Triflic acid mediated sequential cyclization of ortho-alkynylarylesters with ammonium acetate

Article abstract of DOI:10.1016/j.tet.2020.131437

A triflic acid (TfOH) mediated sequential cyclization of ortho-alkynylarylesters and ammonium acetate (NH₄OAc) was reported. The reaction took place via a Br?nsted acid-mediated intramolecular cyclization of ortho-alkynylarylesters followed by an ammonium acetate participated substitution reaction, forming isoquinolin-1-ones as the major products. Different from most of the known synthetic methods of isoquinolin-1-ones, no metal catalyst was required in the reported reaction. The regioisomers – isoindolin-1-ones were obtained together with isoquinolin-1-ones in a few cases. The intermediate compounds – isochromen-1-ones and isobenzofuran-1-ones were also isolated. The interconversion experiments showed that the regioisomers formed during the Br?nsted acid induced intramolecular cyclization of ortho-alkynylarylesters. A natural product – ruprechstyril was prepared in a moderate yield employing the new method.

Full text of DOI:10.1016/j.tet.2020.131437

Journal Pre-proof
Triflic acid mediated sequential cyclization of ortho-alkynylarylesters with ammonium
acetate
Maciej E. Domaradzki, Xiaochen Liu, Jiye Ong, Gyeongah Yu, Gan Zhang, Ariel
Simantov, Eliyahu Perl, Yu Chen
PII:
S0040-4020(20)30609-8
https://doi.org/10.1016/j.tet.2020.131437
TET 131437
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 May 2020
Revised Date: 17 July 2020
Accepted Date: 20 July 2020
Please cite this article as: Domaradzki ME, Liu X, Ong J, Yu G, Zhang G, Simantov A, Perl E, Chen
Y, Triflic acid mediated sequential cyclization of ortho-alkynylarylesters with ammonium acetate,
Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131437.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Triflic Acid Mediated Sequential Cyclization of
Leave this area blank for abstract info.
ortho-Alkynylarylesters with Ammonium Acetate
Maciej E. Domaradzki,[a] Xiaochen Liu,[a],[b] Jiye Ong,[a] Gyeongah Yu,[a] Gan Zhang,[b] Ariel Simantov,[a] Eliyahu
Perl,[a] and Yu Chen*[a],[b]
aDepartment of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd.,
Queens, New York 11367, United States
bPh.D. Program in Chemistry, The Graduate Center of the City University of New York, 365 Fifth Ave., New York, New
York 10016, United States

Triflic Acid Mediated Sequential Cyclization of ortho-
Alkynylarylesters with Ammonium Acetate
Maciej E. Domaradzki,[a] Xiaochen Liu,[a],[b] Jiye Ong,[a] Gyeongah Yu,[a] Gan Zhang,[b] Ariel
Simantov,[a] Eliyahu Perl,[a] and Yu Chen*[a],[b]
[a] Department of Chemistry and Biochemistry, Queens College of the City University of New York,
65-30 Kissena Blvd., Queens, New York 11367, United States
[b] Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, 365 Fifth
Ave., New York, New York 10016, United States
E-mail: yu.chen1@qc.cuny.edu
Abstract
A triflic acid (TfOH) mediated sequential cyclization of ortho-alkynylarylesters and ammonium acetate
(NH4OAc) was reported. The reaction took place via a Brønsted acid-mediated intramolecular
cyclization of ortho-alkynylarylesters followed by an ammonium acetate participated substitution
reaction, forming isoquinolin-1-ones as the major products. Different from most of the known synthetic
methods of isoquinolin-1-ones, no metal catalyst was required in the reported reaction. The
regioisomers – isoindolin-1-ones were obtained together with isoquinolin-1-ones in a few cases. The
intermediate compounds – isochromen-1-ones and isobenzofuran-1-ones were also isolated. The
interconversion experiments showed that the regioisomers formed during the Brønsted acid induced
intramolecular cyclization of ortho-alkynylarylesters. A natural product – ruprechstyril was prepared in
a moderate yield employing the new method.
Key words: Brønsted acid mediated, isoquinolin-1-one, isoindolin-1-one, nitrogen-containing
heterocycle, ruprechstyril synthesis
Introduction
1

Due to the broad application in medicinal chemistry, pharmaceutical industry and material sciences,
great attention has been attracted to nitrogen-containing heterocycles.1 Among the numerous synthetic
methods developed for nitrogen-containing heterocycles, the nitrogen sources employed are generally
nitrogen-containing functional groups, such as amines, amides, imines, imides, azides, nitriles,
isonitriles, oximes, and nitro groups.2 The inexpensive inorganic salt, ammonium acetate, is an excellent
alternative nitrogen source for its stability and readily availability. As a nitrogen source, ammonium
acetate has been employed in the syntheses of quite a few of heterocycles including pyridines,3
pyrimidines,4 imidazoles,5 oxazoles,6 chromene-fused quinolinones,7 triazoles,8 pyrroles,9 isothiazoles,10
isoquinolines,11 isoindolin-1-ones and isoquinolin-1-ones.12
Isoquinolin-1-ones are a group of important nitrogen-containing heterocycles for their known
biological activities such as tumor growth inhibition,13 antithrombotic efficacy,14 and blood pressure
reduction.15 Their synthesis has attracted great interest of both medicinal and synthetic chemists.16 The
majority of the known work employed a cyclization strategy employing benzamides and alkyne
substrates, including 1) transition-metal 17 or iodine reagent 18 mediated intermolecular cyclization
between a directing group activated benzamides and alkynes / alkyne surrogates; 2) transition metal
catalyzed intermolecular cyclization of ortho-halobenzamides and alkynes;19 3) Lewis acid mediated
intramolecular cyclization of ortho-alkynylbenzamides.20 Most of these methods employed nitrogen-
containing organic groups such as amides or azides as the nitrogen source.
On the other hand, only in a few cases were inorganic ammonium salts employed as the nitrogen
source in the isoquinolin-1-one synthesis. These included a copper-catalyzed three-component coupling
of ortho-halobenzoic acid, alkynylcarboxylic acid and ammonium acetate12 and a palladium-catalyzed
three-component coupling of ortho-iodobenzoate, allene and ammonium tartrate.21 In addition, aqueous
ammonia was used in preparing the isoquinolin-1-one core structure in a total synthesis of cassiarin A22
and ruprechstyril.23 To our best knowledge, Brønsted acid-mediated one-pot synthesis of isoquinolin-1-
one using simple inorganic ammonium salts as the nitrogen source still remains unknown.
2

Our group has been developing efficient synthetic methods for nitrogen-containing heterocycles using
cascade/one-pot reaction protocols. We have successfully employed NH4OAc as the nitrogen source in
the synthesis of a variety of isoquinolines, by an intramolecular cyclization of ortho-alkynylaryl
aldehydes/ketones/amides and a subsequent substitution of the oxygen atom in the isochromenylium
intermediate by NH4OAc (Eq 1, Scheme 1).11 We have further extended the cyclization strategy to
ortho-alkynylarylesters, and we herein report our new results on a Brønsted acid mediated one-pot
reaction of ortho-alkynylarylesters and ammonium acetate (Eq 2, Scheme 1).
Scheme 1. Intramolecular Cyclization of ortho-Alkynylaryl Aldehydes/Ketones/Amides/Esters and
Subsequent Ammonium Acetate Participated Substitution
Previous work - Intramolecular Cyclization of ortho-Alkynylaryl Aldehydes/Ketones/Amides
R1
R1
R1
O
NH4OAc
transition metal catalysts
R3
(Eq 1)
N
O
R3
R3
R2
R2
R2
R1 = H, alkyl, aryl, and amino group
isochromenylium
Current work - Intramolecular Cyclization of ortho-Alkynylaryl Esters
O
O
NH
R2
R1
O
O
R1
R2
NH4OAc
+
OMe
R2
TfOH
O
R1
(Eq 2)
O
+
R1
NH
R2
R1
O
R2
H
H
Results and discussion
We chose methyl 2-(phenylethynyl)benzoate (1a) as the model substrate for reaction condition
optimization. After several attempts, we realized the conditions of the intramolecular cyclization of ester
1a and the subsequent NH4OAc participated substitution were incompatible with each other in a cascade
reaction protocol. We, therefore, attempted a one-pot reaction protocol for the designed reaction, and
decided to first optimize the conditions of the intramolecular cyclization of ester 1a. The cyclization
took place smoothly in the presence of NaAuCl4 (10 mol%) / AgSbF6 (10 mol%) and 1.1 equiv TfOH in
3

acetonitrile (CH3CN) at 85 °C, affording the desired product isochromenone 2a in 91% yield (Table 1,
entry 1). Other acids such as trifluoroacetic acid (TFA) and methanesulfonic acid (MsOH) afforded
much lower yields (Table 1, entries 2 and 3). In the presence of 10 mol% CuI and 1.1 equiv TfOH, 2a
was obtained in 81% yield (Table 1, entry 4). When the amount of TfOH was increased to 2.2 equiv, 2a
was obtained in 84% yield even in the absence of any transition metal catalyst (Table 1, entry 5).
Table 1. Condition Optimization for Intramolecular Cyclization of 2-(Phenylethynyl)benzoate (1a)a
2a
catalyst
entry
acid
yield
(%)b
(10 mol%)
TfOH
(1.1 equiv)
TFA
1
2
3
4
5
NaAuCl4/AgSbF6
91
44
42
81
84
NaAuCl4/AgSbF6
(1.1 equiv)
MsOH
NaAuCl4/AgSbF6
(1.1 equiv)
TfOH
CuI
-
(1.1 equiv)
TfOH
(2.2 equiv)
a Representative procedure: A 20 mL glass reaction vial was charged with 1a (2.0 mmol, 1.0 equiv), a
catalyst (0.1 equiv), an acid, and acetonitrile (10 mL). The vial was then flushed with nitrogen and
b
sealed with a pressure relief cap. The reaction mixture was stirred at 85 °C overnight. Isolated yields
after column chromatography.
Considering the chemical yields of 2a and the catalyst cost, we chose the conditions listed in Entry 5
in Table 1 as the first step optimal conditions, and continued optimizing the second step. After several
attempts, we found that the solvent, CH3CN, was incompatible for both steps. Therefore, after the
4

completion of the first step, the reaction mixture was first neutralized by piperidine (2.0 equiv), and
CH3CN was then removed using a rotary evaporator under reduced pressure (20 mmHg). Ammonium
acetate (3.0 equiv) and a new solvent, DMAc (5 mL), were then added to the reaction mixture. The
resulting mixture was heated at 120 °C overnight, affording the desired isoquinolin-1-one 3a in 75%
yield (Table 2, entry 1). Other solvents such as N,N-dimethylformamide (DMF) and N-
methylpyrrolidin-2-one (NMP) provided lower chemical yields (Table 2, entries 2-3).
Table 2. Condition Optimization for the One-Pot Reaction of 2-(Phenylethynyl)benzoate (1a) and
Ammonium Acetatea
3a
entry solvent
yield
(%)b
1
2
3
DMAc
DMF
NMP
75
65
65
a
Representative procedure: A 20 mL glass reaction vial was charged with 1a (2.0 mmol, 1.0 equiv),
triflic acid (660.3 mg, 4.4 mmol, 2.2 equiv) and acetonitrile (10 mL). The vial was then flushed with
nitrogen and sealed with a pressure relief cap. The reaction mixture was stirred at 85 °C overnight, until
the disappearance of starting material 1a was observed. After completion, the reaction mixture was
cooled to room temperature and piperidine (340.6 mg, 4.0 mmol, 2.0 equiv) was added, while stirring
continued for 30 min. The solvent was evaporated using a rotary evaporator. Ammonium acetate (462.5
mg, 6.0 mmol, 3.0 equiv) and a new solvent (5 mL) were then added to the reaction mixture. The
resulting reaction mixture was heated at 120 °C overnight, until the disappearance of intermediate
compound 2a was observed. b Isolated yields after column chromatography.
We next examined the substrate scope of the triflic acid mediated one-pot reaction of ortho-
alkynylarylesters and ammonium acetate, using the optimal conditions listed in Entry 1 in Table 2.
Although aryl, heteroaryl, alkenyl, and alkyl groups were all well accommodated at the distal end of the
alkyne bond (3a, 3b, 3i, 3j, 3k, and 3l in Table 3), a pair of regioisomers – isoquinolin-1-ones (3k and
5

3l) and isoindolin-1-ones (5k and 5l) were obtained when the distal group (R1) was an alkyl. The steric
hindrance from the distal alkyl group seemed to favor the formation of the isoindolin-1-one isomer
(55% yield for 5l, vs, 7% yield for 5k). An interesting electronic effect on both the proximal and distal
phenyl rings on the alkyne bond was also observed. Although both electron-donating and electron-
withdrawing groups on these rings were tolerated in the reaction (3b, 3c, 3d, 3e, 3f, 3g, and 3h), their
locations on the two phenyl rings seemed to have a significant impact on the regioselectivity of the
cyclization. In general, the cyclization took place in a 6-endo-dig mode to form isoquinolin-1-ones (3).
But, the presence of either an electron-donating group at the para-position on the proximal phenyl ring
(3d, 5d, 3h, and 5h) or an electron-withdrawing group at the para-position on the distal phenyl ring (3c
and 5c) led to both 6-endo-dig and 5-exo-dig cyclizations forming a pair of regioisomers. The
cyclization of methyl 2-((trimethylsilyl)ethynyl)benzoate (1m) failed under the optimized conditions
listed in Entry 1 in Table 2. On the other hand, its cyclization was successful in the presence of
NaAuCl4 (10 mol%) / AgSbF6 (10 mol%) and 1.1 equiv TfOH, affording a desilylated isoquinolin-1-one
(3m) in a 60% yield.
Table 3. Triflic Acid Mediated One-pot Reaction of ortho-Alkynylarylesters and Ammonium Acetatea
6

7

a
Representative procedure: A 20 mL glass reaction vial was charged with 1 (2.0 mmol, 1.0 equiv),
triflic acid (663.1 mg, 4.4 mmol, 2.2 equiv) and acetonitrile (10 mL). The vial was flushed with nitrogen
and sealed with a pressure relief cap. The reaction mixture was stirred at 85 °C overnight, until the
disappearance of starting material 1 was observed. The reaction mixture was cooled to room
temperature and piperidine (340.6 mg, 4.0 mmol, 2.0 equiv) was added, while stirring continued for 30
min. The solvent was evaporated using a rotary evaporator. Ammonium acetate (462.5 mg, 6.0 mmol,
3.0 equiv) and DMAc (5 mL) were then added to the reaction. The resulting reaction mixture was
b
heated at 120 °C overnight, until the disappearance of intermediate 2 was observed. Isolated yields
c
after column chromatography.
Product 3m was prepared from methyl 2-
((trimethylsilyl)ethynyl)benzoate (1m) in the presence of NaAuCl4 (10 mol%) / AgSbF6 (10 mol%) and
1.1 equiv TfOH. For details, see the experimental section.
Isochromen-1-ones (2) were the key intermediate compounds in this one-pot reaction. Their synthesis
had also attracted plenty of interest.24 We, therefore, decided to isolate the isochromen-1-ones (2) after
the completion of the first step. The isochromen-1-ones (2) were obtained in moderate to good yields
(Table 4). It is worth noting that the same substituent-induced regioselectivity pattern was also observed
in the isochromen-1-one formation. A pair of regioisomers of isochromen-1-ones (2) and isobenzofuran-
1-ones (4) were obtained, when 1) the distal group (R2) on the alkyne bond was an alkyl (Table 4, 2k,
4k 2l, and 4l); 2) an electron-donating group was present at the para-position on the proximal phenyl
ring (2d, 4d, 2h, and 4h); and 3) an electron-withdrawing group was present at the para-position on the
distal phenyl ring (2c and 4c). A similar substituent effect was also observed by the Abbiati group.24b
Cyclization of methyl 2-((trimethylsilyl)ethynyl)benzoate (1m) was carried out in the presence of
NaAuCl4 (10 mol%) / AgSbF6 (10 mol%) and 1.1 equiv TfOH, and isochromen-1-one (2m) was
obtained in 69% yield. On the other hand, the cyclization of 1m failed under the conditions listed in
Table 4.
Table 4. Triflic Acid Mediated Intramolecular Cyclization of ortho-Alkynylarylestersa
8

9

a
Representative procedure: A 20 mL glass reaction vial was charged with 1 (2.0 mmol, 1.0 equiv),
triflic acid (660.3 mg, 4.4 mmol, 2.2 equiv) and acetonitrile (10 mL). The vial was then flushed with
nitrogen and sealed with a pressure relief cap. The reaction mixture was stirred at 85 °C overnight, until
c
the disappearance of starting material 1 was observed. b Isolated yields after column chromatography.
Product 2m was prepared from methyl 2-((trimethylsilyl)ethynyl)benzoate (1m) in the presence of
NaAuCl4 (10 mol%) / AgSbF6 (10 mol%) and 1.1 equiv TfOH. For details, see the experimental section.
We next examined interconversion reactions of isochromen-1-one (2d) and isobenzofuran-1-one (4d)
in the presence of 3.0 equiv NH4OAc in DMAc. It turned out that in the NH4OAc participated
substitution reaction isochromen-1-ones (2d) solely led to isoquinolin-1-one (3d) and isobenzofuran-1-
one (4d) exclusively led to isoindolin-1-one (5d) (Scheme 2). No interconversion between the five-
membered and six-membered ring products was observed during the substitution step. These results
showed that the regioselectivity observed in the one-pot protocol was determined in the triflic acid
mediated ortho-alkynylarylester cyclization step.
Scheme 2. Interconversion experiments
We further applied the one-pot reaction protocol in the synthesis of a natural product – ruprechstyril25
(3o, Scheme 3). We started from commercially available 2-hydroxy-4-methoxybenzoic acid (6), and
prepared methyl 2-hydroxy-6-iodo-4-methoxybenzoate (10) referring a literature procedure.26 After a
Sonogashira coupling, 10 was converted to 1o. The latter was then subjected to our one-pot cyclization
condition, and ruprechstyril (3o) was prepared in 39% yield.
10

Scheme 3. Synthesis of Ruprechstyril
The one-pot reaction presumably starts from a Brønsted acid mediated 6-endo-dig cyclization of
ortho-alkynylarylester 1 (Scheme 4, path a), leading to isochromenone 2. An NH4OAc participated
substitution then takes place, via a ring opening to form intermediate 11. Subsequent tautomerization,
ring closure and dehydration lead to isoquinolinone 3. On the other hand, when 1) the distal group (R2)
on the alkyne bond is an alkyl; 2) an electron-donating group is present at the para-position on the
proximal phenyl ring; and 3) an electron-withdrawing group is present at the para-position on the distal
phenyl ring, the α-carbon (proximal alkyne carbon) bears more positive character (becoming more
electrophilic), which leads to a competitive 5-exo-dig cyclization affording isobenzofuranone 4 (Scheme
4, path b). The latter undergoes an NH4OAc participated substitution and a subsequent ring opening to
form intermediate 12. After tautomerization, ring closure and dehydration, 12 converts to isoindolinone
5.
Scheme 4. Proposed Mechanism for the Triflic Acid Mediated One-Pot Reaction
11

NH4OAc
NH4OAc
H+
TfO-
Me
H+
TfO-
R1
O
NH3
OMe
O
HOAc
Me
O
HOAc
R1
NH3
O
O
(b)
O
R1
TfO
(path a)
(path b)
R1
O
(a)
R2
O
R1
O
R2
R2
R2
H
R2
2
H
1
H
4
O
NH2
HO NH3
O
HO NH2
H
HO
O
H
HO
H
H
NH2
- H+
O
NH3
NH2
R1
O
R1
R1
- H+
O
H
R2
R1
R1
R1
R2
O
O
H
R2
11
R2
R2
R2
H
12
O
O
NH2
- H2O
NH
R2
O
R1
R1
O
O
NH2
O
R2
- H2O
3
R1
R1
NH
R2
R2
H
H
5
Conclusion
A Brønsted acid mediated one-pot reaction of ortho-alkynylarylesters and ammonium acetate is
reported. The reaction leads to isoquinolinones in general. With specified substitution pattern on the
ortho-alkynylarylesters, a pair of regioisomers – isoindolinones and isoquinolinones were both obtained.
The intermediate compounds isochromenones and isobezofurans were also isolated in good yields.
Interconversion reactions of a sample isochromenone and isobenzofuran showed that the
regioselectivity was determined in the step of triflic acid induced cyclization of ortho-alkynylarylesters,
and the NH4OAc participated substitution did not result in isomerization between the five-membered
and six-membered ring products. The method was employed in the synthesis of a natural product –
ruprechstyril, affording a moderate yield. Further application of NH4OAc in the synthesis of nitrogen-
containing heterocycles is underway in our laboratory and will be reported in due course.
Experimental section
General information.
All reactions were carried out in sealed 20 mL glass reaction vials with pressure relief caps, unless
otherwise indicated. All commercially available chemicals were used as received without further
12

1
purification unless otherwise noted. All H and 13C NMR spectra were recorded at 400 MHz and 100
MHz respectively, using CDCl3 or DMSO-d6 as the solvent. The chemical shifts of all 1H and 13C NMR
spectra are referenced to the residual signal of CDCl3 (δ 7.26 ppm for the 1H NMR spectra and δ 77.23
13
1
ppm for the C NMR spectra) or DMSO-d6 (δ 2.50 ppm for the H NMR spectra and δ 39.51 ppm for
the 13C NMR spectra). The high-resolution mass analysis was carried out on high resolution mass
spectrometers using heated electrospray ionization (HESI) method. Samples were dissolved in
methylene chloride and methanol and analyzed via flow injection into the mass spectrometer at a flow
rate of 200 µL/min. The mobile phase was 90:10 methanol:water. The melting points are uncorrected.
General procedure for the preparation of 2-alkynylarylesters
A 20 mL glass reaction vial was charged with 2-bromoarylester (2.0 mmol, 1.0 equiv), a terminal
alkyne (2.2 mmol, 1.1 equiv), bis(triphenylphosphine)palladium(II) dichloride (28.1 mg, 0.04 mmol, 2
mol%), copper iodide (7.6 mg, 0.04 mmol, 2 mol%), and triethylamine (10 mL). The vial was then
flushed with nitrogen and sealed. The reaction mixture was stirred at 80 °C overnight, until the
disappearance of the starting material was observed, as monitored by thin layer chromatography. The
reaction mixture was diluted with diethyl ether (40 mL), washed with brine (40 mL), and the aqueous
phase was extracted with diethyl ether (2 × 20 mL). The combined organic layers were dried over
anhydrous magnesium sulfate, concentrated using a rotary evaporator under reduced pressure (20
mmHg); the resulting residue was purified by flash column chromatography on silica gel (eluent:
hexane/ethyl acetate).
Methyl 2-(phenylethynyl)benzoate (1a)
This product was obtained as an orange oil (458.4 mg, 97% yield); 1H NMR (400 MHz, CDCl3) δ
7.98 (dd, J = 7.9, 1.0 Hz, 1H), 7.61 (dd, J = 7.7, 0.8 Hz, 1H), 7.57–7.60 (m, 2H), 7.50 (td, J = 7.7, 1.3
1
Hz, 1H), 7.41–7.35 (m, 4H), 3.97 (s, 3H). The H NMR spectral data are in good agreement with the
literature data.27
Methyl 2-((4-methoxyphenyl)ethynyl)benzoate (1b)
13

This product was obtained as a light yellow solid (447.4 mg, 84% yield); mp = 75–76 °C;
1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.9, 0.8 Hz, 1H), 7.60 (dd, J = 7.7, 0.6 Hz, 1H), 7.52 (d, J =
8.8 Hz, 2H), 7.43 (td, J = 7.7, 1.2 Hz, 1H), 7.31 (td, J = 7.8, 1.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.93
(s, 3H), 3.77 (s, 3H). The 1H NMR spectral data are in good agreement with the literature data.28
Methyl 2-((4-(methoxycarbonyl)phenyl)ethynyl)benzoate (1c)
This product was obtained as a yellow solid (559.2 mg, 95% yield); mp = 77–78 °C; 1H NMR (400
MHz, CDCl3) δ 7.95 (dm, J = 8.4 Hz, 2H), 7.91 (dd, J = 7.9, 1.0 Hz, 1H), 7.56–7.58 (m, 3H), 7.41 (td, J
13
= 7.6, 1.3 Hz, 1H), 7.31 (td, J = 7.7, 1.2 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 166.4, 166.2, 134.1, 131.81, 131.76, 131.6, 130.5, 129.6, 129.5, 128.4, 128.0, 123.1, 93.4,
91.2, 52.2, 52.1; HRMS (HESI-ORBITRAP) m/z [M + Na]+ calcd for (C18H14O4Na)+ 317.0784, found
317.0780; IR (neat) νmax 1719, 1707, 1603, 1565, 1479, 1433, 1405, 1289, 1272, 1249, 1169, 1193,
1127, 1104, 1076, 1016, 962, 853, 767, 753, 692 cm-1.
Methyl 5-methoxy-2-(phenylethynyl)benzoate (1d)
This product was obtained as an orange oil (314.2 mg, 59% yield); 1H NMR (400 MHz, CDCl3) δ
7.58–7.53 (m, 3H), 7.49 (d, J = 2.8 Hz, 1H), 7.32–7.37 (m, 3H), 7.04 (dd, J = 8.6, 2.8 Hz, 1H), 3.97 (s,
13
3H), 3.87 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 166.8, 159.3, 135.6, 133.4, 131.8, 128.5, 128.4,
123.8, 118.6, 116.1, 115.2, 92.8, 88.4, 55.8, 52.5; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for
(C17H15O3)+ 267.1016, found 267.1009; IR (neat) νmax 2948, 2837, 1729, 1713, 1594, 1557, 1499, 1434,
1326, 1287, 1245, 1216, 1182, 1070, 1032, 979, 894, 824, 780, 754, 689 cm-1.
Dimethyl 2-(phenylethynyl)terephthalate (1e)
This product was obtained as a white solid (547.4 mg, 93% yield); mp = 93–94 °C; 1H NMR (400
MHz, CDCl3) δ 8.31 (dd, J = 1.3, 0.8 Hz, 1H), 8.01–8.02 (m, 2H), 7.58–7.60 (m, 2H), 7.36–7.39 (m,
1
3H), 3.99 (s, 3H), 3.96 (s, 3H). The H NMR spectral data are in good agreement with the literature
data.29
Methyl 5-bromo-2-(phenylethynyl)benzoate (1f)
14

This product was obtained as a white solid (479.1 mg, 76% yield); mp = 70–71 °C; 1H NMR (400
MHz, CDCl3) δ 8.08 (d, J = 2.0 Hz, 1H), 7.53–7.57 (m, 3H), 7.50 (d, J = 8.3 Hz, 1H), 7.31–7.34 (m,
3H), 3.93 (s, 3H). The 1H NMR spectral data are in good agreement with the literature data.30
Methyl 4-methoxy-2-(phenylethynyl)benzoate (1g)
1
This product was obtained as an orange oil (527.3 mg, 99% yield); H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 1.8 Hz, 1H), 7.58–7.61 (m, 2H), 7.35–7.37 (m, 3H), 7.13 (d, J = 2.7 Hz, 1H), 6.89 (dd, J =
8.8, 2.7 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 162.2, 132.9,
132.0, 128.8, 128.6, 125.9, 124.2, 123.5, 118.6, 114.6, 94.4, 88.6, 55.8, 52.1; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C17H15O3)+ 267.1016, found 267.1011; IR (neat) νmax 2948, 2838,
2212, 1725, 1597, 1564, 1500, 1434, 1337, 1290, 1257, 1234, 1185, 1124, 1084, 1032, 777, 756, 691
cm-1.
Methyl 4,5-dimethoxy-2-(phenylethynyl)benzoate (1h)
1
This product was obtained as an orange solid (586.7 mg, 99% yield); mp = 114–116 °C; H NMR
(400 MHz, CDCl3) δ 7.54–7.57 (m, 2H), 7.47 (s, 1H), 7.29–7.34 (m, 3H), 7.04 (s, 1H), 3.91 (s, 3H),
3.90 (s, 6H). The 1H NMR spectral data are in good agreement with the literature data.29
Methyl 2-(thiophen-3-ylethynyl)benzoate (1i)
1
This product was obtained as an orange oil (460.4 mg, 95% yield); H NMR (400 MHz, CDCl3) δ
7.97 (dd, J = 7.9, 1.0 Hz, 1H), 7.63 (dd, J = 7.8, 0.9 Hz, 1H), 7.57 (dd, J = 3.0, 1.2 Hz, 1H), 7.48 (td, J =
7.7, 1.4 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.31 (dd, J = 5.0, 3.0 Hz, 1H), 7.24 (dd, J = 5.0, 1.2 Hz,
1H), 3.97 (s, 3H). The 1H NMR spectral data are in good agreement with the literature data. 31
Methyl 2-(cyclohex-1-en-1-ylethynyl)benzoate (1j)
This product was obtained as an orange oil (259.5 mg, 54% yield); 1H NMR (400 MHz, CDCl3) δ
7.92 (dd, J = 7.9, 1.0 Hz, 1H), 7.52 (dd, J = 7.8, 1.0 Hz, 1H), 7.43 (td, J = 7.7, 1.4 Hz, 1H), 7.31 (td, J =
7.7, 1.3 Hz, 1H), 6.26–6.29 (m, 1H), 3.92 (s, 3H), 2.24–2.28 (m, 2H), 2.13–2.18 (m, 2H), 1.66–1.72 (m,
2H), 1.59–1.65 (m, 2H). The 1H NMR spectral data are in good agreement with the literature data.32
15

Methyl 2-(hept-1-yn-1-yl)benzoate (1k)
This product was obtained as a yellow oil (382.3 mg, 83% yield); 1H NMR (400 MHz, CDCl3) δ 7.87
(dd, J = 7.9, 0.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41 (td, J = 7.7, 1.3 Hz, 1H), 7.30 (td, J = 7.8, 1.1
Hz, 1H), 3.91 (s, 3H), 2.47 (t, J = 7.1 Hz, 2H), 1.64 (m, J = 7.6 Hz, 2H), 1.42–1.49 (m, 2H), 1.32–1.40
(m, 2H), 0.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.2, 134.4, 132.1, 131.6, 130.3, 127.3,
124.7, 96.2, 79.4, 52.3, 31.3, 28.6, 22.5, 20.0, 14.2; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for
(C15H19O2)+ 231.1380, found 231.1378; IR (neat) νmax 2932, 2860, 2235, 1734, 1596, 1566, 1484, 1447,
1432, 1329, 1293, 1250, 1190, 1162, 1129, 1083, 1043, 963, 757, 702 cm-1.
Methyl 2-(3,3-dimethylbut-1-yn-1-yl)benzoate (1l)
This product was obtained as an orange oil (410.9 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ
7.86 (dd, J = 7.9, 1.0 Hz, 1H), 7.48 (dd, J = 7.7, 0.9 Hz, 1H), 7.40 (td, J = 7.7, 1.4 Hz, 1H), 7.30 (td, J =
7.7, 1.3 Hz, 1H), 3.92 (s, 3H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 134.1, 132.4,
131.6, 130.4, 127.3, 124.4, 103.8, 78.0, 52.1, 31.1, 28.4; HRMS (HESI-ORBITRAP) m/z [M + H]+
calcd for (C14H17O2)+ 217.1223, found: 217.1218; IR (neat) νmax 3066, 2969, 2982, 2902, 2867, 2239,
1732, 1596, 1567, 1484, 1475, 1447, 1432, 1362, 1290, 1249, 1201, 1128, 1081, 1041, 966, 824, 785,
757, 702 cm-1.
Methyl 2-((trimethylsilyl)ethynyl)benzoate (1m)
This product was obtained as an orange oil (446.1 mg, 96% yield); 1H NMR (400 MHz, CDCl3)
δ 7.90 (dd, J = 7.8, 1.0 Hz, 1H), 7.58 (dd, J = 7.7, 1.0 Hz, 1H), 7.44 (td, J = 7.6, 1.5 Hz, 1H), 7.36 (td, J
= 7.6, 1.4 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H). The 1H NMR spectral data are in good agreement with the
literature data.31
Methyl 2-(hept-1-yn-1-yl)-6-hydroxy-4-methoxybenzoate (1o)
1
This product was obtained as a yellow wax (381.3 mg, 69% yield); mp = 41–42 °C; H NMR (400
MHz, CDCl3) δ 11.65 (s, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.41 (d, J = 2.6 Hz, 1H),
3.93 (s, 3H), 3.80 (s, 3H), 2.45 (t, J = 7.1 Hz, 2H), 1.60–1.66 (m, 2H), 1.41–1.49 (m, 2H), 1.34–1.39 (m,
16

2H), 0.93 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 164.7, 163.9, 126.8, 114.2,
106.4, 101.4, 95.9, 80.2, 55.7, 52.1, 31.4, 28.6, 22.5, 20.0, 14.2; HRMS (HESI-ORBITRAP) m/z [M +
H]+ calcd for (C16H21O4)+ 277.1434, found 277.1431; IR (neat) νmax 2949, 1935, 2866, 1650, 1601,
1568, 1432. 1330, 1309, 1253, 1162, 1040, 982, 871, 730 cm-1.
General
procedure
for
the
TfOH
mediated
intramolecular
cyclization
of
2-alkynylarylesters
A 20 mL glass reaction vial was charged with 2-alkynylarylester (1, 2.0 mmol, 1.0 equiv), triflic acid
(660.4 mg, 4.4 mmol, 2.2 equiv), and acetonitrile (10 mL). The vial was then flushed with nitrogen and
sealed. The reaction mixture was stirred at 85 °C overnight, until the disappearance of the starting
material (1) was observed, as monitored by thin layer chromatography. The reaction mixture was diluted
with ethyl acetate (40 mL) and washed with brine (40 mL). The aqueous phase was then extracted with
ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate,
concentrated using a rotary evaporator under reduced pressure (20 mmHg). The resulting residue was
purified by flash column chromatography on silica gel (eluent: hexane/ethyl acetate or
dichloromethane/hexane).
3-Phenyl-1H-isochromen-1-one (2a)
1
This product was obtained as a beige solid (373.4 mg, 84% yield); mp = 83–84 °C; H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 8.2 Hz, 1H), 7.79 (dd, J = 7.9, 1.6 Hz, 2H), 7.63
1
(td, J = 7.8, 1.2 Hz, 1H), 7.36–7.42 (m, 5H), 6.85 (s, 1H). The H NMR spectral data are in good
agreement with the literature data.33
3-(4-Methoxyphenyl)-1H-isochromen-1-one (2b)
1
This product was obtained as a white solid (413.8 mg, 82% yield); mp = 122–123 °C; H NMR (400
MHz, CDCl3) δ 8.19 (d, J = 8.13 Hz, 1H), 7.71 (dm, J = 8.9 Hz, 2H), 7.60 (td, J = 7.6, 1.2 Hz, 1H),
7.35–7.38 (m, 2H), 6.87 (dm, J = 8.9 Hz, 2H), 6.71 (s, 1H), 3.77 (s, 3H). The 1H NMR spectral data are
in good agreement with the literature data.33
Methyl 4-(1-oxo-1H-isochromen-3-yl)benzoate (2c)
17

This product was obtained as a white solid (336.3 mg, 60% yield); mp = 194–195 °C;
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.1 Hz, 1H), 8.07 (dm, J = 8.6 Hz, 2H), 7.89 (dm, J = 8.6 Hz,
2H), 7.71 (td, J = 7.8, 1.2 Hz, 1H), 7.48–7.51 (m, 2H), 7.01 (s, 1H), 3.92 (s, 3H). The 1H NMR spectral
data are in good agreement with the literature data.20a
Methyl (Z)-4-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoate (4c)
This product was obtained as a white solid (112.1 mg, 20% yield); mp = 183–184 °C;
1H NMR (400 MHz, CDCl3) δ 8.02 (dm, J = 8.4 Hz, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.86 (dm, J = 8.4 Hz,
13
2H), 7.71–7.78 (m, 2H), 7.56 (td, J = 7.4, 1.0 Hz, 1H), 6.40 (s, 1H), 3.91 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 166.8, 146.3, 140.4, 137.7, 134.9, 130.5, 130.1, 130.0, 129.5, 125.9, 123.7, 120.3,
105.9, 52.4 (fewer 13C signals were observed due to signal overlapping); HRMS (HESI-ORBITRAP)
m/z [M + H]+ calcd for (C17H13O4)+ 281.0808, found 281.0804; IR (neat) νmax 1797, 1719, 1606, 1472,
1430, 1281, 1184, 1108, 1078, 971, 866, 766, 695 cm-1.
7-Methoxy-3-phenyl-1H-isochromen-1-one (2d)
1
This product was obtained as a beige solid (105.9 mg, 21% yield); mp = 164–165 °C; H NMR (400
MHz, CDCl3) δ 7.86 (dd, J = 7.0, 1.6 Hz, 2H), 7.72 (d, J = 2.7 Hz, 1H), 7.40–7.47 (m, 4H), 7.31 (dd, J
= 8.6, 2.7 Hz, 1H), 6.93 (s, 1H), 3.92 (s, 3H). The 1H NMR spectral data are in good agreement with the
literature data. 34
(Z)-3-Benzylidene-6-methoxyisobenzofuran-1(3H)-one (4d)
1
This product was obtained as a beige solid (292.6 mg, 58% yield); mp = 134–135 °C; H NMR (400
MHz, CDCl3) δ 7.76 (dd, J = 7.4, 1.2 Hz, 2H); 7.60 (d, J = 8.5 HZ, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.26–
7.27 (m, 1H), 7.23–7.24 (m, 1H), 7.21–7.22 (m, 1H), 6.23 (s, 1H), 3.84 (s, 3H). The 1H NMR spectral
data are in good agreement with the literature data.35
Methyl 1-oxo-3-phenyl-1H-isochromene-6-carboxylate (2e)
This product was obtained as a yellow solid (454.1 mg, 81% yield); mp = 202–203 °C; 1H NMR (400
MHz, CDCl3) δ 8.36 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.09 (dd, J = 8.2, 1.5 Hz, 1H), 7.87–
18

1
7.89 (m, 2H), 7.46–7.48 (m, 3H), 7.00 (s, 1H), 3.99 (s, 3H). The H NMR spectral data are in good
agreement with the literature data.36
7-Bromo-3-phenyl-1H-isochromen-1-one (2f)
1
This product was obtained as a white solid (511.9 mg, 85% yield); mp = 187–189 °C; H NMR (400
MHz, CDCl3) δ 8.42 (d, J = 2.0 Hz, 1H), 7.84–7.87 (m, 2H), 7.80 (dd, J = 8.4, 2.1 Hz, 1H), 7.45–7.46
1
(m, 3H), 7.37 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H). The H NMR spectral data are in good agreement with
the literature data.24c
6-Methoxy-3-phenyl-1H-isochromen-1-one (2g)
This product was obtained as a white solid (444.0 mg, 88% yield); mp = 140–141 °C; 1H NMR (400
MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 1H), 7.82–7.84 (m, 2H), 7.39–7.45 (m, 3H), 6.98 (dd, J = 8.8, 2.3
1
Hz, 1H), 6.82–6.83 (m, 2H), 3.88 (s, 3H). The H NMR spectral data are in good agreement with the
literature data.37
6,7-Dimethoxy-3-phenyl-1H-isochromen-1-one (2h)
This product was obtained as an orange solid (287.9 mg, 51% yield); mp = 163–164 °C;
1H NMR (400 MHz, CDCl3) δ 7.82–7.84 (m, 2H), 7.64 (s, 1H), 7.39–7.45 (m, 3H),
6.87 (s, 1H), 6.85 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H). The 1H NMR spectral data are in good agreement
with the literature data.33
(Z)-3-Benzylidene-5,6-dimethoxyisobenzofuran-1(3H)-one (4h)
This product was obtained as a white solid (220.2 mg, 39% yield); mp = 198–199 °C;
1H NMR (400 MHz, CDCl3) δ 7.81–7.83 (m, 2H), 7.38–7.42 (m, 2H), 7.27–7.32 (m, 2H), 7.12 (s, 1H),
6.28 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H). The 1H NMR spectral data are in good agreement with the
literature data.35
3-(Thiophen-3-yl)-1H-isochromen-1-one (2i)
1
This product was obtained as a white solid (369.8 mg, 81% yield); mp = 113–114 °C; H NMR (400
MHz, CDCl3) δ 8.16 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 2.8, 1.2 Hz, 1H), 7.58 (td, J = 7.6, 1.0 Hz, 1H),
19

1
7.28–7.37 (m, 4H), 6.64 (s, 1H). The H NMR spectral data are in good agreement with the literature
data.38
3-(Cyclohex-1-en-1-yl)-1H-isochromen-1-one (2j)
This product was obtained as a yellow solid (230.8 mg, 51% yield); mp = 81–82 °C;
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.9 Hz, 1H), 7.60 (td, J = 7.8, 1.2 Hz, 1H), 7.33–7.39 (m,
2H), 6.75–6.78 (m, 1H), 6.30 (s, 1H), 2.21–2.24 (m, 4H), 1.70–1.76 (m, 2H), 1.59–1.64 (m, 2H). The 1H
NMR spectral data are in good agreement with the literature data.24a
3-Pentyl-1H-isochromen-1-one (2k)
This product was obtained as a yellow oil (315.8 mg, 73% yield); 1H NMR (400 MHz, CDCl3) δ 8.24
(d, J = 8.0 Hz, 1H), 7.66 (td, J = 7.9, 1.2 Hz, 1H), 7.44 (td, J = 7.6, 0.9 Hz, 1H), 7.34 (d, J = 7.9 Hz,
1H), 6.25 (s, 1H), 2.51 (t, J = 7.6 Hz, 2H), 1.67–1.72 (m, 2H), 1.32–1.37 (m, 4H), 0.90 (t, J = 7.0 Hz,
3H). The 1H NMR spectral data are in good agreement with the literature data.39
(Z)-3-Hexylideneisobenzofuran-1(3H)-one (4k)
1
This product was obtained as a yellow oil (47.6 mg, 11% yield); H NMR (400 MHz, CDCl3)
δ 7.87 (d, J = 7.7 Hz, 1H), 7.62–7.68 (m, 2H), 7.49 (t, J = 7.2 Hz, 1H), 5.63 (t, J = 7.8 Hz, 1H), 2.46 (q,
13
J = 7.6 Hz, 2H), 1.52 (p, J = 7.2 Hz, 2H), 1.33–1.35 (m, 4H), 0.89 (t, J = 6.7 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 167.4, 145.8, 139.8, 134.4, 129.5, 125.4, 124.6, 119.8, 110.0, 31.7, 29.1, 26.0,
22.7, 14.2; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for (C14H17O2)+ 217.1223, found 217.1220;
IR (neat) νmax 2956, 2929, 2870, 1773, 1697, 1584, 1402, 1258, 1069, 910, 795, 767, 735, 695, 673 cm-
1
.
3-(tert-Butyl)-1H-isochromen-1-one (2l)
This product was obtained as a yellow oil (101.1 mg, 25% yield); 1H NMR (400 MHz, CDCl3) δ 8.25
(dm, J = 8.0 Hz, 1H), 7.67 (td, J = 7.8, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 1.3 Hz, 1H), 7.38 (d, J = 7.9 Hz,
1
1H), 6.30 (s, 1H), 1.32 (s, 9H). The H NMR spectral data are in good agreement with the literature
data.24a
(Z)-3-(2,2-Dimethylpropylidene)isobenzofuran-1(3H)-one (4l)
20

1
This product was obtained as a beige solid (271.0 mg, 67% yield); mp = 86–87 °C; H NMR (400
MHz, CDCl3) δ 7.86 (dm, J = 7.7 Hz, 1H), 7.59–7.67 (m, 2H), 7.48 (td, J = 7.4, 1.2 Hz, 1H), 5.59 (s,
13
1H), 1.31 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 167.4, 143.8, 140.9, 134.3, 129.5, 125.3, 123.7,
119.7, 118.9, 32.8, 30.7; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for (C13H15O2)+ 203.1067,
found 203.1061; IR (neat) νmax 2955, 2866, 1768, 1722, 1676, 1647, 1469, 1344, 1299, 1266, 1197,
1083, 986, 830, 763, 689 cm-1.
1H-Isochromen-1-one (2m)
A 20 mL glass reaction vial was charged with 1m (532.0 mg, 2.289 mmol, 1.0 equiv), sodium
tetrachloroaurate dihydrate (91.0 mg, 0.229 mmol, 0.1 equiv), silver hexafluoroantimonate (79.0 mg,
0.229 mmol, 0.1 equiv), anhydrous acetonitrile (10 mL) and triflic acid (377.0 mg; 2.515 mmol; 1.1
equiv). The vial was purged with argon and sealed. The reaction mixture was stirred at 85 °C for 6 h.
After cooling to room temperature, the resulting mixture was diluted with ethyl acetate (15 mL) and
washed with brine (15 mL). The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The
combined organic layers were dried over anhydrous magnesium sulfate, and concentrated using a rotary
evaporator, under reduced pressure (20 mmHg). The residue was purified by flash column
chromatography on silica gel (eluent: hexanes/ethyl acetate). This product was obtained as a yellow
1
solid (230.8 mg, 69% yield); mp = 47-49 °C; H NMR (500 MHz, CDCl3) δ 8.30 (dt, J = 7.9, 0.6 Hz,
1H), 7.73 (dt, J = 7.6, 1.3 Hz, 1H), 7.53 (dt, J = 8.2, 1.1 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.28 (d, J =
1
5.6 Hz, 1H), 6.51 (d, J = 5.6 Hz, 1H). The H NMR spectral data are in good agreement with the
literature data.16b
General procedure for the TfOH mediated one-pot reaction of 2-alkynylarylesters and
ammonium acetate
A 20 mL glass reaction vial was charged with 2-alkynylarylester (1, 2.0 mmol, 1.0 equiv), triflic acid
(660.4 mg, 4.4 mmol, 2.2 equiv) and acetonitrile (10 mL). The vial was then flushed with nitrogen and
sealed. The reaction mixture was stirred at 85 °C overnight, until the disappearance of the starting
material
(1)
was
observed,
as
monitored
by
thin
layer
chromatography.
21

After completion, the reaction mixture was cooled down to room temperature and piperidine
(340.8 mg, 4.0 mmol, 2.0 equiv) was added while stirring continued for 30 min. The solvent was
removed using a rotary evaporator under reduced pressure (20 mmHg). Ammonium acetate (462.0 mg,
6.0 mmol, 3.0 equiv) and N,N-dimethylacetamide (5 mL) were then added to the reaction vial. The
resulting reaction mixture was heated at 120 °C overnight, until the disappearance of the intermediate
(2) was observed, as monitored by thin layer chromatography. The reaction mixture was diluted with
ethyl acetate (40 mL) and washed with brine (40 mL), and the aqueous phase was extracted with ethyl
acetate (2 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate,
concentrated using a rotary evaporator under reduced pressure (20 mmHg). The resulting residue was
purified by flash column chromatography on silica gel (eluent: hexane/ethyl acetate).
3-Phenylisoquinolin-1(2H)-one (3a)
This product was obtained as a white solid (331.9 mg, 75% yield); mp = 198–199 °C; 1H NMR (400
MHz, CDCl3)
δ
10.71 (s, 1H), 8.41 (d,
J
=
8.0 Hz, 1H), 7.78–7.80 (m, 2H),
7.68 (td, J = 7.2, 1.4 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.45–7.55 (m, 4H), 6.80 (s, 1H). The 1H NMR
spectral data are in good agreement with the literature data.16e
3-(4-Methoxyphenyl)isoquinolin-1(2H)-one (3b)
This product was obtained as a white solid (341.5 mg, 68%) yield; mp = 238–239 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H),
7.68–7.69 (m, 2H), 7.45 (ddd, J = 8.2, 5.9, 2.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.84 (s, 1H), 3.82 (s,
3H). The 1H NMR spectral data are in good agreement with the literature data.16e
Methyl 4-(1-oxo-1,2-dihydroisoquinolin-3-yl)benzoate (3c)
1
This product was obtained as a white solid (284.8 mg, 51% yield); mp = 270–271 °C; H NMR (400
MHz, DMSO-d6) δ 11.65 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.6 Hz,
2H), 7.75 (dd, J = 4.7, 1.0 Hz, 2H), 7.53 (ddd, J = 8.2, 4.8, 3.5 Hz, 1H), 7.06 (s, 1H), 3.89 (s, 3H). The
1H NMR spectral data are in good agreement with the literature data.20a
Methyl (Z)-4-((3-oxoisoindolin-1-ylidene)methyl)benzoate (5c)
22

This product was obtained as an orange solid (83.8 mg, 15% yield); mp = 163–164 °C; 1H NMR (400
MHz, DMSO-d6) δ 10.88 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.71–7.79 (m, 4H),
7.59 (t, J = 7.4 Hz, 1H), 6.84 (s, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 169.2, 166.0,
139.5, 138.6, 134.5, 132.5, 129.7, 129.5, 129.2, 128.3, 127.6, 122.8, 120.7, 104.5, 52.1; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C17H14NO3)+ 280.0968, found 280.0962; IR (neat) νmax 3205,
2918, 1706, 1685, 1648, 1603, 1441, 1429, 1307, 1272, 1223, 1139, 1113, 1052, 1014, 969, 865, 764,
727, 698, 663 cm-1.
7-Methoxy-3-phenylisoquinolin-1(2H)-one (3d)
1
This product was obtained as a white solid (75.4 mg, 15% yield); mp = 235–236 °C; H NMR (400
MHz, DMSO-d6) δ 11.52 (s, 1H), 7.77 (dd, J = 7.1, 1.3 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.63 (d, J =
2.6 Hz, 1H), 7.41–7.50 (m, 3H), 7.35 (dd, J = 8.7, 2.8 Hz, 1H), 6.92 (s, 1H), 3.88 (s, 3H). The 1H NMR
spectral data are in good agreement with the literature data.40
(Z)-3-Benzylidene-6-methoxyisoindolin-1-one (5d)
This product was obtained as a yellow solid (231.2 mg, 46% yield); mp = 210–211 °C; 1H NMR (400
MHz, DMSO-d6) δ 10.64 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.2 Hz,
2H), 7.24–7.27 (m, 3H), 6.62 (s, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.9,
160.5, 134.9, 132.3, 131.4, 129.9, 128.9, 128.7, 126.9, 121.8, 120.2, 105.6, 104.7, 55.7; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C16H14NO2)+ 252.1019, found 252.1013; IR (neat) νmax 1704,
1694, 1648, 1491, 1453, 1403, 1327, 1290, 1243, 1107, 1051, 1020, 908, 877, 825, 785, 750, 723, 689,
634 cm-1.
Methyl 1-oxo-3-phenyl-1,2-dihydroisoquinoline-6-carboxylate (3e)
This product was obtained as a white solid (368.6 mg, 66% yield); mp = 257–258 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.35 (d, J = 0.9 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.96
(dd, J = 8.3, 1.5 Hz, 1H), 7.80 (dd, J = 7.9, 1.3 Hz, 2H), 7.48–7.54 (m, 3H), 7.10 (s, 1H), 3.92 (s, 3H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 165.8, 162.3, 141.1, 137.9, 133.6, 133.0, 129.5, 128.8, 128.3,
23

127.6, 127.4, 126.8, 125.8, 103.3, 52.6; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for
(C17H14NO3)+ 280.0968, found 280.0968; IR (neat) νmax 1722, 1648, 1432, 1246, 1173, 1032 cm-1.
7-Bromo-3-phenylisoquinolin-1(2H)-one (3f)
This product was obtained as a yellow solid (432.2 mg, 72% yield); mp = 297–298 °C; 1H NMR (400
MHz, DMSO-d6) δ 11.74 (s, 1H), 8.28 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 6.8 Hz, 2H), 7.70
(d, J = 8.5 Hz, 1H), 7.49–7.51 (m, 3H), 6.96 (s, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 161.7,
140.8, 136.9, 135.5, 133.6, 129.5, 129.2, 128.84, 128.81, 126.8, 126.3, 119.1, 102.8; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C15H11BrNO)+ 300.0019, found 300.0013; IR (neat) νmax 1656,
1465, 1285, 1152, 958, 904, 861, 842, 803, 761, 692 cm-1.
6-Methoxy-3-phenylisoquinolin-1(2H)-one (3g)
This product was obtained as a white solid (356.8 mg, 71% yield); mp = 245–246 °C; 1H NMR (400
MHz, DMSO-d6) δ 11.37 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.77 (dm, J = 8.1 Hz, 2H), 7.45–7.52 (m,
13
3H), 7.18 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (s, 1H), 3.88 (s, 3H); C{1H} NMR
(100 MHz, DMSO-d6) δ 162.5, 162.4, 140.6, 140.1, 133.9, 129.3, 128.8, 128.7, 126.6, 118.7, 115.8,
107.6, 103.1, 55.5; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd for (C16H14NO2)+ 252.1019, found
252.1014; IR (neat) νmax 2972, 1629, 1605, 1505, 1489, 1459, 1373, 1281, 1244, 1195, 1170, 1153,
1102, 1024, 896, 850, 831, 763, 691, 680 cm-1.
6,7-Dimethoxy-3-phenylisoquinolin-1(2H)-one (3h)
1
This product was obtained as a colorless solid (258.8 mg, 46% yield); mp = 231–232 °C; H NMR
(400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.76 (dd, J = 8.4, 1.5 Hz, 2H), 7.58 (s, 1H), 7.41–7.50 (m, 3H),
7.22 (s, 1H), 6.85 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.1,
153.3, 148.7, 138.3, 134.1, 133.3, 128.9, 128.8, 126.4, 118.6, 107.2, 106.6, 102.9, 55.7, 55.5; HRMS
(HESI-ORBITRAP) m/z [M + H]+ calcd for (C17H16NO3)+ 282.1125, found 282.1125; IR (neat) νmax
2962, 1631, 1610, 1504, 1463, 1260, 1232, 1172, 1100, 997, 870, 764, 692 cm-1.
(Z)-3-Benzylidene-5,6-dimethoxyisoindolin-1-one (5h)
24

1
This product was obtained as a white solid (191.3 mg, 34% yield); mp = 194–195 °C; H NMR (400
MHz, DMSO-d6) δ 10.39 (s, 1H), 7.63 (s, 1H), 7.60 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.25 (t,
J = 7.4 Hz, 1H), 7.20 (s, 1H), 6.69 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 169.3, 153.0, 150.5, 135.0, 132.8, 132.8, 128.8, 128.7, 126.9, 120.8, 104.8, 104.2, 102.9, 56.1,
55.8; HRMS (HESI-ORBITRAP) m/z [M + H] + calcd for (C17H16NO3)+ 282.1125, found 282.1119; IR
(neat) νmax 2944, 1690, 1499, 1357, 1304, 1211, 1161, 1049, 854, 782, 691 cm-1.
3-(Thiophen-3-yl)isoquinolin-1(2H)-one (3i)
This product was obtained as a white solid (340.9 mg, 75% yield); mp = 257–258 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.27 (t, J = 2.1 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.66
– 7.77 (m, 4H), 7.46 (ddd, J = 8.1, 6.8, 1.5 Hz, 1H), 7.06 (s, 1H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 162.6, 138.0, 135.2, 135.1, 132.7, 127.4, 126.7, 126.5, 126.2, 125.9, 124.8, 123.3, 102.3; HRMS
(HESI-ORBITRAP) m/z [M + H]+ calcd for (C13H10NOS)+ 228.0478, found 228.0474; IR (neat) νmax
3092, 1649, 1606, 1350, 1277, 1152, 1091, 966, 861, 823, 800, 790, 749, 679 cm-1.
3-(Cyclohex-1-en-1-yl)isoquinolin-1(2H)-one (3j)
This product was obtained as a yellow solid (207.2 mg, 46% yield); mp = 113–114 °C; 1H NMR (400
MHz, CDCl3) δ 10.05 (s, 1H), 8.35 (dm, J = 8.0 Hz, 1H), 7.61 (td, J = 7.5, 1.3 Hz, 1H), 7.51 (d, J = 7.9
Hz, 1H), 7.42 (td, J = 7.6, 1.1 Hz, 1H), 6.47–6.49 (m, 2H), 2.40–2.43 (m, 2H), 2.29–2.34 (m, 2H), 1.77–
1
1.83 (m, 2H), 1.66–1.72 (m, 2H). The H NMR spectral data are in good agreement with the literature
data.41
3-Pentylisoquinolin-1(2H)-one (3k)
This product was obtained as a white solid (262.7 mg, 61% yield); mp = 111–112 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.64 (td, J = 7.5, 1.3 Hz, 1H),
7.54 (d, J = 7.8 Hz, 1H), 7.39 (td, J = 7.5, 1.1 Hz, 1H), 6.33 (s, 1H), 2.45–2.47 (m, 2H), 1.62 (p, J = 7.4
Hz, 2H), 1.23–1.33 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.6,
142.7, 138.3, 132.3, 126.5, 125.7, 125.4, 124.3, 102.1, 32.3, 30.7, 27.7, 21.9, 13.9; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C14H18NO)+ 216.1383, found 216.1379; IR (neat) νmax 3157,
25

3093, 3010, 2950, 2926, 2858, 1677, 1640, 1608, 1553, 1476, 1346, 1257, 1174, 992, 886, 755, 727,
619 cm-1.
(Z)-3-Hexylideneisoindolin-1-one (5k)
1
This product was obtained as a beige solid (30.1 mg, 7% yield); mp = 106–107 °C; H NMR (400
MHz, DMSO-d6) δ 10.52 (s, 1H), 7.83–7.86 (m, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H),
7.48 (t, J = 7.4 Hz, 1H), 5.73 (t, J = 8.0 Hz, 1H), 2.32-2.38 (m, 2H), 1.42-1.49 (m, 2H), 1.31–1.33 (m,
4H), 0.87 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.8, 137.4, 133.5, 131.8, 129.4,
128.4, 122.4, 120.0, 108.2, 30.9, 28.8, 26.4, 22.0, 14.0; HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd
for (C14H18NO)+ 216.1383, found 216.1381; IR (neat) νmax 3180, 3050, 2955, 2923, 2852, 1699, 1463,
1373, 1308, 1147, 1071, 760, 693, 619 cm-1.
3-(tert-Butyl)isoquinolin-1(2H)-one (3l)
This product was obtained as a white solid (84.5 mg, 21% yield); mp = 187–188 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.65 (td, J = 7.4, 0.9 Hz, 1H),
7.61 (d, J = 7.2 Hz, 1H), 7.41 (td, J = 7.3, 1.2 Hz, 1H), 6.38 (d, J = 1.2 Hz, 1H), 1.30 (s, 9H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 162.9, 149.8, 138.0, 132.3, 126.4, 125.7, 124.3, 99.2, 34.3, 28.4 (fewer
13C signals were observed due to signal overlapping); HRMS (HESI-ORBITRAP) m/z [M + H]+ calcd
for (C13H16NO)+ 202.1226, found 202.1223; IR (neat) νmax 3165, 2957, 1639, 1605, 1557, 1475, 1396,
1366, 1350, 1274, 1248, 1219, 1160, 967, 888, 870, 828, 754, 678 cm-1.
(Z)-3-(2,2-Dimethylpropylidene)isoindolin-1-one (5l)
This product was obtained as a brown solid (221.4 mg, 55% yield); mp = 146–147 °C; 1H NMR (400
MHz, DMSO-d6) δ 10.14 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.61 (td, J = 7.7,
1.0 Hz, 1H), 7.48 (td, J = 7.4, 0.5 Hz, 1H), 5.77 (s, 1H), 1.24 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 168.3, 138.8, 132.0, 130.9, 128.5, 128.0, 122.4, 119.8, 117.8, 31.5, 30.4; HRMS (HESI-
ORBITRAP) m/z [M + H]+ calcd for (C13H16NO)+ 202.1226, found 202.1222; IR (neat) νmax 3071,
26

2956, 2866, 2297, 1702, 1665, 1612, 1588, 1471, 1399, 1365, 1307, 1290, 1215, 1143, 1092, 1063,
1011, 930, 844, 763, 755, 692 cm-1.
8-Hydroxy-6-methoxy-3-pentylisoquinolin-1(2H)-one (3o)
This product was obtained as a yellow solid (203.8 mg, 39% yield); mp = 134–135 °C; 1H NMR (400
MHz, CDCl3) δ 12.52 (s, 1H), 10.84 (s, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 2.2 Hz, 1H), 6.25 (s,
1H), 3.86 (s, 3H), 2.55 (t, J = 7.7 Hz, 2H), 1.72 (p, J = 7.3 Hz, 2H), 1.36–1.39 (m, 4H), 0.91 (t, J = 6.9
Hz, 3H). The 1H NMR spectral data are in good agreement with the literature data.25
Isoquinolin-1(2H)-one (3m)
A 20 mL glass reaction vial was charged with 1m (532.0 mg; 2.289 mmol; 1.0 equiv), sodium
tetrachloroaurate dihydrate (91.0 mg; 0.229 mmol; 0.1 equiv), silver hexafluoroantimonate (79.0 mg,
0.229 mmol, 0.1 equiv), anhydrous acetonitrile (10 mL) and triflic acid (377.0 mg; 2.515 mmol; 1.1
equiv). The vial was purged with argon and sealed. The reaction mixture was stirred at 85 °C for 6 h.
After completion, the reaction mixture was cooled down to room temperature and piperidine (390.0 mg,
4.578 mmol, 2.0 equiv) was added while stirring continued for 30 min. The solvent was removed using
a rotary evaporator under reduced pressure (20 mmHg). Ammonium acetate (528.8 mg, 6.867 mmol, 3.0
equiv) and N,N-dimethylacetamide (5 mL) were added to the reaction vial. The resulting mixture was
heated at 120 °C overnight, until the disappearance of the intermediate (2m) was observed, as monitored
by thin layer chromatography. The reaction mixture was diluted with ethyl acetate (40 mL) and washed
with brine (40 mL), and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined
organic layers were dried over anhydrous magnesium sulfate, concentrated using a rotary evaporator
under reduced pressure (20 mmHg). The resulting residue was purified by flash column chromatography
on silica gel (eluent: hexane/ethyl acetate). This product was obtained as a yellow solid (199.4 mg; 60%
1
yield); mp = 214–215 °C; H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H),
7.69 (td, J = 7.4, 1.2 Hz, 1H), 7.64 (d, J = 7.1 Hz, 1H), 7.47 (td, J = 7.4, 1.3 Hz, 1H), 7.14–7.18 (m,
1
1H), 6.54 (d, J = 7.11 Hz, 1H). The H NMR spectral data are in good agreement with the literature
data.16b
27

tert-Butyldimethylsilyl 2-((tert-butyldimethylsilyl)oxy)-4-methoxybenzoate (7)
To a flame-dried 100 mL round-bottomed flask was charged with 4-methoxysalicylic acid (6, 1.161 g,
6.9 mmol), CH2Cl2 (20 mL, anhydrous), DMF (2 mL, anhydrous), Et3N (3.491 g, 34.5 mmol, 5.0 equiv),
tert-butyldimethylsilyl chloride (2.607 g, 17.3 mmol, 2.5 equiv), and 4-dimethylaminopyridine (DMAP,
92.8 mg, 0.759 mmol, 0.11 equiv). The mixture was stirred under nitrogen atmosphere at room
temperature for 18 h. The reaction mixture was quenched with H2O (20 mL), and extracted with Et2O (3
× 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous
magnesium sulfate, and concentrated using a rotary evaporator under reduced pressure (20 mmHg). The
residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane), to
afford
a
yellow oil (2.38 g, 87% yield); 1H NMR (400 MHz, CDCl3)
δ 7.77 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 2.5 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 1.01 (s,
9H), 0.99 (s, 9H), 0.34 (s, 6H), 0.21 (s, 6H). The 1H NMR spectral data are in good agreement with the
literature data.26a
2-((tert-Butyldimethylsilyl)oxy)-N,N-diethyl-4-methoxybenzamide (8)
To a flame-dried 100 mL round-bottomed flask was charged with tert-butyldimethylsilyl 2-((tert-
butyldimethylsilyl)oxy)-4-methoxybenzoate (7, 426.1 mg, 1.074 mmol, 1.0 equiv), CH2Cl2 (anhydrous,
20 mL) and DMF (anhydrous, five drops). The reaction mixture was cooled to 0 °C by an ice-water
bath. Oxalyl chloride (273.0 mg, 2.148 mmol, 2.0 equiv) was added dropwise to the reaction mixture.
The mixture was stirred at 0 °C for 1.5 h. The ice bath was removed and the mixture was further stirred
at room temperature overnight. Et2NH (314.0 mg, 4.297 mmol, 4.0 equiv) was added dropwise to the
reaction mixture at room temperature. The reaction was then stirred at room temperature for 5 h,
quenched with 100 mL of saturated aqueous NH4Cl solution, and extracted with CH2Cl2 (5 × 10 mL).
The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated using a
rotary evaporator under reduced pressure (20 mmHg). The residue was purified by flash column
chromatography on silica gel (eluent: ethyl acetate/hexane), to afford a colorless oil (334.8 mg, 92%
yield); 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.4Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 6.29 (d, J
28