Regiospecific carbonylative annulation of iodophenol acetates and acetylenes to construct the flavones by a new catalyst of palladium-thiourea-dppp complex

Article abstract of DOI:10.1021/ol000087t

(matrix presented) Regiospecific carbonylative annulation of o-iodophenol acetates and acetylenes mediated by palladium-thiourea-dppp complex in the presence of base at 40°C under a balloon pressure of CO generates diversified flavones in high yields. This newly developed synthetic technology provides a highly efficient method for potential application to the combinatorial synthesis of those heterocycles on the solid support.

Full text of DOI:10.1021/ol000087t

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1765-1768
Regiospecific Carbonylative Annulation
of Iodophenol Acetates and Acetylenes
To Construct the Flavones by a New
Catalyst of Palladium−Thiourea−dppp
Complex
Hua Miao and Zhen Yang*
HarVard Institute of Chemistry and Cell Biology, HarVard UniVersity,
250 Longwood AVenue, SGM 604, Boston, Massachusetts 02115-5731
zhen_yang@hms.harVard.edu
Received April 14, 2000
ABSTRACT
Regiospecific carbonylative annulation of o-iodophenol acetates and acetylenes mediated by palladium−thiourea−dppp complex in the presence
of base at 40 °C under a balloon pressure of CO generates diversified flavones in high yields. This newly developed synthetic technology
provides a highly efficient method for potential application to the combinatorial synthesis of those heterocycles on the solid support.
Natural products are the richest known sources of small
molecules that bind proteins with high specificity, thanks to
millions of years of evolution and selection. Flavones, also
known as 2-phenylchromones, constitute one of the major
classes of naturally occurring products. Because of their
broad range of significant biological activities,1 this family
of molecules has been extensively investigated and more than
4000 chemically unique flavonoids have been isolated from
plants.2
catalyzed carbonylation of o-iodophenols with acetylenes to
synthesize the scaffold of flavones have shown this meth-
odology to be particularly attractive.6 However, this reaction
(1) (a) Isogi, Y.; Komoda, Y.; Okamoto, T. Chem. Pharm. Bull. 1970,
18, 1872. (b) Roux, D. G. Phytochemistry 1972, 11, 1219. (c) Thompson,
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1 1972, 1387. (d) Fletcher, A. C.; Porter, L. J.; Haslam, E.; Gupta, R. K.
J. Chem. Soc., Perkin Trans. 1 1977, 1628. (e) Gamill, R. B.; Day, C. E.;
Schurr, P. E. J. Med. Chem. 1983, 26, 1672. (f) Fourie, T. G.; Suyckers, F.
O. J. Nat. Prod. 1984, 47, 1057. (g) Yamashita, A. J. Am. Chem. Soc. 1985,
107, 5823. (h) Gabor, M. Prog. Clin. Bio. Res. 1986, 213, 471. (i) Kolodziej,
H. Phytochemistry 1986, 25, 1209. (j) Gerwick, W. H.; Lopez, A.; Van
Duyne, G. D.; Clardy, J.; Ortiz, W.; Baez, A. Tetrahedron Lett. 1986, 27,
1979. (k) Chrisey, L. A.; Bonjar, G. H. S.; Hecht, S. M. J. Am. Chem. Soc.
1988, 110, 644. (l) Gerwick, W. H. J. Nat. Prod. 1989, 52, 252. (m) Fesen,
M. R.; Pommier, Y.; Leteurtre, F.; Hiroguchi, S.; Yung, J.; Kohn, K. W.
Biochem. Pharmacol. 1994, 48, 595. (n) Akama, T.; Ueno, K.; Saito, H.;
Kasai, M.; Synthesis 1997, 1446. (o) Artico, M.; Santo, R. D.; Costi, R.;
Novellino, E.; Greco, G.; Massa, S.; Tramontano, E.; Marongiu, M. E.;
Montis, A. D.; Colla, P. L. J. Med. Chem. 1998, 41, 3949. (p) Ferte´, J.;
Ku¨hnel, J.-M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M. A. J.
Med. Chem. 1999, 42, 478. (q) Costantino, L.; Rastelli, G.; Gamberini, M.
C.; Vinson, J. A.; Bose, P.; Iannone, A.; Staffieri, M.; Antolini, L.; Corso,
A. D.; Mura, U.; Albasini, A. J. Med. Chem. 1999, 42, 1881. (r) Lewis, K.;
Stermitz, F. R.; Collins, F. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1433.
(2) Harborne, J. B., Ed. The FlaVonoids, adVances in research since 1986;
Chapman and Hall: London, 1993.
In connection with our development of a chemical genetic
approach to analyzing biological systems by using interfacing
libraries of small molecules with creative biological assays,3
we were interested in developing improved methods for the
combinatorial synthesis of a flavonoid library.
Although several approaches for the synthesis of flavones
have been developed, most of the methods suffer from harsh
reaction conditions, poor substituent tolerance, and low
yields.4
The use of palladium as a catalyst for the syntheses of
heterocyclic molecules has been a fertile area of research
for the past two decades.5 Recent advances in palladium-
10.1021/ol000087t CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/11/2000

is known to produce a mixture of six-membered flavones 3
and five-membered aurones 4 (Scheme 1).
Our need for a mild and convergent method to be used in
the combinatorial synthesis of a flavonoid library promoted
us to reinvestigate the synthetic approach illustrated in
Scheme 1.
Palladium-based catalysts are renowned for their great
tunability by combining with different ligands. In comparison
with homopalladium catalysts, palladium-thiourea com-
plexes have the advantage of catalyzing a facile carbonylation
reactions.9
Scheme 1. Palladium-Catalyzed Carbonylative Cyclization of
o-Iodophenols and Acetylenes
We previously demonstrated that palladium-thiourea is
an effective cocatalyst for the syntheses of 2,3-disubstituted
benzo[b]furans by carbonylative annulation under very mild
conditions (at 45 °C under a balloon pressure of CO).10 We
reported here our recent results for the use the PdCl2(Ph3P)2-
thiourea-dppp (1:1:1) complex as a powerful catalyst for
the syntheses of flavonoid molecules.
Mechanistically, the formations of six-membered flavones
3 and five-membered aurones 4 presumably result from the
6b,c,7,8
different processes
shown in Figure 1.
Initially, four pairs of iodophenols and acetylenes were
selected as substrates to test this carbonylative annulation
because they are either commercially available or easily
accessible. To our delight, the six-membered flavones (5a-
8a) were obtained in acceptable yields (50-70%) by using
the complex of PdCl2(Ph3P)2-thiourea as a catalyst in the
(3) (a) Stockwell, B. R.; Haggarty, S. J. Schreiber, S. L. Chem. Biol.
1999, 6, 71-83. (b) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King,
R. W.; Schreiber, S. L.; Mitchison, T., J. Science 1999, 286, 971-974.
(4) (a) Allan, J.; Robinson, R. J. Chem Soc. 1926, 2335. (b) Robinson,
R.; Venkataraman, K. J. Chem. Soc. 1926, 2344. (c) Lynch, H. M.; O’Toole,
T. M.; Wheeler, T. S. J. Chem. Soc. 1952, 2063. (d) Ollis, W. D.; Weight,
D. J. Chem. Soc. 1952, 3826. (e) Meyer-Dayan, M.; Bodo B.; Deschamps-
Vallet, C.; Molho, D. Tetrahedron Lett. 1978, 3359. (f) Garcia, H.; Iborra,
S.; Primo, J.; Miranda, M. A. J. Org. Chem. 1986, 51, 4432. (g) McGarry,
L. W.; Detty, M. R. J. Org. Chem. 1990, 55, 4349. (h) Pinto, D. C. G. A.;
Silva, A. M. S.; Cavaleiro, J. A. S. J. Heterocycl. Chem. 1996, 33, 1887.
(i) Riva, C.; Toma, C. D.; Donadel. L.; Boi, C.; Pennini, R.; Motta, G.;
Leonardi, A. Synthesis 1997, 195. (j) Marder, M.; Viola, H.; Bacigaluppo,
J. A.; Colombo, M. I.; Wasowski, C.; Wolfman, C.; Medina, J. H.; Ru´veda,
E. A.; Paladini, A. C. Biochem. Biophys. Res. Commun. 1998, 249, 481.
(k) Costantino, L.; Rastelli, G.; Gamberini, M. C.; Vinson, J. A.; Bose, P.;
Iannone, A.; Staffieri, M.; Antolini, L.; Corso, A. D.; Mura, U.; Albasini,
A. J. Med. Chem. 1999, 42, 1881. (l) Dekermendjian, K.; Kahnberg, P.;
Witt, M.-R.; Sterner, O.; Nielsen, M.; Liljefors, T. J. Med. Chem. 1999,
42, 4343. (m) Lokshin, V.; Heynderickx, A.; Samat, A.; Pe`pe, G.;
Guglielmetti R. Tetrahedron Lett. 1999, 40, 6761. (n) Tabaka, A. C.; Murthi,
K. K.; Pal, K.; Teleha, C. A. Org. Process Res. DeV. 1999, 3, 256.
(5) (a) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106,
4218. (b) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29, 4687. (c)
Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581. (d)
Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J. Org. Chem. 1990, 55,
3447. (e) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B.
Tetrahedron Lett. 1992, 33, 373. (f) Larock, R. C. Berrios-Pena, N. G.;
Fried, C. A.; Yum. E. K.; Tu, C.; Leong, W. J. Org. Chem. 1993, 58, 4509.
(g) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H.
Tetrahedron 1994, 50, 11803. (h) Anacardio, R.; Arcadi, A.; D’Anniballe,
G.; Marinelli, F. Synthesis 1995, 831. (i) Larock, R. C.; Yum, E. K.; Doty,
M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270. (j) Liao, H. Y.; Cheng,
C. H. J. Org. Chem. 1995, 60, 3711. (k) Larock, R. C.; Doty, M. J.; Han,
X.-J. J. Org. Chem. 1999, 64, 8770. (l) Larksarp. C.; Alper, H. J. Org.
Chem. 1999, 64, 9194.
Figure 1. Mechanistic interpretation for the formation of flavone
3 and aurone 4.
In this catalytic cycle, D would be a critical intermediate
in the formation of 3 and 4. The intermediate D might form
a complex G with palladium(0), followed by rearrangement
and reductive elimination to afford aurones 4. On the other
hand, the same intermediate D could either undergo a direct
6-endo-dig cyclization or proceed through E and F stages
to form flavones 3 (see Figure 1).
Torii and Kalinin have nicely resolved this regioselective
problem by using a large excess of diethylamine to com-
petitively generate the intermediate E from D in order to
form the six-membered scaffold of flavone 3 (Figure 1).
However, the employed conditions are rather drastic (120
°C, 20 kg/cm2).6c
(6) (a) Kalinin, V. N.; Shostakovsky, M. V.; Ponamaryov, A. B.
Tetrahedron Lett. 1990, 31, 4073. (b) Ciattini, P. G.; Morera, E.; Ortar, G.;
Rossi, S. S. Tetrahedron 1991, 47, 6449. (c) Torri, S. Okumoto H.; Xu,
L.-H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin,
V. N. Tetrahedron 1993, 49, 6773.
(7) Bhat, A. S.; Whetstone, J. L.; Brueggemeier, R. W. Tetrahedron Lett.
1999, 40, 2469.
Recently, Brueggemeier7 developed a different approach
to the synthesis of flavonoid molecules. Although his method
has resolved the regioselectivity problem for the synthe-
sis of flavones, multiple steps had to be added to achieve
this.
(8) (a) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437. (b) An, Z. W.; Catellani, M.; Chiusoli, G. P. J. Organomet.
Chem. 1990, 397, 371.
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J. Organom. Chem. 1995, 503, 21-28. (b) Gabriele, B. Costa, M.; Salerno,
G.; Chiusoli, G. P. J. Chem. Soc., Chem. Commun. 1992, 1007.
(10) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.
1766
Org. Lett., Vol. 2, No. 12, 2000

presence of diethylamine at 40 °C under a balloon pressure
of CO (see Table 1).
Table 1. Palladium-Thiourea-Catalyzed Carbonyaltive
Annulation of Iodophenols and Acetylenes
Figure 2. Mechanistic interpretation of regio-specific formation
of flavone.
by an amine to afford the corresponding o-hydroxyl-R,â-
unsaturated ketone F, which would finally lead to 6-endo-
trig cyclization to give G and then eliminate the amine to
flavone.
This idea works so well that when both substituted
o-acetoxyiodobenzenes 9 and 12 were reacted with acetylenes
10 and 13, respectively, under a condition listed in Scheme
2, the corresponding flavones 11 and 14 were obtained in
However, there were some problems associated with this
reaction. First, a significant amount of aurone 3 were
observed in all cases (10-20%); second, even though the
reaction proceeded for more than 2 days, about 10-20% of
iodophenols still remained. Efforts to overcome these
problems by changing the catalysts, using different bases or
solvents, and even increasing the reaction temperature (which
leads to decomposition) were unsuccessful. We speculated
that these problems could be resolved by changing a hydroxyl
group to an acetoxy in the substrate of iodophenol.
Scheme 2. Syntheses of Flavones 11 and 14
We reasoned that the following advantages accompany the
use of an acetoxy as a latent hydroxyl group. (1) As an
electron-withdrawing group (cf. hydroxyl group), acetoxy
can reduce the electron density of the aromatic ring in
substrate A (see Figure 2); therefore the reaction rate of
oxidative addition of A to Pd(0) will be increased and the
problem associated with the conversion of starting material
to product might be resolved. (2) Since the hydroxyl group
was converted to the acetoxy, the intermediate D could only
undergo Michael addition to form E, so complex H cannot
be formed. (3) Due to the instability of the phenolic acetoxy
in the intermediate E, it will eventually undergo displacement
79% and 65% yields and only trace amount of aurones 3
were observed in these reactions. This is truly an impressive
improvement since only 0-10% of flavones was obtained
when Ortar utilized the corresponding o-hydroxyliodoben-
zenes as the substrates in his flavone syntheses.6b
To assess the generality of such a method to construct the
scaffold of flavones, eight pairs of o-acetoxyiodobenzenes
and arylacetylenes were utilized for this purpose. Thus, the
o-acetoxyiodobenzenes (15-20) (see Table 2) were synthe-
sized by treatment of the corresponding o-hydroxyliodoben-
zenes with acetyl chloride in the presence of triethylamine
in THF at room temperature in high yields. The correspond-
ing o-hydroxyliodobenzenes (related to the compounds of
16-20) and the arylacetylene (entries 2 and 4) were
(11) (a) Yang, Z,; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N.
C. J. Org. Chem. 1992, 57, 7248-7257, and references therein. (b)
Schreiber, F. G.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1 1977, 1, 90.
(c) Du, X.-H.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5678. (d)
Tsukayama, M.; Utsumi, H.; Kunugi, A.; Nozaki, H. Heterocycles 1997,
45, 1131. (e) Nickon, A.; Aaronoff, B. R. J. Org. Chem. 1964, 29, 3014.
(f) Doria, G. Eur. J. Med. Chem. 1978, 13, 33. (g) Henning, H. G.; Schwabe,
B.; Kernchen, F.; Westphal, G. J. Prakt. Chem. 1984, 326, 49.
Org. Lett., Vol. 2, No. 12, 2000
1767

After considerable experimentation, it was found that the
complex of PdCl2(PPh3)2-thiourea-dppp (1:1:1) is the best
catalyst for this carbonylative annulation, and the results are
summarized in Table 2. The detailed experimental informa-
tion is provided in the Supporting Information.
Table 2. PdCl2(PPh3)2-Thiourea-dppp (1:1:1) Complex
Catalyzed Carbonylative Annulation of o-Acetoxyiodobenzenes
with Arylacetylenes
From the results, we can make the following observations.
(1) Unsubstituted o-acetoxyiodobenzenes give high yields
of flavones (entries 1 and 2). (2) Electron-donating groups
on the aromatic ring of arylacetylenes (entries 3 and 4) give
slightly lower yields of flavones than the corresponding
unsubstituted arylacetylenes (entries 1 and 3). (3) Both
electron-rich (entries 3 and 4) and electron-deficient (entries
5 and 6), as well as multiply substituted o-acetoxyiodoben-
zenes (entries 7 and 8), give satisfactory yields of the
corresponding flavones.
Therefore, by using an acetoxy as a latent hydroxyl group,
we have essentially prevented the five-membered aurone’s
formation and resolved the problem of converting the starting
material to the product.
In summary, we have developed a highly efficient
synthetic technology for carbonylative cyclization of o-
acetoxyiodobenzens with arylacetylenes to construct the
corresponding flavones. This extended carbonylative annu-
lation provides a general method for the syntheses of
flavonoid compounds. Such an efficient manipulation of
multiple steps (one carbon-heteroatom bond and two
carbon-carbon bonds) in this particular catalytic cycle will
make this method a powerful tool for a combinatorial
synthesis of this type of molecules on solid support.
The newly developed synthetic technology provides a
highly efficient method for potential application to the
combinatorial synthesis of those heterocycles on solid
support, and a combinatorial synthesis of flavonoid library
is currently under investigation in our laboratory.
Acknowledgment. We thank Professors Stuart L. Schreiber
and Timothy J. Mitchison and Rebecca Ward for their
invaluable advice during the course of this research. Financial
support from the NIH (Grant 1PO1 CA78048), Merck &
Co. (Grant MCI97MITC804), and Merck KGaA is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and 1H and C13 NMR spectra for all the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
constructed using the known procedure,11 and the rest of
iodophenols and phenylacetylenes are commercially avail-
able.
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