Cu-catalyzed coupling-cyclization in PEG 400 under ultrasound: A highly selective and greener approach towards isocoumarins

Article abstract of DOI:10.1039/c3ra40969d

The combination of CuI-K₂CO₃-PEG 400 facilitated the coupling-cyclization of o-iodobenzoic acid with terminal alkynes under ultrasound, affording a greener and practical approach towards 3-substituted isocoumarins with remarkable regioselectivity. This inexpensive and Pd and ligand free methodology gave rise to various isocoumarins of potential pharmacological interest.

Full text of DOI:10.1039/c3ra40969d

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Cu-catalyzed coupling-cyclization in PEG 400 under
ultrasound: a highly selective and greener approach
towards isocoumarins3
R. Gangadhara Chary,ab G. Rajeshwar Reddy,a Y. S. S. Ganesh,a K. Vara Prasad,a S. K.
Phani Chandra,a Soumita Mukherjeec and Manojit Pal*c
Cite this: DOI: 10.1039/c3ra40969d
Received 25th February 2013,
Accepted 2nd May 2013
DOI: 10.1039/c3ra40969d
www.rsc.org/advances
The combination of CuI–K2CO3-PEG 400 facilitated the coupling-
cyclization of o-iodobenzoic acid with terminal alkynes under
ultrasound, affording a greener and practical approach towards
3-substituted isocoumarins with remarkable regioselectivity. This
inexpensive and Pd and ligand free methodology gave rise to
various isocoumarins of potential pharmacological interest.
cases, the 5-exo-dig cyclization product i.e. the phthalide was
obtained as a major product.5 The formation of phthalide
derivatives were largely avoided by using Pd(PPh3)4–ZnCl2 catalytic
system in DMF6 or Pd/C–CuI in ethanol,7 where the isocoumarin
derivatives were obtained as the major products. These methodol-
ogies however involved the use of expensive and toxic palladium
catalysts or harmful organic solvents. Thus the search for
inexpensive, efficient and safer catalyst/solvent was of particular
interest.8 Accordingly, copper has emerged as an effective and
complementary metal towards the synthesis of isocoumarin.
Earlier in 1963, Stephens and Castro claimed isocoumarin
synthesis via the coupling of o-iodobenzoic acid with stoichio-
metric amount of alkynylcopper (I) species in pyridine.9 While in
the later stage the isolated products were characterized as
phthalides, since then, much effort has been devoted to develop
synthetic route to isocoumarins that would require copper in
catalytic quantity. Miura et al. developed a Cu(I)-catalyzed synthesis
of 3-phenyl isocoumarin in 19% yield via the reaction of
o-iodobenzoic acid and phenylacetylene using triphenyl phos-
phine as a ligand, K2CO3 as a base and DMF as a solvent at 120 uC
for 24 h.10 Later, Wang et al. performed the reaction under
microwave irradiation which reduced the reaction time with
increase in isocoumarin yield (86%).11 A ligand-free copper
mediated isocoumarin synthesis in DMF was also attempted,
where a mixture of desired isocoumarin and the corresponding
The development of highly selective, inexpensive and safer
chemical methods not only considered as important initiatives
in green and sustainable chemistry but also is one of the prime
goals of chemical and pharmaceutical industries. Thus, not
surprisingly enormous efforts have been devoted by organic/
synthetic chemists in this direction.
Isocoumarins are an important class of naturally occurring
lactones with innumerable pharmacological properties including
antifungal, antitumor, antiallergenic, antimicrobial, anti-inflam-
matory, antidiabetic, phytotoxic, and immunomodulatory activ-
ities.1 As a consequence, synthesis of naturally occurring and
biologically active isocoumarins has been an active area of
research for the past 20 years. A significant number of diverse
methodologies have been reported,2 the most explored one being
the transition metal catalyzed intramolecular cyclization of
internal alkynes with proximal carboxylate group. This type of
cyclization is generally promoted by a variety of transition metal
catalysts based on Pd, Zn, Rh, Hg, Ag, Au, Cu, Ru or Ir.3,4 However,
the Pd-catalysed Sonogashira type coupling followed by cyclization
is the widely used method among them. Notably, the intramole-
cular ring closure of the alkynoic acids/esters (1) can give rise to a
mixture of products resulting from 5-exo-dig (a phthalide i.e. 2) and
6-endo-dig cyclization (an isocoumarin i.e. 3) (Scheme 1). In several
aCustom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bollaram Road
Miyapur, Hyderabad 500 049, India
bJNT University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
cOrganic and Medicinal Chemistry Department, Dr Reddy’s Institute of Life Sciences,
University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
E-mail: manojitpal@rediffmail.com
Electronic supplementary information (ESI) available: Experimental Procedures,
3
spectral data and copies of NMR for all new compounds. See DOI: 10.1039/
c3ra40969d
Scheme 1 Intramolecular ring closure of the alkynoic acid/ester 1.
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Table 1 The optimization of coupling of o-iodobenzoic acid (4) with phenyl
acetylene (5a)a
Scheme 2 Cu-mediated synthesis of isocoumarin in PEG 400.
Entry CuI (mol%) Base
Solvent
Time (h) Yieldb (%)
phthalide was obtained.12 Additionally, though the use of
expensive and toxic Pd-catalysts and organic ligands was avoided
in these reactions, the use of hazardous organic solvent as a
reaction medium and lack of selectivity (i.e. the formation of
substantial amount of phthalide along with isocoumarin) has
made this method less attractive. This prompted us to develop an
alternative, highly selective, inexpensive and safer method to
address some of these concerns. Herein, we report for the first
time the use of polyethylene glycol 400 (PEG 400) as a solvent in an
environment friendly, efficient, palladium and ligand-free, Cu-
mediated regioselective synthesis of isocoumarins. Because of its
high boiling, non-hazardous and polar nature the use of PEG as a
solvent in organic reactions is advantageous. Indeed, due to its
easy recovery (from the reaction mixture) and recyclability, PEG
has been used as a solvent in several organometallic reactions
including Cu-mediated Sonogashira, Heck and Suzuki–Miyaura
coupling.13 The ultrasound mediated reactions on the other hand
have become increasingly popular and widely used methodologies
in organic synthesis.14 The present methodology involved Cu-
catalyzed coupling-cyclization of o-iodobenzoic acid with various
terminal alkynes under ultrasound in the presence of K2CO3 in
PEG 400, leading to a range of isocoumarin derivatives as sole or
major products (Scheme 2).
Initially, the coupling of o-iodobenzoic acid (4) and phenyl
acetylene (5a) was performed in water in the presence of 10 mol%
CuI and K2CO3 (entry 1, Table 1) when no progress was observed
after 72 h of sonication (using SONOREX SUPER RK 510H model
producing irradiation of 40 kHz). The increase of catalyst loading
(entry 2 and 3, Table 1) or the use of 1 : 1 water-PEG 400 did not
afford any product (entry 4, Table 1). Finally, the use of only PEG
400 gave the desired isocoumarin 3a in 45% yield (entry 5,
Table 1). The increase of catalyst loading improved the product
yield and decreased the reaction time (entry 6, Table 1) whereas
further increase in the catalyst amount (50 mol%) did not improve
the product yield (entry 7, Table 1). Notably the reaction did not
proceed in the absence of ultrasound (entry 8, Table 1). The use of
other bases e.g. Cs2CO3 and K3PO4 decreased the product yield
(entry 9 and 10, Table 1). Nevertheless, the 6-endo-dig cyclization
product (i.e. isocoumarin 3a) was isolated as the sole product in all
these cases and the formation of phthalide was not observed. In
order to test the recyclability of the used PEG, the aqueous mixture
of PEG collected after usual workup was distilled at 50 uC under
vacuum [until the water content of residual PEG reached y1% (by
Karl Fischer method)]. The recovered PEG was reused for the
reaction of 4 and 5a under the condition of entry 6, Table 1 when
3a was isolated in 75% yield after 6 h.
1
2
3
4
5
6
7
8
9
10
10
20
50
20
10
20
50
20
20
20
K2CO3 H2O
K2CO3 H2O
K2CO3 H2O
72
65
70
0
0
0
K2CO3 H2O : PEG (1 : 1) 72
0
K2CO3 PEG
K2CO3 PEG
K2CO3 PEG
K2CO3 PEG
Cs2CO3 PEG
K3PO4 PEG
24
3
3
48
4
4
45
80
80
0c
69
66
a
All the reactions were carried out by using 2-iodobenzoic acid (4,
1.0 mmol), phenyl acetylene (5a, 1.0 mmol), base (2.0 mmol), and
CuI in a solvent (5.0 mL) at room temp (25 uC) in a sonicator under
b
c
nitrogen. Isolated yield. Reaction was carried out in the absence
of ultrasound.
We then examined the reaction of 5a with o-bromo and
o-chloro benzoic acid separately. While 3a was isolated in poor
yield (y10%) in the first case the reaction did not proceed in the
second case. We also examined the reaction of methyl-2-
iodobenzoate (6) with 5a under the same reaction conditions
(entry 6, Table 1), which gave the o-alkynyl benzoate ester 7 instead
of 3a [even after a long reaction time (72 h) or increasing the
catalyst amount up to 50 mol%] indicating that unlike the –CO2H,
the ester group of 7 was unable to participate in the cyclization
step under the conditions employed (Scheme 3).
The generality of the present PEG based methodology was
examined by coupling 4 with various terminal alkynes under the
optimized reaction conditions. The nature of terminal alkynes
used was varied from aromatic (5a–e, 5l, 5n, 5r, 5s, 5t) to cyclic (5o,
5p) or acyclic (5f–h, 5i–k, 5m and 5q) aliphatics. The reaction
proceeded well with all these alkynes employed affording the
desired product 3 in moderate to good yields within 2–3 h
(Table 2). The reaction also proceeded well when a substituted
2-iodobenzoic acid e.g. 2-iodo-3-methoxybenzoic acid was treated
with 5a affording the desired 5-methoxy-3-phenyl-1H-isochromen-
1-one in 77% yield after 3 h. Notably the reaction of 2-iodo-5-
nitrobenzoic acid with 5a afforded the uncyclized product i.e.
5-nitro-2-(phenylethynyl)benzoic acid instead of desired isocou-
marin. While in most of the cases isocoumarin was isolated as the
only product, traces (.5%) of regioisomeric phthalide was isolated
when alkynes 5f–h were employed. In some of the cases the
unreacted starting material 4 was recovered reducing isocoumarin
yields to 60–65%. All the compounds synthesized were character-
ized by 1H and 13C NMR, IR, and HRMS spectra. The formation of
isocoumarin ring was confirmed by the appearance of an
absorption band at y1750 cm21 (for CLO) in IR, a singlet at
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Table 2 Synthesis of isocoumarins (3) via Cu-mediated coupling-cyclization
strategy in PEG 400 under ultrasound (Scheme 2)a
Entry Alkyne (5), R=
Products (3) Time (h) Yieldb (%)
Fig. 1 Dihydroisocoumarin 8 as an antibacterial agent.
1
2
3
4
5
6
7
8
Ph (5a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3
2
2.5
2.5
3
2
3
2.5
3
2.5
3
80
65
60
60
80
75
60
80
70
80
65
80
–C6H4Br-p (5b)
–C6H4NH2-p (5c)
–C6H4CH3-p (5d)
–C6H4Br-o (5e)
–(CH2)3CH3 (5f)
–(CH2)4CH3 (5g)
–(CH2)5CH3 (5h)
–(CH2)2CH2Cl (5i)
–(CH2)3CH2OH (5j)
acid with terminal alkynes under ultrasound affording a greener
and practical approach towards 3-substituted isocoumarins with
remarkable regioselectivity. This inexpensive and Pd and ligand
free methodology gave rise to various isocoumarins of potential
pharmacological interest. For example, compounds 3b, 3d and 3e
are known to inhibit thymidine phosphorylase15 whereas 3b and
3e are known to possess antimicrobial activities.16 The compound
3g showed promising antibiotic activities comparable to the
standard antibiotics.17 Moreover, hydrogenation of 3g in the
presence of 10%Pd/C in MeOH at room temperature for 12 h
9
10
11
12
3j
–C6H4O(CH2)4CH3-p (5k) 3k
3l
3
(5l)
afforded the dihydroisocoumarin 8 (see ESI ) that showed
antibacterial activities in vitro (Fig. 1).17
3
13
14
–C6H4(CH2)4CH3-p (5m) 3m
2
2
65
80
3n
Based on the results of Table 1 and the fact that PEG plays the
role of a ligand in several Cu-mediated coupling reactions13a,c
a
probable mechanism for the present synthesis of isocoumarin is
shown in Scheme 4. Thus, PEG appeared to play the pivotal role as
a solvent and also as a ligand in the present reaction. Initially, a
Cu(I) complex (A) formed via the interaction of CuI with PEG13c,18
under ultrasound, underwent oxidative addition with o-iodoben-
zoic acid to afford the arene-Cu(III) species B. Subsequently, the
alkyne 5 reacts with B in the presence of K2CO3 leading to the
arene-Cu(III)-alkyne species C, which on reductive elimination
furnished the o-alkynyl benzoate salt (1a) with the regeneration of
active Cu(I) catalyst A. The o-alkynyl benzoate salt (1a) then
underwent intramolecular ring closure in the presence of A in a
regioselective manner to give the desired isocoumarin 3. The
participation of Cu(III) complex B or C which could catalyze the
cyclization of 1a to afford a 4-aryl or 4-alkynyl isocoumarin
derivative, was ruled out as these products were not detected in
the reaction mixture. It seems that the cyclization of 1a therefore
was aided by the combined effect of bulky catalytic species A,
ultrasound and KHCO3 (generated in situ). Though the specific
reasons for the enhanced selectivity was not clearly understood,
the formation of a five-membered ring from D could lead to the
more steric crowding than that in E perhaps account for
somewhat different i.e. better regioselectivity observed in the
present case compared to that reported earlier.12 Nevertheless, the
15
16
3o
3p
2
2
80
80
17
18
–CH2OH (5q)
3q
3r
2
3
85
80
19
20
3s
3t
3
3
70
85
a
All the reactions were carried out by using 4 (1.0 mmol), an
appropriate terminal alkyne (5, 1.0 mmol), K2CO3 (2.0 mmol), and
CuI (20 mol%) in PEG (5.0 mL) at room temp (25 uC) in a sonicator
b
under nitrogen. Isolated yield.
y6.80–6.20 ppm (for CHLC) in 1H NMR and a quaternary carbon
at y167.0 ppm (CLO) in the 13C NMR spectra.
We have demonstrated that the combination of CuI–K2CO3-
PEG 400 can facilitate the coupling-cyclization of o-iodobenzoic
Scheme 3 Cu-mediated coupling of methyl-2-iodobenzoate (6) with phenyl
acetylene (5a).
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Scheme 4 Proposed mechanism for the Cu-mediated coupling-cyclization of 4
with 5 in PEG under ultrasound.
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combination of CuI–K2CO3-PEG400 and ultrasound emerged as a
newer option for isocoumarin synthesis.
In summary, PEG400 has been identified as an efficient, non-
hazardous and reusable solvent for the synthesis of 3-substituted
isocoumarins via a Cu-mediated coupling-cyclization of o-iodo-
benzoic acid with terminal alkynes under ultrasound. Except few
cases the reaction showed remarkable regioselectivity towards the
formation of isocoumarin over phthalide. The present palladium
and ligand free methodology does not require the use of expensive
or toxic catalyst, reagents or solvents and therefore represents a
useful and safer alternative to the existing methods. The
methodology may find wide usage in constructing diversity based
isocoumarin library for chemical and medicinal applications.
The author (RGC) thanks Dr V. Upadhya Timmanna for his
encouragement and analytical group of DRL for spectral data. S.
M. thanks CSIR, New Delhi, India, for a Research Associate
Fellowship.
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