An efficient synthesis of coumestrol and coumestans by iodocyclization and Pd-catalyzed intramolecular lactonization

Article abstract of DOI:10.1021/jo0517038

The iodocyclization of acetoxy-containing 2-(1-alkynyl)anisoles and subsequent direct palladium-catalyzed carbonylation/lactonization provide an efficient route to naturally occurring coumestan and coumestrol, and their related analogues.

Full text of DOI:10.1021/jo0517038

An Efficient Synthesis of Coumestrol and Coumestans by
Iodocyclization and Pd-Catalyzed Intramolecular Lactonization
Tuanli Yao,† Dawei Yue,† and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received August 11, 2005
The iodocyclization of acetoxy-containing 2-(1-alkynyl)anisoles and subsequent direct palladium-
catalyzed carbonylation/lactonization provide an efficient route to naturally occurring coumestan
and coumestrol, and their related analogues.
Introduction
on the human body and the potential of phytoestrogens
for human health, it is highly desirable to develop more
efficient and general methods for the synthesis of
coumestans and their derivatives.
Recently, we reported an efficient synthesis of substi-
tuted 3-iodobenzofurans by iodocyclization of the corre-
sponding o-alkynylanisoles.8 This iodocyclization of func-
tionally substituted aryl acetylenes, when followed by
subsequent Pd-catalyzed lactonization, appeared to pro-
vide a particularly promising route to this important class
of biologically interesting polycyclic lactones.
Palladium-catalyzed lactonization via CO insertion is
a very useful synthetic method that has become an
important tool in organic synthesis.9 The most widely
used process for the conversion of acylpalladium deriva-
tives into lactones is the direct reaction of the derivatives
with a neighboring alcohol group. To the best of our
knowledge, no reaction of acylpalladium species with a
protected alcohol group has been previously reported. We
now disclose an efficient synthetic route to coumestans
Coumestrol was first isolated from alfalfa, strawberry,
Lucerne, and ladino clover by Bickoff et al. in the 1950s.1
Because the structure of coumestrol resembles the well-
known (E)-4,4′-dihydroxystilbene derivatives, which have
potent pharmacological activity, it is not surprising that
coumestrol shows estrogenic activity.2 Coumestrol has
higher binding affinities for ERâ than do other phy-
toestrogen compounds.3 In vitro, coumestrol has been
reported to inhibit bone resorption and stimulate bone
mineralization.4
The total synthesis of coumestrol has been reported
by several groups using quite different approaches.5
However, most of the reported syntheses have required
multiple steps, and produced only modest overall yields.
Recently, a number of naturally occurring coumestan
isoflavones have been discovered,6 and their biological
effects are currently under investigation.7 In view of the
many important physiological effects that estrogens have
† These authors contributed equally to this work.
(1) (a) Bickoff, E. M.; Booth, A. N.; Lyman, R. L.; Livingston, A. L.;
Thompson, C. R.; Deeds, F. Science 1957, 126, 969. (b) Bickoff, E. M.;
Booth, A. N.; Lyman, R. L.; Livingston, A. L.; Thompson, C. R.; Kohler,
G. O. J. Agric. Food Chem. 1958, 6, 536. (c) Bickoff, E. M.; Lyman, R.
L.; Livingston, A. L.; Booth, A. N. J. Am. Chem. Soc. 1958, 80, 3969.
(d) Emerson, O. H.; Bickoff, E. M. J. Am. Chem. Soc. 1958, 80, 4381.
(2) Stadlbauer, W.; Kappe, T. Heterocycles 1993, 35, 1425.
(3) Whitten, P. L.; Naftolin, F. J. Clin. Endocrinol. Metab. 1998,
12, 667.
(6) (a) Kishore, P. H.; Reddy, M. V. B.; Gunasekar, D.; Murthy, M.
M.; Caux, C.; Bodo, B. Chem. Pharm. Bull. 2003, 51, 194. (b) Upadhyay,
R. K.; Singh, S.; Pandey, V. B. Orient. J. Chem. 2001, 17, 369. (c)
Shul`ıts, E. E.; Petrova, T. N.; Shakirov, M. M.; Chernyak, E. I.;
Tolstikov, G. A. Chem. Nat. Compd. 2000, 36, 362.
(7) (a) Boue, S. M.; Carter, C. H.; Ehrlich, K. C.; Cleveland, T. E. J.
Agric. Food Chem. 2000, 48, 2167. (b) da Silva, A. J. M.; Melo, P. A.;
Silva, N. M. V.; Brito, F. V.; Buarque, C. D.; de Souza, D. V.; Rodrigues,
V. P.; Pocas, E. S. C.; Noel, F.; Albuquerque, E. X.; Costa, P. R. R.
Bioorg. Med. Chem. Lett. 2001, 11, 283. (c) Diel, P.; Olff, S.; Schmidt,
S.; Michna, H. J. Steroid Biochem. Mol. Biol. 2002, 81, 61.
(8) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, in press.
(9) (a) Tsuji, J. Palladium Reagents and Catalysis: New Perspectives
for the 21st Century; John Wiley & Sons: New York, 2004; pp 265-
286. (b) Handbook of Organopalladium Chemistry for Organic Syn-
thesis; Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 2,
pp 2313-2399.
(4) Tsutsumi, N. Biol. Pharm. Bull. 1995, 18, 1012.
(5) For previous total syntheses of coumestrol, see: (a) Emerson,
O. H.; Bickoff, E. M. J. Am. Chem. Soc. 1958, 80, 4381. (b) Jurd, L.
Tetrahedron Lett. 1963, 1151. (c) Kappe, T.; Brandner, A. Z. Natur-
forsch., B 1974, 29, 292. (d) Laschober, R.; Kappe, T. Synthesis 1990,
387. (e) Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.; Kasano, A.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 2000, 4339. (f) Kraus, G.
A.; Zhang, N. J. Org. Chem. 2000, 65, 5644.
10.1021/jo0517038 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2005, 70, 9985-9989
9985

Yao et al.
SCHEME 1
involving iodocyclization followed by palladium-catalyzed
carbonylative lactonization. The nucleophile employed in
our lactonization process is an acetoxy group, which
serves as a latent hydroxyl group.10 Deprotection of the
hydroxy group is not necessary in this one-pot carbony-
lation process.
Results and Discussion
We and others have previously reported efficient
approaches to the synthesis of benzofurans,8,11 ben-
zothiophenes,12 indoles,13 quinolines,14 isoquinolines,15
isocoumarins and R-pyrones,16 and naphthalenes and
polycyclic aromatic hydrocarbons17 by the iodocyclization
of the appropriate functionally substituted aryl acety-
lenes. These processes generally provide the desired
aromatic heterocycles in good to excellent yields under
very mild reaction conditions. Although these processes
are very attractive for preparation of the starting materi-
als required in our coumestrol synthesis, protection of
the neighboring hydroxyl group during iodocyclization
and subsequent facile liberation of this functionality
during Pd-catalyzed lactonization are critical to the
efficacious synthesis of the coumestrol ring system. When
an acetyl group was employed as the protecting group,
the desired starting materials could be efficiently pre-
pared by iodocyclization of the appropriate alkynes
(Scheme 1). All of these reactions afforded cyclized
products with excellent chemoselectivity. The acetoxy
group remains intact in all cases, and does not undergo
cyclization. These starting materials are readily avail-
able, which makes our overall process particularly at-
tractive.
The corresponding benzofuran, compound 1 (see Table
1, entry 1), was then treated with a palladium catalyst
and 1 atm of CO in the hope that carbonylation and
lactonization might occur in a single step. After brief
optimization of the reaction conditions, we were pleased
to find that coumestan (2) could be obtained in an almost
quantitative yield by using 5 mol % PdCl2(PPh3)2 and 2.0
equiv of K2CO3 in DMF under a balloon of CO at 60 °C
for 6 h (Table 1, entry 1). The corresponding sulfur
analogue, 6H-benzothieno[3,2-c]benzopyran-6-one (11-
thiacoumestan, 4), can also be prepared in good yield
under these conditions, but at a higher temperature,
which may be because of intermolecular coordination of
the palladium by the sulfur of the benzothiophene (entry
2). When using 3-iodoindole 5, only a 21% yield of the
desired lactone 6 was obtained in 6 h at 60 °C, along with
recovery of 56% of the indole starting material 5 (entry
3). This low yield may be the result of the increased steric
hindrance provided by the methyl group on the nitrogen
of the indole, which hinders free rotation about the
carbon-carbon bond between the two aryl groups. For-
tunately, when the temperature was increased to 90 °C
and the reaction was run for 6 h, the desired lactone 6
was isolated in a 75% yield with complete disappearance
of the starting material (entry 4). This method is not
limited to five-membered heterocyclic starting materials.
Naphthalene 7 and quinoline 9 have also provided the
corresponding lactones in 95 and 73% yields, respectively
(entries 5 and 6), when allowed to react at 90 °C for 6 h.
R-Pyrone 11 provided cyclized product in only a low yield,
presumably because of its instability under the reaction
conditions (entry 7). In none of the above examples is
there observed any direct intramolecular coupling of the
aryl halide and the oxygen without incorporation of CO,
a possible side reaction when using an unprotected
hydroxyl group.18
(10) For the use of an acetoxy group as a latent hydroxy group in
other palladium chemistry, see: (a) Miao, H.; Yang, Z. Org. Lett. 2000,
2, 1765. (b) Rozhkov, R. V.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
(c) Rozhkov, R. V.; Larock, R. C. Org. Lett. 2003, 5, 797.
(11) (a) Arcadi, A.; Cacchi, S.; Giancarlo, F.; Marinelli, F.; Moro, L.
Synlett 1999, 1432. (b) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi,
G.; Marinelli, F. Org. Lett. 2002, 4, 2409.
(12) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.;
Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(13) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M.
Angew. Chem., Int. Ed. 2003, 42, 2406. (b) Yue, D.; Larock, R. C. Org.
Lett. 2004, 6, 1037. (c) Amjad, M.; Knight, D. W. Tetrahedron Lett.
2004, 45, 539.
(14) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005,
7, 763.
(15) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002,
67, 3437.
(16) (a) Yao, T.; Larock, R. C. Tetrahedron Lett. 2002, 43, 7401. (b)
Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Biagetti, M.;
Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58,
5023.
(17) (a) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
(b) Zhang, X.; Larock, R. C. Work in progress.
A proposed mechanism for this carbonylation process
is shown in Scheme 2. Oxidative addition of Pd(0) to aryl
(18) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. C. J. Org.
Chem. 1995, 60, 3270.
9986 J. Org. Chem., Vol. 70, No. 24, 2005

Synthesis of Coumestrol and Coumestans
TABLE 1. Palladium-Catalyzed Intramolecular Lactonizationa
a All reactions were run under the following conditions, unless otherwise specified: 0.25 mmol of the starting material, 5 mol %
PdCl2(PPh3)2, 2.0 equiv of K2CO3 in 1 mL of DMF under CO (1 atm) for 6 h. b Fifty-six percent of the starting material was recovered.
SCHEME 2
ladium-catalyzed carbonylative lactonization, we have
applied this methodology to the synthesis of coumestrol,
a natural product with interesting phytoestrogenic ef-
fects.5 Our synthesis of coumestrol is quite straightfor-
ward, and should be readily adapted to the synthesis of
analogues (Scheme 3). Thus, commercially available
4-bromoresorcinol (13) was selectively tosylated, and the
resulting phenol was converted into the methyl ether 14
in two steps in a 79% overall yield.5e The Sonogashira
coupling of 14 with trimethylsilyl acetylene, followed by
desilylation with TBAF, provides alkyne 15 in an 88%
overall yield.
2,4-Diacetoxyiodobenzene (18) was prepared in almost
a quantitative yield by acetylation of 4-iodoresorcinol
(17), which was in turn prepared by the iodination of
resorcinol using ICl. Our usual Sonogashira reaction
conditions (2 mol % PdCl2(PPh3)2, 1 mol % CuI, and 1.5
equiv of Et3N in DMF at 25 °C) were ineffective for the
coupling of 18 and 15. A large amount of the homocou-
pling product of acetylene 15 was obtained. A brief
optimization showed that using i-Pr2NH as the base and
DMF as the solvent at 60 °C provided the best yield of
acetylene 19 (95%).5e Compound 19 was successfully
cyclized to benzofuran 20 in a 98% yield when employing
2.5 equiv of I2 as the electrophile. With compound 20 in
hand, we examined the Pd-catalyzed carbonylative lac-
tonization. Under our usual carbonylation conditions,
compound 20 was converted to coumestrol (21) in a 20%
yield, along with a 60% yield of the coumestrol tosylate
22. The tosyl derivative was easily converted to coumestrol
in a quantitative yield by using 1.1 equiv of TBAF in
DMF under reflux for 2 h. A separate experiment showed
that without any purification, the mixture of coumestrol
(21) and tosyl derivative 22 could be converted to
iodide I is presumably followed by insertion of CO to
generate the acylpalladium intermediate III. Coordina-
tion of the acetoxy oxygen to the acylpalladium moiety
presumably accelerates deacylation of intermediate III
by the base present in the reaction mixture, as suggested
by previous work on Pd-catalyzed processes.10 Finally,
complex IV undergoes reductive elimination to give the
final product V, and regenerates the palladium catalyst.
To further demonstrate the versatility of this pal-
J. Org. Chem, Vol. 70, No. 24, 2005 9987

Yao et al.
SCHEME 3
SCHEME 4
coumestrol in a 75% yield using 1.2 equiv of TBAF in
DMF under reflux for 4 h.
Hydrolysis of the known chromene carbamate 23,20
followed by protection of the resulting OH group as an
acetoxy group, afforded chromene 25 in a 51% overall
yield (Scheme 4). Sonogashira coupling of 25 with 15
under our previous optimized conditions led to alkyne 26
in a moderate yield. Iodocyclization of 26 afforded 3-
iodobenzofuran 27 in a good yield. Under our optimal
conditions for the Pd-catalyzed lactonization, we con-
verted benzofuran 27 to the proposed plicadin tosylate
28 in a 61% yield, which was nearly quantitatively
converted to the structure proposed for plicadin by
We have also applied our methodology to the synthesis
of another derivative of coumestan, a proposed natural
product “plicadin”, whose structure was originally mis-
assigned.2,19 Plicadin was isolated from the herb Psoralea
plicata and apparently has a compact, oxygen-rich,
heterocyclic structure. A total synthesis by Snieckus et
al. proved the original proposed structure wrong,20 and
since then, a correct structure has not been established.
(19) Hepworth, J. D. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon: New York, 1984; Vol. 4, pp 995-
998.
(20) Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V.
Angew. Chem., Int. Ed. 1999, 38, 1435.
9988 J. Org. Chem., Vol. 70, No. 24, 2005

Synthesis of Coumestrol and Coumestans
(95%): 1H NMR (CDCl3) δ 2.21 (s, 3H), 7.25 (dd, J ) 8.1, 1.2
Hz, 1H), 7.32-7.40 (m, 3H), 7.44-7.53 (m, 3H), 7.82 (dd, J )
7.8, 1.8 Hz, 1H); 13C NMR (CDCl3) δ 21.3, 65.4, 111.4, 122.1,
123.3, 123.7, 123.8, 126.0, 126.1, 131.2, 131.7, 131.9, 148.8,
152.3, 154.6, 169.4; IR (neat) 1771 cm-1; HRMS calcd for
C16H11IO3 377.9758, found 377.9753.
General Procedure for Palladium-Catalyzed Intra-
molecular Lactonization. DMF (1.0 mL), PdCl2(PPh3)2
(0.0125 mmol), K2CO3 (0.5 mmol), and the aryl iodide (0.25
mmol) were stirred under an Ar atmosphere at room temper-
ature for 5 min. The mixture was flushed with CO, and the
flask was fitted with a balloon of CO. The reaction mixture
was heated at the specified temperature with vigorous stirring
for 6 h. The reaction mixture was then cooled to room
temperature, diluted with diethyl ether (35 mL), and washed
with brine (30 mL). The aqueous layer was extracted with
diethyl ether (15 mL). The organic layers were combined, dried
over anhydrous Na2SO4, and filtered, and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography on a silica gel column.
Coumestan (2). This compound was obtained as a white
solid (99%): mp 180-181 °C (lit.21 mp 181-182 °C); 1H NMR
(CDCl3) δ 7.39-7.53 (m, 4H), 7.59-7.69 (m, 2H), 8.04 (dd, J
) 7.8, 1.5 Hz, 1H), 8.13-8.16 (m, 1H); 13C NMR (CDCl3) δ
106.1, 112.0, 112.9, 117.7, 122.1, 123.7, 124.9, 125.4, 127.0,
132.1, 153.9, 155.8, 158.3, 160.2; IR (neat) 1737 cm-1; HRMS
calcd for C15H8O3 236.0476, found 236.0473. The spectral
properties were identical to those previously reported.21
Plicadin (29). Compound 28 was converted to the structure
originally proposed for plicadin (29) by following the same
procedure used to prepare lactone 21. This afforded the
proposed plicadin (94%) as a yellow solid: mp 290-291 °C
(sublim). The spectral properties were identical to those
previously reported.20
1
deprotection with TBAF. The H NMR spectrum of our
synthesized plicadin is identical to that of Snieckus’
plicadin.20 Although it does not establish the correct
structure of plicadin, our iodocyclization/carbonylation
methodology should provide direct access to a large
number of biologically interesting coumestan derivatives.
In summary, we have developed an efficient approach
to biologically interesting coumestans that involves simple,
high-yielding Sonogashira cross-coupling, iodocyclization,
and Pd-catalyzed lactonization using an acetoxy group
as the nucleophile. A variety of biaryls can be utilized in
this process to generate aromatic lactones in good yields.
More importantly, the methodology we have developed
can be applied to the synthesis of coumestan, coumestrol,
plicadin, other coumestan family members, and a wide
variety of coumestan analogues.
Experimental Section
General Procedure for the Sonogashira Cross-Cou-
pling: 2-(2-Methoxyphenylethynyl)phenyl Acetate. A
mixture of 2-ethynylanisole (6.0 mmol), 2-iodophenyl acetate
(5.0 mmol), CuI (0.06 mmol), and PdCl2(PPh3)2 (0.12 mmol) in
a mixture of Et3N (2.0 equiv) and DMF (50 mL) was heated
at 60 °C for 2 h. The precipitate was filtered off, and the filtrate
was concentrated under reduced pressure. The residue was
extracted with Et2O, and the combined extracts were washed
successively with water and satd aq NaCl. The organic solution
was dried over anhydrous Na2SO4 and evaporated. The residue
was purified by flash chromatography on silica gel (4:1 hexane/
EtOAc) to give the above product (96%) as a yellow oil: 1H
NMR (CDCl3) δ 2.37 (s, 3H), 3.87 (s, 3H), 6.88 (d, J ) 8.7 Hz,
1H), 6.92 (td, J ) 7.5, 0.9 Hz, 1H), 7.11 (dd, J ) 8.1, 1.5 Hz,
1H), 7.20 (td, J ) 7.5, 1.5 Hz, 1H), 7.26-7.35 (m, 2H), 7.46
(dd, J ) 7.5, 1.8 Hz, 1H), 7.59 (dd, J ) 7.5, 1.8 Hz, 1H); 13C
NMR (CDCl3) δ 21.0, 55.8, 88.3, 90.9, 110.9, 112.3, 118.0, 120.6,
122.4, 126.0, 129.4, 130.2, 133.1, 133.7, 151.6, 160.1, 169.1;
IR (neat) 1771 cm-1; HRMS calcd for C17H14O3 266.0946, found
266.0943.
General Procedure for Iodocyclization: 2-(2-Acetoxy-
phenyl)-3-iodobenzo[b]furan (1). This compound was pre-
pared according to a literature procedure.8 A solution of 2-(2-
methoxyphenylethynyl)phenyl acetate (2.50 mmol) in dry
CH2Cl2 (10 mL) was stirred at room temperature for 1 min. I2
(2.5 equiv) was added, and the resulting mixture was allowed
to stir at 25 °C for 12 h. Satd aq Na2S2O3 (5 mL) was added to
the mixture, which was further stirred for 2 min. The resulting
mixture was then extracted with Et2O. The combined organic
solution was washed successively with water and satd aq
NaCl, dried over anhydrous Na2SO4, and concentrated under
vacuum. The residue was purified by flash chromatography
on silica gel (4:1 hexane/EtOAc) to afford 1 as a yellow oil
Acknowledgment. We gratefully acknowledge the
University of Kansas Chemical Methodologies and
Library Development Center of Excellence (NIH P50
GM069663), and the National Institutes of General
Medical Sciences and the National Institute of General
Medical Science (GM070620) for financial support of this
work, and Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd., for donations of palladium cata-
lysts.
Supporting Information Available: Characterization
data for the compounds listed in Table 1 and experimental
procedures and characterization data for the reactions sum-
marized in Schemes 3 and 4. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0517038
(21) Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106,
4218.
J. Org. Chem, Vol. 70, No. 24, 2005 9989