative elimination of 3-(methylseleno)butanone.
51.0
84.8
976i
d
d
d
83.0
91.3
d
d
d
a pair of threo (R,R:S,S) diastereomeric selenoxides that need to
be considered separately from a computational perspective.15
Searching of the C5H10SeO2 potential energy surface
located two diastereomeric selenoxides (12). The erythro
structure (12e) proved to be higher in energy than the corre-
sponding threo structure (12t) at all levels of theory used in
this study. At the B3LYP/6-311G** level, the difference in
energies is calculated to be only 3.4 kJ molꢀ1 and this small
difference would lead to an approximately 4:1 ratio of 12t
over 12e at ambient temperature, assuming thermodynamic
control. More likely, the oxidation is under kinetic control
and would lead to an approximately equal distribution of
selenoxides (12).
Further examination of the surface located cyclic transition
states 13t,e for elimination in the threo and erythro manifolds,
respectively. These structures proved to be true transition
states as evidenced by one imaginary frequency in the har-
monic frequency set, and were the lowest energy transition
structures found through conformational searching. The
B3LYP/6-311G** structures of both isomers of 13 are dis-
played in Figure 1. Full details at all levels of theory used in
this study are available as Supplementary data. It is interesting
to note that while 13t is derived from the anti conformation of
12, the lowest energy conformation of 13e has the syn config-
uration. It should also be noted that the corresponding MP2/6-
311G** structures are slightly ‘later’ than that calculated at
B3LYP, with the key distances in 13t, for example, calculated
a
Energies in kJ molꢀ1
.
.
b
Frequencies in cmꢀ1
c
QCISD/6-311G**//MP2/6-311G**.
CCSD(T)/6-311G**//MP2/6-311G**.
d
different to those from MP2 and that these differences are
responsible for the unusual (upward) trend observed when
higher-order correlation is included. These data can be com-
pared to those of Fujimoto; MP2/3-21G(*)//RHF/3-21G(*)
calculations provide a value of 68.4 kJ molꢀ1 for the analo-
gous elimination reaction involving the oxide of 1-methoxy-
2-(methylseleno)propane.3 Unfortunately this study did not
provide product energy data.
It is also interesting to note that while most levels of theory
predict that the elimination reaction involving 12t is exother-
mic, MP2/6-311G** predicts a slightly endothermic reaction.
On the basis of the data provided in Table 1, we conclude that
the elimination of 3-butenone from 12t is most likely an exo-
thermic process with a (gas phase) energy barrier somewhere
in the range 50e70 kJ molꢀ1
.
Energy data for the similar processes involving 12e at
selected levels of theory are provided in Table 2 and clearly
indicate that, apart from 2e3 kJ molꢀ1 increase in both DEz1
and DEz2, the same trends are observed as were evident for
the chemistry involving 12t.
We next turned our attention to chemistry involving substit-
uents of varying electron demand on selenium. To that end, we
examined the chemistry of the oxides (14, 15) of 3-(trifluoro-
methylseleno)butanone and 3-(aminoseleno)butanone, mole-
cules bearing electron-withdrawing and donating groups,
respectively (Scheme 5). Guided by the data obtained for the
methylselenides (above) and with the aim of getting a qualita-
tive picture of the effects of substituents on selenium, we
˚
to be 2.440, 1.305, and 1.288 A. These distances compare fa-
vorably with those calculated by Fujimoto and co-workers for
simple methylselenides at low levels of theory,3 and Bayse and
Allison for similar reactions involving selenocysteine.4
Table 1 lists the calculated energy barriers (DEz1; DE2z,
Scheme 4) for the forward and reverse reactions involving
the threo isomer. As is clearly evident from the data in Table
1, in the absence of electron correlation, high barriers are pre-
dicted for the forward and reverse reactions, with values of
DEz1 in excess of about 150 kJ molꢀ1. When electron correla-
tion is included (MP2), DEz1 drops to about 70 kJ molꢀ1, how-
ever, single-point higher-order correction increases this value
by about 14 kJ molꢀ1 using CCDS(T).
Table 2
Calculated energy barriers ðDEz1; DE2zÞ for the forward and reverse elimination
reactions involving 12e and imaginary frequency (n) associated with transition
state 13e (Scheme 4)
z
DEz1
DE1 þ ZPEa DEz2
DEz2 þ ZPEa nb
a
a
Level
RHF/6-31G*
RHF/6-311G**
MP2/6-311G**
B3LYP/6-311G**
a
174.9 159.2
159.8 144.2
190.1 183.0
232.8 225.3
1894i
1708i
853i
At the B3LYP/6-311G** level of theory, DEz1 is further
reduced to about 65 kJ molꢀ1. The data in Table 1 also reveal
that smaller basis sets like cc-pVDZ also reduce DEz1. It is pos-
sible that the QCISD and CCSD(T) geometries are sufficiently
73.5
65.7
61.4
53.3
67.1
95.0
64.1
90.0
1056i
Energies in kJ molꢀ1
.
b
Frequencies in cmꢀ1
.

P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
2827
O
O
O
O
O
Se
R
Se
O
SeR
O
O
O
R
Se
‡
ΔE1‡
ΔE2
SeR
‡
R
ΔE1
ox
O
O
H
+
H
14: R = CF3
15: R = NH2
16: R = CF3
17: R = NH2
+
RSeOH
18
19
RSeOH
Scheme 5.
Scheme 6.
In order to provide data for systems that more closely
resemble the compounds that were part of our experimental
study, we next examined the analogous elimination chemistry
in conjugated ring systems that bear methyl- and phenylseleno
substituents (Scheme 6) using B3LYP/6-311G**. Once again,
this chemistry involves diastereomeric pairs of oxides (18) and
transition states (19) and, as we observed in the other systems
in this study, the R,R:S,S (threo) pair of oxides (18) proved to
be of lower overall energy and were therefore the threo reac-
tion manifold was chosen as representative of this chemistry.
Calculated energy barriers ðDEz1Þ for the elimination step
itself are listed in Table 4, while a representative transition
state (19t, R¼Ph) is displayed in Figure 3. Full details of all
structures are available as Supplementary data.
Figure 2. B3LYP/6-311G** optimized structures of transition states 16t, 17t
involved in the oxidative elimination of 14t, 15t.
chose to only examine the threo reaction manifold involving
these systems. Figure 2 displays the transition states (16t,
17t) involved in each transformation depicted in Scheme 5,
while Table 3 lists the associated energy barriers at selected
levels of theory.
As is clearly evident from these data, these cyclic systems
eliminate with energy barriers some 11 kJ molꢀ1 lower than
those associated with the parent structures (12). Somewhat
surprising, both methyl and phenyl substituents are predicted
to react with the essentially the same values of DEz1, namely
As is clearly evident in Figure 2, replacement of the methyl
group in 13t with either trifluoromethyl (16t) or amino (17t)
has little effect on the critical distances in the cyclic transition
states for elimination. The data in Table 3 show similar trends
to those previously discussed as the levels of theory are
changed. Most interesting is the observation that at all levels
of theory, the electron-withdrawing (CF3) group has a slight
lowering effect on DE1z (B3LYP: 3.4 kJ molꢀ1) while the
donating group (NH2) has a more significant (B3LYP:
12.1 kJ molꢀ1) raising effect on this barrier. These data, to-
gether with our experimental observations, allow us to con-
clude that substituent demand on the selenium atom appears
to work in opposite directions in the oxidation and elimination
steps that occur during selenoxide elimination chemistry.
55 kJ molꢀ1
.
Finally, we chose to examine the effect of chalcogen in this
chemistry and consequently examined elimination reactions
involving the sulfur (20t) and tellurium (21t) analogues of
Table 4
B3LYP/6-311G** calculated energy barriers ðDEz1Þ for the elimination reac-
tions involving 18t and imaginary frequency (n) associated with transition
states 19t (Scheme 6)
a
R
DEz1
DEz1 þ ZPEa
42.3
42.0
nb
Me
Ph
a
55.3
55.6
937i
919i
Energies in kJ molꢀ1
Frequencies in cmꢀ1
.
b
.
Table 3
Calculated energy barriers ðDEz1; DE2z Þ for the forward and reverse elimination
reactions involving 14 and 15 and imaginary frequency (n) associated with
transition states 16 and 17 (Scheme 5)
z
DEz1
DE1 þ ZPEa DEz2
DEz2 þ ZPEa nb
a
a
14t, 16t
RHF/6-31G*
RHF/6-311G**
MP2/6-311G**
B3LYP/6-311G**
159.6 144.6
144.8 130.2
193.2 185.9
234.5 227.2
1790i
1678i
803i
70.8
61.4
59.2
49.5
72.3
94.4
69.5
89.2
830i
15t, 17t
RHF/6-31G*
RHF/6-311G**
MP2/6-311G**
B3LYP/6-311G**
a
183.7 168.8
169.1 154.5
188.1 181.2
228.2 221.1
1915i
1876i
881i
86.3
76.9
73.5
63.7
64.0
92.8
57.0
86.1
1055i
Energies in kJ molꢀ1
.
Figure 3. B3LYP/6-311G** optimized structures of transition state 19t
(R¼Ph) involved in the oxidative elimination of 18t (R¼Ph).
Frequencies in cmꢀ1
.
b

2828
P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
involving transition state 22t, some 20 kJ molꢀ1 higher that
O
O
O
O
E
Me
E
ΔE2‡
ΔE1‡
calculated for the corresponding selenoxide. Similarly, tellur-
oxide eliminations are calculated to be more favorable, for
example, the MP2/DZP value for DEz1 for 21t is some
15 kJ molꢀ1 lower than the corresponding MP2/6-311G**
value calculated for 12t.
Me
O
H
+
20: E = S
21: E = Se
22: E = S
MeEOH
23: E = Se
Scheme 7.
12t (Scheme 7). Once again, calculated energy barriers
ðDEz1; DEz2Þ are provided in Table 5, with calculated transition
structures (22t, 23t) displayed in Figure 4.
3. Conclusions
Simple competitive experiments have been used to demon-
strate that electron-withdrawing substituents stabilize arylsele-
nides toward oxidative elimination, while electron-donating
groups accelerate the oxidation process. In addition, ab initio
and density functional calculations on model systems reveal
that selenoxides are relatively insensitive to the nature of
substituents on selenium in the elimination step, suggesting
that the oxidation step is rate-determining during oxidative
elimination of selenides. These results allow for the design
of selenides better matched to their oxidative environment.
Unfortunately, for the higher heteroatoms such as tellurium
reliable all-electron basis sets are not available mainly because
of relativistic factors operating in the core region of the atom.
Pseudopotential basis sets offer a solution to this issue and we
have previously employed these in calculations involving tel-
lurium, iodine, and tin. The DZP basis set (see below) has
been shown by us to provide similar data as those generated
by 6-311G** and we consider it reliable for our purposes.16
As expected, the data in Table 5 shows that sulfoxide elim-
inations proceed less readily than their selenium counterparts,
with a B3LYP/6-311G** value of 84.6 kJ molꢀ1 for DE1z
4. Computational methods
Table 5
Calculated energy barriers ðDEz1; DE2z Þ for the forward and reverse elimination
reactions involving 20t and 21t and imaginary frequency (n) associated with
transition states 22t and 23t (Scheme 7)
Ab initio and DFT calculations were carried out on Dell
PowerEdge 400SC computers using the Gaussian 03 pro-
gram.17 Geometry optimizations were performed using stan-
dard gradient techniques. All ground and transition states
were verified by vibrational frequency analysis. Where appro-
priate, zero-point vibrational energy (ZPE) corrections have
been applied. Standard basis sets were used, except for sys-
tems containing tellurium in which the (valence) double-z
pseudopotential basis set of Hay and Wadt18 supplemented
with a single set of d-type polarization was used (exponent
d(z)Te¼0.252), together with the 6-311G** basis set for C,
O, and H. We refer to this basis set as DZP throughout this
work. Optimized geometries and energies for all structures
of transition and ground states in this study (Gaussian Archive
entries) are available as Supplementary data.
z
DEz1
DE1 þ ZPEa DEz2
DEz2 þ ZPEa nb
a
a
20t, 22t (E¼S)
RHF/6-31G*
199.4 183.4
185.0 169.4
187.1 180.3
229.5 222.5
1826i
1831i
d
RHF/6-311G**
RHF/cc-pVDZ
RHF/aug-cc-pVDZ
MP2/6-311G**
QCISD/6-311G**c
173.3
186.2
100.0
127.4
d
d
227.3
224.7
63.3
d
d
d
84.7
59.1
946i
d
d
d
113.5
93.1
90.8
d
d
CCSD(T)/6-311G**d 111.9
d
B3LYP/6-311G**
B3LYP/cc-pVDZ
B3LYP/aug-cc-pVDZ
84.6
74.4
84.2
70.2
84.8
1090i
d
d
d
d
83.0
91.3
d
d
21t, 23t (E¼Te)
RHF/DZPe
145.8 130.7
244.8 235.8
1878i
779i
1000i
MP2/DZPe
57.6
58.6
46.1
46.5
64.7
96.2
60.3
89.8
B3LYP/DZPe
5. Experimental
a
Energies in kJ molꢀ1
.
b
Frequencies in cmꢀ1
.
c
d
e
5.1. General
QCISD/6-311G**//MP2/6-311G**.
CCSD(T)/6-311G**//MP2/6-311G**.
For definition of DZP, see text.
Melting points are uncorrected. All NMR spectra were
recorded in CDCl3 on a Varian Inova 400 spectrometer. For
1H the residual peak of CHCl3 was used as the internal refer-
ence (d 7.26) while the central peak of CDCl3 (d 77.0) was
used as the reference for 13C spectra. 77Se NMR chemical
shifts are given in parts per million relative to externally refer-
enced diphenyl diselenide (d 464). 19F NMR chemical shifts
are given in parts per million relative to externally referenced
trifluoroacetic acid (d ꢀ78.5). EI mass spectra were recorded
at 70 eV on a Shimadzu QP5050 spectrometer. MS data are
given for 80Se. Tetrahydrofuran and diethyl ether were
distilled under nitrogen from sodium/benzophenone. Flash
chromatography was performed using Scharlau Kieselgel 60.
Figure 4. B3LYP/6-311G** optimized structures of transition state 22t, and
B3LYP/DZP optimized structure of transition state 23t.

P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
2829
5.2. 24-Nor-5b-cholan-3-one10
56.1, 56.2, 124.3 (q, JCF¼272.4 Hz), 125.9 (q, JCF¼3.7 Hz),
126.3 (q, JCF¼3.7 Hz), 129.7 (q, JCF¼32.4 Hz), 134.0,
206.6. 19F NMR: d ꢀ65.2. 77Se NMR: d 362.2. MS m/z (rela-
tive intensity) 610 (Mþ, 42), 55 (59), 43 (100). IR nmax 2931,
.
C34H49F3OSe: 611.2974, found 611.2974.
To a solution of PCC (3.78 g, 17.6 mmol) in anhydrous
CH2Cl2 (20.0 mL) was added 24-nor-5b-cholan-3a-ol11
(3.89 g, 11.7 mmol) in CH2Cl2 (30.0 mL). The reaction mix-
ture was stirred for 4.5 h at room temperature under nitrogen
before Et2O (200 mL) was added and the solution concen-
trated in vacuo. Flash chromatography (20% Et2O/petroleum
spirits) gave 24-nor-5b-cholan-3-one as a white solid (3.09 g,
2867, 1738, 1714 cmꢀ1
HRMS (MþH)þ calcd for
5.3.3. 2a-(Phenylseleno)cholest-4-en-3-one (4a)9
The title compound was prepared according to the general
procedure using cholest-4-en-3-one (100 mg, 0.260 mmol) in
EtOAc (2.30 mL) and phenylselenenyl chloride (59.8 mg,
0.312 mmol). Flash chromatography (2.5% Et2O/petroleum
spirits) afforded 4a as a yellow gum (27.4 mg, 20%). Rf
1
96%). Rf (20% Et2O/petroleum spirits) 0.32. H NMR: d 0.68
(s, 3H, 18-CH3), 0.80e1.60 (m, 26H, CH and CH2 of steroid
skeleton), 1.79e1.89 (m, 3H, CH3), 2.01e2.06 (m, 3H, CH3),
2.13e2.18 (m, 1H, 2-CH), 2.29e2.34 (m, 1H, 2-CH), 2.70
(t(ap), 1H, 4-CH, J¼14.3 Hz). 13C NMR: d 10.6, 12.4, 18.4,
21.5, 23.0, 24.5, 26.1, 26.9, 28.5, 28.6, 35.2, 35.8, 37.3, 37.3,
37.5, 40.4, 41.0, 42.7, 43.0, 44.7, 56.1, 56.7, 214.0. MS m/z (rel-
ative intensity) 330 (Mþ, 27), 95 (31), 81 (44), 55 (100), 41 (75).
IR nmax 2931.0, 2867.1, 1737.5, 1713.9 cmꢀ1. Mp 140e142 ꢁC,
(lit.11 141e142 ꢁC).
1
(10% Et2O/petroleum spirits) 0.11. H NMR: d 0.65 (s, 3H,
18-CH3), 0.85e2.42 (m, 38H, CH, CH2 and CH3 of steroid
skeleton), 4.24 (dd, 1H, 2-CH, J¼4.8 Hz, 14.4 Hz), 5.80 (s,
1H, 4-CH), 7.28 (d, 3H, Ar3,4,5-CH, J¼1.5 Hz), 7.57 (d, 2H,
Ar2,6-CH, J¼5.0 Hz). 13C NMR: d 12.2, 17.8, 18.9, 21.1,
22.9, 23.1, 24.1, 24.4, 28.3, 28.4, 30.0, 32.2, 32.9, 35.7,
36.0, 36.4, 39.8, 39.8, 41.0, 42.6, 44.7, 46.6, 54.1, 56.0,
56.3, 122.9, 128.0, 129.3, 135.2, 171.9, 196.1. 77Se NMR:
d 366.4. MS m/z (relative intensity) 540 (Mþ, 19), 197 (77),
5.3. General procedure for the arylselenation of steroidal
ketones
122 (78), 55 (100). IR nmax 2934, 2868, 1670 cmꢀ1
.
5.3.1. 2a-(Phenylseleno)cholestan-3-one (3a)8
To a solution of 3-cholestanone (200 mg, 0.518 mmol) in
EtOAc (4.56 mL) was added phenylselenenyl chloride
(120 mg, 0.621 mmol) under nitrogen. The reaction mixture
was stirred for 1.0 h before being quenched with water
(5 mL), extracted with EtOAc (3ꢂ10 mL), washed with water
(3ꢂ10 mL), dried (Na2SO4), and the solvent was removed in
vacuo. Flash chromatography (10% Et2O/petroleum spirits)
gave the title compound (3a) as a yellow gum (0.159 g, 57%).
5.3.4. 2a-[4-(Trifluoromethyl)phenylseleno]cholest-4-en-3-
one (4b)
The title compound was prepared according to the general
procedure using cholest-4-en-3-one (100 mg, 0.260 mmol) in
EtOAc (2.30 mL) and 4-(trifluoromethyl)phenylselenenyl
chloride (81.1 mg, 0.312 mmol) in EtOAc (1.00 mL). Flash
chromatography (10% Et2O/petroleum spirits) afforded 4b as
a yellow gum (56.3 mg, 36%). Rf (10% Et2O/petroleum spirits)
0.17. 1H NMR: d 0.66e2.39 (m, 41H, CH, CH2 and CH3 of ste-
roid skeleton), 4.33 (dd, 1H, 2-CH, J¼4.8 Hz, 14.4 Hz), 5.83 (s,
1
Rf (10% Et2O/petroleum spirits) 0.17. H NMR: d 0.62e1.94
(m, 41H, CH and CH2 of steroid skeleton), 2.24e2.41 (m, 3H,
CH3), 4.16 (dd, 1H, 2-CH, J¼6.4 Hz, 13.0 Hz), 7.26 (d, 3H,
Ar3,4,5-CH, J¼5.15 Hz), 7.52 (d, 2H, Ar2,6-CH, J¼8.45 Hz).
13C NMR: d 12.0, 12.0, 18.6, 21.3, 22.5, 22.8, 23.8, 24.2,
28.0, 28.2, 28.6, 31.5, 35.1, 35.7, 36.1, 37.6, 39.5, 39.7, 42.5,
44.6, 47.2, 48.0, 50.2, 53.6, 56.1, 56.2, 127.7, 128.3, 129.0,
134.8, 207.2. 77Se NMR: d 358.0. MS m/z (relative intensity)
542 (Mþ, 12), 386 (1), 231 (18), 122 (32), 55 (57), 40 (100).
1H, 4-CH), 7.50 (d, 2H, Ar2,6-CH, J¼7.1 Hz), 7.63 (d, 2H, Ar3,5
-
CH, J¼8.3 Hz). 13C NMR: d 11.8, 17.5, 18.6, 20.8, 22.5, 22.8,
23.8, 24.1, 28.0, 31.8, 32.7, 35.4, 35.7, 35.7, 36.0, 39.4, 39.4,
40.8, 42.3, 44.2, 46.6, 53.8, 55.7, 56.0, 122.4, 125.7 (q,
JCF¼3.7 Hz), 126.0 (q, JCF¼3.7 Hz), 129.4 (q, JCF¼32.4 Hz),
133.7, 134.8, 171.8, 195.2. 19F NMR: d ꢀ65.2. 77Se NMR:
d 371.7. MS m/z (relative intensity) 608 (Mþ, 11), 527 (16),
265 (36), 122 (68), 55 (100). IR nmax 2936, 2868, 1671,
1602.3 cmꢀ1. HRMS (MþH)þ calcd for C34H47F3OSe:
609.2817, found 609.2818.
IR nmax 2971, 1739 cmꢀ1
.
5.3.2. 2a-[4-(Trifluoromethyl)phenylseleno]cholestan-3-one
(3b)
The title compound was prepared according to the general
procedure using 3-cholestanone (100 mg, 0.260 mmol) in
EtOAc (2.30 mL) and 4-(trifluoromethyl)phenylselenenyl
chloride (81.1 mg, 0.312 mmol) in EtOAc (1.00 mL). Flash
chromatography (10% Et2O/petroleum spirits) afforded 3b as
a yellow gum (82.5 mg, 52%). Rf (10% Et2O/petroleum
5.3.5. 4b-(Phenylseleno)-24-nor-5b-cholan-3-one (5a)
The title compound was prepared according to the general
procedure using 24-nor-5b-cholan-3-one (409 mg, 1.24 mmol)
in EtOAc (10.9 mL) and phenylselenenyl chloride (285 mg,
1.49 mmol). Flash chromatography (10% Et2O/petroleum
spirits) afforded 5a as a yellow gum (294 mg, 49%). Rf
(10% Et2O/petroleum spirits) 0.24. 1H NMR: d 0.61e2.86
(m, 36H, CH, CH2 and CH3 of steroid skeleton), 3.74 (d,
1H, 4-CH, J¼7.8 Hz), 7.27 (d, 3H, Ar2,4,6-CH, J¼6.6 Hz),
7.56 (d, 2H, Ar3,5-CH, J¼6.6 Hz). 13C NMR: d 10.0, 11.6,
17.7, 21.0, 22.5, 23.8, 25.7, 26.0, 27.7, 27.9, 34.0, 34.3,
35.0, 35.7, 36.6, 39.4, 41.9, 42.2, 49.8, 52.7, 55.3, 55.7,
1
spirits) 0.21. H NMR: d 0.64e2.46 (m, 44H, CH, CH2 and
CH3 of steroid skeleton), 4.26 (dd, 1H, 2-CH, J¼6.3 Hz,
13.2 Hz), 7.46 (d, 2H, Ar2,6-CH, J¼8.2 Hz), 7.60 (d, 2H,
Ar3,5-H, J¼8.2 Hz). 13C NMR: d 12.0, 12.0, 18.6, 21.4,
22.5, 22.8, 23.8, 24.2, 28.0, 28.2, 28.6, 31.5, 35.1, 35.7,
36.1, 37.8, 39.5, 39.7, 42.5, 44.6, 47.4, 47.9, 50.3, 53.6,

2830
P.E. Macdougall et al. / Tetrahedron 64 (2008) 2824e2831
127.4, 127.9, 128.7, 134.8, 207.5. 77Se NMR: d 351.4. MS m/z
(relative intensity) 485 (Mþ, 8), 484 ([MꢀH]þ, 25), 95 (44),
81 (46), 55 (100). IR nmax 2931, 2867, 1709 cmꢀ1. HRMS
(MþH)þ calcd for C29H42OSe: 487.2474, found 487.2474.
Also isolated were small amounts of 2a-(phenylseleno)-24-
42.6, 46.2, 55.7, 55.7, 126.9, 161.8, 201.0. MS m/z (relative in-
tensity) 328 (Mþ, 13), 122 (100), 109 (59), 79 (68), 55 (82), 41
(73). IR nmax 2932, 2869, 1679, 1614 cmꢀ1. HRMS (MþH)þ
calcd for C22H36O: 329.2839, found 329.2839. Compound 9:14
1
mp 160e164 ꢁC. Rf (15% Et2O/petroleum spirits) 0.11. H
1
nor-5b-cholan-3-one (8a). H NMR: d 0.58e2.80 (m, 36H,
NMR: d 0.71 (s, 3H, 18-CH3), 0.80e2.04 (m, 27H, CH,
CH2 and CH3 of steroid skeleton), 2.23e2.47 (m, 5H, CH,
CH2 and CH3 of steroid skeleton), 5.72 (s, 1H, 4-CH). 13C
NMR: d 10.3, 11.9, 17.4, 18.0, 21.0, 24.1, 28.0, 28.2, 29.7,
32.0, 32.9, 34.0, 35.6, 36.9, 38.6, 39.6, 42.3, 53.8, 55.5,
55.8, 123.7, 171.9, 199.8. MS m/z (relative intensity) 328
(Mþ, 15), 229 (23), 124 (100), 79 (52), 55 (80), 41 (76). IR
nmax 2933, 2870, 1727, 1675, 1617 cmꢀ1. Compound 11:10
mp 166e169 ꢁC (lit.10 168e170 ꢁC). Rf (15% Et2O/petroleum
spirits) 0.07. 1H NMR: d 0.73 (s, 3H, 18-CH3), 0.80e2.06 (m,
26H, CH, CH2 and CH3 of steroid skeleton), 2.33e2.47 (m,
2H), 6.07 (s, 1H, 4-CH), 6.23 (d, 1H, 1-CH, J¼10.1 Hz),
7.06 (d, 1H, 2-CH, J¼10.3 Hz). 13C NMR: d 10.0, 11.7,
17.6, 18.3, 22.5, 24.0, 27.6, 27.9, 29.4, 32.6, 33.4, 35.2,
36.6, 39.1, 42.3, 43.4, 52.1, 55.1, 55.2, 123.4, 127.0, 155.9,
186.2. MS m/z (relative intensity) 326 (Mþ, 3), 122 (100),
91 (40), 79 (27), 55 (69), 41 (77). IR nmax 2938, 2869, 1727,
CH, CH2 and CH3 of steroid skeleton), 4.18 (dd, 1H, 2-CH,
J¼5.27, 14.2), 7.25 (d, 2H, Ar2,6-CH, J¼4.5 Hz), 7.53 (d,
3H, Ar3,4,5-CH, J¼7.6 Hz). 13C NMR: d 10.2, 11.9, 18.0,
20.8, 22.2, 24.1, 25.7, 26.4, 28.0, 28.2, 35.4, 36.9, 37.2,
39.6, 41.1, 42.5, 45.2, 46.2, 49.7, 53.0, 55.6, 56.3, 127.7,
128.1, 128.9, 135.0, 208.6.
5.3.6. 4b-[4-(Trifluoromethyl)phenylseleno]-24-nor-5b-
cholan-3-one (5b)
The title compound was prepared according to the gen-
eral procedure using 24-nor-5b-cholan-3-one (100 mg,
0.303 mmol) in EtOAc (2.67 mL) and 4-(trifluoromethyl)phe-
nylselenenyl chloride (81.1 mg, 0.312 mmol) in EtOAc
(1.00 mL). Flash chromatography (5% Et2O/petroleum spirits)
afforded 5b as a yellow gum (62.5 mg, 37%). Rf (10% Et2O/
1
petroleum spirits) 0.17. H NMR: d 0.65 (s, 3H, 18-CH3),
0.79e1.59 (m, 25H, CH, CH2 and CH3 of steroid skeleton),
1.76e2.00 (m, 6H, CH, CH2 and CH3 of steroid skeleton),
2.32e2.41 (m, 1H, 2-CH), 2.57 2.62 (m, 1H, 2-CH), 3.90
(d, 1H, 4-CH, J¼8.8 Hz), 7.48 (d, 2H, Ar2,6-CH,
J¼8.20 Hz), 7.64 (d, 2H, Ar3,5-CH, J¼8.2 Hz). 13C NMR:
d 10.3, 11.9, 18.0, 21.3, 22.9, 24.1, 26.0, 26.3, 28.0, 28.2,
34.7, 34.9, 35.3, 36.2, 36.9, 39.7, 42.2, 42.5, 50.2, 53.2,
55.6, 56.1, 124.0 (q, JCF¼271.7 Hz), 125.6 (q, JCF¼3.7 Hz),
126.1 (q, JCF¼3.7 Hz), 129.7 (q, JCF¼32.4 Hz), 134.1,
207.4. 19F NMR: d ꢀ65.2. 77Se NMR: d 358.1. MS m/z (rela-
tive intensity) 554 (Mþ, 31), 95 (45), 81 (47), 55 (100). IR
nmax 2936, 2869, 1738, 1716.5 cmꢀ1. HRMS (MþH)þ calcd
for C30H41F3OSe: 555.2348, found 555.2346.
1664, 1626, 1603 cmꢀ1
.
Acknowledgements
The support of the Australian Research Council through the
Centres of Excellence Program and the Victorian Institute for
Chemical Sciences High Performance Computing Facility is
gratefully acknowledged.
Supplementary data
Optimized geometries and energies of structures 12e23 as
Gaussian Archive Entries. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
j.tet.2008.01.044.
5.3.7. 24-Nor-5b-cholan-4-en-3-one (9),14 24-nor-5b-
cholan-1-en-3-one (10), and 24-nor-5b-cholan-1,4-dien-3-
one (11)10
To
a
solution of 24-nor-5b-cholan-3-one (100 mg,
References and notes
0.303 mmol) in EtOAc (2.67 mL) was added phenylselenenyl
chloride (69.6 mg, 0.364 mmol) under nitrogen. The reaction
mixture was stirred for 1 h before being washed with water
(5 mL). The organic phase was returned to a reaction vessel,
THF (1.2 mL) added, followed by the dropwise addition of
30% hydrogen peroxide (75 mL). The reaction mixture was
stirred for 2.5 h, before being washed with water (5 mL),
satd Na2CO3 (5 mL), dried (MgSO4), and the solvent removed
in vacuo. Flash chromatography (15% Et2O/petroleum spirits)
afforded 10 (25.7 mg, 26%), 9 (18.2 mg, 18%), and 11
(13.9 mg, 14%) as a white crystalline solid. Compound 10:
mp 93e95 ꢁC. Rf (15% Et2O/petroleum spirits) 0.25. 1H
NMR: d 0.68 (s, 3H, 18-CH3), 0.78e2.13 (m, 31H, CH,
CH2 and CH3 of steroid skeleton), 2.72e2.81 (m, 1H, 4-
CH), 5.89 (d, 1H, 2-CH, J¼10.1 Hz), 6.84 (d, 1H, 1-CH,
J¼10.3 Hz). 13C NMR: d 10.3, 12.0, 18.0, 20.9, 22.3, 24.2,
26.0, 26.5, 27.9, 28.2, 35.2, 36.9, 38.6, 39.0, 39.8, 41.0,
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