Electron-deficient dienes. 5. An inverse-electron-demand Diels-Alder approach to 2-substituted 4-methoxyxanthones and 3,4-dimethoxyxanthones

Article abstract of DOI:10.1021/ol702614b

(Chemical Equation Presented) Several 4-methoxyxanthones and 3,4-dimethoxyxanthones were synthesized in good yield via inverse-electron- demand Diels-Alder (IEDDA) driven domino reactions between a series of electron-deficient chromone-fused dienes with 1-(2,2-dimethoxyvinyl)pyrrolidine or tetramethoxyethene, respectively.

Full text of DOI:10.1021/ol702614b

ORGANIC
LETTERS
2008
Vol. 10, No. 2
233-236
Electron-Deficient Dienes. 5. An
Inverse-Electron-Demand Diels
Approach to 2-Substituted
4-Methoxyxanthones and
3,4-Dimethoxyxanthones
−Alder
Anh-Thu Dang,† David O. Miller,‡ Louise N. Dawe,† and Graham J. Bodwell*,†
Department of Chemistry, Memorial UniVersity, St. John’s, NL A1B 3X7, Canada, and
CREAIT Network, Memorial UniVesity, St. John’s, NL A1B 3X5, Canada
gbodwell@mun.ca
Received October 26, 2007
ABSTRACT
Several 4-methoxyxanthones and 3,4-dimethoxyxanthones were synthesized in good yield via inverse-electron-demand Diels−Alder (IEDDA)
driven domino reactions between a series of electron-deficient chromone-fused dienes with 1-(2,2-dimethoxyvinyl)pyrrolidine or tetramethoxy-
ethene, respectively.
More than 500 naturally occurring xanthones1 have been
isolated from higher plants, fungi, and lichens. Many of these
compounds exhibit potentially useful pharmaceutical proper-
ties, e.g., antibacterial, anticancer, and inflammatory behav-
ior.2 Consequently, despite their relatively simple structures,
xanthones continue to attract synthetic interest. A variety of
general approaches to the synthesis of xanthones have been
developed.3 Classical methods involve cyclizations of ben-
zophenones or diaryl ethers, but reaction conditions can often
be harsh and the precursors can require lengthy synthesis.
More recently published approaches to xanthones include
1,2-additions of organolithium reagents to dithiane-protected
γ-benzopyrone-fused cyclobutenediones,4 the condensation
of benzopyranonaphthalide with Michael acceptors5 and
reactions between benzynes and 2-hydroxybenzoates.6 Both
normal and inverse-electron-demand Diels-Alder (IEDDA)
reactions of 2-vinylchromone derivatives have also been
applied to xanthone synthesis, but these have suffered from
low to moderate yields.7
We reported previously that the IEDDA reaction between
electron-deficient dienes 1 and electron-rich dienophiles, e.g.,
enamines 2, gave 2-hydroxybenzophenones 4 instead of the
desired xanthones 7 (Scheme 1).8 The formation of 4 was
explained by an elimination reaction of intermediate 3,9
(5) Hauser, K. M.; Dorsch, W. A. Org. Lett. 2003, 5, 3753.
(6) (a) Zhao, J.; Larock, R. C. Org. Lett. 2007, 72, 583. This group has
also recently reported xanthone synthesis via an aryl to imidazoyl migration
process involving C-H activation. See (b) Zhao, J.; Yue, D.; Campo, M.
A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129, 5288.
† Department of Chemistry.
‡ CREAIT Network.
(1) For a recent review, see: Vieira, L. M. M., Kijjoa, A. Curr. Med.
Chem. 2005, 12, 2413.
(2) For a recent review, see: Pinto, M. M. M., Sousa, M. E., Nascimento,
M. S. J. Curr. Med. Chem. 2005, 12, 2517.
(3) For a recent review, see: Sousa, M. E.; Pinto, M. M. M. Curr. Med.
Chem. 2005, 12, 2447.
(7) (a) Ghosh, C. K.; Bhattacharyya, S.; Patra, A. J. Chem. Soc., Perkin
Trans. 1 1997, 15, 2167. (b) Kelkar, A. S.; Letcher, R. M.; Cheung, K. K.;
Chiu, K. F.; Brown, G. D. J. Chem. Soc., Perkin Trans. 1 2000, 3732.
(8) IEDDA reactions of isomeric coumarin-fused electron deficient dienes
with enamines 2 afforded benzocoumarins via a domino IEDDA /
elimination / dehydrogenation sequence. See: Bodwell, G. J.; Pi, Z.; Pottie,
I. R. Synlett 1999, 477.
(4) Sun, L.; Liebeskind, L. J. Am. Chem. Soc. 1996, 118, 12473.
10.1021/ol702614b CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

Scheme 1
Scheme 2
to excellent yield (Table 1). Tlc analysis of these reactions
showed spot-to-spot conversion of the starting materials into
Table 1. Reactions of Dienes 1a-i with Dienophile 8
which was formed upon elimination of pyrrolidine from the
initial IEDDA adduct.10
To block the pathway leading to 4 and thus be able to use
dienes 1 for xanthone synthesis, two criteria were identi-
fied: the carbon atom of the dienophile that reacts with the
more electron-deficient terminus of the diene should (1) bear
no hydrogen atom and (2) bear a leaving group. As such,
intramolecular 1,2-elimination (3 f 4) cannot occur. Instead,
elimination of HX from 6 should furnish xanthones 7.
Dienophiles such as enamine 8 and tetramethoxyethene
(TME, 9)11 meet these criteria and we report their use for
the synthesis of several 2-substituted 4-methoxyxanthones
and 3,4-dimethoxyxanthones.
entry
EWG
product
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
CONEt2
CO2Et
COPh
COMe
SO2Ph
CN
p-C6H4NO2
C6H5
p-C6H4OMe
14a
14b
14c
14d
14e
14f
14g
14h
14i
16
2
6.5
6
16
2
2
50
71
85
90
70
84
70
51
39
17
44
Dienes 1a-i were synthesized in moderate to excellent
yield in one step from 3-formylchromone (10) using either
a Wittig (1d),12 a Horner-Wadsworth-Emmons (HWE)10,12,13
(1a-c,e) or a decarboxylative condensation reaction14 with
the corresponding phenylacetic acid (1f-i) (Scheme 2 and
Supporting Information). Noncommercially available HWE
phophonates were synthesized according to published pro-
cedures.15
the products. The yields and reaction rates show a rough
trend toward increasing with the strength of the electron-
withdrawing group and decreasing with its steric demands.
Among dienes 1a-f (Table 1, entries 1-6), diene 1f, which
has a small and strongly electron-withdrawing substituent
(EWG ) CN), is among the fastest to react and gives one
of the best yields (14g, 84%). The slowest of this group to
react are dienes 1a and 1e, which have either a moderately
electron-withdrawing substituent (EWG ) CONEt2) or a
strongly withdrawing but bulky substituent (EWG )
SO2Ph). The sensitivity of both the rate and yield of the
reaction to electronic effects can be seen in the behavior of
the aryl-substituted dienes 1g-i (Table 1, entries 7-9). All
of these observations are consistent with a rate-limiting,
asynchronous IEDDA reaction,16 followed by two fast
Reaction of dienes 1a-i with freshly generated enamine
8 (from dimethoxyacetaldehyde and pyrrolidine) in benzene
at reflux afforded the expected xanthones 14a-i in moderate
(9) Mechanistically, this is an elimination reaction. Like all elimination
reactions, it is an intramolecular reaction, but it differs from most others in
that the reverse reaction is an intramolecular addition.
(10) Bodwell, G. J.; Hawco, K. M.; da Silva, R. P. Synlett 2003, 179.
(11) Bellus, D.; Fischer, H.; Greuter, H.; Martin, P. HelV. Chim. Acta
1978, 61, 1784.
(12) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. For the
preparation of the ylide leading to 1d, see: Bell, T. W; Sondheimer, F. J.
Org. Chem. 1981, 46, 217.
(13) Wadsworth, W. S. Org. React. (N.Y.) 1977, 25, 73.
(14) (a) Nohara, A.; Umetani, T.; Sanno, Y. Jpn. Kokai Tokyo Koho
1975, JP50052067. (b) Silva, V. L. M. Silva, A. M. S. Pinto, D. C. G. A.
Cavaleiro, J. A. S. Patonay, T. Synlett 2004, 2717.
(15) For 11, see: Watanabe, M.; Hisamatsu, S.; Hotokezaka, H.;
Furukawa, S. Chem. Pharm. Bull. 1986, 34, 2810. For the phosphonate
leading to 1c, see: Mathey, F.; Savignac, P. Tetrahedron 1978, 34, 649.
For the phosphonate leading to 1e, see: Enders, D.; von Berg, S.; Jandeleit,
B. Org. Synth. 2002, 78, 169.
234
Org. Lett., Vol. 10, No. 2, 2008

eliminations (pyrrolidine and methanol, in either order) to
give the observed 4-methoxyxanthones 14.
of the reaction mixture at 135 °C or resubjection of 15d to
the original reaction conditions resulted in the slow formation
of intractable material, but in a TLC experiment, the addition
of Et2O‚BF3 to a pure sample of 15d in dichloromethane at
room temperature induced a rapid, spot-to-spot conversion
to 16d.
Subsequent reactions of dienes 1 with TME (9) were
heated at 135 °C, cooled to room temperature after con-
sumption of the diene or apparent reaction cessation (TLC
analysis), diluted with dichloromethane, and treated with
Et2O‚BF3 (4.0 equiv) to give 3,4-dimethoxyxanthones 16
(Table 2). Good yields were obtained for 16c (84%) and 16d
Attention was then turned to the use of tetramethoxyethene
(TME) (9),11 which was expected to afford 3,4-dimethoxy-
xanthones via an IEDDA/elimination (MeOH)/elimination
(MeOH) sequence. As anticipated for this less polar and more
highly substituted dienophile, it proved to be a more reluctant
reaction partner. Under conditions similar to those used for
the reactions of dienophile 8 with dienes 1a-i, no reaction
was observed between diene 1d (ca. 0.2 M in benzene,
reflux) and TME (5.0 equiv). The same result was obtained
when toluene and then xylenes were used as the solvent.
However, when 1d was reacted with TME at 135 °C (bp
of TME ) 140 °C)11 with no solvent, the diene was
consumed and xanthone 16d (6%) was isolated as well as
an unaromatized product (Scheme 3), the spectroscopic data
Table 2. Reactions of Dienes 1a-i with Dienophile 9
Scheme 3
time (h), yield (%)
no
entry
EWG
product solvent xylenes C2H2Cl4 DMF
1
2
3
4
5
6
7
8
9
CONEt2
CO2Et
COPh
COMe
SO2Ph
CN
p-C6H4NO2
C6H5
p-C6H4OMe
16a 96, 28
16b 24, 36
16c 24, 84
16d 10, 62
16e 2, 29
192, 32 192, 40 192, 12
144, 48 48, 70
26, 90
6, 98
24, 21 4, 18
24, 38
16f
2, 27a
16g 23, 25b
48, tracee
240, 6
240, 0
16h 48, tracec
16i
96, 0d
a 53% without Et2O‚BF3 treatment. b 20% recovery of 1g. c 60% recovery
of 1h. d 60% recovery of 1i. e 59% recovery of 1g.
of which were consistent with one of the expected reac-
tion intermediates, 18d (Scheme 4). However, its identity
as an isomer, 15d (56%), was established by crystallographic
methods (see the Supporting Information). Prolonged heating
(62%), while those for 16a,b and 16e-g were modest
(25-36%). The least electron-deficient dienes 1h and 1i were
unreactive, giving at best only traces of product. As an
exception, 1f gave a better yield of the product (16f, 53%)
without treatment with Et2O‚BF3.
The use of high-boiling solvents (xylenes, 1,1,2,2-tetra-
chloroethane, and DMF), but with more concentrated solu-
tions (ca. 1.0 M) than before, was then revisited. For dienes
1a and 1b, a steady improvement in the yield was observed
in going from no solvent (28% and 36%) to xylenes (32%
and 48%) and then 1,1,2,2-tetrachloroethane (40% and 70%).
In changing to a much more polar solvent (DMF), the yield
of 16a dropped off considerably (12%), and DMF was
consequently excluded from further study. The use of 1,1,2,2-
tetrachloroethane also resulted in significant yield enhance-
ments for xanthones 16c (90%) and 16d (98%).
Scheme 4
Dienes 1e and 1f behaved somewhat differently. Upon
treatment of the crude mixtures with Et2O‚BF3, a yellow
byproduct, 19e (10%) and 19f (4%), formed alongside the
(16) A stepwise reaction (Michael/Mannich) cannot be ruled out at this
time, but we currently favor the asynchronous IEDDA pathway. More
detailed commentary on this subject will be forthcoming.
Org. Lett., Vol. 10, No. 2, 2008
235

desired xanthones 16e (18%) and 16f (38%). The structure
of 19e was determined using single-crystal X-ray analysis,
and that of 19f was assigned by analogy. The aryl substituted
dienes 1g-i exhibited little or no reactivity toward TME (9).
Slow, unproductive consumption of these dienes was ob-
served under prolonged heating.
the Supporting Information for a proposed mechanism). Why
the byproduct formed only in the reactions of 1e,f is unclear.
Like xanthone itself,23 xanthones 14a-f and 16a-h
exhibited very weak fluorescence (φem < 10-3). However,
the behavior of the 2-arylxanthones 14g-i was more
interesting (see the Supporting Information). As the electron-
donating ability of the aryl substituent increased, the lowest
energy absorption bands of 14g-i moved to higher energy
and the emission bands moved to lower energy with a
concomitant increase in intensity, which is inconsistent the
“energy gap law”.24 Furthermore, λt became larger (λt )
1680, 2390, 3030 cm-1 for 14g-i, respectively) as calculated
from the increasing Stokes shifts.25 By comparison, λt ranges
from 1420 to 1720 cm-1 for 14a-f and 16a-h. Quantum
yields (φem) for 16h, 14h and 14i are 0.007, 0.07, and 0.13,
respectively. A tentative interpretation of this data is that
charge transfer becomes more significant along the series
14g-i, which increases λvib due to population of the π*
A proposed reaction landscape that is consistent with the
observations is presented in Scheme 4. IEDDA reaction
between 1 and 9 at 135 °C affords adducts 17, which can
undergo 1,2-elimination of methanol to afford dienes 18. This
elimination is proposed to occur first because the C(2)
hydrogen atom should be the most acidic,17 and by inspec-
tion, an antiperiplanar orientation of the C-H and one of
the adjacent C-O bonds looks to be easily achievable.
Dienes 18 then have two pathways available to them, namely
the 1,2-elimination of a second molecule of methanol18 to
afford xanthones 16 and rearrangement to give dienes 15.19
Rearrangement could conceivably occur either through a 1,5
H
24
shift20 or an acid- or base-catalyzed tautomerization. Regard-
less of which mechanism operates, the partial aromaticity
of the 4-pyrone ring21 in 15 may provide some incentive for
rearrangement. Whatever the case, AM1 calculations22
predict that the lowest energy conformer of 15e is ca. 4 kcal/
mol more stable than that of 18e. The reluctance of the
rearranged dienes 15 to undergo what must surely be a very
exothermic elimination of methanol under quite forcing
conditions (135 °C) is somewhat surprising, even considering
that the C(3)-H bond of 15d is oriented essentially gauche
to both C(4)-O bonds (disfavoring E2-like elimination) in
the crystal (see inset in Scheme 3). Treatment of dienes 15
with Et2O‚BF3 proceeds smoothly under mild conditions,
presumably because an E1-like mechanism becomes avail-
able.
orbitals of the acceptor (the xanthone moiety) and λo due
to changes in the dipole moment on formation of the charge-
transfer excited state.26 A Franck-Condon line-shape analy-
sis of the emission spectra and lifetime studies are currently
underway to test this hypothesis.
In summary, IEDDA reactions between dienes 1 and
dienophiles 8 and 9 afford a range of 4-methoxy- (14) and
3,4-dimethoxyxanthones (16) with useful functionality at the
2 position. Work aimed at the use of this methodology for
the construction of more elaborate xanthonoid systems and
new xanthone-based fluorophores is underway.
Acknowledgment. Financial support of this work from
the Natural Sciences and Engineering Research Council
(NSERC) of Canada is gratefully acknowledged. Dr. D. W.
Thompson (Memorial University) is thanked for valuable
discussions.
The formation of byproducts 19e,f in the reactions of 1e,f
with 9 is difficult to explain without invoking the involve-
ment of dienes 18e,f. Whether these dienes are present at
the end of the thermal stage of the reaction or they come
from 15e,f or 17e,f upon treatment with Et2O‚BF3, the
conversion of 18e,f to 19e,f can be accounted for by a BF3-
catalyzed tautomerism involving the transfer of a methyl
group from one end of a vinylogous ester to the other (see
Supporting Information Available: Experimental pro-
cedures, characterization data, 1H and 13C NMR spectra for
1a-i, 14a-i, 15d, 16a-h, and 19e,f, UV-vis spectra and
fluorescence spectra for 14a-i and 16a-h, crystal structure
data and CIF files for 15d and 19e, and a proposed
mechanism for the conversion of 18e,f to 19e,f. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) For example, in the case of 17b, this H atom is part of a vinylogous
malonate, i.e., glutaconate, system.
OL702614B
(18) On the surface, this elimination doesn’t appear to be disfavored in
any way. In an AM1-calculated (ref 21) structure of 18f, a H-C-C-O
dihedral angle of 164° at the site of elimination is predicted.
(19) The question arises of whether the reactions of dienes 1 with enamine
8 involve a similar rearrangement. Based on the evidence that is currently
available, this possibility cannot be discounted.
(20) Hess, A. B., Jr.; Baldwin, J. E. J. Org. Chem. 2002, 67, 6025.
(21) (a) Zborowski, K.; Ryszard, G.; Proniewicz, L. M. J. Phys. Org.
Chem. 2005, 18, 250. (b) Lumbroso, H.; Cure, J.; Evers, M.; Z. Naturforsch.
A 1986, 41, 1250.
(23) (a) Heinz, B.; Schmidt, B.; Root, C.; Satzger, H.; Milota, F.; Fierz,
B.; Kiefhaber, T.; Zinth, W.; Gilch, P. Phys. Chem. Chem. Phys. 2006, 8,
3432. (b) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of
Photochemistry; Marcel Dekker: New York, 1993.
(24) The intensity changes indicate that there are other (yet to be
identified) nonradiative pathways that lower fm.
(25) Stokes shifts are given by Eabs - Eem ) 2lt, where lt is the total
reorganization energy, which is a linear combination of the vibrational (lvib
)
and solvent reorganization (lo) energies, respectively.
(22) Chem3D, Version 5.0.
(26) Chen, P.; Meyer, T. J. Chem. ReV. 1998, 98, 1439.
236
Org. Lett., Vol. 10, No. 2, 2008