Unprecedented microwave effects on the cycloaddition of fulvenes. A new approach to the construction of polycyclic ring systems

Article abstract of DOI:10.1021/ol017304q

Novel cycloaddition reactions between fulvenes and various alkenes and alkynes are promoted by the use of microwave irradiation. These processes result in the formation of intriguing polycyclic ring systems such as those found in isobarbatene, alcyopteros

Full text of DOI:10.1021/ol017304q

ORGANIC
LETTERS
2002
Vol. 4, No. 4
663-666
Unprecedented Microwave Effects on
the Cycloaddition of Fulvenes. A New
Approach to the Construction of
Polycyclic Ring Systems
Bor-Cherng Hong,* Yeong-Jou Shr, and Ju-Hsiou Liao
Department of Chemistry, National Chung Cheng UniVersity,
Chia-Yi, 621, Taiwan, R.O.C
chebch@ccunix.ccu.edu.tw
Received December 27, 2001
ABSTRACT
Novel cycloaddition reactions between fulvenes and various alkenes and alkynes are promoted by the use of microwave irradiation. These
processes result in the formation of intriguing polycyclic ring systems such as those found in isobarbatene, alcyopterosin, and enokipodin
A. Importantly, these reactions do not occur under conventional thermolytic conditions.
In 1986, Gedye and Giguere independently reported that
organic reactions could be accelerated by microwave ir-
radiation.1 In general, microwave-assisted organic reactions
(MOREs)2 are faster and more efficient than their conven-
tional counterparts.3 The origin of this rate enhancement is
debatable. Some have attributed it to a radiation effect known
as the “microwave effect”,4 while others refer to “hot spots”5
generated within the medium. Regardless of the explanation,
there are many documented cases of improvement or
inversion of stereo-, regio-, or chemoselectivity6 when
microwaves are used instead of conventional heating.7 While
selectivity and yield may be affected, the microwave products
retain the general backbone structure of the thermal products
(e.g., cis/trans, syn/anti, endo/exo). Herein we report that for
certain cycloadditions of fulvenes, the use of microwave
irradiation instead of conventional heating leads to the
formation of structurally unrelated products. These results
suggest that microwaVe irradiation can in fact alter the
reaction pathway.
Under conventional heating (C6H6, 80 °C, 8 h), 6,6-
dimethylfulvene reacts with dimethyl maleate to afford the
Diels-Alder adduct 3 in 84% yield (Table 1, entry 2).
During our studies of fulvene chemistry,8 we subjected a
DMSO solution of 6,6-dimethylfulvene and dimethyl maleate
to microwave irradiation for 2 h.9,10 Surprisingly, the tandem
[6+4]-[4+2] cycloaddition products 1 and 2 were obtained
(1) (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.;
Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279-282. (b) Giguere,
R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 27,
4945-4948.
(2) (a) Majetich, G.; Wheless, K. MicrowaVe-Enhanced Chemistry;
American Chemical Society: Washington, DC, 1997; pp 455-505. (b)
Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1692. (c)
Varma, R. S. Pure Appl. Chem. 2001, 73, 193-198. (d) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-9283.
(3) For a recent example in the [6+4]-cycloaddition, see: Hong, B,-C.;
Jiang, Y.-F.; Kumar, E. S. Biorg. Med. Chem. Lett. 2001, 11, 1981-1984.
(4) Langa, F.; Cruz, P. D. L.; Hoz, A. P. L.; Diaz-Ortiz, A.; Diez-Barra,
E. Contemp. Org. Synth. 1997, 4, 373-386.
(6) (a) Forfar, I.; Cabildo, P.; Claramunt, R. M.; Elguero, J. Chem. Lett.
1994, 2079-2080. (b) Almena, I.; Diaz-Ortiz, A.; Diez-Barra, E.; Hoz, A.;
Loupy, A. Chem. Lett. 1996, 333-334.
(7) Bose, A. K.; Banik, B. K.; Manhas, M. S. Tetrahedron Lett. 1995,
36, 213-216.
(8) For previous papers in this series, see: (a) Hong, B.-C.; Shen, I. C.;
Liao, J. H. Tetrahedron Lett. 2001, 42, 935-938. (b) Hong, B.-C.; Chen,
Z.-Y.; Chen, W.-H. Org. Lett. 2000, 2, 2647-2649 and references therein.
(5) Stuerga, D.; Gaillard, P. Tetrahedron 1996, 52, 5505-5510.
10.1021/ol017304q CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/19/2002

Scheme 1
in 30% (Table 1, entry 1). In fact, the combined yield of 1
H2SO4) in the presence of dimethylfulvene in refluxing C6H6
leads to complete recovery of the starting materials. In
addition, inclusion of acid in the microwave irradiation
reaction of 3 with dimethylfulvene did not result in a rate
enhancement during the formation of 1 and 2. These
observations help rule out pathway C. We also reacted a
series of homologous alkenes and alkynes with dimethyl-
fulvene using microwave heating (Table 1). Interestingly,
different mechanistic pathways are followed in these pro-
cesses. For example, reaction of 6,6-dimethylfulvene with
maleic anhydride under microwave conditions gave the
[4+2]-cycloadduct 13, an analogue of the natural product
alcyopterosin20 (Table 1, entry 3).21 Maleic anhydride appears
to add across the C-1 methyl and C-6 atom of the fulvene.
This is the first example of a fulvene reacting in such a
manner to afford a hydrindane system. In addition, reaction
of maleic anhydride with dimethylfulvene under conventional
heating has been reported to give the Diels-Alder adduct
14 in 67% yield (Table 1, entry 4). A possible mechanism
for the formation of 13 involves microwave-induced isomer-
ization of 6,6-dimethylfulvene to 2-isopropenyl-cyclopenta-
1,3-diene followed by trapping with maleic anhydride via
[4+2]-cycloaddition. Reaction of 6,6-dimethylfulvene with
2(5H)-furanone under microwave conditions afforded adducts
15 and 16 in a 1:2 ratio. These products may also arise by
and 2 increased to 65% when 2 equiv of 6,6-dimethylfulvene
were used. Reductive cleavage of 1 in the presence of Li/
NH3 (55% yield) followed by selective hydrogenation of the
disubstituted alkene (H2, Pd-C) provided diester 5 in 85%
yield. Ozonolysis of 5 afforded ketoester 6 in 60% yield.
The tricyclo[5.3.0.12,5]alkane structure of 6 was unambigu-
ously assigned using single-crystal X-ray analysis (Scheme
1). As shown in Scheme 2, a plausible mechanism for the
formation of 1 under microwave irradiation involves the
competitive and reversible formation of Diels-Alder adduct
3 and facile dimerization of fulvene via a [6+4]-cycloaddition
pathway to give the dimer 7 (pathway A).11 Subsequently,
[4+2]-cycloaddition of 7 with dimethyl maleate occurs to
generate adducts 1 and 2.
Alternatively, dimerization of fulvene via [4+2]-cyclo-
addition affords adduct 8, which can be transformed to dimer
7 by a [3,3]-sigmatropic rearrangement and a 1,5-hydrogen
shift (pathway B). As a third alternative, an acid-catalyzed
Wagner-Meerwein rearrangement pathway can be envisaged
(pathway C). Accordingly, acid-catalyzed reaction of 3 will
generate norbornyl cation 9 and could lead to 10 by a 1,2-
alkyl shift. Cation 10 would then undergo the [4+3]-
cycloaddition with fulvene to provide 11 and 12. However,
we have found that treatment of 3 with acid (PTSA, HCl, or
Scheme 2
664
Org. Lett., Vol. 4, No. 4, 2002

Table 1. Reactions of Fulvenes with Alkenes or Alkynes
a Isolated yield based on starting fulvene. b Two equivalents of fulvene were used. c Recovered 50% of starting fulvene and 25% of fulvene dimer.
d Yield for 19; 2 equiv of fulvene were used. e From this work; no yield was reported in the literature. f Complicated mixtures. Method A: Microwave
irradiation. Method B: Conventional oil bath heating in C6H6. Method C: Conventional oil bath heating in DMSO.
initial isomerization of the fulvene to 2-isopropenylcyclo-
penta-1,3-diene, followed by trapping with furanone via
[4+2]-cycloaddition across C-3 and C-5 of fulvene, i.e., C-4
and C-6 of 2-isopropenyl-cyclopenta-1,3-diene. Reaction of
6,6-dimethylfulvene with 2(5H)-furanone under conventional
heating conditions afforded fulvene dimerization exclusively
(Table 1, entry 6). Microwave reaction of 6,6-dimethylful-
vene with maleimide yielded 18 and 19 in 74% yield and in
a 3:1 ratio (Table 1, entry 7). In the presence of 2 equiv of
dimethylfulvene, the yield of 19 increased to 80%. The
structure of 19 was determined by X-ray analysis (Figure
1). Reaction of dimethylfulvene with maleimide, under
conventional heating conditions, gave adduct 18 in 89% yield
(Table 1, entry 8), while reaction of fulvene with dimethyl
Org. Lett., Vol. 4, No. 4, 2002
665

Figure 1. ORTEP plots for X-ray crystal structures of 19 and 27.
acetylenedicarboxylate or methyl propiolate gave the [4+2]-
adducts 20 and 21, respectively, under both microwave
irradiation and conventional heating conditions (Table 1,
entries 9 and 10).
Reaction of 6-methylfulvene and maleic anhydride also
gave the [4+2]-adduct 22 under both microwave and
conventional heating conditions (Table 1, entry 11). The
reason for the dramatic differences seen in reactions of
6-methylfulvene and 6,6-dimethylfulvene (Table 1, entry 3)
is not clear. This may be a result of the lower reactivity of
methylfulvene by isomerization to 2-vinyl-cyclopenta-1,3-
diene. Reaction of fulvene 23 with maleic anhydride afforded
adducts 24 and 25 in a 1:1 ratio, which is different from the
results produced by conventional heating (Table 1, entries
12 and 13). A similar outcome is seen in the reaction of
6,6-dimethylfulvene with maleic anhydride (Table 1, entries
3 and 4). Reaction of 6,6-dimethylfulvene and benzoquinone
under microwave conditions afforded the hetero-[2+3]-
adduct 27 in a 60% yield (Table 1, entry 14). Adduct 27 is
a structural analogue of aplysin and pannellin22 and differs
completely from the well-known thermal Diels-Alder cy-
cloaddition products of fulvenes and benzoquinone (Table
1, entry 15).
In summary, the processes are facile methods for the
synthesis of densely functionalized polycyclic ring systems.
The study further demonstrates that microwave irradiation
not only enhances the rates of reactions but can also effect
reactions by giving rise to products that do not form under
conventional thermolytic conditions. Mechanistic studies and
applications of this work to the synthesis of naturally
occurring compounds are currently under active investigation.
(9) Focused microwave irradiation was carried out at atmospheric
pressure with a Synthewave S402 Prolabo microwave reactor (300 W,
monomode system, 10 mL reactors). The apparatus has a quartz reactor,
visual control, PC-controlled 300 W irradiation, and infrared temperature
measurement with continuous feedback control.
(10) Typical Procedure for Synthesis of 1 and 2. A mixture of 6,6-
dimethylfulvene (650 mg, 6 mmol), dimethyl maleate (420 mg, 2.9 mmol),
and DMSO (5 mL) were placed in a 10 mL quartz vial and subjected to
programmed microwave irradiation at 30 W for 120 min. After a period of
2-3 min, the temperature reached a plateau of 150 °C where it remained
throughout the reaction. After cooling, the solution was concentrated and
the residue was subjected to flash column chromatography (10% EtOAc-
hexane, Rf ) 0.32 in 15% EtOAc-hexane) to give the adducts 1 and 2 as
colorless liquids (1: 328 mg, 32% yield; 2: 341 mg, 33% yield).
(11) A similar tricyclo[6.2.1.02,6]undecane structure, fulvene dimer, was
proposed as the first step ([6+4]-dimerization) in the trimerization of 6,6-
dimethyl fulvene; see: Uebersax, M.; Neuenschwander, M.; Engel, P. HelV.
Chim. Acta 1982, 65, 89-104.
(12) Duncan, C. D.; Corwin, L. R.; Davis, J. H.; Berson, J. A. J. Am.
Chem. Soc. 1980, 102, 2350-2358.
Acknowledgment. We are grateful to Dr. Sepehr Sarshar
for valuable discussions. Financial support from National
Science Council and National Health Research Institute are
gratefully acknowledged.
(13) Ho, T.-L.; Yeh, W.-L.; Yule, J.; Liu, H.-J. Can. J. Chem. 1992, 70,
1375-1384 and references therein.
(14) Lonergan, D. G.; Riego, J.; Deslongchamps, G. Tetrahedron Lett.
1996, 37, 6109-6112.
(15) Alder, R. Justus Liebigs Ann. Chem. 1950, 566, 1-19.
(16) Herges, R.; Reif, W. Chem. Ber. 1994, 127, 1143-1146.
(17) Uebersax, B.; Neuenschwander, M.; Kellerhals, H.-P. HelV. Chim.
Acta 1982, 65, 74-88.
Supporting Information Available: Crystallographic
information files (CIF) for 6, 19, and 27, experimental
procedures, and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) (a) Woodward, B. J. Am. Chem. Soc. 1944, 66, 645-649. (b) Kohler,
K. J. Am. Chem. Soc. 1935, 57, 917-918.
(19) Singh, A. K.; Yadav, S. Indian J. Chem., Sect. B 1991, 30, 486-
489 and references therein.
(20) Palermo, J. A.; Brasco, M. F. R.; Spagnuolo, C.; Seldes, A. M. J.
Org. Chem. 2000, 65, 4482-4486.
OL017304Q
(21) This indene skeleton is widespread among natural products; for
example, see: (a) for amaminol A and B: Sata, N.; Noriko, U.; Fusetani,
N. Tetrahedron Lett. 2000, 41, 489-492. (b) For isopulo’upone: Evans,
D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786-787.
(22) (a) Shizuri, Y.; Yamada, A.; Yamada, K. Phytochemistry 1984, 23,
2672-2673. (b) Dreyer, M.; Nugroho, B. W.; Bohnenstengel, F. I.; Ebel,
R.; Wray, V.; Witte, L.; Bringmann, G.; Muehlbacher, J.; Herold, M.; Hung,
P. D.; Kiet, L. C.; Proksch, P. J. Nat. Prod. 2001, 64, 415-420.
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