Total synthesis of 7′-desmethylkealiiquinone, 4′- desmethoxykealiiquinone, and 2-deoxykealiiquinone

Article abstract of DOI:10.1021/jo4027337

Synthetic approaches to the imidazonaphthoquinone core of kealiiquinone and related Leucetta-derived alkaloids are described. The polysubstituted benzimidazole framework can be constructed through intramolecular Diels-Alder reactions of propiolate-derived

Full text of DOI:10.1021/jo4027337

Article
pubs.acs.org/joc
Total Synthesis of 7′-Desmethylkealiiquinone, 4′-
Desmethoxykealiiquinone, and 2‑Deoxykealiiquinone
Heather M. Lima, Rasapalli Sivappa,† Muhammed Yousufuddin, and Carl J. Lovely*
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019-0065, United States
S
* Supporting Information
ABSTRACT: Synthetic approaches to the imidazonaphthoquinone core of kealiiquinone and related Leucetta-derived alkaloids
are described. The polysubstituted benzimidazole framework can be constructed through intramolecular Diels−Alder reactions of
propiolate-derived enynes followed by oxidation. Adjustment of the oxidation state of the thus formed lactone allows
introduction of the 2,3-dihydroxybenzoquinone moiety through a presumed benzoin-like condensation between a phthaldehyde
derivative and a masked glyoxal equivalent catalyzed by a cyanide ion. Oxidation of the C2-position can be accomplished through
application of an operationally simple treatment of an imidazolium salt with bleach, thus producing the corresponding 2-
imidazolone. Debenzylation of a late stage intermediate en route to kealiiquinone was compromised by concomitant O-
demethylation upon treatment with triflic acid resulting in the formation of non-natural 7′-desmethylkealiiquinone. Other
endgame strategies were evaluated; however, these efforts did not lead to completion of a synthesis of kealiiquinone but did
provide access to other closely related analogues.
although the presence of the quinone would suggest that they
might be good bio-Michael acceptors. The biosynthetic details
of the Leucetta alkaloids are unknown, although it has been
speculated that kealiiquinone (1) may be derived from the
kealiinines (3−5)13−15 through oxidation of the C-ring.16 An
alternative hypothesis has been posited involving the
intermediacy and subsequent cyclization of the quinone-
containing naamidine F (6).17 Prior to our efforts,18 only one
report of a total synthesis of kealiiquinone has appeared from
the Ohta lab resulting in the synthesis of the 2-keto tautomer of
the natural product.19,20 A second total synthesis of
kealiiquinone (1) and the first of 2-deoxy-2-aminokealiiquinone
(2) have been completed by our lab using a complementary
bioinspired Friedel−Crafts-like strategy to the approach
described by Ohta and co-workers. The synthetic version and
a regioisomer were evaluated in a panel of cancer cell lines and
shown to possess modest activity,21 but the activity profile
suggested a possible unique mechanism of action. However,
this facet does not appear to have been pursued further by the
Ohta group or anyone else. Very recently, syntheses of the less
oxidized kealiinines have been reported independently by two
groups,14 including ours.15 The cytotoxicity of the kealiinines
(3−5), the kealiiquinones (1 and 2), and several intermediates
INTRODUCTION
■
Marine sponges have emerged as excellent sources of
structurally diverse natural products1,2 that possess activities
against a number of important disease targets and as such serve
as leads in medicinal chemistry programs.3 Our laboratories
have developed interests in the imidazole-containing alkaloids4
belonging to the oroidin or the Leucetta families5,6 of natural
products. These synthetic programs have largely centered on
the discovery and development of new methods and strategies
for the elaboration of simple imidazole derivatives rather than
the de novo construction of the imidazole ring.7,8 In this
manuscript, we describe the application of two such methods to
the syntheses of three analogs of the imidazonaphthoquinone
alkaloids kealiiquinone (1)9 and 2-deoxy-2-aminokealiiquinone
(2) (Figure 1).10 Specifically the use of an intramolecular
Diels−Alder reaction to construct a polysubstituted dihydro-
benzimidazole11 and oxidation of the imidazole C2-position via
the intermediacy of imidazolium salts.12
Kealiiquinone (1) was isolated from a Leucetta sp. found off
the islands of Guam and Saipan by the Scheuer lab and
characterized by a combination of spectroscopic methods and
X-ray crystallography.9 More recently Schmitz and co-workers
reported the isolation and characterization of the 2-amino
congener 2 from Leucetta chagosensis collected in Chuuk State
(part of the Federated States of Micronesia).10 In both cases,
biological activity was not reported by the isolation groups,
Received: December 11, 2013
Published: February 17, 2014
© 2014 American Chemical Society
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method was needed for the installation of the 2,3-dimethoxy-
quinone moiety. While there were limited options for this
transformation, chemistry reported by Venuti,33 using a
cyanide-catalyzed, benzoin-like condensation via the dialdehyde
7 offered a potential solution (Figure 2). Elaboration at the C2-
position of the imidazole via metalation and electrophilic
quench would then deliver either of the two kealiiquinone
natural products 1 and 2 from a common late-stage
intermediate (Figure 2).34,35
Initial Experiments. As part of our exploratory efforts on
the intramolecular Diels−Alder and as a prelude to an approach
to kealiiquinone we had prepared dihydrobenzimidazole 14
from N-benzyl protected enyne 13 in 83% yield.11 Initial
experiments directed toward aromatization of the cycloadduct
were performed with 10% Pd−C and air, and while these
conditions provided the required product 15 (Scheme 1), it
Scheme 1. Assembly of the Benzimidazole Core
Figure 1. Naphthimidazole natural products isolated from Leucetta
sponges.
have been investigated and shown for the most part to possess
modest activity (IC50 = 20−95 μM in MTT growth assay with
MCF7 breast cancer cell lines).14,16
RESULTS AND DISCUSSION
■
Synthetic Strategy. We were intrigued by the opportunity
offered by kealiiquinone (1) to demonstrate the utility of
several aspects of imidazole chemistry that we have developed,7
as well as providing a platform to develop novel chemistry
along the way.12 Accordingly, our retrosynthetic analysis of the
target is shown in Figure 2. Our experience with Diels−Alder
gave inconsistent yields and required extended reaction times
for good conversions. Subsequently, we found that the
aromatization could be effected efficiently and reproducibly in
the presence of MnO2, delivering 15 in 91% yield.36
Since these preliminary experiments were successful, we
decided to construct the full substrate which required the
preparation of the anisyl substituted propiolic acid 12. This was
prepared through a Sonogashira cross-coupling between p-
iodoanisole and propargyl alcohol (85%).37 Oxidation of the
product with MnO2 provided the aldehyde (85%)38 and a
subsequent Pinnick oxidation produced the corresponding
propiolic acid 12 (60%).39,40 The acid 12 was coupled with the
benzyl protected vinylimidazole 10 through a DCC-mediated
condensation delivering enyne 9 (Scheme 1). Subjection of the
thus obtained enyne 9 to heating in toluene at reflux for 48 h
resulted in the formation of the dihydrobenzimidazole 8 in
excellent yield. Oxidation with MnO2 affords the aromatized
benzimidazole 16 in good yield (Scheme 1). The structure of
16 was confirmed through X-ray crystallography (see SI) which
nicely illustrated the relative location of the two aromatic
substituents.18 Of note is the slight pyramidalization of the
imidazole N1 (Σ∠ = 353.89°) and the deviation from
orthogonality around the C3−C10 bond (crystallographic
Figure 2. Overview of the synthetic strategy toward kealiiquinone.
reactions of 4-vinylimidazoles suggested that an intramolecular
variant of this chemistry would provide rapid and controlled
access to polysubstituted benzimidazole (8→9, Figure
2).11,22−32 In our hands we have found the 4-isomers to be
superior in the cycloaddition chemistry and thus the choice of a
benzyl protecting group in enyne 9 would permit the position-
selective incorporation of the methyl substituent later in the
synthetic sequence. Whereas the cycloaddition chemistry would
properly position substituents around the core framework, a
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Scheme 2. Initial Approach to Elaboration of Benzimidazole Core
Scheme 3. Early Introduction of 2-Oxo Group
numbering). Presumably both structural effects minimize
nonbonded interactions between the N-benzyl and anisyl
moieties. At this stage, both the unsubstituted and p-methoxy
systems 15 and 16 were taken through the same set of reactions
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Scheme 4. Late Stage Introduction of the 2-Oxo Group
to construct the imidazonaphthoquinone framework but in
slightly different sequences as described in Schemes 2, 3, and 4.
First Generation Approach. Initially, it was decided to
introduce the N-methyl group on the p-anisyl-containing
substrate 16, as this can be accomplished via the intermediacy
of the imidazolium salt by hydrogenolysis of the benzyl group
(Scheme 2). Conversion of 16 to the imidazolium salt 17 was
accomplished uneventfully by treatment with methyl iodide,
and subsequent catalytic hydrogenation of 17 delivered the
corresponding debenzylated N-methyl benzimidazole derivative
18. In our preliminary experiments we noted some variability in
the yield of this reaction. Ultimately however it was recognized
that hydrolysis of the lactone occurred; treatment of the crude
hydrogenation product with aqueous acid recyclized the γ-
hydroxy acid thus providing improved yields and reproduci-
bility. This strategy for introduction of the methyl group has
the advantage of avoiding potential selectivity issues in
comparison to an approach involving direct methylation of
the parent benzimidazole.41 Reduction of the lactone to the
corresponding diol 19 was accomplished effectively with
DIBAL, setting the stage for the installation of the final ring.
In order to accomplish this critical transformation, the
corresponding dialdehyde 7 was required. Initial attempts to
convert diol 19 to the phthaldehyde derivative 7 with common
oxidants were thwarted by the formation of the lactone; only
Swern conditions were partially successful. In this latter case
there was some batch to batch inconsistency, the cause of
which we were unable to track down. Fortunately, this led us to
investigate reagents that behaved mechanistically similarly to
Swern reagents; among these, the best system we identified was
reported by Mukaiyama and co-workers involving sulfinimidoyl
chlorides, e.g., 20 in the presence of DBU.42 This reagent
combination reproducibly resulted in the formation of the
phthaldehyde 7 in yields between 65% and 75%. With the
aldehyde in hand we were in position to evaluate Venuti’s
method for its conversion into the corresponding dihydroxy
benzoquinone 22.33 Gratifyingly, we found that the 2,3-
dihydroxybenzoquinone 22 was produced reproducibly, albeit,
in a modest yield of approximately 40%. At this stage, all that
remained to be done to complete the total synthesis of
kealiiquinone (1) was the conversion of the hydroxyl groups to
methyl ethers and oxidation at C2. The first task was
accomplished by taking advantage of the fact that the OH
groups are part of a vinylogous acid and as such reacted
efficiently with TMS-diazomethane, delivering dimethoxyqui-
none 23. However, the introduction of functionality at C2 was
significantly more difficult. We and others have routinely used
metalation by deprotonation at C2 with a strong base (BuLi or
LDA) and followed that by trapping with a suitable
electrophile:15,16 in this context either (TMSO)2 for
kealiiquinone (1)35 or TsN3 for the amino congener 2.34
Multiple attempts to perform this chemistry with 23 as a
substrate simply failed to produce the anticipated products;
indeed these reactions did not produce any products that we
were able to characterize. Experiments to trap out any
metalated intermediates with D2O or methanol-D4 were
similarly unsuccessful. Although we have no experimental
evidence to support our hypothesis, we suspect that electron
transfer processes are intervening. As a means to circumvent
these issues, we briefly attempted to introduce functionality at
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Scheme 5. Attempted Use of a Temporary Activating Group
C2 earlier in the sequence by metallating with n-BuLi on
lactones 16 or 18; however issues with solubility or
deprotonation occurring on the N-benzyl or the lactone
methylene compromised this strategy. Alternative timings for
introducing the C2-functionality were rejected as these options
invariably increased the step count unacceptably.
demethylation of the 7′-methyl and thus the formation of 7′-
desmethylkealiiquinone (29). In an effort to access the natural
product, various attempts were made to remethylate the
phenolic hydroxyl group. In our hands this resulted in
overmethylation (methylation of the imidazole nitrogen and
the hydroxyl group) or N-methylation under a variety of
different conditions and with different methyl sources.
Second Generation Approach. Given this late stage
failure to functionalize at C2 of the naphthimidazole, we began
to contemplate our options for moving the synthesis forward,
and it occurred to us that the imidazolium salts that were
prepared as a means to selectively methylate the benzimidazoles
may be easier to functionalize given the increased acidity of the
proton at C2 in these systems.43 Based on this hypothesis, we
have developed an extremely mild method for introducing
oxygen at C2 through exposure of the imidazolium ion to
bleach or alternatively nitrogen can be introduced through
exposure to N-chlorosulfonamides or N-chlorocarbamates; this
chemistry has been described in more detail elsewhere.12 With
this method in hand we subjected the lactone imidazolium
species 17 to bleach and found that it too underwent the
oxidation to provide the 2-benzimidazolone 24 in good yield
(Scheme 3). An X-ray structure determination on the DIBAL-
reduction product 25 unequivocally demonstrates the intro-
duction of the 2-oxo moiety and served to confirm the relative
location of the methyl and aryl groups.18 At this point we
elaborated the benzimidazolone 25 in a largely analogous
fashion to the corresponding phthaldehyde 26. Although the
efficiency was lower, dialdehyde 26 was converted into the
dihydroxyquinone 27 and subsequently the hydroxyl groups
were converted into methoxy groups by treatment with TMS-
diazomethane (27 → 28, Scheme 3). All that remained to
complete the revised synthesis of kealiiquinone (1) was
removal of the N-benzyl protecting group; unfortunately this
proved to be exceedingly difficult. While N-benzyl groups can
be removed quite readily from amines under a variety of
conditions, amides on the other hand tend to be much more
challenging substrates. Indeed it was found that standard
reductive or oxidative conditions failed to remove the N-benzyl
moiety.44 Ultimately, we determined that heating the substrates
in neat triflic acid resulted in debenzylation with reasonable
efficiencies.45 Unfortunately, in the case of the precursor to
kealiiquinone, these reaction conditions led to the selective
Late Stage Functionalization. An alternative strategy was
explored concurrently with the one described above in which
the introduction of the C2-substituent was delayed until the
end of the synthesis. In part this was undertaken in order to not
only evaluate the strategy in general but also establish whether
the highly functionalized quinones were viable substrates in our
oxidative chemistry. Thus lactone 15 was reduced to the
corresponding diol 30 and then converted to the phthaldehyde
31 upon treatment with 20 (Scheme 4). Conversion to the 2,3-
dihydroxyquinone 32 was accomplished with glyoxal 21,
followed by methylation with TMS-diazomethane. Methylation
of the imidazole nitrogen to prepare the imidazolium salt 34
was then carried out by exposure of 33 to methyl iodide in
acetonitrile at reflux. Initial oxidation experiments of 34 with
bleach resulted in the formation of the imidazolone 35, but the
yields were rather low, ca. 20%. Fortunately, we had established
previously that other chloronium sources effect this chemistry,
and so exposure of 34 to NCS and aqueous potassium
carbonate delivered the imidazolone 35 in 60% yield.12
Reaction of the imidazolone with TfOH at 55 °C resulted in
debenzylation and the formation of 4′-desmethoxykeali-
iquinone (36). With the imidazolium salt in hand, we also
took the opportunity to evaluate the introduction of an imino
group through exposure to an N-chlorocarbamate (Scheme 4);
to date only simple benzimidazolium and imidazolium salts had
been investigated in this chemistry.12 While the yield turned
out to be quite modest, the reaction of 34 with N-chloro tert-
butylcarbamate (produced in situ from tert-butyl carbamate and
t-BuOCl) did produce the expected product 37 (Scheme 4). A
preliminary attempt to remove the Bn- and BOC-protecting
groups by sequential treatment with TfOH and then TFA was
not successful.
One further strategy was evaluated to prepare the
imidazolium salt near the end of the synthesis with a more
easily removable N-substituent, but one that was capable of
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were recorded by electrospray ionization (ESI-TOF) or atmospheric-
pressure chemical ionization (APCI-TOF) unless otherwise indicated.
(2E)-3-(1-Benzyl-1H-imidazol-4-yl)prop-2-enyl 3-(4-
methoxyphenyl)propynoate (9). Propiolic acid 12 (2.00 g, 11.4
mmol), alcohol 10 (2.94 g, 13.7 mmol), DMAP (0.14 g, 1.2 mmol),
and camphorsulfonic acid (0.16 g, 0.70 mmol) were dissolved in
CH2Cl2 (50 mL) and cooled to −78 °C under N2. DCC (3.50 g, 17.1
mmol) dissolved in CH2Cl2 (20 mL) was added dropwise. The
mixture was allowed to come to rt and stir for 2 h. The solids were
filtered through Celite and washed with CH2Cl2. The filtrate was
reduced, and the resulting brown residue was purified by column
chromatography (8:2 EtOAc/Hexane) to afford 9 as an off-white solid
(2.53 g, 56%). Mp: 65−67 °C; 1H NMR: δ = 7.52 (s, 1H), 7.49 (d, J =
2.1 Hz, 2H), 7.36−7.31 (m, 3H), 7.15−7.13 (m, 2H), 6.86 (m, 3H),
6.58 (d, J = 15.6 Hz, 1H), 6.47−6.38 (dt, J = 15.5, J = 6.2 Hz, 1H),
5.06 (s, 2H), 4.82 (d, J = 6.6 Hz, 2H), 3.81 (s, 3H); 13C NMR: δ =
161.6, 154.2, 139.8, 137.9, 135.9, 135.0, 129.1, 128.5, 127.4, 127.0,
120.6, 117.9, 114.4, 111.5, 87.3, 80.1, 66.5, 55.5, 51.0; IR (KBr, cm−1):
3105, 2195, 1899, 1697, 1602, 1567, 1541; HR-ESIMS (m/z): calcd
for [M + H]+ C23H21N2O3 is 373.1547, found 373.1564.
3-Benzyl-4-(4-methoxyphenyl)-3,7,7a,8-tetrahydro-5H-furo-
[3,4-f ]benzimidazol-5-one (8). Enyne 9 (2.54 g, 6.84 mmol) was
dissolved in toluene (200 mL) and purged with N2 for 15 min. The
solution was then heated at 130 °C in a sealed tube for 48 h. The
solvent was removed, and the resulting solids were washed with diethyl
ether to afford 8 as an off-white solid (2.14 g, 84%). Mp: 199−201 °C;
1H NMR: δ = 7.44 (s, 1H), 7.24−7.10 (m, 5H), 6.85 (dd, J = 5.7, 1.8
Hz, 2H), 6.64 (dd, J = 5.1, 1.5 Hz, 2H), 4.68 (dd, J = 16.5, 7.5 Hz,
2H), 4.43 (d, J = 15.6 Hz, 1H), 4.01 (t, J = 8.7 Hz, 1H), 3.83 (s, 3H),
3.67−3.58 (m, 1H), 3.06 (dd, J = 15.0, 8.7 Hz, 1H), 2.73 (dd, J = 17.1,
15.9 Hz, 1H); 13C NMR: δ = 168.1, 160.3, 144.4, 141.2, 139.4, 135.8,
128.7, 128.4, 128.1, 126.6, 123.9, 117.2, 70.6, 55.4, 50.3, 38.1, 28.0; IR
(KBr, cm−1): 3465, 2946, 1737, 1621, 1512, 1252; HR-ESIMS (m/z):
calcd for [M + H]+ C23H21N2O3 373.1547, found 373.1571.
activating the oxidation (Scheme 5). To test the feasibility of
such an approach given that the N3-position is relatively
hindered, lactone 18 was used as a model and converted to the
corresponding dimethyl imidazolium salt 38. Gratifyingly,
treatment of the salt with bleach resulted in C2-oxidation to
deliver imidazolone 39 in good yield suggesting that late stage
functionalization through application of our chemistry was
achievable. Frustratingly however, extension of this chemistry
with removable substituents on N3 was unsuccessful.
Specifically, attempted introduction of a MOM group was
unsuccessful, whereas the attempted incorporation of a SEM
group35 resulted in the net protonation of the imidazole and
production of the imidazolium salt 41.46 The significant
1
downfield shift of the C2-proton absorbance in the H NMR
spectrum of the product is characteristic of the formation of an
imidazolium species. This was further confirmed when an X-ray
crystal structure of this product was obtained, which clearly
indicates the protonation of the nitrogen along with chloride as
the counterion (see Supporting Information). Our assumption
here is that the proximity of the aryl group to the nitrogen atom
renders it sterically hindered and only small electrophiles can
access it. Attempts to oxidize the protonated imidazolium salt
41 with bleach to the corresponding imidazolone 42 were not
successful. Presumably, the basic nature of the reaction
conditions simply results in deprotonation and inactivation of
the imidazole.
CONCLUSION
■
Efficient routes have been developed to the heterocyclic
framework of kealiiquinone through application of an intra-
molecular Diels−Alder reaction of an enyne, C2-functionaliza-
tion through a novel oxidation of imidazolium salts, and
application of an underutilized method for the formation of
dihydroxy quinones from phthaldehydes. Indeed, this work
constitutes the first application of Venuti’s method for the de
novo construction of a 2,3-dimethoxyquinone. Unfortunately
deprotection of an N-benzyl moiety from the penultimate
intermediate resulted in concomitant demethylation delivering
7′-desmethylkealiiquinone rather than the natural product.
Similar chemistry has been used to obtain related materials
lacking the 4′-methoxy group and the 2-oxo group which will
enable the SAR investigations of this unique family of natural
products.
3-Benzyl-4-phenyl-3,7-dihydro-5H-furo[3,4-f ]benzimidazol-
5-one (15). To 1411 (5.5 g, 16 mmol) in CH2Cl2 (250 mL) was
added MnO2 (∼85% act.) (15 g) followed by heating at 40 °C for 48
h. The solids were filtered through Celite and washed with CH2Cl2.
The filtrate was reduced to give the product as a white solid (5.0 g,
1
91%). Mp: 185−186 °C; H NMR: δ = 8.02 (s, 1H), 7.85 (s, 1H),
7.42 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 7.5 Hz,
1H), 7.18−7.13 (m, 4H), 6.54 (d, J = 7.5 Hz, 2H), 5.37 (s, 2H), 4.93
(s, 2H); 13C NMR: δ = 169.8, 148.9, 140.5, 135.7, 132.3, 129.8, 128.8,
128.6, 128.1, 127.9, 127.6, 126.2, 118.4, 112.6, 68.1, 50.3; IR (cm−1):
3005, 2923, 1752, 1497, 1363, 1251, 1130, 1018; HR-ESIMS (m/z):
calcd for [M + Na]+ C22H16N2O2Na 363.1104, found 363.1114.
3-Benzyl-4-(4-methoxyphenyl)-3,7-dihydro-5H-furo[3,4-f ]-
benzimidazole-5-one (16). 8 (7.0 g, 19 mmol) was dissolved in
CH2Cl2 (500 mL), and MnO2 (18.0 g, 188 mmol) was added. Then
the mixture was stirred at rt for 24 h. The solids were filtered and
washed with CH2Cl2 followed by MeOH. The filtrate was
concentrated to give 16 as an off-white solid (6.24 g, 89%). Mp:
176−178 °C; 1H NMR: δ = 8.01 (s, 1H), 7.82 (s, 1H), 7.21−7.16 (m,
3H), 7.06 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 7.5
Hz, 2H), 5.35 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H); 13C NMR: δ =
170.0, 159.8, 149.4, 148.9, 140.5, 135.8, 132.7, 131.0, 128.7, 128.0,
127.6, 126.2, 124.2, 118.5, 113.3, 112.4, 68.0, 55.3, 50.3; IR (KBr,
cm−1): 2947, 1739, 1614, 1500, 1347, 1253; HR-ESIMS (m/z): calcd
for [M + Na]+ C23H18N2O3Na 393.1210, found 393.1210.
EXPERIMENTAL SECTION
■
Chemicals were used as received unless indicated otherwise. NMR
spectra were obtained at either 500 or 300 MHz (for 1H NMR
spectra) or 125 or 75 MHz (for 13C NMR) in CDCl3 unless indicated
1
otherwise. H NMR spectra were referenced to residual protiosolvent
unless indicated otherwise (CHCl3 δ = 7.26 ppm). For spectra
recorded in other solvents, residual MeOH (δ = 3.31 ppm) or DMSO
(δ = 2.50 ppm) were used as internal references. 13C NMR spectra
were recorded in CDCl3 (unless otherwise indicated) using residual
CHCl3 (δ = 77.2 ppm) as an internal reference. For spectra recorded
in other solvents, residual MeOH (δ = 39.5 ppm) and DMSO (δ =
49.0 ppm) were used as internal references. Infrared (IR) spectra were
obtained on neat samples (ATR spectroscopy) or using either KBr
pellets for solids or neat films on NaCl plates for liquids
(transmission). Analytical thin-layer chromatography (TLC) was
performed on silica gel plates, 200 mesh with F254 indicator.
Visualization was accomplished by UV light (254 nm) and/or a 10%
ethanol solution of KMnO4. Flash column chromatography was
performed with 230−400 silica. High resolution mass spectra (HRMS)
3-Benzyl-4-(4-methoxyphenyl)-1-methyl-5-oxo-5,7-dihydro-
3H-furo[3,4-f ]benzimidazol-1-ium Iodide (17). 16 (0.37 g, 1.0
mmol) was dissolved in toluene (20 mL), and MeI (0.20 mL, 3.2
mmol) was added. The mixture was heated at 120 °C for 24 h during
which additional aliquots of methyl iodide (0.5 equiv) were added
until no starting material could be detected by TLC. The solids were
filtered and washed with EtOAc to afford 17 as a pale yellow solid
(0.48 g, 93%). Mp: 198−200 °C; 1H NMR: δ = 10.50 (s, 1H), 8.03 (s,
1H), 7.25−7.12 (m, 5H), 6.94−6.87 (m, 4H), 5.43 (s, 2H), 5.27 (s,
2H), 4.32 (s, 3H), 3.86 (s, 3H); 13C NMR: δ = 167.7, 160.8, 146.4,
144.8, 136.8, 132.2, 131.4, 131.1, 130.1, 129.2, 127.7, 122.8, 121.0,
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113.9, 106.7, 68.0, 55.5, 53.2, 35.4; IR (cm−1): 2939, 1775, 1612, 1575,
1501, 1451, 1378, 1337; HR-ESIMS (m/z): calcd for [M + H]+
C24H21N2O3 385.1547, found 385.1548.
148.8, 146.8, 141.9, 139.4, 137.1, 135.8, 131.1, 129.9, 127.5, 121.5,
113.4, 109.6, 55.6, 31.9; IR (cm−1): 2981, 1642, 1627, 1608, 1337,
1243, 1211, 1021; HR-ESIMS (negative mode) (m/z): calcd for [M−
H]− C19H13N2O5 349.0830, found 349.0832.
4-(4-Methoxyphenyl)-1-methyl-1,7-dihydrofuro[3,4-f ]-
benzimidazol-5-one (18). To imidazolium salt 17 (0.44 g, 0.86
mmol) was added EtOH (50 mL) and sat. NaHCO3 (5 mL), followed
by 10% Pd/C (0.10 g). The reaction mixture was heated at 80 °C
under H2 (1 atm) for 24 h. The solids were filtered and washed with
CH2Cl2/MeOH followed by water. The aqueous solution was then
acidified to pH = 5 with 3 M HCl and stirred for 2 h. The resulting
aqueous solution was extracted multiple times with CH2Cl2. The
combined organic extracts were dried (Na2SO4) and concentrated.
The resulting solid was recrystallized from MeOH to afford 18 as a
6,7-Dimethoxy-4-(4-methoxyphenyl)-1-methyl-1H-naphtho-
[2,3-d]imidazole-5,8-dione/2-Deoxykealiiquinone (23). To di-
hydroxyquinone 22 (23 mg, 0.066 mmol) in THF (3 mL) were added
MeOH (1 mL) and TMSCHN2 (2.0 M in Et2O) (0.080 mL, 0.16
mmol) with subsequent stirring at rt for 1 h. The reaction mixture was
diluted with CH2Cl2 and washed with sat. NaHCO3, dried (anhyd.
Na2SO4), and concentrated. The resulting residue was purified by
column chromatography (2:8 acetone/hexane to 1:1 acetone/hexane)
1
to give 23 as an orange residue (16 mg, 64%). H NMR: δ = 8.24 (s,
1
white solid (0.19 g, 76%). Mp: >250 °C; H NMR (DMSO-d6): δ =
1H), 8.00 (s, 1H), 7.28 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H),
4.10 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.86 (s, 3H); 13C NMR: δ =
182.3, 182.0, 159.1, 148.9, 147.4, 146.5, 136.8, 130.6, 130.2, 128.8,
128.3, 122.8, 114.5, 113.8, 108.8, 61.4, 61.3, 55.3, 31.7; IR (cm−1):
2924, 2852, 1658, 1618, 1515, 1456, 1341, 1307, 1245, 1215, 1054;
HR-APCIMS (m/z): calcd for [M + H]+ C21H18N2O5 379.1288,
found 379.1296.
8.32 (s, 1H), 7.69 (s, 1H), 7.55 (d, J = 9.2 Hz, 2H), 6.98 (d, J = 9.2
Hz, 2H), 5.39 (s, 2H), 3.89 (s, 3H), 3.80 (s, 3H); 13C NMR (DMSO-
d6): δ = 170.5, 159.7, 147.9, 143.1, 142.6, 139.8, 133.4, 133.2, 125.4,
114.6, 113.2, 102.9, 68.4, 55.7, 31.6; IR (KBr, cm−1): 3044, 2957,
2835, 1739, 1603, 1501, 1453; HR-ESIMS (m/z): calcd for [M + H]+
C17H15N2O3 295.1077, found 295.1092.
[4-(4-Methoxyphenyl)-1-methyl-1H-benzimidazole-5,6-diyl]-
dimethanol (19). Benzimidazole 18 (0.19 g, 0.65 mmol) was
dissolved in CH2Cl2 (5 mL) and cooled to −78 °C under N2. DIBAL-
H (1 M in Hexane) (1.5 mL, 1.5 mmol) was added dropwise, and the
reaction mixture was allowed to warm to rt and stirred for 3 h. The
reaction mixture was cooled to 0 °C, and water was added slowly
followed by MeOH. The solids were filtered and washed with CH2Cl2
and MeOH. The organic extract was separated, and the residual
aqueous solution was extracted multiple times with CH2Cl2. The
combined organic extracts were dried (anhyd. Na2SO4) and
concentrated. The resulting white solid was triturated with Et2O to
3-Benzyl-4-(4-methoxyphenyl)-1-methyl-3,7-dihydro-1H-
furo[3,4-f]benzimidazole-2,5-dione (24). Imidazolium salt 17 (1.0
g, 1.9 mmol) in THF (40 mL) was cooled to 0 °C, and 5% NaOCl (30
mL) was added dropwise. The reaction was allowed to come to rt and
stirred for 30 min. The reaction was diluted with EtOAc, and the
aqueous layer was extracted with EtOAc (2×). The combined organic
extracts were washed with H2O and then brine, dried (anhyd.
Na2SO4), and concentrated. The resulting residue was purified by
column chromatography (7:3 EtOAc/Hexane) to give 24 as an off-
white solid (0.58 g, 75%). Mp: 185−187 °C; 1H NMR: δ = 7.12−7.09
(m, 3H), 7.03 (s, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.9 Hz,
2H), 6.58−6.56 (m, 2H), 5.23 (s, 2H), 4.79 (s, 2H), 3.83 (s, 3H), 3.57
(s, 3H); 13C NMR: δ = 169.8, 159.7, 155.6, 141.8, 136.4, 136.2, 131.3,
128.2, 127.8, 127.2, 126.0, 124.0, 123.6, 117.1, 113.1, 99.5, 67.7, 55.3,
45.8, 27.8; IR (cm−1): 1748, 1705, 1609, 1517, 1496, 1352, 1244,
1028; HR-ESIMS (m/z): calcd for [M + Na]+ C24H20N2O4Na
423.1315, found 423.1316.
1
afford 19 as a white solid (0.15 g, 79%). Mp: 245−247 °C; H NMR
(DMSO-d6): δ = 8.02 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H),
6.98 (d, J = 8.6 Hz, 2H), 5.25 (t, J = 5.5 Hz, 1H), 4.83 (d, J = 5.2 Hz,
2H), 4.79 (t, J = 4.8 Hz, 1H), 4.43 (d, J = 4.5 Hz, 2H), 3.81 (s, 3H),
3.79 (s, 3H); 13C NMR (DMSO-d6): δ = 158.8, 144.7, 141.6, 137.6,
134.2, 133.3, 132.5, 129.9, 129.8, 113.5, 108.4, 62.4, 58.5, 55.6, 31.2; IR
(cm−1): 3074, 2889, 1608, 1574, 1340, 1237, 1174, 1015; HR-ESIMS
(m/z): calcd for [M + H]+ C17H19N2O3 299.1390, found 299.1411.
4-(4-Methoxyphenyl)-1-methyl-1H-benzimidazole-5,6-
dicarbaldehyde (7). Diol 19 (0.10 g, 0.34 mmol) was dissolved in
CH2Cl2, and DBU (0.2 mL, 1.34 mmol) was added. The solution was
cooled to −78 °C under N2, and N-tert-butylbenzenesulfinimidoyl
chloride (20) (0.22 g, 1.02 mmol) dissolved in CH2Cl2 (5 mL) was
added dropwise. The mixture was stirred at −78 °C for 30 min. The
reaction mixture was quenched with sat. NaHCO3, and the organic
layer was separated. The remaining aqueous solution was extracted
with CH2Cl2 (2×). The combined organic extracts were dried (anhyd.
Na2SO4) and concentrated. The resulting residue was purified by
column chromatography (the silica gel was neutralized with 5% Et3N
prior to purification) (EtOAc to 2% MeOH in EtOAc) to afford 7 as
[3-Benzyl-4-(4-methoxyphenyl)-1-methyl-1H-benzim-
idazole-5,6-diyl]dimethanol-2-one (25). Imidazolone 24 (1.4 g,
3.5 mmol) was dissolved in CH2Cl2 (25 mL) and cooled to −78 °C
under N2. DIBAL-H (1 M in hexanes) (9.8 mL, 9.8 mmol) was added
dropwise, then allowed to come to rt, and stirred for 4 h. The reaction
mixture was cooled to 0 °C, and water was added slowly followed by
MeOH. The solids were filtered through Celite and washed with
CH2Cl2. Water was added to the filtrate, and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (2×). The
combined organic extracts were dried (anhyd. Na2SO4) and
concentrated. The resulting solids were washed with hexane and
then Et2O to give 25 as an off-white solid (1.17 g, 83%). Mp: 205−206
1
°C; H NMR: δ = 7.11−7.09 (m, 3H), 7.03 (s, 1H), 6.87 (d, J = 8.6
Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.59−6.57 (m, 2H), 4.81 (s, 2H),
4.64 (s, 2H), 4.38 (s, 2H), 3.82 (s, 3H), 3.46 (s, 3H); 13C NMR: δ =
159.4, 155.5, 137.1, 134.0, 132.5, 131.5, 130.1, 128.1, 127.2, 126.9,
125.8, 125.6, 113.4, 108.5, 65.1, 59.5, 55.4, 45.4, 27.4; IR (cm−1):
3313, 2930, 1669, 1611, 1515, 1398, 1244, 1181; HR-APCIMS (m/z):
calcd for [M + H]+ C24H25N2O4 405.1809, found 405.1826.
1
an off-white solid (0.069 g, 70%). H NMR: δ = 10.61 (s, 1H), 10.16
(s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.49 (d, 2H, J = 8.4 Hz), 7.08 (d,
2H, J = 8.4 Hz), 3.97 (s, 3H), 3.89 (s, 3H); 13C NMR: δ = 193.5,
192.9, 160.2, 147.7, 145.3, 139.8, 136.7, 133.1, 132.7, 129.5, 125.1,
114.1, 109.7, 55.5, 31.7; IR (KBr, cm−1): 3105, 2928, 2881, 1777,
1751, 1682, 1663, 1566; HR-ESIMS (m/z): calcd for [M + H]+
C17H15N2O3 295.1077, found 295.1110.
6,7-Dihydroxy-4-(4-methoxyphenyl)-1-methyl-1H-naphtho-
[2,3-d]imidazole-5,8-dione (22). To phthaldehyde 7 (74 mg, 0.27
mmol) in EtOH (1.5 mL) was added 21 (50 mg, 0.81 mmol) followed
by the simultaneous addition of KCN (0.021 g, 0.33 mmol) in H2O
(0.5 mL) and Et3N (0.040 mL, 0.27 mmol). The reaction was stirred
at rt for 15 min and then quenched with 10% HCl until a pH = 5 was
attained. The aqueous layer was extracted with CH2Cl2 (3×) and
discarded. The aqueous layer was reduced, and the resulting solids
were filtered and washed with acetone to give 22 as a red-orange solid
(35 mg, 39%). 1H NMR (DMSO-d6): δ = 9.73 (brs, 2H), 8.34 (s, 1H),
8.18 (s, 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 3.93
(s, 3H), 3.78 (s, 3H); 13C NMR (DMSO-d6): δ = 181.8, 181.3, 158.9,
3-Benzyl-4-(4-methoxyphenyl)-1-methyl-1H-benzimidazole-
5,6-dicarbaldehyde-2-one (26). Diol 25 (0.22 g, 0.54 mmol) was
dissolved in CH2Cl2 (10 mL) and cooled to −78 °C under N2. DBU
(0.32 mL, 2.2 mmol) was added followed by 20 (0.38 g, 1.7 mmol) in
CH2Cl2 (1 mL), and the reaction was stirred at −78 °C for 30 min.
Sat. NaHCO3 was added, and the solution was allowed to come to rt.
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2×). The combined organic extracts were dried (anhyd.
Na2SO4) and concentrated. The resulting residue was purified by
column chromatography (the silica gel was neutralized with Et3N prior
to purification) (4:6 EtOAc/hexane) to give 26 as an off-white solid
(0.17 g, 77%). Mp: 152−155 °C ; 1H NMR: δ = 10.40 (s, 1H), 9.67 (s,
1H), 7.68 (s, 1H), 7.14−7.08 (m, 3H), 6.92 (d, J = 8.6 Hz, 2H), 6.74
(d, J = 8.6 Hz, 2H), 6.54 (d, J = 6.8 Hz, 2H), 4.74 (s, 2H), 3.84 (s,
2487
dx.doi.org/10.1021/jo4027337 | J. Org. Chem. 2014, 79, 2481−2490

The Journal of Organic Chemistry
Article
1
3H), 3.59 (s, 3H); 13C NMR: δ = 192.6, 192.0, 160.1, 155.6, 136.1,
133.7, 132.2, 131.9, 131.8, 130.2, 128.3, 128.0, 127.3, 125.6, 123.6,
113.7, 106.5, 55.5, 45.8, 27.9; IR (cm−1): 2934, 1701, 1675, 1606,
1513, 1357, 1243, 1076; HR-ESIMS (m/z): calcd for [M + Na]+
C24H20N2O4Na 423.1315, found 423.1309.
g, 63%). Mp: 191−193 °C; H NMR: δ = 7.81 (s, 1H), 7.79 (s, 1H),
7.35 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 7.18−7.12 (m, 3H),
7.08 (d, J = 6.9 Hz, 2H), 6.50 (d, J = 6.9 Hz, 2H), 4.91 (s, 2H), 4.74
(s, 2H), 4.49 (s, 2H); 13C NMR: δ = 146.0, 143.4, 136.5, 135.9, 135.1,
134.1, 131.5, 130.4, 128.6, 128.1, 128.0, 127.7, 127.7, 126.0, 121.2,
65.4, 59.6, 49.6; IR (cm−1): 3056, 2856, 1504, 1441, 1311, 1175, 1018,
1000; HR-ESIMS (m/z): calcd for [M + H]+ C22H21N2O2 345.1598,
found 345.1604.
3-Benzyl-6,7-dihydroxy-4-(4-methoxyphenyl)-1-methyl-1H-
naphtho[2,3-d]imidazole-2,5,8-trione (27). To phthaldehyde 26
(0.10 g, 0.25 mmol) in THF (3 mL) was added 21 (42 mg, 0.75
mmol) followed by the addition of KCN (0.029 g, 0.44 mmol) and
K2CO3 (0.17 g, 1.3 mmol) in H2O (1 mL). The reaction was stirred at
rt for 5 min, then quenched with 6 M HCl, and diluted with H2O (5
mL). The aqueous layer was extracted with EtOAc (2×). The
combined organic extracts were washed with H2O and then brine,
dried (anhyd. Na2SO4), and concentrated. An orange-red residue was
recovered, and cold MeOH was added. The resulting solids were
filtered to give the dihydroxyquinone 27 as an orange solid (22 mg,
20%). Mp: 204−206 °C; 1H NMR (DMSO-d6): δ = 9.65 (s, 1H), 9.60
(s,1H), 7.80 (s, 1H), 7.13−7.11 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H),
6.63 (d, J = 8.6 Hz, 2H), 6.56−6.54 (m, 2H), 4.44 (s, 2H), 3.71 (s,
3H), 3.50 (s, 3H); 13C NMR (DMSO-d6): δ = 181.6, 181.1, 159.1,
155.1, 141.0, 138.4, 137.3, 134.0, 131.2, 130.5, 128.5, 127.7, 127.3,
127.0, 125.7, 125.0, 122.6, 113.5, 106.0, 55.6, 45.5, 28.1; IR (cm−1):
3240, 1697, 1654, 1597, 1514, 1400, 1283, 1243. HRMS-ESI (negative
mode) (m/z): Calcd for C26H19N2O6 [M − H]− 455.1249, found
455.1243.
3-Benzyl-6,7-dimethoxy-4-(4-methoxyphenyl)-1-methyl-1H-
naphtho[2,3-d]imidazole-2,5,8-trione (28). The dihydroxyqui-
none 27 prepared above (22 mg, 0.048 mmol) was dissolved in
THF (3 mL), and MeOH (0.5 mL) was added followed by
TMSCHN2 (2.0 M in Et2O) (0.07 mL, 0.15 mmol) with subsequent
stirring at rt for 30 min. The reaction was diluted with EtOAc and
washed with 2 M Na2CO3 (2×) and then brine. The organic extracts
were dried (anhyd. Na2SO4) and concentrated. The resulting residue
was purified by column chromatography (1:1 EtOAc/Hexane) to give
28 as an orange solid (15 mg, 65%). Mp: 176−178 °C; 1H NMR: δ =
7.82 (s, 1H), 7.13−7.11 (m, 3H), 6.79 (d, J = 8.9 Hz, 2H), 6.89 (d, J =
8.9 Hz, 2H), 6.58−6.56 (m, 2H), 4.60 (s, 2H), 4.03 (s, 3H), 3.92 (s,
3H), 3.81 (s, 3H), 3.60 (s, 3H); 13C NMR: δ = 182.0, 181.5, 159.2,
155.4, 148.1, 145.2, 136.6, 134.0, 130.1, 128.2, 127.1, 127.0, 125.5,
124.0, 113.5, 105.4, 61.4, 61.3, 55.3, 45.8, 27.9; IR (cm−1): 2950, 1716,
1651, 1619, 1601, 1455, 1241, 1211; HR-ESIMS (m/z): calcd for [M
+ Na]+ C28H24N2O6Na 507.1527, found 507.1533.
4-(4-Hydroxyphenyl)-6,7-dimethoxy-1-methyl-1H-naphtho-
[2,3-d]imidazole-2,5,8-trione/7′-Desmethylkealiiquinone (29).
To 28 (30 mg, 0.062 mmol) was added TfOH (2.5 mL), and the
mixture was heated at 55 °C in a vial for 4 h. The reaction was allowed
to cool to rt and poured into EtOAc. Water was added, and the
solution was neutralized with sat. NaHCO3. The aqueous layer was
extracted with EtOAc (2×). The combined organic extracts were
washed with brine, dried (anhyd. Na2SO4). and concentrated. The
resulting residue was purified by column chromatography (8:2 EtOAc/
Hexane) to give 29 as an orange solid (10 mg, 56%). Mp: >290 °C; 1H
NMR (DMSO-d6): δ = 10.95 (s, 1H), 9.41 (s, 1H), 7.63 (s, 1H), 6.96
(d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H), 3.82 (s,
3H), 3.35 (s, 3H); 13C NMR (DMSO-d6): δ = 181.9, 181.7, 157.2,
155.3, 148.4, 145.6, 134.4, 133.1, 130.3, 127.0, 126.4, 124.5, 123.2,
115.8, 104.9, 61.2 (2C), 27.3; IR (cm−1) = 3200, 2921, 2851, 1702,
1656, 1609, 1515, 1105, 1059, 1033; HR-ESIMS (m/z): calcd for [M
+ Na]+ C20H16N2O6Na 403.0901, found 403.0911.
[3-Benzyl-4-phenyl-1H-benzimidazole-5,6-diyl]dimethanol
(30). Benzimidazole 15 (5.0 g, 15 mmol) was dissolved in CH2Cl2
(100 mL) and cooled to −78 °C under N2. DIBAL-H (1 M in
hexanes) (41 mL, 41 mmol) was added dropwise, and the mixture was
allowed to come to rt and stirred overnight. The reaction mixture was
then cooled to 0 °C, and water was added slowly followed by MeOH.
The solids were filtered through Celite and washed with CH2Cl2.
Water was added to the filtrate, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (2×). The combined
organic extracts were dried (anhyd. Na2SO4) and concentrated. The
resulting solids were washed with Et2O to give 30 as a white solid (3.2
3-Benzyl-4-phenyl-1H-benzimidazole-5,6-dicarbaldehyde
(31). Diol 30 (3.0 g, 8.7 mmol) was dissolved in CH2Cl2 (75 mL) and
cooled to −78 °C under N2. DBU (4.8 mL, 35 mmol) was added
followed by 20 (4.7 g, 22 mmol) in CH2Cl2 (3 mL), and the reaction
was stirred at −78 °C for 30 min. Sat. NaHCO3 was added, and the
solution was allowed to come to rt. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2×). The combined
organic extracts were dried (anhyd. Na2SO4) and concentrated. The
resulting residue was purified by column chromatography (the silica
gel was neutralized with Et3N prior to purification) (6:4 EtOAc/
Hexane) to give 31 as a white solid (2.0 g, 68%). Mp: 167−169 °C; 1H
NMR: δ = 10.49 (s, 1H), 9.88 (s, 1H), 8.43 (s,1H), 8.06 (s, 1H), 7.44
(t, J = 7.5 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H),
7.21−7.14 (m, 4H), 6.51 (d, J = 7.5 Hz, 2H), 4.86 (s, 2H); 13C NMR:
δ = 192.8, 192.4, 149.7, 146.8, 135.4, 134.0, 132.9, 132.4, 132.0, 131.4,
130.5, 129.2, 128.9, 128.4, 128.2, 125.9, 121.8, 50.2; IR (cm−1): 3070,
2871, 1756, 1678, 1595, 1488, 1455, 1303, 1213; HR-ESIMS (m/z):
calcd for [M + Na]+ C22H16N2O2Na 363.1104, found 363.1108.
3-Benzyl-6,7-dihydroxy-4-phenyl-1H-naphtho[2,3-d]imid-
azole-5,8-dione (32). To phthaldehyde 31 (150 mg, 0.44 mmol) in
THF was added 21 (0.037 g, 0.66 mmol) followed by the
simultaneous addition of KCN (29 mg, 0.44 mmol) in H2O (1 mL)
and Et3N (0.06 mL, 0.44 mmol). The reaction was stirred at rt for 15
min and then quenched with H2O (5 mL). 1 M HCl was added until
pH = 5 was reached, and the aqueous layer was extracted with EtOAc
(2×). The combined organic extracts were dried (anhyd. Na2SO4) and
concentrated. An orange-red residue was recovered and recrystallized
from MeOH to give 32 as an orange-red solid (74 mg, 43%). Mp: 280
1
°C (decomp.); H NMR (DMSO-d6): δ = 9.71 (brs, 2H), 8.46 (s,
1H), 8.30 (s, 1H), 7.32−7.29 (m, 1H), 7.19−7.16 (m, 5H), 7.01−7.00
(m, 2H), 6.45 (d, J = 4.6 Hz, 2H), 4.75 (s, 2H); 13C NMR (DMSO-
d6): δ = 181.6, 181.1, 151.2, 146.6, 141.8, 139.6, 137.6, 136.5, 135.5,
129.3, 129.1, 128.8, 128.2, 127.8, 127.8, 127.1, 125.9, 122.9, 118.7,
49.3; IR (cm−1): 2831, 1662, 1615, 1595, 1569, 1343, 1315, 1206,
1189, 905; HR-APCIMS (m/z): calcd for [M + H]+ C24H17N2O4
397.1183, found 397.1196.
3-Benzyl-6,7-dimethoxy-4-phenyl-1H-naphtho[2,3-d]-
imidazole-5,8-dione (33). Dihydroxyquinone 32 (84 mg, 0.21
mmol) was suspended in THF (5 mL), and MeOH (2.0 mL) was
added followed by TMSCHN2 (2.0 M in Et2O) (0.37 mL, 0.74 mmol)
with subsequent stirring at rt for 4 h. The reaction was diluted with
EtOAc and washed with sat. NaHCO3 (2×), dried (anhyd. Na2SO4),
and concentrated. The resulting residue was purified by column
chromatography (1:1 EtOAc/Hexane) to give 33 as a yellow solid (45
mg, 54%). Mp: 189−191 °C; 1H NMR: δ = 8.65 (s, 1H), 7.92 (s, 1H),
7.37 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.23−7.18 (m, 3H),
7.04 (d, J = 7.5 Hz, 2H), 6.57 (d, J = 8.0 Hz, 2H), 4.65 (s, 2H), 4.07
(s, 3H), 3.94 (s, 3H); 13C NMR: δ = 182.1, 181.9, 149.5, 148.7, 147.0,
146.4, 136.1, 135.9, 135.8, 129.2, 128.8, 128.5, 128.3, 128.1, 127.9,
127.8, 126.1, 124.0, 120.2, 61.4, 61.3, 50.0; IR (cm−1): 3009, 2940,
1649, 1596, 1441, 1348, 1291, 1027; HR-ESIMS (m/z): calcd for [M
+ H]+ C26H21N2O4 425.1496, found 425.1490.
3-Benzyl-6,7-dimethoxy-1-methyl-4-phenyl-1H-naphtho-
[2,3-d]imidazolium-5,8-dione Iodide (34). To quinone 33 (45 mg,
0.11 mmol) in CH3CN (8 mL) was added MeI (0.20 mL) followed by
heating at 70 °C for 15 h. The reaction mixture was concentrated, and
the resulting residue was triturated with Et2O to give 34 as a red-
orange solid (52 mg, 86%). Mp: 184−188 °C; 1H NMR: δ = 10.33 (s,
1H), 8.49 (s, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H),
7.29−7.27 (m, 3H), 7.18 (d, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H),
4.93 (s, 2H), 4.26 (s,3H), 4.10 (s, 3H), 3.98 (s, 3H); 13C NMR: δ =
180.2, 180.0, 149.3, 147.7, 146.4, 134.9, 132.9, 132.9, 132.3, 132.2,
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131.1, 129.4, 129.3, 128.9, 128.6, 128.0, 127.0, 111.8, 61.6 (2C), 53.0,
34.9; IR (cm−1): 3031, 2945, 1718, 1660, 1609, 1452, 1314, 1209,
1052, 916; HR-ESIMS (m/z): calcd for [M]+ C27H23N2O4 439.1652,
found 439.1634.
extracts were dried (anhyd. Na2SO4) and concentrated. The resulting
solids were purified by PTLC (EtOAc) to give 39 as a white solid (6
mg, 73%). Mp: 239−240 °C; 1H NMR: δ = 7.26 (d, J = 8.6 Hz, 2H),
6.98 (d, J = 8.6 Hz, 2H), 6.98 (s, 1H), 5.25 (s, 2H), 3.87 (s, 3H), 3.49
(s, 3H), 2.92 (s, 3H); 13C NMR: δ = 170.0, 159.9, 155.4, 141.5, 135.8,
131.3, 128.9, 124.1, 123.4, 116.8, 113.3, 99.3, 67.9, 55.3, 30.3, 27.7; IR
(cm−1): 2930, 2838, 1761, 1700, 1609, 1520, 1482, 1357, 1287, 1248,
1196, 1179, 1139, 1078; HR-APCIMS (m/z): calcd for [M + H]+
C18H17N2O4 325.1183, found 325.1191.
4-(4-Methoxyphenyl)-1-methyl-5-oxo-5,7-dihydro-1H-furo-
[3,4f][3,1]benzimidazol-3-ium Chloride (41). To 18 (72 mg, 0.24
mmol) in acetonitrile (10 mL) was added SEMCl (50 mg, 0.30 mmol)
followed by stirring at 60 °C for 1 h. The reaction mixture was cooled
to 0 °C, and the precipitated solids were filtered and washed with Et2O
to give 41 as a white solid (51 mg, 63%). Mp: 255−258 °C; 1H NMR
(CD3OD): δ = 9.56 (d, J = 4.6 Hz, 1H), 8.06 (s, 1H), 7.51 (d, J = 8.6
Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 5.52 (s, 2H), 4.19 (s, 3H), 3.89 (s,
3H); 13C NMR (CD3OD): δ = 169.3, 161.1, 145.7, 145.1, 136.4,
131.3, 130.5, 122.0, 119.9, 113.8, 105.2, 68.5, 54.6, 32.7; IR (cm−1):
3155, 2942, 1728, 1623, 1506, 1392, 1243, 1142, 1110, 1012; HR-
ESIMS (m/z): calcd for [M + Na]+ C17H14N2O3Na 317.0897, found
317.0903.
3-Benzyl-6,7-dimethoxy-1-methyl-4-phenyl-1H-naphtho-
[2,3-d]imidazole-2,5,8-trione (35). To imidazolium salt 34 (31 mg,
0.055 mmol) in THF (1 mL) was added 1 M K2CO3 (0.27 mL) and
NCS (8 mg, 0.06 mmol), followed by stirring at rt for 30 min. The
reaction was diluted with water (4 mL) and extracted with EtOAc (2 ×
5 mL). The combined organic extracts were washed with brine, dried,
and concentrated. The resulting residue was purified by column
chromatography (1:1 EtOAc/Hexane) to give 35 as a yellow solid (15
mg, 60%). Mp: 160−162 °C; 1H NMR: δ = 7.84 (s, 1H), 7.33 (t, J =
7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 2H), 7.13−7.09 (m, 3H), 6.89 (d, J =
6.9 Hz, 2H), 6.53 (d, J = 6.3 Hz, 2H), 4.52 (s, 2H), 4.03 (s, 3H), 3.91
(s, 3H), 3.60 (s, 3H); 13C NMR: δ = 181.9, 181.4, 155.4, 148.1, 145.3,
136.5, 135.2, 134.0, 131.4, 129.0, 128.2, 128.1, 127.9, 127.5, 127.1,
125.6, 125.5, 123.7, 105.5, 61.4, 61.3, 45.7, 27.9; IR (cm−1): 2927,
1709, 1651, 1620, 1601, 1452, 1344, 1209, 1059; HR-ESIMS (m/z):
calcd for [M + Na]+ C27H22N2O5Na 477.1421, found 477.1438.
6,7-Dimethoxy-1-methyl-4-phenyl-1H-naphtho[2,3-d]-
imidazole-2,5,8-trione/4′-Desmethoxykealiiquinone (36). To
imidazolone 35 (25 mg, 0.055 mmol) was added TfOH (2 mL)
followed by heating at 55 °C for 4 h. The reaction was quenched with
water and neutralized with sat. NaHCO3. The aqueous layer was
extracted with EtOAc (2×), and the combined organic extracts were
washed with brine, dried, and concentrated. The resulting residue was
purified by column chromatography (6:4 EtOAc/Hexane) to give 36
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds are
provided. Additional and enlarged figures of the X-ray crystal
structures of compounds 16, 25, and 41. CIF data are provided
for compound 41. These materials are available free of charge
on the Internet via the Internet at http://pubs.acs.org.
1
as a yellow waxy solid (10 mg, 67%). H NMR: δ = 8.11 (brs, 1H),
7.74 (s, 1H), 7.49−7.43 (m, 3H), 7.22−7.21 (m, 2H), 4.07 (s, 3H),
3.97 (s, 3H), 3.47 (s, 3H); 13C NMR: δ = 181.9, 181.5, 154.2, 147.6,
146.0, 135.3, 134.1, 131.6, 129.1, 128.3, 128.1, 127.8, 124.3, 123.0,
105.5, 61.5, 61.4, 27.4; IR (cm−1): 2919, 1708, 1648, 1623, 1443, 1332,
1245, 1194, 1056, 1026; HR-APCIMS (m/z): calcd for [M + H]+
C20H17N2O5 365.1132, found 365.1144.
3-Benzyl-2-tert-butylcarbonylimino-6,7-dimethoxy-1-meth-
yl-4-phenyl-1H-naphtho[2,3-d]imidazole-2,5,8-trione (37). To
tert-butyl carbamate (19 mg, 0.16 mmol) in CH2Cl2 (2 mL) was added
t-BuOCl (0.02 mL, 0.17 mmol), followed by stirring at rt for 20 min.
The reaction mixture was cooled to 0 °C, and DBU (0.033 mL, 0.22
mmol) was added followed by 34 in CH2Cl2 (3 mL). The reaction was
stirred at rt for 30 min and then diluted with water. The aqueous layer
was extracted with CH2Cl2 (2×), and the combined organic extracts
were washed with brine, dried (anhyd. Na2SO4), and concentrated.
The crude residue was purified by column chromatography (1:1
EtOAc/Hexane) to give 37 as a yellow-orange residue (10 mg, 30%).
1H NMR: δ = 7.98 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz,
AUTHOR INFORMATION
Corresponding Author
*E-mail: lovely@uta.edu.
■
Present Address
†Department of Chemistry and Biochemistry, University of
Massachusetts Dartmouth, 285 Old Westport Road, North
Dartmouth, MA 02747.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by the Robert A. Welch
Foundation (Y-1362), the NIH (GM065503), and instrumen-
tation grants through the NSF (CHE-0234811 and CHE-
0840509). We are grateful to Dr. David Powell and Cristina
Dance (University of Florida) for collection of the HRMS data
reported in this paper.
2H), 7.12−7.07 (m, 3H), 6.84 (d, J = 6.9 Hz, 2H), 6.44 (d, J = 6.9 Hz,
2H), 4.70 (s, 2H), 4.03 (s, 3H), 3.90 (s,3H), 3.68 (s,3H), 1.46 (s,9H);
13C NMR: δ = 181.6, 181.1, 158.3, 153.9, 148.3, 145.5, 135.8, 135.4,
134.6, 132.3, 128.9, 128.2, 128.2, 128.1, 128.0, 127.1, 127.1, 125.4,
124.5, 106.6, 78.9, 61.4, 61.3, 47.3, 31.8, 28.3; IR (cm−1): 2929, 1655,
1581, 1443, 1308, 1207, 1147, 1047, 1026; HR-ESIMS (m/z): calcd
for [M + H]+ C32H32N3O6 is 554.2286, found 554.2290.
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