Hydrogen-atom abstraction/cyclization in synthesis. Direct syntheses of coumestan and coumestrol

Article abstract of DOI:10.1021/jo0004198

The synthesis of coumestrol has been achieved in five steps from 1,3-dimethoxybenzene. The key step is a photochemical cyclization of a glyoxylate ester.

Full text of DOI:10.1021/jo0004198

5644
J . Org. Chem. 2000, 65, 5644-5646
Hyd r ogen -Atom Abstr a ction /Cycliza tion in Syn th esis. Dir ect
Syn th eses of Cou m esta n a n d Cou m estr ol
George A. Kraus* and Ning Zhang
Department of Chemistry and Program in Toxicology, Iowa State University, Ames, Iowa 50011
gakraus@iastate.edu
Received March 21, 2000
The synthesis of coumestrol has been achieved in five steps from 1,3-dimethoxybenzene. The key
step is a photochemical cyclization of a glyoxylate ester.
Coumestrol (1) is a phytoestrogen which is found in
generated a phenoxide that reacted with 5 to afford
compound 6 in 65% yield.6 Irradiation of 6 for 48 h,
plants.1 Although it is one of the most potent phyto-
estrogens, its estrogenic activity is approximately 77
times less potent than estradiol, the primary human
estrogen and the standard by which activity is mea-
sured.2 Coumestrol is present in alfalfa, cabbage, and,
to a lesser extent, soybeans. It is the subject of recent
concern in animal reproductive physiology because it
lowers the amount of natural estrogen in animals.3 A few
syntheses of this compound have been reported.4 In these
syntheses, the compound is constructed by an annulation
onto a functionalized coumarin, forming the furan ring
in the last step.
according to the conditions of Neckers,7 produced hydroxy
ester 7 as what appeared to be one stereoisomer on the
basis of the proton NMR spectrum. Pappas studied the
solvent dependence of photocyclizations of o-benzylox-
yphenyl glyoxylate and found that, with benzene as the
solvent, over 95% of the product was the stereoisomer
with the phenyl group cis to the hydroxyl group.5
Therefore, the stereochemistry is tentatively assigned as
shown. These stereogenic centers are eliminated in the
subsequent step. Treatment of 7 with 6 N HCl in THF
for 36 h generated coumestan 2 in 45% yield from 6. This
compound exhibited a melting point of 179-180 °C. The
UV and NMR spectra of our compound were identical to
the spectra reported in the literature.8
Our approach to the synthesis of 1 was based on the
rationale that a flexible synthetic route that could easily
prepare both 1 and 2 plus selected oxygenated analogues
was needed to support the toxicology studies. In view
of the ready availability of hydroxylated analogues of
phenyl glyoxylic acid and the commercial availability
of hydroxylated benzylic alcohols, we developed our
synthesis of 1 along the retrosynthetic analysis shown
below. The hydroxy ester would be derived from a
photochemically mediated hydrogen atom abstraction/
cyclization reaction.5
The synthesis of 1 begins with the acylation of
1,3-dimethoxybenzene with methyl chlorooxalate and
aluminum chloride in dichloroethane at ambient tem-
perature.9 Keto ester 8 was produced in 50% yield. The
The synthesis of coumestan (2) is illustrated below. The
reaction of benzofuran dione 4 with sodium methoxide
phenol subunit of this compound was then coupled with
(1) Endocrine Disrupters: A Scientific Perspective. The American
Council on Science and Health, J uly 1999.
(2) Gaido, K.W.; Leonard, L. S.; Lovell, S. Toxicol. Appl. Pharmacol.
1997, 143, 205-212.
alcohol 910 using a variant of the Mitsunobu reaction. The
(6) Huntress, E. H.; Hearon, W. M. J . Am. Chem. Soc. 1941, 63,
2762-2766.
(3) Solomon, G. L. Environmental Health Perspectives 1994, 102,
Number 8.
(7) Hu, S.; Neckers, D. C. J . Chem. Soc., Perkin Trans 2 1999, 1771-
(4) Emerson, H.; Bickoff, E. M. J . Am. Chem. Soc. 1958, 80, 4381.
Kawase, Y. Bull. Chem. Soc. J pn. 1959, 32, 690. J urd, L. J . Org. Chem.
1964, 29, 3036.
(5) Pappas, S. P.; Pappas, B. C.; Blackwell, J . E. J . Org. Chem. 1967,
32, 3066-3069.
1778.
(8) Majumdar, K. C.; Khan, A. T.; Gupta, A. K.; Kundu, A. K.;
Choudhury, P. K. Ind. J . Chem. 1992, 31B, 667-672.
(9) Gray, T. I.; Pelter, A.; Ward, R. S. Tetrahedron 1979, 35, 2539-
2543.
10.1021/jo0004198 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/11/2000

H-Atom Abstraction/Cyclization
J . Org. Chem., Vol. 65, No. 18, 2000 5645
Meth yl-2-(2-m eth oxym eth oxyben zyloxy)p h en yl Gly-
oxyla te (6). To a freshly prepared NaOMe/MeOH solution
(prepared by dissolving Na (92.0 mg, 4 mmol) in 16 mL of
MeOH) was added benzofuran-2,3-dione13,9 (296.2 mg, 2 mmol)
in 2 mL of MeOH dropwise. After 1 h, a solution of 5 (568.4
mg, 2.2 mmol) in 2 mL MeOH was added, and the reaction
mixture was allowed to react for 24 h at room temperature. It
then was quenched with saturated NH4Cl containing a small
amount of HCl and extracted with ether 3 times. The ether
layer was washed with saturated NaHCO3 solution and brine
and dried over MgSO4. After removal of ether, the crude
product was purified by sgc (H:EA 10:1) to produce 6 as a light
yield of this reaction was 32%. Irradiation of keto ester
10 using conditions developed in the synthesis of 2
furnished a dihydrobenzofuran as a mixture of isomers
which could be converted into the dimethyl ether of
coumestrol (3) in 38% overall yield using aqueous hydro-
chloric acid. Its melting point was 202-203 °C. The
1
yellow oil (428 mg, 65%). H NMR (CDCl3): δ 7.92-7.88 (dd,
1H, J ) 8.1, 1.5 Hz), 7.62-7.56 (td, 1H, J ) 8.0, 1.8 Hz), 7.41-
7.38 (dd, 1H, J ) 7.5, 1.5 Hz), 7.33-7.29 (td, 1H, J ) 7.2, 1.8
Hz), 7.19-7.15 (d, 1H, J ) 8.4 Hz), 7.12-7.02 (m, 3H, 5.22 (s,
2H), 5.16 (s, 2H), 3.47 (s, 3H), 3.34 (s, 3H). 13C NMR (CDCl3):
δ 186.8, 165.7, 160.0, 155.6, 136.5, 131.0, 130.5, 130.2, 124.5,
122.9, 122.0, 121.5, 114.4, 113.1, 94.8, 66.6, 56.2, 52.0. IR
(neat): 1742, 1673 cm-1. UV: λmax (benzene) 279, 323 nm.
Meth yl-(2-h yd r oxy-4-m eth oxyp h en yl) Glyoxyla te (8).
A finely powered anhydrous AlCl3 (666.7 mg, 5 mmol) was
added at 0 °C to a solution of 1,3-dimethoxybenzene (345 mg,
2.50 mmol) and methyloxalyl chloride14 (306.3 mg, 2.5 mmol)
in 5 mL of dry 1,2-dichloroethane under N2 atmosphere. The
resulting dark red mixture was stirred at room temperature
for 24 h, poured into 100 mL of ice water, and extracted with
CH2Cl2 four times. The combined organic layer was washed
with brine and dried over MgSO4. The solvent was removed
in vacuo, and the residue was purified by sgc (H:EA 10:1) to
transformation of 3 into coumestrol was achieved in
75% yield using 10 equiv of BBr3 in methylene chloride
from -78 °C to 25 °C for 12 h.11 The proton NMR
spectrum of this compound was identical to the NMR of
an authentic sample.12
The synthetic route to 1 and 2 is readily adaptable to
scale-up. The synthetic pathway is flexible with regard
to substitution on the both the glyoxylate and the benzyl
alcohol subunits. This route will permit the ready syn-
thesis of analogues.
1
give 8 as a yellow solid (260.7 mg, 50%). H NMR (CDCl3): δ
11.75 (s, 1 H), 7.69-7.66 (d, 1H, J ) 8.8 Hz), 6.51-6.46 (m,
2H), 3.98 (s, 3H), 3.88 (s, 3H). 13C NMR (CDCl3): δ 188.1,
168.1, 167.4, 163.3, 134.1, 110.6, 109.3, 101.2, 56.0, 53.1. IR
(Nujol): 1734, 1635 cm-1. MS m/z: 151, 210. HRMS: found
210.0541; calcd 210.0542.
Exp er im en ta l Section
H:EA refers to hexanes:ethyl acetate solvent mixtures for
thin-layer chromatography and silica gel flash chromatography
(sgc). Infrared spectra (IR) were recorded on a FTS-7 spectro-
photometer. Proton NMR spectra were measured at 300 or 400
MHz with tetramethylsilane as an internal standard. 13C NMR
spectra were recorded in CDCl3 at 75 MHz. High-resolution
mass spectra (HRMS) were EI spectra obtained by a Kratos
MS50 magnetic sector mass spectrometer.
Meth yl 2-(2-m eth oxym eth oxy-4-m eth oxyben zyloxy)-4-
m eth oxy P h en ylglyoxyla te (10).15 To a solution of 8 (105.1
mg, 0.5 mmol), alcohol 910 (99.1 mg, 0.5 mmol), and PPh3 (157.4
mg, 0.6 mmol) in 5 mL of dry DMF was added diethyl
azodicarboxylate (104.5 mg, 94.5 µL, 0.6 mmol) dropwise at
0 °C under N2 atmosphere. The solution was then stirred at
room temperature for 24 h. The solution was concentrated in
vacuo and diluted with a small amount of ether. The precipi-
tate was filtered, the filtrate was concentrated, and the residue
was purified by sgc (H:EA 10:1) to give 10 as a light yellow
solid (125 mg, 32%). 1H NMR (CDCl3): δ 7.94-7.90 (d, 1H,
J ) 8.4 Hz), 7.31-7.27 (d, 1H, J ) 8.7 Hz), 6.77-6.75 (d, 1H,
J ) 2.4 Hz), 6.61-6.56 (m, 3H), 5.20 (s, 2H), 5.04 (s, 2H), 3.88
(s, 3H), 3.81 (s, 3H), 3.47 (s, 3H), 3.30 (s, 3H). 13C NMR
(CDCl3): δ 185.4, 166.9, 166.3, 162.1, 161.6, 157.0, 133.0, 131.9,
116.7, 116.0, 106.8, 106.5, 101.7, 99.1, 95.0, 66.4, 56.4, 55.9,
55.7, 51.8. IR (Nujol): 1732, 1663 cm-1. UV: λmax (benzene) )
280, 316 nm, λmax (CH2Cl2) ) 239, 281, 318 nm. MS m/z: 181,
331, 390. HRMS: found 390.1320; calcd 390.1315.
Gen er a l P r oced u r e for th e Ir r a d ia tion , Deh yd r a tion ,
a n d La cton iza tion . The precursor of the photochemical
reaction (20 mg) was dissolved in 2 mL of dry benzene in a
sealed Pyrex tube. The solution was flushed with argon for 30
min. The irradiation was conducted in a photochemical reactor
(manufactured by Southern New England Ultraviolet Com-
pany, model no. RPR-100) loaded with a circle of UV lamps
(λmax ) 300 nm). The deoxygenated solution was irradiated
for 48 h at room temperature. TLC showed that there was no
starting material present. Benzene was removed in vacuo, and
the crude product was used directly for next step without
purification.
2-Meth oxym eth oxyben zyl Br om id e (5). To a suspension
of NaH (0.96 g, 40 mmol) in 50 mL of dry DMF was added a
solution of o-cresol (2.16 g, 20 mmol) in 5 mL of DMF dropwise.
After the release of hydrogen ceased, a solution of MOMCl
(1.77 g, 22 mmol) in 5 mL of DMF was added slowly. After
the resulting reaction mixture was stirred at room temperature
for 1 h, ice and 1 N HCl were added and the product was
extracted with ether 3 times. The combined ether layer was
washed with saturated NaHCO3 and brine and dried over
MgSO4. After removal of ether in vacuo, 2-methoxymethoxy-
toluene was obtained in quantitative yield that was used for
the bromination without purification. 1H NMR (CDCl3):
δ
7.17-7.10 (t, 2H, J ) 7.1 Hz), 7.06-7.02 (d, 1H, J ) 7.5 Hz),
6.94-6.88 (t, 1H, J ) 7.8 Hz), 5.21 (s, 2H), 3.49 (s, 3H), 2.25
(s, 3H).
A mixture of 2-methoxymethoxytoluene, NBS (3.92 g, 22
mmol) and benzoyl peroxide (0.48 g, 2 mmol), in 40 mL of dry
CCl4 was boiled for 30 min and cooled. The white solid was
filtered, and CCl4 was removed to give 5 in over 80% yield as
a light yellow oil that turned into a white solid when stored
in freezer. Compound 5 can be used for the alkylation without
purification. Pure 5 can be obtained by recrystallization from
1
hexane. H NMR (CDCl3): δ 7.36-7.32 (dd, 1H, J ) 7.5, 1.8
Hz), 7.30-7.24 (m, 1H), 7.12-7.07 (dd, 1H, J ) 8.4, 0.9 Hz),
7.00-6.94 (m, 1H), 5.28 (s, 2H), 4.58 (s, 2H), 3.52 (s, 3H).
(13) Russell, G. A.; Myers, C. L.; Bruni, P.; Neugebaner, F. A.;
Blankespoor, R. J . Am. Chem Soc. 1970, 92 (9), 2762-2769.
(14) Aldrich Chemical Company.
(15) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Manhas, M. S.;
Hoffman, W. H.; Lal, B.; Bose, A. K. J . Chem. Soc., Perkin Trans. 1
1975, 461-463. (c) McCarthy, J . R.; Wiedeman, P. E.; Schuster, A. J .;
Whitten, J . P.; Barbuch, R. J .; Huffman, J . C. J . Org. Chem. 1985, 50,
3095-3103.
(10) Versteey, M.; Bezuidenhoudt, B. C. B.; Ferreira, D. Heterocycles
1998, 48 (7), 1373-1394.
(11) McOmie, J . F. W.; West, D. E. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. 5, pp 412-414.
(12) The authentic sample was obtained from Acros Chemical
Company.

5646 J . Org. Chem., Vol. 65, No. 18, 2000
Kraus and Zhang
The unpurified product of the photoreaction was dissolved
in small amount of THF. After the addition of 6 N HCl (20
equiv), the solution was stirred at 50 °C for 36 h, cooled, poured
into water, and extracted with EtOAc 3 times. The combined
organic layers were washed with brine and dried over MgSO4.
After removal of solvent, the crude product was purified to
give the resulting lactone.
Cou m esta n (2). Data for 2,3-Dihydro-3-hydroxy-2-(2-meth-
oxymethoxyphenyl)benzofuran-3-carboxylic acid methyl ester.
1H NMR (CDCl3): δ 7.61-7.58 (d, 1H, J ) 6.9 Hz), 7.37-7.29
(m, 1H), 7.27-7.20 (m, 1H,), 7.14-6.94 (m, 5H), 6.27 (s, 1H),
5.16-5.08 (dd, 2H, J ) 17.1, 6.6 Hz), 3.91 (s, 3H), 3.46 (s, 3H),
3.41 (s, 1H).
This product was taken directly on to the hydrolysis step.
Compound 2 was obtained as a white solid after purification
by TLC (45% yield from 6). Its melting point was 179-180
°C. 1H NMR (CDCl3): δ 8.17-8.14 (m, 1H), 8.07-8.03 (dd, 1H,
J ) 7.8, 1.5 Hz), 7.70-7.59 (m, 2H), 7.53-7.39 (m, 4H). 13C
NMR (CDCl3): δ 160.2, 158.3, 155.8, 153.9, 132.2, 127.0, 125.5,
124.9, 123.7, 122.11, 122.10, 117.7, 112.9, 112.0, 106.1. IR
(Nujol): 1736 cm-1. UV: λmax (EtOH) 297, 310, 342 nm. MS
m/z: 236 (M+, base peak). HRMS: found 236.047662; calcd
236.047344.
Da ta for Cou m estr ol Dim eth yl Eth er (3). 2,3-Dihydro-
3-hydroxy-6-methoxy-2-(4-methoxy-2-methoxymethoxyphen-
yl)benzofuran-3-carboxylic acid methyl ester (11). 1H NMR
(CDCl3): δ 7.48-7.46 (d, 1H, J ) 6.3 Hz), 7.12-7.10 (d, 1H,
J ) 6.3 Hz), 6.73-6.72 (d, 1H, J ) 1.8 Hz), 6.62-6.51 (m, 3H),
6.23 (s, 1H), 5.13-5.07 (dd, 2H, J ) 11.1, 5.1 Hz), 3.89 (s, 3H),
3.82 (s, 3H), 3.80 (s, 3H), 3.45 (s, 3H), 3.30 (s, 1H).
This compound was taken on to the hydrolysis step.
Compound 3 was obtained as a white solid after purification
by TLC (38% yield from 10). Its melting point was 202-203
°C. 1H NMR (DMSO-d6): δ 7.95-7.93 (d, 1H, J ) 8.8 Hz),
7.81-7.79 (d, 1H, J ) 8.4 Hz), 7.51-7.50 (d, 1H, J ) 2.0 Hz),
7.22-7.21 (d, 1H, J ) 2.4 Hz), 7.12-7.09 (m, 2H), 3.90 (s, 3H),
3.87 (s, 3H). 13C NMR (DMSO-d6): δ 162.5, 159.6, 159.0,
157.4, 156.0, 154.7, 122.5, 120.7, 115.8, 113.6, 113.2, 105.3,
102.6, 101.6, 97.3, 56.1, 55.9. IR (Nujol): 1639 cm-1. UV: λmax
(MeOH/CH2Cl2 1:1) 244, 303, 341 nm. MS m/z: 296 (M+), 281
([M - CH3]+, base peak). HRMS: found 296.0689386; calcd
296.068473.
Cou m estr ol (1). Compound 3 (4 mg, 0.0135 mmol) was
dissolved in 50 µL of dry CH2Cl2, and the solution was cooled
to -78 °C. A solution of BBr3 in CH2Cl2 (1.0 M, 135 µL) was
added via syringe. The reaction mixture was allowed to attain
room temperature overnight, then hydrolyzed by ice water,
extracted with CH2Cl2 3 times, and dried over MgSO4. After
removal of solvent, the residue was purified by TLC to produce
coumestrol 1 as a white solid (2.7 mg, 75%). 1H NMR (DMSO-
d6): δ 7.87-7.84 (d, 1H, J ) 8.4 Hz), 7.71-7.68 (d, 1H, J )
8.4 Hz), 7.17-7.16 (d, 1H, J ) 1.8 Hz), 6.96-6.90 (m, 3H). 13
C
NMR (DMSO-d6): δ 161.2, 159.5, 157.6, 157.0, 155.9, 154.6,
122.7, 120.6, 114.6, 114.0, 113.7, 104.2, 103.0, 102.0, 98.7.
UV: λmax (MeOH) 213, 278, 310, 379 nm. IR (Nujol): 3500-
2800, 1703 cm-1. MS m/z: 268 (M+), 269 ([M + H]+, base peak),
286 ([M + H2O]+). HRMS: found 268.037491; calcd 268.037173.
Ack n ow led gm en t. We thank Iowa State University
for partial support of this research.
Su p p or tin g In for m a tion Ava ila ble: Spectra for com-
pounds 1-3, 6, 8, and 10. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0004198