Asymmetric 1,3-dipolar reactions of 3-sulfinylfuran-2(5H)-ones with 11H-dibenzo[b,e]azepine 5-oxide. Synthesis of pyrroloazepines via isoxazoloazepines

Article abstract of DOI:10.1016/j.tetlet.2004.04.108

The addition of morphanthridine N-oxide (1) to homochiral 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) under mild conditions affords furoisoxazoloazepines (3a and 3b) in high yields and with complete regioselectivity. The π-facial and endo-selectivities

Full text of DOI:10.1016/j.tetlet.2004.04.108

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4653–4656
Asymmetric 1,3-dipolar reactions of 3-sulfinylfuran-
2(5H)-ones with 11H-dibenzo[b,e]azepine 5-oxide.
Synthesis of pyrroloazepines via isoxazoloazepinesq
a,
Jose L. Garcıa Ruano, J. Ignacio Andres Gil, Alberto Fraile,
b
a
*
ꢀ
ꢀ
Ana Marıa Martın Castro and M. Rosario Martın
ꢀ
a
a,
*
ꢀ
ꢀ
ꢀ
aDepartamento de Quꢀımica Orgꢀanica, Universidad Autꢀonoma, Cantoblanco, 28049 Madrid, Spain
bJohnson & Johnson Pharmaceutical Research & Development, Division of Janssen-Cilag,
Medicinal Chemistry Department, Jarama St. s/n, 45007 Toledo, Spain
Received 1 April 2004; revised 15 April 2004; accepted 20 April 2004
ꢀ
This paper is dedicated to Professor Jose Luis Soto
Abstract—The addition of morphanthridine N-oxide (1) to homochiral 3-p-tolylsulfinylfuran-2(5H)-ones (2a and 2b) under mild
conditions affords furoisoxazoloazepines (3a and 3b) in high yields and with complete regioselectivity. The p-facial and endo-
selectivities are also complete from 2a, which yields anti-3a-endo as the only diastereoisomer, whereas cycloreversion determines that
the anti-3b-endo adduct can be almost exclusively isolated from 2b. Proper manipulation of the furoisoxazoloazepines allows the
synthesis of the optically pure isoxazoloazepines and pyrroloazepines.
Ó 2004 Elsevier Ltd. All rights reserved.
The biological activity of molecules containing a modi-
fied azepine ring has been intensively tested, both in
vitro and in vivo, against various diseases.1 In this
context, 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]-
isoxazolo[2,3-a]azepines have been recently reported as
5-HT2A=2C receptor antagonists,2 and pyrroloazepines
have displayed interesting biological activities,3 which
confers relevance to the search of short and highly
stereoselective methods to prepare them. 1,3-Dipolar
cycloadditions involving the use of nitrones as dipoles is
one of the best reported methods to build the isoxa-
zolidine skeleton.4 It was used to prepare 2-(aminoalkyl)-
2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepines
starting from 11H-dibenzo[b,e]azepine 5-oxide (1).2a
Therefore we envisaged that the use of a proper enan-
tiomerically pure dipolarophile would allow the asym-
metric synthesis of the isoxazoloazepines, which in turn
could be used to prepare pyrroloazepines.
In our continuing interest in developing strategies to
afford homochiral organic compounds using sulfoxides
as chiral auxiliaries,5 we have reported the efficiency of
3-p-tolylsulfinyl-5-alkoxyfuran-2(5H)-ones (2a and 2b6)
as chiral dipolarophiles in reactions with diazoalkanes,7
nitrile oxides8 and azomethine ylides.9 In all these
reactions, the sulfinyl group has shown its ability to
improve the dipolarophilic features of the substrates. It
prompted us to study the behaviour of furanones 2a and
2b with nitrone 1 to obtain the optically pure furo-
isoxazoloazepines 3, which have the proper substituents
to be transformed into highly functionalized iso-
xazoloazepines and pyrroloazepines (Scheme 1). The
synthetic results obtained in this study are reported in
this paper.
Keywords: 1,3-Dipolar reaction; Sulfoxides; Dibenzoazepines; Pyr-
roloazepines.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.04.108
* Corresponding authors. Tel.: +34-3991-497-4703; fax: +3491-497-
3966; e-mail addresses: joseluis.garcia.ruano@uam.es; rosario.
martin@uam.es
Results obtained in reactions of nitrones with vinyl
sulfoxides10 and 5-menthyloxyfuran-2(5H)-one11 have
been reported previously. However, none of these
studies dealt with reactions of the nitrone 1, which has
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.108

ꢀ
J. L. Garcıa Ruano et al. / Tetrahedron Letters 45 (2004) 4653–4656
4654
suggested that cycloreversion was very easy. Thus we
investigated the influence of the reaction conditions in
the composition of the reaction mixture, with the results
collected in Table 1. The proportion of the adduct anti-
3b-endo grows larger as the time increases and mainly
when the temperature raises. The highest stereoselec-
tivity was observed under the conditions of the entry 4
(refluxing toluene) yielding a 72:19:9 mixture of the
diastereoisomers A, B and C (Scheme 2). The fact that
the anti-3b-endo-adduct was obtained in a 77% isolated
yield after several crystallizations from this reaction
mixture additionally supports the easy cycloreversion
during the purification process. Cycloreversion has been
reported just occasionally for 1,3-dipolar reactions of
nitrones,13 which suggests that the sulfinyl group could
play a significant role in making this process easier,
although the possible influence of the dibenzazepine ring
cannot be ignored. The relative role of both factors on
the easiness of the cycloreversion, which has allowed us
to use it with synthetic purposes by increasing the stereo-
selectivity under proper conditions, is now being inves-
tigated by theoretical methods as well as by studying the
behaviour of 2a and 2b with other nitrones.
H
OH
OH
Y
H
H
H
N
N
O
OH
H
H
+
Tol
O
N
O
O
-
O
H
O
H
S
1
O
N
O
OEt
H
2
H
OEt
H
Scheme 1.
only been confronted to alkenylamines.2 The addition of
nitrone 1 (prepared as indicated in Ref. 2a) to enantio-
merically pure furanone 2a required less than 5 min at
room temperature to afford anti-3a-endo12 as the sole
product (Scheme 2), which was isolated in 85% yield
after crystallization from acetone. The same adduct was
exclusively detected when the reaction was conducted in
refluxing toluene.
The reaction 11H-dibenzo[b,e]azepine 5-oxide (1)
(1.2 equiv) with sulfoxide 2b (1 equiv) afforded 3b as a
mixture of three stereoisomers (Scheme 2) in propor-
tions dependent on the temperature and the reaction
time, as it is indicated in Table 1. All the chromato-
graphic attempts to separate the adducts 3b where
unsuccessful and decomposition into the starting mate-
rial was observed even at room temperature. This fact
The absolute configuration of anti-3a-endo was
unequivocally established by X-ray analysis (Fig. 1).14
The independent transformation of the adducts anti-3a-
endo and anti-3b-endo into the enantiomeric diols ())-5
and (+)-5 allowed the unequivocal configurational
assignment of anti-3b-endo (Scheme 3). This transfor-
Tol
O
O
O
S
Tol
SO
H
O
+
14b
N
2a
OEt
H
N
1
14c
-
3 O
OEt
O3a
O
1
CHCl3, rt, 5 min
H
H
Tol
O
O
anti-3a-endo
S
O
H
2b
EtO
Tol
Figure 1.
Tol
SO
Tol
H
SO
H
H
O
O
O
O
O
SO
+
O
N
+
N
N
O
O
O
Tol
H
OEt
H
OEt
H
(C)
H
OEt
H
H
O
O
O
O
H
H
H
H
H
SO
H
anti-3b-endo (A)
syn-3b-endo (B)
anti-3b-exo
CH2OH
CH2OH
a)
b)
N
N
N
Scheme 2.
O
O
O
H
H
OEt
OEt
anti-4b-endo
anti-3b-endo
(+)-5
Table 1. Stereoisomeric ratios obtained under different conditions in
the reaction of 1 with 2b
Tol
SO
H
O
Stereoisomer ratioa
A:B:C
H
H
O
O
Entry
Solvent
T
Time
H
H
H
CH2OH
CH2OH
b)
a)
N
O
N
N
O
O
O
1
2
3
4
CHCl3
CHCl3
CHCl3
Toluene
Rt
Rt
10min
1 h
18 h
43:38:19
54:34:12
70:22:8
72:19:9
H
OEt
H
OEt
H
H
anti-3a-endo
anti-4a-endo
(-)-5
Rt
100 °C
5 min
Scheme 3. Reagents and conditions: (a) AI/Hg, THF/H2O (9:1), rt,
30min; (b) LiAIH 4, THF, 30min, rt.
a Determined by 1H NMR on the reaction crudes.

ꢀ
J. L. Garcıa Ruano et al. / Tetrahedron Letters 45 (2004) 4653–4656
4655
mation involved the hydrogenolysis of the C–S bond
with Al/Hg and the reduction of the lactone ring into the
diol system with LiAlH4 at room temperature. The 1,3-
dipolar cycloaddition of nitrone 1 to 2a and 2b and the
subsequent transformation of the adducts affords one of
the most efficient methods to prepare highly function-
alized isoxazoloazepines in optically pure form.
H
H
H
H
H
H
CH2OH
CH2OH
CH2OMs
CH2OMs
a)
N
N
O
O
9
(+)-5
b)
Once unequivocally assigned the absolute configuration
of the major adducts, the configuration of syn-3b-endo
was established by its transformation into the diol ())-5
by using a sequence identical to that depicted in Scheme
3. As the two adducts identified in the mixture obtained
from 2b have the endo-stereochemistry, the third one
must exhibit the exo-stereochemistry. Its assignment as
anti-3b-exo was established on the base of the zero value
of its coupling constant J3;3a, indicative of the anti-spa-
tial arrangement (values ranging between 0and 2 Hz
were measured for the anti-adducts and 5.0Hz for the
syn-ones).
H
H
H
H
H
H
CH2OMs
OH
CH2OMs
CH2OMs
N
NH
HO
10
c)
H
H
H
N
Bn
N
OH
In order to establish the role of the sulfinyl group on the
course of the reactions of the nitrone 1 with 2 we have
studied the reaction of 1 with ( )-6,15 which is the
furanone bearing no sulfinyl group. The reaction
required 2 h at room temperature (Scheme 4) to yield the
anti-7-exo-adduct exclusively. This stereochemistry was
assigned on the base of the coupling constant J3;3a (0),
indicative of the trans-spatial arrangement of the in-
volved protons, as well as its chemical correlation with
diols 5. The adduct anti-7-exo was transformed into
isoxazoloazepine ( )-8 by reaction with LiAlH4. Com-
pound ( )-8 proved to be diastereoisomer of 5;
therefore, protons H14 b and H14 c must exhibit a trans-
arrangement.
(+)-11
Scheme 5. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C,
10min; (b) H 2 (40psi), Pd/C, EtOH, rt, 2 h; (c) 4-benzylpiperidine,
70 °C, 1.5 h.
zines.16 It involved the conversion of the adduct 3 into
the corresponding diol 5 (see Scheme 3) and mesylation
of the two hydroxyl groups as a previous step to the
hydrogenolysis of the N–O bond with H2/Pd in ethanol
(Scheme 5). The aminoalcohol formed in the opening of
the isoxazolidine ring evolved spontaneously into the {2-
hydroxy-2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[2,
1-a]azepin-1-yl}methylethanesulfonate 10, which subse-
quently reacted with 4-benzylpiperidine to afford the
corresponding aminoalcohol (+)-11 in high overall yield
(79% from (+)-5).
The comparison of the results obtained in the reactions
shown in Schemes 2 and 4, indicates that the sulfinyl
group significantly increases the reactivity (it reduces the
reaction times), is the main controller of the endo/exo-
selectivity, which is just the opposite for sulfinylated
(endo) and nonsulfinylated (exo)-5-alkoxy-2(5H)fura-
nones and modulates the p-facial selectivity, which is
mainly governed by the configuration at C-5 [only anti-
adducts were obtained from 2a and ( )-6 but mixtures
containing the syn-adduct as a minor component were
obtained from 2b].
Other dibenzopyrroloazepines could also prepared by
the synthetic method described above, and they were
screened in several in vitro assays to evaluate their
affinity with different G-protein-coupled receptors
(GPCRs). Thus, their affinities for a set of adrenergic,
dopaminergic and serotonergic receptors were measured
by standard procedures.17 Some compounds showed
weak to moderate binding activity for a few of those
receptors. In that respect, the most relevant results were
obtained for the piperidine and the 4-ethoxy-
carbonylpiperidine derivatives 12 and 13 (Fig. 2) that
showed Ki values for the H1 receptor of 9 and 13 nM,
respectively.
The synthesis of pyrroloazepines from the correspond-
ing isoxazolines could be achieved following the pro-
tocol previously described for the transformation of
hexahydropyrrolo[1,2-b]isoxazole to hexahydropyrroli-
O
O
OH
OH
OMe
H
O
O
H
H
H
H
6
LiAlH4
THF, rt
30 min
H
H
N
N
CO2Et
+
N
N
N
N
CHCl3
2 h, rt
N
O
O
-
O
H
OMe
H
H
OH
OH
)-13
( ) anti-7-exo
( )-8
1
(
)-12
(
Scheme 4.
Figure 2.

ꢀ
J. L. Garcıa Ruano et al. / Tetrahedron Letters 45 (2004) 4653–4656
4656
ꢀ
5. (a) Garcıa Ruano, J. L.; Cid, B. Top. Curr. Chem. 1999,
204, 1–126 (Organosulfur Chemistry I); (b) Garcıa Ruano,
In summary, we have demonstrated the high efficiency
of the reactions of 11H-dibenzo[b,e]azepine-5 oxide (1)
with the sulfinylfuranones 2a and 2b in the asymmetric
synthesis of highly functionalized isoxazoloazepines and
pyrroloazepines. The significant role of the sulfinyl
group improving the dipolarophilic features of the
5-alkoxy-3-furanones is also evident from the results
herein presented.
ꢀ
~
J. L.; Carreno, M. C.; Toledo, M. A.; Aguirre, J. M.;
Aranda, M. T. Angew. Chem., Int. Ed. 2000, 39, 2736–
ꢀ
2737; (c) Garcıa Ruano, J. L.; Aleman, J.; Soriano, J. F.
Org. Lett. 2003, 5, 677–680; Garcıa Ruano, J. L.; Aleman,
ꢀ
ꢀ
ꢀ
ꢀ
J. Org. Lett. 2003, 5, 4513–4516; (d) Garcıa Ruano, J. L.;
Alemparte, C. J. Org. Chem. 2004, 69, 1405–1408.
ꢀ
6. Carretero, J. C.; Garcıa Ruano, J. L.; Lorente, A.; Yuste,
F. Tetrahedron: Asymmetry 1993, 2, 177–180.
ꢀ
7. (a) Garcıa Ruano, J. L.; Fraile, A.; Martın, M. R.
Tetrahedron: Asymmetry 1996, 7, 1943–1950; (b) Garcıa
ꢀ
ꢀ
ꢀ
ꢀ
Ruano, J. L.; Fraile, A.; Gonzalez, G.; Martın, M. R.;
Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68,
6522–6534.
Supplementary material
Experimental procedures as well as spectroscopic data
of compound 3–5, 7–8 and 11 are available. This
material is available online with the paper in Science-
Direct.
ꢀ
ꢀ
8. Garcıa Ruano, J. L.; Fraile, A.; Martın, M. R. Tetrahe-
dron 1999, 55, 14491–14500.
ꢀ
9. (a) Garcıa Ruano J. L.; Fraile, A.; Martın, M. R. In 19th
International Symposium Organic Chemistry of Sulfur,
ꢀ
ꢀ
Book of Abstracts, 2000; pp 26; (b) Garcıa Ruano, J. L.;
Tito, A.; Peromingo, M. T. J. Org. Chem. 2003, 68, 10013–
ꢀ
10019; (c) Garcıa Ruano, J. L.; Tito, A.; Peromingo, M. T.
J. Org. Chem. 2002, 67, 981–987.
Acknowledgements
ꢀ
10. (a) Louis, C.; Hootele, C. Tetrahedron: Asymmetry 1997,
8, 109–131, and references cited therein; (b) Aggarwal, V.
K.; Roseblade, S.; Barrell, J. K.; Alexander, K. Org. Lett.
2002, 4, 1227–1229.
We thank CAICYT (Grant BQU2003-04012) and
Janssen-Cilag, S.A. for financial support.
11. Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, W. J.;
Feringa, B. L. Tetrahedron Asymmetry 1994, 4, 607–624,
and references cited therein.
12. The syn- or anti-character of the adducts that indicates the
cis- or trans-relationship between H3 and H3a (Scheme 2),
is related to the face of the dipolarophile, which is attacked
by the dipole, using as a reference the spatial arrangement
of the ethoxy group. The endo- or exo-terms, indicative of
the cis- or trans-arrangement exhibited by furanone and
azepine moieties at the isoxazolidine ring, are related to
the endo- and exo-addition modes of the dipole, using the
ester group at the furanone ring as a reference.
References and notes
1. (a) Guzikowski, A. P.; Espitia, S. A.; Hawkinson, J. E.;
Huettner, J. E.; Nogales, D. F.; Wodward, R. M.; Weber,
E.; Keana, C. J. Med. Chem. 1996, 39, 4643–4653,
and references cited therein; (b) Link, A.; Kunick, C.
J. Med. Chem. 1998, 41, 1299–1305, and references cited
therein.
ꢀ
2. (a) Andres, J. I.; Alcazar, J.; Alonso, J. M.; Dıaz, A.;
Fernandez, J.; Gil, P.; Iturrino, L.; Matesanz, E.; Meert,
ꢀ
ꢀ
13. (a) Merenda, I.; Ottana, R.; Romeo, G.; Rotondo, E.
Heterocycles 1989, 29, 547–555; (b) Burdisco, M.; Gamba,
A.; Gandolfi, R.; Pevarelo, P. Tetrahedron 1988, 44, 3735–
3748.
14. Crystallographic data (excluding structure factors) for
anti-3a-endo have been deposited with the Cambridge
Crystallographic Data Centre as suplementary publication
number CCDC 190809. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
366033 or e-mail: deposit@ccdc.cam.ac.uk].
ꢀ
T. F.; Megens, A.; Sipido, V. K. Bioorg. Med. Chem. Lett.
ꢀ
2002, 12, 243–248; (b) Andres, J. I.; Alcazar, J.; Alonso, J.
M.; Diaz, A.; Fernandez, J.; Gil, P.; Iturrino, L.; Mate-
ꢀ
ꢀ
sanz, E.; Meert, T. F.; Megens, A.; Sipido, V. K. Bioorg.
Med. Chem. Lett. 2002, 12, 249–253.
3. (a) Nickolson, V. J.; Wieringa, J. H. J. Pharm. Pharmacol.
1981, 33, 760–766; (b) Mizuno, A.; Miya, M.; Kamei, T.;
Shibata, M.; Tatsuoka, T.; Nakanishi, K.; Takiguchi, C.;
Hidaka, T.; Yamaki, A.; Inomata, N. Chem. Pharm. Bull.
2000, 48, 1129–1137; (c) Mizuno, A.; Shibata, M.;
Iwamori, T.; Shimamoto, T.; Nakanishi, K.; Inomata,
N. U.S. Patent No 875, 495, 2001; Chem. Abstr. 2001, 135,
92553.
4. (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; John Wiley & Sons: New York, 1984; Vol.
2, pp 83–168; (b) Frederickson, M. Tetrahedron 1997, 53,
403–425; (c) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863–909.
15. Schenck, G. O. Liebigs Ann. 1953, 584, 156–176.
16. (a) Tufariello, J. J.; Tette, J. J. Org. Chem. 1975, 40, 3866–
ꢀꢁ
ꢁ
ꢁ
€
3869; (b) Kuban, J.; Kolarovic, A.; Fisera, L.; Jager, V.;
ꢀ
ꢀ
Humpa, O.; Pronayova, N. Synlett 2001, 1866–1868.
17. The in vitro screening of the compounds was performed at
Johnson & Johnson Pharmaceutical Research & Develop-
ment, Division of Janssen Pharmaceutica N.V., Turnh-
outsweg 30, B2340 Beerse, Belgium. The authors would
like to acknowledge support from this company.