An approach to dibenzofuran heterocycles. 1. Electron-transfer processes en route to dibenzofuran-1,4-diones

Full text of DOI:10.1021/jo971196x

J . Org. Chem. 1997, 62, 9345-9347
9345
Sch em e 1
An Ap p r oa ch to Diben zofu r a n
Heter ocycles. 1. Electr on -Tr a n sfer
P r ocesses en Rou te to
Diben zofu r a n -1,4-d ion es
J ohn W. Benbow,* Bonnie L. Martinez, and
William R. Anderson
Department of Chemistry, Lehigh University,
6 East Packer Avenue, Bethlehem, Pennsylvania 18015-3172
Received J uly 1, 1997
In tr od u ction
The unusual dibenzofuran-1,4-dione heterocycle is the
central architectural feature of popolohuanone E, a
marine natural product that inhibits topoisomerase-II
(IC50 ) 400 nM) and shows good selectivity toward A549
human lung cancer (IC50 ) 2.5 mg/mL), a nonsmall cell
tumor line that is particularly resistant to medical
treatment.1 An approach to this heterocycle could involve
biaryl formation via the oxidative dimerization of two
arenol “monomers” 2 followed by a selective oxidation to
form hydroxyquinone 3 (Scheme 1). A subsequent intra-
molecular phenol cyclization would afford a dihydro-
quinone that would generate the title heterocycle upon
oxidation. Enzymatic oxidative coupling processes fre-
quently provide biaryl bonds in natural systems,2 and
biomimetic oxidation sequences have been utilized in the
total synthesis of several natural products.3 The recent
report4 of a popolohuanone E model system prompts the
disclosure of our approach to this target, an effort that
has uncovered a complex series of redox processes.
Sch em e 2
Resu lts a n d Discu ssion
We envisioned the dimerization of permethylated or
perbenzylated derivatives of 2,3,6-trihydroxytoluene fol-
lowed by cleavage of the ether linkages to afford 3, and
our studies regarding the Suzuki protocol for the forma-
tion of biaryl systems5 afforded ample quantities of the
symmetrically protected biaryls (Scheme 1). While nei-
ther of these compounds could be suitably deprotected,
a differentially protected biaryl (4) circumvented this
problem. This compound cleanly underwent hydro-
genolysis to afford the triol and furnished hydroxy-
quinone 5 upon oxidation with dichlorodicyanoquinone
(DDQ). A spontaneous ring closure to form the central
furan did not occur, nor was any cyclization induced from
treatment of this material with a series of bases (Et3N,
NaH, KH). However, refluxing a benzene solution of 5
for 48 h in the presence of a mild acid catalyst (PPTS)
afforded three new products, 6 (30%), 7 (10%), and 8
(18%), and a fourth fraction that was a mixture of three
dimeric products (7%) (Scheme 2).
The identities of these singular materials were deter-
mined from detailed spectroscopic analysis. The mass
spectral data supported a dimeric structure for 6 (m/e )
602) and indicated that a dehydration had taken place
in its formation. A kinetically favored intramolecular
5-exo-trig cyclization6 provides a hemiketal (Scheme 3)
that, after oxonium formation (-H2O) and reduction via
single electron transfer, produces the ketone-stabilized
radical 10; internal electron transfers are common pro-
cesses in quinone cyclization reactions.7 Dimerization
through C-5 and subsequent tautomerization furnishes
6.
(1) Carney, J . R.; Scheuer, P. J . Tetrahedron Lett. 1993, 34, 3727-
3730.
(2) (a) Wildman, W. C.; Pursey, B. A. The Alkaloids, Vol. 9; Manke,
R. H. F., Ed.; Academic Press: New York, 1968; pp 407-457 and
references therein. (b) Kupchan, S. M.; Kim, C.-K.; Lynn, J . T. J . Chem.
Soc., Chem. Commun. 1976, 86.
(3) (a) Kupchan, S. M.; Dhingra, O. P.; Kim, C.-K. J . Org. Chem.
1978, 43, 4076-4081. (b) Kende, A. S.; Liebeskind, L. S. J . Am. Chem.
Soc. 1976, 98, 267-268. (c) Feldman, K. S.; Ensel, S. M. J . Am. Chem.
Soc. 1993, 115, 1162-1163. (d) Feldman, K. S.; Ensel, S. M.; Minard,
R. D. J . Am. Chem. Soc. 1994, 116, 1742-1745.
(4) Ueki, Y.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron Lett.
1996, 37, 5719-5722.
(5) Benbow, J . W.; Martinez, B. L. Tetrahedron Lett. 1996, 37, 8829-
8832.
(6) Baldwin, J . E.; Cutting, J .; Dupont, W.; Kruse, L.; Silberman,
L.; Thomas, R. C. J . Chem. Soc., Chem. Commun. 1976, 736-738.
S0022-3263(97)01196-1 CCC: $14.00 © 1997 American Chemical Society

9346 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Sch em e 3
Sch em e 4
The mass spectral data for 7 and 8 also identified these
compounds as dimers (m/e ) 632 and 616, respectively)
and provided some indication as to their mode of forma-
tion. The mass for compound 7 suggested an oxidative
dimerization pathway, while that for 8 indicated an
oxidation and dehydration process. Compound 7 arises
by an intermolecular hydroxyquinone cyclization followed
by a second intramolecular addition to provide the bis-
dihydroquinone dimer 11. The four-electron oxidation
to 7 can occur either through an intermolecular electron-
transfer process or by reaction with adventitious O2. The
lowest energy conformer8 of 7 is the saddle, and this
contains a C2 axis that explains the simplified 1H and
the 13C spectra.
The spectroscopic data for 8 reveals an unsymmetrical
molecule with only three CdO’s in the 13C NMR spec-
trum. This structure, a hybrid of 6 and 7, arises from
dibenzofuran radical 10 addition to hydroxyquinone 5 to
provide the dihydroquinone 12 after hydrogen atom
abstraction and tautomerization. A possible mechanism
for the formation of 8 involves four-electron oxidation to
the oxaquinodimethane 13 followed by an electrocyclic
ring closure to generate 8 (Scheme 4); several stepwise
two electron transfers are also viable pathways to 13.
The formation of products 6 and 8 is dependent upon
the formation of 10, which in turn relies on the dihydro-
quinone reductant 11; without a reducing agent, the
intermediate hemiketal would return to the hydroxy-
quinone. While several electron-transfer scenarios can
be envisioned, the exact intermediate(s) responsible for
the transfer are difficult to discern. A model describing
the potential electron-transfer possibilities based on the
present data would not be complete because the mass
balance for the reaction is moderate (66%) and no
consideration has been made of the hydroxyquinone 5 as
a partner in a redox couple.
monomeric dibenzofuran 14 (Scheme 4). Apparently the
lifetime of semiquinone radical 10 is short under these
conditions. This result may be attributed to 1,4-dihy-
droquinone being a smaller, more efficient reducing agent
than more sterically hindered dihydroquinones such as
11 and/or that reduction of the semiquinone ketal occurs
faster than the coupling to form 7 or 8. More impor-
tantly, no 6 was produced, showing that the intramo-
lecular 1,2-addition pathway can be made the major
reaction route.
Our biomimetic sequence to access dibenzofuran-1,4-
dione heterocycles has uncovered a complex system of
electron transfer pathways. The structures of these
materials and a fundamental understanding of the
processes involved in their formation have been pre-
sented. We are currently pursuing a series of experi-
ments to determine the electron-transport intermediates
in order to optimize the formation of each of these
products; the dimeric dibenzofurandiol 6 has potential
as an additive in catalytic processes and the saddle dimer
7 is an excellent substrate from which to examine
quinone photochemistry. These studies are currently in
progress, and the results will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r e. All reactions were run in flame-dried
glassware under a nitrogen atmosphere unless otherwise noted.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were distilled
from sodium/benzophenone ketyl prior to use. Benzene (PhH),
toluene (PhCH3), and methylene chloride (CH2Cl2) were distilled
from calcium hydride. The pyridinium p-toluenesulfonate was
recrystallized from EtOH. All other chemicals were purchased
from Aldrich Chemical Co. and were used as received. Reaction
progress was monitored by TLC using E. Merck silica gel 60
F-254, and preparative TLC was performed with these plates
(10 × 20 × 0.25 cm). Solvents were removed on a Bu¨chi rotary
evaporator at reduced pressure (15-20 Torr).
3-Meth yl-2-m eth oxy-5-(4′,5′-d im eth oxy-2′-ben zyloxy-3′-
m et h ylp h en yl)-1,4-d ih yd r oq u in on e Bis(b en zyl et h er ) 4.
A solution of 50.0 mg (0.133 mmol) of 3,6-bis(benzyloxy)-4-iodo-
2-methylanisole in THF (1.0 mL) was cooled to -78 °C, and a
solution of sec-BuLi (0.306 mmol of a 1.2 M solution in hexanes)
was added in a dropwise fashion. After the solution was stirred
for 40 min, 75.2 mg of B(O-i-Pr)3 was added and the contents
were allowed to warm to room temperature over 2 h. The
resulting dispersion was dissolved by the addition of 10% HCl
These results suggest that the inclusion of an external
reducing agent should decouple the formation of the
intermolecular dimer 6 from the intramolecular systems
7 and 8. Indeed, treatment of the hydroxyquinone 5 with
PPTS in the presence of 1,4-dihydroquinone produced the
(7) (a) Hewgill, F. R.; Kennedy, B. R. J . Chem. Soc. C 1966, 362-
366. (b) Hoegberg, H.-E. J . Chem. Soc., Perkin Trans. 1 1979, 2517-
2520. (c) Brockmann, H. Liebigs Ann. Chem. 1988, 1-8.
(8) Spartan Semiempirical Program: IBM Release 4.1a4, Wave-
function, Inc. Geometry optimization with Model RHF/AM1. The
saddle conformation was 69 kcal/mol more stable than the “planar”
conformer using these calculations.

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9347
solution (40 µL) followed by extraction with Et2O (10 mL). The
organic layer was washed with a 10% HCl solution (2 × 10 mL)
and brine (10 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to provide a yellow oil. Purification by SiO2 chroma-
tography (10% THF/hexanes) provided 38.2 mg (97%) of the
boronic acid as an off-white solid: mp 99-100 °C; Rf ) 0.16 (20%
EtOAc/hexanes); IR (thin film) ν 3494, 2930, 1588, 1374, 1340,
1220, 697 cm-1; 1H NMR (CDCl3) δ 7.39-7.29 (m, 11H), 6.38 (s,
2H), 5.03 (s, 2H), 4.72 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H) ppm. A
solution of 38.2 mg (0.130 mmol) of this boronic acid, 48.9 mg
(0.130 mmol) of 2-benzyloxy-4,5-dimethoxy-3-methyliodoben-
zene, 4.6 mg (3.94 µmol) of tetrakis(triphenylphosphine)-
palladium, and 49.4 mg (0.325 mmol) of CsF in benzene (0.65
mL) was heated to reflux and maintained for 12 h. The resulting
suspension was transferred to a separatory funnel with EtOAc
(10 mL) and washed with H2O (2 × 5 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo, and
the residue was purified by SiO2 chromatography (10% EtOAc/
hexanes) to provide 66.6 mg (86%) of 4 as a colorless oil: Rf )
0.41 (20% EtOAc/hexanes); IR (neat) ν 3037, 2932, 2867, 1088,
1003 cm-1; 1H NMR (CDCl3) δ 7.40-7.25 (m, 15H), 7.00 (s, 1H),
6.89 (s, 1H), 4.97 (s, 2H), 4.53 (s, 2H), 4.49 (s, 2H), 3.91 (s, 3H),
3.86 (s, 3H), 3.75 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H) ppm; 13C NMR
(CDCl3) δ 149.1, 148.7, 148.6, 147.9, 147.7, 147.0, 137.3, 137.2,
137.1, 128.4, 128.2, 128.1, 127.8, 127.7, 127.3, 127.0, 126.9, 126.1,
126.0, 114.3, 112.2, 74.7, 74.6, 70.8, 60.4, 60.3, 55.8, 10.0, 9.90
ppm. Anal. Calcd for C38H38O6: C, 77.27; H, 6.48. Found: C,
77.11; H, 6.71.
2,2′-Dih yd r oxy-3,3′,7,7′,8,8′-h exa m eth oxy-4,4′,6,6′-tetr a -
m eth yl-1,1′-bid iben zofu r a n (6): colorless oil; Rf ) 0.13 (30%
EtOAc/hexanes); UV/vis (λmax (ꢀ)) 312 (38300), 242 (36400); IR
(neat) ν 3434, 3005, 1099, 1001, 757 cm-1 1H NMR (CDCl3) δ
;
6.14 (s, 2H), 5.58 (s, 2H, exchanges with D2O), 3.96 (s, 6H), 3.73
(s, 6H), 3.40 (s, 6H), 2.64 (s, 6H), 2.45 (s, 6H) ppm; 13C NMR
(CDCl3) δ 150.7, 149.8, 149.2, 146.9, 144.7, 143.0, 119.1, 118.7,
115.7, 115.2, 110.4, 101.0, 61.5, 60.7, 55.7, 9.70, 9.13; HRMS
m/e calcd for C34H34O10 (M+) 602.2181, found 602.2133.
3,7,8,12,16,17-H exa m et h oxy-2,6,11,15-t et r a m et h yl-1,4,-
10,13-tetr aoxotetr aben zo[b,d,g,i][5,14]dioxacyclodecen e (7):
orange solid; mp 162-163 °C; Rf ) 0.51 (30% EtOAc/hexanes);
UV/vis (λmax (ꢀ)) 462 (4800), 326 (7780), 252 (34300); IR (thin
film) ν 1667, 1656, 1115, 1088, 671 cm-1 1H NMR (CDCl3) δ
;
7.36 (s, 2H), 4.06 (s, 6H), 3.93 (s, 6H), 3.85 (s, 6H), 2.45 (s, 6H),
2.03 (s, 6H) ppm; 13C NMR (CDCl3) δ 184.2, 172.6, 155.8, 152.9,
151.5, 150.5, 149.6, 129.5, 122.6, 117.4, 117.2, 100.6, 61.3, 60.9,
56.1, 9.04, 8.84 ppm; HRMS m/e cacld for C34H33O12 (MH+)
633.1973, found 633.1972.
2,7-Dim eth yl-3,8,9-tr im eth oxy-6-oxa-1,4-ph en an th r aqu in -
on e-5-sp ir o-1′-(4′,6′-d im eth yl-3′,7′,8′-tr im eth oxy)d iben zofu -
r a n -2′(1′H)-on e (8): brown oil; Rf ) 0.45 (30% EtOAc/hexanes);
UV/vis (λmax (ꢀ)) 552 (1540), 410 (6080), 356 (6110), 282 (9560),
242 (17300); IR (neat) ν 3001, 1681, 1649, 1115, 1091, 754 cm-1
;
1H NMR (CDCl3) δ 8.05 (s, 1H), 5.74 (s, 1H), 3.91 (s, 3H), 3.88
(s, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.41 (s, 3H), 2.38
(s, 3H), 2.36 (s, 3H), 1.95 (s, 3H), 1.88 (s, 3H) ppm; 13C NMR
(CDCl3) δ 192.4, 187.5, 180.3, 154.8, 151.9, 150.5, 149.7, 149.6,
148.3, 147.4, 146.7, 145.6, 132.8, 132.7, 130.4, 128.6, 121.8, 120.4,
116.2, 116.0, 111.9, 109.0, 98.9, 76.3, 61.0, 60.8, 60.6, 60.2, 56.0,
55.6, 10.3, 9.00 ppm; HRMS m/e calcd for C34H33O11 (MH+)
617.2023, found 617.2029.
3-Met h yl-2-m et h oxy-5-(4′,5′-d im et h oxy-2′-h yd r oxy-3′-
m eth ylp h en yl)-1,4-ben zoqu in on e (5). To a solution of 119
mg (0.202 mmol) of biaryl 4 in EtOAc (1.0 mL) was added 12
mg of 10% Pd on activated charcoal. The contents were stirred
under an atmosphere of H2 for 12 h at which point the catalyst
was removed by filtration through a Celite pad and the solids
were washed thoroughly with CH2Cl2. The solvent was removed
in vacuo, and the triol was isolated in quantitative yield as a
clear oil that was used directly without further purification.
Partial characterization for the triol: Rf ) 0.11 (30% EtOAc/
4,6-Dim et h yl-2-h yd r oxy-3,7,8-t r im et h oxyd iben zofu r a n
(14): A solution of 20.0 mg (0.063 mmol) of 5, 6.9 mg (0.063
mmol) of 1,4-dihydroquinone, and 1.0 mg (0.004 mmol) of PPTS
in benzene (1.0 mL) was maintained at a gentle reflux in air for
2 h. The solvent was removed in vacuo, and the residue was
purified by SiO2 chromatography (10% EtOAc/hexanes) to
provide 12.3 mg (65%) of 14 as an off-white solid: mp ) 152-
153 °C; Rf ) 0.22 (30% EtOAc/hexanes); IR (neat) ν 3463, 2943,
1098, 1084, 754, 665 cm-1; 1H NMR (CDCl3) δ 7.23 (s, 1H), 7.14
(s, 1H), 5.59 (s, 1H, exchanges with D2O), 3.96 (s, 3H), 3.88 (s,
3H), 3.87 (s, 3H), 2.54 (s, 3H), 2.50 (s, 3H) ppm; 13C NMR (CDCl3)
δ 150.3, 149.8, 149.5, 146.8, 145.0, 144.3, 120.1, 118.8, 116.1,
114.8, 102.1, 99.8, 61.4, 60.8, 56.2, 9.55, 9.20 ppm. Anal. Calcd
for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.67; H, 5.79.
1
hexanes); H NMR (CDCl3) δ 6.71 (s, 1H), 6.60 (s, 1H), 5.31 (s,
1H), 5.06 (s, 1H), 4.99 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.80 (s,
3H), 2.27 (s, 3H), 2.24 (s, 3H). A solution of 0.487 g (1.52 mmol)
of the triol in dry benzene (7.60 mL) was stirred at 0 °C while
0.346 g (1.52 mmol) of DDQ was added. After 5 min, the solvents
were concentrated in vacuo and the remaining solid was purified
by SiO2 chromatography (10% EtOAc/hexanes) to provide 0.388
g (80%) of 5 as a dark brown solid: mp ) 57-58 °C; Rf ) 0.37
(30% EtOAc/hexanes); UV/vis (λmax (ꢀ)) 354 (3180), 280 (7730),
242 (11540); IR (thin film) ν 3408, 1653, 1601, 1089, 665 cm-1
;
Ack n ow led gm en t. Financial support by the Na-
tional Institutes of Health (Grant 1-R15-CA70990-01)
is gratefully acknowledged. The authors are also in-
debted to J ack Stocker for his assistance in the nomen-
clature for compounds 6 and 8.
1H NMR (CDCl3) δ 7.16 (s, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 4.12
(s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H) ppm;
13C NMR (CDCl3) δ 190.4, 183.2, 155.7, 150.7, 147.2, 147.1,
146.9, 133.0, 128.5, 122.3, 116.7, 111.5, 61.1, 60.4, 56.3, 9.54,
9.11 ppm. Anal. Calcd for
Found: C, 64.05; H, 5.75.
C17H18O6: C, 64.14; H, 5.70.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
and full tabular listings of the 2D-NMR data are provided for
compounds 6, 7, and 8 (13 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
Acid -Ca ta lyzed Cycliza tion of Hyd r oxyqu in on e. A solu-
tion of 100 mg (0.314 mmol) of 5 and 3.0 mg (0.012 mmol) of
PPTS in benzene (2.0 mL) was heated and maintained at a
gentle reflux in air for 36 h. The solvent was removed in vacuo,
and the residue was purified by SiO2 chromatography (10%
EtOAc/hexanes) to provide the intramolecular dibenzofuran
dimer 6 (29.6 mg, 30%), the intermolecular dimer 7 (10.1 mg,
10%), and the spiro-dibenzofuran 8 (17.7 mg, 18%).
J O971196X