Ferrocene Bearing Non-ionic Poly-aryl Tosylates: Synthesis ...
Total Synthesis and Absolute Configuration of the Natural Amino … · 2018. 9. 25. · Synthesis...
Transcript of Total Synthesis and Absolute Configuration of the Natural Amino … · 2018. 9. 25. · Synthesis...
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Rapid Synthesis of 3-Amino Isocoumarin Derivatives from
Ynamides.
Loic Habert,a Pascal Retailleau,b and Isabelle Gillaizeau,a,*
a Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Université d’Orléans, rue de
Chartres, 45100 Orléans, France
bInstitut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université
Paris-Saclay, avenue de la terrasse, 91198 Gif-sur-Yvette, France
Supporting information
1. General Considerations S2
2. General procedure S3-S6
3. Compounds characterization S7-32
4. Crystal structure determination of 6k S33
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2018
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1. General Considerations
Unless otherwise noted, all reagents and solvents were purchased from commercial sources and used as received.
All manipulations were conducted under argon (1atm). The reactions were monitored by thin-layer
chromatography (TLC) using silica gel gel (60 F254) plates. Compounds were visualized using a UV lamp (254
nm) and/or by potassium permanganate stain. Flash column chromatography was carried out on silica gel 60 (230-
400 mesh, 0.040-0.063 mm). Melting points (mp [°C]) were taken on samples in open capillary tubes and are
uncorrected. The infrared spectra of compounds were recorded on a Thermo Scientific Nicolet iS10. 1H, 13C and
19F NMR spectra were recorded on a spectrometer at 250 MHz (13C, 62.9 MHz) or 400 MHz (13C, 100 MHz; 19F:
376 MHz CPD). Chemical shifts are given in parts per million from tetramethylsilane (TMS) as internal standard.
The following abbreviations are used for the proton spectra multiplicities: s: singulet, d: doublet, t: triplet, q:
quartet, qt: quintuplet, m: multiplet, br.: broad, dd: double doublet, dt: double triplet. High-resolution accurate
mass measurements (HRAM) were recorded with a Maxis Bruker 4G instrument and were performed in positive
mode with an ESI source on a Q-TOF mass spectrometer with an accuracy tolerance of 2 ppm by the “Fédération
de Recherche” ICOA/CBM (FR2708) platform. Compounds 1a1 and 1n2 were synthesized according to the
literature procedures. Compounds 2e, 2i, 2m, 2n were not isolated as pure compounds but used as crude products
to afford the corresponding derivatives 3e, 3i, 3m, 3n.
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2. General procedure
Synthesis of 3-halo-(het)aryl-2-carboxylate (1) (GP1). To a solution of 2-halogenated benzoic acid derivative
in dichloromethane (0.5 mL/mmol) were added isopropyl alcohol (1.05 equiv), N,N’-dicyclohexylcarbodiimide
(1.10 equiv) and 4-(dimethylamino)pyridine (10 mol%) at room temperature. The reaction mixture was stirred at
room temperature overnight then filtered through a pad of celite, and the residue was washed with diethyl ether
(2x10 mL). Solvents were removed under vacuum and the expected product was purified by flash-column
chromatography on silica gel with a petroleum ether/AcOEt elution system.
Synthesis of derivatives (2a-d, 2f-h) via Sonogashira cross-coupling from aryl iodide (GP2). To a solution
of aryl iodide (1 equiv) in anhydrous triethylamine (1.5 mL/mmol) was added trimethylsilylacetylene (1.1 equiv).
The solution was degassed under argon then copper iodide (5 mol%) and
dichlorobis(triphenylphosphine)palladium (2.5 mol%) were added at room temperature. The reaction mixture was
stirred at room temperature overnight then filtered through a pad of celite. The residue was washed with diethyl
ether. Solvents were removed under vacuum and the expected product was purified by flash column
chromatography on silica gel with a petroleum ether/AcOEt elution system.
Synthesis of derivatives (2g, 2k-l) via Sonogashira cross-coupling from aryl bromide (GP3). To a solution
of aryl bromide (1 equiv) in anhydrous toluene (1.5 mL/mmol) was added trimethylsilylacetylene (1.2 equiv) and
DIPA (2.5 equiv). The solution was degassed under argon, then copper iodide (2 mol%)
dichlorobis(triphenylphosphine)palladium (2 mol%), triphenylphosphine (5 mol%) were added at room
temperature. The reaction mixture was stirred at room temperature overnight then filtered through a pad of celite.
The residue was washed with diethyl ether. Solvents were removed under vacuum and the expected product was
purified by flash column chromatography on silica gel with a petroleum ether/AcOEt elution system.
Synthesis of derivatives 3a-d, 3f-h, 3j-l (GP4). To a solution of silylated compound 2 in THF (2 mL/mmol)
was added TBAF (1.1 equiv, 1M in THF) at 0 °C. The solution was stirred at this temperature for 5 minutes then
diluted with water. The mixture was extracted with diethyl ether, the combined organic phases were dried over
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anhydrous MgSO4 and concentrated under vacuum. The expected product was purified by flash column
chromatography on silica gel.
Synthesis of derivatives (3e,n) from aryl iodide (1e,n) via Sonogashira cross-coupling and deprotection
step (GP5). To a solution of aryl bromide 1e,n (1 equiv) in anhydrous triethylamine (1.5 mL/mmol) was added
trimethylsilylacetylene (1.1 equiv). The solution was degassed under argon then copper iodide (5 mol%) and
dichlorobis(triphenylphosphine)palladium (2.5 mol%) were added at room temperature. The reaction mixture was
stirred at room temperature overnight then filtered through a pad of celite. The residue was washed with diethyl
ether. Solvents were removed under vacuum and the expected product was used without purification. TBAF (1.1
equiv, 1M in THF) was added to a solution of the crude silylated compound (1 equiv) in THF (2 mL/mmol) at 0
°C. The mixture was stirred at this temperature for 5 minutes then diluted with water. The solution was extracted
with diethyl ether and the combined organic phases were dried over anhydrous MgSO4 before evaporation under
vacuum. The expected product was purified by flash column chromatography on silica gel.
Synthesis of derivatives (3i,m) from aryl bromide (1i,m) via Sonogashira cross-coupling and deprotection
step (GP6). To a solution of aryl bromide 1i,m (1 equiv) in anhydrous toluene (1.5 mL/mmol) were added
trimethylsilylacetylene (1.2 equiv) and DIPA (2.5 equiv). The solution was degassed under argon then copper
iodide (2 mol%), dichlorobis(triphenylphosphine)palladium (2 mol%), and triphenylphosphine (5 mol%) were
added at room temperature. The reaction mixture was stirred at room temperature overnight then filtered through
a pad of celite and washed with diethyl ether. Solvents were removed under vacuum and the expected product was
used without purification. TBAF (1.1 equiv, 1M in THF) was then added to a solution of the crude silylated
compound (1 equiv) in THF (2 mL/mmol) at 0 °C. The solution was stirred at this temperature for 5 minutes then
diluted with water. The mixture was extracted with diethyl ether, the combined organic phases were dried over
anhydrous MgSO4 and concentrated. The expected product 3i,m was purified by flash column chromatography on
silica gel.
Synthesis of derivatives (4a-n) (GP7). To a solution of aryl alkyne 3a-n (1.0 mmol) in MeCN (2.0 mL) was
added NBS (1.5 mmol) and DBU (1.0 mmol). The mixture was stirred at room temperature for 1 min. The reaction
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mixture was then poured into water and then extracted with CH2Cl2 (3×10 mL). The combined organic phases
were washed with water (3×10 mL), filtered and concentrated under reduced pressure. The crude product was
purified by flash-column chromatography on silica gel.
Synthesis of ynamides (5aa-5ag) (GP8). In a sealed tube, flushed with argon and equipped with a stirring bar,
were added bromoalkyne 4 (1.1 equiv.), the protected amine (1.0 equiv.), CuSO4•5H2O (10 mol%), 1,10-
phenantroline (20 mol%), K3PO4 (2.0 equiv.) and toluene (0.33 M). The reaction mixture was heated at 80 °C until
completion (TLC monitoring). The mixture was then allowed to cool down to room temperature and concentrated.
The crude compounds were purified by flash-column chromatography with a petroleum ether/AcOEt elution
system.
Synthesis of 3-amino isocoumarins (6aa-6ag) from (5aa-ag) using TFA (GP9). To a solution of ynamide 5
(0.2 mmol), isolated from GP8, in DCM (2 mL) was added TFA (1 equiv) at room temperature. The reaction was
completed in 1 minute. The crude compounds were purified by flash-column chromatography with a petroleum
ether/AcOEt elution system.
Synthesis of 3-amino isocoumarins (6aa-6ag) from (5aa-ag) using AgOTf (GP10). To a solution of ynamide
5 (0.2 mmol) in DCM (2 mL) was added AgOTf (5 mol%) at room temperature. The reaction was completed in 1
minute. The crude compounds were purified by flash-column chromatography with a petroleum ether/AcOEt
elution system.
Synthesis of 3-amino isocoumarins (6ah-6am, 6b-6e) via a one-pot procedure from (4ah-4am, 4b-e) using
TFA (GP11). In a sealed tube flushed with argon and equipped with a stirring bar were added the bromoalkyne 4
(1.1 equiv.), the protected amine (1.0 equiv.), CuSO4•5H2O (10 mol%), 1,10-phenantroline (20 mol%), K3PO4 (2.0
equiv.) and toluene (0.33 M). The reaction mixture was heated at 80 °C until completion (24-48h) (TLC
monitoring). The mixture was then allowed to cool down to room temperature, and filtrated with DCM or EtOAc
(10 mL). After addition of TFA (1.0 equiv), the reaction was completed in 1 minute. The crude compounds were
purified by flash-column chromatography with a petroleum ether/AcOEt elution system.
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Synthesis of 3-amino isocoumarins (6al-6am, 6b-6e) via a one pot procedure from (4al-am, 4b-e) using
AgOTf (GP12). In a sealed tube flushed with argon and equipped with a stirring bar were added the bromoalkyne
4 (1.1 equiv.), the protected amine (1.0 equiv.), CuSO4•5H2O (10 mol%), 1,10-phenantroline (20 mol%), K3PO4
(2.0 equiv.) and toluene (0.33 M). The reaction mixture was heated at 80 °C until completion (24-48h) (TLC
monitoring). The mixture was then allowed to cool down to room temperature, and filtrated with DCM or EtOAc
(10 mL). After addition of AgOTf (5 mol %), the reaction was completed in 1 minute. The crude compounds were
purified by flash-column chromatography with a petroleum ether/AcOEt elution system.
Synthesis of (7a-b) via Suzuki cross-coupling (GP13). To a mixture of the bromo aryl compound 6b (0.20
mmol, 1 equiv) and the arylboronic acid (0.40 mmol, 2 equiv) in toluene (1.0 mL) was added a solution of aqueous
Na2CO3 (0.30 mL, 2M). The reaction mixture was degassed under argon, Pd(PPh3)4 (0.01 mmol, 5 mol %) was
added and it was heated at reflux for 6 h. After cooling down to room temperature, water (25 mL) was added. The
reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic extracts were combined and washed
with water (2 x 25 mL) and brine (50 mL), and dried over MgSO4. The solvent was evaporated under reduced
pressure and the residue was purified by flash-column chromatography on silica gel with a petroleum ether/AcOEt
elution system.
Synthesis of (7c-e) via Sonogashira cross-coupling (GP14). To a mixture of 6b (0.30 mmol, 1 equiv) and
alkyne (0.33 mmol, 1.1 equiv) in toluene (1.0 mL) were added PPh3 (0.03 mmol, 0.1 equiv), Et3N (60 µl), and CuI
(0.015 mmol, 5 mol%). The reaction mixture was degassed under argon, PdCl2(PPh3)2 (4 mg, 0.006 mmol, 2
mol%) was added and it was heated at reflux for 18 h. After cooling down to room temperature, water (25 mL)
was added. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic extracts were
combined, washed with water (2 x 25 mL) and brine (50 mL), and dried over MgSO4. The solvent was evaporated
under reduced pressure and the residue was purified by flash-column chromatography on silica gel with a
petroleum ether/AcOEt elution system.
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3. Compounds characterization
tert-butyl 5-bromo-2-iodobenzoate (1b). Following the GP1, using 5-bromo-2-iodobenzoic acid (6 g, 18.3
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 1b as a colorless oil (5.10 g, 72 %). 1H NMR (400 MHz, CDCl3): δ
7.78-7.76 (m, 2H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 1.61 (s, 9H).13C NMR (100 MHz, CDCl3): δ 164.7, 142.2, 138.9,
134.9, 133.2, 122.2, 91.4, 83.3, 28.1. HRMS (ESI+): calcd for C11H13IBrO2 [M+H]+ : 382.9138 found 382.9137.
tert-butyl 5-fluoro-2-iodobenzoate (1c). Following the GP1, using 5-fluoro-2-iodobenzoic acid (3 g, 11.3
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 1c as a colorless oil (3.35 g, 92 %). 1H NMR (400 MHz, CDCl3): δ 7.88
(dd, J = 8.7, 5.4 Hz, 1H), 7.42 (dd, J = 9.0, 3.1 Hz, 1H), 6.90-6.85 (m, 1H), 1.62 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 164.9, 161.9 (d, J = 250 Hz), 142.3, 138.9, 119.5, 117.9, 86.4, 83.2, 28.1.19F NMR (376 MHz, CDCl3)
δ -113.68. HRMS (ESI+): calcd for C11H12FIO2 [M+Na]+ : 344.9758 found 344.9760.
tert-butyl 5-chloro-2-iodobenzoate (1d). Following the GP1, using 5-chloro-2-iodobenzoic acid (3 g,
10.62 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (99:1) as eluent to give 1d as a colorless oil (3.3 g, 92 %). 1H NMR (400 MHz,
CDCl3): δ 7.85 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 8.4, 2.6 Hz, 1H), 1.62 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 164.9, 142.0, 138.6, 134.4, 132.0, 130.0, 90.5, 83.3, 28.1. HRMS (ESI+): calcd for
C11H13IClO2 [M+H]+ : 338.9643 found 338.9641.
tert-butyl 2-iodo-5-methoxybenzoate (1e). Following the GP1, using 5-Methoxy-2-iodobenzoic acid (2.5
g, 8.9 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (99:1) as eluent to give 1e as a colorless oil (2.65 g, 89 %). 1H NMR (400 MHz,
CDCl3): δ 7.78 (d, J = 8.7 Hz), 7.42 (d, J = 3.1 Hz), 6.70 (dd, J = 8.7, 3.1 Hz), 3.80 (s, 3H), 1.62 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 166.0, 159.5, 141.4, 138.2, 118.4, 116.1, 82.8, 81.7, 55.5, 28.1. HRMS (ESI+): calcd for
C12H16IO3 [M+H]+ : 335.0138 found 335.0138.
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2-benzyl 1-tert-butyl 3-iodo-1H-indole-1,2-dicarboxylate (1f). Following the GP1, using 3-iodo-2-
naphthoic acid (1 g, 3.3 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica
gel with petroleum ether/ethyl acetate (98:2) as eluent to give 1f as a yellow gum (650 mg, 56 %). 1H NMR (400
MHz, CDCl3): δ 8.44 (s, 1H), 8.19 (s, 1H), 7.85-7.83 (m, 1H), 7.71-7.69 (m, 1H), 7.56-7.49 (m, 2H), 1.67 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 166.3, 140.3, 135.5, 133.8, 131.8, 130.8, 128.6, 128.4, 127.3, 126.6, 88.7, 82.8,
28.3. HRMS (ESI+): calcd for C15H16O2I [M+H]+ : 355.0195 found 355.0192.
tert-butyl 3-bromopyridine-2-carboxylate (1g). Following the GP1, using 3-bromopyridine-2-carboxylic
acid (1 g, 4.95 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (95:5) as eluent to give 1g as a colorless oil (905 mg, 71 %). 1H NMR (400 MHz,
CDCl3): δ 8.53 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 1.64 (s, 9H).13C NMR (100 MHz, CDCl3): δ 164.5,
151.6, 147.7, 141.2, 125.6, 117.6, 83.7, 28.0. HRMS (ESI+): calcd for C10H13NO2Br [M+H]+ : 258.0124 found
258.0116.
Benzyl 3-iodo-1H-indole-2-carboxylate (1h). To a solution of 3-iodo-2-indolecarboxylic acid (3 g, 10.4
mmol, 1 equiv) in dichloromethane (65 mL) were added benzyl alcohol (1.35 mL, 13 mmol, 1.25 equiv), N,N’-
dicyclohexylcarbodiimide (2.15 g, 10.4 mmol, 1.0 equiv) and finally 4-(dimethylamino)pyridine (255 mg, 2.1
mmol, 20 mol%) at room temperature. The reaction mixture was stirred at room temperature overnight then filtered
through a pad of celite and the residue was washed with diethyl ether. Solvents were removed under vacuum and
the expected product was purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate
(70:30) as eluent to give 1h as a white solid (3.1 g, 79 %). 1H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.58-7.52
(m, 3H), 7.44-7.35 (m, 5H), 7.26-7.20 (m, 1H), 5.44 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 160.5, 136.2, 135.3,
131.4, 128.6, 128.6, 128.5, 126.8, 123.5, 121.7, 112.0, 67.1, 66.8. HRMS (ESI+): calcd for C16H13NO2I [M+H]+ :
377.9985 found 377.9984. Mp: 169-170°C.
2-benzyl 1-tert-butyl 3-iodo-1H-indole-1,2-dicarboxylate (1h’). To a solution of benzyl 3-iodo-1H-indole-
2-carboxylate (1h) (3.0 g, 7.95 mmol) in 60 mL of MeCN was added DMAP (97 mg, 0.795 mmol, 0.1 equiv)
followed by Boc2O (1.91 g, 8.74 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature
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overnight and then was concentrated under reduced pressure. The crude product was purified by flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (99:1) as eluent to give 1h’ as a white solid (2.35
g, 62 %). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.4 Hz, 1H), 7.52-7.32 (m, 8H), 5.43 (s, 2H), 1.61 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 161.9, 148.3, 135.9, 134.9, 132.3, 130.8, 128.7, 128.5, 128.5, 127.4, 124.0, 122.9,
115.1, 85.5, 72.5, 67.9, 27.9. HRMS (ESI+): calcd for C21H21NO4I [M+H]+ : 478.0509, found 478.0507. Mp: 107-
108°C.
tert-butyl 5-bromo-2-(methylsulfanyl)pyrimidine-4-carboxylate (1i). Following the GP1, using 5-bromo-
2-methylthiopyrimidine-4-carboxylic acid (640 mg, 2.56 mmol, 1 equiv). The crude product was purified by flash-
column chromatography on silica gel with petroleum ether/ethyl acetate (98:2) as eluent to give 1i as a colorless
oil (180 mg, 23 %). 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 2.58 (s, 3H), 1.65 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 171.7, 162.6, 160.0, 157.5, 110.5, 84.9, 28.0, 14.5. HRMS (ESI+): calcd for C10H14N2O2BrS [M+H]+ :
304.9953, found 304.9951.
tert-butyl 3-chloro-1,4-diazine-2-carboxylate (1j). Following the GP1, using 3-chloro-2-
pyrazinecarboxylic acid (500 mg, 3.16 mmol, 1 equiv). The crude product was purified by flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (90:10) as eluent to give 1j as a colorless oil (410
mg, 60 %). 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 2.4 Hz), 8.45 (d, J = 2.4 Hz, 1H), 1.64 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 162.8, 146.5, 146.5, 144.8, 141.8, 84.6, 28.0. HRMS (ESI+): calcd for C9H12N2O2Cl [M+H]+
: 215.0581, found 215.0578.
tert-butyl 3-bromo-1-benzofuran-2-carboxylate (1k). Following the GP1, using 3-bromo-1-benzofuran-2-
carboxylic acid (460 mg, 1.90 mmol, 1 equiv). The crude product was purified by flash-column chromatography
on silica gel with petroleum ether/ethyl acetate (99:1) as eluent to give 1k as a colorless oil (462 mg, 82 %). 1H
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51-7.47 (m, 1H), 7.39-7.35 (m,
1H), 1.66 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 158.1, 153.7, 142.3, 128.5, 128.2, 124.1, 121.6, 112.4, 104.8,
83.5, 28.2. HRMS (ESI+): calcd for C13H14O3Br [M+H]+ : 297.0120, found 297.0120.
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tert-butyl 3-bromothiophene-2-carboxylate (1l). Following the GP1, using 3-bromothiophene-2-
carboxylic acid (1 g, 4.82 mmol, 1 equiv). The crude product was purified by flash-column chromatography on
silica gel with petroleum ether/ethyl acetate (99:1) as eluent to give 1l as a colorless oil (1.05 g, 83 %). 1H NMR
(400 MHz, CDCl3): δ 7.40 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 5.2 Hz, 1H), 1.59 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 160.0, 132.9, 130.5, 129.4, 115.9, 82.7, 28.2. HRMS (ESI+): calcd for C9H11SO2Br [M+Na]+ : 284.9555 found
284.9553.
tert-butyl 3-bromo-1-benzothiophene-2-carboxylate (1m). Following the GP1, using 3-bromo-1-
benzothiophene-2-carboxylic acid (1.2 g, 4.66 mmol, 1 equiv). The crude product was purified by flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (98:2) as eluent to give 1m as a colorless oil (656
mg, 45 %). 1H NMR (400 MHz, CDCl3): δ 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.53-7.46 (m, 2H), 1.64 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 160.6, 139.1, 138.8, 129.4, 127.8, 125.5, 125.2, 122.5, 113.7, 83.3, 28.2. HRMS
(ESI+): calcd for C13H14SO2Br [M+H]+ : 312.9892, found 312.9891.
tert-butyl 2-((trimethylsilyl)ethynyl)benzoate (2a). Following the GP2, using tert-butyl 2-iodobenzoate
1a17 (1 g, 3.2 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (99:1) as eluent to give 2a as a colorless oil (834 mg, 95 %). 1H NMR (400 MHz,
CDCl3): δ 7.76 (dd, J = 7.8, 1.3 Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.40-7.31 (m, 2H), 1.62 (s, 9H), 0.26 (s,
9H). 13C NMR (100 MHz, CDCl3): δ 166.1, 134.7, 134.6, 130.6, 129.6, 128.1, 122.5, 103.6, 98.9, 81.9, 28.2, -
0.05. HRMS (ESI+): calcd for C16H22O2Si [M+Na]+ : 297.1281 found 297.1283.
tert-butyl 5-bromo-2-((trimethylsilyl)ethynyl)benzoate (2b). Following the GP2, using (1b) (2.53 g, 6.65
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 2b as a colorless oil (1.88 g, 80 %). 1H NMR (400 MHz, CDCl3): δ 7.89
(d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.3, 2.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 1.61 (s, 9H), 0.26 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 164.6, 136.2, 135.8, 133.7, 132.5, 122.1, 121.4, 102.5, 100.4, 82.5, 28.1, -0.1. HRMS (ESI+):
calcd for C16H22BrSiO2 [M+H]+ : 353.0566, found 353.0569.
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tert-butyl 5-fluoro-2-((trimethylsilyl)ethynyl)benzoate (2c). Following the GP2, using (1c) (3 g, 9.31
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 2c as a colorless oil (2.25 g, 83 %). 1H NMR (400 MHz, CDCl3): δ 7.53
(dd, J = 8.6, 5.4 Hz, 1H), 7.46 (dd, J = 9.1, 2.8 Hz, 1H), 7.11-7.07 (m, 1H), 1.61 (s, 9H), 0.26 (s, 9H).13C NMR
(100 MHz, CDCl3): δ 164.8, 161.8 (d, J = 250 Hz), 136.8, 136.5, 118.7, 118.1, 116.7, 102.5, 98.7, 82.5, 28.1, -0.1.
19F NMR (376 MHz, CDCl3) δ -110.3. HRMS (ESI+): calcd for C16H21FSiO2 [M+Na]+ : 315.1187, found
315.1187.
tert-butyl 5-chloro-2-((trimethylsilyl)ethynyl)benzoate (2d). Following the GP2, using (1d) (2 g, 5.9
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 2d as a colorless oil (1.35 g, 74 %). 1H NMR (400 MHz, CDCl3): δ 7.73
(d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.4, 2.3 Hz, 1H), 1.61 (s, 9H), 0.26 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 164.7, 136.1, 135.7, 134.1, 130.8, 129.6, 121.0, 102.4, 100.1, 82.5, 28.1, -0.1. HRMS (ESI+):
calcd for C16H22ClSiO2 [M+H]+ : 331.0891, found 331.0892.
tert-butyl 3-((trimethylsilyl)ethynyl)naphthalene-2-carboxylate (2f). Following the GP2, using (1f) (650
mg, 1.8 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 2f as a colorless oil (503 mg, 86 %). 1H NMR (400 MHz,
CDCl3): δ 8.29 (s, 1H), 8.08 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.57-7.49 (m, 2H), 1.67 (s,
9H), 0.30 (s, 9H).13C NMR (100 MHz, CDCl3): δ 166.3, 135.0, 133.7, 131.9, 131.4, 130.5, 128.7, 128.1, 127.3,
127.3, 118.8, 104.0, 97.8, 82.0, 28.3, 0.05. HRMS (ESI+): calcd for C20H25O2Si [M+H]+ : 325.1618, found
325.1620.
tert-butyl 3-((trimethylsilyl)ethynyl)pyridine-2-carboxylate (2g). Following the GP3, using (1g) (700 mg,
2.7 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (90:10) as eluent to give 2g as a colorless oil (540 mg, 72%). 1H NMR (400 MHz, CDCl3): δ
8.56 (dd, J = 4.7, 1.7 Hz, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 1.65 (s, 9H), 0.26 (s,
12
9H). 13C NMR (100 MHz, CDCl3): δ 164.6, 152.7, 148.2, 141.4, 124.1, 118.5, 102.0, 100.1, 83.0, 28.0, -0.2.
HRMS (ESI+): calcd for C15H22NO2Si [M+H]+ : 276.1414, found 276.1416.
2-Benzyl 1-tert-butyl 3-((trimethylsilyl)ethynyl)-1H-indole-1,2-dicarboxylate (2h). Following the GP2,
using (1h’) (1 g, 2.09 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica
gel with petroleum ether/ethyl acetate (98:2) as eluent to give 2h as a colorless oil (0.750 mg, 80 %). 1H NMR
(400 MHz, CDCl3): δ 8.06 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 6.9 Hz, 2H), 7.45-7.30 (m,
5H), 5.41 (s, 2H), 1.58 (s, 9H), 0.24 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 161.1, 148.6, 136.0, 135.3, 132.1,
128.8, 128.6, 128.5, 128.3, 128.3, 128.2, 127.3, 123.7, 121.6, 114.9, 108.6, 102.8, 95.0, 85.3, 67.5, 27.9, -0.1.
HRMS (ESI+): calcd for C26H30NO4Si [M+H]+ : 448.1938, found 448.1939.
tert-butyl 3-((trimethylsilyl)ethynyl)-1,4-diazine-2-carboxylate (2j). To a solution of (1j) (0.410 g, 1.91
mmol, 1 equiv) in anhydrous THF (3 mL) was added anhydrous Et3N (400 µl, 2.87 mmol, 1.5 equiv),
trimethylsilylacetylene (410 µl, 2.87 mmol, 1.5 equiv), PPh3 (12.5 mg, 0.047 mmol, 2.5 mol %). The solution was
degassed under argon, then copper iodide (4 mg, 0.019 mmol, 1 mol%) and
dichlorobis(triphenylphosphine)palladium (66 mg, 0.095 mmol, 5 mol%) were added at room temperature. The
reaction mixture was stirred at 50°C overnight then filtered through a pad of celite. The residue was washed with
diethyl ether. Solvents were removed under vacuum and the crude product was purified by flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (90:10) as eluent to give 2j as a colorless oil (420
mg, 80 %). 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 1.65 (s, 9H), 0.29
(s, 9H).13C NMR (100 MHz, CDCl3): δ 163.5, 148.5, 145.1, 142.0, 137.3, 103.2, 99.7, 83.9, 28.0, -0.4. HRMS
(ESI+): calcd for C14H21N2O2Si [M+H]+ : 277.1366, found 277.1367.
tert-butyl 3-((trimethylsilyl)ethynyl)-1-benzofuran-2-carboxylate (2k). Following the GP3, using (1k)
(400 mg, 1.34 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 2k as a colorless oil (390 mg, 92 %). 1H NMR (400 MHz,
CDCl3): δ 7.74-7.71 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.44 (m, 1H), 7.37-7.33 (m, 1H), 1.66 (s, 9H), 0.31
13
(s, 9H). 13C NMR (100 MHz, CDCl3): δ 158.1, 154.1, 147.1, 128.6, 128.0, 123.9, 121.8, 112.3, 109.4, 105.1, 94.1,
83.3, 28.2, -0.06. HRMS (ESI+): calcd for C18H23O3Si [M+H]+ : 315.1410, found 315.1414.
tert-butyl 3-((trimethylsilyl)ethynyl)thiophene-2-carboxylate (2l). Following the GP3, using (1l) (400 mg,
1.51 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 2l as a colorless oil (420 mg, 99 %). 1H NMR (400 MHz, CDCl3): δ
7.35 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 5.1 Hz, 1H), 1.60 (s, 9H), 0.26 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 160.7,
137.2, 133.0, 129.4, 125.6, 100.1, 99.0, 82.4, 28.3, -0.1. HRMS (ESI+): calcd for C14H21SO2Si [M+H]+ : 281.1026,
found 281.1026.
tert-butyl 2-ethynylbenzoate (3a). Following the GP4, using (2a) (880 mg, 3.2 mmol, 1 equiv). The crude
product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate (99:1) as
eluent to give 3a as a colorless oil (582 mg, 90 %). 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 7.8, 1.4 Hz), 7.59
(dd, J = 7.8, 1.4 Hz, 1H), 7.45-7.36 (m, 2H), 3.36 (s, 1H), 1.62 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.3,
134.8, 134.4, 131.1, 130.1, 128.4, 122.1, 82.4, 82.0, 81.9, 28.2. HRMS (ESI+): calcd for C13H14O2 [M+Na]+ :
225.0886, found 225.0885.
tert-butyl 5-bromo-2-ethynylbenzoate (3b). Following the GP4, using (2b) (1.88 g, 5.33 mmol, 1 equiv).
The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate
(99:1) as eluent to give 3b as a colorless oil (1.1 g, 74 %). 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 2.1 Hz, 1H),
7.55 (dd, J = 8.3, 2.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 3.40 (s, 1H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 163.9, 136.0, 135.9, 134.1, 133.1, 122.5, 121.1, 83.1, 82.7, 81.4, 28.1. HRMS (ESI+): calcd for C13H14BrO2
[M+H]+ : 281.0171, found 281.0171.
tert-butyl 2-ethynyl-5-fluorobenzoate (3c). Following the GP4, using (2c) (2 g, 6.8 mmol, 1 equiv). The
crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate (99:1)
as eluent to give 3c as a colorless oil (1.31 g, 97 %). 1H NMR (400 MHz, CDCl3): δ 7.62-7.53 (m, 1H), 7.16-7.12
(m, 2H), 3.32 (s, 1H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 164.1, 161.9 (d, J = 250 Hz), 136.7, 136.5,
14
118.5, 118.3, 117.2, 82.6, 81.7, 81.4, 28.1. 19F NMR (376 MHz, CDCl3) δ -109.9. HRMS (ESI+): calcd for
C13H14FO2 [M+H]+ : 221.0972, found 221.0970.
tert-butyl 5-chloro-2-ethynylbenzoate (3d). Following the GP4, using (2d) (1.35 g, 4.33 mmol, 1 equiv).
The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate
(99:1) as eluent to give 3d as a white solid (840 mg, 83 %). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 2.3 Hz,
1H), 7.52 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.3, 2.3 Hz, 1H), 3.39 (s, 1H), 1.61 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 164.0, 135.9, 135.8, 134.5, 131.2, 130.2, 120.6, 82.9, 82.7, 81.4, 28.1. HRMS (ESI+): calcd for
C13H14ClO2 [M+H]+ : 237.0676, found 237.0675.
tert-butyl 3-ethynylnaphthalene-2-carboxylate (3f). Following the GP4, using (2f) (1.9 g, 5.8 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (98:2) as eluent to give 3f as a colorless oil (1.12 g, 76 %). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H),
8.12 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.59-7.52 (m, 2H), 3.36 (s, 1H), 1.66 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 165.5, 135.3, 133.8, 131.9, 131.3, 130.7, 128.8, 128.4, 127.5, 127.3, 118.2, 82.7, 82.0,
80.8, 28.2. HRMS (ESI+): calcd for C17H17O2 [M+H]+ : 253.1223, found 253.1220.
tert-butyl 3-ethynylpyridine-2-carboxylate (3g). Following the GP4, using (2g) (500 mg, 1.81 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (90:10) as eluent to give 3g as a colorless oil (220 mg, 60 %). 1H NMR (400 MHz, CDCl3): δ 8.62 (dd, J
= 4.7, 1.7 Hz, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.35 (dd, J = 7.9, 4.8 Hz, 1H), 3.44 (s, 1H), 1.64 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 164.2, 152.5, 148.6, 141.8, 124.4, 118.2, 84.4, 83.2, 79.4, 28.0. HRMS (ESI+): calcd
for C12H14NO2 [M+H]+ : 204.1019, found 204.1018.
2-benzyl 1-tert-butyl 3-ethynyl-1H-indole-1,2-dicarboxylate (3h). Following the GP4, using (2h) (750
mg, 1.6 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 3h as a colorless oil (402 mg, 66%). 1H NMR (400 MHz,
CDCl3): δ 8.07 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.50-7.31 (m, 7H), 5.42 (s, 2H), 3.38 (s, 1H), 1.59 (s,
15
9H). 13C NMR (100 MHz, CDCl3): δ 161.1, 148.5, 135.8, 135.1, 132.9, 128.6, 128.5, 128.4, 127.3, 123.8, 121.0,
115.0, 107.3, 85.5, 84.6, 74.2, 67.5, 27.8. HRMS (ESI+): calcd for C23H22NO4 [M+H]+ : 376.1543, found
376.1548.
tert-butyl 3-ethynyl-1,4-diazine-2-carboxylate (3j). Following the GP4, using (2j) (420 mg, 1.51 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (90:10) as eluent to give 3j as a colorless oil (220 mg, 70 %). 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J =
2.3 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 3.55 (s, 1H), 1.66 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 163.0 (N-C=O),
148.2 , 145.4 , 142.0 , 137.3 , 84.5, 84.2, 79.4, 28.00 (C3xCMe). HRMS (ESI+): calcd for C11H13N2O2 [M+H]+ :
205.0971, found 205.0970.
tert-butyl 3-ethynyl-1-benzofuran-2-carboxylate (3k). Following the GP4, using (2k) (360 mg, 1.14
mmol, 1 equiv) the crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (98:2) as eluent to give 3k as a colorless oil (174 mg, 63 %). 1H NMR (400 MHz, CDCl3): δ
7.75 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 1H), 7.38-7.34 (m, 1H), 3.63 (s, 1H), 1.66 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 157.8, 154.1, 148.1, 128.3, 128.1, 124.1, 121.7, 112.3, 108.8, 86.7, 83.5, 73.6,
28.2. HRMS (ESI+): calcd for C15H15O3 [M+H]+ : 243.1015, found 243.1014.
tert-butyl 3-ethynylthiophene-2-carboxylate (3l). Following the GP4, using (2l) (0.340 mg, 1.2 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 3l as a colorless oil (160 mg, 64 %). 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J =
5.1 Hz, 1H), 7.14 (d, J = 5.1 Hz, 1H), 3.42 (s, 1H), 1.59 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 160.3, 137.2,
132.6, 129.7, 125.3, 82.7, 82.6, 78.0, 28.2. HRMS (ESI+): calcd for C11H12O2S [M+Na]+ : 231.0450, found
231.0447.
tert-butyl 2-ethynyl-5-methoxybenzoate (3e). Following the GP5, using (1e) (2.65 g, 7.9 mmol, 1 equiv).
The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate
(99:1) as eluent to give 3e as a colorless oil (1.55 g, 84 %). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.6 Hz,
16
1H), 7.38 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 8.6, 2.8 Hz, 1H), 3.84 (s, 3H), 3.24 (s, 1H), 1.61 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 165.3, 159.4, 136.2, 135.9, 117.4, 115.0, 114.2, 82.4, 82.2, 80.2, 55.5, 28.1. HRMS (ESI+):
calcd for C14H17O3 [M+H]+ : 233.1172, found 233.1171.
tert-butyl (2-ethynylphenyl)acetate (3n). Following the GP5, using (1n) (0.2 g, 0.62 mmol, 1 equiv).
The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate
(99:1) as eluent to give 3n as a colorless oil (65 mg, 40 %). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J = 7.6, 1.4
Hz, 1H), 7.33-7.20 (m, 3H), 3.75 (s, 2H), 3.25 (s, 1H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.3, 137.5,
132.7, 129.7, 128.9, 126.8, 122.4, 81.8, 81.2, 80.9, 41.0, 28.0. HRMS (ESI+): calcd for C14H17O2 [M+H]+ :
217.1223, found 217.1220.
tert-butyl 5-ethynyl-2-(methylsulfanyl)pyrimidine-4-carboxylate (3i). Following the GP6, using (1i) (180
mg, 0.58 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 3i as a colorless oil (62 mg, 42 %). 1H NMR (400 MHz,
CDCl3): δ 8.68 (s, 1H), 3.48 (s, 1H), 2.60 (s, 3H), 1.62 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 172.4, 162.5,
161.9, 158.6, 110.3, 86.0, 84.4, 76.6, 28.0, 14.3. HRMS (ESI+): calcd for C12H15N2O2S [M+H]+ : 251.0848, found
251.0846.
tert-butyl 3-ethynyl-1-benzothiophene-2-carboxylate (3m). Following the GP6, using (1m) (600 mg, 1.91
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (98:2) as eluent to give 3m as a colorless oil (350 mg, 71 %). 1H NMR (400 MHz, CDCl3): δ
8.06-8.01 (m, 1H), 7.83-7.79 (m, 1H), 7.51-7.45 (m, 2H), 3.73 (s, 1H), 1.64 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 160.9, 140.2, 139.5, 137.8, 127.5, 125.5, 124.6, 122.5, 121.3, 85.9, 83.1, 76.3, 28.2. HRMS (ESI+): calcd for
C15H14SO2 [M+Na]+ : 281.0606, found 281.0607.
tert-butyl 2-(bromoethynyl)benzoate (4a). Following the GP7, using (3a) (0.2 g, 1 mmol, 1 equiv). The
crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate (99:1)
as eluent to give 4a as a colorless oil (275 mg, 98 %). 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 7.7, 1.5 Hz,
17
1H), 7.54 (dd, J = 7.2, 1.6 Hz, 1H), 7.44-7.35 (m, 2H), 1.62 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.5, 134.5,
131.1, 130.2, 128.3, 122.5, 99.9, 81.9, 78.9, 54.2, 28.2. HRMS (ESI+): calcd for C13H13O2Br [M+Na]+ : 302.9991,
found 302.9992.
Benzyl 2-(bromoethynyl)benzoate (4a’). Following the GP7, using 3a’ (0.8 g, 3.38 mmol, 1 equiv). The
crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate (99:1)
as eluent to give 4a’ as a colorless oil (0.810 g, 76 %). 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 7.8, 1.5 Hz,
1H), 7.57 (dd, J = 7.6, 1.4 Hz, 1H), 7.50-7.33 (m, 7H), 5.39 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 165.7, 135.7,
134.8, 132.2, 131.8, 130.6, 128.6, 128.4, 128.3, 128.2, 123.2, 78.7, 67.2, 55.3. HRMS (ESI+): calcd for C16H12BrO2
[M+H]+ : 315.0015, found 315.0014.
tert-butyl 5-bromo-2-(bromoethynyl)benzoate (4b). Following the GP7, using (3b) (2.150 g, 7.64 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 4b as a brown solid (1.95 g, 71 %). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 2.1
Hz, 1H), 7.54 (dd, J = 8.3, 2.1 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
164.1, 136.0, 135.7, 134.1, 133.2, 122.4, 121.4, 82.5, 78.1, 55.6, 28.1. HRMS (ESI+): calcd for C13H13Br2O2
[M+H]+ : 358.9276, found 358.9269. Mp : 57-58°C.
tert-butyl 2-(bromoethynyl)-5-fluorobenzoate (4c). Following the GP7, using (3c) (1.3 g, 5.9 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 4c as a colorless oil (1.345 g, 76 %). 1H NMR (400 MHz, CDCl3): δ 7.60-7.49 (m,
2H), 7.15-7.10 (m, 1H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 164.2, 161.9 (d, J = 250 Hz), 136.7, 136.4,
118.7, 118.5, 117.4, 82.5, 78.0, 54.0, 28.1. 19F NMR (376 MHz, CDCl3) δ -109.8. HRMS (ESI+): calcd for
C13H13FBrO2 [M+H]+ : 299.0077, found 299.0077.
tert-butyl 2-(bromoethynyl)-5-chlorobenzoate (4d). Following the GP7, using (3d) (850 mg, 3.5 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 4d as a colorless oil (620 mg, 56 %). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J =
18
2.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 8.3, 2.2 Hz, 1H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 164.2, 135.9, 135.6, 134.4, 131.2, 130.3, 120.9, 82.5, 78.0, 55.5, 28.1. HRMS (ESI+): calcd for C13H13ClBrO2
[M+H]+ : 314.9782, found 314.9782.
tert-butyl 2-(bromoethynyl)-5-methoxybenzoate (4e). Following the GP7, using 3e (1.45 g, 6.24 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 4e as a colorless oil (1.6 g, 82 %). 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.6
Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.6, 2.8 Hz, 1H), 3.84 (s, 3H), 1.61 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 165.5, 159.4 , 136.0 , 135.8 , 117.7 , 114.8 , 114.6 , 82.0, 78.9, 55.5, 51.9, 28.2. HRMS (ESI+): calcd
for C14H16BrO3 [M+H]+ : 311.0277, found 311.0278.
tert-butyl 3-(bromoethynyl)naphthalene-2-carboxylate (4f). Following the GP7, using 3f (1.1 g, 4.35
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (98:2) as eluent to give 4f as a colorless oil (910 mg, 63%). 1H NMR (400 MHz, CDCl3): δ 8.41
(s, 1H), 8.06 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.59-7.51 (m, 2H), 1.67 (s, 9H).13C NMR
(100 MHz, CDCl3): δ 165.7, 135.0, 133.9, 131.9, 131.4, 130.9, 128.8, 128.4, 127.5, 127.2, 118.6, 81.9, 79.3, 52.9,
28.2. HRMS (ESI+): calcd for C17H16BrO2 [M+H]+ : 331.0328, found 331.0322.
tert-butyl 3-ethynylpyridine-2-carboxylate (4g). Following the GP7, using (3g) (220 mg, 1.1 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (90:10) as eluent to give 4g as a colorless oil (235 mg, 75 %). 1H NMR (400 MHz, CDCl3): δ 8.63 (dd, J
= 4.7, 1.7 Hz, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.35 (dd, J = 7.9, 4.7 Hz, 1H), 1.65 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 164.1, 152.4, 148.5, 141.6, 124.5, 118.9, 83.1, 76.1, 57.4, 28.1. HRMS (ESI+): calcd for C12H13NBrO2
[M+H]+ : 282.0124, found 282.0123.
2-benzyl 1-tert-butyl 3-(bromoethynyl)-1H-indole-1,2-dicarboxylate (4h). Following the GP7, using (3h)
(400 mg, 1.06 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 4h as a colorless oil (420 mg, 87 %). 1H NMR (400 MHz,
19
CDCl3): δ 8.06 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.46-7.30 (m, 5H), 5.42 (s,
2H), 1.60 (s, 9H), 13C NMR (100 MHz, CDCl3): δ 160.9, 148.5, 135.9, 135.1, 132.7, 128.6, 128.6, 128.4, 128.3,
127.4, 123.8, 121.0, 115.0, 108.0, 85.5, 71.0, 67.7, 57.0, 27.8. HRMS (ESI+): calcd for C23H21NBrO4 [M+H]+ :
454.0648, found 454.0649.
tert-butyl 5-(bromoethynyl)-2-(methylsulfanyl)pyrimidine-4-carboxylate (4i). Following the GP7, using
(3i) (50 mg, 0.2 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel
with petroleum ether/ethyl acetate (98:2) as eluent to give 4i as a white gum (61 mg, 93 %). 1H NMR (400 MHz,
CDCl3): δ 8.65 (s, 1H), 2.60 (s, 3H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 172.1, 162.4, 161.6, 158.6,
111.2, 84.2, 73.3, 59.1, 28.0, 14.3. HRMS (ESI+): calcd for C12H14N2O2SBr [M+H]+ : 328.9953, found 328.9953.
tert-butyl 3-(bromoethynyl)-1,4-diazine-2-carboxylate (4j). Following the GP7, using (3j) (210 mg, 1.02
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (90:10) as eluent to give 4j as a brown solid (215 mg, 76 %). 1H NMR (400 MHz, CDCl3): δ
8.63 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 1.66 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 162.9, 148.1, 145.4
, 142.5, 137.7, 130.9, 84.0, 77.2, 59.6, 28.0. HRMS (ESI+): calcd for C11H12BrN2O2 [M+H]+ : 283.0076, found
283.0077. Mp : 96-97°C.
tert-butyl 3-(bromoethynyl)-1-benzofuran-2-carboxylate (4k). Following the GP7, using (3k) (150 mg,
0.618 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 4k as a colorless oil (152 mg, 76 %). 1H NMR (400 MHz,
CDCl3): δ 7.74 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48-7.44 (m, 1H), 7.37-7.33 (m, 1H), 1.65 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 157.8, 154.2, 148.3, 128.1, 128.1, 124.1, 121.7, 112.4, 109.2, 83.5, 70.4, 59.2,
28.2. HRMS (ESI+): calcd for C15H14O3Br [M+H]+ : 321.0120, found 321.0112.
tert-butyl 3-(bromoethynyl)thiophene-2-carboxylate (4l). Following the GP7, using (3l) (160 mg, 0.768
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (99:1) as eluent to give 4l as a colorless oil (115 mg, 52 %). 1H NMR (400 MHz, CDCl3): δ
20
7.38 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 160.5, 137.8,
132.3, 129.8, 125.3, 82.4, 74.9, 55.5, 28.2. HRMS (ESI+): calcd for C11H11O2SBr [M+Na]+ : 308.9555, found
308.9556.
tert-butyl 3-(bromoethynyl)-1-benzothiophene-2-carboxylate (4m). Following the GP7, using (3m) (300
mg, 1.16 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (98:2) as eluent to give 4m as a colorless oil (250 mg, 64 %). 1H NMR (400 MHz,
CDCl3): δ 8.04-8.00 (m, 1H), 7.85-7.81 (m, 1H), 7.53-7.46 (m, 2H), 1.66 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
161.1, 140.2, 139.4, 138.4, 127.4, 125.2, 124.5, 122.5, 121.4, 82.9, 73.8, 58.7, 28.2. HRMS (ESI+): calcd for
C15H14SBrO2 [M+H]+ : 336.9892, found 336.9894.
tert-butyl (2-(bromoethynyl)phenyl)acetate (4n). Following the GP7, using (3n) (0.650 mg, 3 mmol, 1
equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum ether/ethyl
acetate (99:1) as eluent to give 4n as a colorless oil (469 mg, 53 %). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J =
7.6, 1H), 7.32-7.19 (m, 3H), 3.70 (s, 2H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 170.3, 137.5, 132.6, 129.8,
128.8, 126.9, 122.9, 81.0, 78.5, 53.5, 41.2, 28.0. HRMS (ESI+): calcd for C14H16O2Br [M+H]+ : 295.0328, found
295.0327.
tert-butyl 2-((benzyl((4-methylphenyl)sulfonyl)amino)ethynyl)benzoate (5aa). Following the GP8, using
4aa (0.500 g, 1.94 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel
with petroleum ether/ethyl acetate (85:15) as eluent to give 5aa as a colorless oil (0.651 g, 73 %). 1H NMR (400
MHz, CDCl3): δ 7.82 (d, J = 8.5 Hz, 2H), 7.79-7.75 (m, 1H), 7.44-7.39 (m, 2H), 7.34-7.16 (m, 8H), 4.64 (s, 2H),
2.39 (s, 3H), 1.54 (s, 9H). HRMS (ESI+): calcd for C27H27O4NS [M+Na]+ : 484.1553, found 484.1557.
N-benzyl 2-((benzyl((4-methylphenyl)sulfonyl)amino)ethynyl)benzoate (5aa’). Following the GP8, using
4aa’ (0.400 g, 1.53 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel
with petroleum ether/ethyl acetate (90:10) as eluent to give 5aa’ as a colorless oil (0.447 g, 59 %). 1H NMR (400
21
MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.40-7.23 (m, 15H), 5.33 (s, 2H), 4.57 (s, 2H),
2.41 (s, 3H).
tert-butyl 2-((2-oxoazetidin-1-yl)ethynyl)benzoate (5ab). Following the GP8, using 4ab (0.150 g, 2.1
mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel with petroleum
ether/ethyl acetate (80:20) as eluent to give 5ab as a white solid (250 mg, 44 %). 1H NMR (400 MHz, CDCl3): δ
7.84 (dd, J = 7.8, 1.4 Hz, 1H), 7.49 (dd, J = 7.7, 1.4 Hz, 1H), 7.39 (dt, J = 7.6, 1.4 Hz, 1H), 7.30 (dt, J = 7.6, 1.4
Hz, 1H), 3.74 (t, J = 4.8 Hz, 2H), 3.04 (t, J = 4.9 Hz, 2H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 166.4,
165.5, 133.6, 133.1, 131.0, 130.1, 127.4, 122.5, 83.4, 81.8, 69.6, 43.1, 38.0, 28.2. HRMS (ESI+): calcd for
C16H17O3N [M+Na]+ : 294.1100, found 294.1104. Mp : 73-74°C.
tert-butyl 2-(((4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl)ethynyl)benzoate (5ac). Following the GP8, using
4ac (0.460 g, 2.25 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica gel
with petroleum ether/ethyl acetate (85:15) as eluent to give 5ac as an orange solid (611 mg, 72 %). 1H NMR (400
MHz, CDCl3): δ 7.88 (dd, J = 7.9, 1.4 Hz, 1H), 7.56 (dd, J = 7.7, 1.3 Hz, 1H), 7.43 (dt, J = 8.5, 8.0, 1.4 Hz, 1H),
7.35-7.26 (m, 6H), 4.43-4.34 (m, 2H), 4.21 (dd, J = 8.3, 5.4 Hz, 1H), 3.58 (dd, J = 13.7, 3.3 Hz, 1H), 3.04 (dd, J
= 13.6, 8.7 Hz, 1H), 1.59 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.1, 155.1, 134.8, 132.9, 132.6, 131.3, 130.1
, 129.5, 128.9, 127.3, 127.1, 123.2, 83.4, 81.3, 73.6, 67.6, 59.1, 37.5, 28.2. HRMS (ESI+): calcd for C23H23O4N
[M+Na]+ : 400.1519, found 400.1520. Mp : 86-87°C.
tert-butyl 2-((1,1-dioxo-2,3-dihydro-1H-1,2-benzothiazol-2-yl)ethynyl)benzoate (5ad). Following the
GP8, using 4ad (350 mg, 2.1 mmol, 1 equiv). The crude product was purified by flash-column chromatography
on silica gel with petroleum ether/ethyl acetate (80:20) as eluent to give 5ad as a white solid (550 mg, 72 %). 1H
NMR (400 MHz, CDCl3): δ 7.87-7.83 (m, 2H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.62-7.55 (m, 2H), 7.47-7.39 (m,
2H), 7.30 (td, J = 7.6, 1.3 Hz, 1H), 4.93 (s, 2H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.5, 133.6, 133.3,
133.1, 133.1, 131.8, 131.0, 130.0, 129.7, 127.2, 124.6, 122.8, 121.9, 82.7, 81.6, 73.0, 52.7, 28.2. HRMS (ESI+):
calcd for C20H19O4NS [M+NH4]+ : 405.1478, found 405.1485. Mp : 156-157°C.
22
tert-butyl2-(((2-((tert-butyl(dimethyl)silyl)oxy)ethyl)((4-methylphenyl)sulfonyl)amino)ethynyl)benzoate
(5ae). Following the GP8, using 4ae (450 mg, 1.36 mmol, 1 equiv). The crude product was purified by flash-
column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent to give 5ae as a white
solid (602 mg, 83 %). 1H NMR (400 MHz, CDCl3): δ 7.92 (td, J = 8.4 Hz, 1H), 7.83-7.81 (m, 1H), 7.43-7.36 (m,
1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26-7.22 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.43 (s, 3H),
1.57 (s, 9H), 0.86 (s, 9H), 0.05(s, 6H). 13C NMR (100 MHz, CDCl3): δ 165.0, 144.4, 135.1, 132.8, 132.2, 131.0,
129.9, 129.7, 127.8, 126.5, 123.8, 87.9, 81.1, 70.6, 60.2, 53.4, 28.1, 25.8, 21.6, 18.2, - 5.4. HRMS (ESI+): calcd
for C28H39O5SiNS [M+NH4]+ : 547.2656, found 547.2660. Mp : 69-70°C.
Benzyl 1-((2-(tert-butoxycarbonyl)phenyl)ethynyl)-1H-pyrrole-2-carboxylate (5af). Following the GP8,
using 4af (320 mg, 1.59 mmol, 1 equiv). The crude product was purified by flash-column chromatography on
silica gel with petroleum ether/ethyl acetate (85:15) as eluent to give 5af as a colorless oil (490 mg, 76 %). 1H
NMR (400 MHz, CDCl3): δ 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.50 (dd, J = 7.9, 1.2 Hz, 1H), 7.44-7.37 (m, 3H), 7.37-
7.30 (m, 4H), 7.23 (dd, J = 2.9, 1.7 Hz, 1H), 7.06 (dd, J = 3.9, 1.7 Hz, 1H), 6.28 (dd, J = 3.9, 2.8 Hz, 1H), 5.35 (s,
2H), 1.59 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.3, 159.3, 135.9, 133.8, 133.4, 131.5, 131.2, 130.2, 128.5,
128.2, 128.1, 127.6, 125.6, 122.6, 119.1, 110.9, 85.9, 81.4, 69.5, 66.2, 28.2. HRMS (ESI+): calcd for C25H23O4NS
[M+Na]+ : 424.1529 found 424.1520.
Methyl 1-((2-(tert-butoxycarbonyl)phenyl)ethynyl)-1H-indole-3-carboxylate (5ag). Following the GP8,
using 4ag (350 mg, 2.0 mmol, 1 equiv). The crude product was purified by flash-column chromatography on silica
gel with petroleum ether/ethyl acetate (80/20) as eluent to give 5ag as a white solid (460 mg, 61 %). 1H NMR (400
MHz, CDCl3): δ 8.18 (d, J = 7.4 Hz, 1H), 8.02 (s, 1H), 7.96-7.92 (m, 2H), 7.63 (dd, J = 7.8, 1.1 Hz, 1H), 7.52-
7.35 (m, 4H), 3.95 (s, 3H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 165.0, 164.4, 138.8, 134.6, 133.3, 133.2,
131.3, 130.3, 127.7, 125.4, 124.6, 123.8, 122.3, 121.8, 112.2, 111.3, 84.1, 81.7, 71.8, 51.4, 28.2. HRMS (ESI+):
calcd for C23H21O4N [M+Na]+ : 398.1362, found 398.1366. Mp : 65-66°C.
N-benzyl-4-methyl-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide (6aa). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6aa as a white solid (83
23
mg, 95 % according to GP9, or 96% according to GP10).1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.0 Hz, 1H),
7.77-7.75 (m, 2H), 7.71-7.67 (m, 1H), 7.51-7.47 (m, 1H), 7.11-7.27 (m, 8H), 6.55 (s, 1H), 4.77 (s, 2H), 2.47 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 161.5, 144.6, 144.5, 137.0, 135.5, 135.0, 134.7, 130.0, 129.7, 128.7, 128.6,
128.1, 127.6, 126.4, 120.1, 106.4, 51.4, 21.6. HRMS (ESI+): calcd for C23H20O4NS [M+H]+ : 406.1108, found
406.1107. Mp : 137-138°C.
1-(1-oxo-1H-isochromen-3-yl)azetidin-2-one (6ab). Flash-column chromatography on silica gel with
petroleum ether/ethyl acetate (80:20) as eluent afforded 6ab as a white solid (74 mg, 94 % according to GP9, or
95% according to GP10). 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.5 Hz, 1H), 7.63 (dt, J = 7.6, 1.4 Hz, 1H),
7.36-7.33 (m, 2H), 6.59 (s, 1H), 3.83 (t, J = 4.7 Hz, 2H), 3.17 (t, J = 4.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
163.7, 160.4, 144.1, 138.7, 135.3, 129.8, 126.5, 125.2, 118.4, 89.7, 38.9, 37.2. HRMS (ESI+): calcd for C12H10O3N
[M+H]+ : 216.0655, found 216.0654. Mp : 156-157°C.
(4R)-4-benzyl-3-(1-oxo-1H-isochromen-3-yl)-1,3-oxazolidin-2-one (6ac). Flash-column chromatography
on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6ac as a white gum (80 mg, 94 % according
to GP9, or 83 % according to GP10). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.4 Hz, 1H), 7.71-7.67 (m, 1H),
7.45-7.40 (m, 2H), 7.33-7.22 (m, 5H), 6.99 (s, 1H), 4.90-4.84 (m, 1H), 4.37 (t, J = 8.4 Hz, 1H), 4.25 (dd, J = 9.0,
3.2 Hz, 1H), 3.23 (dd, J = 13.7, 4.1 Hz, 1H), 2.93 (dd, J = 13.7, 8.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
160.4, 153.2, 144.8, 138.4, 135.3, 134.6, 129.6, 129.4, 128.9, 127.4, 127.2, 125.8, 118.4, 93.4, 66.5, 56.0, 39.1.
HRMS (ESI+): calcd for C19H16O4N [M+H]+ : 322.1073, found 322.1073.
2-(1-oxo-1H-isochromen-3-yl)-2,3-dihydro-1H-1,2-benzothiazole-1,1-dione (6ad). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave (6ad) as a white solid (69
mg, 82 % according to GP9, or 94 % according to GP10). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 8.3 Hz,
1H), 7.88 (d, J = 7.8 Hz, 1H), 7.75-7.69 (m, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.47-7.42 (m,
2H), 6.65 (s, 1H), 5.08 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 160.8, 143.9, 138.2, 135.4, 133.8, 133.7, 131.5,
129.8, 129.7, 127.3, 125.7, 124.8, 121.7, 118.8, 92.8, 48.1. HRMS (ESI+): calcd for C16H12O4NS [M+H]+ :
314.0481, found 314.0480. Mp : 225-226°C.
24
N-(2-((tert-butyl(dimethyl)silyl)oxy)ethyl)-4-methyl-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide
(6ae). Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded
6ae as a white solid (78 mg, 88 % according to GP9, or 81 % according to GP10). 1H NMR (400 MHz, CDCl3):
δ 8.22 (d, J = 9.3 Hz, 1H), 7.74-7.67 (m, 3H), 7.52-7.46 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 3.82 (t, J
= 5.7 Hz, 2H), 3.70 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H), 0.77 (s, 9H), -0.03 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
161.6, 145.6, 144.4, 137.3, 135.6, 135.1, 129.9, 129.7, 128.5, 127.5, 126.3, 120.2, 105.2, 61.9, 49.9, 25.6, 21.6,
18.0, -5.5. HRMS (ESI+): calcd for C24H32O5NSiS [M+H]+ : 474.1764, found 474.1764. Mp : 92-93°C.
Benzyl 1-(1-oxo-1H-isochromen-3-yl)-1H-pyrrole-2-carboxylate (6af). Flash-column chromatography on
silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6af as a colorless oil (74 mg, 86 % according
to GP9, or 89 % according to GP10). 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.9 Hz, 1H), 7.78-7.74 (m, 1H,),
7.59-7.54 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.31-7.25 (m, 5H), 7.17 (d, J = 3.9, 1.7 Hz, 1H), 7.08-7.07 (m, 1H),
6.55 (s, 1H), 6.34 (t, J = 3.3 Hz, 1H), 5.23 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 161.1, 159.5, 146.3, 136.8,
135.6, 135.1, 130.1, 129.0, 128.7, 128.4, 128.2, 126.2, 124.4, 120.6, 120.1, 110.5, 101.2, 66.2. HRMS (ESI+):
calcd for C21H16O4N [M+H]+ : 346.1073, found 346.1075. Mp : 132-133°C.
Methyl 1-(1-oxo-1H-isochromen-3-yl)-1H-indole-3-carboxylate (6ag). Flash-column chromatography on
silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6ag as a white solid (75 mg, 89 % according
to GP9, or 94 % according to GP10). 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.3 Hz, 1H), 8.26-8.24 (m, 1H),
8.22 (s, 1H), 7.87-7.85 (m, 1H), 7.80-7.76 (m, 1H), 7.56-7.52 (m, 2H), 7.42-7.36 (m, 2H), 6.63 (s, 1H), 3.95 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 164.5, 160.3, 145.9, 137.4, 135.5, 135.2, 131.3, 130.2, 128.2, 127.3, 125.9,
124.7, 123.7, 122.2, 119.4, 112.4, 111.7, 95.1, 51.4. HRMS (ESI+): calcd for C19H14O4N [M+H]+ : 320.0917, found
320.0917. Mp : 177-178°C.
N-benzyl-N-(1-oxo-1H-isochromen-3-yl)methanesulfonamide (6ah). Flash-column chromatography on
silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6ah as a white solid (328 mg, 74 %
according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 8.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.52-7.48 (m,
1H), 7.40-7.26 (m, 6H), 6.37 (s, 1H), 4.85 (s, 2H), 3.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 144.6, 136.8,
25
135.1, 134.7, 129.8, 128.9, 128.8, 128.7, 128.4, 126.5, 120.4, 106.5, 52.4, 40.1. HRMS (ESI+): calcd for
C17H16O4NS [M+H]+ : 330.0794, found 330.0794. Mp : 135-136°C.
N-benzyl-4-nitro-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide (6ai). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6ai as a white solid (253
mg, 68 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 7.9 Hz, 1H),
8.03-8.01 (m, 2H), 7.72-7.68 (m, 1H), 7.54-7.50 (m, 1H), 7.40 (d, J = 7.8 Hz, 1H),7.33-7.26 (m, 5H), 6.49 (s, 1H),
4.76 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 161.1, 150.5, 144.3, 143.7, 136.5, 135.3, 133.9, 129.9, 129.2, 128.9,
128.8, 128.8, 128.5, 126.6, 124.6, 120.3, 107.2, 52.4. HRMS (ESI+): calcd for C22H17O6N2S [M+H]+ : 437.0801,
found 437.0803. Mp : 196-197°C.
N-(2-bromobenzyl)-4-methyl-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide (6aj). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent gave 6aj as a white solid (455
mg, 64 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H),
7.70-7.66 (m, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.51-7.47 (m, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz,
2H), 7.29-7.24 (m, 1H), 7.13-7.09 (m, 1H), 6.56 (s, 1H), 4.87 (s, 2H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.4, 144.7, 144.6, 136.9, 135.4, 135.0, 134.3, 133.0, 130.7, 130.0, 129.7, 129.6, 128.7, 127.7, 127.6, 126.4,
123.8, 120.3, 106.4, 51.5, 21.7. HRMS (ESI+): calcd for C23H19O4NSBr [M+H]+ : 484.0212, found 484.0210. Mp :
178-179°C.
N-(3-chloropropyl)-4-methyl-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide (6ak). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6ak as a colorless oil (338
mg, 71 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.9 Hz, 1H), 7.76 (dd, J = 7.6, 1.3 Hz,
1H), 7.68 (d, J = 8.4 Hz, 2H), 7.56-7.50 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.71 (s, 1H), 3.72 (t, J = 6.7 Hz, 2H),
3.61 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H), 2.07 (dt, J = 12.7, 6.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 161.5, 144.8,
144.7, 136.9, 135.2, 135.0, 130.0, 129.8, 128.9, 127.6, 126.5, 120.3, 106.2, 45.2, 41.4, 31.4, 21.6. HRMS (ESI+):
calcd for C19H19O4NSCl [M+H]+ : 392.0717. found 392.0718.
26
N-(2-(3,4-dimethoxyphenyl)ethyl)-4-methyl-N-(1-oxo-1H-isochromen-3-yl)benzenesulfonamide (6al).
Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6al as an
orange oil (300 mg, 84 % according to GP11 or 88 % according to GP12). 1H NMR (400 MHz, CDCl3): δ 8.23
(d, J = 7.3 Hz, 1H), 7.73 (dt, J = 7.8, 1.3 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.45 (d, J = 7.8 Hz,
1H), 7.27 (d, J = 9.1 Hz, 2H), 6.71-6.69 (m, 3H), 6.56 (s, 1H), 3.83-3.77 (m, 8H), 2.88-2.85 (m, 2H), 2.41 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 161.7, 148.9, 147.8, 144.9, 144.5, 137.1, 135.4, 135.1, 130.1, 129.9, 129.8, 129.7,
128.7, 127.5, 126.4, 120.9, 120.2, 112.1, 111.2, 106.1, 55.9, 49.1, 34.9, 21.6. HRMS (ESI+): calcd for C26H26O6NS
[M+H]+ : 480.1475, found 480.1475.
tert-butyl (1-oxo-1H-isochromen-3-yl)(phenyl)carbamate (6am). Flash-column chromatography on silica
gel with petroleum ether/ethyl acetate (85:15) as eluent gave 6am as a colorless oil (423 mg, 81% according to
GP11 or 76% according to GP12). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.1 Hz, 1H), 7.73-7.69 (m, 1H),
7.53-7.49 (m, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.39-7.37 (m, 4H), 7.31-7.27 (m, 1H), 6.49 (s, 1H), 1.50 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 162.1, 152.6, 148.5, 140.1, 137.5, 134.9, 129.8, 129.1, 128.2, 127.1, 126.5, 126.0,
120.1, 102.7, 82.8, 28.1. HRMS (ESI+): calcd for C20H20O4N [M+H]+ : 338.1386, found 338.1384.
N-benzyl-N-(7-bromo-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide (6b). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6b as a white solid (1.3 g,
88% according to GP11 or 79 % according to GP12). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 2.0 Hz, 1H),
7.75 (dd, J = 8.4, 2.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 3H), 7.30-7.23 (m, 5H), 6.48 (s, 1H),
4.72 (s, 2H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.2, 144.9, 144.8, 138.1, 135.7, 135.3, 134.5, 132.2,
130.0, 128.7, 128.7, 128.2, 127.9, 127.5, 122.1, 121.5, 105.5, 51.4, 21.6. HRMS (ESI+): calcd for C23H19BrO4SN
[M+H]+ : 484.0212, found 484.0213. Mp : 175-176°C.
N-benzyl-N-(7-fluoro-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide (6c). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6c as a white solid (269
mg, 83 % according to GP11, or 74 % according to GP12). 1H NMR (400 MHz, CDCl3): δ 7.86-7.83 (m, 1H),
7.74 (d, J = 8.3 Hz, 2H), 7.43-7.41 (m, 3H), 7.36 (d, J = 8.2 Hz, 4H), 7.33-7.28 (m, 2H), 6.52 (s, 1H), 4.74 (s, 2H),
27
2.48 (s, 3H), 13C NMR (100 MHz, CDCl3): δ 162.15 (d, J = 250 Hz), 160.7, 144.8, 144.1, 135.4, 134.6, 133.4,
130.1, 128.7, 128.7, 128.6, 128.1, 127.6, 123.4, 121.9, 115.3, 105.9, 51.5, 21.6. 19F NMR (376 MHz, CDCl3) δ -
109.6. HRMS (ESI+): calcd for C23H19FSNO4 [M+H]+ : 424.1013, found 424.1013. Mp : 162-163°C.
N-benzyl-N-(7-chloro-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide (6d). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6d as a white solid (275
mg, 82% according to GP11, or 86 % according to GP12). 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 2.2 Hz,
1H), 7.73 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 8.4, 2.2 Hz, 1H), 7.37-7.34 (m, 6H), 7.33-7.26 (m, 2H), 6.52 (s, 1H),
4.75 (s, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.4, 144.9, 144.8, 135.4, 135.4, 134.6, 134.5, 130.1,
129.2, 128.7, 128.7, 128.2, 127.8, 127.6, 121.3, 105.5, 51.5, 21.6. HRMS (ESI+): calcd for C23H19ClSNO4 [M+H]+
: 440.0717, found 440.0716. Mp : 159-160°C.
N-benzyl-N-(7-methoxy-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide (6e). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6e as a white solid (290
mg, 87 % according to GP11, or 84 % according to GP12). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.3 Hz,
2H), 7.61 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 4H), 7.32-7.25 (m, 5H), 6.49 (s, 1H), 4.73 (s, 2H), 3.89 (s, 3H),
2.47 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.8, 159.9, 144.5, 142.6, 135.5, 134.8, 130.5, 129.9, 128.7, 128.6,
128.1, 128.0, 127.6, 124.6, 121.5, 110.3, 106.8, 55.7, 51.5, 21.6. HRMS (ESI+): calcd for C24H22O5NS [M+H]+ :
436.1213, found 436.1212. Mp : 155-156°C.
N-benzyl-4-methyl-N-(1-oxo-1H-benzo[g]isochromen-3-yl)benzenesulfonamide (6f). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6f as a white solid (245
mg, 47 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.87 (d, J =
8.3 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.65-7.61 (m, 1H), 7.57-7.52 (m, 2H), 7.38-7.22 (m, 6H), 6.62
(s, 1H), 4.74 (s, 2H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.9, 144.5, 143.1, 136.4, 135.6, 134.8, 132.5,
132.1, 131.2, 130.0, 129.7, 129.6, 128.7, 128.6, 128.1, 127.8, 127.6, 127.0, 125.1, 118.3, 107.0, 51.4, 21.6. HRMS
(ESI+): calcd for C27H22NSO4 [M+H]+ : 456.1264, found 456.1267. Mp : 180-181°C.
28
N-benzyl-4-methyl-N-(8-oxo-8H-pyrano[4,3-e]pyridin-6-yl)benzenesulfonamide (6g). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent gave 6g as a white solid (250
mg, 82 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.81 (dd, J = 4.4, 1.6 Hz, 1H), 7.75 (dd, J = 8.1,
1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 8.4, 4.4 Hz, 2H), 7.37-7.24 (m, 8H), 6.52 (s, 1H), 4.75 (s, 2H),
2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.1, 151.1, 145.5, 144.9, 137.2, 135.1, 134.5, 134.4, 134.0, 130.1,
128.7, 128.7, 128.7, 128.2, 127.5, 104.1, 51.3, 21.6. HRMS (ESI+): calcd for C22H19N2SO4 [M+H]+ : 407.1060,
found 407.1058. Mp : 150-151°C.
N-4-dimethyl-N-(1-oxo-1,9-dihydropyrano[3,4-b]indol-3-yl)benzenesulfonamide (6h). According to
GP11 using TFA (3 equiv) with a completion of the reaction in 30 minutes (TLC monitoring). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent gave 6h as a white solid (122
mg, 40 %). 1H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.58-
7.51 (m, 2H), 7.34-7.29 (m, 3H), 7.15 (s, 1H), 3.24 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 156.0,
145.3, 144.5, 139.9, 134.2, 129.9, 128.6 , 127.8, 126.3 , 122.2 , 121.8 , 121.6 , 120.8 , 112.8 , 100.4, 36.0, 21.6.
HRMS (ESI+): calcd for C19H17N2SO4 [M+H]+ : 369.0903, found 369.0903. Mp : 209-210°C.
N,4-dimethyl-N-(2-(methylsulfanyl)-8-oxo-8H-pyrano[3,4-d]pyrimidin-6-yl)benzenesulfonamide (6i).
Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent gave 6i as a white
solid (46 mg, 68 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.2 Hz, 2H), 6.64 (s, 1H), 3.20 (s, 3H), 2.66 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
173.6 , 158.0, 157.5 , 145.1 , 142.3 , 133.9 , 130.1, 127.5, 125.8 , 97.6, 35.0, 21.6, 14.4. HRMS (ESI+): calcd for
C16H16N3O4S2 [M+H]+ : 378.0576, found 378.0576. Mp : 134-135°C.
N,4-dimethyl-N-(5-oxo-5H-pyrano[3,4-e]pyrazin-7-yl)benzenesulfonamide (6j). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (75:25) as eluent gave 6j as a white solid (95 mg,
45 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.86 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 7.74
(d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.85 (s, 1H), 3.31 (s, 3H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3):
29
δ 158.4, 151.8 , 151.4 , 150.5 , 145.2 , 144.7 , 134.3 , 132.4 , 130.1, 127.6, 99.4, 35.0, 21.6. HRMS (ESI+): calcd
for C15H14SN3O4 [M+H]+ : 332.0699, found 332.0700. Mp : 111-112°C.
N,4-dimethyl-N-(1-oxo-1H-pyrano[3,4-b][1]benzofuran-3-yl)benzenesulfonamide (6k). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6k as a white solid (127
mg, 82 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.8 Hz, 1H), 7.69-7.63 (m, 4H), 7.49-
7.45 (m, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.06 (s, 1H), 3.24 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
157.9, 152.9 , 149.0 , 144.9 , 137.8 , 133.9 , 132.4 , 130.6 , 130.0, 127.6, 124.5 , 122.4 , 122.4 , 113.2 , 97.2, 35.5,
21.6. HRMS (ESI+): calcd for C19H16O5SN [M+H]+ : 370.0743, found 370.0742. Mp : 185-186°C.
N-benzyl-4-methyl-N-(7-oxo-7,7a-dihydro-3aH-thieno[2,3-c]pyran-5-yl)benzenesulfonamide (6l). Flash-
column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6l as a white
solid (136 mg, 75 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 8.4
Hz, 2H), 7.33 (dd, J = 8.0, 1.9 Hz, 4H), 7.30-7.24 (m, 3H), 7.12 (d, J = 5.1 Hz, 1H), 6.67 (s, 1H), 4.73 (s, 2H),
2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.0, 147.2 , 147.0 , 144.7 , 137.1 , 135.3 , 134.6 , 130.0, 128.7,
128.6, 128.1 , 127.6, 125.0 , 122.9 , 103.6, 51.6, 21.6. HRMS (ESI+): calcd for C21H18O4S2N [M+H]+ : 412.0671,
found 412.0671. Mp : 156-157°C.
N,4-dimethyl-N-(1-oxo-1H-[1]benzothieno[2,3-c]pyran-3-yl)benzenesulfonamide (6m). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6m as a white solid (229
mg, 88 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H),
7.67-7.55 (m, 4H), 7.31 (d, J = 7.9 Hz, 2H), 7.19 (s, 1H), 3.26 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 157.5, 150.0 , 144.9 , 144.1 , 143.7 , 134.1 , 133.9 , 130.0, 129.5 , 127.6, 125.6 , 124.1 , 123.5 , 121.7 , 98.1,
35.4, 21.6. HRMS (ESI+): calcd for C19H16S2NO4 [M+H]+ : 386.0515, found 386.0515. Mp : 196-197°C.
N-benzyl-4-methyl-N-(4-oxo-4,5-dihydro-3-benzoxepin-2-yl)benzenesulfonamide (6n). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 6n as a white solid (330
mg, 68 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.1 Hz, 2H), 7.35-7.28 (m, 9H), 7.18-
30
7.16 (m, 2H), 6.50 (s, 1H), 4.58 (s, 2H), 3.09 (s, 2H), 2.45 (s, 3H).13C NMR (100 MHz, CDCl3): δ 166.9, 144.4 ,
140.1 , 135.4 , 134.5 , 131.4 , 129.9, 129.7 , 129.4 , 129.2, 128.7 , 128.3 , 128.0 , 127.9, 127.8 , 116.3, 51.7, 40.2,
21.6. HRMS (ESI+): calcd for C24H22O4SN [M+H]+ : 420.1264, found 420.1264. Mp : 78-79°C.
N,4-dimethyl-N-(4-oxo-4,5-dihydro-3-benzoxepin-2-yl)benzenesulfonamide (6o). Flash-column
chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 6o as a colorless oil
(103 mg, 49 % according to GP11). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.3 Hz, 2H), 7.39-7.29 (m, 6H),
6.61 (s, 1H), 3.68 (s, 2H), 3.16 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7, 144.4 , 142.9 , 134.9
, 129.9, 129.7 , 129.6 , 128.9 , 128.2 , 128.1 , 127.8, 113.2, 40.7, 36.5, 21.6. HRMS (ESI+): calcd for C18H18O4SN
[M+H]+ : 344.0951, found 344.0953.
N-benzyl-N-(7-(3,5-dimethoxyphenyl)-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide (7a).
Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 7a as a white
solid (101 mg, 90% according to GP13). 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 1.8 Hz, 1H), 7.87 (dd, J =
8.2, 1.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.41-7.23 (m, 8H), 6.93-6.87 (m, 3H), 6.55 (s, 1H), 4.74 (s, 2H), 3.80
(s, 3H), 3.75 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.6, 153.9 , 150.6 , 144.6 , 144.3 , 139.2 ,
136.5 , 135.7 , 135.5 , 134.7 , 130.1, 130.0 , 129.3 , 128.7, 128.6, 128.1 , 127.6, 126.0 , 120.0 , 116.4 , 114.1 ,
112.5 , 106.3, 56.2, 55.8, 51.4, 21.6. HRMS (ESI+): calcd for C31H27O6NS [M+Na]+ : 564.1451, found 564.1454.
Mp : 159-160°C.
N-(7-(1-benzothiophen-2-yl)-1-oxo-1H-isochromen-3-yl)-N-benzyl-4-methylbenzenesulfonamide (7b).
Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 7b as a
white solid (73 mg, 67 % according to GP13). 1H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 1.9 Hz, 1H), 8.00 (dd,
J = 8.2, 2.0 Hz, 1H), 7.86-7.84 (m, 1H), 7.82-7.80 (m, 1H), 7.78-7.74 (m, 2H), 7.66 (s, 1H), 7.46-7.44 (m, 1H),
7.41-7.27 (m, 9H), 6.57 (s, 1H), 4.78 (s, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.3, 144.7 , 141.9 ,
140.4 , 139.7 , 136.4 , 135.4 , 134.9 , 134.7 , 132.7 , 130.1 , 129.7 , 128.7 , 128.7 , 128.7 , 128.2 , 127.9 , 127.9 ,
127.6 , 127.2 , 127.1 , 126.8 , 125.0 , 124.9 , 124.0 , 122.4 , 120.9 , 120.6 , 106.0, 51.4, 21.6. HRMS (ESI+): calcd
for C31H24O4NS2 [M+H]+ : 538.1141, found 538.1141. Mp : 159-160°C.
31
N-benzyl-N-(7-((4-methoxyphenyl)ethynyl)-1-oxo-1H-isochromen-3-yl)-4-methylbenzenesulfonamide
(7c). Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent afforded 7c
as an orange solid (141 mg, 85% according to GP14). 1H NMR (400 MHz, CDCl3): δ 8.31-8.29 (m, 1H), 7.77-
7.73 (m, 3H), 7.49 (d, J = 8.8 Hz, 2H), 7.38-7.26 (m, 9H), 6.91 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H), 4.76 (s, 2H), 3.86
(s, 3H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.8, 160.1 , 144.9 , 144.7 , 137.3 , 136.0 , 135.4 , 134.7 ,
133.2, 132.4 , 130.0, 128.7, 128.7, 128.1 , 127.6, 126.4 , 124.4 , 120.2 , 114.5, 105.9, 92.1, 86.6, 55.4, 51.4, 21.6.
HRMS (ESI+): calcd for C32H26O5NS [M+H]+ : 536.1526, found 536.1526. Mp : 161-162°C.
N-benzyl-4-methyl-N-(1-oxo-7-((4-(trifluoromethyl)phenyl)ethynyl)-1H-isochromen-3-
yl)benzenesulfonamide (7d). Flash-column chromatography on silica gel with petroleum ether/ethyl acetate
(80:20) as eluent gave 7d as a white solid (138 mg, 78% according to GP14). 1H NMR (400 MHz, CDCl3): δ 8.32
(s, 1H), 7.77-7.71 (m, 3H), 7.62 (s, 3H), 7.37-7.24 (m, 9H), 6.53 (s, 1H), 4.75 (s, 2H), 2.45 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 160.6, 145.4 , 144.8 , 137.5 , 136.9 , 135.4 , 134.6 , 132.9 , 131.9, 130.1, 128.7, 128.2 , 127.6,
126.6 , 125.4 , 125.3 , 123.1 , 120.2 , 105.5, 90.2, 89.9, 51.4, 21.6. HRMS (ESI+): calcd for C32H23O4NSF3 [M+H]+
: 574.1294, found 574.1297. Mp : 174-175°C.
N-benzyl-4-methyl-N-(1-oxo-7-((trimethylsilyl)ethynyl)-1H-isochromen-3-yl)benzenesulfonamide (7e).
Flash-column chromatography on silica gel with petroleum ether/ethyl acetate (80:20) as eluent gave 7e as a white
gum (141 mg, 91 % according to GP14). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 7.71-7.67 (m, 3H), 7.35-
7.23 (m, 9H), 6.49 (s, 1H), 4.72 (s, 2H), 2.44 (s, 3H), 0.25 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 160.6, 145.1 ,
144.7 , 137.7 , 136.5 , 135.4 , 134.6 , 133.2 , 130.0, 128.7, 128.6, 128.1 , 127.5, 126.3 , 123.7 , 120.0 , 105.7, 103.0,
97.3, 51.4, 21.6, -0.2. HRMS (ESI+): calcd for C28H28O4NSSi [M+H]+ : 502.1502, found 502.1502.
N-benzyl-N-(7-((E)-2-(4-methoxyphenyl)ethenyl)-1-oxo-1H-isochromen-3-yl)-4-
methylbenzenesulfonamide (7f). To a mixture of (6b) (100 mg, 0.20 mmol, 1 equiv), Pd(OAc)2 (3 mg, 0.01 mmol,
5 mol %), P(o-tol)3 (6 mg, 0.02 mmol, 0.1 equiv), and Et3N (37 µl, 0.26 mmol, 1.3 equiv) in DMF (1.0 mL) was
added 4-vinylanisole (55 µl, 0.40 mmol, 2 equiv). The reaction mixture was degassed under argon and heated at
100oC for 20 h. After cooling down to room temperature, water (25 mL) was added and the reaction mixture was
32
extracted with ethyl acetate (3 x 30 mL). The organic extracts were combined, washed with water (2 x 25 mL) and
brine (50 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was
purified by flash-column chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent to give
7f as a yellow gum (66 mg, 62 %). 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.80 (dd, J = 8.2, 1.9 Hz, 1H),
7.74 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.38-7.26 (m, 8H), 7.19 (d, J = 16.2 Hz, 1H), 7.00 (d, J = 16.2
Hz, 1H), 6.95-6.93 (m, 2H), 6.54 (s, 1H), 4.76 (s, 2H), 3.86 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
161.7, 159.9 , 144.6 , 144.0 , 138.6 , 135.5 , 135.5 , 134.7 , 132.6 , 130.5 , 130.0, 129.3 , 128.7, 128.6, 128.1 ,
128.0, 127.6, 126.8 , 126.7, 124.4, 120.5 , 114.3 , 106.5, 99.9 , 55.8, 51.4, 21.6. HRMS (ESI+): calcd for
C32H27O5NS [M+H]+ : 538.1682, found 538.1678.
5H-isochromeno[3,4-c]isoquinolin-5-one (8). A mixture of 6aj (100 mg, 0.2 mmol, 1 equiv), TBAB (73 mg,
0.22 mmol, 1.1 equiv) and anhydrous KOAc (49 mg, 5 mmol, 2.5 equiv) in anhydrous DMF (7 mL) was stirred
under argon. Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%) was added, and the mixture was stirred at 140 °C until
completion (16 h). The mixture was cooled down to room temperature, and H2O (3 mL) was added. The organic
phase was extracted with EtOAc (3 x 10 mL) and washed with H2O (2x 10 mL), and brine (15 mL). The organic
layer was dried with MgSO4. Evaporation of solvents furnished a crude residue which was purified by flash-
column chromatography on silica gel with petroleum ether/ethyl acetate (70:30) as eluent to give 8 as a white solid
(5 mg, 10 %). 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H), 8.82 (d, J = 8.7 Hz, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.57
(dd, J = 7.9, 1.5 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.97-7.92 (m, 2H), 7.73-7.68 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 160.8, 153.1 , 134.6 , 133.7 , 132.3 , 131.1 , 129.6 , 129.4 , 128.9 , 127.7 , 127.1 , 126.5 , 126.4 , 124.1
33
4. Crystal structure determination of 6kCrystal Data for C19H15NO5S (M = 369.38 g/mol): triclinic, space group P-1(no. 2), a = 7.0651(2) Å, b = 7.1483(3) Å, c = 17.7906(5) Å, = 83.865(3)°, = 81.293(2)°, = 75.066(3)°,V = 855.96(5) Å3, Z = 2, T = 293 (2) K, μ(MoKα) =0.220 mm-1, Dcalc = 1.433 g/cm3, 16370 reflections measured (3.629° ≤ ≤ 29.645°), 4388 unique (Rint=0.049) which were used in all calculations. The final R1 was 0.0425 (for 3591 I > 2σ(I)) and wR2 was 0.1244 (all data). the final difference Fourier map showed minimum and maximum values of 0.334 and -0.417 e Å–3, respectively. The single crystal X-ray diffraction experiment was carried out using a RIGAKU XtaLabPro diffractometer equipped with a Mo microfocus sealed tube generator coupled to a double-bounce confocal Max-Flux® multilayer optic and a HPAD PILATUS3 R 200K detector, on a colourless crystalline parallelepipedic stick. was the data collection and reduction were performed by the CrysalisPro1 software. The structure was solved by Iterative dual-space direct methods (SHELXD program)2 in the centrosymmetric triclinic space group. Structure refinement was performed by full-matrix least-squares methods (SHELXL-2018/1 program)3 on 238 parameters, weighted refinement: w = 1/[σ2(Fo
2) + (0.0632P)2 + 0.1153P] with P = [max(Fo2,0) + 2Fo
2]/3 and hydrogen atoms located from difference Fourier synthesis and refined isotropically assuming a riding motion model and their isotropic U's were set to -1.2 (-1.5 for methyl) times the equivalent isotropic displacement parameter of the parent atom. The two methyl groups appeared disordered with two sites rotated by 60 degrees from one another. The corresponding site occupation factors were refined via a 'free variable' so that their sum is unity (e.g. 21 and -21) and the recommended HFIX123 riding model was employed. All non-hydrogen atoms were refined with anisotropic displacement parameters.CCDC 1823711(compound 6k) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Ortep view of compound 6k. Disordered methyls are not shown for clarity. Ellipsoids are drawn at 30% of probability.
1 Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, Oxfordshire, England.2 Schneider, T.R., Sheldrick, G. M. (2002). Acta Crystallogr., D58, 1772-1779.3 Sheldrick, G. M. (2015). Acta Crystallogr., C71, 3-8.