Ruthenium-catalyzed diyne hydrative cyclization: Synthesis of substituted 1,3-diene synthons

Article abstract of DOI:10.1021/ol0502937

(Chemical Equation Presented) A novel and versatile strategy for the synthesis of highly functionalized substituted 3-sulfolenes based on [CpRu(CH₃CN)₃]PF₆-catalyzed hydrative cyclization has been developed. A marked keton

Full text of DOI:10.1021/ol0502937

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2097-2099
Ruthenium-Catalyzed Diyne Hydrative
Cyclization: Synthesis of Substituted
1,3-Diene Synthons
Barry M. Trost* and Xiaojun Huang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received February 11, 2005
ABSTRACT
A novel and versatile strategy for the synthesis of highly functionalized substituted 3-sulfolenes based on [CpRu(CH3CN)3]PF6-catalyzed hydrative
cyclization has been developed. A marked ketone directing effect in ruthenium-catalyzed cyclization was observed for the first time. This
provides complementary chemoselectivity for the synthesis of 3-sulfolenes and other cyclic enones. The utility of this method has been
demonstrated by SO2 extrusion of 3-sulfolenes to afford 1,3-dienes and the subsequent inter- and intramolecular Diels−Alder reaction.
The ruthenium-catalyzed hydrative cyclization of diynes
holds promise as a versatile ring-forming process.1 Among
heterocycles, 3-sulfolenes have a special significance as
conjugated diene synthons, since they generate 1,3-dienes
readily by thermal desulfonylation and have been employed
for Diels-Alder reactions in a number of complex synthe-
ses.2,3 Several methods for the synthesis of substituted
3-sulfolenes have been described in the literature. One
approach involves the construction of the corresponding
cyclic sulfides from functionalized precursors that usually
require multistep manipulations, followed by oxidation of
the sulfide to sulfone.4 One of the most common approaches
involves the addition of SO2 to functionalized dienes,5 a
method demanding availability of the type of functionality
that is being made but useful to convert simple 1,3-dienes
to more substituted ones. Most recently, substituted 3-sul-
folenes have been prepared by ring-closing metathesis.6 Our
group has established that the hydrative diyne cyclization
catalyzed by [CpRu(CH3CN)3]PF6 (1) is an excellent method
to prepare cyclic systems,1 although its chemoselectivity with
respect to potential leaving groups such as sulfonyl in the
propargylic position remains to be tested. Further, the
synthetic flexibility for preparation of substrates arising from
the acetylenic functionality facilitates their synthesis. In this
communication, we describe a novel and versatile strategy
for the synthesis of highly functionalized substituted 3-sul-
folenes based on the catalyzed hydrative cyclization of
dipropargylic sulfones (eq 1). During these studies, a marked
ketone directing effect in ruthenium-catalyzed cyclizations
was observed for the first time.
(1) (a) Trost, B. M.; Rudd, M. T. J. Am Chem. Soc. 2002, 124, 4178.
(b) Trost, B. M.; Rudd, M. T. J. Am Chem. Soc. 2003, 125, 11516.
(2) (a) Leonard, J.; Hague, A. B.; Knight, J. A. Organosulfur Chem.
1998, 2, 227. (b) Luh, T. Y.; Wong, K. T. Synthesis 1993, 4, 349. (c) Chou,
S. P.; Tsai, C. J. Org. Chem. 1988, 53, 5305.
(3) (a) Shing, T. K.; Tang, Y. J. Chem. Soc., Perkin Trans. 1 1994, 1625.
(b) Leonard. J.; Hague, A. B.; Jones, M. F. Tetrahedron Lett. 1997, 38,
3071.
Diethyl dipropargylic sulfone 2a (R ) R′ ) Et), which
was efficiently prepared from 1-bromo-2-butyne in two
steps,7 was used as a model substrate. Optimization studies
showed that the presence of an appropriate amount of water
(4) Nakayama, J.; Machida, H.; Saito, R. Chem. Lett. 1985, 1173.
(5) Roversi, E.; Monnat, F.; Vogel, P.; Schenk, K.; Roversi, P. HelV.
Chim. Acta 2002, 85, 733 and references therein.
(7) Cao, X.; Yang, Y.; Wang, X. J. Chem. Soc., Perkin Trans. 1 2002,
(6) Yao, Q. Org. Lett. 2002, 4, 427.
2485.
10.1021/ol0502937 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/06/2005

(∼11 equiv, 2 vol %) was important to secure high yields
of 3-sulfolene 3a (Table 1).
Table 2. Representative Examples of Hydrative Cyclization
Table 1. Optimization of Hydrative Cyclization
entry
substrate
H2O (equiv)
yield (3a)a,b
1
2
3
4
2a
2a
2a
2a
55
11
5
80%
97%
90%
91%
2
a All reactions at 0.1 M in acetone at 60 °C with 10% 1 for 6 h. b Isolated
yields after chromatography.
Table 2 illustrates the scope of the method. The substrates
are easily accessible from a propargylic thioacetate and a
propargylic halide.7 Unsymmetrical dipropargylic sulfone
substrates displayed very good chemoselectivity, and the add-
ition of water usually takes place at the more sterically access-
sible side (entry 2-7).1 A variety of functional groups can
be tolerated in this transformation, including a free hydroxyl
(entry 4), a silyl ether (entry 5), and a chloride (entry 6).
The desilylation product 3g was obtained when an alkynyl-
silane was used as the starting diyne (entry 7). Most inter-
estingly, a carbonyl group was found to direct the addition
of water to the more sterically hindered side to form 3-sul-
folene 3h in excellent yield and with excellent chemoselec-
tivity (entry 8). Carbonyl-group-directed product 3i was still
predominant when the carbonyl group was in the δ-position
with respect to the alkyne function (entry 9). The carbonyl
group directing effect was also observed when the tether was
changed from sulfone to nitrogen (entry 10). A synthetic
application of this ketone-directed addition is demonstrated
by the formation of furan 5 from diketone 3h (eq 2).8
A plausible mechanistic rationalization for the ketone
directing effect is depicted in Scheme 1. The carbonyl oxygen
coordinates with ruthenium in the ruthenacycle (A/B).9 This
facilitates the hydration of the ketone to generate intermediate
C, and subsequent rearrangements (C f D f E) give the
observed carbonyl directing product. This mechanism ex-
plains the results of entries 8 and 9 in Table 2. In entry 8,
the six-membered ruthenacycle in intermediate B gives a
completely carbonyl-directed diketone (3h). In entry 9, there
is a seven-membered ruthenacycle in intermediate B. This
a Reactions were carried out at 0.1 M (in substrate) in 2 vol % water/
acetone at 60 °C. b Isolated yields after chromatography. c Performed with
5 vol % water/acetone.
allows water to add to the less hindered side to form 3i′ as
the minor product.
To demonstrate the synthetic utility of substituted 3-sul-
folenes, compound 3a was transformed into 1,3-diene 6 in
(8) Khan, M.; Hashmi, M.; Ahmad, F.; Osman, S. M. J. Chem. Soc.,
Chem. Commun. 1983, 1057.
(10) Smith Synthesizer from Personal Chemistry was used for the
microwave studies.
(9) (a) Becker, E.; Mereiter, K.; Puchberger, M.; Schmid, R.; Kirchner,
K. Organometallics 2003, 22, 2124-2133. (b) Becker, E.; Ruba, E.;
Mereiter, K.; Schmid, R.; Kirchner, K. Organometallics 2001, 20, 3851-
3853. (c) Le Paih, J.; Monnier, F.; Derien, S.; Dixneuf, P. H.; Clot, E.;
Eisenstein, O. J. Am. Chem. Soc. 2003, 125, 11964-11975. (d) Le Paih,
J.; Derien, S.; Dixneuf, P. H. Chem. Commun. 1999, 1437-1438.
(11) SO2 extrusion was carried out at 160 °C microwave for our
convenience. This reaction could be carried out in refluxing toluene or at
even lower (ambient) temperature: (a) Winkler, J. D.; Quinn, K. J.;
MacKinnon, C. H.; Hiscock, S. D.; McLaughlin, E. C. Org. Lett. 2003, 5,
1805. (b) Yang, T.-K.; Chu, H.-Y.; Lee, D.-S.; Jiang, Y.-Z.; Chou, T.-S.
Tetrahedron Lett. 1996, 37, 4537.
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Org. Lett., Vol. 7, No. 11, 2005

Scheme 1. A Mechanistic Rationale for the Carbonyl-Directed
Hydrative Cyclization
standard ruthenium-catalyzed cyclization conditions, 3-sul-
folene 8 was formed in 50% yield from dipropargylic sulfone
7. Treatment of 8 with methyl acrylate in the presence of
Grubbs II catalyst afforded enoate 9.12 Exposure of 9 to
microwaves at 160 °C in PhMe gave bicyclic enone 10 in
good yield (86%) as a single diastereomer.13
Scheme 2. Formation of Bicyclic Enone 10 by an
Intramolecular Diels-Alder Reaction
good yield under thermal conditions at 160 °C in a
microwave (eq 3).10,11 Such substituted 3-sulfolenes can be
directly used in intermolecular Diels-Alder reactions. The
Diels-Alder adducts were isolated in high yields by heating
a mixture of the sulfolenes with DMAD at 160 °C in a
microwave apparatus (Table 3).
In conclusion, a general and efficient synthesis of substi-
tuted 3-sulfolenes has been developed. Their synthetic utility
has been demonstrated by SO2 extrusion to afford 1,3-dienes,
which can be trapped by either inter- or intramolecular
Diels-Alder reactions. A marked ketone directing effect in
ruthenium-catalyzed cyclizations was observed for the first
time. This phenomenon provides complementary chemose-
lectivity for the synthesis of substituted 3-sulfolenes and other
cyclic enones by this method.
Table 3. Selected Examples of Diels-Alder Reactions Using
Substituted 3-Sulfolenes as 1,3-Diene
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences, for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Regional
Center of the University of California-San Francisco,
supported by the NIH Division of Research Resources.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds as well as
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reactions were carried out at 0.5 M (in substrate) in PhMe at 160 °C
microwave, E′ ) CO2Me. b Isolated yields after chromatography. c DMAD
) dimethyl acetylenedicarboxylate.
OL0502937
(12) (a) Smith, C. M. O’Doherty, G. A. Org. Lett. 2003, 5, 1959. (b)
Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001,
40, 1277. (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783.
(13) The trans-trans relationship assignment of compound 10 was based
on two-dimensional ROESY NMR.
The utility of this method was further showcased in the
preparation of bicyclic enone 10 (Scheme 2). Under our
Org. Lett., Vol. 7, No. 11, 2005
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