Copper-catalyzed rearrangement of vinyl oxiranes

Article abstract of DOI:10.1021/ja067073o

A novel copper-catalyzed vinyl oxirane ring expansion protocol has been developed. A wide range of vinyl oxiranes can be rearranged to 2,5-dihydrofurans in excellent yields in the presence of electrophilic copper(II) acetylacetonate catalysts. Regioisomeric vinyl oxiranes can be converted to a single dihydrofuran product using these conditions. This method uses low catalyst loadings (0.5-5 mol %), has good tolerance of substitution patterns, and can be done in the absence of solvent. Copyright

Full text of DOI:10.1021/ja067073o

Published on Web 11/23/2006
Copper-Catalyzed Rearrangement of Vinyl Oxiranes
Lindsay A. Batory, Christine E. McInnis, and Jon T. Njardarson*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
Received October 2, 2006; E-mail: jn96@cornell.edu
Table 1. Copper-Catalyzed Vinyl Oxirane Rearrangementa
Members of the furan family can be found in thousands of natural
products, bulk commodity chemicals, and a number of pharma-
ceutical agents.1 Despite a host of creative approaches, there is still
a need for simple and scalable synthetic methods for making
dihydro- and tetrahydrofurans.2 We envisioned that a practical
method to form 2,5-dihydrofurans would also serve as an excellent
platform to access tetrahydrofurans. Here we report progress toward
the development of catalytic conditions for the rearrangement of
vinyl oxiranes to 2,5-dihydrofurans.
Vinyl oxiranes are versatile synthons that can be readily accessed
by either oxidation of dienes or nucleophilic addition of activated
allyl or methyl groups to aldehydes or ketones.3 Three types of
vinyl oxirane (1) rearrangements are most relevant to our pursuit
(Scheme 1). First, it is well documented that a number of different
Lewis acids can be used to activate vinyl oxiranes and induce a
hydride shift to form â,γ-unsaturated aldehydes (2).4 Second, it
has been shown that, when vinyl oxiranes are heated above
300 °C, the oxirane ring opens to an oxonium ylide, which then
rapidly rearranges to a 2,3-dihydrofuran (3).5 Third, studies on the
ring expansion of vinyl oxiranes to a 2,5-dihydrofuran (4) have
been performed almost exclusively by industry and have predomi-
nantly focused on butadiene monoxide. Despite decades of effort,
suitable process conditions for this rearrangement have still not been
identified,6 and the full scope of this transformation as a synthetic
method for organic chemistry remains relatively unexplored.
entry
catalystb
mol %
time (h)
6:7c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cu powder
Cu(OAc)2
100
10
10
10
10
5
5
5
1
5
14
14
14
14
15
17
2
0.25
2
4
no rxn
no rxn
>1:20
>1:20
1:8
CuCl2
CuSO4‚5H2O
Cu(TFA)2
Cu(acac)2
Cu(tfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)(BTMSA)
Cu(dbm)2
Cu(ptfm)2
Cu(accy)2
Cu(tfaccy)2
Cu(fod)2
5:1
12:1
13:1
17:1
15:1
4:1
7:1
5:1
8:1
11:1
5
5
5
5
24
4
20
4
5
2
a Reactions are performed in a sealed tube in toluene at 150 °C with the
specified catalyst loading. b See ref 9. c Based on molar ratios as determined
from NMR integration.
material.8 In accordance with our hypothesis, a series of copper
catalysts were examined (Table 1), and from these studies, the
acetylacetonate ligand framework emerged as being superior to all
other catalysts examined thus far. As a result, efforts focused
primarily on Cu(acac)2, Cu(tfacac)2, and Cu(hfacac)2.9 All of these
catalysts successfully rearranged vinyl oxirane 5 to form only 2,5-
dihydrofuran 6 and a mixture of aldehydes (7) (Table 1, entries
6-9). Product ratios varied according to the electronics of the
ligand. The least electrophilic of these catalysts, Cu(acac)2, was
slow and exhibited only moderate product selectivity, while
switching to Cu(tfacac)2 led to significant improvement in both the
reaction rate and product ratio. The rearrangement proceeded even
more rapidly, while maintaining excellent selectivity, when the more
electrophilic Cu(hfacac)2 was used as the catalyst. Further improve-
ments to selectivity were achieved through the use of a lower
catalyst loading (entry 9). In a comparison of copper(II) and cop-
per(I) catalysts (entries 8-10), copper(II) was significantly faster
at obtaining similar product ratios.
In an effort to develop new catalysts for the rearrangement with
more steric and electronic tuning opportunities, dibenzoylmethane
and 2-acetylcyclohexanone were explored as acac surrogates. Each
parent and fluorinated catalyst was successful in rearranging vinyl
oxirane 5 to 2,5-dihydrofuran 6 (entries 11-14). Additionally, a
more functionalized version of Cu(tfacac)2 was shown to be equally
successful in rearranging 5 (entry 15). In agreement with our earlier
observations, the more electrophilic catalysts (entries 12 and 14)
were both faster and more selective than the parent catalyst (entries
11 and 13).
Scheme 1. Vinyl Oxirane Rearrangements
Our objective was to conduct a full study of the rearrangement
of vinyl oxiranes to 2,5-dihydrofurans using a catalyst without any
additives. We hypothesized that an electrophilic metal catalyst
capable of coordinating simultaneously to the olefin and the oxirane
oxygen atom could facilitate the rearrangement by bringing the two
ends into closer proximity. To make the method most practical,
only simple and air-stable catalysts were considered, and specifi-
cally, electrophilic copper(II) catalysts substituted with non-
nucleophilic ligands were selected. This choice is in part based on
the great number of synthetically useful organic transformations
that copper seems best suited to facilitate, many of which are
believed to involve olefin coordination.7
Vinyl oxirane 5 was chosen as a test substrate for our initial
studies. In addition to copper catalysts, a number of other metals
were also surveyed, and these experiments led to the recovery of
epoxide 5, aldehyde formation (7), or decomposition of the starting
9
16054
J. AM. CHEM. SOC. 2006, 128, 16054-16055
10.1021/ja067073o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. 2,5-Dihydrofuran Synthesisa
Scheme 2. Neat Copper-Catalyzed Vinyl Oxirane
Rearrangements12
can be done in the absence of solvent. Further studies on the scope,
limitations, and mechanism of this rearrangement are currently
underway.
Acknowledgment. This paper is dedicated to Professor Samuel
J. Danishefsky on the occasion of his 70th birthday. We thank
Cornell University and the NIH (CBI Training Grant support for
L.A.B.) for financial support. C.E.M. is the recipient of an Einhorn
Discovery Grant and President’s Council of Cornell Women Grant.
Emil B. Lobkovsky obtained the crystal structure data for Cu(ptfm)2.
Supporting Information Available: Full experimental details and
physical data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Reactions are performed in a sealed tube in toluene at 150 °C with
Cu(hfacac)2 at the specified loading. b Cu(tfacac)2 is the catalyst. c Volatile
compound; yield based on molar ratios from NMR integration.
References
The synthetic utility of this copper-catalyzed rearrangement was
explored using a series of monosubstituted vinyl oxiranes (Table
2). Vinyl oxiranes substituted at the 2- or 3-position rearranged
efficiently to form 3-substituted 2,5-dihydrofurans (entries 1, 2, and
5), while 1- and 4-substituted vinyl oxiranes (entries 3 and 4)
rearranged to form 2-substituted 2,5-dihydrofurans. These results
illustrate an important synthetic aspect of this rearrangement where
each dihydrofuran product can originate from at least two regio-
isomeric vinyl oxiranes or even from their mixture.
(1) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. T., Eds.; Pergamon: London, 1996; Vol. 2, pp 259-436.
(2) (a) Slavinskaya, V. A.; Karakhanov, R. A.; Brezhnev, L. Y.; Geiman, I.
I.; Bulenkova, L. F.; Strautinya, A. K. Chem. Heterocycl. Compd. 1982,
18, 997-1008. (b) Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry
1993, 4, 1711-1754. (c) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1
2002, 2301-2323. (d) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett.
2004, 6, 2015-2017. (e) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc.
2004, 126, 1620-1621. (f) Hilt, G.; Bolze, P.; Kieltsch, I. Chem. Commun.
2005, 1996-1998.
(3) (a) Olofsson, B.; Somfai, P. Vinylepoxides in Organic Synthesis. In
Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-
VCH: Weinheim, Germany, 2006; pp 315-347. (b) Sadhu, K. M.;
Matteson, D. S. Tetrahedron Lett. 1986, 27, 795-798.
Next, various disubstituted vinyl oxiranes were evaluated (Table
2, entries 6-11), and these studies revealed that 1,1-, 1,3-, 1,4-,
and 2,3-substitutions on the vinyl oxiranes were well tolerated. The
difference in the regioisomeric and sterically encumbered substrates
of entries 6 and 7 is particularly interesting. The 1,1-disubstituted
vinyl oxirane (entry 6) rearranged slowly to a 2,5-dihydrofuran,
while the 4,4-disubstituted vinyl oxirane (entry 7) rapidly formed
aldehyde. Within these studies, we have explored cyclic diene
monoepoxides (Table 2, entries 10 and 11) and found that both
cycloheptadiene (entry 10) and cyclooctadiene (entry 11) mono-
epoxides rearranged readily to their respective oxabicyclic products.
With a vision toward the development of a greener and more
practical variant of the rearrangement, we have successfully
rearranged oxiranes 5 and 10 in the absence of solvent while
maintaining a high 2,5-dihydrofuran selectivity (Scheme 2). This
may prove useful for the industrial production of 3-methyltetrahy-
drofuran10 and 2-methyltetrahydrofuran11 via a highly atom eco-
nomical route commencing from a mixture of the monoepoxides
of isoprene and piperylene. Unlike current synthetic approaches,
no unnecessary hydroxyl or carbonyl functionalities would need
to be reduced, thus eliminating challenging separations of products
from alcohol and/or water byproducts.
(4) For a recent example, see: Lautens, M.; Ouellet, S. G.; Raeppel, S. Angew.
Chem., Int. Ed. 2000, 39, 4079-4082 and references cited therein.
(5) Crawford, R. J.; Lutener, S. B.; Cockcroft, R. D. Can. J. Chem. 1976,
54, 3364-3376.
(6) Representative patents: (a) Besozzi, A. J.; Cooley, S. D.; Potts, F. E., III.
Petro-Tex Chemical Corporation, U.S. Patent 3812158, 1974. (b) Wall,
R. G.; Kurkov, V. P. Chevron Research Company, U.S. Patent 3996248,
1976. (c) Fischer, M. BASF, U.S. Patent 5034545, 1991. (d) Monnier, J.
R.; Godleski, S. R.; Low, H. M.; McCullough, L. G.; McGarry, L. W.;
Phillips, G. W. Eastman Kodak Company, U.S. Patent 5082956, 1992.
(7) Mori, S.; Nakamura, E. Mechanisms of Copper-Mediated Addition and
Substitution Reactions. In Modern Organocopper Chemistry; Krause, N.,
Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 315-346.
(8) For control experiments and a complete list of catalyst systems explored,
see Supporting Information.
(9) acac ) acetylacetonate, tfacac ) trifluoroacetylacetonate, hfacac )
hexafluoroacetylacetonate, BTMSA ) bis(trimethylsilyl)acetylene, dbm
) dibenzoylmethane, ptfm ) 1,3-bis[(4-fluoromethyl)phenyl]-1,3-pro-
panedionate, accy ) 2-acetylcyclohexanone, tfaccy ) 2-trifluoroacetyl-
cyclohexanone, and fod ) 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-
octanedionate.
(10) Representative patents: (a) Weyer, H.-J.; Fischer, R.; Merger, F.; Frank,
J.; Henkelmann, J.; Siegel, H.; Ruehl, T. BASF, U.S. Patent 5536854,
1996. (b) Takemoto, M.; Abe, T. Mitsubishi Gas Chemical Company,
Inc., U.S. Patent 5990324, 1999. (c) Manzer, L. E. E. I. Du Pont de
Nemours and Company, U.S. Patent 2003/0109724 A1, 2003. (d) Beavers,
W. A.; Ignatchenko, A. V. Eastman Kodak Company, U.S. Patent 6812354
B2, 2004.
(11) (a) Used as a greener replacement for dichloromethane: Ripin, D. H. B.;
Vetelino, M. Synlett 2003, 2353. Representative patents: (b) Elliott, D.
C.; Frye, J. G. Battelle Memorial Institute, U.S. Patent 5883266, 1999.
(c) Ahmed, I. Pure Energy Corporation, U.S. Patent 6852868 B2, 2005.
(12) For a recent example of conversion to a furan, see: Gowrisankar, S.;
Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2005, 46, 4859-4863.
In summary, we have developed conditions for the use of copper-
(II) complexes to catalyze the rearrangement of vinyl oxiranes to
2,5-dihydrofurans. This method is attractive because it uses low
catalyst loadings, has good tolerance of substitution patterns, and
JA067073O
9
J. AM. CHEM. SOC. VOL. 128, NO. 50, 2006 16055