Novel [6 + 2] cycloaddition of fulvenes with alkenes: a facile synthesis of the anislactone and hirsutane framework.

Article abstract of DOI:10.1021/ol026103z

[reaction: see text] In contrast to the Diels-Alder reaction of fulvenes and various alkenes, 6-aminofulvenes react with maleic anhydride (or maleimide) to give [6 + 2] cycloaddition adducts, constituting an efficient and novel route to pentaleno[1,2-c]furan, pentaleno[1,2-c]pyrrole, and cyclopenta[a]pentalene skeleton.

Full text of DOI:10.1021/ol026103z

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2249-2252
Novel [6 + 2] Cycloaddition of Fulvenes
with Alkenes: A Facile Synthesis of the
Anislactone and Hirsutane Framework
,†
Bor-Cherng Hong,* Yeong-Jou Shr,† Jian-Lin Wu,† Arun Kumar Gupta,† and
Kuan-Jiuh Lin‡
Department of Chemistry, National Chung Cheng UniVersity, Chia-Yi, 621,
Taiwan, R.O.C, and Department of Chemistry, National Chung Hsing UniVersity,
Taichung, 400, Taiwan, R.O.C.
chebch@ccunix.ccu.edu.tw
Received April 30, 2002
ABSTRACT
In contrast to the Diels−Alder reaction of fulvenes and various alkenes, 6-aminofulvenes react with maleic anhydride (or maleimide) to give
[6 + 2] cycloaddition adducts, constituting an efficient and novel route to pentaleno[1,2-c]furan, pentaleno[1,2-c]pyrrole, and cyclopenta[a]-
pentalene skeleton.
Cycloadditions of fulvenes (e.g., [4 + 3], [2 + 2], [4 + 2],
[2 + 4], [6 + 4]) provide powerful synthetic approaches to
various polycyclic systems and natural products.1 In addition
to these versatile reactions, we recently reported a novel
hetero [6 + 3] cycloaddition of fulvenes for the synthesis of
11-oxasteroids.2 In conjunction with our continuing efforts
in fulvene chemistry,3 we have now developed a [6 + 2]
cycloaddition using 6-aminofulvenes and maleic anhydride
(or maleimide) for the preparation of pentaleno[1,2-c]furans
and pentaleno[1,2-c]pyrroles. These compounds constitute
the basic skeleton of many natural products such as anis-
lactone A,4 anislactone B,5 merrilactone A,6 merrilactones
B and C,7 and various other important synthetic intermedi-
ates.8
[6 + 2] cycloadditions of cycloheptatriene, vinylcyclobu-
tanones, or azepine with alkenes are well precedented.9
(6) (a) Huang, J.-M.; Yokoyama, R.; Yang, C.-S.; Fukuyama, Y.
Tetrahedron Lett. 2000, 41, 6111-6114. (b) For a recent total synthesis,
see: Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080-
2081.
(7) Huang, J.-M.; Yang, C.-S.; Tanaka, M.; Fukuyama, Y. Tetrahedron
2001, 57, 4691-4698.
(8) (a) Rosenstock, B.; Gais, H.-J.; Herrmann, E.; Raabe, G.; Binger,
P.; Freund, A.; Wedemann, P.; Kruger, C.; Lindner, H. J. Eur. J. Org. Chem.
1998, 257-273. (b) Michael, E. J.; Rayle, H. L. J. Org. Chem. 1997, 62,
4601-4609. (c) Hoberg, H.; Nohlen, M. J. Organomet. Chem. 1991, 412,
225-236. (d) Snyder, J. K.; Chen. Y. Tetrahedron Lett. 1997, 38, 1477-
1480.
(9) (a) Rigby, J. H.; Kondratenko, M. A.; Fiedler, C. Org. Lett. 2000, 2,
3917-3920. (b) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am.
Chem. Soc. 2000, 122, 7815-7816. (c) Chaffee, K.; Huo, P.; Sheridan, J.
B.; Barbieri, A.; Aistars, A.; Lalancette, R. A.; Ostrander, R. L.; Rheingold,
A. L. J. Am. Chem. Soc. 1995, 117, 1900-1907. (d) Schmidt, T.; Bienewald,
F.; Goddard, R. J. Chem. Soc., Chem. Commun. 1994, 1857-1858. (e)
Fischler, I.; Grevels, F. W.; Leitich, J.; Ozkar, S. Chem. Ber. 1991, 124,
2857-2861. (f) Mach, K.; Antropiusova, H.; Petrusova, L.; Hanus, V.;
Turecek, F.; Sedmera, P. Tetrahedron, 1984, 40, 3295-3302.
† National Chung Cheng University.
‡ National Chung Hsing University.
(1) For review of fulvenes and their synthetic applications, see: Neu-
enschwander, M. Chem. Double-Bonded Funct. Groups 1989, 2, 1131-
1268.
(2) Hong, B.-C.; Chen, Z.-Y.; Chen, W.-H. Org. Lett. 2000, 2, 2647-
2649.
(3) For previous papers in this series, see: (a) Hong, B.-C.; Shr, Y.-J.;
Liao, J.-H. Org. Lett. 2002, 4, 663-666. (b) Hong, B.-C.; Shen, I.-C.; Liao,
J.-H. Tetrahedron Lett. 2001, 42, 935-938. (c) Hong, B.-C.; Jiang, Y.-F.;
Kumar, E. S. Bioorg. Med. Chem. Lett. 2001, 11, 1981-1984. (d) Hong,
B.-C.; Sun, H.-I.; Chen, Z.-Y. Chem. Commun. 1999, 2125. (e) Hong, B.-
C.; Chen, Z.-Y.; Kumar, E. S. J. Chem. Soc., Perkin Trans. 1 1999, 1135.
(f) Hong, B.-C.; Hong, J.-H. Tetrahedron Lett. 1997, 38, 255. (g) Hong,
B.-C.; Sun, S.-S.; Tsai, Y.-C. J. Org. Chem. 1997, 62, 7717.
(4) Kouno, I.; Mori, K.; Okamoto, S.; Sato, S. Chem. Pharm. Bull. 1990,
38, 3060-3063.
(5) (a) Schmidt, T. J.; Mueller, E.; Fronczek, F. R. J. Nat. Prod. 2001,
64, 411-414. (b) Huang, J.-M.; Yang, C.-S.; Tanaka, M.; Fukuyama, Y.
Tetrahedron 2001, 57, 4691-4698.
10.1021/ol026103z CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/06/2002

Table 1. Reaction of Alkenes and Alkynes with Fulvenes
a Isolated yield based on starting fulvene. Method A: C6H6, 25 °C. Method B: microwave irradiation at 10 W in DMF, 120 °C. Method C: microwave
irradiation at 30 W in DMSO, 150 °C. Method D: cat. BF3‚OEt2, -78 °C, THF. Method E: 1 equiv of BF3‚OEt2, reflux, THF. Method F: 1 equiv of
BF3‚OEt2, 50 °C, THF.
However, like cycloheptatriene, the [6 + 2] cycloaddition
of fulvene has received little attention.10,11
fulvene. In our hands, addition of 6-dimethylaminofulvene
(1) to a solution of maleic anhydride in benzene at 25 °C
Many papers have reported that, in general, fulvene reacts
with maleic anhydride to give the [4 + 2] cycloaddition
adduct,12 (Scheme 1). In contrast, we have found that reaction
of 6-dimethylaminofulvene (1) with maleic anhydride gave
the intriguing pentalene derivative 2, (Scheme 2). To the best
of our knowledge, this is the first reported synthesis of a
pentaleno[1,2-c]furan system via a [6 + 2] cycloaddition of
Scheme 1
(10) For the intramolecular reaction of 6-(5-dialkylamino-4-pentyl)fulvene
and enamines, see: Wu, T. C.; Houk, K. N. J. Am. Chem. Soc. 1985, 107,
5308-5309.
(11) For addition of 1,3-di-tert-butyl-6-dimethyl-aminofulvene to alkynes,
see: Hafner, K.; Suda, M. Angew. Chem., Int. Ed. Engl. 1976, 15, 314-
315.
2250
Org. Lett., Vol. 4, No. 13, 2002

Scheme 2
for 30 min provided the pentalene derivative 2 in 81% yield
yields (entries 1 and 2, Table 1). Methyl maleic anhydride
and 1 did not react in benzene at reflux; however, microwave
irradiation provided adduct 8 in 63% yield (entry 3, Table
1). Unfortunately, we could not get γ-butyrolactone and 1
to react. In this case, the use of Lewis acids such as BF3‚
Et2O, AlCl3, EtAlCl2, TiCl4, etc. gave decomposition of
fulvene and no other product (entry 4, Table 1). Reaction of
the methylaminofulvene with 2-cyclopentenone did not give
any reaction either (starting materials were recovered).
However, the 1,4-alkylation adduct 10 (ca. 1:1 ratio of
regioisomers) was obtained in the presence of catalytic
amounts of BF3‚Et2O at -78 °C (entry 5, Table 1).
Interestingly, reaction of aminofulvene and 2-cyclopen-
tenone with 1 equiv of BF3‚Et2O (reflux, 240 min) afforded
the tricyclic product 11 in 65% yield (entry 6, Table 1).
Milder conditions could be used for 6-dimethylaminofulvene
(1 equiv of BF3‚Et2O, 50 °C) to provide the tricyclic product
12 in 75% yield (entry 6, Table 1). Cyclopenta[a]pentalene
adducts 11 and 12 are structural analogues of biologically
active natural products incarnal,15 pleurotellol,16 ceratopi-
canol,17 and hypnophilin.
as the only isolable product, (entry 1, Table 1). The structure
1
of 2 was assigned on the basis of IR, H and 13C NMR,
COSY, DEPT, HMQC, HMBC, MS, and HRMS analysis.
This dramatic difference in the chemoselectivity between
6-dimethylaminofulvene (1) and alkylfulvenes may be due
to an increase in the electron density of the 6-dimethylami-
nofulvene π-system. The formation of 2 may be rationalized
by the stepwise mechanism shown in Scheme 2. Initial
addition of 1 to maleic anhydride generates the zwitterionic
intermediate. This is followed by nucleophilic attack at the
C-6 position of fulvene to give the pentalene derivative 2.
A series of homologous maleic anhydrides and maleimide
were then reacted with various aminofulvenes to give the
corresponding products 3-9 (entries 1-4, Table 1).13 Reac-
tion of 1 with maleimide afforded adduct 5. The structure
of 5 was unambiguously assigned by single-crystal X-ray
analysis (Figure 1).14
Reaction of dimethylaminofulvene with dimethyl acetylene-
dicarboxylate and methyl propiolate provided the dimethyl-
amine adducts 1318 and 1419 (entries 7 and 8, Table 1). A
plausible mechanism for this transformation is shown in
Scheme 3. Michael addition of the fulvene amino group to
the triple bond followed by hydrolysis during workup affords
2-dimethylaminomaleic acid dimethylester 13.
In summary, a novel one-pot [6 + 2] cycloaddition of
fulvenes to maleic anhydride, maleimide, and cyclopentenone
has been reported. This constitutes a novel methodology for
Figure 1. ORTEP plots for X-ray crystal structures of 5.
(13) All new compounds were characterized by full spectroscopic (1H
and 13C NMR, DEPT, IR, MS, and HRMS) data. Most of them have COSY
and HMQC data. Yields refer to spectroscopically and chromatographically
homogeneous (>95%) materials.
(14) Crystallographic data for 5: C11H9NO2, M ) 187.19, monoclinic,
space group P21/c, T ) 293 K, a ) 13.6525(16) Å, b ) 8.1225(9) Å, c )
8.4007(10) Å, â ) 97.529(2)°, V ) 923.54(19) Å3, Z ) 4, D ) 1.346
g/cm3, λ (Mo KR) ) 0.71073 Å, 5577 reflections collected, 2114 unique
reflections, 127 parameters refined on F2, R ) 0.0661, wR2[F2] ) 0.2174
[1823 data points with F2 > 2σ(F2)].
(15) Isolated from Gloeostereum incarnatum, with antibacterial activity;
see: Takazawa, H.; Kashino, S. Chem. Pharm. Bull. 1991, 39, 555-557.
(16) Isolated from Pleurotellus hypnophilus, with antibacterial activity;
see: Giannetti, B. M.; Steffan, B.; Steglich, W.; Kupka, J.; Anke, T.
Tetrahedron 1986, 42, 3587-3593.
(17) Isolated from the fungus Ceratocystis piceae Ha 4/82; see: Hanssen,
H.-P.; Abraham, W.-R. Tetrahedron 1988, 44, 2175-2180.
(18) (a) Schwan, A. L.; Warkentin, J. Can. J. Chem. 1988, 66, 1686-
1694. (b) Guzman, A.; Romero, M.; Talamas, F. X.; Villena, R.;
Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1996, 61, 2470-2483.
(19) Roessler, U.; Blechert, S.; Steckhan, E. Tetrahedron Lett. 1999, 40,
7075-7078.
Reaction of various aminofulvenes with maleic anhydride
and maleimide gave similar adducts 3,4 and 6,7 in good
(12) (a) Butler, D. N.; Margetic, D.; O’Neill, P. J. C.; Warrener, R. N.
Synlett 2000, 10, 98-100. (b) Klaerner, F.-G.; Breitkopf, V. Eur. J. Org.
Chem. 1999, 11, 2757-2762. (c) Lonergan, D. G.; Deslongchamps, G.
Tetrahedron 1998, 54, 14041-14052. (d) Nair, V.; Anilkumar, G.;
Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P Tetrahedron 1997, 53,
17361-17372. (e) Nair, V.; Nair, A. G.; Radhakrishnan, K. V.; Nandaku-
mar, M. V.; Rath, N. P. Synlett 1997, 7, 767-768. (f) Lonergan, D. G.;
Riego, J.; Deslongchamps, G. Tetrahedron Lett. 1996, 37, 6109-6112. (g)
Gugelchuk, M. M.; Chan, P. C.-M.; Sprules, T. J. J. Org. Chem. 1994, 59,
7723-7731. (h) Ho, T.-L.; Yeh, W.-L.; Yule, J.; Liu, H.-J. Can. J. Chem.
1992, 70, 1375-1384. (i) Chou, T.-C.; Jiang, T.-S.; Hwang, J.-T.; Lin, C.-
T. Tetrahedron Lett. 1994, 35, 4165-4168. (j) Roth, W. R.; Bartmann,
M.; Maier, G.; Reisenauer, H. P.; Sustmann, R. Angew. Chem. 1987, 99,
271-272.
Org. Lett., Vol. 4, No. 13, 2002
2251

Scheme 3
Science Council and National Health Research Institute are
gratefully acknowledged.
the synthesis of pentaleno[1,2-c]furans (anislactone and
merrilactone skeletons), cyclopenta-[a]pentalenes (hirsutane
skeleton), and pentaleno[1,2-c]pyrroles. We are currently
pursuing the application of this methodology to the synthesis
of various natural products.
Supporting Information Available: Crystallographic
information files (CIF) for 5 and experimental procedures
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Dr. Sepehr Sarshar
for valuable discussions. Financial support from National
OL026103Z
2252
Org. Lett., Vol. 4, No. 13, 2002