Generation and trapping of isobenzofuran intermediates formed in the coupling of Fischer carbene complexes and o-alkynylbenzoyl derivatives

Article abstract of DOI:10.1021/ol005691i

(equation presented) The coupling of o-alkynylbenzoyl derivatives with carbene complexes has been investigated. The reaction initially affords isobenzofuran derivatives, which convert to alkylidenephthalan derivatives or can be trapped by various dienophi

Full text of DOI:10.1021/ol005691i

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1267-1269
Generation and Trapping of
Isobenzofuran Intermediates Formed in
the Coupling of Fischer Carbene
Complexes and o-Alkynylbenzoyl
Derivatives
Delu Jiang and James W. Herndon*
Department of Chemistry and Biochemistry, New Mexico State UniVersity, MSC 3C,
Las Cruces, New Mexico 88003
jherndon@nmsu.edu
Received February 18, 2000
ABSTRACT
The coupling of o-alkynylbenzoyl derivatives with carbene complexes has been investigated. The reaction initially affords isobenzofuran
derivatives, which convert to alkylidenephthalan derivatives or can be trapped by various dienophiles to afford benzo-oxanorbornene derivatives.
Recently, the synthesis of furans (e.g., 3, Scheme 1) through
the coupling of Fischer carbene complexes (2) with enyne-
alkynylbenzaldehyde derivative 4A with carbene complex
2 follows the same course as the reaction of aldehyde 1 and
complex 2, isobenzofuran 5A will be produced. Although
isobenzofurans are unstable, they have been proven to be
very useful synthetic intermediates.2
Scheme 1
(1) Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4563-4564.
(2) Friedrichsen, W. AdV. Heterocycl. Chem. 1999, 73, 1-96.
(3) This compound was a single isomer; the E-Z configuration for this
compound could not be reliably assigned. The depicted configuration has
been suggested (see Supporting Information for a discussion).
(4) The most notable feature is two singlets at δ 4.3 and 4.2, which are
consistent with the alkene protons in a 1,1-disubstituted enol ether. See
methoxypropene in the following: Pouchert, C. J.; Behnke, J. The Aldrich
Library of 13C NMR and 1H NMR Spectra; Aldrich Chemical: Milwaukee,
WI, 1992; Vol. 1, p 334A.
(5) For a theoretical discussion of the interconversion of isobenzofurans
and alkylidenephthalans, see: Friedrichsen, W. Struct. Chem. 1999, 10, 47-
51.
(6) (a) The stereochemical assignment was based on the coupling constant
of 5.5 Hz between the HA and HB, which is expected to be nearly 0 Hz in
the opposite stereoisomer. Yamaguchi, Y.; Yamada, H.; Hayakawa, H.;
Kenematsu, K. J. Org. Chem. 1987, 52, 2040-2046. (b) Chromium carbene-
alkyne coupling affords E enol ethers. McCallum, J. S.; Kunng, F. A.;
Gilberton, S. R.; Wulff, W. D. Organometallics 1988, 7, 2346-2360.
aldehydes (1) or ketones was reported.1 In this Letter, the
effect of replacing the central alkene functionality with an
aromatic ring will be examined. If the coupling of o-
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Coupling of o-alkynylbenzaldeyde derivative 4A and
methylcarbene complex 2 in refluxing dioxane afforded either
enol ether 6A or the corresponding ketone 7A (Scheme 2).
Scheme 3
Scheme 2
4B proceeded similarly to afford a 6:1 ratio of cycloadducts
9B in 91% yield.
A very complex reaction mixture resulted when the
dienophile trap was switched to dimethyl acetylenedicar-
boxylate (Scheme 4). The major product was naphthalene
The ketone3 was the exclusive product of the reaction after
purification using silica gel; however, the 1H NMR spectrum
of the crude product after filtration through Celite was
consistent with that of enol ether 6A.4 A similar reaction
was observed in the coupling of alkynylacetophenone deriva-
tive 4B with carbene complex 2. A likely mechanism in these
reactions is the formation of isobenzofuran derivative 5A
followed by a net 1,7-hydrogen shift5 followed by hydrolysis.
In the case of 5B, none of the 1,5-hydrogen shift isomer 8
was observed. Coupling of phenyl ketone 4C with the
carbene complex afforded a crude product (red oil) consistent
with the isobenzofuran structure 5C (accompanied by the
corresponding phenyl-Cr(CO)3 complex); however, attempts
to purify 4C by chromatography resulted in only ketone 7C.
The reaction process was also examined in the presence
of a dienophile, dimethyl fumarate (Scheme 3). The coupling
of alkynylbenzaldehyde 4A, carbene complex 2, and di-
methyl fumarate (∼1:1:1 ratio) led to the three-component
coupling product 9A6 in 54% yield. Ring-opened product
10 was observed after exposure to mild acids.7 Formation
of compound 9A occurs through generation of isobenzofuran
5A, followed by Diels-Alder reaction with dimethyl fuma-
rate to afford adduct 9A. Use of a large excess of dimethyl
fumarate led to a considerable quantity of alkene cyclopro-
panation product 11.8 The reaction employing acetyl analogue
Scheme 4
derivative 13A, which results from a reductive deoxygenation
of initial Diels-Alder adduct 12A.9 Competing coupling of
the carbene complex with dimethyl acetylenedicarboxylate
might account for the low yield in this case. Complex
reaction mixtures were obtained from three-component
couplings using ethyl acrylate or N-phenylmaleimide.
Since the isobenzofuran derived from benzophenone
analogue 4C appears to be fairly stable, a two-step (sequen-
tial) isobenzofuran synthesis-Diels-Alder coupling was
attempted. The reaction of alkyne 4C with carbene complex
2 for 1 h, followed by addition of N-phenylmaleimide
resulted in endo Diels-Alder adduct 14C (Scheme 5).10
Similar coupling using dimethyl acetylenedicarboxylate
afforded adduct 13C.
(7) Compound 10 (or the corresponding ketone) was observed if the
chloroform NMR sample was kept at room temperature for >12 h or if the
silica gel purification was conducted too slowly.
(8) Wienand, A.; Reissig, H.-U. Organometallics 1990, 9, 3133-3142.
(9) For efficient deoxygenation using chromium(0) species, see: Wulff,
W. D.; Kaesler, R. W.; Peterson, G. A.; Tang, P.-C. J. Am. Chem. Soc.
1985, 107, 1060-1062.
(10) High endo selectivity is observed for coupling of free iosbenzofurans
and N-methylmaleimide. Tobia, D.; Rickborn, B. J. Org. Chem. 1987, 52,
2611-2614. The endo configuration is suggested on the basis of the
chemical shifts of HA and HB at >4 ppm.
(11) The exo stereochemical assignment is based on the 0 Hz coupling
of HA and HB and the chemical shifts of HB and HC (∼3 ppm, see ref 10).
(12) We are not aware of an isolated η5-furan-Cr(CO)3 complex;
however, numerous thiophene and pyrrole complexes have been reported.
For a recent example, see: Loft, M. S.; Mowlem, T. J.; Widdowson, D. A.
J. Chem. Soc., Perkin Trans. 1 1995, 97-104 and references therein.
1268
Org. Lett., Vol. 2, No. 9, 2000

Scheme 5
Scheme 6
In summary, isobenzofuran synthetic equivalents are
readily generated from the coupling of o-alkynylbenzoyl
derivatives with Fischer carbene complexes. The intermedi-
ates can undergo hydrogen shift processes or can be trapped
through Diels-Alder reactions with electron-deficient di-
enophiles. Further research to define the scope of this process
is currently underway in our laboratory.
Surprisingly, alkyne-aldehyde 4A could also undergo a
sequential isobenzofuran formation-Diels-Alder sequence.
Thus, refluxing a mixture of alkyne 4A and carbene complex
2 in dioxane for 0.5 h followed by addition of dimethyl
acetylenedicarboxylate led to the expected Diels-Alder
adduct 13A in 20% yield, accompanied by unreacted
alkyne-aldehyde and ketone 7A (Scheme 6). A similar
reaction sequence employing N-phenylmaleimide led to the
exo11 Diels-Alder adduct 14A. A free isobenzofuran is
unlikely in the reactions of 4A based on the high exo
selectivity, coupled with the substantial lifetime of the
intermediate at 100 °C. The observed isobenzofurans could
be stabilized by complexation to chromium,12 and thus the
adducts would result from an insertion-reductive elimination
sequence.13
Acknowledgment. The authors thank the National Sci-
ence Foundation, the Petroleum Research Fund, administered
by the American Chemical Society, and New Mexico State
University for financial support of this research. We thank
the Mass Spectrometry Facility at the University of Maryland
for acquisition of mass spectra.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and characterization data
for coupling products 7A-C, 9A-B, 13A, 13C, 14A, and
14C. This material is available free of charge via the Internet
at http://pubs.acs.org.
(13) The stereochemistry can be dramatically affected in metal-mediated
processes. Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc.
1995, 117, 1843-1844.
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