Photochemical hydroxylation of 1-methyl-9,10-anthraquinones: Synthesis of 9′-hydroxyaloesaponarin II

Article abstract of DOI:10.1021/jo902247v

(Chemical Equation Presented) Photolysis of 1-methyl-9,10-anthraquinones in the presence of oxygen yields endoperoxides that can be reduced to produce 1-hydroxymethyl-9,10-anthraquinones. The reaction proceeds in a fashion similar to that of other o-alkylphenones which yield either a 1,4-diradical or a "photoenol" upon irradiation. Anthraquinones undergo photochemistry at a wavelength where the endoperoxide is transparent, allowing its isolation. A singlet oxygen quencher had no effect on the rate of formation of the endoperoxide. The photochemical hydroxylation has been used in a total synthesis of a naturally occurring polyketide, 9′-hydroxyaloesaponarin II.

Full text of DOI:10.1021/jo902247v

pubs.acs.org/joc
Photochemical Hydroxylation of 1-Methyl-9,10-anthraquinones:
Synthesis of 90-Hydroxyaloesaponarin II
Salwa Elkazaz and Paul B. Jones*
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27106
jonespb@wfu.edu
Received October 19, 2009
Photolysis of 1-methyl-9,10-anthraquinones in the presence of oxygen yields endoperoxides that can
be reduced to produce 1-hydroxymethyl-9,10-anthraquinones. The reaction proceeds in a fashion
similar to that of other o-alkylphenones which yield either a 1,4-diradical or a “photoenol” upon
irradiation. Anthraquinones undergo photochemistry at a wavelength where the endoperoxide is
transparent, allowing its isolation. A singlet oxygen quencher had no effect on the rate of formation
of the endoperoxide. The photochemical hydroxylation has been used in a total synthesis of a
naturally occurring polyketide, 90-hydroxyaloesaponarin II.
Introduction
SCHEME 1
Anthraquinones are powerful photo-oxidants that absorb
UV-A and blue light.1-5 Quinones can oxidize material by
photoinduced electron transfer (PET) or hydrogen
abstraction.6-8 The reduced form of 9,10-anthraquinones,
9,10-dihydroxyanthracenes, rapidly oxidize to the corre-
sponding 9,10-anthraquinone in the presence of O2 (air).9
Singlet excited anthraquinones undergo ISC to the T1
(lowest triplet) excited state with a quantum yield near
1.0.10 Oxygen quenches the T1 state of most anthraquinones
at a diffusion-controlled rate.11 Anthraquinone photochemistry
is rich; anthraquinones are efficient H atom and electron
acceptors and are useful triplet sensitizers.12-15
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carbonyl.16-28 Such hydrogen abstractions have significant
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Published on Web 12/14/2009
DOI: 10.1021/jo902247v
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2009 American Chemical Society

Elkazaz and Jones
JOCArticle
SCHEME 2
Quinones and anthraquinones are found in a number of
natural products including the angucyclinones.24-26,32-42
Syntheses of angucyclinones have often taken advantage of
the photo-oxidizing ability of the anthraquinone chromo-
phore to install a carbonyl on an alkyl substituent ortho to
one of the quinone carbonyls (e.g., 1 to 2, Scheme 1). The
reaction is dependent on molecular oxygen and reliably
oxidizes only a methylene ortho to the carbonyl.
SCHEME 3
Two possible mechanisms by which an anthraquinone can
oxidize an alkyl group ortho to the carbonyl have been
proposed (Scheme 2).43-46 The more probable pathway is that
the excited quinone (3) abstracts hydrogen through a 6-
membered transition state to afford a 1,4-diradical (4, path a).
The diradical would be trapped by molecular oxygen to give a
1,6-peroxodiradical (5). Cyclization of this diradical would
afford endoperoxide 7. Alternatively, triplet anthraquinone
(3) could sensitize the production of singlet oxygen which then
might react by cycloaddition to a photoenol (6, pathb) togive7.
This route should be less likely as it requires two short-lived
species, a photoenol and singlet oxygen, to interact.
Continued photolysis of 7 (Scheme 3) could result in
homolytic cleavage of the peroxide O-O bond, producing
a diradical (8) which could expel hydroxyl radical via
β-fragmentation to reform the quinone (9). The hydroxyl
radical could then abstract hydrogen from the alkyl group to
produce the final oxidized product (10). Generally, photo-
chemical degradation of the endoperoxide leads to many
products and polymeric material, but it has been known to
give a single product in good yield.43
synthetic utility. The rate of the reaction is fastest if the
hydrogen is transferred through a six-membered transition
state but is an efficient process even when the transfer is
through a five- or seven-membered transition state. In some
molecules, with the proper conformation, hydrogen can be
transferred between remote locations. The hydrogen transfer
produces a 1,x biradical which can then undergo a variety
of reactions including cyclization, oxidation, and frag-
mentation.18-31
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SCHEME 4
SCHEME 5
SCHEME 6
of a caged 4-hydroxy-2-nonenal (4-HNE), 11, resulted in
high yields of 4-HNE when 366 nm light was used but fairly
low yields when 419 nm light was employed. The most
abundant product at the longer wavelength was acetal 12,
which could be converted cleanly to 4-HNE by irradiation
with 366 nm light. Apparently, during photolysis at 366 nm,
acetal 12 was formed but was converted to 4-HNE and 13 by
a second photoreaction. With the loss of the anthraquinone
chromophore, 12 did not absorb at longer wavelengths and,
therefore, no secondary photoreaction could occur when
longer wavelength light was used.
The photochemical formation of endoperoxides such as 7
from o-alkylphenones is known.43-46 However, yields of endo-
peroxide are generally poor. Secondary photochemistry of the
endoperoxide is a possible explanation for the observed low
yields. We speculated that using a chromophore, such as
anthraquinone, that absorbs at longer wavelength may allow
selective excitation of the initial chromophore which would
provide a means to isolate the endoperoxide. Once isolated,
the endoperoxide could then be reduced (or further elaborated)
under milder conditions than photolysis in order to avoid
excessive degradation, allowing the endoperoxide to be a synthe-
tically useful intermediate. A series of 1-methyl-9,10-anthraqui-
nones was thus prepared and their photochemistry investigated.
cleanly (Scheme 5). Irradiation of 3 in O2-saturated benzene
gave an adduct in good yield. The adduct produced 1H NMR
and MS data consistent with endoperoxide 7. The endoper-
oxide was reasonably stable but decomposed upon any
attempt at purification. In solution or in the presence of
sunlight 7 would decompose, with common byproducts
being an aldehyde (such as 10) or alcohol (such as 18),
though neither were obtained in good yield in this manner
and significant amounts of unidentified material accumu-
lated over time.
In contrast, treatment of the endoperoxides with either
NaBH4 or thiourea reduced the peroxide to an alcohol in
good yield.48 Thiourea was a milder reagent, but in some
cases a small amount of aldehyde (e.g., 10) was obtained. In
experiments with NaBH4 no aldehyde was observed, pre-
sumably due to its reduction. However, the reduction was
very sensitive to the amount of NaBH4 used. If too much
NaBH4 was used, the quinone was also reduced, lowering
yields. In the end, thiourea was found to be a superior
reagent, despite a small amount of material being lost as
the aldehyde (<10%).
As expected, the photochemical hydroxylation was selec-
tive toward the ortho methyl (14 to 19). The reaction also
cleanly hydroxylated a single ortho methyl even when two
were present (15 to 20). The latter reaction is consistent with
an endoperoxide intermediate; the endoperoxide (17) chro-
mophore does not absorb blue light well, and so no further
hydrogen abstraction occurs once the endoperoxide is
Results and Discussion
Photolysis of 1-methyl-9,10-anthraquinones using 419 nm
light gave the corresponding endoperoxides relatively
(47) Brinson, R. G.; Jones, P. B. Org. Lett. 2004, 6, 3767–3770.
414 J. Org. Chem. Vol. 75, No. 2, 2010
(48) Balci, M. Chem. Rev. 1981, 81, 91–108.

Elkazaz and Jones
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formed. The anthraquinone chromophore is not regenerated
until the endoperoxide is reduced, which occurs after photo-
lysis is stopped. Thus, the procedure allows oxidation of a
single ortho methyl even where other oxidizable methyls are
present.
The mechanism of the photo-oxidation was probed by
attempting to quench the reaction with dibutyl sulfide, a
known 1O2 quencher.49 The sulfide had no effect on the rate
of formation of 7 by photolysis of 3. This observation rules
out path b (Scheme 2). Therefore, the most likely mechanism
for the reaction is trapping of an intermediate 1,4-diradical
by molecular oxygen (path a) .
The reaction sequence described above could easily be
carried out in a one-pot reaction. The anthraquinone was
dissolved in benzene, O2 was bubbled through the solution
for 15 min, and then, with a continuous flow of O2, the
solution was photolyzed until TLC indicated complete con-
sumption of the anthraquinone. The oxygen purge was then
removed and the reaction mixture diluted with ethanol and
either NaBH4 or thiourea added. Typically, the reduction
was complete in less than 1 h when NaBH4 was used and in a
few hours when thiourea was the reducing agent, though
stirring overnight did not reduce yields. Solvent was removed
and the product purified by chromatography.
hydroxylation developed was used in the first synthesis of
90-hydroxyaloesaponarin II.
Experimental Section
General Procedure for Photochemical Hydroxylation. A 0.003 M
solution of the 1-methyl-9,10-anthraquinone derivative in benzene
was prepared. Oxygen was bubbled through the solution for 20 min
and then while the solution was irradiated at 419 nm. The reaction
was followed by TLC until the starting anthraquinone was com-
pletely consumed. The solution was concentrated immediately in
vacuo in the dark. The crude endoperoxide thus obtained was then
reduced using one of the methods listed below. Safety note:
peroxides are unstable and can explode. On the scale prepared, none
of the endoperoxides described above exhibited such behavior, but
caution should be exercised when repeating these procedures.
Method A. The crude endoperoxide was dissolved in ethanol
and cooled to 0 °C and 0.5 equiv of NaBH4 added. The resulting
mixture was not allowed to stir more than 30 min. It was
important not to stir the reaction longer as continued exposure
to the NaBH4 caused significant product degradation. The
reaction was quenched with a dilute solution of aq HCl which
was then extracted 3ꢀ with EtOAc. The combined organic
layers were washed with 2 ꢀ 30 mL portions of brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude
1-hydroxymethyl-9,10-anthraquinone was purified by column
chromatography over silica gel.
The scope of the reaction was examined by using the
photochemical hydroxylation to synthesize 90-hydroxyaloe-
saponarin II, 21, a naturally occurring polyketide.50-52
Aloesaponarin II (23) was prepared following a literature
synthesis.53 Neither 23 nor a related structure, methyl ether
22,53 gave any hydroxylation products when irradiated in the
presence of oxygen for 6 h. Both 22 and 23 were recovered
unchanged after photolysis. As expected, hydrogen abstrac-
tion from the ortho OH was faster than that from the ortho
methyl, allowing the ortho-OH to serve as an internal
quencher.
Acylation of both phenolic groups in 23 with propionyl
chloride gave dipropionate 24 (Scheme 6). Irradiation of 24
gave endoperoxide 25. Treatment of 25 with thiourea and
K2CO3 in methanol reduced the peroxide and cleaved the
propionate protecting groups to give 21 in 90% yield over
two steps.
Method B. The crude endoperoxide was dissolved in ethanol
and 5 equiv of thiourea added to the solution. The progress of
the reaction was monitored by TLC and was usually found to be
complete in 30 min. However, stirring for 12 h or more in the
dark did not cause degradation of the product. In the case of 22,
5 equiv of K2CO3 was also added. The reaction mixture was
added to brine and extracted with 3 ꢀ 20 mL EtOAc. The
combined organic layers were washed with (2 ꢀ 30 mL) portions
of 1 N HCl, satd aq K2CO3, and brine. The organic layer was
dried over anhydrous MgSO4 and concentrated in vacuo. The
crude product was purified by column chromatography over
silica gel with hexane/EtOAc (3:1) to afford the corresponding
anthraquinone-1-methanol derivative as a pale yellow or yellow
solid.
Endoperoxide 7. The crude endoperoxide was obtained by
evaporation of solvent following photolysis. The endoperoxide
decomposed on all attempts at purification, but a 1H NMR
and MS could be obtained on the crude product. 1H NMR
(300 MHz, CDCl3) δ 4.39 (1H, bs), 5.21 (1H, d, J = 15.3), 5.61
(1H, d, J = 15.3), 7.35 (1H, d, J = 9), 7.59 (3H, m), 7.71 (1H, m),
8.05 (1H, d, J = 9), 8.20 (1H, m).
Conclusion
1-(Hydroxymethyl)anthracene-9,10-dione (18).54 Method A:
An easy, one-pot hydroxylation of 1-alkyl-9,10-anthra-
quinones has been developed. The photoinduced hydroxyla-
tion proceeds through an isolable endoperoxide produced
when an intermediate 1,4-diradical is trapped by molecular
oxygen. Singlet oxygen is not involved in the oxidation.
When the wavelength of excitation is sufficiently long, the
endoperoxide is isolable and relatively stable. This may be a
general method for the isolation of endoperoxide adducts of
photochemically produced diradicals. The method tolerates
the presence of acylated oxygen groups on the quinone rings
but not an unprotected ortho phenol. The photochemical
1
69.7 mg/65%. Method B: 37.5 mg/70%. mp 155-156 °C; H
NMR (300 MHz, CDCl3) δ 3.78 (1H, t, J = 7.4), 5.03 (2H, d,
J = 7.4), 7.77 (4H, m), 8.28 (2H, m), 8.36 (1H, dd, J = 1.5, 6.07);
13C NMR (75 MHz, CDCl3) δ 64.0, 125.9, 126.4, 126.6, 130.3,
131.7, 133.1, 133.2, 133.22, 133.24, 134.1, 134.6, 142.7, 182.0,
185.2; HRMS calcd for C15H10O3Naþ 261.0522 [M þ Naþ],
found 261.0519.
1-(Hydroxymethyl)-3-methylanthracene-9,10-dione (19).
Method A: 7 mg/65%. Method B: 8.8 mg/55%. mp 162-
163 °C; 1H NMR (300 MHz, CDCl3) δ 2.54 (3H, s), 3.87
(1H, t, J = 7.3), 4.97 (2H, d, J = 7.2), 7.65 (1H, m), 7.78
(2H, t, J = 4.4), 8.16 (1H, m), 8.26 (2H, m); 13C NMR
(300 MHz, CDCl3) δ 21.8, 29.73 65.1, 126.9, 127.4, 128.0,
129.1, 132.8, 134.0, 134.2, 135.2, 136.7, 143.8, 145.7, 183.4,
186.0; HRMS calcd for C16H12O3Naþ 275.0678 [M þ Naþ],
found 275.0678.
(49) Gu, C. L.; Foote, C. S. J. Am. Chem. Soc. 1982, 104, 6060–6063.
(50) Cui, H. X.; Shaaban, K. A.; Schiebel, M.; Qin, S.; Laatsch, H. World
J. Microbiol. Biotechnol. 2008, 24, 419–421.
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2006, 22, 1377–1379.
(52) Kalaitzis, J. A.; Moore, B. S. J. Nat. Prod. 2004, 67, 1419–1422.
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Elkazaz and Jones
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1-(Hydroxymethyl)-4-methylanthracene-9,10-dione (20).
Method A: 17.6 mg/55%. Method B: 9 mg/70%. mp
164-165 °C; 1H NMR (300 MHz, CDCl3) δ 2.86 (3H, s),
3.90 (1H, bs), 4.93 (1H, d, J = 5.1), 7.66 (1H, d, J = 7.9),
7.69 (1H, d, J = 7.9), 7.76 (2H, m), 8.2 (2H, m); 13C NMR
(500 MHz, CDCl3) δ 24.2, 30.0 65.8, 110.0, 127.1, 127.2,
133.4, 134.0, 134.5, 135.6, 138.2, 138.98, 142.4, 142.6,
185.2, 185.8; HRMS calcd for C16H12O3Naþ 275.0678
[M þ Naþ], found 275.0678.
13C NMR (300 MHz, CDCl3) δ 62.0, 111.8, 116.4, 118.4, 118.6,
120.9, 124.3, 132.5, 136.0, 136.9, 151.4, 161.4, 163.1, 182.4,
189.2.
Acknowledgment. This work was supported by the NSF
(CHE-0514576). We thank Dr. Marcus Wright for assistance
with NMR spectroscopy.
3,8-Dihydroxy-1-(hydroxymethyl)anthracene-9,10-dione
(9-Hydroxyaloesaponarin II) (21).50-52 Method B: 13 mg/90%.
1H NMR (300 MHz, CDCl3) δ 3.78 (1H, t, J = 7.4), 5.03 (2H, d,
J = 7.4), 7.77 (4H, m), 8.28 (2H, m), 8.36 (1H, dd, J = 1.5, 6.07);
Supporting Information Available: Experimental proce-
dures for the synthesis of 1-methyl-9,10-anthraquinones and
spectral data for all relevant compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
416 J. Org. Chem. Vol. 75, No. 2, 2010