Synthesis of dihydrofurocoumarins via palladium-catalyzed annulation of 1,3-dienes by o-lodoacetoxycoumarins

Article abstract of DOI:10.1021/ol027342p

(Matrix presented) A variety of biologically interesting dihydrofurocoumarins have been synthesized in high yields by the palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins. This reaction is very general and regioselective, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be utilized.

Full text of DOI:10.1021/ol027342p

ORGANIC
LETTERS
2003
Vol. 5, No. 6
797-800
Synthesis of Dihydrofurocoumarins via
Palladium-Catalyzed Annulation of
1,3-Dienes by o-Iodoacetoxycoumarins
Roman V. Rozhkov and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50010
larock@iastate.edu
Received November 23, 2002
ABSTRACT
A variety of biologically interesting dihydrofurocoumarins have been synthesized in high yields by the palladium-catalyzed annulation of
1,3-dienes by o-iodoacetoxycoumarins. This reaction is very general and regioselective, and a wide variety of terminal, cyclic, and internal
1,3-dienes can be utilized.
Dihydrofurocoumarins occur commonly in plants and fruits
and are very important because of their pronounced biologi-
cal properties.1 According to recent reports, dihydrofuro-
coumarins exhibit significant cytotoxicity against KB cells2
and an ability to inhibit c-AMP3 synthetase, as well as
acetylcholinesterase.4
Palladium-catalyzed annulations developed in our labo-
ratories provide a versatile route to the construction of
complex cyclic systems.8 Previously, we reported an efficient
method for the synthesis of cis-dihydrobenzofurans by the
palladium-catalyzed annulation of 1,3-dienes by o-iodophe-
nols (Scheme 1).9 This methodology looked very promising
Because of the biological and pharmaceutical importance
of dihydrofurocoumarins, numerous methods for their syn-
thesis have been developed during the last 30 years. Earlier
methods involved multiple steps and suffered from low
(2-20%) overall yields.5 Recent synthetic approaches based
on the Claisen rearrangement6 and the Sonogashira coupling7
give 40-60% overall yields, but these methods lack broad-
generality and, therefore, cannot be used for the synthesis
of large libraries of biologically active dihydrofurocoumarins.
Scheme 1
(1) (a) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477. (b) Murray, R.
D. H. Prog. Chem. Org. Nat. Prod. 1991, 58, 83.
(2) Guilet, D.; Helesbeux, J.-J.; Seraphin, D.; Sevenet, T.; Richomme,
P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563.
(3) Thastrup, O.; Fjalland, B.; Lemmich, J. Acta Pharmacol. Toxicol.
1983, 52, 246.
for the synthesis of dihydrofurocoumarins. Herein, we report
that the palladium-catalyzed annulation of 1,3-dienes by
(4) Kang, S. Y.; Lee, K. Y.; Sung, S. H.; Park, M. J.; Kim, Y. C. J. Nat.
Prod. 2001, 64, 683.
(5) (a) Steck, W. Can. J. Chem. 1971, 49, 1197. (b) Yamaguchi, S.;
Miyakawa, R.; Yonezawa, S.; Kawase, Y. Bull. Chem. Soc. Jpn. 1989, 62,
3593.
(8) (a) Larock, R. C. J. Organomet. Chem. 1999, 576, 111. (b) Larock,
R. C. Palladium-Catalyzed Annulation. In PerspectiVes in Organopalladium
Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier Press: Lausanne,
Switzerland, 1999; pp 111-124. (c) Larock, R. C. Pure Appl. Chem. 1999,
71, 1435.
(6) Trumble, J. T.; Millar, J. G. J. Agric. Food Chem. 1996, 44, 2859.
(7) Stanjek, V.; Milksch, M.; Boland, W. Tetrahedron 1997, 53, 17699.
(9) Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J. Org. Chem. 1990,
55, 3447.
10.1021/ol027342p CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003

o-iodohydroxycoumarin derivatives provides a very general
and effective route to a wide variety of angular and linear
dihydrofurocoumarins.
Scheme 3
For our initial investigations, the annulation of 1,3-cyclo-
hexadiene by iodocoumarin 1 was selected as a model reac-
tion (Scheme 2). Surprisingly, under the optimal reaction
Scheme 2
the yield of coumarin 2 to 21%. In sharp contrast to the
annulation of coumarin 1, acetoxy derivative 4 did not give
any of the reduced coumarin 3 or its acetoxy analogue.
Besides that, the recovery of 78% of the starting material 4
indicated that the undesired reduction is completely inhibited
under these reaction conditions.
Great improvements were subsequently achieved using a
4:1 1,4-dioxane/water mixture as the solvent at higher
temperatures. Increasing the reaction temperature to 80 and
100 °C improved the yield of the desired product 2 to 44
and 64%, respectively. Besides the desired product, signifi-
cant amounts of Heck-type products 5 and 6 were isolated.
Further optimizations, which utilized Pd(OAc)2 as the
catalyst; dppp, dppb, BINAP, and PPh3 as the phosphine
ligand; and AgOAc, Ag3PO4, and Ag2CO3 as the silver salt,
only resulted in a lower yield of the annulated product 2.
We have thus used the following “optimal” procedure for
all subsequent annulations: the iodoacetoxycoumarin (0.25
mmol), Pd(dba)2 (5 mol %, 0.0125 mmol), dppe (5 mol %,
0.0125 mmol), Ag2CO3 (0.5 mmol), 1,3-diene (1.0 mmol),
and 5 mL of a 4:1 1,4-dioxane/water mixture were stirred at
100 °C for 24 h.
Next, the scope and limitations of this annulation were
studied using various 1,3-dienes, and representative examples
are shown in Table 1. Most terminal 1,3-dienes gave the
expected annulation products in 60 to 80% yields with
excellent regioselectivity (entries 2-5). Running the reaction
on a 2.0 mmol scale resulted in an even higher 91% yield
(entry 5), indicating the utility of this procedure for practical
applications. The regioselectivity in these experiments can
be explained by a greater affinity of the arylpalladium
intermediate for the less hindered terminal CdC double bond
over an internal double bond. The annulation of isoprene
gave a 3:2 mixture of regioisomers in 73% yield (entry 6).
Supposedly, the poor regioselectivity in the annulation of
isoprene results from the negligible steric difference between
the two terminal double bonds.
conditions used in the dihydrobenzofuran project,9 the annu-
lation gave only a 6% yield of the desired cis-dihydrofuro-
coumarin 2. Instead, the reduced coumarin 3 was isolated
in 88% yield. Variation of the bases, phosphine ligands, and
solvents used in this reaction had little effect on the outcome
of the reaction. The best result was achieved using Ag2CO3
as a base, dppe as a ligand, and THF as a solvent at 60 °C.
This provided a 17% yield of the desired product 2, a 15%
yield of the reduced coumarin 3, and 63% of the starting
material 1. The positive effect of Ag2CO3 is presumably due
to abstraction of a halide from the arylpalladium complex
and formation of a cationic arylpalladium intermediate, which
is assumed to be more reactive toward addition to the CdC
bond.10
From our preliminary results, it appeared that electron-
rich aryl iodides have a great propensity to undergo the un-
desired reduction.11 The introduction of an electron-with-
drawing acetyl group on the phenolic oxygen would be ex-
pected to decrease the electron density on the aromatic ring
and might, therefore, be expected to improve the yield of
the desired coumarin 2 if there were some way to remove
the acetyl group during the annulation process. Acylated phe-
nols are sufficiently stable in the pH range from 5 to 8 and,
therefore, would be expected to tolerate our reaction condi-
tions.11
Using the annulation of 1,3-cyclohexadiene by acetoxy-
iodocoumarin 4 as a model system, we have examined the
effect of various reaction parameters such as solvent,
palladium catalyst, silver salt, phosphine ligand, and reaction
temperature on the yield of the desired coumarin 2 (Scheme
3). Although the annulation of coumarin 4 under our best
previous reaction conditions obtained for coumarin 1 did not
show very promising results, the addition of water raised
Surprisingly, 2,4-hexadiene (3:2 mixture of trans-trans
and cis-trans stereoisomers),12 which has generally been
unreactive and afforded dismal yields in most of our previous
palladium annulation chemistry, gave a 3:2 ratio of trans
(10) Kotora, M.; Matsumura, H.; Gao, G.; Takahashi, T. Org. Lett. 2001,
3, 3467.
(11) Greene T. W. ProtectiVe Groups in Organic Synthesis; Wiley and
Sons: New York, 1981; p 308.
(12) Ratio of trans-trans and cis-trans isomers was determined by gas
chromatography.
798
Org. Lett., Vol. 5, No. 6, 2003

Table 1. Synthesis of Dihydrofurocoumarins by the Annulation of 1,3-Dienesa
a See text for the experimental procedure. b All yields are isolated and based on a single run. c This experiment was performed on a 2.0 mmol scale. d No
water was employed in the solvent.
and cis stereoisomers 12a and 12b in a 60% overall yield
(entry 7). Remarkably, in all of our previous annulation
chemistry, relatively hindered 1,3-dienes, like those em-
ployed in entries 4, 5, and 7, were completely unreactive
and only 1,3-dienes bearing monosubstituted terminal double
bonds gave satisfactory results. The exclusive generation
of trans stereochemistry in the newly formed double bond
in products 7, 8, and 12 is consistent with the interme-
diacy of a syn-π-allylpalladium intermediate in these reac-
tions.13
Org. Lett., Vol. 5, No. 6, 2003
799

In an attempt to broaden the scope of this reaction, similar
reactions were performed on other substituted coumarins.
Coumarins 13 and 15 gave the expected products in good
yields even when using the relatively hindered 2,3-dimethyl-
1,3-butadiene (entries 8 and 9). Annulation of coumarin 17
under our “optimal” reaction conditions resulted in hydrolysis
of the acetyl group. The likely reason for the fast hydrolysis
is the higher acidity of 4-hydroxycoumarin than that of
7-hydroxycoumarin.14 The same reaction without the addition
of water gave a 48% yield of dihydrofurocoumarin 18 (entry
10). In this experiment, the acetyl group is hydrolyzed by
trace amounts of water present in commercially available
1,4-dioxane.
stabilized by the neighboring acetyl group. According to our
results, the presence of the acetyl group completely inhibits
formation of the undesired reduced product 3 and dramati-
cally improves the yield of the desired product 2. This may
be due to the lower propensity of complex 21, compared to
its phenol analog, to undergo thermal decomposition. Next,
complex 21 adds to the 1,3-diene to give the π-allylpalladium
intermediate 22. Coordination of the acetoxy oxygen to the
palladium atom gives intermediate 23, which is rapidly
hydrolyzed by water to form intermediate 24. Since no
hydrolysis of starting material 4 was observed under our
reaction conditions, the deacylation of intermediate 23 is
presumably accelerated by coordination of the acetyl oxygen
atom to the cationic palladium center. Finally, complex 24
undergoes reductive elimination to give the final product 2
and the palladium intermediate 19.
The proposed mechanism for this annulation process is
shown in Scheme 4. Initial oxidative addition of iodocou-
In conclusion, we have developed an efficient palladium-
catalyzed annulation of 1,3-dienes by acetoxyiodocoumarins
that affords good yields of dihydrofurocoumarins. The
process is quite general, regioselective, and stereoselective,
and a variety of o-iodoacetoxycoumarins, as well as sym-
metrical and unsymmetrical 1,3-dienes, can be utilized.
Further investigation into the mechanism and the scope of
this process is under way.
Scheme 4
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research and John Matthey, Inc., and Kawaken Fine Chemi-
cals Co., Ltd., for donations of palladium acetate.
Supporting Information Available: General experimen-
tal procedures and spectral data for the compounds listed in
Table 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL027342P
(13) Maitlis, P. M.; Espinet, P.; Russell, M. J. H. Compr. Organomet.
Chem. 1982, 6, 385.
(14) Georgievskii, V. P. Khim. Prir. Soedin. 1995, 6, 770; Chem. Abstr.
1986, 104, 144967.
marin 4 to palladium intermediate 19 generated in situ forms
arylpalladium intermediate 20. Abstraction of the iodide by
silver carbonate leads to cationic intermediate 21 presumably
800
Org. Lett., Vol. 5, No. 6, 2003