Concise approach to 1,4-dioxygenated xanthones via novel application of the Moore rearrangement

Article abstract of DOI:10.1016/j.tet.2012.05.094

The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore rearrangement as a key transformation has been developed. The approach features an acetylide stitching step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone. Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized xanthones. The utility of the approach was demonstrated by its application to a concise and efficient synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named dulcisxanthone C was also corrected to that of the xanthone 1.

Full text of DOI:10.1016/j.tet.2012.05.094

Tetrahedron 68 (2012) 7591e7597
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Concise approach to 1,4-dioxygenated xanthones via novel application of the
Moore rearrangement
*
Alexander L. Nichols, Patricia Zhang, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore
rearrangement as a key transformation has been developed. The approach features an acetylide stitching
step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide
a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone.
Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized
xanthones. The utility of the approach was demonstrated by its application to a concise and efficient
synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named
dulcisxanthone C was also corrected to that of the xanthone 1.
Received 24 March 2012
Received in revised form 1 May 2012
Accepted 22 May 2012
Available online 28 May 2012
Keywords:
1,4-Dioxygenated xanthone
Moore rearrangement
Squarate
Ó 2012 Elsevier Ltd. All rights reserved.
Quinone
Total synthesis
1. Introduction
tree contain the xanthone atroviridin (2), which is commonly used
in traditional medicine as a remedy for earache.2 Two elegant
The 1,4-dioxygenated xanthone moiety is an important struc-
tural feature that is present in numerous natural products, many of
which exhibit significant biological activities and complex struc-
tures (Fig. 1). Tetramethoxy xanthone 1 is reported to inhibit the
formation of osteoclasts in vitro.1 Extracts of the Garcinia atroviridis
syntheses of 2 have been reported recently by Theodorakis3 and
Suzuki.4 Representative of more complex xanthones is the
angularly-fused, heptacyclic xanthone cervinomycin A5 (3), which
exhibits potent activity against numerous bacterial strains and has
been prepared twice by total synthesis.6
Given the widespread occurrence of 1,4-dioxygenated xan-
thones as well as other substituted analogs, it should not occasion
surprise that there are many methods that provide access to this
ring system.7 However, there are numerous disadvantages that are
associated with these methodologies. Many approaches suffer from
high step counts and low yielding sequences. Other procedures
may require the tedious separation of intermediates, harsh reaction
conditions, starting materials that are not readily available, and
a limited substrate scope.8 In order to develop a practical approach
to the xanthones shown in Fig.1 as well as other naturally occurring
1,4-dioxygenated xanthones, there is a need for a method that re-
solves the aforementioned problems. The more general application
of such a method would require readily available starting material
having a diverse array of functional groups and substitution pat-
terns. During the course of work directed toward the total synthesis
of polycyclic xanthones structurally related to 3, the problems in-
herent in the traditional approaches to 1,4-dioxygenated xanthones
became apparent. We thus set to the task of developing a rapid
route to the xanthone core.
Fig. 1. 1,4-Dioxygenated xanthone natural products.
After a survey of the literature, we designed a general approach
to 1,4-dioxygenated xanthones and related natural products of the
form 4, that is, outlined in retrosynthetic format in Scheme 1.9,10 We
* Corresponding author. E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.094

7592
A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
Scheme 1.
envisioned that xanthones related to 4 would be accessible by the
cyclization of phenolic ketones 5 (R¼H) that in turn would be
prepared by oxidation and O-deprotection of 6. An attractive route
to 6 from 7 was inspired by the extensive and elegant work of
Moore and co-workers, who showed that the thermal rearrange-
ment of squarate-derived compounds afforded substituted benzo-
quinones.11 It thus occurred to us that the Moore rearrangement of
intermediates, such as 7 would provide 6. Significantly, analogs of 7
would be readily accessible by a convergent approach that involved
an acetylide stitching process involving a squarate derivative 8, an
acetylene equivalent 9, and a protected derivative of a commer-
cially available salicylaldehyde 10.
Scheme 2.
2. Results and discussion
Initial experiments were directed upon identifying a suitable
protecting group strategy for the phenolic hydroxyl group on the
salicylaldehyde reaction partner and upon establishing the efficacy
of the overall plan outlined in Scheme 1. Indeed, selection of the
appropriate oxygen-protecting group proved to be one of the more
challenging tasks to be confronted. We first explored the possibility
that a di-t-butylsilyl protecting group would protect both the
phenolic and alcohol hydroxy groups in adducts, such as 15a,b.12
Accordingly, ethynylation of salicylaldehyde (11) to afford the cor-
responding propargylic alcohol 12 occurred in essentially quanti-
tative yield. The hydroxy groups in 12 were then protected by
forming the di-t-butylsilyl ether 13 in 99% yield. Addition of the
lithium acetylide ion of 13 to either 14a or 14b then provided the
unstable adducts 15a,b, which were immediately heated in
refluxing toluene to induce the pivotal Moore rearrangement to
deliver the quinones 16a,b in 48e63% overall yield for the 2-step
process from 13. Removal of the bis-silyl protecting group with
HF$pyridine proceeded in quantitative yield to give the quinone
alcohols 17a,b, which were used in subsequent reactions without
further purification (Scheme 2).
Scheme 3.
TEMPO/BAIB, Pd/C, PCC, Swern-type reagents, Al(OiPr)3, Ag2CO3/
Celite, N-bromoacetamide, and CAN were also screened, but these
were also not suitable as they lead to incomplete conversions,
formation of side products, or extensive decomposition pathways.
During the course of these studies, we discovered that the product
xanthones 19a,b were often not stable to the conditions of the re-
action. For example, when 19a was exposed to chromic acid in
acetone, only 10% of 19a was recovered from the mixture. It was
thus apparent that the phenolic moiety in the product of the Moore
rearrangement was unstable toward oxidation, so it was necessary
to modify our original plan and protect this group during the oxi-
dation step.
We first examined the methoxymethyl (MOM) ether as a phe-
nolic protecting group. Salicylaldehyde (11) was thus treated with
MOMeCl in the presence of NaH to give 20 in 96% yield (Scheme 4).
Ethynylation of 20 gave the propargylic alcohol 21 in 88% yield. The
dianion of 21, which was generated with NaH/n-BuLi, was then
allowed to react with 14a to afford the unstable diol 22, which was
Our original plan was that benzylic oxidation of 17a,b would
give the ketoequinones 18a,b that would then undergo facile and
spontaneous cyclization to give the desired xanthones 19a,b
(Scheme 3). In the event, treating 17a,b with a variety of oxidants
including chromic acid, IBX, PDC, and DDQ gave intermediate ke-
tones that cyclized to the desired xanthone 19a,b, but the yields
varied from 10 to 70% and were not reproducible. Other oxidants
including DesseMartin periodinane, MnO2, BaSO4, TPAP/NMO,

A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
7593
overall yield. Jones oxidation of the alcohol gave the ketone 31 in
96% yield, thereby setting the stage for the requisite deprotection to
give 19a.
Traditional reagents for cleaving PMB groups, such as CAN and
DDQ simply returned starting material under mild conditions and
mixtures containing unidentifiable products under more forcing
conditions. When 31 was treated with aqueous acids, the xanthone
19a was obtained as well as the unexpected hydroquinone side
products 25 and 32. After considerable experimentation using
a variety of protic and Lewis acids and reaction conditions, we
discovered serendipitously that treating 31 with CF3CO2H (TFA) in
CH2Cl2 in the absence of light and/or oxygen cleanly provided the
desired xanthone 19a in >95% yield without competing formation
of the undesired hydroquinones 25 or 32. Conversely, when the
deprotection was conducted in the presence of light and oxygen,
the hydroquinones 25 and 32 were formed exclusively in high yield.
Formation of 25 and 32 was also observed when other acids, such as
HCl, TMSI and Ph3CBF4, and other solvents including dioxane, PhCl
and MeOH were used. We currently do not have a satisfactory ex-
planation for this unusual side reaction, although a preliminary
experiment suggested that a simple quinone/hydroquinone equil-
ibration was not involved. Namely, when a solution of 31 and 19a
were stirred in the absence of TFA, neither 32 nor 33 were detected.
Having established the underlying efficacy of our approach to
1,4-dioxygenated xanthones, we explored the scope of the method
by changing the substitution pattern and the functional groups on
the starting salicylaldehyde reaction partner using commercially
available alkyl, methoxy and chloro derivatives. We were delighted
to discover that the chemistry outlined in Scheme 4 was generally
applicable to the salicylaldehydes 34aeh shown in Scheme 5. Pro-
tection of the phenolic hydroxyl group of 34aeh to give 35aeh
occurred in 71e98% yield, and the subsequent ethynylation of the
aldehyde moiety of 35aeh proceeded to give the adducts 36aeh in
87e99% yield. The dianions generated from 36aeh were then
allowed to react with the squarate 14a to provide the sensitive diols
37aeh in 52e65% yield. Although we found that Moore rear-
rangements can be performed in a microwave oven at elevated
temperatures, heating under conventional conditions was more
amenable to conducting larger scale reactions. Thus, heating 37aeh
in refluxing toluene furnished the quinones 38aeh in 60e83% yield.
Subsequent Jones oxidation of 38aeh delivered the ketones 39aeh
in 89e99% yield, setting the stage for the deprotectionecyclization
sequence.
Scheme 4.
heated in a microwave oven to induce the Moore rearrangement
and provide the quinone 23 in 94% yield. Jones oxidation of 22 gave
the ketone 23 in 99% yield.
In the event, treatment of 39a,b,c,f with TFA in oxygen-free
CH2Cl2 cleanly formed the xanthones 42a,b,c,f (Scheme 6, Table
1); the intermediate phenols 40a,b,c,f were not observed. As be-
fore, performing the reaction under oxygen free conditions pre-
cluded the formation of uncyclized hydroquinone side products
related to 25. Surprisingly, exposure of ketoequinones 39d,e,h to
these same deprotection conditions provided varying mixtures of
the spirocycles 41d,e,h and the xanthones 42d,e,h, whereas
deprotection of 39g under identical conditions produced only the
spirocycle 41g. Once again the intermediate phenols 40d,e,g,h were
not observed. It is possible to convert the spirocycles 41d,e,g,h to
their xanthone analogs 42d,e,g,h either by heating in refluxing
DMSO or nitrobenzene or by sublimation at elevated tempera-
ture.13 However, we discovered a simpler expedient whereby this
isomerization could be easily induced by merely stirring the spi-
rocycles 41d,e,g,h with K2CO3 in acetone to give the xanthones
42d,e,g,h in 60e83% yield.
The next step required removing the MOM protecting group, but
use of standard acidic conditions that are typically employed for
this deprotection proved to be somewhat problematic. Namely,
exposure of 24 to protic acids, such as H2SO4, HCl, and AcOH pro-
vided mixtures of the desired xanthone 19a together with variable
amounts of the hydroquinones 25 and 26, the formation of which
was puzzling. Use of TMSI, I2/MeOH, and Ph3CBF4 were also ex-
plored, but in all cases the xanthone 19a was formed in poor yield
and was accompanied with the hydroquinones 25 and 26.
Reasoning that the conditions required for removing the MOM
protecting group were responsible for our difficulties, we decided to
switch to a phenolic protecting group that could be removed under
milder conditions. After a quick survey of several possibilities, the p-
methoxybenzyl group (PMB) emerged as the protecting group of
choice. In the event, 11 was alkylated with p-methoxybenzyl chlo-
ride in the presence of K2CO3 to give 27 in 91% yield (Scheme 4).
Ethynylation of 27 with bromomagnesium acetylide furnished the
propargylic alcohol 28 in 99% yield. Reaction of the dianion of 28
with 14a formed the unstable diol 29, which was then heated in
refluxing toluene to give the quinone 30 in 42% (unoptimized)
The disparate reactivity of phenolic intermediates 40a-h to give
spirocyclic ketones and/or xanthones deserves comment, and we
have formulated a tentative rationalization based upon competing
steric and electronic factors. When substituents are located at the
C(3) and C(5) positions of the starting aroyl benzoquinone 39
(Entries aec, Scheme 6), only xanthone products are observed;

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A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
Table 1
Deprotection of 39aeh
Entry (R¼)
41:42a
42aeh (%)b
a: 3-OMe
b: 5-OMe
c: 5-Cl
d: 4-OMe
e: 4-Me
f: 4-Cl
0:1
0:1
0:1
1:2
1:4
0:1
1:0
7:2
77
81
92c
83
76
63
61d
60
g: 6-OMe
h: 6-Cl
a
Isolated as an inseparable mixture; ratios determined by 1H NMR spectroscopy.
Overall yield from 38aeh.
Reaction required 24 h.
b
c
d
Ethyl acetate was used as solvent for rearrangement; yield in acetone was 30%.
C(4) in 39d results in a 1:2 ratio of 41de42d, whereas a methyl
group at C(4) (Entry e) provides slightly more xanthone than spi-
rocycle. This observation is consistent with the enhanced capability
of a methoxy group to donate electron density via resonance effects
into the carbonyl group as shown in the limiting resonance struc-
ture 43 (Fig. 2). This may reduce the electrophilicity of the carbonyl
group, thereby lessening its ability to activate the quinone toward
1,4-addition to give the xanthone and enabling spirocyclization to
form a five-membered ring to be competitive. Because a methyl
group is less electron releasing than a methoxy group, the initial
ratio of products 42ee41e is greater than that of the corresponding
methoxy compounds 42d and 41d. The inductive electron with-
drawing effect of the 4-chloro substituent on 39f completely sup-
presses spirocycle formation (Entry f), further supporting our
hypothesis that the ketone moiety plays an important role in ac-
tivating the quinone toward 1,4-cyclization via a 6-endo mode to
give the xanthone. Substituents at C(6) may influence the course of
the reaction through both steric and electronic factors. Because of
the severe steric interactions between the keto group and the
substituent R in the transition state for cyclization of 44 to a xan-
thone, the alternate transition state 45, which avoids this in-
teraction and leads to a spirocycle, is favored. The electron donating
ability of a methoxy group apparently reinforces the steric effect,
because 41g is the sole product from 39g, whereas a mixture (7:2)
of spirocycle 41h and xanthone 42h are formed when R is an
electron withdrawing chloro group and 39h is the starting material.
Scheme 5.
Fig. 2. Proposed rationale for formation of the spirocycle.
Scheme 6.
Having thus established a new approach for the facile synthesis
of 1,4-dioxygenated xanthones, we sought to apply it to the syn-
thesis of selected xanthone natural products using intermediates
that had already been accessed during the methodological studies.
Thus, the tetramethoxy xanthones 1 and 46 were simply prepared
by the regioselective methylation of 42a and 42d under basic
substituent effects do not appear to play a role in the course of the
reaction. However, the presence of substituents at C(4) and C(6)
lead to mixtures. Electronic properties of the substituent at C(4)
greatly affect the product ratio. For example, the methoxy group at

A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
7595
conditions in 84 and 99% yields, respectively (Scheme 7). It is
noteworthy that the preparation of xanthone 1 in seven steps and
in 22% overall yield represents a major improvement over the
previously reported synthesis.8b The 1H NMR spectral data of 1 are
in close accord with those reported for the isolated natural product,
numbers (cmꢀ1). 1H and 13C NMR spectra were obtained as solu-
tions in CDCl3 unless otherwise noted, and chemical shifts are
reported in parts per million (ppm) in reference to CDCl3 (7.26 ppm
and 77.0 ppm, respectively). Coupling constants are reported in
hertz (Hz). Spectral splitting patterns are designated as follows: s,
singlet; d, doublet; t, triplet; q, quartet; app, apparent; br, broad; m,
multiplet; comp, overlapping multiplets of magnetically non-
equivalent protons. 2-(1-Hydroxyprop-2-yn-1-yl)phenol (12) was
prepared according to literature procedure.17
but there are some significant differences in the 13C NMR data.14
A
xanthone that has been referred to as dulcisxanthone C was
reported to have the structure of 46;15 however, the 1H and 13C
NMR spectral data reported for dulcisxanthone C do not match
those for synthetic 46, the structure of which was verified by single
crystal X-ray crystallography.16 Comparison of the 1H and 13C NMR
spectral data of dulcisxanthone C actually correspond well to those
obtained for synthetic 1. Accordingly, we believe that the structure
of dulcisxanthone C should be reassigned to that of the known 1.
4.2. Experimental procedures
4.2.1. 2,2-Di-tert-butyl-4-ethynyl-4H-benzo[d][1,3,2]
dioxasiline
(13). Freshly distilled 2,6-lutidine (2.7 mL, 2.5 g, 24 mmol) was
added to a solution of 12 (1.4 g, 9.4 mmol) in CH2Cl2 (25 mL) at 0 ꢁC.
After 5 min, di(tert-butyl)silyl bis(triflate) (3.6 mL, 4.9 g, 11 mmol)
was added, and the reaction was stirred for 3 h at 0 ꢁC. The reaction
was diluted with saturated NH4Cl (15 mL), the ice bath was removed
and the aqueous mixture was extracted with CH2Cl2 (3ꢂ15 mL). The
combined organic layers were washed with brine (1ꢂ15 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography eluting with
hexanes:EtOAc (20:1) to give 2.7 g (99% yield) of 13 as a yellow oil;
1H NMR (400 MHz, C6D6)
d
7.39 (d, J¼8.0 Hz, 1H), 7.02e6.94 (comp,
Scheme 7.
2H), 6.78 (td, J¼8.0, 1.2 Hz, 1H), 5.89 (d, J¼2.0 Hz, 1H), 2.19 (d,
J¼2.0 Hz, 1H), 1.08 (s, 9H), 1.04 (s, 9H); 13C NMR (100 MHz)
d 153.3,
3. Summary and conclusions
129.6, 126.8, 126.1, 121.0, 119.5, 82.7, 74.4, 64.7, 26.94, 26.87, 21.6,
20.9; IR (CH2Cl2) 3073, 2936, 2126, 1186 cmꢀ1; HRMS (CI) m/z cal-
culated for C17H24O2Si (Mþ), 288.1546; found, 288.1539.
In summary, we have developed a general and concise route to
1,4-dioxygenated xanthones that would be otherwise difficult to
access. Preliminary experiments with several different protecting
groups for the hydroxyl group that would eventually become the
oxygen atom in the xanthone ring system led to the identification of
a PMB group as a preferred protecting group. We then discovered
that successful, acid-catalyzed removal of the PMB protecting group
required that the reaction be conducted in the absence of either
light or oxygen because when the reaction was performed under
ambient conditions, the benzoquinone moiety was reduced to
a hydroquinone by an unknown mechanism. This unexpected side
reaction is currently under investigation. The intermediate phenols
40aeh may then cyclize by divergent pathways to give spirocyclic
ketones or the desired xanthones, depending upon the nature and
the position of the substituent R. The regiochemistry of this cycli-
zation appears to arise from an interplay of electronic and steric
effects. This new approach to 1,4-dioxygenated xanthones was then
applied to a more concise and efficient synthesis of 1, a known
natural product. We have also shown that the proposed structure for
dulcisxanthone C is incorrect and likely to be 1 based upon a com-
parison of its spectral data with synthetic 1. The application of this
methodology to the synthesis of other natural products containing
1,4-dioxygenated xanthones is the subject of several ongoing in-
vestigations, the results of which will be reported in due course.
4.2.2. 5-(2,2-Di-tert-butyl-4H-benzo[d][1,3,2]dioxasilin-4-yl)-2,3-
dimethoxycyclohexa-2,5-diene-1,4-dione (16a). n-BuLi (2.1 M in
hexanes, 1.3 mL, 2.7 mmol) was added to a solution of 13 (0.78 g,
2.7 mmol) in THF (15 mL) at ꢀ78 ꢁC. After stirring for 30 min, a so-
lution of 14a (0.32 g, 2.3 mmol) in THF (8 mL) at ꢀ78 ꢁC was
transferred via cannula to the acetylide solution. After stirring for
1 h, AcOH (1 M in THF, 10 mL) was added, the cooling bath was
removed, and the reaction was warmed to room temperature over
30 min. The reaction was concentrated, diluted with Et2O (30 mL),
vacuum filtered, and then concentrated under reduced pressure.
The crude 15a was dissolved in PhCH3 (20 mL), sparged with Ar for
20 min, and then heated under reflux for 4 h. The reaction was
cooled to room temperature and then concentrated under reduced
pressure. The crude product was purified by flash chromatography
eluting with hexanes:EtOAc (20:1 to 10:1) to afford 0.59 g (61%
yield) of 16a as a red oil; 1H NMR (400 MHz)
d
7.20 (t, J¼14.0 Hz,1H),
6.96 (d, J¼8.0 Hz, 1H), 6.83 (t, J¼14.0 Hz, 1H), 6.62 (s, 1H), 6.55 (d,
J¼8.0 Hz, 1H), 6.20 (s, 1H), 4.07 (s, 3H), 4.05 (s, 3H), 1.10 (s, 9H), 0.96
(s, 9H); 13C NMR (100 MHz)
d 184.3, 183.5, 154.2, 147.5, 145.0, 144.7,
132.1,129.5,128.0,126.6,119.7, 68.6, 61.4, 61.3, 27.1, 27.0, 21.7, 21.1; IR
(CH2Cl2) 2931, 2858, 1658, 1603, 1481, 1454, 1247 cmꢀ1; HRMS (CI)
m/z calculated for C23H31O6Si (Mþ1), 431.1890; found, 431.1892.
4. Experimental
4.1. General
4.2.3. 5-(2,2-Di-tert-butyl-4H-benzo[d][1,3,2]dioxasilin-4-yl)-2,3-
dimethylcyclohexa-2,5-diene-1,4-dione (16b). Identical procedure to
that of 16a. Hexanes:EtOAc (30:1), 63% yield over two steps, red oil;
1H NMR (500 MHz)
d
7.17 (td, J¼8.0,1.7 Hz,1H), 6.95e6.93 (dd, J¼8.0,
Solvents and reagents were reagent grade and used without
purification unless otherwise specified. THF was passed through
two columns of neutral alumina. CH3CN and DMF were passed
through two columns of molecular sieves. Reactions involving air-
or moisture-sensitive reagents or intermediates were performed
under an inert atmosphere of argon or nitrogen in glassware that
had been oven dried. Reaction temperatures refer to bath temper-
atures. Melting points are uncorrected. Infrared (IR) spectra were
recorded neat on sodium chloride plates and are reported in wave
1.2 Hz, 1H), 6.79 (td, J¼8.0, 1.2 Hz, 1H), 6.74 (d, J¼1 Hz, 1H), 6.50 (d,
J¼7 Hz,1H), 6.22 (s, 1H), 2.09 (s, 3H), 2.05 (s, 3H),1.09 (s, 9H), 0.95 (s,
9H); 13C NMR (125 MHz)
d 187.8,186.9,154.3,148.7,141.0,140.9,133.7,
129.3,128.4,126.6,120.9,119.6, 68.7, 27.1, 27.0, 21.8, 21.1,12.5,12.2; IR
(CH2Cl2) 2924, 2855, 1651, 1618.2, 1483, 1454, 827 cmꢀ1; HRMS (CI)
m/z calculated for C23H31O4Si (Mþ1), 399.1992; found, 399.1992.
4.2.4. 1,4-Dihydroxy-2,3-dimethoxy-9H-xanthen-9-one (19a). HF$
pyridine (70% HF, 0.004 mL, 0.2 mmol) was added to a solution of

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A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
16a (0.031 g, 0.072 mmol) and pyridine (0.017 mL, 0.017 g,
0.22 mmol) in THF (4 mL). After 1 h, the reaction was diluted with
Et2O (10 mL), and the aqueous layer was washed with brine
(1ꢂ10 mL). The brine was further extracted with Et2O (3ꢂ10 mL),
and the combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude 17a was dissolved
in acetone (10 mL) and cooled to 0 ꢁC. Jones’ reagent (0.14 mL,
0.21 mmol) was added and the reaction was stirred for 1 h, at which
time 2-propanol (1 mL) and saturated aqueous NaHCO3 (10 mL)
were added. The product was extracted with Et2O (3ꢂ12 mL), and
the combined organic layers were washed with brine (1ꢂ15 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by filtering through a plug of silica
gel eluting with CH2Cl2:MeOH (10:1) to give 0.014 g (67% yield) of
19a as a yellow solid (Et2O/hexanes): mp 180e181 ꢁC; 1H NMR
1.7 Hz, 1H), 7.36 (d, J¼8.8 Hz, 2H), 7.29 (dt, J¼7.7, 2.0 Hz, 1H),
7.00e6.97 (m, 2H), 6.91 (d, J¼8.8 Hz, 2H), 5.69 (dd, J¼6.6, 2.0 Hz,1H),
5.08, 5.06 (ABq, J¼11.2 Hz, 2H), 3.80 (s, 3H), 3.10 (d, J¼6.6 Hz, 1H),
2.60 (d, J¼2.2 Hz, 1H); 13C NMR (125 MHz)
d 159.5, 155.9, 129.7,
129.1, 128.6, 128.4, 128.3, 127.9, 121.1, 114.1, 112.3, 83.2, 74.0, 70.1,
61.3, 55.3; IR (CH2Cl2) 3434, 2936, 2112,1515,1029 cmꢀ1; HRMS (CI)
m/z calculated for C17H16O3 (Mþꢃ), 268.1099; found, 268.1099.
4.5. Representative procedure for addition of acetylide
nucleophiles to squarates and subsequent Moore
rearrangement
4.5.1. 5-(Hydroxy(2-(4-methoxybenzyloxy)phenyl)methyl)-2,3-
dimethoxycyclohexa-2,5-diene-1,4-dione (30). A solution of n-BuLi
(2.37 M in hexanes, 3.5 mL, 8.2 mmol) was added to a stirred so-
lution of 28 (1.0 g, 3.7 mmol) in THF (25 mL) at 0 ꢁC. The solution
was stirred for 4 min, at which time a solution of 14a (0.69 g,
4.8 mmol) in THF (10 mL) was transferred via cannula to the dia-
nion solution. The reaction was stirred at 0 ꢁC for 1.5 h, whereupon
saturated aqueous NH4Cl (30 mL) was added, and the reaction was
warmed to room temperature over 10 min. The aqueous layer was
diluted with H2O (20 mL), and then washed with Et2O (3ꢂ30 mL).
The combined organic layers were washed with H2O (1ꢂ20 mL),
brine (1ꢂ20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was rapidly purified by silica gel
chromatography, eluting with hexanes:EtOAc (2:1) to afford 0.79 g
(54% yield) of 29 as a red oil. The diol 29 (0.79 g, 1.9 mmol) was
dissolved in PhCH3 (19 mL), sparged with argon for 15 min, placed
in a preheated oil bath (w130 ꢁC) and heated under reflux for 4 h.
The reaction was cooled to room temperature and concentrated
under reduced pressure. The crude product was purified by silica
gel chromatography, eluting with hexanes:EtOAc (3:1) to afford
0.65 g (78% yield) of 30 as a red oil; 1H NMR (500 MHz, CD3OD)
(400 MHz)
2.0 Hz, 1H), 7.56 (d, J¼7.6 Hz, 1H), 7.40 (t, J¼8.0 Hz, 1H), 5.43 (s, 1H),
4.19 (s, 3H), 3.98 (s, 3H); 13C NMR (100 MHz)
181.7, 156.0, 148.0,
d
12.39 (s, 1H), 8.27 (dd, J¼7.8, 1.2 Hz, 1H), 7.75 (td, J¼8.0,
d
147.1, 139.4, 135.4, 134.8, 128.7, 126.0, 124.1, 120.1, 117.9, 105.2, 61.7,
61.1; IR (CH2Cl2) 3385, 2922, 2851, 1651, 1464 cmꢀ1; HRMS (CI) m/z
calculated for C15H13O6 (Mþ1), 289.0712; found, 289.0713.
4.2.5. 1,4-Dihydroxy-2,3-dimethyl-9H-xanthen-9-one (19b). Identical
procedure to that of 19a. Hexanes:EtOAc (3:1), 57% over two steps,
yellow solid (Et2O/hexanes): mp 265e266 ꢁC (dec); 1H NMR
(400 MHz)
J¼7.2 Hz,1H), 7.50 (d, J¼8.0 Hz,1H), 7.41 (t, J¼7.2 Hz,1H), 5.26 (s,1H),
2.37 (s, 3H), 2.24 (s, 3H); 13C NMR (150 MHz)
181.6, 155.6, 151.5,
d
12.39 (s, 1H), 8.30 (dd, J¼8.4, 1.6 Hz, 1H), 7.75 (t,
d
140.5, 135.2, 133.9, 133.5, 126.4, 124.1, 120.8, 118.4, 117.5, 106.3, 13.1,
10.8; IR (CH2Cl2) 3361, 2923, 2853, 1650 cmꢀ1; HRMS (CI) m/z cal-
culated for C15H13O4 (Mþ1), 257.0809; found, 257.0809.
4.3. Representative procedure for phenol protection
d
7.37 (dd, J¼7.6,1.7 Hz,1H), 7.28e7.23 (comp, 3H), 7.02 (d, J¼8.0 Hz,
4.3.1. 2-(4-Methoxybenzyloxy)benzaldehyde (27). Anhydrous K2CO3
(39.0 g, 283 mmol) was added to a stirred solution of 11 (11.5 g,
10.0 mL, 94.2 mmol) and PMBeCl (19.2 g,16.6 mL,122 mmol) in DMF
(95 mL) at 0 ꢁC. The mixture was stirred at 0 ꢁC for 1 h, and then
warmed to room temperature. The mixture was stirred for 20 h,
whereupon the reactionwas partitioned between H2O (200 mL) and
PhCH3 (100 mL). The layers were separated, and the aqueous layer
was washed with PhCH3 (2ꢂ50 mL). The combined organic layers
were washed with brine (1ꢂ100 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure to afford 20.7 g (91% yield) of
27 (colorless solid from hexanes/EtOAc): mp 86e87 ꢁC; 1H NMR
1H), 6.94 (td, J¼7.5, 0.9 Hz, 1H), 6.84 (d, J¼8.7 Hz, 2H), 6.3 (d,
J¼1.3 Hz, 1H), 6.06 (s, 1H), 4.97, 4.95 (AB q, J¼11.2 Hz, 2H), 3.91 (s,
3H), 3.83 (s, 3H), 3.76 (s, 3H); 13C NMR (125 MHz, CD3OD)
d 185.8,
184.5, 161.0, 156.9, 150.2, 146.3, 146.0, 130.9, 130.7, 130.4, 130.3,
130.2,128.7,121.8,114.9,113.6, 71.2, 65.0, 61.7, 61.6, 55.7; IR (CH2Cl2)
3487, 2950, 1656, 1603, 1515, 1245, 755 cmꢀ1; HRMS (CI) m/z cal-
culated for C23H23O7 (Mþ1), 411.1444; found, 411.1450.
4.6. Representative procedure for oxidation of benzyl
alcohols
(400 MHz)
d
10.52 (s, 1H), 7.85 (dd, J¼8.0, 1.6 Hz, 1H), 7.54 (dt, J¼8.0,
4.6.1. 2,3-Dimethoxy-5-[2-(4-methoxybenzyloxy)benzoyl]-[1,4]ben-
zoquinone (31). A solution of Jones’ reagent (0.061 mL, 0.16 mmol)
was added to a stirred solution of 30 (0.056 g, 0.14 mmol) in acetone
(4 mL) at 0 ꢁC. The solution was stirred for 1 h, at which time 2-
propanol (w1 mL) was added, and the reaction was warmed to
room temperature over 5 min. The reaction was diluted with H2O
(5 mL) and brine (10 mL). The aqueous layer was washed with Et2O
(2ꢂ20 mL), and thecombined organiclayers werewashed with brine
(1ꢂ10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure to afford 0.053 g (96% yield) of 31 as a red oil; 1H NMR
2.0 Hz, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.08e6.94 (comp, 2H), 6.93 (d,
J¼8.0 Hz, 2H), 5.12 (s, 2H), 3.83 (s, 3H); 13C NMR (100 MHz)
d 189.8,
161.1, 159.6, 135.8, 129.1, 128.3, 128.0, 125.1, 120.9, 114.1, 113.0, 70.3,
55.3; IR (CH2Cl2) 2837, 1687, 1598, 1245 cmꢀ1; HRMS (CI) m/z cal-
culated for C15H14O3 (Mþ$), 242.0942; found, 242.0942.
4.4. Representative procedure for preparation of propargyl
alcohols
4.4.1. 1-(2-(4-Methoxybenzyloxy)phenyl)prop-2-yn-1-ol (28). A so-
lution of ethynyl magnesium bromide (24 mL, 12 mmol, 0.5 M in
THF) was added to a solution of 27 (2.4 g, 10 mmol) in THF (100 mL)
at 0 ꢁC. After stirring for 3 h at 0 ꢁC, saturated aqueous NH4Cl (50 mL)
was added, the ice bath was removed, and the reaction was warmed
to room temperature. The aqueous layer was washed with Et2O
(3ꢂ30 mL), and the combined organic layers were washed with
brine (1ꢂ30 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The resulting oil was purified by passing through
a plug of silica gel, eluting with hexanes:EtOAc (1:1) to afford 2.6 g
(400 MHz)
d
7.95 (dd, J¼7.7, 1.4 Hz, 1H), 7.58 (t, J¼7.6 Hz, 1H), 7.17 (d,
J¼8.6 Hz, 2H), 7.12 (t, J¼7.5 Hz, 1H), 7.03 (d, J¼8.2 Hz, 1H), 6.83 (d,
J¼8.6 Hz, 2H), 6.46 (s, 1H), 4.89 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77
(s, 3H); IR (CH2Cl2) 2951, 1653, 1596, 1517, 1454, 1246 cmꢀ1; HRMS
(ESI) m/z calculated for C23H20O7 (MþNa), 431.1107; found, 431.1102.
4.7. Representative procedure of xanthone formation
4.7.1. 1,4-Dihydroxy-2,3-dimethoxy-9H-xanthen-9-one (19a). The
unpurified keto-quinone 31 (0.053 g, 0.13 mmol) was dissolved in
CH2Cl2 (5 mL) and sparged with Ar for 3 min, at which time TFA
(99% yield) of 28 as a yellow oil; 1H NMR (500 MHz)
d
7.55 (dd, J¼7.3,

A.L. Nichols et al. / Tetrahedron 68 (2012) 7591e7597
7597
(0.099 mL, 0.15 g, 1.3 mmol) was added. The Ar sparge was con-
Supplementary data
tinued for 1 min, and the reaction was allowed to stir at room
temperature under Ar for 1 h. The reaction was quenched with
saturated aqueous NaHCO3 (10 mL), and the aqueous layer was
washed with Et2O (3ꢂ10 mL). The combined organic layers were
washed with brine (1ꢂ10 mL), dried (MgSO4), filtered, and con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography, eluting with hexanes:EtOAc (3:1)
to afford 0.037 g (99% yield) of 19a as a yellow solid.
Experimental procedures and characterization for other com-
pounds. Supplementary data related to this article can be found
online at doi:10.1016/j.tet.2012.05.094.
References and notes
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4.8. Representative procedure for rearrangement of
spirocycle to xanthone
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4.8.1. 1,4-Dihydroxy-2,3,6-trimethoxy-9H-xanthen-9-one (42d). A
solution of unpurified 39d (0.066 g, 0.15 mmol) in CH2Cl2 (3 mL)
was sparged with Ar for 3 min. TFA (0.12 mL, 0.17 g, 1.5 mmol) was
added, and sparging was continued for 1 min. The solution was
then stirred under Ar for 1 h, at which time the reaction was
quenched with saturated aqueous NaHCO3 (6 mL). The aqueous
layer was washed with Et2O (3ꢂ10 mL), and the combined organic
layers were washed with brine (1ꢂ10 mL), dried (MgSO4), filtered,
and concentrated under reduced pressure. The mixture (1:2) of
41d:42d was dissolved in acetone (6 mL) and stirred in the pres-
ence of K2CO3 (0.10 g, 0.75 mmol) for 1.5 h. The mixture was filtered
through a Celite plug eluting with acetone, and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with hexanes:EtOAc (5:1 to
3:1) to afford 0.041 g (84% yield) of 42d as a yellow solid; yellow
cubes from hexanes/Et2O: mp 194e195 ꢁC; 1H NMR (500 MHz)
€
9. For a preliminary account of portions of this work see: Nichols, A. L.; Zhang, P.;
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d
12.52 (s, 1H), 8.16 (d, J¼8.8 Hz,1H), 6.97e6.93 (m, 2H), 5.43 (s, 1H),
4.17 (s, 3H), 3.97 (s, 3H), 3.92, (s, 3H); 13C NMR (125 MHz)
180.9,
165.6, 158.1, 148.0, 146.6, 139.4, 134.9, 128.5, 127.4, 113.9, 113.8,
105.0, 100.1, 61.7, 61.1, 56.0; IR (CH2Cl2) 2924, 1607, 1573, 956 cmꢀ1
d
;
HRMS (CI) m/z calculated for C16H13O7 (Mꢀ1), 317.1025; found,
317.1023.
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Acknowledgements
15. Deachathai, S.; Mahabusarakam, W.; Phongpaichit, S.; Taylor, W. C.; Zhang, Y.-J.;
Yang, C.-R. Phytochemistry 2006, 67, 464e469.
16. The supplementary crystallographic data for 46 (CCDC 830944) can be obtained
free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
We thank the National Institutes of Health (GM 31077), the
Robert A. Welch Foundation (F-652) for generous support of this
research. We would also like to thank Vincent Lynch (The Univer-
sity of Texas) for obtaining X-ray data for compound 46.
17. Mann, A.; Muller, C.; Tyrrell, E. J. Chem. Soc., Perkin Trans. I 1998, 1427e1438.