A direct synthesis of O-methyl claussequinone

Article abstract of DOI:10.1021/jo030026j

The reaction of a chromene with BH₃ followed by treatment with benzoquinone and air is the key step in a direct entry to O-methyl claussequinone.

Full text of DOI:10.1021/jo030026j

recovered starting materials to the same reaction condi-
tions increased the yield to 65%. In view of this promising
result, we reacted the borane with methoxybenzoquinone
with the intent of producing 4 in one step. Surprisingly,
the desired adduct was not formed. The major product
was the chromanol derived from oxidation of the borane
with oxygen. This result was surprising in light of a
recent report of the successful regioselective addition of
alkyl radicals to methoxybenzoquinone.12
A Dir ect Syn th esis of O-Meth yl
Cla u ssequ in on e
George A. Kraus* and Ikyon Kim
Department of Chemistry, Iowa State University,
Ames, Iowa 50011
gakraus@iastate.edu
Received J anuary 21, 2003
Abstr a ct: The reaction of a chromene with BH3 followed
by treatment with benzoquinone and air is the key step in
a direct entry to O-methyl claussequinone.
Colutequinone A (1),1 colutequinone B (2),2 and clausse-
quinone (3)3 are members of a growing family of isoflavan
quinones. Claussequinone exhibits potent activity against
bloodstream forms of Trypanosoma cruzi (Chagas’ dis-
ease).4 It also exhibits antiinflammatory activity and
antifertility activity and is a feeding deterrent for the
grass grub Costelytra zealandica.5,6 Claussequinone has
been synthesized by Farkas and co-workers using thal-
lium trinitrate in the key step.7 As part of a program to
develop environmentally benign radical reactions,8
we report a direct synthesis of 4, the O-methyl analogue
of 3.
The regioselective addition of alcohols to benzoquinones
has little precedent. We recently used a Lewis acid
catalyst for the regioselective addition of methanol to a
phenanthrene quinone.13 Using these conditions with 6,
we obtained quinone 7 in 70% yield. The NMR spectrum
shows differences from the reported spectrum for 3. In
7, the proton at C-5 of the quinone (ortho to the methoxyl
group) has a chemical shift of 5.89 with a coupling
constant of 2.4 Hz. The corresponding hydrogen in
astragaluquinone (shown below) has a chemical shift of
about 6.25 with a coupling constant of 2.5 Hz.14
The reaction of 6 with thiophenol and PTSA in metha-
nol at 25 °C followed by oxidation with silver oxide
produced adducts 8 and 9 in a 5:1 ratio in 93% yield.
Although no precedent was found for the directed addi-
tion of thiophenol to substituted benzoquinones, the
regiochemistry of thiophenol addition is in accord with
our observation for the acid-catalyzed addition of metha-
nol to quinones. Oxidation of 8 with m-CPBA in chloro-
form at 0 °C afforded a sulfoxide that was treated with
methanol at reflux to afford compound 4 in 70% yield.
Its proton and carbon NMR were consistent with the
structure of 4. Presumably, this transformation occurs
by way of methanol addition to the activated benzo-
quinone followed by sulfoxide elimination. Compound 9,
the minor product of thiol addition, was treated with
sodium methoxide to afford 4 in 63% yield.
Our synthetic route began with chromene 5, which was
readily prepared in two steps from 3-methoxyphenol and
the diethyl acetal of 3-chloropropanal.9 The reaction of
chromene 5 with BH3 followed by benzoquinone and air
led to quinone 610 in 37% yield.11 Resubmission of the
(1) Grosvenor, P. W.; Gray, D. O. Phytochemistry 1996, 43, 377.
(2) Grosvenor, P. W.; Gray, D. O. J . Nat. Prod. 1998, 61, 99.
(3) Braga de Oliveira, A.; Gottlieb, O. R.; Gonclaves, T. M. M.; Ollis,
W. D. An. Acad. Brasil. Cienc. 1971, 43, 129.
(4) Chiari, E. Cienc. Cult. (Sao Paulo) 1996, 48, 230.
(5) Da Silva Emim, J . A.; Oliveira, A. B.; Lapa, A. J . J . Pharm.
Pharmacol. 1994, 46, 118. Lane, G. A.; Biggs, D. R.; Russell, G. B.;
Sutherland, O. R. W.; Williams, E. M.; Maindonald, J . H.; Donnell, D.
J . J . Chem. Ecol. 1985, 11, 1713.
(6) Guerra, M. de Oliveira; De Oliveira, A. B.; Peters, V. M. Cienc.
Cult. (Sao Paulo) 1985, 37, 1666.
In summary, the reaction of chromene 5 with BH3 and
benzoquinone followed by subsequent elaboration pro-
vides a direct entry to benzoquinones with useful biologi-
cal activity. Convenient procedures for the regiospecific
(7) Farkas, L.; Gottsegen, A.; Nogradi, M.; Antus, S. J . Chem. Soc.,
Perkin Trans. 1 1974, 305-312. See also: Lupi, A.; Marta, M.; Lintas,
G.; Bettolo, G. B. M. Gazz. Chim. Ital. 1980, 110, 625.
(8) Kraus, G. A.; Melekhov, A. Tetrahedron Lett, 1998, 39, 3957.
(9) Cao, Z.; Liehr, J . G. Synth. Commun. 1996, 26, 1233.
(10) Compound 6 has been prepared from an isoflavone: Kurosawa,
K.; Ollis, W. D.; Redman, B. T.; Sutherland, I. O.; Alves, H. M.; Gottlieb,
O. R. Phytochemistry, 1978, 17, 1423. See also: Chang, C.-Y.; Huang,
L.-J .; Wang, J .-P.; Teng, C.-M.; Chen, S.-C.; Kuo, S.-C. Chem. Pharm.
Bull. 2000, 48, 964.
(12) Bieber, L. W.; Neto, P. J . R.; Generino, R. M. Tetrahedron Lett.
1999, 40, 4473.
(13) Kraus, G. A.; Zhang, N. Tetrahedron Lett. 2002, 43, 9597.
(14) El-Sebakhy, N. A.; Asaad, A. M.; Abdallah, R. M.; Toaima,
S. M.; Abdel-Kader, M. S.; Stermitz, F. R. Phytochemistry 1994, 36,
1387.
(11) Radicals from boranes: Olliver, C.; Renaud, P. Chem. Rev. 2001,
101, 3415.
10.1021/jo030026j CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003
J . Org. Chem. 2003, 68, 4517-4518
4517

evaporated in vacuo. The resulting residue was diluted with CH2-
Cl2 and washed with brine. The aqueous layer was extracted
with CH2Cl2 once more. The organic layer was dried over MgSO4,
filtered, and evaporated to dryness. The residue was purified
by SGC (H/EA ) 3:1) to afford a regioisomeric mixture of quinols
(108.8 mg, 93%). The mixture of quinols (108.8 mg, 0.286 mmol)
was dissolved in benzene (10 mL). Then, Na2SO4 (81 mg, 0.572
mmol) and Ag2O (133 mg, 0.572 mmol) were added at rt. After
being stirred at rt for 4 h, the mixture was filtered through Celite
and rinsed with ethyl acetate. The filtrate was evaporated and
purified by SGC (H/EA ) 10:1) to give minor product 9 and major
product 8 (total 108 mg, 100%).
1
8: 300 MHz H NMR (CDCl3) δ 7.49 (5H, br s), 6.95 (1H,d, J
) 8.4 Hz), 6.48 (1H, dd, J ) 8.4, 2.4 Hz), 6.44 (1H, m), 6.37 (1H,
d, J ) 2.7 Hz), 5.84 (1H, d, J ) 2.4 Hz), 4.28 (1H, dd, J ) 10.5,
2.4 Hz), 4.09 (1H, dd, J ) 10.8, 6.3 Hz), 3.75 (3H, s), 3.46 (1H,
m), 3.07 (1H, dd, J ) 16.2, 6.0 Hz), 2.75 (1H, dd, J ) 16.2, 6.6
Hz); 75 MHz 13C NMR (CDCl3) δ 184.6, 183.9, 159.6, 155.0,
154.9, 148.0, 135.9, 133.9, 130.8, 130.6, 130.4, 127.4, 126.1, 112.2,
108.3, 101.8, 68.3, 55.5, 31.4, 29.1;. HRMS m/z for C22H18O4S
calcd 378.0926, measured 378.0931; TLC (3:1 H/EA) Rf ) 0.36.
9: 300 MHz 1H NMR (CDCl3) δ 7.50 (5H, br s), 6.94 (1H, d,
J ) 8.4 Hz), 6.74 (1H, d, J ) 1.2 Hz), 6.48 (1H, dd, J ) 8.4, 2.4
Hz), 6.37 (1H, d, J ) 2.4 Hz), 5.89 (1H, s), 4.23 (1H, ddd, J )
10.8,3.0, 0.9 Hz), 4.04 (1H, ddd, J ) 10.8, 6.0, 0.9 Hz), 3.76 (3
H, s), 3.39 (1H, m), 3.02 (1H, dd, J ) 15.9, 5.7 Hz), 2.72 (1H, dd,
J ) 16.2, 6.9 Hz); 75 MHz 13C NMR (CDCl3) δ 184.3, 183.9,
159.6, 154.9, 154.6, 149.7, 135.9, 132.4, 130.8, 130.6, 130.3, 127.2,
126.3, 112.2, 108.3, 101.8, 68.4, 55.6, 31.2, 29.1; HRMS m/z for
C22H18O4S calcd 378.0926, measured 378.0931; TLC (3:1 H/EA)
Rf ) 0.42.
2-(3,4-Dih yd r o-7-m eth oxyben zop yr a n -3-yl)-5-m eth oxy-
1,4-ben zoqu in on e (4). To a solution of 8 (35 mg, 0.093 mmol)
in CHCl3 (3 mL) was added 77% m-CPBA (23 mg, 0.102 mmol)
at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture
was diluted with CH2Cl2 and washed with saturated NaHCO3.
The aqueous layer was extracted with CH2Cl2 one more time.
The combined organic layers were dried over MgSO4, filtered,
and concentrated. The crude residue was purified by SGC (H/
EA ) 3:1) to give sulfoxide (35 mg, 96% yield).
The sulfoxide (35 mg, 0.089 mmol) was dissolved in MeOH (3
mL). The solution was heated to reflux overnight. The solvent
was evaporated, and the residue was purified by SGC (H/EA )
3:1) to afford compound 4 (18.7 mg, 70% yield): 300 MHz NMR
(CDCl3) δ 6.95 (1H, d, J ) 8.4 Hz), 6.48 (1H, dd, J ) 8.4, 2.4
Hz), 6.48 (1H, d, J ) 1.2 Hz), 6.37 (1H, d, J ) 2.7 Hz), 5.97 (1H,
s), 4.26 (1H, ddd, J ) 11.1, 3.3, 1.2 Hz), 4.07 (1H, ddd, J ) 10.8,
6.0, 1.2 Hz), 3.82 (3H, s), 3.76 (3H, s), 3.46 (1H, m), 3.06 (1H,
dd, J ) 16.5, 6.3 Hz), 2.73 (1H, dd, J ) 15.9, 6.3 Hz); 75 MHz
13C NMR (CDCl3) δ 186.9, 182.3, 159.6, 158.7, 154.9, 149.5,
131.1, 130.3, 112.3, 108.3, 108.1, 101.8, 68.5, 56.5, 55.5, 31.1,
29.1; HRMS m/z for C17H16O5 calcd 300.0998, measured 300.1002;
TLC (2:1 H/EA) Rf ) 0.36.
addition of thiophenol and methanol to substituted
benzoquinones have been developed. These procedures
will be useful for the synthesis of quinone natural
products.
Exp er im en ta l Section
(3,4-Dih ydr o-7-m eth oxyben zopyr an -3-yl)-1,4-ben zoqu in o-
n e (6). To a solution of 3-chromene (800 mg, 4.94 mmol) in THF
(4 mL) was added 1 M BH3‚THF (1.65 mL, 1.65 mmol) at 0 °C.
After the mixture was stirred at rt for 5 h, H2O (89 µL, 4.94
mmol) was added at 0 °C. Then benzoquinone (178 mg, 1.65
mmol) was added at rt in one portion. After the mixture was
stirred at rt for 2 h, the mixture was evaporated in vacuo. The
residue was purified by SGC (H/EA ) 7:1) to give compound 6
(165 mg, 37%): 300 MHz NMR (CDCl3) δ 6.95 (1H, d, J ) 8.4
Hz), 6.81 (1H, d, J ) 10.2 Hz), 6.73 (1H, dd, J ) 10.2, 2.1 Hz),
6.55 (1H, dd, J ) 2.1, 1.2 Hz), 6.49 (1H, dd, J ) 8.4, 2.7 Hz),
6.38 (1H, d, J ) 2.7 Hz), 4.27 (1H, dd, J ) 10.8, 3.0 Hz), 4.07
(1H, dd, J ) 10.8, 6.6 Hz), 3.76 (3H, s,), 3.43 (1H, m), 3.06 (1H,
dd, J ) 15.9, 5.7 Hz), 2.75 (1H, dd, J ) 15.9, 6.9 Hz); 75 MHz
13C NMR (CDCl3) δ 187.6, 186.9, 159.6, 154.9, 148.6, 137.1,
136.5, 133.0, 130.3, 112.2, 108.3, 101.8, 68.3, 55.6, 31.2, 29.0;
HRMS m/z for C16H14O4 calcd 270.0892, measured 270.0895; mp
120-123 °C (lit.10 mp 125 °C); TLC (3:1 H/EA) Rf ) 0.25.
2-(3,4-Dih yd r o-7-m eth oxyben zop yr a n -3-yl)-6-m eth oxy-
1,4-ben zoqu in on e (7). To a solution of 6 (34 mg, 0.126 mmol)
in MeOH (3 mL) were added HgCl2 (34 mg, 0.126 mmol) and I2
(3 mg, 0.013 mmol) at rt. After being stirred at 60 °C for 3 h,
the reaction mixture was evaporated in vacuo. The resulting
residue was diluted with ethyl acetate and washed with brine.
The aqueous layer was extracted with ethyl acetate one more
time. The organic layer was dried over MgSO4, filtered, and
evaporated to dryness. The residue was purified by SGC (H/EA
) 2:1) to give compound 7 (26.5 mg, 70%): 300 MHz 1H NMR
(CDCl3) δ 6.94 (1H, d, J ) 8.4 Hz), 6.48 (1H, dd, J ) 8.4, 2.4
Hz), 6.47 (1H, d, J ) 1.2 Hz), 6.37 (1H, d, J ) 2.4 Hz), 5.89 (1H,
d, J ) 2.4 Hz), 4.27 (1H, ddd, J ) 10.8, 2.7, 0.9 Hz), 4.06 (1H,
ddd, J ) 10.5, 6.3, 1.2 Hz), 3.83 (3H, s), 3.75 (3H, s), 3.45 (1H,
m), 3.04 (1H, dd, J ) 15.9, 5.7 Hz), 2.74 (1H, dd, J ) 15.6, 6.9
Hz); 75 MHz 13C NMR (CDCl3) δ 187.3, 181.6, 159.6, 159.0,
154.8, 146.5, 133.6, 130.3, 112.2, 108.3, 107.5, 101.8, 68.3, 56.6,
55.5, 31.1, 29.1; HRMS m/z for C17H16O5 calcd 300.0998,
measured 300.1004; TLC (3:1 H/EA) Rf ) 0.21.
Ack n ow led gm en t. We thank the Environmental
Protection Agency and Iowa State University for partial
support.
2-(3,4-Dih ydr o-7-m eth oxyben zopyr an -3-yl)-6-ph en ylth io-
1,4-ben zoqu in on e (8) a n d 2-(3,4-Dih yd r o-7-m eth oxyben -
zop yr a n -3-yl)-5-p h en ylth io-1,4-ben zoqu in on e (9). To a mix-
ture of 6 (83 mg, 0.307 mmol) and PhSH (35 µL, 0.338 mmol) in
MeOH (10 mL) was added PTSA‚H2O (117 mg, 0.614 mmol) at
rt. After being stirred at rt for 7 h, the reaction mixture was
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spectra
for compounds 4, 6, 7, 8, and 9. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O030026J
4518 J . Org. Chem., Vol. 68, No. 11, 2003