Ionic liquid-promoted wagner-meerwein rearrangement of 16α,17α- epoxyandrostanes and 16α,17α-epoxyestranes

Article abstract of DOI:10.1021/jo2006285

Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim] ⁺[PF₆]^-) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]⁺[BF₄]^-) were found to promote an unusual Wagner-Meer

Full text of DOI:10.1021/jo2006285

ARTICLE
pubs.acs.org/joc
Ionic Liquid-Promoted WagnerꢀMeerwein Rearrangement of
16r,17r-Epoxyandrostanes and 16r,17r-Epoxyestranes
†,‡
‡
‡
‡
‡
,†
ꢀ
Anita Horvꢀath, Agota Szꢀajli, Rꢀobert Kiss, Jꢀanos Kꢀoti, Sꢀandor Mahꢀo, and Rita Skoda-F€oldes*
†Department of Organic Chemistry, Institute of Chemistry, University of Pannonia, Post Office Box 158, H-8201 Veszprꢀem, Hungary
‡Chemical Works of Gedeon Richter Plc, Budapest, Hungary
S Supporting Information
b
ABSTRACT: Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate
([bmim]+[PF6]ꢀ) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]+-
[BF4]ꢀ) were found to promote an unusual WagnerꢀMeerwein rearrangement of
steroidal 16R,17R-epoxides leading to unnatural 13-epi-18-nor-16-one derivatives
as the main products. These compounds were isolated in good to excellent yields.
16R-Hydroxy-Δ13-18-norsteroids, the results of the usual rearrangement, were
obtained as minor components of the reaction mixtures. The ionic liquid
[bmim]+[PF6]ꢀ was shown to induce C-ring aromatization of 16R,17R-epoxyestranes due to the formation of HF, the hydrolysis
product of [PF6]ꢀ. Increasing amounts of HF and [PO2F2]ꢀ were detected by 19F and 31P NMR when the ionic liquid was reused.
The structures of the steroidal products, 16-oxo-18-nor-13R-steroid derivatives, 16R-hydroxy-Δ13-18-norsteroids, and C-aromatic
compounds were determined by two-dimensional NMR techniques and high-resolution mass spectrometry (HRMS). The ionic
liquids were recirculated efficiently.
’ INTRODUCTION
substrates, we observed an unusual rearrangement of 16R,17R-
epoxides leading to uncommon 17R-methyl-13R-18-norsteroid
derivatives. On the basis of this result, we decided to investigate in
detail the effects of ionic liquid promoter and structure of the
steroidal core on the selectivity of the rearrangement.
The reactions of steroidal epoxides with either Brønsted or
Lewis acids in the absence of effective external nucleophiles can
lead to a wide variety of rearranged structures depending on the
environment of the epoxide system.1 Facile one-step epoxide ring-
openingꢀsteroidal skeletal rearrangements are well-known in the
case of a number of steroidal ring A-, B-, and C-epoxides.2
However, one of the most widely studied reactions of this type
is the ring opening of steroidal 16R,17R-epoxides that usually
leads to 18-norsteroids with a CdC double bond in ring D or C.
The rearranged products are formed as a result of a Wagnerꢀ
Meerwein rearrangement that involves the formation of a carboca-
tion with a 1,2-migration of the angular C-18 methyl group to
C-17. The rearrangements can be induced by either a Brønsted
acid (p-toluenesulfonic acid,3 HF,4 HClO4,5 or HCOOH6) or a
’ RESULTS
Rearrangement of 16r,17r-Epoxyandrostanes. During
our investigations concerning ionic liquid-promoted ring open-
ing of steroidal epoxides,13a we found that in the reaction of
16R,17R-epoxy-5R-androstane (1a, Scheme 1) and 4-methylaniline
in 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]+-
[PF6]ꢀ) solvent, only traces of the awaited amino alcohol was
formed and 1a was converted into a new product with the same
molecular mass (M+ = 274) as the substrate. The same reaction
took place even in the absence of nucleophilic reagent. The
product was identified as a 17-methyl-18-nor-5R-androstan-16-
one that is an unusual rearrangement product of 1a, as the usual
acid-catalyzed reaction of similar compounds was shown to lead
to 16R-hydroxy-Δ13-18-norsteroids.3ꢀ6,8ꢀ10 The structure of 2a
was proved by various spectroscopic methods including 2D
NMR techniques (see below).
9
Lewis acid (AlCl3,7 ZnCl2,8 or BF3 ). The use of 17β-alkyl-
16R,17R-epoxides usually led to the 17R-substituted 16R-hydro-
xy-17β-methyl-Δ13-18-norsteroids. At the same time, Wicha and
co-workers10 obtained a mixture of 16R-hydroxy-Δ12 and -Δ13
compounds in the reaction of a 17β-H 16R,17R-epoxide and
AlCl3. Recently, a Bi(OTf)3-catalyzed rearrangement was shown
to result in a mixture of isomeric 16R- and 16β-hydroxy deriva-
tives, while in the presence of an acylating agent the reaction
afforded the 16R-acyl product selectively.11
In the past few years, ionic liquids have been found to be
effective and reusable catalysts for the ring opening of simple
epoxides in the presence of various nucleophiles.12 Recently, we
have shown that this methodology can efficiently be used for the
synthesis of steroidal vicinal amino alcohols and hydroxysulfides.13
Upon exploring the scope of the reaction with various steroidal
A more detailed investigation of the reaction showed that both
[bmim]+[PF6]ꢀ and 1-butyl-3-methylimidazolium tetrafluorobo-
rate ([bmim]+[BF4]ꢀ) were able to catalyze the skeletal rearran-
gement of 1a (Table 1, entries 1ꢀ6). It should be mentioned that
Received: March 24, 2011
Published: June 13, 2011
r
2011 American Chemical Society
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Scheme 1. Rearrangement of 16r,17r-Epoxy-5r-androstanes 1aꢀ1c in Ionic Liquids
Table 1. Rearrangement of 16r,17r-Epoxy-5r-androstanes
(entries 10ꢀ12). The [bmim]+[PF6]ꢀ-catalyzed reaction resulted
in the formation of a 17R-methyl-16-oxo-18-nor-13R-steroid
derivative (4), but in this case therearrangementwas accompanied
by loss of the 3β-hydroxyl group and formation of the Δ2 double
bond. The ionic liquid was reused without loss of activity and
selectivity(entries 8 and 9). The reaction ofthe tetrahydropyranyl-
(THP-) protected compound 1c led to the formation of the same
Δ2-16-keto derivative (entry 13). At the same time, similarly to the
reaction of 1a, in the presence of [bmim]+[BF4]ꢀ 1b was
converted to a mixture of steroids 2b and 3b (entries 10ꢀ12).
In this case, the 3β-hydroxyl group remained intact during the
reaction. Upon reuse of this ionic liquid, almost no change in
activity and selectivity was observed (entries 11 and 12).
It should be noted that, contrary to the 17β-H epoxides, the
total amount of 17β-acetoxy-16R,17R-epoxy-5R-androstane was
recovered unchanged after heating in either of the ionic liquids
mentioned above.
Rearrangement of 16r,17r-Epoxyestranes. Similarly to
the reactions of the epoxides in the androstane series, the heating
of 3-methoxy- and 3-benzyloxy-16R,17R-epoxyestra-1,3,5(10)-
trienes (5a and 5b, Scheme 2) in [bmim]+[BF4]ꢀ resulted in
formation of the 17R-methyl-16-oxo-18-nor-13R-steroid deriva-
tives 6a and 6b as the main products, together with 20ꢀ30% of
the usual WagnerꢀMeerwein rearrangement products 7a and 7b
(Table 2, entries 1ꢀ3 and 7ꢀ9).
in Ionic Liquidsa
products (%)
entry substrate
ionic liquid
convb (%)
2
3
4
1
2
3
1a
1a
1a
[bmim]+[PF6]ꢀ
[bmim]+[PF6]ꢀ d
[bmim]+[PF6]ꢀe
100
100
100
100c
100c
100c
4
5
6
1a
1a
1a
[bmim]+[BF4]ꢀ
[bmim]+[BF4]ꢀd
[bmim]+[BF4]ꢀe
90
85
80
63b
71b
65b
37b
29b
35b
7
8
9
1b
1b
1b
[bmim]+[PF6]ꢀ
[bmim]+[PF6]ꢀ d
[bmim]+[PF6]ꢀ e
100
100
100
100c
100c
100c
10
11
12
1b
1b
1b
[bmim]+[BF4]ꢀ
[bmim]+[BF4]ꢀd
[bmim]+[BF4]ꢀe
100
100
100
60b
65b
66b
40b
35b
34b
13
1c
[bmim]+[PF6]ꢀ
100
100b
a Reaction conditions: 0.2 mmol of steroids in 600 mg of ionic liquid, 110
°C, 30 h. b Determined by NMR by integration and deconvolution of
1H NMR. c Determined by GC. d First reuse of the ionic liquid. e Second
reuse of the ionic liquid.
At the same time, when [bmim]+[PF6]ꢀ was used as solvent
and catalyst, in addition to the 16-keto derivatives 6a and 6b, a
considerable amount of C-aromatic compounds 8a and 8b were
also formed (entries 4ꢀ6 and 10ꢀ12). Contrary to the previous
reactions, a remarkable change in the selectivities of the reactions
upon reuse of the catalyst was also observed here. After the first
run, the ratios of the 16-keto derivatives 6a and 6b decreased
significantly, and the C-aromatic compounds 8a and 8b were
obtained as the main products (entries 5,6 and 11,12). At the
same time, a notable increase in yields of the third type of product,
a mixture of isomeric 17-methyl compounds (9a or 9b), with
double bonds in various positions of ring D, was also observed.14
When selectivities of the reaction of 5b in various ionic liquids
are compared (entries 7ꢀ15), it can be concluded that the anion
of the ionic liquids plays a decisive role in the rearrangement. In
ionic liquids with [BF4]ꢀ anion, there is no difference between
rearrangement of 16R,17R-epoxides of the androstane and
estrane series and the main products are the 17R-methyl-16-
oxo-18-nor-13R-steroid derivatives 2a,2b and 6a,6b, respectively
At the same time, in ionic liquids with the [PF6]ꢀ anion,
formation of C-aromatic products was observed. No reaction
took place in [bmim]+Brꢀ and the starting material was recov-
ered unchanged.
reactions in [bmim]+[PF6]ꢀ with shorter reaction times resulted
in lower yields of 2a (70% yield after 15 h). An increase in the
reaction temperature to 150 °C led to several unidentified
products. probably due to decomposition. At room temperature,
no reaction took place after 30 h. While the reaction was
completely selective at 110 °C in [bmim]+[PF6]ꢀ (entry 1), the
use of [bmim]+[BF4]ꢀ as solvent and catalyst led to a mixture of
2a and the usual WagnerꢀMeerwein rearrangement product 3a in
a ratio of 63:37 (entry 4). The structure of the latter compound
was proved again by various NMR techniques (see below). The
ratio of the products 2a and 3a was determined from the 1H NMR
spectra of the reaction mixtures, by comparison of the 10β-Me
singlets, or from gas chromatography (GC). At 110 °C,
[bmim]+[PF6]ꢀ could be reused without any loss of activity and
selectivity (entries 2 and 3). Upon reuse of [bmim]+[BF4]ꢀ, a
small loss of activity was observed but the selectivity of the reaction
did not change considerably (entries 5 and 6).
Rearrangement of another epoxide (1b) was also investigated in
[bmim]+[PF6]ꢀ (Table 1, entries 7ꢀ9) and in [bmim]+[BF4]ꢀ
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Scheme 2. Rearrangement of 16r,17r-Epoxyestra-1,3,5(10)-trienes in Ionic Liquids
Table 2. Rearrangement of 16r,17r-Epoxyestra-1,3,5(10)-
trienes 5a and 5b in Ionic Liquidsa
productsb (%)
entry substrate
ionic liquid
convb (%)
6
7
8
9
1
2
3
5a
5a
5a
[bmim]+[BF4]ꢀ
[bmim]+[BF4]ꢀc
[bmim]+[BF4]ꢀd
100
100
92
81
77
76
19
23
24
4
5
6
5a
5a
5a
[bmim]+[PF6]ꢀ
[bmim]+[PF6]ꢀ c
[bmim]+[PF6]ꢀ d
100
100
100
69
21
26
31
71
62
8
12
7
8
9
5b
5b
5b
[bmim]+[BF4]ꢀ
[bmim]+[BF4]ꢀc
[bmim]+[BF4]ꢀd
100
100
83
70
73
70
30
27
30
10
11
12
5b
5b
5b
[bmim]+[PF6]ꢀ
[bmim]+[PF6]ꢀ c
[bmim]+[PF6]ꢀ d
100
100
100
67
24
14
24
52
51
9
24
35
Figure 1. Numbering of compounds 2a,b and 6a,b and some NOE
effects observed.
1
[emim]+[PF6]ꢀ e
[hmim]+[BF4]ꢀ e
[bmim]+Brꢀ
100
86
70
68
30
rearrangement took place. In the H NMR spectrum of 2a, the
13
14
15
5b
5b
5b
signals of 16β-H and 17β-H (3.31 and 3.06 ppm in 1a) disappeared,
and in the 13C NMR spectrum a new carbon signal appeared at
222.2 ppm (this is indicative of a nonconjugated keto group).
Instead of the two singlets at 0.70 and 0.77 ppm corresponding to
the angular methyl groups of 1a, a new singlet (0.66 ppm) and a
doublet (0.99 ppm) methyl peak were observed. The doublet nature
of the latter signal corresponds with the assumption that a Wagnerꢀ
Meerwein rearrangement took place, in which a migration of the
methyl group occurred from the C-13 to the C-17 position. In the
heteronuclear multiple-bond correlation (HMBC) spectrum, the
protons at 0.99 ppm gave a cross-peak with the carbon signal at
222.2 ppm. There was no indication in the 13C NMR spectrum of
any olefinic carbons, so the new compound was definitely not the
usual WagnerꢀMeerwein product (a 16-hydroxy-Δ13 derivative).
32
a Reaction conditions: 0.2 mmol of steroid in 600 mg of ionic liquid,
110 °C, 30 h. b Determined by NMR by integration and deconvolu-
tion of 1H NMR. c First reuse of the ionic liquid. d Second reuse of the
ionic liquid. [emim]+[PF6]ꢀ = 1-ethyl-3-methylimidazolium hexa-
e
fluorophosphate; [hmim]+[BF4]ꢀ = 1-hexyl-3-methylimidazolium
tetrafluoroborate.
Determination of Structures of Rearrangement Pro-
ducts. 16-Keto Compounds 2a,b, 4, and 6a,b. The MS spectrum
of 2a showed a molecular ion peak with the same value (m/z= 274)
as that of 1a, which corresponds with the initial expectation that a
The 1Hꢀ H correlation spectroscopy (COSY) experiment showed
1
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interactions between the methyl protons at 0.99 ppm and the
multiplet of a methine proton at 2.06ꢀ2.11 ppm (assigned as 17-H,
Figure 1) as well as between this latter proton and another methine
multiplet at 1.84 ppm (13-H). The two protons with relatively high
chemical shifts (2.21ꢀ2.24 ppm), corresponding to methylene
protons adjacent to a keto group, showed coupling with a methine
proton at 1.75 ppm (14-H). The chemical shift of 8-H (1.08 ppm)
1
was determined via a 1Hꢀ H COSY experiment that showed the
coupling of this proton with 14-H at 1.75 ppm. The configuration of
the D-ring carbon atoms was determined by nuclear Overhauser
effect (NOE) experiments. NOEs were observed between 17-H and
8β-H, indicating that H-17 is in the β position. The β position of
8-H is supported by its quartetꢀdoublet coupling pattern. More-
over, the coupling constants between 17β-H and 13-H [3J(17β-
H,13R-H) = 14 Hz] and between 8β-H and 14-H [3J(8β-H,14R-
H) = 11 Hz] as well as NOE between 9R-H and 14-H support the
R position of 14-H and the unexpected R position of 13-H.
Analogous observations were made regarding the C/D-ring
constitution and stereochemistry of 2b and 4. In the case of 2b
1
and 4, A-ring protons were assigned by use of the 1Hꢀ H COSY
Figure 2. Numbering of compounds 3a,b and 7a,b and some NOE
effects observed.
spectrum starting from 3-H (3.58ꢀ3.62 ppm) and the multiplet
of 2-H and 3-H (5.57ꢀ5.65 ppm), respectively. The A and B ring
signals of 2a were assigned starting from C19 angular methyl by
use of HMBC, heteronuclear single quantum coherence
chemical shifts of 7-H, 8-H, 11-H, 12-H, 15-H, and 17-H were
1
1
determined from the Hꢀ H COSY and HMBC spectra. The
configuration of the D-ring carbon atoms was determined by use
of NOE experiments and appropriate coupling constants. NOEs
were observed between 15β-H and 17-CH3, 8β-H and 11β-H,
8β-H and 15β-H, and 15β-H and 16-H (Figure 2). The peak of
15β-H was identified by the NOE between 8β-H and 15β-H.
The vicinal HꢀH couplings on 15β-H, namely, 3J(15β-H,16β-
H) = 4 Hz and 3J(17R-H,16β-H) = 8 Hz, together with relative
intensites of NOEs between 15β-H and 16-H as well as 15R-H
and 16-H, indicate that 16-H is in the β configuration.
1
1
(HSQC), and Hꢀ H COSY experiments. One starting point
of our assignment was that the configuration of 8β-H did not
change during the reactions. In the 1H NMR spectra of 6a and
6b, ring A protons and protons of the protecting groups on C-3
were assigned by use of the chemical shifts, coupling constants,
and splitting patterns of the signals. The corresponding carbon
3
signals were determined from the HSQC spectra. J hetero-
nuclear couplings were used to assign 6-H2 [3J(C-4f6-H)] and
9-H [3J(C-1f9-H)] in the spectra of 2b, 4, and 6a,b, as well as
10-CH3 [3J(C-1f10-CH3)] and 5-H [3J(C-1f5-H)] in the
case of 2b and 4. The chemical shifts of 7-H, 8-H, 11-H, 12-H,
C-Aromatic Compounds 8a,b. The MS spectra of 8a and 8b
showed compounds with molecular ion peaks smaller by m/z =
20 than those observed for 6a, 7a and 6b, 7b, respectively. The
lack of a 13C NMR signal around 220 ppm or a broad band
corresponding to an OH around 3300 cmꢀ1 in the IR spectrum
excluded both the 16-keto and 16-hydroxy groups. The appear-
ance of two new doublets in the aromatic region of the 1H NMR
spectra (at 7.55 and 7.11 ppm) and the six new signals between
121.3 and 147.5 ppm in the 13C NMR spectra, as compared to
the number of aromatic signals of the starting epoxides 5a and 5b,
indicated the formation of ring C aromatic compounds. In the 1H
NMR spectra the methyl doublets at 1.31 ppm showed that 8a
and 8b were also obtained via a methyl migration. Compounds
8a and 8b had no observable optical activity, so they probably
were obtained as racemic mixtures.
1
15-H, and 17-H were determined from the 1Hꢀ H COSY and
HMBC spectra. The 13-H and 14-H signals were assigned
3
according to the heteronuclear J couplings with C-16. The
configuration of the D-ring carbon atoms was determined from
NOE experiments. NOEs observed between 17-H and 8-H and
between 17-H and 12β-H showed that 17-H is in the β position.
The NOE between 17-CH3 and 13-H supported the unexpected
13R configuration at C-13.
16-Hydroxy Compounds 3a,b and 7a,b. The main features
of the NMR spectra of the usual WagnerꢀMeerwein rearrange-
ment products 3a,b and 7a,b are the methyl doublets around
0.92ꢀ1.03 ppm that show correlation with the 16-H protons
1
around 3.89ꢀ4.03 ppm in the 1Hꢀ H COSY experiment, as well
as the signals of the two olefinic quaternary carbons at
135.7ꢀ137.0 and 134.1ꢀ134.8 ppm in the HMBC experiment.
The A and B ring signals of 2a were assigned starting from C19
’ DISCUSSION
1
angular CH3 by use of HMBC, HSQC, and 1Hꢀ H COSY experi-
The results presented above show that various ionic liquids
can effectively catalyze the rearrangement of steroidal 16R,17R-
epoxides to the unusual 17R-methyl-16-oxo-18-nor-13R-steroid
derivatives. In addition to the novel structure of the products,
another important feature of the reaction is the excellent
selectivity toward these compounds.
Unnatural 13R steroids have a steroid framework with a
different shape compared to the 13β analogues due to the cis
junction of rings C and D. Some of them were shown to have
unusual conformational patterns15 that leads to a different
distance between the functional groups of rings A and D. This
ments. In the case of 3b, the A-ring protons were assigned by use of
1
1
the Hꢀ H COSY spectrum starting from 3-H (3.53 ppm).
1
In the H NMR spectra of 7a and 7b, the ring A protons and
the protons of the protecting groups on C-3 were assigned by use
of the chemical shifts, coupling constants, and splitting patterns
of the relevant signals. The corresponding carbon signals were
determined from the HSQC spectra. 3J heteronuclear couplings
were used to assign 6-H2 [3J(C-4f6-H)] and 9-H [3J(C-1f
9-H)], as well as C19 angular CH3 [3J(C-1fC19 angular CH3)]
and 5-H [3J(C-1f5-H)] in the case of 3b. In each case the
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Scheme 3. Possible Mechanism for Formation of Usual WagnerꢀMeerwein Rearrangement Products 3 and 7 in the Presence of
[bmim]+ Ionic Liquids
Scheme 4. Possible Mechanism for Formation of Rearrangement Products 2, 4, and 6 in the Presence of [bmim]+ Ionic Liquids
feature may greatly affect the chemical and biological properties
of these molecules, so the synthesis of new compounds may have
pharmacological importance.
reported by Yoshida,16 who observed that the BF3-catalyzed
rearrangement of 17β-acetoxy-A-nor-5R-androstan-1R,2R-ep-
oxide led to a mixture of five products. The structure of the
main product, formed in 40% yield, was established on the basis
of chemical reactions and spectral data as 17β-acetoxy-1R-
methyl-A-nor-5R,10R-estran-2-one. Another example for a simi-
lar rearrangement of an epoxide was reported in a terpenoid
synthesis by Wicha and co-workers.17
Following an analogous mechanism (Scheme 4), after gen-
eration of a carbonium ion at C-13 by cleavage of the C-17—O
bond facilitated by the imidazolium cation, the 13β-methyl group
migrates to C-17. Subsequent migration of 17R-H to C-13 and,
in turn, 16β-H to C-17 (route A) gives rise to the formation of
16-oxo-17R-methyl-18-nor-13R derivatives.16 Another possibi-
lity is loss of a proton after the 17R-H f C-13 hydride shift,
leading to an enolate (route B) that is transformed to the keto
derivative 2, 4, or 617 with the 17-methyl group in the R position
that corresponds to the thermodynamically more stable product.
Although the Lewis acid-catalyzed reactions of the 1R,2R-
epoxy-A-norsteroid investigated by Yoshida16 were not selective,
The Lewis acid-catalyzed rearrangement of similar epoxides
was shown to lead to 17β-methyl-Δ13-18-norsteroids4ꢀ6,8ꢀ11
that were obtained as side products 3a,b and 7a,b here. As
interaction of the C2 proton of the imidazolium cation of the
ionic liquid and the oxygen atom of an epoxide ring was detected
by NMR methods by Yang et al.,12g the formation of products 3a,
b and 7a,b may follow a similar mechanism (Scheme 3) to the
Lewis acid-induced rearrangement. Due to the acidity of the C2
proton of the imidazolium cation, the hydrogen-bond interaction
of the cation with the epoxide oxygen facilitates the opening of
the C-17—O bond, resulting in formation of a C-17 carbocation.
This is followed by migration of the C18 angular methyl group to
C-17, and subsequent loss of 14-H leads to the formation of the
Δ
13 double bond.
At the same time, formation of the products 2a,b and 6a,b in
such reactions is quite unusual. To the best of our knowledge,
the only example for a similar rearrangement for a steroid was
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Scheme 5. Rearrangement of 5b in [bmim]+[BF4]ꢀ in the Presence of Concentrated H2SO4
Scheme 6. Rearrangement of 7b in [bmim]+[PF6]ꢀ
the experiments revealed that the reaction conditions greatly
affected the outcome of the rearrangement. While the BF3-
catalyzed reaction afforded the usual WagnerꢀMeerwein rear-
rangement products in diethyl ether, the use of benzene as
solvent led to the unusual 1R-methyl-2-keto derivative as the
main product.
various conditions has been reported before.23 Accordingly, the
ionic liquid phase of the reaction mixture, obtained by heating 5b
for 30 h at 110 °C in [bmim]+[PF6]ꢀ, was investigated by 19F
and 31P NMR after removal of the steroidal components by
ethereal extraction. In the 19F NMR spectrum, in addition to the
doublet of the [PF6]ꢀ anion [δF = ꢀ72.5 ppm, J(P,F) = 722 Hz],
a small singlet corresponding to Fꢀ was observed at ꢀ151.4 ppm.
After the first reuse of the ionic liquid, the signal of Fꢀ increased
and two new doublets appeared in the 19F NMR spectrum [δF =
ꢀ75.7 ppm, J(P,F) = 936 Hz and δF = ꢀ83.8 ppm, J(P,F) =
966 Hz]. These two signals correspond to the hydrolysis
products [PO3F]2ꢀ and [PO2F2]ꢀ,24 respectively. This is sup-
ported by the 31P NMR spectrum of the reaction mixture contain-
ing a doublet ([PO3F]2ꢀ, δP = ꢀ8.0 ppm, J(P,F) = 936 Hz),
a triplet ([PO2F2]ꢀ, δP = ꢀ15.9 ppm, J(P,F) = 966 Hz) and a
septet ([PF6]ꢀ, δP = ꢀ144.4 ppm, J(P,F) = 715 Hz). The ratio of
[PO2F2]ꢀ/Fꢀ = 18/9/13/60, calculated from the 19F NMR
signals of the corresponding peaks. After the second reuse of the
ionic liquid, the ratio of signals corresponding to [PF6]ꢀ decreased
further ([PF6]ꢀ/[PO3F]2ꢀ/[PO2F2]ꢀ/Fꢀ = 6/9/14/71). The
dramatic change in selectivity of reactions upon reuse of the ionic
liquids supports the assumption that formation of the hydrolysis
products, especially the presence of HF, increases the rate of
aromatization.
Upon addition of concentrated H2SO4 (1 equiv for the steroid
substrate) to the reaction mixture of [bmim]+[BF4]ꢀ and 5b,
products 6b and 8b were obtained together with the debenzy-
lated derivatives 1025 and 1126 (Scheme 5).27
The C aromatic compounds are probably formed by the
aromatization of the usual WagnerꢀMeerwein rearrangement
products 7a and 7b. This is supported by the fact that heating 7b
in [bmim]+[PF6]ꢀ produced 8b in 75% yield, together with a
mixture of isomeric 17-methyl compounds 9b in a combined
yield of 25% (Scheme 6). At the same time, the 16-keto
compound 6b was recovered unchanged after heating under
Similarly, while a mixture of 16R-hydroxy-Δ12 and -Δ13
compounds were obtained by Wicha and co-workers10 starting
from 3β-acetoxy-16R,17R-epoxy-5R-androstane using AlCl3 cat-
alyst in diethyl ether, according to our results, the reaction of 1a
at room temperature in the presence of AlCl3 in toluene gave at
least four derivatives with the molecular mass of 274. On the basis
of GC and gas chromatography/mass spectrometry (GC-MS)
measurements, 2a was among the products, but it was formed
only in 25% abundance.
Another feature of the ionic liquid-catalyzed rearrangement is
the aromatization of ring C of 16R,17R-epoxyestra-1,3,5(10)-
trienes 5a and 5b in ionic liquids containing the [PF6]ꢀ anion.
The main interest of researchers for ring C aromatic steroids
was to evaluate the biological activity of this class of compounds. A
naturally occurring C-ring aromatic steroid showed remarkably
high fungistatic activity,18 and a cholesterol-lowering effect of a
synthetic compound was also observed.19 Accordingly, several
methods have been developed for the formation of ring C
aromatic steroids, a number of them involving a Wagnerꢀ
Meerwein rearrangement step. C aromatic steroids were obtained
starting form 17R-alkyl-17β-hydroxy 9R,11R-epoxides via Lewis
acid-induced methyl migration, epoxide ring opening, and
dehydration.20 Another possibility was the WagnerꢀMeerwein
rearrangement of 17R-hydroxy-19 or 17β-substituted-16R,17R-
epoxy steroids21 followed by oxidation/aromatization. The ne-
cessary number of double bonds could also be introduced into
ring C after a WagnerꢀMeerwein rearrangement by a 2-fold
brominationꢀdehydrobromination reaction sequence.22
In our case, aromatization took place exclusively in ionic
liquids with the [PF6]ꢀ anion. Hydrolysis of this anion under
the components of the mixture was found to be [PF6]ꢀ/[PO3F]2ꢀ
/
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ARTICLE
the same conditions. The increase in the amount of C aromatic
products upon reuse of the [bmim]+[PF6]ꢀ ionic liquid may be
due to increased acidity of the ionic liquid due to the formation of
HF.
(5R,13R,17R)-10,17-Dimethylgonan-16-one (2a). 1H NMR (500 MHz,
CDCl3) δ 2.21ꢀ2.24 (m, 2H, 15-H2); 2.06ꢀ2.10 (m, 1H, 17β-H);
1.70ꢀ1.89 (m, 5H, 1β-H, 7-Ha, 11-Ha, 13R-H, and 14R-H); 1.54ꢀ1.66
(m, 3H, 4-Ha, 11-Hb, and 12-Ha); 1.47ꢀ1.52 (m, 1H, 3-Ha); 1.34ꢀ1.43 (m,
1H, 3-Hb); 1.01ꢀ1.26 (m, 8H, 2-H2, 4-Hb, 6-H2, 12-Hb, 5R-H, and 8β-H);
0.81ꢀ0.89 (m, 2H, 1R-H and 7-Hb);0.99(d,J= 6.9 Hz, 3H, 17R-CH3); 0.66
(s, 3H, 10β-CH3). 13C NMR (125.75 MHz, CDCl3) δ 222.2 (C-16); 52.8
(C-9); 46.6 (C-5); 43.8 (C-15); 43.6 (C-13); 43.0 (C-17); 41.8 (C-14); 38.5
(C-1); 36.9 (C-8); 36.4 (C-10); 32.5 (C-7); 28.9 (C-2); 28.8 (C-6); 26.7
(C-4); 25.7 (C-12); 22.1 (C-3); 18.9 (C-11); 12.7 (17-CH3); 12.2 (10-CH3).
IR(KBr, cmꢀ1) 2922, 1732, 1443, 1374, 1287, 1154, 1038, 901, 870, 795. MS
[(m/z)/rel. intensity, %] 274(M+)/100, 259/20, 217/41, 203/10, 189/9,
163/37, 149/14, 121/8, 110/16, 95/15, 81/18. HRMS M (m/z) 274.229 30;
calcd value for C19H30O 274.229 12 (δ 0.67 ppm). Anal. calcd for C19H30O:
C, 83.15; H, 11.02. Found: C, 83.27; H, 11.11. Isolated yield 89% (48.8 mg,
obtained in [bmim]+[PF6]ꢀ), 62% (34.0 mg, obtained in [bmim]+[BF4]ꢀ);
mp 65ꢀ67 °C, white solid.
’ CONCLUSIONS
Ionic liquids [bmim]+[PF6]ꢀ and [bmim]+[BF4]ꢀ promote
an unusual WagnerꢀMeerwein rearrangement of steroidal
16R,17R-epoxides, leading to unnatural 13-epi-18-nor-16-one
derivatives as the main products. In the androstane series, the
latter compounds were obtained in excellent yields by use of
[bmim]+[PF6]ꢀ as solvent and catalyst. During the conversion of
16R,17R-epoxyestranes, the keto derivatives were isolated in
acceptable yields from the reaction mixtures obtained in
[bmim]+[BF4]ꢀ. The use of [bmim]+[PF6]ꢀ resulted in more
complex mixtures due to aromatization. This side reaction can be
explained by increasing acidity of the ionic liquid caused by
partial hydrolysis of the [PF6]ꢀ anion, producing HF. In the
reactions of 16R,17R-epoxyandrostanes, both ionic liquids can
efficiently be reused. At the same time, in the estranes series,
recirculation of [bmim]+[PF6]ꢀ results in an increasing amount
of side products.
(3β,5R,13R,17R)-3-Hydroxy-10,17-dimethylgonan-16-one (2b).
1H NMR (800.13 MHz, CDCl3) δ 3.58ꢀ3.62 (m, 1H, 3R-H);
2.23ꢀ2.29 (m, 2H, 15-H2); 2.09ꢀ2.13 (m, 1H, 17β-H); 1.76ꢀ1.88
(m, 6H, 12β-H, 13R-H, 7β-H, 2R-H, 1β-H, and 14R-H); 1.56ꢀ1.66 (m,
4H, 12R-H, 11R-H, 4R-H, and OH); 1.38ꢀ1.44 (m, 1H, 2β-H);
0.75ꢀ1.31 (m, 9H, 6R-H, 4β-H, 6β-H, 5R-H, 11β-H, 8β-H, 1R-H,
7R-H, and 9R-H); 1.03 (d, J = 6.9 Hz, 3H, 17R-CH3); 0.73 (s, 3H, 10β-
CH3). 13C NMR (201.21 MHz, CDCl3) δ 221.0 (C-16); 71.2 (C-3);
52.3 (C-9); 44.4 (C-5); 43.7 (C-15); 43.6 (C-13); 42.9 (C-17); 41.6
(C-14); 38.0 (C-4); 36.9 (C-8); 36.8 (C-1); 35.6 (C-10); 32.5 (C-7);
31.3 (C-2); 28.4 (C-6); 25.6 (C-12); 19.3 (C-11); 12.7 (17-CH3); 12.2
(10-CH3). IR (KBr, cmꢀ1) 3424, 2925, 1736, 1464, 1378, 1289, 1052. MS
[(m/z)/rel. intensity, %] 290(M+)/100, 272/40, 257/31, 243/13, 232/
42, 217/26, 201/20, 163/30, 147/21, 121/20, 108/46, 93/33, 81/27,
55/24, 41/20. HRMS M (m/z) 290.224 34, calcd value for C19H30O2
290.224 03 (δ 1.10 ppm). Anal. calcd for C19H30O2: C, 78.57; H, 10.41.
Found: C, 78.48; H, 10.59. Isolated yield 57% (33.0 mg, obtained in
[bmim]+[BF4]ꢀ); mp 119ꢀ122 °C, white solid.
’ EXPERIMENTAL SECTION
All NMR spectra, except for 1H NMR spectra of reaction mixtures and
19F and 31P NMR spectra of ionic liquids, were recorded on an 800 or
500 MHz NMR system, each equipped with a CryoProbe. 1H and 13
C
NMR spectral assignments were in each case supported by 2D 13C-
HSQC, 13C-HMBC and/or COSY spectra. For each molecule the
stereochemistry was deduced with the additional aid of 1D NOESY
spectra (mixing time was 500 ms). Each spectrum was referenced to
tetramethylsilane (TMS). All 1H NMR spectra of reaction mixtures were
recorded at 399.8 MHz, and 19F and 31P NMR spectra of reused ionic
liquids were recorded at 376.2 and 161.8 MHz, respectively. These
(5R,16R,17β)-10,17-Dimethylgon-13-en-16-ol (3a). 1H NMR (500
MHz, CDCl3) δ 3.95 (td, J = 3.9, 6.8 Hz, 1H, 16R-H); 2.53 (dd, J = 6.7
and 16.1 Hz, 1H, 15β-H); 2.37ꢀ2.43 (m, 1H, 17R-1H); 2.14ꢀ2.23 (m,
1H, 15R-H); 2.00ꢀ2.04 (m, 2H, 8β-H and 12-Ha); 1.80ꢀ1.91 (m, 3H,
7-Ha, 11-Ha, and 12-Hb); 1.60ꢀ1.78 (m, 3H, 1-Ha, 4-Ha, and OH);
1.42ꢀ1.55 (m, 2H, 3-H2); 1.15ꢀ1.30 (m, 5H, 2-H2, 4-Hb, and 6-H2);
1.07ꢀ1.15 (m, 3H, 1-Hb, 5R-H, and 11-Hb); 0.99 (d, J = 7.1 Hz, 3H,
17β-CH3); 0.85ꢀ0.97 (m, 2H, 1-Hb and 9R-H); 0.75 (s, 3H, 10β-CH3).
13C NMR (125.75 MHz, CDCl3) δ 135.7 (C-13); 135.1 (C-14); 79.6
(C-16); 52.0 (C-9); 50.7 (C-17); 47.0 (C-5); 40.8 (C-15); 38.2 (C-1);
36.3 (C-8); 36.2 (C-10); 31.4 (C-7); 29.4 (C-6); 28.8 (C-2); 26.8 (C-4);
24.4 (C-12); 22.1 (C-3); 22.0 (C-11); 16.5 (17-CH3); 11.7 (10-CH3).
IR (KBr, cmꢀ1) 3427, 2923, 2855, 1655, 1448, 1382, 1264, 1036, 824.
MS [(m/z)/rel. intensity, %] 274(M+)/100, 259/20, 256/85, 241/85,
217/8, 201/13, 199/13, 173/19, 164/44, 147/95, 135/15, 133/14, 131/
19, 121/27, 109/60, 105/30, 91/33, 81/27, 67/26, 55/23, 43/41.
HRMS M (m/z) 274.229 12, calcd value for C19H30O 274.229 12 (δ
0.00 ppm). Anal. calcd for C19H30O: C, 83.15; H, 11.02. Found: C,
83.29; H, 10.95. Isolated yield 9% (4.9 mg, obtained in [bmim]+-
[BF4]ꢀ); mp 94ꢀ97 °C, white solid.
NMR experiments were carried out in CDCl3 at room temperature. 19
F
NMR and 31P NMR spectra were referenced to the signal of PF6
ꢀ
1
(ꢀ72.5 and ꢀ145.0 ppm, respectively), and all H NMR spectra of
reaction mixtures were referenced to TMS or solvent. On the basis of
structural similarities of different products in reaction mixtures, which let
us suppose that the NMR-active nuclei (e.g., protons) in compounds
have similar spectroscopic character, the ratio of every single product in
reaction mixtures was determined by 1H NMR. Because of overlapping
peaks in the complex 1H NMR spectra of reaction mixtures, the ratio of
1
products was determined by integration and by deconvolution of H
NMR spectra.
Both low- and high-resolution MS measurements were performed
with EI (electron impact) ionization (70 eV, 220 °C source temperature,
perfluorokerosene or perfluorotributyl amine reference compounds).
The relative abundance values of the fragment ions in the MS spectra are
given. IR spectra were recorded in KBr pellets; the resolution was
4 cmꢀ1 and the scanning range was between 4000 and 400 cmꢀ1
.
General Procedure for Ionic Liquid-Promoted Rearrange-
ments. In a typical procedure, the steroidal epoxide (0.2 mmol) and
600 mg of ionic liquid were placed under argon in a Schlenk tube
equipped with a magnetic stirrer and a septum inlet. The reaction
mixture was heated at 110 °C for 30 h. The mixture was extracted three
times with 3 mL of diethyl ether. The combined ethereal extracts were
analyzed by thin-layer chromatography (TLC) and after removal of
(3β,5R,16R,17β)-10,17-Dimethylgon-13-ene-3,16-diol (3b). 1H NMR
(500 MHz, CDCl3) δ 3.89 (td, J = 3.9 and 6.6 Hz, 1H, 16β-H); 3.52ꢀ3.58
(m, 1H, 3R-H); 2.46 (dd, J = 6.6 and 16.1 Hz, 1H, 15β-H); 2.33ꢀ2.37 (m,
1H, 17R-H); 2.08ꢀ2.14 (m, 1H, 15R-H); 1.91ꢀ2.00 (m, 2H, 8β-H and
12R-H); 1.71ꢀ1.84 (m, 5H, 7β-H, 12β-H, 2R-H, 11R-H, and 1β-H);
1.46ꢀ1.53 (m, 3H, 4R-H and 2ꢁOH); 1.34ꢀ1.43 (m, 1H, 2β-H);
1.18ꢀ1.30 (m, 3H, 6β-H, 4β-H, and 6R-H); 1.04ꢀ1.11 (m, 2H, 11β-H
and 5R-H); 0.93ꢀ0.99 (m, 2H, 1R-H and 7R-H); 0.92 (d, J = 7.1 Hz, 3H,
17β-CH3); 0.83ꢀ0.89 (m, 1H, 9R-H); 0.71 (s, 3H, 10β-CH3). 13C NMR
1
diethyl ether, by H NMR. The products were purified by column
chromatography (silica gel, dichloromethane (compounds 2ꢀ4) or
cyclohexane/acetone = 30/1 (compounds 6ꢀ8).
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ARTICLE
(125.75 MHz, CDCl3) δ 135.9 (C-14); 135.8 (C-13); 79.6 (C-16); 71.3
(C-3); 51.7 (C-9); 50.8 (C-17); 44.5 (C-5); 40.7 (C-15); 38.3 (C-10);
38.1 (C-4); 36.8 (C-1); 36.3 (C-8); 31.6 (C-2); 31.5 (C-7); 28.9 (C-6);
24.1 (C-12); 22.7 (C-11); 16.5 (17-CH3); 11.7 (10-CH3). IR
(KBr, cmꢀ1) 3317, 2925, 1453, 1371, 1291, 1174, 1046, 902. MS [(m/z)/
rel. intensity, %] 290(M+)/44, 272/34, 257/27, 254/13, 239/29, 233/6,
215/6, 199/6, 164/15, 147/100, 133/12, 121/15, 107/33, 91/20, 79/14,
55/14. HRMS M (m/z) 290.224 41, calcd value for C19H30O2 290.224 03
(δ 1.30 ppm). Anal. calcd for C19H30O2: C, 78.57; H, 10.41. Found:
C, 78.35; H, 10.55. Isolated yield 29% (16.8 mg, obtained in
[bmim]+[BF4]ꢀ); mp 205ꢀ207 °C, white solid.
(C-11); 25.5 (C-12); 12.8 (17-CH3). IR (KBr, cmꢀ1) 3029, 2922, 1735,
1604, 1580, 1499, 1453, 1381, 1237, 1025, 852, 818, 752, 732, 694. MS
[(m/z)/rel. intensity, %] 360(M+)/30, 270/1, 227/1, 196/1, 172/1, 159/1,
133/1, 115/1, 99/100, 65/2. HRMS M (m/z) 360.208 02, calcd value for
C25H28O2 360.208 38 (δ ꢀ1.00 ppm). Anal. calcd for C25H28O2: C, 83.30;
H, 7.83. Found: C, 83.14; H, 7.91. Isolated yield 63% (45.5 mg, obtained
in [bmim]+[BF4]ꢀ), 31% (22.0 mg, obtained in [bmim]+[PF6]ꢀ); mp
103ꢀ105 °C, white solid.
(16R,17β)-3-Methoxy-17-methylgona-1,3,5(10),13-tetraen-16-ol (7a).
1H NMR (800.13 MHz, CDCl3) δ 7.24 (d, J = 8.2 Hz, 1H, 1-H); 6.71 (dd,
J = 8.2 and 2.3 Hz, 1H, 2-H); 6.64 (d, J = 2.3 Hz, 1H, 4-H); 4.00ꢀ4.03 (m,
1H, 16β-H); 3.77 (s, 3H, OCH3); 2.87ꢀ2.93 (m, 2H, 6-H2); 2.62ꢀ2.66
(m, 1H, 15β-H); 2.53ꢀ2.57 (m, 1H, 17β-H); 2.46ꢀ2.50 (m, 2H, 17R-H
and 9R-H); 2.27ꢀ2.30 (m, 1H, 15R-H); 2.18ꢀ2.20 (m, 1H, 7R-H);
2.05ꢀ2.10 (m, 2H, 11R-H and 7β-H); 2.00ꢀ2.02 (m, 1H, 8β-H); 1.56 (br
s, 1H, OH); 1.47ꢀ1.51 (m, 1H, 11β-H); 1.40ꢀ1.45 (m, 1H, 12R-H); 1.03
(d, J = 7.1 Hz, 3H, 17β-CH3). 13C NMR (201.21 MHz, CDCl3) δ 157.9
(C-3); 138.4 (C-5); 137.0 (C-13); 134.1 (C-14); 132.9 (C-10); 125.7
(C-1); 113.9 (C-4); 111.4 (C-2); 79.8 (C-16); 55.8 (OCH3); 51.0 (C-17);
41.1 (C-9); 41.0 (C-15); 39.8 (C-8); 30.0 (C-6); 27.2 (C-11); 26.7 (C-12);
24.1 (C-7); 16.8 (17-CH3). IR (KBr, cmꢀ1) 3361, 2925, 2834, 1614, 1575,
1500, 1451, 1262, 1135, 1042, 867, 813, 786. MS [(m/z)/rel. intensity, %]
284(M+)/100, 266/82, 251/20, 238/21, 211/15, 174/34, 172/46, 160/49,
147/15, 115/14, 91/14. HRMS M (m/z) 284.176 81, calcd value for
C19H24O2 284.177 08 (δ ꢀ1.00 ppm). Anal. calcd for C19H24O2: C, 80.24;
H, 8.51. Found: C, 80.12; H, 8.55. Isolated yield 17% (9.5 mg, obtained in
[bmim]+[BF4]ꢀ); mp 84ꢀ87 °C, pale yellow solid.
1
(5R,13R,17R)-10,17-Dimethylgon-2-en-16-one (4). H NMR (500
MHz, CDCl3) δ 5.57ꢀ5.65 (m, 2H, 2-H and 3-H); 2.25ꢀ2.29 (m, 2H,
15-H2); 2.10ꢀ2.17 (m, 1H, 17β-H); 2.01 (dd, J = 4.3 and 15.3 Hz, 1H,
1-Ha); 1.84ꢀ1.92 (m, 3H, 4-Ha, 13R-H, and 12-Ha); 1.78ꢀ1.83 (m, 1H,
6-Ha); 1.70ꢀ1.78 (m, 2H, 14R-H and 1-Hb); 1.59ꢀ1.71 (m, 2H, 4-Hb
and 12-Hb); 1.52ꢀ1.55 (m, 1H, 11-Ha); 1.41ꢀ1.48 (m, 1H, 7-Ha);
1.35ꢀ1.40 (m, 1H, 5R-H); 1.12ꢀ1.25 (m, 2H, 7-Hb and 11-Hb); 1.03
(d, J = 6.9 Hz, 3H, 17R-CH3); 0.81ꢀ0.96 (m, 3H, 8β-H, 6-Hb, and
9R-H); 0.68 (s, 3H, 10β-CH3). 13C NMR (125.75 MHz, CDCl3) δ 222.3
(C-16); 125.7 (C-2); 125.6 (C-3); 52.3 (C-9); 43.7 (C-15); 43.6 (C-
13); 42.9 (C-17); 41.5 (C-14); 41.2 (C-5); 39.6 (C-1); 37.0 (C-8); 34.8
(C-10); 32.4 (C-6); 30.4 (C-4); 28.7 (C-7); 25.7 (C-12); 19.2 (C-11);
12.8 (17-CH3); 12.0 (10-CH3). IR (KBr, cmꢀ1) 3019, 2924, 1739, 1444,
1378, 1260, 1157, 913, 734. MS [(m/z)/rel. intensity, %] 272(M+)/63,
257/16, 230/11, 218/100, 189/30, 147/54, 121/24, 108/25, 91/31, 79/
29. HRMS M (m/z) 272.213 33, calcd value for C19H28O 272.213 47
(δ ꢀ0.50 ppm). Anal. calcd for C19H28O: C, 83.77; H, 10.36. Found: C,
83.90; H, 10.25. Isolated yield 86% (46.8 mg, obtained in [bmim]+-
[PF6]ꢀ); yellow viscous oil.
(13R,17R)-3-Methoxy-17-methylgona-1,3,5(10)-trien-16-one (6a).
1H NMR (800.13 MHz, CDCl3) δ 7.24 (d, J = 8.6 Hz, 1H, 1-H); 6.72
(dd, J = 8.6 and 2.1 Hz, 1H, 2-H); 6.61 (d, J = 2.1 Hz, 1H, 4-H); 3.77 (s,
3H, OCH3); 2.77ꢀ2.85 (m, 2H, 6-H2); 2.37ꢀ2.41 (m, 2H, 15-Ha and
9R-H); 2.34ꢀ2.36 (m, 1H, 15-Hb); 2.29ꢀ2.32 (m, 1H, 11R-H);
2.12ꢀ2.16 (m, 1H, 17β-H); 1.99ꢀ2.05 (m, 3H, 11β-H, 14R-H, and
13R-H); 1.92ꢀ1.95 (m, 1H, 7β-H); 1.88ꢀ1.92 (m, 1H, 12R-H);
1.29ꢀ1.37 (m, 2H, 7R-H and 12β-H); 1.07ꢀ1.11 (m, 1H, 8β-H);
1.06 (d, J = 6.9 Hz, 3H, 17R-CH3). 13C NMR (201.21 MHz, CDCl3) δ
221.6 (C-16); 157.0 (C-3); 138.2 (C-5); 132.2 (C-10); 127.0 (C-1);
114.0 (C-4); 112.0 (C-2); 55.8 (OCH3); 43.7 (C-13); 43.5 (C-15); 43.4
(C-17); 42.2 (C-9); 40.5 (C-8); 40.3 (C-14); 30.2 (C-6); 27.9 (C-7);
25.9 (C-11); 25.8 (C-12); 13.0 (17-CH3). IR (KBr, cmꢀ1) 3017, 2914,
1742, 1609, 1578, 1499, 1457, 1238, 1150, 895, 860, 816, 785. MS [(m/z)/
rel. intensity, %] 284(M+)/100, 256/7, 213/8, 186/54, 173/7, 159/6,
147/7, 134/3, 115/5, 91/3, 77/1, 55/1. HRMS M (m/z) 284.176 99,
calcd value for C19H24O2 284.177 08 (δ ꢀ0.30 ppm). Anal. calcd for
C19H24O2: C, 80.24; H, 8.51. Found: C, 80.19; H, 8.66. Isolated yield
69% (39.2 mg, obtained in [bmim]+[BF4]ꢀ), 33% (18.7 mg, obtained in
[bmim]+[PF6]ꢀ); mp 92ꢀ95 °C, white solid.
(16R,17β)-3-(Benzyloxy)-17-methylgona-1,3,5(10),13-tetraen-16-ol
(7b). 1H NMR (800.13 MHz, CDCl3) δ 7.43 [d, J = 7.3 Hz, 2H, 20-H
and 60-H(Ph)]; 7.38 [t, J = 7.3 Hz, 2H, 30-H and 50-H (Ph)]; 7.32 [t, J =
7.3 Hz, 1H, 40-H (Ph)]; 7.25 (d, J = 8.4 Hz, 1H, 1-H); 6.79 (dd, J = 1.7
and 8.4 Hz, 1H, 2-H); 6.75 (d, J = 1.7 Hz, 1H, 4-H); 5.04 (s, 2H, OCH2);
4.03 (td, J = 3.7 and 6.5 Hz, 1H, 16β-H); 2.83ꢀ2.90 (m, 2H, 6-H2);
2.56ꢀ2.60 (m, 1H, 15β-H); 2.46ꢀ2.50 (m, 1H, 17β-H); 2.39ꢀ2.44 (m,
2H, 17R-H and 9R-H); 2.20ꢀ2.24 (m, 1H, 15R-H); 2.11ꢀ2.15 (m, 1H,
7R-H); 2.01ꢀ2.05 (m, 2H, 11R-H and 7β-H); 1.94ꢀ1.98 (m, 1H,
8β-H); 1.54 (br s, 1H, OH); 1.29ꢀ1.44 (m, 2H, 11β-H and 12R-H);
1.05 (d, J = 7.1 Hz, 3H, 17β-CH3). 13C NMR (201.21 MHz, CDCl3) δ
157.0 (C-3); 138.4 (C-5); 137.5 (10-Ph); 137.0 (C-13); 134.1 (C-14);
132.9 (C-10); 128.6 (30,50-Ph); 127.4 (20,60-Ph); 127.9 (40-Ph); 125.8
(C-1);115.1(C-4);112.4(C-2);79.8(C-16);70.0(OCH2);51.4(C-17);
41.1 (C-9); 41.1 (C-15); 39.5 (C-8); 30.0 (C-6); 27.6 (C-11); 26.7 (C-
12); 24.1 (C-7); 16.9 (17-CH3). IR (KBr, cmꢀ1) 3395, 2921, 1607, 1573,
1500, 1454, 1379, 1234, 1059, 731, 696. MS [(m/z)/rel. intensity, %]
360 (M+)/53, 342/5, 251/32, 236/5, 223/5, 195/3, 178/4, 157/4, 91/
100, 65/3. HRMS M (m/z) 360.208 27, calcd value for C25H28O2
360.208 38 (δ ꢀ0.30 ppm). Anal. calcd for C25H28O2: C, 83.30; H, 7.83.
Found: C, 83.46; H, 7.67. Isolated yield 19% (13.7 mg, obtained in
[bmim]+[BF4]ꢀ); mp 122ꢀ125 °C, pale yellow solid.
3-Methoxy-17-methylgona-1,3,5(10),8,11,13-hexaene (8a). 1H NMR
(800.13 MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 1H, 1-H); 7.55 (d, J = 7.8 Hz,
1H, 11-H); 7.11 (d, J = 7.8 Hz, 1H, 12-H); 6.83 (dd, J = 2.6 and 8.5 Hz,
1H, 2-H); 6.77 (d, J = 2.6 Hz, 1H, 4-H); 3.83 (s, 3H, OCH3); 3.20ꢀ3.24
(m, 1H, 17-H); 2.90ꢀ2.94 (m, 1H, 15-Ha); 2.82ꢀ2.85 (m, 2H, 6-H2);
2.74ꢀ2.81 (m, 3H, 15-Hb and 7-H2); 2.33ꢀ2.38 (m, 1H, 16-Ha);
1.61ꢀ1.66 (m, 1H, 16-Hb); 1.31 (d, J = 6.9 Hz, 3H, 17-CH3). 13C
NMR (201.21 MHz, CDCl3) δ 158.6 (C-3); 147.5 (C-13); 141.6 (C-14);
138.4 (C-5); 132.5 (C-9); 132.1 (C-8); 128.2 (C-10); 124.9 (C-1); 121.4
(C-11); 121.3 (C-12); 113.3 (C-4); 112.3 (C-2); 55.3 (OCH3); 39.4 (C-
17); 34.4(C-16); 29.8 (C-15); 29.3 (C-6); 25.5(C-7); 20.2 (17-CH3). IR
(KBr, cmꢀ1) 3001, 2951, 1612, 1568, 1500, 1470, 1277, 1244, 1151, 1070,
1032, 877, 812. MS [(m/z)/rel. intensity, %] 264(M+)/95, 249/100,
234/10, 203/8, 189/4, 132/6, 125/9, 111/3, 101/3, 89/3. HRMS M
(m/z) 264.15106, calcd value for C19H20O 264.15087 (δ 0.70 ppm).
(13R,17R)-3-(Benzyloxy)-17-methylgona-1,3,5(10)-trien-16-one (6b).
1H NMR (800.13 MHz, CDCl3) δ 7.42 [d, J = 7.5 Hz, 2H, 20-H and
H(Ph)]; 7.37 [t, J = 7.5 Hz, 2H, 30-H and 50-H (Ph)]; 7.31 [t, J = 7.5 Hz,
1H, 40-H(Ph)]; 7.23 (d, J = 8.6 Hz, 1H, 1-H); 6.79 (dd, J = 2.2 and 8.6 Hz,
1H, 2-H); 6.70 (d, J = 2.2 Hz, 1H, 4-H); 5.02 (s, 2H, OCH2); 2.76ꢀ2.84
(m, 2H, 6-H2); 2.36ꢀ2.41 (m, 2H, 9R-H and 15-Ha); 2.32ꢀ2.35 (m, 1H,
15-Hb); 2.28ꢀ2.31 (m, 1H, 11R-H); 2.05ꢀ2.16 (m, 1H, 17β-H);
1.99ꢀ2.03 (m, 3H, 11β-H, 14R-H, and 13R-H); 1.88ꢀ1.94 (m, 2H, 7β-
H and 12R-H); 1.30ꢀ1.37 (m, 2H, 7R-H and 12β-H); 1.08ꢀ1.11 (m, 1H,
8β-H); 1.06 (d, J = 6.8 Hz, 3H, 17R-CH3). 13C NMR (201.21 MHz,
CDCl3) δ 221.6 (C-16); 157.0 (C-3); 138.1 (C-5); 137.2 (10-Ph); 132.0
(C-10); 128.5 (30,50-Ph); 127.8 (40-Ph); 127.4 (20,60-Ph); 126.8 (C-1);
114.6 (C-4); 112.6 (C-2); 69.9 (OCH2); 43.5 (C-13); 43.2 (C-15); 43.1
(C-17); 42.2 (C-9); 40.5 (C-8); 40.2 (C-14); 30.2 (C-6); 27.8 (C-7); 25.7
6055
dx.doi.org/10.1021/jo2006285 |J. Org. Chem. 2011, 76, 6048–6056

The Journal of Organic Chemistry
ARTICLE
Anal. calcd for C19H20O: C, 86.32; H, 7.63. Found: C, 86.15; H, 7.72.
Isolated yield 40% (21.3 mg, obtained in [bmim]+[PF6]ꢀ); mp
73ꢀ75 °C, white solid; [R]2D5 = 0 (c = 0.001 g mlꢀ1 CHCl3).
(8) Girdhar, N. K.; Ishar, M. P. S.; Kumar, R.; Singh, R.; Singh, G.
Tetrahedron 2001, 57, 7199–7204.
(9) (a) Schneider, G.; Sch€onecker, B. Acta Chim. Acad. Sci. Hung.
1977, 95, 321–331. (b) Bridgewater, A. J.; Cheung, H. T. A.; Vadasz, A.;
Watson, T. R. J. Chem. Soc., Perkin Trans. 1 1980, 556–562.
(10) Michalak, K.; Michalak, M.; Wicha, J. Molecules 2005, 10,
1084–1100.
(11) Pinto, R. M. A.; Salvador, J. A. R.; Le Roux, C.; Carvalho, R. A.;
Beja, A. M.; Paix~ao, J. A. Tetrahedron 2009, 65, 6169–6178.
(12) (a) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Tetrahedron Lett. 2003, 44, 1047–1050. (b) Ranu, B. C.; Adak, L.;
Banerjee, S. Can. J. Chem. 2007, 85, 366–371. (c) Yadav, J. S.; Reddy,
B. V. S.; Reddy, C. S.; Rajasekhar, K. Chem. Lett. 2004, 33, 476–477.
(d) Yoshino, H.; Nomura, K.; Matsubara, S.; Oshima, K.; Matsumoto,
K.; Hagiwara, R.; Ito, Y. J. Fluorine Chem. 2004, 125, 1127–1129. (e) Xu,
L.-W.; Li, L.; Xia, C.-G.; Zhao, P.-Q. Tetrahedron Lett. 2004,
45, 2435–2438. (f) Ranu, B. C.; Mandal, T.; Banerjee, S.; Dey, S. S.
Aust. J. Chem. 2007, 60, 278–283. (g) Yang, M.-H.; Yan, G.-B.; Zheng,
Y.-F. Tetrahedron Lett. 2008, 49, 6471–6474.
3-(Benzyloxy)-17-methylgona-1,3,5(10),8,11,13-hexaene (8b). 1H NMR
(800.13 MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 1H, 1-H); 7.55 (d, J = 7.8 Hz,
1H, 11-H); 7.45 [d, J = 7.3 Hz, 2H, 20-H and 60-H(Ph)]; 7.40 [t, J = 7.3 Hz,
2H, 30-H and 50-H(Ph)]; 7.33 [t, J = 7.3 Hz, 1H, 40-H(Ph)]; 7.11 (d, J =
7.8 Hz, 1H, 12-H); 6.90 (dd, J= 2.5 and 8.5 Hz, 1H, 2-H); 6.86 (d, J=2.5Hz,
1H, 4-H); 5.10 (s, 2H, OCH2); 3.19ꢀ3.24 (m, 1H, 17-H); 2.89ꢀ2.95 (m,
1H, 15-Ha); 2.76ꢀ2.85 (m, 5H, 6-H2, 7-H2, and 15-Hb); 2.32ꢀ2.39 (m, 1H,
16-Ha); 1.60ꢀ1.68 (m, 1H, 16-Hb); 1.31 (d, J = 6.9 Hz, 3H, 17-CH3). 13
C
NMR (201.21 MHz, CDCl3) δ 158.1 (C-3); 147.5 (C-13); 141.6 (C-14);
138.5 (C-5); 137.2 (C-10); 132.5 (C-9); 132.2 (C-8); 128.6 (C-30, C-50);
128.2 (C-10); 128.0 (C-40); 127.5 (C-20, C-60); 124.9 (C-1); 121.5 (C-11);
121.3 (C-12); 114.5 (C-4); 113.1 (C-2); 70.0 (OCH2); 39.6 (C-17); 34.5
(C-16); 29.8 (C-15); 29.2 (C-6); 25.4 (C-7); 20.1 (17-CH3). IR
(KBr, cmꢀ1) 3063, 3032, 2941, 1603, 1566, 1498, 1452, 1382, 1274, 1242,
1156, 1027, 806, 737, 695. MS [(m/z)/rel. intensity, %] 340(M+)/44, 249/
100, 234/7, 91/11. HRMS M (m/z) 340.182 20, calcd value for C25H24O
340.182 17 (δ0.10 ppm). Anal. calcd for C25H24O: C, 88.20; H, 7.10. Found:
C, 87.97; H, 7.25. Isolated yield 36% (24.5 mg, obtained in [bmim]+[PF6]ꢀ);
mp 115ꢀ118 °C, white solid; [R]2D5 = 0 (c = 0.001 g mlꢀ1 CHCl3).
(13) (a) Horvꢀath, A.; Skoda-F€oldes, R.; Mahꢀo, S.; Berente, Z.;
Kollꢀar, L. Steroids 2006, 71, 706–711. (b) Horvꢀath, A.; Frigyes, D.;
Mahꢀo, S.; Berente, Z.; Kollꢀar, L.; Skoda-F€oldes, R. Synthesis 2009,
4037–4041.
(14) Five compounds with different retention times but with the
same molecular mass were detected by GC-MS in the reaction mixtures
of 5a and 5b. MS of isomers of 9a [(m/z)/rel. intensity, %]: (i) 268
(M+)/22, 253/2, 239/4, 225/6, 211/5, 174/8, 171/14, 160/100, 147/9.
(ii) 268 (M+)/25, 253/3, 239/7, 225/9, 211/4, 174/8, 171/13, 160/
100, 147/17. (iii) 268 (M+)/92, 253/9, 239/20, 225/37, 211/22,
174/100, 171/26, 165/20, 147/52. (iv) 268 (M+)/100, 253/2, 239/
25, 225/35, 211/30, 174/28, 171/20, 165/26. (v) 268 (M+)/100, 253/
7, 239/47, 225/32, 211/57, 174/23, 171/18, 165/26. MS of isomers of
9b [(m/z)/rel. intensity, %]: (i) 344 (M+)/13, 253/6, 147/28, 91/100.
(ii) 344 (M+)/8, 253/4, 236/19, 91/100. (iii) 344 (M+)/13, 253/3,
236/17, 91/100. (iv) 344 (M+)/11, 250/2, 91/100. (v) 344 (M+)/62,
253/43, 197/19, 159/29, 128/21, 93/85, 91/100.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectraof the
S
b
new compounds (2a,b, 3a,b, 4, 6a,b, 7a,b, and 8a,b). This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail skodane@almos.uni-pannon.hu.
(15) Sch€onecker, B.; Lange, C.; K€otteritzsch, M.; G€unther, W.;
Weston, J.; Anders, E.; G€orls, H J. Org. Chem. 2000, 65, 5487–5497.
(16) Yoshida, K. Tetrahedron 1969, 25, 1367–1379.
(17) Michalak, K.; Michalak, M.; Wicha, J. Tetrahedron Lett. 2005,
46, 1149–1153.
’ ACKNOWLEDGMENT
We thank the Hungarian National Science Foundation for
financial support (NK71906), Dr. Zoltꢀan Bꢀeni for his kind help in
assignment of the NMR spectra, and Jꢀanos Horvꢀath for GC-MS
measurements.
(18) Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381–384.
(19) Chinn, L. J.; Salamon, K. W. J. Med. Chem. 1977, 20, 229–233.
(20) (a) Campbell, A. C.; Maidment, M. S.; Pick, J. H.; Stevenson,
D. F. M.; Woods, G. F. J. Chem. Soc., Perkin Trans. 1 1978, 163–171. (b)
Cheung, H. T. A.; McQueen, R. G.; Vadasz, A.; Watson, T. R. J. Chem.
Soc., Perkin Trans. 1 1979, 1048–1055.
’ REFERENCES
(1) Kirk, D. N.; Hartshorn, M. P. Steroid Reaction Mechanisms;
Elsevier: Amsterdam, 1968; Chapt. 8.
(2) (a) Maione, A M.; Torrini, I.; Romeo, A. J. Chem. Soc., Perkin
Trans. 1 1979, 775–776. (b) Lehmann, C.; Schaffner, K.; Jeger, O. Helv.
Chim. Acta 1962, 45, 1031–1035. (c) Flaih, N.; Hanson, J. R.; Hitchcock,
P. B. J. Chem. Soc., Perkin Trans. 1 1991, 2177–2181. (d) Baddeley, G. V.;
Samaan, H. J.; Simes, J. J. H.; Ai, T. H. J. Chem. Soc., Perkin Trans. 1
1979, 7–14. (e) Wechter, W. J.; Slomp, G. J. Org. Chem. 1962, 27,
2549–2554.
(21) Bridgewater, A. J.; Cheung, H. T. A.; Vadasz, A.; Watson, T. R.
J. Chem. Soc., Perkin Trans. 1 1980, 556–562.
(22) Hewett, C. L.; Gilbert, I. M.; Redpath, J.; Savage, D. S.; Strachan,
J.; Sleigh, T.; Taylor, R. J. Chem. Soc., Perkin Trans. 1 1974, 897–903.
(23) Freire, M. G.; Neves, C. M. S. S.; Marrucho, I. M.; Coutinho,
J. A. P.; Fernandes, A. M. J. Phys. Chem. A 2010, 114, 3744–3749.
(24) Plakhotnyk, A. V.; Ernst, L.; Schmutzler, R. J. Fluorine Chem.
2005, 126, 27–31.
(25) Compound 10 was not isolated; its structure was determined by
GC-MS from the reaction mixture [(m/z)/rel. intensity, %] 270(M+)/
75, 242/11, 199/12, 172/100, 159/15, 157/ 16, 145/22, 133/24.
(26) Compound 11 was not isolated; its structure was determined
by GC-MS from the reaction mixture [(m/z)/rel. intensity, %]
250(M+)/74, 235/100, 200/14, 202/16.
(3) Herzog, H. L.; Gentles, M. J.; Mitchell, A.; Hershberg, E. B.;
Mandell, L. J. Am. Chem. Soc. 1959, 81, 6478–6482.
(4) (a) Shapiro, E. L.; Steinberg, M.; Gould, D.; Gentles, M. J.;
Herzog, H. L.; Gilmore, M.; Charney, W.; Hershberg, E. B.; Mandell, L.
J. Am. Chem. Soc. 1959, 81, 6483–6486. See also (b) Herzog, H. L.; Gnoj,
O.; Mandell, L.; Nathansohn, G. G.; Vigevani, A. J. Org. Chem. 1967,
32, 2906–2908.
(27) Reaction mixtures obtained by heating 5b in [bmim]+[PF6]ꢀ
contained less than 3% debenzylated products, according to GC and
GC-MS measurements.
(5) Akhrem, A. A; Vesela, I. V.; Kamernitskii, A. V.; Prokof’ev, E. P.
Russ. Chem. Bull. 1972, 21, 1071–1075.
(6) Morzycki, J. W.; Gryszkiewicz, A.; Jastrzebka, I. Tetrahedron Lett.
)
2000, 41, 3751–3754.
(7) Denny, W. A.; Kumar, V.; Meakins, G. D.; Pragnell, J.; Wicha, J.
J. Chem. Soc., Perkin Trans. 1 1972, 486–492.
6056
dx.doi.org/10.1021/jo2006285 |J. Org. Chem. 2011, 76, 6048–6056