Cyclocarbopalladation: 5-exo-dig cyclization versus direct stille cross-coupling reaction. The influence of the α,β-propargylic substitution

Article abstract of DOI:10.1021/ol034647a

(Matrix presented) Several bicyclic compounds bearing a 1,2-cyclopentanediol have been prepared from various anti- or syn-γ-bromopropargylic diols and cis-dioxolanes under palladium(0) catalysis. The reaction proceeds through a 5-exo-dig cyclocarbopallada

Full text of DOI:10.1021/ol034647a

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2307-2310
Cyclocarbopalladation: 5-Exo-dig
Cyclization versus Direct Stille
Cross-Coupling Reaction. The Influence
of the r,â-Propargylic Substitution
Bahaaˆ Salem, Estelle Delort, Philippe Klotz, and Jean Suffert*
Faculte´ de Pharmacie, UniVersite´ Louis Pasteur de Strasbourg (UMR 7081
CNRS/ULP), 74, route du Rhin, 67401 Illkirch-Cedex, France
jeansu@aspirine.u-strasbg.fr
Received April 16, 2003
ABSTRACT
Several bicyclic compounds bearing a 1,2-cyclopentanediol have been prepared from various anti- or syn-γ-bromopropargylic diols and cis-
dioxolanes under palladium(0) catalysis. The reaction proceeds through a 5-exo-dig cyclocarbopalladation. When the corresponding trans-
dioxolanes are used, the only products isolated are obtained from a direct Stille cross-coupling reaction.
The cyclocarbopalladation process was described for the first
time in 1988 by Grigg1 shortly followed by Negishi.2 This
reaction afforded stereodefined exocyclic alkenes. 5-, 6-, or
7-exo-dig cyclocarbopalladations have been performed with
success. The process can be ended by a terminating cross-
coupling reaction either with a hydride source, an alkene,
CO, or various organometallic reagents (aluminum, zirco-
nium, boron, zinc, or tin derivatives). The cyclizations give
acceptable yields when the substrate bearing the triple bond
is an aromatic, but in most of the cases, the propargylic or
homopropargylic positions are unsubstituted. The corre-
sponding reaction has not been extensively investigated with
acyclic3 or cycloalkyl4 substrates. Our initial studies recently
focused on a rare 4-exo-dig cyclocarbopalladation of anti-
and syn-propargylic-1,2-diols through Pd(0) catalysis.5 De-
pending on the starting substrate, the only isolated product
resulted from the cyclocarbopalladation coupling and not
from a direct Stille cross-coupling reaction. We report herein
an efficient 5-exo-dig cyclocarbopalladation of several pro-
pargylic diols leading to [3.0.3], [4.0.3], [5.0.3], and [6.0.3]
substituted bicyclic diols (Figure 1). These carbon substruc-
Figure 1.
(1) (a) Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Tetrahedron
Lett. 1988, 29, 4325. (b) Burns, B.; Grigg, R.; Ratananukul, P.; Sridharan,
V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron Lett. 1988,
29, 5565.
tures are present in many natural products and can be used
as starting materials for the design of more sophisticated
complex polycyclic compounds.
(2) Zhang, Y.; Negishi, E. J. Am. Chem. Soc. 1989, 111, 3454.
(3) Negishi, E.; Noda, Y.; Lamaty, F.; Vawter, E. Tetrahedron Lett. 1990,
31, 4393.
(4) Burns, B.; Grigg, R.; Sridharan, V.; Stevenson, P. Tetrahedron Lett.
1989, 30, 1135.
(5) Salem, B.; Klotz, P.; Suffert, J. Org. Lett. 2003, 5, 845.
10.1021/ol034647a CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003

First, the starting materials, diols anti 2a-d and syn
3a-d, were prepared in good yields by addition of a properly
protected metalated propargylic alcohol on bromoaldehydes
1a-d (Scheme 1) followed by deprotection and chromato-
prevented the cyclocarbopalladation process on 8. After the
initial oxidative insertion of palladium(0) in the carbon-
bromine bond, the protection of diol as a cis-fused bicyclo-
[3.0.3]dioxolane 7 brought the alkyne function and the
palladated site closer together thereby favoring the cyclization
process. The high yield observed for the formation of 6 (80%,
R1 ) R2 ) H) could be explained by the presence in the
anti diol 5 of a strong hydrogen bond which, closely related
to 7, settles the triple bond in close proximity to the metallic
reactive center resulting in a clean carbopalladation of the
alkyne moiety. This intramolecular pallado-assisted carbocy-
clization is kinetically favored and surely much faster than
an intermolecular addition of the vinylstannane moiety.
Scheme 1
Surprisingly, the unprotected syn diol 4 only gave de-
composition of the reaction mixture when subjected to
the same conditions. The results of the reaction of several
propargylic diols are summarized in Table 1. The reaction
time varied from 14 to 27 h, depending on the starting
substrate, and was stopped when no evolution of the reaction
was observed by TLC. Without any aqueous workup, the
crude reaction mixture was evaporated in vacuum and di-
rectly chromatographed on silica gel pretreated by a solu-
tion of 5% Et3N in diethyl ether to avoid the protodestan-
nation of the product. In some cases (entry 1, 2, and 5) this
reaction also produced a small amount of the other isomer
at the tetrasubstituted exocyclic double bond. The ratio of
the two isomers seems to be dependent on the reaction time.
The origin of this isomerization is not clear but could be
explained by a Pd-assisted isomerization. The stereochem-
istry of the exocyclic diene chain was clearly established by
NOESY experiments on compounds 14a, 14b (entry 1, Table
1), and 26 (entry 1, Table 2). For example, strong correlations
were obtained between protons H2 and the trimethylsilane
group as well as between protons H4 and H8 in compound
26 (Figure 2).
graphic separation of the two anti and syn diastereomers.6
The anti relative stereochemistry of the diol was established
by 1H-NOESY experiments on 24, a derivative of 2b.7 The
initial studies were performed on 7 and 8, and two aromatic
analogues of 2b and 3b were prepared following an identical
route (Scheme 2) as described in a previous paper.6
Scheme 2
Better yields and cleaner reactions were usually obtained
with the anti diols when compared with the syn diols (entry
1 versus 5, 2 versus 6, 3 versus 7). The eight-membered-
ring starting diol 2d (entry 4, Table 1) gave only a 27% yield
in the anti group and a complete decomposition of 3d in the
syn group. This low yield could be due to unfavorable
entropic factors, which disfavored the formation of a bicyclo-
[6.0.3] system.
When the OH group was not present at the benzylic
position in 12, the cyclization still proceeded to give 21 in
61% yield (entry 9). Besides, a 6-exo-dig process afforded
The reaction proceeds at 90 °C in benzene in the presence
of a catalytic amount of Pd(PPh3)4 (10 mol %) and the bis-
(tributylstannyl)ethylene 9.8 When dioxolane 7 was heated
under these conditions, diene 10 was isolated in 80% yield.
The same conditions applied on the trans stereomer 8 only
gave 11 through the direct Stille cross-coupling reaction in
a comparable yield (77%). The difference in reactivity
between these two compounds is explained by the nonfea-
sible formation of a trans-fused bicyclo[3.0.3]dioxolane that
1
22 as a single stereoisomer as determined by H and 13C
NMR analysis, but only in 30% yield (entry 10). The relative
stereochemistry in 22 has not been established because of
the nonsignificant coupling constant observed between the
two vicinal hydrogens R to the hydroxyl groups, which can
be cis or trans.
To extend the scope of the reaction and to study the role
of the two hydroxy groups we investigated the cyclocarbo-
palladation of the anti and syn diols, protected as a dioxolane.
These compounds were easily prepared by mixing the free
diols with an excess of dimethoxypropane in the presence
of a catalytic amount of p-TsOH in acetone at room tem-
(6) Bruckner, S.; Abraham, E.; Klotz, P.; Suffert, J. Org. Lett. 2002, 4,
3391.
(7) Unambiguously assigned by NOESY experiments on the cis-
dioxolane derivative of 2b.
(8) Bottaro, J. C.; Hanson, R. N.; Seitz, D. E. J. Org. Chem. 1981, 46,
5221.
2308
Org. Lett., Vol. 5, No. 13, 2003

Table 1. Cyclocarbopalladation of Anti and Syn Propargylic Diols and Aromatic Propargylic Alcohols
perature. As expected, when dioxolanes 23-25 were submit-
ted to identical reaction conditions, the tricycles 26-28
(Table 2, entries 1-3) were obtained in acceptable yields
when compared with those obtained with the unprotected
diols. No isomerization of the exocyclic tetrasubstituted
double bond was observed in these cases. The protected trans
dioxolane 29-31 gave exclusively the direct Stille cross-
coupling diene (entries 4-6). As such as in 8, the cyclocar-
bopalladation was not feasible due to the highly strained
tricyclic derivatives that should be obtained in theory. As
mentioned above, all the stannylated dienes are sensitive
toward silica gel and give an easy protodestannation during
chromatography. This problem can be avoided by treating
the silica gel with a 5% solution of Et3N in diethyl ether.
The transformation of these polycyclic compounds to many
useful new structures could be envisaged considering the very
different reactive groups contained in these molecules (hy-
droxyl, diene, tin, and trimethylsilyl).
Org. Lett., Vol. 5, No. 13, 2003
2309

Table 2. Cyclocarbopalladation of Trans and Cis Propargylic Dioxolanes
ence of the diol function and the trimethylsilyl group on the
triple bond seems to be crucial for the reaction to proceed
in acceptable yields. The scope and limitations of this method
are currently being investigated and the results obtained will
be reported soon.
Acknowledgment. We thank the CNRS for financial
support and the MNERT (B.S.) for a fellowship.
Figure 2. NOESY studies.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have described an efficient way to pre-
pare highly substituted bicyclic compounds that could be
valuable intermediates in the syntheses of sophisticated
biologically active natural or unnatural products. The pres-
OL034647A
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Org. Lett., Vol. 5, No. 13, 2003