Organocatalyzed reactions involving 3-formylchromones and acetylenedicarboxylates: Efficient synthesis of functionalized benzophenones and polysubstituted xanthones

Article abstract of DOI:10.1055/s-0030-1258969

Organocatalyzed reactions between chromones and acetylenedicarboxylates leading either to xanthone derivatives or to functionalized benzophenones are described. The outcome of the reactions was found to depend both on the nature of the chromone substituen

Full text of DOI:10.1055/s-0030-1258969

PAPER
97
Organocatalyzed Reactions Involving 3-Formylchromones and
Acetylenedicarboxylates: Efficient Synthesis of Functionalized
Benzophenones and Polysubstituted Xanthones
Functionalized
B
enzop
i
henone
c
s
a
nd Poly
h
X
a
anthone
s
el A. Terzidis, Vassilios G. Tsiaras, Julia Stephanidou-Stephanatou,* Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Macedonia, Greece
Fax +30(2310)997679; E-mail: ioulia@chem.auth.gr; E-mail: tsolerid@chem.auth.gr
Received 2 August 2010; revised 28 September 2010
attributes of small organic molecules as catalysts.2 Re-
cently, the possibility of carbon–carbon bond formation
by intermolecular trapping of 1,4-zwitterionic intermedi-
ates generated from pyridine, acting as an organocatalyst,
and acetylenedicarboxylates with aldehydes, and also
with carbonyl compounds more generally, was studied.3
An analogous 4-dimethylaminopyridine (DMAP)-cata-
lyzed reaction between dimethyl acetylenedicarboxylates
(DMAD) and b-ketoesters has also been reported.4
Abstract: Organocatalyzed reactions between chromones and acet-
ylenedicarboxylates leading either to xanthone derivatives or to
functionalized benzophenones are described. The outcome of the
reactions was found to depend both on the nature of the chromone
substituents and on the basicity of the organocatalyst.
Key words: DMAP, hetero-Diels–Alder reactions, Friedel–Crafts
reactions, organocatalysis, xanthones, zwitterions
One of the rapidly growing areas of research in the field
of organic synthesis is that of catalytic transformations
utilizing small organic molecules called organocatalysts.1
Although, for a long time, organocatalysis was not viewed
as a viable alternative to the two main classes of estab-
lished catalysts (transition-metal complexes and en-
zymes) a report, which appeared in 2000, completely
changed this perception and highlighted the fascinating
In a continuation of the above mentioned literature re-
ports, a hetero-Diels–Alder type reaction between formyl-
chromones and acetylenedicarboxylates was studied,5,6
whereupon, by using 4-picoline as organocatalyst, an effi-
cient one-pot approach to a new class of pyrano[4,3-
c]chromenes 3 was possible (Scheme 1). In the course of
further studies on chromone organocatalytic reactions in-
volving zwitterionic intermediates, in the present study
COOR4
H
R2
R1
O
COOR4
R1, R2 = EDG
O
O
3a–e
R3
5
COOR4
4
R3
10
O
COOR4
COOR4
R2
R1
O
O
H
R1, R3 = EWG
4-picoline or DMAP
DME, –18 °C to r.t.
+
2
R1
COOR4
CHO
9
8
1
COOR4
O
1
2
4e–h
COOR4
R1
5'
R2
H
COOR4
1
R1 R2 R3
R4
R1, R2 = EDG
1'
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
Br
H
a
b
Me
Et
COOR4
3
5
2'
Me
i-Pr
O
OH
5a–e,i–j
Cl Me
EDG = electron-donating groups
EWG = electron-withdrawing groups
Cl
H
H
H
Br
g
NO2
Scheme 1 Reaction of substituted 3-formylchromones 1 with acetylenedicarboxylates 2 in the presence of 4-picoline or DMAP as organoca-
talysts
SYNTHESIS 2011, No. 1, pp 0097–0103
x
x
.
x
x
.2
0
1
0
Advanced online publication: 09.11.2010
DOI: 10.1055/s-0030-1258969; Art ID: P12110SS
© Georg Thieme Verlag Stuttgart · New York

98
M. A. Terzidis et al.
PAPER
we extended our investigation by introducing strong elec-
tron-withdrawing substituents into the chromone moiety,
and found that, by using the same organocatalyst, 4-pi-
coline, the reaction followed a completely different path-
way leading to formation of xanthone derivatives 4 in
good yields. The same xanthone derivatives 4 were also
isolated when DMAP was used as organocatalyst. In con-
trast, the use of DMAP with chromones bearing electron-
donating substituents led to formation of functionalized
Table 1 Effect of the Substituents and Organocatalyst on the Reac-
tion of 3-Formylchromones 1 and Acetylenedicarboxylates 2
Entry R1
R2
H
R3
Br
H
H
Br
H
H
H
H
H
H
H
R4
Catalyst
4-picoline
4-picoline
4-picoline
DMAP
Product (%)
4f (64)
1
2
Br
Me
Me
Et
NO2
NO2
Br
H
4g (59)
4h (61)
4f (58)
3
H
4
H
Me
Me
Et
benzophenones
5
instead of either pyrano[4,3-
c]chromenes 3 or xanthones 4.
5
NO2
NO2
H
H
DMAP
4g (53)
4h (55)
5a (62)
5b (61)
5c (59)
5d (63)
Functionalized benzophenones are of considerable inter-
est as pharmacologically relevant natural products and
natural product analogues, and they represent versatile
synthetic building blocks.7 Since classical synthesis
through Friedel–Crafts acylation frequently leads to un-
satisfactory results,8 benzophenone syntheses rely on the
reaction of organometallic reagents with aldehydes and
subsequent oxidation.9 More recently, some functional-
ized benzophenones were also prepared by domino
‘Michael–retro-Michael–aldol’ reactions.10 On the other
hand, xanthones are a class of natural products that have
been shown to possess a wide range of pharmacological
properties,11 and it has been shown that electron-
withdrawing substituents enhance the antimycobacterial
activity of these compounds.12
6
H
DMAP
7
H
Me
Me
Me
Me
Me
DMAP
8
Me
i-Pr
Cl
H
DMAP
9
H
DMAP
10
11
Me
H
DMAP
Cl
DMAP
4e (9)
5e (56)
12
13
H
H
H
H
H
Et
Et
DMAP
DMAP
5i (63)
5j (57)
Me
xanthones 4g and 4h (Table 1, entries 2 and 3). The reac-
tion was then investigated by changing the catalyst to
DMAP, whereupon chromones 1f and 1g reacted analo-
gously to furnish the same xanthones 4f–h, respectively,
as summarized in Table 1 (entries 4–6). In contrast, when
6-chlorochromone (1e) was used, the xanthone derivative
4e (9% yield) was formed as the minor product together
with a second product that was isolated and identified as
the benzophenone tricarboxylate 5e (56% yield; Table 1,
entry 11).
Against this literature background, in the present study we
wish to report our results in detail. Initially, as a continu-
ation of our previous study,6 the 6,8-dibromochromone 1f
(1.0 mmol) was allowed to react with DMAD (2a; 1.2
mmol) in 1,2-dimethoxyethane (DME; 10 mL) at –18 °C
by using 4-picoline (1.0 mmol) as catalyst (Scheme 1).
The reaction mixture was allowed to warm to room tem-
perature and then stirred further for 12 hours, whereupon
xanthone 4f was isolated as the only reaction product in
64% yield. When less catalyst (0.2 mmol) was used, the
reaction proceeded analogously, although much longer re-
action times (7 days) were required to complete the reac-
tion. By increasing the molar ratio of DMAD (2.2 mmol)
the product yield was decreased and the reaction became
turbid due to formation of substantial amounts of poly-
meric material. The reaction of 6-nitrochromone (1g) with
acetylenedicarboxylates 2a and 2b proceeded in the same
manner and resulted in the formation of the corresponding
Functionalized benzophenones 5 were also formed in
good yield (Table 1, entries 7–10, 12 and 13) with all
chromones bearing electron-donating substituents in the
chromone moiety. It is noteworthy that, as was previously
reported,6 the use of 4-picoline with all ‘electron-rich’
chromones resulted in the hetero-Diels–Alder cycloaddi-
tion products 3. As a result, product formation proved to
be greatly affected not only by the organocatalyst but also
by the nature of the chromone substituents. However,
OMe
OMe
O
O
E
N
R3
N
R3
R3
R2
R1
O
N
R2
R1
O
O
R2
R1
O
E
E
H
H
E
O
6
O
C
H
O
C
H
O
O
1
7
8
E = COOR4
– catalyst
3
Scheme 2 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 6, formed from reaction of acetylene-
dicarboxylates 2 with 4-picoline, to afford compounds 3
Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York

PAPER
Functionalized Benzophenones and Polysubstituted Xanthones
99
when the reaction with ‘electron-rich’ chromones was re- after ring closure to form 8, yields compound 3 by regen-
peated with slow, dropwise addition of DMAD over two eration of the catalyst (R1, R2 = electron-donating;
hours, small amounts of pyranochromenes 3 (approxi- Scheme 2). However, when R1 and R3 are electron-
mately 5%) were also detected.
withdrawing, the ring closure to 3 becomes difficult be-
cause the negative charge on the formyl oxygen is sub-
stantially reduced. In this case, zwitterion 6 preferentially
reacts with a second molecule of acetylenic ester 2 to yield
zwitterion 9 which, again, most probably, attacks the C2
chromone carbon to furnish intermediate 10. Depending
Mechanistically, the reaction may be rationalized as in-
volving initial attack of the zwitterion 6, generated from
4-picoline and acetylenedicarboxylate, on the C2
chromone carbon of 1 to give the intermediate 7, which,
R3
E
R2
R1
O
O
E
E
+
N
X
X = Me, NMe2
H
4
– CO
– HCO
R3
R3
R3
E
E
H
E
H
R2
R1
O
O
R2
R1
O
O
R2
R1
O
O
E
E
E
E
E
– R4O
1,5-H
shift
H
E
E
X
12
O
14
13
O
O
O
O
N
N
O
X
R4
X
N
–
R3
R3
E
R3
E
E
b
H
O
E
H
R2
R1
O
O
R2
R1
O
b
E
O
R2
R1
O
O
E
N
X
a
path a
a
O
CHO
OR4
E
E
E
a
OR4
O
E
N
N
O
1
10
11
9
E = COOR4
X
X
path b
9a X = Me, 4-picoline
9b X = NMe2, DMAP
E
E
R1
E
R1
R2
R3
E
R2
E
E
electrocyclic
ring closure
R3
E
N
O
O
E
OH
OH
N
O
O
X
– DMAP
– HCO
E
15
16
X
E
E
H
R1
R1
R1
H
H
H
R2
R3
R2
R3
R2
R3
E
E
E
E
E
E
– DMAP
– CO
– R4O
O
O
C
O
OH
OH
OH
C
O
N
X
N
X
O
O
X = NMe2
R4
5
18
17
Scheme 3 Plausible mechanism for the reaction of substituted 3-formylchromones 1 with zwitterions 9 to afford compounds 4 or 5
Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York

100
M. A. Terzidis et al.
PAPER
on the nature of the chromone substituents, intermediate respectively. Moreover, a hydroxyl proton appears in the
10 can follow two different reaction paths, as shown in 1H NMR spectrum as a singlet at d = 11.74 ppm that cor-
Scheme 3. When R1 and R2 are electron-withdrawing, it is relates with the quaternary carbons at d = 118.5 (C3¢) and
likely that intermediate 10 reacts further by Path a; thus, 163.4 ppm (C2¢). In addition, the proton at d = 7.44 ppm
after ring closure to 11 and elimination of the catalyst, in- shows COLOC correlations with the carbonyl carbon at
termediate 12 is generated, which, by 1,5-H shift, gives d = 198.7 ppm, and also with C2¢ and C4¢. In addition to
13. By attack of the catalyst on the ester carbon13 at the 1- the hydroxybenzoyl moiety, the presence of a symmetri-
position of 13, finally the xanthone derivatives 4 are ob- cally substituted aromatic ring was established as follows.
tained. However, when R1 and R2 are electron-donating A two-proton singlet appears at d = 8.50 ppm with its car-
and the organocatalyst is DMAP, Path b is followed lead- bon at d = 134.3 ppm (C4 and C6) showing COLOC cor-
ing to intermediate 15 through pyran ring opening. Subse- relations with the hydroxybenzoyl carbonyl carbon at d =
quent electrocyclic ring closure to 16 generates the 198.7 ppm, the two identical ester carbonyl carbons at d =
functionalized benzophenone derivatives 5, as depicted in 164.3 ppm and also to C2 (d = 139.3 ppm) bearing the
Scheme 3.
third carbomethoxy group.
The assigned molecular structures of all new compounds In conclusion, a new and efficient protocol for the organo-
4 and 5 are based on rigorous spectroscopic analysis, in- catalytic one-pot synthesis of the otherwise almost inac-
cluding IR, NMR (1H, 13C, DEPT, COSY, NOESY, HET- cessible,
functionalized
benzophenones
and
COR and COLOC), MS and elemental analysis data.
polysubstituted xanthones has been described; their for-
mation depends on the chromone substitution pattern and
on the basicity of the catalyst. The isolated products could
possess valuable biological activities. The experimental
simplicity and metal-free conditions of the synthesis are
especially noteworthy.
Regarding the structure of the xanthones 4, as a represen-
tative example the assignment of 4h is described. In the 1H
NMR spectrum, the presence and position of the three
chromone aromatic protons was unequivocally identified
from their splitting pattern and COLOC correlations
(Figure 1). The presence of one more aromatic proton res-
onating at d = 8.99 ppm with its carbon at d = 131.3 ppm
and of only three ester ethyl groups were also identified.
This proton gave characteristic COLOC correlations with
one of the three ester carbonyl carbons at d = 163.9 ppm,
with the chromone carbonyl carbon at d = 174.1 ppm (the
corresponding carbonyl carbon in 1g resonates at d =
174.5 ppm) and also with the quaternary carbons at d =
Melting points were measured with a Kofler hot-stage apparatus
and are uncorrected. Petroleum ether (PE) refers to the fraction boil-
ing between 60–80 °C. Column chromatography was carried out us-
ing Merck silica gel. TLC was performed using precoated silica gel
glass plates (0.25 mm) containing fluorescent indicator UV254 pur-
chased from Macherey–Nagel (PE–EtOAc, 3:1). NMR spectra were
recorded at r.t. with Bruker AM 300 or AVANCE 300 spectrome-
ters operating at 300 MHz for 1H and 75 MHz for 13C, respectively,
154.5 (C4a) and 140.4 ppm (C3); thus, the whole molec- using CDCl3 as solvent. Chemical shifts (ppm) are expressed in d
values relative to TMS as internal standard for H and relative to
ular carbon connectivity was assigned (Figure 1).
1
TMS (d = 0.00 ppm) or to CDCl3 (d = 77.05 ppm) for 13C NMR
spectra. Coupling constants (nJ) are reported in Hz. Second order 1H
H
COOEt
COOEt
NMR spectra were analyzed by simulation.14 IR spectra were re-
corded with a Perkin–Elmer 1600 series FTIR spectrometer and are
reported in wavenumbers (cm–1). LC-MS (ESI, 1.65 eV) spectra
were recorded with an LCMS-2010 EV system (Shimadzu). Ele-
mental analyses were performed with a Perkin–Elmer 2400-II CHN
analyzer.
H
O
COOEt
O2N
H
O
H
4h
Reaction of Substituted 3-Formylchromones 1 with Acetylene-
dicarboxylates 2 Catalyzed by 4-Picoline or DMAP; Typical
Procedure
COOCH3
COOCH3
H
O
H
H
H
H
DMAD (2a; 0.170 g, 1.2 mmol) was added to a stirred solution of
3-formylchromone (1a; 0.174 g, 1 mmol) and DMAP (0.025 g, 1.0
mmol) in dimethoxyethane (10 mL) at –18 °C. The system was al-
lowed to come to r.t. (~25 °C) and then stirred for 12 h. Distillation
of the solvent in vacuo was followed by column chromatography on
silica gel (PE–EtOAc, 5:1→3:1) to give either 9-oxo-9H-xanthene-
2,3,4-tricarboxylates (4e–h) or 2-hydroxybenzoylbenzene-1,2,3-
tricarboxylates (5a–e, 5i and 5j).
COOCH3
O
H
H
5a
Figure 1 Diagnostic COLOC correlations between protons and car-
bons (via 2JC–H and 3JC–H) in compounds 4h and 5a
Regarding the structure of the polysubstituted benzophe-
nones, the assignment of 5a is described. The assignment
of the four aromatic protons of the hydroxybenzoyl moi-
ety was clear from the splitting patterns, with protons res-
onating as a doublet at d = 7.12 ppm, as a doublet of
doublets at d = 7.58 ppm, as a doublet of doublets at d =
6.93 ppm and as a doublet at d = 7.44 ppm, and their car-
bons resonating at d = 118.9, 137.3, 119.3 and 132.9 ppm,
In all cases some unreacted chromone was also isolated. The yields
were calculated on the basis of acetylene dicarboxylate. In the case
of chromones 1f and 1g the reaction also proceeded analogously
with 4-picoline leading to formation of xanthones 4.
Trimethyl 5-(2-Hydroxybenzoyl)benzene-1,2,3-tricarboxylate
(5a)
Yield: 0.139 g (62%); yellow crystals; mp 141–143 °C.
Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York

PAPER
Functionalized Benzophenones and Polysubstituted Xanthones
101
IR (KBr): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm–1.
(C6¢), 134.1 (C4, C6), 138.3 (C1, C3), 147.0 (C4¢), 139.4 (C2),
161.8 (C2¢), 164.1 (1-CO, 3-CO), 168.0 (2-CO), 197.4 (5-CO).
LC-MS (ESI, 1.65 eV): m/z (%) = 443/445 (100) [M+ + Na].
1H NMR (CDCl3): d = 3.95 (s, 6 H, 1-COOCH3, 3-COOCH3), 4.05
(s, 3 H, 2-COOCH3), 6.93 (ddd, J = 8.1, 7.2, 1.0 Hz, 1 H, H-5¢),
7.11 (dd, J = 8.4, 1.0 Hz, 1 H, H-3¢), 7.44 (dd, J = 8.1, 1.5 Hz, 1 H,
H-6¢), 7.58 (ddd, J = 8.4, 7.2, 1.5 Hz, 1 H, H-4¢), 8.50 (s, 2 H, H-4,
H-6), 11.73 (s, 1 H, OH).
Anal. Calcd for C20H17ClO8: C, 57.09; H, 4.07. Found: C, 57.16; H,
4.20.
13C NMR (CDCl3): d = 53.1 (1-OCH3, 2-OCH3, 3-OCH3), 118.5
(C1¢), 118.9 (C3¢), 119.3 (C5¢), 129.0 (C5), 132.9 (C6¢), 134.3 (C4,
C6), 137.3 (C4¢), 138.7 (C1, C3), 139.3 (C2), 163.4 (C2¢), 164.3 (1-
CO, 3-CO), 167.9 (2-CO), 198.7 (5-CO).
Trimethyl 7-Chloro-9-oxo-9H-xanthene-2,3,4-tricarboxylate
(4e)
Yield: 0.022 g (9%); yellowish crystals; mp 167–169 °C.
IR (KBr): 1743 (C=O), 1728 (C=O), 1671 (C=O) cm–1.
1H NMR (CDCl3): d = 3.96 (s, 3 H, 2-OCH3), 3.97 (s, 3 H, 4-
OCH3), 4.02 (s, 3 H, 3-OCH3), 7.50 (d, J = 9.0 Hz, 1 H, H-5), 7.73
(dd, J = 9.0, 2.7 Hz, 1 H, H-6), 8.29 (d, J = 2.7 Hz, 1 H, H-8), 8.99
(s, 1 H, H-1).
LC-MS (ESI, 1.65 eV): m/z (%) = 427 (95) [M+ + Na + MeOH], 395
(100) [M+ + Na].
Anal. Calcd for C19H16O8: C, 61.29; H, 4.33. Found: C, 61.16; H,
4.28.
13C NMR (CDCl3): d = 53.1 (3-OCH3), 53.4 (2-OCH3, 4-OCH3),
120.2 (C5), 121.8 (C4), 122.3 (C2), 123.0 (C8a), 124.8 (C9a), 126.2
(C8), 131.4 (C7), 131.9 (C1), 135.9 (C6), 139.9 (C3), 154.2 (C10a),
154.8 (C4a), 163.7 (4-CO), 164.4 (2-CO), 166.5 (3-CO), 174.3
(C9).
Trimethyl 5-(2-Hydroxy-5-methylbenzoyl)benzene-1,2,3-tri-
carboxylate (5b)
Yield: 0.161 g (61%); yellow crystals; mp 127–129 °C.
IR (KBr): 1743 (C=O), 1738 (C=O), 1635 (C=O) cm–1.
1H NMR (CDCl3): d = 2.26 (s, 3 H, 5¢-CH3), 3.95 (s, 6 H, 1-
COOCH3, 3-COOCH3), 4.05 (s, 3 H, 2-COOCH3), 7.02 (d,
J = 8.5 Hz, 1 H, H-3¢), 7.17 (d, J = 2.1 Hz, 1 H, H-6¢), 7.39 (dd,
J = 8.5, 2.1 Hz, 1 H, H-4¢), 8.48 (s, 2 H, H-4, H-6), 11.55 (s, 1 H,
OH).
LC-MS (ESI, 1.65 eV): m/z (%) = 443/445 (60) [M+ + K], 319 (60),
274/276 (100).
Anal. Calcd for C19H13ClO8: C, 56.38; H, 3.24. Found: C, 56.16; H,
3.28.
13C NMR (CDCl3): d = 20.4 (5¢-CH3), 53.1 (1-OCH3, 2-OCH3, 3-
OCH3), 118.2 (C1¢), 118.6 (C3¢), 128.5 (C5¢), 128.9 (C5), 132.5
(C6¢), 134.2 (C4, C6), 138.5 (C4¢), 138.9 (C1, C3), 139.0 (C2),
161.4 (C2¢), 164.3 (1-CO, 3-CO), 168.0 (2-CO), 198.6 (5-CO).
Trimethyl 5-(2-Hydroxy-5-chlorobenzoyl)benzene-1,2,3-tricar-
boxylate (5e)
Yield: 0.136 g (56%); yellow crystals; mp 183–185 °C.
IR (KBr): 1745 (C=O), 1739 (C=O), 1686 (C=O) cm–1.
1H NMR (CDCl3): d = 3.96 (s, 6 H, 1-OCH3, 3-OCH3), 4.05 (s, 3 H,
2-OCH3), 7.03 (d, J = 9.0 Hz, 1 H, H-3¢), 7.51 (dd, J = 9.0, 2.4 Hz,
1 H, H-4¢), 7.65 (s, 2 H, H-4, H-6), 8.30 (d, J = 2.4 Hz, 1 H, H-6¢),
11.58 (s, 1 H, OH).
LC-MS (ESI, 1.65 eV): m/z (%) = 441 (95) [M+ + Na + MeOH], 409
(100) [M+ + Na].
Anal. Calcd for C20H18O8: C, 62.17; H, 4.70. Found: C, 62.05; H,
4.78.
13C NMR (CDCl3): d = 53.0 (1-OCH3, 3-OCH3), 53.1 (2-OCH3),
119.2 (C1¢), 120.6 (C3¢), 124.1 (C6¢), 128.5 (C5¢), 129.4 (C5), 134.1
(C4, C6), 137.2 (C4¢), 138.1 (C1, C3), 139.5 (C2), 161.9 (C2¢),
164.1 (1-CO, 3-CO), 167.6 (2-CO), 197.8 (5-CO).
Trimethyl 5-(2-Hydroxy-5-isopropylbenzoyl)benzene-1,2,3-tri-
carboxylate (5c)
Yield: 0.147 g (59%); yellow crystals; mp 61–63 °C.
IR (KBr): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm–1.
1H NMR (CDCl3): d = 1.19 [d, J = 8.5 Hz, 6 H, 5¢-CH(CH3)2], 2.84
[sept, J = 8.5 Hz, 1 H, 5¢-CH(CH3)2], 3.97 (s, 6 H, 1-OCH3, 3-
OCH3), 4.06 (s, 3 H, 2-OCH3), 7.05 (d, J = 8.6 Hz, 1 H, H-3¢), 7.29
(d, J = 2.5 Hz, 1 H, H-6¢), 7.46 (dd, J = 8.6, 2.5 Hz, 1 H, H-4¢), 8.56
(s, 2 H, H-4, H-6), 11.53 (s, 1 H, OH).
13C NMR (CDCl3): d = 20.4 [5¢-CH(CH3)2], 33.1 [5¢-CH(CH3)2],
52.9 (1-OCH3, 3-OCH3), 53.0 (2-OCH3), 118.2 (C1¢), 118.6 (C3¢),
128.5 (C5¢), 128.9 (C5), 132.5 (C6¢), 134.2 (C4, C6), 138.0 (C1,
C3), 139.0 (C4¢), 139.0 (C2), 161.5 (C2¢), 164.2 (1-CO, 3-CO),
167.8 (2-CO), 198.2 (5-CO).
LC-MS (ESI, 1.65 eV): m/z (%) = 406/408 (100) [M+].
Anal. Calcd for C19H15ClO8: C, 56.10; H, 3.72. Found: C, 55.96; H,
3.62.
Trimethyl 5,7-Dibromo-9-oxo-9H-xanthene-2,3,4-tricarboxy-
late (4f)
a) 4-Picoline as catalyst.
Yield: 0.203 g (64%); yellowish crystals; mp 211–213 °C.
IR (Nujol): 1753 (C=O), 1730 (C=O), 1665 (C=O) cm–1.
1H NMR (CDCl3): d = 3.97 (s, 3 H, 2-OCH3),* 3.99 (s, 3 H, 4-
OCH3),* 4.07 (s, 3 H, 3-OCH3), 8.15 (d, J = 2.5 Hz, 1 H, H-6), 8.41
(d, J = 2.5 Hz, 1 H, H-8), 9.00 (s, 1 H, H-1). *The assignments may
be interchanged.
13C NMR (CDCl3): d = 53.1 (OCH3), 53.4 (OCH3), 53.6 (OCH3),
113.2 (C5), 118.5 (C8a), 121.4 (C7), 123.4 (C4), 123.5 (C2), 125.3
(C9a), 128.8 (C8), 131.9 (C1), 140.5 (C3), 141.4 (C6), 151.6 (C4a),
154.6 (C10a), 163.8 (4-CO), 164.3 (2-CO), 167.8 (3-CO), 173.8
(C9).
LC-MS (ESI, 1.65 eV): m/z (%) = 437 (100) [M+ + Na].
Anal. Calcd for C22H22O8: C, 63.76; H, 5.35. Found: C, 63.88; H,
5.46.
Trimethyl 5-(2-Hydroxy-4-methyl-5-chlorobenzoyl)benzene-
1,2,3-tricarboxylate (5d)
Yield: 0.159 g (63%); yellow crystals; mp 156–158 °C.
IR (KBr): 1751 (C=O), 1736 (C=O), 1697 (C=O) cm–1.
1H NMR (CDCl3): d = 2.42 (s, 3 H, 4¢-CH3), 3.97 (s, 6 H, 1-OCH3,
3-OCH3), 4.05 (s, 3 H, 2-OCH3), 7.00 (s, 1 H, H-3¢), 7.36 (s, 1 H,
H-6¢), 8.47 (s, 2 H, H-4, H-6), 11.60 (s, 1 H, OH).
13C NMR (CDCl3): d = 21.0 (4¢-CH3), 53.2 (1-OCH3, 2-OCH3, 3-
OCH3), 117.4 (C1¢), 120.8 (C3¢), 124.8 (C5¢), 129.2 (C5), 132.1
LC-MS (ESI, 1.65 eV): m/z (%) = 581/583/585 (60) [M+ + Na +
MeOH], 565/567/569 (100) [M+ + K], 549/551/553 (50) [M+ + Na].
Anal. Calcd for C19H12Br2O8: C, 43.21; H, 2.29. Found: C, 43.11;
H, 2.28.
b) DMAP as catalyst.
Yield: 0.184 g (58%).
Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York

102
M. A. Terzidis et al.
PAPER
Trimethyl 7-Nitro-9-oxo-9H-xanthene-2,3,4-tricarboxylate (4g)
a) 4-Picoline as catalyst.
Anal. Calcd for C22H22O8: C, 63.76; H, 5.35. Found: C, 63.66; H,
5.28.
Yield: 0.166 g (59%); yellow crystals; mp 181–183 °C.
IR (KBr): 1748 (C=O), 1740 (C=O), 1732 (C=O), 1688 (C=O) cm–1.
Triethyl 5-(2-Hydroxy-5-methylbenzoyl)benzene-1,2,3-tricar-
boxylate (5j)
1H NMR (CDCl3): d = 3.98 (s, 6 H, 2-OCH3, 4-OCH3), 4.04 (s, 3 H,
3-OCH3), 7.71 (d, J = 9.1 Hz, 1 H, H-5), 8.62 (dd, J = 9.1, 2.7 Hz,
1 H, H-6), 9.02 (d, J = 2.7 Hz, 1 H, H-8), 9.02 (s, 1 H, H-1).
Yield: 0.165 g (57%); yellow crystals; mp 129–131 °C.
IR (KBr): 3434 (br, OH), 1747 (C=O), 1729 (C=O), 1712 (C=O),
1633 (C=O) cm–1.
13C NMR (CDCl3): d = 53.2 (3-OCH3), 53.5 (2-OCH3, 4-OCH3),
120.3 (C5), 121.5 (C4),* 121.7 (C2),* 123.2 (C8a), 123.5 (C8),
125.7 (C9a), 130.0 (C6), 131.9 (C1), 140.6 (C3), 144.8 (C7), 154.6
(C4a), 158.6 (C10a), 163.3 (4-CO), 164.2 (2-CO), 166.2 (3-CO),
174.0 (C9). *The assignments may be interchanged.
LC-MS (ESI, 1.65 eV): m/z (%) = 470 (40) [M+ + MeOH + Na], 448
(15) [M+ + H + MeOH], 416 (60) [M+ + H], 386 (95), 371 (50), 328
(100).
1H NMR (CDCl3): d = 1.39 (t, J = 7.2 Hz, 6 H, 1-OCH2CH3, 3-
OCH2CH3), 1.43 (t, J = 6.9 Hz, 3 H, 2-OCH2CH3), 2.26 (s, 3 H, 5¢-
CH3), 4.41 (q, J = 7.2 Hz, 4 H, 1-OCH2CH3, 3-OCH2CH3), 4.51 (q,
J = 6.9 Hz, 2 H, 2-OCH2CH3), 7.02 (d, J = 8.4 Hz, 1 H, H-3¢), 7.19
(d, J = 2.1 Hz, 1 H, H-6¢), 7.39 (dd, J = 8.4, 2.1 Hz, 1 H, H-4¢), 8.45
(s, 2 H, H-4, H-6), 11.60 (s, 1 H, OH).
13C NMR (CDCl3): d = 13.9 (2-OCH2CH3), 14.2 (1-OCH2CH3, 3-
OCH2CH3), 20.4 (5¢-CH3), 62.2 (2-OCH2CH3), 62.3 (1-OCH2CH3,
3-OCH2CH3), 118.3 (C1¢), 118.6 (C3¢), 128.6 (C5¢), 128.9 (C5),
132.6 (C6¢), 134.0 (C4, C6), 138.7 (C1, C3), 138.5 (C4¢), 139.1
(C2), 161.4 (C2¢), 164.0 (1-CO, 3-CO), 167.5 (2-CO), 198.9 (5-
CO).
Anal. Calcd for C19H13NO10: C, 54.95; H, 3.16; N, 3.37. Found: C,
55.06; H, 3.28; N 3.46.
b) DMAP as catalyst.
Yield: 0.149 g (53%).
LC-MS (ESI, 1.65 eV): m/z (%) = 483 (80) [M+ + Na + MeOH], 451
(100) [M+ + Na].
Triethyl 7-Nitro-9-oxo-9H-xanthene-2,3,4-tricarboxylate (4h)
a) 4-Picoline as catalyst.
Anal. Calcd for C23H24O8: C, 64.48; H, 5.65. Found: C, 64.32; H,
5.73.
Yield: 0.167 g (61%); yellowish crystals; mp 159–161 °C.
IR (Nujol): 1752 (C=O), 1735 (C=O), 1696 (C=O) cm–1.
Acknowledgment
1H NMR (CDCl3): d = 1.40 (t, J = 7.3 Hz, 3 H, 2-OCH2CH3), 1.44
(t, J = 7.3 Hz, 3 H, 4-OCH2CH3), 1.47 (t, J = 7.1 Hz, 3 H, 3-
OCH2CH3), 4.43 (q, J = 7.1 Hz, 2 H, 3-OCH2CH3), 4.44 (q,
J = 7.3 Hz, 2 H, 2-OCH2CH3), 4.52 (q, J = 7.3 Hz, 2 H, 4-
OCH2CH3), 7.69 (d, J = 9.3 Hz, 1 H, H-5), 8.62 (dd, J = 9.3, 2.7 Hz,
1 H, H-6), 8.97 (s, 1 H, H-1), 9.19 (d, J = 2.7 Hz, 1 H, H-8).
The authors thank Professor Philip Kocienski for improving consi-
derably the mechanistic discussion.
References
13C NMR (CDCl3): d = 13.9 (OCH2CH3), 14.2 (OCH2CH3), 14.2
(OCH2CH3), 62.4 (OCH2CH3), 62.7 (OCH2CH3), 62.8 (OCH2CH3),
120.2 (C5), 121.5 (C4),* 121.6 (C2),* 123.5 (C8), 123.6 (C8a),
126.3 (C9a), 129.9 (C6), 131.3 (C1), 140.4 (C3), 144.7 (C7), 154.4
(C4a), 158.6 (C10a), 163.0 (4-CO), 163.9 (2-CO), 165.6 (3-CO),
174.1 (C9). *The assignments may be interchanged.
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LC-MS (ESI, 1.65 eV): m/z (%) = 457 (100) [M+].
Anal. Calcd for C22H19NO10: C, 57.77; H, 4.19; N, 3.06. Found: C,
57.86; H, 4.28; N 3.00.
Organocatalysis: From Biomimetic Concepts to
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b) DMAP as catalyst.
Yield: 0.151 g (55%).
Triethyl 5-(2-Hydroxybenzoyl)benzene-1,2,3-tricarboxylate
(5i)
Yield: 0.177 g (63%); yellowish crystals; mp 84–86 °C.
IR (KBr): 1739 (C=O), 1696 (C=O), 1638 (C=O) cm–1.
1H NMR (CDCl3): d = 1.39 (t, J = 7.2 Hz, 6 H, 1-OCH2CH3, 3-
OCH2CH3), 1.43 (t, J = 7.1 Hz, 3 H, 2-OCH2CH3), 4.40 (q,
J = 7.2 Hz, 4 H, 1-OCH2CH3, 3-OCH2CH3), 4.50 (q, J = 7.1 Hz,
2 H, 2-OCH2CH3), 6.92 (ddd, J = 8.1, 7.3, 1.5 Hz, 1 H, H-5¢), 7.12
(dd, J = 8.4, 0.8 Hz, 1 H, H-3¢), 7.44 (dd, J = 8.1, 1.5 Hz, 1 H, H-
6¢), 7.57 (ddd, J = 8.4, 7.3, 1.5 Hz, 1 H, H-4¢), 8.46 (s, 2 H, H-4, H-
6), 11.78 (s, 1 H, OH).
13C NMR (CDCl3): d = 13.9 (2-OCH2CH3), 14.1 (1-OCH2CH3, 3-
OCH2CH3), 62.2 (2-OCH2CH3), 62.3 (1-OCH2CH3, 3-OCH2CH3),
118.6 (C1¢), 118.9 (C3¢), 119.3 (C5¢), 129.6 (C5), 133.0 (C6¢), 134.1
(C4, C6), 137.3 (C4¢), 138.5 (C1, C3), 139.2 (C2), 163.5 (C2¢),
164.0 (1-CO, 3-CO), 167.4 (2-CO), 198.9 (5-CO).
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Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York

PAPER
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Synthesis 2011, No. 1, 97–103 © Thieme Stuttgart · New York