F. Mancuso et al.
Bioorganic & Medicinal Chemistry 44 (2021) 116279
In the second step, TFA (8.56 mmol) was added at 0◦ C and irradiated
4.3.7. 4-(4-(5-Chlorothiophen-2-yl)carbonyl]piperazin-1-yl)carbonyl)
benzenesulfonamide (7e)
in a microwave oven 250 W for 5 min. Upon complete N-Boc-depro-
tection, the reaction mixture was cooled into ice and diluted with DCM
(2 mL) and 2 M K2CO3 solution (2 mL). The mixture was extracted with
DCM (3 × 5 mL), the combined organic layers were dried over Na2SO4,
filtered, and concentrated under vacuo. The residue was treated with
Et2O giving the desired known intermediates 9a-m. The chemical
properties, as well as the structural assignments, for the resulting com-
pounds 9a-m were in good agreement with the literature 39–44. The
registered CAS numbers have been already assigned as reported in
Supplementary Material (Table S2).
Yield: 44% (149 mg); m.p.: 217–219 ◦C; Rf: 0.37. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.68–3.77 (m, 8H, CH2), 7.17 (d, J = 3.9 Hz, 1H, ArH),
7.35 (d, J = 3.9 Hz, 1H, ArH), 7.49 (bs, 2H, NH2), 7.64 (d, J = 8.2 Hz,
2H, ArH), 7.90 (d, J = 8.2 Hz, 2H, ArH). 13C NMR (126 MHz, DMSO-d6):
41.4, 46.4, 125.7, 125.9, 127.0, 127.3, 127.7, 129.5, 132.2, 136.3,
138.6, 144.8, 161.1, 167.9. Anal. for (C16H16ClN3O4S2): C 46.4%, H
3.9%, N 10.15%; Found: C 46.2%, H 3.7%, N 10.3%.
4.3.8. 4-(4-(5-Nitrothiophen-2-yl)carbonyl)piperazin-1-yl)carbonyl)
benzenesulfonamide (7f)
4.3.2. General procedures for the synthesis of 4-(4-(hetero)
Yield: 32% (81 mg); m.p.: 252–254 ◦C; Rf: 0.37. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.43–3.75 (m, 8H, CH2), 7.49 (m, 3H, NH2, ArH), 7.64 (d,
J = 8.2 Hz, 2H, ArH), 7.90 (d, J = 8.2 Hz, 2H, ArH), 8.10 (s, 1H, ArH).
13C NMR (126 MHz, DMSO-d6): 41.7, 46.3, 125.9, 127.69, 127.74,
128.68, 128.79, 129.2, 138.8, 143.7, 145.0, 152.3, 160.6, 168.1. Anal.
for (C16H16N4O6S2): C 45.3%, H 3.8%, N 13.2%; Found: C 45.5%, H
3.7%, N 13.5%.
aroylpiperazine-1-carbonyl)benzenesulfonamide derivatives (7a-m)
The activation of the 4-(aminosulfonyl)benzoic acid (1 M equivalent)
was conducted by addition of HBTU (1 M equivalent) in dime-
thylformamide (DMF) (2 mL); the mixture reaction was stirred for 1 h at
room temperature. Then, a mixture of TEA (2 M equivalents) and
appropriate 4-aroylpiperazine derivatives 9a-m (1 M equivalent) was
added dropwise. The reaction mixture was left overnight at room tem-
perature and then quenched with H2O (10 mL) and extracted with
EtOAc (3 × 10 mL). The organic phase was washed with saturated NaCl
solution, dried with Na2SO4 and concentrated until dryness under
reduced pressure. The residue was purified by crystallization from Et2O
and EtOH to give the desired final compounds 7a-m as white powder.
4.3.9. 4-(4-(1-Benzothiophen-2-ylcarbonyl)piperazin-1-yl]carbonyl)
benzenesulfonamide (7 g)
Yield: 43% (232 mg); m.p.: 244–246 ◦C; Rf: 0.18. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.66–3.82 (m, 8H, CH2), 7.45–7.46 (m, 3H, ArH), 7.49
(bs, 2H, NH2), 7.64 (d, J = 8.2 Hz, 2H, ArH), 7.77 (s, 1H, ArH), 7.90 (d, J
= 8.2 Hz, 2H, ArH), 8.01–8.02 (m, 1H, ArH). 13C NMR (126 MHz,
DMSO-d6): (δ) 41.9, 47.4, 122.8, 125.20, 125.26, 126.06, 126.08, 126.3,
127.9, 128.8, 136.8, 139.0, 139.6, 145.2, 163.0, 168.3. Anal. for
(C20H19N3O4S2): C 55.9%, H 4.5%, N 9.8%; Found: C 55.6%, H 4.3%, N
9.9%.
4.3.3. 4-(4-(2-Naphthoyl)piperazine-1-carbonyl)benzenesulfonamide (7a)
Yield: 56% (286 mg); m.p.: 273–275 ◦C; Rf: 0.39. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.41–3.72 (m, 8H, CH2), 7.50 (s, 2H, NH2), 7.53–7.65 (m,
5H, ArH), 7.90–8.02 (m, 6H, ArH). 13C NMR (126 MHz, DMSO-d6): (δ)
41.9, 47.1, 126.1, 126.9, 127.0, 127.4, 127.5, 127.8, 127.9, 128.4,
128.6, 132.4, 133.1, 133.4, 139.0, 145.2, 168.3, 169.5. Anal. for
(C22H21N3O4S): C 62.4%, H 5.0%, N 9.9%; Found: C 62.5%, H 4.7%, N
9.6%.
4.3.10. 4-(4-(Furan-2-carbonyl)piperazine-1-carbonyl)
benzenesulfonamide (7 h)
Yield: 60% (208 mg); m.p.: 211–213 ◦C; Rf: 0.68. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.37–3.79 (m, 8H, CH2), 6.64 (m, 1H, ArH), 7.04 (m, 1H,
ArH), 7.48 (bs, 2H, NH2), 7.64 (d, J = 8.2, 2H, ArH), 7.89 (m, 1H, ArH),
7.90 (d, J = 8.2, 2H, ArH). 13C NMR (126 MHz, DMSO-d6): (δ) 42.0,
47.2, 111.6, 116.2, 126.1, 127.9, 139.0, 145.1, 145.2, 146.9, 158.8,
168.3. Anal. for (C16H17N3O5S): C 54.1%, H 5.1%, N 11.1%; Found: C
54.3%, H 4.8%, N 10.9%.
4.3.4. 4-(4-(Thiophene-2-carbonyl-)piperazine-1carbonyl)
benzenesulfonamide (7b)
Yield: 40% (144 mg); m.p.: 224–226 ◦C; Rf: 0.49. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.41–3.76 (m, 8H, CH2), 7.14 (t, J1 = 3.2 Hz, J2 = 4.8 Hz,
1H, ArH), 7.45 (d, J = 3.2 Hz, 1H, ArH), 7.48 (bs, 2H, NH2), 7.64 (d, J =
8.2 Hz, 2H, ArH), 7.78 (d, J = 4.8 Hz, 1H, ArH), 7.89 (d, J = 8.2 Hz, 2H,
ArH). 13CNMR (126 MHz, DMSO-d6): (δ) 41.4, 46.4, 125.9, 126.9,
127.4, 127.7, 129.4, 129.7, 132.2, 136.3, 138.6, 144.8, 161.1, 167.9.
Anal. for (C16H17N3O4S2): C 50.6%, H 4.5%, N 11.1%; Found: C 50.5%,
H 4.7%, N 10.9%.
4.3.11. 4-(4-(3-Methylfuran-2-yl)carbonyl]piperazin-1-yl)carbonyl)
benzenesulfonamide (7i)
Yield: 43% (167 mg); m.p.: 189–191 ◦C; Rf: 0.43. 1H NMR (500 MHz,
DMSO-d6): (δ) 2.16 (s, 3H, CH3), 3.37–3.69 (m, 8H, CH2), 6.50 (m, 1H,
ArH), 7.47 (bs, 2H, NH2), 7.61–7.68 (m, 3H, ArH), 7.89 (m, 2H, ArH).
13C NMR (126 MHz, DMSO-d6): 11.3, 41.9, 47.5, 114.6, 125.9, 126.5,
127.8, 138.9, 142.3, 143.4, 145.0, 159.8, 168.1. Anal. for
(C17H19N3O5S): C 54.1%, H 5.1%, N 11.1%; Found: C 53.8%, H 5.2%, N
10.9%.
4.3.5. 4-(4-(3-Methylthiophene-2-carbonyl)piperazine-1-carbonyl)
benzenesulfonamide (7c)
Yield: 35% (109 mg); m.p.: 248–250 ◦C; Rf: 0.34. 1H NMR (500 MHz,
DMSO-d6): (δ) 2.20 (m, 3H, CH3), 3.54–3.68 (m, 8H, CH2), 6.94 (m, 1H,
ArH), 7.47 (bs, 2H, NH2), 7.62 (m, 1H, ArH), 7.63 (d, J = 8.2 Hz, 2H,
ArH), 7.89 (d, J = 8.2 Hz, 2H, ArH). 13C NMR (126 MHz, DMSO-d6):
14.3, 41.2, 47.3, 125.7, 126.8, 127.5, 129.8, 129.9, 136.9, 138.6, 144.7,
163.5, 167.9. Anal. for (C17H19N3O4S2): C 51.9%, H 4.9%, N 10.7%;
Found: C 51.7%, H 5.0%, N 10.8%.
4.3.12. 4-(4-(5-Nitrofuran-2-yl)carbonyl)piperazin-1-yl)carbonyl)
benzenesulfonamide (7j)
Yield: 38% (102 mg); m.p.: 253–255 ◦C; Rf: 0.40. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.74–3.89 (m, 8H, CH2), 7.29 (m, 1H, ArH), 7.48 (bs, 2H,
NH2), 7.64 (d, J = 8.2, 2H, ArH), 7.76 (m, 1H, ArH), 7.90 (d, J = 8.2, 2H,
ArH). 13C NMR (126 MHz, DMSO-d6): 42.3, 46.4, 112.7, 112.8, 116.9,
117.2, 125.8, 127.3, 127.6, 138.5, 144.8, 147.2, 151.1, 156.8, 167.9.
Anal. for (C16H16N4O7S): C 54.1%, H 5.1%, N 11.1%; Found: C 53.7%, H
4.8%, N 11.3%.
4.3.6. 4-(4-(3-Bromothiophene-2-carbonyl)piperazine-1-carbonyl)
benzenesulfonamide (7d)
Yield: 48% (163 mg); m.p.: 218–220 ◦C; Rf: 0.40. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.39–3.72 (m, 8H, CH2), 7.15 (d, J = 5.1 Hz, 1H, ArH),
7.48 (bs, 2H, NH2), 7.63–7.65 (m, 2H, ArH), 7.79 (d, J = 5.1 Hz, 1H,
ArH), 7.90 (m, 2H, ArH). 13C NMR (126 MHz, DMSO-d6): 41.6, 46.9,
109.2, 126.0, 127.8, 127.9, 129.3, 130.0, 130.2, 131.9, 138.9, 145.1,
161.6, 168.2. Anal. for (C16H16BrN3O4S2): C 41.9%, H 3.5%, N 9.2%;
Found: C 41.8%, H 3.7%, N 9.3%.
4.3.13. 4-(4-(1-Benzofuran-2-ylcarbonyl)piperazin-1-yl)carbonyl)
benzenesulfonamide (7 k)
Yield: 55% (318 mg); m.p.: 209–211 ◦C; Rf: 0.24. 1H NMR (500 MHz,
DMSO-d6): (δ) 3.43–3.84 (m, 8H, CH2), 7.33–7.36 (m, 1H, ArH),
7.44–7.49 (m, 4H, NH2, ArH), 7.65–7.66 (m, 3H, ArH), 7.75–7.76 (m,
5