Synthesis of isocoumarins: Rhenium complex-catalyzed cyclization of 2-ethynylbenzoic acids

Article abstract of DOI:10.3987/COM-15-13311

When 2-ethynylbenzoic acids were treated with a catalytic amount of a rhenium complex, such as ReCl(CO)5, 6-endo cyclization of 2-ethynylbenzoic acids proceeded with a high selectivity to give the corresponding isocoumarins in moderate to good yields.

Full text of DOI:10.3987/COM-15-13311

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HETEROCYCLES, Vol. 91, No. 11, 2015
HETEROCYCLES, Vol. 91, No. 11, 2015, pp. 2172 - 2179. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 29th August, 2015, Accepted, 13th October, 2015, Published online, 27th October, 2015
DOI: 10.3987/COM-15-13311
SYNTHESIS OF ISOCOUMARINS: RHENIUM COMPLEX-CATALYZED
CYCLIZATION OF 2-ETHYNYLBENZOIC ACIDS
Rui Umeda, Shunya Yoshikawa, Kouji Yamashita, and Yutaka Nishiyama*
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan; E-mail: nishiya@kansai-u.ac.jp
Abstract – When 2-ethynylbenzoic acids were treated with a catalytic amount of
a rhenium complex, such as ReCl(CO)5, 6-endo cyclization of 2-ethynylbenzoic
acids proceeded with a high selectivity to give the corresponding isocoumarins in
moderate to good yields.
Isocoumarin (1H-2-benzopyran-1-one) is one of the important structural subunits in numerous natural
products that exhibit a wide range of biological properties1 and is a useful intermediate for the preparation
of hetero- and carbocyclic compounds including isocarbostyrils, isochromenes and isoquinolines.2
Therefore, the development of synthetic methods of the isocoumarins has significantly contributed to
organic and medicinal chemistries.3
We and some groups showed that ReX(CO)5 (X = Cl or Br) can be used as a catalyst for organic reactions
instead of various Lewis acid complexes.4,5 Recently, Hou reported that the rhenium complex-catalyzed
addition of carboxylic acids to terminal alkynes proceeded with a high regioselectivity affording the
anti-Markovnikov adduct, i.e., DꢀE-unsaturated carboxylic acids, in moderate to good yields.6 Based on
these results, it is expected that the treatment of 2-ethynylbenzoic acids in the presence of rhenium
catalyst would provide the one of the preparation methods of cyclic esters, isocoumarins or
vinylphthalides, via the intramolecular cyclization of 2-ethynylbenzoic acids.㸵 We now wish to report
the successful example of the rhenium-catalyzed 6-endo intramolecular cyclization of 2-ethynylbenzoic
acids for the synthesis of isocoumarins (Scheme 1).
R
R
cat. ReCl(CO)5
O
CO2H
O
Scheme 1

HETEROCYCLES, Vol. 91, No. 11, 2015
2173
When 2-(phenylethynyl)benzoic acid (1a) was stirred in the presence of a catalytic amount of ReCl(CO)5
(5 mol%) in a hexane at 80 °C for 5 h, the 6-endo cyclization of 1a smoothly proceeded with a high
selectivity to give 3-phenyl-1H-isochromen-1-one (2a) in 80% yield with a small amount of the 5-exo
cyclized product, 3-(1-benzylidene)phthalide (3a) (1%) (Entry 1 in Table 1). No reaction took place in the
absence of the rhenium complex (Entry 2). The yield of 2a was improved by the extended reaction time
(10 h) (Entry 3). At a lower reaction temperature (60 °C), the yield and selectivity of 2a decreased (Entry
4). To explore the effect of the solvents and rhenium complexes, the reaction of 1a was carried out in
various solvents and rhenium complex catalysts. In the toluene solvent, a decrease in both the yield and
selectivity of 2a were observed (Entry 5). In the cases of THF and acetonitrile, which were coordinated
solvents to metals, the yields of 2a dramatically decreased (Entries 6 and 7).
Table 1. Reaction of 2-(phenylethynyl)benzoic acid (1a)a
cat. Re complex
+
O
O
Solvent
CO2H
O
O
1a
2a
3a
Entry
1
Catalyst
Solvent
hexane
hexane
hexane
hexane
toluene
THF
Temp (°C)
Yield (%) (2a : 3a)b
81 (80 : 1)
0
ReCl(CO)5
-
80
80
80
60
80
80
80
80
80
80
80
80
2
3c
ReCl(CO)5
ReCl(CO)5
ReCl(CO)5
ReCl(CO)5
ReCl(CO)5
ReCl(CO)5
ReBr(CO)5
Re2(CO)10
ReCl5
93 (90 : 3)
60 (53 : 7)
66 (53 : 13)
24 (24 : 0)
3 (2 : 1)
4
5
6
7
MeCN
8
ClCH2CH2Cl
hexane
87 (80 : 7)
77 (72 : 5)
19 (2 : 17)
22 (17 : 5)
8 (2 : 6)
9
10
11
12
hexane
hexane
(C5H5)Re(CO)3
hexane
a Reaction conditions: 1a (0.3 mmol), Re catalyst (5 mol%), solvent (2 mL), 5 h.
b 1H NMR yield. The number in parenthesis shows the ratio of 2a and 3a.
c 10 h.

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HETEROCYCLES, Vol. 91, No. 11, 2015
The use of 1,2-dichloroethane, which is often used for the rhenium-catalyzed reaction, led to the good
yield of 2a (80%), but the selectivity slightly decreased (Entry 8). When ReBr(CO)5 was used instead of
ReCl(CO)5 as the catalyst, both the yield and selectivity of 2a were lower than those of ReCl(CO)5 (Entry
9). Other rhenium complexes, such as Re2(CO)10, ReCl5 and (C5H5)Re(CO)3, did not show any high
catalytic activity (entries 10-12).8
To clear the scope and limitation of the rhenium complex catalytic system, various 2-(arylethynyl)benzoic
acids were treated with a catalytic amount of rhenium complex. These results are shown in Table 2. The
6-endo cyclization of 2-(arylethynyl)benzoic acids bearing electron-donating groups on the aromatic ring,
such as the 2-((4-methylphenyl)ethynyl)- and 2-((4-methoxyphenyl)ethynyl)benzoic acid, proceeded with
excellent selectivity to give the corresponding 3-aryl-1H-isochromen-1-one, 2b,c, in 96 and 87% yields,
respectively (Entries 2 and 3). For the reaction of 2-((4-chlorophenyl)ethynyl)benzoic acid, in which the
electron withdrawing group was substituted on the aromatic ring, the yield of
3-(4-chlorophenyl)-1H-isochromen-1-one (2d) decreased (Entry 4). In the case of the
2-((3-methoxyphenyl)ethynyl)benzoic acid, the yield of 3-(3-methoxyphenyl)-1H-isochromen-1-one (2e)
decreased due to the decreasing selectivity (Entry 5). For the sterically hindered 2-(arylethynyl)benzoic
acids, 2-((2-methoxyphenyl)- and 2-((2-methylphenyl)ethynyl)benzoic acid, the yields of products
decreased (Entries 6 and 7). The preparation of the naphthyl and alkyl substituted 1H-isochromen-1-ones
2 was successfully achieved using the rhenium catalytic system (Entries 8-12).
Table 2. Synthesis of 1H-isochromen-1-onesa
R
R
cat. ReCl(CO)5
hexane
R
+
O
O
CO2H
O
O
1
2
3
Entry
R
Yield (%) (2 : 3)b
93 (90 : 3)
1
2
Ph (1a)
4-MeC6H4 (1b)
99 (96 : 3)
3c
4-MeOC6H4 (1c)
4-ClC6H4 (1d)
87 (87 : 0)
4
77 (72 : 5)
5
3-MeOC6H4 (1e)
2-MeOC6H4 (1f)
2-MeC6H4 (1g)
94 (54 : 40)
68 (53 : 15)
45 (40 : 5)
6
7

HETEROCYCLES, Vol. 91, No. 11, 2015
2175
8c
9
1-C10H7 (1h)
n-C3H7 (1i)
n-C4H9 (1j)
c-C6H11 (1k)
t-C4H9 (1l)
80 (80 : 0)
70 (70 : 0)
77 (77 : 0)
81 (81 : 0)
20 (20 : 0)
10
11
12
a Reaction conditions: 1 (0.3 mmol), ReCl(CO)5 (5 mol%), hexane (2 mL) at 80 °C for 10 h.
b Isolated yield. The number in parenthesis shows the ratio of 2 and 3.
c ClCH2CH2Cl was used as a solvent.
We cannot fully explain the reaction pathway for the reaction, however, one of the plausible reaction
pathways for the rhenium-catalyzed reaction is shown in Scheme 2. First, the decarbonylation of
ReCl(CO)5 to form ReCl(CO)4, which is the coordinatively unsaturated 16-electron complex, is the first
step of the catalytic reaction.9 The carbon-carbon triple bond of the 2-ethynylbenzoic acids 1 is activated
by the coordination of the rhenium species. The nucleophilic addition of the carboxy group to the
carbon-carbon triple bond activated by the rhenium complex followed by the protonation then gave the
1H-isochromen-1-ones 2.
R
O
ReCl(CO)5
R
O
'ꢀ/
CO
2
OH
ReCl(CO)4
O
1
H+
ReCl(CO)4
R
(OC)4ClRe
O
O
R
O
H
O
H+
Scheme 2

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HETEROCYCLES, Vol. 91, No. 11, 2015
We developed a new synthetic method of isocoumarins by the rhenium complex-catalyzed 6-endo
cyclization of 2-ethynylbenzoic acids. The application of the reaction and determining the reaction
mechanism are now in progress.
EXPERIMENTAL
Reagents. ReBr(CO)5, ReCl(CO)5, (C5H5)ReO3, Re2(CO)10, and ReCl5 were commercially available and
were used without further purification. 2-(Arylethynyl)benzoic acids were prepared by the hydoration of
corresponding methyl esters, which were prepared by the Sonogashira coupling of methyl 2-iodobenzoate
and arylethyny, 1-pentyne, 1-hexyne, ethynylcyclohexane or 3,3-dimethyl-1-butyne. Other chemical
agents were obtained commercially and were purified if necessary by distillation.
General procedure for rhenium-catalyzed cyclization of 2-ethynylbenzoic acids. A hexane (2.0 mL)
solution of 2-ethynylbenzoic acid (0.3 mmol) and ReCl(CO)5 (5 mol%) was stirred under an atmosphere
of nitrogen at 80 ºC for 10 h. After the reaction was complete, H2O was added to the reaction mixture and
extracted with EtOAc. The organic layer was dried with MgSO4. The resulting mixture was filtered, and
the filtrate was concentrated. Purification of the residue by silica gel column chromatography afforded
1
13
isocoumarins. The structures of the products were assigned by their H and C-NMR, and mass spectra.
The products were characterized by comparing its spectral data with those of authentic samples or
previous reports 2a,3e 2b,3e 2c,3e 2d,3e 2e,10 2f,3e 2g,7b 2h,3e 2i,7b,11 2j,3e 2k,12 2l,13 3a,14 3b,14 3d,15 and
1
13
3g.7b The structures of the products (3e and 3f) were assigned by their H and C NMR, IR and mass
spectrum.
ACKNOWLEDGEMENTS
This work was financially supported by the Grant-in-Aid for Scientific Research and the Kansai
University Research Grants: Grant-in-Aid for Encouragement of Scientists.
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