Synthesis of unusual bridged steroid alkaloids by an iminium ion induced 1,5-shift of a benzylic hydride

Full text of DOI:10.1002/(SICI)1521-3773(19990115)38:1/2<200::AID-ANIE200>3.0.CO;2-L

COMMUNICATIONS
O
O
Synthesis of Unusual Bridged Steroid
Alkaloids by an Iminium Ion Induced
1,5-Shift of a Benzylic Hydride**
H
H
H
14
H
H
H
H
Â
Â
Janos Wölfling, Eva Frank, Gyula Schneider,*
and Lutz F. Tietze*
MeO
RO
1
2
H2/Pd/C
95%
3 : propyl at C-14
instead of propenyl
a : R = Me
O
O
Dedicated to Professor Armin de Meijere
on the occasion of his 60th birthday
O
b : R = H
c : R = Ac
2a
O
A main principle in organic synthesis is the
displacement of a suitable leaving group or the
replacement of a hydrogen atom as a proton in a-
position to an electron-withdrawing group. In addi-
tion, several examples of intramolecular free radical
reactions at unactivated C H bonds, such as the
Barton reaction,[1] are also known. In contrast, a
cationic attack at a C H bond with a hydride shift is
rather uncommon. Here we describe a transforma-
tion of an iminium ion of a primary amine on a
steroid skeleton to give the novel unusually bridged
steroid alkaloids 12 ± 14; a reaction that presumably
proceeds by a 1,5-hydride shift from a benzylic
position to the iminium ion under formation of a
carbocation that reacts with the resulting secondary
amine.
Recently, we have developed the synthesis of d-
homosteroid 5 by a domino Knoevenagel hetero
Diels ± Alder reaction[2] of Meldrumꢁs acid 4 and the
steroid derivative 2a,[3] which was obtained from
estrone 3-methyl ether 1 in four steps.[4] In this
sequence a 1-oxa-1,3-butadiene is formed as an
intermediate. Similarly, 2-aza-1,3-butadienes can be
synthesized by condensation of 2 with aniline
derivatives which also undergo a hetero Diels ±
Alder reaction.[2, 5] However, a completely different
pathway dominates if one hydrogenates the pro-
penyl side chain in 2a first to give the aldehyde 3a.
Reaction of 3a with aniline 6a and its derivatives 6b
and 6c, which contain an electron-withdrawing
4
H2N
X
92%
6
X
N
O
H
O
H
H
MeO
5
H
H
6, 7, 12
X
H
Br
NO2
OMe
H
H
a
b
c
RO
7a-c : R=Me
8 : R = H, X = NO2
9 : R = Ac, X = NO2
d
BF3·OEt2
For 7:
–
+
N
F3B
ArX
H
NHArX
H
85-93 %
based on 3
H
H
H
X
+
Pr
Pr
H
H
H
N
H
14
10
11
H
RO
H
N
X
12a-d : R=Me
13 : R = H, X = NO2
14 : R = Ac, X = NO2
15 : R = Me, X = Br
2-propenyl at C-14
instead of propyl
H
RO
16
a: R=Me, X=H
domino process[6] to afford 12a ± c in 85 ± 93% yield by
preparing the imines in situ. In this way, we have also
synthesized the imine 8, which contains a hydroxyl group at
C-3 of the steroid skeleton, and 9, which contains an acetoxy
group at C-3, starting from 6c and the derivatives 3b and 3c,
respectively, and treated them with BF3 ´ OEt2. In the case of
8, 13 was obtained in 63% yield together with some
unsaturated material 16 within 6 h at room temperature,
whereas in the case of 9 after reaction for 24 h at room
temperature only 16% of the desired product 14 together with
56% of the starting material was isolated; a compound of type
16 was not found in the reaction of 9. For the transformation
of 3a and 6c we have also employed other Lewis acids and
Brùnsted acids such as AlCl3, SnCl4, SnMe2Cl2, TiCl4, HBF4 ´
OEt2, p-TsOH, and trimethylsilyl trifluoromethanesulfonate
at room temperature for 24 ± 48 h; however, the yields were
much lower and the transformations less clean compared to
the reactions with BF3 ´ OEt2. Either the reaction did not
proceed at all as in the case of SnMe2Cl2 or the unsaturated
derivative 16 is the main compound, which is formed in a
group in para-position, led to the imines 7a ± c which are
rather unstable and difficult to isolate. Quite unexpectedly,
treatment of crude 7a ± c with BF3 ´ OEt2 in dichloromethane
gave the novel unnatural bridged steroid alkaloids 12a, 12b,
and 12c in over 80% yield as single diastereomers. The
reaction sequence can also be performed more efficiently as a
Â
[*] Prof. Dr. G. Schneider, Dr. J. Wölfling, Dipl.-Chem. E. Frank
Â
Institute of Organic Chemistry of Jozsef Attila University
Â
Â
Dom ter 8, H-6720 Szeged (Hungary)
Fax : (‡ 36)62-454276
E-mail: schneider@chem.u-szeged.hu
Prof. Dr. L. F. Tietze
Institut für Organische Chemie der Universität
Tammannstrasse 2, D-37077 Göttingen (Germany)
Fax : (‡ 49)551-399476
E-mail: ltietze@gwdg.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 416), the OTKA Grants (T016122 and F016119), and the Fonds
der Chemischen Industrie. The authors thank for the Hungarian ±
German Intergovernmental S & T Cooperation Program (UNG-061-
96).
200
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Angew. Chem. Int. Ed. 1999, 38, No. 1/2

COMMUNICATIONS
[1] D. H. R. Barton, Pure Appl. Chem. 1968, 16, 1 ± 15.
consequential reaction from 12c by elimination of the amino
function. Thus, treatment of 12a with BF3 ´ OEt2 at room
temperature for 24 h led to 16a in 85% yield. The structures
of the steroid azacycles 12a ± d, 13, and 14 were determined by
NMR spectroscopy[7] based on an X-ray crystal structure
analysis of 15.[8]
[2] Reviews: a) L. F. Tietze, G. Kettschau, J. A. Gewert, A. Schuffen-
hauer, Curr. Org. Chem. 1998, 2, 19 ± 62; b) L. F. Tietze, G. Kettschau,
Top. Curr. Chem. 1997, 189, 1 ± 101.
Â
[3] G. Schneider, S. Bottka, L. Hackler, J. Wölfling, P. Sohar, Liebigs Ann.
Chem. 1989, 263 ± 267.
[4] L. F. Tietze, J. Wölfling, G. Schneider, Chem. Ber. 1991, 124, 591.
Â
[5] J. Wölfling, E. Frank, Gy. Schneider, M. T. Bes, L. F. Tietze, Synlett
We assume that during the reaction of the imines 7a ± c, 8,
and 9 with the Lewis acid BF3 ´ OEt2 first an iminium ion 10 is
formed. This undergoes a 1,5-hydride shift to give 11, which
contains a secondary amine moiety and a carbocation. A 1,2-
or a 1,3-hydride shift is not observed, which was to be
expected because of the higher activation energy of these
rearrangements. Addition of the amino group to the carbo-
cationic center in 11 then yields 12a ± c, 13, or 14, The
proposed mechanism is consistent with the lower reactivity of
9 compared to that of 7 and 8, which can easily be explained
by a reduced stabilization of the intermediately formed
benzylic cation 11. This again is consistent with the observa-
tion that the p-methoxybenzyl group, which is used as a
protecting group,[9] can easily be removed by an oxidative
hydride transfer by using cerium ammonium nitrate (CAN) or
other oxidants, whereas a benzyl group without an electron-
donating group does not undergo this reaction.
To the best of our knowledge the described domino process
is a new type of transformation, though the opposite reaction,
namely the formation of an iminium ion from an amine and a
carbocation, is a well known process.[10] In addition, examples
of a formal insertion of an iminium ion derived from an oxime
into a suitably oriented C ± H bond have been described.[11]
According to the electrophilicity scale, which has recently
been published by Mayr and Ofial,[12] the iminium ion 10 is
comparable with the tropylium cation and the phenyldiazo-
nium ion. Therefore it is not unexpected that iminium ions
obtained from 3a and an aniline derivative containing an
electron-donating group in para position such as 6d gave the
corresponding steroid alkaloids 12d with only 2% yield.
Reactions of 3a with ortho-substituted anilines did not lead to
the desired products at all, presumably due to steric reasons.
1998, 1205 ± 1206.
[6] Reviews: a) L. F. Tietze, Nachr. Chem. Techn. Lab. 1997, 45, 1181;
b) L. F. Tietze, Chem. Rev. 1996, 96, 139 ± 148; c) L. F. Tietze, U.
Beifuss, Angew. Chem. 1993, 105, 137 ± 169; Angew. Chem. Int. Ed.
Engl. 1993, 32, 131 ± 163.
[7] 12a: M.p. 61 ± 638C; [a]2D0 ˆ ‡373.9 (c ˆ 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d ˆ 0.92 (t, 3H, J ˆ 7.2 Hz, 16a-H3), 0.93 (s, 3H,
18-H3), 1.10 ± 1.95 (m, 11H), 2.52 (m, 1H), 2.85 (m, 2H, 6-H2), 2.94
(dd, 1H, J ˆ 9.4 Hz, J ˆ 2.8 Hz, N-CH2,ax), 3.52 (d, 1H, J ˆ 9.4 Hz,
N-CH2,eq), 3.75 (s, 3H, 3-OMe), 6.31 (d, 2H, J ˆ 8.3 Hz, 2'- and 6'-H),
6.52 (m, 2H, 2- and 4'-H), 6.64 (d, 1H, J ˆ 2.6 Hz, 4-H), 6.86 (m, 3H,
1-, 3'- and 5'-H); 13C NMR (100 MHz, CDCl3) d ˆ 14.9 (C-16a), 22.3,
23.7 (C-18), 26.3, 28.6, 30.5, 33.4, 34.3, 35.0, 46.5 (C-14), 48.8 (C-8),
55.1 (3-OMe), 57.7 (C-9), 61.5 (N-CH2), 111.8 (C-2), 113.2 (C-4), 116.9
(C-4'), 118.2 (2C, C-2' and C-6'), 127.6 (2C, C-3' and C-5'), 129.9 (C-1),
131.7 (C-10), 138.8 (C- 5), 149.1 (C-1'), 158.1 (C-3). 12b: M.p. 127 ±
1298C; [a]2D0 ˆ ‡307.1 (c ˆ 1.0, CHCl3). 12c: Oil; [a]2D0 ˆ ‡610.4 (c ˆ
1.0, CHCl3).
[8] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no.
CCDC-102885. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[9] a) P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994; b) T. W.
Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd
ed., Wiley, Toronto, 1991.
[10] a) S. Laschat, Liebigs Ann. 1997, 1 ± 11; b) C. H. Heathcock, M. M.
Hansen, R. B. Ruggeri, J. C. Kath, J. Org. Chem. 1992, 57, 2544 ± 2553.
[11] a) G. Neef, G. Michl, Tetrahedron Lett. 1991, 32, 5071 ± 5072; b) P. T.
Lansbury, Nitrenium Cations in Nitrenes (Ed.: W. Lowowski),
Interscience, New York, 1970, 404 ± 419.
[12] H. Mayr, A. R. Ofial, Tetrahedron Lett. 1997, 38, 3503 ± 3506.
Peryleneimidazoloimides: Highly Fluorescent
and Stable Replacements of Terrylene**
Heinz Langhals*, Harald Jaschke, Ulrike Ring, and
Petra von Unold
Experimental Section
Terrylene[1] (1) is an important compound for physicochem-
ical investigations,[2] for example for single-molecule spectro-
scopy,[3] because its UV/Vis absorption spectrum closely
matches the operation region of the easily controllable
rhodamine 6G dye laser (about 555 ± 560 nm). The prepara-
tion of terrylene is however laborious, high purification very
difficult, and the chemical persistency low. Moreover, the
12a: A mixture of 3a (298 mg, 1 mmol), freshly distilled aniline (0.9 mL,
1 mmol), and molecular sieves (4 Š, 150 mg) in dichloromethane (10 mL)
was stirred under an argon atmosphere for 4 h at 408C. After filtration
BF3 ´ OEt2 (0.15 mL, 0.5 mmol) in dichloromethane (1 mL) was added
slowly at room temperature, and stirring was continued for 12 h. After a
addition of further BF3 ´ OEt2 (0.15 mL, 0.5 mmol) in dichloromethane
(1 mL) and stirring until completion (TLC), the reaction was quenched by
adding ice-cold 1n NaOH (30 mL). The organic phase was separated, the
aqueous phase extracted with dichloromethane (3 Â 30 mL), and the
combined organic phases washed with brine and dried over Na2SO4.
Evaporation in vacuo and purification of the residue by chromatography
(silica gel, tert-butyl methyl ether/petroleum etherˆ 1:4) afforded 12a
(319 mg, 85%).
[*] Prof. Dr. H. Langhals, Dr. H. Jaschke, Dr. U. Ring, Dr. P. von Unold
Institut für Organische Chemie der Universität
Karlstrasse 23, D-80333 Munich (Germany)
Fax: (‡49)89-5902-483
E-mail langhals@lrz.uni-muenchen.de
[**] This work was financially supported by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie. We thank Prof.
Received: March 30, 1998 [Z11662IE]
German version: Angew. Chem. 1999, 111, 151 ± 152
Â
T. Basche and Prof. C. Bräuchle for the single-molecule measurement.
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the au-
thor.
Keywords: alkaloids ´ domino reactions ´ iminium ions ´
rearrangements ´ steroids
Angew. Chem. Int. Ed. 1999, 38, No. 1/2
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