Divergent Syntheses of (Z)-3-Alkylideneisobenzofuran-1(3 H)-ones and 1 H-Isochromen-1-ones by Copper-Catalyzed Cycloisomerization of 2-Alkynylbenzoic Acids in Ionic Liquids

Article abstract of DOI:10.1021/acs.joc.8b00923

The cycloisomerization of readily available 2-alkynylbenzoic acids 1 in ionic liquids (ILs) as recyclable reaction media has been studied under the catalytic action of CuCl₂. With substrates bearing an aryl group on the triple bond, a mixture o

Full text of DOI:10.1021/acs.joc.8b00923

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Article
Divergent Syntheses of (Z)-3-Alkylideneisobenzofuran-1(3H)-
ones and 1H-Isochromen-1-ones by Copper-Catalyzed
Cycloisomerization of 2-Alkynylbenzoic Acids in Ionic Liquids
Raffaella Mancuso, Christian S Pomelli, Piera Chiappetta, Katia Francesca Gioia,
Asif Maner, NADIA MARINO, Lucia Veltri, Cinzia Chiappe, and Bartolo Gabriele
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00923 • Publication Date (Web): 24 May 2018
Downloaded from http://pubs.acs.org on May 25, 2018
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Divergent Syntheses of (Z)-3-Alkylideneisobenzofuran-1(3H)-ones and 1H-Isochromen-1-
ones by Copper-Catalyzed Cycloisomerization of 2-Alkynylbenzoic Acids in Ionic Liquids
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,
‡
$
Raffaella Mancuso,* † Christian S. Pomelli, Piera Chiappeꢀa,† Kaꢁa F. Gioia,† Asif Maner,† Nadia Marino,
‡
,
Lucia Veltri,† Cinzia Chiappe, and Bartolo Gabriele* †
†
Laboratory of Industrial and Syntheꢁc Organic Chemistry (LISOC), Department of Chemistry and Chemical
Technologies, University of Calabria, Via Pietro Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
‡
Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy
$
Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci 14/C, 87036
Arcavacata di Rende (CS), Italy
raffaella.mancuso@unical.it; bartolo.gabriele@unical.it
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Abstract
The cycloisomerization of readily available 2-alkynylbenzoic acids 1 in ionic liquids (ILs) as recyclable
reaction media has been studied under the catalytic action of CuCl . With substrates bearing an aryl group
on the triple bond, a mixture of (Z)-3-alkylideneisobenzofuran-1(3H)-ones (from 5-exo-dig cyclization) and
H-isochromen-1-ones (from 6-endo-dig cyclization) was observed in 1-ethyl-3-methylimidazolium ethyl
sulfate (EmimEtSO ), while the reaction turned out to be selective toward the formation of the
2
0
1
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4
isobenzofuranone only using N-ethyl-N-methylmorpholinium dicyanamide [Mor1,2N(CN)
The 5-membered product was also obtained selectively when the substrate bearing a terminal triple bond
was employed, either in EmimEtSO or Mor1,2N(CN) . On the other hand, 2-alkynylbenzoic acids bearing an
alkyl or an alkenyl group on the triple bond selectively led, in EmimEtSO , to 1H-isochromen-1-ones, while
the formation of a regioisomeric mixture was observed in Mor1,2N(CN) . In any case, the solvent/catalyst
2
], as the solvent.
4
2
4
2
system could be easily recycled after extraction of the product from the reaction mixture with diethyl
ether. DFT calculations have been carried out to clarify the reaction outcome depending on reaction
conditions, and the structures of two representative products, that are, (Z)-3-benzylideneisobenzofuran-
1
(3H)-one and (Z)-3-(4-methylphenylmethylidene)isobenzofuran-1(3H)-one, have been confirmed by X-ray
diffraction analysis.
Introduction
1
-3
Cycloisomerization of 2-alkynylbenzoic acids is a convenient method for the direct and atom-economical
4
,5
synthesis of important heterocyclic derivatives, with important biological activities. Depending on the
substitution pattern of the substrate and reaction conditions, the process may lead to either 3-
alkylideneisobenzofuran-1(3H)-ones (from 5-exo-dig cyclization) or 1H-isochromen-1-ones (from 6-endo-dig
cyclization) (Scheme 1).
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CHR
O
5-exo-dig
path a
R
O
OH
R
1
1
1
1
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1
1
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1
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0
O
6-endo-dig
O
path b
O
Scheme 1. Cycloisomerization of 2-alkynylbenzoic acids leading to either 3-alkylideneisobenzofuran-1(3H)-
ones (from 5-exo-dig mode, path a) or 1H-isochromen-1-ones (from 6-endo-dig mode, path b).
1
1a,2
Although different catalysts have been proposed for promoting this reaction, including acid, basic,
3
and transition-metal catalysts, to the best of our knowledge the use of copper-based catalytic systems has
not been reported so far. Moreover, the process has been previously reported to occur in conventional
1
-3
volatile organic solvents, while the use of non-conventional solvents, such as ionic liquids (ILs), has not
been investigated. In this paper, we wish to fill this gap, by reporting on the cycloisomerization of 2-
2
alkynylbenzoic acids under the catalytic action of CuCl as very simple catalyst and using ILs as safer
6
unconventional solvents.
Results and Discussion
Copper–Catalyzed Divergent Syntheses of (Z)-3-Alkylideneisobenzofuran-1(3H)-ones 2 and 1H-
Isochromen-1-ones 3 by Copper-Catalyzed Cycloisomerization of 2-Alkynylbenzoic Acids 1 in Ionic Liquids,
and Recycling Experiments
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We firstly tested 2-alkynylbenzoic aids bearing an aryl group on the triple bond. 2-(2-Phenylethynyl)benzoic
acid 1a was initially allowed to react in 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO
4
) (substrate
concentration = 0.2 mmol / mL of solvent) in the presence of 5 mol % of CuCl . After 3 h at 100 °C, a mixture
2
of (Z)-3-benzylideneisobenzofuran-1(3H)-one 2a and 3-phenyl-1H-isochromen-1-one 3a was obtained, with
a total yield of 88% (2a/3a ratio ca. 0.6; Table 1, entry 1). The process took place also in the absence of
catalyst, even though with significantly less satisfactory results (total yield 48%, Table 1, entry 2). These
results confirmed the possibility to perform the cycloisomerization of a 2-alkynylbenzoic acid in an ionic
0
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2
3
4
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9
0
liquid as the solvent, using CuCl as simple and inexpensive catalyst. To assess the influence of the solvent
2
on the reaction outcome, several ILs were then tested. In 1-butyl-3-methylimidazolium
trifluoromethanesulfonate (BmimOTf), 1-ethyl-3-methylimidazolium tosylate (EmimOTs), and 1,3-
2 2
dimethylimidazolium dimethyl phosphate (Mmim(MeO) PO ), again a mixture of 2a and 3a was obtained,
3a being still formed preferentially (entries 3-5). On the other hand, in 3-butyl-1-methylimidazolium
dicyanamide [BmimN(CN) ], N-(cyanopropyl)-N-methyl pyrrolidinium triflimide [C CNmpyr)(NTf) ], and N-
2
3
2
2
ethyl-N-methylmorpholinium dicyanamide [Mor1,2N(CN) ], the process turned out to be completely
selective toward the formation of the 5-membered product 2a (Table 1, entries 6-8), whose structure was
confirmed by X-ray diffraction analysis (see the Supporting information for details). In particular, the
2
highest yield (70%) was obtained in Mor1,2N(CN) , as shown in Table 1 (entry 8). Under these latter
conditions, we then tested the recyclability of the catalyst/solvent system, by extracting the product from
the reaction mixture with diethyl ether and adding fresh substrate to the ionic liquid residue, still
containing the catalyst dissolved in it. As shown in Table 1, entry 8, the CuCl /Mor N(CN) system could be
2
1,2
2
successfully recycled up to 5 times, without appreciable loss of activity. It is worth noting that the same
reaction, carried out in the absence of CuCl , led to 2a in a significantly lower yield (35%, Table 1, entry 9).
2
Under the same conditions as those reported in Table 1, entry 8, other 2-alkynylbenzoic acids, bearing a
tolyl (1b) or a 3-thienyl (1c) substituent, behaved similarly, with selective formation of the corresponding
(Z)-3-alkylideneisobenzofuran-1(3H)-ones 2b and 2c in good yields and excellent recyclability of the
solvent/catalyst system (Table 1, entries 10 and 11, respectively). The structure of (Z)-3-(4-
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methylphenylmethylidene)isobenzofuran-1(3H)-one 2b was also confirmed by X-ray diffraction analysis
(see the Supporting information for details). Isobenzofuranone derivative 2d was also selectively obtained
2
starting from 2-ethynylbenzoic acid 1d, bearing a terminal triple bond, in Mor1,2N(CN) (Table 1, entry 12) as
well as in EmimEtSO (Table 1, entry 13).
4
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6
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8
9
0
The behavior of substrates substituted with an alkyl group on the triple bond was quite different from
that observed with those bearing an aryl group. The reaction of 2-(hex-1-ynyl)benzoic acid 1e, carried out in
Mor1,2N(CN)
2
under the same conditions as those of Table 1, entry 8, led to the formation of a mixture of
the corresponding 5-membered and 6-membered cycloisomerization products (2e and 3e, respectively)
Table 2, entry 14). However, the process turned out to be selective toward the formation of the
isochromenone derivative 3e when it was conducted in EmimEtSO , with a high product yield and an
(
4
excellent catalyst/solvent recyclability (Table 1, entry 15). The same reaction, carried out in the absence of
catalyst, also selectively led to the 6-membered product 3e, even though in a significant lower yield (Table
1
, entry 16). Under the optimized conditions of entry 15 (Table 1), other substrates bearing a phenethyl (1f,
Table 1, entry 17), an alkenyl group such as 1-cyclohexenyl (1g, Table 1, entry 18), or even a sterically
demanding alky group such as tert-butyl (1h, Table 1, entry 19) behaved similarly, leading to the
corresponding isochromenones 3f-h in a selective manner and in high yields (80-84%).
a
Table 1. Copper-Catalyzed Cycloisomerization Reactions of 2-Alkynylbenzoic acids 1 in Ionic Liquids.
R
R
R
CuCl (5 mol %)
2
O
+
OH
Ionic Liquid
100 °C, 3 h
O
1
2
O
3
O
O
Entry
1
Ionic Liquid
2
3
2/3
Total
c
molar
Yield (%)
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6
b
ratio
Ph
1
EmimEtSO4
0.60
88
OH
1
a
O
1a
1a
1a
1a
1a
1a
1a
1a
0
1
2
3
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0
1
2
3
4
5
6
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8
9
0
d
2
3
4
5
6
7
8
9
1
EmimEtSO4
BmimOTf
EmimOTs
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
1.67
0.11
48
49
65
60
58
64
0.08
Mmim(MeO)
2
PO
2
0.46
BmimN(CN)2
2a only
2a only
2a only
2a only
2b only
3 2
(C CNmpyr)(NTf)
e
Mor1,2N(CN)2
70
34
d
Mor1,2N(CN)
2
f
Me
0
Mor1,2N(CN)2
Me
71
O
OH
O
2
b
1
b
O
g
S
S
11
Mor1,2N(CN)
2
2c only
70
65
O
OH
1
c
O
2c
O
h
12
Mor1,2N(CN)
2
2d only
O
OH
1
d
O
O
2
d
i
1
3
4
1d
EmimEtSO
4
2d
2d only
86
j
Bu
Bu
Bu
1
Mor1,2N(CN)
2
1.34
54
O
O
OH
3e
O
1e
O
2e
O
k
15
1e
EmimEtSO4
3e
3e only
84
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d
16
1e
EmimEtSO
4
3e
3e only
3f only
48
l
CH
2
CH
2
Ph
2 2
CH CH Ph
17
EmimEtSO
4
80
O
OH
3
f
O
1
f
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
m
18
EmimEtSO
4
3g only
84
O
OH
3g
O
1
g
O
n
t-Bu
t-Bu
19
EmimEtSO
4
3h only
82
O
OH
3
h
O
1h
O
a
Unless otherwise noted, all reactions were carried out under nitrogen at 100 °C for 3 h with a substrate concentration of 0.2 mmol
b
c
d
of 1 per mL of ionic liquid, in the presence of 5 mol % of CuCl
2
.
Determined by GLC. Based on starting 1. The reaction was
e
f
carried out in the absence of CuCl
2
.
The yields in the next catalyst/solvent recycles (see text for details) were 71, 70, 70, 70%.
g
The yields in the next catalyst/solvent recycles (see text for details) were 69, 70, 69, 69%. The yields in the next catalyst/solvent
h
i
recycles were 71, 70, 71, 71%. Traces of regioisomeric 1H-isochromen-1-one were observed by GLC-MS analysis. The yields in
j
k
the next catalyst/solvent recycles were 82, 84, 84, 85%. Substrate conversion was 86%, by GLC.
The yields in the next
l
m
catalyst/solvent recycles were 80, 82, 83, 82%. The yields in the next catalyst/solvent recycles were 80, 77, 79, 80%. The yields
n
in the next catalyst/solvent recycles were 80, 82, 82, 83%. The yields in the next catalyst/solvent recycles were 80, 81, 81, 83%.
Reaction mechanism and DFT Calculations
As previously evidenced, the IL nature – and more in particular the anion structure- strongly affects the
product selectivity. This effect is not surprising considering the peculiar solvent properties of ionic liquids,
which are mainly related to the ability of IL components (cation and/or anion) to give specific interactions
with substrate, transition states and intermediates. In this case, moreover, the IL can interact also with the
catalytic system, both at the stage of dissolved salt or after interaction with the triple bond. According to
7
other CuCl
2
-catalyzed cyclization processes of functionalized alkynes, formation of products 2 and 3 should
occur through an anti 5-exo-dig (path a), or 6-endo-dig (path b), nucleophilic attack of the carboxylate
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1
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1
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1
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2
2
2
2
2
2
2
2
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3
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6
group to the triple bond coordinated to CuCl , followed by protonolysis (Scheme 2). As shown in Scheme 2,
2
the anti attack is in perfect agreement with the (Z) stereochemistry observed in the 3-
alkylideneisobenzofuran-1(3H)-ones 2, as confirmed by the X-ray diffraction analysis of products 2a and 2b
(see the Experimental Section for details).
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
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7
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0
ClCu
CuCl2
R
R
CuCl
R
5-exo-dig
6-endo-dig
O
path a
HCl
path b
HCl
OH
O
O
O
O
HCl CuCl2
R
HCl CuCl2
R
O
O
2
O
3 O
2
Scheme 2. Divergent CuCl -catalyzed cycloisomerization of 2-alkynylbenzoic acids 1 leading to either 3-
alkylideneisobenzofuran-1(3H)-ones 2 or 1H-isochromen-1-ones 3, occurring through anti 5-exo-dig (path
a) or 6-endo-dig (path b), respectively, nucleophilic attack of the carboxylate group to the triple bond
2
coordinated to CuCl , followed by protonolysis.
The relationship between the deprotonation of the carboxylic group and the regiochemical output of
the cyclization of 2-alkynylbenzoic acids, performed under acidic or basic conditions in conventional organic
1
a
solvents, was previously investigated by Uchiyama and coworkers. In the present reaction, the IL anion
could determine the regiochemical behavior of the reaction affecting 1) the complexation shell of Cu(II)
center; 2) acting as a base so favoring the proton removal from the carboxylic group. It is noteworthy that
most of the selected ILs are characterized by relatively strong hydrogen bonding acceptor anions. The
−
−
≤ EtSO −
−,
Kamlet-Taft β parameters ranges indeed from 0.5 to 1, in the order TfO < N(CN)
2
4
< (MeO)
2
PO
2
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the sole exception being represented by Tf N (β around 0.25). This parameter, however, appears unable
2
to determine the product distribution: ILs with anions having similar β values give a completely different
product distribution (runs 1,6) whereas ILs having anions with different β values give the same product
(
2 3 2
runs 6,7). Nonetheless, BmimN(CN) and (C CNmpyr)(NTf) present also a completely different water
1
1
1
1
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1
1
1
1
2
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2
2
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2
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affinity, the first one is hydrophilic the second hydrophobic: the observed similar product distribution
strongly suggests that also this parament is not relevant. In a similar manner, polarizability, π*, and
9
hydrogen bond acidity, α, are unable to explain the observed reaction behavior.
Thus, to rationalize the effect of the nature of the IL on the regioselectivity of the process we decided to
carry out DFT calculations, which have been proven to be useful to describe the behavior of similar
7
a
−
and EtSO −
reactions. In particular, we decided to focalize our attention on two IL anions, N(CN)
2 4
, taking
into account the following aspects:
1
.
anion can coordinate the Cu(II) center. Since the catalytic role of Cu(II) is the activation of
2
the triple bond via a η coordination, two anions are necessary to saturate the metal atom
coordination sphere. With respect to the previously investigated iodocyclization reaction, where
9
copper is replaced by a positively charged iodine atom, here there is a higher structural rigidity,
9
due to the coordination of a d center instead of the formation of two partial halogen-carbon bonds
and a higher steric hindrance (two anions are coordinate to the copper center whereas the
2
iodonium ion forms a far less rigid ionic pair with a counteranion). Since CuCl has been used as
catalyst, and this small anion can be strongly coordinated to the metal center, two subcases have
been considered:
1
1
.1. chloride ion is still coordinated to copper atom;
.2. chloride ion is replaced by the IL anion [N(CN) −
or EtSO −
in our specific cases]
4
2
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2
. Furthermore, since the anion could act as base in the proton removal from the carboxylic group also in
this case, we have considered two possible situations:
2
.1. The anion acting as base is also involved in the coordination of the copper center. Given the
geometry and possible conformations of the 2-alkynylbenzoic acid molecule, this possibility is
reasonable. Therefore, chloride, N(CN) − and EtSO − have been considered obtaining an electrical
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neutral model system consisting of a 2-alkynylbenzoic acid molecule and two anions (Figure 1a). In
this scenario, the coordinated anion practically “fishes” the carboxylic group proton. We refer to
this mechanism as “internal mechanism”;
2.2. The anion acting as base is different from those coordinating the copper center. In this role, we
have considered only N(CN) − and EtSO −
since the probability that the chloride ion, present in
2
4
catalytic quantities, replaces the solvent anions is negligible. For steric reasons, the anion acting as
a base should approach the carboxylic group from the opposite side with respect the acetylenic
moiety. This model system presents three anions and an unitary negative charge. We refer to this
mechanism as “external mechanism”.
These two mechanisms have been previously considered for substrates characterized by the presence of
7a
an amidic group instead of carboxylic one. In the case of amides, the external mechanism presented
always lower energy barriers than the internal one. However, considering the structural difference and the
different reactivity of carboxylic and amidic groups, we have checked both mechanisms. For all the above
outlined possibilities, the two paths that lead to five or six ring products have been considered for the 2-
alkynylbenzoic acid with R = Ph (1a). For some external mechanisms, moreover, the case of R = H (1d) has
been taken into account. The most relevant results are shown in Table 2.
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Table 2: Some energetic values related to the reaction paths. Energies in KJ/mol.
Five-membered product
Six-membered product
R
Anion 1 Anion 2
ꢀGR→TS ꢀGP→TS ꢀGR→P
ꢀGR→TS ꢀGP→TS ꢀGR→P
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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Cl−
N(CN) −
EtSO −
Ph
130.30 73.00
121.57 187.52
248.69 93.39
19.64 103.31
57.30 149.35 129.76
19.59
none
-65.96 407.56 527.53 -119.98
2
155.30 173.38 143.73
29.95
4
Cl−
Cl−
N(CN) −
-83.67
-52.90
23.49 128.27 -104.78
2
EtSO −
-
-
-
-
-152.46
4
N(CN) −
N(CN) −
2.60 132.76 -130.17
28.10 181.37 -153.27
77.78 226.77 -148.99
2
2
EtSO −
N(CN) − N(CN) −
EtSO −
13.54 63.25
-48.71
4
4
H
6.65 145.07 -138.43 447.17 618.29 -171.12
67.60 182.45 -114.86 386.51 619.90 -233.39
2
2
EtSO −
EtSO −
4
4
Except for the case where the Cu(II) is still coordinated to chloride and the external ion is EtSO −
, all the
4
reaction paths present barriers. In the above-mentioned case, instead, the reaction path is monotone with
the energies of the products lower than the energies of the reactants. It is to note that the energy of six
member ring product is always lower than one of the five member ring: this pathway favors the formation
of compounds 3. All the internal paths present transition states with barrier values higher than those
characterizing the external mechanisms (of course, when this latter present a barrier). Thus, the internal
mechanism is never energetically favored (as in the case of amides). Probably, this kind of structure forces
the carboxylic group to be considerably rotated with respect the central aromatic ring and the leaving
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proton is forced to migrate toward the metal center, a situation which is not electrostatically favored. In
any case, this geometry, as it is evident from Figure 1a, would promote the formation of 2: the carboxylic
group is oriented in a way that facilitates the closing of a five-membered ring. Since we can consider that
this kind of mechanism is not relevant for the reaction, given its high barriers, we can pass to discuss in
more detail the external paths.
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(a)
(b)
(c)
(d)
Figure 1: (a) Starting structure related to internal mechanism: when the proton migrates toward the anion, it
also approaches the metal ion. This is not energetically favorable. (b) Six-membered ring product ensuing
−
from the external mechanism with the EtSO anion: it is evident the steric hindrance and the deformation of
4
the lactone ring. (c) The same structure as (b), but with chlorine coordinated to Cu(II): the sterical hindering
disappears. (d) The same structure of (b) with R = H: also in this case, there is no sterical hindering.
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In all the paths with a barrier, the energetic profile leads to a preference for the five-membered ring
compound, while the six-membered one is consistently the most stable from the energetic point of view.
7
a
This scenario is like the one reported in our previous paper about amides cyclization. The experimental
1
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−
data show that, when the solvent anion is EtSO and R = Ph, both five and six membered ring products are
4
formed, whereas when R = H the five-membered isomer is the only product formed; moreover, in all cases,
the five-membered product is preferred where the anion is N(CN) −
. A possible rationalization of these
2
results can be found analyzing the different situations from the point of view of steric hindrance,
considering that:
2
1
. In the activated reactant, the catalytic center Cu(II) is coordinated by the acetylenic mojety via a η
coordination. The other two coordination sites can be occupied by the original catalyst anion
−
(
chlorine) or by the ionic liquid anion (EtSO − or N(CN) ). The steric hindrance of chloride and of
4 2
the flat N(CN) −
anion is relatively small, while that of EtSO −
, organized about a tetrahedral
4
2
phosphorous atom, is comparatively large.
2
. The R group of the substrate is nearby the metallic center. When R = Ph, its size can exert steric
interactions, thus affecting the reaction path.
These steric effects are more relevant in the case of the path that leads to the six-membered product,
where the double bond is part of the ring. The structures reported in Figure 1b-d show that, when the Cu(II)
center is coordinated to EtSO −
, there is an appreciable deformation of the ring (Figure 1b) that disappears
4
when copper is coordinated to the smaller chloride, Figure 1c, or hydrogen replaces the phenyl ring, Figure
1d. In ILs, metal salts dissolution generally occurs through the formation of metal anionic complexes, in our
x-
10
−
case of the type [CuCl
n
A
m
] where A is the IL anion. The large concentration of A with respect to
−
chlorine can lead to a replacement of chloride by A , although it is well-known that is not easy to remove a
10
chloride ligand from copper. However, some of the Cu(II) ligands must be removed to allow the
2
formation of the η bond with the reactant. As evidenced, in the presence of a hindered R group on triple
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bond, the size of the anion coordinated to the metal center can induce a significant deformation of the
-
starting structure. In the examined cases, this condition is verified only when the anion is EtSO
4
and the R
group is phenyl. In this case, probably also favored by the relatively low coordinating ability of this anion,
the reaction prevalently occurs through a starting complex having chloride as metal ligand, i.e. through the
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-
monotone pathway bearing preferentially to 3. At variance, in the case of N(CN)
2
based ILs the strong
complexing ability of this anion can facilitate the displacement of chloride, giving a starting complex with
dicyanamide ligands at copper center and the external mechanism leads to 2, having this pathway a lower
barrier than that bearing to 3. These considerations, which are valid for any sterically hindered group
(including also tert-butyl or cyclohexyl) can qualitatively explain the regioselectivity of the investigated
reaction in ILs. A more quantitative analysis would require an evaluation of the relative quantities of these
different complexes, which depend also on factors that our simplified model does not take in account, such
as cation anion interaction, ions and molecules diffusion in the ionic liquid environment, kinetic of ligand
exchange, etc.
Conclusions
We have shown that it is possible to efficiently carry out the cycloisomerization of readily available 2-
2
alkynylbenzoic acids using an ionic liquid as the reaction medium in the presence of CuCl as a simple and
inexpensive catalyst. Although in principle two different cyclization pathways can be followed, leading to
either (Z)-3-alkylideneisobenzofuran-1(3H)-ones (from 5-exo-dig mode) or 1H-isochromen-1-ones (from 6-
endo-dig mode), we have found that substrates bearing an aryl group on the triple bond or a terminal triple
bond can be selectively converted into the isobenzofuranone derivatives, using N-ethyl-N-
2
methylmorpholinium dicyanamide [Mor1,2N(CN) ] as the solvent. On the other hand, and in a
complementary manner, substrates substituted with an alkyl or an alkenyl group on the triple bond
selectively led to isochromenones when the reaction was carried out in 1-ethyl-3-methylimidazolium ethyl
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sulfate (EmimEtSO ). In all cases, products were obtained in good to high yields and with excellent
4
recyclability of the catalyst/ionic liquid system. The DFT calculations show that the selectivity is related to
the sterical interactions between the anion and the 2-alkynylbenzoic acid substrate.
1
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Experimental Section
General Experimental Methods. Solvent and chemicals were reagent grade and were used without
further purification. All reactions were analyzed by TLC on silica gel 60 F254 and by GLC using capillary
columns with polymethylsilicone + 5% phenylsilicone as the stationary phase. Column chromatography was
performed on silica gel 60 (70-230 mesh). Evaporation refers to the removal of solvent under reduced
1
13
1
pressure. Melting points are uncorrected. H NMR and C{ H}NMR spectra were recorded at 25 °C on a 300
Spectrometer in CDCl with Me Si as internal standard. Chemical shifts ( ) and coupling constants (J) are
3
4
δ
given in ppm and in Hz, respectively. IR spectra were taken with an FT-IR spectrometer. Mass spectra were
obtained using a GC-MS apparatus at 70 eV ionization voltage (normal resolution) and by electrospray
ionization mass spectrometry (ESI-MS) (high resolution). The LC-MS was operated in the positive ion mode.
Water and acetonitrile were of HPLC/MS grade. Formic acid was of analytical quality. A reversed-phase C18
column with a C18 security guard column (4mm×3mm) was used. The flow-rate was 0.4 mL/min and the
column temperature was set to 30°C. The eluents were formic acid–water (0.1:99.9, v/v) (phase A) and
formic acid–acetonitrile (0.1:99.9, v/v) (phase B). The following gradient was employed: 0–10 min, linear
gradient from 5% to 95% B; 10–15 min, washing and reconditioning of the column to 5% B. Injection
volume was 10 mL. The eluate was monitored through MS TIC. Mass spectra were obtained on a UHD
2
accurate-mass Q-TOF spectrometer equipped with a Dual AJS ESI source working in positive mode. N was
employed as desolvation gas at 300°C and a flow rate of 8 L/min. The nebulizer was set to 45 psig. The
Sheat gas temperature was set at 400°C and a flow of 12 L/min. A potential of 3.5 kV was used on the
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capillary for positive ion mode. The fragmentor was set to 175 V. MS spectra were recorded in the 150–
1000 m/z range.
Computational Details. All calculation has been performed at B3LYP/def-sv[p] level using the Terachem
1
1
12
package version 1.5k. Grimme’s dispersion correction has been included. A GPU workstation with four
0
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GeForce GTX Titanium Z has been used for all calculations.
8
8
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13
14
Preparation of ILs. The ILs EmimEtSO , BmimN(CN) , Mor N(CN) , Mmim(MeO) PO , BmimOTf,
4
2
1,2
2
2
2
1
4
14
2
EmimOTs, and (C
3
CNmpyr)(NTf)
were prepared according to literature procedures.
Preparation of Substrates. 2-Alkynylbenzoic acids 1a-e and 1g-h were prepared by Sonogashira coupling
between the corresponding methyl 2-iodobenzoates (commercially available) and terminal alkynes
8
followed by hydrolysis, as we already reported. Substrates 1f was prepared in a similar way, according to
the procedure given below.
Sonogashira Coupling Between Methyl 2-Iodobenzoates and But-3-ynylbenzene to Give Methyl 2-(4-
1
5
Phenylbut-1-ynyl)benzoate. The method of Kundu was adapted. A solution of methyl 2-iodobenzoate
(
4.0 mmol; 1.05 g), PdCl (PPh (99.2 mg, 0.14 mmol), CuI (61.0 mg, 0.32 mmol) and Et N (1.9 mL) in
2
3
)
2
3
anhydrous DMF (10 mL) was allowed to stir under nitrogen for 1 h. The but-3-ynylbenzene, 625 mg (4.8
mmol), was then added under nitrogen, and the resulting mixture was heated at 85 °C (oil bath) for 15 h.
After cooling, CH
2 2
Cl (100 mL) was added, and the mixture washed with water (3 × 100 mL). After drying
over Na SO , the solvent was evaporated, and the residue purified by column chromatography on silica gel
2
4
using hexane-AcOEt from 99:1 to 95:5 as eluent.
Methyl 2-(4-Phenylbut-1-ynyl)benzoate. Yield: 856 mg, starting from 1.05 g of methyl 2-iodobenzoate
–1
1
(
81%). Yellow oil. IR (film): ν = 2228 (w), 1733 (s), 1252 (m), 1083 (m), 757 (m), 698 (m) cm ; H NMR (300
MHz, CDCl ): δ = 7.88 (d, J = 7.8, 1 H), 7.50-7.46 (m, 1 H), 7.39 (td, J = 7.4, 1.4, 1 H), 7.35-7.16 (m, 6 H), 3.86
3
1
3
1
(
s, 3 H), 2.96 (t, J = 7.5, 2 H), 2.76 (t, J = 7.5, 2 H); C{ H}NMR (75 MHz, CDCl
3
): δ = 166.8, 140.7, 134.2,
1
31.8, 131.5, 130.1, 128.5, 128.4, 127.3, 126.3, 124.3, 95.0, 79.9, 52.0, 35.0, 22.0; GC-MS: m/z = 264 (22)
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+
[
M ], 263 (56), 249 (35), 231 (69), 143 (35), 91 (100). The spectroscopic data were in good agreement with
1
6
those reported.
Hydrolysis of Methyl 2-(4-Phenylbut-1-ynyl)benzoate to Give 2-(4-Phenylbut-1-ynyl)benzoic acid 1f.
1
5
The method of Kundu was adapted. A stirred solution of methyl 2-(4-phenylbut-1-ynyl)benzoate (2.5
1
1
1
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1
1
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0
mmol; 661 mg) and 1 N NaOH (14.0 mL) in THF (3.0 mL) was heated at 50 °C for 12 h. After cooling to room
temperature, the mixture was washed with Et O (3 × 15 mL), further cooled with the aid of an ice bath, and
2
neutralized with 1 N HCl. The resulting mixture was extracted at room temperature with CH
2 2
Cl (3 × 50 mL),
and the collected organic layers dried over Na SO . Filtration and evaporation of the solvent afforded crude
2
4
2
-(4-phenylbut-1-ynyl)benzoic acid. The product 1f was further purified by crystallization with Et
-(4-Phenylbut-1-ynyl)benzoic acid (1f). Yield: 513 mg, starting from 661 mg of methyl 2-(4-phenylbut-1-
ynyl)benzoate (82%). White solid, mp = 54-56°C, IR (KBr): ν = 2220 (w), 1704 (s), 1303 (m), 933 (m), 758 (s)
2
O/hexane.
2
–
1 1
3
cm ; H NMR (300 MHz, CDCl ): δ = 10.95 (s, br, 1 H), 8.04 (d, J = 7.9, 1 H), 7.54-7.41 (m, 2 H), 7.38-7.15 (m,
1
3
1
6
1
H), 2.95 (t, J = 7.4, 2 H), 2.75 (t, J = 7.4, 2 H); C{ H}NMR (75 MHz, CDCl ): δ =171.5, 140.6, 134.4, 132.4,
3
+
31.1, 130.6, 128.5, 128.4, 127.4, 126.3, 124.8, 96.3, 79.8, 34.8, 22.0; HRMS-ESI [(M+H) ]: m/z calcd for
(
C H O ): 251.1072; found, 250.1070.
17 15 2
General Procedure for the Recyclable Copper-Catalyzed Cycloisomerization of of 2-Alkynylbenzoic
Acids in Ionic Liquids (Table 2). To a solution of 1 (0.4 mmol) (1a, 90.0 mg; 1b, 95.0 mg; 1c, 91.5 mg; 1d,
5
4 2
9.0 mg; 1e, 81.5 mg; 1f, 100.5 mg; 1g, 91.5 mg; 1h, 81.0 mg) in EmimEtSO or MorfN(CN) (2 mL) were
−2
added CuCl (2.7 mg, 2.0 × 10 mmol) under nitrogen in a Schlenk flask. The mixture was allowed to stir at
2
1
00 °C for 3 h. After cooling, the product was extracted with diethyl ether (6 × 5 mL), and the residue (still
containing the catalyst dissolved in the IL) was used as such for the next recycle (see below). The collected
ethereal phases were concentrated. After evaporation of the solvent, the products 2a-d and 3e-3h were
purified by column chromatography on silica gel using 98 : 2 hexane–AcOEt as the eluent. Mixtures 2a+3a
and 2e+3e were collected by column chromatography on silica gel using 9 : 1 hexane–AcOEt as the eluent.
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Recycling Procedure. To the residue obtained as described above, still containing the catalyst dissolved
2 2
in the ionic liquid, was added a solution of fresh 1 (0.4 mmol) in Et O (3 mL). Et O was removed under
vacuum, and then the same procedure described above was followed.
Mixture of (Z)-3-Benzylidene-3H-isobenzofuran-1-one (2a) + 3-Phenylisochromen-1-one (3a). Total yield:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
1
9.1 mg, starting from 90.0 mg of 1a (88%; 2a / 3a = 0.60, determined by GLC and H NMR; Table 1, entry
–1
1
). IR (KBr): ν = 1752 (s), 1717 (m), 1473 (w), 1072 (m), 983 (m) cm ; H NMR (300 MHz, CDCl ): δ = 8.30 (d,
3
J = 9.0, 1 H, 3a), 7.95-7.90 (m, 1 H, 2a), 7.90-7.82 [m, 2 H (2a) + 2 H (3a)], 7.78-7.66 [m, 2 H (2a) + 1 H (3a)],
7
1
.57-7.52 (m, 1 H, 2a), 7.52-7.37 [m, 2 H (2a) + 5 H (3a)], 7.37-7.30 (m, 1 H, 2a), 6.95 (s, br, 1 H, 3a), 6.42 (s,
1
3
1
3
H, 2a); C{ H}NMR (75 MHz, CDCl ): δ = 167.1 (2a), 162.3 (3a), 153.6 (3a), 144.6 (2a), 140.6 (2a), 137.5
(
3a), 134.9 (3a), 134.5 (2a), 133.1 (2a), 132.0 (3a), 130.1 (2a), 130.0 (3a), 129.8 (2a), 129.7 (3a), 128.83 (3a),
1
28.77 (2a), 128.4 (2a), 128.2 (3a), 126.0 (3a), 125.6 (2a), 125.2 (3a), 123.4 (2a), 120.5 (3a), 119.8 (2a),
+
+
107.1 (2a), 101.8 (3a); GC-MS: 2a: m/z = 222 (M ) (100), 194 (15), 165 (58), 139 (5); 3a: m/z =222 (M ) (100),
194 (63), 165 (61), 105 (24). The spectroscopic data for 2a and 3a were in good agreement with those
1
6
reported.
(Z)-3-Benzylidene-3H-isobenzofuran-1-one (2a). Yield: 62.5 mg, starting from 90.0 mg of 1a (70%; Table
–1
1
1
, entry 8). White solid, mp = 80-83 °C. IR (KBr): ν = 1774 (s), 1473 (m), 1085 (m), 978 (s), 764 (s) cm ; H
NMR (300 MHz, CDCl ): δ = 7.93 (dt, J = 7.7, 0.9, 1 H), 7.88-7.82 (m, 2 H), 7.80-7.73 (m, 1 H), 7.73-7.68 (m, 1
H), 7.58-7.51 (m, 1 H), 7.46-7.37 (m, 2 H), 7.36-7.28 (m, 1 H), 6.42 (s, 1 H); C{ H}NMR (75 MHz, CDCl
67.1, 144.6, 140.6, 134.5, 133.1, 130.2, 129.8, 128.8, 128.4, 125.6, 123.5, 119.8, 107.1; GC-MS: m/z = 222
3
1
3
1
3
): δ =
1
+
(
M ) (100), 194 (14), 165 (41), 139 (3). The spectroscopic data were in good agreement with those
1
7
reported.
(Z)-3-(4-Methyl-benzylidene)-3H-isobenzofuran-1-one (2b). Yield: 67.0 mg, starting from 95.0 mg of 1b
(71%; Table 1, entry 10). White solid, mp = 109-111 °C. IR (KBr): ν = 1780 (s), 1472 (m), 1077 (m), 972 (m),
–
1 1
7
7
1
1
60 (m) cm ; H NMR (300 MHz, CDCl
3
): δ = 7.92 (d, J = 7.7, 1 H), 7.79-7.67 (m, 4 H), 7.52 (t, J = 7.2, 1 H),
13
1
.28-7.17 (m, 2 H), 6.40 (s, 1 H), 2.38 (s, 3 H); C{ H}NMR (75 MHz, CDCl
3
): δ = 167.2, 144.0, 140.7, 138.7,
+
34.4, 130.3, 130.1, 129.5, 125.5, 123.3, 119.7, 107.2, 21.4; GC-MS: m/z = 236 (M ) (100), 218 (6), 193 (13),
17
78 (13), 165 (32). The spectroscopic data were in good agreement with those reported.
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(
Z)-3-Thiophen-3-ylmethylene-3H-isobenzofuran-1-one (2c). Yield: 64.0 mg, starting from 91.5 mg of 1c
(70%; Table 1, entry 11). White solid, mp = 54.1-55.1 °C. IR (KBr): ν = 1775 (s), 1474 (w), 1078 (m), 982 (m),
–
1 1
689 (m) cm ; H NMR (300 MHz, CDCl
3
): δ = 7.92-7.86 (m, 1 H), 7.74-7.66 (m, 3 H), 7.60-7.55 (m, 1 H), 7.55-
1
3
1
7.47 (m, 1 H), 7.33 (dist dd, J = 5.0, 3.0, 1 H), 6.49 (s, 1 H); C{ H}NMR (75 MHz, CDCl
3
): δ = 166.9, 143.6,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
2
40.2, 134.4, 134.2, 129.5, 128.8, 126.7, 125.9, 125.5, 123.5, 119.6, 101.5; GC-MS: m/z = 228 (M ) (100),
18
00 (9), 171 (58), 127 (8). The spectroscopic data were in good agreement with those reported.
(Z)-3-Methylene-3H-isobenzofuran-1-one (2d). Yield: 50.5 mg, starting from 59.0 mg of 1d (86%; Table 1,
–1 1
entry 13). White solid, mp = 50-51 °C. IR (KBr): ν = 1779 (s), 1469 (m), 1288 (m), 759 (m), 691 (w) cm ; H
NMR (300 MHz, CD CN): δ = 7.89 (d, J = 7.7, 1 H), 7.73 (d, J = 4.0, 2 H), 7.63-7.53 (m, 1 H), 5.24 (s, br, 2 H);
3
1
3
1
3
C{ H}NMR (75 MHz, CD CN): δ = 166.9, 151.8, 139.0, 134.5, 130.5, 125.2, 125.0, 120.7, 91.3; GC-MS: m/z =
+
1
46 (M ) (100), 118 (21), 104 (58), 76 (66). The spectroscopic data were in good agreement with those
1
9
reported.
3-Butylisochromen-1-one (3e). Yield: 68.0 mg, starting from 81.5 mg of 1e (84%; Table 1, entry 15).
–1 1
White solid, mp = 30-32 °C. IR (KBr): ν = 1718 (s), 1656 (m), 1481 (w), 1138 (w) cm ; H NMR (300 MHz,
CDCl ): δ = 8.25 (dd, J = 8.0, 0.6, 1 H), 7.71-7.62 (m, 1 H), 7.50-7.40 (m, 1 H), 7.33 (d, J = 7.8, 1 H), 6.26 (s, 1
3
13
1
H), 2.53 (t, J = 7.5, 2 H), 1.77-1.63 (m, 2 H), 1.48-1.34 (m, 2 H), 1.00-0.90 (m, 3 H); C{ H}NMR (75 MHz,
CDCl
3
): δ = 163.1, 158.3, 137.6, 134.7, 129.5, 127.5, 125.0, 120.1, 102.9, 33.2, 29.0, 22.1, 13.8; GC-MS:
+
m/z=202 (M ) (27), 160 (26), 131 (15), 118 (100). The spectroscopic data were in good agreement with
2
0
those reported.
3
-Phenethylisochromen-1-one (3f). Yield: 80.4 mg, starting from 100.5 mg of 1f (80%; Table 1, entry 17).
–1 1
White solid, mp = 32-34 °C. IR (KBr): ν = 1728 (s), 1654 (m), 1481 (w), 1161 (w), 1074 (m) cm ; H NMR (300
MHz, CDCl ): δ = 8.26 (d, J = 8.0, 1 H), 7.72-7.62 (m, 1 H), 7.50-7.41 (m, 1 H), 7.37-7.16 (m, 6 H), 6.22 (s, 1 H),
3
1
3
1
3.10-2.97 (m, 2 H), 2.90-2.87 (m, 2 H); C{ H}NMR (75 MHz, CDCl
3
): δ = 163.0, 156.9, 140.3, 137.4, 134.8,
+
1
29.6, 128.6, 128.4, 127.7, 126.3, 125.1, 120.2, 103.5, 35.5, 33.2; GC-MS: m/z = 250 (M ) (27), 159 (3), 131
20
(
7), 91 (100). The spectroscopic data agreed with those reported.
3
-Cyclohex-1-enylisochromen-1-one (3g) Yield: 76.3 mg, starting from 91.5 mg of 1g (84%; Table 1, entry
1
8). White solid, mp = 80-82 °C. IR (KBr): ν = 1715 (s), 1640 (m), 1621 (m), 1482 (w), 1221 (w), 1076 (m)
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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5
6
–
1 1
cm ; H NMR (300 MHz, CDCl ): δ = 8.24 (d, J = 7.6, 1 H), 7.65 (t, J = 7.6, 1 H), 7.47-7.34 (m, 2 H), 6.82 (s, br,
3
1
3
1
3
1 H), 6.37 (s, 1 H), 2.35-2.20 (m, 4 H), 1.85-1.73 (m, 2 H), 1.73-1.62 (m, 2 H); C{ H}NMR (75 MHz, CDCl ): δ
= 162.4, 154.4, 137.9, 134.6, 130.1, 129.5, 127.6, 125.8, 120.6, 100.1, 25.6, 24.1, 22.3, 21.8; GC-MS: m/z =
+
226 (M ) (100), 211 (13), 183 (16), 141 (15), 89 (47). The spectroscopic data were in good agreement with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
those reported.
3
-tert-Butylisochromen-1-one (3h). Yield: 66.7 mg, starting from 81.0 mg of 1h (82%; Table 1, entry 19).
–1
1
White solid, mp = 63-64 °C. IR (KBr): ν = 1735 (s), 1648 (m), 1340 (w), 1086 (m) cm ; H NMR (300 MHz,
CDCl ): δ = 8.26 (d, J = 8.0, 1 H), 7.67 (td, J = 7.6, 0.9, 1 H), 7.44 (t, J = 7.6, 1 H), 7.38 (dist d, J = 7.9, 1 H), 6.31
3
13
1
(
3
s, 1 H), 1.33 (s, 9 H); C{ H}NMR (75 MHz, CDCl ): δ = 165.1, 163.0, 137.7, 134.6, 129.4, 127.6, 125.5,
+
1
20.1, 99.7, 35.6, 28.0; GC-MS: m/z = 202 (M ) (63), 187 (100), 169 (18), 160 (60), 145 (47), 131 (32), 89
1
6,22
(
60). The spectroscopic data were in good agreement with those reported.
Supporting Information. X-ray data for compounds 2a and 2b, Tables of absolute energies, optimized
1
13
1
structures, copy of HRMS spectrum for compound 1f, and copies of H NMR and C{ H}NMR spectra.
Acknowledgements. We thank the University of Calabria and the University of Pisa for financial support.
Thanks are also due to Dr. Antonio Palumbo Piccionello (University of Palermo, Italy) for HRMS
measurements and to Dr. Rosanna Adduci (Department of Chemistry and Chemical Technologies,
University of Calabria), for some IR measurements.
References
(
1) (a) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T.
Regiocontrolled Intramolecular Cyclizations of Carboxylic Acids to Carbon−Carbon Triple Bonds Promoted
by Acid or Base Catalyst. Org. Lett. 2006, 8, 5517-5520. (b) Zhang, X.; Hou, W.; Zhang-Negrerie, D.; Zhao, K.;
Du, Y. Hypervalent Iodine-Mediated Intramolecular trans-Aminocarboxylation and Oxoaminocarboxylation
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of Alkynes: Divergent Cascade Annulations of Isocoumarins under Metal-Free Conditions. Org. Lett. 2015,
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(2) (a) Kanazawa, C.; Terada, M. Organic-Base-Catalyzed Synthesis of Phthalides via Highly Regioselective
Intramolecular Cyclization Reaction. Tetrahedron Lett. 2007, 48, 933-935. (b) Terada, M.; Kanazawa, C.;
Yamanaka, M. Theoretical Studies of 5-exo Selective Intramolecular Cyclization of o-Alkynylbenzoic Acid
Catalyzed by Organic Base. Heterocycles 2007, 74, 819-825.
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1
2
3
4
5
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1
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4
5
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9
0
(3) For recent examples, see: (a) Umeda, R.; Yoshikawa, S.; Yamashita, K.; Nishiyama, Y. Synthesis of
Isocoumarins: Rhenium Complex-Catalyzed Cyclization of 2-Ethynylbenzoic Acids. Heterocycles 2015, 91,
2172-2179. (b) Doherty, S.; Knight, J. G.; Perry, D. O.; Ward, N. A. B.; Bittner, D. M.; McFarlane, W.; Wills, C.;
Probert, M. R. Triaryl-Like MONO-, BIS-, and TRISKITPHOS Phosphines: Synthesis, Solution NMR Studies, and
a Comparison in Gold-Catalyzed Carbon–Heteroatom Bond Forming 5-exo-dig and 6-endo-dig Cyclizations.
Organometallics 2016, 35, 1265-1278. (c) Conde, N.; SanMartin, R.; Herrero, M. T.; Domínguez, E. Palladium
NNC Pincer Complex as an Efficient Catalyst for the Cycloisomerization of Alkynoic Acids. Adv. Synth. Catal.
2
016, 358, 3283–3292.
(4) For very recent examples of bioactive 3-(alkylidene)isobenzofuran-1(3H)-one derivatives, see: (a) Su,
Y.-J.; Huang, S.-Y.; Ni, Y.-H.; Liao, K.-F.; Chiu, S.-C. Anti-Tumor and Radiosensitization Effects of N-
Butylidenephthalide on Human Breast Cancer Cells. Molecules 2018, 23, art. no. 240. (b) Giap, T. H.; Dung,
N. A.; Thoa, H. T.; Dang, N. H.; Dat, N. T.; Hang, N. T. M.; Cuong, P. V.; Hung, N. V.; Minh, C. V.; Mishchenko,
N. P.; Fedoreev, S. A.; Thanh, L. N. Phthalides and Other Metabolites from Roots of Ligusticum wallichii.
Chem. Nat. Compds. 2018, 54, 34–37. (c) Yen, S.-Y.; Chuang, H.-M.; Lin, S.-Z.; Chiou, T.-W.; Harn, H.-J. n-
Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in
Glioblastoma. Int. J. Mol. Sci. 2017, 18, art. no. 372.
(5) For very recent examples of bioactive 1H-isochromen-1-one derivatives, see: (a) Chen, Y.; Liu, Z.; Liu,
H.; Pan, Y.; Li, J.; Liu, L.; She, Z. Dichloroisocoumarins with Potential Anti-Inflammatory Activity from the
Mangrove Endophytic Fungus Ascomycota sp. CYSK-4. Mar. Drugs 2018, 16, art. no. 54. (b) Casnati, A.;
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Maggi, R.; Maestri, G.; Della Ca’, N.; Motti, E. Pd-Catalyzed/Iodide-Promoted α-Arylation of Ketones for the
Regioselective Synthesis of Isocoumarins. J. Org. Chem. 2017, 82, 8296–8303. (c) Hussain, H.; Green, I. R. A
Patent Review of Two Fruitful Decades (1997-2016) of Isocoumarin Research. Expert Opin. Ther. Patents
2017, 27, 1267-1275.
0
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9
0
(6) For some very recent reviews on the use of ILs in organic synthesis, see: (a) Bodachivskyi, I.;
Kuzhiumparambil, U.; Williams, D. B. G. Acid-Catalyzed Conversion of Carbohydrates into Value-Added
Small Molecules in Aqueous Media and Ionic Liquids. ChemSusChem 2018, 11, 642-660. (b) Kaur, N.
Perspectives of Ionic Liquids Applications for the Synthesis of Five- and Six-Membered O,N-Heterocycles.
Synth. Commun. 2018, 48, 473-495. (c) Itoh, T. The Beneficial Sinergy of MW Irradiation and Ionic Liquids in
Catalysis of Organic Reactions. Chem. Rev. 2017, 117, 10567-10607.
(7) For recent examples from our laboratories, see: (a) Mancuso, R.; Pomelli, C. S.; Raut, D. S.; Marino,
N.; Giofrè, S. V.; Romeo, R.; Sartini, S.; Chiappe, C.; Gabriele, B. Copper-Catalyzed Recyclable Synthesis of
(Z)-3-Alkylideneisoindolinones by Cycloisomerization of 2-Alkynylbenzamides in Ionic Liquids.
ChemistrySelect 2017, 2, 894-899. (b) Gabriele, B.; Veltri, L.; Plastina, P.; Mancuso, R.; Vetere, M. V.;
Maltese, V. Copper-Catalyzed Synthesis of Substituted Furans and Pyrroles by Heterocyclodehydration and
Tandem Heterocyclodehydration−Hydraꢁon of 3
Yne-1,2-diols and 1
Amino-3-yn-2-ol Derivatives. J. Org.
Chem. 2013, 78, 4919-4928. (c) Gabriele, B.; Mancuso, R.; Lupinacci, E.; Spina, R.; Salerno, G.; Veltri, L.;
Dibenedetto, A. Recyclable Catalytic Synthesis of Substituted Quinolines: Copper-Catalyzed
Heterocyclization of 1-(2-Aminoaryl)-2-yn-1-ols in Ionic Liquids. Tetrahedron 2009, 65, 8507-8512. (d)
Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. Novel and Convenient Synthesis of
Substituted Quinolines by Copper- or Palladium-Catalyzed Cyclodehydration of 1-(2-Aminoaryl)-2-yn-1-ols.
J. Org. Chem. 2007, 72, 6873-6877.
(8) Mancuso, R.; Pomelli, C. S.; Malafronte, F.; Maner, A.; Marino, N.; Chiappe, C.; Gabriele, B. Divergent
Syntheses of Iodinated Isobenzofuranones and Isochromenones by Iodolactonization of 2-Alkynylbenzoic
Acids in Ionic Liquids. Org. Biomol. Chem. 2017, 15, 4831-4841.
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