A new approach to promoting sluggish Diels-Alder reactions: Dihapto-coordination of the diene

Article abstract of DOI:10.1021/ja0553654

The cycloaddition between 1,3-cyclohexadiene and various enones and enals (methyl vinyl ketone, ethyl vinyl ketone, methacrolien) is accomplished at room temperature in yields ranging from 51 to 68% without the use of Lewis acids, high pressures, or microwave reactors. This normally sluggish cyclization is accomplished by precoordination of the diene to a π-basic molybdenum complex. The η²-bound metal is thought to promote a Michael reaction between the uncoordinated portion of the diene and the enone, and the resulting enolate then closes to form the cycloalkene product. The organic cycloadduct is removed by oxidation with air or with silver triflate in nearly quantitative yield. For more sterically hindered enones (e.g., mesityl oxide) and for methyl acrylate, the desired outcome requires the use of BF₃·OEt₂, and yields are significantly lower (15-35%) Copyright

Full text of DOI:10.1021/ja0553654

Published on Web 01/11/2006
A New Approach to Promoting Sluggish Diels-Alder Reactions:
Dihapto-Coordination of the Diene
Weijun Liu, Fei You, Christopher J. Mocella, and W. Dean Harman*
Department of Chemistry, UniVersity of Virginia, P.O. Box 400319, CharlottesVille, Virginia, 22904-4319
Received August 5, 2005; E-mail: wdh5z@virginia.edu
Metals have played an important role in the development and
1
refinement of Diels-Alder reactions. From diverse parts of the
periodic table, often in conjunction with chiral auxiliary ligands,
they have been used to enhance both the rate and stereoselectivity
of this venerable reaction of organic synthesis. While most methods
involve the metal assuming the role of Lewis acid in the activation
of the dienophile (Figure 1),1 an alternative strategy is to activate
the diene with a metal complex. Most commonly, this approach
has been used in the context of inverse-electron-demand Diels-
Alder reactions, but not universally so. For instance, seminal
research by Welker et al. has shown that cobalt-substituted dienes
show dramatically enhanced reactivity and stereoselectivity with
-7
8
conventional (i.e., electron-poor) dienophiles. Herein we explore
an alternative approach to promoting a classical Diels-Alder
reaction in which the reactivity of the diene is enhanced by its
coordination to a π-base (Figure 1). While disruption of the diene
π-system may seem counterintuitive for promoting a Diels-Alder
9
reaction, for a nonconcerted (i.e., ionic) mechanism, the metal could
facilitate the conjugate addition by stabilizing the allyl cation
intermediate as shown in Figure 1.
We chose as our test case the reaction of ethyl vinyl ketone with
cyclohexadiene, a reaction which is reported to have a 90%
completion period of >100 000 h at 25 °C.6
Figure 1. Metal-promoted Diels-Alder reactions.
The fragment {TpMo(NO)(MeIm)} (where Tp ) hydridotris-
pyrazolyl)borate and MeIm ) 1-methylimidazole) was chosen as
8
0% yield. Repeating the reaction in methanol at 25 °C also
(
delivered the complex 2 in 60% yield, without the aid of a Lewis
acid. For comparison, a similar solution of 1,3-cyclohexadiene and
the π-base because of its exceptionally low reduction potential,
which renders it a powerful π-base that can be easily air-oxidized
to obtain the desired organic product.10,11 Previously, we have shown
that this system can form robust dihapto-coordinated complexes
with conjugated dienes and that it resists conversion to the more
pedestrian tetrahapto coordination.1 Furthermore, {TpMo(NO)-
EVK, in CH
5 °C, failed to give any trace of cycloadduct over a similar time
frame.
Key spectroscopic features for the bicyclooctene complex 2
include an anodic wave in a cyclic voltammogram of 2 at Ep,a
0.280 V (NHE; 100 mV/s) and a ν(NO) of 1560 cm-1, each
2
Cl
2
with BF
3
‚OEt
2
at -40 °C or in methanol alone at
2
2,13
)
(
MeIm)} has been shown to both protect the bound CdC bond
-
1
0
and to activate the uncoordinated alkene toward protonation.
10
indicative of a TpMo(MeIm)(NO)(alkene) complex. In addition,
the absence of any olefinic signals in the 1H or 13C NMR spectrum
of 2 confirms that this species does not contain an uncoordinated
alkene. 1-Methylimidizole signals at 3.77 and 3.76 ppm point to a
mixture of two dominant diastereomers in a 1.5:1 ratio. Exposure
of a solution of 2 (prepared in situ from 1) to air for 3 h affords
1
2
Preparation of TpMo(NO)(MeIm)(η -cyclohexadiene) 1 is achieved
by reduction of TpMo(NO)(MeIm)Br (THF, sodium dispersion)
in the presence of 1,3-cyclohexadiene. Two coordination dia-
stereomers (1A and 1B) are isolated in a kinetic ratio of 1.5:1,
differing only by which face of the diene is coordinated by the
metal.11
14
-bicyclo[2.2.2]oct-5-en-2-ylpropan-1-one 3 in >95% yield from
the metal complex after isolation via thin-layer chromatography
6
(
Scheme 1). The bicyclooctene 3 can also be demetalated by
treatment with AgOTf. The product is isolated as a 6:1 ratio of
1
endo/exo isomers, and H NMR data of 3 are consistent with those
of previous reports.6
Other R,â-unsaturated ketones were screened for reactivity with
the molybdenum-bound cyclohexadiene; methyl vinyl ketone,
3-penten-2-one, mesityl oxide, methacrolein, and methyl acrylate
all gave products similar to that of ethyl vinyl ketone as shown in
Table 1. The reactions were all carried out under two sets of
When a solution of 1 is treated with ethyl vinyl ketone in
CH
the experiment is repeated at -40 °C with the addition of 25 mol
of BF ‚OEt , a molybdenum-bound 1-bicyclo[2.2.2]oct-5-en-2-
ylpropan-1-one complex 2 can be isolated (after basic workup) in
2 2
Cl , no reaction occurs after 3 days (25 °C). However, when
%
3
2
2 2
conditions, methanol at 25 °C or CH Cl at -40 °C with the
addition of BF ‚OEt . Due to the reduced electrophilicity of an ester
3
2
1426
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J. AM. CHEM. SOC. 2006, 128, 1426-1427
10.1021/ja0553654 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Scheme 2
Table 1
3
Liebeskind, in which η -bound pyranyl and pyridinyl complexes
of TpMo(CO)
cyclizations.16
2
undergo electrophile-led [4 + 2] and [5 + 3]
In conclusion, a [4 + 2] cyclization between cyclohexadiene and
2
various dienophiles is promoted by the η -coordination of the diene
to a π-basic transition metal complex. While the present system
may have its practical limitations, it demonstrates a novel approach
to facilitating the Diels-Alder reaction without Lewis acids,
microwave reactors,5 or high pressures.7 Efforts are currently
17
underway in our group to use an R-pinene-resolved form of 1 to
access enantioenriched cycloadducts.
Acknowledgment. This work was partially supported by the
NSF (CHE0111558 and 9974875) and the NIH (NIGMS; R01-
GM49236).
Supporting Information Available: Full synthetic details for
the preparation of cycloadducts 3-8 and characterization of com-
pound 2. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
a
b
(1) Evans, D. A.; Johnson, J. S. Diels-Alder Reactions. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 3, pp 1177-1235.
CH2Cl2 + 25 mol % BF3‚OEt2, -40 °C. MeOH, 25 °C. Yields
determined from proton NMR data using durene as an integration standard.
c
d
Methyl is trans to acetyl in both isomers. Best results.
(
(
(
2) Hollis, T. K.; Odenkirk, W.; Robinson, N. P.; Whelan, J.; Bosnich, B.
Tetrahedron 1993, 49, 5415-5430.
group (cf. aldehyde or ketone), methyl acrylate required several
equivalents of BF ‚OEt and a longer reaction period for the starting
material to be consumed. In methanol, 3-penten-2-one, mesityl
oxide, and methyl acrylate failed to yield cycloadducts. Dimethyl
fumarate, dimethyl maleate, and acrylamide were also tested, but
failed to give the intended product for either set of reaction
conditions. These results are outlined in Table 1.
In earlier work, we demonstrated that diene complex 1 can be
protonated to form the allyl species [TpMo(NO)(MeIm)(η -C
which has been spectroscopically and structurally characterized.
We hypothesize that the net [4 + 2] cycloaddition is proceeding
3) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808-
3809.
3
2
4) Pignat, K.; Vallotto, J.; Pinna, F.; Strukul, G. Organometallics 2000, 19,
160-5167.
(5) Chen, I.-H.; Young, J.-N.; Yu, J. Tetrahedron 2004, 60, 11903-11909.
6) Hollis, T. K.; Robinson, N. P.; Bosnich, B. J. Am. Chem. Soc. 1992, 114,
464-5466.
5
(
5
(7) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2000, 2, 3517-3520.
(
8) Hayes, B. L.; Adams, T. A.; Pickin, K. A.; Day, C. S.; Welker, M. E.
Organometallics 2000, 19, 2730-2740.
(9) A Lewis acid would be expected to catalyze both ionic and concerted
mechanisms.
3
+
6 9
H )] ,
(
10) Mocella, C. J.; Delafuente, D. A.; Keane, J. M.; Warner, G. R.; Friedman,
11
L. A.; Sabat, M.; Harman, W. D. Organometallics 2004, 23, 3772-3779.
(11) Keane, J. M.; Chordia, M. D.; Mocella, C. J.; Sabat, M.; Trindle, C. O.;
Harman, W. D. J. Am. Chem. Soc.2004, 126, 6806-6815.
through a conjugate addition to the unbound olefin to afford an
(
12) Knolker, H.-J. Chem. Soc. ReV. 1999, 28, 151-157.
(13) Complex 1 can be heated to 100 °C without any sign of decomposition.
2
10
“
η ” cyclohexadienium intermediate, which subsequently isomer-
(
14) The two major isomers account for approximately 85% of the total isomer
mixture. The two exo-isomer complexes were not characterized.
izes and closes to afford the six-membered ring according to Scheme
. The TBS-promoted reaction of an η -naphthalene complex and
acrylonitrile has been reported to operate by a similar reaction
mechanism.15
While there appear to be no other reports of η -diene complexes
participating in [4 + 2] cycloaddition reactions, this concept is
2
2
(
15) Ding, F.; Valahovic, M. T.; Keane, J. M.; Anstey, M. R.; Sabat, M.;
Trindle, C. O.; Harman, W. D. J. Org. Chem. 2004, 69, 2257-2267.
(16) Arrayas, R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 9026-
9
027.
(17) Meiere, S. H.; Valahovic, M. T.; Harman, W. D. J. Am. Chem. Soc. 2002,
24, 15099-15103.
2
1
similar to an elegant methodology developed by Arrayas and
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