TBAF-Catalyzed Cyclization Reactions of o-(Alkynyl)phenyl Propargyl Alcohols with Malonate Esters: A Possible Cation–π Interaction as The Activation Approach

Article abstract of DOI:10.1002/ejoc.201901790

An efficient method has been devised for the synthesis of dihydroisobenzofuran derivatives through the reaction of in situ generated ynones with potentially C-nucleophilic malonate esters. All the products are capable to be prepared by applying the tandem

Full text of DOI:10.1002/ejoc.201901790

A Journal of
Accepted Article
Title: TBAF-Catalyzed Cyclization Reactions of o-(Alkynyl)phenyl
Propargyl Alcohols with Malonate Esters: A Possible Cation-π
Interaction as The Activation Approach
Authors: Yulei Zhao, Xuqiang Guo, Zongkang Wang, Duyi Shen,
Tingting Chen, Nan Wu, Shina Yan, and Jinmao You
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901790
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10.1002/ejoc.201901790
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TBAF-Catalyzed Cyclization Reactions of o-(Alkynyl)phenyl
Propargyl Alcohols with Malonate Esters: A Possible Cation-π
Interaction as The Activation Approach
Yulei Zhao,*[a] Xuqiang Guo,[a] Zongkang Wang,[a] Duyi Shen,*[a] Tingting Chen,[a] Nan Wu,[a] Shina
Yan,[a] and Jinmao You[a,b]
Dedication ((optional))
Abstract: An efficient method has been devised for the synthesis of
dihydroisobenzofuran derivatives through the reaction of in situ
generated ynones with potentially C-nucleophilic malonate esters. All
of the products are capable to be prepared by applying the tandem
strategy at room temperature. The reaction was realized through a
combination of the pivotal TBAF-catalyzed conjugate addition and
selective O-nucleophilic cyclization. As revealed by the control
experiments, both the basicity of fluoride anion and ammonium
cation-π interaction with alkyne unit might play crucial roles in the
cyclization reaction.
characteristics of ammonium cation-π interaction with alkyne,
experimental exploration remains limited.
Introduction
Tetrabutylammonium fluoride (TBAF), known as a soluble
source of fluoride,[1] has been widely applied as fluorinated
reagent,[2] reagent for the cleavage of silyl ethers,[3] basic
catalyst,[4] etc.[5-7] The application of TBAF is primarily dependent
on the effect of fluoride anion. However, due to its noticeable
catalytic activity for the cyclization of alkyne, the effect of
tetraalkylammonium ion has recently drawn increasing attention
for research.[8] In 2011, Lepore et al. reported a unique
cyclization of β-alkynyl hydrazines to synthesize azaproline
derivatives, which was mediated by nonmetal ammonium cation
catalysts.[8b] Subsequently, they came up with the direct
Scheme 1. Construction of dihydroisobenzofuran structures.
Dihydroisobenzofuran is key structural subunit and widely
present in a variety of different biologically active structures.[11]
Despite advances, the synthetic routes to dihydroisobenzofuran
derivatives are primarily concentrated on high temperatures[12] or
precious metal-catalyzed[13] approaches (Scheme 1a and 1b). It
remains essential to explore new convenient procedures to
synthesize dihydroisobenzofuran derivatives using accessible
starting materials and low-cost catalyst under mild conditions.
evidence for ammonium cation-π interaction with
a non-
conjugated alkyne by Raman spectroscopy.[8a] As demonstrated
by their study on the homogeneous systems, the ammonium
agent is conducive to the formation of nitrogen-carbon bond[8b]
(cyclization process) through a cation-π interaction with the
alkyne unit.[8a] In 2017, Lepore’s group further developed a
TBAF-catalyzed approach to the synthesis of isoxazolines and
pyrazolines through the cyclization of alkyne substrates.[8c]
Enaminone, exhibiting high N-[14], C-[15] and O-nucleophilicity[16]
,
shows a wide range of synthetic applications[17]. Based on our
research on tandem reactions,[18] a bifunctional TBAF catalyzed
selective O-nucleophilic cyclization of enaminone was reported
recently for the synthesis of dihydroisobenzofuran derivatives
(Scheme 1c),[19] wherein a cation-π interaction as the activated
process might be necessitated. In this intramolecular
isomerization reaction, the nitrogen atom of enaminone acts as
an electron-donor to initiate the nucleophilic cyclization to
intramolecular alkyne moiety. Accordingly, it is speculated that
an appropriate independent C-nucleophile is also suited to the
construction of dihydroisobenzofuran derivatives. Herein, the
intermolecular cyclization reaction of o-(alkynyl)phenyl propargyl
alcohols with potentially C-nucleophilic malonate esters is
Although cation-π interaction is known as
a
sort of
intermolecular force,[9] this cation binding force was
demonstrated more in aromatic systems.[10] For the
[a]
[b]
Dr. Y. Zhao, X. Guo, Z. Wang, Dr. D. Shen, T. Chen, N. Wu, S. Yan,
Prof. Dr. J. You. School of Chemistry and Chemical Engineering,
Qufu Normal University, Qufu, 273165, China
E-mail: zhaoyulei86@126.com
shendy@qfnu.edu.cn
Prof. Dr. J. You, Northwest Institute of Plateau Biology, Chinese
Academy of Science, Xining, 810001, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901790
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developed to construct dihydroisobenzofurans through
possible ammonium cation-π interaction process (Scheme 1d).
a
detected (entry 17), which suggested that TBAF was requisite
for the cyclization process to take place. In addition, it is worth
noting that the slight [4+2] cycloaddition as the side reaction
exists in most investigations catalyzed by TBAF. X-ray
crystallography was performed to confirm the structure of 3a.[22]
Table 1. Optimization of the reaction conditions[a]
Results and Discussion
Our initial efforts focused on the reaction of o-(alkynyl)phenyl
propargyl alcohol[20] 1a and diethyl malonate 2a using 2-
Iodoxybenzoic acid (IBX) as the oxidant and TBAF as the
subsequent catalyst (Scheme 2). Nevertheless, it was inevitable
for all the attempts to partly result in intramolecular [4+2]
cycloaddition[21]. Acidic IBX has a potential to promote the
occurrence of this side reaction. In order to inhibit the undesired
cycloaddition, pyridinium dichromate (PDC) was taken as the
oxidant. To our delight, when PDC was employed, only an
extremely small amount of [4+2] cycloaddition was detected as
the oxidation process proceeded. This result encouraged us to
optimize the reaction conditions with 1a and 2a as model
substrates (Table 1).
Scheme 2. Initial exploration with IBX as oxidant.
Firstly, a variety of different catalysts were examined for the
subsequent addition-cyclization process (Table 1, entries 1-9).
When the reaction occurred in the presence of 2.0 equiv of
TBAF as the catalyst at room temperature, the desired product
3a was obtained in 91% yield within 2 hours (entry 1).
Nevertheless, other quaternary ammonium salt represented by
tetrabutylammonium bromide (TBAB), tetrabutylammonium
chloride (TBAC) and tetrabutylammonium iodide (TBAI) were
identified as ineffective for the formation of 3a (entries 2-4). As
demonstrated by these results (entry 1 vs entries 2-4), the
basicity offered by fluoride anion may play a significant role.
Based on this discovery, the alkaline Bu4NOH was employed,
and 3a was obtained in 64% yield (entry 5). When TBAF·3H2O
was taken as the catalyst, 88% yield could be achieved within 2
hours (entry 6). Despite the investigation conducted into other
common Brønsted base (such as, sodium carbonate,
triethylamine or potassium hydroxide), no significant catalytic
activity was observed for the cyclization process (entries 7-9).
Secondly, different varieties of solvents (such as, ethyl acetate,
dichloromethane, toluene and acetonitrile) were screened, only
resulting in 78-84% yields for the desired dihydroisobenzofuran
(entries 10-13). Finally, the optimization usage of reagents was
scheduled. When the amount of TBAF declined from 2.0 equiv
to 0.5 equiv, the yield of 3a was found to be slightly up-regulated
to 91% (entry 14). When the amount of 2a was reduced to 1.2
equiv from 2.0 equiv, 91% yield could also be achieved (entry
15). Further reduce the dosage of TBAF to 0.2 equiv led to a
slightly raised yield (entry 16, 92%). Without TBAF, no 3a was
With the optimal reaction conditions established (Table 1, entry
16), the scope and generality of this methodology was then
explored (Table 2). Firstly, an investigation was conducted into
the effect of different malonate esters. It was discovered that
dimethyl malonate or dibenzyl malonate substrates underwent
the reaction smoothly to afford 3b and 3c in 87% and 74% yield,
respectively. When sterically-hindered diisopropyl malonate was
involved in for the reaction, the corresponding product 3d could
also be derived in 65% yield as well. Next, the electronic effect
of R2 substituents was closely examined. The substrates with
electron-withdrawing (e.g., 3e, R2 = 6-F, 93%) or electron-
donating (e.g., 3f, R2 = 5,6-dimethoxy, 94%) groups were all
tolerable to furnish the corresponding products in excellent
yields. Then, the electronic effect of R3 was explored. Substrates
with both p-ClPh and p-OMePh groups were suitable for the
reaction, thus offering the desired isobenzofuran diesters in
moderate to good yields (3g, 72%; 3h, 66%). When R3 was 2-
naphthyl group, the corresponding 3i was formed in 90% yield.
n-Butyl also exhibited an excellent compatibility, thus offering the
corresponding product 3j in 94% yields. For R4, the p-ClPh, p-
OMePh, and 2-naphthyl were all well tolerated, furnishing 3k-3n
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10.1002/ejoc.201901790
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in 70-86% yields. However, alkyl-substituted (R4 = n-butyl)
propargyl alcohol failed to give the desired product. Additionally,
trimethylsilyl (R4) was compatible to generate the corresponding
terminal olefin 3o in 81% yield (In this reaction, 1.5 equiv of
TBAF·3H2O was taken both as the catalyst and as the reagent
for the cleavage of C-Si bond).
Scheme 4. Gram-Scale Preparation.
Table 2. The scope of the reaction.[a]
In order for deepened understanding as to the reaction
mechanism, a series of control experiments were conducted
using propargyl alcohol 1a and diethyl malonate 2a (Table 3).
Under the standard reaction conditions, 3a was obtained in 91%
yield (entry 1). Nevertheless, no further O-nucleophilic
cyclization reaction occurred only with TBAC as the sole catalyst
(entry 2), indicating that fluoride anion was vital for the onset of
the cyclization reaction (entry 2 vs 1). It is noteworthy that an
excessively long reaction time could result in slightly undesired
intramolecular [4+2] cycloaddition from ynone 1a' (Scheme 2).
When the reaction was carried out with NaF (0.5 equiv) as the
base, intermediate 1a' was isolated in 84% yield but no 3a was
detected (entry 3). It was initially suspected that the failure of
NaF could be attributable to its poor solubility in THF. In order to
improve the solubility of sodium salt, 15-crown-5 was introduced.
However, no desired O-nucleophilic cyclization reaction was
observed to take place in the presence of 15-crown-5 (0.5 eq.)
and NaF (0.5 eq.) (entry 4), which implied that the ammonium
salt not only played a single role in phase transfer catalysis, but
also promoted an additional catalytic activity for subsequent
cyclization process (entry 4 vs 1). To further validate our
hypothesis, the reaction was carried out by using TBAC (0.5 eq.),
15-crown-5 (0.5 eq.) and NaF (0.5 eq.) as the catalyst, based on
which 3a could be isolated in 28% yield (entry 5). These
mentioned above results (entries 1-5) implied that both the
fluoride anion and ammonium cation might play the significant
roles in the efficient tandem cyclization. In addition, it has also
been proved that acidic conditions are ineffective for the
cyclization reaction (entries 6-8).
Table 3. Control experiments.
When R1 substituent was sterically hindered t-butyl group, no
desired diester product was observed. Interestingly, when
TBAF·3H2O was taken as the catalyst, ketone 4 was obtained
instead (Scheme 3, 45%). In the absence of di-tert-butyl
malonate (2d), 4 could also be generated in a moderate yield
(44%). These results showed in Scheme 3 indicated a possibility
that ketone 4 is derived from a certain amount of H2O and
propargyl alcohol 1b. A similar reaction between ynones and
water is under investigation in our laboratory. In addition, the
scalability of this method was demonstrated in the reaction
occurring between propargyl alcohol 1a and diethyl malonate 2a,
thus providing a gram quantity of the dihydroisobenzofuran 3a
with a good yield (Scheme 4, 87%).
On the basis of all the above controlled experiments and the
previous literature[23], a plausible reaction mechanism has been
proposed (Scheme 5). Initially, propargyl alcohol 1a is oxidized
by PDC to generate ynone intermediate 1a’. Then,
a
nucleophilic attack of deprotonated diethyl malonate 2a’ to 1a’
gives rise to intermediate A (path a). Subsequently, A is further
Scheme 3. Formation of ketone 4.
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10.1002/ejoc.201901790
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125 MHz, and in CDCl3 or (CD3)2SO (containing 0.03% TMS) solutions.
1H NMR spectra were recorded with Me4Si (δ = 0.00) as the internal
reference and 13C NMR spectra were recorded with CDCl3 (δ = 77.00) or
DMSO-d6 (δ = 39.52) as the internal reference. High-resolution mass
spectra were obtained using a Bruker Maxis Impact mass spectrometer
with a TOF (for ESI) analyzer. Single crystal X-ray diffraction data was
collected in Bruker SMARTAPEX diffractiometers with molybdenum
cathodes. The compounds 1 are known compounds and are prepared
according to the reported literature methods.[24]
converted to the oxygen anion intermediate
B
via
a
deprotonation-rearrangement process (A to B). Under a possible
activation initiated by cation-π interaction,[8a] the formed oxygen
anion launched attacks on the intramolecular alkyne moiety (B
to C, 5-exo-dig) to furnish C. Tetrabutylammonium cation was
also speculated to serve as a noncoordinating cation to stabilize
oxygen anion intermediate B. Finally, the desired product 3a
was obtained after the protonation process. Alternatively,
allenoate ion A' could be formed by nucleophilic attack of 2a' to
1a' (path b). Then, the produced allenoate ion can directly attack
to the activated alkyne moiety (B' to C'). The resulting anion C'
can be protonated and tautomerized to furnish the product 3a.
A typical procedure for the synthesis of dihydroisobenzofurans 3
To a well-dried 25 mL Schlenk tube containing a magnetic stirring bar
was added PDC (225 mg, 0.6 mmol). Then, the vessel was evacuated
and refilled with N2 for three times. Under a stream of N2, to this vessel
were added DCM (4 mL) and propargyl alcohol 1 (0.2 mmol). The
mixture was stirred at room temperature till 1 disappeared by TLC
analysis (about 8 hours). The resulting mixture was then filtered and
washed with DCM (about 20 mL). The filtrate was concentrated under
reduced pressure and transferred to
a vial using THF (2 mL).
Subsequently, to the vial was added 1,3-dicarbonyl compound 2 (0.24
mmol) and TBAF (the corresponding amount of TBAF, see: Table 2). The
mixture was stirred at room temperature till ynone intermediate 1’
disappeared by TLC analysis. The resulting mixture was concentrated
under reduced pressure and subjected to column chromatography for
purification directly, using petroleum ether/ethyl acetate (20:1-10:1) as
the eluent.
diethyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
phenylethylidene)malonate (3a): Yellow solid; 92% yield (86 mg); mp
141-143 oC; 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 7.5 Hz, 1H), 7.57
(d, J = 7.3 Hz, 1H), 7.48-7.42 (m, 7H), 7.25 (s, 1H), 7.16-7.12 (m, 3H),
6.78 (d, J = 6.5 Hz, 2H), 6.03 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.94 (q, J
= 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 167.0, 164.6, 157.6, 151.3, 150.6, 139.2, 134.9,
133.7, 133.1, 130.6, 129.2, 129.0, 128.7, 128.5, 128.4, 128.3, 126.6,
123.6, 121.2, 119.5, 102.2, 97.0, 61.0, 60.9, 14.2, 13.7; IR (KBr): 2972,
2901, 1622, 1406, 1394, 1250, 1066, 880, 759 cm−1; HRMS (ESI) calcd
for C30H27O5 [M+H]+: 467.1853, found 467.1849.
Scheme 5. The possible reaction mechanism.
Conclusions
In conclusion, an efficient method has been developed to
construct dihydroisobenzofuran derivatives starting from
malonate esters and o-(alkynyl)phenyl propargyl alcohols. All
resulting products can be prepared by applying this tandem
strategy at room temperature. These dihydroisobenzofuran
diesters were selectively formed via the oxidation process of
propargyl alcohols, and the subsequent bifunctional TBAF
catalyzed conjugate addition and selective O-nucleophilic
cyclization processes. This methodology is characterized by
fluoride anion as a Brønsted base and a possible cation-π
interaction as the approach to activation.
dimethyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
phenylethylidene)malonate (3b): Yellow solid; 87% yield (76 mg); mp
121-122 oC; 1H NMR (500 MHz, CDCl3): δ 7.80 (d, J = 7.4 Hz, 1H), 7.58
(d, J = 7.3 Hz, 1H), 7.49-7.43 (m, 7H), 7.30 (s, 1H), 7.14-7.12 (m, 3H),
6.79-6.77 (m, 2H), 6.04 (s, 1H), 3.83 (s, 3H), 3.45 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 167.7, 164.9, 158.0, 152.2, 150.6, 139.1, 134.9, 133.7,
133.0, 130.7, 129.3, 129.1, 128.7, 128.4, 128.3, 128.3, 126.7, 122.6,
121.3, 119.6, 102.3, 96.8, 52.1, 52.0; IR (KBr): 2970, 1630, 1210, 1081,
755, 584 cm−1; HRMS (ESI) calcd for C28H23O5 [M+H]+: 439.1540, found
439.1546.
dibenzyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
(4-chlorophenyl)ethylidene) malonate (3c): Yellow solid; 74% yield (93
mg); mp 130-132 oC; 1H NMR (500 MHz, CDCl3): δ 7.60-7.56 (m, 2H),
7.48-7.45 (m, 1H), 7.41-7.32 (m, 8H), 7.31-7.26 (m, 5H), 7.18-7.17 (m,
4H), 7.10-7.08 (m, 2H), 6.80-6.79 (m, 2H), 6.05 (s, 1H), 5.29 (s, 2H), 4.92
(s, 2H); 13C NMR (125 MHz, CDCl3): δ 166.6, 164.2, 158.1, 150.7, 150.4,
137.4, 135.8, 135.1, 135.1, 134.9, 133.5, 132.8, 130.9, 129.9, 129.3,
128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 128.1, 127.9, 127.1, 122.8,
121.3, 119.6, 102.7, 96.5, 67.1, 66.6; IR (KBr): 2980, 1724, 1626, 1549,
1187, 1005, 762, 699 cm−1; HRMS (ESI) calcd for C40H30ClO5 [M+H]+:
625.1776, found 625.1782.
Experimental Section
General Methods. All reactions were carried out in air except noted. The
TBAF (1 mol/L in THF) was purchased from Sigma-Aldrich Co. and Sun
Chemical Technology (Shanghai) Co., Ltd. Unless noted, all commercial
reagents were used without further purification. Reactions were
monitored by thin layer chromatography using UV light to visualize the
course of reaction. Purification of reaction products was carried out by
flash chromatography on silica gel (300~400 mesh). 1H NMR spectra
were recorded at 500 or 300 MHz, 13C NMR spectra were recorded at
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10.1002/ejoc.201901790
European Journal of Organic Chemistry
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diisopropyl
2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-
diethyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
(naphthalen-2-yl)ethylidene) malonate (3i): Red solid; 90% yield (93
mg); mp 141-143 oC; 1H NMR (500 MHz, CDCl3): δ 8.01 (s, 1H), 7.93-
7.92 (m, 1H), 7.85-7.81 (m, 3H), 7.57-7.54 (m, 4H), 7.50-7.44 (m, 2H),
7.36 (s, 1H), 6.77-6.74 (m, 1H), 6.46 (d, J = 7.7 Hz, 2H), 6.18-6.15 (m,
2H), 5.98 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.83 (q, J = 7.1 Hz, 2H), 1.34
(t, J = 7.1 Hz, 3H), 0.81 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
167.1, 164.6, 157.7, 151.1, 150.4, 137.0, 134.8, 133.6, 133.2, 133.1,
133.0, 130.6, 129.2, 128.5, 128.3, 128.0, 128.0, 127.8, 127.4, 126.5,
126.4, 126.3, 123.8, 121.1, 119.5, 102.2, 96.6, 60.9, 60.9, 14.2, 13.5; IR
ylidene)-1-(4-chlorophenyl)ethylidene) malonate (3d): Yellow solid;
65% yield (69 mg); mp 151-152 oC; 1H NMR (500 MHz, CDCl3): δ 7.76 (d,
J = 7.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.48-7.38 (m, 6H), 7.24-7.18 (m,
4H), 6.82 (d, J = 6.9 Hz, 2H), 6.05 (s, 1H), 5.20-5.15 (m, 1H), 4.89-4.84
(m, 1H), 1.32 (d, J = 6.2 Hz, 6H), 1.07 (d, J = 6.3 Hz, 6H); 13C NMR (125
MHz, CDCl3): δ 166.2, 164.0, 157.5, 150.5, 149.0, 137.7, 134.8, 133.6,
133.0, 130.7, 130.1, 129.3, 128.5, 128.5, 127.0, 124.6, 121.1, 119.6,
102.3, 96.5, 68.6, 68.5, 21.8, 21.3; IR (KBr): 2942, 1630, 1210, 1081,
756, 584 cm−1; HRMS (ESI) calcd for C32H30ClO5 [M+H]+: 529.1776,
found 529.1781.
(KBr): 3061, 2974, 1695, 1619, 1544, 1212, 1107, 1013, 760, 670 cm−1
HRMS (ESI) calcd for C34H29O5 [M+H]+: 517.2010, found 517.2016.
;
diethyl
2-(2-((Z)-3-((Z)-benzylidene)-6-fluoroisobenzofuran-1(3H)-
ylidene)-1-phenylethylidene) malonate (3e): Yellow solid; 93% yield
(90 mg); mp 129-130 oC; 1H NMR (500 MHz, CDCl3): δ 7.73 (dd, J = 8.5,
4.6 Hz, 1H), 7.47-7.43 (m, 5H), 7.22-7.21 (m, 2H), 7.15-7.12 (m, 4H),
6.77-6.76 (m, 2H), 5.98 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.94 (q, J = 7.2
Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 167.0, 164.6, 164.5 (d, JC-F = 249.6 Hz), 156.8, 151.1,
149.7 (d, JC-F = 4.6 Hz), 139.1, 136.9 (d, JC-F = 9.9 Hz), 133.3, 129.2,
129.0, 128.9, 128.5, 128.4, 128.3, 127.0, 123.7, 123.2 (d, JC-F = 9.6 Hz),
117.6 (d, JC-F = 24.6 Hz), 106.0 (d, JC-F = 24.5 Hz), 103.2, 96.8, 61.0,
61.0, 14.2, 13.7; IR (KBr): 2928, 1718, 1618, 1534, 1479, 1298, 1192,
1011, 768, 692 cm−1; HRMS (ESI) calcd for C30H26FO5 [M+H]+: 485.1759,
found 485.1764.
diethyl
2-(1-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-
ylidene)hexan-2-ylidene)malonate (3j): Yellow oil; 94% yield (84 mg);
1H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.7 Hz,
1H), 7.64 (d, J = 7.7 Hz, 1H), 7.48-7.45 (m, 1H), 7.43-7.41 (m, 1H), 7.39-
7.36 (m, 2H), 7.26-7.23 (m, 1H), 7.12 (s, 1H), 6.23 (s, 1H), 4.31 (q, J =
7.1 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.02 (t, J = 7.9 Hz, 2H), 1.68-1.62
(m, 2H), 1.46-1.39 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz,
3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 167.0, 165.3,
156.0, 153.2, 151.1, 134.4, 134.1, 133.5, 130.4, 129.3, 128.7, 128.5,
127.1, 122.3, 121.0, 119.6, 101.7, 96.3, 61.0, 60.7, 32.7, 32.0, 22.9, 14.1,
14.1, 14.0; IR (KBr): 2959, 1726, 1621, 1561, 1210, 1012, 759, 691 cm−1
HRMS (ESI) calcd for C28H31O5 [M+H]+: 447.2166, found 447.2162.
;
diethyl
2-(2-((Z)-3-((Z)-benzylidene)-5,6-dimethoxyisobenzofuran-
diethyl
2-(2-((Z)-3-((Z)-4-chlorobenzylidene)isobenzofuran-1(3H)-
1(3H)-ylidene)-1-phenylethylidene) malonate (3f): Yellow solid; 94%
yield (99 mg); mp 182-183 oC; 1H NMR (500 MHz, CDCl3): δ 7.47-7.42
(m, 5H), 7.15-7.09 (m, 5H), 6.95 (s, 1H), 6.76-6.74 (m, 2H), 5.89 (s, 1H),
4.30 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.93 (q, J = 7.2 Hz,
2H), 1.33 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 167.2, 164.8, 158.1, 152.6, 151.9, 151.4, 150.6, 139.5, 133.9,
128.9, 128.7, 128.5, 128.4, 128.2, 126.3, 126.2, 122.5, 101.9, 100.9,
100.6, 95.8, 60.9, 60.8, 56.4, 56.3, 14.2, 13.7; IR (KBr): 2931, 1701,
1618, 1499, 1310, 1213, 1024, 829, 697 cm−1; HRMS (ESI) calcd for
C32H31O7 [M+H]+: 527.2064, found 527.2059.
ylidene)-1-phenylethylidene) malonate (3k): Yellow solid; 86% yield
o
1
(86 mg); mp 143-144 C; H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 7.2
Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.46-7.41 (m, 7H), 7.24 (s, 1H), 7.07 (d,
J = 8.5 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 5.94 (s, 1H), 4.31 (q, J = 7.2 Hz,
2H), 3.95 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 166.9, 164.6, 157.4, 151.0, 150.9,
139.2, 134.6, 133.2, 132.3, 132.1, 130.7, 129.9, 129.5, 129.0, 128.5,
128.5, 128.3, 123.9, 121.2, 119.6, 100.8, 97.3, 61.0, 61.0, 14.2, 13.7; IR
(KBr): 2977, 1702, 1623, 1546, 1489, 1206, 1068, 752, 696 cm−1; HRMS
(ESI) calcd for C30H26ClO5 [M+H]+: 501.1463, found 501.1469.
diethyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
(4-chlorophenyl)ethylidene) malonate (3g): Red solid; 72% yield (72
diethyl
2-(2-((Z)-3-((Z)-4-chlorobenzylidene)isobenzofuran-1(3H)-
ylidene)-1-(4-chlorophenyl) ethylidene)malonate (3l): Red solid; 71%
yield (76 mg); mp 149-151 oC; 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J =
7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.50-7.44 (m, 2H), 7.41 (s, br, 4H),
7.23 (s, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.01 (s,
1H), 4.31 (q, J = 7.1 Hz, 2H), 3.99 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz,
3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 166.7, 164.5,
157.6, 150.8, 149.6, 137.6, 135.1, 134.6, 133.0, 132.6, 132.1, 130.9,
130.0, 129.6, 129.5, 128.7, 128.6, 124.0, 121.3, 119.6, 101.1, 96.8, 61.2,
61.1, 14.2, 13.7; IR (KBr): 2980, 1727, 1617, 1489, 1203, 1013, 843, 759
cm−1; HRMS (ESI) calcd for C30H25Cl2O5 [M+H]+: 535.1074, found
535.1082.
o
1
mg); mp 135-137 C; H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz,
1H), 7.57 (d, J = 7.6 Hz, 1H), 7.48-7.38 (m, 6H), 7.22-7.18 (m, 4H), 6.82-
6.81 (m, 2H), 6.05 (s, 1H), 4.31 (q, J = 7.2 Hz, 2H), 3.98 (q, J = 7.2 Hz,
2H), 1.33 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 166.8, 164.5, 157.8, 150.4, 149.8, 137.7, 134.9, 134.8, 133.5,
132.9, 130.8, 130.0, 129.3, 128.6, 128.5, 128.5, 127.0, 123.7, 121.2,
119.6, 102.5, 96.4, 61.1, 61.0, 14.2, 13.7; IR (KBr): 2926, 1707, 1620,
1491, 1366, 1207, 760, 700 cm−1; HRMS (ESI) calcd for C30H26ClO5
[M+H]+: 501.1463, found 501.1460.
diethyl 2-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-
(4-methoxyphenyl)ethylidene) malonate (3h): Yellow solid; 66% yield
(66 mg); mp 133-135 oC; 1H NMR (500 MHz, DMSO-d6): δ 7.95-7.90 (m,
2H), 7.64-7.57 (m, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.20-7.10 (m, 3H), 7.05
(d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 6.91-6.80 (m, 2H), 6.47 (s, 1H), 4.22 (q,
J = 7.0 Hz, 2H), 3.95 (q, J = 7.0 Hz, 2H), 3.76 (s, 3H), 1.22 (t, J = 7.1 Hz,
3H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4, 164.8,
160.2, 157.5, 151.2, 150.6, 134.8, 133.7, 133.2, 131.5, 130.6, 130.0,
129.2, 128.8, 128.3, 126.7, 123.0, 121.2, 119.6, 113.8, 102.0, 97.4, 60.9,
60.8, 55.1, 14.2, 13.8; IR (KBr): 2978, 1708, 1624, 1480, 1444, 1193,
1069, 1014, 768, 698 cm−1; HRMS (ESI) calcd for C31H29O6 [M+H]+:
497.1959, found 497.1955.
diethyl 2-(2-((Z)-3-((Z)-4-methoxybenzylidene)isobenzofuran-1(3H)-
ylidene)-1-phenylethylidene) malonate (3m): Red solid; 70% yield (70
o
1
mg); mp 143-145 C; H NMR (500 MHz, CDCl3): δ 7.76 (d, J = 7.6 Hz,
1H), 7.53 (d, J = 7.7 Hz, 1H), 7.49-7.38 (m, 7H), 7.24 (s, 1H), 6.73-6.67
(m, 4H), 5.99 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H),
3.81 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 167.1, 164.7, 158.4, 157.9, 151.5, 149.2, 139.2,
135.0, 132.8, 130.6, 130.2, 128.9, 128.8, 128.5, 128.2, 126.6, 123.1,
121.2, 119.2, 113.9, 102.0, 96.4, 60.9, 60.9, 55.2, 14.2, 13.7; IR (KBr):
2982, 1701, 1625, 1510, 1210, 1109, 761, 697 cm−1; HRMS (ESI) calcd
for C31H29O6 [M+H]+: 497.1959, found 497.1966.
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10.1002/ejoc.201901790
European Journal of Organic Chemistry
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diethyl
2-(2-((1Z,3Z)-3-(naphthalen-2-ylmethylene)isobenzofuran-
[2]
a) B. Yang, K. Chansaenpak, H. Wu, L. Zhu, M. Wang, Z. Li, H. Lu,
Chem. Commun. 2017, 53, 3497; b) Zhao, M. L. Ming, J. Tang, X. Zhao,
Org. Lett. 2016, 18, 416; c) M. A. C. González, P. Nordeman, A. B.
Gómez, D. N. Meyer, G. Antoni, M. Schou, K. J. Szabó, Chem.
Commun. 2018, 54, 4286.
1(3H)-ylidene)-1-phenylethylidene) malonate (3n): Red solid; 75%
yield (77 mg); mp 127-129 oC; 1H NMR (500 MHz, CDCl3): δ 7.79-7.72
(m, 3H), 7.63-7.60 (m, 2H), 7.53-7.41 (m, 10H), 7.19 (s, 1H), 6.72 (d, J =
8.6 Hz, 1H), 6.22 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.98 (q, J = 7.1 Hz,
2H), 1.30 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 167.1, 164.7, 157.6, 151.2, 150.8, 139.1, 134.9, 133.2, 133.1,
132.2, 131.8, 130.6, 129.3, 129.1, 128.6, 128.3, 128.2, 128.1, 127.9,
127.5, 126.0, 125.9, 125.8, 123.7, 121.2, 119.6, 102.4, 97.2, 61.0, 61.0,
14.2, 13.7; IR (KBr): 2923, 1720, 1619, 1535, 1443, 1199, 1073, 815,
761 cm−1; HRMS (ESI) calcd for C34H29O5 [M+H]+: 517.2010, found
517.2017.
[3]
[4]
a) T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis;
3rd ed; Wiley: New York, 1999 pp 113-149; b) E. J. Corey, B. B. Snider,
J. Am. Chem. Soc. 1972, 94, 2549.
a) R. Devi, J. Das, B. Sarma, S. K. Das, Org. Biomol. Chem. 2018, 16,
5846; b) K. Pandurangan, A. B. Aletti, D. Montroni, J. A. Kitchen, M.
Martínez-Calvo, S. Blasco, T. Gunnlaugsson, E. M. Scanlan, Org. Lett.
2017, 19, 1068; c) K. Ermanis, Y.-T. Hsiao, U. Kaya, A. Jeuken, P. A.
Clarke, Chem. Sci. 2017, 8, 482.
[5]
[6]
For cyclization reactions, see: a) X. Huang, A. Bugarin, Chem. - Eur. J.
2016, 22, 12696; b) K. Hiroya, R. Jouka, M. Kameda, A. Yasuhara, T.
Sakamoto, Tetrahedron 2001, 57, 9697.
diethyl
(Z)-2-(2-(3-methyleneisobenzofuran-1(3H)-ylidene)-1-
phenylethylidene)malonate (3o): Yellow solid; 81% yield (63 mg); mp
o
1
91-92 C; H NMR (500 MHz, DMSO-d6): δ 7.89-7.87 (m, 1H), 7.84-7.82
(m, 1H), 7.60-7.56 (m, 2H), 7.43-7.37 (m, 3H), 7.25 (d, J = 6.5 Hz, 2H),
6.72 (s, 1H), 5.05 (d, J = 2.7 Hz, 1H), 4.38 (d, J = 2.7 Hz, 1H), 4.21 (q, J
= 7.1 Hz, 2H), 3.87 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H), 0.86 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6): δ 175.9, 174.5, 166.7,
166.2, 159.5, 149.0, 143.2, 142.6, 140.4, 138.5, 138.1, 137.9, 133.5,
131.2, 106.4, 95.7, 70.6, 70.5, 23.9, 23.4; IR (KBr): 2976, 1701, 1561,
1230, 1195, 827, 768, 704 cm−1; HRMS (ESI) calcd for C24H23O5 [M+H]+:
319.1540, found 319.1543.
For reduction reactions, see: a) X.-F. Liu, R. Ma, C. Qiao, H. Cao, L.-N.
He, Chem. - Eur. J. 2016, 22, 16489; b) S. Das, D. Addis, L. R. Knçpke,
U. Bentrup, K. Junge, A. Brückner, M. Beller, Angew. Chem. Int. Ed.
2011, 50, 9180.
[7]
For elimination reactions, see: a) C. Souli, N. Avlonitis, T.
Calogeropoulou, A. Tsotinis, G. Maksay, T. Bírꢀ, A. Politi, T.
Mavromoustakos, A. Makriyannis, H. Reis, M. Papadopoulos, J. Med.
Chem. 2005, 48, 5203; b) M. Okutani, Y. Mori, J. Org. Chem. 2009, 74,
442.
[8]
[9]
a) E. Nagy, E. S. Germain, P. Cosme, P. Maity, A. C. Terentis, S. D.
Lepore, Chem. Commun. 2016, 52, 2311; b) P. Maity, S. D. Lepore,
Angew. Chem. Int. Ed. 2011, 50, 8338; c) E. Nagy, S. D. Lepore, Org.
Lett. 2017, 19, 3695.
Compound 1a’ and 4 was prepared according to the general procedure
for 3.
3-phenyl-1-(2-(phenylethynyl)phenyl)prop-2-yn-1-one (1a’): Yellow oil;
The corresponding yields, see Table 2; 1H NMR (300 MHz, CDCl3): δ
8.22 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.65-7.61 (m, 3H),
7.60-7.56 (m, 2H), 7.52-7.44 (m, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.35-7.33
(m, 3H); 13C NMR (125 MHz, CDCl3): δ 177.5, 138.2, 134.3, 133.0, 132.4,
131.9, 131.5, 130.6, 128.5, 128.2, 127.9, 123.1, 123.0, 120.1, 95.4, 93.3,
a) A. S. Mahadevi, G. N. Sastry, Chem. Rev. 2013, 113, 2100; b) D. A.
Dougherty, Acc. Chem. Res. 2013, 46, 885.
[10] a) S. Yamada, Org. Biomol. Chem. 2007, 5, 2903; b) S. Yamada, J. S.
Fossey, Org. Biomol. Chem. 2011, 9, 7275.
[11] a) C. D. Iverson, S. Zahid, Y. Li, A. H. Shoqafi, A. Ata, R.
Samarasekera, Phytochem. Lett. 2010, 3, 207; b) N. Moore, H.
Verdoux, B. Fantino, Int. Clin. Psychopharmacol. 2005, 20, 131; c) B.
Verastegui-Omaꢁa, D. Rebollar-Ramos, A. Pꢂrez-Vꢃsquez, A. L.
Martínez, A. Madariaga-Mazꢀn, L. Flores-Bocanegra, R. Mata, J. Nat.
Prod. 2017, 80, 190.
88.2, 88.1; IR (KBr): 3059, 2196, 1644, 1491, 1442, 994, 756, 689 cm−1
;
HRMS (ESI) calcd for C23H15O [M+H]+: 307.1117, found 307.1121.
2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-1-(4-
chlorophenyl)ethan-1-one (4): Yellow solid; 45% yield (32 mg); mp
[12] a) D. Y. Li, X. S. Shang, G. R. Chen, P. N. Liu, Org. Lett. 2013, 15,
3848; b) X. S. Shang, N. T. Li, Z. Q. Guo, P. N. Liu, Dyes and Pigments
2016, 132, 167.
o
168-169 C; 1H NMR (500 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2H), 7.91
(d, J = 7.7 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H),
7.62-7.59 (m, 1H), 7.52-7.42 (m, 5H), 7.31-7.28 (m, 1H), 6.62 (s, 1H),
6.38 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 187.6, 162.3, 150.5, 138.4,
138.2, 135.8, 133.7, 132.0, 129.5, 129.5, 129.4, 128.9, 128.8, 127.9,
121.5, 120.0, 105.2, 93.6; IR (KBr): 2953, 1629, 1611, 1465, 1279, 1003,
832, 763, 692 cm−1; HRMS (ESI) calcd for C23H16ClO2 [M+H]+: 359.0833,
found 359.0837.
[13] a) S. K. Pawar, C.-D. Wang, S. Bhunia, A. M. Jadhav, R.-S. Liu, Angew.
Chem. Int. Ed. 2013, 52, 7559; b) K. Sekine, A. Takayanagi, S. Kikuchi,
T. Yamada, Chem. Commun. 2013, 49, 11320.
[14] a) Y. Zhao, F. Zhang, W. Yao, C. Wang, Y. Liu, Y. Li, Eur. J. Org.
Chem. 2015, 7984; b) A. Saito, T. Konishi, Y. Hanzawa, Org. Lett. 2010,
12, 372.
[15] a) C. Wang, C. Dong, L. Kong, Y. Li, Y. Li, Chem. Commun. 2014, 50,
2164; b) N. S. V. M. R. Mangina, V. Kadiyala, R. Guduru, K. Goutham,
B. Sridhar, G. V. Karunakar, Org. Lett. 2017, 19, 282.
Acknowledgments ((optional))
[16] a) J. Shen, L. Xue, X. Lin, G. Cheng, X. Cui, Chem. Commun. 2016, 52,
3292; b) G. Cheng, Y. Weng, X. Yang, X. Cui, Org. Lett. 2015, 17, 3790.
[17] For reviews, see: a) J. V. Greenhill, Chem. Soc. Rev. 1977, 6, 277; b)
A.-Z. A. Elassar, A. A. El-Khair, Tetrahedron 2003, 59, 8463.
[18] a) Y. Zhao, M. Xu, Z. Zheng, Y. Yuan, Y. Li, Chem. Commun. 2017, 53,
3721; b) Y. Zhao, Z.-Y. Cao, X.-P. Zeng, J.-M. Shi, Y.-H. Yu, J. Zhou,
Chem. Commun. 2016, 52, 3943; c) Z.-Y. Cao, Y. Zhao, J. Zhou, Chem.
Commun. 2016, 52, 2537; d) J. Luo, Y.-B. Fang, X.-Y. Mao, M. Yang,
Y.-L. Zhao, Y.-L. Liu, G.-S. Chen, Y.-F. Ji, Adv. Synth. Catal. 2019, 361,
1408.
We thank the Natural Science Foundation of Shandong
Province (ZR2018BB026, ZR2019BB021), the National Natural
Science Foundation of China (21802084) and the Doctoral Start-
Up Scientific Research Foundation of Qufu Normal University.
Keywords: TBAF • cation-π interaction • dihydroisobenzofuran •
malonate ester • cyclization reaction
[19] Y. Zhao, Z. Zhang, X. Liu, Z. Wang, Z. Cao, L. Tian, M. Yue, J. You, J.
Org. Chem. 2019, 84, 1379.
[1]
J. H. Clark, Chem. Rev. 1980, 80, 429.
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10.1002/ejoc.201901790
European Journal of Organic Chemistry
FULL PAPER
[20] The application of o-(alkynyl)phenyl propargyl alcohol, see: a) Y. Chen,
G. Li, Y. Liu, Adv. Synth. Catal. 2011, 353, 392; b) J. Zhao, W. Xu, X.
Xie, N. Sun, X. Li, Y. Liu, Org. Lett. 2018, 20, 5461.
[21] D. Rodríguez, A. Navarro, L. Castedo, D. Domínguez, C. Saá, Org. Lett.
2000, 2, 1497.
[23] S. Fustero, B. Fernández, P. Bello, C. del Pozo, S. Arimitsu, G. B.
Hammond, Org. Lett. 2007, 9, 4251. And ref. 8.
[24] a) L.-J. Wang, H.-T. Zhu, L. Lu, F. Yang, X.-Y. Liu, Y.-M. Liang, Org.
Lett. 2012, 14, 1990; b) J.-J. Lian, R.-S. Liu, Chem. Commun. 2007,
1337.
[22] CCDC 1947706
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10.1002/ejoc.201901790
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Cation-π interaction
Yulei Zhao,* Xuqiang Guo, Zongkang
Wang, Duyi Shen,* Tingting Chen, Nan
Wu, Shina Yan, Jinmao You
Page No. – Page No.
An efficient method has been devised for the synthesis of dihydroisobenzofuran
derivatives through the reaction of in situ generated ynones with potentially C-
nucleophilic malonate esters. Both the basicity of fluoride anion and ammonium
cation-π interaction with alkyne unit might play a crucial role in the cyclization
reaction.
TBAF-Catalyzed Cyclization
Reactions of o-(Alkynyl)phenyl
Propargyl Alcohols with Malonate
Esters: A Possible Cation-π
Interaction as The Activation
Approach
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