Regioselective one-pot synthesis of isocoumarins and phthalides from 2-iodobenzoic acids and alkynes by temperature control

Article abstract of DOI:10.1002/adsc.201300561

Copper-catalyzed coupling reaction of 2-iodobenzoic acids and alkynes such as terminal acetylenes, alkynyl carboxylic acids, and trimethylsilylacetylene selectively afforded isocoumarins and phthalides in the presence of cesium carbonate (Cs₂CO₃) and dimethyl sulfoxide (DMSO). Among the regioselective products, only the 6-endo-dig product, isocoumarin, was formed at 100 °C, and the 5-exo-dig product, phthalide, was formed as a major product at 25 °C. A variety of alkynes produced the corresponding isocoumarins and phthalides in good yields. A mechanism is suggested in which the formation of 2-alkynylbenzoic acid as an intermediate via Sonogashira-type coupling was ruled out in the reaction pathway. Copyright

Full text of DOI:10.1002/adsc.201300561

FULL PAPERS
DOI: 10.1002/adsc.201300561
Regioselective One-Pot Synthesis of Isocoumarins and Phthalides
from 2-Iodobenzoic Acids and Alkynes by Temperature Control
Manian Rajesh Kumar,a,b Francis Mariaraj Irudayanathan,a Joong Ho Moon,b
and Sunwoo Leea,*
a
Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
Fax : (+82)-62-530-3389; e-mail: sunwoo@chonnam.ac.kr
Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA
b
Received: June 26, 2013; Revised: September 5, 2013; Published online: November 8, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300561.
Abstract: Copper-catalyzed coupling reaction of 2-io- 258C. A variety of alkynes produced the correspond-
dobenzoic acids and alkynes such as terminal acety- ing isocoumarins and phthalides in good yields. A
lenes, alkynyl carboxylic acids, and trimethylsilylace- mechanism is suggested in which the formation of 2-
tylene selectively afforded isocoumarins and phthal- alkynylbenzoic acid as an intermediate via Sonoga-
ACHTUNGTRENNUNGides in the presence of cesium carbonate (Cs2CO3) shira-type coupling was ruled out in the reaction
and dimethyl sulfoxide (DMSO). Among the regio- pathway.
selective products, only the 6-endo-dig product, iso-
coumarin, was formed at 1008C, and the 5-exo-dig Keywords: alkynes; copper; decarboxylative cou-
product, phthalide, was formed as a major product at pling; isocoumarins; phthalides
Introduction
endo-dig cyclization of 2-alkynylbenzoic acid/esters,
which are obtained[15] or generated in situ[16] from the
One of the most striking features in the synthesis of Sonogashira-type coupling reaction, was one of the
natural products and bioactive molecules is the con- most attractive methods for the synthesis of phthal-
trol of the regioselectivity.[1] Regarding economy and
ACHTUNGTRENiNGNU des and isocoumarins. Depending on the cyclization
diversity, it is important to synthesize a variety of pathway, 5-exo-dig cyclization afforded phthalides and
compounds with similar structures from single starting 6-endo-dig cyclization afforded isocoumarins. Despite
materials through the control of the regioselectivity. having high substrate scopes, these methods often
For example, phthalide, which has a 5-membered ring, suffer from low regioselectivity. Even though addi-
and isocoumarin, which has a 6-membered ring, can tional methodologies have been reported to selective-
be obtained from the selective ring closing reactions ly synthesize either phthalide or isocoumarin, control
of the same starting substrates. They are important of the regioselectivity has been lacking.[17] Uchiyama
building blocks in many biological and material mole- et al. reported that 5-exo-dig and 6-endo-dig products
cules, as well as natural products. Isocoumarins exhib- were selectively obtained from 2-phenylethynylbenzo-
it bioactivities, such as antifungal,[2] antimicrobial,[3] ic acid by using a weak base and strong acid, respec-
anticancer,[4] anti-HIV[5] properties and enzyme inhib- tively. However, only one example of the substrate
ition activities.[6] Phthalides have also shown a wide was shown, which was 2-phenylethynylbenzoic acid,
range of biological activities acting as antispasmod- and only the 6-endo-dig product was employed for
ic,[7] antifungal,[8] and pesticidic agents.[9]
the synthesis of natural products. The one-pot synthe-
Traditionally, phthalide-containing products can be sis of isocoumarins from the copper-catalyzed cou-
prepared by the reaction of phthalic anhydride with pling reaction of 2-iodobenzoic acid and terminal al-
acetic anhydride/acid at high temperature[10] and the kynes was described by Abarbri and Parrain et al.
condensation of phthalides (or phthalide phosphate) However, their system afforded a mixture of isocou-
with aldehyde.[11] Isocoumarin-containing products are marins and phthalides with low regioselectivity. To
also obtained from similar traditional methods,[12] the best of our knowledge, there is no report on the
electrophilic,[13] or transition metal-catalyzed reac- selective control of 5-exo-dig and 6-endo-dig modes
tions.[14] Above all, the metal-catalyzed 5-exo-dig or 6- from the coupling of 2-halobenzoic acids and corre-
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vious report in which a mixture of 5-exo-dig and 6-
endo-dig products was formed in the presence of
K2CO3. We envisioned that this transformation could
be selectively controlled by tuning the reaction pa-
rameters. This has stimulated considerable effort to
develop a selective control reaction method for 5-exo-
dig and 6-endo-dig products by tuning the reaction
parameters (Scheme 1).
Results and Discussion
To investigate the effect of regioselectivity in the for-
mation of phthalides and isocoumarins, the reaction
of 2-iodobenzoic acid and phenylpropiolic acid (or
Scheme 1. Synthesis of isocoumarins and phthalides.
sponding alkynes in situ. Therefore, more studies for phenylacetylene) was run in the presence of CuI
the development of a regioselective control method (10 mol%) under various conditions. The results are
are desirable.
summarized in Table 1. When Cs2CO3 and K2CO3
As part of our ongoing development of decarboxy- were used as bases, only the 6-endo-dig product was
lative coupling reactions, the selective synthesis of iso- formed in 85% and 76% yields, respectively (entries 1
coumarins and phthalides has retained our attention. and 2). Et3N, an organic base, showed a low yield of
We found that the 6-endo-dig product was only product mixtures with an 80/20 ratio of 4aa and 5aa
formed when 2-iodobenzoic acid and phenylpropiolic (entry 3). With DMF and K2CO3, mixtures of product
acid were reacted in the presence of Cs2CO3 and were formed, which was similar to the result reported
a copper catalyst. This result was different from a pre- by Muthusubramanian et al.[18] (entry 4). The use of
Table 1. Optimization of the selective synthesis of isocoumarin and phthalide.[a]
Entry
Alkyne
Base
Solvent
Temperature [8C]
Yield [%][b]
Ratio[c] of 4aa/5aa
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
Cs2CO3
K2CO3
Et3N
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
65
25
25
25
25
25
100
25
100
25
100
25
85
76
32
58
49
81
71
61
54
29
34
88
84
62
75
60
32
84
>99/0
>99/0
80/20
61/39
98/2
>99/0
9/91
8/92
22/78
3/97
1/99
>99/0
0/>99
23/77
50/50
20/80
13/87
0/>99
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
DMSO
DMSO
DMF
CH3CN
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMF
9
10
11
12
13
14
15
16
17
18d
DMF
DMSO
25, 100
[a]
Reaction conditions: 1a (2.0 mmol), 2a or 3a (2.2 mmol), CuI (0.2 mmol) and base (4.0 mmol) for 12 h.
Isolated yield.
[b]
[c]
[d]
The ratio of 4aa/5aa was determined by 1H NMR.
258C for 12 h and then 1008C for 6 h.
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Regioselective One-Pot Synthesis of Isocoumarins and Phthalides from 2-Iodobenzoic Acids
Cs2CO3 provided 4aa as a major product with a ratio
of 98/2, but its yield was low (entry 5). The regioselec-
tivity of the product was not changed at 658C, but the
yield was a bit decreased (entry 6). Interestingly,
when the reaction temperature was reduced to 258C,
the regioselectivity of the product showed an opposite
trend in which 5aa was formed as a major product
with a small amount of 4aa (entry 7). A similar trend
was found in the case of K2CO3 (entry 8). Keeping
Cs2CO3 as the base, we tried to screen a variety of
solvents, but the formation of 4aa was inevitable (en-
tries 9–11). We then decided to employ phenylacety-
lene as a coupling reagent instead of phenylpropiolic
acid. As expected, when Cs2CO3 was used in DMSO,
the reaction at 1008C afforded only 4aa (entry 12).
Surprisingly, only 5aa was selectively formed when
the reaction was conducted at 258C (entry 13). How-
ever, when other bases and solvents were used, all of
them produced mixtures of products with low regiose-
lectivity (entries 14–17). From these results, we found
that DMSO and Cs2CO3 are important factors to
obtain either 4aa or 5aa with high regioselectivity. In-
terestingly, to the best of our knowledge, there is no
example of the employment of both Cs2CO3 and
DMSO in the synthesis of phthalides and isocoumar-
ins. This regioselectivity markedly in favor of the de-
sired products 4aa or 5aa was dependent on the reac-
tion temperature in the presence of Cs2CO3 and
DMSO. In addition, we found that the yield and the
regioselectivity of 5aa were not changed, even though
the reaction temperature was increased to 1008C
after the reaction was conducted at 258C for 12 h
(entry 18). When the reactions were monitored by
1H NMR, the formation of phthalide was detected at
258C and the formation of isocoumarin was detected
at 1008C.
To evaluate this catalytic system for the regiosele-
tive synthesis of isocoumarin, a variety of 2-iodoben-
zoic acids and terminal alkynes were reacted with
Cs2CO3 in DMSO at 1008C. The results are summar-
ized in Scheme 2.
The reaction of 2-iodobenzoic acid and phenylace-
tylene afforded the phenylisocoumarin 4aa in 85%
yield. Alkyl-, alkoxy-, and amine-substituted phenyla-
cetylenes produced the corresponding isocoumarins
Scheme 2. Synthesis of isocoumarins from the coupling reac-
tions of 2-iodobenzoic acids and terminal alkynes. Reaction
conditions: 1 (2.0 mmol), 3 (2.2 mmol), CuI (0.2 mmol) and
Cs2CO3 (4.0 mmol) at 1008C for 12 h.
4ab, 4ac, 4ad, 4ae, and 4af in good yields. Phenylace- the reaction with halo-substituted 2-iodobenzoic acids
tylenes bearing halide groups such as fluoride and 1d and 1e.
chloride showed yields in the range of 41 to 51%.
Alkyl-substituted terminal alkynes, such as pent-1-yne
Next, to obtain the 5-exo-dig product, the phthal-
AHCTUNGTREGiNNUN de, as a major product, the coupling reactions were
(3j), oct-1-yne (3k), ethynylcyclopropane (3l), and 3- carried out at 258C. As shown in Scheme 3, phenyl-
methoxyprop-1-yne (3m) produced only correspond- acetylene afforded only phthalide 5aa in 84% yield.
AHCTUNGTRENNUNG
ing 6-endo-dig products in 51%, 78%, 63%, and 57% Arylalkynes, which have an electron-donating group
yields, respectively. When halo- or methoxy-substitut- at the phenyl group, produced phthalides as the major
ed 2-iodobenzoic acids 1b and 1c were reacted with product, but they all gave the corresponding isocou-
phenylacetylenes, the corresponding isocoumarins marins as by-products. 2’-Fluorophenylacetylene (3g)
were obtained in good yields. However, substituted produced only phthalide 5ag in 62% yield. Other
phenylacetylene showed lower yields than others in halide-substituted phenylacetylenes such as 3h and 3i
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Scheme 4. Synthesis of isocoumarins from the coupling reac-
tions of 2-iodobenzoic acids and alkynyl carboxylic acids.
Reaction conditions:
1 (2.0 mmol), 2 (2.2 mmol), CuI
(0.2 mmol) and Cs2CO3 (4.0 mmol) at 1008C for 12 h.
stituted 2-iodobenzoic acids 1b and 1c were reacted
with terminal acetylenes at room temperature, they
produced mixtures of phthalides and isocoumarins.
Instead of arylalkynes, the employment of arylalk-
AHCTUNGTREGyNNUN nyl carboxylic acids has several advantages. They are
easily prepared from the coupling reaction with aryl
halides and propiolic acid. Alkynyl carboxylic acids
with low molecular weight were used as good alkyne
sources, because their terminal alkynes are too vola-
tile to handle. A variety of alkynyl carboxylic acids
were reacted with 2-iodobenzoic acid at 1008C. As
shown in Scheme 4, they all provided only isocoumar-
ins in good yields. Particularly, but-2-ynoic acid,
which is a propyne surrogate, gave the isocoumarin
4as in 64% yield. When the alkynyl carboxylic acids
were reacted with 2-iodobenzoic acid at 258C for the
synthesis of phthalides, the desired product was not
formed, because the decarboxylative coupling of al-
kynyl carboxylic acid requires a high temperature.
In addition, protected terminal alkynes such as tri-
methylsilylalkynes also provided the isocoumarins
when the reaction was conducted with CuI, Cs2CO3,
Scheme 3. Synthesis of phthalides from the coupling reac-
tions of 2-iodobenzoic acids and terminal alkynes. Reaction
conditions: 1 (2.0 mmol), 3 (2.2 mmol), CuI (0.2 mmol) and
Cs2CO3 (4.0 mmol) at 258C for 12 h.
afforded the phthalides 5ah and 5ai as major products, and CsF at 1008C. As shown in Scheme 5, isocoumar-
but the corresponding isocoumarin was formed as ins 4aa and 4at were formed in 62% and 51% yields,
a minor product.
respectively. At 258C, phthalide 5aa was formed as
In the case of the alkyl-substituted alkynes, some major product.
substrates showed the reversed regioselectivity. Pent-
This reaction consists of the Sonogashira-type cou-
1-yne (3j) produced a trace amount of phthalide 5aj, pling and the addition of carboxylic acid to the cou-
however, the corresponding isocoumarin 4aj was pled alkyne to produce the cyclized product. To inves-
formed as major product. Ethynylcyclopropane (3l) tigate the reaction pathway and the regioselectivity,
afforded the mixture of 5al and 4al with a ratio of 58/ we first studied the Sonogashira coupling reaction of
42. 3-Methoxyprop-1-yne (3m) gave the desired phenyl iodide (7) and phenylpropiolic acid (2a) or
phthalide 5am as major product. Benzylacetylene phenylacetylene (3a) in this catalytic system. As
gave only phthalide 5an in 79% yield. When halo-sub- shown in Table 2, only phenylpropiolic acid afforded
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Regioselective One-Pot Synthesis of Isocoumarins and Phthalides from 2-Iodobenzoic Acids
Scheme 6. Cyclization of 2-(phenylethynyl)benzoic acid
under this catalytic system.
both cases showed the same regioselectivity and pro-
duced 4aa as major product. The regioselectivity of
this transformation at 258C was opposite to that of
the coupling reaction of 2-iodobenzoic acid and phe-
nylacetylene or phenylpropiolic acid.
Based on these results, we proposed the reaction
pathway as shown in Scheme 7. We do not suggest
that the path A, which is the formation of 2-(phenyl-
Scheme 5. Synthesis of isocoumarins from the coupling reac-
tions of 2-iodobenzoic acids and trimethylsilylacetylenes. Re-
action conditions:
1
(2.0 mmol),
3
(2.2 mmol), CuI
(0.2 mmol), CsF (2.0 mmol) and Cs2CO3 (4.0 mmol) for
12 h.
AHCTUNGTREGeNNUN thynyl)benzoic acid through Sonogashira coupling
Table 2. Sonogashira coupling reactions under this catalytic
reaction, is a major pathway. Unfortunately, we failed
to isolate any intermediate compounds in this reac-
tion pathway. Instead, we propose that the addition of
the carboxylic acid of 2-iodobenzoic acid to the
alkyne proceeds first (path B) or at the same time
with the Sonogashira-type coupling reaction (path C).
In these pathways, path a might be the predominant
route at 1008C, and path b might be the predominant
route at 258C. The detailed reaction mechanism is
currently being studied in our laboratory.
system.[a]
Entry ArI Alkyne Temperature
[oC]
Product Yield
[%][b]
1
2
3
4
5
6
7
7
7
7
8
8
2a
2a
3a
3a
2a
3a
100
25
100
25
100
100
9
9
9
9
10
10
37
0
4
0
0
Conclusions
In summary, we have developed a simple copper cata-
lytic system for the regioselective synthesis of isocou-
marins and phthalides from the coupling reaction of
2-iodobenzoic acids and alkynes. The isocoumarins
were obtained at 1008C, and the phthalides were ob-
tained at 258C in the presence of Cs2CO3 and DMSO.
We found that: (i) the electronic properties of differ-
0
[a]
Reaction conditions:
7 or 8 (2.0 mmol), 2a or 3a
(2.2 mmol), CuI (0.2 mmol) and Cs2CO3 (4.0 mmol).
Determined by H NMR.
[b]
1
the coupled product 9 in 37% yield at 1008C. Phenyl- ent substituents on the aryl rings did not affect the
acetylene did not give any coupled product at either formation of isocoumarins at high temperature very
1008C or 258C. In addition, an aryl iodide bearing an much, but it did affect the formation of phthalide at
electron-withdrawing group, methyl 2-iodobenzoate low temperature; (ii) arylalkynyl carboxylic acid, and
(8), did not give any coupled product at 1008C.
trimethylsilylacetylene were also good substrates for
Next, we investigated the yields and the regioselec- the formation of isocoumarins; (iii) this reaction path-
tivity of the product. As shown in Scheme 6, 2-(phe- way might be different from the previously reported
nylethynyl)benzoic acid (11), which has been reported one, and the formation of a previously reported inter-
as an intermediate in the reaction of 2-halobenzoic mediate, 2-alkynylbenzoic acid, might not be in the
acid and alkyne, was employed under this catalytic major pathway; (iv) the survival of halide groups such
system.
as bromide and chloride offered an opportunity for
When 2-(phenylethynyl)benzoic acid (11) was em- further functionalization; (v) this copper-catalyzed re-
ployed under this catalytic system at 1008C and 258C, action system does not need any ligand.
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Manian Rajesh Kumar et al.
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Scheme 7. Proposed the reaction pathway.
d=162.3, 153.7, 145.1, 137.6, 134.7, 129.4, 129.2, 128.7, 127.7,
125.7, 125.0, 120.2, 100.9, 35.4, 33.2, 22.3, 13.8; HR-MS
(APCI): m/z=279.1382, calcd. for C19H19O2 [M+H]+:
279.1385.
Experimental Section
General Procedure for Synthesis of Isocoumarin from
Terminal Alkynes or Alkynyl Carboxylic Acids
3-(2-Methoxyphenyl)-1H-isochromen-1-one (4ad):[20] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 1-ethynyl-2-
2-Iodobenzoic acid derivative (2.0 mmol) and Cs2CO3
(1.30 g, 4.0 mmol) were added in a vial containing anhy-
drous DMSO (8 mL), followed by addition of the appropri-
ate acetylene derivative (2.2 mmol) and CuI (38 mg,
0.2 mmol). The suspension was stirred for 12 h at 1008C.
After cooling, the mixture was poured into the EtOAc
(50 mL) and washed with water (2ꢁ25 mL), brine (2ꢁ
25 mL), then dried over Na2SO4. Evaporation of the solvent
under reduced pressure provided the crude product, which
was purified by column chromatography (hexane: EtOAc=
20:1) or re-crystallized from hexane to afford the final prod-
uct.
methoxyACTHNUTRGNEUGbN enzene (291 mg, 2.2 mmol) afforded 4ad as
a white solid; yield: 408 mg (1.62 mmol, 81%); mp 115–
1
1178C; H NMR (300 MHz, CDCl3): d=8.29 (m, 1H), 7.96
(dd, J=7.9, 1.7 Hz, 1H), 7.68 (m, 1H), 7.49–7.41 (m, 2H),
7.41–7.31 (m, 2H), 7.11–6.92 (m, 2H), 3.95 (s, 3H);
13C NMR (75 MHz, CDCl3): d=162.6, 157.2, 150.4, 138.0,
134.6, 130.7, 129.4, 128.8, 127.9, 126.3, 120.8, 111.3, 106.9,
55.6.
3-(4-Methoxyphenyl)-1H-isochromen-1-one (4ae):[19] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 1-ethynyl-4-
methoxyACTHNUTRGENUGbN enzene (291 mg, 2.2 mmol) afforded 4ae as a pale
3-Phenyl-1H-isochromen-1-one (4aa):[15c] 2-Iodobenzoic
acid (496 mg, 2.0 mmol) and phenyl acetylene (225 mg,
2.2 mmol) afforded 4aa as a pale yellow solid; yield: 377 mg
(1.70 mmol, 85%); mp 80–858C; 1H NMR (300 MHz,
CDCl3): d=8.30 (m, 1H), 7.88–7.85 (m, 2H), 7.77 (m, 1H),
7.50–7.40 (m, 5H), 6.94 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=162.3, 153.6, 137.5, 134.8, 131.9, 129.9, 129.6,
128.8, 128.1, 125.9, 125.2, 120.5, 101.8.
yellow solid; yield: 343 mg (1.36 mmol, 68%); mp 112–
1158C; H NMR (300 MHz, CDCl3): d=8.26 (d, J=0.7 Hz,
1
1H), 7.81 (d, J=9.1 Hz, 2H), 7.67 (m, 1H), 7.47–7.41 (m,
2H), 6.96 (d, J=9.1 Hz, 2H), 6.82 (s, 1H), 3.85 (s, 3H);
13C NMR (75 MHz, CDCl3): d=162.5, 161.0, 153.7, 137.9,
134.8, 129.6, 127.7, 126.8, 125.7, 124.5, 120.2, 114.2, 100.2,
55.4.
3-[4-(Dimethylamino)phenyl]-1H-isochromen-1-one
(4af):[21] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 4-ethyn-
yl-N,Nꢀ-dimethylaniline (319 mg 2.2 mmol) afforded 4af as
a greenish yellow solid; yield: 392 mg (1.48 mmol, 74%); mp
3-p-Tolyl-1H-isochromen-1-one (4ab):[19] 2-Iodobenzoic
acid (496 mg, 2.0 mmol) and 1-ethynyl-4-methylbenzene
(255 mg, 2.2 mmol) afforded 4ab as white solid; yield:
368 mg (1.56 mmol, 78%); mp 107–1108C; 1H NMR
(300 MHz, CDCl3): d=8.27 (m, 1H), 7.75–7.65 (m, 3H),
7.47–7.41 (m, 2H), 7.26-7.21 (m, 2H), 6.86 (s, 1H), 2.37 (s,
3H); 13C NMR (75 MHz, CDCl3): d=162.3, 153.7, 140.1,
137.6, 134.7, 129.5, 129.4, 129.0, 127.8, 125.8, 125.0, 120.3,
101.0, 21.3.
1
171–1748C; H NMR (300 MHz, CDCl3): d=8.28 (m, 1H),
7.77–7.68 (m, 2H), 7.63 (m, 1H), 7.43–7.34 (m, 2H), 6.72 (d,
J=1.2 Hz, 2H), 6.69 (s, 1H), 3.01 (s, 6H); 13C NMR
(75 MHz, CDCl3): d=162.8, 154.6, 151.3, 138.5, 134.6, 129.5,
126.9, 126.4, 125.3, 119.7, 119.3, 111.7, 98.4, 40.1.
3-(2-Fluorophenyl)-1H-isochromen-1-one (4ag):[21] 2-Iodo-
benzoic acid (496 mg, 2.0 mmol) and 1-ethynyl-2-fluoroben-
zene (264 mg, 2.2 mmol) afforded 4ag as a white solid;
3-(4-Butylphenyl)-1H-isochromen-1-one (4ac): 2-Iodoben-
zoic acid (496 mg, 2.0 mmol) and 1-butyl-4-ethynylbenzene
(348 mg, 2.2 mmol) afforded 4ac as a pale-yellow solid;
1
yield: 244 mg (1.02 mmol, 51%); mp 110–1158C; H NMR
1
(300 MHz, CDCl3): d=8.31 (d, J=7.3 Hz, 1H), 8.00 (m,
1H), 7.76 (m, 1H), 7.54–7.48 (m, 2H), 7.40 (m, 1H), 7.26
(m, 1H), 7.20 (s, 1H), 7.18 (m, 1H); 13C NMR (75 MHz,
yield: 434 mg (1.56 mmol, 78%); mp 110–1128C; H NMR
(300 MHz, CDCl3): d=8.25 (d, J=8.4 Hz, 1H), 7.76 (d, J=
8.5 Hz, 2H), 7.66 (m, 1H), 7.42 (m, 2H), 7.25–7.20 (m, 2H),
6.85 (s, 1H), 2.66 (t, J=7.6 Hz, 2H), 1.63 (m, 2H), 1.36 (m,
2H), 0.93 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
CDCl3): d=162.0, 160.0 (d, JC,F =252.6 Hz), 148.0 (d, JC,F
=
5.1 Hz), 137.4, 134.9, 131.1 (d, JC,F =9.0 Hz), 129.5, 128.6,
3226
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3221 – 3230

Regioselective One-Pot Synthesis of Isocoumarins and Phthalides from 2-Iodobenzoic Acids
128.4, 126.4, 124.6 (d, JC,F =3.6 Hz), 120.8, 120.1 (d, JC,F
10.0 Hz), 116.4 (d, JC,F =22.9 Hz), 107.2 (d, JC,F =15.6 Hz).
=
161.3, 154.8, 140.1(d, JC,F=10.9 Hz), 132.9 (d, JC,F =10.4 Hz),
131.5, 130.3, 128.8, 125.3, 116.9 (d, JC,F =2.0 Hz), 116.4 (d,
3-(4-Fluorophenyl)-1H-isochromen-1-one (4ah):[21] 2-Iodo-
benzoic acid (496 mg, 2.0 mmol) and 1-ethynyl-4-fluoroben-
zene (264 mg, 2.2 mmol) afforded 4ah as a white solid;
J
C,F =23.3 Hz), 116.5 (d, JC,F =22.6 Hz), 101.1 (d, JC,F
=
2.9 Hz).
6,8-Dimethoxy-3-phenyl-1H-isochromen-1-one (4ca):[23] 2-
Iodo-4,6-dimethoxybenzoic acid (616 mg, 2.0 mmol) and
ethynylbenzene (224 mg, 2.2 mmol) afforded 4ca as a white
solid; yield: 350 mg (1.24 mmol, 62%); mp 158–1608C;
1H NMR (300 MHz, CDCl3): d=7.83 (m, 2H), 7.40–7.37 (m,
2H), 7.30 (m, 1H), 6.73 (d, J=1.8 Hz, 1H), 6.44 (d, J=
1.7 Hz, 1H), 6.32 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H);
13C NMR (75 MHz, CDCl3): d=167.0, 164.8, 159.6, 144.9,
144.5, 133.2, 130.1, 128.7, 128.4, 128.3, 106.7, 100.1, 94.8,
56.2, 56.0.
1
yield: 201 mg (0.84 mmol, 42%); mp 127–1308C; H NMR
(300 MHz, CDCl3): d=8.29 (m, 1H), 7.87-7.82 (m, 2H), 7.70
(m, 1H), 7.50- 7.45 (m, 2H), 7.16–7.09 (m, 2H), 6.86 (s,
1H); 13C NMR (75 MHz, CDCl3): d=163.7 (d, JC,F
=
244.6 Hz), 162.0, 152.7, 137.4, 134.9, 129.7, 128.2, 127.3,
127.2, 125.9, 120.3, 116.1 (d, JC,F =22.0 Hz), 115.8, 101.5 (d,
J
C,F =1.6 Hz).
3-(3-Chlorophenyl)-1H-isochromen-1-one (4ai):[21] 2-Iodo-
benzoic acid (496 mg, 2.0 mmol) and 1-ethynyl-3-chloroben-
zene (300 mg, 2.2 mmol) afforded 4ai as a white solid; yield:
210 mg (0.82 mmol, 41%); mp 158–1608C; 1H NMR
(300 MHz, CDCl3): d=8.31 (m, 1H), 7.86 (m, 1H), 7.75–
7.72 (m, 2H), 7.53–7.48 (m, 2H), 7.41–7.37 (m, 2H), 6.95 (s,
1H); 13C NMR (75 MHz, CDCl3): d=161.9, 152.1, 137.1,
135.0, 133.7, 130.1, 129.9, 129.8, 128.6, 126.1, 125.3, 123.3,
120.7, 102.7.
6-Chloro-3-(4-methoxyphenyl)-1H-isochromen-1-one
(4dd): 4-Chloro-2-iodobenzoic acid (565 mg, 2.0 mmol) and
1-ethynyl-4-methoxybenzene (291 mg, 2.2 mmol) afforded
4dd as a white solid; yield: 275 mg (0.96 mmol, 48%); mp
132–1358C; 1H NMR (300 MHz, CDCl3): d=8.19 (d, J=
8.4 Hz, 1H), 7.79 (d, J=9.1 Hz, 2H), 7.42 (m, 2H), 6.96 (d,
J=9.1 Hz, 2H), 6.73 (s, 1H), 3.85 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=161.7, 161.4, 155.0, 141.4, 139.3, 131.3,
128.1, 127.0, 125.1, 124.0, 118.3, 114.3, 99.2, 55.4; HR-MS
(APCI): m/z=287.0477, calcd. for C16H12ClO3 [M+H]+:
287.0475.
3-Propyl-1H-isochromen-1-one (4aj):[15b] 2-Iodobenzoic
acid (496 mg, 2.0 mmol) and pent-1-yne (150 mg, 2.2 mmol)
afforded the 4aj as a pale yellow oil; yield: 192 mg
1
(1.02 mmol, 51%); H NMR (300 MHz, CDCl3): d=8.21 (m,
1H), 7.63 (m, 1H), 7.43 (m, 1H), 7.33 (d, J=7.8 Hz, 1H),
6.22 (s, 1H), 2.46 (m, 2H), 1.71 (m, 2H), 0.96 (t, J=7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=163.1, 157.9, 137.5,
134.6, 129.4, 127.5, 124.9, 120.0, 102.9, 35.3, 20.2, 13.4.
8-Fluoro-3-p-tolyl-1H-isochromen-1-one (4eb): 2-Fluoro-
6-iodobenzoic acid (532 mg, 1.61 mmol) and 1-ethynyl-4-
methylbenzene (255 mg, 2.2 mmol) afforded 4eb as a white
solid; yield: 193 mg (0.76 mmol, 38%); mp 161–1658C;
1H NMR (300 MHz, CDCl3): d=7.79–7.76 (m, 2H), 7.69 (m,
1H), 7.29–7.25 (m, 3H), 7.16 (m, 1H), 6.89 (s, 1H), 2.41 (s,
3-Hexyl-1H-isochromen-1-one (4ak):[16d] 2-Iodobenzoic
acid (496 mg, 2.0 mmol) and oct-1-yne (242 mg, 2.2 mmol)
afforded 4ak as
a
pale yellow solid; yield: 359 mg
3H); 13C NMR (75 MHz, CDCl3): d=163.0 (d, JC,F
=
(1.56 mmol, 78%); mp 122–1258C; 1H NMR (300 MHz,
CDCl3): d=8.23 (m, 1H), 7.6 (m, 1H), 7.39 (m, 1H), 7.35
(m, 1H), 6.25 (s, 1H), 2.50 (m, 2H), 1.68 (m, 2H), 1.38–1.27
(m, 6H), 0.88 (m, 3H);13C NMR (75 MHz, CDCl3): d=
162.7, 157.9, 137.3, 134.4, 129.0, 127.1, 124.7, 119.7, 102.5,
33.2, 31.2, 28.4, 26.5, 22.2, 13.7.
266.3 Hz), 154.8, 140.7, 140.3, 136.1 (d, JC,F =10.1 Hz), 129.6,
128.7, 125.3, 121.6, 121.5, 114.9 (d, JC,F =21.3 Hz), 100.4 (d,
J
C,F =3.1 Hz), 21.4; HR-MS (APCI); m/z=255.0822, calcd.
for C16H12FO2 [M+H]+: 255.0821.
3-(Naphthalen-1-yl)-1H-isochromen-1-one (4ao):[20] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 3-(napthalen-2-yl)
propiolic acid (431 mg, 2.2 mmol) afforded 4ao as a white
solid; yield: 419 mg (1.54 mmol, 77%); mp 150–1548C;
1H NMR (300 MHz, CDCl3): d=8.40 (m, 1H), 8.27 (m,
1H), 7.96–7.89 (m, 2H), 7.79–7.74 (m, 2H), 7.59-7.51 (m,
3-Cyclopropyl-1H-isochromen-1-one (4al):[22] 2-Iodoben-
zoic acid (496 mg, 2.0 mmol) and 1-ethynyl-cyclopropane
(145 mg, 2.2 mmol) afforded 4al as a pale yellow oil; yield:
1
234 mg (1.26 mmol, 63%); H NMR (300 MHz, CDCl3): d=
8.18 (d, J=8.0 Hz, 1H), 7.63 (m, 1H), 7.37 (m, 1H), 7.30
(m, 1H), 6.28 (s, 1H) 1.79 (m, 1H), 1.05 (m, 2H), 0.92 (m,
2H); 13C NMR (75 MHz, CDCl3): d=162.5, 158.1, 137.7,
134.5, 129.2, 126.8, 124.4, 119.6, 101.2, 13.6, 6.8.
5H), 6.91ACTHNGUTERNNUG
(s, 1H); 13C NMR (75 MHz, CDCl3): d=162.6,
154.7, 137.4, 134.9, 133.7, 130.5, 129.7, 128.6, 128.4, 127.7,
127.1, 126.3, 125.9, 125.1, 120.5, 107.1.
3-(4-Bromophenyl)-1H-isochromen-1-one (4ap):[24] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 3-(4-bromophenyl)-
propiolic acid (495 mg, 1.76 mmol) afforded 4ap as a white
solid; yield: 378 mg (1.26 mmol, 63%); mp 133–1378C;
1H NMR (300 MHz, CDCl3): d=8.30 (m, 1H), 7.75–7.67 (m,
3H), 7.58 (m,1H), 7.56 (m, 1H), 7.52–7.46 (m, 2H), 6.93 (s,
1H);13C NMR (75 MHz, CDCl3): d=162.0, 152.5, 137.2,
134.9, 132.0, 130.9, 129.7, 128.4, 126.7, 126.0, 124.3, 120.6,
102.1.
3-(Methoxymethyl)-1H-isochromen-1-one (4am):[16b] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 3-methoxyprop-1-
yne (154 mg, 2.2 mmol). afforded 4am as a pale yellow
solid; yield: 217 mg (1.14 mmol, 57%); mp 48–508C;
1H NMR (300 MHz, CDCl3): d=8.18 (m, 1H), 7.66 (m,
1H), 7.42 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 6.47 (s, 1H),
4.20 (d, J=0.9 Hz, 2H), 3.42 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=162.0, 153.4, 136.6, 134.7, 129.4, 128.1, 125.5,
120.5, 103.7, 70.3, 58.8.
3-(4-tert-Butylphenyl)-1H-isochromen-1-one (4aq): 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and 3-(4-tert-butylphe-
nyl)propiolic acid (445 mg, 2.2 mmol) afforded 4aq as
a white solid; yield: 434 mg (1.56 mmol, 78%); mp 121–
6-Fluoro-3-phenyl-1H-isochromen-1-one
(4ba):[14k]
4-
Fluoro-2-iodobenzoic acid (532 mg, 2.0 mmol) and ethynyl-
benzne (224 mg, 2.2 mmol) afforded 4ba as a white solid;
1
1
yield: 326 mg (1.36 mmol, 68%); mp 158–1618C; H NMR
1258C; H NMR (300 MHz, CDCl3): d=8.27 (m, 1H), 7.80
(300 MHz, CDCl3): d=8.29 (dd, J=8.7, 5.6 Hz, 1H), 7.86–
7.82 (m, 2H), 7.47–7.40 (m, 3H), 7.13 (m, 2H), 6.88 (s, 1H);
13C NMR (75 MHz, CDCl3): d=166.6 (d, JC,F =256.3 Hz),
(m, 2H), 7.67 (m, 1H), 7.47–7.41 (m, 4H), 6.89 (s, 1H), 1.33
(s, 9H); 13C NMR (75 MHz, CDCl3): d=162.4, 153.7, 153.3,
137.6, 134.7, 129.5, 129.0, 127.8, 125.8, 125.7, 124.9, 120.3,
Adv. Synth. Catal. 2013, 355, 3221 – 3230
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asc.wiley-vch.de
3227

Manian Rajesh Kumar et al.
FULL PAPERS
101.1, 34.8, 31.1; HR-MS (APCI): m/z=279.1384, calcd. for
C19H19O2 [M+H]+: 279.1385.
20:1) or re-crystallized from hexane to afford the final prod-
uct.
(Z)-3-Benzylideneisobenzofuran-1(3H)-one (5aa):[19] 2-Io-
dobenzoic acid (496 mg, 2.0 mmol) and phenylacetylene
(225 mg, 2.2 mmol) afforded 5aa as a pale yellow solid;
yield: 373 mg (1.68 mmol, 84%); mp 82–858C; 1H NMR
(300 MHz, CDCl3): d=7.92 (m, 1H), 7.85–7.81 (m, 2H),
7.77–7.67 (m, 2H), 7.55–7.50 (m, 1H), 7.42–7.37 (m, 2H),
7.32 (m, 1H), 6.41 (s, 1H); 13C NMR (75 MHz, CDCl3): d=
167.0, 144.5, 140.6, 134.5, 133.0, 130.1, 129.8, 128.7, 128.4,
125.6, 123.4, 119.8, 107.0.
3-(4-Acetylphenyl)-1H-isochromen-1-one (4ar): 2-Iodo-
benzoic acid (496 mg, 2.0 mmol) and 3-(4-acetylphenyl)pro-
piolic acid (414 mg, 2.2 mmol) afforded 4ar as a white solid;
1
yield: 327 mg (1.24 mmol, 62%); mp 140–1438C; H NMR
(300 MHz, CDCl3): d=8.33 (m, 1H), 8.04–7.95 (m, 4H),
7.74 (m, 1H), 7.54–7.51 (m, 2H), 7.07 (s, 1H), 2.63 (s, 3H);
13C NMR (75 MHz, CDCl3): d=197.3, 161.9, 152.3, 137.7,
136.9, 136.0, 135.1, 129.8, 128.8, 126.3, 125.3, 120.9, 103.6,
26.7; HR-MS (APCI): m/z=265.0865, calcd. for C17H13O3
[M+H]+: 265.0865.
(Z)-3-(4-Methylbenzylidene)isobenzofuran-1(3H)-one
(5ab):[19] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-eth-
ynyl-4-methylbenzene (255 mg, 2.2 mmol) afforded a mixture
of 5ab and 4ab in the ratio of 93:7 as a pale yellow solid;
3-Methyl-1H-isochromen-1-one (4as):[14m] 2-Iodobenzoic
acid (496 mg, 2.0 mmol) and but-2-ynoic acid (186 mg,
2.2 mmol) afforded 4as as a white solid; yield: 205 mg
(1.02 mmol, 64%); mp 70–758C; 1H NMR (300 MHz,
CDCl3): d=8.20 (m, 1H), 7.62 (m, 1H), 7.40 (m, 1H), 7.28
(d, J=7.9 Hz, 1H), 6.21 (s, 1H), 2.23 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=162.9, 154.4, 137.5, 134.7, 129.3, 127.4,
124.8, 119.7, 103.4, 19.5.
1
yield: 363 mg (1.54 mmol, 77%); mp 147–1508C; H NMR
(300 MHz, CDCl3): d=7.90 (m, 1H), 7.73–7.65 (m, 4H),
7.50 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 6.37 (s, 1H), 2.36 (s,
3H); 13C NMR (75 MHz, CDCl3): d=167.1, 143.9, 140.6,
138.6, 134.3, 130.2, 130.0, 129.5, 127.8, 125.4, 123.2, 119.6,
107.1, 21.2; (peaks for 4ab: 134.8, 127.8, 125.8, 125.1, 101.1).
(Z)-3-(4-Butylbenzylidene)isobenzofuran-1(3H)-one
(5ac): 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-butyl-4-
ethynylbenzene (348 mg, 2.2 mmol) afforded a mixture of
5ac and 4ac in the ratio of 91:9 as a pale yellow solid; yield:
345 mg (1.24 mmol, 62%); mp 152–1548C; 1H NMR
(300 MHz, CDCl3): d=7.84 (m, 1H), 7.72–7.68 (m, 2H),
7.67–7.62 (m, 2H), 7.46 (m, 1H), 7.17 (d, J=8.3 Hz, 2H),
6.33 (s, 1H), 2.61 (m, 2H), 1.59 (m, 2H), 1.35 (m, 2H), 0.92
(t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=166.9,
143.7, 143.4, 140.4, 134.6, 130.3, 129.9, 129.3, 128.6, 125.2,
122.9, 119.5, 107.0, 35.4, 33.2, 22.2, 13.8, (peaks for
4ac:162.1, 153.6, 145.0, 137.5, 134.5, 127.6, 125.7, 125.0,
120.1, 100.9); EI-MS: m/z=278 (M+, 100), 250 (75), 235
(100), 207 (50), 178 (40), 89 (30); anal calcd. for C19H18O2: C
81.99, H 6.52; found: C 82.12, H 6.41.
General Procedure for Synthesis of Isocoumarins
from Trimethylsilylacetylenes
2-Iodobenzoic acid derivative (2.0 mmol), CsF (304 mg,
2.0 mmol) and Cs2CO3 (1.30 g, 4.0 mmol) were added to
a vial containing anhydrous DMSO (8 mL), followed by ad-
dition of appropriate the trimethylsilylacetylene derivative
(2.2 mmol) and CuI (38 mg, 0.2 mmol). The suspension was
stirred for 12 h at 1008C. After cooling, the mixture was
poured into the EtOAc (50 mL) and washed with water (2ꢁ
25 mL), brine (2ꢁ25 mL), then dried over Na2SO4. Evapora-
tion of the solvent under reduced pressure provided the
crude product, which was purified by column chromatogra-
phy (hexane: EtOAc=20:1) or re-crystallized from hexane
to afford the final product.
3-(Quinolin-2-yl)-1H-isochromen-1-one (4at): 2-Iodoben-
zoic acid (496 mg, 2.0 mmol) and 2-((trimethylsilyl)ethynyl)-
quinoline (384 mg, 2.2 mmol) afforded 4at as a white solid;
(Z)-3-(4-Methoxybenzylidene)isobenzofuran-1(3H)-one
(5ae):[15d] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-eth-
ynyl-4-methoxybenzene (291 mg, 2.2 mmol) afforded 5ae
and 4ae in the ratio of 70:30 as a white solid; yield: 343 mg
(1.36 mmol, 68%); mp 108–1108C; 1H NMR (300 MHz,
CDCl3): d=7.90 (m, 1H), 7.80–7.75 (m, 2H), 7.71 (m, 1H),
7.54–7.43 (m, 2H), 6.95-6.91 (m, 2H), 6.36 (s, 1H), 3.83 (s,
3H); 13C NMR (75 MHz, CDCl3): d=167.2, 159.7, 143.1,
140.8, 134.3, 131.7, 129.2, 126.8, 125.8, 125.5, 123.1, 119.5,
114.2, 106.9, 55.3, (peaks for 4ae: 162.4, 161.0, 153.7, 137.9,
134.8, 129.6, 127.6, 125.7, 124.5, 120.1, 114.2, 101.2, 55.4).
(Z)-3-[4-(Dimethylamino)benzylidene]isobenzofuran-
1(3H)-one (5af):[25] 2-Iodobenzoic acid (496 mg, 2.0 mmol)
and 4-ethynyl-N,N’-dimethylaniline (319 mg 2.2 mmol) af-
forded 5af and 4af in the ratio of 50:50 as a pale yellow
solid; yield: 307 mg (1.16 mmol, 58%); mp 121–1248C;
1H NMR (300 MHz, CDCl3): d=7.87 (m, 1H), 7.76–7.73 (m,
2H), 7.63 (m, 1H), 7.46–7.41 (m, 2H), 6.72–6.70 (m, 2H),
6.35 (s, 1H), 3.01 (s, 6H); 13C NMR (75 MHz, CDCl3): d=
167.6, 150.3, 141.6, 141.1, 134.1, 131.6, 128.5, 125.4, 122.7,
121.1, 119.2, 111.8, 112.1, 108.1, 108.1, 40.2, (peaks for 4af:
162.8, 154.7, 151.4, 138.5, 134.7, 129.6, 126.9, 126.5, 125.4,
119.7, 119.3, 98.4, 40.2).
1
yield: 278 mg (1.02 mmol, 51%); mp 163–1688C; H NMR
(300 MHz, CDCl3): d=9.32 (d, J=2.3 Hz, 1H), 8.72 (d, J=
2.2 Hz, 1H), 8.35 (m, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.92 (d,
J=8.1 Hz, 1H), 7.76-7.73 (m, Hz, 2H), 7.63-7.52 (m, 3H),
7.18 (s, 1H); 13C NMR (126 MHz, CDCl3): d=161.9, 151.2,
148.2, 146.7, 137.0, 135.2, 132.7, 130.7, 129.9, 129.3, 128.8,
128.6, 127.6, 127.4, 126.3, 124.9, 120.8, 103.1; HR-MS
(APCI): m/z=274.0869, calcd. for C18H12O2 [M+H]+:
274.0868.
General Procedure for Synthesis of Phthalides from
Terminal Alkynes
2-Iodobenzoic acid derivative (2.0 mmol) and Cs2CO3
(1.30 g, 4.0 mmol) were added to a vial containing anhy-
drous DMSO (8 mL), followed by addition of the appropri-
ate acetylene derivative (2.2 mmol) and CuI (38 mg,
0.2 mmol). The suspension was stirred for 12 h at 258C.
After cooling, the mixture was poured into the EtOAc
(50 mL) and washed with water (2ꢁ25 mL), brine (2ꢁ
25 mL), then dried over Na2SO4. Evaporation of the solvent
under reduced pressure provided the crude product, which
was purified by column chromatography (hexane: EtOAc=
(Z)-3-(2-Fluorobenzylidene)isobenzofuran-1(3H)-one
(5ag):[26] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-eth-
ynyl-2-fluorobenzene (264 mg, 2.2 mmol) afforded 5ag as
3228
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 3221 – 3230

Regioselective One-Pot Synthesis of Isocoumarins and Phthalides from 2-Iodobenzoic Acids
a white solid; yield: 299 mg (1.24 mmol, 62%); mp 151–
1548C; H NMR (300 MHz, CDCl3): d=8.33 (m, 1H), 7.94
solid; yield: 373 mg (1.58 mmol, 79%); mp 68–728C;
1H NMR (300 MHz, CDCl3): d=8.21 (m, 1H), 7.61 (m,
1H), 7.45–7.39 (m, 2H), 7.35–7.23 (m, 5H), 6.14 (s, 1H),
3.81 (s, 2H); 13C NMR (75 MHz, CDCl3): d=162.5, 156.8,
137.2, 135.5, 134.6, 129.27, 129.1, 128.6, 127.7, 127.0, 125.1,
119.9, 103.7, 39.3; HR-MS (APCI): m/z=237.0917, calcd.
for C16H13O2 [M+H]+: 237.0916.
1
(m, 1H), 7.82–7.69 (m, 2H), 7.55 (m, 1H), 7.29–7.24 (m,
2H), 7.10 (m, 1H), 6.70 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=166.8, 160.3 (d, JC,F =251.0 Hz), 145.6 (d, JC,F
=
2.4 Hz), 140.4, 134.6, 131.3 (d, JC,F =1.9 Hz), 130.1, 129.8 (d,
J
J
C,F =8.6 Hz), 125.5, 124.5 (d, JC,F =3.6 Hz), 123.4, 121.1 (d,
C,F =11.2 Hz), 120.1, 115.2 (d, JC,F =22.0 Hz), 97.9 (d, JC,F
(Z)-3-Benzylidene-5-chloroisobenzofuran-1(3H)-one
(5da): 4-Chloro-2-iodobenzoic acid (450 mg, 1.61 mmol) and
phenylacetylene (180 mg, 1.76 mmol) afforded the product
5da; yield: 210 mg (0.73 mmol, 57%); mp 118–1208C;
1H NMR (300 MHz, CDCl3): d=7.86–7.83 (m, 2H), 7.76 (m,
1H), 7.50–7.46 (m, 2H), 7.41-7.38 (m„ 2H), 7.34 (m, 1H),
6.40 (s, 1H); 13C NMR (75 MHz, CDCl3): d=165.9, 143.3,
142.1, 141.3, 132.6, 131.3, 130.3, 128.9, 126.8, 125.4, 121.7,
119.9, 108.3; HR-MS (APCI): m/z=257.0368, calcd. for
C15H10ClO2 [M+H]+: 257.0369.
=
8.0 Hz).
(Z)-3-(4-Fluorobenzylidene)isobenzofuran-1(3H)-one
(5ah):[19] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-eth-
ynyl-4-fluorobenzene (264 mg, 2.2 mmol) afforded 5ah and
4ah in the ratio of 85:15 as a white solid; yield: 350 mg
(1.46 mmol, 73%); mp 148–1508C; 1H NMR (300 MHz,
CDCl3): d=7.92 (m, 1H), 7.87–7.78 (m, 2H), 7.76–7.66 (m,
2H), 7.60 (m, 1H), 7.19–7.02 (m, 2H), 6.37 (s, 1H);
13C NMR (75 MHz, CDCl3): d=167.1, 142.2 (d, JC,F
=
244.2 Hz), 140.1, 138.5, 134.3, 130.2, 130.0, 129.4, 125.3,
125.0, 123.1, 119.6, 107.1, (peaks for 4ah: 162.3, 153.7, 137.6, General Procedure for Synthesis of Phthalides from
134.7, 129.0, 127.7, 125.8, 100.9).
Trimethylsilylacetylenes
(Z)-3-(3-Chlorobenzylidene)isobenzofuran-1(3H)-one
(5ai):[16c] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-ethyn-
yl-3-chlorobenzene (300 mg, 2.2 mmol) afforded 5ai and 4ai
in the ratio of 96:4 as a pale yellow solid; yield: 302 mg
(1.18 mmol, 59%); mp 147–1508C; 1H NMR (300 MHz,
CDCl3): d=7.92 (m, 1H), 7.80 (m, 1H), 7.74–7.71 (m, 3H),
7.55 (m, 1H), 7.34-7.26 (m, 2H), 6.32 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=166.7, 145.4, 140.2, 134.8, 134.6, 134.6,
130.2, 129.9, 129.7, 128.3, 128.1, 125.7, 123.5, 119.9, 105.4.
(Z)-3-Butylideneisobenzofuran-1(3H)-one (5aj): 2-Iodo-
benzoic acid (496 mg, 2.0 mmol) and pent-1-yne (150 mg,
2.2 mmol) afforded 5aj and 4aj in the ratio of 4:96 as a pale-
yellow oil; yield: 106 mg (0.70 mmol, 35%); only one proton
peak was detected due to its low yield and low selectivity.
1H NMR (300 MHz, CDCl3, peak for 5aj): d=5.63 (t, J=
7.8 Hz, 1H).
2-Iodobenzoic acid derivative (2.0 mmol), CsF (304 mg,
2.0 mmol) and Cs2CO3 (1.30 g, 4.0 mmol) were added to
a vial containing anhydrous DMSO (8 mL), followed by ad-
dition of the appropriate trimethylsilylacetylene derivative
(2.2 mmol) and CuI (38 mg, 0.2 mmol). The suspension was
stirred for 12 h at 258C. After completion of the reaction,
the mixture was poured into the EtOAc (50 mL) and
washed with water (2ꢁ25 mL), brine (2ꢁ25 mL), then dried
over Na2SO4. Evaporation of the solvent under reduced
pressure provided the crude product, which was purified by
column chromatography (hexane: EtOAc=20:1) or re-crys-
tallized from hexane to afford the final product.
(Z)-3-Benzylideneisobenzofuran-1(3H)-one
dobenzoic acid (496 mg, 2.0 mmol) and trimethyl(phenyl-
AHCTUNGTREGeNNNU thynyl)silane (384 mg, 2.2 mmol) afforded 5aa and 4aa in
the ratio of 91:9 as a pale yellow solid; yield: 154 mg
(0.69 mmol, 35%).
(5aa):[19] 2-Io-
ACHTUNGTRENNUNG
(Z)-3-(Cyclopropylmethylene)isobenzofuran-1(3H)-one
(5al):[22] 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 1-ethyn-
ACHTUNGTRENNUNGylcyclopropane (145 mg, 2.2 mmol) afforded 5al and 4al in
the ratio of 58:42 as a pale-yellow oil; yield: 153 mg
1
(0.82 mmol, 41%); H NMR (300 MHz, CDCl3): d=7.89 (m,
1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.32 (m, 1H), 5.10 (d, J=
10.2 Hz, 1H), 2.10 (m, 1H), 1.04–0.98 (m, 2H), 0.66–0.63
(m, 2H); 13C NMR (75 MHz, CDCl3): d=167.3, 145.1, 139.3,
134.1, 128.9, 125.2, 123.7, 119.1, 114.4, 9.4, 8.4, (peaks for
4al: 162.7, 158.3, 137.9, 134.7, 129.5, 127.1, 124.6, 119.9,
101.3, 13.8, 6.9)
Acknowledgements
This research was supported by Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (NRF-2012R1A1B3000871).
(Z)-3-(2-Methoxyethylidene)isobenzofuran-1(3H)-one
(5am): 2-Iodobenzoic acid (496 mg, 2.0 mmol) and 3-me-
thoxyprop-1-yne (154 mg, 2.2 mmol) afforded 5am and 4am
in the ratio of 83:17 as a pale yellow oil; yield: 121 mg
References
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(0.64 mmol, 32%); H NMR (300 MHz, CDCl3): d=7.92 (m,
1H), 7.74–7.64 (m, 1H), 7.61ACTHNUGRTNEUNG(m, 1H), 5.75 (t, J=7.0 Hz,
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Adv. Synth. Catal. 2013, 355, 3221 – 3230