Reliable synthesis of 9-aryl-substituted 2,6,7-trihydroxyxanthen-3-ones

Article abstract of DOI:10.1055/s-2008-1078447

2,6,7-Trihydroxyxanthen-3-ones are reliably prepared by a one-pot protocol using alkali peroxosulfates in the key step. NMR spectra in deuterated sodium hydroxide confirm the anticipated structures and allow the determination of the dye contents by an internal standard. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078447

PAPER
2211
Reliable Synthesis of 9-Aryl-Substituted 2,6,7-Trihydroxyxanthen-3-ones
S
ynthesis of
9
e
t
d
r
a
hydroxyxanthen-
S
3-one
s
chrick,a Klaus Geick,b Siegfried R. Waldvogel*a
a
Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Straße 1,
53121 Bonn, Germany
Fax +49(228)739608; E-mail: waldvogel@uni-bonn.de
Hach Lange GmbH, Willstätterstraße 11, 40549 Düsseldorf, Germany
b
Received 27 April 2008
Dedicated to Prof. Reinhard W. Hoffmann on the occasion of his 75th birthday
OAc
Abstract: 2,6,7-Trihydroxyxanthen-3-ones are reliably prepared
H2SO4, EtOH,
H2O, reflux
OAc
by a one-pot protocol using alkali peroxosulfates in the key step.
NMR spectra in deuterated sodium hydroxide confirm the anticipat-
ed structures and allow the determination of the dye contents by an
+
Ar CHO
internal standard.
OAc
Key words: heterocycles, oxidations, condensation, dye, xan-
1
2
thenones
Ar
HO
OH
OH
oxidation
Hydroxylated 9-substituted xanthenones represent an im-
portant class of dyes. Although these compounds exhibit
splendid absorption and fluorescence characteristics they
show limited photochemical stability. The most promi-
nent examples as dyes are 6-hydroxy derivatives, for ex-
ample, fluorescein or eosin.1 Beside the application in
inks, the xanthenone-based dyes are employed for analyt-
ical purposes. Combined with specific crown ethers a
fluorimetric determination of Hg2+ in fish or Pb2+ in living
cells was demonstrated.2,3 Early transition metal cations,
for example, Zr4+ as well as cations of main group ele-
ments like tin can be detected photometrically by 9-aryl-
substituted 2,6,7-trihydroxyxanthen-3-one derivatives.4
The specific binding of these particular heterocycles to hi-
stones – DNA binding proteins – or specific amino acids
renders them useful for molecular biological studies.5,6 In
contrast to the 6-hydroxyxanthen-3-ones the 2,6,7-trihy-
droxy congeners exhibit an extremely low solubility.
HO
OH HO
3
Ar
HO
O
HO
– H2O
OH
OH
Ar
O
HO
OH
O
HO
O
4
Scheme 1 One-pot sequence to 9- aryl-2,6,7-trihydroxyxanthen-3-
ones
Since usually only small quantities are required for photo-
metric investigations, all reported preparations of 9-aryl-
2,6,7-trihydroxyxanthen-3-ones follow the protocol of
Liebermann and Lindenbaum.7 After a two-fold Friedel–
Crafts alkylation of 1,2,4-triacetoxybenzene (1),8 the ace-
tates are cleaved under acidic alcoholic conditions. In the
original protocol, the oxidation of 3 occurs under aerobic
conditions over an extended period of time. Since the
transformation is accompanied by a series of decomposi-
tion reactions, the desired compound 4 is only collected in
low yield, typically in the range of 4–20%9 (Scheme 1).
Due to the low solubility, 4 is only characterized by pho-
tometric data and elemental analysis. In general, structural
elucidations are missing.
9-(3-Pyridyl)-2,6,7-trihydroxyxanthen-3-one (4d) was
described by Fogl and Vrbsky.10 Following precisely their
protocol yields not the desired compound 4a, but a com-
plex mixture of higher molecular by-products.11 Since 4a
has a technical relevance for the photometric determina-
tion of heavy metal cations we reinvestigated the prepara-
tion of this particular class of compounds. For
accomplishing the transformation a single trihydroxy ben-
zene moiety of 3 has to be oxidized to the corresponding
p-benzoquinone, which subsequently undergoes a cyclo-
condensation reaction to the xanthenone fragment.
Thus, typical oxidation conditions for hydroquinones to
quinones have been tested. A wide variety of reagents ac-
complish this transformation including stoichiometric
amounts of chromium trioxide,12 sodium hypochlorite,13
iron(III) chloride,14 and silver oxide15 as oxidants. Alter-
natively, the oxidation can be performed using nitrogen
SYNTHESIS 2008, No. 14, pp 2211–2216
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078447; Art ID: C01608SS
© Georg Thieme Verlag Stuttgart · New York

2212
P. Schrick et al.
PAPER
Table 1 Variation of the Oxidative Conditions to 4a
N
Entry
Method and conditions
air, r.t., 30 d, darkness
air, r.t., 30 d, sunlight
H2O2, r.t., 24 h
Yield (%) Dye content (%)a
CHO
1 + H2SO4, EtOH,
H2O, reflux
HO
HO
OH
O
1
2
3
4
5
6
7
8
–
–
N
then oxidation
traces
3
n.d.
n.d.
n.d.
42
O
4a
C4H9OOC4H9, r.t., 24 h
C4H9OOC4H9, 80 °C, 3 h
K2S2O8, r.t., 24 h
traces
9
Scheme 2 Screening of reaction conditions for the technically rele-
vant derivative 4a
oxides/O2,16 alumina supported copper sulfate/O2,17 and
VO(acac)2/O2,18 or electrochemical methods.19 However,
we focused on oxidants which result in easily removable
reagent waste. In particular, the by-product has to be ei-
ther volatile or a salt which can be removed by washing.
Consequently, quinones like DDQ or chloranil were not
considered. Furthermore, reagents based on transition
metals in high oxidation states have to be strictly avoided
because of the potential interference in the latter applica-
tion. The screening for suitable reaction conditions was
performed on the transformation to 4 (Ar = 3-pyridyl)
since this particular compound was technically required
(Scheme 2).
34
45
K2S2O8, 80 °C, 1.5 h
58
76
K2S2O8, 97 °C, 1.5 h
(propan-1-ol as solvent)
83
81
9
Na2S2O8, 97 °C, 1.5 h
(propan-1-ol as solvent)
79
89
10
11
anodic treatmentb
7
9
n.d.c
41
(NH4)2S2O8, 80 °C, 1.5 h
a Consistent data by 1H NMR assessment and microanalysis.
b Platinum electrodes in an undivided cell, 2F, current density: 20 mA/
cm2.
c Very complex mixture.
The method at ambient conditions as reported by Fogl and
Vrbsky10 results in no dye formation in the absence of
light, whereas sunlight allows the formation of traceable
amounts of 4a in a complex tarry mixture (Table 1, entries
1, 2). Employing hydrogen peroxide (30 wt% in water)
leads to very small amounts of 4a (entry 3). Prolonged re-
action times and elevated temperatures did not signifi-
cantly improve the situation. However, organic peroxides
were envisioned to be the reagents of choice but under
various conditions at ambient conditions almost no forma-
tion of the desired 2,6,7-trihydroxyxanthen-3-one oc-
curred. Elevated reaction temperatures afforded 4a with a
moderate dye content (Table 1, entries 4, 5). Therefore,
peroxodisulfates, which represent stronger oxidants, were
applied. The most common reagent, potassium peroxodi-
sulfate provides even at ambient temperature a tremen-
dously increased yield with a dye content of about 45%
(entry 6). Elevated temperatures rendered ameliorated re-
sults in yield as well as dye content (entry 7). Best results
were obtained when the oxidant was added in small por-
tions over a range of about 50 minutes. Additional reflux
of 40 minutes completes the conversion providing a
strongly colored slurry. The subsequent time for precipi-
tation by slow cooling is crucial for a good yield of 4a, be-
cause filterable crystals are formed. This protocol can be
scaled up to a multimolar range. By switching to a higher
boiling primary alcohol as solvent yield and product qual-
ity are significantly increased (Table 1, entry 9). When the
corresponding sodium salt of the peroxide is used as re-
agent, the yield is slightly decreased, whereas the dye con-
tent increases because of the better solubility of the by-
products based on sodium sulfates. The strongly colored
washings indicate that the sodium cations solubilize 4a to
some extent by complex formation. Ammonium peroxo-
sulfate gives at various reaction conditions the desired
compound 4a surprisingly only in low yield and with
modest dye content (entry 11). With our experience in an-
odic treatment of phenols,20–24 we considered the electro-
chemical conversion as ideal because no reagent waste is
produced. Unfortunately, the conversion in an undivided
standard electrolysis cell25 at platinum electrodes ren-
dered a very complex reaction mixture (Table 1, entry
10).
Assessment of the dye content was carried out by combus-
tion analysis.26 This particular method is time-consuming
and often not available, but required for UV/Vis charac-
terization of a novel compound. We used alternatively
NMR spectroscopy. In 5 wt% NaOD in D2O compounds
like 4a exhibit sufficient solubility to acquire NMR data.
As internal standard sodium 3-trimethylsilyl-2,2,3,3-
[d4]propionate was employed. If the NMR measurements
are performed immediately after preparation of the sam-
ple the resulting dye content is in complete accordance to
the combustion analysis or photometric determination.
Due to slow degradation of the 2,6,7-trihydroxyxanthen-
3-one system by hydroxide ions a continuously decreas-
ing dye content is observed.27 The significant advantages
of this approach are the quick procedure and the addition-
al structural information on the studied compounds.
Microscopic investigations on the crude 4a reveal that the
crystals of the desired compound are tightly bound to
crystals of K2SO4 and KHSO4, respectively. Extensive
washings with water do not enhance the dye content sig-
nificantly. Aqueous treatment of crude 4a at elevated tem-
peratures for a prolonged time in a Soxhlet apparatus can
increase the dye content only unsatisfactorily. Since the
Synthesis 2008, No. 14, 2211–2216 © Thieme Stuttgart · New York

PAPER
Synthesis of 9-Aryl-Substituted 2,6,7-Trihydroxyxanthen-3-ones
2213
Ar
Table 2 Scope of the Transformation
8
5
1
9a
4a
8a
HO
HO
OH
O
9
Product Yield (%) Dye content (%)a
2
7
6
Entry Aryl
1
10a
3
O
4b
4c
59
71
98
80
4
10
Figure 1 Numbering of the positions at the xanthen-3-one moiety
2
F
O
O
O
3
4d
4e
4f
74
81
97
97
92
87
Cl
4
Br
OH
O
HO
HO
HO
HO
OH
O
5
O
Scheme 3 Mesomeric structures of 4h
Br
6
4g
4h
4i
65
76
59
53
86
81
81
96
75
92
that have been identified for 4a. Table 2 displays the gen-
erality of this protocol.
O2N
7
Conversion of benzaldehyde results in the compound
known as Fluorone Black with excellent quality (Table 2,
entry 1).28 Substituents on the phenyl group such as halo-
gens, nitro, hydroxy or carboxy moieties allow reliable
transformations (entries 2–8). The 4-pyridylcarbaldehyde
renders lower yield and dye content since 4j exhibits a
similar affinity to the potassium salts as the structurally
related 4a (entry 9). Halogen-substituted salicylaldehydes
are also successful reaction partners in this transformation
providing almost pure dye material in the crude precipi-
tate (entries 10–12). Polycyclic aldehydes undergo the
same reaction sequence, which is demonstrated by both
the naphthyl derivatives (entries 13, 14). 9-Anthranyl-
carbaldehyde can be converted in the same manner, but
the resulting product turned out to be completely insolu-
ble, thereby preventing any unequivocal characterization.
HO
8
HOOC
9
4j
N
10
4k
Br
OH
11
12
4l
73
80
86
98
Cl
OH
OH
4m
Cl
Cl
The acquisition of NMR spectra in deuterated sodium hy-
droxide solution allows not only the assessment of the dye
content but also the structural confirmation of the formed
molecules 4. Since no detailed NMR reference data were
available for the 9-aryl-substituted 2,6,7-trihydroxyxan-
then-3-ones we used HMQC and HMBC experiments to
assign most of the NMR signals unequivocally. A com-
plete set of data is given for 4a. Especially, the 13C NMR
signals of all 9-aryl-substituted 2,6,7-trihydroxyxanthen-
3-ones 4 appear in well defined and narrow ranges for the
chemical shifts and can therefore be used as model com-
pounds of similar structures (Figure 1).
13
14
4n
4o
96
74
98
98
a Consistent data by 1H NMR assessment and microanalysis.
Significant variation in the 13C NMR chemical shifts is
found in position 9 where the different aryl substituents
are attached and the adjacent positions 8a/9a (Table 3).
The unusual different shifts for 4h indicate the partial
quinoide nature of the aryl moiety in position 9
(Scheme 3).
by-product from the preparation of 4a mostly consists of
KHSO4 treatment with 0.1 equivalent of NaOH in water
provides a purified residue with a dye content of 95%. If
necessary, this seems to be the best way for purification of
9-aryl-substituted 2,6,7-trihydroxyxanthen-3-ones with
an acceptable loss of about 15–22% of the dye material.
In conclusion, 9-aryl-substituted 2,6,7-trihydroxyxan-
then-3-ones are reliably and easily synthesized when alka-
li peroxosulfates are employed. This method is applicable
to a broad variety aromatic aldehydes and feasible on a
Various aromatic and heteroaromatic aldehydes were sub-
jected to the same reaction conditions (Table 1, entry 7)
Synthesis 2008, No. 14, 2211–2216 © Thieme Stuttgart · New York

2214
P. Schrick et al.
PAPER
13C NMR (100 MHz, NaOD/D2O): d = 104.80 (C-1, C-8), 107.24
(C-4, C-5), 116.34 (C-9a, C-8a), 126.45 (C-15), 134.32 (C-11),
141.22 (C-16), 142.13 (C-9), 150.82 (C-14), 151.11 (C-12), 154.13
(C-4a, C-10a), 162.50 (C-2, C-7), 177.31 (C-3, C-6).
HMQC NMR (100 MHz/400 MHz, NaOD/D2O): d (13C)/d
(1H) = 104.80 (C-1, C-8)/6.17 (H-1, H-8), 107.24 (C-4, C-5)/5.64
(H-4, H-5), 126.45 (C-15)/7.27 (H-15), 141.22 (C-16)/7.11 (H-16),
150.82 (C-14)/8.31 (H-14), 151.11 (C-12)/7.88 (H-12).
HMBC NMR (100 MHz/400 MHz, NaOD/D2O): d (13C)/d
(1H) = 104.80 (C-1, C-8)/5.64 (H-4, H-5), 107.24 (C-4, C-5)/6.17
(H-1, H-8), 116.34 (C-9a, C-8a)/6.17 (H-1, H-8), 126.45 (C-15)/
7.88 (H-12), 8.31 (H-14), 134.32 (C-11)/6.17 (H-1, H-8), 7.88 (H-
12), 8.31 (H-14), 141.22 (C-16)/7.88 (H-12), 8.31 (H-14), 142.13
(C-9)/5.64 (H-4, H-5), 6.17 (H-1, H-8), 7.88 (H-12), 150.82 (C-14)/
7.11 (H-16) 7.88 (H-12), 151.11 (C-12)/7.11 (H-16), 8.31 (H-14),
154.13 (C-4a, C-10a)/5.64 (H-4, H-5), 6.17 (H-1, H-8), 162.50 (C-
2, C-7)/5.64 (H-4, H-5), 6.17 (H-1, H-8), 177.31 (C-3, C-6)/5.64
(H-4, H-5), 6.17 (H-1, H-8).
Table 3 13C NMR Shift Ranges for 4
Entry
Position at xanthen-3one
C-1/C-8
Range of shifts (ppm)
104.40–104.83
1
2
3
4
5
6
7
C-2/C-7
162.09–162.93
C-3/C-6
176.98–177.79
C-4/C-5
107.13–108.78
C-4a/C-10a
C-8a/C-9a
C-9
154.13–154.91
115.50–117.57
(134.38)a 142.13–149.18
a Data for 4h.
multimolar scale. The structural confirmation and assess-
ment of the dye content can quickly be performed by
NMR spectroscopy using NaOD/D2O and an internal
standard.
HRMS: m/z calcd for C18H10NO5 [M – H]–: 320.0564; found:
320.0559.
UV/Vis: lmax = 556.5 nm; e (1/M–1 cm) = 2.55·104.
9-Phenyl-2,6,7-trihydroxyxanthen-3-one (4b)
Crude material: 1.94 g; cadmium-red crystals; dye content: 98%;
yield (corrected): 1.90 g (59%).
1H NMR (300 MHz, NaOD/D2O): d = 6.08 (s, 2 H, H-4, H-5), 6.57
(s, 2 H, H-1, H-8), 7.19 (br, 1 H, H-14), 7.30 (br, 2 H, H-13, H-15),
7.53 (br, 2 H, H-12, H-16).
13C NMR (75 MHz, NaOD/D2O): d = 104.64 (C-1, C-8), 108.06 (C-
4, C-5), 116.62 (C-9a, C-8a), 131.00 (C-12, C-16), 132.07 (C-13, C-
15), 138.22 (C-14), 148.00 (C-9, C-11), 154.91 (C-4a, C-10a),
162.52 (C-2, C-7), 177.50 (C-3, C-6).
All reagents used were analytical grades. Solvents were dried if nec-
essary by standard methods. NMR spectra were recorded at 25 °C
on a Bruker DPX 300 or DPX 400 spectrometer using sodium 3-tri-
methylsilyl-2,2,3,3-[d4]propionate as an internal standard. Chemi-
cal shifts (d) are reported in parts per million (ppm) relative to
internal standard and/or HDO signal of the deuterated solvent (15%
NaOD in D2O). 19F NMR shift refers to external calibration. High-
resolution mass spectra were obtained on a FT-ICR APEX IV
(Bruker, Karlsruhe, Germany) employing ESI techniques. Stock so-
lutions of samples (1 mM) in 10% NaOH were prepared and diluted
with MeOH to 50 mM. UV/Vis spectra were recorded on a UV 2010
(Shimadzu, Japan) using 50 mM solutions in 10% NaOH as solvent.
Microanalyses were determined on a Vario EL III (Elementarana-
lysensysteme, Hanau, Germany). The appearance of the products is
described according to common color charts. Despite the crystalline
nature of the products, defined melting points or decomposition
points could not be determined <250 °C.
HRMS: m/z calcd for C19H11O5 [M – H]–: 319.0612; found:
319.0615.
UV/Vis: lmax = 545.5 nm, e (1/M–1 cm): 3.24·104.
9-(4-Fluorophenyl)-2,6,7-trihydroxyxanthen-3-one (4c)
Crude material: 3.00 g; cadmium-red crystals; dye content: 80%;
yield (corrected): 2.40 g (71%).
1H NMR (300 MHz, NaOD/D2O): d = 5.87 (s, 2 H, H-4, H-5), 6.33
(s, 2 H, H-1, H-8), 6.93 (br, 2 H, H-13, H-15), 7.08 (br, 2 H, H-12,
H-16).
13C NMR (75 MHz, NaOD/D2O): d = 104.40 (C-1, C-8), 107.64 (C-
4, C-5), 116.26 (C-9a, C-8a), 117.45 (C-13, C-15), 133.62 (C-12, C-
16), 133.73 (C-11), 146.42 (C-9), 154.25 (C-4a, C-10a), 162.12,
162.92 (C-2, C-7), 166.15 (C-14), 177.04 (C-3, C-6).
9-Aryl-2,6,7-trihydroxyxanthen-3-ones 4; General procedure
A round-bottomed flask equipped with a condenser and a mechani-
cal stirrer was charged with 1,2,4-triacetoxybenzene (1; 5.00 g, 20
mmol) in 50% EtOH (75 mL). Concd H2SO4 (3 mL) was added and
the white suspension was heated to reflux, resulting in a clear, hon-
ey-colored solution. To this boiling mixture was added dropwise the
aldehyde 2 (10 mmol) within 2 min. The stirred mixture was kept at
reflux for another 60 min. Subsequently, K2S2O8 (2.70 g, 10 mmol)
was added at 80 °C within a period of 50 min in small portions. The
mixture turned from a brown solution into a viscous and dark col-
ored suspension. The contents were brought to reflux for another 20
min and then poured onto ice water (1 L). The strongly colored fine
crystals were collected by filtration under suction and thoroughly
washed with distilled H2O (ca. 100 mL). In order to minimize the
salt content of the crude material, the filter cake had to be pressed
during the filtration step and subsequent washings. The residue was
dried under high vacuum (10–3 mbar) at 60 °C.
19F NMR (282 MHz, NaOD/D2O): d= –114.55.
HRMS: m/z calcd for C19H10FO5 [M – H]–: 337.0518; found:
337.0511.
UV/Vis: lmax = 547.0 nm, e (1/M–1 cm): 5.55·104.
9-(4-Chlorophenyl)-2,6,7-trihydroxyxanthen-3-one (4d)
Crude material: 2.72 g; cadmium-red crystals; dye content: 97%;
yield (corrected): 2.64 g (74%).
1H NMR (400 MHz, NaOD/D2O): d = 6.00 (s, 2 H, H-4, H-5), 6.49
(s, 2 H, H-1, H-8), 7.18 (br, 2 H, H-13, H-15), 7.49 (br, 2 H, H-12,
H-16).
13C NMR (100 MHz, NaOD/D2O): d = 104.68 (C-1, C-8), 107.77
(C-4, C-5), 116.39 (C-9a, C-8a), 130.94 (C-12, C-16), 133.60 (C-
13, C-15), 136.49, 136.51 (C-14, C-11), 146.26 (C-9), 154.56 (C-
4a, C-10a), 162.48 (C-2, C-7), 177.42 (C-3, C-6).
9-(3-Pyridyl)-2,6,7-trihydroxyxanthen-3-one (4a)
Crude material: 2.43 g; auburn-colored crystals; dye content: 76%;
yield (corrected): 1.85 g (58%).
1H NMR (400 MHz, NaOD/D2O): d = 5.64 (s, 2 H, H-4, H-5), 6.17
(s, 2 H, H-1, H-8), 7.11 (br, 1 H, H-16), 7.27 (br, 1 H, H-15), 7.88
(s, 1 H, H-12), 8.31 (s, 1 H, H-14).
Synthesis 2008, No. 14, 2211–2216 © Thieme Stuttgart · New York

PAPER
Synthesis of 9-Aryl-Substituted 2,6,7-Trihydroxyxanthen-3-ones
2215
HRMS: m/z calcd for C19H10ClO5 [M – H]–: 353.0222; found:
353.0216.
UV/Vis: lmax = 549.5 nm, e (1/M–1 cm): 1.20·104.
9-(4-Carboxyphenyl)-2,6,7-trihydroxyxanthen-3-one (4i)
Crude material: 3.11 g; deep red crystals; dye content: 96%; yield
UV/Vis: lmax = 550.0 nm, e (1/M–1 cm): 4.57·104.
(corrected): 2.15 g (59%).
9-(4-Bromophenyl)-2,6,7-trihydroxyxanthen-3-one (4e)
Crude material: 3.52 g; deep red crystals; dye content: 92%; yield
(corrected): 3.24 g (81%).
1H NMR (400 MHz, NaOD/D2O): d = 5.85 (s, 2 H, H-4, H-5), 6.36
(s, 2 H, H-1, H-8), 6.97 (d, J = 6.8 Hz, 2 H, H-12, H-16), 7.52 (d,
J = 6.8 Hz, 2 H, H-13, H-15).
13C NMR (100 MHz, NaOD/D2O): d = 104.72 (C-1, C-8), 107.85
(C-4, C-5), 116.45 (C-9a, C-8a), 124.51 (C-14), 133.92, 134.05 (C-
12, C-16), 137.09 (C-13, C-15), 146.42 (C-9, C-11), 154.78 (C-4a,
C-10a), 162.57 (C-2, C-7), 177.53 (C-3, C-6).
1H NMR (400 MHz, NaOD/D2O): d = 5.61 (s, 2 H, H-4, H-5), 6.11
(s, 2 H, H-1, H-8), 6.70 (d, J = 8.0 Hz, 2 H, H-12, H-16), 7.60 (d,
J = 8.0 Hz, 2 H, H-13, H-15).
13C NMR (100 MHz, NaOD/D2O): d = 104.61 (C-1, C-8), 107.65
(C-4, C-5), 116.03 (C-9a, C-8a), 131.05 (C-12, C-16), 131.96 (C-
13, C-15), 138.14 (C-14), 140.85 (C-11), 146.57 (C-9), 154.24 (C-
4a, C-10a), 162.31 (C-2, C-7), 177.22 (C-17), 177.47 (C-3, C-6).
HRMS: m/z calcd for C20H11O7 [M – H]–: 363.0510; found:
363.0495.
HRMS: m/z calcd for C19H10BrO5: [M – H]–: 396.9717; found:
396.9714.
UV/Vis: lmax = 548.0 nm, e (1/M–1 cm): 5.28·104.
9-(4-Pyridyl)-2,6,7-trihydroxyxanthen-3-one (4j)
Crude material: 2.26 g; black crystals; dye content: 75%; yield (cor-
rected): 1.69 g (53%).
1H NMR (400 MHz, NaOD/D2O): d = 5.72 (s, 2 H, H-4, H-5), 6.28
(s, 2 H, H-1, H-8), 6.90 (d, J = 4.4 Hz, 2 H, H-12, H-16,), 8.42 (d,
J = 4.4 Hz, 2 H, H-13, H-15).
13C NMR (100 MHz, NaOD/D2O): d = 104.81 (C-1, C-8), 107.13
(C-4, C-5), 115.50 (C-9a, C-8a), 127.51 (C-12, C-16), 143.02 (C-9),
147.60 (C-11), 151.33 (C-13, C-15), 154.39 (C-4a, C-10a), 162.68
(C-2, C-7), 177.58 (C-3, C-6).
UV/Vis: lmax = 552.5 nm, e (1/M–1 cm): 6.50·104.
9-(2-Bromophenyl)-2,6,7-trihydroxyxanthen-3-one (4f)
Crude material: 4.47 g; burnt umber crystals; dye content: 87%;
yield (corrected): 3.89 g (97%).
1H NMR (400 MHz, NaOD/D2O): d = 5.65 (s, 2 H, H-4, H-5), 6.39
(s, 2 H, H-1, H-8), 6.97 (d, J = 6.9 Hz, 1 H, H-16), 7.22 (m, 1 H, H-
15), 7.32 (m, 1 H, H-14), 7.59 (d, J = 7.9 Hz, 1 H, H-13).
13C NMR (100 MHz, NaOD/D2O): d = 104.82 (C-1, C-8), 107.48
(C-4, C-5), 116.45 (C-9a, C-8a), 124.75 (C-12), 130.40 (C-15),
132.80 (C-16), 133.62 (C-14), 135.20 (C-13), 139.16 (C-11),
145.96 (C-9), 154.84 (C-4a, C-10a), 162.82 (C-2, C-7), 177.79 (C-
3, C-6).
HRMS: m/z calcd for C18H10NO5 [M – H]–: 320.0564; found:
320.0551.
UV/Vis: lmax = 556.5 nm, e (1/M–1 cm): 4.47·104.
HRMS: m/z calcd for C19H10BrO5 [M – H]–: 396.9717; found:
396.9712.
9-(5-Bromo-2-hydroxyphenyl)-2,6,7-trihydroxyxanthen-3-one
(4k)
UV/Vis: lmax = 556.5 nm, e (1/M–1 cm): 4.68·104.
Crude material: 3.87 g; dark red crystals; dye content: 92%; yield
(corrected): 3.56 g (86%).
9-(4-Nitrophenyl)-2,6,7-trihydroxyxanthen-3-one (4g)
Crude material: 2.94 g; dark red crystals; dye content: 81%; yield
(corrected): 2.38 g (65%).
1H NMR (400 MHz, NaOD/D2O): d = 5.89 (s, 2 H, H-4, H-5), 6.47
(s, 2 H, H-1, H-8), 7.35 (br, 2 H, H-12, H-16), 8.27 (br, 2 H, H-13,
H-15).
13C NMR (100 MHz, NaOD/D2O): d = 104.83, 104.84 (C-1, C-8),
107.42, 107.43 (C-4, C-5), 115.97, 115.99 (C-9a, C-8a), 126.20 (C-
13, C-15), 133.25, 133.28 (C-12, C-13), 144.47, 145.41 (C-9, C-
11), 149.74 (C-14), 154.50, 154.51 (C-4a, C-10a), 162.65, 162.66
(C-2, C-7), 177.58 (C-3, C-6).
1H NMR (400 MHz, NaOD/D2O): d = 6.09 (s, 2 H, H-4, H-5), 6.50
(s, 2 H, H-1, H-8), 6.53 (d, J = 8.8 Hz, 1 H, H-15), 6.96 (d, J = 2.7
Hz, 1 H, H-12), 7.23 (dd, J = 8.8, 2.7 Hz, 1 H, H-14).
13C NMR (100 MHz, NaOD/D2O): d = 104.37 (C-1, C-8), 105.90
(C-13), 108.74 (C-4, C-5), 117.52 (C-9a, C-8a), 124.11 (C-15),
130.38 (C-11), 134.64 (C-12), 134.75 (C-14), 149.00 (C-9), 154.77
(C-4a, C-10a), 162.09 (C-2, C-7), 166.50 (C-16), 177.37 (C-3, C-6).
HRMS: m/z calcd for C19H10BrO6: [M – H]–: 412.9666, found:
412.9663.
UV/Vis: lmax = 526.5 nm, e (1/M–1 cm): 5.94·104.
HRMS: m/z calcd for C19H10NO7 [M – H]–: 364.0463; found:
364.0472.
9-(5-Chloro-2-hydroxyphenyl)-2,6,7-trihydroxyxanthen-3-one
(4l)
UV/Vis: lmax = 552.5 nm, e (1/M–1 cm): 5.23·104.
Crude material: 3.15 g; raw umber crystals; dye content: 86%; yield
(corrected): 2.71 g (73%).
1H NMR (400 MHz, NaOD/D2O): d = 6.14 (s, 2 H, H-4, H-5), 6.55
(s, 2 H, H-1, H-8), 6.63 (d, J = 8.8 Hz, 1 H, H-15), 6.89 (d, J = 2.9
Hz, 1 H, H-12), 7.16 (dd, J = 8.8, 2.9 Hz, 1 H, H-14).
13C NMR (100 MHz, NaOD/D2O): d = 104.41 (C-1, C-8), 108.78
(C-4, C-5), 117.57 (C-9a, C-8a), 119.13 (C-15), 123.44 (C-11),
129.61 (C-13), 131.87 (C-12, C-14), 149.18 (C-9), 154.82 (C-4a, C-
10a), 162.11 (C-2, C-7), 166.03 (C-16), 177.38 (C-3, C-6).
9-(4-Hydroxyphenyl)-2,6,7-trihydroxyxanthen-3-one (4h)
Crude material: 3.14 g; auburn crystals; dye content: 81%; yield
(corrected): 2.54 g (76%).
1H NMR (400 MHz, NaOD/D2O): d = 6.44 (s, 2 H, H-4, H-5), 6.59
(s, 2 H, H-1, H-8), 6.78 (d, J = 8.4 Hz, 2 H, H-13, H-15), 7.15 (d,
J = 8.4 Hz, 2 H, H-12, H-16).
13C NMR (100 MHz, NaOD/D2O): d = 104.65 (C-1, C-8), 109.01
(C-4, C-5), 116.71 (C-9a, C-8a), 120.81 (C-13, C-15), 123.47 (C-
11), 134.38 (C-9), 150.38 (C-12, C-16), 154.82 (C-4a, C-10a),
162.16 (C-2, C-7), 169.72 (C-14), 176.98 (C-3, C-6).
HRMS: m/z calcd for C19H10ClO6 [M – H]–: 369.0717; found:
369.0170.
HRMS: m/z calcd for C19H11O6 [M – H]–: 335.0561; found:
335.0559.
UV/Vis: lmax = 521.5 nm, e (1/M–1 cm): 2.51·103.
Synthesis 2008, No. 14, 2211–2216 © Thieme Stuttgart · New York

2216
P. Schrick et al.
PAPER
9-(3,5-Dichloro-2-hydroxyphenyl)-2,6,7-trihydroxyxanthen-3-
one (4m)
Crude material: 2.15 g; cadmium-red crystals; dye content: 98%;
yield (corrected): 2.11 g (80%).
(2) Yoon, S.; Albers, A. E.; Wong, A. P.; Chang, C. J. J. Am.
Chem. Soc. 2005, 127, 16030.
(3) He, Q.; Miller, E. W.; Wong, A. P.; Chang, C. J. J. Am.
Chem. Soc. 2006, 128, 9316.
(4) (a) Sano, H. Bull. Chem. Soc. Jpn. 1958, 31, 974. (b) Sano,
H. Bull. Chem. Soc. Jpn. 1959, 32, 299.
(5) Kadobayashi, H.; Nakamori, T.; Yamaguchi, T.; Fujita, Y.
Chem. Lett. 2004, 610.
1H NMR (400 MHz, NaOD/D2O): d = 5.99 (s, 2 H, H-4, H-5), 6.46
(s, 2 H, H-1, H-8), 6.72 (d, J = 2.7 Hz, 1 H, H-12,), 7.27 (d, J = 2.7
Hz, 1 H, H-14).
13C NMR (100 MHz, NaOD/D2O): d = 104.36 (C-1, C-8), 108.47
(C-4, C-5), 117.41 (C-9a, C-8a), 118.01 (C-15), 126.81 (C-11),
130.13 (C-12), 130.49 (C-13), 130.99 (C-14), 148.15 (C-9), 154.77
(C-4a, C-10a), 161.69 (C-16), 162.16 (C-2, C-7), 177.44 (C-3, C-6).
HRMS: m/z calcd for C19H9Cl2O6 [M – H]–: 402.9782; found:
402.9779.
UV/Vis: lmax = 528.5 nm, e (1/M–1 cm): 5.17·104.
(6) Wang, W.; Escobedo, J. O.; Lawrence, C. M.; Strongin, R.
M. J. Am. Chem. Soc. 2004, 126, 3400.
(7) (a) Liebermann, C.; Lindenbaum, S. Ber. Dtsch. Chem. Ges.
1904, 37, 1171. (b) Liebermann, C.; Lindenbaum, S. Ber.
Dtsch. Chem. Ges. 1904, 37, 2728.
(8) Vliet, E. B. Org. Synth. Coll. Vol. 1; Wiley: New York,
1967, 317.
(9) In most reports no yield is given. The described time range
for aerobic oxidations covers several days up to few weeks.
(10) Fogl, J.; Vrbsky, J. Scientific Papers of the Prague Institute
of Chemical Technology 1979, Vol. H14, 223; CAS
94:57418.
(11) After several weeks, a tarry residue was formed. The
influence of light and temperature was intensively studied
and indicated no amelioration.
9-(Naphthyl)-2,6,7-trihydroxyxanthen-3-one (4n)
Crude material: 3.62 g; scarlet-red crystals; dye content: 98%; yield
(corrected): 3.54 g (96%).
1H NMR (400 MHz, NaOD/D2O): d = 5.51 (s, 2 H, H-4, H-5), 6.40
(s, 2 H, H-4, H-5), 7.01 (br, 2 H, H-16, H-17), 7.09 (br, 1 H, H-12),
7.23 (br, 1 H, H-18), 7.42 (br, 1 H, H-13), 7.74 (d, J = 7.8 Hz, 1 H,
H-14), 7.79 (d, J = 7.8 Hz, 1 H, H-15).
13C NMR (100 MHz, NaOD/D2O): d = 104.50 (C-1, C-8), 107.83
(C-4, C-5), 117.53 (C-9a, C-8a), 128.00 (C-12), 128.20 (C-18),
128.95 (C-13), 129.22 (C-16), 129.90 (C-17), 130.89 (C-14, C-15),
133.45 (C-18a), 135.40 (C-14a), 135.99 (C-11), 146.05 (C-9),
154.61 (C-4a, C-10a), 162.53 (C-2, C-7), 177.65 (C-3, C-6).
(12) Kohn, M.; Sussmann, J. Monatsh. Chem. 1927, 48, 203.
(13) Ishii, F.; Kishi, K.-I. Synthesis 1980, 706.
(14) Jempty, T. C.; Gogins, K. A. Z.; Mazur, Y.; Miller, L. L.
J. Org. Chem. 1981, 46, 4545.
(15) Willstätter, R.; Pfannenstiel, A. Ber. Dtsch. Chem. Ges.
1904, 37, 4744.
(16) Bosch, E.; Rathore, R.; Kochi, J. K. J. Org. Chem. 1994, 59,
2529.
(17) Sakamoto, T.; Yonehara, H.; Pac, C. J. Org. Chem. 1997, 62,
3194.
(18) Hwang, D. R.; Chang, Y. C.; Wang, S. K.; Uang, B. J.
Synlett 1999, 77.
(19) Eggins, B. R.; Chambers, J. Q. J. Chem. Soc., Chem.
Commun. 1969, 232.
HRMS: m/z calcd for C23H13O5 [M – H]–: 369.0768; found:
369.0777.
UV/Vis: lmax = 550.0 nm, e (1/M–1 cm): 6.20·104.
9-(Naphth-2-yl)-2,6,7-trihydroxyxanthen-3-one (4o)
Crude material: 2.80 g; raw umber crystals; dye content: 98%; yield
(corrected): 2.74 g (74%).
(20) Malkowsky, I. M.; Rommel, C. E.; Wedeking, K.; Fröhlich,
R.; Bergander, K.; Nieger, M.; Quaiser, C.; Griesbach, U.;
Pütter, H.; Waldvogel, S. R. Eur. J. Org. Chem. 2006, 241.
(21) Malkowsky, I. M.; Rommel, C. E.; Fröhlich, R.; Griesbach,
U.; Pütter, H.; Waldvogel, S. R. Chem. Eur. J. 2006, 12,
7482.
(22) Griesbach, U.; Pütter, H.; Waldvogel, S. R.; Malkowsky, I.
M. Patent WO 2005075709, 2005.
(23) Malkowsky, M. I.; Griesbach, U.; Pütter, H.; Waldvogel, S.
R. Eur. J. Org. Chem. 2006, 4569.
1H NMR (400 MHz, NaOD/D2O): d = 6.03 (s, 2 H, H-4, H-5), 6.54
(s, 2 H, H-1, H-8), 7.34 (br, 1 H, H-12), 7.46 (br, 2 H, H-15, H-16),
7.72 (br, 1 H, H-13), 7.80 (br, 1 H, H-14), 7.88 (br, 1 H, H-17), 7.95
(br, 1 H, H-18).
13C NMR (100 MHz, NaOD/D2O): d = 104.71 (C-1, C-8), 108.14
(C-4, C-5), 116.70 (C-9a, C-8a), 129.43 (C-12, C-15), 130.19 (C-
16, C-18), 131.04 (C-14), 134.93 (C-13, C-17), 135.70 (C-13a, C-
17a), 147.48 (C-9, C-11), 154.74 (C-4a, C-10a), 162.39 (C-2, C-7),
177.36 (C-3, C-6).
HRMS: m/z calcd for C23H13O5 [M – H]–: 369.0768; found:
369.0778.
UV/Vis: lmax = 549.0 nm, e (1/M–1 cm): 6.80·104.
(24) Griesbach, U.; Pütter, H.; Waldvogel, S. R.; Malkowsky, I.
M. Patent WO 2006077204, 2006.
(25) Schäfer, H. J. In Radicals in Organic Synthesis, Vol. 1;
Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001,
Chap. 2.6, 257.
(26) Determination and quantification of carbon, hydrogen,
nitrogen, and sulfur by microanalysis. Amount of carbon
indicates dye content.
(27) After 60 min storage of the NMR samples at r.t., a loss of
about 10% dye content was observed compared to the other
quantification methods.
Acknowledgment
The work was generously supported by Hach Lange GmbH and the
University of Bonn (Germany).
References
(28) 4b: Fluorone Black; medicinal application: Lillie, R. D.;
Pizzolato, P.; Donaldson, P. T. Stain Technol. 1975, 50, 127.
(1) Zollinger, H. Color Chemistry – Synthesis, Properties, and
Applications of Organic Dyes and Pigments, 3rd ed.;
VHCA: Zürich, 2003, 18.
Synthesis 2008, No. 14, 2211–2216 © Thieme Stuttgart · New York