An efficient approach to dihydrofurocoumarins via palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins

Article abstract of DOI:10.1021/jo034571w

The palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins provides an efficient method for the synthesis of biologically interesting dihydrofurocoumarins. The presence of the acetyl group on the phenolic oxygen and the use of silver carbonate as a base are crucial for this process. This reaction is very general and regio- and stereoselective, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be utilized. Derivatization of the annulation products provides an efficient approach to numerous analogues of natural products.

Full text of DOI:10.1021/jo034571w

An Efficien t Ap p r oa ch to Dih yd r ofu r ocou m a r in s via
P a lla d iu m -Ca ta lyzed An n u la tion of 1,3-Dien es by
o-Iod oa cetoxycou m a r in s
Roman V. Rozhkov and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received May 1, 2003
The palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumarins provides an efficient
method for the synthesis of biologically interesting dihydrofurocoumarins. The presence of the acetyl
group on the phenolic oxygen and the use of silver carbonate as a base are crucial for this process.
This reaction is very general and regio- and stereoselective, and a wide variety of terminal, cyclic,
and internal 1,3-dienes can be utilized. Derivatization of the annulation products provides an
efficient approach to numerous analogues of natural products.
Dihydrofurocoumarins, such as compounds 1-7, are
generality and, therefore, cannot be used for the synthe-
sis of large libraries of biologically active dihydrofuro-
coumarins.
commonly occurring plant metabolites that exhibit pro-
1
nounced biological properties. Derivatives of columbi-
anetin (2) exhibit significant cytotoxicity against KB
Palladium-catalyzed annulations developed in our
laboratories have provided a versatile route for the
construction of complex cyclic systems. Previously we
2
cells. Derivatives of norpterophyllin (3) have high anti-
3
12
coagulant and antifungal activities. Marmesin (6) is an
4
effective inhibitor of c-AMP synthetase and acetylcho-
reported an efficient method for the synthesis of cis-
linesterase,5 and prandiol (7) is an effective antidote
dihydrobenzofurans by the palladium-catalyzed annula-
against rattlesnake poison.6
13
tion of 1,3-dienes by o-iodophenols (eq 1). Recently we
Numerous attempts to synthesize dihydrofurocou-
marins have been reported during the last 30 years. Early
methods have involved multiple steps and generally
7
suffer from low (2-20%) overall yields. Modern synthetic
approaches involving the Claisen rearrangement of 7-(al-
8
lyloxy)coumarins, the Sonogashira coupling of o-iodohy-
9
droxycoumarins with terminal alkynes, Ag(I)- and Ce-
(
IV)-promoted oxidative cycloadditions of 4-hydroxycou-
communicated a significantly modified procedure for the
synthesis of dihydrofurocoumarins.14 Herein, we report
our complete results on the palladium-catalyzed annu-
lation of 1,3-dienes by o-iodohydroxycoumarin derivatives
that provides a very general and effective route to a wide
variety of angular and linear dihydrofurocoumarins.
For our initial optimization work, the annulation of 1,3-
cyclohexadiene by iodocoumarin 8 was selected as a
1
0
marin to alkenes and dienes, and the Rh(II)-catalyzed
annulation of alkenes by 3-diazo-2,4-chromenediones11
give 30-60% overall yields, but these methods lack broad
*
(
Corresponding author.
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) Feuer, G. In Progress in Medicinal Chemistry; Ellis, G. P., West,
G. B., Eds; North-Holland Publishing Co.: New York, 1974.
4) Thastrup, O.; Fjalland, B.; Lemmich, J . Acta Pharmacol. Toxicol.
983, 52, 246.
5) Kang, S. Y.; Lee, K. Y.; Sung, S. H.; Park, M. J .; Kim, Y. C. J .
Nat. Prod. 2001, 64, 683.
6) (a) Tovar-Miranda, R.; Cortes-Garcia, R.; Santos-Sanchez, N. F.;
(
(
(10) (a) Lee, Y. R.; Kim, B. S.; Wang, H. C. Tetrahedron 1998, 54,
122159. (b) Appendino, G.; Cravotto, G.; Giovenzana, G. B.; Palmisano,
G. J . Nat. Prod. 1999, 62, 1627. (c) Lee, Y. R.; Kim, B. S.; Kim, D. H.
Tetrahedron 2000, 56, 8845. (d) Nair, V.; Treesa, P. M.; Maliakal, D.;
Rath, N. P. Tetrahedron 2001, 57, 7705.
(11) Lee, Y. R.; Suk, J . Y.; Kim B. S. Tetrahedron Lett. 1999, 40,
6603.
(12) (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.
(
1
(
(
J oseph-Nathan, P. J . Nat. Prod. 1998, 61, 1216. (b) Tovar-Miranda,
R.; Cortes-Garcia, R.; J oseph-Nathan, P. Tetrahedron: Asymmetry
2
002, 13, 1147.
7) (a) Steck, W. Can. J . Chem. 1971, 49, 1197. (b) Yamaguchi, S.;
Miyakawa, R.; Yonezawa, S.; Kawase, Y. Bull. Chem. Soc. J pn. 1989,
(
6
2, 3593.
(
(
8) Trumble, J . T.; Millar, J . G. J . Agric. Food Chem. 1996, 44, 2859.
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(13) Larock, R. C.; Berrios-Pe n˜ a, N.; Narayanan, K. J . Org. Chem.
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1
7699.
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1
0.1021/jo034571w CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003
6
314
J . Org. Chem. 2003, 68, 6314-6320

An Efficient Approach to Dihydrofurocoumarins
TABLE 1. Op tim iza tion of th e An n u la tion (Eq 3)a
model reaction (eq 2). Surprisingly, under the optimal
entry
solvent(s) (ratio)
temp (°C)
% 9
% 11
1
2
3
4
5
THF
THF-H2O (4:1)
1,4-dioxane-H2O (4:1)
1,4-dioxane-H2O (4:1)
1,4-dioxane-H2O (1:1)
60
60
80
100
100
5
21
44
64
40
90
78
50
13
10
a
Coumarin 11 (0.25 mmol), Pd(dba)2 (5 mol %, 0.0125 mmol),
dppe (5 mol %, 0.0125 mmol), Ag2CO3 (0.5 mmol), 1,3-cyclohexa-
diene (1.0 mmol), and 5 mL of the solvent were stirred at 100 °C
for 24 h.
improve the yield of the desired coumarin 9 if there were
some way to remove the acetyl group during the annu-
lation process. Acylated phenols are fairly stable in the
pH range from 5 to 8 and, therefore, would be expected
to tolerate our reaction conditions.16
Using the annulation of 1,3-cyclohexadiene by iodo-
acetoxycoumarin 11 as a model system, we have exam-
ined the effect on the yield of the desired coumarin 9 of
various reaction parameters, including the solvent, pal-
ladium catalyst, silver salt, phosphine ligand, and reac-
tion temperature (eq 3). Several representative examples
reaction conditions used in the dihydrobenzofuran project
see eq 1),13 the annulation gave only a 6% yield of the
(
desired cis-dihydrofurocoumarin 9. Instead, the reduced
coumarin 10 was isolated in 88% yield. Possible pathways
for formation of product 10 include reduction of the
arylpalladium intermediate by formate formed from the
DMF solvent and thermal decomposition of the starting
aryl iodide or arylpalladium intermediate. Carrying out
this reaction without any palladium catalyst resulted in
9
5% recovery of the starting coumarin 8. On the other
hand, the use of nonreducing solvents, such as N,N-
dimethylacetamide (DMA), acetonitrile, and THF, did not
inhibit the undesired reduction. Therefore, formation of
the undesired product 10 might reasonably be attributed
to thermal decomposition of the arylpalladium interme-
diate. 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 by
2 3
using Ag CO as a base, dppe as a ligand, and THF as
the solvent at 60 °C. This provided a 17% yield of the
desired product 9, a 15% yield of the reduced coumarin
1
0, and 63% of the starting material 8. The positive effect
of the Ag CO is presumably due to abstraction of a halide
2
3
are shown in Table 1. Although the annulation with
coumarin 11 under our best previous reaction conditions
obtained for coumarin 8 did not show very promising
results (entry 1), the addition of water raised the yield
of coumarin 9 to 21% (entry 2). In sharp contrast to the
annulation of coumarin 8, the acetoxy derivative 11 did
not give any of the reduced coumarin 10 or its acetoxy
analogue. Besides that, the recovery of 78% of the
starting material 11 indicated that the undesired reduc-
tion is completely inhibited under these reaction condi-
tions.
from an intermediate arylpalladium halide complex and
formation of a cationic arylpalladium intermediate, which
is assumed to be more reactive toward addition to the
CdC bond.15
From our preliminary results, it appeared that electron-
rich aryl iodides have a great propensity to undergo the
undesired reduction.13 The introduction of an electron-
withdrawing acetyl group on the phenolic oxygen would
be expected to decrease the electron density of the
aromatic ring and might, therefore, be expected to
(
15) Kotora, M.; Matsumura, H.; Gao, G.; Takahashi, T. Org. Lett.
(16) Greene T. W. Protective Groups in Organic Synthesis; J ohn
Wiley and Sons: New York, 1981; p 308.
2
001, 3, 3467.
J . Org. Chem, Vol. 68, No. 16, 2003 6315

Rozhkov and Larock
Great improvements were subsequently achieved by
using a 4:1 1,4-dioxane/water mixture as the solvent at
higher temperatures. Increasing the reaction tempera-
ture to 80 and 100 °C improved the yield of the desired
product 2 to 44% (entry 3) and 64% (entry 4), respectively.
Besides the desired product, significant amounts of Heck-
type products 12 and 13 were detected among the
inseparable mixture of side products. A further increase
in the water concentration resulted in a decrease in the
yield of 9, perhaps due to partial hydrolysis of the
starting material 11 (entry 5). The use of polar solvents,
such as DMF, DMA, and acetonitrile, apparently resulted
in rapid hydrolysis of the starting material 11. Further
(entry 13). Surprisingly, the use of 95% pure trans,trans-
2,4-hexadiene gave a 20:1 ratio of isomers 25a and 25b
in a 70% yield (entry 13). This result will be discussed
further in our later discussion of the reaction mechanism.
Remarkably, in all of our previous palladium annulation
chemistry, relatively hindered 1,3-dienes, like those
employed in entries 2, 3, 9-11, and 13, were completely
unreactive and only 1,3-dienes bearing monosubstituted
terminal double bonds have given satisfactory results.
The exclusive generation of E-stereochemistry in the
newly formed double bond in products 17, 18, 20, and
21 is consistent with the intermediacy of a syn-π-
allylpalladium intermediate in these reactions. The
annulation of methyl trans,trans-2,4-hexadienoate failed,
presumably because of the low affinity of the cationic
arylpalladium intermediate for the electron-deficient
double bond. Relatively sterically hindered 2,3-diphenyl-
1,3-butadiene gave only a 10% yield of the desired
product 26 (entry 14), while the even more hindered
dienes 1,4-diphenyl-1,3-butadiene and 2,5-dimethyl-2,4-
hexadiene were completely unreactive. The attempted
annulations of 2,3-dimethoxy-1,3-butadiene, 1-methoxy-
1,3-cyclohexadiene, 1,4-pentadiene, cycloheptatriene, and
cyclohexene did not afford any recognizable products.
1
8
optimizations, which utilized Pd(OAc)
dppp, dppb, BINAP, and PPh as the phosphine ligand;
and AgOAc, Ag PO and Ag O as the silver salt, only
2
as the catalyst;
3
3
4
2
resulted in a lower yield of the annulated product 9. 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 %,
CO (0.5 mmol), 1,3-diene (1.0 mmol),
0
.0125 mmol), Ag
2
3
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 have
been studied by using various 1,3-dienes and representa-
tive examples are shown in Table 2. An increase in the
ring size of the cyclic 1,3-diene leads to a significantly
lower yield of annulation product (entries 1-3). Cyclo-
pentadiene failed to give any annulation products, pre-
sumably due to rapid dimerization or some other side
reaction. Most terminal 1,3-dienes have given the ex-
pected annulation products 16-23 in 61 to 83% yields
with excellent regioselectivity (entries 4-11). Running
the reaction of 2,3-dimethyl-1,3-butadiene on a 2.0-mmol
scale with only 10 mL of the 4:1 1,4-dioxane/water
mixture resulted in an even higher 91% yield (entry 11),
indicating the utility of this procedure for practical
applications. The higher yield in the larger scale reaction
is presumably due to an increase in the concentration of
the reagents by a factor of 4 that facilitates coordination
of the 1,3-diene to the arylpalladium intermediate. The
regioselectivity in these experiments can be explained by
the greater affinity of the arylpalladium intermediate for
the less hindered terminal double bond over an internal
double bond. The annulation of isoprene gave a 3:2
mixture of regioisomers 24a and 24b in a 73% yield
In an effort to broaden the scope of this reaction,
similar reactions have been performed on coumarins 27,
35, and 37. All 1,3-dienes investigated have reacted with
coumarin 27 to give the expected annulation products
28-34 in high yields (entries 15-21). Coumarin 35 gave
the expected product 36 in a good yield, even when using
relatively hindered 2,3-dimethyl-1,3-butadiene (entry 22).
Annulation of the coumarin 37 under our “optimal”
reaction conditions resulted in hydrolysis of the acetyl
group. The facile hydrolysis is consistent with the higher
1
9
acidity of 4-hydroxycoumarin than 7-hydroxycoumarin.
The same reaction without the addition of water gave a
48% yield of dihydrofurocoumarin 38 (entry 23). In this
experiment, the acetyl group is quite possibly still being
hydrolyzed by trace amounts of water present in com-
mercial 1,4-dioxane.
Chemical modification of the prepared dihydrofuro-
coumarins enhances the utility of our approach for the
synthesis of various potentially biologically interesting
products. For example, the hydroxymercuration/demer-
20
21
curation and dihydroxylation of coumarin 23 gave the
corresponding alcohol 39 and diol 40, close analogues of
columbianetin (2) and prandiol (7), respectively, in high
(entry 12). The annulation of isoprene by o-iodophenol
is mostly governed by steric factors, favoring addition to
the less hindered double bond and affording a 7:1 ratio
of the corresponding annulation products.13 The poor
regioselectivity in entry 12 presumably results from the
higher reactivity of the presumed cationic arylpalladium
intermediate toward the more electron-rich disubstituted
double bond leading to a competition between steric and
electronic factors, which produces the two different
products.
22
yields (Scheme 1). The dehydrogenation of coumarin 9
afforded benzofurocoumarin 41 in a 90% yield. According
to previous reports benzofurocoumarins, have a high
potential for the treatment of psoriasis and related
22,23
diseases.
A proposed mechanism for this annulation process is
shown in Scheme 2. Initial oxidative addition of the
(18) Maitlis, P. M.; Espinet, P.; Russell, M. J . H. Compr. Organomet.
2
,4-Hexadiene (a 3:2 mixture of trans,trans and cis,-
Chem. 1982, 6, 385.
(19) Georgievskii, V. P. Khim. Prir. Soedin. 1985, 6, 770; Chem.
Abstr. 1986, 104: 144967.
1
7
trans stereoisomers), which has generally been unre-
active and afforded dismal yields in most of our previous
palladium annulation chemistry, gave a 3:2 ratio of trans-
and cis-stereoisomers 25a and 25b in a 60% overall yield
(20) Noland, W. E. Organic Syntheses; J ohn Wiley and Sons: New
York, 1988; Collect. Vol. VI, p 766.
(21) Panek, J . S.; Cirillo, P. F. J . Am. Chem. Soc. 1990, 112, 4873.
(
22) Via, L. D.; Gia, O.; Magno, S. M.; Santana, L.; Teijeira, M.;
Uriarte, E. J . Med. Chem. 1999, 42, 4405.
(23) Vedaldi, D.; Caffieri, S.; Miolo, G.; Guiotto, A.; Dall’Acqua, F.
J . Photochem. Photobiol. B 1992, 14, 81.
(
17) The ratio of trans,trans to cis,trans isomers was determined
by gas chromatography.
6
316 J . Org. Chem., Vol. 68, No. 16, 2003

An Efficient Approach to Dihydrofurocoumarins
TABLE 2. Syn th esis of Dih yd r ofu r ocou m a r in s by th e An n u la tion of 1,3-Dien esa
J . Org. Chem, Vol. 68, No. 16, 2003 6317

Rozhkov and Larock
Ta ble 2 (Con tin u ed )
6
318 J . Org. Chem., Vol. 68, No. 16, 2003

An Efficient Approach to Dihydrofurocoumarins
Ta ble 2 (Con tin u ed )
a
See the text for the experimental procedure. All yields are isolated and based on a single run. c This experiment was performed on
b
a 2.0-mmol scale. A 3:2 mixture of trans,trans and cis,trans isomers was used. e The diene used was 95% trans,trans. f No water has
d
been employed in the solvent.
iodocoumarin 11 to palladium(0) intermediate 42 gener-
ated in situ forms arylpalladium intermediate 43. Ab-
straction of the iodide by Ag CO leads to a cationic
2 3
intermediate 44, presumably stabilized by coordination
to the neighboring acetyl group. According to our results,
the presence of the acetyl group completely inhibits
formation of the undesired reduction product 10 and
dramatically improves the yield of the desired product
Coordination of the acetoxy oxygen to the palladium atom
leading to the formation of intermediate 46 restricts
rotation of the C-C bonds in the allyl moiety, and is,
presumably, responsible for the high stereoselectivity
when trans,trans-2,4-hexadiene is utilized (Table 2,
entries 13 and 21). Since no hydrolysis of the starting
material 11 has been observed under our reaction condi-
tions, the deacylation of intermediate 46 is presumably
accelerated by coordination of the acetyl oxygen atom to
the cationic palladium center. Finally, complex 47 un-
dergoes reductive elimination to give the final product 9
and regenerates the palladium catalyst 42.
9
4
. This may be due to the lower propensity of complex
4, compared to its phenol analogue, to undergo thermal
decomposition. Next, complex 44 adds to the 1,3-diene
in a cis-fashion to give π-allylpalladium intermediate 45.
J . Org. Chem, Vol. 68, No. 16, 2003 6319

Rozhkov and Larock
SCHEME 1
provides an efficient approach to numerous analogues of
a very important class of biologically active natural
products.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P d -Ca ta lyzed An n u la tion
of 1,3-Dien es by o-Iod oa cetoxycou m a r in s. o-Iodoacetoxy-
coumarin (0.25 mmol), Pd(dba)
2
(5 mol %, 0.0125 mmol), dppe
(
(
(
5 mol %, 0.0125 mmol), Ag CO (0.5 mmol), and 1,4-dioxane
4 mL) were stirred in a capped vial for 5 min, and then water
1 mL) and the 1,3-diene (1.0 mmol) were added. The resulting
2 3
reaction mixture was stirred at 100 °C for 24 h, cooled to room
temperature, and filtered, and the filtrate was concentrated
to give a yellow residue. The resulting residue was purified
by column chromatography with use of silica gel as a solid
phase and 4:1 hexanes-ethyl acetate as the eluent to afford
after solvent removal the final product. Solid products were
then recrystallized from 1:1 ethanol-water.
SCHEME 2
7
a,10,11,11a-Tetr ah ydr o-4-m eth ylben zo[b]-2H-fu r o[2,3-
h ]-1-ben zop yr a n -2-on e (9). 9 was obtained in 64% yield:
1
white solid, mp 164-165 °C; H NMR (CDCl
H), 2.40 (d, J ) 1.2 Hz, 3H), 3.67 (m, 1H), 5.07 (m, 1H), 6.04
m, 1H), 6.11 (d, J ) 1.2 Hz, 1H), 6.21 (m, 1H), 6.76 (d, J )
3
) δ 1.43-2.32 (m,
4
(
8
2
1
.5 Hz, 1H), 7.41 (d, J ) 8.5 Hz, 1H); 13C NMR (CDCl
3.3, 24.2, 38.4, 80.6, 107.2, 111.4, 114.3, 118.6, 123.3, 125.6,
3
) δ 19.2,
-
1
34.8, 151.3, 153.4, 161.4, 163.1; IR (neat) 1733, 1615 cm
, 254.0943).
;
HRMS m/z 254.0946 (calcd for C16
14 3
H O
The product characterization data for all other dihydrofuro-
coumarins and derivatives prepared appears in the Supporting
Information.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research and J ohnson Matthey, Inc. and Kawak-
en Fine Chemicals Co., Ltd. for donations of palladium
acetate.
Con clu sion s
In summary, we have developed an efficient palladium-
catalyzed annulation of 1,3-dienes by o-iodoacetoxycou-
marins, which affords good yields of dihydrofurocou-
marins. The process is quite general and regio- and
stereoselective, and a variety of o-iodoacetoxycoumarins,
as well as symmetrical and unsymmetrical 1,3-dienes,
can be utilized. Derivatization of the annulation products
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and spectral data for the compounds listed in
Table 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O034571W
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320 J . Org. Chem., Vol. 68, No. 16, 2003