Indium-mediated γ-pentadienylation of aldehydes and ketones: Cross-conjugated trienes for diene-transmissive cycloadditions

Article abstract of DOI:10.1021/ol990695c

(Matrix presented) Treatment of 5-bromo-1,3-pentadiene with indium metal in the presence of carbonyl compounds results in γ-pentadienylation to generate the 1,4-diene. Elimination of the resulting alcohol affords cross-conjugated triene systems which rapi

Full text of DOI:10.1021/ol990695c

ORGANIC
LETTERS
1999
Vol. 1, No. 4
573-575
Indium-Mediated γ-Pentadienylation of
Aldehydes and Ketones:
Cross-Conjugated Trienes for
Diene-Transmissive Cycloadditions
Simon Woo, Neil Squires, and Alex G. Fallis*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
afallis@science.uottawa.ca
Received May 27, 1999
ABSTRACT
Treatment of 5-bromo-1,3-pentadiene with indium metal in the presence of carbonyl compounds results in γ-pentadienylation to generate the
1,4-diene. Elimination of the resulting alcohol affords cross-conjugated triene systems which rapidly react with appropriate dienophiles to give
tandem intermolecular Diels−Alder adducts.
Metal allyl reagents are among the most studied systems for
the addition of a three-carbon unit to carbonyl groups under
a variety of conditions. Similarly, the corresponding penta-
dienyl moiety 1 is known to condense with both aldehydes
and ketones (Scheme 1). However, in many circumstances
Our synthetic interests required the introduction of diene
and triene units under mild conditions in highly functional-
ized, sensitive molecules. Chan and colleagues7 have dem-
onstrated the utility of allyl indium species in water for the
allylation of carbonyl compounds bearing labile dimethyl
acetals where the tin and zinc reagents failed.7a They also
established that allyl indium reagents react at the γ position8
and are compatible with free hydroxyl groups.9 We have been
pleased to discover that the reagent generated from 5-bromo-
1,3-pentadiene10 and indium metal also adds in a regio-
selective manner to give nonconjugated compounds of type
Scheme 1. Pentadienyl Anion Condensations
(1) (a) Gerard, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1974, 1924. (b)
Gerard, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1974, 2527. (c) Ghosez, L.;
Marko, I.; Hesbain-Frisque, A.-M. Tetrahedron Lett. 1986, 27, 5211. (d)
Chen, L.; Ghosez, L. Tetrahedron Asym. 1991, 2, 1181. (e) Jung, M. E.;
Nichols, C. J. Tetrahedron Lett. 1996, 37, 7667.
(2) (a) Fujita, K.; Schlosser, M. HelV. Chim. Acta 1982, 65, 1258. (b)
Suginome, M.; Yamamoto, Y.; Fujii, K.; Ito, Y. J. Am. Chem. Soc. 1995,
117, 9608.
(3) Yasuda, H.; Yamauchi, M.; Nakamura, A.; Sei, T.; Kai, Y.; Yasuoka,
N.; Kasai, N. Bull. Chem. Soc. Jpn. 1980, 53, 1089.
(4) Yasuda, H.; Ohnuma, Y.; Nakamura, A.; Kai, Y.; Yasuoka, N.; Kasai,
N. Bull. Chem. Soc. Jpn. 1980, 53, 1101.
(5) Nishigaichi, Y.; Fujimoto, M.; Takuwa, A. Synlett 1994, 731.
(6) Kobayashi, S.; Nishio, K. Chem. Lett. 1994, 1773.
(7) For organoindium reviews, see: (a) Chan, T. H.; Li, C. J.; Lee, M.
C.; Wei, Z. Y. Can. J. Chem. 1994, 72, 1181. (b) Li, C. J. Chem. ReV.
1993, 93, 2023. (c) Cintas, P. Synlett 1995, 1087.
(8) Isaac, M. B.; Chan, T. H. Tetrahedron Lett. 1995, 36, 8957.
(9) Li, C. J.; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017.
the reaction is not regioselective, and the delocalized anion
may react at either the R or γ position. This usually results
in a mixture of the conjugated diene 3 and the skipped diene
system 4. Clearly, for synthetic applications, it is important
to control this product distribution.
Previous investigations have reported varying levels of
selectivity. Examples include organolithium,1 zinc,1 borane,2
magnesium,3 beryllium,4, tin,5 and silicon6 reagents of various
types.
10.1021/ol990695c CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/16/1999

4 even with sensitive substrates. For example, as illustrated
in Scheme 2, the lactol 5 reacted slowly, but cleanly, in DMF
at 21 °C to give the secondary diol-diene 6 in 96% yield
(1:1 ratio of diastereomers). In contrast, the diastereoselec-
tivity increased to 12:1 when THF was used as the solvent.
During these investigations Araki and co-workers11 reported
related studies with substituted penta-2,4-dienyl indiums,
including an example of a pentadienyl indium condensation
with benzaldehyde.
Table 1. Pentadienylindium Condensations with Aldehydes
and Ketones
Scheme 2. Pentadienyl Anion Condensation with Lactol 5
Table 1 summarizes the results of experiments with several
substrates.12 In all cases the only addition product detected
from reactions in water or DMF was the γ-substituted isomer.
The R,â-unsaturated aldehyde (entry 4) afforded the 1,2-
addition product preferentially rather than the product from
Michael addition. The yields in the ketone condensations are
lower, probably due to a combination of reduced electro-
philicity and greater steric bulk compared to the aldehydes
(entries 5 and 6). Consistent with this analysis, 4-heptanone
(entry 7) was unreactive possibly due to the increased steric
encumbrance from the freely rotating alkyl substituents
compared to cyclohexanone (entry 5). This result implied
that selective addition to an aldehyde should occur in the
presence of a ketone. Entry 8 confirmed that this was the
case and that selective addition should prove useful in
complex systems.
It is of interest that the reactivity of the pentadienyl indium
reagent differed from the 1-bromo-2,4-hexadiene-indium
system studied by Araki and co-workers11 in two important
aspects. Their reactions were sluggish and gave reduced
yields in water compared to DMF, and the reagent was
unreactive toward ketones. The reasons for these subtle
differences are not clear at present. Recently Chan and
Yang13 have established that allyl indium additions to ketones
proceed via the formation of an indium(I) species rather than
indium(III). A parallel process involving metal surface
mediated allyl radical anions is also possible. In view of the
close structural similarity between pentadienyl and allyl-
indium species, the mechanisms are likely closely related.
Dehydration of these diene products under Mitsunobu type
conditions (Ph3P, DEAD, C6H6, 80 °C) generated the
corresponding cross-conjugated trienes. For example, the
alcohol 15, derived from 8, was converted to the triene 16
which is appropriately functionalized for diene transmissive
tandem Diels-Alder reactions14 upon exposure to various
dienophiles (Scheme 3). The reaction of 16 with N-
phenylmaleimide (17) afforded 18 in situ which reacted
spontaneously with a second mole of the dienophile to give
19 (81%). In a similar manner benzoquinone (20) added to
(10) Prevost, C.; Miginiac, P.; Miginiac-Groizeleau, L. Bull. Soc. Chim.
Fr. 1964, 2485.
(11) Hirashita, T.; Inoue, S.; Yamamura, H.; Kawai, M.; Araki, S. J.
Organomet. Chem. 1997, 549, 305.
(12) General Procedure for the Preparation of Diene-Alcohols.
Indium powder (100 mesh, 0.223 g, 1.94 mmol) was added in portions to
a mixture of 5-bromo-1,3-pentadiene (0.504 g, 3.43 mmol) and the carbonyl
compound (1.48 mmol) in either water or DMF (0.3 mL). The reaction is
exothermic, and thus it is important to adjust the rate of indium addition to
control the rate of temperature increase. The reaction mixture was stirred
for the allotted time. The aqueous reactions were diluted with water (1 mL)
and extracted with ether (3×), and the organic extracts were dried (MgSO4)
and concentrated in vacuo. The reactions in DMF were diluted with CH2-
Cl2 (2 mL) and then added to ether (25 mL). The resulting mixture was
filtered through a pad of silica gel. The silica was washed with additional
solvent, and the filtrate was concentrated. The products were purified by
flash chromatography.
(13) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.
(14) Winkler, J. D. Chem. ReV. 1996, 96, 167.
Org. Lett., Vol. 1, No. 4, 1999
574

skeleton 23 as a mixture of diastereomers. This tetracycload-
dition sequence may be run stepwise or in one reaction vessel
(16 h, 48 h, 21 °C) to give 23 in 71% yield accompanied by
9% of 24. These examples illustrate the ease with which
multicyclic ring systems may be constructed directly from
repetitive cycloadditions in a facile manner.
Scheme 3. Diene-Transmissive Cycloadditions
In conclusion, we have established that the organoindium
reagent derived from 5-bromo-1,3-pentadiene and indium
metal reacts with excellent regioselectivity with a variety of
aldehydes and ketones to afford the nonconjugated, (γ-
pentadienylation) diene products in respectable yields. These
are straightforward reactions that do not require inert
atmospheres nor anhydrous solvents. In addition, the trienes
derived from dehydration of the condensation products afford
rapid entry to complex multicyclic skeletons from tandem
[4 + 2] cycloadditions. Synthetic applications of this
condensation-elimination-cycloaddition strategy are cur-
rently under investigation, as are Cope rearrangement
combinations.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada, the
Canadian Breast Cancer Research Initiative (NCI, Canada),
and the Saunders-Matthey Foundation for Breast Cancer
Research for financial support of this research. S. Woo thanks
NSERC for a Postdoctoral Fellowship.
16 at 21 °C to afford the tetracyclic skeleton 21. The
stereochemistry of 21 was established by X-ray analysis.
Further reaction of the bis-quinone adduct 21 with excess
cyclopentadiene (22) at 21 °C afforded the octacyclic
OL990695C
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