Tandem Enyne Metathesis-Diels-Alder Reaction for Construction of Natural Product Frameworks

Article abstract of DOI:10.1021/jo0356311

Enynes connected through aromatic rings are used as substrates for metathesis reactions. The reactivity of three ruthenium carbene complexes is compared. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels-Alder process.

Full text of DOI:10.1021/jo0356311

Ta n d em En yn e Meta th esis-Diels-Ald er Rea ction for Con str u ction
of Na tu r a l P r od u ct F r a m ew or k s
Marta Rosillo,† Gema Dom´ınguez,† Luis Casarrubios,†,§ Ulises Amador,‡ and
J avier Pe´rez-Castells*,†
Universidad San Pablo-CEU, Departamento de Qu´ımica and Servicio de rayos-X, Facultad de Ciencias
Experimentales y de la Salud, Urb. Montepr´ıncipe, 28668 Boadilla del Monte (Madrid), Spain
jpercas@ceu.es
Received November 6, 2003
Enynes connected through aromatic rings are used as substrates for metathesis reactions. The
reactivity of three ruthenium carbene complexes is compared. The resulting 1,3-dienes are suitable
precursors of polycyclic structures via a Diels-Alder process. Some domino RCM-Diels-Alder
reactions are performed, suggesting a possible beneficial effect of the ruthenium catalyst in the
cycloaddition process. Other examples require Lewis acid cocatalyst. When applied to aromatic
ynamines or enamines, a new synthesis of vinylindoles is achieved. Monitorization of several
metathesis reactions with NMR shows the different behavior for ruthenium catalysts. New carbenic
species are detected in some reactions with an important dependence on the solvent used.
SCHEME 1
In tr od u ction
Multiple bond metathesis reactions are synthetically
useful tools to achieve molecular complexity in an elegant
way.1 Both double-double bond and double-triple bond
processes are possible, being the mos-used intramolecular
reactions. The ring-closing alkene-alkyne reaction2 for-
mally implies the formation of a carbon-carbon bond and
the migration of the alkylidene part onto the alkyne
carbon, to form a diene, constituting a complete atom
economical reaction (Scheme 1). This reaction has been
developed later than the diene version. However, in the
past 5 years there has been great interest in intramo-
lecular enyne metathesis especially with regard to fur-
ther transformations of the resulting conjugated dienes.3
Thus, tandem transformations have led to synthetic
applications in the field of polycycle construction and
natural product syntheses.
The success of the metathesis reactions involving metal
carbenes has arrived after the development of new stable
and easy to handle catalysts. In this work we will use
some of the ruthenium alkylidene complexes developed
by Grubbs.4 Three generations of complexes are depicted
in Chart 1 and are thought to present, in general,
increasing activities in the olefin RCM. Catalyst 1 is the
CHART 1
cheapest one but is thermally unstable and, in general,
fails to react with substituted olefins. Catalyst 2 is
described to give better results when using substituted
olefin fragments. Finally the latter complex 3, is a
representative of the third generation of ruthenium
catalysts, in which a tethered oxygen substitutes the
ligand that is dissociated. There are efficient methods for
the synthesis5 of these new catalysts, although there are
(3) Recent references on intramolecular ruthenium-based enyne
metathesis: (a) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654.
(b) Duboc, R.; Henaut, C.; Savignac, M.; Geneˆt, J .-P. Bhatnagar, N.
Tetrahedron Lett. 2001, 42, 2461. (c) Ru¨ckert, A.; Eisele, D.; Blechert,
S. Tetrahedron Lett. 2001, 42, 5245. (d) Yao, Q. Org. Lett. 2001, 3,
2069. (e) Kotha, S.; Sreenivasachary, N.; Brahmachary, E. Eur. J . Org.
Chem. 2001, 787. (f) Marco-Contelles, J .; Arroyo, N.; Ruiz-Caro, J .
Synlett 2001, 652. (g) Ackermann, L.; Bruneau, C.; Dixneuf, P. H.
Synlett 2001, 397. (h) Clark, J . S. Townsend, R. J .; Blake, A. J .; Teat,
S. J .; J ohns, A. Tetrahedron Lett. 2001, 42, 3235. (i) Bentz, D.; Laschat,
S. Synthesis 2000, 1766. (j) Smulik, J . A.; Diver, S. T. J . Org. Chem.
2000, 65, 1788. (k) Trost, B. M.; Doherty, G. A. J . Am. Chem. Soc.
2000, 122, 3801. (l) Stragies, R.; Voigtmann, U.; Blechert, S. Tetrahe-
dron Lett. 2000, 41, 5465. (m) Mori, M.; Kitamura, T.; Sakakibara,
N.; Sato, Y. Org. Lett. 2000, 2, 543. (n) Kotha, S.; Sreenivasachary, N.
Chem. Commun. 2000, 503.
† Departamento de Qu´ımica.
‡ Servicio de rayos-X.
§ Present address: Centro de investigacio´n Lilly S. A., Avda. de la
industria 30, 28108 Alcobendas, Madrid, Spain.
(1) For recent reviews on the olefin metathesis reaction, see: (a)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Schrock, R. R.
Tetrahedron 1999, 55, 8141. (c) Wright, D. L. Curr. Org. Chem. 1999,
3, 211. (d) Philips, A. J .; Abell, A. D. Aldrichimica Acta 1999, 32, 75.
(e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (f) Armstrong,
S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371. (g) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 37.
(2) For recent reviews on enyne metathesis, see: (a) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1. (b) Mori, M. Top. Organomet. Chem.
1998, 1, 133.
(4) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
10.1021/jo0356311 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004
2084
J . Org. Chem. 2004, 69, 2084-2093

Tandem Enyne Metathesis-Diels-Alder
SCHEME 2
SCHEME 3
still few data about their practical results, especially in
enyne metathesis.6 There is not a clear rule that indicates
the best catalyst to use in each example. Subtle varia-
tions in the substrate structure and in the type of final
product may lead to different results with each type of
carbene complex. In particular, the substitution pattern,
the steric demand of the substrate, the ring size to be
formed, and the presence of coordinating heteroatoms
have important influence on the results.
With regard to the mechanism, the metathesis reaction
begins with the dissociative loss of a phosphine and the
formation of a 14 e- intermediate (Scheme 2). The
formation of this infrequent unsaturated complex was
demonstrated with kinetic studies.7 The increase in the
activity of the second generation catalysts is not due to
increase in the rate of the phosphine dissociation but to
a better ratio of the coordination of the olefin constant
(k2) and that for the phosphine recovery (k-1). This stage
was studied for the alkene-alkene reaction but is shared
by the enyne process.
In contrast to diene metathesis there are still some
obscure points in the following stages of the enyne
reaction. In principle, up to three reaction courses would
be possible, depending on the type of coordination of the
metal with the system. The metal may coordinate with
the double bond (path a, Scheme 3) or with the triple
bond with two possible regiochemistries (paths b and c).
Hoye has monitored the reaction by NMR and shown the
formation of carbenes compatible with the first reaction
course (path a).8 Additionally, this path explains better
the results obtained in cascade metathesis reactions with
dienynes. Nevertheless, with substituted alkynes, Mori
has obtained products coming from path c, which implies
the initial coordination of the metal with the triple bond.9
Probably several reaction mechanisms are competing and
operate depending on the substrate (steric and electronic
effects) and the reaction conditions. In addition, the
intermolecular reaction developed more recently after
pioneering studies by Blechert10 is better explained by
first coordination of the metal with the triple bond. One
possible explanation would be the kinetic versus ther-
modynamic control of the addition of metal alkylidenes
to triple bonds, which might depend on the substitution
of the triple bond.
cyclization is attractive and allows great increment of the
molecular complexity. This approach can be accomplished
by addition of all of the reactives from the beginning of
the process or by addition of the dienophyle when the
metathesis is completed. In the first case only electron-
deficient dienophyles can be used in order to avoid
undesired cross-metathesis reactions.11 The latter ap-
proach has been used for the synthesis of indenes12 and
polycyclic â-lactams.13 Some examples in which this
approach is carried out in a stepwise fashion have also
been reported.14
In a preliminary communication of this work,15 we
showed the formation of tri- and tetracyclic compounds
by the tandem metathesis-Diels-Alder reaction of aro-
matic enynes. Herein we describe the complete results
of our study in which we have compared the reactivity
of the different generations of catalysts. We have moni-
torized some reactions by NMR to give some more data
on the enyne metathesis reaction course. This methodol-
ogy is also applied to the synthesis of the indole nucleus.
Resu lts a n d Discu ssion
As ring-closing enyne metathesis provides 1,3-dienes,
the combination of this reaction with a Diels-Alder
Enynes connected through an aromatic ring are inter-
esting substrates that have found scarce use in this
(5) (a) Synthesis of 2: Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R.
H. Org. Lett. 1999, 1, 953. (b) Synthesis of 3: Kingsbury, J . S.; Harrity,
J . P. A.; Bonitatebus, P. J ., J r.; Hoveyda, A. H. J . Am. Chem. Soc. 1999,
121, 791.
(11) See: (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803.
(b) Moreno-Man˜as, M.; Pleixats, R.; Santamaria, A. Synlett 2001, 1784
(6) Wakamatsu, H.; Blechert, S. Angew. Chem, Int. Ed. 2002, 41,
794. (b) Garber, S. B.; Kingsbury, J . S.; Gray, B. L.; Hoveyda, A. H. J .
Am. Chem. Soc. 2000, 122, 8168. (c) Van Veldhuizen, J . J .; Garber, S.
B.; Kingbury, J . S.; Hoveyda, A. H. J . Am. Chem. Soc. 2002, 124, 4954.
(7) See: (a) Sanford, M. S.; Love, J . A.; Grubbs, R. H. J . Am. Chem.
Soc. 2001, 123, 6543. (b) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J .
Am. Chem. Soc. 2001, 123, 749. (c) Aagaard, O. M.; Meier, R. J .; Buda,
F. J . Am. Chem. Soc. 1998, 120, 7174.
(8) Hoye, T. R.; Donaldson, S. M.; Vos, T. J . Org. Lett. 1999, 1, 277.
(9) Kitamura, T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258.
(10) For a recent review on olefin cross metathesis see: Connon, S.
J .; Blechert, S. Angew. Chem, Int. Ed. 2003, 42, 1900.
and ref 3i. For a recent example of a three-component tandem
metathesis/Diels-Alder reaction, see: Lee, H.-Y.; Kim, H. Y.; Tae, H.;
Kim, B. G.; Lee, J . Org. Lett. 2003, 5, 3439.
(12) Lane, C.; Snieckus, V. Synlett 2000, 1294.
(13) Schurer, S. C.; Blechert, S. Tetrahedron Lett. 1999, 40, 1877.
(14) See: (a) Banti, D.; North, M. Tetrahedron Lett. 2002, 43, 1561.
(b) Guo, H.; Madhushaw, R. J .; Shen, F.-M.; Liu, R.-S. Tetrahedron
2002, 58, 5627. (c) Schu¨rer, S. C.; Blechert, S. Chem. Commun. 1999,
1203.
(15) For a preliminary communication of part of this work, see:
Rosillo, M.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-Castells, J . Tetra-
hedron Lett. 2001, 42, 7029.
J . Org. Chem, Vol. 69, No. 6, 2004 2085

Rosillo et al.
SCHEME 4
SCHEME 5
chemistry.11b However, these compounds can be easily
prepared and would give, upon metathesis, dienes con-
taining fused bicycles that may undergo a Diels-Alder
process to give finally two or three new cycles in one step.
We first carried out the synthesis of 1,6-, 1,7- and 1,8
enynes. Starting from 2-iodobenzyl alcohol, a Sonogashira
coupling with trimethylsilylacetylene gave quantitatively
alcohol 4, which was oxidized with MnO2 to give 5 in 99%
yield. This aldehyde was treated with suitable Grignard
reagents to afford the corresponding enynes 6, which
were deprotected to give compounds 7. These alcohols
were protected to give the silylderivatives 8. Additionally
compound 6b was mesylated and treated with superhy-
dride to give 9 (Scheme 4).
To effect a new approach to Dane’s diene, a well-known
substrate thoroughly used for the synthesis of estradiol
derivatives, we carried out the synthesis of the corre-
sponding enyne precursor. Thus, 4-bromo-3-methylani-
sole was dibromated with NBS to give a dibromide
intermediate, which upon basic treatment gave aldehyde
10 in 82% yield after the two steps. Sonogashira coupling
afforded 11 quantitatively, which was treated with
allylmagnesium bromide to give 12. The final step was
the elimination of the hydroxyl group via mesilation-
superhydride reduction, yielding 13. We have to note the
excellent yield of all steps of this synthesis, the global
yield from commercial 4-bromo-3-methylanisole being
68%. The order of the reactions is important. When we
tried the Sonogashira coupling with the starting anisole
or after treating aldehyde 10 with the Grignard reagent,
the yields were much lower (Scheme 5).
monium iodide.16 In this reaction the TMS group is also
lost, giving directly the desired enyne 20a in 98% yield
(Scheme 6).
All previously prepared substrates were reacted in the
presence of ruthenium catalysts 1 and 2. Compound 8b
was used as a model to study the best reaction conditions.
Temperature, solvent, and catalyst loading were com-
pared using first generation catalyst, and the results are
summarized in Table 1. Following these results the
selected reaction conditions consisted of using 7% catalyst
in refluxing dichloromethane. With regard to catalyst 2,
the current thinking is that intermediates coming from
this complex are able to complete more turnovers than
those derived from 1 although they are formed in less
extension. Thus, the amount of catalyst loading would
be less important. As the reaction of compound 8b did
not complete with catalyst 2 in any of the conditions used,
we used 8c. We reacted this compound (entries 8-10)
with 3%, 5%, and 7% of catalyst 2 and found similar
results. We selected a 5% loading for the rest of reactions.
The above selected conditions were used with the rest
of substrates (entry 6, Table 1 for catalyst 1 and entry 9
for catalyst 2). Table 2 summarizes the results obtained
in these reactions.
2-Iodophenol and 2-iodoaniline were selected as start-
ing materials for the synthesis of enynes containing
heteroatoms. These were submitted to Sonogashira cou-
pling conditions to give 14 and 15. Mitsunobu reaction
with allyl and homolallyl alcohols afforded enynes 17a ,b,
whereas 18 was obtained via nucleophilic substitution.
Amine 18 was acetylated to give compound 19. The final
deprotection of the alkyne yielded the desired enynes
20b, 21a ,b, and 22. The synthesis of 20a was a slight
modification of this route, as the amine was acetylated
after the Sonogashira reaction and the resulting amide
16 was allylated following the Smith procedure that uses
powdered KOH in anhydrous THF with tetrabutylam-
Alcohol 7a gave the corresponding diene, which could
only be observed in the spectrum of the crude mixture.
(16) Keusenkothen, P. F.; Smith, M. B. Tetrahedron Lett. 1992, 48,
2977.
2086 J . Org. Chem., Vol. 69, No. 6, 2004

Tandem Enyne Metathesis-Diels-Alder
TABLE 2. Meta th esis Rea ction s w ith Ar om a tic En yn es
SCHEME 6
yielda (%)
sub-
cat. cat. cat.
entry strate
X
n
R
product
1
2
3
1
2
3
4
5
6
7
8
9
7a CHOH
7b CHOH
8a CHOTBDMS
8b CHOTBDMS
8c CHOTBDMS
0
1
0
1
2
1
1
1
2
2
1
2
H
H
H
H
H
H
24a
23b
24a
24b
24c
25
50b nr
68 76
nr
nr
85
c
84 93
56 60
9
CH2
13 CH2
OCH3
26
c
77
c
70
20a NCOCH3
20b NCOCH3
22 NH
H
H
H
H
H
27a
27b
28
29a
29b
95
c
85 93
10
11
12
nr
nr
21a
21b
O
O
65d c,e 72
60d c,e 70
a
b
Of pure product with correct spectroscopic data. Yield of
protected compound 24a after two steps. See Scheme 7. c The
d
reaction did not complete. 10% catalyst was added in four
portions. e Partitioned addition of catalysts was also tried without
reaching completion of the reaction.
SCHEME 7
TABLE 1. Selection of Rea ction Con d ition s
2 h, and it was not improved after 18 h. Thus, we added
a total of 10% catalyst divided into four equal portions,
which were added every 30 min. Before each addition,
the reaction mixture was filtered trough Celite. With this
procedure, the remaining starting material was reduced
to less than 10% and we isolated the dienes 29 with good
yields. When using catalyst 2 the results were similar
with one portion of complex while it was not possible to
complete the reaction using partitioned addition of the
catalyst. The reaction did not complete when carried out
in toluene at 80 °C or at reflux. In this latter case we
obtained complex mixtures in the reaction of 21a .
With respect to second-generation catalyst 2, it is
possible that this complex is more sensitive to steric
hindrance as reactions with 8b, 20a , and 21a ,b gave
conversions of only 50-65% in the crude 1H NMR
spectra. These results were not improved when changing
solvents or temperatures or when adding the catalysts
in portions. On the other hand, complex 2 improves the
results with less hindered substrates such as 7b, 8c, 9,
20b, or 13. The latter substrate yields compound 26, the
well-known Dane’s diene.
entry substrate solvent
temp catalyst, loading yielda
1
2
3
4
5
6
7
8
9
8b
8b
8b
8b
8b
8b
8b
8c
8c
8c
benzene rt
1, 5%
1, 5%
1, 5%
1, 5%
1, 3%
1, 7%
1, 10%
2, 3%
2, 5%
2, 7%
60%
58%
70%
79%
75%
85%
85%
88%
93%
94%
toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
rt
rt
reflux
reflux
reflux
reflux
reflux
reflux
reflux
10
a
Of pure product.
This reaction product decomposed after few hours at
room temperature. All attempts to isolate it were unsuc-
cessful. In addition, no reaction was observed with the
TBDMS-protected compound 8a with any of the catalysts,
probably because of steric hindrance of the substrate. We
opted thus to react 7a and protect the hydroxydiene in
the crude mixture with a TBDMS group, obtaining 24a
with 50% yield after the two reaction steps (Scheme 7).
The rest of the examples selected yielded the desired
products with, in general, good yields. The exception was
22, which did not react, probably as a result of interaction
with the unprotected amine. The reaction of the two
ethers 21 using complex 1 gave only 50% conversion after
Some of the substrates shown in Table 2 were also
reacted with the Hoveyda-Grubbs catalyst, 3. This
complex has the advantage that it can be purified by
column chromatography and recovered at the end of the
reaction. It is also stable at higher temperatures. We
tried to improve results with ethers 21a ,b. Metathesis
reaction with enynes bearing oxygen are somewhat
J . Org. Chem, Vol. 69, No. 6, 2004 2087

Rosillo et al.
SCHEME 8
SCHEME 10
SCHEME 9
SCHEME 11
erratic: there are results in the literature in which this
functionality seems to be beneficial, others in which no
influence is observed, and in the majority of cases, a
negative influence is reported.17 A coordination of the
oxygen with the catalyst is usually claimed as the reason
for this result. In our hands, the reaction of compounds
21 with 5% complex 3 did not complete using DCM as
solvent, even at reflux. Thus we used toluene at 80 °C,
and we were pleased to observe total conversion with both
ethers and a final yield of 72% and 70%, respectively.
This result avoids the partitioned addition of the catalyst.
The same conditions were used with enynes 13 and 20a .
Whereas the reaction of 13 did not complete after 12 h,
compound 20a gave 70% yield and total conversion, a
worse result than when using catalyst 1 (see entry 8,
Table 2).
When designing the type of substrates used for these
studies we had observed that when using compounds in
which the double bond was conjugated with the aromatic
ring, the cyclization did not occurr. We used compound
30 to test the previously optimized conditions.18 Neither
complexes 1 nor 2 were able to catalyze the cyclization.
Starting material was recovered in both cases. On the
other hand, compound 30 reacted with 5% 3 and was
totally converted into 31, which was isolated in 65% yield
(Scheme 8).
Scheme 9 by analogy with related structures described
in the literature.19
The latter conditions were used with compound 27a
and with Dane’s diene, 26. Compound 27a completed the
reaction after 48 h (TLC), yielding 60% of compound rac-
34 (endo adduct). A minor isomer of this compound was
1
detected in less than 10% in the H NMR spectrum of
the crude. The yield of this cyclization improved up to
75% when using refluxing bromobenzene as solvent. The
relative configuration of this adduct was determined by
analogy with previously reported compounds.19 On the
other hand, compound 26 reacted in 60% yield under
standard conditions, giving rac-35 as the only isomer.
We tried the one-pot obtention of these adducts from
enynes 20a and 13 by adding the dienophyle to the
metathesis reaction mixture, once total conversion of the
enyne was verified (TLC). Regarding compound rac-34
the yield of the two-step one-pot process was 85%, after
36 h of reaction in refluxing dichloromethane. This result
shows a possible beneficial action of the ruthenium
complex in the Diels-Alder reaction (Scheme 10).20
Compound rac-35 reached 68% yield, also improving
the two-step procedure. As this latter case is a possible
entry to new estradiol-related compounds, we tried to
improve this result by adding a Lewis acid as cocatalyst.
Scheme 11 shows the results obtained when adding 1
equiv of several Lewis acids jointly with the dienophile.
TiCl4 at low temperature gave the best results (90%).
At this point we thought it was worth trying this
methodology to obtain indoles.21 This would imply the
synthesis of aromatic enamines or ynamines. Both ap-
proaches were addressed. We prepared enamine 36 and
ynamine 37 following our previously reported proce-
dure.22 When reacting these compounds with catalyst 1,
no conversion was detected (TLC) and decomposition of
starting material occurred when the reaction time was
prolonged. Catalyst 2 gave the desired cyclization prod-
Next we addressed the Diels-Alder reaction of some
of these products. As a model we performed the cycliza-
tion of compound 25 with maleic anhydride (Scheme 9).
We used toluene and DCM as solvents, at room temper-
ature, observing in both cases after 3 days a 2:1 mixture
of rac-32 and rac-33. When using refluxing DCM, the
reaction completed in 24 h and resulted in a 3:1 mixture
of the same compounds (71% yield in mixture). The major
adduct, rac-32, was isolated in 50% yield. These com-
pounds were assigned as the stereoisomers depicted in
(17) (a) Maishal, T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.;
Sarkar, A. Tetrahedron Lett. 2002, 43, 2263. (b) Gurjar, M. K.;
Yakambram, P. Tetrahedron Lett. 2001, 42, 3633. (c) Paquette, L. A.;
Efremov, I. J . Am. Chem. Soc. 2001, 123, 4492. (d) Davoille, R. J .;
Rutherford, D. T.; Christie, S. D. R. Tetrahedron Lett. 2000, 41, 1255.
(e) Krikstolaityte, S.; Hammer, K.; Undheim, K. Tetrahedron Lett.
1998, 39, 7595. In intermolecular enyne reactions coordination effects
of oxygen atoms have also been identified sometimes with an accelerat-
ing result. See: Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43,
2235. Other authors circumvented this problem with adequate choice
of the catalyst. Smulik, J . A.; Diver, S. T. Org. Lett. 2000, 2, 2271.
(18) Compound 30 was obtained from 2-iodoacetanilide by Stille
reaction with tributylvinyltin and subsequent propargylation of the
amide. See Supporting Information for details.
(19) (a) Schuster, T.; Kurz, M.; Go¨bel, M. W. J . Org. Chem. 2000,
65, 1697. (b) Garc´ıa Ruano, J . L.; Alemparte, C.; Mart´ın Castro, A.;
Adams, H.; Rodr´ıguez Ramos, J . J . Org. Chem. 2000, 65, 7938.
(20) This would imply a nonmetathetic behavior of the ruthenium
complex. See: Alcaide, B.; Almendros, P. Chem. Eur. J . 2003, 9, 1258.
(21) The only example of indole synthesis using olefin RCM:
Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem,
Int. Ed. 2002, 41, 4732.
(22) Dom´ınguez, G.; Casarrubios, L.; Rodriguez-Noriega, J .; Pe´rez-
Castells, J . Helv. Chim. Acta 2002, 85, 2856.
2088 J . Org. Chem., Vol. 69, No. 6, 2004

Tandem Enyne Metathesis-Diels-Alder
SCHEME 12
CHART 2
SCHEME 13
SCHEME 14
centers are positioned on the same face. We assume the
same relative stereochemistry for compounds rac-41 and
rac-42.
ucts when toluene at 80 °C was used.11a Compound 37
gave a complex crude mixture in which N-tosyl-2-vinylin-
dole was the major product. However, it was impossible
to purify it probably as a result of instability of this
product in the presence of traces of ruthenium species
(Scheme 12).
From the results we have shown here it is clear that
there is not a simple and predictable behavior of the three
catalysts used. The claimed greater efficiency of second-
generation complexes is true for substituted olefins and
nonhindered substrates, whereas complex 1 gives better
results with hindered ones. This differences may have
their origin in the reaction course, which may be slightly
or even completely different from one catalyst to another.
To have more information on these reactions, we pro-
ceeded to follow some of them by 1H NMR. The reactions
were carried out with 25% catalyst in a 0.025 M solution
of starting material.19 We selected as starting materials
compounds 20a , 43, and 44. Compound 43 was synthe-
sized to see the influence of substituted olefin fragments
in the reaction, and 44 was selected as a parent olefin
RCM substrate to check possible differences in the
reaction course (Scheme 14).23
On the other hand, compound 36 gave a clean conver-
sion into a mixture of the vinylindole 38 and its dimmer
39. As 38 is not a diene, a partial cross metathesis
reaction had occurred after cyclization. When using
catalyst 3 in the same conditions, yields improved for
both products although there was a similar ratio of both.
We were unable to find conditions that would allow the
synthesis of only one of these products. When using
catalyst 2, high dilution (100 mL/mmol), and short
reaction times (2 h) in toluene (80 °C) we reached 60%
yield of 38 and 25% yield of 39. With catalyst 3, longer
reaction time (18 h) and addition of a further 2% portion
of catalyst, we reached 70% yield of 39 and 20% yield of
38 (Scheme 13).
We registered a proton spectrum every 5 min during
the first hour and every 15 min until total completion or
4 h of reaction. We followed the transformation of the
starting material into the final product, the possible
appearance of signals corresponding to styrene, and the
changes in the signal of the carbene proton of the
catalyst. The results are summarized in Table 3. We
indicate the initial position of this carbene C-H signal
and its eventual changes at the end of the reactions. We
One possible way to obtain only one reaction product
would be performing a tandem RCM/Diels-Alder process
in which the cycloaddition would be more rapid than the
cross metathesis reaction. When carrying out the domino
process from 36, using maleic anhydride as dienophyle,
we observed in the crude a (1:1.5) mixture of rac-40 and
rac-41, which could not be separated. On the other hand,
with dimethyl acetylenedicarboxylate we were pleased
to obtain only compound rac-42 with 65% yield. This
latter compound is related with carbazole alkaloids.
Additionally, compounds 38 and 39 were separately
reacted with maleic anhydride. They gave the corre-
sponding adducts rac-40 and rac-41 in good yields (Chart
2).
1
also made H NMR spectra of complexes 1, 2, and 3 in
the different solvents used for these reactions. The
position of the carbene C-H signal in the spectra of the
catalyst alone is also indicated.
When used, the first generation catalyst 1 produces
styrene, and its carbenic signal disappears during the
reaction (entries 1 and 6), any other carbenic species not
being detectable at the end. During the enyne metathesis
(entry 1) two new carbenic species are detected, a triplet
(J ) 4.3 Hz) at 18.28 ppm and a singlet at 20.7 ppm. As
To assign the relative configuration of these com-
pounds, a single crystal of rac-40 was submitted to X-ray
diffraction analysis. This analysis shows a (3aS*,3bS*,-
10S*,10aS*) relative stereochemistry for this compound
in which all hydrogen atoms present in the stereogenic
(23) See Supporting Information for data on the synthesis of
compounds 43 and 44.
J . Org. Chem, Vol. 69, No. 6, 2004 2089

Rosillo et al.
TABLE 3. Meta th esis Rea ction s in NMR Tu bes
1H NMR signala
entry
substrate
catalyst
solvent
temp
product
time (h)
conversion (%)
catalyst
initial
final
1
2
3
4
5
6
7
8
9
20a
20a
20a
20a
43
44
44
44
44
1
2
2
3
2
1
2
2
2
CDCl3
CDCl3
C6D6
CDCl3
CD2Cl2
CDCl3
CDCl3
Xyl-d10
C6D6
rt
rt
rt
rt
rt
rt
rt
rt
rt
27a b
27a
27a
27a
45
3c
3d
5
65
>95
>95
83
>95
>95
>95
>95
>95
19.98
19.13
19.63
16.56
19.07
19.98
19.13
19.22
19.63
19.98
19.13
19.62
16.57
19.07
19.98
19.13
19.22
19.62
none
19.13
19.62; 18.41
16.57
19.07
none
19.13
19.22; 17.96
18.41
3c
3
46b
46
0.5
1
5
46
46
6
a
b
d
Position of the carbene C-H signal. Styrene was formed in the reaction. c The reaction was not totally completed. Some cross
metathesis (dimeric) product is detected.
F IGURE 1. Comparative evolution of the carbenic signal of catalysts 1, 2 and 3 in the reactions of compound 20a (entries 1, 2,
and 4, Table 3).
Hoye has reported recently,8 these signals may cor-
respond with the carbenic species consistent with path
a, Scheme 3, supporting that this reaction course is
operating with catalyst 1, although other paths may also
operate at the same time. With catalyst 2, the ruthenium
complex remains apparently unaltered during the whole
reaction when using CD2Cl2 or CDCl3 (entries 2, 5, and
7) and is partially transformed into a new complex when
using aromatic solvents (entries 3, 8, and 9). In all of
these reactions no styrene was detected. This would
discard path a and suggests path b is predominant.
Finally the carbenic signal of complex 3 diminishes
during the first hour (when final product is hardly
detected) and reappears after 2 h. A comparative figure
of the evolution of the low field signals of the reactions
of entries 1, 2, and 4 from Table 3 is shown in Figure
1.24
The three reaction pathways generally discussed for
enyne metathesis (paths a-c, Scheme 3) involve the
formation of styrene (path a) or products with a pending
phenyl that comes from the first catalytic cycle (paths b
and c). We have seen styrene when using complex 1 but
not with complexes 2 or 3. This may be due to the fact
that complex 2 may create active catalyst species to a
lesser extent (not detectable by NMR), but that these give
(24) See Supporting Information for complete spectra of these
reactions and of the rest of the Table 3 reactions.
2090 J . Org. Chem., Vol. 69, No. 6, 2004

Tandem Enyne Metathesis-Diels-Alder
SCHEME 15
more turnovers than the intermediate coming from 1.
This agrees with the values of the dissociation constants
found by Grubbs and would explain that styrene is not
detected.7 One other possible explanation for this un-
changing benzylidene signal would be that this catalyst
begins transferring the benzylidene onto the substrate
releasing a RudCH2 complex. This methylidene would
react with the alkyne to give a vinylcarbene that would
ring close with the alkene (a 3-phenylallylamide), regen-
erating the benzylidene complex 2 in each turnover
(Scheme 15).25
The apparent disappearance of the signal of catalyst
3 and its recovery after 1 h of reaction is something
consistent with the ability of this complex to regenerate
after the reactions. This has been shown in olefin
metathesis reactions, and it also occurs in these enyne
processes. As proposed by Hoveyda this complex reacts
with the olefin (in alkene metathesis), releasing the
corresponding styrene derivative. Upon consumption of
the reactives, this styrene reacts with the metal carbene
complex to regenerate the initial catalyst.5b According
with our observations similar behavior is assumable with
enyne reactions.
On the other hand, Mori has recently reported a new
cyclization process catalyzed by ruthenium species in
which a ruthenacyclopentene is proposed as intermedi-
ate.26 Our observations in the reactions with complexes
2 and 3 may indicate that a possible reaction course in
which this kind of metallocycles would be formed followed
by cyclobutene formation and cyclorreversion may not be
completely discarded.27 It is clear that more evidence
would be necessary, but this reaction course would also
explain the behavior of complex 2, which may be recov-
ered after every cycle by recomplexation of the phosphine.
Also in olefin RCM reactions (entries 6 and 7) the same
pattern is observed, catalyst 2 remaining unaltered in
the reaction, while 1 produces styrene and disappears
during the process.
that also would be capable of catalyzing the metathesis
reaction. No change in the spectrum was observed when
heating the catalyst alone in xylene for 2 h at 40 °C. The
reactions in aromatic solvents need more time to com-
plete. We are investigating the nature of these species
that may resemble the η6 complexes described in the
literature,28 some of them reported as efficient catalyst
for metathesis reactions.29
In conclusion, we have described the use of enynes
connected through aromatic rings as substrates for the
enyne metathesis reaction that affords quinoline, ben-
zoazepine, chromane, hydronaphthalene, indole ,and
other polycyclic derivatives. The reactivity of the most
popular ruthenium complexes is studied and affords no
exact rule for their preferable use, although second
generation complexes give better results with monosub-
stituted olefins and worse with hindered substrates.
Some polycyclic compounds are obtained in a tandem or
stepwise RCM-Diels-Alder process. We have shown here
some data on the enyne RCM reaction course. These data
support the first complexation of the alkene with the
ruthenium as has been proposed by other groups.3a,m,8
They also point to possible differences in the reaction
course when using the different catalysts.
Exp er im en ta l Section
Gen er a l P r oced u r es for Meta th esis Rea ction . Meth od
A. A 1 mmol portion of enyne was dissolved in 20 mL of dry
dichloromethane under argon. To this solution was added
0.05-0.07 mmol of Grubbs catalyst (1 or 2), and the reaction
was refluxed until completion (TLC). Filtration though Celite,
evaporation of the solvent, and purification by column cro-
matography yielded the corresponding diene.
Meth od B. A 1 mmol portion of enyne was dissolved in 20
mL of dry dichloromethane under argon. To this solution was
added 0.10 mmol of catalyst 2, divided into four equal portions,
which were added every 30 min, while the mixture was
refluxed. Before each addition, the reaction mixture was cooled
and filtered trough Celite. Evaporation of the solvent and
purification by column chromatography yielded the corre-
sponding diene.
Another interesting aspect of this experiments is the
changes observed when switching the solvent to an
aromatic one. When using xylene or benzene, new car-
benic species are formed. It would be possible that these
solvents interact with the metal, forming new complexes
Meth od C. A 1 mmol portion of enyne was dissolved in 50
mL of dry toluene under argon. To this solution was added
0.05 mmol of catalyst 3, and the reaction was heated at 80 °C
until completion (TLC). Evaporation of the solvent and puri-
fication by column chromatography yielded the corresponding
diene.
(25) We thank one of the referees of this work for useful proposals
on these mechanistic aspects.
(26) Mori, M.; Saito, N.; Tanaka, D.; Takimoto, M.; Sato, Y. J . Am.
Chem. Soc. 2003, 125, 5606.
(27) These ruthenium metalacycles have been proposed in cycliza-
tions catalysed by noncarbene ruthenium(II) species: (a) Trost, B. M.;
Toste, F. D. J . Am. Chem. Soc. 2000, 122, 714. (b) Chatani, N.; Kataoka,
K.; Murai, S. J . Am. Chem. Soc. 1998, 120, 9104.
(28) Hansen, H. D.; Nelson, J . H. Organometallics 2000, 19, 4740.
(29) Cetinkaya, B.; Demir, S.; Ozdemir, I.; Toupet, L.; Semeril, D.;
Bruneau, C.; Dixneuf, P. H. New J . Chem. 2001, 25, 519.
J . Org. Chem, Vol. 69, No. 6, 2004 2091

Rosillo et al.
1-ter t-Bu tyld im eth ylsilyloxy-3-vin yl-1H-in d en e (24a ).
Following method A, 150 mg (0.95 mmol) of 7a and 55 mg (0.07
mmol) of 1 gave a crude mixture that was dissolved in 5 mL
of DMF and treated with 162 mg (2.4 mmol) of imidazole and
286 mg (1.9 mmol) of tert-butyldimethylsilyl chloride. The
resulting mixture was stirred for 2 h. The reaction was
quenched with 20 mL of ice-H2O/Et2O (1:1). The organic layer
was washed with abundant H2O, dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexane) afforded 81
37.7, 22.1. IR (neat): ν 2240, 1660, 1600, 1590 cm-1. Anal.
Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C,
78.09; H, 6.25; N, 6.85.
(3a R*,3bS*,11a S*)-3a ,3b,4,5,11,11a -Hexa h yd r op h en a n -
th r o[1,2-c]fu r a n -1,3-d ion e (r a c-32). To a solution of 50 mg
(0.32 mmol) of 25 in 4 mL of DCM was added 32 mg (32 mmol)
of maleic anhydride, and the mixture was refluxed for 24 h.
The reaction was concentrated giving a 3:1 mixture of rac-32
and rac-33 (1H NMR). Crystallization of the mixture afforded
32 mg of rac-32 as a white solid (50%, mp 217-218 °C
(toluene)). 1H NMR: δ 2.09-2.32 (m, 2H), 2.34-2.42 (m, 1H),
2.61-2.77 (m, 2H) 2.85 (dt, 1H, J 1 ) 14.8 Hz, J 2 ) 3.8 Hz),
2.98 (ddd, 1H, J 1 ) 15.6 Hz, J 2 ) 7.1 Hz, J 3 ) 1.1 Hz), 3.47-
3.58 (m, 2H), 6.40-6.44 (m, 1H), 7.11-7.21 (m, 3H), 7.47-
7.50 (m, 1H). 13C NMR: δ 174.3, 171.4, 138.6, 137.5, 133.0,
128.3, 127.7, 126.7, 123.5, 119.9, 44.4, 41.6, 36.2, 29.7, 24.9,
24.2. IR (KBr): ν 1840, 1770 cm-1. Anal. Calcd for C16H14O3:
C, 75.57; H, 5.55. Found: C, 75.79; H, 5.69.
(3a R*,3bS*,11a S*)-7-Meth oxy-3a ,3b,4,5,11,11a -h exa h y-
d r op h en a n th r o[1,2-c]fu r a n -1,3-d ion e (r a c-35). To a solu-
tion of 100 mg (0.54 mmol) of 13 in 20 mL of dry dichlo-
romethane was added 32 mg (0.04 mmol) of catalyst 2, and
the mixture was refluxed for 6 h. After cooling to -78 °C, the
reaction was treated with 53 mg (0.54 mmol) of maleic
anhydride and 0.06 mL (0.54 mmol) of TiCl4, which was added
dropwise. The reaction was left to reach room temperature
during 12 h, and stirring was continued at room temperature
for 2 h. EtOAc/H2O was added to the crude, which was
extracted, dried, filtered, and concentrated. Purification by
column chromatography (hexane/EtOAc 4:1 and hexane/EtOAc
2:1) gave 138 mg (90%) of rac-35 as a white solid (mp 205-
206 °C (toluene)). 1H NMR: δ 2.10-2.21 (m, 1H), 2.27 (dd,
1H, J 1 ) 12.4 Hz, J 2 ) 3.6 Hz), 2.33-2.40 (m, 1H), 2.60-2.75
(m, 2H), 2.80 (dt, 1H, J 1 ) 15.4 Hz, J 2 ) 3.8 Hz), 2.95 (ddd,
1H, J 1 ) 15.9 Hz, J 2 ) 7.4 Hz, J 3 ) 1.4 Hz), 3.45-3.56 (m,
2H), 3.80 (s, 3H), 6.26-6.28 (m, 1H), 6.65 (d, 1H, J ) 2.8 Hz),
6.74 (dd, 1H, J 1 ) 8.8 Hz, J 2 ) 2.8 Hz), 7.42 (d, 1H, J ) 8.8
Hz).13C NMR: δ 174.4, 171.5, 159.2, 139.1, 138.2, 126.0, 125.0,
117.3, 112.9, 112.8, 55.3, 44.4, 41.6, 36.1, 30.0, 24.9, 24.3. IR
(neat): ν 1840, 1770, 1610 cm-1. Anal. Calcd for C17H16O4: C,
71.82; H, 5.67. Found: C, 71.47; H, 5.64.
1
mg (50%) of 24a as a yellow solid (mp 97-98 °C (EtAcO)). H
NMR: δ 0.09 (s, 3H), 0.18 (s, 3H), 0.96 (s, 9H), 5.28 (s, 1H),
5.40 (d, 1H, J ) 11.5 Hz), 5.86 (d, 1H, J ) 17.6 Hz), 6.33 (s,
1H), 6.68 (dd, 1H, J 1 ) 17.6 Hz, J 2 ) 11.5 Hz), 7.18-7.32 (m,
3H), 7.45 (t, 1H, J ) 7.1 Hz). 13C NMR: δ 174.0, 141.3, 141.1,
134.3, 130.0, 127.9, 126.1, 123.5, 120.2, 117.6, 76.6, 25.9, 18.3,
-4.2. IR (neat): ν 1630, 1610 cm-1. Anal. Calcd for C17H24
OSi: C, 74.94; H, 8.88. Found: C, 74.69; H, 8.71.
-
1-ter t-Bu t yld im et h ylsilyloxy-5-vin yl-2,3-d ih yd r o-1H -
ben zocycloh ep ten e (24c). Following method A, from 100 mg
(0.33 mmol) of 8c and 34 mg (0.02 mmol) of catalyst 2, 93 mg
1
(93%) of 24c was obtained as a yellow oil. H NMR: δ 0.00 (s,
3H), 0.03 (s, 3H), 0.92 (s, 9H), 1.68-1.79 (m, 1H), 1.83-1.99
(m, 2H), 2.33-2.46 (m, 1H), 4.69 (dd, 1H, J 1 ) 9.9 Hz, J 2
)
7.7 Hz), 5.08 (d, 1H, J ) 11.0 Hz), 5.13 (d, 1H, J ) 18.1 Hz),
6.19 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 7.2 Hz), 6.52(dd, 1H, J 1 ) 17.3
Hz, J 2 ) 10.7 Hz) 7.23-7.35 (m, 3H), 7.71 (d, 1H, J ) 7.2 Hz).
13C NMR: δ 143.5, 140.4, 137.7, 133.8, 130.8, 127.8, 127.0,
125.8, 124.1, 114.6, 70.9, 43.5, 25.9, 23.2, 18.3, -4.9, -5.0. IR
(neat): ν 1630, 1590 cm-1. Anal. Calcd for C19H28OSi: C, 75.94;
H, 9.39. Found: C, 76.26; H, 9.34.
7-Meth oxy-4-vin yl-1,2-d ih yd r on a p h th a len e (26). Fol-
lowing method A, from 200 mg (1.07 mmol) of 13 and 63 mg
(0.07 mmol) of catalyst 2, 174 mg (77%) of 26 was obtained as
a colorless oil. 1H NMR: δ 2.27-2.34 (m, 2H), 2.74 (t, 2H, J )
7.7 Hz), 3.82 (s, 3H), 5.19 (dd, 1H, J ) 11.0 Hz, J ) 1.6 Hz),
5.53 (dd, 1H, J 1 ) 17.0 Hz, J 2 ) 1.6 Hz), 6.08 (t, 1H, J ) 5.0
Hz), 6.61 (dd, 1H, J 1 )18.1 Hz, J 2 ) 11.0 Hz), 6.72-6.75 (m,
2H), 7.29 (d,1H, J ) 8.8 Hz). 13C NMR: δ 158.5, 138.4, 136.1,
135.7, 127.1, 125.0, 124.1, 114.9, 113.8, 110.8, 55.2, 28.7, 23.1.
IR (neat): ν 3090, 2940, 1610, 1570 cm-1. Anal. Calcd for
C
13H14O: C, 83.83; H, 7.58. Found: C, 83.91; H, 7.63.
P r ep a r a tion of 38 a n d 39. A 100 mg (0.50 mmol) portion
of 36 was dissolved in 10 mL of dry toluene under argon. To
this solution was added 16 mg (0.025 mmol) of 3, and the
reaction was heated to 80 °C. After 4 h, 6 mg (0.01 mmol) of
catalyst 3 was added to the reaction, and it was heated to 80
°C for 14 h. Evaporation of the solvent and purification by
column chromatography (hexane/EtOAc 9:1 and hexane/EtOAc
4:1) afforded 20 mg (20%) of 38 and 60 mg (70%) of 39 both as
pale yellow oils.
1-Acetyl-4-vin yl-1,2d ih yd r oqu in olin e (27a ). Following
method A, from 150 mg (0.75 mmol) of 20a and 43 mg (0.05
mmol) of catalyst 1, 143 mg (95%) of 27a was obtained as pale
1
yellow oil. H NMR (DMSO-d6, 80 °C): δ 1.52 (s, 3H), 3.72 (d,
2H, J ) 4.3 Hz), 4.69 (d, 1H, J ) 11.0 Hz), 5.47 (d, 1H, J )
17.7 Hz), 5.67 (t, 1H, J ) 4.3 Hz), 6.05 (dd, 1H, J 1 ) 17.7 Hz,
J 2 ) 11.0 Hz), 6.58-6.71 (m, 3H), 6.82 (d, 1H, J ) 7.3 Hz).13
C
NMR (DMSO-d6, 80 °C): δ 168.2, 136.9, 134.0, 132.8, 128.1,
126.9, 124.7, 124.1, 124.0, 123.6, 116.3, 41.3, 21.6. IR (neat):
ν 1660, 1600, 1490 cm-1. Anal. Calcd for C13H13NO: C, 78.36;
H, 6.58; N, 7.03. Found: C, 78.01; H, 6.43; N, 6.90.
1
(E)-1-Acetyl-3-p r op -1-en ylin d ole (38). H NMR: δ 1.96
(dd, 3H, J 1 ) 6.6 Hz, J 2 ) 1.1 Hz), 2.63 (s, 3H), 6.30-6.41 (m,
1H), 6.50 (d, 1H, J ) 15.9 Hz), 7.29-7.41 (m, 3H), 7.76 (d,
1H, J ) 7.7 Hz), 8.47 (d, 1H, J ) 7.7 Hz). 13C NMR: δ 168.4,
127.3, 125.3, 123.7, 123.6, 121.6, 121.6, 120.9, 119.8, 119.0,
5-Vin yl-2,3-d ih yd r oben zo[b]oxep in e (29b). Following
method B, from 100 mg (0.58 mmol) of 21b, 60 mg (60%) of
1
29b was obtained as a colorless oil. H NMR: δ 2.36 (q, 2H, J
116.7, 24.0, 19.0. IR (neat): ν 3020, 1705, 1600, 1550 cm-1
.
) 6.6 Hz), 4.43 (t, 2H, J ) 6.0 Hz), 5.16 (dd, 1H, J 1 ) 11.5 Hz,
J 2 ) 1.1 Hz), 5.33 (dd, 1H, J 1 ) 17.6 Hz, J 2 ) 1.1 Hz), 6.26 (t,
1H, J ) 6.6 Hz), 6.56 (dd, 1H, J 1 ) 17.6 Hz, J 2 ) 11.0 Hz),
7.10-7.16 (m, 2H), 7.23-7.26 (m, 1H), 7.38 (dd, 1H, J 1 ) 7.7
Hz, J 2 ) 1.6 Hz).13C NMR: δ 156.8, 139.5, 138.1, 131.1, 129.7,
128.6, 128.5, 123.3, 122.2, 115.3, 77.8, 28.6. IR (neat): ν 1630,
1600 cm-1. Anal. Calcd for C12H12O: C, 83.69; H, 7.02.
Found: C, 83.51; H, 6.99.
Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found:
C, 78.58; H, 6.32; N, 7.18.
(E)-1-Acetyl-3-[2-(1-a cetylin d ol-3-yl)vin yl]-in d ole (39).
1H NMR: δ 2.70 (s, 6H), 7.34 (s, 2H), 7.38-7.47 (m, 4H), 7.60
(s, 2H), 7.68 (dd, 2H, J 1 ) 6.3 Hz, J 2 ) 1.4 Hz), 8.52 (d, 2H, J
) 7.7 Hz). 13C NMR: δ 168.3, 136.4, 128.6, 125.7, 124.0, 122.7,
120.8, 120.6, 119.8, 116.8, 24.0. IR (neat): ν 1710, 1560, 1450,
1380 cm-1. Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N,
8.18. Found: C, 77.01; H, 5.16; N, 8.03.
(3a S*,3bS*,10S*,10a S*)-4-Acetyl-10-m eth yl-3b,4,10,10a -
tetr a h yd r o-3a H-fu r o[3,4-a ]ca r ba zole-1,3-d ion e (r a c-40).
To a solution of 144 mg (0.72 mmol) of 38 in 40 mL of
anhydrous toluene was added 62 mg (0.72 mmol) of maleic
anhydride, and the mixture was refluxed for 20 h. The crude
was concentrated and purified by flash chromatography (hex-
ane/EtOAc 1:1), and 132 mg (62%) of rac-40 was obtained as
1-Acetyl-3-vin yl-1,2-d ih yd r oqu in olin e (31). Following
method C, from 100 mg (0.50 mmol) of 30, 65 mg (65%) of 31
was obtained as a pale yellow oil. 1H NMR: δ 1.80 (s, 3H),
4.15 (dd, 1H, J 1 ) 17.0 Hz, J 2 ) 2.5 Hz), 4.75 (dd, 1H, J 1
)
17.0 Hz, J 2 ) 2.7 Hz), 5.39 (dd, 1H, J 1 ) 11.0 Hz, J 2 ) 1.1
Hz), 5.80 (dd, 1H, J 1 ) 17.6 Hz, J 2 ) 1.1 Hz), 6.79 (dd, 1H, J 1
) 17.6 Hz, J 2 ) 11.0 Hz), 7.26-7.29 (m, 2H), 7.33-7.43 (m,
2H), 7.67 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 1.6 Hz). 13C NMR: δ 170.4,
139.3, 135.6, 131.4, 129.0, 128.9, 128.8, 126.3, 117.3, 78.5, 72.2,
2092 J . Org. Chem., Vol. 69, No. 6, 2004

Tandem Enyne Metathesis-Diels-Alder
1
a white solid (mp 272-273 °C (EtOAc)). H NMR: δ 1.63 (d,
stirred at room temperature for 3 h. Then 0.12 mL (1.0 mmol)
of dimethyl acetylenedicarboxylate was added, and the reaction
was refluxed for 12 h. The mixture was concentrated and
purified by flash chromatography (hexane/EtOAc 2:1), and 212
mg (65%) of rac-42 was obtained as a white solid (mp 154-
3H, J ) 7.1 Hz), 2.54-2.61 (m, 1H), 2.61 (s, 3H), 3.33-3.39
(m, 1H), 4.63-4.69 (m, 1H), 4.89-4.91 (m, 1H), 6.06 (t, 1H, J
) 3.8 Hz), 7.06-7.12 (m, 1H), 7.32-7.33 (m, 2H), 7.47 (d, 1H,
J ) 7.8 Hz). 13C NMR: δ 170.6, 169.0, 168.7, 144.0, 136.5,
130.3, 126.6, 123.6, 121.7, 119.0, 114.3, 59.1, 43.6, 42.1, 32.1,
1
155 °C (EtOAc)). H NMR: δ 1.38 (d, 3H, J ) 7.1 Hz), 2.48 (s,
25.5, 16.6. IR (KBr): ν 1850, 1770, 1640, 1480, 1470 cm-1
.
3H), 3.15-3.27 (m, 1H), 3.74 (s, 3H), 3.78 (s 3H), 5.13-5.17
(m, 1H), 6.03 (m, 1H), 7.10, (t, 1H, J ) 7.7 Hz), 7.27-7.33 (m,
2H), 7.50 (d, 1H, J ) 7.7 Hz). 13C NMR: δ 170.2, 168.1, 129.5,
128.1, 123.8, 123.6, 123.3, 121.3, 120.6, 120.3, 115.0, 114.8,
60.4, 52.4, 52.2, 33.7, 25.0, 17.3. IR (KBr): ν 1730, 1670, 1600
cm-1. Anal. Calcd for C19H19NO5: C, 66.85; H, 5.61; N, 4.10.
Found: C, 66.60; H, 5.57; N, 4.03.
Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found:
C, 68.72; H, 5.13; N, 4.76.
(3a S*,3bS*,10S*,10aS*)-4-Acetyl-10-(1-a cetylin d ol-3-yl)-
3b,4,10,10a -t et r a h yd r o-3a H-fu r o[3,4-a ]ca r b a zole-1,3-d i-
on e (r a c-41). To a solution of 147 mg (0.43 mmol) of 39 in 20
mL of anhydrous toluene was added 37 mg (0.43 mmol) of
maleic anhydride, and the mixture was refluxed for 20 h. The
crude was concentrated and purified by flash chromatography
(hexane/EtOAc 1:1), and 103 mg (55%) of 41 was obtained as
Ack n ow led gm en t. The authors are grateful to the
DGES (MEC-Spain, grant BQU2002-00137), the Uni-
versidad San Pablo-CEU (grant 07/03), and the Comu-
nidad Auto´noma de Madrid (Project CAM Expt. 25/
2001-CET2001) for financial support. M.R. acknowledges
the Spanish MEC (MCYT) for a predoctoral fellowship.
1
a white solid (mp 261-262 °C (EtOAc)). H NMR: δ 2.66 (s,
3H), 2.72 (s, 3H), 3.82-3.87 (m, 1H), 3.95-3.99 (m, 1H), 4.79-
4.85 (m, 1H), 5.15-5.17 (m, 1H), 6.55 (t, 1H, J ) 3.8 Hz), 7.12-
7.18 (m, 1H), 7.34-7.47 (m, 3H), 7.39 (s, 1H), 7.53-7.60 (m,
3H), 8.52 (d, 1H, J ) 7.7 Hz). 13C NMR: δ 169.4, 169.1, 168.5,
168.1, 144.2, 138.0, 135.9, 130.9, 126.3, 125.8, 124.0, 123.8,
123.8, 122.1, 118.6, 117.8, 117.1, 117.1, 115.1, 114.5, 59.4, 43.0,
41.7, 34.2, 25.6, 24.2. IR (KBr): ν 1850, 1780, 1710, 1650, 1450,
1390 cm-1. Anal. Calcd for C26H20N2O5: C, 70.90; H, 4.58; N,
6.36. Found: C, 70.55; H, 4.64; N, 6.31.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion of compounds 6a ,b,c, 7a ,b,c, 8a ,b,c, 9, 10-13, 17b, 18,
19, 20b, 21b, 22, 23b, 24b, 25, 27b, 29a , 30, rac-34, and 43-
46; ORTEP drawing for rac-40; spectra of reactions described
in Table 3; and cif file with details on the X-ray analysis of
compound rac-40. This material is available free of charge via
the Internet at http://pubs.acs.org.
(3S*,9a R*)-Dim eth yl 9-Acetyl-3-m eth yl-9,9a -d ih yd r o-
3H-ca r ba zole-1,2-d ica r boxyla te (r a c-42). To a solution of
200 mg (1.0 mmol) of 36 in 85 mL of anhydrous toluene was
added 60 mg (0.07 mmol) of catalyst 2, and the reaction was
J O0356311
J . Org. Chem, Vol. 69, No. 6, 2004 2093