Stereoselective synthesis of novel Δ5- androstenoarylpyrazoline derivatives by BF3·OEt 2-induced intramolecular 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-2007-977452

The phenylhydrazones of an unsaturated D-seco-pregnene aldehyde underwent BF₃·OEt₂-induced intramolecular 1,3-dipolar cycloaddition to afford new pyrazoline-fused Δ⁵-androstene derivatives under extremely mild conditions.

Full text of DOI:10.1055/s-2007-977452

LETTER
1311
Stereoselective Synthesis of Novel D5-Androstenoarylpyrazoline Derivatives
by BF3·OEt2-Induced Intramolecular 1,3-Dipolar Cycloaddition
5
Stereoselective
v
S
ynthesis of
a
Novel
D
-Andros
F
tenoarylpyraz
r
oline De
a
rivatives nk,* Zsolt Kardos, János Wölfling, Gyula Schneider
Department of Organic Chemistry, University of Szeged, 6720 Szeged, Hungary
Fax +36(62)544199; E-mail: frank@chem.u-szeged.hu
Received 19 February 2007
Dedicated to Lutz F. Tietze on the occasion of his 65th birthday
reported to exhibit noteworthy in vivo antiandrogenic
Abstract: The phenylhydrazones of an unsaturated D-seco-preg-
nene aldehyde underwent BF3·OEt2-induced intramolecular 1,3-di-
polar cycloaddition to afford new pyrazoline-fused D5-androstene
derivatives under extremely mild conditions. The ring closures
occurred stereoselectively in good to excellent yields via the corre-
sponding azomethine imine intermediates and showed marked de-
pendence on the electronic feature of the p-phenyl substituent.
activity.9
The D-seco-pregnene aldehyde (2), containing a propenyl
side chain, can be obtained in several steps from the readi-
ly available pregnadienolone acetate (1, Scheme 1).10
This compound was considered to be of use for pyrazoline
formation, after preparation of the corresponding phenyl-
hydrazones. Besides study of the stereoselectivity of the
BF3·OEt2-catalyzed processes, our present aim was to
investigate the electronic effects of different phenyl sub-
stituents on the cyclization reactions and to synthesize po-
tentially bioactive androstenopyrazolines. The results of
the pharmacological tests will be published elsewhere.
Key words: steroids, hydrazones, 1,3-dipolar cycloaddition, ste-
reoselectivity, Lewis acid
The thermally induced 1,3-dipolar cycloaddition of
hydrazones with multiple-bond systems is a well-known
procedure for the formation of N-containing five-mem-
bered heterocycles.1 When protic acid catalysts are used,
protonated hydrazone intermediates have been suggested
to act as quasi-azomethine imine 1,3-dipoles, which readi-
ly react even with nonactivated olefinic dipolarophiles.2
While inter- and intramolecular Lewis acid catalyzed
[3+2] cycloadditions using nitrones or nitrile oxides have
been intensively investigated,3 the corresponding reac-
tions of olefinic hydrazones have less been studied.4 A
dramatic rate acceleration and improvements in diaste-
reoselectivity have been reported for the intramolecular
cyclization of a hydrazone/olefin system in the presence
of a catalytic amount of Sc(OTf)3 as compared with the
thermal reactions.4a The use of BF3·OEt2 as Lewis acid,
leastwise for intermolecular reactions, proved to enhance
the yields of the desired product, but with lower diaste-
reoselectivity.4b
Me
O
O
H
H
C
H
H
H
H
H
AcO
AcO
1
2
Scheme 1
The reactions of aldehyde 2 with phenylhydrazine 3a or
its para-substituted derivatives 3b–f, respectively, in
MeOH at room temperature yielded the corresponding
(E)-phenylhydrazones 4a–f in good to excellent yields
(Scheme 2). The 1H NMR spectra of 4a–f, recorded at dif-
ferent times for each compound, revealed E/Z isomeriza-
tion in CDCl3 solution, the amount of the E-isomer
predominating. As reported earlier, the isomeric ratio of
the aldehyde phenylhydrazones in solution is solvent-de-
pendent; equilibration can be observed after a period.11a
Traces of acids11b or free phenylhydrazine11c can catalyze
the isomerization. The intramolecular cyclization of
phenylhydrazones 4a–f, induced by a catalytic amount of
BF3·OEt2, led to androstene-fused pyrazoline derivatives
6a–f via the presumed intermediate 5. No traces of the
corresponding pyrazolidine derivatives were observed.
The intramolecular cycloadditions of unsaturated hydra-
zones usually lead to pyrazolidine derivatives. However,
these are not always sufficiently stable and they undergo
facile dehydrogenation to the corresponding pyrazolines
or pyrazoles under the given reaction conditions and/or
during the purification procedures.5 A number of com-
pounds containing a pyrazoline moiety possess marked
pharmacological effects; thus, compounds with analgesic,
antipyretic, antirheumatic, anti-inflammatory and antidia-
betic activities have been described.6 The wide spectrum
of synthetic heterosteroids include pyrazoline7 and
pyrazole derivatives,8 and some D-ring-fused an-
drostano[17,16-c]-5¢-arylpyrazolines have recently been
The conversions proceeded in a stereoselective manner to
furnish 6a–f as the only diastereomers, with 17-H in the a-
1
and 20-H in the b-position. Comparison of the H NMR
spectra of the corresponding pyrazolines 6a–f with those
of the phenylhydrazones 4a–f, respectively, demonstrated
an upfield shift of the 18-H3 signal for 6a–f. The aniso-
SYNLETT 2007, No. 8, pp 1311–1313
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977452; Art ID: G06007ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
5.
2
0
0
7

1312
É. Frank et al.
LETTER
2
between the closely situated angular methyl function. The
relative configurations were confirmed by NOESY mea-
surement, for 6c,12 which indicated a cross-peak between
18-H3 and 20-H.
R1
NH NH2
3
The reaction rates and yields of the products 6a–f seemed
to depend strongly on the nature of the group R1 on the Ph
moiety in 5. Internal cyclization of the unsubstituted
phenylhydrazone 4a in the presence of BF3·OEt2 in ice-
cold CHCl3, proved to be slow, but after stirring for three
hours, the corresponding pyrazoline 6a could be obtained
in good yield besides a minor amount of residual 4a.
Better conversion could be achieved at room temperature
after 24 hours (Table 1). In this latter case all of the
phenylhydrazone 4a was converted and, without purifica-
tion by column chromatography, compound 6a was ob-
tained in a crystalline form from CH2Cl2 after alkaline
workup.
H
N
N
H
R1
H
H
AcO
4
BF3·OEt2
H
N
H
N
R1
H
H
BF3
AcO
5
The para-substituted phenylhydrazones 4b–f were cy-
clized at the same temperature to give the desired products
6b–f. A yellowish discolouration of the mixtures was ob-
served at the moment the Lewis acid catalyst was added.
Compounds 4b and 4c, containing electron-donating
groups (Me and OMe) were readily involved in pyrazoline
formation to furnish 6b and 6c12 in excellent yields. Elec-
tron-withdrawing groups (Cl, NO2 and CF3), however,
seemed to stabilize the related phenylhydrazones 4d–f,
decreasing the reaction rate and reducing the yields of the
products 6d–f. The reaction time also proved to be impor-
tant as some polar decomposition products were produced
when the pyrazolines 6a–f formed were allowed to stand
in the acidic mixtures for longer than the optimum time.
Compounds 6a–f were assumed to be formed by auto-
oxidation of the corresponding pyrazolidine derivative
during the workup.
– BF3
– 2[H]
R1
5'
4'
6'
21
3'
18 H
1'
12
2'
N
20
16
11
R1
3–7
17
14
19
5
N
H 13
1
4
9
a
H
2
15
10
8
Me
H
H
b
c
7
R2O
OMe
Cl
3
6
d
e
f
6
7
R
R
2 = Ac
2 = H
NO2
CF3
Scheme 2
tropic shielding effect attributed to the N–Ph ring can be
observed only when the newly formed pyrazoline ring, to-
gether with its N–Ph moiety, is bent towards the C-18 an-
gular methyl group, and 17-H therefore assumes the a-
position. The a-orientation of the 21-Me group, and thus
the b-position of 20-H, follows from the steric repulsion
Pyrazolines 6a–f were deacetylated in alkaline MeOH to
furnish the corresponding 3-OH derivatives 7a–f, which
were subjected to pharmacological investigation.
Table 1 Intramolecular 1,3-Dipolar Cycloaddition of 4 in the Presence of a Catalytic Amount of BF3·OEt2
Entry
Phenylhydrazonea R1
Reaction conditions
0 °C, 3 hb
Products
Yield (%)
71c
Mp (°C)
220–222
194–196
181–183
204–206
210–212
168–170
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
6a
6b
6c
6d
6e
6f
Me
OMe
Cl
0 °C, 20 min
0 °C, 20 min
0 °C, 3 h
92d
95d
74c
NO2
CF3
0 °C, 3 h
64c
0 °C, 3 h
67c
a Synthesized from 2 with phenylhydrazine 3a or p-substituted phenylhydrazines 3b–f, respectively. In cases of 3b–f, the hydrochloride salts
were used in basic MeOH.
b The yield can be enhances to 78% at r.t. after 24 h.
c After purification by column chromatography.
d After recrystallization.
Synlett 2007, No. 8, 1311–1313 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Novel D5-Androstenoarylpyrazoline Derivatives
1313
(7) (a) Camoutsis, C.; Nicolaropoulos, S.; Catsoulacos, P. J.
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In conclusion, we have demonstrated that the stereoselec-
tive synthesis of androstenopyrazolines can be achieved
by the BF3·OEt2-catalyzed intramolecular 1,3-dipolar cy-
clization of D-seco-hydrazones. The efficacy of pyrazo-
line formation was strongly influenced by substituents on
the phenyl moiety and the reaction conditions.
Acknowledgment
The authors thank I. Simon (University of Szeged, Hungary) for the
NMR spectra. Financial support by the Hungarian Scientific
Research Fund (OTKA T 049366) is gratefully acknowledged.
References and Notes
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(12) Procedure for the Synthesis of 6c
A mixture of 2 (359 mg, 1.00 mmol), 4-methoxyphenyl-
hydrazine hydrochloride (3c, 175 mg, 1.00 mmol) and
NaOAc (200 mg, 2.44 mmol) in MeOH (5 mL) was stirred
for 1 h at r.t. The white precipitate was filtered off and dried
to give pure 4c (407 mg, 85%). Compound 4c was dissolved
in CH2Cl2 (10 mL) and BF3·OEt2 (0.09 mL, 0.3 mmol) was
added dropwise at 0 °C under a nitrogen atmosphere. After
20 min, the reaction was quenched by the addition of 1 M aq
NaHCO3 (20 mL). The organic phase was separated, the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL) and
the combined organic phases were dried over Na2SO4.
Evaporation in vacuo and recrystallization from CH2Cl2–
hexane afforded 453 mg (95%) of 6c as white crystals;
Rf = 0.32 (EtOAc–CH2Cl2, 10:90). 1H NMR (400 MHz,
CDCl3): d = 0.76 (s, 3 H, 18-H3), 1.05 (s, 3 H, 19-H3), 1.16
(m, 2 H), 1.39 (m, 1 H), 1.44 (d, 3 H, J = 6.0 Hz, 21-H3), 1.51
(m, 1 H), 1.58–1.69 (m, 6 H), 1.80–1.91 (m, 4 H), 2.03 (s, 3
H, 3-Ac-H3), 2.45 (m, 2 H), 2.49 (m, 1 H), 2.77 (d, 1 H,
J = 11.2 Hz, 17-H), 3.65 (m, 1 H, 20-H), 3.78 (s, 3 H, 4¢-
OMe), 4.62 (m, 1 H, 3-H), 5.39 (d, 1 H, J = 4.8 Hz, 6-H),
6.85 (d, 2 H, J = 8.8 Hz, 2¢-H, 6¢-H), 7.05 (d, 2 H, J = 8.8 Hz,
3¢-H, 5¢-H). 13C NMR (100 MHz, CDCl3): d = 14. 4 (C-18),
19.3 (C-19), 20.4 (C-21), 20.7 (CH2), 21.4 (3-Ac-CH3), 25.4
(CH2), 27.7 (CH2), 31.5 (C-8), 31.8 (CH2), 36.8 (C-10), 36.9
(CH2), 37.3 (CH2), 38.1 (CH2), 40.0 (C-13), 50.0 (C-9), 55.6
(4¢-OMe), 57.6 (C-14), 61.3 (C-20), 72.2 (C-17), 73.7 (C-3),
114.3 (2 C, C-2¢, C-6¢), 118.3 (2 C, C-3¢, C-5¢), 121.9 (C-6),
139.9 (C-5), 142.3 (C-1¢), 154.7 (C-4¢), 164.3 (C-16), 170.5
(Ac-CO). MS (EI): m/z (relative intensity) = 476 (100) [M+],
461 (18), 187 (30) [C30H40N2O3].
Synlett 2007, No. 8, 1311–1313 © Thieme Stuttgart · New York

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