Novel and efficient one-step parallel synthesis of dibenzopyranones via suzuki-miyaura cross coupling

Article abstract of DOI:10.1021/cc100068a

Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic analogues from bromo arylcarboxylates and o-hydroxyarylboronic acids via Suzuki-Miyaura cross coupling reaction is described. Spontaneous lactonization

Full text of DOI:10.1021/cc100068a

664
J. Comb. Chem. 2010, 12, 664–669
Novel and Efficient One-Step Parallel Synthesis of Dibenzopyranones
via Suzuki-Miyaura Cross Coupling
Kodumuru Vishnumurthy* and Alexandros Makriyannis
Center for Drug DiscoVery, 360 Huntington AVenue, 116 Mugar Hall,
Boston, Massachusetts 02115-5000
ReceiVed April 21, 2010
Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic
analogues from bromo arylcarboxylates and o-hydroxyarylboronic acids via Suzuki-Miyaura cross coupling
reaction is described. Spontaneous lactonization gave dibenzopyranones and heterocyclic analogues bearing
electron-donating and -withdrawing groups on both aromatic rings in good to excellent yields.
Introduction
for the treatment of neuropathic pain, inflammation, and
Alzheimer’s diseases. As part of an ongoing lead optimiza-
tion project, we required a facile route to prepare a library
of dibenzopyranones and heterocyclic analogues 3. We have,
therefore, investigated a straightforward route for diben-
zopyranones 3 via tandem Suzuki coupling of bromo
arylcarboxylates 1 with o-hydroxyarylboronic acids 2, fol-
lowed by lactonization (Scheme 1).
In addition, we utilized microwave-assisted organic syn-
thesis, which has attracted increasing attention because of
its potential to accelerate drug discovery research.15 Reaction
times of many organic transformations are often dramatically
reduced from hours to minutes or seconds. Moreover, there
have been several reports of microwave-assisted syntheses
of combinatorial libraries.16 We now report a novel and
efficient one step parallel synthesis of a library of diben-
zopyaranones and heterocyclic analogues 3 via Suzuki-
Miyaura cross coupling of bromo arylcarboxylates 1 with
o-hydroxylarylboronic acids 2.
Dibenzopyranone is a privileged scaffold in many natural
products,1 such as alternariol, graphislactones, autumnariol,
autumnariniol, and altenuisol, and in biologically active
compounds.2 Such lactones have been used as intermediates
in the synthesis of several pharmaceutically interesting
compounds including progesterone, androgen, glucocorticoid
modulators,3 and endothelial cell proliferation inhibitors.4
Furthermore, dibenzopyranones occur naturally in many food
sources including citrus fruits, herbs, and vegetables.5 There
are several methods available for the synthesis of diben-
zopyranones. The most popular involves Suzuki-Miyaura
cross coupling followed by Lewis acid6 or metal7 mediated
lactonization. More recently the Diels-Alder cycloaddition
of 4-cyanocoumarins,8 tert-butyllithium-mediated cyclization
of bromobenzylfluorophenyl ethers,9 and ruthenium-cata-
lyzed cyclotrimerization of aryl diynes10 have been reported.
In 2002, Abbott Laboratories reported a practicable and
scalable synthesis of glucocorticoid receptor A-224817.0
through a Negishi cross coupling.11 However, none of these
methods are suitable for the parallel synthesis approach to
generating large numbers of analogues for drug discovery
research. The disadvantages include low overall yields, long
reaction times, low temperature conditions, multistep se-
quences, and the need to purify intermediates. Although the
previous method of coupling of o-methoxyphenylboronic
acids with bromo arylcarboxylates 1, followed by borontri-
bromide6 or hydroiodic acid mediated lactonization,12 has
potential for parallel synthesis, but suffers from the following
drawbacks: (a) it is two step procedure requiring minimum
the purification of two intermediates, (b) alkoxy and alkoxy-
ester substituents undergo demethylation in the presence of
borontribromide,13 and (c) BBr3-mediated lactonization6
requires the reaction to be performed at -78 °C, while HI-
mediated lactonization requires to be conducted at 110 °C.12
Recently, we reported13 that dibenzopyranone analogues
act as CB2 agonists and that they are being investigated
Results and Discussion
To develop an efficient methodology for the synthesis of
dibenzopyranones and heterocyclic analogues 3, using bromo
arylcarboxylates 1 and o-hydroxylarylboronic acids 2, various
catalysts, ligands, bases, and solvents were first screened for
the Suzuki-Miyaura cross coupling reaction (Table 1). At
the outset of the studies, commercially available methyl
2-bromo-5-methoxybenzoate 1{1}, methyl 2-bromo-4-fluo-
robenzoate 1{2}, and o-hydroxyphenylboronic acid 2{1}
were selected as representative reactants (Table 1). We
initially examined the reaction conditions reported for
Scheme 1. Suzuki-Miyaura Cross Coupling of Bromo
Arylcarboxylates 1 and o-Hydroxyarylboronic Acids 2
* To whom correspondence should be addressed. Tel.: 617-373-7620; Fax:
617-373-7493; E-mail: kvishnumurthy@hotmail.com; v.kodumuru@neu.edu.
10.1021/cc100068a  2010 American Chemical Society
Published on Web 07/20/2010

Parallel Synthesis of Dibenzopyranones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 665
Table 1. Optimization of Suzuki-Miyaura Cross Coupling
Reaction Conditions
bromopyridine carboxylates (entries 22 and 23), and fused
bromoaryl carboxylates (entries 24 and 25) also reacted well
to give the corresponding products (entries 20-25, Table
2). Clearly, the tandem coupling followed by lactonization
is a facile protocol to generate a library of compounds 3.
Conclusion
A simple, rapid and versatile one-step synthetic route to
dibenzopyranones 3 and their heterocyclic analogues has
been developed. The tandem C-C bond formation via
Suzuki-Miyaura cross coupling, followed by lactonization
affords the desired dibenzopyranones 3 in a manner suitable
for parallel synthesis. The protocol is complementary to the
existing syntheses for dibenzopyranones in terms of number
of synthetic steps, ease of accessibility of starting materials,
and suitability for combinatorial format.
yielda (%)
3{1} 3{2}
entry
1
conditions
chloro(di-2-norbornylphosphino)(2′-dimethylamino-
1,1′-biphenyl-2yl)palladium(II) (5 mol %),
KF (5 equiv), dioxane, 130 °C, 15 min
Pd(OAc)2 (1 mol %), (o-biphenyl)P(t-Bu)2 (2 mol %),
KF (3 equiv), THF, rt, 24 h
PdCl2(PPh3)2 (10 mol %), Cs2CO3 (4 equiv), DME,
H2O, 130 °C, 15 min
1,1′-bis(diphenylphosphino) ferrocene
dichloropalladium(II) (10 mol %), NaOAc (5 equiv),
DME, H2O, 150 °C, 15 min
Pd(PCy3)2Cl2 (5 mol %), CsF (2 equiv), NMP,
130 °C, 15 min
Pd(PPh3)4 (10 mol %), Cs2CO3 (4 equiv), DME, H2O,
125 °C, 15 min
54
48
2
3
4
45
38
31
47
41
29
Experimental Section
5
6
31
98
32
96
General. Unless otherwise noted, reagents and solvents
were used as received from commercial suppliers. All
palladium catalysts were purchased from Strem chemicals,
Inc., and boronic acids were purchased from Combi-Blocks
a Isolated product after purification by silica gel column chro-
matography.
1
Inc., unless otherwise mentioned. H NMR spectra were
chloro(di-2-norbornylphosphino)(2′-dimethylamino-1,1′-bi-
phenyl-2yl)palladium(II), an air-stable catalyst that is highly
active for C-C and C-N coupling reactions with aryl
chlorides.17 When a solution of 1{1} or 1{2} (1 equiv), 2{1}
(1.2 equiv), potassium fluoride (5 equiv), and 5 mol % of
the above catalyst in dioxane was heated in a microwave
reactor at 130 °C for 15 min, the desired product, that is,
8-methoxy-6H-benzo[c]chromen-6-one 3{1} or 9-fluoro-6H-
benzo[c]chromen-6-one 3{2}, was obtained in 54 and 48%
isolated yields, respectively (entry 1, Table 1). Coupling
under Buchwald’s conditions using highly active palladium
catalyst, that is,18 potassium fluoride, Pd(OAc)2 and (o-
biphenyl)P(t-Bu)2 in THF at room temperature, afforded 3{1}
and 3{2} in 45% and 47% yields, respectively (entry 2, Table
1). To improve the yields for the desired products 3,
we screened several catalysts, such as Pd(PCy3)2Cl2,
PdCl2(PPh3)2, Pd(PPh3)4, and 1,1′-bis(diphenylphosphino)
ferrocene dichloropalladium(II), bases, such as NaOAc,
Cs2CO3, CsF, and KF, and ligand (o-biphenyl)P(t-Bu)2) with
different equivalents and combinations of reagents and
microwave irradiation temperatures in THF, NMP, DME,
or dioxane. The results of formation of products 3{1} and
3{2} are shown in Table 1. From the screening results, the
best conditions for coupling of 1{1} or 1{2} with 2{1} were
found to be the use of Pd(PPh3)4 as a catalyst in the presence
of Cs2CO3 in DME at 125 °C under microwave irradiation
for 15 min (Table 1, entry 6).
recorded on a Varian Inova 500 and 400 MHz spectrometers;
the chemical shifts are reported in parts per million (δ), and
the coupling constants are reported in hertz. IR spectra were
obtained on a Bruker ALPHA ATR spectrometer. The high-
resolution mass spectral (HRMS) data (EI) were obtained
on a Micromass 70-VSE instrument. The final compounds
were purified with WATERS preparative LC/MS autopuri-
fication system, unless otherwise mentioned. The microwave
reactions were conducted in a Emrys optimizer from Personal
Chemistry, and generally, 10 reactions were performed
sequentially for parallel library synthesis.
Methyl 2-Bromo-5-(trifluoromethyl)benzoate (1{7}). To
a solution of 2-bromo-5-(trifluoromethyl) benzoic acid (5.00
g, 18.58 mmol) in methanol (20 mL) was added thionyl
chloride (1.0 mL, 13.7 mmol), and the resulting mixture was
refluxed for 8 h. After the mixture was cooled to room
temperature, the solvent was concentrated to dryness under
reduced pressure. The residue was dissolved in dichlo-
romethane (40 mL) and washed with saturated aqueous
sodium bicarbonate solution (50 mL) and water (100 mL).
The organic layer was dried over anhydrous Na2SO4, and
the filtrate was concentrated to dryness under reduced
pressure to give 1{7} (4.98 g, 95% yield). 1H NMR (CDCl3,
400 MHz): δ 8.07 (s, 1H), 7.81 (d, J ) 8.0 Hz, 1H),
7.59-7.56 (m, 1H), 3.97 (s, 3H).
General Procedure for the Preparation of 2-Hy-
droxyarylboronic Acids (1{27-32}). To a solution of
corresponding methoxy boronicacids (1 mmol) in anhydrous
dichloromethane (15 mL), was added boron tribromide (1.2
mmol) at -78 °C under nitrogen atmosphere. The resulting
solution was stirred for 15 min at -78 °C. The cooling bath
was removed, and the reaction mixture was continued to stir
for 30 min at room temperature. The reaction was quenched
with anhydrous methanol (1 mL) at -78 °C, concentrated
in vacuo to dryness. The desired corresponding o-hydroxy
Utilizing the above optimized conditions, Suzuki-Miyaura
cross coupling of various bromo arylcarboxylates 1 (Figure
1) with o-hydroxyarylboronic acids 2 (Figure 2) was
conducted and the results are summarized in Table 2. The
coupling of o-hydroxyarylboronic acids 2 with bromo
arylcarboxylates 1 bearing a range of electron-donating and
electron-withdrawing groups gave corresponding benzo-
pyaranones 3 in good to excellent yields (entries 1-19, Table
2). In addition, bromothiophene carboxylates (entry 20, 21),

666 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Vishnumurthy and Makriyannis
Figure 1. Diversity of bromo arylcarboxylates 1.
1H), 7.95 (d, J ) 8.0 Hz, 1H), 7.74-7.72 (m, 1H),
7.54-7.50 (m, 1H), 7.38-7.34 (m, 2H), 7.29-7.25 (m, 1H).
IR (cm-1): 1731.6, 1611.2, 1420.8, 1300.8, 1187.5, 877.3,
742.1. LC/MS: 215.0 (M + 1). HRMS (EI): m/z calcd for
C13H7FO2 214.0430, found 214.0422.
8-Fluoro-6H-benzo[c]chromen-6-one (3{3}). Yield 88%,
white solid. 1H NMR (CDCl3, 500 MHz): δ 8.14-8.12 (m,
1H), 8.06-8.03 (m, 1H), 8.02-7.99 (m, 1H), 7.57-7.53 (m,
1H), 7.50-7.47 (m, 1H), 7.38-7.34 (m, 2H). LC/MS: 214.9
(M + 1). HRMS (EI): m/z calcd for C13H7FO2 214.0430,
found 214.0437.
Figure 2. Diversity of o-hydroxyarylboronic acids 2.
boronic acids were confirmed by LC/MS and used without
further purification.
8-Methyl-6H-benzo[c]chromen-6-one (3{4}).6a Yield:
Illustrative Example: Preparation of 8-Methoxy-6H-
benzo[c]chromen-6-one (3{1}).19 A solution of methyl
3-methoxybenzoate (1{1}, 0.5 mmol), 2-hydroxyarylboronic
acid (2{1}, 0.65 mmol, 1.3 equiv), and cesium carbonate (2
mmol, 4 equiv) in a mixture of dimethoxyethane (5 mL) and
water (0.75 mL) was degassed with argon for 5 min.
Tetrakis(triphenylphosphine)palladium (0) (10 mol %) was
added, and the reaction tube was sealed. The reaction mixture
was heated in a microwave (Emrys optimizer from Personal
Chemistry) at 125 °C (power 300 W) for 15 min. After it
was cooled at room temperature, the reaction mixture was
diluted with water (30 mL) and extracted with dichlo-
romethane (2 × 15 mL). The combined organic layers were
passed through a phase separator and concentrated in vacuo.
The residue was purified with WATERS preparative LC/
MS autopurification system to afford the title compound in
98% yield. 1H NMR (CDCl3, 500 MHz): δ 8.05 (d, J ) 8.5
Hz, 1H), 7.99 (d, J ) 8.0 Hz, 1H), 7.82 (d, J ) 3.0 Hz,
1H), 7.45-7.31 (m, 4H), 3.95 (s, 3H). IR (cm-1): 1707.9,
1610.1, 1479.8, 1276.1, 1024.4, 824.1, 742.1. LC/MS: 226.98
(M + 1). HRMS (EI): m/z calcd for C14H10O3 226.0630,
found 226.0635.
1
88%, white solid. H NMR (CDCl3, 500 MHz): δ 8.18 (s,
1H), 8.02-7.98 (m, 2H), 7.63-7.61 (m, 1H), 7.46-7.43 (m,
1H), 7.35-7.30 (m, 2H), 2.49 (s, 3H). LC/MS: 211.0 (M +
1). HRMS (EI): m/z calcd for C14H10O2 210.0681, found
210.0682.
8-(Trifluoromethoxy)-6H-benzo[c]chromen-6-one (3{5}).
1
Yield: 80%, white solid. H NMR (CDCl3, 500 MHz): δ
8.25 (s, 1H), 8.19 (d, J ) 8.5 Hz, 1H), 8.04 (d, J ) 8.0,
1H), 7.69-7.66 (m, 1H), 7.54-7.51 (m, 1H), 7.41-7.36 (m,
2H). LC/MS: 280.9 (M + 1). HRMS (EI): m/z calcd for
C14H7F3O2 280.0347, found 280.0388.
8-Nitro-6H-benzo[c]chromen-6-one (3{6}).6a Yield: 88%,
1
white solid. H NMR (CDCl3, 500 MHz): δ 9.25 (d, J )
2.5 Hz, 1H), 8.09 (d, J ) 9.0, 2.5 Hz, 1H), 8.31 (d, J ) 8.5
Hz, 1H), 8.14-8.12 (m, 1H), 7.65-7.62 (m, 1H), 7.46-7.42
(m, 2H). LC/MS: 241.9 (M + 1). HRMS (EI): m/z calcd for
C13H7NO4 241.0375, found 241.0358.
8-(Trifluoromethyl)-6H-benzo[c]chromen-6-one (3{7}).
1
Yield: 83%, white solid. H NMR (CDCl3, 500 MHz): δ
8.70 (s, 1H), 8.27 (d, J ) 8.0 Hz, 1H), 8.11 (dd, J ) 8.0,
1.5 Hz, 1H), 8.05 (dd, J ) 8.5, 2.0 Hz, 1H), 7.60-7.56 (m,
1H), 7.43-7.39 (m, 2H). LC/MS: 264.9 (M + 1). HRMS
(EI): m/z calcd for C14H7F3O2 264.0398, found 264.0407.
9-Fluoro-6H-benzo[c]chromen-6-one (3{2}). Yield: 96%,
white solid. 1H NMR (CDCl3, 500 MHz): δ 8.44-8.41 (m,

Parallel Synthesis of Dibenzopyranones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 667
Table 2. Synthesis of a Library of Benzopyranone and Heterocyclic Analogues 3
a Isolated product after purification by silica gel column chromatography. b For known compounds, see refs 6a and 19.

668 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Methyl 6-Oxo-6H-benzo[c]chromene-8-carboxylate (3{8}).
Vishnumurthy and Makriyannis
(CDCl3, 500 MHz): δ 8.52 (d, J ) 3.0 Hz, 1H), 7.82 (dd, J
) 8.0, 1.5 Hz, 1H), 7.79-7.78 (m, 1H), 7.43-7.40 (m, 1H),
7.35-7.33 (m, 1H), 7.30-7.26 (m, 1H). LC/MS: 230.9,
232.9 (M + 1). HRMS (EI): m/z calcd for C13H7ClO2
230.0134, found 230.0126.
8,9-Difluoro-6H-benzo[c]chromen-6-one (3{18}). Yield:
86%, white solid. 1H NMR (CDCl3, 500 MHz): δ 8.21-8.18
(m, 1H), 7.92-7.86 (m, 2H), 7.55-7.51 (m, 1H), 7.40-7.36
(m, 2H). LC/MS: 232.9 (M + 1). HRMS (EI): m/z calcd for
C13H6F2O2 232.0335, found 232.0342.
2,9-Difluoro-6H-benzo[c]chromen-6-one (3{19}). Yield:
94%, white solid. 1H NMR (CDCl3, 500 MHz): δ 8.47-8.44
(m, 1H), 7.67-7.62 (m, 2H), 7.39-7.31 (m, 2H), 7.27-7.23
(m, 1H). LC/MS: 232.9 (M + 1). HRMS (EI): m/z calcd for
C13H6F2O2 232.0335, found 232.0343.
1
Yield: 80%, white solid. H NMR (CDCl3, 500 MHz): δ
9.08 (s, 1H), 8.47 (d, J ) 8.5 Hz, 1H), 8.23 (d, J ) 8.5 Hz,
1H), 8.13-8.11 (m, 1H), 7.57-7.55 (m, 1H), 7.42-7.39 (m,
2H), 3.99 (s, 3H). LC/MS: 254.9 (M + 1). HRMS (EI): m/z
calcd for C15H10O4 254.0579, found 254.0570.
6H-Benzo[c]chromen-6-one (3{9}). Yield: 85%, white
1
solid. H NMR (CDCl3, 500 MHz): δ 8.42 (d, J ) 8.0 Hz,
1H), 8.14 (d, J ) 7.5 Hz, 1H), 8.08 (d, J ) 8.0 Hz, 1H),
7.86-7.83 (m, 1H), 7.61-7.58 (m, 1H), 7.51-7.48 (m, 1H),
7.39-7.33 (m, 2H). IR (cm-1): 1725.5, 1604.9, 1431.6,
1302.1, 1262.2, 1076.2, 743.9. LC/MS: 196.9 (M + 1).
HRMS (EI): m/z calcd for C13H8O2 196.0529, found 196.0524.
Methyl 6-Oxo-6H-benzo[c]chromene-9-carboxylate
1
(3{10}). Yield: 90%, white solid. H NMR (CDCl3, 500
MHz): δ 8.79 (s, 1H), 8.47 (d, J ) 8.5 Hz, 1H), 8.20-8.15
(m, 2H), 7.53-7.51 (m, 1H), 7.40-7.37 (m, 2H), 4.03 (s,
3H). LC/MS: 254.9 (M + 1). HRMS (EI): m/z calcd for
C15H10O4 254.0579, found 254.0571.
4H-Thieno[3,4-c]chromen-4-one (3{20}). Yield: 85%,
white solid. H NMR (CDCl3, 500 MHz): δ 8.52 (d, J )
3.0 Hz, 1H), 7.82 (dd, J ) 8.0, 1.5 Hz, 1H), 7.79-7.78 (m,
1H), 7.43-7.40 (m, 1H), 7.35-7.33 (m, 1H), 7.30-7.26 (m,
1H). LC/MS: 202.9 (M + 1). HRMS (EI): m/z calcd for
C11H6O2S 202.0088, found 202.0083.
1
9-Chloro-6H-benzo[c]chromen-6-one (3{11}). Yield: 92%,
1
white solid. H NMR (CDCl3, 500 MHz): δ 8.35 (d, J )
8.5 Hz, 1H), 8.64 (d, J ) 2.0 Hz, 1H), 8.02-8.00 (m, 1H),
7.56-7.51 (m, 2H), 7.40-7.35 (m, 2H). LC/MS: 230.9,
232.9 (M + 1). HRMS (EI): m/z calcd for C13H7ClO2
230.0140, found 230.0134.
4H-Thieno[2,3-c]chromen-4-one (3{21}). Yield: 84%,
white solid. H NMR (CDCl3, 500 MHz): δ 7.94 (d, J )
5.0 Hz, 1H), 7.86 (d, J ) 8.0 Hz, 1H), 7.67 (d, J ) 5.0 Hz,
1H), 7.53-7.45 (m, 2H), 7.38-7.34 (m, 1H). LC/MS: 202.9
(M + 1). HRMS (EI): m/z calcd for C11H6O2S 202.0088,
found 202.0093.
1
2-Chloro-8-methoxy-6H-benzo[c]chromen-6-one (3{12}).
1
Yield: 89%, white solid. H NMR (CDCl3, 500 MHz): δ
7.97 (d, J ) 8.5 Hz, 1H), 7.93 (d, J ) 2.5 Hz, 1H), 7.80 (d,
J ) 2.0 Hz, 1H), 7.41 (dd, J ) 8.5, 2.5 Hz, 1H), 7.37 (dd,
J ) 8.5, 2.5 Hz, 1H), 7.30 (d, J ) 8.5 Hz, 1H). LC/MS:
260.9, 263.0 (M + 1). HRMS (EI): m/z calcd for C14H9ClO3
260.0240, found 260.0225.
5H-Chromeno[4,3-b]pyridin-5-one (3{22}). Yield: 95%,
white solid. 1H NMR (CDCl3, 500 MHz): δ 9.03-9.02 (m,
1H), 8.63-8.57 (m, 2H), 7.60-7.57 (m, 1H), 7.54-7.51 (m,
1H), 7.42-7.38 (m, 2H). LC/MS: 197.9 (M + 1). HRMS
(EI): m/z calcd for C12H7NO2 197.0476, found 197.0482.
5H-Chromeno[4,3-c]pyridin-5-one (3{23}). Yield: 83%,
9-Methyl-6H-benzo[c]chromen-6-one (3{13}).6a Yield: 92%,
1
1
white solid. H NMR (CDCl3, 500 MHz): δ 8.27 (d, J )
white solid. H NMR (CDCl3, 500 MHz): δ 9.58 (s, 1H),
8.0 Hz, 1H), 8.05 (d, J ) 1.0 Hz, 1H), 7.89 (s, 1H),
7.48-7.45 (m, 1H), 7.39-7.31 (m, 2H), 2.56 (s, 3H). LC/
MS: 211.0 (M + 1). HRMS (EI): m/z calcd for C14H10O2
210.0680, found 210.0674.
8,9-Dimethoxy-6H-benzo[c]chromen-6-one (3{14}). Yield:
84%, white solid. 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, J
) 8.00 Hz, 1H), 7.75 (s, 1H), 7.61-7.28 (m, 2H), 7.37-7.31
(m, 2H). LC/MS: 257.0 (M + 1). HRMS (EI): m/z calcd for
C15H12O4 256.0735, found 256.0729.
7-Methyl-6H-benzo[c]chromen-6-one (3{15}). Yield:
92%, white solid. 1H NMR (CDCl3, 500 MHz): δ 8.04-7.98
(m, 2H), 7.67-7.64 (m, 1H), 7.46-7.43 (m, 1H), 7.38-7.37
(m, 1H), 7.33-7.28 (m, 2H), 2.87 (s, 3H). IR (cm-1): 1716.2,
1461.1, 1242.9 1206.4, 1049.0, 785.1, 751.5. LC/MS: 211.0
(M + 1). HRMS (EI): m/z calcd for C14H10O2 210.0680,
found 210.0675.
10-Methyl-6H-benzo[c]chromen-6-one (3{16}). Yield:
86%, white solid. 1H NMR (CDCl3, 500 MHz): δ 8.39-8.30
(m, 2H), 7.66-7.64 (m, 1H), 7.49-7.46 (m, 2H), 7.42-7.39
(m, 1H), 7.35-7.32 (m, 1H), 2.91 (s, 3H). LC/MS: 211.0
(M + 1). HRMS (EI): m/z calcd for C14H10O2 210.0680,
found 210.0682.
8.88-8.87 (m, 1H), 8.21-8.16 (m, 2H), 7.58-7.55 (m, 1H),
7.44-7.41 (m, 2H). LC/MS: 198.0 (M + 1). HRMS (EI):
m/z calcd for C12H7NO2 197.0476, found 197.0469.
6H-Naphtho[2,1-c]chromen-6-one (3{24}). Yield: 87%,
1
white solid. H NMR (CDCl3, 500 MHz): δ 8.87 (d, J )
7.5 Hz, 1H), 8.52 (d, J ) 8.0 Hz, 1H), 8.33 (d, J ) 8.5 Hz,
1H), 8.01-7.94 (m, 2H), 7.75-7.68 (m, 2H), 7.56-7.49 (m,
2H), 7.42-7.39 (m, 1H). LC/MS: 246.9 (M + 1). HRMS
(EI): m/z calcd for C17H10O2 246.0680, found 246.0689.
6H-[1]Benzothieno[2,3-c]chromen-6-one (3{25}). Yield:
94%, white solid. 1H NMR (CDCl3, 500 MHz): δ 8.65-8.62
(m, 1H), 8.49 (d, J ) 8.0 Hz, 1H), 8.03-8.01 (m, 1H),
7.65-7.61 (m, 2H), 7.58-7.52 (m, 2H), 7.47-7.44 (m, 1H).
LC/MS: 252.9 (M + 1). HRMS (EI): m/z calcd for C15H8O2S
252.0245, found 252.0241.
Methyl 3-Fluoro-6-oxo-6H-benzo[c]chromene-8-car-
boxylate (3{26}). Yield: 88%, white solid. 1H NMR (CDCl3,
500 MHz): δ 9.05 (s, 1H), 8.46 (dd, J ) 7.0, 2.0 Hz, 1H),
8.13-8.12 (m, 2H), 7.14-7.12 (m, 2H), 3.99 (s, 3H); LC/
MS 273.2 (M + 1). HRMS (EI): m/z calcd for C15H9FO4
272.0430, found 272.0428.
2-Methyl-8-(trifluoromethyl)-6H-benzo[c]chromen-6-
one (3{27}). The residue was purified with Biotage SP1 flash
autopurification system to afford the white solid in 69% yield.
1H NMR (CDCl3, 500 MHz): δ 8.67 (s, 1H), 8.24-8.23 (d,
7-Chloro-6H-benzo[c]chromen-6-one (3{17}). The resi-
due was purified with Biotage SP1 flash autopurification
1
system to afford the white solid in 68% yield. H NMR

Parallel Synthesis of Dibenzopyranones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 669
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J ) 8.0 Hz, 1H), 8.03-8.02 (d, J ) 2.0, 1H), 7.87 (s, 1H),
7.35-7.27 (m, 2H), 2.49 (s, 3H). LC/MS: 279.9 (M + 1).
HRMS (EI): m/z calcd for C15H9F3O2 278.0554, found
278.0545.
4-Chloro-9-fluoro-6H-benzo[c]chromen-6-one (3{28}).
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1
Yield: 71%, white solid. H NMR (CDCl3, 500 MHz): δ
8.47-8.44 (m, 1H), 7.88 (dd, J ) 7.0, 1.0 Hz, 1H), 7.74
(dd, J ) 7.5, 2.5 Hz, 1H), 7.59 (dd, J ) 6.0, 1.5 Hz, 1H),
7.34-7.28 (m, 2H). LC/MS: 249.8 (M + 1). HRMS (EI):
m/z calcd for C13H6ClFO2 248.0040, found 248.0029.
2-Methoxy-8-(trifluoromethyl)-6H-benzo[c]chromen-6-
one (3{29}). Yield: 85%, white solid. 1H NMR (CDCl3, 500
MHz): δ 8.69 (s, 1H), 8.19 (d, J ) 8.5 Hz, 1H), 8.04 (d, J
) 2.0 Hz, 1H), 7.51 (s, 1H), 7.34 (m, 1H), 7.14-7.12 (m,
1H). LC/MS: 295.1 (M + 1). HRMS (EI): m/z calcd for
C15H9F3O3 294.0503, found 294.0512.
3-Chloro-8-methyl-6H-benzo[c]chromen-6-one (3{30}).
1
Yield: 92%, white solid. H NMR (CDCl3, 500 MHz): δ
8.19 (s, 1H), 7.97-7.94 (m, 2H), 7.65-7.64 (m, 1H),
7.36-7.28 (m, 2H), 2.50 (s, 3H). LC/MS: 245.6, 247.2 (M
+ 1). HRMS (EI): m/z calcd for C14H9ClO2 244.0291, found
244.0306.
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9-Chloro-1,2-difluoro-6H-benzo[c]chromen-6-one (3{31}).
Yield: 70%, white solid. H NMR (CDCl3, 500 MHz): δ
1
8.51-8.50 (m, 1H), 8.40 (d, J ) 8.0 Hz, 1H), 7.64 (dd, 7.0,
2.0 Hz, 1H), 7.37-7.33 (m, 1H), 7.19-7.17 (m, 1H). LC/
MS 267.8, 269.9 (M + 1). HRMS (EI): m/z calcd for
C13H5ClF2O2 266.9946, found 265.9955.
2-Hydroxy-8-(trifluoromethyl)-6H-benzo[c]chromen-6-
one (3{32}). The residue was purified with Biotage SP1 flash
autopurification system to afford the white solid in 72% yield.
1H NMR (CD3OD, 500 MHz): δ 9.33-9.30 (m, 1H), 9.24
(s, 1H), 9.05-9.03 (m, 1H), 8.48-8.47 (m, 1H), 8.13-8.11
(m, 1H), 7.90-7.87 (m, 1H). LC/MS: 281.1 (M + 1). HRMS
(EI): m/z calcd for C14H7F3O3 280.0428, found 280.0431.
Acknowledgment. This research work was supported by
Grants DA007215 and DA003801 from the National Institute
of Health and National Institute of Drug Abuse. This paper
is dedicated to Prof. John R. Scheffer, University of British
Columbia on the occasion of his 70th birthday. One of the
authors (K.V.) would like to thank Prof. J. Narasimha
Moorthy, Indian Institute of Technology, Kanpur for helpful
suggestions.
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Supporting Information Available. General experimental
details, yields, and compound characterization data (1H NMR,
IR, and MS analysis) of all final products. This information
is available free of charge via the Internet at http://
pubs.acs.org.
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References and Notes
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