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A facile method for regioselective synthesis of new N-acetyl/thioacetyl-(E)-

stilbene benzenesulfonamide derivatives via N-acetyl/thioacetyl sulfonamide

formation

Maryam Ahmadian-Moghaddam a , Ahmadreza Bekhradnia a, b*, and Monire Tatar a

aPharmaceutical Sciences Research Center, Department of Medicinal Chemistry, Mazandaran

University of Medical Sciences, Sari, Iran

bDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg,

Sweden

Email: [email protected]

Supplemental Materials

General Procedure for the Synthesis of 4-bromobenzenesulfonyl chloride

In order to produce the desired sulfonyl chloride, TMSCl (15 mmol) and KNO3 (15 mmol) were

added to a mixture of 4-bromothiophenol (7 mmol) dissolved in dichloromethane (40 mL). The

glass vessel was then sealed and the reaction mixture was allowed to be stirred at 30˚C. The

progress of the reaction was monitored by TLC. After completion, the mixture was cooled to

room temperature and then filtered. The filtrate was washed with water and brined and dried

using anhydrous MgSO4. Finally, the solvent was evaporated to yield the desired sulfonyl

chloride.

Yield: 90%, mp: 74⁰C; 73-75 ˚C [lit.21], C6H4BrClO2S; MW: 255.3. IR (KBr,cm-1) νmax: 1166.4,

1374.4 (S=O). 1H-NMR (400 MHz, CDCl3): δ 7.7-8.0 (m, 4H, phenyl hydrogens).

13C-NMR (100 MHz, CDCl3): δ 128,130,133,143 (Aromatic carbons).

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General procedure for the synthesis of the corresponding acetyl/thioacetyl sulfonamide

A solution of acetamide/thioacetamide (7 mmol) in acetonitrile (20 mL) was added gradually to a

solution of p-bromosulfonyl chloride (7 mmol) in acetonitrile (20 mL). The reaction vessel was

sealed and the mixture was stirred for 24 h at room temperature. The highly purified

corresponding acetyl/thioacetyl sulfonamide was obtained by the recrystallization of the desired

product in ethanol and water

N-Acetyl-4-bromobenzenesulfonamide

Yield: 90%, mp: 100 C; C⁰ 8H8BrNO3S; MW: 277.9. IR (KBr,cm-1) νmax : 1811.6 (C=O), 2872. 1

(sp3 C-H). 1H-NMR (400 MHz, CDCl3): δ 3.44 (s, 3H, -CH3), 7.36-7.43 (m, 4H, phenyl

hydrogens). 13C-NMR (100 MHz, CDCl3): δ 24.0 (CH3); 121.6, 129.4, 132.2, 135.7 (Aromatic

carbons); 170.3 (C=O).

N-Thioacetyl-4-bromobenzenesulfonamide

Yield: 91%, mp: 119 C;⁰ C8H8BrNO2S2; MW: 293.9. IR (KBr, cm-1) νmax : 1060.7 (C=S), 2871.7

(sp3 C-H), 3428.1 (N-H). 1H-NMR (400 MHz, CDCl3): δ 3.32 (s,3H,-CH3) , 7.36 (d, J=8.7 Hz,

2H, phenyl, H-3, H-5), 7.45 (d, J=8.7 Hz, 2H, phenyl, H-2, H-6).

General procedure for the synthesis of the stilbene derivatives

To a mixture of the synthesized acetyl/thioacetyl sulfonamide derivative (7 mmol), LiOAc-H2O

(1.5g, 22.7 mmol), LiCl (0.4 g, 9.4 mmol), Bu4N+Cl- (3.5 g, 12.5 mmol) and Pd(OAc)2 (50 mg) in

DMF, p-bromostyrene (6 mmol) was added gradually. The mixture was then heated for 18 hours

at a temperature of about 118˚C while being stirred. The resultant mixture was then cooled to

room temperature. After adding a saturated solution of sodium bicarbonate, the crude product

was extracted by ethyl acetate. The resulting mixture was dried with Na2SO4 and the organic

solvent evaporated under reduced pressure. Subsequent recrystallization of the crude product in

ethanol and water furnished the pure products

(E)-N-Acetyl/Thioacetyl–4-(2-(phenyl)ethenyl)benzenesulfonamide (7a-b)

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7a: Yield: 73%; 1H-NMR (400 MHz, CDCl3): δ 2.40 (s, 3H, -CH3); 7.50-7.80 (m, 9H, phenyl

hydrogens); 7.85 (d, Jab=14 Hz, 1H, Ha); 7.95 (d, Jab=14 Hz, 1H, Hb). 13C-NMR (100 MHz,

CDCl3): δ 21.1 (CH3); 119.4, 121.7(Olefinic carbons); 125.2, 128.3, 130.5, 132.0, 137.1, 141.1,

149.1, 150.0 (Aromatic carbons); 168.2 (C=O). Elem. Anal. for (E)-N-Acetyl–4-(2-

(phenyl)ethenyl)benzenesulfonamide: C, 63.85%; N, 4.61%; H, 5.05%. Anal. Calcd.: C, 63.77%;

N. 4.65%; H, 5.02%.

7b: Yield: 75%, mp ~160 ˚C; C16H15NO2S2; MW: 317.4. 1H-NMR (400 MHz, CDCl3): δ 2.20 (s,

3H, -CH3); 7.36-7.44 (m, 9H, phenyl hydrogens); 7.56 (d, Jab=12 Hz, 1H, Ha); 7.65 (d, Jab=12

Hz, 1H, Hb). Elem. Anal. for (E)-N-Thioacetyl–4-(2-(phenyl)ethenyl) benzenesulfonamide is the

following: C, 60.59%; N, 4.39%; H, 4.79%. Anal. Calcd.: C, 60.56%; N.

4.1%; H, 4.76%.

(E)-N-Acetyl/Thioacetyl–4-(2-(methylphenyl)ethenyl)benzenesulfonamide (7c-d)

7c: Yield: 79%, mp ~ 170 ˚C; C17H17O3NS; MW: 309.95 IR (KBr,cm-1) νmax: 1643.1 (C=C). 1H-

NMR (400 MHz, CDCl3), δ 3.1-3.2 (s, 6H, -CH3); 7.35-7.5, 8.03-8.08 (8H, phenyl hydrogens);

8.1 (d, 1H, Ha, J=8.8); 8.3 (d, 1H, Hb, J =8.4).13C-NMR (100 MHz, CDCl3), δ 27, 48, 121, 125,

128, 131, 133, 145, 150, 150, 153; 172 (C=O). Elem. Anal. for (E)-N-Acetyl–4-(2-

(methylphenyl)ethenyl) benzenesulfonamide: C, 64.79%; N, 4.40%; H, 5.42%. Anal. Calcd.: C,

64.76%; N. 4.44%; H, 5.39%.

7d: Yield: 82%, mp ~160 ˚C; C17H18O2NS2; MW: 331. 1H-NMR (400 MHz, CDCl3), δ 2-3 (s, 6H,

-CH3); 7.46-74, 8.04-8.07 (8H, phenyl); 8.2 (d, 1H, Ha, J=10); 8.4 (d, 1H, Hb, J =10). Elem.

Anal. for (E)-N-Thioacetyl–4-(2-(methylphenyl)ethenyl) benzenesulfonamide: C, 61.58%; N,

4.25%; H, 5.11%. Anal. Calcd.: C, 61.63%; N. 4.23%; H, 5.13%.

(E)-N-Acetyl/Thioacetyl–4-(2-(methoxyphenyl)ethenyl)benzenesulfonamide(7e-f)

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7e: Yield: 91%; 1H-NMR (400 MHz, CDCl3): δ 2.32 (s, 3H,-CH3); 7.15-7.25 (m, 4H, 4-

methoxyphenyl hydrogens); 7.33-7.55 (m, 4H, acetylsulfonamidophenyl hydrogens); 7.75 (d,

1H, Ha); 7.83 (d, 1H, Hb). 13C-NMR (100 MHz, CDCl3): δ 18.5 (CH3); 115.3, 118.2(Olefinic

carbons); 122.5, 126.8, 129.2, 130.1, 133.6, 139.3, 141.1, 143.5 (Aromatic carbons); 183.6

(C=O). Elem. Anal. for (E)-N-Acetyl–4-(2-(methoxyphenyl)ethenyl) benzenesulfonamide: C,

61.58%; N, 4.24%; H, 5.15%. Anal. Calcd.: C, 61.61%; N. 4.22%; H,

5.17%.

7f: Yield: 90%; 1H-NMR (400 MHz, CDCl3): δ 2.15 (s, 3H,-CH3); 7.10-7.23 (m, 4H, 4-

methoxyphenyl hydrogens); 7.28-7.48 (m, 4H, acetylsulfonamidophenyl hydrogens); 7.60 (d,

1H, Ha); 7.69 (d, 1H, Hb). 13C-NMR (100 MHz, CDCl3): δ 16.2 (CH3); 110.3, 114.5(Olefinic


(C=S). Elem. Anal. for (E)-N-Thioacetyl–4-(2-(methoxyphenyl)ethenyl) benzenesulfonamide: C,

58.73%; N, 3.99%; H, 4.95%. Anal. Calcd.: C, 58.76%; N. 4.03%; H,

4.93%.

(E)-N-Acetyl/Thioacetyl–4-(2-(4-chlorophenyl)ethenyl)benzenesulfonamide(7g-h)

7g: Yield: 90%, mp ~ 170 ˚C; C16H14ClNO3S; MW: 335.4. IR (KBr,cm-1) νmax: 1643.1 (C=C).

1H-NMR (400 MHz, CDCl3): δ 2.62 (s,3H,-CH3); 7.40-7.48 (m, 4H, 4-chlorophenyl hydrogens);

7.67-7.71 (m, 4H, acetylsulfonamidophenyl hydrogens); 7.98 (d, 1H, Ha); 8.19 (d, 1H, Hb); 10.09

(-NH). 13C-NMR (100 MHz, CDCl3): δ 25.6 (CH3); 119.7, 124.1(Olefinic carbons); 125.6, 127.9,

130.9, 131.7, 134.7, 150.1, 150.9, 153.3 (Aromatic carbons); 209.4 (C=O). Elem. Anal. for (E)-

N-Acetyl–4-(2-(4-chlorophenyl)ethenyl) benzenesulfonamide: C, 57.20%; N, 4.20%; H, 4.21%.

Anal. Calcd.: C, 57.23%; N. 4.17%; H, 4.20%.

7h: Yield: 85%; 1H-NMR (400 MHz, CDCl3): δ 2.81 (s, 3H,-CH3); 7.55-7.75 (m, 4H, 4-

chlorophenyl hydrogens); 7.85-8.00 (m, 4H, acetylsulfonamidophenyl hydrogens); 8.15 (d, 1H,

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Ha); 8.27 (d, 1H, Hb). 13C-NMR (100 MHz, CDCl3): δ 27.1 (CH3); 123.5, 126.8(Olefinic


(C=S). Elem. Anal. for (E)-N-Thioacetyl–4-(2-(chlorophenyl)ethenyl) benzenesulfonamide: C,

54.58%; N, 4.04%; H, 4.05%. Anal. Calcd.: C, 54.61%; N. 3.98%; H, 4.01%.

(E)-N-Acetyl/Thioacetyl–4-(2-(fluorophenyl)ethenyl)benzenesulfonamide (7i-j)

7i: Yield: 72%; 1H-NMR (400 MHz, CDCl3): δ 2.85 (s,3H,-CH3); 7.58-7.70 (m, 4H, 4-




(C=O). Elem. Anal. for (E)-N-Acetyl–4-(2-(fluorophenyl)ethenyl) benzenesulfonamide: C,

60.22%; N, 4.41%; H, 4.44%. Anal. Calcd.: C, 60.18%; N. 4.38%; H, 4.42%.

7j: Yield: 70%; 1H-NMR (400 MHz, CDCl3): δ 2.85 (s,3H,-CH3); 7.60-7.77 (m, 4H, 4-




(C=S). Elem. Anal. for (E)-N-Thioacetyl–4-(2-(fluorophenyl)ethenyl) benzenesulfonamide: C,

57.26%; N, 4.22%; H, 4.22%. Anal. Calcd.: C, 57.29%; N. 4.17%; H, 4.20%.

(E)-N- Thioacetyl–4-(2-(butyl)ethenyl)benzenesulfonamide (7l)

Yield: 75%, mp ~ 160 ˚C; C14H19NO3S; MW: 281.3. 1H-NMR (250 MHz, DMSO): δ 0.92 (t,

3H,-CH3); 1.55 (s, 3H, -CH3); 6.16 (d, 1H, Ha); 5.55 (m, 1H, Hb); 1.55 (m, 1H, Hc); 1.25-1.34 (m,

4H, Hd, He); 7.51-7.59 (m, 4H, phenyl hydrogens); 8.90 (-NH).

(E)-N-Acetyl/Thioacetyl–4-((2-methyl-2-methoxycarbonyl)ethenyl) benzenesulfonamide (7m-n)

7m: Yield: 70%, mp ~ 150 ˚C. C13H15NO5S; MW: 297.2. 1H-NMR (250 MHz, DMSO): δ 0.94 (d,

3H, -CH3); 1.25 (s, 3H, -CH3); 1.55 (s, 3H, -CH3 ); 7.40-7.55 (m, 4H, phenyl hydrogens); 1.00

(s, 1H, Ha).

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7n: Yield: 65%, mp ~ 150 ˚C. C13H15NO4S2; MW: 313.3. IR (KBr,cm-1) νmax: 1730.4 (C=O);

1638.2 (C=C); 1149.3-1388.0 (S=O); 3443.8 (N-H).

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Figure S 1: Infrared spectrum of 4-bromobenzenesulfonyl chloride

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Figure S 2: 1H-NMR spectrum of 4-bromobenzenesulfonyl chloride

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Figure S 3: 13C-NMR spectrum of 4-bromobenzenesulfonyl chloride

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Figure S 4: Infrared spectrum of N-thioacetyl-4-bromobenzenesulfonamide

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Figure S 5: 1H-NMR spectrum of N-thioacetyl-4-bromobenzenesulfonamide

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Figure S 6: Expanded 1H-NMR spectrum of

N-thioacetyl-4-bromobenzenesulfonamide

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Figure S 7: Infrared spectrum of N-acetyl-4-bromobenzenesulfonamide

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Figure S 8: 1H-NMR spectrum of N-acetyl-4-bromobenzenesulfonamide

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Figure S 9: 13C-NMR spectrum of N-acetyl-4-bromobenzenesulfonamide

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Figure S 10: 1H-NMR spectrum of Compound 7b:

(E)-N-thioacetyl–4-(2-(phenyl)ethenyl)benzenesulfonamide

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Figure S 11: Expanded 1H-NMR spectrum of Compound 7b:

(E)-N-thioacetyl–4-(2-(phenyl)ethenyl)benzenesulfonamide

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Figure S 12: Infrared spectrum of Compound 7g:

(E)-N-acetyl–4-(2-(4-chlorophenyl)ethenyl)benzenesulfonamide

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Figure S 13: 1H-NMR spectrum of compound 7g:


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Figure S 14: 13C-NMR spectrum of compound 7g:


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Figure S 15: 1H-NMR spectrum of compound 7c:

(E)-N-acetyl–4-(2-(methylphenyl)ethenyl)benzenesulfonamide

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Figure S 16: 1H-NMR spectrum of compound 7d:

(E)-N-thioacetyl–4-(2-(methylphenyl)ethenyl)benzenesulfonamide

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Figure S 17: 1H-NMR spectrum of compound 7e:

(E)-N-acetyl–4-(2-(methoxyphenyl)ethenyl)benzenesulfonamide

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Figure S 18: Infrared spectrum of compound 7n:

(E)-N- thioacetyl–4-((2-methyl-2-methoxycarbonyl)ethenyl)benzenesulfonamide

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