Palladium-catalyzed one-pot Suzuki-Miyaura cross coupling followed by oxidative lactonization: A novel and efficient route for the one-pot synthesis of benzo[c]chromene-6-ones

Article abstract of DOI:10.1016/j.tetlet.2012.11.144

A number of 6H-benzo[c]chromene-6-ones, 5H-naphtho[1,2-c]chrome-5-ones, and 6H-naphtho[2,1-c]chromene-6-one have been synthesized starting with 2-hydroxyphenylboronic acid and o-bromobenzaldehyde or o-bromonaphthalene carboxaldehyde derivatives via a one-pot Suzuki-Miyaura cross coupling followed by oxidative lactonization reactions. The overall transformation consists of three reactions: Suzuki-Miyaura cross coupling, hemi-acetal formation, and oxidation.

Full text of DOI:10.1016/j.tetlet.2012.11.144

Tetrahedron Letters 54 (2013) 657–660
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed one-pot Suzuki–Miyaura cross coupling followed by
oxidative lactonization: a novel and efficient route for the one-pot synthesis
of benzo[c]chromene-6-ones
⇑
Raju Singha, Soumyabrata Roy, Sukla Nandi, Priyanka Ray, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t s
Article history:
A number of 6H-benzo[c]chromene-6-ones, 5H-naphtho[1,2-c]chrome-5-ones, and 6H-naphtho[2,1-
c]chromene-6-one have been synthesized starting with 2-hydroxyphenylboronic acid and o-bromobenz-
aldehyde or o-bromonaphthalene carboxaldehyde derivatives via a one-pot Suzuki–Miyaura cross
coupling followed by oxidative lactonization reactions. The overall transformation consists of three
reactions: Suzuki–Miyaura cross coupling, hemi-acetal formation, and oxidation.
Received 18 October 2012
Revised 27 November 2012
Accepted 30 November 2012
Available online 7 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
Benzo[c]chromene-6-one
Naphtho[1,2-c]chrome-5-one
Naphtho[2,1-c]chromene-6-one
Suzuki–Miyaura cross coupling
Oxidative lactonization
Benzo[c]chromen-6-ones and the relevant lactones serve as the
core structure of many natural products,1 such as autumnariol
(Fig. 1, 1), alternariol, altenuisol, autumnariniol, and graphislac-
tones (Fig. 1, 2) and in biologically important compounds.2 They
are also present in a number of natural antitumor and antibiotic
agents, such as chrysomycins (Fig. 1, 3), gilvocarcins, and ravid-
omycins.3 In addition, such lactones are also important as interme-
diates for the synthesis of several pharmaceutically important
compounds, such as progesterone, androgen, glucocorticoid
receptor agonists,4 and endothelial cell proliferation inhibitors.5
Benzo[c]chromen-6-ones also occur naturally in a number of food
resources including citrus fruits, herbs, and vegetables.6
There are several methods available for the synthesis of
benzo[c]chromen-6-ones which usually are multi-step processes.
Some of these recent methods are the Diels–Alder cycloaddition
of 4-cyanocumarins,7 tert-butyllithium-mediated cyclization of
bromobenzylfluorophenyl ethers,8 and ruthenium-catalyzed
cyclotrimerization of aryl diynes.9 The most used method involves
Suzuki–Miyaura cross coupling of methyl 2-bromobenzoate and
2-methoxyphenylboronic acids followed by Lewis acid10 or metal11
mediated lactonization. There are also some other synthetic routes
for the lactonization step, such as, the direct lactonization of car-
boxylic acid to an aromatic ring,12 the displacement of a nitro
group with carboxylic acid,13 and the displacement of a benzyl
O
OR1
Me
O
OH
O
O
R
O
O
OR2
MeO
OMe
Me
OH
OMe
OMe OH
R1, R2 = H, Me
R = sugar
1
2
3
Figure 1. Structure of some natural products and bioactive compounds.
group.14 However, these methods are the multi-step sequences
and need purification of intermediates. Thus, a new route for the
synthesis of benzo[c]chromen-6-ones from readily available start-
ing materials in a single step is still of critical importance.
Herein, we have reported a novel and efficient methodology for
the one pot synthesis of benzo[c]chromen-6-ones and its higher
analogues by reacting 2-bromobenzaldehyde or o-bromonaphtha-
lene carboxaldehyde derivatives with 2-hydroxyphenylboronic
acid via Suzuki–Miyaura cross coupling followed by oxidative lact-
onization15 of aldehyde and hydroxy groups.
Our investigation began with an effort to optimize reaction con-
ditions for the one-pot synthesis of benzo[c]chromen-6-ones and
its higher analogues and for that 2-bromobenzaldehyde and
2-hydroxyphenylboronic acid were chosen as the coupling
partners for Suzuki–Miyaura cross coupling reaction. Then various
⇑
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.144

658
R. Singha et al. / Tetrahedron Letters 54 (2013) 657–660
Table 1
Screening of the reaction conditions*
O
CHO
HO
catalyst, ligand
O
base, solvent, heat
Br
(HO)2B
Entry
Catalyst
Ligand
Base
Solvent
Temperature (°C)
Time (h)
Yield**
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2(CH3CN)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
NaOAc
Na2CO3
K2CO3
Cs2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
CH3CN
80
80
80
80
80
80
80
80
80
80
90
95
90
90
90
6
6
6
6
6
6
6
6
6
6
4
4
4
4
4
63
86
89
87
47
81
80
75
78
67
90
89
82
76
62
—
—
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
*
Reactions were carried out with 0.2 mmol of 2-bromobenzaldehyde, 2-hydroxyphenylboronic acid (1 equiv), catalyst (5 mol %), ligand (0.25 equiv), base (1 equiv), and
solvent (1 mL).
**
Isolated yield by column chromatography.
Table 2
One-pot synthesis of benzo[c]chromen-6-ones*
O
R1
R2
R1
R2
CHO
X
HO
Pd(OAc)2, PPh3
O
K2CO3, DMF, 90oC
(HO)2B
R3
R3
5
4
6
Entry
1
o-Bromobenzaldehyde
Product
Time (h)
Yield** (%)
CHO
O
O
X = Cl, 8
X = Br, 4
X = I ,3
X = Cl, 87
X = Br, 90
X = I ,91
X
X = Cl, Br, I
4a
6a
CHO
O
O
Me
F
Br
2
3
4
4
4
4
89
92
93
Me
F
4b
6b
O
CHO
Br
O
4c
6c
MeO
MeO
CHO
O
MeO
MeO
O
O
Br
4d
6d
MeO
MeO
CHO
X
O
MeO
MeO
X = Br, trace
X = I, 68
5
6
OMe
X = Br, I
OMe
6e
Reactions were carried out with 1 mmol of 2-bromobenzaldehyde derivatives, 2-hydroxyphenylboronic acid (1 equiv), Pd(OAc)2 (5 mol %), PPh3 (0.25 equiv), K2CO3
4e
*
(1 equiv), DMF (3 mL), and heated at 90 °C.
**
Isolated yield by column chromatography.

R. Singha et al. / Tetrahedron Letters 54 (2013) 657–660
659
catalysts, ligands, bases, and solvents were used for screening the
Suzuki–Miyaura cross coupling followed by oxidative lactonization
reactions. Progress of the reaction was monitored by TLC and the
results are shown in Table 1.
good to excellent yields. For 2-halobenzaldehyde (Table 2, entry
1) when X = Cl, it took 8 h for completion of the reaction and when
X = I, the reaction completed within 3 h. For 2-bromo-3,4,5-
trimethoxybenzaldehyde (Table 2, entry 5), the yield of the
reaction was trace and for 2-iodo-analogue the yield was 68% after
6 h (Table 2, entry 5). This poor reactivity is probably due to the
sterically hindered position of halogens. After this, the methodol-
ogy was applied on fused o-bromoarylcarboxaldehydes (Table 3).
2-bromonaphthalene-1-carboxaldehydes gave good yields (Table 3,
entries 2,3) while 1-bromonaphthalene-2-carboxaldehyde gave
comparatively lower yield probably due to the sterically hindered
location of bromine at 1-position of naphthalene. The results are
shown in Table 3.
A set of initial conditions were selected consisting 0.2 mmol of
2-bromobenzaldehyde, 2-hydroxyphenylboronic acid (0.2 mmol),
Pd(OAc)2 (5 mol %), PPh3 (0.25 equiv), base (1 equiv), DMF (1 mL)
under nitrogen atmosphere with stirring at 80 °C for 6 h. The first
reaction was carried out with NaOAc base and it gave the desired
product benzo[c]chromen-6-one in 63% yield. Then different bases
were used (Table 1, entries 1–5) and the best result was obtained
with K2CO3. The next task was to find the best catalyst for the reac-
tion and for that a series of six catalysts was used (Table 1, entries
5–10). The catalyst Pd(OAc)2 was found to be the prominent cata-
lyst and gave the highest yield for the transformation whereas
Pd2(dba)3 gave the poorest result. On increasing the temperature
to 90 °C, the time for completion of the reaction decreased to 4 h
(Table 1, entry 11). On further increasing the temperature to
95 °C, the reaction time remained the same (Table 1, entry 12).
Then different solvents were employed (Table 1, entries 13–15)
and the best yields were obtained from DMF. Thus, the optimized
reaction condition for the one-pot synthesis of benzo[c]chromen-
6-ones was 5 mol % of Pd(OAc)2, K2CO3 (1 equiv) in DMF solvent
heated at 90 °C for 4 h.16
A plausible mechanism for the formation of the products is
shown in Scheme 1. At first, the Suzuki–Miyaura cross coupling
of o-bromoarylcarboxaldehyde and o-hydroxyphenylboronic acid
affords the intermediate A. The intermediate A equilibrates to
form hemi-acetal
B
which afforded the desired product
benzo[c]chromen-6-one by palladium-catalyzed aerial oxida-
tion,17 that is, oxidative lactonization. Thus, the oxidative lacton-
ization is the key step of this transformation. The development
of exact reaction mechanism and application of this methodology
in the synthesis of some bioactive natural products are in
progress.
After developing the optimized reaction condition, the scope of
this methodology was explored. Thus several substituted 2-bromo-
benzaldehyde derivatives were employed to prepare the corre-
sponding benzo[c]chromen-6-ones. The results are shown in
Table 2.
The coupling of o-hydroxyphenylboronic acid 5 and o-haloaryl-
carboxaldehydes 4 bearing both electron donating and withdraw-
ing groups gave the corresponding benzo[c]chromen-6-ones in
In summary, we have developed an advanced methodology for
the one-pot synthesis of benzo[c]chromen-6-ones and its higher
analogues via tandem Suzuki–Miyaura cross coupling followed
by oxidative lactonization in good to excellent yields. In addition,
such oxidative lactonization will be helpful for the synthesis of a
number of natural products and bioactive molecules having phar-
maceutical importance. The bio-activity test of some compounds is
in progress.
Table 3
One-pot synthesis of naphthochromens
Entry
o-Bromobenzaldehyde
Product
Time (h)
Yield (%)
71*
CHO
O
O
O
O
Br
1
6
4f
6f
CHO
Br
2
3
4
4
86**
4g
6g
MeO
MeO
O
CHO
O
83**
Br
6h
4h
*
Entry 1, the reactions were carried out at 110 °C.
Other reactions were carried with the optimized reaction conditions.
**
OH
O
CHO
CHO
HO
O
O
Br (HO)2B
HO
A
B
Scheme 1. Plausible rational for the formation of the product.

660
R. Singha et al. / Tetrahedron Letters 54 (2013) 657–660
8. Sanz, R.; Fernandez, Y.; Castroviejo, M. P.; Perez, A.; Fananas, F. J. Eur. J. Org.
Acknowledgment
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We gratefully acknowledge DST for providing funds and R.S.
thanks CSIR, New Delhi for the fellowship.
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16. General procedure for the one-pot synthesis of benzo[c]chromen-6-ones: 2-
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Supplementary data
Supplementary data (detailed experimental procedure and
spectral data for the compounds (6a–h)) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.11.144.
References and notes
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K2CO3 (1 mmol), PPh3 (0.25 mmol) were taken in
a two-necked round
bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added
and degassed with N2. The catalyst Pd(OAc)2 (5 mol %) was added to the
reaction mixture and heated at 90 °C for 4 h. After completion of the reaction,
the reaction mixture was allowed to cool to room temperature, diluted with
water, and extracted with ethyl acetate (3 Â 20 mL). The combined organic
layer was dried over Na2SO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography using silica gel (60–
120 mesh) and hexane/EtOAc as eluent.
Spectral data for the representative compound 6H-benzo[c]chromen-6-one
(6a):10a white solid; yield 90%; 1H NMR (CDCl3, 200 MHz) d 7.30–7.39 (2H,
m), 7.45–7.63 (2H, m), 7.79–7.87 (1H, m), 8.04–8.14 (2H, m), 8.40 (1H, d,
J = 8 Hz); 13C NMR (CDCl3, 50 MHz) d 117.9, 118.2, 121.4, 121.9, 122.9, 124.7,
129.1, 130.6, 130.8, 134.9, 135.0, 151.5, 161.4. HRMS (ESI) for C13H8O2: Calcd
197.0603 (M++H); Found: 197.0609.
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