A new method for the synthesis of 2-hydroxy-3-nitro-1,4-naphthoquinones: Application to regiospecific preparation of unsymmetrical nitrobiquinones

Article abstract of DOI:10.1021/jo060825c

Novel 2-hydroxy-3-nitro-1,4-naphthoquinones were synthesized by an improved method utilizing nitronium tetrafluoroborate in high yields. A subsequent conversion to 2-chloro-3-nitro-1,4-naphthoquinones and a substitution of the chlorine by hydroxyquinone anions yielded 3-nitro-2,2′-binaphthoquinones with a complete regiocontrol.

Full text of DOI:10.1021/jo060825c

on a quinone core represents an attractive method for the
formation of the quinone-quinone linkage since, in contrast to
the biomimetic coupling,3 no further oxidation of the resulting
adducts is required, and the preparation of haloquinones is
usually less challenging than the synthesis of stannyl- or
boronylquinones, or the transition metal complexes. Investiga-
tions by Smith12 and others13 revealed that 2,3-dihaloquinones
could undergo stepwise substitutions by two different active
methylene anions. Although a wide variety of active methylene
nucleophiles have been used, reactions with hydroxyquinone
anions and their synthetic equivalents remain rare,13 and the
problematic regiocontrol in the substitution on unsymmetrical
biselectrophilic quinone cores has not been satisfactorily ad-
dressed. As a part of our program aimed at the preparation of
biologically active natural and unnatural biquinones and triquino-
nes related to the anti-HIV active natural product conocurvone
1,1 we have been pursuing the design of biselectrophilic quinone
synthons, which would allow us to control the regiochemistry
of coupling reactions of quinone nucleophiles with unsymmetri-
cally substituted quinone cores (Figure 1). We have demon-
strated an efficient assembly of trimeric quinones via addition-
elimination reactions of a hydroxyquinone anion to a symmetrical
2,3-dihaloquinone affording a good yield of a chlorohydroxy-
biquinone, which could be methylated and subjected to a second
addition-elimination reaction to yield trimeric quinones.14
Although this method permitted the stepwise attachment of two
different hydroxyquinone units to a symmetrical quinone core,
regiocontrolled coupling to an unsymmetrical (e.g., unsym-
metrically substituted in the fused aryl ring) naphthoquinone
core with a complete regiocontrol was not permitted. A
regioselective substitution of the 2-trifluoromethanesulfonyl-3-
iodo-6-methoxy-1,4-naphthoquinone providing 3′-hydroxy-3-
iodo-6-methoxy-2,2′-binaphthoquinone exclusively proved to be
an exception, arising due to the electronic effect exerted by the
6-methoxy substitutent.15 Attempted stepwise substitution reac-
tions in other doubly activated unsymmetrical quinone cores
bearing two different halogens, or a halogen and the trifluo-
romethanesulfonyl activating groups (e.g., 2-chloro-3-bromo-
6-methoxy-1,4-naphthoquinone, 2-trifluoromethanesulfonyl-3-
chloro(or 3-iodo)-7-methoxy-1,4-naphthoquinone), with 2-hydoxy-
naphthoquinone anions revealed that mixtures of hydroxy-
biquinones with compositions ranging from 65:35 to 90:10 were
obtained.15
A New Method for the Synthesis of
2-Hydroxy-3-nitro-1,4-naphthoquinones:
Application to Regiospecific Preparation of
Unsymmetrical Nitrobiquinones
Min Yu,† Helena C. Malinakova,*,‡ and
Kenneth W. Stagliano†
Department of Biological, Chemical and Physical Sciences,
Illinois Institute of Technology, Chicago, Illinois 60616, and
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe
Hall DriVe, Lawrence, Kansas 66045
hmalina@ku.edu
ReceiVed April 19, 2006
Novel 2-hydroxy-3-nitro-1,4-naphthoquinones were synthe-
sized by an improved method utilizing nitronium tetrafluo-
roborate in high yields. A subsequent conversion to 2-chloro-
3-nitro-1,4-naphthoquinones and a substitution of the chlorine
by hydroxyquinone anions yielded 3-nitro-2,2′-binaphtho-
quinones with a complete regiocontrol.
Biquinones and higher quinone oligomers, which contain two
or more quinone units linked together at the quinone double
bond, are a unique group of natural products. Their diverse
biological activities, including anti-HIV activity,1,2 and syntheti-
cally challenging structures have stimulated interest in the design
of efficient and regiocontrolled methods for the construction
of bi- and triquinones. An original biomimetic route to biquino-
nes is based on oxidative dimerization of phenols to form the
key quinone-quinone bond.3-5 Palladium-catalyzed coupling
approaches involving 2-quinonylstannanes6-8 and 2-quinonyl-
boronic esters9 have also been developed allowing for a
regiocontrolled preparation of biquinones. Elegant strategies for
the assembly of triquinones relying on transition metal-mediated
annulations of cobalt complexes10 or chromium Fisher car-
benes11 have been reported. The substitution of a halogen atom
Herein, we describe a solution to the problem of regiocontrol
in the substitution of unsymmetrical doubly activated quinone
(8) Bringmann, G.; Gotz, R.; Keller, P. A.; Walter, R.; Boyd, M. R.;
Lang, F.; Garcia, A.; Walsh, J. J.; Tellitu, I.; Bhaskar, K. V.; Kelly, T. R.
J. Org. Chem. 1988, 63, 1090-1097.
† Illinois Institute of Technology.
‡ University of Kansas.
(1) Decosterd, L. A.; Parsons, I. C.; Gustafson, K. R.; Cardellina, J. H.,
II; McMahon, J. B.; Gragg, G. M.; Murata, Y.; Pannell, L. K.; Steiner, J.
R.; Boyd, M. R. J. Am. Chem. Soc. 1993, 115, 6673-6679.
(2) Thomson, R. H. Naturally Occurring Quinones IV. Recent AdVances;
Chapman & Hall: London, Great Britain, 1997.
(3) Laatsch, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 423-424.
(4) Okamoto, I.; Dio, H.; Kotani, E.; Takeya, T. Tetrahedron Lett. 2001,
42, 2987-2989.
(9) Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. J. Org. Chem. 2001,
66, 3525-3532.
(10) Yin, J.; Liebeskind, L. S. J. Org. Chem. 1998, 63, 5726-5727.
(11) Jiang, M. X.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004,
126, 5970-5971.
(12) Smith, L. I.; Austin, F. L. J. Am. Chem. Soc. 1942, 64, 528-533.
(13) Finley, K. T. The Chemistry of the Functional Groups. The
Chemistry of the Quinonoid Compounds; John Wiley & Sons: New York,
1974; Vol. 2, pp 1047-1072.
(14) Emadi, A.; Harwood, J. S.; Kohanim, S.; Stagliano, K. W. Org.
Lett. 2002, 4, 521-525.
(15) Stagliano, K. W.; Emadi, A.; Lu, Z.; Malinakova, H. C.; Twenter,
B.; Yu, M.; Holland, L. E.; Rom, A. M.; Harwood, J. S.; Amin, R.; Johnson,
A. A.; Pommier, Y. Bioorg. Med. Chem. Lett. 2006, 14, 5651-5665.
(5) Ogata, T.; Okamoto, I.; Dio, H.; Kotani, E.; Takeya, T. Tetrahedron
Lett. 2003, 44, 2041-2044.
(6) Liebeskind, L. S.; Yu, M. S.; Yu, R. H.; Wang, J.; Hagen, K. S. J.
Am. Chem. Soc. 1993, 115, 9048-9055.
(7) Liebeskind, L. S.; Riesinger, S. W. Tetrahedron Lett. 1991, 32, 5681-
5682.
10.1021/jo060825c CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/27/2006
6648
J. Org. Chem. 2006, 71, 6648-6651

and IR data confirmed the presence of the nitro group (C-
1
NO2),19 and the H and 13C NMR analyses indicated that the
nitration occurred exclusively at the C-3 position on hydroxy-
quinone 5.
Seeking a protocol for the conversion of the hydroxy group
in quinone 6 into a leaving group, quinone 6 was subjected to
the conditions previously used by us for the synthesis of
dihalogenated quinones ((COCl)2 (10 equiv), cat. DMF, rt, 20
h).14 However, we were surprised to note that both the hydroxy
and nitro groups were replaced with chlorine, providing 2,3-
dichloronaphthoquinone. Careful experimentation revealed that
the rate of substitution of the hydroxy group in quinone 6 with
chlorine was faster than the substitution of the nitro group
(chlorination of the hydroxy group was completed within 15
min with only a trace of dichloro product present), and we
reasoned that a pure 2-chloro-3-nitronaphthoquinone 7 would
be accessible after limiting the amount of oxalyl chloride and
the reaction time. Under the optimized conditions employing
oxalyl chloride (1.5-2.0 equiv), anhydrous CH2Cl2 with 10%
DMF for 15 min at room temperature, 2-chloro-3-nitronaph-
thoquinone 7 was isolated as a bright yellow solid in an excellent
yield (98%) (Scheme 1).
FIGURE 1. Stepwise substitution approach to trimeric quinones.
SCHEME 1. Synthesis of Simple 3-Nitro-2,2′-biquinonesa
Anticipating that the nitro group would direct a regiospecific
substitution of the chlorine atom at C-2 with hydroxyquinone
anions regardless of the potential presence of substituents in
the aromatic ring of the naphthoquinone skeleton, a model
reaction of 2-chloro-3-nitronaphthoquinone 7 with 2-hydroxy-
6-methoxynaphthoquinone in the presence of cesium carbonate
(2 equiv) in dry acetonitrile14 was investigated. As expected,
the substitution provided 3-nitro-2,2′-biquinone 8 in 92% yield
(Scheme 1). The 1H and 13C NMR spectra indicated that a single
regioisomer 8 was formed, and the presence of the nitro group
in biquinone 8 was unequivocally established by IR spectros-
copy.20 The hydroxy group in biquinone 8 was then methylated
with trimethyloxonium tetrafluoroborate providing nitromethoxy-
biquinone 9 in an excellent yield (81%).
Taking advantage of our earlier observation, optimum condi-
tions for the conversion of the nitro group in biquinone 9 to
chlorine were sought. The treatment of biquinone 9 with oxalyl
chloride (10 equiv) under catalysis with DMF in CH2Cl2 at room
temperature afforded chloromethoxybiquinone 10 in a good
yield (61%) (Scheme 1).
a Reagents and conditions: (a) Method A: conc HNO3, CHCl3, rt, 1 h
(65%). Method B: NO2BF4 (1.2 equiv), MeCN, rt, 30 min (92%). (b)
(COCl)2 (2 equiv), cat. DMF, CH2Cl2, rt, 15 min (98%). (c) 2-Hydroxy-
6-methoxy-1,4-naphthoquinone, Cs2CO3 (2 equiv), MeCN, rt, 3 days (92%).
(d) (CH3)3OBF4, ((CH3)2CH)2NC2H5, CH2Cl2, rt, 6 h (81%). (e) (COCl)2
(10 equiv), cat. DMF, CH2Cl2, rt, 24 h (61%).
cores, exploiting the reactivity of 2-chloro-3-nitronaphthoquino-
nes 3 (Figure 1). A new methodology for the conversion of
2-hydroxynaphthoquinones into 2-chloro-3-nitronaphthoquino-
nes16 under exceedingly mild conditions has been developed,
and the 2-chloro-3-nitronaphthoquinones 3 were used in a
regiocontrolled substitution of the 2-chloro substituent with
hydroxyquinone anions 4 to afford nitrohydroxybiquinones 2a
(X ) NO2). An unprecedented conversion of 2-nitrobiquinone
into 2-chlorobiquinones was discovered, providing chloro-
biquinone synthons 2b (X ) Cl), which were previously
converted to trimeric quinones.14 This study opens up new
synthetic applications of previously unexplored nitroquinones,
and delineates a strategy for a future stepwise assembly of
trimeric quinones featuring unsymmetrical center cores.
We became intrigued with the possibility of using 2-chloro-
3-nitronaphthoquinone 7 as a doubly activated quinone equiva-
lent for the synthesis of trimeric quinones via a stepwise sub-
stitution (Scheme 1). The method for the preparation of 2-
hydroxy-3-nitronaphthoquinone 6 previously reported by Buckle16
utilized highly acidic conditions, and would not be useful for
functionalization of acid-sensitive derivatives of naturally oc-
curring pyranylquinones.1,2 After much experimentation, we
discovered that the treatment of 2-hydroxynaphthoquinone 5
with commercially available nitronium tetrafluoroborate17,18 (1.2
equiv) in dry acetonitrile for 30 min at room temperature
afforded the nitrohydroxynaphthoquinone 6 as a bright yellow
solid in 92% yield (Scheme 1, Method B). Notably, the trans-
formation proceeds under virtually neutral conditions. The MS
To test the utility of the described methodology in the
synthesis of pyranylated biquinones structurally related to the
naturally occurring anti-HIV active conocurvone,1 an unsym-
metrically substituted hydroxyquinone 11 accessible by con-
densation of naphthalene-2,7-diol and 3-methylbut-2-enal fol-
lowed by oxidation21,22 was converted into pyranylated 2-hydroxy-
3-nitronaphthoquinone 12 in 77% yield using the nitration with
NO2BF4 (Method B) (Scheme 2). Treatment of nitrohydroxy-
(19) HRMS (FAB) calculated for C10H6NO5 (M + H)+ 220.0246, found
220.0239. The fragment mass (174) in the MS(FAB) spectrum indicated
the fragmentation of the C-N bond in nitrohydroxyquinone 6. The two
absorptions (1535 (s), 1334 (m) cm-1) in the IR spectrum confirmed the
presence of a nitro group, the signal at 1535 cm-1 corresponding to the
asymmetrical stretch of the N-O bond and the signal at 1334 cm-1
corresponding to the symmetrical stretch of the N-O bond.
(20) The two peaks (1547 cm-1, asymmetrical stretch of the N-O bond;
and 1334 cm-1, symmetrical stretch of the N-O bond) in the IR spectrum
confirmed the presence of a nitro group in nitrobiquinone 8.
(21) Cannon, J. R.; Josshi, K. R.; McDonald, I. A.; Retallack, R. W.;
Sierakowski, A. F.; Wong, L. C. H. Tetrahedron Lett. 1975, 32, 2795-2798.
(22) Jacobsen, E. N.; Vander Velde, S. L. J. Org. Chem. 1995, 60, 5380-
5381.
(16) Buckle, D. R.; Cantello, B. C. C.; Smith, H.; Smith, R. J.; Spicer,
B. A. J. Med. Chem. 1977, 20, 1059-1064.
(17) Kuhn, S. J.; Olah, G. A. J. Am. Chem. Soc. 1958, 80, 6541-6545.
(18) Kuhn, S. J.; Olah, G. A. J. Am. Chem. Soc. 1961, 83, 4564-4571.
J. Org. Chem, Vol. 71, No. 17, 2006 6649

SCHEME 2. Regiospecific Synthesis of Pyranylated
at room temperature was added nitronium tetrafluoroborate (0.152
g, 1.150 mmol). The resulting reaction mixture was stirred for 30
min during which the light yellow suspension turned into a
transparent yellow solution. The solvent (acetonitrile) was evapo-
rated followed by the addition of 4 N HCl (50 mL). The resulting
aqueous suspension was extracted with ethyl ether (2 × 50 mL).
The combined organic layers were dried (MgSO4), filtered, and
evaporated to yield nitrohydroxynaphthoquinone 6 (0.201 g, 92%)
as a yellow solid: mp 154-156 °C (lit.16 mp 162-163 °C); Rf
3-Nitro-2,2′-biquinonesa
1
0.23 (EtOAc); H NMR (300 MHz, CDCl3) δ 7.82-7.96 (m, 2
H), 8.19-8.26 (m, 2 H), 8.68 (s, br, 1 H); 13C NMR (75 MHz,
DMSO-d6) δ 126.3, 131.0, 132.3, 133.4, 135.0, 135.4, 136.7, 161.9,
172.0, 184.0; FT-IR (KBr) 3317 (s and br), 1688, 1651, 1607, 1536,
1334, 779, 722 cm-1; MS (FAB) m/z (rel intensity) 220 [(M +
H)+, 48], 195 (37), 171 (15), 154 (100), 136 (96), 124 (18), 107
(34); HRMS (FAB) calcd for C10H6NO5 (M + 1)+ 220.0246, found
220.0239.
2-Hydroxy-3-nitronaphthalene-1,4-dione (6) was also prepared
using fuming HNO3 in CHCl3 (method A) as previously described.16
2-Chloro-3-nitronaphthalene-1,4-dione (7). To a suspension
of 2-hydroxy-3-nitronaphthoquinone 6 (0.300 g, 1.37 mmol) in dry
CH2Cl2 (30 mL) was added oxalyl chloride (0.239 mL, 2.74 mmol)
and DMF (0.011 mL, 0.14 mmol). The reaction mixture was stirred
for 15 min at room temperature during which a transparent yellow
solution formed. The solution was poured into cold H2O (100 mL)
and stirred for 10 min to quench the excess oxalyl chloride. The
mixture was extracted with CH2Cl2 (1 × 50 mL). The combined
organic layers were washed with H2O (4 × 70 mL), dried (MgSO4),
filtered, and evaporated. The crude product was purified by flash
chromatography on silica eluting with 10% EtOAc in hexanes to
yield 0.317 g (98%) of the chloronitronaphthoquinone 7 as a bright
a Reagents and conditions: (a) NO2BF4 (1.2 equiv), MeCN/CH2Cl2, 0
°C, (77%). (b) (COCl)2 (2 equiv), cat. DMF, CH2Cl2, rt, 15 min (69%). (c)
Cs2CO3 (2 equiv), MeCN, rt, 3 days, quinones 11 or 14.
naphthoquinone 12 under the established chlorination conditions
afforded the pyranylated 2-chloro-3-nitronaphthoquinone 13 as
a deep red solid in 69% yield. Both the pyranylated nitroquino-
nes 12 and 13 could be purified by flash column chromatog-
raphy; however, a careful selection of the adsorbent and the
elution system was necessary. Best results were obtained with
silica instead of Florisil and eluting quinone 12 with 80% EtOAc
and 5% AcOH in hexanes, and quinone 13 with 10% EtOAc in
hexanes.
The tolerance of the acid-sensitive pyran ring of hydroxy-
quinone 11 to the novel nitration conditions is notable and
significant from the standpoint of the synthesis of complex
naturally occurring quinones.
The pyranylated hydroxyquinone 11 and naturally occurring
Teretifolione B 14,21 which was prepared by published proce-
dures,22 were treated with 2-chloro-3-nitronaphthoquinone 13
in the presence of a mild base (Cs2CO3) to afford biquinones
15 and 16 as single regioisomers in quantitative yields with a
complete control of the substitution patterns (Scheme 2).
Quinones 15 (96%) and 16 (95%) were obtained as pure red
solids after chromatographic purification. Our previously pub-
lished work indicated the compatibility of pyranylquinones with
the O-methylation, and demonstrated the conversion of biquino-
ne 10 into a trimeric quinone via substitution.14
In conclusion, a novel method for the preparation of 2-hy-
droxy-3-nitronaphthoquinones and 2-chloro-3-nitronaphtho-
quinones under mild conditions was described. The chloroni-
tronaphthoquinones were successfully used in a regiospecific
synthesis of 3-nitro-3′-hydroxy-2,2′-biquinones. Feasibility of
the conversion of 3-nitro-3′-methoxy-2,2′-biquinones into 3-chloro-
3′-methoxy-2,2′-biquinones was established, providing an access
to unique activated biquinone synthons poised for a future
conversion to trimeric quinones.
1
yellow solid: mp 155 °C; Rf 0.29 (10% EtOAc in hexanes); H
NMR (300 MHz, CDCl3) δ 7.80-7.84 (m, 2 H), 8.19-8.24 (m, 2
H); 13C NMR (75 MHz, CDCl3) δ 127.6 (2 C), 128.1, 129.6, 130.4,
135.4, 135.6, 151.1, 173.5, 176.2; FT-IR (KBr) 1689, 1677, 1550,
1369, 789, 715, 691 cm-1; MS (EI) m/z (rel intensity) 238.9 [(M
+ 2H)+, 22], 236.9 (M+, 63), 190.9 (100), 162.9 (40), 134.9 (58);
HRMS (FAB) calcd for C10H6NO4Cl (M + 2H)+ 238.9985, found
238.9964.
3′-Nitro-3-hydroxy-7-methoxy-2,2′-binaphthalenyl-1,4,1′,4′-
tetraone (8). The mixture of 2-chloro-3-nitronaphthoquinone 7
(0.150 g, 0.63 mmol), 2-hydroxy-6-methoxynaphthoquinone23
(0.129 g, 0.63 mmol), and cesium carbonate (0.411 g, 1.26 mmol)
was stirred in anhydrous CH3CN (7 mL) at room temperature for
3 days during which the color changed from deep red to dark purple.
The mixture was acidified with concentrated HCl to pH 2 (litmus)
forming a yellow precipitate. The suspension was poured into water
(100 mL) and stirred for 30 min to dissolve remaining traces of
cesium carbonate. The precipitate was filtered and the product air-
dried for 3 days at room temperature to yield the nitrohydroxy-
biquinone 8 (0.234 g, 92%) as a yellow solid: mp 214-216 °C; Rf
0.38 (CHCl3 and 3 drops of MeOH); 1H NMR (300 MHz, DMSO-
d6) δ 3.93 (s, 3 H), 7.34 (dd, J ) 8.7 Hz, 2.7 Hz, 1 H), 7.40 (d, J
) 2.7 Hz, 1 H), 7.98-8.00 (m, 2 H), 8.02 (d, J ) 8.7 Hz, 1 H),
8.07-8.10 (m, 1 H), 8.13-8.16 (m, 1 H);24 13C NMR (75 MHz,
DMSO-d6) δ 56.5, 110.6, 111.2, 119.9, 123.7, 127.2, 127.3, 129.7,
130.2, 131.6, 134.5, 134.6, 135.8, 136.0, 151.7, 160.2, 165.0, 175.2,
179.1, 180.9, 181.8; FT-IR (KBr) 3321 (s and br), 1679, 1664, 1590,
1547, 1334, 785, 762 cm-1; MS (FAB) m/z (rel intensity) 407 [(M
+ 2H)+, 4], 391 (5), 371 (2), 307 (66), 286 (56), 220 (27), 205
(12), 154 (100), 136 (96). Repeated attempts to detect a molecular
ion in the high-resolution mass spectra were unsuccessful. The use
of 8 in subsequent reactions yielded the expected product 9, which
was fully characterized.
In conjunction with our prior studies, this protocol opens up
for the first time a pathway to a stepwise regiocontrolled
elaboration of unsymmetrical biselectrophilic quinone cores via
a stepwise double substitution.
Experimental Section
(23) Kasturi, T. R.; Arunachalam, T. Can. J. Chem. 1966, 44, 1086-
1089.
2-Hydroxy-3-nitronaphthalene-1,4-dione (6) (Method B). To
a vigorously stirred suspension of the 2-hydroxynaphthoquinone
(0.174 g, 1.000 mmol) in dry acetonitrile (15 mL) under nitrogen
(24) The signal for the H-O in quinone 8 and 12 was not detected in
1H NMR spectra due to significant broadening.
6650 J. Org. Chem., Vol. 71, No. 17, 2006

3′-Nitro-3,7-methoxy-2,2′-binaphthalenyl-1,4,1′,4′-tetraone (9).
To a solution of nitrohydroxybiquinone 8 (0.304 g, 0.75 mmol)
and trimethyloxonium tetrafluoroborate (0.133 g, 0.90 mmol) in
dry methylene chloride (20 mL) was added N,N′-diisopropylethyl-
amine (0.116 g, 0.90 mmol). The resulting dark purple solution
was stirred under nitrogen for 6 h at room temperature during which
the reaction mixture turned a brown-yellow color. The solution was
diluted with CH2Cl2 (50 mL) and successively washed with water
containing 3 drops of HCl (3 × 100 mL) and 10% NaHCO3 (3 ×
100 mL). The organic layer was dried (MgSO4), filtered, and
evaporated yielding the nitromethoxybiquinone 9 (0.255 g, 81%)
as a yellow solid: mp 230-232 °C; Rf 0.25 (20% EtOAc in
160.4, 172.7, 178.2; FT-IR (KBr) 1676, 1664, 1553, 1368, 770,
743 cm-1; MS (FAB) m/z (rel intensity) 320 [(M + H)+, 27], 306
(22), 289 (12), 239 (4), 213 (10), 179 (8), 167 (20), 154 (100), 136
(91), 107 (37); HRMS (FAB) calcd for C15H11ClNO5 (M + H)+
320.0326, found 320.0321.
9-(9-Hydroxy-3,3-dimethyl-3H-benzo[f]chromen-8-yl)-3,3-di-
methyl-8-nitro-3H-benzo[f]chromene-7,10-dione (15). Reaction
of pyranylated 2-chloro-3-nitronaphthoquinone 13 (0.060 g, 0.19
mmol) with hydroxyquinone 11 (0.048 g, 0.19 mmol) in the
presence of Cs2CO3 (0.122 g, 0.38 mmol) for 3 days, as described
above for the preparation of 8, yielded biquinone 15 (0.097 g, 96%)
(after purification by flash chromatography on silica eluting with
35% EtOAc and 5% AcOH in hexanes) as a red solid: mp 129-
1
hexanes); H NMR (300 MHz, CDCl3) δ 3.95 (s, 3 H), 4.24 (s, 3
1
H), 7.22 (dd, J ) 8.7 Hz, 2.7 Hz, 1 H), 7.51 (d, J ) 2.7 Hz, 1 H),
7.87-7.91 (m, 2 H), 8.06 (d, J ) 8.7 Hz, 1 H), 8.17-8.20 (m, 1
H), 8.23-8.26 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 55.8, 56.1,
109.9, 118.7, 120.5, 124.6, 127.3 (2C), 127.6, 129.2, 129.5, 130.1,
131.4, 133.1, 133.4, 135.1, 158.5, 164.8, 174.9, 179.0, 181.3, 181.6;
FT-IR (KBr) 1678, 1591, 1545, 1329, 760, 742 cm-1; MS (FAB)
m/z (rel intensity) 420 [(M + H)+, 8], 391(4), 360 (4), 359 (3),
307 (27), 285 (13), 220 (14), 205 (7), 179 (6), 154 (100), 136 (84),
107 (26); HRMS (FAB) calcd for C22H14NO8 (M + H)+ 420.0719,
found 420.0703.
3′-Chloro-3,7-methoxy-2,2′-binaphthalenyl-1,4,1′,4′-tetra-
one (10). The reaction of the nitromethoxybiquinone 9 (0.045 g,
0.11 mmol), oxalyl chloride (0.094 mL, 1.07 mmol), and DMF (1
drop), according to the general procedure described above for the
preparation of 7, yielded chlorobiquinone 10 (0.027 g, 61%) as a
dark yellow solid: mp 290-292 °C. Compound 10 was also
prepared by the published procedures.14
132 °C; Rf 0.25 (50% EtOAc in hexanes); H NMR (300 MHz,
CDCl3) δ 1.49 (s, 12 H), 5.97 (d, J ) 10.5 Hz, 1 H), 6.04 (d, J )
10.5 Hz, 1 H), 7.14 (d, J ) 7.8 Hz, 1 H), 7.17 (d, J ) 8.4 Hz, 1
H), 7.58 (d, J ) 10.2 Hz, 1 H), 7.73 (d, J ) 10.5 Hz, 1 H), 8.00
(d, J ) 8.4 Hz, 1 H), 7.90-8.00 (s, br, 1 H), 8.07 (d, J ) 8.4 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ (27.9), (28.0), 28.1 (2 C),
29.70 (2 C), 77.7 (2 C), 110.3, 119.3, 119.4, 121.8, 122.2, 122.4,
123.0, 123.1, 124.4, 126.2, 126.4, 129.5, 129.7, 132.3, 136.1, 136.9,
151.1, 153.9, 158.5, 160.2, 174.0, 180.6, 181.7, 183.5 (signals for
the minor atropisomer arising from a hindered rotation about the
quinone-quinone bond are given in parentheses); FT-IR (KBr)
3316 (s and br), 1671, 1664, 1642, 1554, 1356, 774, 731 cm-1
;
MS (FAB) m/z (rel intensity) 540 [(M + H)+, 10], 524 (12), 479
(18), 464 (11), 307 (8), 289 (8), 239 (7), 213 (46), 165 (16), 154
(100), 107 (38); HRMS (FAB) calcd for C30H21NO9 (M)+ 539.1216,
found 539.1229.
9-(9-Hydroxy-3-methyl-3-(4-methylpent-3-enyl)-3H-benzo[f]-
chromen-8-yl)-3,3-dimethyl-8-nitro-3H-benzo[f]chromene-7,10-
dione (16). Reaction of pyranylated 2-chloro-3-nitronaphthoquinone
13 (0.060 g, 0.19 mmol) with hydroxyquinone 14 (0.061 g, 0.19
mmol) in the presence of Cs2CO3 (0.122 g, 0.38 mmol) for 3 days,
as described above for the preparation of 8, yielded biquinone 16
(0.108 g, 95%) (after purification by flash chromatography on silica
eluting with 15% EtOAc and 5% AcOH in hexanes) as a red solid:
mp 127-131 °C; Rf 0.25 (50% EtOAc in hexanes); 1H NMR (300
MHz, CDCl3) δ 1.47 (s, 3 H), 1.49 (s, 6 H), 1.57 (s, 3 H), 1.66 (s,
3 H), 1.71-1.79 (m, 2 H), 2.05-2.13 (m, 2 H), 5.08 (t, J ) 2.0
Hz, 1 H), 5.97 (d, J ) 11.1 Hz, 1 H), 6.00 (d, J ) 10.2 Hz, 1 H),
7.13 (d, J ) 8.4 Hz, 1 H), 7.17 (d, J ) 8.7 Hz, 1 H), 7.58 (d, J )
10.5 Hz, 1 H), 7.81 (d, J ) 10.2 Hz, 1 H), 7.90-8.00 (s, br, 1 H),
8.00 (d, J ) 8.4 Hz, 1 H), 8.08 (d, J ) 8.4 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 17.7, 22.6, 25.7 (26.7) (2 C), 28.1 (29.7) (2
C), 41.4 (41.3), 77.7, 79.8, 110.3, 119.4, 119.8, 121.8, 122.1, 122.4,
122.5, 122.7, 123.0, 123.3 (123.4), 124.4, 126.2, 126.3, 129.6, 129.7,
132.3 (132.4), 136.1, 136.2, 151.1, 153.9, 158.8, 160.2, 174.0, 180.5,
181.7, 183.5 (signals for the minor atropisomer arising from a
hindered rotation about the quinone-quinone bond are given in
parentheses); FT-IR (KBr) 3317 (s and br), 1672, 1665, 1641, 1545,
1356, 772, 755 cm-1; MS (FAB) m/z (rel intensity) 608 [(M +
H)+, 37], 562(32), 524 (43), 479 (44), 478 (18), 307 (18), 285 (10),
220 (21), 205 (10), 154 (100), 136 (73); HRMS (FAB) calcd for
C35H30NO9 (M)+ 608.1921, found 608.1949.
9-Hydroxy-8-nitro-3,3-dimethyl-3H-benzo[f]chromene-7,10-
dione (12). To a vigorously stirred solution of the pyranylated
hydroxynaphthoquinone 11 (0.256 g, 1.00 mmol) in dry CH2Cl2
(30 mL) under nitrogen at 0 °C was added a solution of nitronium
tetrafluoroborate (0.159 g, 1.20 mmol) in dry acetonitrile (10 mL)
dropwise over 20 min. The resulting reaction mixture was warmed
to room temperature and stirred for an additional 10 min. The
solvents (acetonitrile and CH2Cl2) were evaporated under reduced
pressure at room temperature. The crude product was quenched
with water (100 mL) followed by the addition of concentrated HCl
to pH 2 (litmus). The resulting aqueous suspension was extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were dried
(MgSO4), filtered, and evaporated. The crude product was purified
by flash chromatography on silica eluting with 80% EtOAc and
5% AcOH in hexanes to yield the pyranylated nitrohydroxynaph-
thoquinone 12 (0.230 g, 77%) as a red solid: mp 165-166 °C; Rf
1
0.26 (EtOAc); H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 6 H),
6.06 (d, J ) 10.2 Hz, 1 H), 7.14 (d, J ) 8.4 Hz, 1 H), 7.48 (d, J
) 10.5 Hz, 1 H), 7.85 (d, J ) 8.4 Hz, 1 H); 13C NMR (200 MHz,
DMSO-d6) δ 27.6 (2 C), 76.3, 119.8, 120.2, 121.6, 125.9, 127.6,
127.8, 134.1, 135.0, 155.9, 163.1, 171.3, 186.8; FT-IR (KBr) 3321
(s and br), 1665, 1655, 1536, 1334, 756, 749 cm-1; MS (FAB) m/z
(rel intensity) 302 [(M + H)+, 37], 286 (17), 255 (22), 231 (35),
213 (46), 187 (17), 165 (22), 154 (77), 136 (73), 115 (39), 107
(36); HRMS (FAB) calcd for C15H12NO6 (M + H)+ 302.0665,
found 302.0688.
9-Chloro-8-nitro-3,3-dimethyl-3H-benzo[f]chromene-7,10-di-
one (13). Reaction of nitrohydroxynaphthoquinone 12 (0.230 g,
0.77 mmol) with oxalyl chloride (0.067 mL, 0.77 mmol) in the
presence of DMF (0.006 mL, 0.08 mmol) for 15 min, as described
above for the preparation of 7, yielded pyranylated 2-chloro-3-
nitronaphthoquinone 13 (0.168 g, 69%) (after purification by flash
chromatography on silica eluting with 10% EtOAc in hexanes) as
a red solid: mp 149-151 °C; Rf 0.28 (10% EtOAc in Hexanes);
1H NMR (300 MHz, CDCl3) δ 1.51 (s, 6 H), 6.07 (d, J ) 10.5 Hz,
1 H), 7.17 (d, J ) 8.1 Hz, 1 H), 7.65 (d, J ) 10.5 Hz, 1 H), 8.02
(d, J ) 8.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 28.1 (2 C),
77.9, 119.1, 122.8, 123.6, 124.9, 130.0, 130.8, 135.3, 137.2, 150.1,
Acknowledgment. We acknowledge the National Institutes
of Health (Grant AI43687) to K.W.S. for support of this
research, and thank the University of Notre Dame Mass
Spectrometry Facility for assistance with low- and high-resolu-
tion mass spectra, and thank Mr. Chad D. Hopkins (University
of Kansas) for assistance with recording the 13C NMR spectra.
Supporting Information Available: General experimental
1
details and H and 13C NMR spectra for 6-9, 12, 13, 15, and 16.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060825C
J. Org. Chem, Vol. 71, No. 17, 2006 6651