The transition metal-catalyzed intermolecular [5+2] cycloaddition: The homologous Diels-Alder reaction [1]

Full text of DOI:10.1021/ja982196x

10976
J. Am. Chem. Soc. 1998, 120, 10976-10977
Communications to the Editor
The Transition Metal-Catalyzed Intermolecular
Table 1. The Transition Metal-Catalyzed [5+2] Cycloadditions of
1
-(tert-Butyldimethylsilyloxy)-1-vinylcyclopropane with Alkynes
[
5+2] Cycloaddition: The Homologous Diels-Alder
Reaction
Paul A. Wender,* Heiko Rieck, and Masahiro Fuji
Department of Chemistry, Stanford UniVersity
Stanford, California 94305
ReceiVed June 24, 1998
Cycloaddition reactions are among the most frequently used
processes in organic synthesis, providing practical access to
complex molecules of theoretical, technological, commercial, and
1
medical interest, often from simple starting materials. In 1959,
2
a homologue of the Diels-Alder cycloaddition was reported
involving the [5+2] cycloaddition of a vinylcyclopropane and
maleic anhydride to form a seven-membered-ring product. Efforts
to reproduce this reaction have, however, not been successful,3,4
and its extension to other simple vinylcyclopropanes has not been
reported.5 Thus far, this reaction has been limited to a few
examples of conformationally constrained, heteroatom- or strain-
activated substrates and activated alkynes.6 Simple vinylcyclo-
propanes do not react “even [with] the strongest dienophiles”.4
In 1995, as part of our studies on [m+n] cycloadditions which
in the absence of catalysts are theoretically forbidden or difficult
to achieve,8 we reported the first examples of a transition metal-
catalyzed intramolecular [5+2] cycloaddition of simple vinyl-
cyclopropanes and alkynes.10 This reaction has more recently
,7
,9
11
been achieved with alkenes and with asymmetric catalysis. We
now report the first metal-catalyzed intermolecular [5+2] cy-
cloadditions of simple vinylcyclopropanes and alkynes, the long
sought homologue of the Diels-Alder cycloaddition, and a
fundamentally new and remarkably general process for the
synthesis of seven-membered rings.
Our initial attempts to effect the metal-catalyzed intermolecular
[5+2] cycloaddition failed with various vinylcyclopropanes and
(
1) For a discussion of complexity increasing reactions in synthesis, see:
Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 3, 67 and
references cited therein.
(
(
2) Sarel, S.; Breuer, E. J. Am. Chem. Soc. 1959, 81, 6522.
3) Pasto, D. J.; Chen, A. F.-T.; Binsch, G. J. Am. Chem. Soc. 1973, 95,
1
553.
(
4) Herges, R. In Chemical Structures; Warr, W. A., Ed.; Springer-
Verlag: Berlin, 1988; p 385. Herges, R. In Methods of Organic Chemistry;
a
E ) CO
2
Me. b See General Procedure in footnote 16. c Overall
de Meijere, A., Ed.; Thieme Verlag: Stuttgart, 1997; Vol. E17c, p 2154.
(
5) For related studies on vinylcyclopropanes, see: Effenberger, F.;
yields for cycloaddition and hydrolysis steps.
Podszun, W. Angew. Chem., Int. Ed. Engl. 1969, 8, 976. Nishida, S.; Moritani,
I.; Teraji, T. J. Chem. Soc., Chem. Commun. 1970, 501. Sarel, S.; Felzenstein,
A.; Yovell, J. J. Chem. Soc., Chem Commun. 1974, 753. For a review, see:
Tsuji, T.; Nishida, S. Acc. Chem. Res. 1984, 17, 56.
alkynes using Wilkinson’s catalyst (Rh(PPh ) Cl), even when
3 3
conditions were employed for which the corresponding intramo-
lecular reaction worked well. Either the starting materials did
not react or under more forcing conditions the alkyne cyclotri-
(
6) Tanny, S. R.; Fowler, F. W. J. Org. Chem. 1974, 39, 2715. Herges, R.;
Ugi, I. Angew. Chem., Intl. Ed. Engl. 1985, 24, 594.
7) Fenton, G.; Isaacs, N. S.; Gilbert, A. Tetrahedron Lett. 1985, 26, 1597.
Baldwin, J. E.; Pinschmidt, R. K., Jr. Tetrahedron Lett. 1971, 14, 935.
(
12
merized or the vinylcyclopropane isomerized. A solution to
these relative rate problems was fashioned from our previous
(
8) Representative examples include [4+4] cycloadditions (Wender, P. A.;
Ihle, N. C.; Correia, C. R. D. J. Am. Chem. Soc. 1988, 110, 5904) and [4+2]
observations that oxygen substitution of the vinylcyclopropane
cycloadditions (Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc.
995, 117, 1843. Wender, P. A.; Smith, T. E. J. Org. Chem. 1996, 61, 824).
13
facilitates the intramolecular cycloaddition and that [Rh(CO)
2
-
1
14
Cl]
2
can be used to effect intramolecular [5+2] cycloadditions
of unreactive substrates. Thus, when siloxycyclopropane 1 was
(
9) For reviews on metal-catalyzed cycloadditions, see: Lautens, M.; Klute,
15
W.; Tam, W. Chem. ReV. 1996, 96, 49. Hegedus, L. S. Coord. Chem. ReV.
1
997, 161, 129. Dell, C. P. Contemp. Org. Synth. 1997, 4, 87.
10) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995,
treated with dimethyl acetylenedicarboxylate in the presence of
(
2 2 3
[Rh(CO) Cl] in CDCl at 40 °C, the facile formation of a single
1
17, 4720. For recent applications, see: Gilbertson, S. R.; Hoge, G. S.
Tetrahedron Lett. 1998, 39, 2075. Binger, P.; Wedemann, P.; Kozhushkov,
S. I.; de Meijere, A. Eur. J. Org. Chem. 1998, 113.
cycloadduct 2 was observed by NMR spectroscopy. For ease of
(11) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem.
(12) For a review on transition metal-mediated reactions of vinylcyclo-
propanes, see: Khusnutdinov, R. I.; Dzhemilev, U. M. J. Orgmet. Chem. 1994,
471, 1.
Soc. 1998, 120, 1940. Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J.
A.; Pleuss, N. Tetrahedron 1998, 54, 7203.
1
0.1021/ja982196x CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/13/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 42, 1998 10977
characterization, 2 was hydrolyzed during workup by brief
treatment of the reaction mixture with 1% HCl/EtOH to give
ketone 3 in >90% yield. In the absence of catalyst, no reaction
was observed even after 3 days. The reaction can be conducted
in a variety of solvents (e.g., THF, toluene, and EtOH) although
Scheme 1
3 2 2
the use of weakly coordinating solvents (CHCl and CH Cl )
allows for shorter reaction times (ca. 1-3 h) and milder
conditions (40 °C).
cycloadduct of the diester was obtained. The functional group
tolerance of this reaction is also noteworthy as ketones, esters,
ethers, and even unprotected alcohols do not inhibit catalysis.
Two general mechanisms, differing by the sequence of cyclo-
propane cleavage, are possible for this cycloaddition (Scheme 1).
While studies on these (and other) pathways are in progress, the
The scope of this new cycloaddition reaction was investigated
with a range of alkynes, representing the types required in fine,
bulk, and complex chemical synthesis. As summarized in Table
1
7
1, the reaction is remarkably general. To allow for comparisons,
all reactions were conducted with 5 mol % catalyst on a 1 mM
scale and 1.2-1.5 equiv of the alkyne (except in the case of
acetylene, entry 12). Reactions were not individually optimized
to establish the generality of the procedure. The initial cycload-
2 2
reaction of 1 with a stoichiometric amount of [Rh(CO) Cl] has
been found to produce an equilibrium mixture of two spectro-
scopically observable complexes.18 When an alkyne is added to
this mixture, the expected cycloadduct is formed, indicating that
these complexes might be competent intermediates in the catalytic
cycle or more likely could serve as a resting state for the catalyst.
Overall, a new class of cycloaddition reactions has been
developed that offers a strategically novel and practical route to
an otherwise difficult-to-prepare but common ring system, based
on simple vinylsiloxycyclopropanes and alkynes. The reaction
works well with a broad range of alkynes. The siloxy substituent
on the cyclopropane has the special synthetic advantage of
providing access to silylenol ether cycloadducts and their ketone
derivatives. It is of further synthetic significance that these
cycloadducts possess differentiated functionality, allowing for their
flexible use as building blocks for complex molecules and for
combinatorial libraries. Further studies are in progress.
16
duct was hydrolyzed upon workup to provide the ketone product.
Electron rich, electron poor, conjugated, internal, and terminal
alkynes, eVen acetylene itself, were found to proVide cycloadducts
in good to excellent yields. Most reactions were complete in 1-3
h at 40 °C. Competition experiments showed that the relative
rates of cycloadditions for different alkynes differ sufficiently to
allow for chemoselective reactions. Thus, when 1 equiv of 1
was mixed with 1.1 equiv each of dimethyl acetylenedicarboxy-
late, phenyl acetylene, and methyl propargyl ether, only the
(
13) Replacement of hydrogen by an ethoxy group results in a 5-10-fold
rate acceleration in the intramolecular reaction (Heiko Rieck, unpublished
results, Stanford University). For other reactions of donor-substituted cyclo-
propanes, see: Jun, C.-H.; Kang, J.-B.; Lim, Y.-G. Tetrahedron Lett. 1995,
3
6, 277. Ryu, I.; Ikura, K.; Tamura, Y.; Maenaka, J.; Ogawa, A.; Sonoda, N.
Synlett 1994, 941. Ryu, I.; Murai, S. In Methods of Organic Chemistry; de
Meijere, A., Ed.; Georg Thieme Verlag: Stuttgart, 1997; Vol. E17c, p 1985.
Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky,
T. Chem. ReV. 1989, 89, 165. Trost, B. M. Top. Curr. Chem. 1986, 133, 1.
Acknowledgment. This research was supported by a grant (CHE-
9321676) from the National Science Foundation and fellowship support
from Deutsche Forschungsgemeinschaft (H.R.) and from Shionogi & Co.,
Ltd. (M.F.). Mass spectra were provided by the Mass Spectrometry
Facility, University of CaliforniasSan Francisco.
(
14) Wender, P. A.; Sperandio, D. J. Org. Chem. 1998, 63, 4164.
(
15) Prepared on a large scale by analogy to the methods in the following:
Sala u¨ n, J.; Marguerite, J. Org. Synth. 1985, 63, 147. Wasserman, H. H.; Hearn,
M. J.; Cochoy, R. E. J. Org. Chem. 1980, 45, 2874.
(
16) General procedure: To an oven-dried, argon-purged Schlenk flask was
Cl] (0.05 mmol) and anhydrous CH Cl (10 mL) under an
argon atmosphere. Argon was bubbled through the resultant yellow solution
1 min) and 1 was added (1 mmol). After an additional argon purge (1 min),
Supporting Information Available: Procedures and spectroscopic
data for representative products (9 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
added [Rh(CO)
2
2
2
2
(
the alkyne (1.1-1.5 mmol) was added. The flask was placed in an oil bath
preheated to 40 °C. The reaction was monitored by TLC. Upon completion,
the reaction was usually dark in color. The reaction mixture was treated with
JA982196X
1
% HCl in EtOH (0.2 mL) and the resulting mixture was filtered through a
(17) Substituted vinylsiloxycyclopropanes can also be used (Hartung, I.;
Rieck, H. Unpublished results, Stanford University). For example, the use of
propenylsiloxycyclopropane with HCCCOOMe gives a 92% yield of 3-methyl-
5-carbomethoxycyclohept-4-en-1-one.
short pad of silica gel (Et O eluant) and concentrated in vacuo. The residue
2
was purified by flash column chromatography. This procedure was not
optimized for the isolation of the silylenol ether cycloadducts. With unsym-
metrical alkynes, spectroscopic studies suggest that one regioisomer is
preferentially formed.
1
(18) The NMR spectrum of this mixture is consistent with the σ,η -allyl
3
and σ,η -allyl complexes 4 and 5.