Use of 4-cyanocoumarins as dienophiles in a facile synthesis of highly substituted dibenzopyranones

Article abstract of DOI:10.1021/ol802792g

(Chemical Equation Presented) A new synthesis of dibenzopyranones 14 is reported via the Diels-Alder cycloaddition of 4-cyanocoumarins 12 with 1-silyloxydienes 10 to give the adducts 13 which are then converted into 14 in one step via treatment with base and loss of the cyano and silyloxy groups.

Full text of DOI:10.1021/ol802792g

ORGANIC
LETTERS
2
009
Vol. 11, No. 3
57-760
Use of 4-Cyanocoumarins as
Dienophiles in a Facile Synthesis of
Highly Substituted Dibenzopyranones
7
Michael E. Jung* and Damian A. Allen
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095
jung@chem.ucla.edu
Received December 3, 2008
ABSTRACT
A new synthesis of dibenzopyranones 14 is reported via the Diels-Alder cycloaddition of 4-cyanocoumarins 12 with 1-silyloxydienes 10 to
give the adducts 13 which are then converted into 14 in one step via treatment with base and loss of the cyano and silyloxy groups.
Dibenzopyranones serve as the structural core for many
natural products including the structurally similar compounds
Scheme 1
autumnariol, autumnariniol, altenuisol, and alternariol (Scheme
1
1
, 1). They also occur in a number of natural antitumor
and antibiotic agents such as the gilvocarcins, ravidomycins,
2
and chrysomycins (Scheme 1, 2). In addition, dibenzopy-
ranones have been used as intermediates in the syntheses of
several pharmaceutically interesting compounds including
3
progesterone, androgen, and glucocorticoid receptor agonists
4
and endothelial cell proliferation inhibitors. There are several
(
1) (a) Sidwell, W. T. L.; Fritz, H.; Tamm, C. HelV. Chim. Acta 1971,
5
5
1
4, 207. (b) Raistrick, H.; Stilkings, C. E.; Thomas, R. Biochemistry 1953,
5, 421. (c) Pero, R. W.; Harvan, D.; Blois, M. C. Tetrahedron Lett. 1973,
4, 945.
methods for the synthesis of dibenzopyranones, with most
involving a Suzuki cross-coupling reaction followed by metal
5
(
2) (a) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am.
or Lewis acid mediated lactonization. More recently the tert-
butyl-lithium-mediated cyclization of bromobenzylfluorophe-
Chem. Soc. 1994, 116, 1004. (b) McGee, L. R.; Confalone, P. N. J. Org.
Chem. 1988, 53, 3695. (c) Findlay, J. A.; Daljeet, A.; Murray, P. J.; Rej,
R. N. Can. J. Chem. 1987, 65, 427. (d) Hart, D. J.; Merriman, G. H.; Young,
D. G. J. Tetrahedron 1996, 52, 14437. (e) James, C. A.; Snieckus, V.
Tetrahedron Lett. 1997, 38, 8149. (f) Parker, K. A.; Coburn, C. A. J. Org.
Chem. 1991, 56, 1666.
(4) Schmidt, J. M.; Tremblay, G. B.; Page, M.; Mercure, J.; Feher, M.;
Dunn-Dufault, R.; Peter, M. G.; Redden, P. R. J. Med. Chem. 2003, 46,
1289.
(
3) (a) Edwards, J. P.; West, S. J.; Marschke, K. B.; Mais, D. E.;
Gottardis, M.; Jones, T. K. J. Med. Chem. 1998, 41, 303. (b) Hamann,
L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.; Wang, X.; Marschke, K. B.;
Kong, J. W.; Farmer, L. J.; Jones, T. K. J. Med. Chem. 1998, 41, 623. (c)
Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly, J. R.;
Wilcox, D.; Stashko, M.; Lin, C. W.; Miner, J.; Tyree, C.; Nakane, M.;
Jacobson, P.; Lane, B. C. J. Med. Chem. 2001, 44, 2879.
(5) (a) Kemperman, G. J.; Ter Horst, B.; Van de Goor, D.; Roeters, T.;
Bergwerff, J.; van der Eem, R.; Basten, J. Eur. J. Org. Chem. 2006, 61,
3169. (b) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young,
L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379. (c) Hussain, I.; Nguyen,
V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P.
J. Org. Chem. 2007, 72, 6255.
10.1021/ol802792g CCC: $40.75
Published on Web 01/12/2009
 2009 American Chemical Society

6
nyl ethers and the ruthenium-catalyzed cyclotrimerization
7
of aryl diynes have been reported. Such existing methods,
however, require the use of palladium catalysts, aryl fluorides
and iodides, and ionic liquids. Finally the synthesis of
Scheme 3
7
-hydroxydibenzopyranones via addition of bissilyl enol
8
ethers to chromones has been reported. In this paper, we
present a simple, general, palladium-free method for the
synthesis of highly substituted dibenzopyranones using a
Diels-Alder reaction between 4-cyanocoumarins and 1-ox-
ygenated dienes followed by elimination-aromatization with
potassium tert-butoxide. Diels-Alder reactions of 3-nitro-
9
10
coumarins and 4-cyanoquinolones are known. However,
to the best of our knowledge, this is the first report of the
use of a 4-substituted coumarin as the dienophile in a [4 +
2
] cycloaddition process.
The 4-cyanocoumarin 5 was prepared in two steps without
purification from the commercially available 4-hydroxycou-
1
1
4 2 5
marin 3 (Scheme 2). Bromination with Bu NBr/P O
Scheme 2
directs the regiochemistry over the lactone because the
lactone is slightly cup-shaped and consequently partially out
of conjugation with the olefin. In addition, the Diels-Alder
adduct was isolated as an ca. 5:1 mixture of endo to exo
stereoisomers 8n and 8x which was then recrystallized to
1
2
afford the pure endo isomer 8n in 70% yield. However,
the stereochemistry is of little consequence in this case
because it is destroyed in the subsequent elimination step.
The reaction time can be decreased significantly from 2 days
to 0.5 h by conducting the reaction in the microwave without
the loss of either regio- or stereocontrol. Finally, the
followed by cyanation with CuCN gave the 4-cyanocoumarin
in 57% yield over two steps. Many other substituted
4
-hydroxycoumarins are commercially available but are
4
-formylcoumarin 6 was treated with the silyloxydiene 7 at
generally expensive. However, they can be made from
inexpensive staring materials in three simple steps without
purification (see Supporting Information).
Initially various 4-substituted coumarins were screened as
dienophiles by treatment with excess cyclopentadiene.
Among the 4-substituted coumarins screened (R ) H, Cl,
only 60 °C and afforded the Diels-Alder adduct in 93%
yield, again with complete regiocontrol but as a 1:1 mixture
of endo and exo stereoisomers, 9n and 9x.
The effect of substitution on the diene on the Diels-Alder
reaction was then tested by treating the 4-cyanocoumarin 5
with a number of oxygenated dienes 10a-f (Scheme 4).
3
Br, I, N , OH, OTs, CN, and CHO), only the 4-cyanocou-
marin 5 and the 4-formylcoumarin 6 afforded the Diels-Alder
products. Presumably, the additional electron-withdrawing
group, cyano or formyl, is needed to activate the coumarin
sufficiently for the Diels-Alder reaction, even with cyclo-
pentadiene. The regioselectivity of the reaction was then
investigated, and the results are shown in Scheme 3.
Treatment of 4-cyanocoumarin 5 with the 1-silyloxydiene 7
in toluene at 120 °C for 2 days gave the Diels-Alder adduct
Scheme 4
1
in 92% yield as a single regioisomer as observed by H NMR
spectroscopy. We presume that the cyano group exclusively
(6) Sanz, R.; Fernandez, Y.; Castroviejo, M. P.; Perez, A.; Fananas, F. J.
Eur. J. Org. Chem. 2007, 62, 69.
(
(
7) Teske, J. A.; Deiters, A. Org. Lett. 2008, 10, 2195.
8) Appel, B.; Saleh, N. N. R.; Langer, P. Chem.-Eur. J. 2006, 12,
1
221.
(
9) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J.
Org. Chem. 2003, 68, 9263.
10) Fujita, R.; Watanabe, K.; Yoshisuji, T.; Matsuzaki, H.; Harigaya,
Y.; Hongo, H. Chem. Pharm. Bull. 2001, 49, 407.
11) Kato, Y.; Okada, S.; Tomimoto, K.; Mase, T. Tetrahedron Lett.
001, 42, 4849.
(
Overall, the Diels-Alder adducts were isolated in excellent
yields as single regioisomers. The 2-allyl-1-silyloxydiene 10b
(
2
758
Org. Lett., Vol. 11, No. 3, 2009

and the 2,4-dimethyl-1-silyloxydiene 10c gave the Diels-Alder
adducts 11b and 11c, respectively, both as 5:1 mixtures of
endo and exo stereoisomers. Reaction with Danishefsky’s
diene 10d or its OTBS analogue 10e resulted in a slight
decrease in stereoselectivity from 5:1 to 2:1 endo:exo but
still with complete regioselectivity, compounds 11d and 11e.
Lastly, treatment with the very hindered 4,4-dimethyl-2-
silyloxydiene 10f afforded the expected product 11f in 89%
yield but after 2 h rather than 0.5 h.
Scheme 6
The effect of substitution on the coumarin was also
explored by treating a number of analogues with the
1
-silyloxydiene 7 (Scheme 5). The 6-chloro-7-methyl ana-
Scheme 5
1
the intermediate 15 and the product 14g by crude H NMR
spectroscopy (Scheme 7). Attempts to purify the intermediate
Scheme 7
logue 12b gave the Diels-Alder adduct 13b in 82% yield
as a 4:1 mixture of endo and exo stereoisomers. The electron-
rich 6,7-dimethyl analogue 12c and the 7-methoxy analogue
1
5 by silica gel chromatography led to elimination of the
1
2d afforded the Diels-Alder adducts 13c and 13d in 89%
silanol to give the product 14g. There are two possible
mechanisms for the aromatization process, either initial
and 84% yield, respectively, again as 4:1 mixtures of endo
and exo stereoisomers. Initially, we were afraid that electron-
rich 4-cyanocoumarins might require higher reaction tem-
peratures which would likely result in lower yields. However,
the reactions proceeded smoothly at 120 °C simply by
increasing the reaction time from 0.5 to 4 h.
The Diels-Alder adduct 11a was treated with several
bases in an attempt to induce elimination of both the cyano
and silyloxy groups. Although both of these are only
moderately good leaving groups, we believed that aromati-
zation of the ring would provide a strong driving force for
the reaction. Treatment with various carbonate bases in
methanol or THF gave either low conversion of starting
material, even upon heating to reflux, or yields less than 50%.
However, treatment of 11a with 2.5 equiv of potassium tert-
butoxide in THF at 0 °C for 15 min provided the diben-
zopyranone 14a in 92% yield (Scheme 6). Treatment of each
of the Diels-Alder adducts with potassium tert-butoxide led
to the aromatized products 14b-14g in 85-95% yield.
ꢀ
-elimination of cyanide to the diene followed by loss of
TBSOH or initial elimination of the silanol followed by loss
of cyanide. Our observation of the intermediate 15 implies
the reaction must proceed, at least to some extent, through
the first mechanism, but does not completely rule out the
possibility that the reaction occurs simultaneously through
the second mechanism as well. The mechanism of the
elimination was further explored by methylation of the
Diels-Alder adduct 11a at low temperature. As expected,
treatment of the adduct 11a with 2.5 equiv of LDA at -78
°
C and warming to 0 °C afforded the dibenzopyranone 14a
in 76% yield. However, deprotonation of 11a with 2.5 equiv
of LDA at -78 °C followed by sequential addition of HMPA
and MeI and warming to -40 °C gave the methylated
product 16 in 79% yield with less than 5% of the diben-
zopyranone 14a being isolated (Scheme 8). These results
suggest that the elimination proceeds through an E1cb-type
mechanism; namely, treatment of the Diels-Alder adduct
with base leads to rapid deprotonation of the acidic proton
R to the lactone. However, at low temperatures, the ring is
in a conformation such that the carbanion orbital does not
align well with the σ* orbital of the carbon-cyano bond.
Compound 14c was isolated as the phenol (R
4
) OH) rather
than the silyl ether (R ) OTBS) in 88% yield. Interestingly,
4
the complete conversion of the Diels-Alder adduct 11c to
the dibenzopyranone 14g required 60 min at 23 °C, rath-
er than at 0 °C, as did the other examples. In fact, quenching
the reaction after 15 min at 0 °C revealed complete
conversion of the starting material to a 1.0:1.8 mixture of
(
12) The stereochemistry was confirmed through an X-ray crystal
structure analysis of the product 16 of methylation of 8n.
Org. Lett., Vol. 11, No. 3, 2009
759

Scheme 8
Scheme 9
dienophiles since they are stable and can be synthesized in
only a few steps from inexpensive, commercially available
starting materials in high yields without column chromatog-
raphy. Their cycloaddition to 1-silyloxydienes is highly
regioselective and proceeds in excellent yields. The mech-
anism of the elimination/aromatization is likely an E1cb-
type process, namely, formation of the anion R to the nitrile
followed by elimination of cyanide and then aromatization
via loss of the silanol to give the aromatic products.
Only on warming the reaction to above -40 °C does the
ring adopt a conformation which allows for facile ꢀ-elimina-
tion. Further support for the E1cb mechanism was obtained
from the regioisomeric Diels-Alder adduct 17, prepared in
good yield from the reaction of 3-cyanocoumarin and the
1
-silyloxybutadiene 7. Treatment of 17 with potassium tert-
butoxide afforded none of the elimination product, but rather
the hindered tert-butoxide acted as a nucleophile and opened
the lactone with displacement of phenoxide to afford clean-
ly the substitution product 18 in 83% yield (Scheme 9).
In summary, we have developed a novel route for the
preparation of highly substituted dibenzopyranones in excel-
lent yield through the Diels-Alder reaction of 4-cyanocou-
marins and 1-oxygenated dienes followed by elimination/
aromatization with base. 4-Cyanocoumarins are excellent
Acknowledgment. We thank the National Science Foun-
dation (CHE0614591) for generous support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802792G
760
Org. Lett., Vol. 11, No. 3, 2009