Ionic Liquid-Promoted Wagner–Meerwein ... - ACS Publications

ARTICLE pubs.acs.org/joc

Ionic Liquid-Promoted Wagner
Meerwein Rearrangement of 16r,17r-Epoxyandrostanes and 16r,17r-Epoxyestranes
gota Sz
ajli,‡ R
obert Kiss,‡ J
anos K
oti,‡ S
andor Mah
o,‡ and Rita Skoda-F€oldes*,† Anita Horv
ath,†,‡ A † ‡

Department of Organic Chemistry, Institute of Chemistry, University of Pannonia, Post Office Box 158, H-8201 Veszpr
em, Hungary Chemical Works of Gedeon Richter Plc, Budapest, Hungary

bS Supporting Information ABSTRACT: Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]+[PF6]
) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]+[BF4]
) were found to promote an unusual Wagner
Meerwein 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 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 ringopening
steroidal 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 Wagner
Meerwein rearrangement that involves the formation of a carbocation 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 Lewis acid (AlCl3,7 ZnCl2,8 or BF39). The use of 17β-alkyl16R,17R-epoxides usually led to the 17R-substituted 16R-hydroxy-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 derivatives, 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 r 2011 American Chemical Society

substrates, we observed an unusual rearrangement of 16R,17Repoxides 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.

’ RESULTS Rearrangement of 16r,17r-Epoxyandrostanes. During our investigations concerning ionic liquid-promoted ring opening 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-16one 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.3
6,8
10 The structure of 2a was proved by various spectroscopic methods including 2D NMR techniques (see below). A more detailed investigation of the reaction showed that both [bmim]+[PF6]
and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]+[BF4]
) were able to catalyze the skeletal rearrangement of 1a (Table 1, entries 1
6). It should be mentioned that Received: March 24, 2011 Published: June 13, 2011 6048

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Scheme 1. Rearrangement of 16r,17r-Epoxy-5r-androstanes 1a
1c in Ionic Liquids

Table 1. Rearrangement of 16r,17r-Epoxy-5r-androstanes in Ionic Liquidsa products (%) entry

convb (%)

substrate

ionic liquid

1

1a

+

[bmim] [PF6]

100

100

2

1a

[bmim]+[PF6]
d

100

100c

100

100c

90

63b

37b

85

b

29b

b

35b

+





e

3

1a

[bmim] [PF6]

4

1a

[bmim]+[BF4]


5

1a

+


d

+


e

[bmim] [BF4]

2

3

4

c

71

6

1a

[bmim] [BF4]

80

7

1b

[bmim]+[PF6]


100

100c

100

100c

100

100c

8

1b

+


d

+


e

[bmim] [PF6]

9

1b

[bmim] [PF6]

10

1b

[bmim]+[BF4]


11

1b

+


d

+


e

[bmim] [BF4]

65

100

60b

40b

100

b

35b

b

34b

12

1b

[bmim] [BF4]

100

13

1c

[bmim]+[PF6]


100

65 66

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 1 H NMR. c Determined by GC. d First reuse of the ionic liquid. e Second reuse of the ionic liquid.

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 Wagner
Meerwein 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 7
9) and in [bmim]+[BF4]


(entries 10
12). 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 the rearrangement was 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 of the 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 10
12). 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 derivatives 6a and 6b as the main products, together with 20
30% of the usual Wagner
Meerwein rearrangement products 7a and 7b (Table 2, entries 1
3 and 7
9). 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 4
6 and 10
12). 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 7
15), 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-16oxo-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]+Br
and the starting material was recovered unchanged. 6049

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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

5a

[bmim]+[BF4]


100

81

19

2 3

5a 5a

[bmim]+[BF4]
c [bmim]+[BF4]
d

100 92

77 76

23 24

4

5a

[bmim]+[PF6]


100

69

31

5

5a

[bmim]+[PF6]
c

100

21

71

8

6

5a

[bmim]+[PF6]
d

100

26

62

12

7

5b

[bmim]+[BF4]


100

70

30

8 9

5b 5b

[bmim]+[BF4]
c [bmim]+[BF4]
d

100 83

73 70

27 30

10

5b

[bmim]+[PF6]


100

67

24

9

11

5b

[bmim]+[PF6]
c

100

24

52

24

12

5b

[bmim]+[PF6]
d

100

14

51

35

13

5b

[emim]+[PF6]
e

100

70

30

14

5b

[hmim]+[BF4]
e

86

68

15

5b

[bmim]+Br


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 deconvolution of 1H NMR. c First reuse of the ionic liquid. d Second reuse of the ionic liquid. e [emim]+[PF6]
= 1-ethyl-3-methylimidazolium hexafluorophosphate; [hmim]+[BF4]
= 1-hexyl-3-methylimidazolium tetrafluoroborate.

Determination of Structures of Rearrangement Products. 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

Figure 1. Numbering of compounds 2a,b and 6a,b and some NOE effects observed.

rearrangement took place. In the 1H NMR spectrum of 2a, the 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 Wagner
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 Wagner
Meerwein product (a 16-hydroxy-Δ13 derivative). The 1H
1H correlation spectroscopy (COSY) experiment showed 6050

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The Journal of Organic Chemistry interactions between the methyl protons at 0.99 ppm and the multiplet of a methine proton at 2.06
2.11 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 (2.21
2.24 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) was determined via a 1H
1H 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 quartet
doublet coupling pattern. Moreover, the coupling constants between 17β-H and 13-H [3J(17βH,13R-H) = 14 Hz] and between 8β-H and 14-H [3J(8β-H,14RH) = 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 and 4, A-ring protons were assigned by use of the 1H
1H COSY spectrum starting from 3-H (3.58
3.62 ppm) and the multiplet of 2-H and 3-H (5.57
5.65 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 (HSQC), and 1H
1H 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 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-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, 15-H, and 17-H were determined from the 1H
1H COSY and HMBC spectra. The 13-H and 14-H signals were assigned according to the heteronuclear 3J 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 Wagner
Meerwein rearrangement products 3a,b and 7a,b are the methyl doublets around 0.92
1.03 ppm that show correlation with the 16-H protons around 3.89
4.03 ppm in the 1H
1H COSY experiment, as well as the signals of the two olefinic quaternary carbons at 135.7
137.0 and 134.1
134.8 ppm in the HMBC experiment. The A and B ring signals of 2a were assigned starting from C19 angular CH3 by use of HMBC, HSQC, and 1H
1H COSY experiments. In the case of 3b, the A-ring protons were assigned by use of the 1H
1H COSY spectrum starting from 3-H (3.53 ppm). In the 1H 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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Figure 2. Numbering of compounds 3a,b and 7a,b and some NOE effects observed.

chemical shifts of 7-H, 8-H, 11-H, 12-H, 15-H, and 17-H were determined from the 1H
1H 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 H
H couplings on 15β-H, namely, 3J(15β-H,16βH) = 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. 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 cm
1 in the IR spectrum excluded both the 16-keto and 16-hydroxy groups. The appearance 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.

’ DISCUSSION The results presented above show that various ionic liquids can effectively catalyze the rearrangement of steroidal 16R,17Repoxides 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 6051

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Scheme 3. Possible Mechanism for Formation of Usual Wagner
Meerwein 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. The Lewis acid-catalyzed rearrangement of similar epoxides was shown to lead to 17β-methyl-Δ13-18-norsteroids4
6,8
11 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 Δ13 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

reported by Yoshida,16 who observed that the BF3-catalyzed rearrangement of 17β-acetoxy-A-nor-5R-androstan-1R,2R-epoxide 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-1Rmethyl-A-nor-5R,10R-estran-2-one. Another example for a similar rearrangement of an epoxide was reported in a terpenoid synthesis by Wicha and co-workers.17 Following an analogous mechanism (Scheme 4), after generation 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 possibility 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,2Repoxy-A-norsteroid investigated by Yoshida16 were not selective, 6052

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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 BF3catalyzed reaction afforded the usual Wagner
Meerwein rearrangement products in diethyl ether, the use of benzene as solvent led to the unusual 1R-methyl-2-keto derivative as the main product. 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 catalyst 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 Wagner
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 Wagner
Meerwein rearrangement of 17R-hydroxy-19 or 17β-substituted-16R,17Repoxy steroids21 followed by oxidation/aromatization. The necessary number of double bonds could also be introduced into ring C after a Wagner
Meerwein rearrangement by a 2-fold bromination
dehydrobromination reaction sequence.22 In our case, aromatization took place exclusively in ionic liquids with the [PF6]
anion. Hydrolysis of this anion under

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 F
was observed at
151.4 ppm. After the first reuse of the ionic liquid, the signal of F
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]2
and [PO2F2]
,24 respectively. This is supported by the 31P NMR spectrum of the reaction mixture containing a doublet ([PO3F]2
, 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 the components of the mixture was found to be [PF6]
/[PO3F]2
/ [PO2F2]
/F
= 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]2
/[PO2F2]
/F
= 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 debenzylated derivatives 1025 and 1126 (Scheme 5).27 The C aromatic compounds are probably formed by the aromatization of the usual Wagner
Meerwein 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 6053

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The Journal of Organic Chemistry 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.

’ CONCLUSIONS Ionic liquids [bmim]+[PF6]
and [bmim]+[BF4]
promote an unusual Wagner
Meerwein 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. ’ EXPERIMENTAL SECTION All NMR spectra, except for 1H NMR spectra of reaction mixtures and F and 31P NMR spectra of ionic liquids, were recorded on an 800 or 500 MHz NMR system, each equipped with a CryoProbe. 1H and 13C NMR spectral assignments were in each case supported by 2D 13CHSQC, 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 NMR experiments were carried out in CDCl3 at room temperature. 19F NMR and 31P NMR spectra were referenced to the signal of PF6
(
72.5 and
145.0 ppm, respectively), and all 1H 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 products was determined by integration and by deconvolution of 1H 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 cm
1 and the scanning range was between 4000 and 400 cm
1. 19

General Procedure for Ionic Liquid-Promoted Rearrangements. 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 diethyl ether, by 1H NMR. The products were purified by column chromatography (silica gel, dichloromethane (compounds 2
4) or cyclohexane/acetone = 30/1 (compounds 6
8).

ARTICLE

(5R,13R,17R)-10,17-Dimethylgonan-16-one (2a). 1H NMR (500 MHz, CDCl3) δ 2.21
2.24 (m, 2H, 15-H2); 2.06
2.10 (m, 1H, 17β-H); 1.70
1.89 (m, 5H, 1β-H, 7-Ha, 11-Ha, 13R-H, and 14R-H); 1.54
1.66 (m, 3H, 4-Ha, 11-Hb, and 12-Ha); 1.47
1.52 (m, 1H, 3-Ha); 1.34
1.43 (m, 1H, 3-Hb); 1.01
1.26 (m, 8H, 2-H2, 4-Hb, 6-H2, 12-Hb, 5R-H, and 8β-H); 0.81
0.89 (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, cm
1) 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 65
67 °C, white solid. (3β,5R,13R,17R)-3-Hydroxy-10,17-dimethylgonan-16-one (2b). 1 H NMR (800.13 MHz, CDCl3) δ 3.58
3.62 (m, 1H, 3R-H); 2.23
2.29 (m, 2H, 15-H2); 2.09
2.13 (m, 1H, 17β-H); 1.76
1.88 (m, 6H, 12β-H, 13R-H, 7β-H, 2R-H, 1β-H, and 14R-H); 1.56
1.66 (m, 4H, 12R-H, 11R-H, 4R-H, and OH); 1.38
1.44 (m, 1H, 2β-H); 0.75
1.31 (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, 10βCH3). 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, cm
1) 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 119
122 °C, white solid. (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); 2.37
2.43 (m, 1H, 17R-1H); 2.14
2.23 (m, 1H, 15R-H); 2.00
2.04 (m, 2H, 8β-H and 12-Ha); 1.80
1.91 (m, 3H, 7-Ha, 11-Ha, and 12-Hb); 1.60
1.78 (m, 3H, 1-Ha, 4-Ha, and OH); 1.42
1.55 (m, 2H, 3-H2); 1.15
1.30 (m, 5H, 2-H2, 4-Hb, and 6-H2); 1.07
1.15 (m, 3H, 1-Hb, 5R-H, and 11-Hb); 0.99 (d, J = 7.1 Hz, 3H, 17β-CH3); 0.85
0.97 (m, 2H, 1-Hb and 9R-H); 0.75 (s, 3H, 10β-CH3). 13 C 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, cm
1) 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 94
97 °C, white solid. (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); 3.52
3.58 (m, 1H, 3R-H); 2.46 (dd, J = 6.6 and 16.1 Hz, 1H, 15β-H); 2.33
2.37 (m, 1H, 17R-H); 2.08
2.14 (m, 1H, 15R-H); 1.91
2.00 (m, 2H, 8β-H and 12R-H); 1.71
1.84 (m, 5H, 7β-H, 12β-H, 2R-H, 11R-H, and 1β-H); 1.46
1.53 (m, 3H, 4R-H and 2OH); 1.34
1.43 (m, 1H, 2β-H); 1.18
1.30 (m, 3H, 6β-H, 4β-H, and 6R-H); 1.04
1.11 (m, 2H, 11β-H and 5R-H); 0.93
0.99 (m, 2H, 1R-H and 7R-H); 0.92 (d, J = 7.1 Hz, 3H, 17β-CH3); 0.83
0.89 (m, 1H, 9R-H); 0.71 (s, 3H, 10β-CH3). 13C NMR 6054

dx.doi.org/10.1021/jo2006285 |J. Org. Chem. 2011, 76, 6048–6056

The Journal of Organic Chemistry (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, cm
1) 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]+ [BF 4 ]
); mp 205
207 °C, white solid. (5R,13R,17R)-10,17-Dimethylgon-2-en-16-one (4). 1H NMR (500 MHz, CDCl3) δ 5.57
5.65 (m, 2H, 2-H and 3-H); 2.25
2.29 (m, 2H, 15-H2); 2.10
2.17 (m, 1H, 17β-H); 2.01 (dd, J = 4.3 and 15.3 Hz, 1H, 1-Ha); 1.84
1.92 (m, 3H, 4-Ha, 13R-H, and 12-Ha); 1.78
1.83 (m, 1H, 6-Ha); 1.70
1.78 (m, 2H, 14R-H and 1-Hb); 1.59
1.71 (m, 2H, 4-Hb and 12-Hb); 1.52
1.55 (m, 1H, 11-Ha); 1.41
1.48 (m, 1H, 7-Ha); 1.35
1.40 (m, 1H, 5R-H); 1.12
1.25 (m, 2H, 7-Hb and 11-Hb); 1.03 (d, J = 6.9 Hz, 3H, 17R-CH3); 0.81
0.96 (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 (C13); 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, cm
1) 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). 1 H 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); 2.77
2.85 (m, 2H, 6-H2); 2.37
2.41 (m, 2H, 15-Ha and 9R-H); 2.34
2.36 (m, 1H, 15-Hb); 2.29
2.32 (m, 1H, 11R-H); 2.12
2.16 (m, 1H, 17β-H); 1.99
2.05 (m, 3H, 11β-H, 14R-H, and 13R-H); 1.92
1.95 (m, 1H, 7β-H); 1.88
1.92 (m, 1H, 12R-H); 1.29
1.37 (m, 2H, 7R-H and 12β-H); 1.07
1.11 (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, cm
1) 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 92
95 °C, white solid. (13R,17R)-3-(Benzyloxy)-17-methylgona-1,3,5(10)-trien-16-one (6b). 1 H 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); 2.76
2.84 (m, 2H, 6-H2); 2.36
2.41 (m, 2H, 9R-H and 15-Ha); 2.32
2.35 (m, 1H, 15-Hb); 2.28
2.31 (m, 1H, 11R-H); 2.05
2.16 (m, 1H, 17β-H); 1.99
2.03 (m, 3H, 11β-H, 14R-H, and 13R-H); 1.88
1.94 (m, 2H, 7βH and 12R-H); 1.30
1.37 (m, 2H, 7R-H and 12β-H); 1.08
1.11 (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

ARTICLE

(C-11); 25.5 (C-12); 12.8 (17-CH3). IR (KBr, cm
1) 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 103
105 °C, white solid. (16R,17β)-3-Methoxy-17-methylgona-1,3,5(10),13-tetraen-16-ol (7a). 1 H 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); 4.00
4.03 (m, 1H, 16β-H); 3.77 (s, 3H, OCH3); 2.87
2.93 (m, 2H, 6-H2); 2.62
2.66 (m, 1H, 15β-H); 2.53
2.57 (m, 1H, 17β-H); 2.46
2.50 (m, 2H, 17R-H and 9R-H); 2.27
2.30 (m, 1H, 15R-H); 2.18
2.20 (m, 1H, 7R-H); 2.05
2.10 (m, 2H, 11R-H and 7β-H); 2.00
2.02 (m, 1H, 8β-H); 1.56 (br s, 1H, OH); 1.47
1.51 (m, 1H, 11β-H); 1.40
1.45 (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, cm
1) 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 84
87 °C, pale yellow 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); 2.83
2.90 (m, 2H, 6-H2); 2.56
2.60 (m, 1H, 15β-H); 2.46
2.50 (m, 1H, 17β-H); 2.39
2.44 (m, 2H, 17R-H and 9R-H); 2.20
2.24 (m, 1H, 15R-H); 2.11
2.15 (m, 1H, 7R-H); 2.01
2.05 (m, 2H, 11R-H and 7β-H); 1.94
1.98 (m, 1H, 8β-H); 1.54 (br s, 1H, OH); 1.29
1.44 (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 (C12); 24.1 (C-7); 16.9 (17-CH3). IR (KBr, cm
1) 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 122
125 °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); 3.20
3.24 (m, 1H, 17-H); 2.90
2.94 (m, 1H, 15-Ha); 2.82
2.85 (m, 2H, 6-H2); 2.74
2.81 (m, 3H, 15-Hb and 7-H2); 2.33
2.38 (m, 1H, 16-Ha); 1.61
1.66 (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 (C17); 34.4 (C-16); 29.8 (C-15); 29.3 (C-6); 25.5 (C-7); 20.2 (17-CH3). IR (KBr, cm
1) 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). 6055

dx.doi.org/10.1021/jo2006285 |J. Org. Chem. 2011, 76, 6048–6056

The Journal of Organic Chemistry 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
1 73
75 °C, white solid; [R]25 CHCl3). D = 0 (c = 0.001 g ml 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 = 2.5 Hz, 1H, 4-H); 5.10 (s, 2H, OCH2); 3.19
3.24 (m, 1H, 17-H); 2.89
2.95 (m, 1H, 15-Ha); 2.76
2.85 (m, 5H, 6-H2, 7-H2, and 15-Hb); 2.32
2.39 (m, 1H, 16-Ha); 1.60
1.68 (m, 1H, 16-Hb); 1.31 (d, J = 6.9 Hz, 3H, 17-CH3). 13C 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, cm
1) 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 (δ 0.10 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]
);
1 CHCl3). mp 115
118 °C, white solid; [R]25 D = 0 (c = 0.001 g ml

’ ASSOCIATED CONTENT H and 13C NMR spectra of the 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.

bS

Supporting Information.

1

’ AUTHOR INFORMATION Corresponding Author

*E-mail [email protected].

’ ACKNOWLEDGMENT We thank the Hungarian National Science Foundation for financial support (NK71906), Dr. Zolt
an B
eni for his kind help in assignment of the NMR spectra, and J
anos Horv
ath for GC-MS measurements. ’ 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. (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. (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.; Jastrze) bka, 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.

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(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. (13) (a) Horv
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ar, 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. (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. (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. (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. (27) Reaction mixtures obtained by heating 5b in [bmim]+[PF6]
contained less than 3% debenzylated products, according to GC and GC-MS measurements.

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