An efficient approach to dihydrofuroflavonoids via palladium-catalyzed annulation of 1,3-dienes by 0-iodoacetoxyflavonoids

Article abstract of DOI:10.1002/adsc.200404226

The palladium-catalyzed annulation of 1,3-dienes by o-iodoacetoxyflavonoids provides an efficient approach to biologically interesting dihydrofuroflavonoids. This reaction is very general, stereo-and regioselective, and a wide variety of terminal, cyclic and internal 1,3-dienes can be utilized.

Full text of DOI:10.1002/adsc.200404226

FULL PAPERS
An Efficient Approach to Dihydrofuroflavonoids via
Palladium-Catalyzed Annulation of 1,3-Dienes by
o-Iodoacetoxyflavonoids
Roman V. Rozhkov, Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
Fax: (þ1)-515-294-0105, e-mail: larock@iastate.edu
Received: July 13, 2004; Accepted: September 9, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The palladium-catalyzed annulation of 1,3- Keywords: annulation; catalysis; dihydrofuroflava-
dienes by o-iodoacetoxyflavonoids provides an effi- none; dihydrofuroflavone; dihydrofuroisoflavone; ho-
cient approach to biologically interesting dihydrofur- mogeneous; palladium
oflavonoids. This reaction is very general, stereo-
and regioselective, and a wide variety of terminal, cy-
clic and internal 1,3-dienes can be utilized.
Introduction
have been studied using various o-iodoacetoxyflavo-
noids and 1,3-dienes, and representative examples are
Naturally occurring in plants and fruits, dihydrofurofla- shown in Table 1.
vonoids display a broad array of biological properties.[1]
Analogous to the annulation of o-iodoacetoxycou-
For example, dihydrofuroflavones (1) have high cyto- marins,[7] the annulation of various 1,3-dienes by the fla-
toxicity against P-388 cells.[2] Dihydrofuroflavanones vone 4 has given the expected products 5–12 in 62 to
(2) are effective inhibitors of protein kinase,[3] aroma- 96% yields with excellent regioselectivity (entries 1–
tase,[4] and larvae growth,[5] and dihydrofuroisoflavones 8). This reaction is pretty general for a wide variety of
(3) exhibit high antifungal activity.[6]
1,3-dienes. Highly substituted mono- and disubstituted
Recently, we reported an efficient method for the syn- terminal dienes give excellent yields and even internal
thesis of dihydrofurocoumarins[7] and dihydrofuroflavo- double bonds, such as those in 1,3-cyclohexadiene,
noids.[8] As of today, despite significant interest in dihy- work well. Running the preparation of 12 on a 2.0-
drofuroflavonoids, no efficient, general alternative mmol scale resulted in an even higher 90% yield (en-
method for the synthesis of dihydrofuroflavonoids has try 8), indicating the utility of this procedure for practi-
really been developed. Herein, we report our results cal applications. The annulation of isoprene gave a 3:2
on the palladium-catalyzed annulation of 1,3-dienes by mixture ofregioisomers 13a and 13bin an 86% yield (en-
o-iodoacetoxyflavonoids that provides a very general try 9). The analogous annulation of isoprene by o-iodo-
and effective route to a wide variety of dihydrofurofla- phenol has been shown to be mostly governed by steric
vonoids.
factors, favoring addition to the less hindered double
bond and thus affording a 7:1 ratio of the corresponding
annulation products.[9] The poor regioselectivity in en-
try 9 presumably results from the higher reactivity of
the cationic arylpalladium intermediate (see the later
Results and Discussion
Using our previously developed reaction conditions,[7,8] mechanistic discussion) towards the more electron-
the scope and limitations of this annulation (Scheme 1)
Scheme 1.
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DOI:10.1002/adsc.200404226
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Pd-Catalyzed Annulation of 1,3-Dienes by o-Iodoacetoxyflavonoids
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Table 1. Synthesis of dihydrofuroflavonoids by palladium-catalyzed annulation.[a]
Entry
1
Flavonoid
1,3-Diene
Product(s)
Yield [%][b]
(ratio of isomers)
62
75
2
”
3
4
5
”
”
”
80
82
76
6
7
8
”
”
”
96
85
77, 90[c]
9
”
”
86 (3: 2)
68 (20: 1)[d]
25
10
11
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Roman V. Rozhkov, Richard C. Larock
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Table 1 (cont.)
Entry
12
Flavonoid
1,3-Diene
Product(s)
Yield [%][b]
(ratio of isomers)
”
16
90
13
14
60
15”
16
92
72 (2: 1)
17
18
70
”
95
19
88, 96[c]
[a]
The iodoacetoxyflavonoid (0.25mmol), Pd(dba) 2 (5mol %, 0.0125mmol), dppe (5mol %, 0.0125mmol), Ag 2CO3
(0.5mmol), the 1,3-diene (1.0 mmol), and 5mL of a 4: 1 1,4-dioxane/water mixture were stirred at 100 8C for 24 h.
All yields are isolated and based on a single run.
This experiment was performed on a 2.0-mmol scale.
The diene used was 95% trans, trans.
[b]
[c]
[d]
rich disubstituted double bond, leading to a competition
In order to broaden the scope of this reaction, similar
between steric and electronic factors, which produces a reactions have been performed on flavonoids 15, 18, 20,
mixture of the two isomeric products. The use of trans, 23, 25, and 28. Steric hindrance in the vicinity of the iodo
trans-2,4-hexadiene (95% purity) gave a 20:1 ratio of group in the flavone 15 gave much lower yields of the de-
isomers 14a and 14b in a 68% yield (entry 10). The ex- sired annulation products 16 and 17, presumably due to
clusive generation of E-stereochemistry in the newly slower oxidative addition to the Pd(0) catalyst or inser-
formed carbon-carbon double bond in products 7, 9, tion of the diene (entries 11 and 12).
10 and 14 is consistent with the intermediacy of a syn-
Since annulations of 1,3-dienes with electron-rich o-
iodophenols have given lower yields of the desired an-
p-allylpalladium intermediate in these reactions.[10]
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Pd-Catalyzed Annulation of 1,3-Dienes by o-Iodoacetoxyflavonoids
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Scheme 2.
nulation products in previous studies in our group,[9] an- annulations,[11b] although it also results in lower regiose-
nulations employing the electron-rich flavones 18, 20 lectivity in the anulation of isoprene. Next, complex 32
and 23 presented a significant challenge to our method- adds to the 1,3-diene in a cis-fashion to give a s-allylpal-
ology. Contrary to our earlier results,[9] using our current ladium complex, which rapidly forms p-allylpalladium
reaction conditions, the annulation of 2,3-dimethyl-1,3- intermediate 33.[9] Coordination of the acetoxy oxygen
butadiene by flavone 18 gave a 90% yield of the expect- to the palladium atom, leading to the formation of inter-
ꢀ
ed annulation product 19 (entry 13). Despite a longer re- mediate 34, restricts rotation of the C C bonds in the all-
action time (96 h), the annulation of 1,3-cyclohexadiene yl moiety, and is, presumably, responsible for the high
and 2,3-dimethyl-1,3-butadiene by flavone 20, followed stereoselectivity when trans, trans-2,4-hexadiene is uti-
by a basic work-up, afforded the annulated products 21 lized (Table 1, entry 10). Since no hydrolysis of the start-
and 22 in 60% and 92% yields, respectively (entries 14 ing material 4has been observed underour reaction con-
and 15). Our attempts to accomplish a bis-annulation us- ditions, the deacylation of intermediate 34 is presumably
ing electron-rich flavone 23 failed, presumably due to accelerated by coordination of the acetyl oxygen atom
significant steric hindrance at the C-6 position of the fla- to the cationic palladium center. Finally, complex 35 un-
vone moiety. Instead, this process gave a 2:1 mixture of dergoes reductive elimination to give the final product 5
monoannulated product 24 and deiodinated monoannu- and simultaneously regenerates the palladium catalyst
lated product 22 in a 72% overall yield (entry 16).
The annulation of 1,3-cyclohexadiene and 2,3-dimeth-
yl-1,3-butadiene by isoflavone 25 produced the desired
annulation products 26 and 27 in 70 and 95% yields, re-
spectively (entries 17 and 18). Finally, the annulation of
2,3-dimethyl-1,3-butadiene by flavanone 28 afforded
the desired annulation product 29 in an 88% yield (en-
try 19). Running the latter reaction on a 2.0-mmol scale
increased the isolated yield to 96%. Thus, the annulation
works well on a variety of substituted flavonoids. Elec-
tron-rich systems are readily accommodated, but steric
hindrance about the iodide can be a problem.
30.
Conclusion
We have developed an efficient palladium-catalyzed ap-
proach to dihydrofuroflavonoids including dihydrofuro-
flavones, dihydrofuroflavanones and dihydroisofla-
vones. The process is quite general, regio- and stereose-
lective, and a variety of o-iodoacetoxyflavonoids, as well
as symmetrical and unsymmetrical 1,3-dienes can be uti-
lized.
A proposed mechanism for this annulation process is
shown in Scheme 2. Initial oxidative addition of the io-
doflavone 4 to palladium intermediate 30 generated in
situ forms arylpalladium intermediate 31.[11] Abstraction
of the iodide by Ag2CO3 leads to a cationic intermediate
32,[12] presumably stabilized by coordination to the
neighboring acetyl group. The higher reactivity of these
cationic arylpalladium complexes towards alkenes,
compared to the neutral arylpalladium complexes, is
Experimental Section
Palladium-Catalyzed Annulation of 1,3-Dienes by o-
Iodoacetoxyflavonoids
The o-iodoacetoxyflavonoid (0.25mmol), Pd(dba) 2 (5mol %,
0.0125mmol), dppe (5mol %, 0.0125mmol), Ag 2CO3
presumably responsible for the excellent yields in our (0.5mmol) and 1,4-dioxane (4 mL) were stirred in a capped
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Roman V. Rozhkov, Richard C. Larock
FULL PAPERS
vial for 5min, and then water (1 mL) and the 1,3-diene
(1.0 mmol) were added. The resulting reaction mixture was
stirred at 1008C for 24 h, cooled to room temperature, filtered
and the filtrate was concentrated to give a yellow residue. This
residue was purified bycolumn chromatography using 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. Experimental
procedures and spectral data for all newly synthesized flavo-
noids are available in the Supporting Information.
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Acknowledgements
We gratefully acknowledge the donors of the PetroleumRe-
search Fund, administered by the American Chemical Society,
for partial support of this research and Johnson Matthey, Inc.
and Kawaken Fine Chemicals Co., Ltd. for donations of palla-
diumacetate.
[8] R. V. Rozhkov, R. C. Larock, Tetrahedron Lett. 2004, 45,
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