total synthesis and absolute configuration of the natural amino … · 2018. 9. 25. · synthesis...

1

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

2

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.

3

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

4

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

5

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.

6

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.

7

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


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.

8

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

9

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.

10

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


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.

11

tert-butyl 5-fluoro-2-((trimethylsilyl)ethynyl)benzoate (2c). Following the GP2, using (1c) (3 g, 9.31


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


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).


(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


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


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


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


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).


(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).


(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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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.

total synthesis and absolute configuration of the natural amino … · 2018. 9. 25. · synthesis...

Documents