Triflic acid-mediated rearrangements of 3-methoxy-8-oxabicyclo[3.2.1]octa- 3,6-dien-2-ones: Synthesis of methoxytropolones and furans

Article abstract of DOI:10.1021/jo401617r

Methoxytropolones are useful scaffolds for therapeutic development because of their known biological activity and established value in the synthesis of α-hydroxytropolones. Upon treatment with triflic acid, a series of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones rearrange rapidly and cleanly to form methoxytropolones. Interestingly, bicycles that are derived from dimethyl acetylenedicarboxylate (R² = R³ = CO ₂Me) instead form furans as the major product.

Full text of DOI:10.1021/jo401617r

Article
pubs.acs.org/joc
Triflic Acid-Mediated Rearrangements of 3‑Methoxy-8-
oxabicyclo[3.2.1]octa-3,6-dien-2-ones: Synthesis of
Methoxytropolones and Furans
Yvonne D. Williams,†,‡ Christine Meck,†,‡ Noushad Mohd,† and Ryan P. Murelli*,†,‡
†Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, New York, 11210,
United States
‡Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, New York 10016,
United States
S
* Supporting Information
ABSTRACT: Methoxytropolones are useful scaffolds for
therapeutic development because of their known biological
activity and established value in the synthesis of α-
hydroxytropolones. Upon treatment with triflic acid, a series
of 3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones rear-
range rapidly and cleanly to form methoxytropolones.
Interestingly, bicycles that are derived from dimethyl
acetylenedicarboxylate (R2 = R3 = CO2Me) instead form furans as the major product.
bound to the binuclear active site of RNase H reveal an ordered
three oxygen, two metal binding pattern that likely provides this
potency.8 Similar binding is thought to be responsible for α-
hydroxytropolone inhibition of other binuclear metalloenzymes
such as inositol monophosphatase, alkaline phosphatase,9 and
phospholipase C,10 and it is possible that this binding mode
may lead to the pharmacophore having privilege for many other
similar metalloenzymes.
INTRODUCTION
MY3-469 (Figure 1) is a methoxytropolone inhibitor of
platelet-type 12-lipoxygenase, an enzyme that has been
■
Despite the potential of hydroxytropolones and methoxy-
tropolones as therapeutic leads, very few synthetic-chemistry-
driven structure−function studies have been conducted on
them,11 perhaps because of the scarcity of synthetic methods
available to access them.12 Early strategies to access this class of
molecules focused on tropone oxidation (Scheme 1A), which
can be an efficient method for generating the parent α-
hydroxytropolone but can make introduction of functionality
with control challenging.13 This has led to efforts to generate
the α-hydroxytropolones through other, more controlled,
strategies. One method that could be particularly useful in
structure−function studies is a cyclopropanation/ring-opening
strategy used extensively by the Banwell group for tropone and
tropolone synthesis.14 In one representive example of this work,
the group leveraged a bromine handle to perform cross-
coupling chemistry to synthesize different α-hydroxytropolones
Figure 1. Methoxytropolones and hydroxytropolones and examples of
their bioactivity.
implicated in cardiovascular and renal diseases as well as
cancer and inflammatory responses.1 In addition, the
methoxytropolone-containing natural product pareirubrine A
has demonstrated potent antileukemic properties.2 Our lab’s
interest in methoxytropolones stem from their demonstrated
value as intermediates in the synthesis of α-hydroxytropolones,
which have a broad range of bioactivity.3 For example, α-
hydroxytropolones are the most potent known inhibitors of
ANT(2″),4 a major enzyme associated with bacterial resistance
to aminoglycoside antibiotics,5 and are among the most potent
inhibitors of HIV RT RNase H,6 which is a promising target for
HIV treatment.7 Crystal structures of α-hydroxytropolones
(Scheme 1B).14a More recently, Fohlisch and co-workers
̈
showed a very efficient route to α-hydroxytropolones starting
with furans that they then converted to dialkoxy-8-
oxabicyclo[3.2.1]oct-6-en-3-ones (Scheme 1C).15 These bicy-
clic substrates were then opened with the aid of base and heat
Received: July 29, 2013
Published: October 30, 2013
© 2013 American Chemical Society
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Scheme 1. Representative Examples Illustrating Established
Strategies for the Synthesis of α-Hydroxytropolones
Scheme 2. Precedence (A and B) for Oxidopyrylium
Cycloaddition/Ring-Opening Strategy toward Substituted α-
Hydroxytropolones (C)
to produce methoxytropolones, which could be converted to α-
hydroxytropolones through standard demethylation reaction
conditions.
Inspired by literature examples where oxidopyrylium cyclo-
addition chemistry and ring-opening methods were used in
tropolone synthesis (Scheme 2A), we have been studying
similar strategies toward α-hydroxytropolones.16 Adapting this
approach required an α-hydroxy-γ-pyrone oxidopyrylium cyclo-
addition reaction17 that was modified for intermolecular
for this ring-opening. The following outlines our studies on
triflic acid-mediated ring-openings of 3-methoxy-8-
oxabicyclo[3.2.1]octa-3,6-dien-2ones to generate methoxytro-
polones.
RESULTS AND DISCUSSION
reactions by Wender and Mascarenas (Scheme 2B).18 Using
■
̃
Early studies focused on phenyl acetylene-derived 3-methoxy-8-
oxabicyclo[3.2.1]octa-3,6-dien-2-one 4a because of its problem-
atic nature under the previously described conditions,19 and
deuterated chloroform was used to readily monitor reaction
an optimized version of the Wender−Mascarenas oxidopyry-
̃
lium cycloaddition procedure along with a demethylative boron
trichloride ring-opening, we demonstrated that α-hydroxytro-
polones can be synthesized from kojic acid through a two-step
sequence (Scheme 2C).19 Among the benefits of this route are
the low cost of the kojic acid starting material (10 kg can be
purchased for $850 through Chem Impex), the scalability of the
synthesis of 2, which can be made on a gram scale within a few
days without any need for chromatography, and the ability to
quickly generate di- and polysubstituted α-hydroxytropo-
lones.20 Among the limitations to the process are the need
for electronically stabilizing groups in conjugation with the
alkynes (i.e., aryl acetylenes, propiolates, or ynones). The
synthesis of various hydroxytropolones can be achieved in two
to three steps from a common, scalable intermediate, making
the route very appealing for SAR studies. Moreover, the boron
trichloride method that we have reported led directly to α-
hydroxytropolones for several substrates tested. However, in
some instances, methoxytropolones were also generated, either
as byproducts or, in once instance, the only product formed. In
addition, a phenylacetylene-derived bicycle led to a mixture of
at least three compounds that were inseparable. During the
course of medicinal-chemistry-driven pursuits on these
molecules, the unpredictable nature of the boron trichloride
chemistry became an apparent barrier and thus we became
interested in developing a more robust and predictable method
1
progress by H NMR (Scheme 3). Although milder acids,
including trifluoroacetic acid and toluenesulfonic acid, were not
capable of mediating the ring-opening, sulfuric acid and triflic
acid both led to methoxytropolone 6a within a half of an hour
Scheme 3. Prior Results from Aryl-Substituted Bicycles 4a
and 4b with Boron Trichloride (A) and under Triflic Acid
Conditions (B and C)
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under ambient temperature and atmosphere, with triflic acid
promoting a considerably cleaner reaction. During these
studies, substoichiometric amounts of triflic acid (0.5 equiv)
were found to be capable of leading to quantitative yields of 6a
(Scheme 3, conditions B).21 When similar conditions were
attempted on nitroaryl 4b, incomplete conversion and other
byproducts were observed. Fortunately, increasing the amount
of acid to 4 equiv led to a near quantitative reaction (conditions
C). This was in contrast to our previous studies with BCl3 in
which a 1:1 mixture of hydroxytropolone and methoxytropo-
lone was obtained (conditions A).19 Higher concentrations of
triflic acid were also found to work well on 4a. Thus, 4 equiv
were identified as an optimal amount to use for our substrate
scope studies.
Scheme 5. Synthesis of Halogen-Containing Bicycles 4f and
4g and Ring-Expansion Using Triflic Acid
Gratifyingly, both bicycles rearranged cleanly to afford the
anticipated products in excellent yields.
An example of the utility can be seen in the synthesis of
biphenyl methoxytropolone 7 from bromophenyl 6f (Scheme
6). Although the (PPh3)2Pd(II)Cl2/ dioxane Stille conditions
Our attention was next turned toward cycloadducts arising
from alkynyl caboxylates because some of these provided yield
and selectivity issues under our previous conditions (Scheme 4,
Scheme 6. Stille Cross-Coupling of 6f to Afford 7 and
Demethylation to Afford 8
Scheme 4. Prior Results from Bicycles Derived from Alkynyl
Carboxylates (4c−e) with Boron Trichloride (A) and under
New and Methoxytropolone-Selective Triflic Acid
Conditions (C)
previously described by Banwell did not work in this case, we
found that the use of Pd(PPh3)4 in refluxing toluene provided
the anticipated cross-coupling product in yields ranging from
44 to 55%. These compounds can also be demethylated under
known conditions to provide α-hydroxytropolone 8.
Attempts at similar cross-coupling reactions with chlor-
omethyl-containing compound 6g were unsuccessful. However,
6g does react with nucleophiles such as sodium acetate and
sodium azide to generate new methoxytropolones 9 and 10, the
latter of which will undergo copper-catalyzed Huisgen [3 + 2]
dipolar cycloaddition coupling with phenyl acetylene to
generate triazole 11 (Scheme 7).22
conditions A).19 Ethyl ester bicycle 4c had previously been
found to lead to low yields, which we suspect may be due to
hydrolysis of an exposed ester during the longer quench used in
the boron trichloride reaction workup. Gratifyingly, we found
that using the new triflic acid conditions (conditions C)
methoxytropolone 6c was formed in excellent yields. Another
substrate, phenyl ketone bicycle 4d, had previously led to a
completely unselective 1:1 ratio of hydroxy- and methoxy-
tropolone. Under the new conditions, methoxytropolone was
formed exclusively in near quantitative yields. Finally, the
compound bearing a methyl substituent at R2 previously led to
6e in 77% yield, which was satisfactory. However, under the
new conditions, this reaction was again near quantitative,
representing a significant improvement.
Scheme 7. Modifications of Methoxytropolone 6g
Cross-coupling of methoxytropolones have been widely
precedented by the work of Banwell (Scheme 1B) and thus
we also wanted to synthesize methoxytropolones with halogen
handles that may be useful for structure−function studies. Two
halogen-containing bicycles were synthesized through the
optimized oxidopyrylium cycloaddition reaction previously
described. One of these, 4f, contained a bromide on the
phenyl appendage, whereas the other, 4g, had an alkyl chloride
(Scheme 5). Of note was the sluggish reaction toward 4g that
employed a chloromethyl triflate salt 2b and phenylacetylene
(3a). In this instance, 4 h under microwave irradiation at 100
°C was necessary to obtain respectable yields of the bicycle.
When bicycle 4h was subjected to the triflate reaction
conditions, we noticed a surprising change in reactivity. In this
instance, the anticipated methoxytropolone was only a minor
component (<20%), and the major isolated compound was
instead furan 12h,23 as confirmed by comparison to known H
1
NMR spectral data (Scheme 8A). Given the surprising nature
of this discovery and our initial skepticism, we synthesized 4i,
which would lead to another known furan that had symmetry
and would thus confirm this discovery. The oxidopyrylium
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Scheme 8. Unanticipated Furan Rearrangement of
Dimethylacetylene Dicarboxylate-Derived Bicycles 4h and 4i
(A) and Mechanistically Similar Rearrangement Reported by
Mann and Co-workers (B)
Scheme 9. Oxidopyrylium Cycloaddition/Ring-Opening (A)
and Oxazole/Oxadiazole Diels−Alder/retro-Diels−Alder
a
(B) Strategy for Furan Synthesis
a
R1, R2, and R3 are labeled as such for comparative purposes.
synthesis (ambient atmosphere and temperature) and rapid
conversion (30 min) makes it an excellent method for quickly
generating methoxytropolones, and it should have value in
structure−function studies on methoxy and hydroxytropolones.
EXPERIMENTAL SECTION
■
General Experiments Methods. All starting materials and
reagents were purchased from commercially available sources and
used without further purification with the exception of dichloro-
methane, which was purified on a solvent-purification system prior to
the reaction. Microwave reactions were carried out in a Biotage
Initiator (External IR Temperature Sensor). 1H NMR shifts are
measured using the solvent residual peak as the internal standard
(CDCl3 δ 7.26) and are reported as follows: chemical shift, multiplicity
(s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = doublet of
doublet, q = quartet, m = multiplet), coupling constant (Hz),
integration. 13C NMR shifts are measured using the solvent residual
peak as the internal standard (CDCl3 δ 77.20) and are reported as
chemical shifts. Infrared (FTIR) spectral bands are characterized as
broad (br), strong (s), medium (m), and weak (w).
cycloaddition chemistry with triflate salt 2c did not react at all
at 100 °C and had to be heated at 150 °C to promote the
conversion to 4i. With 4i in hand, treatment of the molecule
under these reaction conditions led to the known, symmetric
furan 12i,24 which helped confirm this rearrangement.
Our current hypothesis is that furan formation is favored
when the two ethyl esters destabilize the allylic carbocation
character necessary for ring-opening. This may allow for
protonation of the enol ether, which may initiate a cation-
mediated cycloreversion reaction (as is illustrated in Scheme
8A). Mann and co-workers disclosed a mechanistically related
fragmentation that supports this proposal (Scheme 8B).25 This
could happen either through sp hybridized oxonium formation
(as shown) or through a hemiacetal or hydrate intermediate.
However, no noticeable differences in reactivity were observed
when the reaction was run over molecular sieves. Another
possibility is that protonation of one or multiple carbonyls may
promote a cycloreversion reaction, generating cyclopropenone
byproducts. Unfortunately, we have been unable to identify any
byproducts that could provide insight into the reaction, which
may be the result of polymerization of acrylate-like byproducts.
Mechanistic studies are currently underway.
Although the synthesis of furan and furan-containing
compounds were described as early as the 19th century,26
polysubstituted furan synthesis remains a significant challenge
and one of high interest to chemists.27 This serendipitous
finding reveals a two-step oxidopyrylium cycloaddition/
fragmentation strategy to furans that is reminiscent of widely
used thermal processes involving oxazole or 1,3,4-oxadiazole-
based Diels−Alder/retro-Diels−Alder processes (Scheme 9)28
and could find complementary use. The development of
conditions for this fragmentation that would work for a broader
range of substrates is clearly needed to meet this potential.
General Procedure for Oxidopyrylium Cycloaddition. Known
3-methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones 4a−e and 4h were
synthesized as previously described. New 3-methoxy-8-
oxabicyclo[3.2.1]octa-3,6-dien-2-ones 4f, 4g, and 4i were synthesized
under previously described conditions.19 In short, into a microwave
reactor vial was added triflate salt (2a−c), alkyne (20 equiv), and
CHCl3 (0.2 M). N,N-Diisopropylaniline (1.2 or 2.0 equiv) was added,
and the reaction vessel was sealed and heated under microwave
irradiation at 100 °C (controlled temperature). The reaction was
1
monitored periodically by H NMR and was deemed complete when
the oxidopyrylium dimer was no longer observable.
6-(4-Bromophenyl)-3-methoxy-5-methyl-8-oxabicyclo-
[3.2.1]octa-3,6-dien-2-one (4f). 5-Hydroxy-4-methoxy-2-methyl-
pyrylium 2a (100 mg, 0.34 mmol) and 1-ethynyl-4-bromobenzene
(1.0 g, 6.9 mmol) were suspended in CHCl3 (2 mL). N,N-
Diisopropylaniline (81 μL, 0.41 mmol) was added to the reaction,
the reaction vessel was sealed, and the reaction mixture was heated
under microwave irradiation at 100 °C (controlled temperature) for 30
min. The reaction mixture was then concentrated and purified by
chromatography (silica gel, 18 × 1.8 cm, 50 mL of hexanes, 200 mL of
2% EtOAc in hexanes, 100 mL of 10% EtOAc in hexanes, 200 mL of
15% EtOAc in hexanes) to lead to 4f as a light-yellow solid (68 mg,
61% yield). mp 192−200 °C. Rf = 0.17 in 16% EtOAc/hexanes. FTIR
(KBr, thin film): 525 (m), 714 (m), 1057 (w), 1132 (m), 1606 (s),
1708 (s), 1905 (w), 2978 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ
7.49 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.29 (d, J = 2.5 Hz,
1H), 6.14 (s, 1H), 4.96 (d, J = 2.5 Hz, 1H), 3.58 (s, 3H), 1.64 (s, J =
3H). 13C NMR (100 MHz, CD3CN/CDCl3): δ 189.43, 157.75,
145.66, 132.19, 131.73, 127.99, 124.04, 122.10, 119.73, 86.16, 85.77,
54.47, 21.35. HRMS m/z m/z (ESI+): calcd for C15H14BrO3 (M + H),
321.0121; found, 321.0114.
CONCLUSIONS
■
We have demonstrated that several methoxytropolones can be
readily synthesized through acid-mediated ring-openings of 3-
methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones. The high-
yielding nature of the chemistry along with the ease of
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5-(Chloromethyl)-3-methoxy-6-phenyl-8-oxabicyclo[3.2.1]-
octa-3,6-dien-2-one (4g). 2-(Chloromethyl)-5-hydroxy-4-methoxy-
pyrylium 2b (200 mg, 0.616 mmol) and phenylacetylene (1.35 mL,
12.3 mmol) were dissolved in CHCl3 (3.08 mL). N,N-Diisopropylani-
line (240 μL, 1.23 mmol) was added to the reaction, the reaction
vessel was sealed, and the reaction mixture was heated under
microwave irradiation at 100 °C (controlled temperature) for 4 h.
The reaction mixture was then concentrated and purified by
chromatography (silica gel, 18 × 1.8 cm, 50 mL of hexanes, 200 mL
of 2% EtOAc in hexanes, 100 mL of 10% EtOAc in hexanes, 200 mL of
15% EtOAc in hexanes) to lead to 4g as a highly viscous yellow oil
(114 mg, 67% yield). Rf = 0.14 in 20% EtOAc in hexanes. FTIR (KBr,
thin film): 656 (w), 798 (s), 1078 (m), 1261 (s), 1607 (b), 1709 (b)
2H), 7.45 (d, J = 8.6 Hz, 2H), 7.29 (s, 1H), 7.14 (s, 1H), 4.05 (s, 3H),
2.26 (s, 3H).
Ethyl 6-Hydroxy-4-methoxy-2-methyl-5-oxocyclohepta-
1,3,6-trienecarboxylate (6c). Ethyl 3-methoxy-5-methyl-2-oxo-8-
oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate 4c (40 mg, 0.168 mmol)
was dissolved in CDCl3 (1.68 mL), and trifluoromethanesulfonic acid
(59 μL, 0.672 mmol) was added to the reaction. The reaction was
stirred for 30 min and was quenched with phosphate buffer (1.6 M,
pH 7, 50 mL), extracted with CH2Cl2 (3 × 50 mL), dried over
Na2SO4, filtered, and concentrated to yield 6c as an orange solid (35.7
mg, 89% yield). mp 99−106 °C. FTIR (KBr, thin film): 750 (s), 1056
(w), 1457 (s), 1561 (s), 1717 (s), 2927 (w), 3252 (b) cm−1. 1H NMR
(400 MHz, CDCl3): δ 7.60 (s, 1H), 7.03 (s, 1H), 4.46−4.29 (q, J = 7.1
Hz, 2H), 4.02 (s, 3H), 2.56 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 171.2, 168.9, 159.8, 137.4, 132.4, 121.9, 117.8,
62.3, 56.8, 26.2, 14.5. HRMS m/z (ESI+): calcd for C12H15O5 (M +
H), 239.0914; found, 239.0913.
4-Benzoyl-2-hydroxy-7-methoxy-5-methylcyclohepta-2,4,6-
trienone (6d). 6-Benzoyl-3-methoxy-5-methyl-8-oxabicyclo[3.2.1]-
octa-3,6-dien-2-one 4d (20 mg, 0.074 mmol) was dissolved in
CDCl3 (0.74 mL), and trifluoromethanesulfonic acid (26.2 uL, 0.30
mmol) was added to the reaction. The reaction was stirred for 30 min
and was quenched with phosphate buffer (1.6 M, pH 7, 25 mL),
extracted with CH2Cl2 (3 × 25 mL), dried over Na2SO4, filtered, and
concentrated to yield 6d as a dark yellow solid (19.7 mg, >95% yield).
1H NMR matched previously reported.20 1H NMR (400 MHz,
1
1960 (w), 2254 (w), 2838 (w), 2962 (s) cm−1. H NMR (400 MHz,
CDCl3): δ 7.36−7.09 (m, 5H), 6.22 (d, J = 2.4 Hz, 1H), 6.11 (s, 1H),
4.98 (d, J = 2.4 Hz, 1H), 3.94 (d, J = 12.4 Hz, 1H), 3.77 (d, J = 12.4
Hz, 1H), 3.52 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 189.2, 156.3,
146.9, 132.7, 129.4, 129.2, 125.9, 124.9, 114.8, 88.7, 86.4, 55.2, 45.9.
HRMS m/z (ESI+): calcd for C15H13ClO3 (M + H), 276.0553; found,
276.0552.
Dimethyl 3-Methoxy-2-oxo-8-oxabicyclo[3.2.1]octa-3,6-
diene-6,7-dicarboxylate (4i). 3-Hydroxy-4-methoxypyrylium29 2c
(108 mg, 0.391 mmol) and dimethylacetylene dicarboxylate (1.11 mg,
7.82 mmol) were dissolved in CHCl3 (780 μL). N,N-Diisopropylani-
line (91 μL, 0.47 mmol) was added to the reaction, the reaction vessel
was sealed, and the reaction mixture was heated under microwave
irradiation at 150 °C (controlled temperature) for 5 min. The reaction
mixture was then concentrated and purified by chromatography (silica
gel, 18 × 1.8 cm, 50 mL of hexanes, 75 mL of 10% EtOAc in hexanes,
100 mL of 20% EtOAc in hexanes, 200 mL of 30% EtOAc in hexanes)
to lead to 4i as a white solid (64 mg, 61% yield). mp 113−116 °C. Rf =
0.15 in 25% EtOAc/hexanes. FTIR (KBr, thin film): 688 (m), 794
(w), 1000 (b), 1129 (s), 1611 (s), 1654 (m), 1716 (b), 2838 (m),
2956 (s), 3019 (w) cm−1. 1H NMR (400 MHz, CDCl3): δ 6.17 (d, J =
4.8 Hz, 1H), 5.46 (d, J = 4.8 Hz, 1H), 5.28 (s, 1H), 3.86 (s, 3H), 3.81
(s, 3H), 3.60 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 186.8, 162.7,
161.9, 149.5, 146.9, 138.5, 114.2, 88.9, 80.9, 55.2, 53.2, 53.1. HRMS
m/z (ESI+): calcd for C12H13O7 (M + H), 269.0656; found, 269.0652.
General Procedure for Methoxytropolone Synthesis. 3-
Methoxy-8-oxabicyclo[3.2.1]octa-3,6-dien-2-ones (4a−g) were dis-
solved in CHCl3 (0.1 M), and trifluoromethanesulfonic acid (4
equiv) was added to the reaction. The reaction was stirred for 30 min,
at which time it was quenched with phosphate buffer (1.6 M, pH 7),
extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated
to yield methoxytropolones (6a−g).
2-Hydroxy-7-methoxy-5-methyl-4-phenylcyclohepta-2,4,6-
trienone (6a). 3-Methoxy-5-methyl-6-phenyl-8-oxabicyclo[3.2.1]octa-
3,6-dien-2-one 4a (10 mg, 0.041 mmol) was dissolved in CDCl3 (410
μL), and trifluoromethanesulfonic acid (15 μL, 0.165 mmol) was
added to the reaction. The reaction was stirred for 30 min and was
quenched with phosphate buffer (1.6 M, pH 7, 20 mL), extracted with
CH2Cl2 (3 × 20 mL), dried over Na2SO4, filtered, and concentrated to
yield 6a as a yellow solid (9.5 mg, 95% yield) that decomposes at 175
°C . FTIR (KBr, thin film): 799 (s), 1095 (s), 1260 (s), 1451 (w),
1726 (b), 2923 (w), 2962 (m) cm−1. 1H NMR (400 MHz, CDCl3): δ
7.45−7.24 (m, 5H), 7.23 (s, 1H), 7.18 (s, 1H), 4.04 (s, 3H), 2.27 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 169.9, 158.9, 158.4, 143.9,
143.6, 135.4, 128.9, 128.6, 128.0, 122.7, 122.4, 56.8, 27.0. HRMS m/z
(ESI+): calcd for C15H15O3 (M + H), 243.1016; found, 243.1019.
2-Hydroxy-7-methoxy-5-methyl-4-(4-nitrophenyl)-
cyclohepta-2,4,6-trienone (6b). 3-Methoxy-5-methyl-6-(4-nitro-
phenyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one 4b (29 mg, 0.10
mmol) was dissolved in CDCl3 (1.0 mL), and trifluoromethanesul-
fonic acid (61 μL, 0.41 mmol) was added to the reaction. The reaction
was stirred for 30 min and was quenched with phosphate buffer (1.6
M, pH 7, 20 mL), extracted with CH2Cl2 (3 × 20 mL), dried over
Na2SO4, filtered, and concentrated to yield 6b as a fine, powdery
yellow solid (30 mg, >95% yield). 1H NMR matched previously
reported data.20 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.6 Hz,
CDCl3): δ 7.82 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.0 Hz, 1H), 7.49 (t, J
= 7.3 Hz, 2H), 7.19 (d, J = 29.1 Hz, 1H), 7.10 (s, 1H), 4.05 (s, 3H),
2.33 (s, 3H).
Ethyl 6-Hydroxy-4-methoxy-2,7-dimethyl-5-oxocyclohepta-
1,3,6 trienecarboxylate (6e). Ethyl 3-methoxy-5,7-dimethyl-2-oxo-
8-oxabicyclo[3.2.1]octa-3,6-diene-6-carboxylate 4e (19 mg, 0.075
mmol) was dissolved in CDCl3 (750 μL), and trifluoromethanesul-
fonic acid (26 μL, 0.30 mmol) was added to the reaction. The reaction
was stirred for 30 min and was quenched with phosphate buffer (1.6
M, pH 7, 30 mL), extracted with CH2Cl2 (3 × 30 mL), dried over
Na2SO4, filtered, and concentrated to yield 6e as a red solid (18.5 mg,
20
1
>95% yield). H NMR matched previously reported data. 1H NMR
(400 MHz, CDCl3): δ 6.97 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.97 (s,
3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).
4-(4-Bromophenyl)-2-hydroxy-7-methoxy-5-methylcyclo-
hepta-2,4,6-trienone (6f). 6-(4-Bromophenyl)-3-methoxy-5-methyl-
8-oxabicyclo[3.2.1]octa-3,6-dien-2-one 4f (70.1 mg, 0.22 mmol) was
dissolved in CDCl3 (2.2 mL) and trifluoromethanesulfonic acid (77
μL, 0.87 mmol) was added to the reaction. The reaction was stirred for
30 min and was quenched with phosphate buffer (1.6 M, pH 7, 50
mL), extracted with CH2Cl2 (3 × 50 mL), dried over Na2SO4, filtered,
and concentrated to yield 6f as a yellow solid (70 mg, >95% yield). mp
110−115 °C. FTIR (KBr, thin film): 815.4 (w), 1211.4 (s), 1264.2 (s),
1713.9 (w), 2939.4 (w), 3259.2 (b) cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.56 (d, J = 8.3 Hz, 2H), 7.32 (s, 1H), 7.14 (s, 1H), 7.12 (d,
J = 8.3 Hz, 2H), 4.02 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.1, 158.8, 158.5, 142.7, 141.8, 135.1, 132.1, 130.4, 122.4,
122.2, 121.7, 56.7, 26.9. HRMS m/z (ESI+): calcd for C15H14BrO3 (M
+ H), 321.0121; found, 321.0128.
4-(Chloromethyl)-7-hydroxy-2-methoxy-5-phenylcyclohep-
ta-2,4,6-trienone (6g). 5-(Chloromethyl)-3-methoxy-6-phenyl-8-
oxabicyclo[3.2.1]octa-3,6-dien-2-one 4g (37 mg, 0.13 mmol) was
dissolved in CDCl3 (1.34 mL), and trifluoromethanesulfonic acid (47
μL, 0.54 mmol) was added to the reaction. The reaction was stirred for
20 min and was quenched with phosphate buffer (1.6 M, pH 7, 25
mL), extracted with CH2Cl2 (3 × 25 mL), dried over Na2SO4, filtered,
and concentrated to yield 6g as a brownish solid (34 mg, 92% yield).
mp 159−167 °C. FTIR (KBr, thin film): 702 (s), 735 (m), 762 (w),
1157 (w), 1261 (s), 1559 (b), 1713 (b), 2927 (b), 3247 (b) cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.39−7.14 (m, 7H), 4.31 (s, 2H), 3.99 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 170.49, 159.48, 158.96, 144.55,
141.92, 134.06, 129.04, 128.72, 128.57, 122.05, 121.37, 56.97, 49.01.
HRMS m/z (ESI+): calcd for C15H14ClO3 (M + H), 277.0626; found,
277.0627.
11711
dx.doi.org/10.1021/jo401617r | J. Org. Chem. 2013, 78, 11707−11713

The Journal of Organic Chemistry
Article
4-([1,1′-Biphenyl]-4-yl)-2-hydroxy-7-methoxy-5-methylcy-
clohepta-2,4,6-trienone (7). 4-(4-Bromophenyl)-2-hydroxy-7-me-
thoxy-5-methylcyclohepta-2,4,6-trienone (6f) (28 mg, 0.087 mmol)
was suspended in toluene (1.75 mL), and trimethyl(phenyl)tin (47.6
uL, 62 mg, 0.25 mmol) and tetrakis(triphenylphosphine)palladium(0)
(10.02 mg, 0.0088 mmol) were added. The reaction was stirred
vigorously for 4 days at reflux under argon. The solution was cooled to
room temperature, and the solvent was removed under reduced
pressure. The resulting residue was dissolved in CH2Cl2 (2 mL). The
solution was then treated with aqueous NaOH (1 M, 25 mL) and
aqueous KF (saturated, 25 mL) and stirred vigorously for 30 min. The
solution was acidified with aqueous HCl (2M, 25 mL) to a pH of 3.
The solution was extracted with CH2Cl2 (3 × 25 mL), dried over
Na2SO4, filtered, and concentrated. Chromatography (C18 column
[10 g], 35% MeCN/H2O [0.05% TFA] to 100% MeCN [0.05% TFA]
gradient over 20 column volumes) followed by concentration of
product peaks yielded 7 as a light-yellow solid (15 mg, 55% yield). mp
174−180 °C. FTIR (KBr, thin film): 1113 (s), 1132 (w), 1211 (s),
1554 (s), 1774 (w), 2933 (w), 2986 (w), 3018 (w), 3257 (s) cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.70−7.21 (m, 11H), 4.04 (s, 3H), 2.35
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.79, 158.77, 158.24,
143.03, 142.66, 140.69, 140.57, 135.29, 129.06, 128.97, 127.77, 127.40,
127.26, 122.54, 122.18, 56.61, 26.89. HRMS m/z (ESI+): calcd for
C21H18O3 (M + H), 318.1251; found, 318.1256.
4-([1,1′-Biphenyl]-4-yl)-2,7-dihydroxy-5-methylcyclohepta-
2,4,6-trienone (8). 4-([1,1′-Biphenyl]-4-yl)-2-hydroxy-7-methoxy-5-
methylcyclohepta-2,4,6-trienone (7) (16.5 mg, 0.052 mmol) was
dissolved in 33%HBr/AcOH (0.52 mL). The reaction was heated to
reflux for 3 h with constant stirring. The solution was cooled to room
temperature, quenched with phosphate buffer (pH 7), extracted with
CH2Cl2 (3 × 20 mL), dried over Na2SO4, filtered, and concentrated to
yield 8 as a light-yellow solid (16.1 mg, >95% yield). mp 170−175 °C.
FTIR (KBr, thin film): 1525 (s), 2923 (w), 3246 (br), cm−1. 1H NMR
(400 MHz, CDCl3): δ 7.79−7.20 (m, 11H), 2.32 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 167.35, 158.12, 156.87, 143.80, 142.84, 140.92,
140.70, 139.41, 129.24, 129.13, 127.96, 127.58, 127.44, 126.51, 124.79,
26.86. HRMS m/z (ESI+): calcd for C20H16O3 (M + H), 304.1099;
found, 304.1105.
2-Hydroxy-7-methoxy-4-phenyl-5-((4-phenyl-1H-1,2,3-tria-
zol-1-yl)methyl)cyclohepta-2,4,6-trien-1-one (11). To a suspen-
sion of azidomethoxytropolone 10 (21 mg, 0.074 mmol) in water (800
mL) and tert-butanol (800 mL) were added phenylacetylene (20 mL,
0.18 mmol), copper sulfate pentahydrate (2 mg, 0.008 mmol), and
sodium ascorbate (3 mg, 0.015 mmol). The reaction mixture was
heated under microwave irradiation at 110 °C (controlled temper-
ature) for 30 min. The t-BuOH/H2O was evaporated, and the reaction
was then resuspended in NaCl(aq) (1 mL), extracted with CH2Cl2 (3
× 1 mL), dried over Na2SO4, filtered, and concentrated to yield 11 as a
brown solid (14 mg, 50% yield). mp 171−173 °C. FTIR (KBr, thin
film): 3221 (s), 2939 (s), 1568 (s), 1467 (s), 1229 (s), 1121 (s) cm−1.
1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 2H), 7.63−7.29
(m, 10H), 7.23 (s, 1H), 5.42 (s, 2H), 3.91 (s, 3H). 13C NMR (100
MHz, CDCl3/CD3OD): δ 170.33, 159.35, 158.48, 147.62, 143.59,
141.20, 130.17, 129.42, 128.56, 128.40, 128.02, 128.00, 127.87, 125.16,
121.44, 120.40, 118.95, 55.62, 54.72. HRMS m/z (ESI+) m/z calcd for
C23H20N3O3 (M + H), 386.1499; found, 386.1492.
General Procedure for Furan Synthesis. 3-Methoxy-8-
oxabicyclo[3.2.1]octa-3,6-dien-2-ones (4h, 4i) were dissolved in
CHCl3 (0.1 M), and trifluoromethanesulfonic acid (4 equiv) was
added to the reaction. The reaction stirred for 30 min, at which time
the reaction was quenched with triethylamine, concentrated, and
purified by silica gel chromatography.
Dimethyl 2-Methylfuran-3,4-dicarboxylate (12h). Dimethyl 3-
methoxy-1-methyl-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-6,7-dicar-
boxylate 4h (20 mg, 0.071 mmol) was dissolved in CHCl3 (0.71 mL),
and trifluoromethanesulfonic acid (25 μL, 0.283 mmol) was added to
the reaction. The reaction was stirred for 30 min and was quenched
with triethylamine (50 μL). The reaction mixture was then
concentrated and purified by chromatography (silica gel, 18 × 1.8
cm, 50 mL of hexanes, 100 mL of 5% EtOAc in hexanes, 100 mL of
10% EtOAc in hexanes, 200 mL of 20% EtOAc in hexanes) to lead to
1
12h as a light-yellow solid (10.9 mg, 78% yield). H NMR matched
previously reported data.22 1H NMR (400 MHz, CDCl3): δ 7.73 (s,
1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.50 (s, 3H).
Dimethyl Furan-3,4-dicarboxylate (12i). Dimethyl 3-methoxy-
2-oxo-8-oxabicyclo[3.2.1]octa-3,6-diene-6,7-dicarboxylate 4i (20 mg,
0.074 mmol) was dissolved in CHCl3 (0.746 mL), and trifluor-
omethanesulfonic acid (0.026 mL, 0.289 mmol) was added to the
reaction. The reaction was stirred for 30 min and was quenched with
triethylamine (50 μL). The reaction mixture was then concentrated
and purified by chromatography (silica gel, 18 × 1.8 cm, 50 mL of
hexanes, 100 mL of 2% EtOAc in hexanes, 100 mL of 5% EtOAc in
hexanes, 100 mL of 8% EtOAc in hexanes) to lead to 12i as a light-
(4-Hydroxy-6-methoxy-5-oxo-2-phenylcyclohepta-1,3,6-
trien-1-yl)methyl acetate (9). To a solution of chloromethoxy-
tropolone 6g (33 mg, 0.1191 mmol) in acetonitrile (11.9 mL) was
added sodium acetate (195 mg, 2.38 mmol). The reaction was stirred
for 12 h at ambient temperature and atmosphere, and phosphate buffer
(pH 6) was added. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure to yield 7 as a light-yellow solid
(20 mg, 56% yield). mp 159−161 °C. FTIR (KBr, thin film): 3243 (s),
1
yellow solid (8.6 mg, 63% yield). H NMR matched that previously
reported.23 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 2H), 3.86 (s, 6H).
1
1743 (s), 1579 (s), 1478 (s), 1264 (s), 1103 (s), 704 (m) cm−1. H
ASSOCIATED CONTENT
* Supporting Information
NMR (200 MHz, CDCl3): δ 7.72−6.96 (m, 7H), 4.88 (s, 2H), 4.04 (s,
3H), 2.08 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 170.70, 159.53,
158.55, 144.72, 141.82, 131.75, 128.74, 128.57, 128.39, 121.45, 120.33,
67.72, 56.63, 21.16. 13C NMR (50 MHz, CDCl3/CD3CN): δ 169.82,
169.73, 158.64, 157.85, 143.49, 141.20, 131.33, 127.95, 127.86, 127.54,
120.40, 119.76, 66.76, 55.89, 20.08. HRMS m/z (ESI+) m/z calcd for
C17H17O5 (M + H), 301.1071; found, 301.1071.
■
S
1H and 13C NMR spectra of all new compounds and 1H NMR
data of all known compounds with new experimental
procedures. HMBC and HSQC spectra of 6f with assignments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4-(Azidomethyl)-7-hydroxy-2-methoxy-5-phenylcyclohep-
ta-2,4,6-trien-1-one (10). To a solution of chloromethoxytropolone
6g (62 mg, 0.22 mmol) in acetonitrile (22 mL) was added sodium
azide (285 mg, 4.39 mmol). The reaction was stirred for 12 h under
ambient temperature and atmosphere, and phosphate buffer (pH 6)
was added. The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure to yield 10 as a brown solid (40
mg, 64% yield). mp 115−119 °C. FTIR (KBr, thin film): 3228 (s),
AUTHOR INFORMATION
Corresponding Author
*E-mail: rpmurelli@brooklyn.cuny.edu.
Notes
■
The authors declare no competing financial interest.
1
2102 (s), 1524 (s), 1463 (s), 1228 (s), 1128 (s), 703 (s) cm−1. H
ACKNOWLEDGMENTS
■
NMR (400 MHz, CDCl3): δ 7.71−7.37 (m, 7H), 4.22 (s, 2H), 4.08 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 170.57, 159.18, 158.56, 143.64,
141.67, 131.40, 128.81, 128.42, 128.30, 121.13, 119.56, 56.54, 56.16.
HRMS m/z (ESI+) m/z calcd for C15H14N3O3 (M + H), 284.1030;
found, 284.1024.
We are grateful to Brooklyn College and the National Institutes
of Health (SC2GM099596) for generous funding. We also
thank Connie M. David (Louisiana State University) for mass
spectroscopy studies.
11712
dx.doi.org/10.1021/jo401617r | J. Org. Chem. 2013, 78, 11707−11713

The Journal of Organic Chemistry
Article
Adv. Synth. Catal. 2011, 353, 189. (k) McBride, B. J.; Garst, M. E.
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