Electrocyclic ring closure of the enols of vinyl quinones. A 2H-chromene synthesis

Article abstract of DOI:10.1021/ol0167199

equation presented Thermolysis of enolizable vinyl quinones in polar, aprotic media provides 2H-chromenes. Experimental evidence supports a two-step mechanism in which enolization is followed by a thermal 6π-electrocyclic reaction of an intermediate quinone methide. Application of this method led to the total synthesis of the reputed structure of an Ageratum juvenile hormone. When enolizable vinyl quinones are the products of Stille coupling, the chromene annulation product is obtained directly.

Full text of DOI:10.1021/ol0167199

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3875-3878
Electrocyclic Ring Closure of the Enols
of Vinyl Quinones. A 2H-Chromene
Synthesis
,#
Kathlyn A. Parker* and Thomas L. Mindt
Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
kathlyn_parker@brown.edu
Received September 7, 2001
ABSTRACT
Thermolysis of enolizable vinyl quinones in polar, aprotic media provides 2H-chromenes. Experimental evidence supports a two-step mechanism
in which enolization is followed by a thermal 6π-electrocyclic reaction of an intermediate quinone methide. Application of this method led to
the total synthesis of the reputed structure of an Ageratum juvenile hormone. When enolizable vinyl quinones are the products of Stille
coupling, the chromene annulation product is obtained directly.
Although the science of organic synthesis offers countless
predictable methods for functional group conversions, prac-
titioners continue to be surprised by the appearance of
unexpected transformations. These fortuitous discoveries
enrich and expand the collection of design principles
available for the planning of synthetic schemes. In this Letter,
we report a new, efficient, and serendipitously discovered
2H-chromene preparation and its subsequent application in
a rationally designed synthesis.
1). This assignment was later confirmed by X-ray crystal-
lography (Figure 1).
Scheme 1. Fortuitous Discovery of the Formation of
2H-Chromene 5 from a Stille Coupling Procedurea
In the context of the total synthesis of quinonoid natural
products,1 we attempted the preparation of quinone 3 by Stille
coupling of bromobenzoquinone (1)2 with stannane 2.3
Instead of affording the expected product, this reaction
yielded a mixture of hydroquinone 4 and a compound to
which we assigned the 2H-chromene structure 5 (Scheme
# Current address: Department of Chemistry, State University of New
York at Stony Brook, Stony Brook, NY 11794.
(1) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2 (4), 497-499 and
references therein.
(2) From the KBrO3 oxidation of commercially available bromo hyd-
roquinone according to McElvain, S. M.; Engelhardt, E. L. J. Am. Chem.
Soc. 1944, 66, 1077-1080.
(3) Collins, P. W.; Kramer, S. W.; Gasiecki, A. F.; Weier, R. M.; Jones,
P. H.; Gullikson, G. W.; Bianchi, R. G. J. Med. Chem. 1987, 30, 193-
197.
a (a) 5 mol % of (Ph3P)4Pd, toluene, reflux.
10.1021/ol0167199 CCC: $20.00 © 2001 American Chemical Society
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cleanly from ethyl acetate/hexane, and the cis isomer 4b was
recovered from the mother liquor as an oil. Oxidation
completed the synthesis of the desired quinones trans 3a and
cis 3b.
Exposure of either isomer of quinone 3 to the conditions
of the Stille coupling resulted in the formation of products
4 and 5 in yields similar to those in the original experiment.
A trace of a new side product, benzofuran 9, was also
recovered in each case. This result is consistent with a
mechanistic picture in which both products 4 and 5 arise
from subsequent transformations of coupling products 3a and
3b.
Figure 1. ORTEP plot of 2H-chromene 5.
We therefore focused on discovery of the requirements
for the conversion of quinones 3 to benzopyran 5 and on its
optimization. We soon learned that neither the palladium
reagent nor the phosphine ligand was needed. Experiments
with a Stille catalyst in which there was no phosphine ligand7
left the substrate 3a or 3b unchanged. However, experiments
with a variety of phosphorus reagents (phosphine oxides as
well as phosphines)8 in the absence of palladium catalysts
effected conversion to product mixtures. Because the rate
enhancement of the conversion appeared to be independent
of the functional group of the phosphorus reagent, we
concluded that these additives do not participate in the
reaction but facilitate it by altering the polarity of the reaction
medium. Examination of a variety of media revealed that
no reaction occurred in the absence of a polar additive and
that the polar additive need not be a phosphorus compound
(for example, nontoxic DMPU9 proved to be an effective
additive). However, the additive must be aprotic; for
example, the presence of water led to decomposition products
at the elevated temperatures required for the cyclization. Of
those procedures tested, the most effective involved heating
of a dilute solution of substrate, in the dark, in dry toluene
that contains traces of HMPA (0.5%). We also found that
the addition of mild Lewis acids, most conveniently FeCl3,
improved the conversion of the less reactive trans 3a but
that it had no effect on the conversion of cis 3b. These
optimized conditions precluded the formation of side prod-
ucts and provided chromene 5 in yields up to 86% from cis
3b and 76% from trans 3a (Scheme 3).
The chromane or benzopyran substructure is frequently
found in naturally occurring heterocycles, many of which
exhibit biological activity.4 The key bicyclic ring system has
inspired a number of different synthetic approaches.5 How-
ever, that represented by Scheme 1 is novel and its possible
utility prompted us to investigate the mechanism of the
formation of chromene 5 and the generality of the conversion.
To determine whether the expected coupling product 3
was an intermediate on the path to the chromene product,
we decided to prepare this compound by an independent
synthesis (Scheme 2) and to study its chemistry. Thus, bromo
Scheme 2. Synthesis of Proposed Intermediate 3 and Its
Conversion to 2H-Chromene 5 under Stille Coupling
Conditionsa
Consideration of the possible mechanism by which product
chromene 5 might arise led to the postulate that o-quinone
methide intermediate 10 might undergo a 6π-electrocyclic
reaction (Scheme 3). The formation of a long-lived inter-
mediate was suggested by the impressive, transient red color10
a (a) TESOTf, imidazole, DMF; (b) 5 mol % of (Ph3P)4Pd,
toluene, reflux; (c) AcOH, H2O, THF; (d) Ag2O, O2, THF.
(5) (a) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; daSilva, A. J. M.;
Snieckus, V. Synthesis 1998, 279-282 and references therein. (b) Schweizer,
E. E.; Minami, T.; Crouse, D. M. J. Org. Chem. 1971, 36 (26), 4028-
4032. (c) Zsindely, J.; Schmid, H. HelV. Chim. Acta 1968, 51 (7), 1510-
1514.
(6) The NMR spectra of this product are complex because of Sn coupling.
(7) Tris(dibenzylideneacetone)dipalladium(0) ) Pd2(dba)3.
(8) The following additives were tested in amounts of 0.5-5 equiv of
Ph3P, (MeO)3P, (Me2N)3P, (MeO)2P(OH), Ph3PO, (MeO)3PO, MeP(O)-
(OMe)2, and (Me2N)3PO.
hydroquinone 6 was protected as its di-TES derivative 7.
Coupling with stannane 2 (presumably a cis/trans mixture)6
provided intermediate 8. Deprotection gave hydroquinone 4
as a cis/trans (1:3) mixture. The trans isomer 4a crystallized
(4) (a) Bowers, R. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science
1976, 193, 542-547. (b) Ellis, G. P. Chromenes, Chromanones and
Chromones. In Chemistry of Heterocyclic Compounds; John Wiley&
Sons: New York, 1977; Vol. 31, pp 11-141.
(9) DMPU ) 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
(10) The intermediate was characterized by the absorbance spectrum of
the reaction mixture which underwent a bathochromic shift from 333 nm
(yellow) to 485 nm (dark red).
3876
Org. Lett., Vol. 3, No. 24, 2001

Scheme 3. Optimized Reaction Conditions and Mechanism of
the Transformation of Quinone 3 to 2H-Chromene 5a
Figure 2. Reported structure of the juvenile hormone from
Ageratum conyzoides.
a (a) 5mM 3a in toluene, 0.5% HMPA, FeCl3, reflux, dark, 45
min; (b) 5 mM 3b in toluene, 0.5% HMPA, reflux, dark, 2 h.
from Ageratum conyzoides (Figure 2),15 we turned our
attention to studies in which the quinonoid moiety was the
2-substituted 5-methoxybenzoquinone.
that appeared when HMPA was added to a toluene solution
of substrate. The intermediate could not be trapped or
isolated. However, it is sufficiently stable at 10 °C to allow
characterization by NMR experiments.11 Although quinone
methides have been postulated as intermediates in the
formation of chromene products,12 these structures have not
previously been directly observed in these transformations.
The potential of the benzopyran annulation methodology
in total synthesis led us to examine its generality.13 First we
tested the conversion of the naphthoquinone 1114 to the
tricyclic product 12. This reaction provided cleanly the
anticipated naphthopyran (Scheme 4).
Quinone 14a proved to be a good substrate for the thermal
isomerization, giving 15a in good yield (Scheme 5). There-
Scheme 5. Annulation of a Variety of Benzoquinone
Substratesa
Scheme 4. Synthesis of Tricyclic Naphthopyran 12 by Means
of the Novel Annulation Methodologya
a (a) 5 mM in toluene, 0.5% HMPA, reflux, dark.
fore, our next experiments in which we varied the enolizable
functional group and the substitution on the side chain were
carried out with this system. Yields for cyclization of
R-substituted ester 14b, ketone 14c, and R-substituted ketone
14d14 were uniformly good.
a (a) 5 mM in toluene, 0.5% HMPA, reflux, dark, 8 h.
Although methylation of phenol 15d (methyl iodide,
potassium carbonate, 18-crown-6, DMF) provided the target
structure 13 in 79% yield, comparison of the spectroscopic
data for this product with those reported in the literature
revealed that our synthetic material does not correspond to
the Ageratum juvenile hormone. Close examination of the
NMR data listed for the natural product indicates that it is
Next, because we were interested in the eventual applica-
tion of our methodology to the synthesis of 2H-chromene
13, reported to be the structure of a juvenile hormone (JH)
1
(11) The H and 13C NMR spectra of this solution are contained in the
Supporting Information. These spectra support the conclusion that >80%
of the quinone 3 had isomerized to enol 10.
(12) (a) Kopanski, L.; Karbach, D.; Selbitschka, G.; Steglich, W. Liebigs
Ann. Chem. 1987, 793-796. (b) Iyer, M. R.; Baskaran, S.; Trivedi, G. K.
J. Indian Chem. Soc. 1994, 71, 341-343. (c) Bissada, S.; Lau, C. K.;
Bernstein, M. A.; Dufresne, C. Can. J. Chem. 1994, 72, 1866-1869. (d)
See also refs 4b and 5.
(13) Similar electrocyclic closures of dienones give mixtures of products;
these do not benefit from the restoration of aromaticity obtained when the
product is a benzopyran. See, for example: (a) Bu¨chi, G.; Yang, N. C. J.
Am. Chem. Soc. 1957, 79, 2318-2323. (b) Ishii, K.; Mathies, P.; Nishio,
T.; Wolf, H. R.; Frei, B.; Jeger, O. HelV. Chim. Acta 1984, 67, 1175-
1183.
(14) The preparation of these substrates is described in the Supporting
Information. Quinones were prepared immediately before use, and all except
substrates 3a and 3b were used as cis/trans mixtures. All new compounds
were fully characterized. NMR spectra of quinones 11 and 14 show
impurities which may be the corresponding enols. Quinones and benzopyran
products bearing a hydrogen at the C-2 position were notably less stable
than the C-2 (R to carbonyl) alkylated analogues.
(15) Pari, K.; Rao, P. J.; Subrahmanyam, B.; Rasthogi, J. N.; Devakumar,
C. Phytochemistry 1998, 49 (5), 1385-1388.
Org. Lett., Vol. 3, No. 24, 2001
3877

not a 2H-chromene.16 We have not been able to obtain a
sample of the natural material for comparison or for the
collection of additional structural data.
lization/electrocyclization strategy to the preparation of other
ring systems is currently under investigation.
Acknowledgment. This work was supported by the
National Institutes of Health (CA-87503). T.L.M. is a Fellow
of the Graduate Assistance in Areas of National Need
program of the U.S. Department of Education. We thank
Professor Gene B. Carpenter for solving the crystal structure
of 2H-chromene 5, Ivan Keresztes and Madeleine Jacobson
for assistance with the low-temperature NMR experiments,
and Dr. Tun Li Shen for the mass spectroscopic measure-
ments.
A scheme in which a halo hydroquinone is elaborated to
a benzopyran by protection, Stille coupling, deprotection,
oxidation, and thermolysis in better than 50% yield overall
(Scheme 2, steps a-d followed by Scheme 3) may be
considered relatively efficient by today’s standards. However,
the one-pot Stille coupling (of a haloquinone), enolization,
and cyclization method (Scheme 1) provides 30% of the
chromene product directly. The efficiency of this approach
to 2H-chromenes (which does require a chromatographic
separation of the chromene from the byproducts) may be
competitive in some situations. The extension of the eno-
Supporting Information Available: Detailed description
of the experimental procedures and complete analytical data
of all new compounds. X-ray crystallographic data of 2H-
chromene 5 in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) For a tabular comparison of the 1H NMR data for compounds 5,
13, and the reputed Ageratum juvenile hormone, see the Supporting
Information.
OL0167199
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