A Regio- and Stereoselective Carbonylative Approach to Alkyl (Z)-2-[3-Oxoisobenzofuran-1-(3H)-ylidene]acetates

Article abstract of DOI:10.1002/adsc.201801308

The first example of the oxidative carbonylation of 2-ethynylbenzoic acid derivatives, leading to alkyl (Z)-2-[3-oxoisobenzofuran-1-(3H)-ylidene]acetates in a regio- and stereoselective manner, is reported. Under the catalytic action of PdI₂ (2

Full text of DOI:10.1002/adsc.201801308

Title: A novel regio- and stereoselective carbonylative approach to
Z)-3-[(alkoxycarbonyl)methylene]isobenzofuranones
(
Authors: Raffaella Mancuso, Ida Ziccarelli, Francesco Fini, Nicola Della
Ca', Nadia Marino, Carla Carfagna, and Bartolo Gabriele
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801308
Link to VoR: http://dx.doi.org/10.1002/adsc.201801308

Advanced Synthesis & Catalysis
10.1002/adsc.201801308
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Regio- and Stereoselective Carbonylative Approach to Alkyl
Z)-2-[3-Oxoisobenzofuran-1-(3H)-ylidene]acetates
(
a,
a
b
c
Raffaella Mancuso, * Ida Ziccarelli, Francesco Fini, Nicola Della Ca’, Nadia
d
e
a,
Marino, Carla Carfagna, and Bartolo Gabriele *
a
Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical
Technologies, University of Calabria, Via Pietro Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
E-mail: raffaella.mancuso@unical.it (Raffaella Mancuso), bartolo.gabriele@unical.it (Bartolo Gabriele)
Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy
b
c
Department of Chemistry, Life Sciences and Environmental Sustainability (SCVSA), University of Parma, Parco Area
delle Scienze 17 A, 43124 Parma (Italy)
Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci 14/C, 87036
d
Arcavacata di Rende (CS), Italy
Department of Industrial Chemistry “T. Montanari”, University of Bologna, Viale Risorgimento 4, 40136 Bologna,
e
Italy
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The first example of the oxidative carbonylation derivatives
of 2-ethynylbenzoic acid derivatives, leading to alkyl oxoisobenzofuran-1-(3H)-ylidene]acetates.
Z)-2-[3-oxoisobenzofuran-1-(3H)-ylidene]acetates in
process is carried out using a very simple catalytic
leading
to
alkyl
(Z)-2-[3-
The
(
a
regio- and stereoselective manner, is reported. Under the system (PdI in conjunction with an excess of KI)
catalytic action of PdI (2 mol%) in conjuction with KI (20 under relatively mild conditions (80 °C and under 40
2
2
mol%), different 2-[(trimethylsilyl)ethynyl]benzoic acids
were converted into the corresponding isobenzofuranones
in high to excellent yields (70-98%). The proposed reaction
mechanism involves syn 5-exo-dig cyclization, carbon
monoxide insertion, and nucleophilic displacement by an
alcohol. Desilylation occurred under the reaction
conditions. The structure of a representative product, that
atm of a 4:1 mixture of CO-air, in a dioxane-ROH
medium, R = alkyl).
[4]
We started our investigation with simple 2-
ethynylbenzoic acid 1a. In principle, different
reaction pathways could be followed when allowing
to react 1a under PdI
carbonylation conditions, carried out in the presence
of O as oxidant and ROH as nucleophile (Scheme 1;
anionic iodide ligands are omitted for clarity). A first
possibility corresponds to the formation of a
palladium carboxylate intermediate I from the
2
-catalyzed oxidative
is,
methyl
(Z)-2-[3-oxoisobenzofuran-1(3H)-
2
ylidene]acetate, was confirmed by XRD analysis.
Keywords: carbonylation; cyclization; 2-ethynylbenzoic
acids; isobenzofuranones; palladium
reaction between 1a and PdI
Scheme 1, pathway a). Stereospecific carbon
2
, with elimination of HI
(
monoxide insertion, followed by nucleophilic
displacement by ROH, would then lead to the final
Palladium-catalyzed carbonylative heterocyclization
of suitably substituted acetylenic substrates, carried
out under oxidative conditions, is one of the most
important methods for the synthesis of carbonylated
alkyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-
ylidene]acetate 2 with Z stereochemistry. Another
possible pathway would involve an initial anti
intramolecular nucleophilic attack of the carboxylic
group to the triple bond coordinated to the metal
center, a kind of reactivity that has often been
observed with nucleophilic groups different from
[1]
heterocycles. Numerous examples of this approach
have been reported in the literature with ortho-
[1,2]
functionalized arylacetylenes as starting materials.
[1,5]
However, to the best of our knowledge, the direct use
of readily available 2-alkynylbenzoic acids has not
carboxylate.
Either 5-exo-dig (Scheme 1, pathway
b) or 6-endo-dig (Scheme 1, pathway c) cyclization
may take place, with formation of the corresponding
regiosomeric vinylpalladium complexes II and III.
Alkoxycarbonylation of the latter would then lead to
the final regioisomeric heterocyclic derivatives (3 and
[3]
been reported so far in this kind of process. This is
probably due to the low nucleophilicity of the free
carboxylic group associated with its coordinating
ability, which may cause catalyst deactivation.
In this Communication, we wish to fill this gap, by
reporting our preliminary results on the direct
oxidative carbonylation of 2-ethynylbenzoic acid
4, respectively). In any case, Pd(0) would be formed,
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
which would then be reoxidized by the action of
oxygen.
Figure 1. Molecular structure of methyl (Z)-2-(3-
oxoisobenzofuran-1(3H)-ylidene)acetate 2a showing the
atom-labeling scheme. See Supporting Information for
details.
We then tried to improve the selectivity toward
the carbonylated product 2a by changing several
reaction parameters. In particular, to minimize the
protonolysis by-reaction leading to non-carbonylated
5
a (Equation 2), an experiment was carried out in a
less protic medium, that is, a dioxane/MeOH mixture
1.2:1, v/v). In fact, it is known from the literature
that protonolysis may be favored by a protic
(
[6]
medium. In agreement with this hypothesis, the
reaction carried out in the dioxane/MeOH mixture
turned out to be selective toward the formation of 2a,
obtained in 49% yield, with no formation of 5a
Scheme 1. Possible divergent pathways in the PdI
2
-
catalyzed oxidative cyclization-alkoxycarbonylation of
2
-ethynylbenzoic acid 1a.
(
Equation 1). The variation of other parameters, such
as the substrate concentration or the reaction
temperature, did not lead to
a
significant
The first experiment carried out with 1a was
improvement of this result in terms of yield and
performed under the following reaction conditions: 2
selectivity of 2a (data not shown).
mol % of PdI , 20 mol % of KI, at 80 °C in MeOH as
2
the solvent (1a concentration: 0.05 mmol per mL of
MeOH) and under 40 atm of a 4:1 mixture of CO-air.
After 5 h, analysis of the reaction crude showed the
formation of a mixture of cyclized products, that are,
A dramatic augment of the 2a yield was instead
observed when the oxidative carbonylation reaction
was carried out on 2-[(trimethylsilyl)ethynyl]benzoic
acid 6a, bearing the trimethylsilyl group on the triple
bond (Equation 3). In this case, in fact, the oxidative
carbonylation, carried out in dioxane-MeOH (1.2:1,
v/v) as the solvent, selectively afforded the
desilylated carbonylated isobenzofuranone derivative
methyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-
ylidene]acetate
2a
(10%
yield)
(23%
and
3-
methyleneisobenzofuranone
5a
yield)
(
Equation 1). The structure of 2a, including the Z
configuration, was confirmed by XRD analysis (see
Figure 1 and the Supporting Information for details).
2
a in almost quantitative yield (98%) (Equation 3 and
[7,8]
Table 1, entry 1).
The process also worked nicely when employing a
lower catalyst loading, even though the 2a yield
decreased to some extent: with 1, 0.33, and 0.2 mol%
Formation of 2a, with Z stereochemistry, was
clearly in agreement with pathway a of Scheme 1,
while 5a corresponded to protonolysis of either
intermediate I or II (Equation 2).
of PdI , the 2a yields were 75, 69, and 58%
2
respectively (Table 1, entry 1). Thus, with 0.2 mol%
catalyst, a turnover number (TON) as high as 290
mmol of 2a per mmol of palladium employed was
obtained.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
Other differently substituted substrates 6b-d,
Table 1. Regio- and stereoselective synthesis of alkyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-ylidene]acetates 2 by
bearing on the aromatic ring either an electron-
withdrawing group (Cl, Table 1, entries 2) or a -
donating group (Me or OMe, Table 1, entry 3 and 4,
respectively), were then tested. Under the same
conditions employed for 6a (Table 1, entry 1),
substrates 6b-d afforded the corresponding alkyl (Z)-
PdI
2
/KI-catalyzed
oxidative
cyclization-
alkoxycarbonylation of 2-[(trimethylsilyl)ethynyl]benzoic
[
a]
acids 6.
2
-[3-oxoisobenzofuran-1-(3H)-ylidene]acetates 2b-d
in high to excellent yields (70-95%; Table 1, entries
-4). Very good results were also obtained using
2
different alcohols as nucleophiles, such as EtOH (2e
yield, 90%; Table 1, entry 5), or i-PrOH (2f yield,
9
3%: Table 1, entry 6). A remarkable yield of 74% of
isobenzofuranone 2g was observed even with a
sterically demanding alcohol, such as t-BuOH (Table
1, entry 7).
We also tested the reactivity of (Z)-5-
(
trimethylsilyl)pent-2-en-4-ynoic acid 7 under the
[9]
optimized conditions. As shown in Equation 4, this
substrate was converted into a mixture of desilylated
and silylated carbonylation products (8 and 8’,
respectively) in 65% total yield.[10]
In conclusion, we have reported the first example
of the oxidative carbonylation of 2-ethynylbenzoic
acid derivatives 1 and 6, carried out with PdI in
2
conjunction with KI as catalyst under relatively mild
reaction conditions (80 °C under 40 atm of a 4:1
mixture of CO-air) to give alkyl (Z)-2-[3-
oxoisobenzofuran-1-(3H)-ylidene]acetates 2 in a
regio- and stereoselective manner. The process works
much better, in terms of product yield and catalytic
efficiency, starting directly from substrates 6, bearing
the triple bond substituted with the TMS group (70-
9
8% yields of 2 and turnover numbers up to 290
mmol of product per mmol of palladium were
achieved). This is a clear practical advantage,
considering that 2-[(trimethylsilyl)ethynyl]benzoic
acids 6 are synthetic precursors of unprotected 2-
ethynylbenzoic acids 1. The method disclosed here
therefore represents a valuable novel entry to an
[a]
Unless otherwise noted, all reactions were carried out
with in a dioxane-MeOH mixture (1.2:1, v/v)
(
substrate concentration: 0.02 mmol of substrate 6 per
mL of solvent) at 80 °C under 40 atm (at 25 °C) of a
:1 mixture of CO-air, in the presence of PdI (2
[11]
important class of heterocyclic derivatives, starting
from simple and readily available substrates (2-
4
2
mol%) and KI (20 mol%) for 5 h.
Isolated yield based on starting 6.
The reaction was carried out with 1 mol % of PdI
and 10 mol % of KI.
The reaction was carried out with 0.33 mol % of PdI
and 3.3 mol % of KI for 15 h.
The reaction was carried out with 0.2 mol % of PdI
and 2 mol % of KI for 15 h.
The reaction was carried out for 2 h.
[(trimethylsilyl)ethynyl]benzoic acids, CO, ROH, and
O ).
[b]
[c]
2
2
2
2
[
[
[
d]
e]
f]
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
=
7.5, 0.7, 1 H, aromatic), 6.16 (s, 1 H, =CH), 3.84 (s, 3H,
Experimental Section
13
CO
2
Me); C NMR (75 MHz, CDCl
3
): δ = 166.0, 165.7,
1
5
58.0, 136.1, 135.3, 132.6, 128.2, 126.7, 125.4, 102.0,
General Methods
+
1.9; GC/MS: m/z = 204 [M , 35], 173 (100), 163 (5), 146
(
15), 133 (4), 104 (7), 89 (36); HRMS-ESI (m/z):
+
Solvents and chemicals were reagent grade and used
without further purification. All reactions were analyzed
by TLC on silica gel 60 F254 (Merck) and by GLC
11 9 4
[(M+H) ] calcd for (C H O ): 205.0495; found, 205.0493.
The spectroscopic data were in good agreement with those
[
12]
reported.
CCDC 841258 contains the supplementary
(
Shimadzu GC-2010) using capillary columns with
crystallographic data for this compound. These data can be
obtained free of charge from The Cambridge
polymethylsilicone +5% phenylsilicone as the stationary
phase (HP-5). Column chromatography was performed on
silica gel 60 (Merck, 70−230 mesh). Evaporation refers to
the removal of solvent under reduced pressure. Melting
points are uncorrected. IR spectra were taken with a
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
1
13
Methyl
(Z)-2-[5-chloro-3-oxoisobenzofuran-1-(3H)-
JASCO FTIR 4200 spectrometer. H NMR and C NMR
spectra were recorded at 25 °C on a 300 MHz spectrometer
ylidene]acetate (2b). Yield: 57.4 mg, starting from 76.3
mg of 5-chloro-2-[(trimethylsilyl)ethynyl]benzoic acid 6b
(
3 4
Bruker DPX Avance 300) in CDCl solutions with Me Si
(
80%). White solid, mp = 96-98 °C. IR (KBr): ν = 1795 (s),
as the internal standard. Chemical shifts (δ) and coupling
constants (J) are given in ppm and Hz, respectively. Mass
1
9
9
712 (s), 1659 (s), 1465 (w), 1239 (s), 1163 (s), 1055 (s),
–1 1
84 (w), 869 (m) cm ; H NMR (300 MHz, CDCl
.02 (d, br, J = 8.5,1 H, aromatic), 7.92 (s, br, 1 H,
3
): δ =
spectra were obtained using
a
GC-MS apparatus
(
Shimadzu QP-2010) at 70 eV ionization voltage or an
aromatic), 7.76 (dd, J = 8.5, 1.8, 1 H, aromatic), 6.17 (s, 1
HPLC/ESI/Q‐ TOF HRMS apparatus; HPLC conditions
were as follows: water, acetonitrile, and formic acid were
of HPLC/MS grade; the HPLC system was an Agilent
13
2
H, =CH), 3.85 (s, 3 H, CO Me); C NMR (75 MHz,
CDCl
3
): δ =165.9, 164.4, 157.2, 139.1, 135.5, 134.3, 129.5,
+
1
2
(
(
28.2, 125.3, 102.5, 52.1; GC/MS: m/z = 240 [(M+2) , 13],
1
260 Infinity; a reversed‐ phase C18 column (ZORBAX
+
38 [M , 38], 209 (33), 207 (100), 180 (14), 151 (4), 123
Extended‐ C18 2.1 × 50 mm, 1.8 µm) with a Phenomenex
C18 security guard column (4 mm × 3 mm) were used; the
flow‐ rate was 0.4 mL/min and the column temperature
was set to 30 °C; the eluents were formic acid–water
+
37), 110 (10); HRMS-ESI (m/z): [(M+H) ] calcd for
C
11
H
9
ClO
4
): 239.0106; found, 239.0111.
Methyl
(Z)-2-(5-Methyl-3-oxoisobenzofuran-1-(3H)-
(
(
0.1:99.9, v/v) (phase A) and formic acid–acetonitrile
0.1:99.9, v/v) (phase B); the following gradient was
ylidene]acetate (2c). Yield: 46.1 mg, starting from 70.5
mg of 5-(methyl)-2-[(trimethylsilyl)ethynyl]benzoic acid
employed: 0–10 min, linear gradient from 5% to 95% B;
6
1
1
7
c (70%). White solid, mp = 108-109 °C. IR (KBr): ν =
798 (s), 1717 (s), 1659 (s), 1435 (w), 1385 (w), 1250 (m),
215 (m), 1165 (w), 1092 (w), 1057 (s), 984 (m), 841 (s),
1
5
0–15 min, washing and reconditioning of the column to
% B; injection volume was 10 µL; the eluate was
monitored through MS TIC. The mass spectra were
recorded using an Agilent 6540 UHD accurate‐ mass
Q‐ TOF spectrometer equipped with a Dual AJS ESI
source working in negative mode, under the following
–
1 1
3
06 (w) cm ; H NMR (300 MHz, CDCl ): δ = 8.90 (d, J
=
8.1, 1 H aromatic), 7.75 (s, 1 H, aromatic), 7.62 (d, J =
8
.1, 1 H, aromatic), 6.09 (s, 1 H, =CH), 3.83 (s, 3 H,
13
CO
2
Me), 2.53 (s, 3 H, Me); C NMR (75 MHz, CDCl
3
): δ
2
conditions: N was employed as desolvation gas at 300 °C
=
166.2, 165.8, 158.3, 143.8, 136.4, 133.7, 128.0, 126.9,
and a flow rate of 9 L/min; the nebulizer was set to 45
psig; the sheath gas temperature was set at 400 °C and a
flow of 12 L/min; a potential of 2.7 kV was used on the
capillary for positive ion mode; the fragmentor was set to
+
1
25.5, 101.0, 51.9, 21.7; GC/MS: m/z = 218 [M , 39], 187
(
(
100), 160 (18), 147 (6), 103 (48), 77 (20); HRMS-ESI
+
m/z): [(M+H) ] calcd for (C12
19.0653.
11 4
H O ): 219.0652; found,
2
1
75 V; the MS spectrum was recorded in the 150–1000 m/z
range.
Methyl (Z)-2-[6-methoxy-3-oxoisobenzofuran-1-(3H)-
ylidene]acetate (2d). Yield: 67.2 mg, starting from 75.1
mg of 4-methoxy-2-[(trimethylsilyl)ethynyl]benzoic acid
Preparation of Substrates
6
1
1
d (95%). White solid, mp = 169-170. °C. IR (KBr): ν =
Substrates 1a, 6a-d, and 7 were prepared as described in
the Supporting Information.
793 (s), 1712 (s), 1653 (s), 1600 (s), 1492 (m), 1445 (w),
–1 1
260 (s), 1200 (s), 1150 (w), 1044 (m), 860 (m) cm ; H
NMR (300 MHz, CDCl
3
): δ = 8.63 (s, br, 1 H, aromatic),
General Procedure for the Oxidative Carbonylation of
7.84 (d, J = 8.5, 1 H, aromatic), 7.19 (d, br, J = 7.4, 1 H,
2
-[(Trimethylsilyl)ethynyl]benzoic Acids 6 (Table 1)
aromatic), 6.11 (s, 1 H, =CH), 3.98 (s, 3 H, OMe), 3.83 (s,
1
3
3
1
1
1
2 3
H, CO Me); C NMR (75 MHz, CDCl ): δ = 166.1,
65.6, 165.3, 158.1, 138.6, 126.7, 120.7, 118.7, 111.1,
A 250 mL stainless steel autoclave was charged in the
+
–
3
01.8, 56.1, 52.0; GC/MS: m/z = 234 [M , 60], 203 (100),
presence of air with PdI (2.2 mg, 6.1  10 mmol), KI
2
–
2
76 (25), 163 (5), 147 (18), 119 (33); HRMS-ESI (m/z):
(
10.1 mg, 6.1  10 mmol) and a solution or 6 (0.30
+
[
(M+H) ] calcd for (C12
H
11
O
5
): 235.0601; found, 235.0595.
mmol; 6a, 65.6 mg; 6b, 76.3 mg; 6c, 70.5 mg; 6d, 75.1
mg) in a mixture of dioxane (8.2 mL) and ROH (6.8 mL; R
=
Me, Et, i-Pr, t-Bu). The autoclave was sealed and, while
Ethyl (Z)-2-[3-oxoisobenzofuran-1-(3H)-ylidene]acetate
(2e). Yield: 59.0 mg, starting from 65.4 mg of 2-[2-
(trimethylsilyl)ethynyl]benzoic acid 6a (90%). White solid,
mp = 45-46 °C. IR (KBr): ν = 1788 (s), 1712 (s), 1654 (s),
1471 (w), 1359 (m), 1242 (s), 1200 (m), 1145 (m), 1046
the mixture was stirred, the autoclave was pressurized with
CO (32 atm) and air (up to 40 atm). After being stirred at
8
0°C for the required time (5 h for 6a with MeOH, EtOH,
i-PrOH, t-BuOH, 5 h for 6c and 6d with MeOH, 2 h for 6b
with MeOH, see Table 1), the autoclave was cooled,
degassed and opened. The solvent was evaporated, and the
products were purified by column chromatography on
silica gel using as eluent hexane to hexane/AcOEt 98:2.
–1 1
(s), 861 (m), 774 (w) cm ; H NMR (300 MHz, CDCl ): δ
3
= 9.05 (d, J = 7.9, 1 H, aromatic), 7.98-7.93 (m, 1 H,
aromatic), 7.82 (td, J = 7.5, 1.1, 1 H, aromatic), 7.71 (td, J
= 7.5, 0.9, 1 H, aromatic), 6.14 (s, 1 H, =CH), 4.30 (q, 2 H,
1
3
J = 7.1, 2 H, CH
NMR (75 MHz, CDCl
35.3, 132.5, 128.2, 126.5, 125.3, 102.5, 60.9, 14.3;
2
CH
3
), 1.37 (t, J = 7.1, 3 H, CH
2 3
CH ); C
): δ =165.7, 165.5. 157.8, 136.1,
Methyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-
3
1
ylidene]acetate (2a). Yield: 60.3 mg, starting from 65.6
mg of 2-[2-(trimethylsilyl)ethynyl]benzoic acid 6a (98%).
White solid, mp = 92-93°C. IR (KBr): ν = 1806 (s), 1719
+
GC/MS: m/z = 218 (M , 18), 190 (24), 173 (100), 146 (66),
18 (5), 105 (17), 89 (46), 76 (17); HRMS-ESI (m/z):
1
+
[
(M+H) ] calcd for (C12
11 4
H O ): 219.0652; found, 219.0648.
(
s), 1653 (s), 1588 (w), 1460 (w), 1435 (m), 1381 (m),
The spectroscopic data were in good agreement with those
1
7
9
244 (s), 1209 (m), 1148 (w), 1036 (s), 974 (m), 849 (m),
[
13]
–1 1
reported.
76 (m), 690 (m) cm ; H NMR (300 MHz, CDCl
3
): δ =
.05 (d, J = 8.0, 1 H, aromatic), 7.96 (d, 1 H, J = 7.6, 1 H,
aromatic), 7.83 (td, J = 7.6, 1.0, 1 H, aromatic), 7.71 (dd, J
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
Isopropyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-
Methyl
(Z)-2-[5-oxofuran-2(5H)-ylidene]acetate
8.
ylidene]acetate (2f). Yield: 64.9 mg, starting from 65.3
mg of 2-[2-(trimethylsilyl)ethynyl]benzoic acid 6a (93%).
White solid, mp = 57-58 °C. IR (KBr): ν = 1791 (s), 1710
Yield: 15.0 mg, starting from 50.5 mg of (Z)-5-
(trimethylsilyl)pent-2-en-4-ynoic acid 7 (32%) White solid,
mp = 59-60 °C. IR (KBr): ν = 1786 (s), 1709 (s), 1651 (m),
–
1
1
(
s), 1652 (s), 1589 (w), 1469 (m), 1377 (m), 1243 (s), 1142
1443 (w), 1057 (w), 883 (w), 826 (s), 748 (m) cm ; H
–1
(
m), 1105 (m), 1027 (m), 972 (m), 833 (m), 774 (m), cm ;
NMR (300 MHz, CDCl
3
): δ = 8.39 (d, J = 5.3, 1 H, =CH,
1
3
H NMR (300 MHz, CDCl ): δ = 9.06 (d, br, J = 7.9, 1 H,
8), 6.48 (d, J = 5.3, 1 H, =CH, 8), 5.95 (s, 1 H,
13
aromatic), 7.99-7.93 (m, 1 H, aromatic), 7.82 (td, J = 7.7,
=CHCO
3
MHz, CDCl ): δ = 167.8, 165.4, 160.4, 142.0, 124.5, 102.2,
+
2 2
Me, 1 H, 8), 3.81 (s, 3 H, CO Me); C NMR (75
1
6
.1, 1 H, aromatic), 7.70 (td, J = 7.5, 0.9, 1 H aromatic),
.12 (s, 1 H, =CH), 5.16 (hept, J = 6.2, 1 H, CHMe ), 1.34
]; C NMR (75 MHz, CDCl ): δ
165.8, 165.1, 157.6, 136.2, 135.2, 132.4, 128.2, 126.5,
2
52.1; GC/MS: m/z = 154 [M , 27], 123 (100), 95 (24), 69
1
3
[
d, J = 6.2, 6H, CH(CH
3
)
2
3
(36).
=
+
1
25.3, 103.0, 68.5, 21.9; GC/MS: m/z =232 [M , 8], 191
(
12), 173 (94), 146 (100), 105 (27), 89 (46), 76 (17);
Acknowledgements
+
HRMS-ESI (m/z): [(M+H) ] calcd for (C13
H
13
O
4
):
2
33.0808; found, 233.0802.
Thanks are also due to Dr. Antonio Palumbo Piccionello
(University of Palermo, Italy) for HRMS measurements.
tert-Butyl
(Z)-2-[3-oxoisobenzofuran-1-(3H)-
ylidene]acetate (2g). Yield: 55.0 mg, starting from 65.6
mg of 2-[2-(trimethylsilyl)ethynyl]benzoic acid 6a (74%).
White solid, mp = 73-74 °C. IR (KBr): ν = 1800 (s), 1717
(
m), 1650 (s), 1472 (w), 1366 (m), 1252 (s), 1140 (m),
–
1
1
1
028 (s), 972 (w), 847 (m), 788 (m), 687 (m) cm ; H
): δ =9.03 (d, J = 7.9, 1 H,
NMR (300 MHz, CDCl
3
References
aromatic), 7.95 (d, J = 7.5, 1 H, aromatic), 7.81 (t, J = 7.5,
H aromatico), 7.69 (t, J = 7.5, 1 H, aromatic), 6.09 (s, 1
1
1
3
[
1] For recent reviews, see: a) B. Gabriele, Synthesis of
Heterocycles by Palladium-Catalyzed Carbonylative
Reactions, in Advances in Transition-Metal Mediated
Heterocyclic Synthesis, 1st ed. (Eds.: D. Solé, I.
Fernández), Academic Press-Elsevier, London, 2018,
Chapter 3; b) Transition Metal Catalyzed
Carbonylative Synthesis of Heterocycles, in Topics in
Heterocyclic Chemistry, Vol. 42 (Eds.: X.-F. Wu, M.
Beller), Springer, Berlin, 2016; c) C. Shen, X.-F. Wu,
Chem. Eur. J. 2017, 23, 2973-2987; d) S. T. Gadge, B.
M. Bhanage, RSC Adv. 2014, 4, 10367-10389; e) X.-F.
Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6,
H, =CH), 1.57 (s, 9 H, t-Bu); C NMR (75 MHz, CDCl
δ = 165.9, 164.8, 157.0, 136.3, 135.2, 132.2, 128.2, 126.5,
3
):
+
1
25.2, 104.5, 81.5, 28.2; GC/MS: m/z = 246 [M , 3], 191
(
(
(
76), 173 (100), 162 (11), 149 (22), 146 (52), 105 (30), 89
+
37), 57 (48); HRMS-ESI (m/z): [(M+Na) ] calcd for
14 4
C H14NaO ): 269.0784; found, 269.0779.
Oxidative Carbonylation of (Z)-5-(Trimethylsilyl)pent-
-en-4-ynoic acid 7 (Equation 4)
2
A 250 mL stainless steel autoclave was charged in the
–
3
presence of air with PdI
2
(2.2 mg, 6.1  10 mmol), KI
10.1 mg, 6.1  10 mmol) and a solution or 7 (50.5 mg,
.30 mmol) in a mixture of dioxane (8.2 mL) and MeOH
–
2
(
0
(
6.8 mL). The autoclave was sealed and, while the mixture
2
29-241; f) X.-F. Wu, H. Neumann, M. Beller, Chem.
was stirred, the autoclave was pressurized with CO (32
atm) and air (up to 40 atm). After being stirred at 80°C for
Rev. 2013, 113, 1-35; g) B. Gabriele, R. Mancuso, G.
Salerno, Eur. J. Org. Chem. 2012, 825-6839.
5
h, the autoclave was cooled, degassed and opened. The
solvent was evaporated (first at 60 °C and 600 mmHg to
remove MeOH, and then at 75 °C and 300 mmHg to
remove dioxane), and the residue was subjected to column
chromatography on silica gel using as eluent hexane to
hexane/AcOEt 95:5. A mixture of methyl (Z)-2-[5-
oxofuran-2(5H)-ylidene]acetate 8 and methyl (E)-2-[5-
oxofuran-2(5H)-ylidene]-2-(trimethylsilyl)acetate 8’ (35
[2] For representative recent examples, see: a) A. Acerbi,
C. Carfagna, M. Costa, R. Mancuso, B. Gabriele, N.
Della Ca’, Chem. Eur. J. 2018, 24, 4835; b) T.
Klucznik, B. Mikulak-Klucznik, M. P. McCormack, H.
Lima, S. Szymkuć, M. Bhowmick, K. Molga, Y. Zhou,
L. Rickershauer, E. P. Gajewska, A. Toutchkine, P.
Dittwald, M. P. Startek, G. J. Kirkovits, R. Roszak, A.
Adamski, B. Sieredzińska, M. Mrksich, S. L. J. Trice,
B. A. Grzybowski, Chem 2018, 4, 522-532; c) Y. Hu,
H. Huang, Org. Lett. 2017, 19, 5070-5073; d) R.
Mancuso, D. S. Raut, N. Marino, G. De Luca, C.
Gordano, S. Catalano, I. Barone, S. Andò, B. Gabriele,
Chem. Eur. J. 2016, 22, 3053-3064; e) R. Shen, T.
Kusakabe, T. Yatsu, Y. Kanno, K. Takahashi, K.
Nemoto, K. Kato, Molecules 2016, 21, article no. 1177;
f) S. V. Giofrè, S. Cirmi, R. Mancuso, F. Nicolò, G.
Lanza, L. Legnani, A: Campisi, M. A. Chiacchio, M.
Navarra, B. Gabriele, R. Romeo, Beilstein J. Org.
Chem. 2016, 12, 2793-2807; g) F. Araniti, R. Mancuso,
A. Lupini, S. V. Giofrè, F. Sunseri, B. Gabriele, M. R.
Abenavoli, Molecules 2015, 20, 17883-17902; h) L. A.
Aronica, L. Giannotti, G. Tuci, F. Zinna, Eur. J. Org.
Chem. 2015, 4944-4949; i) R. Mancuso, B. Gabriele,
Chem. Heterocycl. Compds. 2014, 50, 160-170; j) R.
Mancuso, I. Ziccarelli, D. Armentano, N. Marino, S. V.
Giofrè, B. Gabriele, J. Org. Chem. 2014, 79, 3506-
1
mg) was obtained, as confirmed by H NMR analysis.
From the proton spectrum, the 8:8’ ratio was about 1:0.8,
which corresponded to a yield of 8 of about 41% and of 8’
of 24%. This mixture was further subjected to PTLC using
hexane/AcOEt 93:7, which allowed to obtain ca. 15 mg of
pure 8 (32% yield), while 8’ was still obtained impure with
1
8
(ca. 8 mg; 8’:8 ratio ca. 1:0.3, by HNMR).
Mixture
of
methyl
(Z)-2-[5-oxofuran-2(5H)-
ylidene]acetate 8 and methyl (E)-2-[5-oxofuran-2(5H)-
ylidene]-2-(trimethylsilyl)acetate 8’. Yield: 35 mg,
starting from 50.5 mg of (Z)-5-(trimethylsilyl)pent-2-en-4-
ynoic acid 7. White solid. IR (KBr): ν = 1790 (s), 1713 (s),
1
612 (m), 1558 (w), 1439 (m), 1235 (s), 1714 (m), 1042
–1 1
(
(
3
m), 826 (m) cm ; H NMR (300 MHz, CDCl ): δ = 8.39
d, J = 5.3, 1 H, =CH, 8), 7.83 (d, J = 5.3, 1 H, =CH, 8’),
6
.48 (d, J = 5.3, 1 H, =CH, 8), 6.36 (d, J = 5.3, =CH, 1 H,
’), 5.95 (s, 1 H, =CHCO Me, 1 H, 8), 3.81 (s, 3 H,
Me for 8 + 3 H, CO Me for 8’), 0.31 (s, 9 H, 8’);
): δ = 168.83 (8’), 168.77 (8’),
8
2
13
CO
2
2
C
NMR (75 MHz, CDCl
3
1
67.8 (8), 165.3 (8), 161.4 (8’), 160.4 (8), 142.0 (8), 141.8
(
(
(
(
8’), 124.5 (8), 122.6 (8’), 120.7 (8’), 102.2 (8), 52.1
+
8+8’), ‒0.46 (8’); GC/MS: for 8: m/z = 154 [M , 27], 123
+
100), 95 (24), 69 (36); for 8’: m/z = 226 [M , <0.5], 195
3), 89 (100), 59 (22).
3
518; k) Y. Jiang, T. Kusakabe, K. Takahashi, K. Kato,
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
Org. Biomol. Chem. 2014, 12, 3380-3385; l) F. Araniti,
R. Mancuso, I. Ziccarelli, F. Sunseri, M. R. Abenavoli,
B. Gabriele, Molecules 2014, 19, 8261-8275.
[8] It is likely that the TMS group is removed at the end of
the process, that is, after cyclization and
alkoxycarbonylation. This phenomenon was already
2
observed in other PdI /KI-catalyzed oxidative
[
3] The palladium-catalyzed non-carbonylative cyclization
of 2-ethynylbenzoic acids and alkynoic acids has been
reported; see: a) H. Sashida, A. Kawamukai, Synthesis
carbonylation reactions; see, for example: a) F.
Pancrazzi, E. Motti, M. Costa, R. Mancuso, B. Gabriele,
N. Della Ca’, Molbank 2017, 2017, M927; b) N. Della
Ca’, F. Campanini, B. Gabriele, G. Salerno, C. Massera,
M. Costa, Adv. Synth. Catal. 2009, 351, 2423-2432; c)
B. Gabriele, R. Mancuso, G. Salerno, E. Lupinacci, G.
Ruffolo, M. Costa, J. Org. Chem. 2008, 73, 4971-4977;
d) B. Gabriele, G. Salerno, A. Fazio, L. Veltri, Adv.
Synth. Catal. 2006, 348, 2212-2222; e) M. Costa, N.
Della Ca’, B. Gabriele, C. Massera, G. Salerno, M.
Soliani, J. Org. Chem. 2004, 69, 2469-2477; f) A.
Bacchi, M. Costa, N. Della Ca’, M. Fabbricatore, A.
Fazio, B. Gabriele, C. Nasi, G. Salerno, Eur. J. Org.
Chem. 2004, 574-585.
1
999, 1145-1148; b) R.Rossi, F. Bellina, M. Biagetti, A.
Catanese, L. Mannina, Tetrahedron Lett. 2000, 41,
281-5286. c) N. Nebra, J. Monot, R. Shaw, B. Martin-
5
Vaca, D. Bourissou, ACS Catal. 2013, 3, 2930-2934; d)
N. Conde, R. SanMartin, M. T. Herrero, E. Domínguez,
Adv. Synth. Catal. 2016, 358, 3283-3292. The copper-
catalyzed cycloisomerization of 2-alkynylbenzoic acids
in ionic liquids was also recently reported by our
research group: e) R. Mancuso, C. S. Pomelli, P.
Chiappetta, K. F. Gioia, A. Maner, N. Marino, L. Veltri,
C. Chiappe, B. Gabriele, J. Org. Chem. 2018, 83, 6673-
6
680.
[
9] We thank a referee for suggesting to test this substrate.
[
4] These conditions (32 atm of CO together with 9 atm
total pressure of air, if we consider that the autoclave
was loaded under 1 atm of air) corresponded to 78% of
CO in air and were outside the explosion limits for CO
in air, which are ca. 16–70% at 18–20 °C and
atmospheric pressure, 14.8–71.4% at 100 °C and
atmospheric pressure; at higher total pressure, the range
of flammability decreases: for example, at 20 atm and
[10] Similar results were obtained after 15 h reaction time.
[11] 2-[3-Oxoisobenzofuran-1(3H)-ylidene]acetic acid
derivatives have shown interesting biological activity
or are useful precursors for the synthesis of biologically
active molecules. For some representative examples,
see: a) A. M. Sridhara, K. R. V. Reddy, J. Keshavayya,
D. M. S. Ambika, V. S. Gopinath, P. Bose, S. K. Goud,
S. K. Peethambar, J. Braz. Chem. Soc. 2011, 22, 849-
2
0 °C the limits are ca. 19 and 60%. See: C. M. Bartish,
G. M. Drissel in Kirk-Othmer Encyclopedia of
Chemical Technology, Vol. 4, 3rd ed. (Eds.: M.
Grayson, D. Eckroth, G. J. Bushey, L. Campbell, A.
Klingsberg, L. van Nes), Wiley, New York 1978, pp.
8
56; b) A. M. Sridhara, K. R. V. Reddy, J. Keshavayya,
P. S. K. Goud, B. C. Somashekar, P. Bose, S. K.
Peethambar, S. K. Gaddam, Eur. J. Med. Chem. 2010,
4
5, 4983-4989; c) K. Babaoglu, A. Simeonov, J. J.
7
74-775.
Irwin, M. E. Nelson, B. Feng, C. J. Thomas, L. Cancian,
M. P. Costi, D. A. Maltby, A. Jadhav, J. Inglese, C. P.
Austin, B. K. Shoichet, J. Med. Chem. 2008, 51, 2502-
[
[
[
5] B. Gabriele, G. Salerno, M. Costa, Top. Organomet.
Chem. 2006, 18, 239-272.
2
511; d) C. Lüthy, H. Zondler, T. Rapold, G. Seifert, B.
6] See, for example, L. Veltri, V. Paladino, P. Plastina, B.
Urwyler, T. Heinis, H. C. Steinrücken, J. Allen, Pest
Manag. Sci. 2001, 57, 205-224.
Gabriele, J. Org. Chem. 2016, 81, 6106-6111.
7] We believe that the role of the TMS group is to protect
the triple bond from possible by-reactions leading to
heavy products, ensuing from triple bond
decomposition and/or oligomerization. This ensured a
higher product yield, because the starting material was
less prone to undergo unwanted decomposition by-
reactions.
[
12] L. Zhou, H.-F. Jiang, Tetrahedron Lett. 2007, 48,
8
449-8452.
[13] C. Niebel, V. Lokshin, M. Sigalov, P. Krief, V.
Khodorkovsky, Eur. J. Org. Chem. 2008, 3689-3699.
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201801308
COMMUNICATION
A regio- and stereoselective carbonylative
approach to alkyl (Z)-2-[3-oxoisobenzofuran-1-
(
3H)-ylidene]acetates
Adv. Synth. Catal. Year, Volume, Page – Page
a,
a
Raffaella Mancuso, * Ida Ziccarelli, Francesco
b
c
d
Fini, Nicola Della Ca’, Nadia Marino, Carla
Carfagna, and Bartolo Gabriele *
e
a,
7
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