Catalytic Carbonylative Double Cyclization of 2-(3-Hydroxy-1-yn-1-yl)phenols in Ionic Liquids Leading to Furobenzofuranone Derivatives

Article abstract of DOI:10.1021/acs.joc.9b00952

A catalytic carbonylative double cyclization method for the synthesis of furo[3,4-b]benzofuran-1(3H)-ones is reported. It is based on the reaction between readily available 2-(3-hydroxy-1-yn-1-yl)phenols, CO, and oxygen carried out in the presence of cata

Full text of DOI:10.1021/acs.joc.9b00952

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Catalytic Carbonylative Double Cyclization of 2‑(3-Hydroxy-1-yn-1-
yl)phenols in Ionic Liquids Leading to Furobenzofuranone
Derivatives
†
‡
§
Raffaella Mancuso,*,† Rossana Milie, Antonio Palumbo Piccionello, Diego Olivieri,
̀
Nicola Della Ca’,∥ Carla Carfagna,§ and Bartolo Gabriele*,†
†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, Cosenza, Italy
‡Department of Biological, Chemical and Pharmaceutical Science and Technology-STEBICEF, University of Palermo, Viale delle
Scienze Ed. 17, 90128 Palermo, Italy
§Department of Industrial Chemistry “T. Montanari”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
∥Department of Chemistry, Life Sciences and Environmental Sustainability (SCVSA), University of Parma, Parco Area delle Scienze,
17/A, I-43124 Parma, Italy
S
* Supporting Information
ABSTRACT: A catalytic carbonylative double cyclization
method for the synthesis of furo[3,4-b]benzofuran-1(3H)-
ones is reported. It is based on the reaction between readily
available 2-(3-hydroxy-1-yn-1-yl)phenols, CO, and oxygen
carried out in the presence of catalytic amounts of PdI2 (1 mol
%) in conjunction with KI (20 mol %) and 2 equiv of
diisopropylethylamine at 80 °C for 24 h under 30 atm of a 1:4
mixture of CO−air. Interestingly, the process was not selective
when carried out in classical organic non-nucleophilic solvents
(such as MeCN or DME), leading to a mixture of the
benzofurofuranone derivative and the benzofuran ensuing
from simple cycloisomerization, whereas it turned out chemoselective toward the formation of the double cyclization compound
in BmimBF4 as the reaction medium. Moreover, the ionic liquid solvent containing the catalyst could be easily recycled several
times without appreciable loss of activity.
two other methods, which are the reaction between 2-
iodophenols and tetronic acid in a basic ionic liquid (IL)6
and the PdCl2(PPh3)2-promoted carbonylative double cycliza-
tion of 2-(3-hydroxy-1-yn-1-yl)phenols, conducted under
stoichiometric conditions.7
INTRODUCTION
■
Palladium-catalyzed double cyclization processes are a power-
ful method for the construction of complex functionalized
molecules starting from readily available acyclic substrates in a
single operation, and impressive progress has been made in this
field during the last decades.1,2 In particular, we have very
recently developed in our laboratories important processes of
this kind, under oxidative carbonylative conditions and with
the promotion of a very simple catalytic system, consisting of
PdI2 in conjunction with an excess of KI,3 with molecular
oxygen as oxidant. Thus, dihydrofurofuranones with antitumor
activity4 and furo[3,4-b]indol-1-ones5 were obtained in good
to high yields from CO, O2, and 4-yne-1,3-diols or 3-(2-
aminophenyl)prop-2-yn-1-ols, respectively.
In this work, we report a remarkable example of the
synthesis of furo[3,4-b]benzofuran-1(3H)-ones by oxidative
carbonylative double cyclization of 2-(3-hydroxy-1-yn-1-yl)-
phenols carried out under catalytic conditions (1 mol % of
PdI2 in conjunction with 20 mol % of KI) and with the
possibility to easily recycle the catalyst. To the best of our
knowledge, this scaffold has so far been constructed by only
RESULTS AND DISCUSSION
■
PdI2/KI-Catalyzed Carbonylative Double Cyclization
of 2-(3-Hydroxy-1-yn-1-yl)phenols 1 to Furo[3,4-b]-
benzofuran-1(3H)-ones 2 in Conventional Solvents.
We first tested 2-(3-hydroxy-3-methylpent-1-yn-1-yl)phenol
1a (readily prepared by Sonogashira coupling between 2-
iodophenol and 3-methylpent-1-yn-3-ol, see the Experimental
Section for details), which was allowed to react with CO and
O2 under conditions similar to those used before for the
synthesis of furo[3,4-b]indol-1-ones.5 Using 2 mol % of PdI2
and 20 mol % of KI,8 under 6 atm of CO and 24 atm of air, in
MeCN as the solvent (0.25 mmol of 1a per mL of MeCN) at
Received: April 6, 2019
Published: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00952
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The Journal of Organic Chemistry
Article
Scheme 1. Mechanistic Hypotheses for the PdI2-Catalyzed Carbonylative Double Cyclization of 2-(3-Hydroxy-3-methylpent-1-
yn-1-yl)phenol 1a under Oxidative Conditions Leading to 3-Ethyl-3-methylfuro[3,4-b]benzofuran-1(3H)-one 2a (Path a) and
the PdI2-Catalyzed Cycloisomerization of 1a To Give 2-(Benzofuran-2-yl)butan-2-ol 3a (Path b) (B = Base)
80 °C for 15 h, no reaction took place. Considering the low
nucleophilicity of the phenolic hydroxyl, we then tried the
same reaction in the presence of a base (B) to favor the
formation in situ of the more nucleophilic phenate oxygen,
more prone to attack the triple bond coordinated to the metal
center (Scheme 1; anionic iodide ligands are omitted for
clarity). The vinylpalladium species I resulting from 5-endo-dig
cyclization would then undergo carbon monoxide insertion to
give complex II, from which the final carbonylated double
cyclization product 2a would be formed by intramolecular
trapping by the alcoholic hydroxyl (possibly through the
formation of a palladacycle intermediate III); the ensuing
Pd(0) would then be reoxidized by oxygen (Scheme 1,
pathway a).
According to this hypothesis, using the same conditions as
above, but in the presence of morpholine as the base, the
desired product (3-ethyl-3-methylfuro[3,4-b]benzofuran-
1(3H)-one, 2a) was indeed formed, albeit in low yield (14%;
Table 1, entry 2). Analysis of the reaction mixture also
evidenced the formation of smaller amounts (11% yield) of 2-
(benzofuran-2-yl)butan-2-ol 3a (from a simple cycloisomeriza-
tion process, ensuing from protonolysis of intermediate I,
Scheme 1, pathway b) together with chromatographically
immobile materials, deriving from substrate decomposition,
which were not investigated further. Gratifyingly, using
diisopropylethylamine (DIPEA) instead of morpholine led to
a significant higher yield of 2a up to 55%, 3a being still formed
in 20% yield (Table 1, entry 3). To further improve these
initial promising results, we changed the reaction operative
parameters, such as temperature, pressure, and so on; the
results obtained are shown in Table 1, entries 4−12. As can be
seen from the table, better results in terms of yield and
selectivity toward the carbonylated product 2a were obtained
by carrying out the process in MeCN under more diluted
conditions, still at 80 °C and under 30 atm of a 1:4 mixture of
CO−air (yields of 2a and 3a were 65 and 5%, respectively,
Table 1, entry 10). The reaction could successfully be
performed even with a lower catalyst loading (1 mol % of
PdI2), again with good results (Table 2, entry 1).
Table 1. PdI2/KI-Catalyzed Reactions of 2-(3-Hydroxy-3-
methylpent-1-yn-1-yl)phenol 1a under Oxidative
Carbonylation Conditions in Conventional Solvents
a b
,
concn.
c
yield of yield of
d d
entry
solvent
base
none
of 1a
T (°C) 2a (%) 3a (%)
e
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DME
dioxane
MeCN
MeCN
MeCN
MeCN
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.10
0.05
0.05
0.05
80
2
3
4
5
6
7
morpholine
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
80
80
100
70
60
80
80
80
80
80
80
14
55
35
53
45
34
11
20
12
17
12
10
e
8
9
50
65
28
21
22
5
5
10
f
11
g
12
2
a
Unless otherwise noted, all reactions were carried out for 15 h in the
presence of 2 mol % of PdI2, 20 mol % of KI, and 2 equiv of base,
b
under 30 atm of a 1:4 mixture of CO−air. Unless otherwise noted,
c
substrate conversion was quantitative. mmol of 1a per mL of solvent.
d
e
f
Based on starting 1a. No reaction took place. The reaction was
g
carried out under 60 atm of a 1:4 mixture of CO−air. The reaction
was carried out under 20 atm of a 4:1 mixture of CO−air.
entry 3). The substrate conversion rate was slightly slower in
the presence of a methoxy group at C-5, as in 1d, or when the
alkyl group α to the alcoholic hydroxyl was replaced by a
phenyl, as in 1e. In fact, these substrates achieved complete
conversion after 15 h instead of 8 h, with a yield of the
corresponding furobenzofuranones 2d and 2e of 60 and 57%,
respectively (Table 2, entries 4 and 5, respectively). However,
no cyclocarbonylation took place with a substrate bearing a
secondary alcoholic function, such as 1f, which afforded the
benzofuran product 3f deriving from simple cycloisomeriza-
tion. These results suggest that the second cyclization step
(cyclocarbonylation by intramolecular trapping of acylpalla-
dium complex II by the alcoholic hydroxyl; Scheme 1, path a)
is strongly favored, with respect to protonolysis, leading to
cycloisomerization product 3 (Scheme 1, path b), by the
We then assessed the generality of the process starting from
differently substituted substrates; the results are shown in
Table 2, entries 2−7. As could be expected, 2-(3-hydroxy-3-
methylbut-1-yn-1-yl)phenol 1b behaved similarly to 1a (Table
2, entry 2). 2-[(1-Hydroxycyclopentyl)ethynyl]phenol 1c led
to the corresponding tetracyclic product in 74% yield (Table 2,
B
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Article
a
Table 2. PdI2/KI-Catalyzed Oxidative Carbonylation of 2-(3-Hydroxy-1-yn-1-yl)phenols 1 in MeCN
a
All reactions were carried out at 80 °C under 30 atm (at 25 °C) of a 1:4 mixture of CO−air, in MeCN as the solvent (substrate concentration:
b
0.05 mmol of 1 per mL of solvent), and in the presence of 1 mol % of PdI2, 20 mol % of KI, and 2 equiv of DIPEA. Based on starting 1.
reactive rotamer effect9 exerted by the geminal substituents at
the alcoholic carbon. To verify this hypothesis, we also
synthesized and tested the reactivity of 2-(3-hydroxy-4-
methylpent-1-yn-1-yl)phenol 1g, bearing a single but bulky
substituent (isopropyl) α to the alcoholic group, able to exert a
sufficient steric effect to allow for an efficient second
cyclization. In perfect agreement with this hypothesis, substrate
1g was converted into the corresponding carbonylated product
in good yield (63%, Table 2, entry 7), comparable to that
obtained with α,α-dialkylsubstituted 2-(3-hydroxy-1-yn-1-yl)-
phenols 1a−e.10
as ILs may affect the selectivity of catalytic processes and may
also permit the recycle of the catalytic system,11 we also
performed our reaction in different ILs as the reaction
medium. The results obtained with 1a, reported in Table 3,
allowed us to draw the following conclusions: (a) the process
took place in all the ILs tested, even though with different
performances in terms of substrate conversion rate and
product yield; (b) the optimal reaction time was 24 h,
substrate conversion being incomplete after 15 h (Table 3,
entry 1); (c) with the exception of Mor1,2N(CN)2 (Table 3,
entry 7), the desired cyclocarbonylated product 2a was formed
selectively in a consistent manner (Table 3, entries 1−5); (d)
as in the case of the reaction carried out in MeCN (Table 1,
entry 1), no reaction took place in the absence of the base
(Table 3, entry 6); (e) the best results in terms of 2a yield
PdI2/KI-Catalyzed Carbonylative Double Cyclization
of 2-(3-Hydroxy-1-yn-1-yl)phenols 1 to Furo[3,4-b]-
benzofuran-1(3H)-ones 2 in ILs. Considering that, under
certain circumstances, the use of unconventional solvents such
C
DOI: 10.1021/acs.joc.9b00952
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Article
an unconventional solvent such as BmimBF4 can be used as
reaction medium; however, better selectivities and yields are
observed in the latter case, with the additional advantage of
catalyst recyclability.
Table 3. PdI2/KI-Catalyzed Reactions of 2-(3-Hydroxy-3-
methylpent-1-yn-1-yl)phenol 1a under Oxidative
Carbonylation Conditions in Different ILs.
a b
,
EXPERIMENTAL SECTION
■
General Experimental Methods. Solvents and chemicals were
of reagent grade and were used without further purification. All
reactions were analyzed by thin-layer chromatography on silica gel 60
F254 and by gas−liquid chromatography (GLC) using capillary
columns with polymethylsilicone + 5% phenylsilicone as the
stationary phase. Column chromatography was performed on silica
gel 60 (70−230 mesh) or neutral alumina (90−170). Evaporation
refers to the removal of solvent under reduced pressure. Melting
substrate
conversion
yield of
c
yield of
c
b
entry
IL
t (h)
2a (%)
3a (%)
1
2
3
4
5
BmimBF4
BmimBF4
BmimCl
BmimPF6
EmimEtSO4
EmimEtSO4
Mor1,2N(CN)2
BmimBF4
15
24
24
24
24
24
24
24
65
100
68
100
100
NR
100
100
59
80
20
51
67
1
points are uncorrected. H NMR and 13C{1H} NMR spectra were
recorded at 25 °C on a 300 spectrometer in CDCl3 and DMSO-d6
with Me4Si as internal standard. 19F{1H} NMR spectra were recorded
on a 500 spectrometer in CDCl3 solutions at 471 MHz with CFCl3 as
internal standard. Chemical shifts (δ) and coupling constants (J) are
given in ppm and in Hz, respectively. Infrared (IR) spectra were taken
with a Fourier transform-IR spectrometer. Mass spectra were obtained
using a gas chromatography (GC)/mass spectrometry (MS)
apparatus at 70 eV ionization voltage (normal resolution) and by
electrospray ionization MS (ESI-MS) (high-resolution) with an ultra-
high-definition accurate-mass quadrupole time of flight spectrometer
equipped with a Dual AJS ESI source working in positive mode, and
were recorded in the 150−1000 m/z range. The LC−MS
experimental conditions were as follows: N2 was employed as de-
solvation gas at 300 °C and a flow rate of 9 L/min. The nebulizer was
set to 45 psig. The sheath gas temperature was set at 350 °C and a
flow of 12 L/min. A potential of 3.5 kV was used on the capillary for
positive ion mode. The fragmentor was set to 175 V.
Preparation of Substrates 1a−j. 2-(3-Hydroxy-1-yn-1-yl)-
phenols 1 was prepared by Sonogashira coupling between
commercially available 2-iodophenols and propargyl alcohols
according to the following procedure. A solution of 2-iodophenol
(1.0 g, 4.55 mmol) or 5-methoxy-2-iodophenol (1.14 g, 4.55 mmol),
PdCl2(PPh3)2 (32.0 mg, 0.045 mmol), CuI (7.0 mg, 0.036 mmol),
and propargyl alcohol [5.63 mmol; 3-methylpent-1-yn-3-ol, 552.6 mg;
2-methylbut-3-yn-2-ol, 473.6 mg; 1-ethynylcyclopenten-1-ol, 620.2
mg; 2-phenylbut-3-yn-2-ol, 823.6 mg; but-3-yn-2-ol, 394.5 mg; 1-
phenylprop-2-yn-1-ol, 744.1 mg; 4-methylpent-1-yn-3-ol, 552.6 mg; 1-
ethynylcyclohexan-1-ol, 699.1 mg; 2-(4-fluorophenyl)but-3-yn-2-ol,
924.3 mg] in Et3N (12 mL) was allowed to stir for 4 h (for 1a, 1c, 1e,
1h, and 1j), 5 h (for 1d and 1i), or 6 h (1b, 1f, and 1g) at room
temperature under nitrogen. Saturated solutions of NH4Cl (50 mL)
and CH2Cl2 (30 mL) were sequentially added. The phases were
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 30
mL). The aqueous phase was acidified either with 1 M HCl until pH
= 5 (for 1a−d, 1f, 1g−i) or with 0.1 M HCl (3 × 50 mL) (for 1e and
1j). Et2O (100 mL) was added to the resulting aqueous phase, the
phases were separated, and the aqueous phase was extracted with
Et2O (3 × 100 mL). All the collected organic layers were washed with
H2O (until neutral pH) and brine (40 mL) and then dried over
Na2SO4. After filtration and evaporation of the solvent, the product
was purified by column chromatography on silica gel using as eluent
hexane−AcOEt from 99:1 to 9:1 (for 1a−h), CHCl3/MeOH from
99:1 to 98:2 (for 1i), or CHCl3/MeOH from 99:1 to 95:5 (for 1j).
2-(3-Hydroxy-3-methylpent-1-yn-1-yl)phenol (1a). Yield: 691.2
mg, starting from 1.0 g of 2-iodophenol (80%). White solid, mp =
43−45 °C. IR (KBr) ν: 3383 (m, br), 3089 (s, br), 2231 (w), 1449
(m), 1125 (m), 754 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.29
(d, J = 7.6, 1H), 7.22 (t, J = 7.7, 1H), 6.95 (d, J = 8.2, 1H), 6.83 (t, J =
7.4, 1H), 6.77 (s, br, 1H), 3.20 (s, br, 1H), 1.92−1.73 (m, 2H), 1.60
(s, 3H), 1.10 (t, J = 7.4, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
156.9, 131.8, 130.3, 120.1, 115.2, 109.1, 99.0, 78.3, 69.7, 36.6, 29.2,
9.2. GC/MS m/z: 190 (M+, 5), 172 (69), 161 (30), 157 (45). HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C12H14O2Na+, 213.0886;
found, 213.0886.
d
6
7
8
53
75
10
e
a
Unless otherwise noted, all reactions were carried out at 80 °C under
30 atm (at 25 °C) of a 1:4 mixture of CO−air, in an IL as the solvent
(substrate concentration: 0.05 mmol of 1a per mL of solvent, 0.5
mmol scale), and in the presence of 1 mol % of PdI2, 20 mol % of KI,
b
c
and 2 equiv of DIPEA. Determined by GLC. Based on starting 1a.
The experiment was carried out in the absence of DIPEA. NR = no
reaction. The experiment was carried out on a larger scale (2.5 mmol
of 1a).
d
e
(80%) were observed with 1-butyl-3-methylimidazolium
tetrafluoroborate (BmimBF4; Table 3, entry 2).12 An experi-
ment carried out in this IL on a larger scale (2.5 mmol of 1a
rather than 0.5 mmol) also led to satisfactory results (the yield
of 2a was 75%, Table 3, entry 8).
Our next step was to assess the possibility to recycle the
catalyst and to generalize the process to other variously
substituted substrates, using BmimBF4 as unconventional
solvent. The results obtained with 2-(3-hydroxy-1-yn-1-yl)-
phenols 1a−g, already tested in MeCN, together with the
additional substrates 1h−j (bearing different α,α-dialkyl
substituents) are shown in Table 4. Gratifyingly, the process
turned out to be selective toward the formation of the
corresponding furobenzofuranones 2 with all the α,α-
dialkylsubstituted substrates examined 1a−e and 1h−j
(Table 4, entries 1−5 and 7−9, respectively) as well as with
substrate 1g bearing a bulky isopropyl group α to the alcoholic
function (Table 4, entry 6), with yields ranging from 74 to
87%.13 Moreover, the catalytic system dissolved in the IL
medium could be easily recycled up to six times without
appreciable loss of activity. In detail, after extraction of the
product with diethyl ether, fresh substrate and DIPEA were
added to the residue, and the carbonylation was carried out
again under the same conditions of the parent experiment.
CONCLUSIONS
■
We have reported the first example of carbonylative double
cyclization of 2-(3-hydroxy-1-yn-1-yl)phenols (α,α-dialkylsub-
stituted or α-monosubstituted with a sufficiently bulky group)
carried out under catalytic conditions. The process, leading to
tricyclic furo[3,4-b]benzofuran-1(3H)-ones in one synthetic
step from readily available substrates, is catalyzed by a simple
system, consisting of PdI2 (1 mol %) in conjunction with KI
(20 mol %) and takes place in the presence of DIPEA as the
base (2 equiv) and molecular oxygen as the oxidant. Either a
classical non-nucleophilic organic solvent (such as MeCN) or
D
DOI: 10.1021/acs.joc.9b00952
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Article
Table 4. Synthesis of Furo[3,4-b]benzofuran-1(3H)-ones 2 by PdI2/KI-Catalyzed Oxidative Carbonylation of 2-(3-Hydroxy-1-
a
yn-1-yl)phenols 1 in BmimBF4
a
All reactions were carried out at 80 °C under 30 atm (at 25 °C) of a 1:4 mixture of CO−air, in BmimBF4 as the solvent (substrate concentration:
b
0.05 mmol of 1 per mL of solvent), and in the presence of 1 mol % of PdI2, 20 mol % of KI, and 2 equiv of DIPEA. Based on starting 1. The first
run corresponds to the parent experiment, the next runs to recycles. See the text for details.
E
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2-(3-Hydroxy-3-methylbut-1-yn-1-yl)phenol (1b). Yield: 576.3
mg, starting from 1.0 g of 2-iodophenol (72%). White solid, mp =
131−132 °C lit.,14 131−132 °C. IR (KBr) ν: 3393 (s), 3084 (s, br),
(m, 2H), 1.79−1.48 (m, 7H), 1.35−1.17 (m, 1H). 13C{1H} NMR (75
MHz, CDCl3): δ 156.9, 131.9, 130.3, 120.1, 115.3, 109.2, 99.1, 79.3,
69.7, 40.0, 25.1, 23.4. GC/MS m/z: 216 (M+, 5), 198 (100), 183
(41), 170 (71), 131 (26). The spectroscopic data agreed with those
reported.7
1
2224 (w), 1450 (m), 1285 (m), 1154 (s), 761 (m) cm−1. H NMR
(300 MHz, DMSO-d6): δ 9.65 (s, 1H), 7.27 (dd, J = 7.6, 1.6, 1H),
7.23−7.13 (m, 1H), 6.94 (dist d, J = 8.2, 1H), 6.83−6.74 (m, 1H),
5.48 (s, br, 1H), 1.53 (s, 6H). 13C{1H} NMR (75 MHz, DMSO-d6): δ
158.4, 133.2, 129.8, 119.4, 115.8, 110.4, 99.5, 77.9, 64.3, 32.1. GC/
MS m/z: 176 (M+, 9), 158 (100), 143 (31), 131 (14), 115 (18). The
spectroscopic data agreed with those reported.14
2-[(1-Hydroxycyclopentyl)ethynyl]-5-methoxyphenol (1i). Yield:
528.4 mg, starting from 1.14 g of 5-methoxy-2-iodophenol (50%).
White solid, mp = 137−138 °C. IR (KBr) ν: 3330 (s, br), 3083 (m,
br), 2220 (m), 1518 (m), 1425 (m), 1209 (s), 1032 (m), 993 (m)
1
cm−1. H NMR (300 MHz, DMSO-d6): δ 9.77 (s, 1H), 7.13 (d, J =
2-[(1-Hydroxycyclopentyl)ethynyl]phenol (1c). Yield: 688.8 mg,
starting from 1.0 g of 2-iodophenol (75%). Yellow solid, mp = 95−96
°C. IR (KBr) ν: 3378 (s, br), 3078 (s, br), 2224 (w), 1454 (m), 989
(s), 752 (m) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 9.72 (s, 1H),
7.22 (dd, J = 7.6, 1.6, 1H), 7.19−7.11 (m, 1H), 6.87 (dist d, J = 8.2,
1H), 6.76 (td, J = 7.5, 1.0, 1H), 5.26 (s, 1H), 1.90−1.81 (m, 4H),
1.80−1.61 (m, 4H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 158.4,
133.2, 129.8, 119.3, 115.8, 110.6, 98.5, 78.8, 73.4, 42.5, 23.5. GC/MS
m/z: 202 (M+, 5), 201 (6), 184 (100), 169 (42), 145 (28), 131 (32).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H14O2Na+,
225.0886; found, 225.0890.
8.5, 1H), 6.41 (d, J = 1.8, 1H), 6.36 (dd, J = 8.5, 1.8, 1H), 5.19 (s,
1H), 3.70 (s, 3H), 1.94−1.79 (m, 4H), 1.79−1.59 (m, 4H). 13C{1H}
NMR (75 MHz, DMSO-d6): δ 160.1, 159.1, 133.5, 105.1, 102.6,
100.9, 96.5, 78.3, 72.6, 54.2, 42.0, 23.0. GC/MS m/z: 232 (M+, 17),
214 (100), 199 (36), 189 (12), 161 (11), 115 (13). HRMS (ESI-
+
TOF) m/z: [M−H2O + H]+ calcd for C14H15O2 , 215.1067; found,
215.1062.
2-[3-(4-Fluorophenyl)-3-hydroxybut-1-yn-1-yl]phenol (1j). Yield:
814.5 mg, starting from 1.0 g of 2-iodophenol (70%). White solid, mp
= 95−96 °C. IR (KBr) ν: 3336 (s, br), 3067 (m, br), 2240 (w), 1589
1
(m), 1455 (s), 1270 (m), 1089 (m), 751 (s) cm−1; H NMR (300
2-(3-Hydroxy-3-methylpent-1-yn-1-yl)-5-metoxyphenol (1d).
Yield: 500.3 mg, starting from 1.14 g of 5-metoxy-2-iodophenol
(50%). Yellow solid, mp = 105−107 °C. IR (KBr) ν: 3373 (s, br),
MHz, DMSO-d6): δ 10.0 (s, br, 1H), 7.60−7.35 (m, 3H), 7.30 (d, J =
7.6, 1H), 7.25−7.04 (m, 2H), 6.91 (d, J = 8.1, 1H), 6.80 (t, J = 7.4
1H), 6.30 (s, br, 1H), 1.71 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-
d6): δ 162.2 (d, J = 242.7), 158.3, 150.3 (d, J = 6.9), 132.7, 129.8,
121.4 (d, J = 2.8), 118.9, 115.3, 113.7 (d, J = 20.8), 112.0 (d, J =
22.9), 109.5, 96.7, 80.4, 68.2, 33.7. 19F{1H} NMR (471 MHz,
CDCl3): δ −112.7. HRMS (ESI-TOF) m/z: [M−H2O + H]+ calcd
for C16H12FO+, 239.0867; found, 239.0857.
1
3130 (s, br), 2223 (w), 1321 (m), 1260 (s), 1031 (m) cm−1. H
NMR (300 MHz, CDCl3): δ 7.19 (d, J = 8.5, 1H), 6.51 (d, J = 2.3,
1H), 6.42 (dd, J = 8.5, 2.3, 1H), 3.78 (s, 3H), 2.75 (s, br, 1H), 1.90−
1.72 (m, 2H), 1.60 (s, 3H), 1.10 (t, J = 7.4, 3H) (Note: one −OH
signal was too broad to be detected). 13C{1H} NMR (75 MHz,
CDCl3): δ 161.5, 158.2, 132.5, 107.1, 101.4, 100.3, 98.1, 78.0, 69.6,
55.4, 36.6, 29.4, 9.2. GC/MS m/z: 220 (M+, 31), 202 (100), 191
(60), 187 (80), 149 (18). HRMS (ESI-TOF) m/z: [M−H2O + H]+
Preparation of ILs. ILs 1-butyl-3-methylimidazolium chloride
(BmimCl),16 1-butyl-3-methylimidazolium hexafluorophosphate
(BmimPF6),16 1-butyl-3-methylimidazolium tetrafluoroborate
(BmimBF4),16 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEt-
SO4),17 and N-ethyl-N-methylmorpholinium dicyanamide [Mor1,2N-
(CN)2]17 were prepared according to literature procedures: the
+
calcd for C13H15O2 , 203.1067; found, 203.1066.
2-[(3-Hydroxy-3-cyclopentyl)ethynyl]phenol (1e). Yield: 736.1
mg, starting from 1.0 g of 2-iodophenol (68%). White solid, mp =
78−79 °C. IR (KBr) ν: 3333 (s, br), 2237 (vw), 1453 (m), 1056 (w),
1
structure and purity of all ILs were confirmed by H and 13C NMR
1
764 (s), 699 (s) cm−1. H NMR (300 MHz, CDCl3): δ 7.66 (d, J =
spectroscopy.
7.5, 2H), 7.43−7.17 (m, 5H), 6.93 (d, J = 8.2, 1H), 6.84 (t, J = 7.5,
1H), 6.60 (s, 1H), 3.48 (s, br, 1H), 1.86 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 157.0, 145.0, 132.0, 130.6, 128.5, 128.0, 124.9,
120.3, 115.3, 108.9, 99.0, 79.7, 70.7, 33.1. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C16H14O2Na+, 261.0886; found, 261.0879. The
spectroscopic data agreed with those reported.15
2-(3-Hydroxybut-1-yn-1-yl)phenol (1f). Yield: 515.3 mg, starting
from 1.0 g of 2-iodophenol (70%). White solid, mp = 73−74 °C. IR
(KBr) ν: 3372 (s, br), 2226 (w), 1485 (m), 1451 (s), 1289 (m), 1030
(m), 752 (s) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.27 (dd, J = 7.7,
1.5, 1H), 7.25−7.17 (m, 1H), 6.98−6.91 (m, 1H), 6.82 (td, J = 7.5,
1.1, 1H), 4.82 (q, J = 6.6, 1H), 2.17 (s, 1H), 1.56 (d, J = 6.6) (Note:
the phenolic −OH signal was too broad to be detected). 13C{1H}
NMR (75 MHz, CDCl3): δ 156.9, 131.9, 130.5, 120.2, 115.3, 109.0,
97.1, 79.0, 59.0, 24.3. GC/MS m/z: 162 (M+, 25), 144 (100), 115
(56), 91 (60). HRMS (ESI-TOF) m/z: [M−H2O + H]+ calcd for
C10H9O+, 145.0648; found, 145.0650.
General Procedure for the Cyclization of 2-(3-Hydroxy-1-
yn-1-yl)phenols 1a−h in MeCN under Oxidative Carbon-
ylation Conditions (Table 2). A 250 mL stainless-steel autoclave
was charged in the presence of air with PdI2 (1.9 mg, 5.3 × 10−3
mmol), KI (17.5 mg, 0.105 mmol), DIPEA (136 mg, 1.05 mmol), and
compounds 1 (0.53 mmol; 101.0 mg, 1a; 93.2 mg, 1b; 107.5, 1c;
117.2 mg, 1d; 126.6 mg, 1e; 86.2 mg, 1f; 101.0 mg, 1g) in 10.5 mL of
MeCN. The autoclave was pressurized with CO (6 atm) and air (up
to 30 atm). After stirring at 80 °C for 8−15 h (see Table 2), the
autoclave was cooled and degassed. The solvent was evaporated, and
the crude products purified by column chromatography on silica gel
(eluent: 99:1 to 9:1 hexane−ethyl acetate) to give pure
furobenzofurane derivatives 2 (78.2 mg, 68%, 2a; 64.6 mg, 60%,
2b; 89.7 mg, 74%, 2c; 78.6 mg, 60%, 2d; 80.0 mg, 57%, 2e; 72.5 mg,
63%, 2g) and benzofuran derivatives 3 (5.2 mg, 5%, 3a; 8.6 mg, 9%,
3b; 23.7 mg, 22%, 3c; 11.4 mg, 10%, 3d; 25.7 mg, 20%, 3e; 50.1 mg,
58%, 3f; 5.2 mg, 5%, 3g). The isolated yields obtained in each
experiment are given in Table 2.
2-(3-Hydroxy-4-methylpent-1-yn-1-yl)phenol (1g). Yield: 535.6
mg, starting from 1.0 g of 2-iodophenol (62%). Yellow solid, mp =
81−82 °C. IR (KBr) ν: 3381 (m, br), 3077 (m, br), 2223 (w), 1451
(s), 1385 (m), 1011 (s), 748 (s) cm−1. 1H NMR (300 MHz, CDCl3):
δ 7.30 (dd, J = 7.8, 1.8, 1H), 7.27−7.18 (m, 2H), 6.96 (dd, J = 8.3,
1.0, 1H), 6.84 (td, J = 7.5, 1.0, 1H), 4.47 (d, J = 5.6, 1H), 2.08−1.92
(m, 1H), 1.08 (d, J = 6.8, 3H), 1.05 (d, J = 6.8, 3H). 13C{1H} NMR
(75 MHz, CDCl3): δ 157.0, 131.9, 130.4, 120.2, 115.2, 109.1, 95.1,
80.5, 68.6, 34.6, 18.2, 17.6. GC/MS m/z: 190 (M+, 9), 172 (20), 147
(45), 91 (100). The spectroscopic data agreed with those reported.7
2-[(1-Hydroxycyclohexyl)ethynyl]phenol (1h). Yield: 589.3 mg,
starting from 1.0 g of 2-iodophenol (60%). Yellow solid, mp = 114−
116 °C. IR (KBr) ν: 3485 (m, br), 3330 (m, br), 3149 (m, br), 2219
3-Ethyl-3-methylfuro[3,4-b]benzofuran-1(3H)-one (2a). Yield:
78.2 mg, starting from 101.0 mg of 2-(3-hydroxy-3-methylpent-1-
yn-1-yl)phenol (68%). Yellow solid, mp = 40−41.0 °C. IR (KBr) ν:
1773 (s), 1616 (m), 1443 (m), 1155 (m), 1083 (m), 942 (m), 877
1
(m), 752 (m) cm−1; H NMR (300 MHz, CDCl3): δ 7.86−7.77 (m,
1H), 7.63−7.54 (m, 1H), 7.46−7.35 (m, 2H), 2.08 (q, J = 7.4, 2H),
1.74 (s, 3H), 0.93 (t, J = 7.4, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 182.1, 163.7, 161.6, 125.7, 125.0, 121.21, 121.15, 112.7, 112.2, 84.2,
31.1, 23.4, 8.1. GC/MS m/z: 216 (M+, 28), 201 (7), 187 (100), 173
(49), 145 (47). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
+
C13H13O3 , 217.0859; found, 217.0861.
3,3-Dimethylfuro[3,4-b]benzofuran-1(3H)-one (2b). Yield: 64.6
mg, starting from 93.2 mg of 2-(3-hydroxy-3-methylbut-1-yn-1-
yl)phenol (60%). Colorless solid, mp = 59−60 °C. IR (KBr) ν:
1
(w), 1489 (m), 1453 (s), 1055 (m), 752 (s) cm−1. H NMR (300
MHz, CDCl3): δ 7.29 (dd, J = 7.7, 1.6, 1H), 7.24−7.17 (m, 1H), 6.95
(dd, J = 8.3, 0.6, 1H), 6.89−6.79 (m, 2H), 3.49 (s, br, 1H), 2.12−1.97
1
1760 (s), 1626 (m), 1161 (m), 1080 (m), 761 (m) cm−1; H NMR
F
DOI: 10.1021/acs.joc.9b00952
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(300 MHz, CDCl3): δ 7.84−7.76 (m, 1H), 7.61−7.54 (m, 1H),
7.44−7.36 (m, 2H), 1.77 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3):
δ 182.9, 163.4, 161.5, 125.8, 125.1, 121.3, 121.2, 112.7, 111.2, 81.1,
25.1. GC/MS m/z: 202 (M+, 44), 187 (69), 159 (100), 145 (49).
7.53−7.46 (m, 1H), 7.45−7.39 (m, 1H), 7.27−7.14 (m, 2H), 6.57 (d,
J = 0.8, 1H), 2.32 (s, br, 1H), 2.23−2.06 (m, 2H), 2.05−1.83 (m,
4H), 1.83−1.72 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 162.0,
154.8, 128.4, 123.8, 122.6, 120.8, 111.1, 101.0, 79.9, 39.8, 23.7. GC/
MS m/z: 202 (M+, 80), 185 (63), 173 (100), 160 (49), 145 (52), 131
(39). The spectroscopic data agreed with those reported.20
+
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H11O3 , 203.0703;
found, 203.0706.
1′H-Spiro[cyclopentane-1,3′-furo[3,4-b]benzofuran]-1′-one (2c).
Yield: 89.7 mg, starting from 107.5 mg of 2-[(1-hydroxycyclopentyl)-
ethynyl]phenol (74%). Yellow solid, mp = 53−55 °C. IR (KBr) ν:
2-(6-Methoxybenzofuran-2-yl)butan-2-ol (3d). Yield: 11.4 mg,
starting from 117.2 mg of 2-(3-hydroxy-3-methylpent-1-yn-1-yl)-5-
metoxyphenol (10%). Yellow oil. IR (film) ν: 3430 (m, br), 1618
(m), 1441 (m), 1294 (m), 1147 (m), 824 (m) cm−1. 1H NMR (300
MHz, CDCl3): δ 7.39 (d, J = 8.5, 1H), 7.01 (d, J = 1.9, 1H), 6.85 (dd,
J = 8.5, 2.3, 1H), 6.51 (s, br, 1H), 3.84 (s, 3H), 2.09 (s, br, 1H), 1.95
(q, J = 7.4, 2H), 1.60 (s, 3H), 0.88 (t, J = 7.4, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ 161.3, 157.7, 155.6, 121.5, 120.9, 111.6, 101.3,
96.0, 72.3, 55.7, 34.2, 26.1, 8.5; GC/MS m/z: 220 (M+, 21), 202 (73),
191 (100), 187 (72), 175 (7). HRMS (ESI-TOF) m/z: [M−H2O +
1
1768 (s), 1443 (m), 1085 (m), 952 (m), 756 (m) cm−1. H NMR
(300 MHz, CDCl3): δ 7.85−7.74 (m, 1H), 7.63−7.51 (m, 1H),
7.45−7.33 (m, 2H), 2.37−1.87 (m, 8H). 13C{1H} NMR (75 MHz,
CDCl3): δ 180.8, 163.7, 161.7, 125.7, 125.0, 121.4, 121.1, 112.7,
112.0, 90.5, 36.9, 24.8. GC/MS m/z: 228 (M+, 100), 200 (89), 171
(79), 159 (48), 144 (83), 115 (25). HRMS (ESI-TOF) m/z: [M +
+
H]+ calcd for C14H13O3 , 229.0859; found, 229.0866.
+
3-Ethyl-6-methoxy-3-methylfuro[3,4-b]benzofuran-1(3H)-one
(2d). Yield: 78.6 mg, starting from 117.2 mg of 2-(3-hydroxy-3-
methylpent-1-yn-1-yl)-5-metoxyphenol (60%). Yellow solid, mp =
73−75 °C. IR (KBr) ν: 1777 (s), 1499 (w), 1401 (m), 1080 (m),
H]+ calcd for C13H15O2 , 203.1067; found, 203.1072.
1-(Benzofuran-2-yl)-1-phenylethan-1-ol (3e). Yield: 25.7 g,
starting from 126.6 mg of 2-[(3-hydroxy-3-cyclopentyl)ethynyl]-
phenol (20%). Yellow oil. IR (film) ν: 3409 (m, br), 1453 (s), 1372
1
1058 (m) cm−1. H NMR (300 MHz, CDCl3): δ 7.67 (d, J = 8.6,
1
(w), 1251 (m), 1066 (w), 751 (m), 700 (m) cm−1. H NMR (300
1H), 7.10 (d, J = 2.2, 1H), 7.00 (dd, J = 8.6, 2.2, 1H), 3.88 (s, 3H),
2.06 (q, J = 7.5, 2H), 1.72 (s, 3H), 0.92 (t, J = 7.5, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 181.2, 163.9, 162.6, 158.6, 121.2, 114.3,
113.1, 112.2, 97.9, 84.2, 55.8, 31.2, 23.4, 8.1. GC/MS m/z: 246 (M+,
52), 217 (100), 203 (74), 175 (36), 119 (17). HRMS (ESI-TOF) m/
MHz, CDCl3): δ 7.57−7.52 (m, 1H), 7.50−7.44 (m, 2H), 7.44−7.17
(m, 6H), 6.64 (d, J = 0.9, 1H), 2.71 (s, br, 1H), 1.97 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 161.4, 154.9, 145.1, 128.3, 128.1, 127.6,
125.3, 124.3, 122.9, 121.2, 111.4, 103.0, 73.4, 29.1. GC/MS m/z: 238
(M+, 33), 223 (100), 195 (21), 145 (39). HRMS (ESI-TOF) m/z:
[M−H2O + H]+ calcd for C16H13O+, 221.0961; found, 221.0965.
1-(Benzofuran-2-yl)-1-phenylethan-1-ol (3f). Yield: 50.1 mg,
starting from 86.2 mg of 2-(3-hydroxybut-1-yn-1-yl)phenol (58%).
Yellow oil. IR (film) ν: 3375 (m, br), 1454 (s), 1254 (s), 1076 (m),
+
z: [M + H]+ calcd for C14H15O4 , 247.0965; found, 247.0958.
3-Methyl-3-phenylfuro[3,4-b]benzofuran-1(3H)-one (2e). Yield:
80.0 mg, starting from 126.6 mg of 2-[(3-hydroxy-3-cyclopentyl)-
ethynyl]phenol (57%). Yellow solid, mp = 78−79.0 °C. IR (KBr) ν:
1
1779 (s), 1613 (w), 1440 (m), 749 (m), 700 (m) cm−1. H NMR
1
806 (m), 752 (s) cm−1. H NMR (300 MHz, CDCl3): δ 7.56−7.50
(300 MHz, CDCl3): δ 7.84−7.78 (m, 1H), 7.64−7.56 (m, 3H),
7.44−7.31 (m, 5H), 2.07 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3):
δ 181.5, 163.2, 161.8, 138.1, 128.9, 128.8, 126.0, 125.2, 124.9, 121.3,
121.1, 112.8, 111.3, 83.9, 26.8. GC/MS m/z: 264 (M+, 17), 249 (38),
221 (100), 159 (17). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
(m, 1H), 7.48−7.42 (m, 1H), 7.30−7.17 (m, 2H), 6.60 (t, J = 0.9,
1H), 5.01 (qd, J = 6.6, 0.6, 1H), 2.22 (s, br, 1H), 1.63 (d, J = 6.6, 3H).
13C{1H} NMR (75 MHz, CDCl3): δ 160.2, 154.8, 128.1, 124.2, 122.8,
121.1, 111.2, 101.8, 64.2, 21.4. GC/MS m/z: 162 (M+, 38), 147
(100), 103 (17), 91 (82). The spectroscopic data agreed with those
reported.21
+
C17H13O3 , 265.0859; found, 265.0862.
3-Isopropylfuro[3,4-b]benzofuran-1(3H)-one (2g). Yield: 72.5
mg, starting from 101.0 mg of 2-(3-hydroxy-4-methylpent-1-yn-1-
yl)phenol (63%). Yellow solid, mp = 71.0−73 °C. IR (KBr) ν: 1765
1-(Benzofuran-2-yl)-2-methylpropan-1-ol (3g). Yield: 5.2 mg,
starting from 101.0 mg of 2-(3-hydroxy-4-methylpent-1-yn-1-yl)-
phenol (5%). Yellow oil. IR (film) ν: 3390 (m, br), 1455 (s), 1254
1
(s), 1606 (w), 1281 (m), 954 (m), 765 (m) cm−1. H NMR (300
1
(m), 1015 (m), 742 (m) cm−1. H NMR (300 MHz, CDCl3): δ
MHz, CDCl3): δ 7.86−7.78 (m, 1H), 7.63−7.55 (m, 1H), 7.46−7.36
(m, 2H), 5.24 (d, J = 6.8, 1H), 2.30 (octuplet, J = 6.8, 1H), 1.12 (d, J
= 6.8, 3H), 1.09 (d, J = 6.8, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
179.1, 164.3, 161.8, 125.9, 125.1, 121.2, 121.0, 113.6, 112.7, 81.6,
31.5, 17.5, 17.2. GC/MS m/z: 216 (M+, 26), 187 (26), 173 (100),
145 (20). The spectroscopic data agreed with those reported.7
2-(Benzofuran-2-yl)butan-2-ol (3a). Yield: 5.2 mg, starting from
101.0 mg of 2-(3-hydroxy-3-methylpent-1-yn-1-yl)phenol (5%).
Yellow oil. IR (film) ν: 3416 (m, br), 1455 (s), 1374 (w), 1249
(m), 1143 (m), 752 (s) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.54−
7.48 (m, 1H), 7.46−7.40 (m, 1H), 7.27−7.15 (m, 2H), 6.56 (d, J =
0.9, 1H), 2.37 (s, br, 1H), 1.94 (q, J = 7.5, 2H), 1.59 (s, 3H), 0.86 (t, J
= 7.5, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 162.4, 154.7, 128.3,
123.8, 122.7, 120.9, 111.1, 101.5, 72.3, 34.2, 26.2, 8.4. GC/MS m/z:
190 (18), 175 (8), 161 (100), 145 (6). The spectroscopic data agreed
with those reported.18
2-(Benzofuran-2-yl)propan-2-ol (3b). Yield: 8.6 mg, starting from
93.2 mg of 2-(3-hydroxy-3-methylbut-1-yn-1-yl)phenol (9%). Yellow
oil. IR (film) ν: 3389 (m, br), 1454 (m), 1253 (s), 1166 (m), 751 (s)
cm−1; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J = 7.1, 1H), 7.44 (d, J
= 7.8, 1H), 7.32−7.12 (m, 2H), 6.55 (s, br, 1H), 2.34 (s, br, 1H), 1.66
(s, 6H). 13C{1H} NMR (75 MHz, CDCl3): δ 163.1, 154.7, 128.3,
124.0, 122.7, 121.0, 111.2, 100.3, 69.3, 28.7. GC/MS m/z: 176 (M+,
50), 161 (100), 133 (10), 115 (9). The spectroscopic data agreed
with those reported.19
7.56−7.49 (m, 1H), 7.44 (d, J = 7.9, 1H), 7.30−7.15 (m, 2H), 6.60
(s, 1H), 4.52 (d, J = 6.6, 1H), 2.30−2.13 (m, 2H), 1.04 (d, J = 6.7,
3H), 0.92 (d, J = 6.7, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
158.9, 154.7, 128.1, 123.9, 122.7, 120.9, 111.2, 103.3, 73.8, 33.2, 18.8,
17.9. GC/MS m/z: 190 (M+, 29), 147 (100), 91 (49). HRMS (ESI-
TOF) m/z: [M−H2O + H]+ calcd for C12H13O+, 173.0961; found,
173.0958.
General Procedure for the Carbonylative Double Cycliza-
tion of 2-(3-Hydroxy-1-yn-1-yl)phenols 1a−e, 1g−1j in
BmimBF4 (Table 4). A 250 mL stainless-steel autoclave was charged
in the presence of air with PdI2 (1.9 mg, 5.3 × 10−3 mmol), KI (17.5
mg, 0.105 mmol), DIPEA (130 mg, 1.01 mmol), and compounds 1
(0.53 mmol; 100.8 mg, 1a; 93.6 mg, 1b; 107.9, 1c; 117.0 mg, 1d;
126.8 mg, 1e; 101.3 mg, 1g; 115.0 mg, 1h; 123.5 mg, 1i; 136.5 mg,
1j). BmimBF4 (10.5 mL) was then added, and the autoclave was
pressurized with CO (6 atm) and air (up to 30 atm). After stirring at
80 °C for 24 h, the autoclave was cooled and degassed. The mixture
was then extracted with Et2O (6 × 10 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 and the product purified by column chromatography
on silica gel to give pure furobenzofurane derivatives 2 (eluent: 99:1
to 9:1 hexane−AcOEt; 92.1 mg, 80%, 2a; 80.8 mg, 75%, 2b; 105.6
mg, 87%, 2c; 102.9 mg, 79%, 2d; 113.2 mg, 81%, 2e; 93.1 mg, 81%,
2g; 106.9 mg, 83%, 2h; 117.5 mg, 86%, 2i; 111, 0 mg, 74%, 2j). The
isolated yields obtained in each experiment are given in Table 4.
Recycling Procedure. After removal of Et2O under vacuum, the
residue obtained as described above, still containing the catalyst
dissolved in the IL, was transferred into the autoclave. Compounds 1
1-(Benzofuran-2-yl)cyclopentan-1-ol (3c). Yield: 23.7 mg, starting
from 107.5 mg of 2-[(1-hydroxycyclopentyl)ethynyl]phenol (22%).
Yellow solid, mp = 52−54 °C. IR (KBr) ν: 3278 (m, br), 1454 (m),
1255 (m), 1064 (w), 807 (m) cm−1; 1H NMR (300 MHz, CDCl3): δ
G
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The Journal of Organic Chemistry
Article
(0.53 mmol) and DIPEA (130 mg, 1.00) were added, and then the
same procedure described above was followed.
Notes
The authors declare no competing financial interest.
Carbonylative Double Cyclization of 2-(3-Hydroxy-3-meth-
ylpent-1-yn-1-yl)phenol 1a on a Larger Scale (Table 3, entry
8). A 250 mL stainless-steel autoclave was charged in the presence of
air with PdI2 (9.0 mg, 0.025 mmol), KI (83.0 mg, 0.50 mmol), DIPEA
(645.0 mg, 4.99 mmol), and 2-(3-hydroxy-3-methylpent-1-yn-1-
yl)phenol 1a (475.1 mg, 2.50 mmol). BmimBF4 (50 mL) was then
added, and the autoclave was pressurized with CO (6 atm) and air
(up to 30 atm). After stirring at 80 °C for 24 h, the autoclave was
cooled and degassed. The mixture was then extracted with Et2O (6 ×
30 mL), the collected ethereal phases were concentrated and the
product purified by column chromatography on silica gel (eluent:
99:1 to 9:1 hexane−AcOEt) to give pure 3-ethyl-3-methylfuro[3,4-
b]benzofuran-1(3H)-one (2a) (403 mg, 75%).
DEDICATION
■
Dedicated to the memory of Professor Cinzia Chiappe.
REFERENCES
■
(1) For recent reviews on Pd-catalyzed double cyclization processes,
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1′H-Spiro[cyclohexane-1,3′-furo[3,4-b]benzofuran]-1′-one (2h).
Yield: 106.9 mg, starting from 115.0 mg of 2-[(1-Hydroxycyclohexyl)-
ethynyl]phenol (83%). Yellow solid, mp = 61−63 °C. IR (KBr) ν:
1
1768 (s), 1441 (m), 1148 (m), 927 (m), 755 (m) cm−1. H NMR
(300 MHz, CDCl3): δ 7.89−7.76 (m, 1H), 7.63−7.54 (m, 1H),
7.46−7.34 (m, 2H), 2.05−1.76 (m, 8H), 1.70−1.54 (m, 2H).
13C{1H} NMR (75 MHz, CDCl3): δ 183.4, 163.7, 161.3, 125.7, 125.0,
121.1, 112.7, 111.2, 83.5, 34.6, 24.4, 22.4. GC/MS m/z: 242 (M+,
99), 214 (46), 199 (36), 171 (100), 147 (60). The spectroscopic data
agreed with those reported.7
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Advances in Transition-Metal Mediated Heterocyclic Synthesis; Sole, D.,
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Fernandez, I., Eds.; Academic Press-Elsevier: London, UK, 2018;
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A Personal Account. Targets Heterocycl. Syst. 2019, 22, 41−55.
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Top. Organomet. Chem. 2006, 18, 239−272. (c) Gabriele, B.; Salerno,
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(4) (a) Gabriele, B.; Chimento, A.; Mancuso, R.; Pezzi, V.; Ziccarelli,
I.; Sirianni, R. 6,6a-Dihydrofuro[3,2-b]furan-2-(5H)one derivatives,
their preparation and use for treating tumors. Eur. Pat. Appl.
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Catalytic Double Cyclization Process for Antitumor Agents against
Breast Cancer Cell Lines. iScience 2018, 3, 279−288.
6′-Methoxy-1′H-spiro[cyclopentane-1,3′-furo[3,4-b]-
benzofuran]-1′-one (2i). Yield: 117.5 mg, starting from 123.5 mg of
2-[(1-hydroxycyclopentyl)ethynyl]-5-methoxyphenol (86%). Yellow
solid, mp = 103−104 °C. IR (KBr) ν: 1767 (s), 1497 (m), 1273 (w),
1
1080 (m), 953 (m), 756 (s) cm−1; H NMR (300 MHz, CDCl3): δ
7.64 (d, J = 8.6, 1H), 7.10 (d, J = 2.2, 1H), 6.98 (dd, J = 8.6, 2.2, 1H),
3.88 (s, 3H), 2.38−1.85 (m, 8H); 13C NMR (75 MHz, CDCl3): δ
179.8, 163.9, 162.7, 158.6, 121.0, 114.5, 113.0, 111.9, 97.9, 90.5, 55.9,
36.9, 24.7; GC/MS m/z: 258 (M+, 78), 230 (24), 214 (27), 201 (25),
189 (100), 174 (48). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
+
C15H15O4 , 259.0965; found, 259.0959.
3-(4-Fluorophenyl)-3-methylfuro[3,4-b]benzofuran]-1(3H)-one
(2j). Yield: 111.0 mg, starting from 136.5 mg of 2-[3-(4-
fluorophenyl)-3-hydroxybut-1-yn-1-yl]phenol (74%). Yellow solid,
mp = 75−77 °C. IR (KBr) ν: 1771 (s), 1443 (m), 1266 (m), 1150
1
(m), 945 (m) cm−1. H NMR (300 MHz, CDCl3): δ 7.85−7.77 (m,
1H), 7.66−7.57 (m, 1H), 7.47−7.30 (m, 5H), 7.11−6.99 (m, 1H),
2.07 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 180.9, 162.9 (d, J =
248.0), 162.8, 161.8, 140.6 (d, J = 7.4), 130.6 (d, J = 8.3), 126.2,
125.3, 121.4, 121.0, 120.6 (d, J = 3.3), 115.8 (d, J = 21.1), 112.9,
112.4 (d, J = 23.6), 111.4, 83.1, 26.8. 19F{1H} NMR (471 MHz,
CDCl3): −111.6. GC/MS m/z: 282 (M+, 28), 267 (43), 239 (100),
183 (14), 159 (30). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
(5) Acerbi, A.; Carfagna, C.; Costa, M.; Mancuso, R.; Gabriele, B.;
Della Ca’, N. An Unprecedented Pd-Catalyzed Carbonylative Route
to Fused Furo[3,4-b ]indol-1-ones. Chem.Eur. J. 2018, 24, 4835−
4840.
+
C17H12FO3 , 283.0765; found, 283.0770.
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I. R. [BmIm]OH catalyzed coupling: Green and efficient synthesis of
2,8 dioxacyclopenta [a] inden-3-one derivatives in an aqua media.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00952.
■
S
(7) Hu, Y.; Yang, Z. Palladium-Mediated Intramolecular Carbon-
ylative Annulation of o-Alkynylphenols To Synthesize Benzo[b]furo-
[3,4-d]furan-1-ones. Org. Lett. 2001, 3, 1387−1390.
Copies of HRMS spectra for all news compounds, and
copies of 1H NMR, 13C{1H} NMR, and 19F NMR
spectra for all compounds (PDF)
(8) As we have already observed in many other PdI2/KI-catalyzed
carbonylation processes,3 the use of KI, besides favoring PdI2
solubilization, can be beneficial, since it may stabilize the intermediate
organometallic complexes leading to the final carbonylated product.
(9) (a) Jung, M. E.; Piizzi, G. gem-Disubstituent effect: Theoretical
basis and synthetic applications. Chem. Rev. 2005, 105, 1735−1766.
(b) Sammes, P. G.; Weller, D. J. Steric promotion of ring formation.
Synthesis 1995, 10, 1205−1222.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: raffaella.mancuso@unical.it (R.M.).
*E-mail: bartolo.gabriele@unical.it (B.G.).
■
(10) Interestingly, the same phenomenon was not observed in the
conversion of 2-(hydroxypropyn-1-yl)anilines into fused furo[3,4-b]
indol-1-ones, recently reported by our research group, where the
carbonylative double cyclization also took place with substrates
bearing a primary or a secondary alcoholic function.5 However, the
substrates used in the present work have a different reactivity with
ORCID
Raffaella Mancuso: 0000-0001-7514-6096
Diego Olivieri: 0000-0001-9411-4487
Nicola Della Ca’: 0000-0002-7853-7954
Bartolo Gabriele: 0000-0003-4582-1489
H
DOI: 10.1021/acs.joc.9b00952
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
respect to 2-(hydroxypropyn-1-yl)anilines; in fact, they need to be
deprotonated in situ by the DIPEA base to give a more nucleophilic
phenate intermediate before cyclization may occur (Scheme 1 and
Table 1, entry 1). This makes them particularly prone to undergo Pd-
catalyzed simple cycloisomerization, which leads to undesired
byproducts 3 (Scheme 1, path b). Accordingly, in the absence of
some effect promoting the carbonylative cyclization step (Scheme 1,
path a), such as the reactive rotamer effect exerted by double
substitution α to the hydroxyl (or monosubstitution with a bulky
group), the cycloisomerization pathway tends to be faster with respect
to carbonylative double cyclization, and benzofurans 3 are formed
preferentially, as observed for 1f (Table 2, entry 6).
(11) For recent books, see: (a) Sustainable Catalysis in Ionic Liquids;
Lozano, P., Ed.; CRC Press: Roca Baton, FL, 2018. (b) Ionic Liquids
́
(ILs) in Organometallic Catalysis; Dupont, J., Kollar, L., Eds.; Springer:
Berlin, Germany, 2015. (c) Catalysis in Ionic Liquids: From Catalyst
Synthesis to Application; Hardacre, C., Parvulescu, V., Eds.; Royal
Society of Chemistry: Cambridge, UK, 2014.
(12) The study of the effect of the nature of the IL on the reaction
outcome, which would require extensive additional investigation, was
outside the scope of the present work.
(13) As in the case of the reaction carried out in MeCN (Table 2,
entries 6 and 7), no carbonylation took place with substrate 1f,
substituted in α with a simple methyl group.
(14) Alberola, A.; Calvo, B.; Ortega, A. G. l.; Pedrosa, R. Reaction of
4-chlorocoumarin with organometallic reagents. Synthesis of
Trialkylbenzopyrans, 4-Chlorobenzopyrans, 4-Alkylcoumarins and o-
Hydroxyphenylprop-2-ynyl Alcohols. J. Chem. Soc., Perkin Trans. 1
1992, 3075−3080.
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(19) Zhou, R.; Wang, W.; Jiang, Z.-j.; Wang, K.; Zheng, X.-l.; Fu, H.-
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DOI: 10.1021/acs.joc.9b00952
J. Org. Chem. XXXX, XXX, XXX−XXX