Intramolecular hydro-n-alkylation of hydrazones and oxime ethers: Synthesis of novel d-secoestrone isoquinuclidines via domino 1, 5-hydride shift/cyclization

Article abstract of DOI:10.1002/ejoc.200900301

The direct transformation of a benzylic C(sp³)-H bond into a C-N bond from steroidal hydrazones 10b, 10f-1 and oxime ethers 28b-d under the action of a stoichiometric amount: of Lewis acid is reported. The mechanism of functionalization to give

Full text of DOI:10.1002/ejoc.200900301

FULL PAPER
DOI: 10.1002/ejoc.200900301
Intramolecular Hydro-N-alkylation of Hydrazones and Oxime Ethers:
Synthesis of Novel
D
-Secoestrone Isoquinuclidines via Domino 1,5-Hydride
Shift/Cyclization
Éva Frank,*[a] Gyula Schneider,[a] Zalán Kádár,[a] and János Wölfling[a]
Keywords: Domino reactions / 1,5-Hydride shift / Hydrazones / Oxime ethers / Lewis acids
The direct transformation of a benzylic C(sp3)–H bond into a
C–N bond from steroidal hydrazones 10b, 10f–l and oxime
ethers 28b–d under the action of a stoichiometric amount of
Lewis acid is reported. The mechanism of functionalization
to give novel types of isoquinuclidine derivatives 25b, 25f–l
and 32b–d is assumed to involve an intramolecular domino
1,5-hydride transfer/cyclization sequence. Azomethine im-
ines 23b, 23f–l and oxyiminium ions 29b–d are proposed as
intermediates, which undergo 1,5-hydride shift to give the
tertiary carbocation 24b, 24f–l or 31b–d. The nucleophilic ad-
dition of the hydrazine or hydroxylamine moiety to the ben-
zylic C-9 carbon led to bridged azaestrone derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
in Lewis acid media to be able to induce a 1,5-hydride shift
from the benzylic carbon C-9 (Figure 1). The subsequent
addition of the amino group to the carbocation center in 3
led to a series of unusual 9,13-bridged steroidal azacycles
4.[6] Several Lewis and Brønsted acids were then examined,
of which BF3·OEt2 was found to be best, as concerns the
Introduction
Heteroatom-containing polycycles continue to be attract-
ive target molecules for stereoselective syntheses due to the
diversity of their biological activity. Especially significant
are those among the possible reactions leading to such com-
pounds which can be run as domino processes, in which
two or more bond-forming transformations occur, involving
functionalities formed in the previous step.[1] Following this
conception, a number of complex heterocyclic ring systems
have been constructed so far with high efficiency and in a
stereocontrolled manner.[2]
One of the widespread synthetic applications of domino
reactions is the direct conversion of a C–H into a C–C or
C–O bond via a Lewis acid-catalyzed cationic-cationic
pathway, although only few examples of this type are to be
found in the literature.[3] However, these hydroalkylation
and hydro-O-alkylation reactions, involving an oxonium
ion-induced 1,5-hydride transfer and a subsequent intramo-
lecular ring-closure step, were performed with aldehydes,
which are known to possess a high degree of electrophilicity
in the presence of a Lewis acid[4] and therefore the ability
to induce a through-space hydride shift. In contrast, the
similar ionic transformations of a C–H into a C–N bond is
rather uncommon, although nitrenium ions derived from
ortho-substituted aryl oximes have been reported to un-
dergo a formal C(sp3)–H activated cyclization.[5] In this re-
gard, we previously demonstrated first on a steroid model
that arylimines 1 containing an electron-withdrawing group
R on the aromatic moiety, possess sufficient electrophilicity
[a] Department of Organic Chemistry, University of Szeged
6720 Szeged, Dóm tér 8., Hungary
Fax: +36-62-544199
Figure 1. -Secoestrone isoquinuclidines synthetized earlier in an
aryliminium ion-induced cationic-cationic domino reaction.
E-mail: frank@chem.u-szeged.hu
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Eur. J. Org. Chem. 2009, 3544–3553

Synthesis of Novel -Secoestrone Isoquinuclidines
chemoselectivity of the domino process and the yields of
the desired products 4. All other acids favored formation of
the unsaturated secondary amine 5 through abstraction of
Results and Discussion
During our recent interest in taking advantage of the re-
the proton on C-8 in 3. However, 5 was also obtained on actions of -seco aldehyde 7,[11] a precursor of 8, which is
treatment of 4 with an excess of BF3·OEt2. In addition, in- readily accessible from estrone 3-methyl ether 6,[12] an inter-
termediates 3 with an ortho R function on the aromatic esting transformation of 7 with hydrazine hydrate was dis-
moiety were observed to undergo elimination to give 5 ex- covered. When 7 was treated with half an equivalent of hy-
clusively, instead of 4, presumably because of the steric hin- drazine, aldazine 9 was obtained, which served as a conve-
drance of intramolecular cyclization by the ortho substitu- nient starting material for criss-cross 1,3-dipolar cycload-
ent. Although position C-9 in aromatic 19-norsteroids is dition (Scheme 1).[13] However, treatment of 7 with an ex-
activated thanks to its benzylic nature, only few intermo- cess of the same reagent under similar conditions furnished
lecular examples of substitution at this carbon have been monohydrazone 10a with simultaneous reduction of the
reported.[7]
propenyl side-chain, presumably by the diimide generated
We demonstrate here that steroidal aldehyde hydrazones in situ from hydrazine.[14] As expected, monohydrazone 10a
and aldoxime ethers are also suitable in the presence of proved to be quite unstable in the presence of BF3·OEt2 in
BF3·OEt2 to induce an intramolecular hydro-N-alkylation solution, and was easily converted to 8, which was further
domino process, whereby a tertiary benzylic C(sp3)–H bond transformed to 11 with the releasing hydrazine. Interest-
is transformed directly into a N-substituted quaternary cen- ingly, acetylhydrazone 10b, obtained from 10a by simple
ter to give novel -secoestrone derivatives with an isoquinu- acetylation, readily underwent transformation through the
clidine substructure. Several synthetic molecules containing use of a stoichiometric amount of BF3·OEt2 to give the
an isoquinuclidine moiety possess valuable pharmacological bridged azaestrone derivative 25b (Table 1, entry 1) via pre-
activity, such as 5-HT3 antagonists,[8] epibatidine ana- sumed ionic intermediates 22b–24b. This latter reaction re-
logues[9] and expectorants.[10]
vealed that not only arylimines, but also hydrazones are
Scheme 1. BF3·OEt2-promoted hydro-N-alkylation of hydrazones.
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É. Frank, G. Schneider, Z. Kádár, J. Wölfling
FULL PAPER
able to induce a 1,5-hydride shift from a benzylic carbon electron-donating group (CH3 or OMe) on the aromatic
under Lewis acid conditions, and further motivated us to ring, as in 10d or 10e, is presumed to be somewhat more
investigate the mechanism of the process. Accordingly, favorable than that of phenylhydrazones with an electron-
starting from aldehyde 8 with phenylhydrazine 12 and its withdrawing group (NO2, CN, CF3) in 10f–i or of acetylhy-
substituted derivatives 13–19, a series of phenylhydrazones drazone 10b.[16] Nevertheless, complexation and the follow-
10c–j were prepared in good to excellent yields. In view of ing N,NЈ-proton shift are assumed to occur under the given
the chemical shift of the 17-CH proton in 10c–j of about reaction conditions to afford intermediates 23b–l. Earlier,
7.00 ppm, formation of the corresponding (E) isomers dur- monosubstituted hydrazones as in situ azomethine imine
ing the condensation reactions is assumed. However, phen- precursors were reported to undergo 1,3-dipolar cycload-
ylhydrazones 10c–e proved to be quite unstable on treat- dition reactions with unsaturated dipolarophiles under ther-
ment with BF3·OEt2 and were easily converted into the mal and Lewis acid conditions to give N-containing five-
starting material 8. In contrast, phenylhydrazones 10f–j, membered heterocycles.[16,17] The overall electrophilicity
containing one or two electron-withdrawing groups on the scale established by Pérez et al.[18] for a series of dipoles and
aromatic ring, underwent facile 1,5-hydride shift/cyclization dipolarophiles commonly used in 1,3-dipolar cycloaddition
to afford isoquinuclidine derivatives 25f–j (Table 1, entries reactions indicates that azomethine imine 1,3-dipoles may
2–6). Since the reaction of 2Ј,4Ј-phenylhydrazone 10i also be regarded as marginal electrophiles and hence will more
led to exclusively 25i, instead of the unsaturated hydrazine probably behave as electron donor species. However, the
derivative 26i, the ortho substituent on the phenyl ring electrophilicity of such dipoles may be drastically changed
seems to have no influence on the intramolecular cylization by suitable substitution, i.e. the presence of a strong elec-
of carbocation 24i. The absence of steric hindrance in this tron-withdrawing group on the dipole and/or coordination
case is not surprising, as an –NH– linker is located between of a dipole with a Lewis acid, results in a large increase
the C=N bond and the aromatic moiety. Moreover, on in the overall electrophilicity of these systems. Accordingly,
treatment of 25 with an excess of BF3·OEt2, the bridged azomethine imines 23b and 23f–i seem to possess sufficient
six-membered ring remained stable, and conversion to 26 electrophilic character to promote hydride transfer from the
was not observed. Similarly to phenylhydrazones 10c–j, the activated benzylic carbon C-9 to give carbocations 24b and
semicarbazone 10k and thiosemicarbazone 10l of 8 with 20 24f–i, respectively, which are stabilized by intramolecular
and 21 were also prepared and subjected to Lewis acid addition of the hydrazine moiety to afford 25b and 25f–i.
treatment. In this way, the corresponding azacycles 25k and Dipolar intermediates 23d and 23e, on the other hand,
25l were obtained in lower yields than those from phenylhy- rather acquire increased nucleophilicity due to the electron-
drazones 10f–i (Table 1, entries 7 and 8).
donating groups on the phenyl ring and they are therefore
unsuitable for hydride abstraction. These dipoles are rather
converted into the starting aldehyde 8, such as 23c, where
the unsubstituted aromatic ring can not change the extant
reactivity of the dipole. The domino 1,5-hydride shift/cycli-
zation of 23j–l can also furnish the corresponding products
25j–l, but with lower conversion during a longer reaction
time. This can easily be explained by the decreased electron-
withdrawing effect of the substituents R in 23j–l, due to
positive mesomeric effects and thus the smaller increase in
the overall electrophilicity of the related azomethine imine
dipoles.
Since hydrazones proved to be suitable precursors for this
domino process, our attention next focused on an investiga-
tion as to whether the oxime and oxime ethers of aldehyde
8 can undergo similar transformation. First, the aldoxime
28a of 8 with hydroxylamine hydrochloride was prepared in
basic 2-propanol under reflux (Scheme 2), and proved to be
quite stable on treatment with a stoichiometric amount of
BF3·OEt2. Although the isomerization of intermediate 29a
to nitrone 1,3-dipole 30a through an O,N-hydrogen shift is
conceivable,[19] the nitrone structure is presumed to be the
less stable tautomer in the equilibrium.[20] The oxyiminium
Table 1. Stereoselective synthesis of 9,13-bridged steroidal aza-
cycles.
Entry
Substrate
R
t [h]
Product
Yield[a]
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
10b
10f
10g
10h
10i
10j
10k
10l
Ac
4
4
4
4
4
6
8
8
6
4
8
25b
25f
25g
25h
25i
25j
25k
25l
78
98
92
89
93
56
66
63
71
78
72
4Ј-NO2-C6H4
4Ј-CN-C6H4
4Ј-CF3-C6H4
2Ј,4Ј-NO2-C6H3
4Ј-Cl-C6H4
C(O)NH2
C(S)NH2
28b
28c
28d
Bn
32b
32c
32d
4Ј-NO2-C6H4-CH2
allyl
[a] Determined after purification by column chromatography.
The following mechanism is proposed for the described ion 29a, however, did not seem to have enough electrophilic
transformation. Reaction of monosubstituted hydrazones force to induce a hydride shift. Interestingly, when the ox-
10b–l with BF3·OEt2 results in ionic intermediates 22b–l, ime ethers 28b–d of 8 were subjected to similar Lewis acid
which can undergo tautomerization to give the quasi-azo- treatment, formation of the corresponding 9,13-bridged
methine imine 1,3-dipolar intermediates 23b–l.[15] Coordi- products 32b–d was observed (Table 1, entries 9–11). These
nation to the Lewis acid of phenylhydrazones containing an results indicate that O-substituted oxyiminium ions and
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Novel -Secoestrone Isoquinuclidines
Scheme 2. BF3·OEt2-promoted hydro-N-alkylation of oxime ethers.
chromatography: silica gel 60, 40–63 µm. Melting points were de-
termined on a Kofler block and are uncorrected. EI mass spectra
were obtained with a Varian MAT 311A spectrometer with ioniza-
azomethine imines have similar electrophilicity to that of
aryliminium ions and are able to cleave a hydride from the
activated benzylic position. Therefore, the reactivity scale of
Mayr and Ofial[21] may be completed additionally with
these two types of ionic intermediates.
1
tion energy 70 eV. H NMR spectra were obtained in CDCl3 or in
[D6]DMSO solution at 400 MHz (Bruker DRX 400) or 500 MHz
(Bruker DRX 500), and the 13C NMR spectra at 100 or 125 MHz
with the same instruments. Chemical shifts are reported relative to
TMS; J values are given in Hz. 13C NMR spectra are 1H-decou-
pled. For determination of the multiplicities, the J-MOD pulse se-
quence was used. Elemental analyses were carried out with a Per-
The structures of the newly synthetized steroid azacycles
25b,f–l and 32b–d were determined by NMR spectroscopy.
1
In the H NMR spectra of compounds 25b,f–l and 32b–d,
a triplet is observed for 16a-H3 at δ = 0.94–0.99 ppm with
J = 6.9–7.0 Hz. In all cases, the corresponding proton reso- kin–Elmer model 2400 CHN analyzer.
nated at higher fields (ca. 0.85 ppm) in the starting phenyl-
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al Hydrazone (10a):
hydrazones 10b,f–l and oxime ethers 28b–d. The 13C NMR
spectra of 25b,f–l and 32b–d obtained by a J-MOD pulse
sequence, contain the expected signals; the peaks for C-9
To a solution of 7 (298 mg, 1.00 mmol) in CH2Cl2 (10 mL), hydraz-
ine hydrate (98%, 1 mL, 20 mmol) and 1 drop of acetic acid were
added. The mixture was stirred overnight at room temperature and
and C-17 appear at relatively high chemical shifts, at around the solvent was then evaporated in vacuo. The residue was dis-
solved in MeOH (5 mL) and diluted with water. The crude product
10a (289 mg, 92%) was filtered off as a white precipitate, washed
with water and dried; m.p. 68–70 °C; Rf = 0.79 (MeOH/CH2Cl2 =
5:95). H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H,
16a-H3), 1.05 (s, 3 H, 18-H3), 1.14–1.62 (m, 10 H), 2.08 (m, 1 H),
δ = 57.5 ppm for C-9 and δ = 68.5 ppm for C-17.
1
Conclusions
In conclusion, a new type of domino reaction leading to 2.31 (m, 2 H), 2.86 (m, 2 H, 6-H2), 3.78 (s, 3 H, 3-OMe), 6.63 (d,
J = 2.3 Hz, 1 H, 4-H), 6.72 (dd, J = 8.6, J = 2.3 Hz, 1 H, 2-H),
6.94 (s, 1 H, 17-H), 7.21 (d, J = 8.6 Hz, 1 H, 1-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.6 (C-16a), 15.8 (C-18), 24.4 (CH2), 26.2
(CH2), 27.3 (CH2), 30.5 (CH2), 32.1 (CH2), 37.6 (CH2), 41.2 (C-8),
41.8 (C-13), 43.4 (C-9), 48.0 (C-14), 55.1 (3-OMe), 111.7 (C-2),
113.4 (C-4), 126.5 (C-1), 132.5 (C-10), 137.8 (C-5), 155.5 (C-17),
157.5 (C-3) ppm. MS (70 eV, EI): m/z (%) = 314 (100) [M+], 271
(100), 174 (23), 112 (30). C20H30N2O (314.46): calcd. for C 76.39,
H 9.62; found C 76.52, H 9.47.
steroidal isoquinuclidines has been described. The intramo-
lecular hydride ion abstraction induced by azomethine im-
ines and oxyiminium ions, generated in situ from hydra-
zones and oxime ethers in Lewis acid media, is a rather
unusual process and to the best of our knowledge has not
been reported previously. Besides their simplicity, the trans-
formations display high chemo- and regioselectivity.
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al Hydrazone Acetate
(10b): Compound 10a (250 mg, 0.80 mmol) was dissolved in a mix-
ture of pyridine (5 mL) and acetic anhydride (5 mL) and the solu-
tion was stirred at room temperature for 2 h. The mixture was then
poured onto a mixture of sulfuric acid (5 mL) and ice (10 g). The
crude product 10b (242 mg, 85%) was filtered off as a white precipi-
tate, washed with water and dried; m.p. 158–161 °C; Rf = 0.39
(MeOH/CH2Cl2 = 5:95). 1H NMR (400 MHz, CDCl3): δ = 0.86 (t,
J = 6.5 Hz, 3 H, 16a-H3), 1.08 (s, 3 H, 18-H3), 1.14–1.70 (m, 10
Experimental Section
General Methods: All solvents were distilled and dried prior to use.
Reagents and materials were obtained from commercial suppliers
and were used without purification. The reactions were monitored
by TLC on Kieselgel-G (Merck Si 254F) layers (0.25 mm thick-
ness). The spots were detected by spraying with 5% phosphomolyb-
dic acid in 50% aqueous phosphoric acid. The Rf values were deter-
mined for spots observed in UV light (λ = 254 and 365 nm). Flash
Eur. J. Org. Chem. 2009, 3544–3553
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É. Frank, G. Schneider, Z. Kádár, J. Wölfling
H), 2.08 (m, 1 H), 2.31 (m, 2 H), 2.28 (s, 3 H, Ac-H3), 2.86 (m, 2 (90) [M+], 298 (100). C27H36N2O (404.59): calcd. for C 80.15, H
FULL PAPER
H, 6-H2), 3.78 (s, 3 H, 3-OMe), 6.63 (d, J = 2.3 Hz, 1 H, 4-H),
6.72 (dd, J = 8.6, J = 2.3 Hz, 1 H, 2-H), 7.00 (s, 1 H, 17-H), 7.21
(d, J = 8.6 Hz, 1 H, 1-H), 9.51 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.6 (C-16a), 15.6 (C-18), 20.3 (Ac-CH3),
24.4 (CH2), 26.1 (CH2), 27.3 (CH2), 30.5 (CH2), 32.3 (CH2), 37.4
(CH2), 41.2 (C-8), 42.4 (C-13), 43.3 (C-9), 47.6 (C-14), 55.2 (3-
OMe), 111.7 (C-2), 113.5 (C-4), 126.5 (C-1), 132.2 (C-10), 137.8
(C-5), 155.6 (C-17), 157.5 (C-3), 173.6 (Ac-CO) ppm. MS (70 eV,
EI): m/z (%) = 356 (82) [M+], 313 (100), 174 (69), 126 (40), 112
(58). C22H32N2O2 (356.50): calcd. for C 74.12, H 9.05; found C
73.96, H 9.32.
8.97; found C 80.29, H 9.05.
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al 4Ј-Methoxyphenyl-
hydrazone (10e): 4-Methoxyphenylhydrazine hydrochloride 14
(175 mg) was used for the synthesis as described in the General
Procedure, Method A. Reaction time: 1 h. The crude product 10e
(328 mg, 78%) was obtained as a white precipitate; m.p. 108–
1
110 °C; Rf = 0.75 (hexane/CH2Cl2 = 20:80). H NMR (400 MHz,
CDCl3): δ = 0.85 (t, J = 6.6 Hz, 3 H, 16a-H3), 1.13 (s, 3 H, 18-H3),
1.16–1.52 (m, 8 H), 1.65 (m, 2 H), 2.08 (m, 1 H), 2.30 (m, 2 H),
2.87 (m, 2 H, 6-H2), 3.77 (s, 3 H) and 3.78 (s, 3 H): 3-OMe and 4Ј-
OMe, 6.63 (d, J = 2.2 Hz, 1 H, 4-H), 6.72 (dd, J = 8.5, J = 2.2 Hz,
1 H, 2-H), 6.84 (d, J = 8.8 Hz, 2 H, 2Ј-H and 6Ј-H), 6.89 (s, 1 H,
NH), 6.97 (m, 3 H, 3Ј-H, 5Ј-H and 17-H), 7.22 (d, J = 8.5 Hz, 1
H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (C-16a), 16.1
(C-18), 24.6 (CH2), 26.4 (CH2), 27.4 (CH2), 30.6 (CH2), 32.2 (CH2),
38.1 (CH2), 41.4 (C-8), 42.1 (C-13), 43.4 (C-9), 48.2 (C-14), 55.2
(3-OMe), 55.8 (4Ј-OMe), 111.7 (C-2), 113.5 (C-4), 113.9 (2 C, C-3Ј
and C-5Ј), 114.7 (2 C, C-2Ј and C-6Ј), 126.5 (C-1), 132.3 (C-10),
137.9 (C-5), 140.0 (C-1Ј), 149.6 (C-17), 153.4 (C-4Ј), 157.5 (C-3)
ppm. MS (70 eV, EI): m/z (%) = 420 (94) [M+], 298 (100), 122 (29).
C27H36N2O2 (420.59): calcd. for C 77.10, H 8.63; found C 76.93,
H 8.84.
General Procedure for the Synthesis of Hydrazones 10c–l
Method A: Compound 8 (300 mg, 1.00 mmol) and (substituted) hy-
drazine hydrochloride derivative (1.00 mmol) were suspended in
MeOH (5 mL),
a solution of anhydrous NaOAc (150 mg,
1.80 mmol) in MeOH (5 mL) was added, and the mixture was
stirred for a given time at room temperature. The resulting precipi-
tate was filtered off, washed with a small amount of MeOH and
allowed to stand at room temperature until completely dry.
Method B: A solution of compound 8 (300 mg, 1.00 mmol) and
substituted hydrazine derivative (1.00 mmol) in MeOH (5 mL) was
stirred in the presence of 2 drops of AcOH for a given time at room
temperature. The resulting precipitate was filtered off, washed with
a small amount of MeOH and dried.
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al (4Ј-Nitrophenyl)hy-
drazone (10f): 4-Nitrophenylhydrazine hydrochloride 15 (190 mg)
was used for the synthesis as described in the General Procedure,
Method A. Reaction time: 2 h. The crude product 10f (418 mg,
96%) was obtained as an orange precipitate; m.p. 213–215 °C; Rf
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al
Phenylhydrazone
(10c): Phenylhydrazine hydrochloride 12 (145 mg) was used for the
synthesis as described in the General Procedure, Method A. Reac-
tion time: 1 h. The crude product 10c (336 mg, 86%) was obtained
as a white precipitate; m.p. 148–150 °C; Rf = 0.58 (hexane/CH2Cl2
1
= 0.49 (hexane/CH2Cl2 = 20:80). H NMR (400 MHz, CDCl3): δ
= 0.84 (t, J = 6.5 Hz, 3 H, 16a-H3), 1.16 (s, 3 H, 18-H3), 1.20–1.55
(m, 8 H), 1.68 (m, 2 H), 2.09 (m, 1 H), 2.32 (m, 2 H), 2.88 (m, 2
H, 6-H2), 3.79 (s, 3 H, 3-OMe), 6.64 (d, J = 2.5 Hz, 1 H, 4-H),
6.73 (dd, J = 8.6, J = 2.5 Hz, 1 H, 2-H), 7.00 (d, J = 9.1 Hz, 2 H,
2Ј-H and 6Ј-H), 7.03 (s, 1 H, 17-H), 7.22 (d, J = 8.6 Hz, 1 H, 1-
H), 7.75 (br. s, 1 H, NH), 8.15 (d, J = 9.1 Hz, 2 H, 3Ј-H and 5Ј-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (C-16a), 15.9 (C-
18), 24.5 (CH2), 26.2 (CH2), 27.3 (CH2), 30.5 (CH2), 32.3 (CH2),
37.8 (CH2), 41.3 (C-8), 42.6 (C-13), 43.4 (C-9), 48.0 (C-14), 55.2
(3-OMe), 111.2 (2 C, C-2Ј and C-6Ј), 111.8 (C-2), 113.5 (C-4), 126.2
(2 C, C-3Ј and C-5Ј), 126.5 (C-1), 132.2 (C-10), 137.8 (C-5), 139.7
(C-4Ј), 150.3 (C-1Ј), 153.8 (C-17), 157.5 (C-3) ppm. MS (70 eV, EI):
m/z (%) = 435 (50) [M+], 298 (100). C26H33N3O3 (435.56): calcd.
for C 71.70, H 7.64; found C 71.85, H 7.54.
1
= 40:60). H NMR (400 MHz, CDCl3): δ = 0.84 (t, J = 6.7 Hz, 3
H, 16a-H3), 1.13 (s, 3 H, 18-H3), 1.18–1.53 (m, 8 H), 1.66 (m, 2
H), 2.09 (m, 1 H), 2.32 (m, 2 H), 2.86 (m, 2 H, 6-H2), 3.78 (s, 3 H,
3-OMe), 6.63 (d, J = 2.4 Hz, 1 H, 4-H), 6.72 (dd, J = 8.6, J =
2.4 Hz, 1 H, 2-H), 6.81 (m, 1 H, 4Ј-H), 6.89 (br. s, 1 H, NH), 7.00
(d, J = 7.8 Hz, 2 H, 2Ј-H and 6Ј-H), 7.14 (s, 1 H, 17-H), 7.22 (m,
2 H, 3Ј-H and 5Ј-H), 7.25 (d, J = 8.6 Hz, 1 H, 1-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.6 (C-16a), 16.1 (C-18), 24.6 (CH2), 26.4
(CH2), 27.4 (CH2), 30.6 (CH2), 32.3 (CH2), 38.1 (CH2), 41.4 (C-8),
42.1 (C-13), 43.4 (C-9), 48.2 (C-14), 55.2 (3-OMe), 111.7 (C-2),
112.5 (2 C, C-2Ј and C-6Ј), 113.5 (C-4), 119.3 (C-4Ј), 126.5 (C-1),
129.2 (2 C, C-3Ј and C-5Ј), 132.5 (C-10), 137.9 (C-5), 145.7 (C-1Ј),
149.9 (C-17), 157.5 (C-3) ppm. C26H34N2O (390.56): calcd. for C
79.96, H 8.77; found C 80.14, H 8.54.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al (4Ј-Cyanophenyl)-
16,17-seco-3-Methoxyestra-1,3,5(10)trien-17-al 4Ј-Tolylhydrazone hydrazone (10g): 4-Cyanophenylhydrazine hydrochloride 16
(10d): 4-Tolylhydrazine hydrochloride 13 (159 mg) was used for the
synthesis as described in the Geneal Procedure, Method A. Reac-
tion time: 2 h. The crude product 10d (327 mg, 81%) was obtained
as a white precipitate; m.p. 143–146 °C; Rf = 0.75 (hexane/CH2Cl2
= 20:80). H NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 6.6 Hz, 3
H, 16a-H3), 1.12 (s, 3 H, 18-H3), 1.17–1.55 (m, 8 H), 1.65 (m, 2
(170 mg) was used for the synthesis as described in the General
Procedure, Method A. Reaction time: 2 h. The crude product 10g
(407 mg, 98%) was obtained as a white precipitate; m.p. 184–
186 °C; Rf = 0.42 (hexane/CH2Cl2 = 20:80). H NMR (400 MHz,
CDCl3): δ = 0.86 (t, J = 6.5 Hz, 3 H, 16a-H3), 1.15 (s, 3 H, 18-H3),
1.20–1.55 (m, 8 H), 1.68 (m, 2 H), 2.10 (m, 1 H), 2.33 (m, 2 H),
1
1
H), 2.08 (m, 1 H), 2.26 (s, 3 H, 4Ј-CH3), 2.31 (m, 2 H), 2.86 (m, 2 2.88 (m, 2 H, 6-H2), 3.79 (s, 3 H, 3-OMe), 6.65 (d, J = 2.4 Hz, 1
H, 6-H2), 3.77 (s, 3 H, 3-OMe), 6.63 (d, J = 2.1 Hz, 1 H, 4-H),
6.71 (dd, J = 8.5, J = 2.1 Hz, 1 H, 2-H), 6.86 (s, 1 H, NH), 6.91
(d, J = 8.2 Hz, 2 H, 2Ј-H and 6Ј-H), 7.03 (m, 3 H, 3Ј-H, 5Ј-H and
17-H), 7.21 (d, J = 8.5 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz,
H, 4-H), 6.74 (dd, J = 8.6, J = 2.4 Hz, 1 H, 2-H), 6.98 (s, 1 H, 17-
H), 7.02 (d, J = 8.6 Hz, 2 H, 2Ј-H and 6Ј-H), 7.22 (d, J = 8.6 Hz,
1 H, 1-H), 7.49 (d, J = 8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 7.58 (br. s, 1
H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (C-16a), 15.9
CDCl3): δ = 14.6 (C-16a), 16.1 (C-18), 20.5 (4Ј-CH3), 24.6 (CH2), (C-18), 24.5 (CH2), 26.2 (CH2), 27.3 (CH2), 30.5 (CH2), 32.3 (CH2),
26.4 (CH2), 27.4 (CH2), 30.6 (CH2), 32.2 (CH2), 38.1 (CH2), 41.4
(C-8), 42.1 (C-13), 43.4 (C-9), 48.2 (C-14), 55.2 (3-OMe), 111.7 (C-
37.9 (CH2), 41.3 (C-8), 42.4 (C-13), 43.4 (C-9), 48.0 (C-14), 55.2
(3-OMe), 100.9 (C-4Ј), 111.8 (C-2), 112.2 (2 C, C-2Ј and C-6Ј),
2), 112.7 (2 C, C-2Ј and C-6Ј), 113.5 (C-4), 126.5 (C-1), 128.5 (C- 113.5 (C-4), 120.2 (4Ј-CN), 126.5 (C-1), 132.3 (C-10), 133.6 (2 C,
4Ј), 129.6 (2 C, C-3Ј and C-5Ј), 132.6 (C-10), 137.9 (C-5), 143.6 (C-
1Ј), 149.5 (C-17), 157.5 (C-3) ppm. MS (70 eV, EI): m/z (%) = 404
C-3Ј and C-5Ј), 137.8 (C-5), 148.6 (C-1Ј), 152.6 (C-17), 157.5 (C-
3) ppm. MS (70 eV, EI): m/z (%) = 415 (42) [M+], 298 (100), 257
3548
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3544–3553

Synthesis of Novel -Secoestrone Isoquinuclidines
(35). C27H33N3O (415.57): calcd. for C 78.03, H 8.00; found C
77.86, H 8.12.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al
Semicarbazone
(10k): Semicarbazide hydrochloride 20 (112 mg) was used for the
synthesis as described in the General Procedure, Method A. Reac-
tion time 8 h, under reflux. The crude product 10k (293 mg, 82%)
was obtained as a white precipitate; m.p. 163–166 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 0.87 (t, J = 6.6 Hz, 3 H, 16a-H3), 1.10
(s, 3 H, 18-H3), 1.19–1.42 (m, 8 H), 1.55–1.71 (m, 2 H), 2.08 (m, 1
H), 2.34 (m, 2 H), 2.86 (m, 2 H, 6-H2), 3.77 (s, 3 H, 3-OMe), 6.17
(m, 2 H, NH2), 6.68 (d, J = 2.1 Hz, 1 H, 4-H), 6.76 (dd, J = 8.5,
J = 2.1 Hz, 1 H, 2-H), 7.13 (s, 1 H, 17-H), 7.26 (d, J = 8.5 Hz, 1 H,
1-H), 9.75 (s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 14.3 (C-16a), 15.3 (C-18), 23.8 (CH2), 25.7 (CH2), 26.7 (CH2),
29.8 (CH2), 31.4 (CH2), 37.0 (CH2), 40.7 (C-8), 41.3 (C-13), 42.6
(C-9), 47.2 (C-14), 54.7 (3-OMe), 111.6 (C-2), 113.0 (C-4), 126.2
(C-1), 131.8 (C-10), 137.2 (C-5), 151.5 (C-17), 156.7 and 156.9 (C-
3 and C=O) ppm. C21H31N3O2 (357.49): calcd. for C 70.55, H 8.74;
found C 70.36, H 8.83.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al 4Ј-(Trifluoromethyl)-
phenylhydrazone (10h): 4-(Trifluoromethyl)phenylhydrazine 17
(176 mg) was used for the synthesis as described in the General
Procedure, Method B. Reaction time: 4 h. The crude product 10h
(357 mg, 78%) was obtained as a white precipitate; m.p. 118–
120 °C; Rf = 0.46 (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.86
(t, J = 6.7 Hz, 3 H, 16a-H3), 1.16 (s, 3 H, 18-H3), 1.20–1.56 (m, 8
H), 1.68 (m, 2 H), 2.11 (m, 1 H), 2.33 (m, 2 H), 2.88 (m, 2 H, 6-
H2), 3.80 (s, 3 H, 3-OMe), 6.66 (d, J = 2.6 Hz, 1 H, 4-H), 6.75 (dd,
J = 8.6, J = 2.6 Hz, 1 H, 2-H), 6.94 (s, 1 H, 17-H), 7.05 (d, J =
8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 7.23 (d, J = 8.6 Hz, 1 H, 1-H), 7.37
(br. s, 1 H, NH), 7.48 (d, J = 8.5 Hz, 2 H, 3Ј-H and 5Ј-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.6 (C-16a), 16.0 (C-18), 24.6
(CH2), 26.3 (CH2), 27.4 (CH2), 30.6 (CH2), 32.3 (CH2), 38.0 (CH2),
41.4 (C-8), 42.3 (C-13), 43.4 (C-9), 48.1 (C-14), 55.2 (3-OMe), 111.7
(C-2), 111.8 (2 C, C-2Ј and C-6Ј), 113.5 (C-4), 115.0 (C-4Ј), 120.7
(4Ј-CF3), 126.5 (3 C, C-1, C-3Ј and C-5Ј), 132.4 (C-10), 137.9 (C-
5), 148.0 (C-1Ј), 151.4 (C-17), 157.5 (C-3) ppm. MS (70 eV, EI):
m/z (%) = 458 (6) [M+], 165 (100). C27H33F3N2O (458.56): calcd.
for C 70.72, H 7.25; found C 70.94, H 7.12.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al Thiosemicarbazone
(10l): Thiosemicarbazide 21 (91 mg) was used for the synthesis as
described in the General Procedure, Method A. Reaction time 6 h,
under reflux. The crude product 10l (276 mg, 74%) was obtained
as a white precipitate; m.p. 126–128 °C; Rf = 0.18 (CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 6.7 Hz, 3 H, 16a-H3),
1.06 (s, 3 H, 18-H3), 1.19–1.50 (m, 8 H), 1.57–1.72 (m, 2 H), 2.07
(m, 1 H), 2.32 (m, 2 H), 2.86 (m, 2 H, 6-H2), 3.78 (s, 3 H, 3-OMe),
6.52 (br. s, 1 H, one proton of NH2), 6.63 (d, J = 2.5 Hz, 1 H, 4-
H), 6.72 (dd, J = 8.6, J = 2.5 Hz, 1 H, 2-H), 7.08 (br. s, 1 H, the
other proton of NH2), 7.18 (d, J = 8.6 Hz, 1 H, 1-H), 7.21 (s, 1 H,
17-H), 9.91 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ =
14.6 (C-16a), 15.4 (C-18), 24.4 (CH2), 26.0 (CH2), 27.2 (CH2), 30.4
(CH2), 32.3 (CH2), 37.2 (CH2), 41.1 (C-8), 42.7 (C-13), 43.2 (C-9),
47.6 (C-14), 55.2 (3-OMe), 111.8 (C-2), 113.4 (C-4), 126.4 (C-1),
132.0 (C-10), 137.7 (C-5), 156.9 (C-17), 157.5 (C-3), 178.1 (C = S)
ppm. MS (70 eV, EI): m/z (%) = 373 (54) [M+], 297 (77), 174 (78),
126 (58), 102 (100). C21H31N3OS (373.56): calcd. for C 67.52, H
8.36; found C 67.41, H 8.18.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al (2Ј,4Ј-Dinitrophen-
yl)hydrazone (10i): 2,4-Dinitrophenylhydrazine 18 (198 mgl) was
used for the synthesis as described in the General Procedure,
Method B. Reaction time: 4 h. The crude product 10i (456 mg,
95%) was obtained as an orange precipitate; m.p. 234–236 °C; Rf
1
= 0.59 (hexane/CH2Cl2 = 20:80). H NMR (400 MHz, CDCl3): δ
= 0.87 (t, J = 6.4 Hz, 3 H, 16a-H3), 1.21 (s, 3 H, 18-H3), 1.27–1.57
(m, 8 H), 1.73 (m, 2 H), 2.11 (m, 1 H), 2.36 (m, 2 H), 2.89 (m, 2
H, 6-H2), 3.79 (s, 3 H, 3-OMe), 6.64 (d, J = 2.5 Hz, 1 H, 4-H),
6.73 (dd, J = 8.5, J = 2.5 Hz, 1 H, 2-H), 7.22 (d, J = 8.5 Hz, 1 H,
1-H), 7.39 (s, 1 H, 17-H), 7.95 (d, J = 9.6 Hz, 1 H, 6Ј-H), 8.31 (dd,
J = 9.6, J = 2.2 Hz, 1 H, 5Ј-H), 9.12 (dd, J = 2.2 Hz, 1 H, 3Ј-H),
11.0 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (C-
16a), 15.7 (C-18), 24.4 (CH2), 26.0 (CH2), 27.2 (CH2), 30.4 (CH2),
32.5 (CH2), 37.5 (CH2), 41.2 (C-8), 43.3 (C-9), 43.4 (C-13), 47.7
(C-14), 55.2 (3-OMe), 111.8 (C-2), 113.5 (C-4), 116.6 (C-6Ј), 123.5
(C-3Ј), 126.4 (C-1), 128.9 (C-2Ј), 129.9 (C-5Ј), 132.0 (C-10), 137.7
(2 C, C-5 and C-4Ј), 145.3 (C-1Ј), 157.6 (C-3), 160.7 (C-17) ppm.
MS (70 eV, EI): m/z (%) = 480 (29) [M+], 298 (100). C26H32N4O5
(480.56): calcd. for C 64.98, H 6.71; found C 65.14, H 6.93.
Bis[16,17-seco-3-methoxyestra-1,3,5(10)-trien-17-al] Bishydrazone
(11): Compound 10a (280 mg, 0.89 mmol) was dissolved in CH2Cl2
(10 mL) and BF3·OEt2 (a 48% solution in diethyl ether, 0.26 mL,
0.89 mmol) was added dropwise under a nitrogen atmosphere. The
mixture was stirred for 4 h at 0 °C, then quenched by the addition
of NaHCO3 (1 , 10 mL) and extracted with CH2Cl2 (3ϫ10 mL).
The combined organic layers were washed with brine, dried with
Na2SO4 and concentrated in vacuo. The crude product was purified
by column chromatography (CH2Cl2) and recrystallized from
CH2Cl2/hexane to give 11 (494 mg, 93%) as white crystals; m.p.
171–172 °C; Rf = 0.34 (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al (4Ј-Chlorophenyl)-
hydrazone (10j): 4-Chlorophenylhydrazine hydrochloride 19
(180 mg) was used for the synthesis as described in the General
Procedure, Method A. Reaction time: 4 h. The crude product 10j
(319 mg, 75%) was obtained as a white precipitate; m.p. 145– = 0.86 (t, J = 6.5 Hz, 6 H, 16a-H3 and 16aЈ-H3), 1.14 (s, 6 H, 18-
1
147 °C; Rf = 0.44 (hexane/CH2Cl2 = 20:80). H NMR (400 MHz,
H3 and 18Ј-H3), 1.18–1.55 (m, 16 H), 1.71 (m, 4 H), 2.11 (m, 2 H),
CDCl3): δ = 0.84 (t, J = 6.7 Hz, 3 H, 16a-H3), 1.14 (s, 3 H, 18-H3), 2.34 (m, 4 H), 2.87 (m, 4 H, 6-H2 and 6Ј-H2), 3.79 (s, 6 H, 3-OMe
1.16–1.52 (m, 8 H), 1.65 (m, 2 H), 2.08 (m, 1 H), 2.31 (m, 2 H), and 3Ј-OMe), 6.64 (d, J = 2.3 Hz, 2 H, 4-H and 4Ј-H), 6.74 (dd, J
2.87 (m, 2 H, 6-H2), 3.80 (s, 3 H, 3-OMe), 6.65 (d, J = 2.5 Hz, 1
H, 4-H), 6.74 (dd, J = 8.6, J = 2.5 Hz, 1 H, 2-H), 6.91 (s, 1 H, 17-
H), 6.95 (d, J = 8.8 Hz, 2 H, 2Ј-H and 6Ј-H), 7.15 (br. s, 1 H, NH),
= 8.6, J = 2.3 Hz, 2 H, 2-H and 2Ј-H), 7.23 (d, J = 8.6 Hz, 2 H,
1-H and 1Ј-H), 7.61 (s, 2 H, 17-H and 17Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.6 (2 C, C-16a and C-16aЈ), 15.6 (2 C,
7.19 (d, J = 8.8 Hz, 2 H, 3Ј-H and 5Ј-H), 7.23 (d, J = 8.6 Hz, 1 H, C-18 and C-18Ј), 24.3 (2 CH2), 26.0 (2 CH2), 27.3 (2 CH2), 30.5 (2
1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.6 (C-16a), 16.0
CH2), 32.3 (2 CH2), 37.1 (2 CH2), 41.1 (2 C, C-8 and C-8Ј), 42.4
(C-18), 24.6 (CH2), 26.4 (CH2), 27.4 (CH2), 30.6 (CH2), 32.3 (CH2), (2 C, C-13 and C-13Ј), 43.3 (2 C, C-9 and C-9Ј), 47.5 (2 C, C-14
38.0 (CH2), 41.4 (C-8), 42.2 (C-13), 43.4 (C-9), 48.1 (C-14), 55.2 and C-14Ј), 55.2 (2 C, 3-OMe and 3Ј-OMe), 111.7 (2 C, C-2 and
(3-OMe), 111.7 (C-2), 113.5 (C-4), 113.6 (2 C, C-2Ј and C-6Ј), 123.8 C-2Ј), 113.5 (2 C, C-4 and C-4Ј), 126.5 (2 C, C-1 and C-1Ј), 132.4
(C-4Ј), 126.5 (C-1), 129.0 (2 C, C-3Ј and C-5Ј), 132.4 (C-10), 137.9
(C-5), 144.3 (C-1Ј), 150.5 (C-17), 157.5 (C-3) ppm. MS (70 eV, EI):
m/z (%) = 426 (12), 424 (38) [M+], 298 (100). C26H33ClN2O
(425.01): calcd. for C 73.48, H 7.83; found C 73.61, H 7.72.
(2 C, C-10 and C-10Ј), 137.8 (2 C, C-5 and C-5Ј), 157.5 (2 C, C-3
and C-3Ј), 171.0 (2 C, C-17 and C-17Ј) ppm. MS (70 eV, EI): m/z
(%) = 596 (100) [M+], 112 (14). C40H56N2O2 (596.88): calcd. for C
80.49, H 9.46; found C 80.69, H 9.33.
Eur. J. Org. Chem. 2009, 3544–3553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3549

É. Frank, G. Schneider, Z. Kádár, J. Wölfling
FULL PAPER
General Procedure for the Synthesis of Isoquinuclidines 25b and
25f-l: Without purification by column chromatography, the crude
hydrazone 10b or 10f–l was dissolved in CH2Cl2 (10 mL), and
BF3·OEt2 (a 48% solution in diethyl ether, 1 equiv.) was added
slowly at room temperature under a nitrogen atmosphere. The mix-
ture was then refluxed for a given time (see, Table 1). The reaction
was next quenched by the addition of ice-cold NaHCO3 (1 ,
2-H, 4-H, 2Ј-H and 6Ј-H), 7.16 (overlapping m, 3 H, 1-H, 3Ј-H and
5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.7 (C-16a), 21.4
(CH2), 23.2 (C-18), 27.8 (CH2), 28.2 (2 C, 2ϫ CH2), 30.3 (C-6),
32.8 (C-13), 34.2 (CH2), 47.2 and 47.5 (C-8 and C-14), 55.0 (3-
OMe), 57.3 (C-9), 68.9 (C-17), 98.7 (C-4Ј), 111.0 (C-2), 111.2 (2 C,
C-2Ј and C-6Ј), 112.9 (C-4), 120.6 (4Ј-CN), 129.1 (C-10), 129.6 (C-
1), 132.9 (2 C, C-3Ј and C-5Ј), 139.0 (C-5), 152.9 (C-1Ј), 158.2
10 mL) and the mixture was extracted with CH2Cl2 (3ϫ10 mL). (C-3) ppm. MS (70 eV, EI): m/z (%) = 415 (44) [M+], 298 (100).
The combined organic layers were washed with brine, dried with
Na2SO4 and concentrated in vacuo.
C27H33N3O (415.57): calcd. for C 78.03, H 8.00; found C 78.32, H
8.22.
Cyclization of 10b to 25b: Compound 10b (200 mg, 0.56 mmol) and
BF3·OEt2 (0.16 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (EtOAc/CH2Cl2 = 50:50) and recrystallized from
CH2Cl2/hexane to give 25b (156 mg) as white crystals; m.p. 78–
80 °C; Rf = 0.50 (EtOAc/CH2Cl2 = 50:50). 1H NMR (400 MHz,
Cyclization of 10h to 25h: Compound 10h (229 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (hexane/diisopropyl ether = 90:10) to give 25h
(204 mg) as a colorless oil. Rf = 0.44 (hexane/diisopropyl ether =
70:30). 1H NMR (400 MHz, CDCl3): δ = 0.82 (s, 3 H, 18-H3), 0.97
CDCl3): δ = 0.79 (s, 3 H, 18-H3), 0.95 (t, J = 6.9 Hz, 3 H, 16a-H3), (t, J = 6.9 Hz, 3 H, 16a-H3), 1.12–1.61 (overlapping m, 9 H), 1.82
1.04–1.22 (overlapping m, 2 H), 1.31 (m, 2 H), 1.36 (s, 3 H, Ac- (m, 2 H, 7-H2), 2.63 (m, 1 H, 17-H2,ax), 2.65 (m, 1 H), 2.87 (m, 2
H3), 1.41 (m, 1 H), 1.54 (m, 3 H), 1.70–1.85 (overlapping m, 2 H),
H, 6-H2), 3.25 (m, 1 H, 17-H2,eq), 3.65 (s, 3 H, 3-OMe), 4.96 (s, 1
2.23 (m, 1 H), 2.53 (d, J = 10.2 Hz, 1 H, 17-H2,ax), 2.62 (m, 1 H), H, NH), 6.45 (d, J = 2.5 Hz, 1 H, 4-H), 6.48 (dd, J = 8.6, J =
2.86 (m, 2 H, 6-H2), 3.25 (d, J = 10.2 Hz, 1 H, 17-H2,eq), 3.74 (s, 3 2.5 Hz, 1 H, 2-H), 6.56 (d, J = 8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 7.16
H, 3-OMe), 6.57 (d, J = 2.6 Hz, 1 H, 4-H), 6.68 (dd, J = 8.7, J =
2.6 Hz, 1 H, 2-H), 6.92 (br. s, 1 H, NH), 7.15 (d, J = 8.7 Hz, 1 H,
1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.7 (C-16a), 19.2
(Ac-CH3), 21.2 (CH2), 23.0 (C-18), 25.0 (CH2), 27.4 (CH2), 27.9
(d, J = 8.5 Hz, 2 H, 3Ј-H and 5Ј-H), 7.19 (d, J = 8.6 Hz, 1 H, 1-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.8 (C-16a), 21.5
(CH2), 23.2 (C-18), 27.8 (CH2), 28.3 (2 C, 2ϫ CH2), 30.4 (C-6),
32.9 (C-13), 34.2 (CH2), 47.3 and 47.7 (C-8 and C-14), 55.0 (3-
(CH2), 30.4 (CH2), 32.2 (C-13), 34.2 (CH2), 46.9 and 47.5 (C-8 and OMe), 57.2 (C-9), 69.2 (C-17), 111.1 (C-2), 111.3 (2 C, C-2Ј and
C-14), 55.0 (3-OMe), 57.5 (C-9), 68.6 (C-17), 110.8 (C-2), 113.6 (C- C-6Ј), 112.9 (C-4), 116.5 (C-4Ј) 118.6 (4Ј-CF3), 125.8 (2 C, C-3Ј and
4), 128.9 (C-10), 130.2 (C-1), 139.1 (C-5), 158.5 (C-3), 175.7 (Ac-
CO) ppm. MS (70 eV, EI): m/z (%) = 356 (46) [M+], 313 (100), 174
(25), 87 (22). C22H32N2O2 (356.50): calcd. for C 74.12, H 9.05;
found C 74.27, H 8.92.
C-5Ј), 129.6 (C-10), 129.8 (C-1), 139.0 (C-5), 152.2 (C-1Ј), 158.1 (C-
3) ppm. MS (70 eV, EI): m/z (%) = 458 (35) [M+], 298 (80), 173
(100), 147 (98). C27H33F3N2O (458.56): calcd. for C 70.72, H 7.25;
found C 70.65, H 7.33.
Cyclization of 10f to 25f: Compound 10f (418 mg, 0.96 mmol) and
BF3·OEt2 (0.29 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (CH2Cl2) and recrystallized from diisopropyl
ether/hexane to give 25f (410 mg) as orange crystals; m.p. 202–
Cyclization of 10i to 25i: Compound 10i (240 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (hexane/diisopropyl ether = 80:20) and recrys-
tallized from MeOH/H2O to give 25i (223 mg) as orange crystals;
204 °C; Rf = 0.54 (CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 0.83 m.p. 59–61 °C; Rf = 0.50 (hexane/CH2Cl2 = 20:80). 1H NMR
(s, 3 H, 18-H3), 0.97 (t, J = 6.9 Hz, 3 H, 16a-H3), 1.17–1.62 (over- (400 MHz, CDCl3): δ = 0.87 (s, 3 H, 18-H3), 0.99 (t, J = 7.0 Hz, 3
lapping m, 9 H), 1.84 (m, 2 H, 7-H2), 2.57 (m, 1 H, 17-H2,ax), 2.66 H, 16a-H3), 1.21–1.63 (overlapping m, 8 H), 1.89 (m, 2 H), 2.33
(m, 1 H), 2.86 (m, 2 H, 6-H2), 3.34 (m, 1 H, 17-H2,eq), 3.62 (s, 3
H, 3-OMe), 5.47 (s, 1 H, NH), 6.45 (overlapping m, 4 H, 2-H, 4-
H, 2Ј-H and 6Ј-H), 7.11 (d, J = 8.8 Hz, 1 H, 1-H), 7.82 (d, J =
9.0 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. 13C NMR (125 MHz, CDCl3):
(m, 1 H), 2.72 (d, J = 11.2 Hz, 1 H, 17-H2,ax), 2.77 (m, 1 H), 2.86
(m, 2 H, 6-H2), 3.38 (d, J = 11.2 Hz, 1 H, 17-H2,eq), 3.65 (s, 3 H,
3-OMe), 6.34 (d, J = 8.6 Hz, 1 H, 2-H), 6.41 (s, 1 H, 4-H), 7.01 (d,
J = 8.6 Hz, 1 H, 1-H), 7.19 (d, J = 9.5 Hz, 1 H, 6Ј-H), 7.84 (dd, J
δ = 14.7 (C-16a), 21.4 (CH2), 23.1 (C-18), 25.0 (CH2), 28.1 (2 C, = 9.5, J = 2.1 Hz, 1 H, 5Ј-H), 8.85 (d, J = 2.1 Hz, 1 H, 3Ј-H), 9.34
C-7 and C-12), 30.3 (C-6), 32.9 (C-13), 34.1 (CH2), 47.1 and 47.5
(C-8 and C-14), 55.0 (3-OMe), 57.6 (C-9), 68.6 (C-17), 109.9 (2 C,
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.7 (C-
16a), 21.4 (CH2), 23.0 (C-18), 25.2 (CH2), 27.6 (CH2), 27.9 (CH2),
C-2Ј and C-6Ј), 111.2 (C-2), 113.0 (C-4), 125.7 (2 C, C-3Ј and C- 30.1 (C-6), 32.4 (C-13), 34.1 (CH2), 46.7 and 47.4 (C-8 and C-14),
5Ј), 128.7 (C-10), 129.6 (C-1), 138.0 (C-4Ј), 139.1 (C-5), 154.8 (C-
1Ј), 158.3 (C-3) ppm. MS (70 eV, EI): m/z (%) = 435 (24) [M+], 298
(100). C26H33N3O3 (435.56): calcd. for C 71.70, H 7.64; found C
71.92, H 7.46.
55.0 (3-OMe), 58.3 (C-9), 67.9 (C-17), 111.0 (C-2), 113.4 (C-4),
115.8 (C-6Ј), 123.3 (C-3Ј), 127.6 (C-10), 129.0 (2 C, C-1 and C-5Ј),
136.0 (C-2Ј), 139.2 (2 C, C-5 and C-4Ј), 149.9 (C-1Ј), 158.6 (C-3)
ppm. MS (70 eV, EI): m/z (%) = 480 (13) [M+], 298 (100).
C26H32N4O5 (480.56): calcd. for C 64.98, H 6.71; found C 65.15,
H 6.54.
Cyclization of 10g to 25g: Compound 10g (208 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (hexane/diisopropyl ether = 80:20) and recrys-
tallized from hexane/diisopropyl ether to give 25g (191 mg) as white
crystals; m.p. 178–180 °C; Rf = 0.60 (hexane/diisopropyl ether =
Cyclization of 10j to 25j: Compound 10j (212 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (hexane/diisopropyl ether = 70:30) to give 25j
20:80). 1H NMR (400 MHz, CDCl3): δ = 0.82 (s, 3 H, 18-H3), 0.97 (119 mg) as a colorless oil. Rf = 0.83 (hexane/diisopropyl ether =
(t, J = 6.9 Hz, 3 H, 16a-H3), 1.13–1.25 (overlapping m, 2 H), 1.32–
1.62 (overlapping m, 7 H), 1.84 (m, 2 H, 7-H2), 2.62 (m, 1 H, 17- (t, J = 7.0 Hz, 3 H, 16a-H3), 1.17–1.62 (overlapping m, 9 H), 1.81
70:30). 1H NMR (400 MHz, CDCl3): δ = 0.81 (s, 3 H, 18-H3), 0.97
H2,ax), 2.65 (m, 1 H), 2.86 (m, 2 H, 6-H2), 3.27 (m, 1 H, 17-H2,eq),
3.65 (s, 3 H, 3-OMe), 5.24 (s, 1 H, NH), 6.47 (overlapping m, 4 H,
(m, 2 H, 7-H2), 2.63 (m, 1 H, 17-H2,ax), 2.65 (m, 1 H), 2.86 (m, 2
H, 6-H2), 3.25 (dd, J = 10.9, J = 2.9 Hz, 1 H, 17-H2,eq), 3.65 (s, 3
3550
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3544–3553

Synthesis of Novel -Secoestrone Isoquinuclidines
H, 3-OMe), 4.67 (br. s, 1 H, NH), 6.51 (overlapping m, 4 H, 2-H,
δ = 14.5 (C-16a), 15.4 (C-18), 24.3 (CH2), 26.0 (CH2), 27.3 (CH2),
4-H, 2Ј-H and 6Ј-H), 6.89 (d, J = 8.8 Hz, 2 H, 3Ј-H and 5Ј-H), 30.5 (CH2), 32.1 (CH2), 37.4 (CH2), 41.0 (C-8), 41.3 (C-13), 43.3
7.22 (d, J = 8.7 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): (C-9), 47.9 (C-14), 55.2 (3-OMe), 111.7 (C-2), 113.5 (C-4), 126.5
δ = 14.8 (C-16a), 21.5 (CH2), 23.3 (C-18), 27.8 (2ϫ CH2), 28.3 (C-1), 132.2 (C-10), 137.8 (C-5), 157.5 (C-3), 160.4 (C-17) ppm. MS
(CH2), 30.4 (C-6), 33.0 (C-13), 34.2 (CH2), 47.4 and 47.7 (C-8 and
(70 eV, EI): m/z (%) = 315 (8) [M+], 298 (70), 112 (100). C20H29NO2
C-14), 55.1 (3-OMe), 57.0 (C-9), 69.5 (C-17), 111.0 (C-2), 112.8 (C- (315.45): calcd. for C 76.15, H 9.27; found C 75.93, H 9.35.
4), 113.5 (2 C, C-2Ј and C-6Ј), 122.1 (C-4Ј), 128.2 (2 C, C-3Ј and
General Procedure for the Synthesis of Oxime Ethers 28b-d: Com-
C-5Ј), 129.8 (C-1), 130.1 (C-10), 138.9 (C-5), 148.3 (C-1Ј), 158.0
pound 8 (300 mg, 1.00 mmol) and O-substituted hydroxylamine hy-
(C-3) ppm. MS (70 eV, EI): m/z (%) = 426 (6) [M+], 424 (15), 174
drochloride 27b, 27c or 27d (1.00 mmol, respectively) were sus-
(100), 147 (70). C26H33ClN2O (425.01): calcd. for C 73.48, H 7.83;
pended in 2-PrOH (10 mL) and a solution of NaOAc (150 mg,
found C 73.21, H 7.95.
1.80 mmol) in 2-PrOH (10 mL) was added. The mixture was re-
fluxed for 8 h, poured into cold water and then extracted with
CH2Cl2 (3ϫ10 mL). The combined organic layers were washed
with brine, dried with Na2SO4 and concentrated in vacuo.
Cyclization of 10k to 25k: Compound 10k (178 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (EtOAc) to give 25k (118 mg) as white crystals;
m.p. 220–222 °C; Rf = 0.13 (EtOAc). 1H NMR (400 MHz, CDCl3):
δ = 0.79 (s, 3 H, 18-H3), 0.95 (t, J = 6.9 Hz, 3 H, 16a-H3), 1.13–
1.57 (overlapping m, 8 H), 1.79 (m, 2 H), 2.07 (m, 1 H), 2.59 (d, J
= 11.2 Hz, 1 H, 17-H2,ax), 2.66 (m, 1 H), 2.86 (m, 2 H, 6-H2), 3.28
(d, J = 11.2 Hz, 1 H, 17-H2,eq), 3.74 (s, 3 H, 3-OMe), 6.46 (br. s, 1
H, NH), 6.55 (d, J = 2.5 Hz, 1 H, 4-H), 6.68 (dd, J = 8.7, J =
2.5 Hz, 1 H, 2-H), 7.27 (d, J = 8.7 Hz, 1 H, 1-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.7 (C-16a), 21.2 (CH2), 23.0 (C-18), 25.2
(CH2), 27.7 (CH2), 27.8 (CH2), 30.3 (CH2), 32.2 (C-13), 34.3 (CH2),
46.7 and 47.7 (C-8 and C-14), 55.0 (3-OMe), 57.1 (C-9), 68.7 (C-
17), 111.0 (C-2), 113.5 (C-4), 128.9 (C-10), 130.0 (C-1), 138.4 (C-
5), 158.5 (C-3), 160.5 (C=O) ppm. MS (70 eV, EI): m/z (%) = 357
(86) [M+], 313 (100), 298 (70), 174 (38), 88 (42). C21H31N3O2
(357.49): calcd. for C 70.55, H 8.74; found C 70.41, H 8.96.
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al Oxime Benzyl
Ether (28b): For the synthesis, given in the General Procedure, O-
benzylhydroxylamine hydrochloride 27b (160 mg) was used. The
crude product was purified by column chromatography (CH2Cl2)
to give 28b (357 mg, 88%) as a colorless oil. Rf = 0.43 (EtOAc/
CH2Cl2 = 10:90). 1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J =
6.8 Hz, 3 H, 16a-H3), 1.07 (s, 3 H, 18-H3), 1.16–1.51 (overlapping
m, 8 H), 1.64 (m, 2 H), 2.06 (m, 1 H), 2.28 (m, 2 H), 2.87 (m, 2 H,
6-H2), 3.79 (s, 3 H, 3-OMe), 5.10 (s, 2 H, OCH2), 6.64 (d, J =
2.4 Hz, 1 H, 4-H), 6.73 (dd, J = 8.6, J = 2.4 Hz, 1 H, 2-H), 7.21
(d, J = 8.6 Hz, 1 H, 1-H), 7.30–7.41 (overlapping m, 6 H, 17-H,
2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H and 6Ј-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.5 (C-16a), 15.5 (C-18), 24.4 (CH2), 26.0 (CH2), 27.3
(CH2), 30.5 (CH2), 32.3 (CH2), 37.6 (CH2), 41.1 (C-8), 41.4 (C-13),
43.3 (C-9), 47.8 (C-14), 55.2 (3-OMe), 75.5 (OCH2), 111.7 (C-2),
113.5 (C-4), 126.5 (C-1), 127.7 (C-4Ј), 128.2 (2 C) and 128.3 (2 C):
C-2Ј, C-3Ј, C-5Ј and C-6Ј, 132.3 (C-10), 137.8 (C-5), 138.0 (C-1Ј),
157.5 (C-3), 159.6 (C-17) ppm. MS (70 eV, EI): m/z (%) = 405 (9)
[M+], 314 (49), 298 (88), 112 (100), 91 (38). C27H35NO2 (405.57):
calcd. for C 79.96, H 8.70; found C 79.84, H 8.94.
Cyclization of 10l to 25l: Compound 10l (187 mg, 0.50 mmol) and
BF3·OEt2 (0.15 mL) were used for the synthesis as described in
the General Procedure. The crude product was purified by column
chromatography (EtOAc/CH2Cl2 = 10:90) and recrystallized from
EtOAc/CH2Cl2 to give 25l (118 mg) as white crystals; m.p. 211–
1
213 °C; Rf = 0.51 (EtOAc/CH2Cl2 = 10:90). H NMR (400 MHz,
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al Oxime 4Ј-Nitro-
benzyl Ether (28c): For the synthesis, given in the General Pro-
cedure, O-(4-nitrobenzyl)hydroxylamine hydrochloride 27c
(204 mg) was used. The crude product was purified by column
chromatography (CH2Cl2/hexane = 50:50) and recrystallized from
CH2Cl2/hexane to give 28c (385 mg, 85%) as white crystals; m.p.
116–118 °C; Rf = 0.63 (CH2Cl2/hexane = 50:50). 1H NMR
(400 MHz, CDCl3): δ = 0.81 (t, J = 6.8 Hz, 3 H, 16a-H3), 1.03 (s,
3 H, 18-H3), 1.13–1.50 (overlapping m, 8 H), 1.63 (m, 2 H), 2.06
(m, 1 H), 2.31 (m, 2 H), 2.85 (m, 2 H, 6-H2), 3.78 (s, 3 H, 3-OMe),
5.17 (s, 2 H, OCH2), 6.63 (d, J = 2.4 Hz, 1 H, 4-H), 6.71 (dd, J =
8.6, J = 2.4 Hz, 1 H, 2-H), 7.20 (d, J = 8.6 Hz, 1 H, 1-H), 7.35 (s,
1 H, 17-H), 7.52 (d, J = 8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 8.22 (d, J =
8.5 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.5 (C-16a), 15.4 (C-18), 24.4 (CH2), 26.0 (CH2), 27.2 (CH2),
30.5 (CH2), 32.3 (CH2), 37.5 (CH2), 41.0 (C-8), 41.5 (C-13), 43.2
(C-9), 47.6 (C-14), 55.2 (3-OMe), 73.9 (OCH2), 111.7 (C-2), 113.4
(C-4), 123.5 (2 C, C-3Ј and C-5Ј), 126.5 (C-1), 128.2 (2 C, C-2Ј and
C-6Ј), 132.1 (C-10), 137.8 (C-5), 146.0 (2 C, C-1Ј and C-4Ј), 157.5
(C-3), 160.5 (C-17) ppm. MS (70 eV, EI): m/z (%) = 450 (2) [M+],
314 (22), 298 (90), 112 (100). C27H34N2O4 (450.57): calcd. for C
71.97, H 7.61; found C 72.08, H 7.55.
CDCl3): δ = 0.79 (s, 3 H, 18-H3), 0.95 (t, J = 6.9 Hz, 3 H, 16a-H3),
1.13–1.58 (overlapping m, 8 H), 1.81 (m, 2 H), 2.06 (m, 1 H), 2.69
(d, J = 11.4 Hz, 1 H, 17-H2,ax), 2.75 (m, 1 H), 2.87 (m, 2 H, 6-H2),
3.25 (dd, J = 11.4, J = 2.7 Hz, 1 H, 17-H2,eq), 3.74 (s, 3 H, 3-OMe),
5.49 (br. s, 1 H) and 6.30 (br. s, 1 H): NH2, 6.54 (d, J = 2.5 Hz, 1
H, 4-H), 6.71 (dd, J = 8.7, J = 2.5 Hz, 1 H, 2-H), 7.30 (d, J =
8.7 Hz, 1 H, 1-H), 7.67 (s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.6 (C-16a), 21.2 (CH2), 22.9 (C-18), 25.8 (CH2), 27.7
(CH2), 27.9 (CH2), 30.3 (CH2), 32.1 (C-13), 34.2 (CH2), 46.9 and
47.6 (C-8 and C-14), 55.0 (3-OMe), 57.5 (C-9), 67.5 (C-17), 111.3
(C-2), 113.6 (C-4), 128.0 (C-10), 129.7 (C-1), 138.2 (C-5), 158.7 (C-
3), 181.2 (C = S) ppm. MS (70 eV, EI): m/z (%) = 373 (37) [M+],
313 (100), 298 (98), 174 (96). C21H31N3OS (373.56): calcd. for C
67.52, H 8.36; found C 67.38, H 8.21.
Synthesis of 16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al Oxime
(28a): Compound 8 (300 mg, 1.00 mmol) and hydroxylamine hy-
drochloride 27a (70 mg, 1.00 mmol) were suspended in 2-PrOH
(10 mL) and a solution of NaOAc (150 mg, 1.80 mmol) in 2-PrOH
(10 mL) was added. The mixture was refluxed for 4 h, and then
poured into cold water. The white precipitate was filtered off and
dried to give 28a (290 mg, 92%); m.p. 131–133 °C; Rf = 0.39
1
(CH2Cl2). H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 6.8 Hz, 3
16,17-seco-3-Methoxyestra-1,3,5(10)-trien-17-al Oxime Allyl Ether
(28d): For the synthesis, given in the General Procedure, O-allylhy-
H, 16a-H3), 1.08 (s, 3 H, 18-H3), 1.16–1.53 (overlapping m, 8 H),
1.69 (m, 2 H), 2.09 (m, 1 H), 2.33 (m, 2 H), 2.87 (m, 2 H, 6-H2), droxylamine hydrochloride 27d (110 mg) was used. The crude prod-
3.79 (s, 3 H, 3-OMe), 6.64 (d, J = 2.5 Hz, 1 H, 4-H), 6.73 (dd, J =
8.7, J = 2.5 Hz, 1 H, 2-H), 7.21 (d, J = 8.7 Hz, 1 H, 1-H), 7.31 (s,
uct was purified by column chromatography (CH2Cl2/hexane =
50:50) to give 28d (316 mg, 89%) as a colorless oil. Rf = 0.57
1
1 H, 17-H), 8.21 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): (EtOAc/CH2Cl2 = 10:90). H NMR (400 MHz, CDCl3): δ = 0.89
Eur. J. Org. Chem. 2009, 3544–3553
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3551

É. Frank, G. Schneider, Z. Kádár, J. Wölfling
FULL PAPER
(t, J = 6.9 Hz, 3 H, 16a-H3), 1.07 (s, 3 H, 18-H3), 1.13–1.50 (over-
(C-5), 146.1 and 147.1 (C-1Ј and C-4Ј), 158.2 (C-3) ppm. MS
lapping m, 8 H), 1.64 (m, 2 H), 2.07 (m, 1 H), 2.29 (m, 2 H), 2.86 (70 eV, EI): m/z (%) = 450 (2) [M+], 241 (15), 165 (14), 314 (100).
(m, 2 H, 6-H2), 3.79 (s, 3 H, 3-OMe), 4.55 (d, J = 5.6 Hz, 2 H, 1Ј-
C27H34N2O4 (450.57): calcd. for C 71.97, H 7.61; found C 71.86,
H2), 5.22 (d, J = 10.5 Hz, 1 H) and 5.31 (d, J = 17.3 Hz, 1 H): 3Ј- H 7.85.
H2, 6.01 (m, 1 H, 2Ј-H), 6.64 (d, J = 2.5 Hz, 1 H, 4-H), 6.73 (dd,
Cyclization of 28d to 32d: Compound 28d (178 mg) was used for
J = 8.6, J = 2.5 Hz, 1 H, 2-H), 7.21 (d, J = 8.6 Hz, 1 H, 1-H), 7.30
(s, 1 H, 17-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.5 (C-
16a), 15.5 (C-18), 24.5 (CH2), 26.0 (CH2), 27.3 (CH2), 30.5 (CH2),
32.3 (CH2), 37.7 (CH2), 41.1 (C-8), 41.3 (C-13), 43.3 (C-9), 47.8
(C-14), 55.2 (3-OMe), 74.3 (C-1Ј), 111.7 (C-2), 113.5 (C-4), 117.3
(C-3Ј), 126.5 (C-1), 132.3 (C-10), 134.4 (C-2Ј), 137.8 (C-5), 157.5
(C-3), 159.4 (C-17) ppm. C23H33NO2 (355.51): calcd. for C 77.70,
H 9.36; found C 77.93, H 9.48.
the synthesis, as described in the General Procedure. The crude
product was purified by column chromatography (diisopropyl
ether/hexane = 10:90) to give 32d (128 mg) as a colorless oil. Rf =
0.48 (hexane/diisopropyl ether = 20:80). 1H NMR (400 MHz,
CDCl3): δ = 0.79 (s, 3 H, 18-H3), 0.94 (t, J = 7.0 Hz, 3 H, 16a-H3),
1.02–1.57 (overlapping m, 8 H), 1.67 (m, 2 H), 2.16 (m, 1 H), 2.71
(m, 1 H), 2.82 (m, 2 H, 6-H2), 2.99 (m, 1 H), 3.20 (d, J = 12.1 Hz,
1 H, one proton of 1Ј-H2), 3.38 (m, 1 H), 3.51 (dd, J = 12.1, J =
6.1 Hz, 1 H, the other proton of 1Ј-H2), 3.78 (s, 3 H, 3-OMe), 4.98
(m, 2 H, 3Ј-H2), 5.64 (m, 1 H, 2Ј-H), 6.59 (d, J = 2.6 Hz, 1 H, 4-
H), 6.68 (dd, J = 8.7, J = 2.6 Hz, 1 H, 2-H), 7.44 (d, J = 8.7 Hz,
1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.8 (C-16a),
21.6 (CH2), 23.1 (C-18), 27.1 (2 C, 2ϫ CH2), 27.7 (CH2), 30.8 (C-
6), 34.2 (2 C, CH2 and C-13), 46.8 and 47.1 (C-8 and C-14), 55.1
(3-OMe), 57.8 (C-9), 68.3 (C-17), 74.7 (C-1Ј), 111.0 (C-2), 112.7
(C-4), 116.5 (C-3Ј), 130.3 (C-1), 131.3 (C-10), 135.2 (C-2Ј), 139.2
(C-5), 158.1 (C-3) ppm. MS (70 eV, EI): m/z (%) = 355 (3) [M+],
314 (100), 241 (18), 165 (36). C23H33NO2 (355.51): calcd. for C
77.70, H 9.36; found C 77.83, H 9.21.
General Procedure for the Synthesis of Isoquinuclidines 32b-d: Ox-
ime ether 28b, 28c or 28d (0.50 mmol) was dissolved in CH2Cl2
(10 mL), and BF3·OEt2 (a 48% solution in diethyl ether, 0.16 mL,
1 equiv.) was added slowly at room temperature under a nitrogen
atmosphere. The mixture was then refluxed for a given time (see,
Table 1). The reaction was next quenched by the addition of ice-
cold NaHCO3 (1 , 10 mL) and the mixture was extracted with
CH2Cl2 (3ϫ10 mL). The combined organic layers were washed
with brine, dried with Na2SO4 and concentrated in vacuo.
Cyclization of 28b to 32b: Compound 28b (203 mg) was used for
the synthesis, as described in the General Procedure. The crude
product was purified by column chromatography (diisopropyl
ether/hexane = 50:50) to give 32b (144 mg) as a colorless oil. Rf =
0.25 (diisopropyl ether/hexane = 5:95). 1H NMR (400 MHz,
CDCl3): δ = 0.77 (s, 3 H, 18-H3), 0.95 (t, J = 7.0 Hz, 3 H, 16a-H3),
1.01 (m, 1 H), 1.14 (m, 1 H), 1.26–1.53 (overlapping m, 6 H), 1.68
(m, 2 H), 2.18 (m, 1 H), 2.71 (m, 1 H), 2.86 (m, 2 H, 6-H2), 2.98
(m, 1 H), 3.08 (dd, J = 11.8, J = 2.9 Hz, 1 H, one proton of OCH2),
Acknowledgments
This work was supported financially by the Hungarian Scientific
Research Fund (OTKA PD-72403 and K-72309). É. F.’s work was
supported by an award (Bolyai János Research Fellowship).
3.81 (s, 3 H, 3-OMe), 3.95 (m, 1 H), 3.99 (m, 1 H, the other proton [1] a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; b) L. F. Tietze,
G. Brasche, K. M. Gericke, Domino Reactions in Organic Syn-
thesis, Wiley-VCH, Weinheim, 2006.
[2] a) L. F. Tietze, N. Rackelmann, Pure Appl. Chem. 2004, 76,
1967–1983; b) A. Padwa, S. K. Bur, Tetrahedron 2007, 63,
5341–5378; c) L. F. Tietze, N. Rackelmann, in: Multicomponent
Reactions (Eds.: J. Zhu, H. Bienaymé), Wiley-VCH, Weinheim,
2005, pp. 121–168.
[3] a) S. J. Pastine, D. Sames, Org. Lett. 2005, 7, 5429–5431; b) S. J.
Pastine, K. M. McQuaid, D. Sames, J. Am. Chem. Soc. 2005,
127, 12180–12181; c) M. R. Attwood, P. S. Gilbert, M. L.
Lewis, K. Mills, P. Quayle, S. P. Thompson, S. Wang, Tetrahe-
dron Lett. 2006, 47, 3607–3611.
[4] H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66–
77.
of OCH2), 6.64 (d, J = 2.6 Hz, 1 H, 4-H), 6.73 (dd, J = 8.7, J =
2.7 Hz, 1 H, 2-H), 7.09 and 7.24 (m, 2 H; m, 3 H, 2Ј-H, 3Ј-H, 4Ј-
H, 5Ј-H, 6Ј-H), 7.50 (d, J = 8.7 Hz, 1 H, 1-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.8 (C-16a), 21.6 (CH2), 23.1 (C-18), 27.2
(2 C, 2ϫ CH2), 27.7 (CH2), 30.8 (C-6), 34.2 (2 C, CH2 and C-13),
46.7 and 47.1 (C-8 and C-14), 55.1 (3-OMe), 57.9 (C-9), 68.1 (C-
17), 75.8 (OCH2), 111.2 (C-2), 112.8 (C-4), 127.2 (2 C, C-2Ј and C-
6Ј), 127.9 (3 C, C-3Ј, C-4Ј and C-5Ј), 128.9 (C-1), 138.4 (2 C, C-1Ј
and C-10), 139.3 (C-5), 158.1 (C-3) ppm. MS (70 eV, EI): m/z (%)
= 405 (6) [M+], 314 (100), 241 (16). C27H35NO2 (405.57): calcd. for
C 79.96, H 8.70; found C 79.78, H 8.61.
Cyclization of 28c to 32c: Compound 28c (225 mg) was used for
the synthesis, as described in the General Procedure. The crude
product was purified by column chromatography (diisopropyl
ether/hexane = 20:80) and recrystallized from hexane to give 32c
(176 mg) as white crystals; m.p. 64–66 °C; Rf = 0.87 (diisopropyl
ether/hexane = 50:50). 1H NMR (400 MHz, CDCl3): δ = 0.77 (s, 3
H, 18-H3), 0.93 (t, J = 7.0 Hz, 3 H, 16a-H3), 0.99 (m, 1 H), 1.16
(m, 1 H), 1.27–1.55 (overlapping m, 6 H), 1.67 (m, 2 H), 2.07 (m,
1 H), 2.69 (m, 1 H), 2.83 (m, 2 H, 6-H2), 2.97 (m, 1 H), 3.05 (dd,
J = 11.6, J = 2.6 Hz, 1 H, one proton of OCH2), 3.79 (s, 3 H, 3-
OMe), 3.99 (m, 1 H, the other proton of OCH2), 4.04 (m, 1 H),
6.58 (d, J = 2.3 Hz, 1 H, 4-H), 6.66 (dd, J = 8.7, J = 2.3 Hz, 1 H,
2-H), 7.19 (d, J = 8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 7.42 (d, J = 8.7 Hz,
1 H, 1-H), 8.06 (d, J = 8.5 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 14.8 (C-16a), 21.6 (CH2), 23.1 (C-
18), 27.1 (2 C, 2ϫ CH2), 27.6 (CH2), 30.7 (C-6), 34.1 (2 C, CH2
and C-13), 46.6 and 47.0 (C-8 and C-14), 55.1 (3-OMe), 58.0 (C-
9), 68.0 (C-17), 74.3 (OCH2), 111.3 (C-2), 112.8 (C-4), 123.1 (3 C,
C-1, C-3Ј and C-5Ј), 129.2 (2 C, C-2Ј and C-6Ј), 136.9 (C-10), 139.3
[5] a) P. T. Lansbury, N. R. Mancuso, J. Am. Chem. Soc. 1966, 88,
1205–1212; b) G. Neef, G. Michl, Tetrahedron Lett. 1991, 32,
5071–5072; c) C. G. Savarin, C. Grisé, J. A. Murry, R. A.
Reamer, D. L. Hughes, Org. Lett. 2007, 9, 981–983.
[6] a) J. Wölfling, É. Frank, Gy. Schneider, L. F. Tietze, Angew.
Chem. 1999, 111, 151–152; Angew. Chem. Int. Ed. 1999, 38,
200–201; b) J. Wölfling, É. Frank, Gy. Schneider, L. F. Tietze,
Eur. J. Org. Chem. 2004, 90–100.
[7] a) A. Guy, J. Doussot, M. Lemaire, Synthesis 1991, 460–462;
b) S. Schwarz, M. Schumacher, S. Ring, A. Nanninga, G. We-
ber, I. Thieme, B. Undeutsch, W. Elger, Steroids 1999, 64, 460–
471; c) P. Bovicelli, P. Lupattelli, E. Mincione, T. Prencipe, R.
Curci, J. Org. Chem. 1992, 57, 2182–2184; d) R. Tedesco, J. A.
Katzenellenbogen, E. Napolitano, Bioorg. Med. Chem. Lett.
1997, 7, 2919–2924.
[8] I. Iriepa, F. J. Villasante, E. Gálvez, L. Labeaga, A. Innerarity,
A. Orjales, Bioorg. Med. Chem. Lett. 2002, 12, 189–192.
[9] G. R. Krow, O. H. Cheung, Z. Hu, Q. Huang, J. Hutchinson,
N. Liu, K. T. Nguyen, S. Ulrich, J. Yuan, Y. Xiao, D. M. Wypij,
F. Zuo, P. J. Carroll, Tetrahedron 1999, 55, 7747–7756.
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www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3544–3553

Synthesis of Novel -Secoestrone Isoquinuclidines
[10] M. Yokota, E. Takizawa, Y. Ohkura, C. Fukai, T. Tomiyama,
Eur. J. Med. Chem. 1997, 32, 377–384.
[16] É. Frank, Z. Mucsi, I. Zupkó, B. Réthy, G. Falkay, Gy. Schnei-
der, J. Wölfling, J. Am. Chem. Soc. 2009, 131, 3894–3904.
[17] a) R. Grashey, in: 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley, New York, 1984, vol. 1, pp. 741–743; b) R.
Grigg, J. Kemp, N. Thompson, Tetrahedron Lett. 1978, 31,
2827–2830; c) V. V. Khau, M. J. Martinelli, Tetrahedron Lett.
1996, 37, 4323–4326; d) S. Kobayashi, H. Shimizu, Y. Yamash-
ita, H. Ishitani, J. Kobayashi, J. Am. Chem. Soc. 2002, 124,
13678–13679; e) Y. Yamashita, S. Kobayashi, J. Am. Chem.
Soc. 2004, 126, 11279–11282; f) É. Frank, Zs. Kardos, J.
Wölfling, Gy. Schneider, Synlett 2007, 1311–1313.
[18] P. Pérez, L. R. Domingo, M. J. Aurell, R. Contreras, Tetrahe-
dron 2003, 59, 3117–3125.
[11] a) L. F. Tietze, Gy. Schneider, J. Wölfling, A. Fecher, T. Nöbel,
S. Petersen, I. Schuberth, C. Wulff, Chem. Eur. J. 2000, 6, 3755–
3760; b) L. F. Tietze, Gy. Schneider, J. Wölfling, T. Nöbel, C.
Wulff, I. Schuberth, A. Rübeling, Angew. Chem. 1998, 110,
2644–2646; Angew. Chem. Int. Ed. 1998, 37, 2469–2470; c) É.
Frank, E. Mernyák, J. Wölfling, Gy. Schneider, Synlett 2002,
419–422; d) É. Frank, E. Mernyák, J. Wölfling, Gy. Schneider,
Synlett 2002, 1803–1806; e) J. Wölfling, É. Frank, E. Mernyák,
G. Bunkóczi, J. A. C. Seijo, Gy. Schneider, Tetrahedron 2002,
58, 6851–6861.
[12] a) Gy. Schneider, S. Bottka, L. Hackler, J. Wölfling, P. Sohár,
Liebigs Ann. Chem. 1989, 263–267; b) L. F. Tietze, J. Wölfling,
Gy. Schneider, Chem. Ber. 1991, 124, 591–594.
[13] É. Frank, J. Wölfling, B. Aukszi, V. König, T. R. Schneider, Gy.
Schneider, Tetrahedron 2002, 58, 6843–6849.
[19] M. J. Uddin, M. Kikuchi, K. Takedatsu, K.-I. Arai, T. Fujim-
oto, J. Motoyishiya, A. Kakehi, R. Iriye, H. Shirai, I. Yamam-
oto, Synthesis 2000, 3, 365–374.
[20] M. Noguchi, H. Okada, S. Nishimura, Y. Yamagata, S. Taka-
mura, M. Tanaka, A. Kakehi, H. Yamamoto, J. Chem. Soc.
Perkin Trans. 1 1999, 185–191.
[14] G. A. Potter, S. E. Barrie, M. Jarman, M. G. Rowlands, J. Med.
Chem. 1995, 38, 2463–2471.
[15] a) T. Shimizu, Y. Hayashi, M. Miki, K. Teramura, J. Org.
Chem. 1987, 52, 2277–2285; b) C. Gergely, J. B. Morgan, L. E.
Overman, J. Org. Chem. 2006, 71, 9144–9152.
[21] H. Mayr, A. R. Ofial, Tetrahedron Lett. 1997, 38, 3503–3506.
Received: March 20, 2009
Published Online: June 5, 2009
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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