Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins

Article abstract of DOI:10.1039/c8ra03926g

Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11-16 and isocoumarins 17-20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.

Full text of DOI:10.1039/c8ra03926g

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Ag2O nanoparticle-catalyzed substrate-controlled
regioselectivities: direct access to 3-
Cite this: RSC Adv., 2018, 8, 23152
ylidenephthalides and isocoumarins†
*
Sandeep Chaudhary,
and Krishan Kumar
Bharti Rajesh K. Shyamlal, Lalit Yadav, Mohit K. Tiwari
Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct
regioselective synthesis of 3-ylidenephthalides 11–16 and isocoumarins 17–20 via sonogashira type
coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively.
This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted
and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the
formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with
complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions,
operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition
experiments and gram-scale synthesis further highlight the importance and versatility of the
methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially
being controlled by the substituent(s) present on the acetylenic phenyl ring.
Received 8th May 2018
Accepted 15th June 2018
DOI: 10.1039/c8ra03926g
rsc.li/rsc-advances
earlier methods suffer from low regioselectivities affording
mixture of phthalides and isocoumarins.6a,b
Introduction
The controlled regioselectivity is an important concept for
the synthesis of pharmaceutically important molecules with
denite regio- and stereo-selectivities. Pertaining to the present
study that is the regioselective synthesis of 5-exo-dig and 6-endo-
dig cyclization; only a few regioselective methods, i.e., Cu2+-NCS
catalyzed (Scheme 1a),7 acid–base controlled,8 and temperature
controlled synthesis (Scheme 1b),9 have been reported to
synthesize 3-ylidenephthalides 2 and 7 as well as isocoumarins
6 via C–C and C–O bond formations. Recently, Rh-catalyzed
oxidative coupling/annulation of benzoic acids with terminal
alkynes has been reported to construct 3-ylidenephthalides 8
with complete Z-selectively via C–H bond activation concept
(Scheme 1c).10
In general, transition metal-catalyzed cross coupling reac-
tions have been conveniently established for carrying out C–H
bond activation via new systems that exhibit extremely high
catalytic activity and/or unique reactivity. In recent years, the
use of metal catalysts of Cu, Mn, Co, and Fe in C–H bond
activation has gained signicant attention over Pd and Ni
catalysts. Since, Ag(I) salt have been reported to show excep-
tional potential to explicit tremendous affinity especially
towards terminal alkynes11 and several Ag-catalyzed C–C
coupling reaction have been well reported in the literature;12 we
envisaged that if terminal alkynes with electron rich substitu-
ents at o-, m-, or p-position be chosen as starting material for the
reaction with 2-iodobenzoic acid, then Ag(I) may coordinate
simultaneously with triple bond as well as with electron-rich
Phthalide (isobenzofuran-1(3H)-one) is an important building
block present in many natural products, pharmaceuticals, and
biological materials, and shows a wide range of biological
activities, such as anti-HIV, antidiabetic, antispasmodic, anti-
allergic, antifungal, pesticidal, herbicidal, insecticidal, and
anticancer activity.1a–d It has been used as an intermediate for
the synthesis of various phthalide-based natural products and
therapeutics.2 Similarly, an inverted d-lactone moiety, i.e., iso-
coumarin (1H-2-benzopyran-1-one), also displays astounding
bio-activities, namely antitumor, antiallergenic, antimicrobial,
anti-inammatory, antidiabetic, phytotoxic, anti-HIV and
immunomodulatery responses.3,1b
Consequently, a number of methods have been reported to
construct 3-ylidenephthalides and isocoumarins via traditional
methods as well as C–H bond functionalization.4 It has been
reported that 3-ylidenephthalides and isocoumarins can be
easily prepared, respectively, from metal-catalyzed 5-exo-dig and
6-endo-dig cyclization of 2-alkynylbenzoic acid/esters, which can
be generated in situ from the Sonogashira-type coupling reac-
tion of 2-halobenzoic acids with terminal alkynes.5 However,
Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya
National Institute of Technology Jaipur, Jawaharlal Nehru Marg, Jaipur-302017, India.
E-mail: schaudhary.chy@mnit.ac.in
† Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra of all synthesized compounds 11–16, 17–20, 21, 22a–c. See DOI:
10.1039/c8ra03926g
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Results and discussions
In our endeavors in search for potent bioactive compounds;13
we were interested in the synthesis of 3-ylidenephthalides 11a
and isocoumarins 11aa0 regioselectively (Table 1).
Consequently, we started our synthetic investigation via the
reaction of 2-iodobenzoic acid 9a with phenylacetylene 5 as
model reaction for the optimization study of the reaction. We
initiated our investigation by carrying out the reaction using
CuI in DMF which furnished the desired 3-ylidenephthalide 11a
in 10% yield only (Table 1, entry 1). Since [Ag] salts have high
affinity towards terminal alkynes; we used Ag2O to carry out our
model reaction. To our surprise, we obtained only 11a in 45%
yield (Table 1, entry 2) and 11aa0 was not detected at all. The
structure of the desired compound was well characterized via
1H NMR, 13C NMR, FT-IR and HRMS analysis and it demon-
strated complete Z-selectivity. Then, the same reaction has been
carried out in the presence of pivalic acid as an additive which
furnished 11a in 75% yield (Table 1, entry 3). Once realizing the
unique nature of Ag2O; we also screened various other salts of
silver, i.e., acetate, chloride, and nitrate. Among them, only
silver acetate/pivalic acid combination furnished 11a in 43%
yields (Table 1, entry 4–6). In addition, screening of metal oxides
of Zn, Cu, Cd, Pb, Al, Cr, Ni, Mn, Fe, etc. were carried out. Either
reaction does not occur at all or 11a was obtained in traces (see
ESI†).
It has been known that nanoparticle leveraged C–H activa-
tion has been identied as an efficient sustainable approach for
industrial applications by transforming unactivated C(sp3)–H
Table 1 Optimization study: synthesis of 3-ylidene-phthalides from the
coupling reaction of 2-iodobenzoic acid 9a with phenyl acetylene 5a
Scheme 1 Present study versus previous representative approaches
for the regioselective synthesis of 3-ylidenephthalides and iso-
coumarins. (a) Miyata et al., (b) Manian et al., (c) Liu et al., (d) present
work.
substituents (more likely with o- as compared to m- and p-
position) e.g., Cl, Br, OMe etc. which could undergo 5-exo-dig or
6-endo-dig cyclisation in a regioselective manner (Fig. 1).
To the best of our knowledge, there is no report on the silver-
catalyzed substrate-controlled regioselectivities on 5-exo-dig or
6-endo-dig cyclization reaction of 2-iodobenzoic acid with o-, m-,
or p-substituted terminal alkynes. Herein, we report an efficient,
one-pot, silver oxide nanoparticle (Ag2ONPs) catalyzed
substrate-controlled synthesis of 3-ylidenephthalides and iso-
Entry Metal
Add.
Solvent Temp. Time (h) Yield (%)
1
CuI
—
—
DMF
DMF
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
100 ꢀC
120 ꢀC
130 ꢀC
3
3
3
3
3
3
3
3
24
3
3
3
10b
45
75
43
Nil
Nil
83
46
59
90
95
88
2
3
4
5
Ag2O
Ag2O
AgOAc
AgCl
PivOH DMF
PivOH DMF
PivOH DMF
PivOH DMF
6
AgNO3
coumarins in
(Scheme 1d).
a regioselective manner upto 95% yields
7
8
9
10
11
12
13
14
15
Ag2ONPs PivOH DMF
Ag2ONPs AcOH DMF
Ag2ONPs PivOH DMF
Ag2ONPs PivOH DMF
Ag2ONPs PivOH DMF
Ag2ONPs PivOH DMF
Ag2ONPs PivOH DMF
Ag2ONPs PivOH DMF
120 ꢀC 1.5
88
120 ꢀC
120 ꢀC
2
3
88
—
PivOH DMF
No reaction
a
Reaction conditions: 9a (1 eq.), 5 (1 eq.), Ag2ONPs (1 eq.), pivalic acid
(0.4 eq.), 120 ꢀC, 3 h. b Isocoumarin 11aa0 was also obtained in 5% yield
in this reaction.
Fig. 1 Structures depicting the probable interaction between Ag(I)
compounds with terminal alkynes and electron rich substituents.
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and C(sp2)–H bonds present in feedstock into important bio-
active molecules.14 We anticipated that silver oxide nano-
particles (Ag2ONPs), having larger surface area, may results in
high yield of our desired products.15 Thus, the model reaction
was carried out using Ag2ONPs/pivalic acid in DMF which, to
our expectation, furnished the desired 11a in 83% yields (Table
1, entry 7). Decrease in catalytic loading of Ag2ONPs leads to
decrease in yield of the reaction (see ESI†). The model reaction
has been also carried out using Ag2ONPs/acetic acid in DMF
which furnished 11a in only 46% yield (Table 1, entry 8).
Extending the reaction for 24 h at the same temperature leads to
decrease in reaction yield (Table 1, entry 9). Further examina-
tion of variation in temperature and time interval were carried
out. Increasing the temperature from 80 ꢀC to 100 ꢀC furnished
11a in 90% yield (Table 1, entry 10). Interestingly, we further
increase the temperature to 120 ꢀC for 3 h which furnished the
desired product 11a in excellent (95%) yield (Table 1, entry 11).
Further increase in temperature or decrease in time interval do
not have much benecial effects on the yield of the reaction
(Table 1, entry 12–14). While the reaction in other solvents such
as DMSO, 1,4-dioxane, toluene, o-xylene, diminishes the cata-
lytic activity; the reaction in PEG and water did not occur at all
(see ESI†). Further, change in the nature of additives such as
Na2CO3, Cs2CO3, NaOH, 1,10-phenanthroline etc. do not fur-
nished the desired product 11a or 11aa0 (see ESI†). This infer us
that our model reaction facilitates under acidic conditions. It
has been also observed that no reaction occur when Ag2ONPs is
not added to the optimized reaction conditions (Table 1, entry
15). Overall, Ag2ONPs/pivalic acid in DMF at 120 ꢀC for 3 h was
found to be the best optimized reaction conditions for this
regioselective reaction.
Scheme 2 Substrate scope: synthesis of 3-ylidenephthalides 11–16.
To explore the substrate scope and generality of the present
methodology, various substituted 2-iodobenzoic acids 9a–f were
reacted with several o-/m-/p-substituted alkynes 10a–i under
optimized reaction conditions. Thus, 9a–f were reacted with
para-and meta-substituted alkynes 10a–f under optimized
reaction conditions, which undergoes substrate-controlled 5-
exo-dig cyclization to furnish 3-ylidenephthalides 11–16 upto
95% yields in a highly regioselective manner (Scheme 2).
Then, 9a was reacted with 10g under optimized conditions.
As envisioned in the case of ortho-substitutent in acetylenic
phenyl ring, instead of getting 3-ylidenephthalides; we obtained
only isocoumarin 17a in 42% yield. This encourage us to
investigate this unusual observation in details to understand
the cause of regioselectivity. Since chlorine having lone pair of
electrons at ortho-position of the acetylenic phenyl ring dis-
played different behaviour, we analyzed other groups contain-
ing lone pair of electrons such as Br, OMe at ortho-position of
phenyl acetylenes. Thus, substituted 2-iodobenzoic acid 9a–c
were reacted with ortho-substituted alkynes 10g–j under opti-
mized reaction conditions which furnished isocoumarins 17–20
upto 85% yields via substrate-controlled 6-endo-dig cyclization
reaction (Scheme 3). These groups also furnished isocoumarins
regioselectively.
Scheme 3 Substrate scope: synthesis of isocoumarins 17–20.
respectively. In order to check the competition between 5-exo-
dig and 6-endo-dig cyclization reaction, reaction of 9a with an
equimolar ratio of 10f and 10i was carried out which furnished
17c/16a in 1.1 : 1 ratio. This infer us that the 5-exo-dig and 6-
endo-dig cyclization occurs in almost equal proportion under
optimized reaction conditions. Furthermore, competition
reaction between 9a with an equimolar ratio of 10d and 10f
furnished 11d/16a in 1.2 : 1 ratio which indicates that m- and p-
The generality of the reaction was demonstrated by carrying
out gram-scale synthesis of 3-ylidinephthalides 11a as well as
Scheme 4 Substrate scope: Synthesis of alicyclic 3-ylidenephthalides
isocoumarins 17b which were obtained in 89% and 80% yields, 21a–c.
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that the reaction involves cationic mechanism rather than
free-radical process.
To study the mechanistic role of groups having lone pair of
electrons at ortho-position of acetylenic phenyl ring; we were
also interested to depict the role of group(s) without having lone
pair of electrons at ortho-position. Thus, isocoumarin 20a was
obtained as major isomer along with 3-ylidenephthalides
(minor) via reaction of 9a with 10j which infer us that ortho-
group having lone pair of electrons furnish isocoumarins
exclusively; this regioselective methodology is also applicable
with ortho-group without having lone pair of electrons.
Presumably, the formation of 20a was due to the coordinated
association of electron clouds of CH3 group with [Ag] complex
which facilitates oxyanion attacks at C-2 position of acetylenic
bond via 6-endo-dig cyclization more favourably than 5-exo-dig
cyclization which generated 3-ylidenephthalides 20b as minor
product (see ESI†).
Thus, the tentative mechanism of this heterogeneous
reaction may be proposed based on previous similar studies
(Fig. 2).16 It involves deprotonation of 5 which furnishes the
silver phenylacetylide in situ.17 Due to the ligand to metal
charge transfer (LMCT),18 partial positive charge developed at
the acetylene site which favour the attack of 9a and gives 2-
(phenylethynyl)benzoic acid on which residual Ag2ONPs could
coordinate with electron rich alkynyl bond as well as with the
carboxylate oxyanion [I].19 In the case of m-/p-substituted
terminal alkynes as in intermediate [I] (path A), no interaction
of lone pair electrons or electron cloud between [Ag] and m-/p-
substituent on acetylenic phenyl ring occurs and hence,
carboxylate oxyanion undergoes attack at C-1 position of
acetylenic bond via 5-exo-dig cyclization to give intermediate
[II], which is further converted into 3-ylidenephthalides upon
protonation with PivOH. However, in the case o-substituted
terminal alkynes as in intermediate [III] (path B), there is
Scheme 5 Intermolecular competition experiments.
substituted phenylacetylenes undergoes 5-exo-dig cyclization in
almost equal proportion (Scheme 5).
Like aromatic terminal alkynes, aliphatic terminal alkyne
10k was also attempted to perform this reaction under opti-
mized reaction conditions; however, we obtained an insepa-
rable mixture of 5-exo-dig and 6-endo-dig cyclized products.
Hence, it may be inferred that the regioselectively of this reac-
tion is favourable with aromatic alkynes as compared to
aliphatic alkynes. In addition, when alicyclic acetylene 10l, was
subjected to optimized reaction conditions; cyclopropyl-based
3-ylidenephthalides 21a–c were obtained favouring 5-exo-dig
product regioselectively (Scheme 4).
In consideration of the unique features of the Ag2ONPs-
catalyzed substrate-controlled regioselective 5-exo-dig or 6-
endo-dig cyclization reaction, we were interested in delineating
the tentative mechanism of this reaction. The evidence for the
occurrence of the Sonogashira type C–H activation followed by
oxycation-mediated cyclization was gathered by carrying out
reactions in the presence of typical free-radical scavenger such
as 2,2,6,6,-tetramethylpiperidine-N-oxyl (TEMPO, 20 mole%)
under the same optimized conditions. The occurrence of 11a
in 93% yields and 17b in 82% yields, respectively, indicates
Fig. 2 Plausible mechanism
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signicant electronic interaction between the [Ag] and the
electronic lobe or lone pair of electrons containing group at o-
substituted acetylenic phenyl ring. Consequently, oxyanion
attacks at C-2 position of acetylenic bond via 6-endo-dig
cyclization to give intermediate [IV], which is further converted
into isocoumarins upon protonation with PivOH.
General procedure (GP) for the synthesis of 3-
ylidenephthalides 11–16
To a stirred mixture of substituted halo-aromatic carboxylic acid
9a–f (1.209 mmol, 1.0 eq.), terminal alkynes 10a–e/10f
(1.209 mmol, 1.0 eq.), Ag2ONPs (1.209 mmol, 1.0 eq.), and
PivOH (0.484 mmol, 0.4 eq.) in dry DMF (2 mL) at 120 ꢀC for 3 h.
The reaction mixture was then cooled to ambient temperature;
diluted with ethyl acetate (10 mL), ltered through a celite pad
and washed further with ethyl acetate (15 mL). The combined
organic solvents were extracted with ethyl acetate (3 ꢁ 10 mL),
washed with distilled water (2 ꢁ 20 mL) and then with brine
solution (20 mL). The combined organic layer was dried over
anhyd. Na2SO4 & concentrated under reduced pressure. The
crude product was puried by column chromatography over
silica gel (100–200 mesh size) using 2% ethyl acetate: hexane as
eluant to furnish 11–16.
Conclusions
For the rst time, we have developed a highly efficient and
straightforward route to access two bioactive moieties, 3-yli-
dinephthalides and isocoumarins, via Ag2O nanoparticle-
catalyzed Sonogashira type coupling followed by substrate-
controlled 5-exo-dig or 6-endo-dig cyclization in a highly
regioselective manner, respectively, with complete Z-
selectivity. This protocol features relatively broad substrate
scope, mild conditions, operationally simple, and is more
favorable with aromatic/alicyclic terminal alkynes as
compared to aliphatic terminal alkynes. The intermolecular
competition experiments and gram-scale synthesis further
highlights the importance and versatility of the newly devel-
oped methodology. The proposed mechanistic pathways
interprets that the regioselectivity is substantially being
controlled by the substituent(s) present on the acetylenic
phenyl ring.
(Z)-3-Benzylideneisobenzofuran-1(3H)-one
(11a).
This
compound was prepared according to the GP and obtained in
2% EtOAc/hexane solution as white solid having mp 92–94 ꢀC in
95% yield. IR (Neat, cmꢂ1): 1760, 1660, 1607, 1469, 1447, 1270,
754, 682; 1H NMR (400 MHz, CDCl3) d 7.94 (d, J ¼ 7.76 Hz, 1H),
7.85 (d, J ¼ 7.28 Hz, 2H), 7.79–7.70 (m, 2H), 7.55 (t, J ¼ 7.40 Hz,
1H), 7.41 (t, J ¼ 7.36 Hz, 2H), 7.33–7.29 (m, 1H), 6.43 (s, 1H); 13
C
NMR (100 MHz, CDCl3) d 167.16, 144.67, 140.71, 134.57, 133.17,
130.21, 129.87, 128.87, 128.52, 125.69, 123.53, 119.90, 107.15;
HRMS (ESI/QTOF) m/z [M + H]+ calculated for [C15H12O2]+:
223.0754, found: 223.0755.
(Z)-3-(4-Chlorobenzylidene)isobenzofuran-1(3H)-one (11b).
This compound was prepared according to the GP and was
obtained in 2% EtOAc/hexane solution as white solid having mp
142–146 ꢀC in 70% yield. IR (Neat, cmꢂ1): 1790, 1655, 1488,
1470, 1268, 686; 1H NMR (400 MHz, CDCl3) d 7.93 (d, J ¼ 7.6 Hz,
1H), 7.78–7.70 (m, 4H), 7.57–7.53 (m, 1H), 7.38–7.34 (m, 2H),
6.36 (s, 1H); 13C NMR (100 MHz, CDCl3) d 166.93, 145.00,
140.46, 134.70, 134.30, 131.69, 131.33, 130.08, 129.05, 125.79,
123.49, 119.93, 105.83 ppm; HRMS (ESI/QTOF) m/z [M + H]+
calculated for [C15H10ClO2]+: 257.0314, found 257.0366.
(Z)-3-(4-Bromobenzylidene)isobenzofuran-1(3H)-one (11c).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as white solid having mp 174–
176 ꢀC in 67% yield. IR (Neat, cmꢂ1) 1791, 1631, 1487, 1470,
1269, 515; 1H NMR (400 MHz, CDCl3) d 7.94 (d, J ¼ 7.68 Hz, 1H),
7.78–7.69 (m, 4H), 7.58–7.51 (m, 3H), 6.35 (s, 1H); 13C NMR (100
MHz, CDCl3) d 166.87, 145.13, 140.46, 134.69, 132.12, 132.04,
131.56, 130.13, 125.80, 123.53, 122.63, 119.95, 105.85; HRMS
(ESI/QTOF) m/z [M + H]+ calculated for [C15H10BrO2]+: 300.9859,
found 300.9860.
Experimental section
All glass apparatus were oven dried prior to use. High quality
reagents were purchased from Sigma Aldrich (USA), TCI
Chemicals (Tokyo, Japan) and Spectrochem (India) and were
used without further purication. Laboratory grade commercial
reagents and solvents were puried by standard procedures
prior to use. Infrared spectra were recorded on a FT-IR Spec-
trum 2 (Perkin-Elmer) spectrophotometer. NMR spectra were
obtained on a Jeol resonance ECS 400 MHz spectrometer
(operating at 400 MHz respectively for 1H; 100 MHz respectively
for 13C). The 1H-NMR (400 MHz) chemical shis were measured
relative to CDCl3 or DMSO-d6 as the internal reference (CDCl3:
d ¼ 7.249 ppm; DMSO-d6: d ¼ 2.50 ppm). The 13C-NMR (100
MHz) chemical shis were given using CDCl3 or DMSO-d6 as the
internal standard (CDCl3: d ¼ 77.16 ppm; DMSO-d6: d ¼ 39.52
ppm). Tetramethylsilane (d ¼ 0.00 ppm) served as an internal
standard in 1H-NMRand CDCl3 (d 77.16 ppm) in 13C NMR.
Chemical shis are reported in parts per million. Splitting
patterns are described as singlet (s), doublet (d), triplet (t) and
multiplet (m). Electrospray emission mass spectrometry (ESI-
MS) and high resolution mass spectra (HRMS) were obtained
with a Gevo G-2 S Q-TOF (Waters). Melting points were taken in
open capillaries on Complab melting point apparatus and are
presented uncorrected. Unless otherwise noted, column chro-
matography was performed over Rankem silica gel (particle
size: 100–200 mesh) procured from Rankem™ (India).
(Z)-3-(4-Methoxybenzylidene)isobenzofuran-1(3H)-one (11d).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as slight greenish blue solid
having mp 136–140 ꢀC is 70% yield. IR (Neat, cmꢂ1): 2927, 2844,
1
1780, 1650, 1601, 1511, 1471, 1258; H NMR (400 MHz, CDCl3)
d 7.92 (d, J ¼ 7.08 Hz, 1H), 7.81–7.67 (m, 4H), 7.52–7.48 m, 1H),
6.95–6.92 (m, 2H), 6.38 (s, 1H), 3.84 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 167.36, 159.89, 143.17, 140.89, 134.44, 131.79, 129.38,
125.97, 125.64, 123.21, 119.60, 114.38, 107.04, 55.43; HRMS
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(ESI/QTOF) m/z [M + H]+ calculated for [for C16H13O3]+:
253.0859, found 253.0860.
(Z)-3-Benzylidene-6-methylisobenzofuran-1(3H)-one (13a).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as off-white solid having mp 140–
(4-Methyl-benzylidene)-3H-isobenzofuran-1-one (11e). This
compound was prepared according to the GP and obtained in
2% EtOAc/hexane solution as off-white solid having mp 140–
144 C in 63% yield. IR (Neat, cmꢂ1): 2920, 2852, 1776, 1600,
ꢀ
1492, 1447, 1272; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J ¼
7.32 Hz, 2H), 7.70 (s, 1H), 7.64 (d, J ¼ 8.0 Hz, 1H), 7.52 (d, J ¼
8 Hz, 1H), 7.41–7.37 (m, 2H), 7.30–7.27 (m, 1H), 6.37 (s, 1H),
2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.32, 144.82,
140.56, 138.33, 135.90, 133.35, 130.09, 128.83, 128.29, 125.32,
123.75, 119.71, 106.33, 21.65; HRMS (ESI/QTOF) m/z [M + H]+
calculated for [C16H13O2]+: 237.0910, found 237.0911.
(Z)-3-(4-Chlorobenzylidene)-6-methylisobenzofuran-1(3H)-
one (13b). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as white solid
having mp 182–184 ꢀC in 60% yield. IR (Neat, cmꢂ1): 2922, 2840,
1756, 1666, 1490, 1250, 675; 1H NMR (400 MHz, CDCl3) d 7.74–
7.69 (m, 3H), 7.63 (d, J ¼ 7.92 Hz, 1H), 7.52 (d, J ¼ 8.0 Hz, 1H),
7.35–7.32 (m, 2H), 6.27 (s, 1H), 2.48 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 167.04, 145.15, 140.84, 138.08, 135.97, 134.02, 131.88,
131.19, 128.99, 125.62, 123.75, 119.72, 104.98, 21.63; HRMS
(ESI/QTOF) m/z [M + H]+ calculated for [C16H12ClO2]+: 271.0521,
found 271.0520.
144 C in 59% yield. IR (Neat, cmꢂ1): 2922, 1765, 1660, 1604,
ꢀ
1510, 1471, 1269, 856, 814; 1H NMR (400 MHz, CDCl3) d 7.82 (d,
J ¼ 7.32 Hz, 2H), 7.70–7.50 (m, 3H), 7.41–7.37 (m, 2H), 7.31–7.27
(m, 1H), 6.34 (s, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 167.27, 144.05, 140.82, 138.76, 134.48, 130.37, 130.19, 129.63,
125.64, 125.28, 123.41, 119.76, 107.29, 21.51; HRMS (ESI/QTOF)
m/z [M + H]+ calculated for [C16H13O2]+: 237.0910, found
237.0913.
(Z)-3-Benzylidene-6-bromoisobenzofuran-1(3H)-one (12a).
This compound was prepared according to the GP and obtained in
2% EtOAc/hexane solution as white solid having mp 176–178 ꢀC in
63% yield. IR (Neat, cmꢂ1): 1773, 1665, 1491, 1461, 1250, 522; 1H
NMR (400 MHz, CDCl3) d 8.06–8.05 (m, 1H), 7.83–7.81 (m, 3H),
7.64 (d, J ¼ 8.28 Hz, 1H), 7.43–7.39 (m, 2H), 7.35–7.31 (m, 1H), 6.42
(s, 1H); 13C NMR (100 MHz, CDCl3) d 165.62, 145.96, 143.90,
139.31, 137.71, 132.83, 130.30, 128.95, 128.60, 125.19, 123.78,
121.32, 108.08; HRMS (ESI/QTOF) m/z [M + H]+ calculated for
C15H9BrO2 [C15H10BrO2]+: 300.9859, found 300.9861.
(Z)-3-(4-Methoxybenzylidene)-6-methylisobenzofuran-1(3H)-
one (13c). This compound was prepared according to the GP and
obtained in 2% EtOAc/hexane solution as slight greenish white
solid having mp 152–154 ꢀC in 67% yield. IR (Neat, cmꢂ1): 2927,
(Z)-6-Bromo-3-(4-chlorobenzylidene)-isobenzofuran-1(3H)-
one (12b). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as off-white solid
having mp 194–196 ꢀC in 61% yield. IR (Neat, cmꢂ1): 1779, 1684,
1
2840, 1761, 1663, 1603, 1509, 1255; H NMR (400 MHz, CDCl3)
1
1491, 1463, 1249, 622, 520; H NMR (400 MHz, CDCl3) d 8.06–
d 7.78 (d, J ¼ 8.8 Hz, 2H), 7.69 (s, 1H), 7.62 (d, J ¼ 8.0 Hz, 1H), 7.50
(d, J ¼ 8.0 Hz, 1H), 6.93 (d, J ¼ 8.88 Hz, 2H), 6.30 (s, 1H), 3.83 (s,
3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.53, 159.68,
143.34, 140.00, 138.52, 131.62, 126.75, 126.14, 125.54, 123.46,
119.41, 118.33, 106.20, 55.42, 21.60; HRMS (ESI/QTOF) m/z [M +
H]+ calculated for [C17H14 O3]+: 267.1016, found 267.1015.
(Z)-6-Methyl-3-(4-methylbenzylidene)-isobenzofuran-1(3H)-
one (13d). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as white solid
having mp 170–172 ꢀC in 60% yield. IR (Neat, cmꢂ1): 2921, 1762,
1663, 1487, 1270; 1H NMR (400 MHz, CDCl3) d 7.72–7.69 (m,
3H), 7.62 (d, J ¼ 8.0 Hz, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H), 7.20 (d, J ¼
8.08 Hz, 2H), 6.31 (s, 1H), 2.47 (s, 3H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3) d 167.46, 144.49, 140.27, 138.49, 138.45, 135.82,
130.54, 130.06, 129.63, 125.47, 123.64, 119.54, 106.47, 21.61,
21.49; HRMS (ESI/QTOF) m/z [M + H]+ calculated for [C17H15O2]+
251.1067, found 251.1068.
8.05 (m, 1H), 7.84–7.81 (m, 1H), 7.77–7.74 (m, 2H), 7.64–7.61
(m, 1H), 7.38–7.35 (m, 2H), 6.36 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 165.37, 144.23, 139.06, 137.83, 134.68, 131.42, 131.36,
129.18, 128.70, 125.18, 124.05, 121.34, 106.71; HRMS (ESI/
QTOF) m/z [M + H]+ calculated for [C15H9BrClO2]+: 334.9469,
found 334.9470.
(Z)-6-Bromo-3-(4-bromobenzylidene)isobenzofuran-1(3H)-
one (12c). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as slight greenish
white solid having mp 210–212 ꢀC in 62% yield. IR (Neat, cmꢂ1):
1767, 1667, 1581, 1459, 1408, 1246, 1065, 972, 823, 518; 1H NMR
(400 MHz, CDCl3) d 8.07–8.06 (m, 1H), 7.85–7.82 (m, 1H), 7.70–
7.68 (m, 2H), 7.63 (d, J ¼ 8.28 Hz, 1H), 7.53 (d, J ¼ 8.6 Hz, 2H),
6.35 (s, 1H); 13C NMR (100 MHz, CDCl3) d 165.35, 144.46,
139.06, 137.85, 132.15, 131.78, 131.64, 128.73, 125.21, 124.09,
123.04, 121.35, 106.77; HRMS (ESI/QTOF) m/z [M + H]+ calcu-
lated for [C15H9Br2O2]+: 378.8964, found 378.8962.
(Z)-3-Benzylidene-6-uoroisobenzofuran-1(3H)-one
(14a).
(Z)-6-Bromo-3-(4-methylbenzylidene)-isobenzofuran-1(3H)-
one (12d). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as slight greenish
white solid having mp 162–164 ꢀC in 46% yield. IR (Neat, cmꢂ1):
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as white solid having mp 172–
174 C in 61% yield. IR (Neat, cmꢂ1): 1763, 1668, 1610, 1478,
ꢀ
1256, 1063, 982, 919, 681, 529; 1H NMR (400 MHz, CDCl3) d 7.83
(d, J ¼ 7.44 Hz, 2H), 7.77–7.74 (m, 1H), 7.58 (dd, J ¼ 7.04 Hz,
2.28 Hz, 1H), 7.47–7.39 (m, 3H), 7.32 (t, J ¼ 7.32 Hz, 1H), 6.38 (s,
1H); 13C NMR (100 MHz, CDCl3) d 165.98, 164.78, (JC–F ¼ 251
Hz), 143.89, 136.71, 132.94, 130.16, 128.92, 128.68, 125.36, (JC–F
¼ 9 Hz), 123.00, (JC–F ¼ 25 Hz), 121.85, (JC–F ¼ 9 Hz), 111.87, (JC–F
¼ 24 Hz), 107.29; HRMS (ESI/QTOF) m/z [M + H]+ calculated for
[C15H10FO2]+: 241.0659, found 241.0662.
1
2917, 2830, 1764, 1668, 1606, 1509, 1459, 1286, 525; H NMR
(400 MHz, CDCl3) d 8.05–8.04 (m, 1H), 7.80 (dd, J ¼ 8.24,
1.72 Hz, 1H), 7.72 (d, J ¼ 8.12 Hz, 2H), 7.62 (d, J ¼ 8.36 Hz, 1H),
7.21 (d, J ¼ 8.04 Hz, 2H), 6.40 (s, 1H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) d 165.75, 143.28, 139.43, 139.19, 137.62, 130.29,
130.05, 129.72, 128.55, 125.08, 123.47, 121.19, 108.23, 21.57;
HRMS (ESI/QTOF) m/z [M + H]+ calculated for [C16H12BrO2]+:
315.0015, found 315.0013.
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144.98, 140.61, 138.29, 135.88, 134.61, 129.74, 125.54, 123.80,
122.79, 119.72, 114.94, 114.37, 106.21, 55.42, 21.64; HRMS
(ESI/QTOF) m/z [M + H]+ calculated for [C17H15O3]+: 267.1016,
found 267.1017.
(Z)-3-(4-Chlorobenzylidene)-6-uoroisobenzofuran-1(3H)-
one (14b). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as yellow solid
having mp 166–168 ꢀC in 44% yield. IR (Neat, cmꢂ1): 1764, 1665,
1
1597, 1481, 1261, 1071, 984, 922, 824, 681, 530; H NMR (400
MHz, CDCl3) d 7.76–7.72 (m, 3H), 7.58 (dd, J ¼ 7 Hz, 2.28 Hz,
1H), 7.47–7.42 (m, 1H), 7.38–7.36 (m, 2H), 6.32 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 165.68, 163.63, (JC–F ¼ 251 Hz), 144.21,
136.46 (JC–F ¼ 1 Hz), 134.48, 131.46, 131.28, 129.14, 125.37, (JC–F
¼ 9 Hz), 123.12, (JC–F ¼ 24 Hz), 121.91, (JC–F ¼ 9 Hz), 112.00, (JC–F
¼ 24 Hz), 105.96; HRMS (ESI/QTOF) m/z [M + H]+ calculated for
[C15H9ClFO2]+: 275.0270, found 275.0270.
General procedure (GP) for the synthesis of isocoumarins 17–
20
To a stirred mixture of substituted halo aromatic carboxylic acid
9a–c (1.209 mmol, 1.0 eq.), terminal alkynes 10g–j (1.209 mmol,
1.0 eq.), Ag2ONPs (1.209 mmol, 1.0 eq.)ꢀ, and PivOH
(0.484 mmol, 0.4eq.) in dry DMF (2 mL) at 120 C for 3 h. The
reaction mixture was then cooled to ambient temperature;
diluted with ethyl acetate (10 mL), ltered through a celite pad
and washed further with ethyl acetate (15 mL). The combined
organic solvents were extracted with ethyl acetate (3 ꢁ 10 mL),
washed with distilled water (2 ꢁ 20 mL) and then with brine
solution (20 mL). The combined organic layer was dried over
anhyd. Na2SO4 & concentrated under reduced pressure. The
crude product was puried by column chromatography over
silica gel (100–200 mesh size) using 2% ethyl acetate: hexane as
eluant to furnish 17–20.
(Z)-3-Benzylidene-6-methoxyisobenzofuran-1(3H)-one (15a).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as white solid having mp 146–
150 C in 72% yield. IR (Neat, cmꢂ1): 2935, 2841, 1759, 1658,
ꢀ
1
1605, 1448, 1486, 1283, 1071, 975, 781, 687, 544; H NMR (400
MHz, CDCl3) d 7.82–7.79 (m, 2H), 7.66 (d, J ¼ 8.48 Hz, 1H), 7.41–
7.37 (m, 2H), 7.33 (d, J ¼ 2.28 Hz, 1H), 7.30–7.26 (m, 2H), 6.28 (s,
1H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.25, 161.45,
144.68, 133.72, 133.44, 129.95, 128.83, 128.16, 125.06, 124.12,
121.18, 106.86, 105.73, 55.99; HRMS (ESI/QTOF) m/z [M + H]+
calculated for [C16H13O3]+: 253.0859, found 253.0861.
3-(2-Chlorophenyl)-1H-isochromen-1-one
(17a).
This
compound was prepared according to the GP and obtained in
(Z)-6-Methoxy-3-(4-methylbenzylidene)isobenzofuran-1(3H)-
one (15b). This compound was prepared according to the GP
and obtained in 2% EtOAc/hexane solution as greenish white
solid having mp 178–180 ꢀC in 50% yield. IR (Neat, cmꢂ1): 2922,
2837, 1755, 1615, 1487, 1229, 1019, 978, 815, 539, 495; 1H NMR
(400 MHz, CDCl3) d 7.71 (d, J ¼ 8.16 Hz, 2H), 7.63 (d, J ¼ 8.6 Hz,
1H), 7.32 (d, J ¼ 2.24 Hz, 1H), 7.28–7.25 (m, 1H), 7.20 (d, J ¼
8.04 Hz, 2H), 6.26 (s, 1H), 3.89 (s, 3H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) d ¼ 167.36, 161.27, 144.05, 138.33, 133.87, 130.62,
129.91, 129.58, 124.91, 124.10, 121.04, 106.76, 105.85, 55.88,
2% EtOAc/hexane solution as off-white solid having mp 176–
178 C in 42% yield. IR (Neat, cmꢂ1): 1769, 1654, 1601, 1465,
ꢀ
1267, 1074, 949, 746, 681, 523; 1H NMR (400 MHz, CDCl3)
d 8.32–8.30 (m, 1H), 7.95 (d, J ¼ 7.72 Hz, 1H), 7.86 (d, J ¼
7.88 Hz, 1H), 7.78–7.74 (m, 1H), 7.60–7.56 (m, 1H), 7.43 (dd, J ¼
8.04 Hz, 1.16 Hz, 1H), 7.36–7.32 (m, 1H), 7.24–7.22 (m, 1H), 6.91
(s, 1H); 13C NMR (100 MHz, CDCl3) d 166.99, 145.90, 140.57,
134.77, 133.90, 131.85, 131.03, 130.35, 129.71, 129.41, 127.32,
125.73, 123.59, 120.41, 102.39; HRMS (ESI/QTOF) m/z [M + H]+
calculated for [C15H10ClO2]+: 257.0364, found 257.0365.
21.49; HRMS (ESI/QTOF) m/z [M
+
H]+ calculated for
[C17H15O3]+: 267.1016, found 267.1018.
3-(2-Bromophenyl)-1H-isochromen-1-one
(17b).
This
compound was prepared according to the GP and obtained in
(Z)-3-(3-Methoxybenzylidene)isobenzofuran-1(3H)-one (16a).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution off-white solid having mp 118–
2% EtOAc/hexane solution as off-white solid having mp 160–
162 C in 85% yield. IR (Neat, cmꢂ1): 1768, 1652, 1601, 1463,
ꢀ
1357, 1266, 1075, 945, 746, 678, 522; 1H NMR (400 MHz, CDCl3)
d 8.29 (d, J ¼ 7.92 Hz, 1H), 7.95 (d, J ¼ 7.72 Hz, 1H), 7.87 (d, J ¼
7.8 Hz, 1H), 7.77–7.73 (m, 1H), 7.63–7.56 (m, 2H), 7.39–7.36 (m,
1H), 7.17–7.13 (m, 1H), 6.87 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 166.96, 145.76, 140.52, 134.78, 133.05, 132.65, 131.98, 130.37,
129.62, 127.92, 125.72, 124.71, 123.56, 120.41, 105.15; HRMS
(ESI/QTOF) m/z [M + H]+ calculated for [C15H10BrO2]+: 300.9859,
found 300.9861.
120 C in 71% yield. IR (Neat, cmꢂ1): 2923, 2861, 1765, 1665,
ꢀ
1600, 1570, 1472, 1453, 1434, 1276, 1047, 970, 756, 685, 634,
476; 1H NMR (400 MHz, CDCl3) d 7.93 (d, J ¼ 8.44 Hz, 1H), 7.77–
7.69 (m, 2H), 7.55–7.52 (m, 1H), 7.41–7.40 (m, 2H), 7.33–7.29
(m, 1H), 6.88–6.86 (m, 1H), 6.38 (s, 1H), 3.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 167.04, 159.86, 144.82, 140.66, 134.57,
134.42, 129.92, 129.79, 125.70, 123.53, 122.91, 119.92, 115.09,
114.58, 107.58, 55.43; HRMS (ESI/QTOF) m/z [M + H]+ calculated
for [C16H13O3]+: 253.0859, found 253.0862.
3-(2-Methoxyphenyl)-1H-isochromen-1-one
(17c).
This
compound was prepared according to the GP and obtained in
2% EtOAc/hexane solution as yellowish green solid having mp
158–160 ꢀC in 60% yield. IR (Neat, cmꢂ1): 2922, 2851, 1761,
1596, 1462, 1241, 1076, 966, 740, 684; 1H NMR (400 MHz,
CDCl3) d 8.28–8.25 (m, 1H), 7.92 (d, J ¼ 7.72 Hz, 1H), 7.83 (d, J ¼
7.8 Hz, 1H), 7.72–7.68 (m, 1H), 7.54–7.50 (m, 1H), 7.31–7.27 (m,
1H), 7.05–7.01 (m, 1H), 6.96 (s, 1H), 6.91 (d, J ¼ 8.28 Hz, 1H),
3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.45, 151.11,
144.56, 141.08, 134.44, 131.43, 129.85, 129.57, 125.53, 123.26,
122.04, 121.18, 120.14, 110.53, 100.91, 55.70; HRMS (ESI/QTOF)
(Z)-3-(3-Methoxybenzylidene)-6-methylisobenzofuran-
1(3H)-one (16b). This compound was prepared according to
the GP and obtained in 2% EtOAc/hexane solution as white
solid having mp 128–130 ꢀC in 80% yield. IR (Neat, cmꢂ1):
3073, 3001, 2913, 2830, 1758, 1661, 1567, 1465, 1277, 969, 890,
779, 690, 494; 1H NMR (400 MHz, CDCl3) d 7.70 (s, 1H), 7.64 (d,
J ¼ 8.0 Hz, 1H), 7.52 (d, J ¼ 8.36 Hz, 1H), 7.40–7.39 (m, 2H),
7.32–7.28 (m, 1H), 6.87–6.84 (m, 1H), 6.31 (s, 1H), 3.85 (s, 3H),
2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.18, 159.84,
23158 | RSC Adv., 2018, 8, 23152–23162
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m/z [M + H]+ calculated for [C16H13O3]+: 253.0859, found MHz, CDCl3) d 165.89, 157.19, 143.78, 139.71, 137.55, 131.04,
253.0861.
3-(2-Chlorophenyl)-7-methyl-1H-isochromen-1-one
130.22, 128.44, 125.01, 123.40, 121.73, 121.56, 121.24, 110.58,
(18a). 101.85, 55.70; HRMS (ESI/QTOF) m/z [M + H]+ calculated for
This compound was prepared according to the GP and obtained [C16H12BrO3]+: 330.9965, found 330.9966.
in 2% EtOAc/hexane solution as off-white solid having mp 186–
3-(o-Tolyl)-1H-isochromen-1-one (20a). This compound was
188 C in 66% yield. IR (Neat, cmꢂ1): 2920, 1776, 1654, 1482, prepared according to the GP and obtained in 2% EtOAc/hexane
ꢀ
1437, 1280, 1105, 964, 756, 538, 486; 1H NMR (400 MHz, CDCl3) solution as white solid having mp 120–122 C in 75% yield. IR
ꢀ
d 8.31–8.28 (m, 1H), 7.74 (d, J ¼ 7.84 Hz, 2H), 7.56–7.54 (m, 1H), (Neat, cmꢂ1): 3059, 2922, 2851, 1758, 1664, 1608, 1461, 1346,
7.41 (dd, J ¼ 7.96 Hz, 1.24 Hz, 1H), 7.34–7.30 (m, 1H), 7.24–7.19 1269, 1073, 959, 855, 748, 687; 1H NMR (400 MHz, CDCl3) d 8.16
(m, 1H), 6.82 (s, 1H), 2.50 (s, 3H); 13C NMR (100 MHz, CDCl3) (d, J ¼ 7.68 Hz, 1H), 7.95 (d, J ¼ 7.72 Hz, 1H), 7.82 (d, J ¼ 7.88 Hz,
d 167.12, 146.07, 141.11, 138.20, 136.05, 133.75, 131.76, 131.20, 1H), 7.75–7.71 (m, 1H), 7.57–7.53 (m, 1H), 7.30–7.25 (m, 1H),
129.67, 129.18, 127.27, 125.58, 123.86, 120.19, 101.55, 21.71; 7.22–7.20 (m, 2H), 6.63 (s, 1H), 2.47 (s, 3H); 13C NMR (100 MHz,
HRMS (ESI/QTOF) m/z [M + H]+ calculated for [C16H12ClO2]+: CDCl3) d 167.31, 144.82, 140.74, 136.75, 134.54, 131.57, 130.68,
271.0521, found 271.0523.
130.41, 129.91, 128.52, 126.59, 125.67, 123.61, 119.96, 104.10,
3-(2-Bromophenyl)-7-methyl-1H-isochromen-1-one
(18b). 20.37; HRMS (ESI/QTOF) m/z [M +
H]+ calculated for
This compound was prepared according to the GP and obtained [C16H13O2]+: 237.0910, found 237.0914.
in 2% EtOAc/hexane solution as white solid having mp 182–
184 C in 67% yield. IR (Neat, cmꢂ1): 2916, 2857, 1776, 1654,
ꢀ
General procedure for the reaction of 9a with 10k
1
1486, 1433, 1281, 1103, 964, 755, 534, 483; H NMR (400 MHz,
To a stirred mixture of substituted 2-iodobenzoic acid 9a
(1.209 mmol, 1.0 eq.), 1-pentyne 10k (1.209 mmol, 1.0 eq.),
Ag2ONPs (1.209 mmol, 1.0ꢀeq.), and PivOH (0.484 mmol, 0.4eq.)
in dry DMF (2 mL) at 120 C for 3 h. The reaction mixture was
then cooled to ambient temperature; diluted with ethyl acetate
(20 mL), ltered through a celite pad and washed further with
ethyl acetate (25 mL). The combined organic solvents were
extracted with ethyl acetate (3 ꢁ 20 mL), washed with distilled
water (2 ꢁ 20 mL) and then with brine solution (20 mL). The
CDCl3) d 8.27 (dd, J ¼ 7.96 Hz, 1.56 Hz, 1H), 7.74 (d, J ¼ 8.28 Hz,
2H), 7.61–7.59 (m, 1H), 7.56–7.54 (m, 1H), 7.38–7.34 (m, 1H),
7.15–7.11 (m, 1H), 6.79 (s, 1H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 167.08, 146.02, 141.13, 138.15, 136.04, 133.06, 132.87,
131.90, 129.39, 127.88, 125.58, 124.58, 123.85, 120.19, 104.31,
21.70; HRMS (ESI/QTOF) m/z [M
[C16H12BrO2]+: 315.0015, found 315.0018.
+
H]+ calculated for
3-(2-Methoxyphenyl)-7-methyl-1H-isochromen-1-one (18c).
This compound was prepared according to the GP and obtained
in 2% EtOAc/hexane solution as yellowish green solid having
mp 156–158 ꢀC in 80% yield. IR (Neat, cmꢂ1): 2920, 2847, 1755,
1588, 1471, 1237, 969, 808, 740, 501; 1H NMR (400 MHz, CDCl3)
d 8.25 (dd, J ¼ 7.8 Hz, 1.2 Hz, 1H), 7.71 (d, J ¼ 7.6 Hz, 2H), 7.51
(d, J ¼ 8.24 Hz, 1H), 7.29–7.27 (m, 1H), 7.15 (t, J ¼ 7.56 Hz, 1H),
6.90–6.88 (m, 2H), 3.89 (s, 3H), 2.48 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 167.57, 157.00, 144.73, 140.20, 138.73, 135.77, 131.34,
129.59, 125.36, 123.67, 122.21, 121.16, 119.93, 110.50, 100.02,
55.69, 21.64; HRMS (ESI/QTOF) m/z [M + H]+ calculated for
[C17H15O3]+: 267.1016, found 267.1018.
combined organic layer was dried over anhyd. Na2SO4
&
concentrated under reduced pressure. The crude product was
puried by column chromatography over silica gel (100–200
mesh size) using 2% ethyl acetate: hexane as eluant which
furnished an inseparable mixture of 5-exo-dig and 6-endo-dig
cyclized product in 72% yields.
General procedures for the synthesis of alicyclic 3-
ylidenephthalides 21a–c
To a stirred mixture of substituted halo-aromatic carboxylic acid
7-Bromo-3-(2-chlorophenyl)-1H-isochromen-1-one
(19a). 9a–c (1.209 mmol, 1.0 eq.), alicyclic terminal alkyne 10l
This compound was prepared according to the GP and obtained (1.209 mmol, 1.0 eq.), Ag2ONPs (1.209 mmol, 1.0 eq.), and
in 2% EtOAc/hexane solution as slight yellowish white solid PivOH (0.484 mmol, 0.4 eq.) in dry DMF (2 mL) at 120 ꢀC for 3 h.
having mp 174–178 ꢀC in 60% yield. IR (Neat, cmꢂ1): 1748, 1444, The reaction mixture was then cooled to ambient temperature;
1364, 1213, 1038, 969, 827, 738, 531; 1H NMR (400 MHz, CDCl3) diluted with ethyl acetate (10 mL), ltered through a celite pad
d 8.29–8.27 (m, 1H), 8.07–8.06 (m, 1H), 7.87–7.83 (m, 1H), 7.74– and washed further with ethyl acetate (15 mL). The combined
7.71 (m, 1H), 7.44–7.41 (m, 1H), 7.36–7.31 (m, 1H), 7.27–7.23 organic solvents were extracted with ethyl acetate (3 ꢁ 10 mL),
(m, 1H), 6.91 (s, 1H); 13C NMR (100 MHz, CDCl3) d 165.40, washed with distilled water (2 ꢁ 20 mL) and then with brine
139.17, 137.88, 134.03, 131.83, 130.72, 129.79, 129.71, 128.64, solution (20 mL). The combined organic layer was dried over
127.38, 125.29, 124.32, 121.79, 103.23; HRMS (ESI/QTOF) m/z [M anhyd. Na2SO4 & concentrated under reduced pressure. The
+ H]+ calculated for [C15H9BrClO2]+: 334.9469, found 334.9470. crude product was puried by column chromatography over
7-Bromo-3-(2-methoxyphenyl)-1H-isochromen-1-one (19b). silica gel (100–200 mesh size) using 2% ethyl acetate: hexane as
This compound was prepared according to the GP and obtained eluant to furnish 21a–c in 61–69% yield range.
in 2% EtOAc/hexane solution as green solid having mp 138–
(Z)-3-(Cyclopropylmethylene)isobenzofuran-1(3H)-one (21a).
140 C in 65% yield. IR (Neat, cmꢂ1): 2920, 2857, 1767, 1588, This compound was prepared according to the GP and obtained
1458, 1241, 969, 744, 639, 500; 1H NMR (400 MHz, CDCl3) d 8.24 in 2% EtOAc/hexane solution as white solid having mp 88–90 ꢀC
(dd, J ¼ 7.8 Hz, 1.2 Hz, 1H), 8.04 (m, 1H), 7.81–7.79 (m, 1H), 7.70 in 69% yield. IR (Neat, cmꢂ1): 2925, 2857, 1750, 1689, 1460,
(d, J ¼ 8.32 Hz, 1H), 7.32–7.28 (m, 1H), 7.05–7.01 (m, 1H), 6.96 1240, 510; 1H NMR (400 MHz, CDCl3) d 7.88–7.86 (m, 1H), 7.65–
(s, 1H), 6.91 (d, J ¼ 8.28 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 7.61 (m, 1H), 7.55–7.53 (m, 1H), 7.47–7.43 (m, 1H), 5.08 (d, J ¼
ꢀ
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10.28 Hz, 1H), 2.12–2.03 (m, 1H), 1.02–0.97 (m, 2H), 0.65–0.62 with brine solution (20 mL). The combined organic layer was
(m, 2H); 13C NMR (100 MHz, CDCl3) d ¼ 167.40, 145.23, 139.43, dried over anhyd. Na2SO4 & concentrated under reduced pres-
134.25, 129.02, 125.36, 123.83, 119.24, 114.57, 9.47, 8.48; HRMS sure. The crude product was puried by column chromatog-
(ESI/QTOF) m/z [M + H]+ calculated for [C12H11O2]+: 187.0754, raphy over silica gel (100–200 mesh size) using 2% ethyl
found 187.0757.
acetate:hexane as eluant to get 11d and 16a in 55% and 50%
yield respectively (11d/16a ratio ¼ 1.2 : 1).
(Z)-6-Bromo-3-(cyclopropylmethylene)-isobenzofuran-1(3H)-
one (21b). This compound was prepared according to the GP
and obtained in ꢀ2% EtOAc/hexane solution as white solid
Free-radical scavenger experiments
TEMPO-mediated reaction in the case of 3-ylidenephthalides. To
having mp 84–86 C in 65% yield. IR (Neat, cmꢂ1): 2922, 2853, a stirred mixture of 2-iodo benzoic acid 9a (1.209 mmol, 1.0 eq.),
1759, 1684, 1459, 1242, 508; 1H NMR (400 MHz, CDCl3) d 7.99– phenylacetylene 5 (1.209 mmol, 1.0 eq.), Ag2ONPs (1.209 mmol,
7.98 (m, 1H), 7.73 (dd, J ¼ 8.32, 1.72 Hz, 1H), 7.42 (d, J ¼ 8.32 Hz, 1.0 eq.), PivOH (0.484 mmol, 0.4 eq.) and TEMPO (0.242 mmol,
1H), 5.10 (d, J ¼ 10.24 Hz, 1H), 2.10–2.02 (m, 1H), 1.04–0.99 (m, 0.2 eq.) in dry DMF (2 mL) at 120 ꢀC for 3 h. The reaction mixture
2H), 0.67–0.63 (m, 2H); 13C NMR (100 MHz, CDCl3) d 165.83, was then cooled to ambient temperature; diluted with ethyl
144.55, 138.01, 137.38, 128.26, 125.54, 122.76, 120.73, 115.82, acetate (20 mL), ltered through a celite pad and washed further
9.69, 8.67; HRMS (ESI/QTOF) m/z [M + H]+ calculated for with ethyl acetate (20 mL). The combined organic solvents were
[C12H10BrO2]+: 264.9859, found 264.9863.
(Z)-3-(Cyclopropylmethylene)-6-methylisobenzofuran-1(3H)-
one (21c). This compound was prepared according to the GP combined organic layer was dried over anhyd. Na2SO4
extracted with ethyl acetate (3 ꢁ 10 mL), washed with distilled
water (2 ꢁ 20 mL) and then with brine solution (20 mL). The
&
and obtained in 2% EtOAc/hexane solution as liquid having in concentrated under reduced pressure. The crude product was
61% yield. IR (Neat, cmꢂ1): 3057, 2920, 2851, 1748, 1680, 1450, puried by column chromatography over silica gel (100–200
1
1239, 502; H NMR (400 MHz, CDCl3) d 7.65 (s, 1H), 7.45–7.41 mesh size) using 2% ethyl acetate: hexane as eluant which fur-
(m, 2H), 5.01 (d, J ¼ 10.2 Hz, 1H), 2.44 (s, 3H) 2.11–2.02 (m, 1H), nished 11a in 93% yield. This illustrates that the mechanism of
1.00–0.95 (m, 2H), 0.63–0.59 (m, 2H); 13C NMR (100 MHz, the reaction do not occur via free-radical pathway.
CDCl3) d 167.54, 145.26, 137.32, 136.16, 129.26, 125.23, 124.62,
TEMPO-mediated reaction in the case of isocoumarins. To a stirred
119.03, 113.50, 21.56, 9.37, 8.23; HRMS (ESI/QTOF) m/z [M + H]+ mixture of 2-iodo benzoic acid 9a (1.209 mmol, 1.0 eq.), 2-bromo
calculated for [C13H13O2]+: 201.0910, found 201.0911.
phenylacetylene 10h (1.209 mmol, 1.0 eq.), Ag2ONPs (1.209 mmol,
1.0 eq.), PivOH (0.484 mmol, 0.4 eq.) and TEMPO (0.242 mmol, 0.2
eq.) in dry DMF (2 mL) at 120 ꢀC for 3 h. The reaction mixture was
then cooled to ambient temperature; diluted with ethyl acetate (15
Control experiments
General synthetic procedure for the intermolecular compe- mL), ltered through a celite pad and washed further with ethyl
tition reaction between o- and m-substituted terminal alkynes. acetate (20 mL). The combined organic solvents were extracted
To a stirred mixture of 2-iodobenzoic acid 9a (2.418 mmol, 2.0 with ethyl acetate (3 ꢁ 10 mL), washed with distilled water (2 ꢁ 20
eq.), 2-ethynylanisole 10i (1.209 mmol, 1.0 eq.), 3-ethynylanisole mL) and then with brine solution (20 mL). The combined organic
10f (1.209 mmol, 1.0 eq.), Ag2ONPs (2.418 mmol, 2.0 eq.) and layer was dried over anhyd. Na2SO4 & concentrated under reduced
PivOH (0.968 mmol, 0.8 eq.), in dry DMF (4 mL) at 120 ꢀC for 3 h. pressure. The crude product was puried by column chromatog-
The reaction mixture was then cooled to ambient temperature; raphy over silica gel (100–200 mesh size) using 2% ethyl acetate:
diluted with ethyl acetate (10 mL), ltered through a celite pad hexane as eluant which furnished 17b in 82% yield. This also
and washed further with ethyl acetate (15 mL). The combined illustrates that the mechanism of the reaction do not occur via free-
organic solvents were extracted with ethyl acetate (3 ꢁ 20 mL), radical pathway.
washed with distilled water (2 ꢁ 20 mL) and then with brine
Gram scale synthesis of 3-ylidenephthalide 11a. To a stirred
solution (20 mL). The combined organic layer was dried over mixture of 2-iodobenzoic acid 9a (2.5 g, 10.0 mmol), phenyl-
anhyd. Na2SO4 & concentrated under reduced pressure. The acetylene 5 (1.10 mL, 10.0 mmol), Ag2ONPs (2.3 g, 10.0 mmol),
crude product was puried by column chromatography over and PivOH (0.46 mL, 4.0 mmol.) in dry DMF (16 mL) at 120 ꢀC for
silica gel (100–200 mesh size) using 2% ethyl acetate: hexane as 3 h. The reaction mixture was then cooled to ambient tempera-
eluant furnished 17c and 16a in 64% and 56% yield, respectively ture; diluted with ethyl acetate (40 mL), ltered through a celite
(17c/16a ratio ¼ 1.1 : 1).
pad and washed further with ethyl acetate (35 mL). The
General synthetic procedure for the intermolecular compe- combined organic solvents were extracted with ethyl acetate (3 ꢁ
tition reaction between p- and m-substituted terminal alkynes. 30 mL), washed with distilled water (2 ꢁ 30 mL) and then with
To a stirred mixture of 2-iodobenzoic acid 9a (2.418 mmol, 2.0 brine solution (30 mL). The combined organic layer was dried
eq.), 4-ethynylanisole 10d (1.209 mmol, 1.0 eq.), 3-ethynylani- over anhyd. Na2SO4 & concentrated under reduced pressure. The
sole 10f (1.209 mmol, 1.0 eq.), Ag2ONPs (2.418 mmol, 2.0 eq.) crude product was puried by column chromatography over
ꢀ
and PivOH (0.968 mmol, 0.8 eq.), in dry DMF (4 mL) at 120 C silica gel (100–200 mesh size) using 2% ethyl acetate: hexane as
for 3 h. The reaction mixture was then cooled to ambient eluant which furnished 11a as a white solid (2.0 gm, 89% yield).
temperature; diluted with ethyl acetate (10 mL), ltered through
Gram scale synthesis of isocoumarin 17b. To a stirred
a celite pad and washed further with ethyl acetate (15 mL). The mixture of 2-iodobenzoic acid 9a (2.5 gm, 10.0 mmol), 2-bro-
combined organic solvents were extracted with ethyl acetate (3 mophenylacetylene 10h (1.26 mL, 10.0 mmol), Ag2ONPs (2.3
ꢁ 30 mL), washed with distilled water (2 ꢁ 20 mL) and then gm, 10.0 mmol), and PivOH (0.46 mL, 4.0 mmol) in dry DMF (16
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mL) at 120 ꢀC for 3 h. The reaction mixture was then cooled to
ambient temperature; diluted with ethyl acetate (40 mL),
ltered through a celite pad and washed further with ethyl
acetate (40 mL). The combined organic solvents were extracted
with ethyl acetate (3 ꢁ 35 mL), washed with distilled water (2 ꢁ
30 mL) and then with brine solution (30 mL). The combined
organic layer was dried over anhyd. Na2SO4 & concentrated
under reduced pressure. The crude product was puried by
column chromatography over silica gel (100–200 mesh size)
using 2% ethyl acetate: hexane as eluant which furnished 17b as
a white solid (2.48 gm, 82% yield).
Notes and references
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To study the mechanistic role of groups with or without
having lone pair of electrons at ortho-substituted phenyl-
acetylenes: synthesis of 20a (major) and 20b (minor). To a stir-
red mixture of 2-iodobenzoic acid 9a (1.209 mmol, 1.0 eq.), 1-
ethynyl-2-methylbenzene 10l (1.209 mmol, 1.0 eq.), Ag2ONPs
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mL), ltered through a celite pad and washed further with ethyl
acetate (25 mL). The combined organic solvents were extracted
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30 mL) and then with brine solution (20 mL). The combined
organic layer was dried over anhyd. Na2SO4 & concentrated
under reduced pressure. The crude product was puried by
column chromatography over silica gel (100–200 mesh size)
using 2% ethyl acetate: hexane as eluant which furnished 20a
(major) and 20b (minor) in 75% and 25% yields, respectively.
3-(o-Tolyl)-1H-isochromen-1-one (20a). See spectral data of 20a.
(Z)-3-(2-Methylbenzylidene)isobenzofuran-1(3H)-one (20b). This
compound was prepared according to the GP and obtained in
2% EtOAc/hexane solution as light yellow liquid in 25% yield. IR
(Neat, cmꢂ1): 3067, 2923, 2863, 1727, 1639, 1481, 1331, 1228,
1050, 757, 687; 1H NMR (400 MHz, CDCl3) d 8.33 (d, J ¼ 7.96 Hz,
1H), 7.74–7.70 (m, 1H), 7.53–7.46 (m, 3H), 7.36–7.32 (m, 1H),
7.28 (d, J ¼ 7.4 Hz, 2H), 6.60 (s, 1H), 2.50 (s, 3H); 13C NMR (100
MHz, CDCl3) d 162.69, 155.67, 137.58, 136.87, 134.92, 132.85,
131.14, 129.80, 129.28, 128.33, 125.99, 120.42, 106.01, 20.87;
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237.0910, found 237.0914.
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Conflicts of interest
All the authors declare no conict of interest.
Acknowledgements
S. C. acknowledges CSIR, New Delhi for CSIR-EMR Grant [02
(0189)/14/EMR-II]; DST, New Delhi for DST-RFBR Indo-Russian
Joint Research Project (INT/RUS/RFBR/P-169) and SERB, New
Delhi for Fast Track young scientist scheme (Grant No. CS-037/
2013). B. R. K.$S., L. Y., M. K. T. and K. K. thanks UGC, New
Delhi; DST, New Delhi; MNIT, Jaipur and CSIR, New Delhi for
providing nancial assistance in the form of fellowships,
respectively. Materials Research Centre (MRC), MNIT, Jaipur is
gratefully acknowledged for providing analytical facilities.
8 M. Uchiyama, H. Ozawa, K. Takuma, Y. Mastumoto,
M. Yonehara, K. Hiroya and T. Sakamoto, Org. Lett., 2006,
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(d)
A.
Negi,
N.
Bhandari, 17 (a) 9a was reacted with silver phenylacetylide under
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26(4), 546–567; (e) V. Sharma, P. K. Jaiswal, D. K. Yadav,
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P. K. Jaiswal, M. Mathur, A. K. Swami and S. Chaudhary,
optimized reaction conditions which furnished the desired
11a in 35% yield.; (b) Following a suggestion from one of
the reviewers, the reusability of the silver oxide
nanoparticle was checked. It was observed that the
reaction diminished tremendously by using recovered
residue.
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mechanism. 9a was reacted with either 10a or 10g under
optimized conditions (DMF as solvent at 120 ꢀC for 3 h).
The desired 3-ylidinephthalides 11a and isocoumarins 17a
were obtained in 51% and 35% yield, respectively.
23162 | RSC Adv., 2018, 8, 23152–23162
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