A new pd-catalyzed cascade reaction for the synthesis of strained aromatic polycycles

Article abstract of DOI:10.1021/ol702855h

Two new palladium catalyzed cascade reactions involving a 4-exo-dig cyclocarbopalladation are described. These processes are shown to convert bromoenediynes and bromodienynes into strained aromatic compounds in a single step.

Full text of DOI:10.1021/ol702855h

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1075-1078
A New Pd-Catalyzed Cascade Reaction
for the Synthesis of Strained Aromatic
Polycycles
Gae1lle Blond, Christophe Bour, Bahaaˆ Salem, and Jean Suffert*
UniVersite´ Louis Pasteur de Strasbourg (LC01 UMR 7175 CNRS/ULP), Faculte´ de
Pharmacie, 74, route du Rhin 67401 Illkirch-Cedex, France
jean.suffert@pharma.u-strasbg.fr
Received November 26, 2007
ABSTRACT
Two new palladium catalyzed cascade reactions involving a 4-exo-dig cyclocarbopalladation are described. These processes are shown to
convert bromoenediynes and bromodienynes into strained aromatic compounds in a single step.
The generation of complex molecules from simple starting
materials in a minimum number of steps is one of the most
challenging goals in organic synthesis.1 Toward this end,
cascade reactions using transition-metal-catalyzed processes
have become powerful tools for the construction of func-
tionalized polycyclic molecules.2 In particular, the develop-
ment of new methods to generate cyclooctanoid ring systems
remains an attractive objective.3 Along those lines, we have
disclosed an efficient process that leads to the formation of
unusual polycyclic compounds through an initial 4-exo-dig
cyclocarbopalladation of bromopropargylic diols.4 Specifi-
cally, we have shown that a 4-exo-dig cyclocarbopalladation,
followed by a Stille cross-coupling, and finally a concerted
conrotatory 8π electrocyclization allows the preparation of
highly functionalized tetracyclic compounds containing an
eight-membered ring.5
In an effort to extend this method, we examined an
intramolecular version of this reaction sequence. As il-
lustrated in Scheme 1, three different cascades were envis-
aged. Depending on the substrate, an initial 4-exo-dig,
followed by a 5-exo-dig, cyclocarbopalladation should lead
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley: Weinheim, 2006. (b) Wender, P. A.; Miller, B.
L. Org. Synth. Theory Appl. 1993, 2, 27. (c) Malacria, M. Chem. ReV. 1996,
96, 289. (d) Ang, K. H.; Bra¨se, S. A.; Steinig, G.; Meyer, F. E.; Llebaria,
A.; Voigt, K.; de Meijere, A. Tetrahedron 1996, 52, 11503. (e) Henniges,
H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A.
Tetrahedron 1996, 52, 11545.
(3) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b)
Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881.
(2) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. (b) Nicolaou, K. C.; Edmonds, D. J.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442. (c) Poli, G.; Giambastiani, G.;
Heumann, A. Tetrahedron 2000, 56, 5959. (d) de Meijere, A.; Bra¨se, S. J.
Organomet. Chem. 1999, 576, 88. (e) Heumann, A.; Re´glier, M. Tetrahedron
1996, 52, 9289.
(4) (a) Suffert, J.; Salem, B.; Klotz, P. J. Am. Chem. Soc. 2001, 123,
12107. (b) Salem, B.; Klotz, P.; Suffert, J. Org. Lett. 2003, 5, 845. (c)
Salem, B.; Klotz, P.; Suffert, J. Synthesis 2004, 2, 298. (d) Bour, C.; Suffert,
J. Eur. J. Org. Chem. 2006, 1390.
(5) (a) Salem, B.; Suffert, J. Angew. Chem., Int. Ed. 2004, 43, 2826. (b)
Bour, C.; Blond, G.; Salem, B.; Suffert, J. Tetrahedron 2006, 62, 10567.
10.1021/ol702855h CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

Scheme 1. Strategies for the Synthesis of Cyclooctanoidsa
Scheme 2. First Experiments
a (1) Stille cross coupling, (2) 5-exo-dig, (3) 5-exo-trig, (4) 8π
electrocyclization.
to the palladated trienes of type A, B, or C. Then, a Stille
cross-coupling (path 1), 5-exo-dig cyclocarbo-palladation
(path 2), or 5-exo-trig cyclocarbopalladation (path 3) should
occur, which in all cases would be terminated by an 8π
electrocyclization (path 4) to give the expected cyclooctanoid
compounds.
ficiently. We expect the vinylstannane is serving as either a
base or reducing agent in this transformation (vide infra).
These results were not expected but are understandable.
Of the several mechanistic possibilities, two are suggested
in Scheme 3. Indeed, instead of realizing the Stille cross
As shown in Scheme 2, when substrates 1-8 were treated
with vinyltributylstannane in the presence of Pd(PPh3)4 (10
mol %) in benzene at 90 °C, the expected eight-membered
ring-containing products were not observed. Instead, several
unique polycyclic aromatic ring-containing systems (10-
11, 13-14, and 16) were isolated as the main products of
this transformation. The structures of these new compounds
Scheme 3. Possible Mechanisms
1
were determined through a combination of 1D and 2D H
and 13C NMR experiments. The fused four-membered ring
embedded in each of these products suggested that initial
4-exo-dig cyclocarbopalladation had proceeded as expected;
however, the subsequent transformations may have deviated
from the pathway outlined in Scheme 1.
During optimization studies, it was noted that several
structural features were required to obtain higher yields. First,
a terminal trimethylsilyl group on the alkyne is required to
obtain the aromatic product; indeed, only decomposition of
the starting material was observed if a terminal alkyne
compound was used. Second, the five-membered ring-
protected diol 1 did not give any product even after 40 h of
reaction (n ) 0, starting material). Moreover, the reaction
appeared to be dependent on the amount of vinyltributyl-
stannane used. Without it, or when used in small quantities,
the yield of the reaction decreased significantly (11, 12%,
16%). In comparison, when used in excess (5 equiv), the
reaction provide product 11 in 86% yield. Although not
incorporated into the final product, the vinyltributylstannane
appears necessary for the catalytic cycle to proceed ef-
a 6π electrocyclization. bSyn dehydropalladation elimination.
d
cHeck addition. Anti dehydropalladation elimination.
coupling (path 1, Scheme 1), or the second 5-exo-dig (path
2) or 5-exo-trig (path 3), a concerted disrotatory 6π elec-
trocyclization on the palladated triene 17 occurred. The
hydrogen and the palladium are in a cis configuration in 18,
allowing a syn dehydropalladation elimination and giving
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Org. Lett., Vol. 10, No. 6, 2008

the final strained aromatic derivatives 20 (path a and b,
Scheme 3). A second mechanism is also possible; the reaction
could occur via a Heck-type addition after the initial 4-exo-
dig and 5-exo-dig cyclocarbopalladation. In this case, a rare
but known anti dehydropalladation elimination on 19 could
be operative (paths c and d, Scheme 3).6
2 with Pd(PPh3)4 (10 mol %) for 20 min at 130 °C in a
mixture of benzene and diisopropylamine gave a significant
improvement in the final yield. Different reaction concentra-
tions were used (0.02 or 0.1 M), and the results were similar,
although less desilylation byproducts were observed at the
high concentrations.
As summarized in Figure 1, a variety of substrates were
In the past, regioselective construction of polysubstituted
aromatics has been achieved mainly through stepwise
introduction of substituents via electrophilic substitutions or
cross-coupling reactions. These are useful methods, but
particularly in the case electrophilic substitutions, high
regioselectivity can only be achieved by careful choice of
reagents and synthetic route. Alternatively, transition-metal-
catalyzed approaches employing single operation tricycliza-
tions of bromoenediynes have been used to prepare carbocy-
clic, as well as heterocyclic, angularly bis-annelated benzene
derivatives,1d,7 but none begin with a 4-exo-dig cyclocarbo-
palladation, a transformation that eventually leads to func-
tionalized and highly strained products.
In our initial experiments, we showed that the vinyltribu-
tylstannane was necessary but not incorporated into the
product. As it may act as a base that regenerates the active
palladium species, we decided to replace the stannane with
organic bases. Several organic amines were tested (Table
1). The most efficient additive was diisopropylamine, which
Figure 1. Synthesized compounds.
treated under the optimized conditions to provide the
aromatic compounds in 50-92% yields. After the 4-exo-
dig cyclocarbopalladation, a 6-exo-dig cyclocarbopalladation
followed by aromatization was shown to lead to products
22, 26, and 27, or alternatively, a 7-exo-dig cyclocarbopal-
ladation followed by aromatization provided the seven-
membered ring-containing product 23.
Table 1. Reaction Optimizations
As indicated in Scheme 4, when the unprotected anti and
Scheme 4. Cyclobutanediol Ring Opening
a Thermic conditions: Pd(PPh3)4 90 °C, 3 h gave only 56% yield.
syn diols 29 were used, the reaction resulted in the ring
opening of the strained cyclobutanediol to give compound
28, in 46 and 58% yield, respectively, from the corresponding
anti and syn diastereomers.
The starting enediynes 1-8 and 35-40 are prepared easily
in relatively good yields from the protected diols 30 and 314a,8
in a sequence of 2-5 steps (Scheme 5). After removal of
the trimethylsilyl group with K2CO3/MeOH, the free alkyne
was metalated with n-butyllithium in THF at -78 °C
followed by addition of different aldehydes (paraformalde-
hyde, 41 and 42).
gave product 10 in 89% yield, as well as a small amount of
the desilylated compound 21.
We reported previously that the yield of the 4-exo-dig
cyclocarbopalladation was improved by the use of microwave
irradiation while also shortening the reaction time.4d A much
cleaner reaction was observed for these substrates as well
under these conditions. Microwave irradiation of compound
(6) Lautens, M.; Fang, Y. Q. Org. Lett. 2003, 5, 3679.
(7) (a) de Meijere, A.; von Zezschwitz, P.; Bra¨se, S. Acc. Chem. Res.
2005, 38, 413. (b) Schweizer, S.; Schelper, M.; Thies, C.; Parsons, P. J.;
Noltemeyer, M.; de Meijere, A. Synlett 2001, 920. (c) Meyer, F. E.; de
Meijere, A. Synlett 1991, 777. (d) de Meijere, A.; Bra¨se, S. J. Organomet.
Chem. 1999, 576, 88. (e) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100,
2901. (f) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421.
(8) (a) Salem, B.; Klotz, P.; Suffert, J. Synthesis 2003, 1, 1. (b) Bour,
C.; Suffert, J. Org. Lett. 2005, 5, 653.
Org. Lett., Vol. 10, No. 6, 2008
1077

dienynes 51 and 52. Indeed, a sequence of a 4-exo-dig
cyclocarbopalladation, 6π electrocyclisation, or a Heck-type
addition and dehydropalladation elimination should give the
corresponding aromatic compounds (Scheme 7). Bromodi-
Scheme 5. Substrate Synthesis
Scheme 7. Related Strategy
enynes were prepared in 4 steps from commercially available
cyclohexane-1,3-dione 48.
The starting enediynes 35-37 are obtained from com-
pounds 30 and 31 by desilylation and reaction with aldehyde
41 and 42. Propargylic alcohols 32 and 33 were isolated in
87 and 73% yield, respectively. Intermediate 32 was
transformed into the propargylic bromine in the presence of
CBr4/PPh3 in 82% yield. The desired enediynes 1-8 and
38-40 were obtained from compounds 32-34 through a
Williamson etherification.
After bromination, formation of the enol ether with NaH
in THF, and reaction with triflic anhydride,9 the resulting
triflate was subjected to a Stille cross coupling with the
vinyltributylstannane to afford compounds 49.10 Anti and syn
diol 51 were prepared by addition of a suitable protected
metalated propargylic alcohol on bromocycloalkenones fol-
lowed by deprotection and chromatographic separation of
the two anti and syn diastereomers.4 The cascade was realized
with the same conditions described earlier, and aromatic
compound 54 was obtained. In these cases, the formation of
the aromatic derivatives were followed by the opening of
the cyclobutanediol moiety, and ketone 54 was isolated in
64 and 70% yields. When 51 was protected as a dioxolane,
the cyclocarbopalladation of 52 produced compound 53 in
66% yield.
As illustrated in Scheme 6, identical conditions were
Scheme 6. Acyclic Compound Reactions
In conclusion, we have described a reaction cascade that
produces highly functionalized, strained polycyclic aromatic
compounds through a 4-exo-dig cyclocarbopalladation. The
reaction proved to be general, avoiding the use of trialkyl-
stannylated reagents, and will be applied on more sophisti-
cated systems, which will be published in the near future.
Acknowledgment. We thank the CNRS for financial
support and MNERT (C.B. and B.S.) for fellowships and
Prof. Marc Snapper (Boston College) for helpful discussions.
applied successfully to the corresponding acyclic cis-vinyl
bromide 45 to give the aromatic tricyclic compounds 47 in
65% yield. When the reaction was carried out on the trans
derivative 46, no trace of cyclized product 47 was observed;
the starting material was mostly recovered. Compounds 45
and 46 were prepared from 434d and 444d with the same
reaction steps as described in Scheme 5 for 1-8.
Supporting Information Available: Experimental pro-
cedures, physical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL702855H
(9) Shepherd, R. G.; White, A. C. J. Chem. Soc., Perkin Trans. 1 1987,
2153.
To generate other types of aromatic compounds by a
complementary strategy, we considered the use of bromo-
(10) von Zezschwitz, P.; Petry, F.; de Meijere, A. Chem.-Eur. J. 2001,
7, 4035.
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Org. Lett., Vol. 10, No. 6, 2008